Fused tricyclic pyridazinone compounds useful to treat orthomyxovirus infections

Abstract

To provide compounds and pharmaceutical compositions for treatment of certain viral disorders, including influenza, as well as methods for using them.SOLUTION: The present invention provides a compound of formula (I). In the formula, Z1 is N and Z2 is C(R)2; or Z1 is CH and Z2 is NR, O, S, or CH2; Z3 is CH2, Q, -CH2-CH2-, -Q-CH2-, or the like; Q is selected from -NR-, O, S, SO, and SO2; Ar1 and Ar2 each independently represent a phenyl group or a 5- to 6-membered heteroaryl ring containing 1 to 3 heteroatoms selected from N, O, and S as ring members; and R1, R2, and R3 are C1-C6 alkyl, optionally substituted.SELECTED DRAWING: None

Description

Technical Field

[0001] Cross - reference to related applications This application claims the benefit of priority of U.S. Provisional Patent Application No. 62 / 380,712, filed on August 29, 2016, the content of which is incorporated herein by reference.

[0002] The present invention provides compounds that inhibit orthomyxovirus replication and are therefore useful for the treatment of 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.

[0003]

Background Art

[0003] Orthomyxoviruses have a negative - sense single - stranded RNA genome and lack a mechanism to generate a cap structure for producing their own mRNA, so they replicate in the nucleus of infected cells. Members of the orthomyxovirus family have an RNA - dependent RNA polymerase that has an endonuclease activity that cleaves a part of the capped 5' end of cellular mRNA; then, the RNA polymerase uses the cleavage product as a primer for the synthesis of viral mRNA. This process is known as cap - snatching. This endonuclease has been recognized as a target for which there is hope of developing effective antiviral agents against orthomyxoviruses. ACS Med.Chem.Lettters, 2014, vol.5, 61 - 64. Inhibitors of this endonuclease are, for example, International Publication No. WO 2015 / 038660 pamphlet, U.S. Patent No. 8,987,4 ​​​​​​​​​Specification No. 41, Pamphlet of International Publication No. 2010 / 147068, and U.S. Patent Application Publication No. 2012 / 022251, U.S. Patent Application Publication No. 2013 / 0197219 Specification, U.S. Patent Application Publication No. 2014 / 256937, and U.S. Patent Application Publication No. 2015 / 0072982 disclose that such inhibitors are useful for the treatment of influenza infections in mammals .

[0004] All viruses in the Orthomyxovirus family can infect humans, including Influenza A, Influenza B, and Influenza C, as well as several other genera of viruses that generally do not infect humans . Influenza A is the most virulent of these pathogens in humans and often accounts for the majority of severe cases of influenza during typical influenza epidemics. Despite the widespread use of vaccines to reduce the incidence of influenza, it is estimated that influenza still causes approximately 40,000 deaths per year in the United States; therefore, there is a great need for effective antiviral treatments for influenza, particularly Influenza A . The present invention provides compounds that inhibit the replication of Orthomyxoviruses, including Influenza A, Influenza B, and Influenza C. Without being bound by theory, it is believed that these compounds achieve their antiviral effects by inhibiting the endonuclease function of the viral polymerase . Since this endonuclease is highly conserved throughout the Influenza A virus (ibid.), the compounds are particularly useful for the treatment of Influenza A . . . . . . . . . SUMMARY OF THE INVENTION

Means for Solving the Problem

[0005] In one aspect, the present invention provides a compound of formula (A) further described herein:

Chemical formula

[0006] In another aspect, the present invention provides a compound of formula (I) as further described herein:

Chemical formula

[0007] The present invention, as further described herein, provides these compounds, their pharmaceutically acceptable Salts, and compositions and combinations comprising these compounds (including pharmaceutically acceptable salts), as well as methods of using the same are included.

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

[0009] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (A) mixed with at least one pharmaceutically acceptable carrier or excipient, optionally mixed with two or more pharmaceutically acceptable carriers or excipients. The compound can be used as a pharmaceutically acceptable salt.

[0010] In another aspect, the present invention provides a method of treating a subject infected with influenza A, B, or C, the method comprising administering to a subject in need of such treatment an effective amount of a compound of formula (A) or any subclass or species thereof described herein, or a pharmaceutical composition comprising such a compound. The subject can be a mammal, preferably a human, but the compounds and methods of the present invention are suitable for the treatment of other species infected with influenza A, B, or C, as well as other orthomyxoviruses. is suitable. The present invention relates to compounds of formula (A) and subgenera of formula (I) described herein, and includes all stereoisomers (including diastereoisomers and enantiomers), but specific isomers, as well as their tautomers and isotope-enriched forms (including deuterium substitution), and pharmaceutically acceptable salts of these compounds are excluded when expressly described. The compounds of the present invention also include polymorphs of compounds of formula (A) (or its subformulae) and their salts.

Mode for Carrying Out the Invention

[0011] The following definitions apply unless otherwise expressly specified:

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

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

[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 methyl, ethyl, n-propyl , iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl , n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2 ​, 2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n -nonyl, n-decyl, etc., but not limited thereto. The alkyl that is substituted is , instead of hydrogen, up to the number of hydrogens present on the unsubstituted alkyl group, an alkyl group containing one or more substituents such as 1, 2, or 3 substituents. Suitable substituents for the alkyl group are, unless otherwise specified, halogen, CN, oxo, hydroxy, C alkoxy 1~4 , substituted or unsubstituted C cycloalkyl, substituted or unsubstituted phenyl, amino, ( 3~6 C 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, but here, the substituents for the substituted cycloalkyl or phenyl are up to 3 groups selected from Me, Et, -OMe, -OEt 1~4 , CF , halo, CN, OH, and NH 3 2 2 2 from.

[0015] In this specification, the term "alkylene" refers to a divalent alkyl group having 1 to 10 carbon atoms and two open valences bonded to other features (feat ures). Unless otherwise specified, alkylene refers to a moiety having 1 to 6 carbon atoms. Representative of alkylene Examples include, but are not limited to, methylene, ethylene, n-propylene, iso-propylene, n-butylene, s ec-butylene, iso-butylene, tert-butylene, n-pentylene, isopentyl ene, neopentylene, n-hexylene, 2,2-dimethylbutylene, etc. The alkylene that is substituted is an alkylene group containing one or more substituents, such as 1, 2, or 3; unless otherwise specified, suitable substituents for the alkylene group are selected from the substituents listed above for the alkyl group. As used herein, the term "haloalkyl" refers to an alkyl as defined herein that is substituted by one or more halo groups. Haloalkyl can be monohaloalkyl, dihaloalkyl , trihaloalkyl, or polyhaloalkyl including perhaloalkyl. Monohaloalkyl can have one chloro or fluoro within the alkyl group. Chloro and fluoro

[0016] are typically present as substituents on an alkyl or cycloalkyl group; fluoro, chloro , and bromo are often present on an aryl or heteroaryl group. Dihaloalkyl and polyhaloalkyl groups can have two or more of the same halo atoms, or combinations of different halo groups, on the alkyl. Typically, polyhaloalkyl contains up to 12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups. Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoro ethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, etc. 8, or 6, or 4, or 3, or 2 halo groups. Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoro ethyl, heptafluoropropyl, difluorochloromethyl, dichlorofluoromethyl, etc. There are difluoroethyl, difluoropropyl, dichloroethyl, and dichloropropyl. . Perhalo-alkyl refers to an alkyl in which all hydrogen atoms are replaced by halo atoms, for example trifluoromethyl.

[0017] In this specification, the term "alkoxy" refers to alkyl-O- where alkyl is as previously defined . Representative examples of alkoxy include methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy, etc., but are not limited to these . Typically, an alkoxy group has 1 to 6 carbons, more commonly 1 to 4 carbon atoms.

[0018] "Substituted alkoxy" is an alkoxy group containing one or more substituents, such as 1, 2, or 3 , on the alkyl portion of the alkoxy. Unless otherwise specified, suitable substituents are selected from the substituents listed previously for the alkyl group, provided that hydroxyl and amino do not normally exist on the carbon directly bonded to the oxygen of the substituted "alkyl-O" group.

[0019] Similarly, each alkyl portion of other groups such as "alkylaminocarbonyl", "alkoxyalkyl", "alkoxycarbonyl", "alkoxy-carbonylalkyl", "alkylsulfonyl", "alkylsulfoxyl", "alkylamino", "haloalkyl" shall have the same meaning as described in the above definition of "alkyl". When used in this way, unless otherwise specified, the alkyl group is often an alkyl of 1 to 4 carbons and is not further substituted by groups other than the specified elements. Such alkyl When the base is substituted, suitable substituents are, unless otherwise specified, those previously specified for alkyl groups.

[0020] As used herein, the term "haloalkoxy" refers to haloalkyl-O- where haloalkyl is previously defined as haloalkyl. Representative examples of haloalkoxy include, but are not limited to, fluoromethoxy, difluoromethoxy, trifluoromethoxy, trichloromethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 1,1,1,3,3,3-hexafluoro-2-propoxy, and the like. Typically, the 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 having 3 to 12 carbon atoms: The cycloalkyl group, even if unsaturated, is condensed to another ring that can be saturated, unsaturated, or aromatic, provided that the ring atoms of the cycloalkyl group connected to the target molecular formula are not aromatic ring carbons. Unless otherwise specified, cycloalkyl refers to a cyclic hydrocarbon group having 3 to 9 ring carbon atoms or 3 to 7 ring carbon atoms. Preferably, the cycloalkyl group is, unless otherwise specified, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl, etc., a saturated monocyclic ring having 3 to 7 ring

[0022] Substituted cycloalkyl is a cycloalkyl group substituted by 1, or 2, or 3, or 4 or more substituents up to the number of hydrogens on the unsubstituted group. Typically, substituted cycloalkyl has, unless otherwise specified, 1 to 4 substituents. Suitable Unless otherwise specified, the substituent is halogen, hydroxyl, thiol, cyano, nitro, oxo, oxo, C 1 ~C 4 -alkylimino, C 1 ~C 4 -alkoximino o), hydroxyimino, C 1 ~C 4 -alkyl, C 2 ~C 4 -alkenyl, C 2 ~C 4 -alkynyl, C 1 ~C 4 -alkoxy, C 1 ~C 4 -thioalkyl, C 2 ~C 4 -al kenyloxy, C 2 ~C 4 -alkynyloxy, C 1 ~C 4 -alkylcarbonyl, car boxy, C 1 ~C 4 -alkoxycarbonyl, amino, C 1 ~C 4 -alkylamino, di -C 1 ~C 4 -alkylamino, C 1 ~C 4 -alkylaminocarbonyl, di-C 1 ~C 4 -alkylaminocarbonyl, C 1 ~C 4 -alkylcarbonylamino, C 1 ~C 4 - alkylcarbonyl(C 1 ~C 4 -alkyl)amino, C 1 ~C 4 -alkylsulfonyl 、C 1 ~C 4 -alkylsulfamoyl, and C 1 ~C4 - alkylaminosulfonyl or independently selected from the group consisting of, wherein each of the above-mentioned hydrocarbon groups (e.g., alkyl, alkenyl yl, alkynyl, alkoxy residue) may be further substituted by one or more groups independently selected in each occurrence from the list of substituents for the "alkyl" group herein. For cycloalkyl groups, preferred substituents include C ~C 1 alkyl and the substituents listed above as suitable substituents for alkyl groups 4 are present. Exemplary monocyclic hydrocarbon groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenthenyl, cyclohexyl, and cyclohexenyl. Exemplary bicyclic hydrocarbon groups include, but are not limited to, 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, bicyclo[2.2.2]octyl, etc. Exemplary tricyclic hydrocarbon groups include, but are not limited to, adamantyl.

[0023] Similarly, each cycloalkyl moiety of other groups such as "cycloalkyloxy", "cycloalkoxyalkyl", "cycloalkoxycarbonyl", "cycloalkoxy-carbonylalkyl", "cycloalkylsulfonyl", "halocycloalkyl" shall have the same meaning as described in the above definition of "cycloalkyl". For these terms

[0024]

[0024] When used, the cycloalkyl is typically a monocyclic 3- to 7-carbon ring that is unsubstituted or substituted with 1 to 2 groups. When optionally substituted, the substituents are typically selected from those previously described as being suitable for C ~C 1 ~C 4 alkyl and alkyl groups.

[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 having 6 to 14 carbon atoms, often 6 to 10 carbon atoms, and examples include phenyl or naphthyl. Further, the term "aryl" as used herein refers to an aromatic substituent that may be a single aromatic ring or multiple fused aromatic rings. Non-limiting examples include phenyl, naphth yl, and 1,2,3,4-tetrahydronaphthyl where the 1,2,3,4-tetrahydronaphthyl is attached to the formula as described by the carbon atoms of the aromatic ring of the tetrahydronaphthyl group. Unless otherwise specified, the preferred aryl group is phenyl. Substituted aryl is hydroxyl, thiol, cyano, nitro, C ~C alkyl, C

[0026] ~C 1 ~C 4 - alkenyl, C 2 ~C 4 -alkynyl, C 2 ~C 4 -alkoxy 1 ~C 4 -alkylthio, C ~C 1 ~C 4 -alkenyloxy, C 2 ~C 4 -alkynyloxy, halogen, C 2 ~C 4 -alkynyl oxy, halogen, C​​1 ~C 4 -alkylcarbonyl, carboxy, C 1 ~C 4 -alko xycarbonyl, amino, C 1 ~C 4 -alkylamino, di-C 1 ~C 4 -alkylami no, C 1 ~C 4 -alkylaminocarbonyl, di-C 1 ~C 4 -alkylaminocarbo yl, C 1 ~C 4 -alkylcarbonylamino, C 1 ~C 4 -alkylcarbonyl(C 1 ~ C 4 -alkyl)amino, C 1 ~C 4 -alkylsulfonyl, sulfamoyl, C 1 ~C 4 -alkylsulfamoyl, and C 1 ~C 4 -alkylaminosulfonyl selected independently from the group consisting of 1 to 5 (1, or 2, or 3, etc.) substituents substituted, and is an aryl group, where each of the above hydrocarbon groups (e.g., alkyl, alkenyl, alk ynyl, alkoxy residue) may be further substituted by one or more groups independently selected from the groups listed above as suitable substituents for an alkyl group at each occurrence. Preferred substituents for the substituted aryl group are C alkyl and oxo and other divalent groups are the groups specified above as suitable substituents for an alkyl group excluding them. Similarly, "aryloxy", "aryloxyalkyl", "aryloxycarbo 1~4 xy", etc.

[0027] Similarly, "aryloxy", "aryloxyalkyl", "aryloxycarbonyl" Each aryl moiety of other groups such as "nil" and "aryloxy-carbonylalkyl" shall have the same meaning as described in the above definition of "aryl". The term "aryl" as used herein has the same meaning as described in the above definition.

[0028] As used herein, the term "heterocyclyl" refers to a saturated or partially unsaturated, but non-aromatic, monocyclic or polycyclic ring (in the case of a polycyclic ring, particularly bicyclic, tricyclic, or spirocyclic rings); having 3 to 14, more generally 4 to 10, and most preferably 5 or 6 ring atoms; having one or more, preferably 1 to 4, particularly 1 or 2 ring atoms that are heteroatoms independently selected from O, S, and N (thus, the remaining ring atoms are carbon), and refers to a heterocyclic radical. For example, even when described as a C ~ ~atom ring, the heterocycle contains at least one heteroatom as a ring atom, and the other ring atoms are carbon, and has the number of ring atoms described, for example, 5 to 6 in this example. Preferably, the heterocyclyl group has one or two such heteroatoms as ring atoms, and preferably, the heteroatoms are not directly bonded to each other. The ring to which it is attached (i.e., the ring attached to the target formula) preferably has 4 to 12, particularly 5 to 7 ring atoms, unless otherwise specified. The heterocyclic group can be fused to an aromatic ring provided that the atoms of the heterocyclic group attached to the target formula are not aromatic. The heterocyclic group can be attached to the target formula either through a heteroatom (typically nitrogen) of the heterocyclic group or through a carbon atom. Heterocyclyl can include fused or bridged rings as well as spirocyclic rings, and only one ring of a polycyclic heterocyclic group needs to contain a heteroatom as a ring atom. Examples of heterocyclyl include tetrahydrofuran (THF), dihydrofuran radicals. 5 ~ 6 Even when described as a carbon atom ring, the heterocycle contains at least one heteroatom as a ring atom, and the other ring atoms are carbon, and has the number of ring atoms described, for example, 5 to 6 in this example. Preferably, the heterocyclyl group has one or two such heteroatoms as ring atoms, and preferably, the heteroatoms are not directly bonded to each other. The ring to which it is attached (i.e., the ring attached to the target formula) preferably has 4 to 12, particularly 5 to 7 ring atoms, unless otherwise specified. The heterocyclic group can be fused to an aromatic ring provided that the atoms of the heterocyclic group attached to the target formula are not aromatic. The heterocyclic group can be attached to the target formula either through a heteroatom (typically nitrogen) of the heterocyclic group or through a carbon atom. Heterocyclyl can include fused or bridged rings as well as spirocyclic rings, and only one ring of a polycyclic heterocyclic group needs to contain a heteroatom as a ring atom. Preferably, the heterocyclyl group has one or two such heteroatoms as ring atoms, and preferably, the heteroatoms are not directly bonded to each other. The ring to which it is attached (i.e., the ring attached to the target formula) preferably has 4 to 12, particularly 5 to 7 ring atoms, unless otherwise specified. The heterocyclic group can be fused to an aromatic ring provided that the atoms of the heterocyclic group attached to the target formula are not aromatic. The heterocyclic group can be attached to the target formula either through a heteroatom (typically nitrogen) of the heterocyclic group or through a carbon atom. Heterocyclyl can include fused or bridged rings as well as spirocyclic rings, and only one ring of a polycyclic heterocyclic group needs to contain a heteroatom as a ring atom. Examples of heterocyclyl include tetrahydrofuran (THF), dihydrofuran radicals. The ring to which it is attached (i.e., the ring attached to the target formula) preferably has 4 to 12, particularly 5 to 7 ring atoms, unless otherwise specified. The heterocyclic group can be fused to an aromatic ring provided that the atoms of the heterocyclic group attached to the target formula are not aromatic. The heterocyclic group can be attached to the target formula either through a heteroatom (typically nitrogen) of the heterocyclic group or through a carbon atom. Heterocyclyl can include fused or bridged rings as well as spirocyclic rings, and only one ring of a polycyclic heterocyclic group needs to contain a heteroatom as a ring atom. Examples of heterocyclyl include tetrahydrofuran (THF), dihydrofuran radicals. The heterocyclic group can be attached to the target formula either through a heteroatom (typically nitrogen) of the heterocyclic group or through a carbon atom. Heterocyclyl can include fused or bridged rings as well as spirocyclic rings, and only one ring of a polycyclic heterocyclic group needs to contain a heteroatom as a ring atom. Examples of heterocyclyl include tetrahydrofuran (THF), dihydrofuran radicals. The heterocyclic group can be attached to the target formula either through a heteroatom (typically nitrogen) of the heterocyclic group or through a carbon atom. Heterocyclyl can include fused or bridged rings as well as spirocyclic rings, and only one ring of a polycyclic heterocyclic group needs to contain a heteroatom as a ring atom. Examples of heterocyclyl include tetrahydrofuran (THF), dihydrofuran N, 1,4 - dioxane, morpholine, 1,4 - dithiane, piperazine, piperidine, 1 ,3 - dioxolane, imidazolidine, imidazoline, pyrroline, pyrrolidine, tetrah dropyran, dihydropyran, oxathiolane, dithiolane, 1,3 - dioxane, 1, 3 - dithiane, oxathiane, thiomorpholine, and the like.

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

[0030] Similarly, each heterocyclyl moiety of other groups such as "heterocyclyloxy", "heterocyclyloxyalkyl", and "heterocyclyl oxycarbonyl" shall have the same meaning as that described in the above definition of "heterocyclyl".

[0031] In this specification, the term "heteroaryl" has 1 to 8 heteroatoms as ring members, the remaining ring atoms are carbon, and the heteroatoms are selected from N, O, and S, and refers to a 5 - to 14 - membered monocyclic - or bicyclic - or tricyclic - aromatic ring system. Typically, heteroaryl is a 5 - to 10 - membered ring system, particularly a 5 - to 6 - membered monocyclic or 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 - oxa zolyl, 3 -, 4 -, or 5 - isoxazolyl, 3 - or 5 - 1,2,4 - triazolo ​​​​Ril, 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 are present.

[0032] The term "heteroaryl" also refers to a group in which the heteroaromatic ring 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 are present.

[0033] Substituted heteroaryl is a heteroaryl group containing one or more substituents selected from the substituents described above as being suitable for an aryl group, typically one or two substituents.

[0034] Similarly, each heteroaryl moiety of other groups such as "heteroaryloxy", "heteroaryloxyalkyl", "heteroary lcarbonyl" shall have the same meaning as those described in the above definition of "heteroaryl".

[0035] Various embodiments of the present invention are described herein. It is recognized that the features specified in each embodiment can be combined with the features specified in other embodiments to give further embodiments of the present invention. It will be. The following listed embodiments represent aspects of the present invention:

[0036] In one embodiment, the present invention provides a compound of formula (A):

Chemical formula

Chemical formula

[0037] Compounds of formula (A) in which G is not H can act as prodrugs that are readily converted in vivo to compounds in which G is H. In one embodiment of the compound of formula (A), G is H.

[0038] In another embodiment of the compound of formula (A), G is -C(O)R

[0039] -C(O)-OR 0 , -C(R 0 ), G ) 2 -O-C(O)R 0 , -C(R G )2 -O-C(O)-OR 0 、 -C (O)-N(R 0 ) 2 、 and -C(R G ) 2 -O-C(O)N(R 0 ) 2 selected from, where each R 0 is independently H or C 1 ~C 4 alkyl, phenyl, pyridyl, C 3 ~C 7 cycloalkyl, and a 3- to 6-membered heterocyclic ring containing one or two heteroatoms selected from N, O, and S as ring members; each R that is not H is optionally substituted by one or two groups selected from halo, CN, - OH, amino, C 1~4 alkyl, phenyl, C 1~4 alkoxy, C 1~4 haloalkyl le, and C 1~4 haloalkoxy. is substituted.

[0040] In some of the foregoing embodiments, G is -C(O)R 0 , -C(O)-OR 0 , - C(R G ) 2 -O-C(O)R 0 , and -C(R G ) 2 -O-C(O)-OR 0 selected from where each R 0 is independently H or C 1 ~C 4 alkyl, each R G is H or C 1 ~C 4 alkyl. In some of these embodiments, each R G is H, R 0 is C1 ~C 4 is alkyl.

[0041] In some of the foregoing embodiments, the compound of formula (A) has the formula:

Chemical formula

[0042] In a specific compound of this formula, Z 2 is CH 2 and Z 3 is CH 2 n is 0 , 1, or 2, and each R 3 is Me.

[0043] In another embodiment (Embodiment 1), the present invention provides a compound of formula (I):

Chemical formula

[0044] In a preferred embodiment of any of the compounds of formula (G) or formula (I) in the above embodiment wherein Z 2 is NR, O, or S, Z 3 is CH 2 CH 2 CH 2 or C H 2 CH 2 CH 2 is.

[0045] The following listed embodiments describe and explain specific aspects of the present invention.

[0046] 2. A compound according to any of embodiment 1 where Z 1 is CH or an embodiment of formula (A), or a pharmaceutically acceptable salt thereof.

[0047] 3. A compound according to any of embodiment 1 or embodiment 2 where Z 1 is N, or an embodiment of formula (A), or a pharmaceutically acceptable salt thereof.

[0048] 4. A compound according to any one of embodiments 1 to 3 where Z 2 is CH 2 or -CH 2 -CH 2 -, or a compound according to any of the embodiments of formula (A), or a pharmaceutically acceptable salt thereof.

[0049] 5. Z 3 is CH 2 , -CH 2 -CH 2 , -CH 2 -CH 2 -CH 2 , -CH 2 - A compound according to any of the foregoing embodiments that is O- or O, or a pharmaceutically acceptable salt thereof.

[0050] 6.R 1 A compound according to any of the foregoing embodiments in which R is H, or a pharmaceutically acceptable salt thereof.

[0051] 7.R 2 A compound according to any of the foregoing embodiments in which R is H, or a pharmaceutically acceptable salt thereof.

[0052] 8.Ar 1 and Ar 2 are both phenyl, and are each independently substituted by up to two groups selected from halo, C 1~4 alkyl, C 1~4 halo alkyl, C 1~4 alkoxy, C 1~4 haloalkoxy, C 2~4 alkyne, and C N, of a compound according to any of the foregoing embodiments, or a pharmaceutically acceptable salt thereof.

[0053] 9. Formula:

Chemical formula

Chemical formula

[0054] 10. The formula

Chemical formula

[0055] 11. A compound of Embodiment 1 or any of the embodiments of formula (A) selected from the group consisting of Examples 1 to 149, or a pharmaceutically acceptable salt thereof. Each of the compounds of the examples is a specific embodiment of the present invention. Therefore, the present invention provides the following: 1 12-Benzhydryl-4-hydroxy-7,8,9,10-tetrahydro-12H -dipyridazino[1,2-a:1’,6’-d][1,2,4]triazine-3,5-dione; 2 12-(Bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,1 0-tetrahydro-12H-dipyridazino[1,2-a:1’,6’-d][1,2,4 triazine-3,5-dione; 3 12-(Bis(4-chlorophenyl)methyl)-4-hydroxy-7,8,9,10 -tetrahydro-12H-dipyridazino[1,2-a:1’,6’-d][1,2,4] triazine-3,5-dione; 4 12-(Bis(3-chlorophenyl)methyl)-4-hydroxy-7,8,9,10 -tetrahydro-12H-dipyridazino[1,2-a:1’,6’-d][1,2,4] triazine-3,5-dione; 4 12-(Bis(3-chlorophenyl)methyl)-4-hydroxy-7,8,9,10 -tetrahydro-12H-dipyridazino[1,2-a:1’,6’-d][1,2,4] Triazine-3,5-dione; 5 12-(Bis(4-fluorophenyl)methyl)-4-hydroxy-7,8,9,1 0-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-7H ,13H-pyridazino[1’,6’:4,5][1,2,4]triazino[1,2-a] [1,2]diazepin-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]diazepin-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,1 0-tetrahydro-7H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyrida dine-3,5-dione; 11 (9aR,10R)-10-Benzhydryl-4-hydroxy-8,9,9a,1 0-tetrahydro-7H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyrida dine-3,5-dione; 12 (9aS,10R)-10-benzhydryl-4-hydroxy-8,9,9a,1 0-tetrahydro-7H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyrida dine-3,5-dione; 13 (9aS,10S)-10-benzhydryl-4-hydroxy-8,9,9a,1 0-tetrahydro-7H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyrida dine-3,5-dione; 14 (9aR,10S)-10-((R)-(3-fluorophenyl)(phenyl)meth yl)-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-hyd roxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1’,2’:4,5]pyra dino[1,2-b]pyridazine-3,5-dione; 16 (9aR,10S)-10-(bis(3-fluorophenyl)methyl)-4-hyd roxy-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)meth yl)-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]oxadi n-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]oxadi n-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-tetra hydro-12H-dipyridazino[1,2-a:1’,6’-d][1,2,4]tri azine-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-tetra hydro-12H-dipyridazino[1,2-a:1’,6’-d][1,2,4]tri azine-3,5-dione; 23B 12-Benzhydryl-4-hydroxy-10-methyl-7,8,9,10-tetra hydro-12H-dipyridazino[1,2-a:1’,6’-d][1,2,4]tri azine-3,5-dione; 24 12-Benzhydryl-4-hydroxy-7-methyl-7,8,9,10-tetrahydro Hydro-12H-dipyridazino[1,2-a:1’,6’-d][1,2,4]triaz ine-3,5-dione; 25A 12-benzhydryl-4-hydroxy-7,10-dimethyl-7,8,9,1 0-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 0-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-dipyrida dino[1,2-a:1’,6’-d][1,2,4]triazin-3,5-dione; 28B 12-(7,8-difluoro-6,11-dihydrodibenzo[b,e]thiepin -11-yl)-4-hydroxy-7,8,9,10-tetrahydro-12H-dipyrida dino[1,2-a:1’,6’-d][1,2,4]triazin-3,5-dione; 29 (S)-12-benzhydryl-4-hydroxy-7,8,9,10-tetrahydro ro-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]triazin-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]triazin-3,5-dione; 32 (9aR,10S)-10-((R)-(2-fluorophenyl)(phenyl)meth yl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1’,2 ’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 33 (9aR,10S)-10-((R)-(3,4-difluorophenyl)(2-flu orophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H -pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 34 (9aR,10S)-10-((S)-(3,4-difluorophenyl)(3-fluoro rophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H -pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 35 (9aR,10S)-10-((R)-(2-fluorophenyl)(4-fluoro phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrro lo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 36 (9aR,10S)-10-((S)-(3,5-difluorophenyl)(3-fluoro rophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H -pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-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]pyridazin-3,5-di one; 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]pyridazin-3,5-dione; 39 (9aR,10S)-10-((R)-(2-fluorophenyl)(3-fluoro fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrro lo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 40 (9aR,10S)-10-((R)-(3,5-difluorophenyl)(2-flu ((R)-(4-fluorophenyl)(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-fluorophenyl)( (2-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro -7H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazine-3,5-di one; 42 (9aR,10S)-10-((R)-(2-fluorophenyl)(2-methoxy phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrro lo[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]pyra dino[1,2-b]pyridazine-3,5-dione; 45 (9aR,10S)-10-((R)-(3,5-difluorophenyl)(3-fluoro phenyl)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-fluoro phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrro lo[1’,2’:4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 48 (9aR,10S)-10-((R)-(2,6-difluorophenyl)(4-f luorophenyl)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-f luorophenyl)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-d one; 51 (9aR,10S)-10-((S)-(2-fluorophenyl)(phenyl)m ethyl)-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)(phen yl)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-fluoro rophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H -pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 54 (9aR,10S)-10-((S)-(3,5-Difluorophenyl)(2-fluoro rophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H -pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 55 (9aR,10S)-10-((S)-(2-Fluorophenyl)(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrro lo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-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]pyridazin-3,5-di one; 57 (9aR,10S)-10-((S)-(2-Fluorophenyl)(4-fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrro lo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 58 (9aR,10S)-10-((S)-(4-Fluorophenyl)(phenyl)methy l)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1’,2 ’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 59 (9aR,10S)-10-((S)-(4-Fluorophenyl)(phenyl)methy l)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1’,2 59 (9aR,10S)-10-((S)-(3-Fluorophenyl)(phenyl)meth yl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1’,2 ’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 60 (9aR,10S)-10-((S)-(3-Fluorophenyl)(4-fluoro phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrro lo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 61 (9aR,10S)-10-((S)-(2,6-Difluorophenyl)(phenyl )methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1 ’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 62 (9aR,10S)-10-((S)-(2,6-Difluorophenyl)(3-f luorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H -pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 63 (9aR,10S)-10-((S)-(2,6-Difluorophenyl)(4-f luorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H -pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-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]pyridazin-3,5-d ione; 65 (9aR,10S)-10-((R)-(2,3-Difluorophenyl)(4-f (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]pyridazin-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]pyridazin-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]pyridazin-3,5-dione; 68 (9aR,10S)-10-((R)-(4-Fluorophenyl)(phenyl)me thyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1’,2 ’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 69 (9aR,10S)-10-(Bis(4-fluorophenyl)methyl)-4-hyd roxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1’,2’:4,5]pyra dino[1,2-b]pyridazin-3,5-dione; 70 (9aR,10S)-10-((S)-(3,4-Difluorophenyl)(4-f luorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H -pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-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]pyra zino[1,2-b]pyridazine-3,5-dione; 74 (9aR,10S)-10-((R)-(2,3-difluorophenyl)(3-fluoro phenyl)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-fluoro phenyl)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-fluoro phenyl)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-fluoro phenyl)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-di one; 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-fluoro rophenyl)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-di one; 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-fluoro rophenyl)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-fluoro rophenyl)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 (R)-methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1 ’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 91 (9aR,10S)-10-((S)-(2,3-difluorophenyl)(4-f luorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H -pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-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]pyridazin-3,5-di one; 93 (9aR,10S)-10-((R)-(3,4-difluorophenyl)(4-f luorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H -pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 94 (9aR,10S)-10-((R)-(3,4-difluorophenyl)(4-f luorophenyl)methyl)-4-hydroxy-2-(hydroxymethyl)-8,9,9a ,10-tetrahydro-7H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b]p ridazin-3,5-dione; 95 (9aR,10S)-10-((S)-(2,3-difluorophenyl)(3-f luorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H -pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-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]pyridazin-3,5-di one; 97 (9aR,10S)-10-((R)-(3,5-difluorophenyl)(4-fluoro phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H -pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-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]pyridazin-3,5-dione; 99 (9aR,10S)-10-((S)-(2,5-difluorophenyl)(4-fluoro phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H -pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-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]pyridazin-3,5- dione; 101 (9aR,10S)-10-((R)-(3,5-difluorophenyl)(phenyl methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo 1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 102 (9aR,10S)-10-((S)-(2,4-difluorophenyl)(4- (fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7 H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione ; 103 (9aR,10S)-10-((S)-(2,4-difluorophenyl)(phen yl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo 1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 104 (9aR,10S)-10-((S)-(2,4-difluorophenyl)(3- fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7 H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione ; 105 (9aR,10S)-10-((S)-(2,4-difluorophenyl)(3, 4-difluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro ro-7H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-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] pyridazin-3,5-dione; 107 4-((R)-(3-fluorophenyl)((9aR,10S)-4-hydroxy -3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1 ’,2’:4,5]pyrazino[1,2-b]pyridazin-10-yl)methyl)benzoni trile; 108 (9aR,10S)-10-((S)-(4-chlorophenyl)(3-fluoro (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrro lo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 109 (9aR,10S)-10-((R)-(3-chlorophenyl)(3-fluoro (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrro lo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 110 (9aR,10S)-10-((S)-(2-bromophenyl)(4-fluoro (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrro lo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 111 (9aR,10S)-10-((R)-(2-bromophenyl)(4-fluoro (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrro lo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-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]pyridazin-3,5-dione; 113 (9aR,10S)-10-((S)-(3-chlorophenyl)(3-fluoro (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrro lo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione; 114 (9aR,10S)-10-((R)-(3-chlorophenyl)(4-fluoro (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrro L[1’,2’:4,5]pyrazino[1,2-b]pyridazine-3,5-dione; 115 (9aR,10S)-10-((R)-(3-Fluorophenyl)(4-fluoro rophenyl)methyl)-4-hydroxy-7,7-dimethyl-8,9,9a,10-tetra hydro-7H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazine-3 ,5-dione; 116 (9aR,10R)-10-((S)-(3-Fluorophenyl)(4-fluoro rophenyl)methyl)-4-hydroxy-7,7-dimethyl-8,9,9a,10-tetra hydro-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-tetra hydro-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-tetra hydro-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-tetra hydro-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-tetra rahydrido-7H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-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]pyridazin-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]pyridazin-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]oxa dine-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]pyridaz ine-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-dioxo -3,5,7,8,9,10-hexahydro-12H-dipyridazino[1,2-a:1 ’,6’-d][1,2,4]triazin-4-yl)oxy)methyl ethyl carbonate; 135 (((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3 ,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1’,2 ’:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl(2-methoxy ethyl) 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)methylmethylcar Bonate; 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)methylethylcar Bonate; 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)methylmethylcar Bonate; 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)methylethylcar Bonate; 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)methylisoprop ylcarbonate; 142 (((9aR,10S)-10-((R)-(4-fluorophenyl)(phenyl 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) methylmethylcarbonate; 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-dioxo -3,5,7,8,9,10-hexahydro-12H-dipyridazino[1,2-a:1 ’,6’-d][1,2,4]triazin-4-yl)oxy)methyl methylcarbamate ; 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-yl dimethylcarbamate; 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)methyl ethyl(methyl )carbamate; 148 Methyl 2-(((((9aR,10S)-10-(bis(4-fluorophenyl )methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-py ((9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1’,2’:4,5]pyridazino[1,2-b]pyridazin-4-yl)oxy) (ethoxy)phosphoryl)oxy)acetate; and 149 methyl 2-((((((9aR,10S)-10-(bis(4-fluorophenyl methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H- (9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-dioxo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1’,2’:4,5]pyridazino[1,2-b]pyridazin-4-yl)oxy) (methoxy)carbonyl)oxy)-2-methylpropanoate; and a compound selected from pharmaceutically acceptable salts of these compounds are provided.

[0056] 12. A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt thereof according to any of the foregoing embodiments and one or more pharmaceutically acceptable carriers.

[0057] 13. A combination comprising a therapeutically effective amount of a compound according to any one of Embodiments 1 to 11 or an embodiment of Formula (A) or a pharmaceutically acceptable salt thereof and one or more co-agents having therapeutic activity.

[0058] 14. A method for treating influenza, comprising administering to a subject in need thereof a therapeutically effective amount of a compound according to any of Embodiments 1 to 11 or an embodiment of Formula (A) or a pharmaceutically acceptable salt thereof.

[0059] 15. A compound according to any one of Embodiments 1 to 11 or an embodiment of Formula (A ) or a pharmaceutically acceptable salt thereof for use as a medicament.

[0060] 16. A compound according to any one of Embodiments 1 to 11 or an embodiment of Formula (A) for use in the treatment of influenza. a compound according to any of the embodiments of formula (A) or a pharmaceutically acceptable salt thereof.

[0061] 17. In the manufacture of a medicament for the treatment of influenza, any one of embodiments 1 to 11 or a compound according to any of the embodiments of formula (A) or a pharmaceutically acceptable salt thereof.

[0062] In some embodiments, the compound of formula (A) is of the following formula:

Chemical formula

Chemical formula

[0063] In some embodiments, the compound of formula (I) is of the following formula: [Chemical formula] one of the compounds of; (wherein n is 0, 1, or 2; each R 3 represents Me, OH, OMe, or halo; and Y is [Chemical formula] represents (wherein each R y is independently selected from H, F, Cl, Me, OMe, CF 3 , OCF 3 , and CN)). ))

[0064] As used herein, the terms "optical isomer" or "stereoisomer" refer to any of the various stereoisomeric arrangements that may exist for a given compound of the invention, including geometric isomers. It is understood that substituents may be attached to the chiral centers of carbon atoms . The term "chiral" refers to a molecule having the property of not being superimposable on its mirror image partner, and the term "achiral" refers to a molecule that can be superimposed on its mirror image partner . Thus, the present invention includes enantiomers, diastereomers, or racemates of the compounds. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term indicates a racemic mixture where appropriate . . Thus, the present invention includes enantiomers, diastereomers, or racemates of the compounds. "Enantiomers" are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term indicates a racemic mixture where appropriate . . A 1:1 mixture of a pair of enantiomers is a "racemic" mixture. The term indicates a racemic mixture where appropriate It is used for sea urchins. "Diastereoisomers" are stereoisomers that have at least two asymmetric atoms but are not mirrors of each other. Absolute stereochemistry is specified according to the "R-S" system of Cahn-Ingold-Prelog . When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by R or S. For a resolved compound with unknown absolute configuration, they can be indicated by (+) or (-) according to the direction in which they rotate plane-polarized light at the wavelength of the sodium D line (right-handed or left-handed). Certain compounds described herein contain one or more asymmetric centers or axes, and thus can give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- in terms of absolute stereochemistry.

[0065] Depending on the choice of starting materials and synthetic procedures, a compound can exist in one form of the possible isomers, or as a mixture thereof, for example, as a pure optical isomer, or as a mixture of isomers such as a racemate and a mixture of diastereoisomers. The present invention is intended to include all possible isomers such as racemic mixtures, mixtures of diastereomers, and optically pure forms. Optically active (R)- and (S)- isomers can be prepared using a chiral synthon or chiral reagent, or can be resolved using conventional techniques. When a compound contains a double bond, the substituents can be in the E configuration or the Z configuration unless otherwise specified. When a compound contains a disubstituted cycloalkyl, the cycloalkyl substituents can have the cis configuration or the trans configuration unless otherwise noted. All tautomeric forms are also intended to be included.

[0066] In many cases, the compounds of the present invention can form acid and / or base salts due to the presence of amino groups and / or carboxyl groups or similar groups 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. "Salt" specifically includes "pharmaceutically acceptable salts". The term "pharmaceutically acceptable salts" refers to salts that retain the biological effects and properties of the compounds of the present invention and are typically not undesirable biologically or otherwise. Biologically, and in other respects.

[0067] Pharmaceutically acceptable acid addition salts can be formed by inorganic acids and organic acids. For example, acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, theoc late, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate salt, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandel ate, mesylate, methyl sulfate, naphthoate, napsylate, nicotinate, nitrate , octadecanoate, oleate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, polygalacturonate, propionate, stearin ate, succinate, sulfosalicylate, tartrate, tosylate, and trifluoroacetate salt. A list of additional suitable salts is, for example, "Remington’s Pharm aceutical Sciences", 20th ed., Mack Publis hing Company, Easton, Pa., (1985); and Stahl and​ "Handbook of Pharmaceutical S by Wermuth alts: Properties, Selection, and Use" (Wiley -VCH, Weinheim, Germany, 2002).

[0068] Inorganic acids capable of inducing salts include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid , phosphoric acid, etc.

[0069] Organic acids capable of inducing salts include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, sulfosalicylic lic acid, etc.

[0070] Pharmaceutically acceptable base addition salts can be formed by inorganic bases or organic bases and may have inorganic or organic counterions.

[0071] Such inorganic counterions of base salts include, for example, ammonium salts and metals in Groups I-XII of the periodic table I. In certain embodiments, the counterion is selected from sodium, potassium, ammonium, alkylammonium having 1-4 C ~C 1 ~C 4 alkyl groups, calcium , magnesium, iron, silver, zinc, and copper; particularly preferred salts include ammonium , potassium, sodium, calcium, and magnesium salts.

[0072] Organic bases capable of inducing salts include, for example, primary, secondary, and tertiary amines, natural ​There are substituted amines containing substituted amines present therein, cyclic amines, basic ion exchange resins, etc. . Suitable organic amines include isopropylamine, benzathine, cholin ate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0073] 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 a suitable base (such as hydroxides, carbonates, bicarbonates of Na, Ca, Mg, or K), or by reacting the free base form of these compounds with a stoichiometric amount of a suitable acid. Typically, such reactions are carried out in water or an organic solvent, or a mixture of both. Generally, when feasible, the use of a non-aqueous medium such as ether, ethyl acetate, tetrahydrof uran, toluene, chloroform, dichloromethane, methanol, ethanol, isopropa nol, or acetonitrile is desirable.

[0074] Every formula given herein is intended to represent both unlabeled forms (i.e., compounds in which all atoms are present in natural isotopic abundances and are not isotopically enriched) and isotopically enriched or labeled forms of the compounds. Isotopically enriched or labeled compounds have a structure depicted by the formula given herein, except that at least one atom of the compound has been replaced by an atom having an atomic mass or mass number different from the natural atomic mass or atomic mass distribution. Examples of isotopic elements that can be incorporated into the enriched or labeled compounds of the present invention include . 2 H, 3H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P , 35 S, 36 Cl, and 125 I, etc., there are isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, and chlorine. The present invention includes various isotopically labeled compounds as defined herein, such as those in which 3 radioisotopes such as H and 14 C, or 2 non-radioisotopes such as H and 13 C, are present at levels significantly exceeding their natural abundances. These isotopically labeled compounds are useful in detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including metabolic studies (e.g., with C), reaction rate studies (e.g., with H or 14 H), drug or substrate tissue distribution assays, or in the radiotherapy of patients. In particular, F-labeled compounds may be particularly desirable for PET or SPECT studies. Isotopically labeled compounds of formula (I) 2 H or 3 can generally be prepared by conventional techniques known to those skilled in the art or by processes similar to those described in the appended examples, using appropriate isotopically labeled reagents in place of the unlabeled reagents utilized otherwise. Furthermore, substitution with heavier isotopes, particularly deuterium (i.e., H or D), results in certain therapeutic advantages due to higher 18 metabolic stability, such as an increase in the in vivo half-life or a reduction in the dose requirement of the compound. Isotopically labeled compounds of formula (I) are generally prepared by conventional techniques known to those skilled in the art or by processes similar to those described in the appended examples, using appropriate isotopically labeled reagents in place of the unlabeled reagents utilized otherwise. When not otherwise indicated, the isotopically labeled compounds of formula (I) can be prepared using appropriate isotopically labeled reagents in place of the unlabeled reagents utilized otherwise.

[0075] In addition, substitution with heavier isotopes, particularly deuterium (i.e., 2 H or D), results in certain therapeutic advantages due to higher metabolic stability, such as an increase in the in vivo half-life or a reduction in the dose requirement may provide a reduction in the number of pieces or an improvement in the therapeutic index. Such heavier isotopes, specifically heavy The concentration of hydrogen can be defined by the isotopic enrichment factor r). As used herein, the term "isotope enrichment factor" means the ratio of the isotopic abundance to the natural abundance of the specified isotope . When a substituent in a compound of the present invention is deuterium is indicated, such a compound has an isotope enrichment factor of at least 3500 (52.5% deuterium incorporation for each specified 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 663 3.3 (99.5% deuterium incorporation) for each specified deuterium atom. .

[0076] Pharmaceutically acceptable solvates according to the present invention include those in which the crystallization solvent is isotopically substituted, e.g., those of D2O, d6-acetone, d6-DMSO, as well as solvates with non-enriched solvents.

[0077] Compounds of the present invention that can act as hydrogen bond donors and / or acceptors, i.e., compounds of formula (I), may be able to form co-crystals with suitable co-crystal formers. These co-crystals can be prepared from the compounds of formula (I) by known co-crystallization procedures. Such procedures include grinding, heating, co-sublimation , etc. ng), co-melting, or contacting a compound of formula (I) in solution with a co-crystal former under crystallization conditions. and isolating the co-crystal thereby formed. Suitable co-crystal formers include: The present invention is described in the pamphlet of International Publication No. 2004 / 078163. Ming further provides a co-crystal comprising a compound of formula (I).

[0078] As used herein, the term "pharmaceutical acceptable carrier" refers to a pharmaceutical composition for administration to a human subject. Any and all solvents, dispersion media, coating media, etc., as known to those skilled in the art for use in the agents, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonicity agents, absorption retarding agents Supplementary agents, salts, preservatives, drug stabilizers, binders, excipients, disintegrants, lubricants, sweeteners, flavorings, dyes and combinations thereof (e.g., Remington: The Science nce and Practice of Pharmacy, 22nd ed.) Except insofar as any conventional carrier is incompatible with the active ingredient, its use in a therapeutic agent or pharmaceutical composition is not prohibited. Use is intended.

[0079] The term "therapeutically effective amount" of a compound of the invention refers to a therapeutically effective amount that induces a biologically or medically effective effect in a subject. The amount of a compound of the invention that elicits a desired response, e.g., reduces one or more symptoms and alleviates a condition. "Amount" refers to an amount sufficient to slow or retard the progression of a disease or to prevent a disease. In one non-limiting embodiment, the term "therapeutically effective amount" refers to an amount that, when administered to a subject, Reduce one or more symptoms associated with influenza virus infection or shorten the duration of the symptomatic stage of influenza virus infection or Slow the progression or reduce the progression of the underlying pathology caused by influenza virus infection refers to the amount of a compound of the invention that is effective to initiate or stop.

[0080] In another non-limiting embodiment, the term "therapeutically effective amount" refers to the amount of a compound of the invention that, when administered to a cell, or tissue, or acellular biological material, or medium, is effective to cause a statistically significant decrease in the rate of replication or growth of a strain of orthomyxovirus.

[0081] As used herein, the term "subject" refers to an animal. Typically, the subject is a human.

[0082] As used herein, the terms "inhibit", "inhibiting", or "inhibition" refer to a decrease or suppression of a given pathological condition, symptom, or disorder, or disease, or a marked decrease in the baseline activity of a biological activity or process.

[0083] As used herein, the terms "treat", "treating", or "treatment" of any disease or disorder, in one embodiment, refer to ameliorating the disease or disorder (i.e., slowing, or stopping, or reducing the occurrence of at least one of the clinical symptoms of the disease or disorder). In another embodiment, "treat", "treating", or "treatment" refer to alleviating or improving at least one physical parameter that may not be recognized by a patient, including. In yet another embodiment, "treat", "treating", or "treatment" refer to modulating a disease or disorder, either physically (e.g., stabilization of a recognizable symptom), physiologically (e.g., stabilization of a physical parameter), or both. In yet another embodiment, "treat", "treating", or "treatment" refer to preventing or delaying the occurrence or progression of a disease or disorder. ​

[0084] As used herein, a subject "requires" such treatment when such subject would benefit biologically, medically, or in terms of quality of life from such treatment.

[0085] As used herein, the terms "a", "an", "the", and similar terms used in the context of the present invention (especially in the context of the claims) are to be construed to cover both the singular and the plural unless otherwise specified herein or clearly contradicted by context.

[0086] All methods described herein can be performed in any suitable order unless otherwise specified herein or clearly contradicted by context in another way. Any examples provided herein, or the use of exemplary language (e.g., "such as") are intended merely to better illustrate the invention and do not impose a limitation on the scope of the invention as claimed in another way.

[0087] The asymmetric atoms (e.g., carbon, etc.) of the compounds of the present invention can exist in racemic form, enantiomerically enriched form, for example, in (R)-, (S)-, or (R,S)-configuration. In certain embodiments, each asymmetric atom has at least 50% enantiomeric excess, at least 60% enantiomeric excess, at least 70% enantiomeric excess, at least 80% enantiomeric excess, at least 90% enantiomeric excess, at least 95% enantiomeric excess, or at least 99% enantiomeric excess of either the (R)- or (S)-configuration; that is, in the case of an optically active compound, one enantiomer is used substantially excluding the other enantiomer. ​ Preferably, therefore, typically at least 95% enantiomeric purity is preferred. Substituents at atoms having unsaturated double bonds can, where possible, be present in either the cis-(Z)-form or the trans-(E)-form.

[0088] Accordingly, in the present specification, the compounds of the present invention are in one form of possible isomers, rotamers, conformational isomers, tautomers, or mixtures thereof, for example, substantially pure geometric (cis or trans) isomers, diastereomers, optical isomers (enantiomers), racemates, or mixtures thereof. As used herein, "substantially pure" or "substantially free of other isomers" means that the product contains less than 5% by weight, preferably less than 2% by weight, of other isomers with respect to the preferred isomer.

[0089] Mixtures of the resulting isomers can typically be separated into pure or substantially pure geometric or optical isomers, diastereomers, racemates, based on the physicochemical differences of the components, for example, by chromatography and / or fractional crystallization.

[0090] Racemates of the final product or intermediate can typically be resolved into optical enantiomers by known methods, for example, by separation of their diastereomeric salts obtained with an optically active acid or base and liberation of the optically active acidic or basic compound. In particular, the basic moiety can be utilized in this way, for example, by fractional crystallization of salts formed with an optically active acid, such as tartaric acid, dibenzoyl tartaric acid, diacetyl tartaric acid, di-O,O'-p-toluoyl tartaric acid, mandelic acid, malic acid, or camphor-10-sulfonic acid, to obtain the compounds of the present invention in their optical enantiomers. It can be divided into bodies. The racemic product can also be separated by chiral chromatography, for example, high performance liquid chromatography (HPLC) using a chiral stationary phase. It can also be separated by high performance liquid chromatography (HPLC) using a chiral stationary phase .

[0091] Furthermore, the compounds of the present invention containing the salts thereof may be obtained in the form of their hydrates, or contain other solvents used for their crystallization. The compounds of the present invention may form solvates with pharmaceutically acceptable solvents (including water), either essentially or deliberately; therefore, the present invention is intended to include both solvated and non-solvated forms. The term "solvate" refers to a molecular complex of a compound of the present invention (including its pharmaceutically acceptable salts) with one or more solvent molecules. Such solvent molecules are those commonly used in the pharmaceutical field and known to be harmless to the recipient, for example, water, ethanol, etc. The term " hydrate" refers to a complex in which the solvent molecule is water. In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises at least two pharmaceutically acceptable excipients or carriers. Pharmaceutically acceptable carriers and other excipients are known to those skilled in the art and can be selected from, for example, the carriers and excipients used in approved (registered) formulated therapeutic agents administered by similar routes of administration. The pharmaceutical composition can be formulated for specific routes of administration such as oral administration, parenteral administration, and rectal administration. Furthermore, the pharmaceutical composition of the present invention can also be in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories), or in liquid form (including, but not limited to, solutions ). In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises at least two pharmaceutically acceptable excipients or carriers. Pharmaceutically acceptable carriers and other excipients are known to those skilled in the art and can be selected from, for example, the carriers and excipients used in approved (registered) formulated therapeutic agents administered by similar routes of administration. The pharmaceutical composition can be formulated for specific routes of administration such as oral administration, parenteral administration, and rectal administration. Furthermore, the pharmaceutical composition of the present invention can also be in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories), or in liquid form (including, but not limited to, solutions ).

[0092] In another aspect, the present invention provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition comprises at least two pharmaceutically acceptable excipients or carriers. Pharmaceutically acceptable carriers and other excipients are known to those skilled in the art and can be selected from, for example, the carriers and excipients used in approved (registered) formulated therapeutic agents administered by similar routes of administration. The pharmaceutical composition can be formulated for specific routes of administration such as oral administration, parenteral administration, and rectal administration. Furthermore, the pharmaceutical composition of the present invention can also be in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories), or in liquid form (including, but not limited to, solutions ). In some embodiments, the pharmaceutical composition comprises at least two pharmaceutically acceptable excipients or carriers. Pharmaceutically acceptable carriers and other excipients are known to those skilled in the art and can be selected from, for example, the carriers and excipients used in approved (registered) formulated therapeutic agents administered by similar routes of administration. The pharmaceutical composition can be formulated for specific routes of administration such as oral administration, parenteral administration, and rectal administration. Furthermore, the pharmaceutical composition of the present invention can also be in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories), or in liquid form (including, but not limited to, solutions ). Pharmaceutically acceptable carriers and other excipients are known to those skilled in the art and can be selected from, for example, the carriers and excipients used in approved (registered) formulated therapeutic agents administered by similar routes of administration. The pharmaceutical composition can be formulated for specific routes of administration such as oral administration, parenteral administration, and rectal administration. Furthermore, the pharmaceutical composition of the present invention can also be in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories), or in liquid form (including, but not limited to, solutions ). In some embodiments, the pharmaceutical composition comprises at least two pharmaceutically acceptable excipients or carriers. Pharmaceutically acceptable carriers and other excipients are known to those skilled in the art and can be selected from, for example, the carriers and excipients used in approved (registered) formulated therapeutic agents administered by similar routes of administration. The pharmaceutical composition can be formulated for specific routes of administration such as oral administration, parenteral administration, and rectal administration. Furthermore, the pharmaceutical composition of the present invention can also be in solid form (including, but not limited to, capsules, tablets, pills, granules, powders, or suppositories), or in liquid form (including, but not limited to, solutions ). ). It can also be formulated into (including agents, suspensions, or emulsions). The pharmaceutical composition can be subjected to conventional formulation operations such as sterilization, and / or can include conventional inert diluents, lubricants, or buffering agents, as well as auxiliary agents such as preservatives, stabilizers, wetting agents, emulsifying agents, and buffering agents. .

[0093] In one embodiment, the compound of the present invention is formulated for oral delivery. Typically, these pharmaceutical compositions contain the active ingredient (at least one compound of formula (I)) with a) diluents such as lactose, dextrose, sucrose, mannitol, sorbitol, cellulose, and / or glycine; b) lubricants such as silica, talc, stearic acid, its magnesium or calcium salts, and / or polyethylene glycol; for tablets, c) binders such as magnesium aluminum silicate, starch paste, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone; if desired d) disintegrants such as starch, agar, alginic acid or its sodium salt, or effervescent mixtures; and / or e) absorbents, coloring agents, flavors, and sweetening agents and are tablets or gelatin capsules containing one or more excipients selected from.

[0094] Tablets can be film-coated or enteric-coated according to methods known in the art.

[0095] Suitable compositions for oral administration contain an effective amount of the compound of the present invention in tablets, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsions, hard or soft capsules​​​​​ or in the form of a syrup or elixir. It may be prepared according to any method known in the art for the manufacture of pharmaceutical compositions, Such compositions are pharma- ceutically elegant and In order to provide a palatable preparation, a sweetening agent, a flavoring agent, a coloring agent, and a preservative may be added. The tablet may contain one or more selected active substances. The tablet may be formulated with non-toxic pharmaceutical agents suitable for tablet formulation. The active ingredient may be mixed with commercially acceptable excipients. These excipients may include, for example, carbonates, Calcium, sodium carbonate, lactose, calcium phosphate, or sodium phosphate any inert diluent; granulating and disintegrating agents, such as corn starch or alginic acid; Additives such as starch, gelatin, or gum arabic; and lubricants such as stearin. The tablets may be uncoated or coated with any of the known techniques. The drug is coated by a process that slows down disintegration and absorption in the digestive tract, allowing the drug to be administered for a long period of time. Provides sustained action. For example, glyceryl stearate or glyceryl distearate. Time delay materials are available for oral use. The formulation for the purpose of the present invention is such that the active ingredient is dissolved in an inert solid diluent, e.g., calcium carbonate, calcium phosphate, etc. The active ingredient is also available as a hard gelatin capsule mixed with sodium or kaolin. Mixed with water or an oily medium, such as peanut oil, liquid paraffin, or olive oil It may also be presented as a soft gelatin capsule containing

[0096] Certain injectable compositions are aqueous isotonic solutions or suspensions, and suppositories are conveniently prepared in the form of lipophilic It is prepared from an emulsion or suspension containing fat. The composition may also be sterilized and / or contain auxiliary agents such as preservatives, stabilizers, wetting agents, or emulsifying agents, solubilizing agents, salts and / or buffers for controlling osmotic pressure . Furthermore, they may also contain other substances of therapeutic value. The compositions are each prepared according to conventional mixing, granulation, or coating methods and contain from about 0.1 to 75%, or from about 1 to 50%, of the active ingredient.

[0097] Suitable compositions for transdermal application contain an effective amount of the compound of the invention together with a suitable carrier. Carriers suitable for transdermal delivery include absorbent pharmacologically acceptable solvents that assist passage through the host's skin. For example, a transdermal device is in the form of a bandage containing a support member, a reservoir containing the compound, optionally together with a carrier, and optionally a rate control barrier that delivers the compound of the host's skin at a controlled predetermined rate over a long period of time , and means for securing the device to the skin.

[0098] Suitable compositions for topical application to, for example, the skin and eyes include aqueous solutions, suspensions, ointments , creams, gels, or spray formulations for delivery, for example, by aerosol. Such topical delivery systems may be suitable, for example, for use in the treatment of influenza and may be related to inhalation or intranasal application and may contain solubilizing agents, stabilizers, tonicity increasing agents, buffers, and preservatives . They may be in the form of dry powder inhalers from dry powder (alone, as a mixture, for example, a dry blend with lactose, or mixed component particles, for example, with phospholipids) or in the form of an aerosol spray presentation, with or without the use of a suitable propellant , from a pressurized container, pump, spray, atomizer, or nebulizer - can be easily delivered.

[0099] Since water can promote the decomposition of certain compounds, the present invention further provides anhydrous pharmaceutical compositions and dosage forms containing the compounds of the present invention as active ingredients. and dosage forms.

[0100] The anhydrous pharmaceutical compositions and dosage forms of the present invention can be prepared using anhydrous or low-moisture-containing components and low-moisture or low-humidity conditions. The anhydrous pharmaceutical compositions can be prepared and stored so that their anhydrous nature is maintained. Therefore, the anhydrous compositions are packaged using materials known to prevent exposure to water so that they can be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, sealed foils, plastics, unit-dose containers (e.g., vials), blister packs, and strip packs. and stored. Thus, the anhydrous compositions are packaged using materials known to prevent exposure to water so that they can be included in suitable formulation kits. Examples of suitable packaging include, but are not limited to, sealed foils, plastics, unit-dose containers (e.g., vials), blister packs, and strip packs. Examples of suitable packaging include, but are not limited to, sealed foils, plastics, unit-dose containers (e.g., vials), blister packs, and strip packs. and strip packs.

[0101] The present invention further provides pharmaceutical compositions and dosage forms containing one or more agents that reduce the rate at which the compounds of the present invention as active ingredients decompose. Such agents are referred to herein as "stabilizers" and include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers. and dosage forms. Such agents are referred to herein as "stabilizers" and include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers. and include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers. and include, but are not limited to, antioxidants such as ascorbic acid, pH buffers, or salt buffers.

[0102] The compounds of formula (I) in free or salt form exhibit valuable pharmacological properties. For example, they inhibit or prevent the replication of orthomyxoviruses as shown by the data given in the following section and are therefore applicable for use in therapy or as research reagents, for example, as tool compounds in tests for the replication of orthomyxoviruses, particularly influenza A, influenza B, or influenza C. Thus, the compounds of the present invention are inhibit or prevent the replication of orthomyxoviruses as shown by the data given in the following section and are therefore applicable for use in therapy or as research reagents, for example, as tool compounds in tests for the replication of orthomyxoviruses, particularly influenza A, influenza B, or influenza C. inhibit or prevent the replication of orthomyxoviruses as shown by the data given in the following section and are therefore applicable for use in therapy or as research reagents, for example, as tool compounds in tests for the replication of orthomyxoviruses, particularly influenza A, influenza B, or influenza C. orthomyxoviruses, particularly influenza A, influenza B, or influenza C. orthomyxoviruses, particularly influenza A, influenza B, or influenza C. Orthomyxovirus, particularly influenza A, influenza B, or influenza C is useful for the treatment of infectious diseases, particularly in human subjects. In some embodiments the subject to be treated is a human having or at risk of having an influenza virus infection. For example, subjects having pre-existing conditions such as asthma or COPD that can be severely exacerbated by influenza infection are at risk of having or appearing to have influenza if they are near people such as a family member who has influenza. In particular, the methods or compounds of the present invention can be used to treat such subjects before the symptoms of influenza infection appear. In other embodiments, the subject for treatment with the methods and compositions of the present invention is one diagnosed as having symptoms consistent with an influenza infection. In other embodiments, the subject is tested by known diagnostic methods such as a rapid influenza diagnostic test (RIDT) for detecting the presence of influenza virus or by reverse transcriptase PCR (RT-PCR) method and is found to be infected with influenza, regardless of the presence of typical influenza symptoms.

[0103] In a further embodiment, the present invention provides the use of a compound of formula (I) or any embodiment within the scope of formula (I) described herein in therapy. In particular, the compound is suitable for use in treating a subject having or at particular risk of having an orthomyxovirus infection, particularly influenza A, influenza B, or influenza C.

[0104] In another embodiment, the present invention treats diseases caused by orthomyxovirus A method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I) or within the scope of formula (I) described herein is provided. 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 to a subject in need thereof an effective amount of a compound described herein or a pharmaceutical composition comprising an effective amount of such a compound The compound can be administered by any suitable method such as those described herein, and the administration can be repeated at intervals selected by the treating physician In some embodiments, the compound or pharmaceutical composition is administered orally Therefore, as a further embodiment, the present invention provides the use of a compound of formula (I) or any of the embodiments of such a compound described herein for the manufacture of a medicament In certain embodiments, the medicament is for the treatment of orthomyxovirus infections, particularly influenza A

[0105] influenza B, or influenza C The compounds of the present invention can be administered simultaneously with, before, or after one or more therapeutic co-agents The compounds of the present invention can be administered separately from the co-agent by the same or different routes of administration or together in the same pharmaceutical composition. Suitable co-agents for use with the compounds of the present invention include antiviral agents active against influenza virus, such as oseltamivir

[0106] peramivir, zanamivir and laninamivir, and neuraminidase inhibitors including laninamivir octanoate ​​​​ There are, for example, neuraminidase inhibitors and adamantanes such as amantadine and rimantadine. Additional co-drugs for use in these methods include M2 protein inhibitors, polymerase inhibitors, PB2 inhibitors, favipiravir, fludase, ADS-8902, veraprost, Neugene®, ribavirin, CAS registration number 1422050-75 -6, VX-787, Flu Mist Quadrivalent®, Fluarix® Quadrivalent, Fluzone® Quadrivalent, Flucelvax®, and FluBlok® (there are).

[0107] In one embodiment, the present invention provides a product comprising a compound of formula (I) and at least one other therapeutic co-drug as a combined preparation for simultaneous, separate, or sequential use in therapy. In one embodiment the therapy is the treatment of a viral infection caused by an orthomyxovirus, particularly influenza A, influenza B, or influenza C. The products provided as combined preparations include compositions comprising both the compound of formula (I) and at least one other therapeutic co-drug in the same pharmaceutical composition, or in another form, for example, the compound of formula (I) and at least one other therapeutic co-drug in the form of a kit for use in the treatment of a subject by the methods described herein.

[0108] In one embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and another therapeutic co-drug. Suitable co-drugs include antiviral agents active against influenza virus Agents, for example, neuraminidase inhibitors including oseltamivir, peramivir, zanamivir and laninamivir, and adamantanes such as amantadine and rimantadine. Optionally, the pharmaceutical composition may contain a pharmaceutically acceptable carrier as described herein .

[0109] In one embodiment, the present invention provides a kit comprising two or more different pharmaceutical compositions, at least one of which contains a compound of formula (I). The other pharmaceutical composition may contain one of the suitable co-agents. In one embodiment, the kit comprises means for separately holding the compositions, such as a container, a divided vial, or a divided foil packet. An example of such a kit is a blister pack as typically used in packaging tablets, capsules, etc .

[0110] The kits of the present invention can be used to administer the separate compositions at different dosing intervals or to titrate the separate compositions against each other, for example, by administering different dosage forms, such as oral and parenteral. To assist compliance, the kits of the present invention typically include instructions for administration .

[0111] In the combination therapies of the present invention, the compounds of the present invention and the therapeutic co-agents can be manufactured and / or formulated by the same manufacturer or by different manufacturers. Further, the compounds of the present invention and the therapeutic co-agents can be (i) combined before disclosure to the physician (e.g., in the case of a kit containing a compound of the present invention and other therapeutic agents); (ii) combined by the physician himself (or under the guidance of the physician) immediately prior to administration; (iii) combined by the patient himself, for example, in the case of sequential administration of a compound of the present invention and a therapeutic co-agent . ; ​​​​​​​In between, they may be combined and used in combination therapy.

[0112] Accordingly, the present invention provides the use of a compound of formula (I) for treating a viral infection caused by an orthomyxovirus, in particular influenza A, influenza B, or influenza C, which may be influenza, wherein the pharmaceutical is formulated for co-administration with a therapeutic co-agent. Typically, in the method of using the compounds of the present invention, the influenza serotype is not determined prior to treatment. The present invention also provides the use of a therapeutic co-agent for treating a disease or condition, wherein the pharmaceutical is administered together with a compound of formula (I). In the method of using the compounds of the present invention, the influenza serotype is not determined prior to treatment. The present invention also provides the use of a therapeutic co-agent for treating a disease or condition, wherein the pharmaceutical is administered together with a compound of formula (I).

[0113] The present invention provides a compound of formula (I) for use in a method of treating a viral infection caused by an orthomyxovirus, in particular influenza A, influenza B, or influenza C, which is prepared for co-administration with a therapeutic co-agent. The present invention also provides another therapeutic co-agent for use in a method of treating a viral infection caused by an orthomyxovirus, in particular influenza, such as influenza A, influenza B, or influenza C, which is prepared for co-administration with a compound of formula (I). The present invention also provides a compound of formula (I) for use in a method of treating a viral infection caused by an orthomyxovirus, in particular influenza A, influenza B, or influenza C, which is administered together with a therapeutic co-agent. The present invention also provides a compound of formula (I) for use in a method of treating a viral infection caused by an orthomyxovirus, in particular influenza A, influenza B, or influenza C, which is administered together with a therapeutic co-agent. The present invention also provides a compound of formula (I) for use in a method of treating a viral infection caused by an orthomyxovirus, in particular influenza A, influenza B, or influenza C, which is administered together with a therapeutic co-agent. The present invention also provides another therapeutic co-agent for use in a method of treating a viral infection caused by an orthomyxovirus, in particular influenza A, influenza B, or influenza C, which is prepared for co-administration with a compound of formula (I). The present invention also provides a compound of formula (I) for use in a method of treating a viral infection caused by an orthomyxovirus, in particular influenza A, influenza B, or influenza C, which is administered together with a therapeutic co-agent. The present invention also provides a compound of formula (I) for use in a method of treating a viral infection caused by an orthomyxovirus, in particular influenza A, influenza B, or influenza C, which is prepared for co-administration with a therapeutic co-agent. The present invention also provides a compound of formula (I) for use in a method of treating a viral infection caused by an orthomyxovirus, in particular influenza A, influenza B, or influenza C, which is administered together with a therapeutic co-agent. The present invention also provides a compound of formula (I) for use in a method of treating a viral infection caused by an orthomyxovirus, in particular influenza A, influenza B, or influenza C, which is caused by an orthomyxovirus, in particular influenza A, influenza B, or influenza C.​ A therapeutic co-agent for use in a method of treating a viral infection that occurs, which is a therapeutic co-agent administered together with a compound of formula ( I) is also provided.

[0114] The present invention relates to a case where a patient has been previously treated (e.g., within 24 hours) with another therapeutic agent against orthomyxovirus, particularly influenza, such as influenza A, influenza B or influenza C. The use of a compound of formula ( I) for treating a viral infection caused by orthomyxovirus is also provided. The present invention also relates to the use of another therapeutic agent for treating a viral infection caused by orthomyxovirus, particularly influenza A influenza, influenza B, or influenza C, in a case where a patient has been previously treated (e.g., within 24 hours) with a compound of formula ( I). is also provided.

[0115] In one embodiment, the therapeutic co-agent is selected from neuraminidase inhibitors including oseltamivir, peramivir, zanamivir and laninamivir, and antiviral agents such as amantadine and rimantadine which are considered useful for treating infections caused by influenza virus. is selected from.

[0116] The pharmaceutical composition or combination of the present invention may be in a unit dose containing about 1 to 1 000 mg of the active ingredient, or about 1 to 500 mg, or about 1 to 250 mg, or about 1 to 15 0 mg, or about 0.5 to 100 mg, or about 1 to 50 mg of the active ingredient for a human subject weighing about 50 - 70 kg. The therapeutically effective dose of the compound, pharmaceutical composition, or combination thereof depends on the species, body weight, age, and individual pathological conditions of the subject, the disorder or disease being treated or its severity. . Physicians, clinicians, or veterinarians with ordinary skill can readily determine the effective amount of each of the active ingredients necessary to prevent, treat, or inhibit the progression of a disorder or disease. .

[0117] . The properties of the dosages mentioned above are advantageously revealed in in vitro and in vivo tests using mammals such as mice, rats, dogs, monkeys or isolated organs, tissues, and specimens thereof. The compounds of the present invention can be used in vitro in the form of a solution, for example, an aqueous solution, or in vivo, either orally, preferably intravenously, for example, as a suspension or in an aqueous solution. . The in vitro dosage can range from about 10 molar concentration to 10 molar concentration. The therapeutically effective amount in vivo can range from about 0.1 to 500 mg / -3 kg, or from about 0.1 to 50 mg / kg, depending on the route of administration. -9 . . .

[0118] . The present invention further includes a process for producing the compounds of formula (I) disclosed herein, and any variant of such a process, in which an intermediate product obtained at any stage is used as a starting material and the remaining steps are carried out, or the starting material is formed in situ under reaction conditions, or the reaction components are used in the form of their salts or optically pure substances. . . . .

[0119] . The compounds and intermediates of the present invention can be converted into each other according to methods generally known to those skilled in the art. .

[0120] . The method for synthesizing the compounds of formula (I) is depicted in Schemes A - C and is illustrated in the examples herein. Scheme A shows that Z1 is N, Z2 is C(R)2, and Z3 is . Describes a method for preparing a compound of -CR2-CR2-, enabling the synthesis of compounds with other Z3 linkages. It starts with a 5-hydroxypyridazin-4-one- 3-carboxylic acid compound, where both the 5-hydroxy and the ring NH are protected with suitable protecting groups that can be easily removed. The carboxylic acid is condensed with a cyclic hydrazine linkage to give two outer rings. After deprotection of the ring nitrogen, the central ring is formed by condensation with an aldehyde.

Chemical formula

Chemical formula

[0121] is CR 1 and Z 2 is CR 2 and Z 3 is CR 2 . Using these synthetic schemes and the given examples, one skilled in the art can prepare the compounds of formula (I).

Chemical formula

Chemical formula

[0122]

Examples

[0123] under reduced pressure, typically at about 15 mmHg to 100 mmHg (about 20 to 133 mbar). are carried out under reduced pressure, typically at about 15 mmHg to 100 mmHg (about 20 to 133 mbar). Perform. The structures of the final products, intermediates, and starting materials are confirmed by standard analytical methods, for example, micro analysis and spectroscopic properties, such as MS, IR, NMR. The abbreviations used are , those conventional in the art.

[0124] All starting materials, building blocks, reagents, acids, salts groups, dehydrating agents, solvents, and catalysts used in the synthesis of the compounds of the present invention are commercially available or can be produced by organic synthesis methods known to those skilled in the art (Houben-Weyl 4th Ed.1952,Methods of Org anic Synthesis,Thieme,Volume 21). Furthermore, the compounds of the present invention can be produced by organic synthesis methods known to those skilled in the art in consideration of the following examples .

[0125] Abbreviations ATP Adenosine 5'-triphosphate Bn Benzyl BOC Tert-butyl carboxy 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 HBTU 1-[Bis(dimethylamino)methylene]-1H-benzotriazolium hexa fluorophosphate(1-) 3-oxide HOBt 1-Hydroxy-7-azabenzotriazole HPLC High performance liquid chromatography IR Infrared spectroscopy LCMS Liquid chromatography and mass spectrometry MeOH Methanol MS Mass spectrometry MW Microwave m Multiplet min Minute mL Milliliter 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 hexa fluorophosphate 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

[0126] Example 1: 12-Benzhydryl-4-hydroxy-7,8,9,10-tetrahydro- 3H-Dipyridazino[1,2-a:1’,6’-d][1,2,4]triazine-3,5 (12H)-dione Intermediate 1.1: 1-Benzyl-5-(benzyloxy)-4-oxo-1,4-dihydro pyridazine-3-carboxylic acid

Chem.

[0127] Intermediate 1.2: tert-Butyl 2-(1-benzyl-5-(benzyloxy)-4-oxo -1,4-dihydropyridazine-3-carbonyl)tetrahydropyridazine-1(2 H)-carboxylate

Chem.

[0128] Intermediate 1.3: tert-Butyl 2-(5-hydroxy-4-oxo-1,4-dihydro pyridazine-3-carbonyl)tetrahydropyridazine-1(2H)-carboxylate

Chemical Structure

[0129] Example 1: 12-Benzhydryl-4-hydroxy-7,8,9,10-tetrahydro- 3H-dipyridazino[1,2-a:1’,6’-d][1,2,4]triazine-3,5 (12H)-dione

Chemical Structure

[0130] Example 2. 2-(Bis(3-fluorophenyl)methyl)-4-hydroxy-7,8, 9,10-tetrahydro-3H-dipyridazino[1,2-a:1’,6’-d][1,2 ,4]triazine-3,5(12H)-dione

Chemical Structure

[0131] Example 3. 12 - (Bis(4 - chlorophenyl)methyl)-4 - hydroxy - 7,8,9 ,10 - tetrahydro - 3H - dipyridazino[1,2 - a:1’,6’ - d][1,2, 4]triazine - 3,5(12H) - dione

Chemical formula

[0132] Example 4. 12 - (Bis(3 - chlorophenyl)methyl)-4 - hydroxy - 7,8,9 ,10 - tetrahydro - 3H - dipyridazino[1,2 - a:1’,6’ - d][1,2, 4]triazine - 3,5(12H) - dione

Chemical formula

[0133] Example 5. 12-(Bis(4-fluorophenyl)methyl)-4-hydroxy-7,8, 9,10-tetrahydro-3H-dipyridazino[1,2-a:1’,6’-d][1,2 ,4]triazine-3,5(12H)-dione

Chemical Structure

[0134] Example 6. 13 - Benzhydryl - 4 - hydroxy - 8,9,10,11 - tetrahydro pyridazino[1’,6’:4,5][1,2,4]triazino[1,2 - a][1,2] diazepin - 3,5(7H,13H) - dione

Chemical Structure

[0135] Example 7. 13 - (Bis(3 - fluorophenyl)methyl) - 4 - hydroxy - 8,9, 10,11 - tetrahydropyridazino[1’,6’:4,5][1,2,4]triazino [1,2 - a][1,2]diazepin - 3,5(7H,13H) - dione

Chemical Structure

[0136] Example 8. (R)-12-(Bis(3-fluorophenyl)methyl)-4-hydroxy- 7,8,9,10-tetrahydro-3H-dipyridazino[1,2-a:1’,6’-d] [1,2,4]triazine-3,5(12H)-dione Intermediate 8.1. (R)-12-(Bis(3-fluorophenyl)methyl)-3,5-dioxo- 3,5,7,8,9,10-hexahydro-12H-dipyridazino[1,2-a: 1’,6’-d][1,2,4]triazin-4-yl (S)-3,3,3-trifluoro -2-methoxy-2-phenylpropanoate and (S)-12-(bis(3-fluoro phenyl)methyl)-3,5-dioxo-3,5,7,8,9,10-hexahydro- 12H-dipyridazino[1,2-a:1’,6’-d][1,2,4]triazin-4- (S)-3,3,3-Trifluoro-2-methoxy-2-phenylpropanoate [Chemical formula] 12-(Bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10 -tetrahydro-3H-dipyridazino[1,2-a:1’,6’-d][1,2,4]tri azine-3,5(12H)-dione (127 mg, 0.290 mmol) was dissolved in dry THF (volume: 4 mL) under stirring and nitrogen, and then TEA (0.081 mL, 0.579 mmol) was added. (R)-3,3,3-Trifluoro-2-methoxy-2 -phenylpropanoyl chloride (73.2 mg, 0.290 mmol) was added dropwise. The reaction mixture was stirred at room temperature for 90 minutes and then partitioned between EtOAc (10 mL) and water (10 mL). The phases were separated, the organic layer was washed with brine, dried over Na SO and concentrated. 2 SO 4 The residue was purified by ISCO (24 g silica gel column, 0 - 100% EtOAc in heptane). The diastereomers were then separated by chiral HPLC (IC column, heptane / EtOH = 80 / 20) to give the following. The diastereomers were then separated by chiral HPLC (IC column, heptane / EtOH = 80 / 20) to give the following. The following was obtained.

[0137] (R)-12-(Bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5 ,7,8,9,10-hexahydro-12H-dipyridazino[1,2-a:1’,6’- d][1,2,4]triazine-4-yl (S)-3,3,3-trifluoro-2-meth oxy-2-phenylpropanoate (63 mg, 0.096 mmol, yield 33%, 99 % ee). 1 1H NMR (400 MHz, chloroform-d) δ 7.90 (d, J = 7 .5 Hz, 2H), 7.62 (s, 1H), 7.54 - 7.29 (m, 4H), 7.19 (q, J = 7.8 Hz, 1H), 7.07 - 6.81 (m, 6H), 5.57 (d, J = 10.2 Hz, 1H), 4.68 - 4.43 (m, 2H), 3.83 (s, 3H), 3. 08 (d, J = 10.5 Hz, 1H), 3.03 - 2.87 (m, 1H), 2.66 (t , J = 11.5 Hz, 1H), 1.93 - 1.46 (m, 4H). MS m / z 655 .3 (M + 1).

[0138] (S)-12-(Bis(3-fluorophenyl)methyl)-3,5-dioxo-3,5 ,7,8,9,10-hexahydro-12H-dipyridazino[1,2-a:1’,6’- d][1,2,4]triazin-4-yl (S)-3,3,3-trifluoro-2-meth oxy-2-phenylpropanoate (57 mg, 0.087 mmol, yield 30%, 99 % ee). 1H NMR (400 MHz, chloroform-d) δ 7.94 (s, 2H) , 7.64 (s, 1H), 7.50 - 7.41 (m, 3H), 7.35 (q, J = 7.5 Hz, 1H), 7.19 (q, J = 7.6 Hz, 1H), 7.02 (dd, J = 14.8 , 8.4 Hz, 3H), 6.96 - 6.88 (m, 2H), 6.85 (d, J = 7.6 H z, 1H), 5.57 (d, J = 9.9 Hz, 1H), 4.62 (s, 1H), 4.49 (s, 1H), 3.84 (s, 3H), 3.09 (d, J = 10.8 Hz, 1H), 2. 93 (s, 1H), 2.66 (td, J = 12.5, 3.3 Hz, 1H), 1.82 (s , 2H), 1.58 (s, 1H), 1.27 (s, 1H). MS m / z 655.3 ( M + 1).

[0139] Example 8. (R)-12-(Bis(3-fluorophenyl)methyl)-4-hydroxy- 7,8,9,10-tetrahydro-3H-dipyridazino[1,2-a:1’,6’-d] [1,2,4]triazine-3,5(12H)-dione

Chemical formula

[0140] Example 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

Chemical Structure

[0141] Example 10. (9aR,10S)-10-benzhydryl-4-hydroxy-8,9,9 a,10-tetrahydro-3H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b] Pyridazine-3,5(7H)-dione Intermediate 10.1. (R)-2,2-Diphenyl-1-((R)-1-tritylpyrrolidin -2-yl)ethan-1-ol and (S)-2,2-Diphenyl-1-((R)-1- tritylpyrrolidin-2-yl)ethan-1-ol [Chemical formula] To a solution of diphenylmethane (2.155 mL, 12.89 mmol) in THF (volume: 5 8.6 mL) at room temperature was added a solution of n-butyllithium (2.5 M in hexane) (4.69 mL, 11 .71 mmol). After 10 minutes, the mixture was added to a solution of (R)-1-tritylpyrrolidin -2-carbaldehyde (2 g, 5.86 mmol; see J. Am. Chem. Soc., 2008, 130, 7562 - 7563) in THF (6 mL). After 15 minutes , the reaction mixture was quenched with saturated NH 4 Cl aqueous solution and extracted with EtOAc (twice ). The combined organic extracts were washed with brine and dried over Na 2 SO 4 , filtered, and concentrated in vacuo . The residue was purified by ISCO (220 g silica gel column, 0 - 40% Et in heptane OAc) to give (R)-2,2-Diphenyl-1-((R)-1-trityl pyrrolidin-2-yl)ethan-1-ol (1.64 g, 3.22 mmol, 54 .9% yield) (peak 1) as a sticky white solid (1H NMR (400 MHz, chloro form-d) δ 7.50 - 7.43 (m, 6H), 7.41 - 7.36 (m, 2H), 7.36 - 7.09 (m, 17H), 5.90 (s, 1H), 3.96 - 3.79 (m, 2H), 3.62 (t, J = 6.8 Hz, 1H), 3.18 (ddd, J = 12.9, 9 .3, 6.9 Hz, 1H), 3.04 (ddd, J = 13.3, 8.9, 4.9 Hz, 1 H), 1.45 - 1.35 (m, 1H), 0.76 (ddd, J = 12.1, 8.9, 2 .8 Hz, 1H), 0.65 (ddd, J = 13.0, 5.9, 2.6 Hz, 1H), 0 .59 - 0.46 (m, 1H)) and (S)-2,2-diphenyl-1-((R)-1- tritylpyrrolidin-2-yl)ethan-1-ol (0.62 g, 1.216 mmol , yield 20.77%) (peak 2) was obtained as a white solid (1H NMR (400 M Hz, chloroform-d) δ 7.41 (dt, J = 6.2, 1.6 Hz, 6H), 7. 30 - 7.01 (m, 17H), 6.67 - 6.61 (m, 2H), 4.81 (dd, J = 10.9, 2.4 Hz, 1H), 3.64 (d, J = 10.9 Hz, 1H), 3.32 (ddd, J = 8.9, 6.8, 2.4 Hz, 1H), 3.16 (ddd, J = 12.1 , 10.4, 6.3 Hz, 1H), 2.96 (ddd, J = 11.6, 7.8, 2.5 H z, 1H), 2.65 (s, 1H), 1.82 (dddd, J = 12.4, 10.0, 8 .0, 6.6 Hz, 1H), 1.23 (ddp, J = 14.9, 8.8, 3.2 Hz, 1 H), 1.17 - 1.03 (m, 1H), -0.01 - -0.15 (m, 1H)).

[0142] Intermediate 10.2. (R)-2,2-diphenyl-1-((R)-pyrrolidin-2-yl) ethanol

Chem.

[0143] Intermediate 10.3.1-Benzyl-5-(benzyloxy)-3-((R)-2-((R) -1-hydroxy-2,2-diphenylethyl)pyrrolidine-1-carbonyl)pyridazi n-4(1H)-one

Chemical Structure

[0144] Intermediate 10.4. (R)-1-((R)-1-(1-benzyl-5-(benzyloxy) -4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl) -2,2-diphenylethyl methanesulfonate [Chemical formula] 1-benzyl-5-(benzyloxy)-3-((R)-2-((R)-1-hydroxy -2,2-diphenylethyl)pyrrolidin-1-carbonyl)pyridazin-4(1H) -one (315 mg, 0.538 mmol) in pyridine (volume: 5378 μl) at 0 °C, MsCl (168 μl, 2.151 mmol) was added. The ice bath was removed and the mixture was stirred at room temperature for 1 hour. Another 100 μL of mesyl chloride was added. Stirred for 30 minutes. The reaction mixture was diluted with DCM and washed with water, then 0.5 N HCl aqueous solution (twice), and again with water. The organic layer was dried over Na 2 SO 4 and filtered, and concentrated in vacuo. The residue was purified by ISCO( 80 g silica gel column, 5 - 100% EtOAc in heptane (containing 10% MeOH) ) to give (R)-1-((R)-1-(1-benzyl-5-(benzyloxy ((R)-1-((R)-1-(5-Hydroxy-4-oxo-1,4-dihydropyridazin-3-carbonyl)pyrrolidin-2-yl)-2,2-diphenylethyl methanesulfonate (120 mg, 0.181 mmol yielded 33.6%) as a yellow solid. MS m / z 664.3 (M+1).

[0145] Intermediate 10.5. (R)-1-((R)-1-(5-Hydroxy-4-oxo-1,4- dihydropyridazin-3-carbonyl)pyrrolidin-2-yl)-2,2-diphenylethyl methanesulfonate

Chemical Structure

[0146] Example 10. (9aR,10S)-10-Benzhydryl-4-hydroxy-8,9,9 a,10-tetrahydro-3H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b] pyridazine-3,5(7H)-dione [Chemical] Crude (R)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydro pyridazine-3-carbonyl)pyrrolidin-2-yl)-2,2-diphenylethyl meth anesulfonate (61.4 mg, 0.127 mmol) in DMF (volume: 2 mL) at room temperature was added potassium carbonate (52.7 mg, 0.381 mmol). After overnight at room temperature , the reaction mixture was filtered through a 1 micron filter and purified directly by reversed-phase preparative HP LC (eluent of H 2 O containing MeCN / 0.1% TFA), to give (9aR,10 S)-10-benzhydryl-4-hydroxy-8,9,9a,10-tetrahydro-3 H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazine-3,5(7H) -dione (18 mg, 0.036 mmol, yield 28.0%) as a gray solid . 1H NMR (400 MHz, DMSO-d6) δ 7.63-7.57 (m, 2H) , 7.38 (t, J = 7.6 Hz, 2H), 7.29-7.23 (m, 1H), 7.22 (s, 1H), 7.04 (td, J = 4.9, 2.3 Hz, 3H), 6.95 (dd, J = 7.6, 2.0 Hz, 2H), 5.68 (dd, J = 9.6, 3.6 Hz, 1H), 4 . 55 (d, J = 9.5 Hz, 1H), 4.48 (ddd, J = 10.1, 5.9, 4. 0 Hz, 1H), 3.76-3.58 (m, 2H), 1.91 (tdd, J = 9.5, 5 . 0, 3.0 Hz, 1H), 1.82-1.63 (m, 2H), 1.51-1.40 (m , 1H). MS m / z 388.3 (M+1).

[0147] Example 11. (9aR,10R)-10-benzhydryl-4-hydroxy-8,9,9 a,10-tetrahydro-3H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b] pyridazine-3,5(7H)-dione

Chemical formula

[0148] Example 12. (9aS,10R)-10-benzhydryl-4-hydroxy-8,9,9 a,10-tetrahydro-3H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b] pyridazine-3,5(7H)-dione

Chemical formula

[0149] Example 13. (9aR,10R)-10-benzhydryl-4-hydroxy-8,9,9 a,10-tetrahydro-3H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b] pyridazine-3,5(7H)-dione

Chemical formula

[0150] Example 14. (9aR,10S)-10-((R)-(3-Fluorophenyl)(phenyl methyl)-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1 ’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5(7H)-dione Intermediate 14.1. (R,E)-tert-Butyl 2-(3-fluorostyryl)pyrrolid ine-1-carboxylate

Chemical formula

[0151] Intermediate 14.2. (R)-tert-Butyl 2-((2S,3S)-3-(3-fluoro ((R)-tert-Butyl 2-((2R,3R)-3-(3-Fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate and (R)-tert-Butyl 2-((2S,3S)-3-(3-Fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate (R,E)-tert-Butyl 2-(3-Fluorostyryl)pyrrolidine-1-carboxylate ((R)-tert-Butyl 2-((2S,3S)-3-(3-Fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate [Chemical Structure] mCPBA (1327 mg, 7.69 mmol) was added to a solution of (R,E)-tert-butyl 2-(3-fluorostyryl)pyrrolidine-1-carboxylate (640 mg, 2.19 mmol) in DCM (volume: 20 mL) at room temperature. The reaction mixture was stirred at room temperature overnight (R,E)-tert-Butyl 2-(3-Fluorostyryl)pyrrolidine-1-carboxylate (640 mg, 2.19 mmol) in DCM (volume: 20 mL) at room temperature. The reaction mixture was stirred at room temperature overnight (R,E)-tert-Butyl 2-(3-Fluorostyryl)pyrrolidine-1-carboxylate (640 mg, 2.19 mmol) in DCM (volume: 20 mL) at room temperature. The reaction mixture was stirred at room temperature overnight The reaction was quenched with water and extracted with DCM. The combined organic extracts were washed with saturated sodium thiosulfate, sodium bicarbonate, and brine The reaction was quenched with water and extracted with DCM. The combined organic extracts were washed with saturated sodium thiosulfate, sodium bicarbonate, and brine 2 SO 4 The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by ISCO (40 g silica gel column, 0 - 40% EtOAc in heptane) to give a mixture of (R)-tert-butyl 2-((2S,3S)-3-(3-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate and (R)-tert-butyl 2-((2R,3R)-3-(3-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate (0.35 g, 1.025 mmol, 46.7% yield). MS m / z 308.3 (M+1) ((R)-tert-Butyl 2-((2S,3S)-3-(3-Fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate ((R)-tert-Butyl 2-((2S,3S)-3-(3-Fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate and (R)-tert-butyl 2-((2R,3R)-3-(3-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate ((R)-tert-Butyl 2-((2S,3S)-3-(3-Fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate and (R)-tert-butyl 2-((2R,3R)-3-(3-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate (0.35 g, 1.025 mmol, 46.7% yield). MS m / z 308.3 (M+1) (0.35 g, 1.025 mmol, 46.7% yield). MS m / z 308.3 (M+1)

[0152] Intermediate 14.3. (R)-tert-Butyl 2-((1R,2R)-2-(3-Fluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylate ((R)-tert-Butyl 2-((1R,2R)-2-(3-Fluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylate and (R)-tert-butyl 2-((1S,2S)-2-(3-fluorophenyl)- 1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylate

Chem.

[0153] Intermediate 14.4. (R)-tert-butyl 2-((1R,2R)-2-(3-fluoro phenyl)-1-((methylsulfonyl)oxy)-2-phenylethyl)pyrrolidine- 1-carboxylate

Chemical Structure

[0154] ((R)-pyrrolidin-2-yl)ethyl methanesulfonate

Chemical Structure

Chemical Structure

[0155] Intermediate 14.6. (1R,2R)-1-((R)-1-(1-Benzyl-5-(benzyloxy -4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2 -yl)-2-(3-fluorophenyl)-2-phenylethyl methanesulfonate

Chemical formula

[0156] Intermediate 14.7. (1R,2R)-2-(3-Fluorophenyl)-1-((R)-1- (5-Hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrro din-2-yl)-2-phenylethyl methanesulfonate

Chemical formula

[0157] Example 14. (9aR,10S)-10-((R)-(3-Fluorophenyl)(phenyl yl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1 ’,2’:4,5]pyrazino[1,2-b]pyridazine-3,5(7H)-dione

Chemical formula

[0158] Example 15. (9aR,10R)-10-(Bis(3-fluorophenyl)methyl)-4 -hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1’,2’:4,5 pyrazino[1,2-b]pyridazin-3,5(7H)-dione

Chemical Structure

[0159] Example 16. (9aR,10S)-10-(Bis(3-fluorophenyl)methyl)-4 -hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1’,2’:4,5 pyrazino[1,2-b]pyridazin-3,5(7H)-dione

Chemical Structure

[0160] Example 17. (9aS,10R)-10-((S)-(3-chlorophenyl)(phenyl )methyl)-4-hydroxy-8,9,9a,10-tetrahydro-3H-pyrrolo[1’ ,2’:4,5]pyrazino[1,2-b]pyridazin-3,5(7H)-dione

Chemical Structure

[0161] Example 18. (10aS)-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

Chem.

[0162] Examples 19A and 19B.

Chem.

[0163] Intermediate 19.2. 3-((tert-butyldimethylsilyl)oxy)-1,1-diphe nylpropan-2-yl methanesulfonate Methanesulfonyl chloride (1.4 mL, 17.8 mmol) was added to 3-((tert- (Butyldimethylsilyl)oxy)-1,1-diphenylpropan-2-ol (4.70 g, 13.7 mmol) and triethylamine (3.8 mL, 27.4 mmol) were added dropwise to a solution of DCM (137 mL) at 0 °C . The solution was stirred for 30 minutes and then diluted with DCM and washed with water. The organic layer was dried over Na 2 SO 4 and filtered, and concentrated in vacuo to give crude 3-((tert-butyldimethylsilyl)oxy)-1,1-diphenylpropan- 2-ylmethanesulfonate as a colorless oil. It was used without further purification. MS m / z 421.4 (M+1).

[0164] Intermediate 19.3. 3-Hydroxy-1,1-diphenylpropan-2-ylmethanesulfo nate A solution of hydrogen chloride (4.0 M in dioxane, 5.2 mL, 20.6 mmol) was added to a solution of crude 3-((tert-butyldimethylsilyl)oxy)-1,1-diphenylpropan-2 -ylmethanesulfonate (5.8 g, 13.7 mmol) in methanol (137 mL) at room temperature. The mixture was stirred for 1 hour and then concentrated in vacuo. Silica gel column chromatography (25 - 80% EtOAc in heptane) gave 3-hydroxy -1,1-diphenylpropan-2-ylmethanesulfonate (3.81 g, colorless oil ) in 91% yield. 1H NMR (400 MHz, chloroform-d) δ 7.4 5 - 7.38 (m, 2H), 7.37 - 7.29 (m, 6H), 7.29 - 7.20 (m , 2H), 5.46 (ddd, J = 10.2, 5.4, 2.6 Hz, 1H), 4.33( d, J = 10.2 Hz, 1H), 3.87 (dd, J = 12.9, 2.6 Hz, 1H), 3.68 (dd, J = 12.9, 5.5 Hz, 1H), 2.37 (s, 3H).

[0165] Intermediate 19. 4. 2-((Methylsulfonyl)oxy)-3,3-diphenylpropyl 5 -(Benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl yl)-1,4-dihydropyridazine-3-carboxylate 5-(Benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy) methyl)-1,4-dihydropyridazine-3-carboxylic acid (700 mg, 1.86 mmol l) in DCM (6 mL) at 0 °C was added Hunig's base (812 μl, 4.65 mmol l) and HATU (848 mg, 2.23 mmol). The mixture was stirred for 15 minutes and then 3-hydroxy-1,1-diphenylpropan-2-yl methanesulfonate (854 mg, 2.79 mmol) in DCM (3 mL) was added. The mixture was stirred overnight at room temperature diluted with DCM and washed with water. The organic layer was dried over Na 2 SO 4 filtered and concentrated in vacuo Silica gel column chromatography (5 - 80% EtOAc in heptane) gave 2-((methylsulfonyl)oxy)-3,3-diphenylpropyl 5-(ben zyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)- 1,4-dihydropyridazine-3-carboxylate (878 mg, white foam) in 71% yield MS m / z 665.2 (M + 1).

[0166] Intermediate 19. 5. 2-((Methylsulfonyl)oxy)-3,3-diphenylpropyl 5 -hydroxy-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1 ,4-Dihydropyridazine-3-carboxylate 2-((Methylsulfonyl)oxy)-3,3-diphenylpropyl 5-(benzylo xy)-4-oxo-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4- Dihydropyridazine-3-carboxylate (1.0 g, 1.5 mmol) in methanol (40 mL) solution was purged with nitrogen. 10% Palladium on carbon (160 mg, 0.15 m mol) was added, the flask was evacuated and filled with hydrogen from a balloon (3 times). The mixture was vigorously stirred under a hydrogen atmosphere for 30 minutes. Then the flask was purged with nitrogen and the mixture was filtered through a plug of celite, washing the filter cake with methanol. Concentration of the filtrate in vacuo gave crude 2-((methylsulfonyl)oxy)-3 ,3-diphenylpropyl 5-hydroxy-4-oxo-1-((2-(trimethylsily l)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxylate, which was used without further purification. MS m / z 575.4 (M+1).

[0167] Intermediate 19.6. 2-((Methylsulfonyl)oxy)-3,3-diphenylpropyl 5 -hydroxy-4-oxo-1,4-dihydropyridazine-3-carboxylate Trifluoroacetic acid (20 mL) was added to a solution of crude 2-((methylsulfonyl)oxy)-3, 3-diphenylpropyl 5-hydroxy-4-oxo-1-((2-(trimethylsilyl )ethoxy)methyl)-1,4-dihydropyridazine-3-carboxylate (864 m g, 1.50 mmol) in DCM (5 mL) at room temperature. The mixture was stirred for 5 hours and then concentrated in vacuo to give crude 2-((methylsulfonyl)oxy)-3,3-di​​ Phenylpropyl 5-hydroxy-4-oxo-1,4-dihydropyridazine-3-car boxylate was given and used without further purification. MS m / z 445.3 (M +1).

[0168] Intermediate 19. 7,8-Benzhydryl-4-(benzyloxy)-7,8-dihydropyr idazino[6,1-c][1,4]oxazine-3,5-dione Cesium carbonate (5.39 g, 16.5 mmol) was added to a room temperature DMF solution of crude 2-((methylsulfonyl )oxy)-3,3-diphenylpropyl 5-hydroxy-4-oxo-1,4-dihyd ropyridazine-3-carboxylate (840 mg, 1.50 mmol). The mixture was then stirred at 45 °C for 3 h. Then, benzyl bromide (1 mL ) was added and the mixture was stirred at 45 °C for an additional 1 h. The mixture was then cooled to room temperature and filtered to remove solids. The filtrate was concentrated in vacuo and the residue was purified by preparative reverse phase HPLC (M eCN / 0.1% TFA containing H 2 O eluent) to give, after lyophilization, 8-ben zhydryl-4-(benzyloxy)-7,8-dihydropyridazino[6,1-c] 1,4]oxazine-3,5-dione (91 mg, white solid) in 11% yield. 1 H NMR (400 MHz, DMSO-d6) δ 7.61 - 7.07 (m, 16H), 5.63 (ddd, J = 11.7, 2.4, 1.3 Hz, 1H), 5.46 (d, J = 1 1.3 Hz, 1H), 5.33 (d, J = 11.3 Hz, 1H), 4.92 (dd, J = 12.1, 2.6 Hz, 1H), 4.40 (d, J = 11.5 Hz, 1H), 4.23( dd, J = 12.2, 1.3 Hz, 1H). MS m / z 439.2 (M+1).

[0169] Intermediate 19.8. Isopropyl 4-(benzyloxy)-2-(3-hydroxy-1,1 -diphenylpropan-2-yl)-5-oxo-2,5-dihydropyridazine-3-car boxylate Titanium isopropoxide (0.11 mL, 0.37 mmol) was added to a suspension of 8-benzhydryl -4-(benzyloxy)-7,8-dihydropyridazino[6,1-c][1,4]ox azine-3,5-dione (34 mg, 0.062 mmol) in 2-propanol (6 mL ). The mixture was heated at 75 °C for 3 h and then cooled to room temperature. The mixture was diluted with EtOAc and brine. The layers were separated and the aqueous layer was extracted with EtOAc (2 times) , and the combined organic extracts were dried over Na 2 SO 4 and filtered, and concentrated in vacuo to give a white residue which was triturated with DCM, the DCM layer was removed by pipette, and concentrated in vacuo to give a mixture of starting material and crude isopropyl 4-(benzyloxy)-2-(3- hydroxy-1,1-diphenylpropan-2-yl)-5-oxo-2,5-dihydro pyridazine-3-carboxylate which was used without further purification. MS m / z 499.3 (M+1). MS m / z 499.3 (M+1).

[0170] Intermediate 19.9. Isopropyl 4-(benzyloxy)-5-oxo-2-(3-oxo -1,1-diphenylpropan-2-yl)-2,5-dihydropyridazine-3-carbo xylate Dess-Martin periodinane (37 mg, 0.087 mmol) was added to the crude isop ropyl 4-(benzyloxy)-2-(3-hydroxy-1,1-diphenylpropan- A room temperature solution of 2-yl)-5-oxo-2,5-dihydropyridazine-3-carboxylate in was added to DCM (1 mL). The mixture was stirred for 1 h and then diluted with DCM and successively washed with saturated aqueous sodium bisulfate and brine. The organic layer was dried over 2 Na 4 SO filtered, and concentrated in vacuo to give crude isopropyl 4-(benzyloxy)-5- oxo-2-(3-oxo-1,1-diphenylpropan-2-yl)-2,5-dihydropyridazine-3-carboxylate, which was used without further purification. MS m / z 497.2 (M+1).

[0171] Intermediate 19. 12-benzhydryl-7-(benzyloxy)-3,4,12,12a- tetrahydro-2H-pyridazino[1’,6’:4,5]pyrazino[2,1-b][1, 3]oxazine-6,8-dione

Chemical Structure

[0172] Diastereomer 1: LCMS Rt 0.91 / 1.50 min, m / z 494.2 (M + 1). 1H NMR (400 MHz, DMSO-d6) δ 7.63 - 7.57 (m, 2H), 7.53 - 7.48 (m, 2H), 7.44 - 7.26 (m, 7H), 7.16 (dd, J = 6.7, 3.0 Hz, 2H), 7.09 (dd, J = 5.0, 1.9 Hz, 3H), 5.45 (dd, J = 11.4, 1.3 Hz, 1H), 5.35 (d, J = 11 .2 Hz, 1H), 5.20 (d, J = 11.1 Hz, 1H), 4.77 (d, J = 1. 4 Hz, 1H), 4.55 - 4.45 (m, 1H), 4.37 (d, J = 11.3 Hz, 1H), 4.01 (dd, J = 11.5, 4.7 Hz, 1H), 3.85 - 3.75 (m , 1H), 3.00 (td, J = 12.8, 3.0 Hz, 1H), 1.66 (ddd, J = 17.0, 8.4, 4.7 Hz, 1H), 1.44 (d, J = 13.6 Hz, 1H).

[0173] Diastereomer 2: LCMS Rt 0.92 / 1.50 min, m / z 494.2 (M + 1). 1H NMR (400 MHz, DMSO-d6) δ 7.70 (s, 1H), 7 .51 - 7.44 (m, 4H), 7.40 - 7.28 (m, 5H), 7.27 - 7.20 (m, 1H), 7.16 - 7.03 (m, 5H), 5.61 (dd, J = 7.2, 3.3 Hz, 1H), 5.07 (d, J = 3.3Hz, 1H), 4.96 (d, J = 1.9Hz , 2H), 4.88 (d, J = 7.1Hz, 1H), 4.26 (ddd, J = 13.4, 5.1, 2.9Hz, 1H), 3.94 (dd, J = 11.1, 4.5Hz, 1H), 3 .45 - 3.39 (m, 1H), 3.13 (ddd, J = 13.2, 11.7, 4.0H z, 1H), 1.93 - 1.79 (m, 1H), 1.66 (dt, J = 13.8, 3.4 Hz, 1H).

[0174] Examples 19A and 19B. 12 - Benzhydryl - 7 - hydroxy - 3,4,12,12 a - tetrahydro - 2H - pyridazino[1’,6’:4,5]pyrazino[2,1 - b] 1,3]oxazine - 6,8 - dione

Chemical formula

[0175] Example 19A. LCMS Rt 0.80 / 1.50 min, m / z 404.2 (M+1 ). 1H NMR (400 MHz, DMSO-d6) δ 7.62 - 7.57 (m, 2H ), 7.42 - 7.25 (m, 7H), 7.13 (dd, J = 4.9, 2.7 Hz, 2H ), 5.50 (dd, J = 11.2, 1.2 Hz, 1H), 4.87 (d, J = 1.3H z, 1H), 4.48 (dd, J = 11.9, 7.0 Hz, 2H), 4.04 (dd, J = 11.4, 4.9 Hz, 1H), 3.91 - 3.79 (m, 1H), 3.12 (td, J = 12.8, 3.1 Hz, 1H), 1.64 (dt, J = 12.8, 6.6 Hz, 1H ), 1.54 - 1.45 (m, 1H).

[0176] Example 19B. LCMS Rt 0.82 / 1.50 min, m / z 404.2 (M+1 ). 1H NMR (400 MHz, DMSO-d6) δ 7.53 (s, 1H), 7.5 0 - 7.44 (m, 2H), 7.38 - 7.02 (m, 8H), 5.64 (dd, J = 7 .0, 3.5 Hz, 1H), 5.11 (d, J = 3.4 Hz, 1H), 4.90 (d, J = 7.0 Hz, 1H), 4.28 (qd, J = 7.1, 6.0, 3.7 Hz, 1H), 3 .98 (dd, J = 11.2, 4.7 Hz, 1H), 3.43 (td, J = 11.8, 2 .4 Hz, 1H), 3.19 (td, J = 12.9, 3.8 Hz, 1H), 1.93 (d ddd, J = 12.5, 9.0, 7.1, 5.2 Hz, 1H), 1.68 (ddd, J = 14.1, 4.0, 2.1 Hz, 1H).

[0177] Examples 19A and 19B and other example numbers containing A or B were separated into individual isomers and tested, and it should be noted that the biological activity was reported for each isolated isomer . However, since the absolute stereochemistry of the two isomers was not determined, the structures shown in these examples do not depict the stereochemistry, and the A and B structures appear the same, but each represents a single diastereomer.

[0178] [Table 1]

[0179] [Table 2]

[0180] [Table 3]

[0181] [Table 4]

[0182] [Table 5]

[0183] [Table 6]

[0184] [Table 7]

[0185] [Table 8]

[0186] General synthesis of chiral N-Boc amino alcohol

Chem.

[0187] Step G-2: tert-Butyl (R)-2-((2S,3S)-3-(2-fluorophenyl) oxiran-2-yl)pyrrolidine-1-carboxylate and tert-butyl (R)-2-((2R,3R)-3-(2-fluorophenyl)oxiran-2-yl) ​​Pyrrolidine-1-carboxylate tert-Butyl (R,E)-2-(2-fluorostyryl) in DCM (60 mL) to pyrrolidine-1-carboxylate (1.85 g, 6.35 mmol) was added mCPBA (7 .83 g, 31.7 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction was quenched with water and extracted with DCM (twice). The combined organic extracts were washed successively with saturated Na 2 S 2 O 3 aqueous solution, saturated NaHCO 3 aqueous solution, and brine. The organic layer was then dried over Na 2 SO 4 filtered, concentrated. Silica gel column chromatography( EtOAc / heptane) gave a inseparable mixture of tert-butyl (R)-2-((2S,3S)-3 -(2-fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate and tert-butyl (R)-2-((2R,3R)-3-(2-fluorophenyl)ox irane-2-yl)pyrrolidine-1-carboxylate (1.6 g , colorless oil) in 41% yield. The mixture was used in the next step without further purification.

[0188] Step G-3: tert-Butyl (R)-2-((1R,2R)-2-(2-fluorophen yl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylate and tert-butyl (R)-2-((1S,2S)-2-(2-fluorophenyl)-1- hydroxy-2-phenylethyl)pyrrolidine-1-carboxylate Copper(I) bromide-dimethyl sulfide complex (0.495 g, 2.408 mmol) was added at room tert-Butyl (R)-2-((2S,3S)-3-(2 -fluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate and te rt-butyl (R)-2-((2R,3R)-3-(2-fluorophenyl)oxirane -2-yl)pyrrolidine-1-carboxylate mixture (0.74 g, 2.41 mmo l) was added. It was cooled to -20~-30 °C in an acetone bath with dry ice added periodically. Phenylmagnesium bromide solution (1.0 M in THF, 9.63 mL, 9.63 mmol) was added dropwise. Stir for 15 minutes and let stand to warm the temperature to 0 °C. Another 2 equivalents of phenylmagnesium bromide were added and stirred for another 20 minutes. Another 2 equivalents of phenylmagnesium bromide were added and stirred for another 20 minutes. The reaction mixture was quenched with saturated aqueous NH Cl and extracted with EtOAc (twice). The combined organic extracts were dried over Na SO 4 and filtered and concentrated. Silica gel column chromatography (EtOAc / heptane) gave tert-butyl (R)-2-((1R,2R)-2-(2-fluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-carboxylate (35 2 SO 4 3 mg, colorless oil, eluted first) in 38% yield and tert-butyl (R)-2-( (1S,2S)-2-(2-fluorophenyl)-1-hydroxy-2-phenylethyl )pyrrolidine-1-carboxylate (300 mg, white foam, eluted second) in 3 2% yield. MS m / z 286.2 (MH+-Boc). 3 mg, colorless oil, eluted first) in 38% yield and tert-butyl (R)-2-( (1S,2S)-2-(2-fluorophenyl)-1-hydroxy-2-phenylethyl )pyrrolidine-1-carboxylate (300 mg, white foam, eluted second) in 3 2% yield. MS m / z 286.2 (MH+-Boc).

[0189] Example 32. (9aR,10S)-10-((R)-(2-fluorophenyl)(pheny (R)-methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1 ’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione

Chemical formula

[0190] Step 2: (1R,2R)-2-(2-fluorophenyl)-2-phenyl-1-((R) ((1R,2R)-2-(2-Fluorophenyl)-2-phenyl-1-((R)-pyrrolidin-2-yl)ethyl)methanesulfonate hydrochloride HCl (4.0 M in dioxane, 5 ml, 20 mmol) was added to tert-butyl (R) -2-((1R,2R)-2-(2-Fluorophenyl)-1-((methylsulfonyl) oxy)-2-phenylethyl)pyrrolidine-1-carboxylate (350 mg, 0. 755 mmol). The mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was concentrated to give (1 R,2R)-2-(2-Fluorophenyl)-2-phenyl-1-((R)-pyrrolidin -2-yl)ethyl)methanesulfonate hydrochloride, which was used in the next step without further purification MS m / z 364.5 (MH + +).

[0191] Step 3: (1R,2R)-1-((R)-1-(1-Benzyl-5-(benzyloxy) -4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl) -2-(2-Fluorophenyl)-2-phenylethyl methanesulfonate Hünig's base (0.519 mL, 2.97 mmol) and HATU (367 mg, 0.966 mmol) were added to a solution of 1-benzyl-5-(benzyloxy)-4-oxo-1,4 -dihydropyridazine-3-carboxylic acid (275 mg, 0.817 mmol) in DCM (6 mL) at room temperature. The mixture was stirred at room temperature for 15 minutes, and then a solution of crude (1R,2R)- 2-(2-Fluorophenyl)-2-phenyl-1-((R)-pyrrolidin-2-yl) ethyl)methanesulfonate hydrochloride (270 mg, 0.743 mmol) in DCM (4 mL ) and 2 equivalents of Hünig's base were added. The mixture was stirred at room temperature for 1 hour. Then , the reaction mixture was diluted with DCM and washed with water and brine. The organic layer was dried over Na 2SO 2 44 Dried and filtered and concentrated. Silica gel column chromatography (EtOAc / EtOH / heptane) gave (1R,2R)-1-((R)-1-(1-benzyl-5-(ben zyloxy)-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin -2-yl)-2-(2-fluorophenyl)-2-phenylethyl methanesulfonate (470 mg) in 93% yield. MS m / z 682.5 (MH + +).

[0192] Step 4: (1R,2R)-2-(2-Fluorophenyl)-1-((R)-1-(5-h ydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2 -yl)-2-phenylethyl methanesulfonate (1R,2R)-1-((R)-1-(1-Benzyl-5-(benzyloxy)-4- oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2- (2-fluorophenyl)-2-phenylethyl methanesulfonate (470 mg, 0. 689 mmol) in methanol (12 mL) was purged with nitrogen. 10% palladium on car bon (220 mg, 0.207 mmol) was added and a hydrogen balloon was attached. The flask was evacuated and filled with hydrogen (3 times), then stirred vigorously at room temperature for 6 hours under a hydrogen balloon . The reaction mixture was filtered through celite and the filter cake was washed with MeOH. Concentration of the filtrate gave crude (1R,2R)-2-(2-fluorophenyl)-1-((R )-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl )pyrrolidin-2-yl)-2-phenylethyl methanesulfonate, which was further It was used in the next step without purification. MS m / z 502.4 (MH + ).

[0193] Step 5: (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]pyridazin-3,5-dione Crude (1R,2R)-2-(2-fluorophenyl)-1-((R)-1-(5-hy droxy-4-oxo-1,4-dihydropyridazin-3-carbonyl)pyrrolidin-2 -yl)-2-phenylethyl methanesulfonate (345 mg, 0.619 mmol) in DMF (10 mL) solution, potassium carbonate (342 mg, 2.476 mmol) was added , and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through a 1 micron filter and purified by reverse-phase H PLC. The product fractions were combined, frozen, and lyophilized to give (9 aR,10S)-10-((R)-(2-fluorophenyl)(phenyl)methyl)-4 -hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1’,2’:4,5 pyrazino[1,2-b]pyridazin-3,5-dione formate (125 mg, 0.27 5 mmol, white solid) in a 44% yield over two steps. 1 H NMR (400 MHz ,CD 3 OD) δ ppm 7.91 (td, J = 7.36, 2.01 Hz, 1H) 7. 26 - 7.42 (m, 3H) 7.02 - 7.17 (m, 4H) 6.96 (dd, J = 6. 38, 2.96 Hz, 2H) 5.79 (dd, J = 9.56, 3.59 Hz, 1H) 4. 69 (d, J = 9.63 Hz, 1H) 4.52 (dt, J = 9.96, 5.12 Hz, 1 H) 3.84 - 3.99 (m, 1H) 3.57 - 3.73 (m, 1H) 2.01 - 2.1 2 (m, 1H) 1.91 - 2.00 (m, 1H) 1.78 - 1.91 (m, 1H) 1.5 5 (qd, J = 11.56, 6.80 Hz, 1H). MS m / z 406.4 (MH + ).

[0194]

Table 9

[0195]

Table 10

[0196]

Table 11

[0197]

Table 12

[0198] Example 51. (9aR, 10S)-10-((S)-(2-Fluorophenyl)(phenyl yl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1 ’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione

Chemical Structure

[0199] Step 2: (1R,7aR)-1-((S)-(2-Fluorophenyl)(phenyl)meth yl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3-one A solution of tert-butyl (R)-2-((1S,2S)-2-(2-fluorophenyl)-1 -((methylsulfonyl)oxy)-2-phenylethyl)pyrrolidine-1-carboxy late (325 mg, 0.701 mmol) in pyridine (4 mL) was heated in a microwave reactor at 120 °C for 2 hours. Silica gel column chromatography (EtOA c / heptane) gave (1R,7aR)-1-((S)-(2-fluorophenyl) (phenyl)methyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazole- 3-One (150 mg) was obtained in 69% yield. MS m / z 312.4 (MH + ).

[0200] Step 3: (1R,2S)-2-(2-Fluorophenyl)-2-phenyl-1-((R) -Pyrrolidin-2-yl)ethan-1-ol hydrochloride 6N aqueous HCl solution was added to a solution of (1R,7aR)-1-((S)-(2-fluorophenyl) (phenyl)methyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazole- 3-one (150 mg, 0.482 mmol) in dioxane (2 mL), and the mixture was heated at 90 °C for 2 days in a sealed vial until the reaction was complete. Then, concentration of the reaction mixture gave crude (1R,2S)-2-(2-fluorophenyl)-2-phe nyl-1-((R)-pyrrolidin-2-yl)ethan-1-ol hydrochloride, which was used in the next step without further purification. MS m / z 286.4 (MH ). +

[0201] Step 4: 1-Benzyl-5-(benzyloxy)-3-((R)-2-((1R,2S) -2-(2-Fluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidin- 1-carbonyl)pyridazin-4(1H)-one Hünig's base (0.331 mL, 1.892 mmol) and HATU (234 mg , 0.615 mmol) were added to a solution of 1-benzyl-5-(benzyloxy)-4-oxo-1, 4-dihydropyridazine-3-carboxylic acid (175 mg, 0.520 mmol) in DCM (2 mL) at room temperature . The mixture was stirred at room temperature for 15 minutes, and then crude (1R,2S) -2-(2-Fluorophenyl)-2-phenyl-1-((R)-pyrrolidin-2-yl ​) A solution of ethan-1-ol hydrochloride (135 mg, 0.473 mmol) in DCM (2 mL) and Hunig's base (0.331 mL, 1.892 mmol) were added. The mixture was stirred at room temperature for 30 minutes. Then, the mixture was diluted with DCM and washed with water and brine. The organic layer was dried over Na SO and filtered and concentrated. Silica gel column chromatography 2 SO 4 (EtOAc / EtOH / heptane) gave 1-benzyl-5-(benzyloxy )-3-((R)-2-((1R,2S)-2-(2-fluorophenyl)-1-hyd roxy-2-phenylethyl)pyrrolidine-1-carbonyl)pyridazin-4(1H)- one (270 mg, foamy solid) in 95% yield. MS m / z 604.7 (M H )). +

[0202] Step 5: (1R,2S)-1-((R)-1-(1-benzyl-5-(benzyloxy) -4-oxo-1,4-dihydropyridazin-3-carbonyl)pyrrolidin-2-yl) -2-(2-fluorophenyl)-2-phenylethyl methanesulfonate To a solution of 1-benzyl-5-(benzyloxy)-3-((R)-2-((1R,2S)-2- (2-fluorophenyl)-1-hydroxy-2-phenylethyl)pyrrolidine-1-ca rbonyl)pyridazin-4(1H)-one (270 mg, 0.447 mmol) in 2,6 -lutidine (6 mL, 51.5 mmol) was added methanesulfonyl chloride (0.69 7 mL, 8.95 mmol) in an ice bath. After 5 minutes, the bath was removed and the reaction mixture was stirred for 3 hours at room temperature. LC-MS showed that the major, [M+H]+ 682.5 / 1.07 min was the desired It indicates corresponding to the product. Subsequently, the reaction mixture was partitioned between DCM and water. DC The M layer was separated and successively 3 washed with 1N aqueous HCl solution, saturated NaHCO aqueous solution, and brine. Then, the DCM layer was dried over Na 2 SO 4 and filtered and concentrated. Silica gel column chromatography (EtOAc / heptane) gave (1R,2S)-1-( (R)-1-(1-benzyl-5-(benzyloxy)-4-oxo-1,4-dihydro pyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(2-fluorophenyl) -2-phenylethyl methanesulfonate (245 mg, brown solid) in 80% yield. MS m / z 682.6 (MH ) + .

[0203] Step 6: (1R,2S)-2-(2-Fluorophenyl)-1-((R)-1-(5-h ydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2 -yl)-2-phenylethyl methanesulfonate (1R,2S)-1-((R)-1-(1-benzyl-5-(benzyloxy)-4- oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2- (2-fluorophenyl)-2-phenylethyl methanesulfonate (245 mg, 0. 359 mmol) in methanol (6 mL) was added with HCl (4.0 M in dioxane, 0. 180 mL, 0.719 mmol), and then the solution was purged with nitrogen. 10% palladium on carbon (115 mg, 0.108 mmol) was added and a hydrogen balloon was attached. The flask was evacuated and filled with hydrogen (3 times), and then under a hydrogen balloon at room temperature for 2 hours It was stirred vigorously. Further, palladium carbon (115 mg, 0.108 mmol) was added , and it was further stirred 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-(2-fluoro phenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyr idazin-3-carbonyl)pyrrolidin-2-yl)-2-phenylethyl methanesulfo nate, which was used in the next step without further purification. MS m / z 502.3 (MH + ).

[0204] Step 7: (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 To a solution of crude (1R,2S)-2-(2-fluorophenyl)-1-((R)-1-(5-h ydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2 -yl)-2-phenylethyl methanesulfonate (180 mg, 0.341 mmol) in DMF (5 mL) was added potassium carbonate (188 mg, 1.364 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through a 1 micron filter and purified by reverse phase HP LC. The product fractions were combined, frozen, and lyophilized to give the formate salt of (9a R,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 (69 mg, 0.151 m mol, a white solid) was obtained in a 44% yield in two steps. 1 H NMR (400 MHz, C D 3 OD) δ ppm 7.55 (d, J = 7.63 Hz, 2H) 7.42 (t, J = 7 .65 Hz, 2H) 7.37 (s, 1H) 7.27 - 7.34 (m, 1H) 7.03 - 7 .13 (m, 2H) 6.88 - 6.95 (m, 1H) 6.83 (dd, J = 10.37, 8.31 Hz, 1H) 5.82 (dd, J = 9.88, 3.57 Hz, 1H) 4.92 ( br d, J = 9.98 Hz, 1H) 4.49 - 4.62 (m, 1H) 3.82 - 4.0 0 (m, 1H) 3.57 - 3.73 (m, 1H) 1.98 - 2.10 (m, 1H) 1.7 7 - 1.94 (m, 2H) 1.56 - 1.70 (m, 1H). MS m / z 406.4 (MH + ).

[0205]

Table 13

[0206]

Table 14

[0207]

Table 15

[0208] General Synthesis of Chiral N-CBZ Amino Alcohol

Chemical Formula

[0209] Step G-2: (R,E)-2-(2,3-Difluorostyryl)pyrrolidine hydrochloride 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 h. Then the reaction mixture was 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 + +).

[0210] ​​​Project G-3: Benzyl (R,E)-2-(2,3-difluorostyryl)pyrrolidine-1 -carboxylate 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. The mixture was left to warm to room temperature and stirred overnight. The reaction was then diluted with additional DCM and washed successively with water and then brine, dried over Na SO 2 SO 4 , filtered and concentrated. Silica gel column chromatography (EtOAc / heptane) gave benzyl (R,E)-2-(2,3-difluorostyryl)pyrrolidine-1-carbox ylate (6.67 g, colorless oil) in 99% yield over two steps. MS m / z 3 44.3 (MH + +).

[0211] Project G-4: Benzyl (R)-2-((2S,3S)-3-(2,3-difluorophenyl yl)oxirane-2-yl)pyrrolidine-1-carboxylate and benzyl (R)-2 -((2R,3R)-3-(2,3-difluorophenyl)oxirane-2-yl)pyrro lidine-1-carboxylate To (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 with saturated Na S 2 S 2 O 3aqueous solution, saturated NaHCO 3 The organic layer was washed successively with aqueous solution, saturated NaHCO 2 SO 4 and brine, dried over Na SO and filtered. The filtrate was concentrated. Purification by silica gel column chromatography (EtOAc / hexane) gave 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 (5.16 g, colorless oil) in 84% yield. The mixture was used in the next step without further purification. -2-((2R,3R)-3-(2,3-difluorophenyl)oxiran-2-yl)pyrrolidine-1-carboxylate that could not be separated (5.16 g, colorless oil) in 84% yield. The mixture was used in the next step without further purification.

[0212] Step G-5: 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 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 reaction mixture was cooled to -20 to -30 °C in an acetone bath with the periodic addition of dry ice. ​​​​​​​​​​​-Solution of (4-fluorophenyl)magnesium bromide (1.0 M in THF, 8.35 mL, 8.35 mmol) was added dropwise. Stirred for 10 minutes and warmed the temperature to 0 °C. Further, 2 equivalents of (4-fluorophenyl)magnesium bromide was added and stirred for an additional 30 minutes. The reaction mixture was quenched with saturated NH 4 Cl aqueous solution and extracted with EtOAc (twice). The combined organic extracts were dried over Na 2 SO 4 , filtered, and concentrated. Silica gel column chromatography (EtOAc / heptane) gave benzyl (R)-2-((1R,2R)-2-(2 ,3-difluorophenyl)-2-(4-fluorophenyl)-1-hydroxyethyl) pyrrolidine-1-carboxylate (88 mg, colorless oil, eluted first) in 14% yield and benzyl (R)-2-((1S,2S)-2-(2,3-difluorophenyl)-2- (4-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate (350 mg, eluted second) in 55% yield. MS m / z 456.4 (MH +).

[0213] Example 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]pyridazin-3,5-di one

Chemical Structure

[0214] Step 2: (1R,2R)-2-(2,3-Difluorophenyl)-2-(4-fluorophenyl)-1-((R)-pyrrolidin-2-yl)ethyl methanesulfonate hydrochloride 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 and ​Added 10% palladium on carbon (68 mg, 0.064 mmol), and attached a hydrogen balloon. The flask was evacuated and filled with hydrogen (3 times), and then stirred vigorously at room temperature under the hydrogen balloon. After 2 hours, the reaction mixture was filtered through celite, and the filter cake was washed with MeOH. Concentration of the filtrate gave 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+).

[0215] Example 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]pyridazin-3,5-dione (1R,2R)-2-(2,3-Difluorophenyl)-2-(4-fluorophenyl )-1-((R)-pyrrolidin-2-yl)ethyl methanesulfonate hydrochloride was prepared by the method of Example 32, Steps 3 to 5. 1 H NMR (400 MHz, CD 3 OD) 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). MS m / z 442.4 (MH+).

[0216]

Table 16

[0217]

Table 17

[0218]

Table 18

[0219]

Table 19

[0220]

Table 20

[0221]

Table 21

[0222] Example 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]pyridazin-3,5-di one

Chemical Structure

[0223] Step 2: (1R,7aR)-1-((S)-(2,3-difluorophenyl)(4-fluoro phenyl)methyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazole -3-one Benzyl (R)-2-((1S,2S)-2-(2,3-difluorophenyl)-2- (4-fluorophenyl)-1-((methylsulfonyl)oxy)ethyl)pyrrolidine- A solution of 1-carboxylate (370 mg, 0.693 mmol) in pyridine (2 mL) was , heated in a microwave reactor at 150 °C for 3 hours. Silica gel column chromatography (EtOAc / heptane) gave (1R,7aR)-1-((S)-(2,3 -difluorophenyl)(4-fluorophenyl)methyl)tetrahydro-1H,3H- pyrrolo[1,2-c]oxazol-3-one (200 mg) in 83% yield. M S m / z 348.4 (MH+).

[0224] Example 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]pyridazin-3,5-di one (1R,7aR)-1-((S)-(2,3-difluorophenyl)(4-fluorop enyl)methyl)tetrahydro-1H,3H-pyrrolo[1,2-c]oxazol-3- one was prepared by the method of Example 51, Steps 3 to 7. 1 H NMR (400 MHz , CD3OD) δ ppm 7.61 (dd, J = 8.6, 5.2 Hz, 2H), 7.4 2 (s, 1H), 7.16 (t, J = 8.7 Hz, 2H), 7.01 (dtd, J = 9. 9, 7.9, 1.7 Hz, 1H), 6.96 - 6.80 (m, 2H), 5.85 (dd, J = 10.0, 3.6 Hz, 1H), 4.95 - 4.90 (m, 1H), 4.54 (dt , J = 10.6, 4.9 Hz, 1H), 3.89 (dd, J = 12.5, 8.7 Hz, 1 H), 3.72 - 3.60 (m, 1H), 2.04 (qd, J = 7.3, 3.2 Hz, 1 H), 1.98 - 1.78 (m, 2H), 1.57 (qd, J = 11.5, 6.6 Hz, 1H). MS m / z 442.4 (MH+).

[0225]

Table 22

[0226]

Table 23

[0227]

Table 24

[0228] Example 106. 10 - (Bis(3 - fluorophenyl)methyl)-4 - hydroxy - 8, 9,9a,10 - tetrahydro - 7H - pyrrolo[1’,2’:4,5]pyrazino[1,2 -b]pyridazin - 3,5 - dione

Chem.

[0229] Example 107. 4 - ((R)-(3 - fluorophenyl)((9aR, 10S)-4 - hydroxy -3,5 - dioxo - 3,5,8,9,9a,10 - hexahydro - 7H - pyrro [1’,2’:4,5]pyrazino[1,2 - b]pyridazin - 10 - yl)methyl)be nzonitrile

Chemical formula

[0230] Step 2: (R)-tert-butyl 2-((1R,2R)-2-(4-cyanophenyl) -2-(3-fluorophenyl)-1-((methylsulfonyl)oxy)ethyl)pyrrol idine-1-carboxylate (R)-tert-butyl 2-((1R,2R)-2-(4-cyanophenyl)-2- (3-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate (110 mg, 0.268 mmol) in pyridine (4 mL) at 0 °C was treated with methanesulfonyl chloride (0.251 mL, 3.22 mmol). After 5 minutes, the ice bath was removed and the reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was then partitioned between DCM and water. The DCM layer was washed with saturated NaHCO 3 aqueous solution and then with brine, dried over Na 2 SO 4 and filtered and concentrated. Silica gel column chromatography (EtOAc / heptane) gave (R)-tert-butyl 2-((1R,2R)-2-(4-cyanophenyl) -2-(3-fluorophenyl)-1-((methylsulfonyl)oxy)ethyl)pyrrol idine-1-carboxylate The resulting product was 105 mg of zinzyl-1-carboxylate in 80% yield. MS m / z 48 9.3(MH+).

[0231] Step 3: (1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl) -1-((R)-pyrrolidin-2-yl)ethyl methanesulfonate hydrochloride HCl (4.0 M in dioxane, 2 ml, 8 mmol) was added to (R)-tert-butyl 2-((1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl)- 1-((methylsulfonyl)oxy)ethyl)pyrrolidine-1-carboxylate(10 5 mg, 0.215 mmol) was added to the reaction mixture. The mixture was stirred at room temperature for 1 h. The reaction was then concentrated. Then, (1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl) 1-((R)-pyrrolidin-2-yl)ethyl methanesulfonate hydrochloride, Used in the next step without further purification: MS m / z 389.3 (MH+).

[0232] Step 4: (1R,2R)-1-((R)-1-(5-(benzyloxy)-4-oxo- 1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine- 3-carbonyl)pyrrolidin-2-yl)-2-(4-cyanophenyl)-2-(3-furan (fluorophenyl)ethyl methanesulfonate Hunig's base (0.142 mL, 0.812 mmol) and HATU (100 mg , 0.264 mmol) to 5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)oxy)-1-(2-phenylpropanediol). Methylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-carboxylic acid (8 4 mg, 0.223 mmol: U.S. Patent Application Publication No. 2015 / 0072982A1 It was added to a solution of DCM (1 mL) at room temperature (see reference). The mixture was stirred at room temperature for 15 minutes, and then the crude of (1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl)-1- ((R)-pyrrolidin-2-yl)ethyl methanesulfonate hydrochloride (83 mg, 0.2 03 mmol) in DCM (1 mL) and 2 equivalents of Hunig's base were added. The mixture was stirred at room temperature for 1 hour. Then, the reaction mixture was diluted with DCM and washed with water and brine . The organic layer was dried over Na 2 SO 4 and filtered, and then concentrated. Silica gel column chromatography (EtOAc / EtOH / heptane) gave (1R,2R)-1-((R)- 1-(5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy yl)methyl)-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl) -2-(4-cyanophenyl)-2-(3-fluorophenyl)ethyl methanesulfonate (130 mg) in 86% yield. MS m / z 747.4 (MH+).

[0233] Step 5: (1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl) -1-((R)-1-(5-hydroxy-4-oxo-1-((2-(trimethylsilyl )ethoxy)methyl)-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2 -yl)ethyl methanesulfonate (1R,2R)-1-((R)-1-(5-(benzyloxy)-4-oxo-1-( (2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-ca rbonyl)pyrrolidin-2-yl)-2-(4-cyanophenyl)-2-(3-fluoro (Phenyl)ethyl methanesulfonate (70 mg, 0.094 mmol) in methanol ( 5 mL) was purged with nitrogen. 10% Palladium on carbon (29.9 mg, 0.028 m mol) was added and a hydrogen balloon was attached. The flask was evacuated and filled with hydrogen (3 times) , and then stirred vigorously at room temperature for 1 hour under a hydrogen balloon. The reaction mixture was passed through celite and filtered, and the filter cake was washed with MeOH. Concentration of the filtrate gave crude (1R ,2R)-2-(4-Cyanophenyl)-2-(3-fluorophenyl)-1-((R) -1-(5-Hydroxy-4-oxo-1-((2-(trimethylsilyl)ethoxy)meth yl)-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)ethyl methanesulfonate, which was used in the next step without further purification. MS m / z 657.4 (MH+).

[0234] Step 6: (1R,2R)-2-(4-Cyanophenyl)-2-(3-fluorophenyl) -1-((R)-1-(5-Hydroxy-4-oxo-1,4-dihydropyridazine-3 -carbonyl)pyrrolidin-2-yl)ethyl methanesulfonate To the crude (1R,2R)-2-(4-cyanophenyl)-2-(3-fluorophenyl) -1-((R)-1-(5-Hydroxy-4-oxo-1-((2-(trimethylsilyl )ethoxy)methyl)-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2 -yl)ethyl methanesulfonate (61 mg, 0.088 mmol) was added TFA (1. 2 ml, 15.58 mmol). The reaction mixture was stirred at room temperature for 2 hours. The solvent was concentrated , and the residue was azeotroped with toluene to give crude (1R,2R)-2-(4-cyanophenyl (R)-2-(3-Fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)ethyl methanesulfonate was obtained and used in the next step without further purification. MS m / z 527.3 (MH+).

[0235] 1 3 ​​​​​​​​​​​​​​​​​​​​7.53 (m, 5H) 7.22 (d, J = 8.27 Hz, 2H) 7.00 - 7.14 (m , 1H) 5.83 (dd, J = 9.93, 3.62 Hz, 1H) 4.72 (d, J = 9. 93 Hz, 1H) 4.46 - 4.59 (m, 1H) 3.78 - 3.94 (m, 1H) 3. 68 (td, J = 11.09, 7.51 Hz, 1H) 1.99 - 2.11 (m, 1H) 1 .73 - 1.96 (m, 2H) 1.49 - 1.65 (m, 1H). MS m / z 431 .2 (MH+).

[0236] Example 108. (9aR,10S)-10-((S)-(4-Chlorophenyl)(3-flu orophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H -pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione

Chemical Structure

[0237] Step 2: (1R,2S)-1-((R)-1-(5-(benzyloxy)-4-oxo- 1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine- 3-carbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)-2-(3-furan (fluorophenyl)ethyl methanesulfonate 5-(benzyloxy)-3-((R)-2-((1R,2R)-2-(4-chlorophenyl) (phenyl)-2-(3-fluorophenyl)-1-hydroxyethyl)pyrrolidine-1-carboxylate 1-((2-(trimethylsilyl)ethoxy)methyl)pyridazine-4(1 H)-one (280 mg, 0.413 mmol) was dissolved in 2,6-lutidine (4 mL) at 0 °C. To the solution, methanesulfonyl chloride (0.643 mL, 8.26 mmol) was added. After 5 minutes the ice bath was removed and the reaction mixture was stirred at room temperature for 3 hours. Then, the reaction mixture was partitioned between DCM and water. The DCM layer was separated and washed with 1N HCl, saturated NaHCO 3 aqueous solution, brine, dried over Na 2 SO 4 filtered, and concentrated. Silica gel column chromatography (EtOAc / EtOH / heptane) gave (1R,2S)-1-((R)-1 -(5-(benzyloxy)-4-oxo-1-((2-(trimethylsilyl)ethoxy ))methyl)-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)- 2-(4-chlorophenyl)-2-(3-fluorophenyl)ethyl methanesulfonate (280 mg) in 90% yield. MS m / z 756.6 (MH+).

[0238] Step 3: To (1R,2S)-2-(4-chlorophenyl)-2-(3-fluorophenyl) -1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3 -carbonyl)pyrrolidin-2-yl)ethyl methanesulfonate (1R,2S)-1-((R)-1-(5-(benzyloxy)-4-oxo-1-( (2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazine-3-ca rbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)-2-(3-fluoro phenyl)ethyl methanesulfonate (240 mg, 0.286 mmol), TFA ( 4 mL, 51.9 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour and then heated at 80 °C for 20 minutes in a microwave reactor. The solvent was concentrated and the residue was azeotroped with toluene. ​When subjected to this, crude (1R,2S)-2-(4-chlorophenyl)-2-(3-fluorophenyl) -1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine -3-carbonyl)pyrrolidin-2-yl)ethyl methanesulfonate was obtained and used in the next step without further purification. MS m / z 536.2 (MH+).

[0239] Step 4: (9aR,10S)-10-((S)-(4-chlorophenyl)(3-fluoro phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrro lo[1’,2’:4,5]pyrazino[1,2-b]pyridazine-3,5-dione To a solution of crude (1R,2S)-2-(4-chlorophenyl)-2-(3-fluorophenyl) -1-((R)-1-(5-hydroxy-4-oxo-1,4-dihydropyridazine-3 -carbonyl)pyrrolidin-2-yl)ethyl methanesulfonate (175 mg, 0.3 27 mmol) in DMF (6 mL) was added potassium carbonate (181 mg, 1.306 mmol) , and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through a 1 micron filter and purified by reverse-phase HPLC. The product fractions were combined, frozen, and lyophilized to give the formate salt of (9aR,10S)-10-((S)-(4-chlorophenyl)(3-fluoro phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrro lo[1’,2’:4,5]pyrazino[1,2-b]pyridazine-3,5-dione (33.5 mg, 0.068 mmol, white solid) in 29% yield. 1 H NMR (400 MHz, CD 3 OD) δ ppm 7.57 (d, J = 8.46 Hz, 2H) 7 .35 - 7.48 (m, 3H) 7.02 - 7.13 (m, 1H) 6.78 - 6.86 (m , 1H) 6.68 - 6.77 (m, 2H) 5.74 (dd, J = 9.59, 3.52Hz , 1H) 4.60 (d, J = 9.59Hz, 1H) 4.50 (br dd, J = 10.4 7, 5.18Hz, 1H) 3.82 - 3.94 (m, 1H) 3.67 (td, J = 11. 00, 7.58Hz, 1H) 2.01 - 2.13 (m, 1H) 1.75 - 1.97 (m, 2H) 1.51 - 1.64 (m, 1H) MS m / z 440.3 (MH+).

[0240]

Table 25

[0241] Example 111. (9aR, 10S)-10-((R)-(2-Bromophenyl)(4-flu orophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-3H -pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5(7H)- dione

Chemical Structure

[0242] Example 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]pyridazin-3,5-dione

Chemical Structure

[0243] Step 2: (1R,2S)-2-(3-fluorophenyl)-1-((R)-1-(5-hy droxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2 -yl)-2-(o-tolyl)ethyl methanesulfonate (1R,2S)-2-(3-fluorophenyl)-1-((R)-1-(4-oxo- 5-((2-(trimethylsilyl)ethoxy)methoxy)-1-((2-(trimethylsily ly)ethoxy)methyl)-1,4-dihydropyridazine-3-carbonyl)pyrrolidine -2-yl)-2-(o-tolyl)ethyl methanesulfonate (48 mg, 0.062 m mol) was treated with TFA (1.2 mL, 15.6 mmol). The reaction mixture was stirred at room temperature for 1.5 hours. The solvent was concentrated and the residue was azeotroped with toluene to give crude (1R,2S )-2-(3-fluorophenyl)-1-((R)-1-(5-hydroxy-4-oxo -1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2-yl)-2-(o- -tolyl)ethyl methanesulfonate was obtained and used in the next step without further purification. . MS m / z 516.3 (MH+).

[0244] Step 3: (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 To a solution of crude (1R,2S)-2-(3-fluorophenyl)-1-((R)-1-(5-hy droxy-4-oxo-1,4-dihydropyridazine-3-carbonyl)pyrrolidin-2 -yl)-2-(o-tolyl)ethyl methanesulfonate (32 mg, 0.062 mmo l) in DMF (1 mL) was added potassium carbonate (30 mg, 0.217 mmol) , and the mixture was stirred at room temperature overnight. The reaction mixture was filtered through a 1 micron filter and purified by reverse-phase H PLC. The product fractions were combined, frozen, and lyophilized to give (9 aR,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 TFA salt (3 mg, 0.00 5 mmol, white solid) in 2 steps in 21% yield. 1H NMR (400 MHz, MeOD) δ ppm 1.49 - 1.68 (m, 1H) 1.76 - 2.11 (m, 4H ) 2.14 - 2.39 (m, 3H) 3.66 (td, J = 11.36, 7.12 Hz, 1 H) 3.80 - 3.96 (m, 1H) 4.46 - 4.64 (m, 1H) 5.74 - 6.0 2(m, 1H) 6.84 - 7.09 (m, 4H) 7.16 (br s, 1H) 7.25 - 7.55 (m, 4H), MS m / z 420.3 (MH+).

[0245]

Table 26

[0246] Example 115. (9aR,10S)-10-((R)-(3-Fluorophenyl)(4- fluorophenyl)methyl)-4-hydroxy-7,7-dimethyl-8,9,9a,10 -tetrahydro-7H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridaz ine-3,5-dione

Chemical Structure

[0247] Step 2: tert-Butyl (R)-5-formyl-2,2-dimethylpyrrolidine-1-car boxylate DMSO (1.431 ml, 20.15 mmol) was added dropwise to a solution of oxalyl chloride (0.942 m l, 10.99 mmol) in DCM (volume: 41.6 ml, ratio: 10) at -78 °C, and the solution was stirred for 15 minutes. Then, a solution of tert-butyl (R)-5-(hydroxy methyl)-2,2-dimethylpyrrolidine-1-carboxylate in DCM (volume: 4.1 6 ml, ratio: 1.000) was added, and the solution was stirred at -78 °C for 1 hour. Then, DI PEA (6.40 ml, 36.6 mmol) was added, and the solution was warmed to room temperature. Then, the mixture was successively washed with 1 M HCl, water, and then brine, and dried over Na SO 2 SO 4 and concentrated to give tert-butyl (R)-5-formyl-2,2-dimethylpyrrol idine-1-carboxylate (1.9 g, yield 91%) as a yellow oil, which was used in the next step without further purification. LCMS [MH+] 228.2 / 0.82 min and used in the next step without further purification. LCMS [MH+] 228.2 / 0.82 min LCMS [MH+] 228.2 / 0.82 min

[0248] Example 115: (9aR,10S)-10-((R)-(3-Fluorophenyl)(4- fluorophenyl)methyl)-4-hydroxy-7,7-dimethyl-8,9,9a,10 -tetrahydro-7H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridaz ine-3,5-dione tert-Butyl (R)-5-formyl-2,2-dimethylpyrrolidine-1-carboxy Prepared from the silylate by the method of Example 32. LCMS (m / z): 452.3 (M H+), 1H NMR (500 MHz, CD3OD) δ ppm 7.45 (q, J = 7 .8 Hz, 1H), 7.41 - 7.34 (m, 3H), 7.06 (t, J = 8.1 Hz, 1H), 7.04 - 6.98 (m, 2H), 6.82 (t, J = 8.5 Hz, 2H), 5 .70 (d, J = 10.1 Hz, 1H), 4.67 - 4.58 (m, 1H), 4.42( d, J = 9.9 Hz, 1H), 1.89 - 1.79 (m, 2H), 1.75 (d, J = 1 2.3 Hz, 1H), 1.69 (s, 3H), 1.63 (s, 3H), 1.60 - 1.5 0 (m, 1H).

[0249] Example 116. (9aR,10R)-10-((S)-(3-Fluorophenyl)(4- fluorophenyl)methyl)-4-hydroxy-7,7-dimethyl-8,9,9a,10 -tetrahydro-7H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridaz ine-3,5-dione

Chemical Structure

[0250] Example 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]pyridaz ine-3,5-dione tert-Butyl (2R,5S)-2-formyl-5-methylpyrrolidine-1-carbox ylate:

Chemical Structure

[0251] Example 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]pyridaz ine-3,5-dione tert-Butyl (2R,5S)-2-formyl-5-methylpyrrolidine-1-carbo xylate was prepared by the method of Example 32. LCMS (m / z): 438.5( MH+), 1H NMR (500 MHz, CD 3 OD) δ ppm 7.47 - 7.37 (m, 4H), 7.07 - 7.02 (m, 1H), 7.00 (dd, J = 8.7, 5.3 Hz, 2H), 6.81 (t, J = 8.7 Hz, 2H), 5.70 (dd, J = 9.5, 3.9 Hz, 1H), 4.69 - 4.63 (m, 1H), 4.56 (d, J = 9.5 Hz , 1H), 4.41 (q, J = 6.4 Hz, 1H), 2.26 - 2.18 (m, 1H), 1.95 - 1.88 (m, 1H), 1.63 - 1.55 (m, 2H), 1.48 (d, J = 6.3 Hz, 3H).

[0252] Example 118. (7S,9aR,10R)-10-((S)-(3-Fluorophenyl) (4-Fluorophenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10 -tetrahydro-3H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridaz in-3,5(7H)-dione

Chemical Structure

[0253] Example 119. (7R,9aR,10S)-10-((R)-(3-Fluorophenyl) (4-Fluorophenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10 -tetrahydro-3H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridaz in-3,5(7H)-dione

Chemical Structure

[0254] Example 120. (7R,9aR,10R)-10-((S)-(3-Fluorophenyl) (4-Fluorophenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10 -tetrahydro-3H-pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridaz in-3,5(7H)-dione [Chemical Structure] tert-Butyl (2R,5R)-2-formyl-5-methylpyrrolidine-1-carbo xylate (for synthesis, see US Patent Application Publication No. 20120195857, tert-Butyl (2R,5R)-2-(hydroxymethyl)-5-methylpyrrolidine- 1-carboxylate was used), prepared by the method of Example 32. LCMS (m / z ): 438.4 (MH+), 1H NMR (500 MHz, CD 3 OD) δ ppm 7 .70 (s, 1H), 7.37 (dd, J = 8.7, 5.3 Hz, 2H), 7.30 (t d, J = 8.0, 6.2 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 7.0 8 (t, J = 8.7 Hz, 2H), 7.03 (d, J = 10.6 Hz, 1H), 6.96 (td, J = 8.4, 2.3 Hz, 1H), 5.36 (dd, J = 11.4, 4.6 Hz , 1H), 5.15 (d, J = 4.5 Hz, 1H), 4.37 - 4.26 (m, 1H), 4.08 (d, J = 5.4 Hz, 1H), 2.07 - 1.96 (m, 1H), 1.91 ( dd, J = 11.6, 6.2 Hz, 1H), 1.87 - 1.80 (m, 1H), 1.73 (dd, J = 12.3, 6.0 Hz, 1H), 1.38 (d, J = 6.5 Hz, 3H).

[0255] Example 121. (8S,9aR,10S)-10-(Bis(3-fluorophenyl)meth yl)-4-hydroxy-8-methoxy-8,9,9a,10-tetrahydro-3H-pyrro lo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5(7H)-dione

Chemical formula

[0256] Example 122. (8R,9aR,10S)-10-(Bis(3-fluorophenyl)meth yl)-4-hydroxy-8-methoxy-8,9,9a,10-tetrahydro-7H-pyrro lo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-3,5-dione

Chemical formula

[0257] Example 123. (10aR,11S)-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

Chem.

[0258] Examples 124A and 124B.

Chem.

[0259] Step 2: tert-butyl 2-(2,2-diphenylacetyl)piperidine-1-carboxylate To a solution of tert-butyl 2-(1-hydroxy-2,2-diphenylethyl)piperidine-1-carboxylate (2.80 g, 7.34 mmol) in DCM (volume: 73.4 mL) was added Dess-Martin periodinane (DMP) (6.23 g, 14.68 mmol ) at 5-10 °C. The reaction mixture was stirred at room temperature for 4 hours. After completion of the reaction, it was quenched with aqueous sodium sulfite solution (20 mL) and stirred for 1 hour. Then the product was extracted with dichloromethane (2×20 mL). The combined organic layers were washed with water (20 mL) and concentrated. Silica gel chromatography (EtOAc / heptane) gave tert-butyl 2-(2,2-diphenylacetyl)piperidine-1-carboxylate (1 .76 g) in 63% yield. MS m / z 380.4 (MH

[0260] + +).

[0260] Step 3: 2,2-diphenyl-1-(piperidin-2-yl)ethanone A solution of hydrochloric acid (4.0 M in dioxane) (23.19 mL, 93 mmol) was added to tert-butyl 2-(2,2-diphenylacetyl)piperidine-1-carboxylate (1.76 g, 4.64 mmol), and the mixture was stirred at room temperature for 1.5 hours. Then, the mixture was concentrated and left under high vacuum overnight to give the hydrochloride salt of 2,2-diphenyl-1-(piperidin-2-yl) ethanone (1.37 g, white powder) in 94% yield. MS m / z 28 0.3 (MH + ).

[0261] Step 4: 3-(2-(2,2-Diphenylacetyl)piperidine-1-carbonyl)-5 -((2-(Trimethylsilyl)ethoxy)methoxy)-1-((2-(trimethylsilyl ethoxy)methyl)pyridazin-4(1H)-one DIPEA (4.27 mL, 24.52 mmol) and HATU (2.424 g, 6. 37 mmol) were added to a solution of 4-oxo-5-((2-(trimethylsilyl)ethoxy)methoxy )-1-((2-(trimethylsilyl)ethoxy)methyl)-1,4-dihydropyridazin ine-3-carboxylic acid (2.247 g, 5.39 mmol; see US Patent Application Publication No. 2015 / 0072982A1) in DCM (volume: 50 mL) at room temperature. The mixture was stirred at room temperature for 15 minutes, then a solution of crude 2,2-diphenyl-1-(piperidin- 2-yl)ethanone hydrochloride (1.37 g, 4.90 mmol) and DIPEA (2 mL) in DCM (volume: 25) was added. The mixture was stirred overnight at room temperature, then diluted with DCM and washed with water and brine. The organic layer was dried over Na 2 SO 4 and filtered and concentrated. Silica gel column chromatography (EtOAc / heptane / MeOH) gave 3 -(2-(2,2-diphenylacetyl)piperidine-1-carbonyl)-5-((2- (trimethylsilyl)ethoxy)methoxy)-1-((2-(trimethylsilyl)eth yl)methyl)pyridazin-4(1H)-one (1.85 g) in 56% yield. MS m / z 678.5 (MH + ).

[0262] Step 5: 3-(2-(2,2-Diphenylacetyl)piperidine-1-carbonyl)-5 -hydroxypyridazin-4(1H)-one 3-(2-(2,2-Diphenylacetyl)piperidine-1-carbonyl)-5-(( (2-(trimethylsilyl)ethoxy)methoxy)-1-((2-(trimethylsilyl)e thoxy)methyl)pyridazin-4(1H)-one (83.4 mg, 0.123 mmol) in TFA (1.5 ml, 19.47 mmol) was stirred at room temperature for 2 days. The reaction mixture was concentrated and the residue was azeotroped with benzene (3×) to give crude 3-(2-(2,2-diphe nylacetyl)piperidine-1-carbonyl)-5-hydroxypyridazin-4(1H) -one (yield 51 mg), which was used in the next step without purification. MS m / z 418.3 (MH + ).

[0263] Step 6: 11-(Diphenylmethylene)-4-hydroxy-7,8,9,10,10a, 11-hexahydropyrido[1’,2’:4,5]pyrazino[1,2-b]pyridazine- 3,5-dione and 11-benzhydryl-4-hydroxy-7,8,9,10-tetra hydropyrido[1’,2’:4,5]pyrazino[1,2-b]pyridazine-3,5-dio n 3-(2-(2,2-Diphenylacetyl)piperidine-1-carbonyl)-5-hydr oxy-pyridazin-4(1H)-one (867 mg, 2.077 mmol) in 1,4-di oxane (volume: 29.7 ml) was added concentrated sulfuric acid (221 μl, 4.15 mmol). The mixture was heated to 115 °C in a microwave reactor for 90 minutes. The reaction product was filtered and the filtrate was purified by reverse-phase HPLC. The product fractions were combined, frozen, and freeze-dried to give 11-(diphenylmethylene)-4-hydroxy-7,8,9,10,10 a,11-hexahydropyrido[1’,2’:4,5]pyrazino[1,2-b]pyridaz ine-3,5-dione (peak 1, MS m / z 400.3 (MH + )) and 11-ben zhydryl-4-hydroxy-7,8,9,10-tetrahydropyrido[1’,2’:4 ,5]pyrazino[1,2-b]pyridazine-3,5-dione (peak 2, MS m / z 400.3 (MH + )).

[0264] Step 7A: 11-Benzohydryl-4-hydroxy-7,8,9,10,10a,11- hexahydropyrido[1’,2’:4,5]pyrazino[1,2-b]pyridazine-3,5 -dione To a solution of 11-(diphenylmethylene)-4-hydroxy-7,8,9,10,10a,11- hexahydropyrido[1’,2’:4,5]pyrazino[1,2-b]pyridazine-3,5 -dione (22.8 mg, 0.044 mmol) in MeOH (volume: 1 mL) was added water palladium oxide / carbon (20%) (31.2 mg, 0.044 mmol) and ammonium formate Nickel (28.0 mg, 0.444 mmol) was added. The vial was sealed and the reaction mixture was heated at 7 0 °C for 2 hours. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was dissolved in DM F and purified by reverse-phase HLPC. The product fractions were combined, frozen, and lyophilized to give the TFA salt of 11-benzhydryl-4-hydroxy-7,8,9,10,10a, 11-hexahydropyrido[1’,2’:4,5]pyrazino[1,2-b]pyridazine- 3,5-dione (4.1 mg, white solid) in 17% yield. 1 H NM R (500 MHz, methanol-d 4 ) δ 7.65 - 7.55 (m, 2H), 7.51 (s, 1H), 7.40 (t, J = 7.8 Hz, 2H), 7.33 - 7.26 (m, 1H ), 7.05 (s, 6H), 5.58 (dd, J = 8.0, 3.1 Hz, 1H), 4.7 9 (d, J = 8.0 Hz, 1H), 4.40 (d, J = 13.8 Hz, 1H), 4.18 (d, J = 9.6 Hz, 1H), 3.15 - 3.06 (m, 1H), 1.89 (d, J= 13.6 Hz, 1H), 1.83 - 1.75 (m, 1H), 1.70 - 1.61 (m, 2 H), 1.51 (qd, J = 12.9, 3.9 Hz, 1H), 1.37 (tt, J = 12 .2, 3.6 Hz, 1H). MS m / z 402.2 (MH + ).

[0265] Step 7B: 11-benzhydryl-4-hydroxy-7,8,9,10,10a,11- hexahydropyrido[1’,2’:4,5]pyrazino[1,2-b]pyridazine-3,5 -dione 11-benzhydryl-4-hydroxy-7,8,9,10-tetrahydropyrido[1 ’,2’:4,5]Pyrazino[1,2-b]pyridazine-3,5-dione (8.3 mg, 0.016 mmol) in MeOH (1 mL) was added with palladium hydroxide / carbon (20%) (11.35 mg, 0.016 mmol) and ammonium formate (10.19 mg, 0. 162 mmol). The vial was sealed and the reaction mixture was heated at 70 °C for 2 h. The reaction mixture was filtered through celite and the filtrate was concentrated. The residue was dissolved in DMF and purified by reverse-phase HLPC . The product fractions were combined, frozen and lyophilized to give 11-benzylhydryl-4-hydroxy-7,8,9,10,10a,11-hexahydropyrido [1’,2’:4,5]pyrazino[1,2-b]pyridazine-3,5-dione TFA salt ( 1.5 mg) in 17% yield. 1 H NMR (500 MHz, methanol-d 4 ) δ 7.53 - 7.49 (m, 2H), 7.41 (t, J = 7.7 Hz, 2H), 7.3 5 (s, 1H), 7.34 - 7.30 (m, 1H), 7.15 (tt, J = 5.5, 2. 6 Hz, 5H), 5.37 - 5.27 (m, 1H), 4.62 (s, 1H), 4.48 ( d, J = 11.1 Hz, 1H), 3.69 (d, J = 11.4 Hz, 1H), 2.81 - 2.67 (m, 1H), 1.92 (d, J = 18.0 Hz, 2H), 1.70 - 1.49 (m, 4H). MS m / z 402.1 (MH+).

[0266] Example 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

Chemical Structure

[0267] Example 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

Chemical Structure

[0268] Example 126. 11 - Benzhydryl - 4 - hydroxy - 7,8,10a,11 - tetra hydro - 10H - pyridazino[1’,6’:4,5]pyrazino[2,1 - c][1,4] oxazine - 3,5 - dione

Chemical Structure

[0269] Example 127. 11 - Benzhydryl - 4 - hydroxy - 7 - methyl - 7,8,9,10 , 10a,11 - hexahydropyrido[1’,2’:4,5]pyrazino[1,2 - b]p Ridazine-3,5-dione [ka] Step 1: tert-Butyl 2-(1-hydroxy-2,2-diphenylethyl)-6-methyl Tyl piperidine-1-carboxylate tert-Butyl 2-methylpiperidine-1-carboxylate (1 mL, 4.70 m mol) and TMEDA (0.745 mL, 4.94 mmol) cooled to -78 °C. WaterEt 2 A solution of isopropyl lithium (0.7 M in pentane) (8.0 The reaction mixture was stirred for 15 min and gradually cooled to -20 °C. The mixture was stirred at this temperature for 60 minutes and then cooled to -72°C. Cetaldehyde (1.251 mL, 7.05 mmol) was added to the reaction mixture and it was dissolved in water. After stirring for 30 min, the mixture was quenched by the addition of saturated aqueous ammonium chloride solution (40 mL). The mixture was allowed to warm to room temperature and was diluted with ether (100 ml) and water (50 ml). The aqueous phase was extracted with ether (2 x 25 ml). The combined organic phase was diluted with Na 2 SO 4 The mixture was dried at 40° C. and concentrated. Silica gel column chromatography (EtOAc / heptane) This gives tert-butyl 2-(1-hydroxy-2,2-diphenylethyl)-6- Methyl piperidine-1-carboxylate (711 mg) was obtained in 38% yield. MS m / z 396.4(MH+).

[0270] Example 127. 11-Benzhydryl-4-hydroxy-7-methyl-7,8,9,10 ,10a,11-Hexahydropyrido[1',2':4,5]pyrazino[1,2-b]pyrido ... Ridazine-3,5-dione tert-Butyl 2-(1-hydroxy-2,2-diphenylethyl)-6-methylpi peridine-1-carboxylate was prepared by the method of Example 124A, Steps 2 to 7A obtained. LCMS (m / z): 416.4 (MH+), 1H NMR (500 MHz, methano -l-d4) δ 7.57-7.53 (m, 2H), 7.42 (t, J = 7.6 Hz, 2 H), 7.33 (d, J = 8.4 Hz, 2H), 7.19-7.15 (m, 2H), 7. 13 (dd, J = 5.2, 2.1 Hz, 4H), 5.35-5.25 (m, 1H), 4. 35 (d, J = 11.5 Hz, 1H), 3.84 (d, J = 10.1 Hz, 1H), 1. 88-1.81 (m, 1H), 1.79-1.69 (m, 2H), 1.65-1.58( m, 2H), 1.50-1.32 (m, 1H), 1.06 (d, J = 7.0 Hz, 3H) .

[0271] Example 128. (9aR,10S)-10-(Bis(4-fluorophenyl)methyl)- 3,5-dioxo-5,7,8,9,9a,10-hexahydro-3H-pyrrolo[1’, 2’:4,5]pyrazino[1,2-b]pyridazin-4-yl 3-methylbutanoate

Chemical Structure

[0272]

Table 27

[0273] Example 13 3.1 - (((9aR,10S)-10-(bis(4-fluorophenyl)meth yl)-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 [Chemical formula] K 2 CO 3 (93 mg, 0.670 mmol), KI (111 mg, 0.670 mmo l), and 1-chloroethyl ethyl carbonate (90 μl, 0.670 mmol) were added to (9aR,10S)-10-(bis(4-fluorophenyl)methyl)-4-hydroxy -8,9,9a,10-tetrahydro-7H-pyrrolo[1’,2’:4,5]pyrazino 1,2-b]pyridazin-3,5-dione (90 mg, 0.167 mmol) in room temperature D MF (volume: 3.3 mL) solution. The mixture was stirred at 60 °C for 4 hours, and by that time the reaction was complete. Then, the reaction mixture was filtered through a frit funnel and purified by SFC (CO 2 / MeO H) to give 1-(((9aR,10S)-10-(bis(4-fluorophen 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 )ethyl ethyl carbonate (17 mg) in 19% yield. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.75 (d, J = 2.9 Hz, 1H), 7.68 (dd , J = 8.6, 5.4 Hz, 2H), 7.28 - 7.13 (m, 2H), 6.90 (dd t, J = 27.1, 8.7, 4.6 Hz, 3H), 6.68 (dq, J = 15.4, 5. 2 Hz, 1H), 5.71 (ddd, J = 9.4, 8.0, 3.3 Hz, 1H), 4.5 6 (dd, J = 9.5, 2.5 Hz, 1H), 4.46 (t, J = 7.8 Hz, 1H), 4.09 (dqd, J = 14.3, 7.1, 2.6 Hz, 2H), 3.67 - 3.52( m, 2H), 1.91 - 1.58 (m, 3H), 1.46 (d, J = 5.2 Hz, 3H) , 1.37 (t, J = 10.1 Hz, 2H), 1.18 (dt, J = 11.7, 7.1H z, 3H). MS m / z 540.6 (M + 1).

[0274]

Table 28

[0275] Example 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)methylmeth yl carbonate

Chemical formula

[0276]

Table 29

[0277]

Table 30

[0278] Example 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

Chemical Structure

[0279] Step 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)methyl L-valine ate (((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-but oxycarbonyl)-L-valinate(38 mg,0.058 mmol)in DCM( volume:582 μl)at 0 °C was added dropwise with HCl(Et 2 O,1.0 M,2.9 mL,2.9 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 triturated with Et O.The solid was filtered and dried under high vacuum to give(( 2 O.The solid was filtered and dried under high vacuum to give(( (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 hydrochloride (15 mg)in a yield of 46%. 1 H NMR(400 MHz,DMSO-d6)δ 7.66 (dd, J = 8.6, 5.4 Hz, 2H), 7.50 (s, 1H), 7.20 (t, J = 8.7 Hz, 2H), 6.99 - 6.82 (m, 4H), 5.77 (d, J = 6.3 Hz, 1H), 5.69 (d, J = 6.2 Hz, 1H), 5.64 (dd, J = 9 .8, 3.4 Hz, 1H), 4.52 (d, J = 9.7 Hz, 1H), 4.39 (t, J = 9.6 Hz, 1H), 3.66 - 3.50 (m, 2H), 3.14 (d, J = 5.1 H z, 1H), 1.92 - 1.72 (m, 1H), 1.60 (d, J = 33.1 Hz, 1H ), 1.35 (dd, J = 19.1, 8.7 Hz, 1H), 1.21 (d, J = 4.2 H z, 2H), 0.86 (d, J = 6.8 Hz, 3H), 0.80 (t, J = 7.3 Hz, 3H). MS m / z 553.4 (M + 1).

[0280] Example 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-yl dimethylcarbamate [Chem.] (9aR,10S)-10-(Bis(4-fluorophenyl)methyl)-4-hydroxy -8,9,9a,10-tetrahydro-3H-pyrrolo[1’,2’:4,5]pyrazino [1,2-b]pyridazin-3,5(7H)-dione (25 mg, 0.047 mmol) in 1.5 ml of dry CH 2 Cl 2 solution, trimethylamine (0.1 mL), 2 drops of N,N-dimethylcarbamoyl chloride and a catalytic amount of DMAP were added. The mixture was stirred at room temperature Stirred overnight. Further add 0.1 ml of Et 3 N and 3 drops of N,N-dimethylcarbamoyl chloride (×3), and stir until completion. Wash the reaction product with 5% NaHCO 3 aqueous solution, and wash with brine. Dry the organic layer with sodium sulfate and concentrate. Purify by SFC (CO (CO 2 / MeOH) to give (9aR,10S)-10-(bis(4-fluorophen yl)methyl)-3,5-dioxo-5,7,8,9,9a,10-hexahydro-3H -pyrrolo[1’,2’:4,5]pyrazino[1,2-b]pyridazin-4-yl dimethyl carbamate (12 mg) in 50% yield. 1 H NMR (400 MHz, chloro form-d) δ 7.50 (d, J = 18.0 Hz, 1H), 7.34 (s, 2H), 7 .12 (t, J = 8.4 Hz, 2H), 6.97 - 6.71 (m, 4H), 5.32 (s , 1H), 4.36 (d, J = 58.5 Hz, 2H), 3.89 - 3.77 (m, 1H) , 3.59 (dq, J = 11.8, 7.2 Hz, 1H), 3.08 (d, J = 73.7 H z, 6H), 1.89 (d, J = 50.3 Hz, 3H), 1.48 (s, 1H). MS m / z 495.1 (MH+).

[0281] Example 147. (((9aR,10S)-10-(bis(4-fluorophenyl)methyl )-3,5-dioxo-5,7,8,9,9a,10-hexahydro-3H-pyrrolo[1 ’,2’:4,5]pyrazino[1,2-b]pyridazin-4-yl)oxy)methyl ethyl yl(methyl)carbamate

Chemical formula

[0282] Example 148. Methyl 2 - ((((9aR,10S) - 10 - (bis(4 - fluorophenyl)methyl) - 3,5 - dioxo - 3,5,8,9,9a,10 - hexahydro - 7 H - pyrrolo[1’,2’:4,5]pyrazino[1,2 - b]pyridazin - 4 - yloxy (ethoxy)phosphoryl)oxy)acetate

Chemical Structure

[0283] Example 149. Methyl 2 - ((((9aR,10S)-10 - (bis(4 - fluoro phenyl)methyl)-3,5 - dioxo - 5,7,8,9,9a,10 - hexahydro - 3H - pyrrolo[1’,2’:4,5]pyrazino[1,2 - b]pyridazin - 4 - yl)oxy )carbonyl)oxy)-2 - methylpropanoate

Chemical Structure

[0284] Biological assays and data The activity of the compounds according to the present invention can be evaluated by the following in vitro and in vivo methods Using the test assays disclosed herein, the compounds of the present invention exhibit inhibitory efficacy consistent with Tables 2 and 3.

[0285] Influenza virus neuraminidase assay (NA assay) For the influenza NA assay, MDCK cells were seeded in a 384-well format at a cell density of 1.8×10 cells / well in phenol red-free DMEM (Gibco) supplemented with 2 mM L-glutamine, 1% sodium pyruvate (Cellgro, Manassas, VA), and 0.1% BSA. 4 The compounds were added to the cells 2 hours prior to infection. Infection was performed at an MOI of 0.005, and the plates were incubated at 37 °C, 5% CO₂ for 48 hours. After incubation, neuraminidase activity was evaluated using a NA assay kit (ThermoFisher, Carlsbad, CA). For cell toxicity measurement, CellTiter-Glo® (Promega, Madison, WI) was added to the treated cells according to the manufacturer's instructions. 2 For the influenza virus minigenome assay (RNP assay), 293T cells were transfected with expression vectors encoding PB2, PB1, PA, NP proteins, and an A-type influenza luciferase reporter plasmid. The cells were cultured in phenol red-free DMEM supplemented with 10% heat-inactivated FBS (fetal bovine serum), 1% sodium pyruvate, and 1% L-glutamine (Cellgro, Manassas, VA).

[0286] Influenza virus minigenome assay (RNP assay) Collected in Dulbecco's Modified Eagle Medium (DMEM). Five plasmids were co-transfected in OptiMEM (registered trademark) (Gibco, Carlsbad, CA) with Fugene 6 transfection reagent (Promega, Madison, WI) at a ratio of DNA (μg):Fugene 6 (μl) of 1:3. Transfection was performed at a cell density of 1.8×10 cells / well in a 384-well format. Two hours after transfection, the compound was added and the plates were incubated at 37°C, 5% CO for 48 hours 4 . After incubation, the cells were lysed and luciferase production was quantified by the addition of Britelite e Plus (registered trademark) (Perkin-Elmer, Waltham, MA). For cytotoxicity measurement, CellTiter-Glo (registered trademark)( 2 Promega, Madison, WI) was added to the treated cells according to the manufacturer's instructions .

[0287]

Table 31

[0288]

Table 32

[0289]

Table 33

[0290]

Table 34

[0291]

Table 35

[0292]

Table 36

Claims

1. Formula (A): 【Chemistry 1】 (In the formula: Y is of the formula 【Chemistry 2】 where the dashed line represents the bond connecting this group to formula (A); G is H or -C(O)R ０ , -C(O)-OR ０ , -C(R Ｇ ), ２ -O-C(O)R ０ 、-C(R Ｇ ) ２ -O-C(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 -O -C(O)N(R ０ ) ２ is a group selected from In the formula, each R ０ are independently H or C １ ~C ６ Alkyl, phenyl, pyridyl, C ３ ~C ７ Cycloalkyl and 1 or 2 heteroatoms selected from N, O, and S in the ring and each R that is not H is a group selected from 3- to 6-membered heterocycles containing ０ Ha, Hello, CN, -OH, amino, C １～４ Alkyl, COOR, Phenyl, C １～４ Alkoxy, C １～４ Haloalkyl, and C １～４ haloalkoxy is optionally replaced by; And each R Ｇ is H and C １～４ independently selected from alkyl; R １ H, halo, CN, COOR ＊ , -CONR ＊ ２ , or halo, -OR ＊ , and- N.R. ＊ ２ C optionally substituted with one or two groups selected from １ ~C ６ a It is Rukyr; R ＊ is independently at each occurrence H or -OR or -NR ２ Optionally replaced by There is C １ ~C ６ is alkyl; Z １ is N, and Z ２ is C(R) ２ and Or Z. １ is CH, and Z ２ is NR, O, S, or CH ２ and Z ３ は、CH ２ 、Q、-CH ２ -CH ２ -、-Q-CH ２ -、-CH ２ -Q-、-CH ２ -Q-CH ２ - or -CH ２ -CH ２ -CH ２ - and Q is -NR-, O, S, SO, or SO ２ Selected from: R ２ H, halo, CN, halo, CN, C １～４ Alkyl, -OR, C １～４ Haloal Koxy, -NR ２ , and C １～４ and up to three groups independently selected from haloalkyl. Optionally substituted C １～４ Alkyl, OR, and C １ ~C ４ From haloalkyl Selected; Each R ３ Is, Z ２ and Z ３ A substituent that is optionally present on any carbon atom of the ring containing Ri, halo, -OR, C １～４ Haloalkyl, C １～４ Haloalkoxy, oxo, CN, - N.R. ２ , as well as Halo, CN, C １～４ Alkyl, -OR, C １～４ Haloalkoxy, -N R ２ , and C １～４ Optionally substituted with up to three groups independently selected from haloalkyl C being replaced １～４ independently selected from alkyl; n is 0 to 2; Ar １ and Ar ２ are each independently phenyl or one selected from N, O, and S; represents a 5- to 6-membered heteroaryl ring containing 1 to 3 heteroatoms as ring members, and Ar １ Reach Ar ２ each independently represents halo, C １～４ Alkyl, C １～４ Haloalkyl, C １～ ４ Alkoxy, C １～４ Haloalkoxy, C ２～４ alkyne, and CN substituted with up to groups; And Ar １ and Ar ２ is represented by the formula -C(R Ｌ ) ２ Optionally linked by a bridge of -L- to form a tricyclic ring Form a group of the formula, where Ar １ and Ar ２ Ha, Haro, C １～４ Alkyl, C １～４ HelloA Rukill, C １～４ Alkoxy, C １～４ Haloalkoxy, C ２～４ Alkyne and CN each optionally substituted with up to two groups independently selected from: R is independently at each occurrence H or halo, OH, oxo, C １～４ Alkyl, C １～４ Al Koki, C. １～４ Haloalkoxy and C １～４ three independently selected from haloalkyl C optionally substituted with groups up to １ ~C ４ is alkyl; L is S, S=O, SO ２ , O, NR, C(R Ｌ ) ２ , and C.F. ２ and Each R Ｌ are independently H or C １～２ is alkyl) or a pharma- ceutically acceptable salt thereof.

2. 2. The compound of claim 1, wherein G is H, or a pharma- ceutically acceptable salt thereof.

3. Gが、-C(O)R ０ 、-C(O)-OR ０ 、-C(R Ｇ ) ２ -O-C(O)R ０ 、- C(R Ｇ ) ２ -O-C(O)-OR ０ , -C(O)-N(R ０ ) ２ , and -C(R Ｇ ) ２ -O-C(O)N(R ０ ) ２ Each R ０ are independently H or halo, CN, -O H, 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 C １ ~C ４ 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof, Salt.

4. G is -C(O)R ０ , -C(O)-OR ０ , -C(R Ｇ ), ２ -O-C(O)R ０ , and Bi-C(R Ｇ ) ２ -O-C(O)-OR ０ Each R ０ is independently H or C １ ~C ４ alkyl, and each R Ｇ is H or C １ ~C ４ Alkyl, The compound according to claim 3; or a pharma- ceutically acceptable salt thereof.

5. G is -C(O)R ０ , —C(O)—OR ０ , -CH ２ -O-C(O)R ０ , and -C H ２ -O-C(O)-OR ０ Each R ０ C １ ~C ４ Alkyl.

5. A compound according to any one of claims 1 to 4; or a pharma- ceutically acceptable salt thereof.

6. formula: 【Chemistry 3】 A compound according to any one of claims 1 to 5, which is or a pharma- ceutically acceptable salt thereof.

7. Z ２ CH ２ And Z ３ CH ２ where n is 0, 1, or 2, and each R ３ but 7. The compound of claim 6, wherein:

8. Formula (I): 【Chemistry 4】 (In the formula: R １ H, halo, CN, COOR ＊ , -CONR ＊ ２ , or -OR ＊ and -NR ＊ ２ , C １ ~C ４ and optionally substituted with 1 or 2 groups selected from haloalkyl. There is C １ ~C ６ is alkyl; R ＊ is independently at each occurrence H or -OR or -NR ２ Optionally replaced by There is C １ ~C ６ is alkyl; Z １ is N, and Z ２ is C(R) ２ and Or Z. １ is CH, and Z ２ is NR, O, S, or CH ２ and Z ３ は、CH ２ 、Q、-CH ２ -CH ２ -、-Q-CH ２ -、-CH ２ -Q-、-CH ２ -Q-CH ２ - or -CH ２ -CH ２ -CH ２ - and Q is -NR-, O, S, SO, or SO ２ Selected from: R ２ H, halo, CN, halo, CN, C １～４ Alkyl, -OR, C １～４ Haloal Koxy, -NR ２ , and C １～４ and up to three groups independently selected from haloalkyl. Optionally substituted C １～４ Alkyl, OR, and C １ ~C ４ From haloalkyl Selected; Each R ３ Is, Z ２ and Z ３ A substituent that is optionally present on any carbon atom of the ring containing Ri, -OR, C １～４ Haloalkyl, C １～４ Haloalkoxy, oxo, CN, -NR ２ , as well as Halo, CN, C １～４ Alkyl, -OR, C １～４ Haloalkoxy, -NR ２ , and C １～４ and optionally substituted with up to three groups independently selected from haloalkyl. C １～４ independently selected from alkyl; n is 0 to 2; Ar １ and Ar ２ are each independently phenyl or one selected from N, O, and S; represents a 5-6 membered heteroaryl ring containing 1 to 3 heteroatoms 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; the law of nature; And Ar １ and Ar ２ is represented by the formula -C(R Ｌ ) ２ Optionally linked by a bridge of -L- to form a tricyclic ring Form a group of the formula, where Ar １ and Ar ２ Ha, Haro, C １～４ Alkyl, C １～４ HelloA Rukill, C １～４ Alkoxy, C １～４ Haloalkoxy, C ２～４ Alkyne and CN each optionally substituted with up to two groups independently selected from: R is independently at each occurrence H or halo, OH, oxo, C １～４ Alkyl, C １～４ Al Koki, C. １～４ Haloalkoxy and C １～４ three independently selected from haloalkyl C optionally substituted with groups up to １ ~C ４ is alkyl; L is S, S=O, SO ２ , O, NR, C(R Ｌ ) ２ , and C.F. ２ is selected from; and Each R Ｌ are independently H or C １～２ is alkyl) 2. The compound of claim 1, which is:

9. Z １ is CH, or a pharma- ceutically acceptable salt thereof. Acceptable salt.

10. Z １ is N, or a pharma- ceutically acceptable salt thereof. 。

11. Z ２ CH ２ The compound according to any one of claims 1 to 10, Acceptable salts.

12. Z ３ が、CH ２ 、-CH ２ -CH ２ -、-CH ２ -CH ２ -CH ２ -、-CH ２ -O- or O. A pharma- ceutically acceptable salt of.

13. Z ３ CH ２ 13. The compound of claim 12, wherein:

14. R １ is H, A pharma- ceutically acceptable salt of.

15. R ２ is H, or a pharma- ceutically acceptable salt thereof, of the compound according to any one of claims 1 to 14. Possible salt.

16. Ar １ and Ar ２ are both phenyl, halo, C １～４ Alkyl, C １～４ HelloA Rukill, C １～４ Alkoxy, C １～４ Haloalkoxy, C ２～４ Alkyne and CN Any of claims 1 to 15, each independently substituted with up to two groups selected from 2. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof.

17. formula: 【Chemistry 5】 (wherein Y represents a group selected from the following: 【Chemistry 6】 (In the formula, each R ｙ Ha, Haro, C １～４ Alkyl, C １～４ Haloalkyl, C １～４ Alcoki C, １～４ Haloalkoxy, C ２～４ alkyne, and CN; and Each q is independently 0, 1, or 2. Item 1. A compound according to item 1, or a pharma- ceutically acceptable salt thereof.

18. formula 【Chemistry 7】 (In the formula, Z １ is N or CH; and Z ３ is CH ２ or -CH ２ -CH ２ - is) 18. The compound of claim 17 which is: or a pharma- ceutically acceptable salt thereof.

19. Ar １ and Ar ２ are both phenyl, and Ar １ and Ar ２ are independently F, Cl, and C １ ~C ４ Optionally substituted with 1 or 2 groups independently selected from alkyl The compound according to any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof, 。

20. Compound: 12-Benzhydryl-4-hydroxy-7,8,9,10-tetrahydro-12H- Dipyridazino[1,2-a:1',6'-d][1,2,4]triazine-3,5-di hmm; 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; 12-(bis(4-chlorophenyl)methyl)-4-hydroxy-7,8,9,10- Tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]tetrahydro- riazine-3,5-dione; 12-(bis(3-chlorophenyl)methyl)-4-hydroxy-7,8,9,10- Tetrahydro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]tetrahydro- riazine-3,5-dione; 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; 13-Benzhydryl-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; 13-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9,10,1 1-Tetrahydro-7H,13H-pyridazino[1',6':4,5][1,2,4]t Riazino[1,2-a][1,2]diazepine-3,5-dione; (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; (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; (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; (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; (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; (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; (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; (9aR,10R)-10-(bis(3-fluorophenyl)methyl)-4-hydroxy C-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino [1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-(bis(3-fluorophenyl)methyl)-4-hydroxy C-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino [1,2-b]pyridazine-3,5-dione; (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; (10aS,11R)-11-Benzhydryl-4-hydroxy-7,8,10a,1 1-Tetrahydro-10H-pyridazino[1',6':4,5]pyrazino[2,1-c] [1,4]oxazine-3,5-dione; 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; 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; 11-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9-dihydro -7H,11H-Pyrazolo[1,2-a]pyridazino[1,6-d][1,2,4]trimethyl Azine-3,5-dione; 12-(1,1-diphenylethyl)-4-hydroxy-7,8,9,10-tetrahydrofuran Dro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine -3,5-dione; 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; 12-Benzhydryl-4-hydroxy-10-methyl-7,8,9,10-tetrahydrofuran Dro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine -3,5-dione; 12-Benzhydryl-4-hydroxy-10-methyl-7,8,9,10-tetrahydrofuran Dro-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine -3,5-dione; 12-Benzhydryl-4-hydroxy-7-methyl-7,8,9,10-tetrahydrofuran rho-12H-dipyridazino[1,2-a:1',6'-d][1,2,4]triazine- 3,5-dione; 12-Benzhydryl-4-hydroxy-7,10-dimethyl-7,8,9,10-tetrahydrofuran 12H-dipyridazino[1,2-a:1',6'-d][1,2,4]trihydro Azine-3,5-dione; 12-Benzhydryl-4-hydroxy-7,10-dimethyl-7,8,9,10-tetrahydrofuran 12H-dipyridazino[1,2-a:1',6'-d][1,2,4]trihydro Azine-3,5-dione; 12-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-4-hydro 1,2-a:1',6 '-d][1,2,4]triazine-3,5-dione; 12-(6,11-dihydrodibenzo[b,e]thiepin-11-yl)-4-hydro 1,2-a:1',6 '-d][1,2,4]triazine-3,5-dione; 12-(6,11-dihydrodibenzo[b,e]oxepin-11-yl)-4-hydro roxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1', 6′-d][1,2,4]triazine-3,5-dione; 12-(6,11-dihydrodibenzo[b,e]oxepin-11-yl)-4-hydro roxy-7,8,9,10-tetrahydro-12H-dipyridazino[1,2-a:1', 6′-d][1,2,4]triazine-3,5-dione; 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; 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; (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; (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; (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; (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; (9aR,10S)-10-((R)-(3,4-difluorophenyl)(2-fluoro (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((S)-(3,4-difluorophenyl)(3-fluoro (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((R)-(2-fluorophenyl)(4-fluorophenyl) Nyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[ 1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((S)-(3,5-difluorophenyl)(3-fluoro (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((S)-(4-fluoro-2-methylphenyl)(3- Fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7 H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione ； (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; (9aR,10S)-10-((R)-(2-fluorophenyl)(3-fluorophenyl) Nyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[ 1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((R)-(3,5-difluorophenyl)(2-fluoro (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((R)-(4-fluoro-2-methylphenyl)(2- Fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7 H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione ； (9aR,10S)-10-((R)-(2-fluorophenyl)(2-methoxyphenyl) Nyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[ 1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((R)-(2-fluorophenyl)(o-tolyl)methyl 1',2'-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2' : 4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-(bis(2-fluorophenyl)methyl)-4-hydroxy C-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino [1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((R)-(3,5-difluorophenyl)(3-fluorophenyl) (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (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; (9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluorophenyl) Nyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[ 1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((R)-(2,6-difluorophenyl)(4-fluorophenyl) (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((R)-(2,6-difluorophenyl)(3-fluorophenyl) (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((S)-(3-fluorophenyl)(3,4,5-trifluorophenyl) Fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7 H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione ； (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; (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; (9aR,10S)-10-((S)-(3,4-difluorophenyl)(2-fluoro (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((S)-(3,5-difluorophenyl)(2-fluoro (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((S)-(2-fluorophenyl)(3-fluorophenyl) Nyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[ 1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((S)-(4-fluoro-2-methylphenyl)(2- Fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7 H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione ； (9aR,10S)-10-((S)-(2-fluorophenyl)(4-fluorophenyl) Nyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[ 1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (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; (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; (9aR,10S)-10-((S)-(3-fluorophenyl)(4-fluorophenyl) Nyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[ 1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (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; (9aR,10S)-10-((S)-(2,6-difluorophenyl)(3-fluorophenyl) (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((S)-(2,6-difluorophenyl)(4-fluorophenyl) (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((R)-(3-fluorophenyl)(3,4,5-triphenyl) Fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7 H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione ； (9aR,10S)-10-((R)-(2,3-difluorophenyl)(4-fluorophenyl) (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((R)-(4-fluorophenyl)(o-tolyl)methyl 1',2'-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2' : 4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10R)-10-((S)-(4-fluorophenyl)(o-tolyl)methyl 1',2'-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2' : 4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (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; (9aR,10S)-10-(bis(4-fluorophenyl)methyl)-4-hydroxy C-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino [1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((S)-(3,4-difluorophenyl)(4-fluoro (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((S)-(4-fluoro-2-methylphenyl)(4- Fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7 H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione ； (9aR,10S)-10-((R)-(2,3-difluorophenyl)(2,4-di Fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7 H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione ； (9aR,10R)-10-(bis(4-fluorophenyl)methyl)-4-hydroxy C-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino [1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((R)-(2,3-difluorophenyl)(3-fluorophenyl) (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((S)-(3,5-difluorophenyl)(4-fluorophenyl) (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((S)-(3,4-difluorophenyl)(3,5-di Fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7 H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione ； (9aR,10S)-10-((R)-(3,4-difluorophenyl)(3-fluoro (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-(bis(3,4-difluorophenyl)methyl)-4-phenyl Hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyridyl Ladino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-(bis(2,4-difluorophenyl)methyl)-4-phenyl Hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2':4,5]pyridyl Ladino[1,2-b]pyridazine-3,5-dione; (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; (9aR,10S)-10-((R)-(2,5-difluorophenyl)(4-fluorophenyl) (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((R)-(2,5-difluorophenyl)(3,4-di Fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7 H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione ； (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; (9aR,10S)-10-((R)-(2,5-difluorophenyl)(3-fluorophenyl) (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((R)-(2,4-difluorophenyl)(3,4-di Fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7 H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione ； (9aR,10S)-10-((S)-(4-fluorophenyl)(o-tolyl)methyl 1',2'-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2' : 4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((R)-(2,4-difluorophenyl)(4-fluoro (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (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; (9aR,10S)-10-((R)-(2,4-difluorophenyl)(3-fluorophenyl) (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (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; (9aR,10S)-10-((S)-(2,3-difluorophenyl)(4-fluorophenyl) (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((R)-(4-fluoro-2-methylphenyl)(4- Fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7 H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione ； (9aR,10S)-10-((R)-(3,4-difluorophenyl)(4-fluorophenyl) (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((R)-(3,4-difluorophenyl)(4-fluorophenyl) (phenyl)methyl)-4-hydroxy-2-(hydroxymethyl)-8,9,9a,1 0-Tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyrida Din-3,5-dione; (9aR,10S)-10-((S)-(2,3-difluorophenyl)(3-fluorophenyl) (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((R)-(3,4-difluorophenyl)(3,5-di Fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7 H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione ； (9aR,10S)-10-((R)-(3,5-difluorophenyl)(4-fluorophenyl) (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (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; (9aR,10S)-10-((S)-(2,5-difluorophenyl)(4-fluorophenyl) (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((S)-(2,5-difluorophenyl)(3,4-di Fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7 H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione ； (9aR,10S)-10-((R)-(3,5-difluorophenyl)(phenyl) methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1', 2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((S)-(2,4-difluorophenyl)(4-fluoro (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((S)-(2,4-difluorophenyl)(phenyl) methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1', 2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((S)-(2,4-difluorophenyl)(3-fluorophenyl) (phenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-py Rolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((S)-(2,4-difluorophenyl)(3,4-di Fluorophenyl)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7 H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione ； 10-(bis(3-fluorophenyl)methyl)-4-hydroxy-8,9,9a,1 0-Tetrahydro-7H-pyrrolo[1',2':4,5]pyrazino[1,2-b]pyrida Din-3,5-dione; 4-((R)-(3-fluorophenyl)((9aR,10S)-4-hydroxy-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 ； (9aR,10S)-10-((S)-(4-chlorophenyl)(3-fluorophenyl) (1)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1 ',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((R)-(3-chlorophenyl)(3-fluorophenyl) (1)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1 ',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((S)-(2-bromophenyl)(4-fluorophenyl) (1)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1 ',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((R)-(2-bromophenyl)(4-fluorophenyl) (1)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1 ',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((S)-(3-fluorophenyl)(o-tolyl)methyl 1',2'-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2' : 4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((S)-(3-chlorophenyl)(3-fluorophenyl) (1)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1 ',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((R)-(3-chlorophenyl)(4-fluorophenyl) (1)methyl)-4-hydroxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1 ',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluorophenyl) (nyl)methyl)-4-hydroxy-7,7-dimethyl-8,9,9a,10-tetrahydro 7H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5- Zion; (9aR,10R)-10-((S)-(3-fluorophenyl)(4-fluorophenyl) (nyl)methyl)-4-hydroxy-7,7-dimethyl-8,9,9a,10-tetrahydro 7H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5- Zion; (7S,9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluoro (phenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro 7H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5- Zion; (7S,9aR,10R)-10-((S)-(3-fluorophenyl)(4-fluoro (phenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro 7H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5- Zion; (7R,9aR,10S)-10-((R)-(3-fluorophenyl)(4-fluoro (phenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro 7H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5- Zion; (7R,9aR,10R)-10-((S)-(3-fluorophenyl)(4-fluoro (phenyl)methyl)-4-hydroxy-7-methyl-8,9,9a,10-tetrahydro 7H-Pyrrolo[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5- Zion; (8S,9aR,10S)-10-(bis(3-fluorophenyl)methyl)-4-phenyl Hydroxy-8-methoxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2 ': 4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (8R,9aR,10S)-10-(bis(3-fluorophenyl)methyl)-4-phenyl Hydroxy-8-methoxy-8,9,9a,10-tetrahydro-7H-pyrrolo[1',2 ': 4,5]pyrazino[1,2-b]pyridazine-3,5-dione; (10aR,11S)-11-Benzhydryl-4-hydroxy-7,8,10a,1 1-Tetrahydro-10H-pyridazino[1',6':4,5]pyrazino[2,1-c] [1,4]oxazine-3,5-dione; 11-Benzhydryl-4-hydroxy-7,8,9,10,10a,11-hexahydryl Dolopirido[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione ； 11-Benzhydryl-4-hydroxy-7,8,9,10,10a,11-hexahydryl Dolopirido[1',2':4,5]pyrazino[1,2-b]pyridazine-3,5-dione ； 11-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10 , 10a,11-Hexahydropyrido[1',2':4,5]pyrazino[1,2-b]pyrido ... Ridazine-3,5-dione; 11-(bis(3-fluorophenyl)methyl)-4-hydroxy-7,8,9,10 , 10a,11-Hexahydropyrido[1',2':4,5]pyrazino[1,2-b]pyrido ... Ridazine-3,5-dione; 11-Benzhydryl-4-hydroxy-7,8,10a,11-tetrahydro-10 H-pyridazino[1',6':4,5]pyrazino[2,1-c][1,4]oxazine- 3,5-dione; 11-Benzhydryl-4-hydroxy-7-methyl-7,8,9,10,10a,1 1-Hexahydropyrido[1',2':4,5]pyrazino[1,2-b]pyridazine-3 ,5-dione; (9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-diamine Xo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5 ]pyrazino[1,2-b]pyridazin-4-yl 3-methylbutanoate; (9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-diamine Xo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5 ]pyrazino[1,2-b]pyridazin-4-yl 3-methylbutanoate; (9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-diamine Xo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5 ]pyrazino[1,2-b]pyridazin-4-yl acetate; (9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-diamine Xo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5 ]pyrazino[1,2-b]pyridazin-4-yl isobutyrate; (9aR,10S)-10-(bis(3-fluorophenyl)methyl)-3,5-diamine Xo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5 ]pyrazino[1,2-b]pyridazin-4-yl isopropyl carbonate; 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 carbo Nath; (S)-((12-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3 ,5,7,8,9,10-Hexahydro-12H-dipyridazino[1,2-a:1',6 '-d][1,2,4]triazin-4-yl)oxy)methyl ethyl carbonate; (((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) Chill) carbonate; 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 carbo Nath; (((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 carbonat to; (((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)methylethylcarbonate to; (((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 carbonat to; (((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)methylethylcarbonate to; (((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)methylisopropylcarboxamide Bonato; (((9aR,10S)-10-((R)-(4-fluorophenyl)(phenyl)methyl ethyl)-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; (((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; (S)-((12-(bis(3-fluorophenyl)methyl)-3,5-dioxo-3 ,5,7,8,9,10-Hexahydro-12H-dipyridazino[1,2-a:1',6 '-d][1,2,4]triazin-4-yl)oxy)methyl methyl carbonate; (((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; (9aR,10S)-10-(bis(4-fluorophenyl)methyl)-3,5-diamine Xo-3,5,8,9,9a,10-hexahydro-7H-pyrrolo[1',2':4,5 ]pyrazino[1,2-b]pyridazin-4-yldimethylcarbamate; (((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) Carbamates; 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) (Si) phosphoryl)oxy) acetate; and Methyl 2-((((((9aR,10S)-10-(bis(4-fluorophenyl)methyl) ethyl)-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 C) carbonyl)oxy)-2-methylpropanoate; 2. The compound of claim 1 selected from:

21. A compound according to any one of claims 1 to 20 or a pharma- ceutically acceptable salt thereof, and A pharmaceutical composition comprising one or more pharma- ceutically acceptable carriers.

22. A therapeutically effective amount of a compound according to any one of claims 1 to 20 or a pharma- ceutically acceptable salt thereof. Possible salts, and combinations including one or more therapeutically active co-agents.

23. A method of treating influenza comprising administering to a subject in need thereof a therapeutically effective amount of Administering a compound according to any one of claims 1 to 20 or a pharma- ceutically acceptable salt thereof. The method includes:

24. A compound according to any one of claims 1 to 20 or a compound thereof for use as a medicament. Pharmaceutically acceptable salts.

25. A compound according to any one of claims 1 to 20 for use in the treatment of influenza. or a pharma- ceutically acceptable salt thereof.

26. A method according to any one of claims 1 to 20 in the manufacture of a medicament for the treatment of influenza.

2. Use of a compound according to claim 1 or a pharma- ceutically acceptable salt thereof.

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