Polycyclic-carbamoylpyridone compounds and their pharmaceutical use

Abstract

Disclosed are compounds useful for the treatment of human immunodeficiency virus (HIV) infection. The compounds have the following formula (I): including stereoisomers and pharmaceutically acceptable salts thereof, wherein R 1 , X, W, Y 1 , Y 2 , Z 1 , and Z 4 are as defined herein. Also disclosed are methods relating to the preparation and use of such compounds and pharmaceutical compositions comprising such compounds.

Description

[0001] This application is a divisional application (application number 202010188107.9) of the Chinese patent application (application number 201380073134.X, application date December 19, 2013, entitled "Polycyclic carbamoylpyridinone compounds and their pharmaceutical uses") which entered the Chinese national phase of the international application PCT / US2013 / 076367.

[0002] Cross-reference to related applications

[0003] This patent application claims the benefit of U.S. Provisional Patent Application No. 61 / 745,375, filed December 21, 2012; U.S. Provisional Patent Application No. 61 / 788,397, filed March 15, 2013; and U.S. Provisional Patent Application No. 61 / 845,803, filed July 12, 2013, under 35 U.S. SC § 119(e). The entire contents of the foregoing applications are incorporated herein by reference. Background Technology

[0004] Invention Field

[0005] Compounds, compositions, and methods for treating human immunodeficiency virus (HIV) infection are disclosed. In particular, novel polycyclic carbamoylpyridinone compounds, methods for their preparation, and their use as therapeutic or preventative agents are disclosed.

[0006] Description of related technologies

[0007] Human immunodeficiency virus infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus type 1 (HIV-1) encodes three enzymes required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are widely available and have shown efficacy, especially when used in combination, their usefulness is limited by the development of toxicity and resistant strains (Palella, et al. N. Engl. J Med. (1998) 338:853-860; Richman, DDNature (2001) 410:995-1001).

[0008] Pregnane X receptor (PXR) is a nuclear receptor that is one of the key regulators of enzymes involved in metabolism and the elimination of small molecules from the body. Activation of PXR is known to upregulate or induce the production of metabolic enzymes such as cytochrome P450 3A4 (CYP3A4) and enzymes involved in the transport of OATP2, such as in the liver and intestine (Endocrine Reviews (2002) 23(5):687-702). When a drug causes upregulation of these and other enzymes by PXR activation, this can reduce the absorption and / or exposure of co-administered drugs sensitive to the upregulated enzymes. To minimize the risk of this type of drug-drug interaction, it is desirable to minimize PXR activation. Furthermore, PXR is known to be activated by many different types of molecules (Endocrine Reviews (2002) 23(5):687-702). Therefore, for drugs to be co-administered with other drugs, it is important to test for and minimize PXR activation.

[0009] Transporters have been identified as playing a role in pharmacokinetics, safety and efficacy properties or drugs, and certain drug-drug interactions are mediated by transporters. See, Giacomini KM, et al. “Membranetransporters in drug development,” Nat. Rev. Drug Discov. 9:215-236, 2010; Zhang L, et al. “Transporter-Mediated Drug-Drug Interactions,” Clin. Pharm. Ther. 89(4):481-484 (2011). One transporter (organic cation transporter 2 (OCT2; SLC22A2)) is a member of the solute carrier (SLC) superfamily of transporters and is primarily located on the basolateral membrane of the proximal tubules of the kidney. OCT2, involved in the apical expression of multidrug and toxin excretion (MATE) transporters 1 and 2-K, is considered to form the major cation secretion pathway in the kidney and has been shown to transport endogenous compounds including creatinine and exogenous compounds including metformin. Therefore, inhibition of OCT2 may lead to increased serum creatinine levels and potentially increased levels of other OCT2 substances. Testing and reducing OCT2 inhibition by drugs is also important.

[0010] The goal of antiretroviral therapy is to achieve viral suppression in patients infected with HIV. Treatment guidelines published by the United States Department of Health and Human Services state that achieving viral suppression requires the use of combination therapy, i.e., several drugs from at least two or more drug classes. (Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human Services. Available at http: / / aidsinfo.nih.gov / ContentFiles / AdultandAdolescentGL.pdf. Section accessed March 14, 2013.). Furthermore, treatment decisions for HIV-infected patients are complex when patients require treatment for other medical conditions (Id., E-12). Because the standard of care requires the use of multiple different drugs to suppress HIV, and to treat other conditions the patient may experience, the possibility of drug interactions is a criterion for selecting a drug regimen. Therefore, there is a need for antiretroviral therapies with a reduced likelihood of drug interactions. Therefore, there is a need for new agents that inhibit HIV replication and minimize PXR activation when co-administered with other drugs. Invention Summary

[0011] This invention relates to novel polycyclic carbamoylpyridinone compounds with antiviral activity, including their stereoisomers and pharmaceutically acceptable salts, and the use of such compounds in the treatment of HIV infection. The compounds of this invention can be used to inhibit the activity of HIV integrase and to reduce HIV replication.

[0012] In one embodiment of the invention, a compound having the following formula (I) is provided:

[0013]

[0014] Or its stereoisomers or medicinal salts.

[0015] in:

[0016] X is either -O- or -NZ 3 -or-CHZ 3 -;

[0017] W is -CHZ 2 -;

[0018] Z 1 Z 2 and Z 3 Each is independently hydrogen or C 1-3 Alkyl, or Z 1 and Z 2 or Z 1 and Z 3 They combine to form -L-, where L is -C(R) a )2-、-C(R a )2C(R a )2-、-C(R a )2C(R a )2C(R a )2- or -C(R a )2C(R a )2C(R a )2C(R a )2-, where Z 1 and Z 2 or Z 1 and Z 3 At least one group together forms -L-;

[0019] Z 4 For bonds, -CH2- or -CH2CH2-;

[0020] Y 1 and Y 2 Each independently is hydrogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups;

[0021] R 1 A phenyl group substituted with one to three halogens; and

[0022] Each R a Independently hydrogen, halogen, hydroxyl or C 1-4 alkyl.

[0023] In another embodiment of the invention, a compound having the following formula (I) is provided:

[0024]

[0025] Or its stereoisomers or medicinal salts.

[0026] in:

[0027] X is either -O- or -NZ 3 -or-CHZ 3 -;

[0028] W is either -O- or -NZ 2 -or-CHZ 2 -;

[0029] Z 1 Z 2 and Z 3 Each is independently hydrogen or C 1-3 Alkyl, or Z 1 and Z 2 or Z 1 and Z 3 They combine to form -L-, where L is -C(R) a )2-、-C(R a )2C(R a )2-、-C(R a )2C(R a )2C(R a )2-、-C(R a )2C(R a )2C(R a )2C(R a )2-、-C(R a )2OC(R a )2-、-C(R a )2NR a C(R a )2-、-C(R a )2SC(R a )2-、-C(R a )2S(O)C(R a )2-、-C(R a )2SO2C(R a )2-、-C(R a )2OC(R a )2C(R a )2-、-C(R a )2C(R a )2OC(R a )2-、-C(R a )2NR a C(R a )2C(R a )2-、-C(R a )2C(R a )2NR a C(R a )2-、-C(R a )2SC(R a )2C(R a )2-、-C(R a )2C(R a )2SC(Ra )2-、-C(R a )2S(O)C(R a )2C(R a )2-、-C(R a )2C(R a )2S(O)C(R a )2-、-C(R a )2SO2C(R a )2C(R a )2-、-C(R a )2C(R a )2SO2C(R a )2-、-C(R a )2SO2NR a C(R a )2-or-C(R a )2NR a SO2C(R a )2-;

[0030] Z 4 For bonds or -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2NR a CH2-, -CH2SCH2-, -CH2S(O)CH2- or -CH2SO2CH2-;

[0031] Y 1 and Y 2 Each independently is hydrogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl, or Y 1 and Y 2 Together with the carbon atoms connected to them, they form a carbon ring or a heterocyclic ring having 3 to 6 ring atoms, wherein the carbon ring or heterocyclic ring is optionally surrounded by one or more R atoms. a replace;

[0032] R 1 For optionally substituted aryl or optionally substituted heteroaryl; and

[0033] Each R a Independently hydrogen, halogen, hydroxyl or C 1-4 Alkyl, or two of the Rs a The radicals, together with the carbon atoms they are attached to, form C=O, and

[0034] At least one of the following: (i)Z 1 and Z 2 or Z 1 and Z 3 Together they form -L-; or (ii)Y1 and Y 2 Together with the carbon atoms attached to them, they form carbon rings or heterocyclic rings with 3 to 6 ring atoms.

[0035] In another embodiment, a pharmaceutical composition is provided comprising a compound having formula (I) or a stereoisomer thereof or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, diluent or excipient.

[0036] The present invention also provides the use of the pharmaceutical composition described above for treating HIV infection in persons who have or are at risk of infection.

[0037] In another embodiment, a method of using a compound having formula (I) in treatment is provided. In particular, a method of treating HIV viral replication in mammals (e.g., humans), treating AIDS, or delaying the onset of AIDS or ARC symptoms is provided, comprising administering to said mammal a compound having formula (I), or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0038] In another embodiment, the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, is disclosed for the treatment of HIV infection in persons who have or are at risk of infection.

[0039] In another embodiment, the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, is disclosed in the preparation of a medicament for treating HIV infection in persons who have or are at risk of infection.

[0040] In another embodiment, an article of manufacture is disclosed comprising a composition effective in treating HIV infection; and packaging material comprising a label indicating that the composition can be used to treat HIV infection. Exemplary compositions comprise compounds of formula (I) according to the invention or pharmaceutically acceptable salts thereof.

[0041] In yet another embodiment, a method for inhibiting HIV replication is disclosed. The method comprises exposing the virus to an effective amount of a compound of formula (I) or a salt thereof, wherein HIV replication is inhibited.

[0042] In another embodiment, the use of the compound of formula (I) to inhibit the activity of HIV integrase is disclosed.

[0043] In another embodiment, the use of compounds of formula (I) or salts thereof to inhibit HIV replication is disclosed.

[0044] Other embodiments, objects, features, and advantages will be set forth in the detailed description of the embodiments that follow, and will be apparent in part from the description of the claimed invention, or may be learned by practicing the claimed invention. These objects and advantages will be realized and obtained through the methods and compositions particularly pointed out in its written description and claims. The foregoing summary should be understood as a brief and general summary of some embodiments disclosed herein, provided only for the benefit and convenience of the reader, and is not intended in any way to limit the legally conferred scope of the appended claims or the scope of their equivalents. Detailed description

[0045] In the following description, certain details are set forth in order to provide a detailed understanding of various embodiments of the invention. However, those skilled in the art will understand that the invention can be practiced without these details. It should be understood that the following description of several embodiments is intended to be illustrative of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments set forth. Headings used throughout the specification are provided for convenience only and should not be construed as limiting the claims in any way. Embodiments set forth under any heading may be combined with embodiments set forth under any other heading.

[0046] definition

[0047] Unless the context otherwise requires, throughout the specification and claims, the term "comprise" and its variations such as "comprises" and "comprising" shall be interpreted as openly including, that is, "including but not limited to".

[0048] Throughout the specification, references to "one embodiment" or "an embodiment" indicate that the specific feature, structure, or characteristic described in that embodiment is included in at least one embodiment of the invention. Therefore, the appearance of the phrase "in one embodiment" or "in an embodiment" at different points throughout the specification does not necessarily refer to the same embodiment. Furthermore, the specific feature, structure, or characteristic can be combined in any suitable manner in one or more embodiments.

[0049] Unless the context otherwise requires, “compound of formula (I)” or “compound of formula (I)” as used throughout the specification means all embodiments of formula (I), including, for example, compounds of the following formulas: (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH), as well as the specific compounds disclosed herein.

[0050] "Amino" refers to the -NH2 group.

[0051] “Cyano” refers to the -CN group.

[0052] "Hydroxy" refers to the -OH group.

[0053] "Imine" refers to the =NH substituent.

[0054] "Nitro" refers to the -NO2 group.

[0055] "Oxyto" refers to the =O substituent.

[0056] "Thio" refers to the =S substituent.

[0057] "Alkyl" refers to a straight-chain or branched hydrocarbon consisting only of carbon and hydrogen atoms, which may be saturated or unsaturated (i.e., containing one or more double and / or triple bonds) and has one to twelve carbon atoms (C1-C2). 12 The alkyl group, preferably one to eight carbon atoms (C1-C8 alkyl) or one to six carbon atoms (C1-C6 alkyl), and is linked to the remainder of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (tert-butyl), 3-methylhexyl, 2-methylhexyl, vinyl, prop-1-enyl, but-1-enyl, pent-1-enyl, pent-1,4-dienyl, ethynyl, propynyl, butynyl, pentyynyl, hexynyl, etc. Unless otherwise specifically stated in the specification, the alkyl group may optionally be substituted.

[0058] "alkylene" or "alkylene chain" refers to a straight-chain or branched divalent hydrocarbon chain consisting only of carbon and hydrogen, in which the rest of the molecule is connected to a group. It may be saturated or unsaturated (i.e., containing one or more double and / or triple bonds) and has one to twelve carbon atoms, such as methylene, vinyl, propenyl, n-butenyl, vinylene, propenyl, n-butenyl, propynyl, n-butynyl, etc. The alkylene chain is connected to the rest of the molecule and to the group via single or double bonds. The connection point between the alkylene chain and the rest of the molecule and the group can be via one or any two carbons within the chain. Unless otherwise specified in the specification, the alkylene chain may optionally be substituted.

[0059] "Alkoxy" refers to -OR A The group, wherein R A Alkyl groups containing one to twelve carbon atoms as defined above. Unless otherwise specified in the specification, alkoxy groups may optionally be substituted.

[0060] "alkylamino" refers to -NHR A or -NR A R A The groups, wherein each R A Alkyl groups, as defined above, contain one to twelve carbon atoms. Unless otherwise specified in the specification, alkylamino groups may optionally be substituted.

[0061] "Thioalkyl" refers to -SR A The group, wherein R A Alkyl groups as defined above, containing one to twelve carbon atoms. Unless otherwise specified in the specification, thioalkyl groups may optionally be substituted.

[0062] "Aryl" refers to a monocyclic hydrocarbon ring system group containing hydrogen and 6 to 18 carbon atoms. Aryl groups include, but are not limited to, aromatic groups derived from benzene. Unless otherwise specified in the specification, the term "aryl" or the prefix "ar-" (e.g., "arylalkyl") means to include optionally substituted aryl groups.

[0063] "Aryl" refers to -R B -R C The group, wherein R B It is an alkylene chain as defined above, and R C It can be one or more aryl groups as defined above, such as benzyl. Unless otherwise specified in the specification, the aryl group may optionally be substituted.

[0064] "Cycloalkyl" or "carbocyclic" refers to a stable non-aromatic monocyclic hydrocarbon group consisting only of carbon and hydrogen atoms, having three to fifteen carbon atoms, preferably three to ten carbon atoms, and being saturated or unsaturated and connected to the rest of the molecule by single bonds. Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Unless otherwise specified in the specification, cycloalkyl groups may optionally be substituted.

[0065] "Cycloalkylalkyl" indicates -R B R D The group, wherein R B It is an alkylene chain as defined above and R D The alkyl group is as defined above. Unless otherwise specified in the specification, the alkyl group may optionally be substituted.

[0066] "Halogen" or "halogen" refers to bromine, chlorine, fluorine, or iodine.

[0067] "Halogenated alkyl" refers to an alkyl group as defined above that is substituted with one or more halogenated groups as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromomethyl, etc. Unless otherwise specified in the specification, halogenated alkyl groups may optionally be substituted.

[0068] "Heterocyclic group" or "heterocyclic ring" refers to a stable 3- to 18-membered non-aromatic cyclic group consisting of two to twelve carbon atoms and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. In the embodiments disclosed herein, the heterocyclic group is a monocyclic system; and the heterocyclic group may be partially or fully saturated. Examples of such heterocyclic groups include, but are not limited to, dioxolane, thiophene, [1,3]dithiaalkyl, imidazolinyl, imidazoalkyl, isothiazolyl, isoxazolyl, morpholine. The heterocyclic groups include 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopiperylalkyl, oxazolylalkyl, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolylalkyl, pyrazolylalkyl, thiazolylalkyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl, 1-oxothiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Unless otherwise specified in the specification, the heterocyclic groups may optionally be substituted.

[0069] "N-Heterocyclic group" refers to a heterocyclic group as defined above that contains at least one nitrogen atom and is connected to the remainder of the molecule by a nitrogen atom in the heterocyclic group. Unless otherwise specified in the specification, the N-heterocyclic group may optionally be substituted.

[0070] "Heterocyclic alkyl" indicates -R B R EThe group, wherein R B For alkylene chains as defined above and R E The heterocyclic group is as defined above, and if the heterocyclic group is a nitrogen-containing heterocyclic group, the nitrogen atom may be linked to an alkyl group. Unless otherwise specifically stated in the specification, the heterocyclic alkyl group may optionally be substituted.

[0071] "Heteroaryl" refers to a 5- to 14-membered monocyclic group comprising a hydrogen atom, one to thirteen carbon atoms, and one to six heteroatoms selected from nitrogen, oxygen, and sulfur. Examples include, but are not limited to, nitrogen-containing heteroatoms. Furanyl, furanyl, furanoneyl, isothiazolyl, imidazoleyl, isoxazolyl, oxadiazolyl, 2-oxoazoni The alkyl groups are: alkyl group, oxazolyl group, ethylene oxide group, 1-oxidopyridinyl group, 1-oxidopyrimidinyl group, 1-oxidopyazinyl group, 1-oxidopyridinyl group, pyrazolyl group, pyridinyl group, pyrimidinyl group, pyridazinyl group, thiazolyl group, thiadiazolyl group, triazolyl group, tetrazolyl group, triazinyl group, thiophenyl group, and thiophenyl group. Unless otherwise specified in the specification, heteroarylalkyl groups may optionally be substituted.

[0072] "N-Heteroaryl" refers to a heteroaryl group as defined above, containing at least one nitrogen atom and wherein the connection point between the heteroaryl group and the rest of the molecule is through the nitrogen atom in the heteroaryl group. Unless otherwise specified in the specification, the N-heteroaryl group may optionally be substituted.

[0073] "Heteroarylalkyl" indicates -R B R F The group, wherein R B It is an alkylene chain as defined above, and R FThe heteroaryl group is defined above. Unless otherwise specified in the specification, the heteroaryl alkyl group may optionally be substituted. As used herein, the term "substituted" refers to any of the aforementioned groups (i.e., alkyl, alkylene, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclic, N-heterocyclic, heterocyclic, heteroalkyl, heteroaryl, N-heteroaryl and / or heteroarylalkyl), wherein at least one hydrogen atom is replaced by a bonded to a non-hydrogen atom, such as, but not limited to: halogen atoms, such as F, Cl, Br and I; oxygen atoms in groups such as hydroxyl, alkoxy and ester groups; sulfur atoms in groups such as thiol, thioalkyl, sulfonyl, sulfonyl and sulfoxide groups; nitrogen atoms in groups such as amine, amide, alkylamine, dialkylamine, arylamine, alkylarylamine, diarylamine, N-oxide, diimide and enamine; silicon atoms in groups such as trialkylsilyl, dialkylarylsilyl, alkyldiarylsilyl and triarylsilyl; and other heteroatoms in various other groups. "Substitution" also means any of the above-mentioned groups in which one or more hydrogen atoms are replaced by a higher-valence bond (e.g., a double or triple bond) to a heteroatom such as oxygen in an oxo, carbonyl, carboxyl, or ester group; and nitrogen in groups such as imines, oximes, hydrazones, and nitriles. For example, "substituted" includes any of the above-mentioned groups in which one or more hydrogen atoms are replaced by a group with the following group: -NR G R H -NR G C(=O)R H -NR G C(=O)NR G R H -NR G C(=O)OR H -NR G C(=NR g )NR G R H -NR G SO2R H -OC(=O)NR G R H -OR G -SR G -SOR G -SO2R G -OSO2R G -SO2OR G =NSO2R G and -SO2NR G R H "Substituted" also means that in any of the above groups, one or more hydrogen atoms are replaced by the following group: -C(=O)R G -C(=O)OR G-C(=O)NR G R H -CH2SO2R G -CH2SO2NR G R H In the foregoing, R G and R H The same or different substituents are independently hydrogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. "Substituted" further indicates that in any of the above groups, one or more hydrogen atoms are bonded to the following bonds: amino, cyano, hydroxyl, imino, nitro, oxo, thio, halogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclic, N-heterocyclic, heterocyclic alkyl, heteroaryl, N-heteroaryl, and / or heteroarylalkyl. Additionally, each of the aforementioned substituents may optionally be substituted by one or more of the above substituents.

[0074] As used herein, the term "protecting group" refers to an unstable chemical moiety known in the art to protect reactive groups (including, but not limited to, hydroxyl and amino groups) from undesirable reactions during the synthetic process. Hydroxyl groups and amino groups protected by protecting groups are referred to herein as "protected hydroxyl" and "protected amino," respectively. Protecting groups are typically used selectively and / orthogonally to protect sites during reactions at other reactive sites and can then be removed, leaving unprotected groups intact or participating in further reactions. Protecting groups known in the art are generally described in Greene and Wuts, *Protective Groups in Organic Synthesis*, 3rd edition, John Wiley & Sons, New York (1999). Typically, the group is protected or a precursor is present that is inert to reactions that modify other regions of the parent molecule at appropriate times to convert them into their final groups. Other representative protecting groups or precursor groups are discussed in Agrawal, et al., *Protocols for Oligonucleotide Conjugates*, Eds, Humana Press; New Jersey, 1994; Vol. 26, pp. 1-72. Examples of “hydroxyl protecting groups” include, but are not limited to, tert-butyl, tert-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, 2,6-dichlorobenzyl, diphenyl-methyl, p-nitrobenzyl, triphenylmethyl, trimethylsilyl, triethylsilyl, tert-butyldimethylsilyl, tert-butyl-diphenylsilyl (TBDPS), triphenylsilyl, benzoyl carbamate, acetate, chloroacetate, trichloroacetate, trifluoroacetate, pivaloate, benzoate, phenyl p-benzoate, 9-fluorenylmethyl carbonate, methanesulfonate, and toluenesulfonate. Examples of “amino protecting groups” include, but are not limited to, urethane protecting groups such as 2-trimethyl-silylethoxycarbonyl (Teoc), 1-methyl-1-(4-biphenyl)-ethoxycarbonyl (Bpoc), tert-butoxycarbonyl (BOC), allyloxycarbonyl (Alloc), 9-fluorenylmethyloxycarbonyl (Fmoc), and benzyloxycarbonyl (Cbz); amide protecting groups such as formyl, acetyl, trichloroacetyl, benzoyl, and nitrophenylacetyl; sulfonamide protecting groups such as 2-nitrobenzenesulfonyl; and imine and cyclic imine protecting groups such as phthalimide and dithiosuccinyl.

[0075] The invention disclosed herein also implies coverage of all pharmaceutically acceptable compounds of formula (I) that are isotopically labeled by substituting one or more atoms with atoms having different atomic masses or mass numbers. Examples of isotopes that may be incorporated into the disclosed compounds include hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as... 2 H, 3 H, 11 C 13 C 14 C 13 N、 15 N、 15 O、 17 O、 18 O、 31 P, 32 P, 35 S, 18 F, 36 Cl、 123 I and 125 I. These radiolabeled compounds can be used to determine or measure the efficacy of compounds by characterizing, for example, the site or mode of action or the affinity for binding to pharmacologically important sites of action. Certain isotope-labeled compounds of formula (I) (e.g., those doped with a radioisotope) are used in drug and / or substrate tissue distribution studies. Radioisotope tritium (i.e. 3 H) and carbon-14 ( 14 C) It is specifically used for this purpose due to its ease of bonding and alternative detection methods.

[0076] Using heavy isotopes such as deuterium (i.e. 2 Substitution with H can impart certain therapeutic advantages resulting from greater metabolic stability. For example, the in vivo half-life can be increased or the dosage requirement can be reduced. Therefore, in some cases, heavy isotopes may be preferred.

[0077] Positron-emitting isotopes, such as 11 C 18 F, 15 O and 13 N-substitution can be used in positron emission tomography (PET) studies to examine substrate acceptor occupancy. Isotopically labeled compounds of formula (I) can generally be prepared using conventional techniques known to those skilled in the art or by methods similar to those described in the examples below, using a suitable isotopically labeled reagent instead of the unlabeled reagent used in the above-described form.

[0078] The invention disclosed herein also encompasses the in vivo metabolites of the disclosed compounds. Such products can be obtained, for example, by oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily due to enzymatic catalysis. Therefore, the invention includes compounds produced by a method comprising administering the compounds of the invention to a mammal for a sufficient period of time to produce their metabolites. Such products are typically identified by administering the radiolabeled compound of the invention at a detectable dose to an animal (e.g., rat, mouse, guinea pig, monkey, or human) for a sufficient period of time to allow for metabolism, and by isolating its metabolites from urine, blood, or other biological samples.

[0079] "Stable compound" and "stable structure" mean a compound that is robust enough to be isolated from the reaction mixture to a useful purity and formulated into an effective therapeutic agent. "Mammalian" includes humans and livestock such as laboratory animals and domestic pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits) and non-domestic animals such as wild animals.

[0080] "Optional" or "optionally" means that the subsequent occurrence of the event or situation may or may not occur, and the description includes both the case in which the event or situation occurs and the case in which it does not occur. For example, "optionally substituted aryl" means that the aryl group may or may not be substituted, and the description includes substituted aryl groups and unsubstituted aryl groups.

[0081] "Pharmaceutical-grade carriers, diluents, or excipients" include, but are not limited to, any adjuvant, carrier, excipient, flow aid, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersant, suspending agent, stabilizer, isotonic agent, solvent, or emulsifier that has been approved by the U.S. Food and Drug Administration for use in humans or livestock.

[0082] "Pharmacologically acceptable salt" refers to a salt of a compound that is pharmaceutically acceptable and possesses the desired pharmacological activity of the parent compound (or can be converted into a form possessing the pharmacological activity of the parent compound). Examples of "pharmacologically acceptable salts" of compounds disclosed herein include those derived from suitable bases such as alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and NX4. +Salts of compounds containing a nitrogen atom or an amino group (where X is a C1-C4 alkyl group). Pharmaceutically acceptable salts include, for example, salts of organic carboxylic acids, organic sulfonic acids, and inorganic acids, such as acetic acid, benzoic acid, camphor sulfonic acid, citric acid, glucoheponic acid, gluconic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, malonic acid, malic acid, mandelic acid, hydroxyethanesulfonic acid, lactobionic acid, succinic acid, 2-naphthalenesulfonic acid, oleic acid, palmitic acid, propionic acid, stearic acid, and trimethylacetic acid; organic sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid; and inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and aminosulfonic acid. Pharmaceutically acceptable salts of hydroxyl compounds include the anion of the compound and a suitable, for example, Na+. + and NX4 + (where X is independently selected from H or C1-C4 alkyl groups). Pharmacologically acceptable salts also include those formed by substitution with metal ions, such as alkali metal ions, alkaline earth metal ions, or aluminum ions, when an acidic proton is present in the parent compound; or those formed by coordination with organic bases such as diethanolamine, triethanolamine, or N-methylglucosamine. Ammonium and substituted or quaternized ammonium salts are also included in this definition. A representative non-limiting list of pharmaceutically acceptable salts can be found in SMBerge et al., J. Pharma Sci., 66(1), 1-19 (1977), and Remington: The Science and Practice of Pharmacy, R. Hendrickson, ed., 21st edition, Lippincott, Williams & Wilkins, Philadelphia, PA, (2005), at p. 732, Table 38-5, both of which are incorporated herein by reference.

[0083] For therapeutic purposes, the salts of the active ingredients of the compounds disclosed herein are generally pharmaceutically acceptable, i.e., they are salts derived from physiologically acceptable acids or bases. However, salts of acids or bases that are not found to be pharmaceutically acceptable may also be used, for example, to prepare or purify compounds of formula (I) of the present invention or other compounds. All salts, whether or not derived from physiologically acceptable acids or bases, are within the scope of the present invention.

[0084] Metal salts are typically prepared by reacting a metal hydroxide with the compounds of this invention. Examples of metal salts prepared in this manner include those containing Li. + Na + and K + Salts. Less soluble metal salts can be precipitated from solutions of more soluble salts by adding a suitable metal compound.

[0085] Additionally, salts can be formed by adding certain organic and inorganic acids, such as HCl, HBr, H2SO4, H3PO4, or organic sulfonic acids, to a basic center (usually an amine). Finally, it should be understood that the compositions herein include the non-ionized and zwitterionic forms of the compounds disclosed herein, as well as those in hydrate form with stoichiometric amounts of water.

[0086] Crystallization typically produces solvates of the compounds of the present invention. As used herein, the term "solvate" refers to an aggregate comprising one or more molecules of the compounds of the present invention and one or more solvent molecules. The solvent may be water, in which case the solvate may be a hydrate. Alternatively, the solvent may be an organic solvent. Therefore, the compounds of the present invention can exist as hydrates, including monohydrates, dihydrates, hemihydrates, sesquihydrates, trihydrates, tetrahydrates, etc., and corresponding solvated forms. The compounds of the present invention may be true solvates, while in other cases, the compounds of the present invention may simply retain the external water or be a mixture of water and certain external solvents.

[0087] "Pharmaceutical composition" refers to formulations of the compounds of the present invention and generally accepted media in the art for delivering biologically active compounds to mammals, such as humans. Such media include all pharmaceutically acceptable carriers, diluents, or excipients. "Effective amount" or "therapeutic effective amount" refers to the amount of the compound according to the invention that, when administered to a patient in need, is sufficient to produce an effective treatment of the disease-state, symptom, or disorder to which the compound has an effect. Such an amount is sufficient to elicit a biological or medical response in the tissue or patient sought by the researcher or clinician. The amount of the compound according to the invention constituting a therapeutically effective amount should vary depending on factors such as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type and severity of the disease-state or symptom to be treated, the drugs used in combination with or in conjunction with the compounds of the present invention, the patient's age, weight, general health status, sex, and diet. Such a therapeutically effective amount can be conventionally determined by those skilled in the art considering their own knowledge, state of the art, and the disclosure.

[0088] As used herein, the term "treatment" refers to administering a compound or composition according to the invention to alleviate or eliminate symptoms of HIV infection and / or reduce the viral load in a patient. The term "treatment" also encompasses administering a compound or composition according to the invention after an individual's exposure to the virus, but before the onset of symptoms of the disease, and / or before a viral load is detected in blood pressure, to prevent the onset of symptoms of the disease and / or to prevent the virus from reaching detectable levels in the blood, and to administering a compound or composition according to the invention to prevent HIV transmission from the mother to the infant during the perinatal period by administering the compound or composition to the mother before delivery and to the infant on the first day after birth.

[0089] As used herein, the term "antiviral agent" refers to an agent (compound or organism) that effectively inhibits the formation and / or replication of a virus in humans, including but not limited to agents that interfere with the host or viral mechanisms required for the formation and / or replication of a virus in humans.

[0090] As used in this article, the term "HIV replication inhibitor" means an agent that can reduce or eliminate the ability of HIV to replicate in host cells, whether in vitro, outside the body, or in vivo.

[0091] The compounds of the present invention, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers, thus producing enantiomers, diastereomers, and other stereoisomers that can be defined according to absolute stereochemistry as (R)- or (S)- or (D)- or (L)- for amino acids. The present invention refers to all such possible isomers as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or using conventional methods such as chromatography and fractional crystallization. Conventional methods for preparing / separating individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution using, for example, chiral high-performance liquid chromatography (HPLC) of racemates (or racemates of salts or derivatives). When the compounds described herein contain an alkene double bond or other geometrically asymmetric centers, unless otherwise stated, it means that the compounds include E and Z geometric isomers. Furthermore, all tautomeric forms are also included.

[0092] "Stereoisomers" refer to compounds composed of identical atoms bonded by the same bonds but with different three-dimensional structures, and are not interchangeable. This invention contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-overlapping mirror images of each other.

[0093] "Tautomer" refers to the transfer of a proton from one atom of a molecule to another atom of the same molecule. This invention includes tautomers of any of the compounds described.

[0094] "Prodrug" refers to a chemically engineered compound that effectively releases a parent drug after overcoming the biological barriers of oral delivery. In some embodiments, the present invention includes a prodrug of a compound of formula (I).

[0095] compound

[0096] As described above, in one embodiment of the present invention, a compound having antiviral activity is provided, said compound having the following formula (I):

[0097]

[0098] Or its stereoisomers or medicinal salts.

[0099] in:

[0100] X is either -O- or -NZ 3 -or-CHZ 3 -;

[0101] W is -CHZ 2 -;

[0102] Z 1 Z 2 and Z 3 Each is independently hydrogen or C 1-3 Alkyl, or Z 1 and Z 2 or Z 1 and Z 3 They combine to form -L-, where L is -C(R) a )2-、-C(R a )2C(R a )2-、-C(R a )2C(R a )2C(R a )2- or -C(R a )2C(R a )2C(R a )2C(R a )2-, where Z 1 and Z 2 or Z 1 and Z 3 At least one of them combines to form -L-;

[0103] Z 4 For bonds, -CH2- or -CH2CH2-;

[0104] Y 1 and Y 2 Each independently is hydrogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups;

[0105] R 1 A phenyl group substituted with one to three halogens; and

[0106] Each R a Independently hydrogen, halogen, hydroxyl or C 1-4 alkyl.

[0107] In another embodiment, a compound having the following formula (II-A) is provided:

[0108]

[0109] In another embodiment, a compound having the following formula (II-B) is provided:

[0110]

[0111] In another embodiment, a compound having the following formula (II-C) is provided:

[0112]

[0113] In another implementation, L is -C(R) a )2-. In a further embodiment, L is -C(R) a )2C(R a )2-. In yet another further implementation, L is -C(R) a )2C(R a )2C(R a )2-. In yet another further implementation, each R a For hydrogen. In yet another further embodiment, an R a It is methyl and each of the remaining R a For hydrogen. In yet another further embodiment, an R a It is halogen and each of the remaining R a For hydrogen. In yet another further embodiment, the two R... a It is halogen and each of the remaining R a For hydrogen. In yet another further embodiment, an R a It is halogen and each of the remaining R a It is hydrogen.

[0114] In another implementation, X is -O-. In yet another implementation, X is -NZ. 3 - In another embodiment, X is -NH-. In another embodiment, X is -CHZ. 3 -and Z 1 and Z 3 Together they form -L-. In a further implementation, Z 2 X is hydrogen. In another embodiment, X is -CH2-.

[0115] In another implementation scheme, Z 4 For the key or -CH2-. In another implementation, Z 4 For -CH2-. In another implementation, Z 4 For key.

[0116] In another implementation scheme, Y 1and Y 2 Each can be independently hydrogen, methyl, or trifluoromethyl.

[0117] In another implementation, R 1 It is replaced by a halogen. In a further embodiment, R 1 It is 4-fluorophenyl or 2-fluorophenyl.

[0118] In another implementation, R 1 It is replaced by two halogens. In a further embodiment, R 1 It is 2,4-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 3-fluoro-4-chlorophenyl, 3,4-difluorophenyl, 2-fluoro-4-chlorophenyl, or 3,5-difluorophenyl. In yet another further embodiment, R 1 It is 2,4-difluorophenyl.

[0119] In another implementation, R 1 It is replaced by three halogens. In a further implementation, R 1 It is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl. In yet another further embodiment, R 1 It is 2,4,6-trifluorophenyl.

[0120] In one embodiment, a pharmaceutical composition is provided comprising any one of the compounds of formula (I), (II-A), (II-B) or (II-C) as described above, or a stereoisomer thereof, or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, diluent, or excipient.

[0121] Another embodiment is provided, comprising a method of treating HIV infection in a patient who is infected or at risk of infection by administering to a person a therapeutically effective amount of a compound or pharmaceutical composition thereof of any one of the above-described formulas (I), (II-A), (II-B), or (II-C) as described above. Another embodiment is provided, comprising a method of treating or preventing HIV infection in a patient who is infected or at risk of infection by administering to a person a therapeutically effective amount of a compound or pharmaceutical composition thereof of any one of the above-described formulas (I), (II-A), (II-B), or (II-C) as described above.

[0122] In another embodiment, the use of any one of the compounds of formula (I), (II-A), (II-B), or (II-C) as described above, or a pharmaceutical composition thereof, is provided for the treatment of HIV infection in patients who are infected or at risk of infection. In another embodiment, the use of any one of the compounds of formula (I), (II-A), (II-B), or (II-C) as described above, or a pharmaceutical composition thereof, is provided for the treatment or prevention of HIV infection in patients who are infected or at risk of infection. In another embodiment, the use of any one of the compounds of formula (I), (II-A), (II-B), or (II-C) as described above, or a pharmaceutical composition thereof, is provided for medical treatment.

[0123] In another embodiment, the use of any one of the compounds of formula (I), (II-A), (II-B), or (II-C) as described above, or a pharmaceutical composition thereof, is provided for the therapeutic treatment of HIV infection. In another embodiment, the use of any one of the compounds of formula (I), (II-A), (II-B), or (II-C) as described above, or a pharmaceutical composition thereof, is provided for the preventive or therapeutic treatment of HIV infection.

[0124] As further described above, in one embodiment of the present invention, a compound having antiviral activity is provided, said compound having the following formula (I):

[0125]

[0126] Or its stereoisomers or medicinal salts.

[0127] in:

[0128] X is either -O- or -NZ 3 -or-CHZ 3 -;

[0129] W is either -O- or -NZ 2 -or-CHZ 2 -;

[0130] Z 1 Z 2 and Z 3 Each independently is hydrogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl, or wherein Z 1 and Z 2 or Z 1 and Z 3 They combine to form -L-, where L is -C(R) a )2-、-C(R a )2C(R a )2-、-C(R a)2C(R a )2C(R a )2-、-C(R a )2C(R a )2C(R a )2C(R a )2-、-C(R a )2OC(R a )2-、-C(R a )2NR a C(R a )2-、-C(R a )2SC(R a )2-、-C(R a )2S(O)C(R a )2-、-C(R a )2SO2C(R a )2-、-C(R a )2OC(R a )2C(R a )2-、-C(R a )2C(R a )2OC(R a )2-、-C(R a )2NR a C(R a )2C(R a )2-、-C(R a )2C(R a )2NR a C(R a )2-、-C(R a )2SC(R a )2C(R a )2-、-C(R a )2C(R a )2SC(R a )2-、-C(R a )2S(O)C(R a )2C(R a )2-、-C(R a )2C(R a )2S(O)C(R a )2-、-C(R a )2SO2C(R a )2C(R a )2-、-C(R a )2C(R a )2SO2C(R a )2-、-C(R a )2SO2NR a C(Ra )2- or -C(R a )2NR a SO2C(R a )2-;

[0131] Z 4 For bonds or -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2NR a CH2-, -CH2SCH2-, -CH2S(O)CH2- or -CH2SO2CH2-;

[0132] Y 1 and Y 2 Each is independently hydrogen or C 1-3 Alkyl, or Y 1 and Y 2 Together with the carbon atoms connected to them, they form a carbon ring or a heterocyclic ring having 3 to 6 ring atoms, wherein the carbon ring or heterocyclic ring is optionally connected by one or more R atoms. a replace;

[0133] R 1 For optionally substituted aryl or optionally substituted heteroaryl; and

[0134] Each R a Independently hydrogen, halogen, hydroxyl or C 1-4 Alkyl, or two of the Rs a The radicals, together with the carbon atoms they are attached to, form =O, and

[0135] At least one of the following: (i)Z 1 and Z 2 or Z 1 and Z 3 Together they form -L-; or (ii)Y 1 and Y 2 Together with the carbon atoms attached to them, they form carbon rings or heterocyclic rings with 3 to 6 ring atoms.

[0136] In another implementation, W is -CHZ 2 -

[0137] In another implementation scheme, Z 1 and Z 2 or Z 1 and Z 3 Together they form -L-.

[0138] In another embodiment, a compound having one of the following formulas (II-A), (II-B), or (II-C) is provided:

[0139]

[0140]

[0141] wherein L is -C(R a )2-, -C(R a )2C(R a )2-, -C(R a )2C(R a )2C(R a )2-, -C(R a )2C(R a )2C(R a )2C(R a )2-, -C(R a )2OC(R a )2-, -C(R a )2NR a C(R a )2-, -C(R a )2SC(R a )2-, -C(R a )2S(O)C(R a )2-, -C(R a )2SO2C(R a )2-, -C(R a )2OC(R a )2C(R a )2-, -C(R a )2C(R a )2OC(R a )2-, -C(R a )2NR a C(R a )2C(R a )2-, -C(R a )2C(R a )2NR a C(R a )2-, -C(R a )2SC(R a )2C(R a )2-, -C(R a )2C(R a )2SC(R a )2-, -C(R a )2S(O)C(R a )2C(R a )2-, -C(R a )2C(R a )2S(O)C(R a )2-, -C(Ra )2SO2C(R a )2C(R a )2-、-C(R a )2C(R a )2SO2C(R a )2-、-C(R a )2SO2NR a C(R a )2- or -C(R a )2NR a SO2C(R a )2-.

[0142] In another implementation scheme, Y 1 and Y 2 Together with the carbon atoms attached to them, they form carbon rings or heterocyclic rings with 3 to 6 ring atoms.

[0143] In another embodiment, a compound having one of the following formulas (III-A), (III-B), (III-C), or (III-D) is provided:

[0144]

[0145]

[0146] Z 1 and Z 3 Each is independently hydrogen or C 1-3 alkyl.

[0147] In another embodiment, a compound having one of the following formulas (III-E), (III-F), (III-G), or (III-H) is provided:

[0148]

[0149]

[0150] Z 1 and Z 3 Each is independently hydrogen or C 1-3 alkyl.

[0151] In another implementation, (i)Z 1 and Z 2 or Z 1 and Z 3 Together they form -L-, and (ii)Y 1 and Y 2 Together with the carbon atoms attached to them, they form carbon rings or heterocyclic rings with 3 to 6 ring atoms.

[0152] In another embodiment, a compound having one of the following formulas is provided: (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), or (IV-AH):

[0153]

[0154]

[0155]

[0156] Where L is -C(R) a )2-、-C(R a )2C(R a )2-、-C(R a )2C(R a )2C(R a )2-、-C(R a )2C(R a )2C(R a )2C(R a )2-、-C(R a )2OC(R a )2-、-C(R a )2NR a C(R a )2-、-C(R a )2SC(R a )2-、-C(R a )2S(O)C(R a )2-、-C(R a )2SO2C(R a )2-、-C(R a )2OC(R a )2C(R a )2-、-C(R a )2C(R a )2OC(R a )2-、-C(R a )2NR a C(R a )2C(R a )2-、-C(R a )2C(R a )2NR a C(R a )2-、-C(R a )2SC(R a )2C(R a )2-、-C(R a)2C(R a )2SC(R a )2-、-C(R a )2S(O)C(R a )2C(R a )2-、-C(R a )2C(R a )2S(O)C(R a )2-、-C(R a )2SO2C(R a )2C(R a )2-、-C(R a )2C(R a )2SO2C(R a )2-、-C(R a )2SO2NR a C(R a )2- or -C(R a )2NR a SO2C(R a )2-.

[0157] In another embodiment, a compound having one of the following formulas is provided: (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), or (IV-BH):

[0158]

[0159]

[0160] Where L is -C(R) a )2-、-C(R a )2C(R a )2-、-C(R a )2C(R a )2C(R a )2-、-C(R a )2C(R a )2C(R a )2C(R a )2-、-C(R a )2OC(R a )2-、-C(R a )2NR a C(R a )2-、-C(R a )2SC(R a )2-、-C(R a )2S(O)C(R a )2-、-C(R a)2SO2C(R a )2-、-C(R a )2OC(R a )2C(R a )2-、-C(R a )2C(R a )2OC(R a )2-、-C(R a )2NR a C(R a )2C(R a )2-、-C(R a )2C(R a )2NR a C(R a )2-、-C(R a )2SC(R a )2C(R a )2-、-C(R a )2C(R a )2SC(R a )2-、-C(R a )2S(O)C(R a )2C(R a )2-、-C(R a )2C(R a )2S(O)C(R a )2-、-C(R a )2SO2C(R a )2C(R a )2-、-C(R a )2C(R a )2SO2C(R a )2-、-C(R a )2SO2NR a C(R a )2- or -C(R a )2NR a SO2C(R a )2-.

[0161] In another implementation, L is -C(R) a )2-、-C(R a )2C(R a )2-、-C(R a )2C(R a )2C(R a )2- or -C(R a )2C(R a )2C(R a )2C(R a)2-. In a further embodiment, L is -C(R) a )2-. In yet another further implementation, L is -C(R) a )2C(R a )2-. In yet another further implementation, L is -C(R) a )2C(R a )2C(R a )2-. In yet another further implementation, each R a For hydrogen. In yet another further embodiment, an R a It is methyl and each of the remaining R a For hydrogen. In yet another further embodiment, an R a It is halogen and each of the remaining R a For hydrogen. In yet another further embodiment, the two R... a It is halogen and each of the remaining R a For hydrogen. In yet another further embodiment, an R a It is halogen and each of the remaining R a It is hydrogen.

[0162] In another implementation, L is -C(R) a )2OC(R a )2-、-C(R a )2NR a C(R a )2-、-C(R a )2SC(R a )2-、-C(R a )2S(O)C(R a )2- or -C(R a )2SO2C(R a )2-. In a further embodiment, L is -C(R) a )2OC(R a )2-. In yet another further implementation, each R a For hydrogen. In yet another further embodiment, an R a It is methyl and each of the remaining R a For hydrogen. In yet another further embodiment, an R a It is halogen and each of the remaining R a For hydrogen. In yet another further embodiment, the two R... a It is halogen and each of the remaining R a For hydrogen. In yet another further embodiment, an R a It is halogen and each of the remaining R a It is hydrogen.

[0163] In another implementation, X is -O-. In a further implementation, Z 2 X is hydrogen. In another embodiment, X is -NZ. 3 - In another embodiment, X is -NH-. In another embodiment, X is -CHZ. 3 - In another implementation, X is -CH2-.

[0164] In another implementation scheme, Z 4 For the key or -CH2-. In another implementation, Z 4 For -CH2-. In another implementation, Z 4 For key.

[0165] In another implementation scheme, Y 1 and Y 2 Each can be independently hydrogen, methyl, or trifluoromethyl.

[0166] In another implementation, R 1 It is replaced by a halogen. In a further embodiment, R 1 It is 4-fluorophenyl or 2-fluorophenyl.

[0167] In another implementation, R 1 It is phenyl. In another embodiment, R 1 It is pyridyl.

[0168] In another implementation, R 1 It is replaced by at least one halogen.

[0169] In another implementation, R 1 It is replaced by a halogen. In a further embodiment, R 1 It is 4-fluorophenyl or 2-fluorophenyl.

[0170] In another implementation, R 1 It is replaced by two halogens. In a further embodiment, R 1 It is 2,4-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 3-fluoro-4-chlorophenyl, 3,4-difluorophenyl, 2-fluoro-4-chlorophenyl, or 3,5-difluorophenyl. In yet another further embodiment, R 1 It is 2,4-difluorophenyl.

[0171] In another implementation, R 1 It is replaced by three halogens. In a further implementation, R 1It is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl. In yet another further embodiment, R 1 It is 2,4,6-trifluorophenyl.

[0172] In another implementation, R 1 It is 3-trifluoromethyl-4-fluorophenyl or 2-cyclopropyl-4-fluorophenyl.

[0173] In one embodiment, a pharmaceutical composition is provided comprising a compound of any one of the formulas (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH) as described above, or a stereoisomer or pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0174] Another embodiment is provided, which includes a method of treating a person who is infected or at risk of being infected with HIV by administering to a person a therapeutically effective amount of a compound or a pharmaceutical composition thereof of any one of the formulas (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH) as described above. Another embodiment is provided, which includes a method of treating or preventing HIV infection in a person who is infected or at risk of infection by administering to a person a therapeutically effective amount of a compound or a pharmaceutical composition thereof of any one of the formulas (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH) as described above.

[0175] In another embodiment, a compound or pharmaceutical composition thereof of any one of the formulas (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH) as described above is provided for the treatment of HIV infection in persons who are infected or at risk of being infected. In another embodiment, a compound or pharmaceutical composition thereof of any one of the formulas (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH) is provided for the treatment or prevention of HIV infection in persons who are infected or at risk of being infected.

[0176] In another embodiment, the use of any of the formulas (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH) or pharmaceutical compositions thereof as described above in medical treatment is provided.

[0177] In another embodiment, a compound or pharmaceutical composition thereof of any one of the formulas (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH) as described above is provided for the therapeutic treatment of HIV infection. In another embodiment, any of the formulas (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH) or pharmaceutical compositions thereof described above are provided for use in the preventive or therapeutic treatment of HIV infection.

[0178] It should be understood that any embodiment of the compounds of formulas (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH) as described above The schemes, and the R in the compounds of formulas (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH) as described above. 1 R a X, W, Y 1 Y 2 L, Z 1 Z 2 Z 3 or Z 4 Any specific substituent described in the group may be independently combined with substituents of other embodiments and / or compounds of formulas (I), (II-A), (II-B), (II-C), (III-A), (III-B), (III-C), (III-D), (III-E), (III-F), (III-G), (III-H), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH) to form embodiments of the invention not specifically as described above. Additionally, in specific embodiments and / or claims, for any specific R... 1 R a X, W, Y 1 Y 2 L, Z 1 Z 2 Z3 or Z 4 In the case of the list of substituents, it should be understood that each individual substituent may be removed from a particular embodiment and / or claim and the remaining list of substituents is considered to be within the scope of the invention.

[0179] As will be understood by those skilled in the art, compounds of formulas (I), (II-A), (II-B), (II-C), (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), (IV-AH), (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), and (IV-BH), wherein Z 1 and Z 2 or Z 1 and Z 3 Together they form -L-, which can be displayed in several different ways. For example, compound 3 of Example 3 can be displayed as:

[0180]

[0181] Pharmaceutical Composition

[0182] For administration purposes, in some embodiments, the compounds described herein are administered as raw material chemicals or formulated into pharmaceutical compositions. The pharmaceutical compositions disclosed herein comprise compounds of formula (I) and one or more of the following: pharmaceutically acceptable carriers, diluents, or excipients. The compound of formula (I) is present in the composition in an amount sufficient to effectively treat a particular disease or condition of interest. The activity of the compound of formula (I) can be determined by those skilled in the art, for example, as described below. Suitable concentrations and dosages can be readily determined by those skilled in the art. In some embodiments, the compound of formula (I) is present in the pharmaceutical composition in an amount from about 25 mg to about 500 mg. In some embodiments, the compound of formula (I) is present in the pharmaceutical composition in an amount from about 100 mg to about 300 mg. In some embodiments, the compound of formula (I) is present in the pharmaceutical composition in amounts of about 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, or about 500 mg.

[0183] The compounds of the present invention, or pharmaceutically acceptable salts thereof, are administered in their pure form or in suitable pharmaceutical compositions via any route of administration acceptable for use as a reagent for similar purposes. Pharmaceutical compositions of the present invention are prepared by mixing the compounds of the present invention with suitable pharmaceutically acceptable carriers, diluents, or excipients, and in certain embodiments, are formulated into formulations in solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalers, gels, microspheres, and aerosols. Exemplary routes of administration for such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal routes. Pharmaceutical compositions of the present invention are formulated to allow the active ingredients contained therein to be bioavailable when the composition is administered to a patient. Compositions administered to subjects or patients are in the form of one or more dose units, wherein, for example, tablets may be a single dose unit, and containers of compounds of the present invention in aerosol form may contain multiple dose units. Practical methods for preparing such dosage forms are known or obvious to those skilled in the art, for example, see Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). In any case, the composition to be administered contains a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof for the treatment of a disease or condition of interest in accordance with the teachings described herein.

[0184] The pharmaceutical compositions disclosed herein are prepared by methods well known in the pharmaceutical field. For example, in some embodiments, the pharmaceutical composition intended for injection is prepared by mixing the compound of the present invention with sterile distilled water to form a solution. In some embodiments, a surfactant is added to promote the formation of a homogeneous solution or suspension. The surfactant is a compound that non-covalently interacts with the compound of the present invention to promote the dissolution or homogeneous suspension of the compound in an aqueous delivery system.

[0185] The compounds of the present invention or their pharmaceutically acceptable salts are administered in therapeutically effective amounts, which will vary depending on a variety of factors, including the activity of the specific compound used; the metabolic stability and duration of action of the compound; the patient's age, weight, general health status, sex, and diet; the route and timing of administration; the rate of excretion; the combination of drugs; the severity of the specific disorder or condition; and the treatment the subject is currently undergoing.

[0186] Combination therapy

[0187] In one embodiment, a method for treating or preventing HIV infection in a person who is infected or at risk of infection is provided, comprising administering to the person a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more other therapeutic agents.

[0188] In one embodiment, a pharmaceutical composition is provided comprising the compounds disclosed herein, pharmaceutically acceptable salts thereof, in combination with one or more other therapeutic agents, and pharmaceutically acceptable carriers, diluents, or excipients.

[0189] In one embodiment, a pharmaceutical preparation is provided, comprising a combination of the compounds disclosed herein or their pharmaceutically acceptable salts with one or more other therapeutic agents.

[0190] In the above embodiments, the additional therapeutic agent may be an anti-HIV agent. For example, in some embodiments, the additional therapeutic agent is selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, entry inhibitors (e.g., CCR5 inhibitors, gp41 inhibitors (i.e., fusion inhibitors), and CD4 linker inhibitors), CXCR4 inhibitors, gp120 inhibitors, G6PD and NADH-oxidase inhibitors, compounds that target the HIV shell (“shell inhibitors”; such as shell polymerization inhibitors or shell-disrupting compounds, such as those disclosed in WO 2013 / 006738 (Gilead Sciences), US 2013 / 0165489 (University of Pennsylvania), and WO 2013 / 006792 (Pharma Resources), pharmacokinetic enhancers, and other medicines for the treatment of HIV, and combinations thereof. In a further embodiment, the additional therapeutic agent is selected from one or more of the following;

[0191] (1) HIV protease inhibitors selected from Ampravir, Atazanavir, Fosanavir, Indinavir, Lopinavir, Ritonavir, Neferunavir, Saquinavir, Tiranavir, Brennavir, Darunavir, TMC-126, TMC-114, Mozenavir (DMP-450), JE-2147 (AG1776), L-756423, RO0334649, KNI-272, DPC-681, DPC-684, GW640385X, DG17, PPL-100, DG35 and AG 1859;

[0192] (2) HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, selected from capvirine, emivirine, delaviridine, efavirenz, nevirapine, (+)calanolide A, ectavirine, GW5634, DPC-083, DPC-961, DPC-963, MIV-150, TMC-120, rilpivirene, BILR 355BS, VRX 840773, lesivirine (UK-453061), RDEA806, KM023 and MK-1439;

[0193] (3) HIV nucleoside inhibitors of reverse transcriptase, selected from zidovudine, emtricitabine, doxorinosine, stavudine, zalcitabine, lamivudine, abacavir, amdoxovir, avtabin, allovudine, MIV-210, ±-FTC, D-d4FC, emtricitabine, phosphatidylcholine, fozivudine tidoxil, apricotibine (AVX754), KP-1461, GS-9131 (Gilead Sciences) and fozivudine tidoxil (formerly HDP 99.0003);

[0194] (4) HIV nucleotide inhibitors of reverse transcriptase, selected from tenofovir, tenofovir alafenamide fumarate, tenofovir alafenamide fumarate (Gilead Sciences), GS-7340 (Gilead Sciences), GS-9148 (Gilead Sciences), adefovir, adefovir dipivoxil, CMX-001 (Chimerix) or CMX-157 (Chimerix);

[0195] (5) HIV integrase inhibitors selected from curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, quinoyl tricarboxylic acid, quinoyl tricarboxylic acid derivatives, phenethyl caffeate, phenethyl caffeate derivatives, tyrphostin, tyrphostin derivatives, quercetin, quercetin derivatives, S-1360, AR-177, L-870812, and L-870810, raltegravir, BMS-538158, GSK364735C, BMS-707035, MK-2048, BA 011, elvitegravir, dolutegravir, and GSK-744;

[0196] (6) HIV non-catalytic site or allosteric integrase inhibitors (NCINIs), including but not limited to: BI-224436, CX0516, CX05045, CX14442, and compounds disclosed in WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO2013 / 159064 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO2012 / 003497 (Gilead Sciences), and WO 2012 / 003498 (Gilead Sciences), the entire contents of each of which are incorporated herein by reference.

[0197] (7) gp41 inhibitors, selected from enfuvirtide, sifuvirtide, albuvirtide, FB006M and TRI-1144;

[0198] (8) CXCR4 inhibitor AMD-070;

[0199] (9) Entering the inhibitor SP01A;

[0200] (10) gp120 inhibitor BMS-488043;

[0201] (11) G6PD and NADH-oxidase inhibitor immunoitin;

[0202] (12) CCR5 inhibitors selected from alaviroc, vicriviroc, maraviroc, cenicriviroc, PRO-140, INCB15050, PF-232798 (Pfizer) and CCR5mAb004.

[0203] (13) CD4 linker inhibitors, selected from ibacillinumab (TMB-355) and BMS-068 (BMS-663068);

[0204] (14) Pharmacokinetic enhancers selected from cobicistat and SPI-452; and

[0205] (15) Other drugs used to treat HIV, selected from: BAS-100, SPI-452, REP 9, SP-01A, TNX-355, DES6, ODN-93, ODN-112, VGV-1, PA-457 (bevirimat), HRG214, VGX-410, KD-247, AMZ 0026, CYT99007A-221HIV, DEBIO-025, BAY 50-4798, MDX010 (ipilimumab), PBS 119, ALG 889 and PA-1050040 (PA-040),

[0206] and their combinations.

[0207] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with two, three, four, or more additional therapeutic agents. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with two additional therapeutic agents. In other embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with three additional therapeutic agents. In a further embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with four additional therapeutic agents. The two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, or they may be selected from different classes of therapeutic agents. In one particular embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with HIV nucleotide inhibitors and HIV non-nucleoside inhibitors of reverse transcriptase. In another particular embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with HIV nucleotide inhibitors, HIV non-nucleoside inhibitors, and HIV protease inhibitors of reverse transcriptase. In a further embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with HIV nucleotide inhibitors, HIV non-nucleoside inhibitors, and HIV protease inhibitors of reverse transcriptase. In another embodiment, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with HIV nucleotide inhibitors of reverse transcriptase, HIV non-nucleoside inhibitors of reverse transcriptase, and pharmacokinetic enhancers.

[0208] In some embodiments, when the compounds disclosed herein are combined with one or more additional therapeutic agents as described above, the components of the composition are administered simultaneously or sequentially. When administered sequentially, the combination may be administered in two or more doses.

[0209] In some embodiments, the compounds disclosed herein are combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, such as a solid dosage form for oral administration.

[0210] In some embodiments, the compounds disclosed herein are administered with one or more additional therapeutic agents. Co-administration of the compounds disclosed herein with one or more additional therapeutic agents generally refers to the simultaneous or sequential administration of the compounds disclosed herein and one or more additional therapeutic agents such that therapeutically effective amounts of the compounds disclosed herein and one or more additional therapeutic agents are both present in the patient.

[0211] Co-administration includes administering a unit dose of the compound disclosed herein before or after administering a unit dose of one or more other therapeutic agents, for example, within seconds, minutes, or hours after administering one or more other therapeutic agents. For example, in some embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one or more other therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein within seconds or minutes. In some embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one or more other therapeutic agents after a period of several hours (e.g., 1-12 hours). In other embodiments, a unit dose of one or more other therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein after a period of several hours (e.g., 1-12 hours).

[0212] The following examples illustrate the preparation method of the compound of the present invention (i.e., the compound of formula (I)):

[0213]

[0214] Where R 1 X, W, Y 1 Y 2 Z 1 Z 2 or Z 4 As defined above. Those skilled in the art will understand that these compounds may be prepared by similar methods or by combining other methods known to them. Those skilled in the art will also understand that compounds of other formulas (I) not explicitly stated below can be prepared by using suitable starting components and adjusting synthetic parameters as needed, in a similar manner as described below. Typically, the starting components may be obtained from sources such as Sigma-Aldrich, Lancaster Synthesis, Inc., Maybridge, Matrix Scientific, TCI, and Fluorochem USA, or synthesized from sources known to them (see, for example, Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, 5th Edition (Wiley, December 2000)) or prepared as described herein.

[0215] For illustrative purposes only, the present invention includes, but is not limited to, the following technical solutions:

[0216] Technical solution 1. A compound having the following formula (I):

[0217]

[0218] Or its stereoisomers or medicinal salts.

[0219] in:

[0220] X is either -O- or -NZ 3 -or-CHZ 3 -;

[0221] W is -CHZ 2 -;

[0222] Z 1 Z 2 and Z 3 Each is independently hydrogen or C 1-3 Alkyl, or Z 1 and Z 2 or Z 1 and Z 3 They combine to form -L-, where L is -C(R) a )2-、-C(R a )2C(R a )2-、-C(R a )2C(R a )2C(R a )2-、or -C(R a )2C(R a )2C(R a )2C(R a )2-, where Z 1 and Z 2 or Z 1 and Z 3 At least one of them together forms -L-;

[0223] Z 4 For bonds, -CH2- or -CH2CH2-;

[0224] Y 1 and Y 2 Each independently is hydrogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl groups;

[0225] R 1 A phenyl group substituted with one to three halogens; and

[0226] Each R a Independently hydrogen, halogen, hydroxyl or C 1-4 alkyl.

[0227] Technical Solution 2. The compound of Technical Solution 1 has the following formula (II-A):

[0228]

[0229] Technical Solution 3. The compound of Technical Solution 1 has the following formula (II-B):

[0230]

[0231] Technical Solution 4. The compound of Technical Solution 1 has the following formula (II-c):

[0232]

[0233] Technical Solution 5. A compound of any one of Technical Solutions 1-4, wherein L is -C(R a )2-.

[0234] Technical Solution 6. A compound of any one of Technical Solutions 1-4, wherein L is -C(R a )2C(R a )2-.

[0235] Technical Solution 7. A compound of any one of Technical Solutions 1-4, wherein L is -C(R a )2C(R a )2C(R a )2-.

[0236] Technical solution 8. A compound of any one of technical solutions 1-7, wherein each R a It is hydrogen.

[0237] Technical Solution 9. A compound of any one of Technical Solutions 1-7, wherein one of the R... a It is methyl and each of the remaining R a It is hydrogen.

[0238] Technical Solution 10. A compound of any one of Technical Solutions 1-7, wherein at least one R a It is halogen and each of the remaining R a It is hydrogen.

[0239] Technical Solution 11. A compound of any one of Technical Solutions 1-7, wherein two R... a It is halogen and each of the remaining R a It is hydrogen.

[0240] Technical Solution 12. A compound of any one of Technical Solutions 1-7, wherein one of the R a It is halogen and each of the remaining R a It is hydrogen.

[0241] Technical solution 13. A compound of any one of technical solutions 1-2 or 5-12, wherein X is -O-.

[0242] Technical Solution 14. A compound of any one of Technical Solutions 1-2 or 5-12, wherein X is -NZ 3 -

[0243] Technical Solution 15. A compound of any one of Technical Solutions 1-2 or 5-12, wherein X is -NH-.

[0244] Technical Solution 16. A compound of any one of Technical Solutions 1-2 or 5-12, wherein X is -CHZ 3 -and Z 1 and Z 3 Together they form -L-.

[0245] Technical solution 17. The compound of technical solution 16, wherein Z 2 It is hydrogen.

[0246] Technical Solution 18. A compound of any one of Technical Solutions 1-2 or 5-12, wherein X is -CH2-.

[0247] Technical Solution 19. A compound of any one of Technical Solutions 1 or 5-18, wherein Z 4 For the bond or -CH2-.

[0248] Technical solution 20. A compound of any one of technical solutions 1 or 5-18, wherein Z 4 It is -CH2-.

[0249] Technical Solution 21. A compound of any one of Technical Solutions 1 or 5-18, wherein Z 4 For key.

[0250] Technical solution 22. A compound of any one of technical solutions 1 or 5-21, wherein Y 1 and Y 2 Each can be independently hydrogen, methyl, or trifluoromethyl.

[0251] Technical Solution 23. A compound of any one of Technical Solutions 1-22, wherein R 1 It was replaced by a halogen.

[0252] Technical solution 24. The compound of technical solution 23, wherein R 1 It is 4-fluorophenyl or 2-fluorophenyl.

[0253] Technical Solution 25. A compound of any one of Technical Solutions 1-22, wherein R 1 It was replaced by two halogens.

[0254] Technical solution 26. The compound of technical solution 25, wherein R 1 It is 2,4-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 3-fluoro-4-chlorophenyl, 3,4-difluorophenyl, 2-fluoro-4-chlorophenyl, or 3,5-difluorophenyl.

[0255] Technical solution 27. The compound of technical solution 26, wherein R 1 It is 2,4-difluorophenyl.

[0256] Technical solution 28. A compound of any one of technical solutions 1-22, wherein R 1 It was replaced by three halogens.

[0257] Technical solution 29. The compound of technical solution 28, wherein R 1 It is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl.

[0258] Technical solution 30. The compound of technical solution 29, wherein R 1 It is 2,4,6-trifluorophenyl.

[0259] Technical Solution 31. The compound of Technical Solution 1 is selected from:

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267]

[0268]

[0269]

[0270]

[0271]

[0272] Technical Solution 32. The compound of Technical Solution 1, selected from:

[0273]

[0274]

[0275] Technical Solution 33. A pharmaceutical composition comprising a compound or stereoisomer thereof or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, diluent or excipient of any one of Technical Solutions 1-32.

[0276] Technical Solution 34. The pharmaceutical composition of Technical Solution 33 further includes one or more additional therapeutic agents.

[0277] Technical solution 35. The pharmaceutical composition of technical solution 34, wherein the one or more additional therapeutic agents are anti-HIV agents.

[0278] Technical Solution 36. The pharmaceutical composition of Technical Solution 35, wherein the one or more additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, and combinations thereof.

[0279] Technical Solution 37. A method for treating HIV infection in a person who is infected or at risk of infection, wherein the person is given a therapeutically effective amount of a compound of any one of Technical Solutions 1-32 or a pharmaceutical composition of Technical Solution 33.

[0280] Technical solution 38. The method of technical solution 37 further includes administering a therapeutically effective amount of one or more other therapeutic agents to the person.

[0281] Technical solution 39. The method of technical solution 38, wherein the one or more additional therapeutic agents are anti-HIV agents.

[0282] Technical Solution 40. The method of Technical Solution 39, wherein the one or more additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, and combinations thereof.

[0283] Technical Solution 41. The use of any compound of any one of Technical Solutions 1-32 or the pharmaceutical composition of Technical Solution 33 for treating HIV infection in a person who is infected or at risk of being infected.

[0284] Technical solution 42. The use of technical solution 41 further includes administering a therapeutically effective amount of one or more other therapeutic agents to the person.

[0285] Technical solution 43. Use of technical solution 42, wherein the one or more additional therapeutic agents are anti-HIV agents.

[0286] Technical Solution 44. Use of Technical Solution 43, wherein the one or more additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, and combinations thereof.

[0287] Technical Solution 45. The compound or its pharmaceutically acceptable salt as described in any one of Technical Solutions 1-32, for use in medical treatment.

[0288] Technical Solution 46. The compound or its pharmaceutically acceptable salt as described in any one of Technical Solutions 1-32, for the therapeutic treatment of HIV infection.

[0289] Technical solution 47. A compound having the following formula (I):

[0290]

[0291] Or its stereoisomers or medicinal salts.

[0292] in:

[0293] X is either -O- or -NZ 3 -or-CHZ 3 -;

[0294] W is either -O- or -NZ 2 -or-CHZ 2 -;

[0295] Z 1 Z 2 and Z 3 Each is independently hydrogen or C 1-3 Alkyl, or Z 1 and Z 2 or Z 1 and Z 3 They combine to form -L-, where L is -C(R) a )2-、-C(R a )2C(R a )2-、-C(R a )2C(R a )2C(R a )2-、-C(R a )2C(R a )2C(R a )2C(R a )2-、-C(R a )2OC(R a )2-、-C(R a )2NR a C(R a )2-、-C(R a)2SC(R a )2-、-C(R a )2S(O)C(R a )2-、-C(R a )2SO2C(R a )2-、-C(R a )2OC(R a )2C(R a )2-、-C(R a )2C(R a )2OC(R a )2-、-C(R a )2NR a C(R a )2C(R a )2-、-C(R a )2C(R a )2NR a C(R a )2-、-C(R a )2SC(R a )2C(R a )2-、-C(R a )2C(R a )2SC(R a )2-、-C(R a )2S(O)C(R a )2C(R a )2-、-C(R a )2C(R a )2S(O)C(R a )2-、-C(R a )2SO2C(R a )2C(R a )2-、-C(R a )2C(R a )2SO2C(R a )2-、-C(R a )2SO2NR a C(R a )2- or -C(R a )2NR a SO2C(R a )2-;

[0296] Z 4 For bonds or -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2OCH2-, -CH2NR a CH2-, -CH2SCH2-, -CH2S(O)CH2- or -CH2SO2CH2-;

[0297] Y 1 and Y 2 Each independently is hydrogen, C 1-3 Alkyl or C 1-3 Halogenated alkyl, or Y 1 and Y 2 Together with the carbon atoms connected to them, they form a carbon ring or a heterocyclic ring having 3 to 6 ring atoms, wherein the carbon ring or heterocyclic ring is optionally connected by one or more R atoms. a replace;

[0298] R 1 For optionally substituted aryl or optionally substituted heteroaryl; and

[0299] Each R a Independently hydrogen, halogen, hydroxyl or C 1-4 Alkyl, or two of the Rs a The radicals, together with the carbon atoms they are attached to, form C=O, and

[0300] At least one of the following: (i)Z 1 and Z 2 or Z 1 and Z 3 Together they form -L-; or (ii)Y 1 and Y 2 Together with the carbon atoms attached to them, they form carbon rings or heterocyclic rings with 3 to 6 ring atoms.

[0301] Technical solution 48. The compound of technical solution 47, wherein W is -CHZ 2 -

[0302] Technical solution 49. The compound of technical solution 47 or 48, wherein Z 1 and Z 2 or Z 1 and Z 3 Together they form -L-.

[0303] Technical solution 50. The compound of technical solution 49 has one of the following formulas (II-A), (II-B) or (II-C):

[0304]

[0305] Where L is -C(R) a )2-、-C(R a )2C(R a )2-、-C(R a )2C(R a )2C(R a )2-、-C(R a )2C(Ra )₂C(R a )₂C(R a )₂-, -C(R a )₂OC(R a )₂-, -C(R a )₂NR a C(R a )₂-, -C(R a )₂SC(R a )₂-, -C(R a )₂S(O)C(R a )₂-, -C(R a )₂SO₂C(R a )₂-, -C(R a )₂OC(R a )₂C(R a )₂-, -C(R a )₂C(R a )₂OC(R a )₂-, -C(R a )₂NR a C(R a )₂C(R a )₂-, -C(R a )₂C(R a )₂NR a C(R a )₂-, -C(R a )₂SC(R a )₂C(R a )₂-, -C(R a )₂C(R a )₂SC(R a )₂-, -C(R a )₂S(O)C(R a )₂C(R a )₂-, -C(R a )₂C(R a )₂S(O)C(R a )₂-, -C(R a )₂SO₂C(R a )₂C(R a )₂-, -C(R a )₂C(R a )₂SO₂C(R a )₂-, -C(R a )₂SO₂NR a C(R a )₂- or -C(R a )₂NR a SO₂C(R a)2-.

[0306] Technical solution 51. The compound of technical solution 47 or 48, wherein Y 1 and Y 2 Together with the carbon atoms attached to them, they form carbon rings or heterocyclic rings with 3 to 6 ring atoms.

[0307] Technical solution 52. The compound of technical solution 51, having one of the following formulas (III-A), (III-B), (III-C) or (III-D):

[0308]

[0309] Z 1 and Z 3 Each is independently hydrogen or C 1-3 alkyl.

[0310] Technical solution 53. The compound of technical solution 51 has one of the following formulas: (III-E), (III-F), (III-G) or (III-H):

[0311]

[0312] Z 1 and Z 3 Each is independently hydrogen or C 1-3 alkyl.

[0313] Technical solution 54. The compound of technical solution 47 or 48, wherein (i) Z 1 and Z 2 or Z 1 and Z 3 Together they form -L-, and (ii)Y 1 and Y 2 Together with the carbon atoms attached to them, they form carbon rings or heterocyclic rings with 3 to 6 ring atoms.

[0314] Technical Solution 55. The compound of Technical Solution 54 has one of the following formulas: (IV-AA), (IV-AB), (IV-AC), (IV-AD), (IV-AE), (IV-AF), (IV-AG), or (IV-AH):

[0315]

[0316]

[0317] Where L is -C(R) a )2-、-C(R a )2C(R a)2-、-C(R a )2C(R a )2C(R a )2-、-C(R a )2C(R a )2C(R a )2C(R a )2-、-C(R a )2OC(R a )2-、-C(R a )2NR a C(R a )2-、-C(R a )2SC(R a )2-、-C(R a )2S(O)C(R a )2-、-C(R a )2SO2C(R a )2-、-C(R a )2OC(R a )2C(R a )2-、-C(R a )2C(R a )2OC(R a )2-、-C(R a )2NR a C(R a )2C(R a )2-、-C(R a )2C(R a )2NR a C(R a )2-、-C(R a )2SC(R a )2C(R a )2-、-C(R a )2C(R a )2SC(R a )2-、-C(R a )2S(O)C(R a )2C(R a )2-、-C(R a )2C(R a )2S(O)C(R a )2-、-C(R a )2SO2C(R a )2C(R a )2-、-C(R a )2C(R a )2SO2C(R a )2-、-C(R a )2SO2NRa C(R a )2- or -C(R a )2NR a SO2C(R a )2-.

[0318] Technical Solution 56. The compound of Technical Solution 54 has one of the following formulas: (IV-BA), (IV-BB), (IV-BC), (IV-BD), (IV-BE), (IV-BF), (IV-BG), or (IV-BH):

[0319]

[0320]

[0321]

[0322] Where L is -C(R) a )2-、-C(R a )2C(R a )2-、-C(R a )2C(R a )2C(R a )2-、-C(R a )2C(R a )2C(R a )2C(R a )2-、-C(R a )2OC(R a )2-、-C(R a )2NR a C(R a )2-、-C(R a )2SC(R a )2-、-C(R a )2S(O)C(R a )2-、-C(R a )2SO2C(R a )2-、-C(R a )2OC(R a )2C(R a )2-、-C(R a )2C(R a )2OC(R a )2-、-C(R a )2NR a C(R a )2C(R a )2-、-C(R a )2C(R a )2NR aC(R a )2-、-C(R a )2SC(R a )2C(R a )2-、-C(R a )2C(R a )2SC(R a )2-、-C(R a )2S(O)C(R a )2C(R a )2-、-C(R a )2C(R a )2S(O)C(R a )2-、-C(R a )2SO2C(R a )2C(R a )2-、-C(R a )2C(R a )2SO2C(R a )2-、-C(R a )2SO2NR a C(R a )2- or -C(R a )2NR a SO2C(R a )2-.

[0323] Technical solution 57. A compound of any one of technical solutions 47-50 or 54-56, wherein L is -C(R a )2-、-C(R a )2C(R a )2-、-C(R a )2C(R a )2C(R a )2- or -C(R a )2C(R a )2C(R a )2C(R a )2-.

[0324] Technical solution 58. The compound of technical solution 57, wherein L is -C(R a )2-.

[0325] Technical solution 59. The compound of technical solution 57, wherein L is -C(R a )2C(R a )2-.

[0326] Technical solution 60. The compound of technical solution 57, wherein L is -C(R a )2C(R a )2C(R a)2-.

[0327] Technical solution 61. A compound of any one of technical solutions 47-50 or 54-60, wherein each R a It is hydrogen.

[0328] Technical solution 62. A compound of any one of technical solutions 47-50 or 54-60, wherein one of the R a It is methyl and each of the remaining R a It is hydrogen.

[0329] Technical solution 63. A compound of any one of technical solutions 47-50 or 54-60, wherein at least one R a It is halogen and each of the remaining R a It is hydrogen.

[0330] Technical solution 64. A compound of any one of technical solutions 47-50 or 54-60, wherein two R a It is halogen and each of the remaining R a It is hydrogen.

[0331] Technical solution 65. A compound of any one of technical solutions 47-50 or 54-60, wherein one of the R a It is halogen and each of the remaining R a It is hydrogen.

[0332] Technical solution 66. A compound of any one of technical solutions 47-50 or 54-56, wherein L is -C(R a )2OC(R a )2-、-C(R a )2NR a C(R a )2-、-C(R a )2SC(R a )2-、-C(R a )2S(O)C(R a )2- or -C(R a )2SO2C(R a )2-.

[0333] Technical solution 67. A compound of any one of technical solutions 47-50 or 54-56, wherein L is -C(R a )2OC(R a )2-.

[0334] Technical solution 68. The compound of technical solution 66 or 67, wherein each R a It is hydrogen.

[0335] Technical solution 69. The compound of technical solution 66 or 67, wherein one of R aIt is methyl and each of the remaining R a It is hydrogen.

[0336] Compounds of technical solutions 70, 66, or 67, wherein at least one R a It is halogen and each of the remaining R a It is hydrogen.

[0337] Technical solution 71. The compound of technical solution 66 or 67, wherein two R a It is halogen and each of the remaining R a It is hydrogen.

[0338] Technical solution 72. The compound of technical solution 66 or 67, wherein one of R a It is halogen and each of the remaining R a It is hydrogen.

[0339] Technical solution 73. A compound of any one of technical solutions 47-55 or 57-72, wherein X is -O-.

[0340] Technical solution 74. The compound of technical solution 73, wherein Z 2 It is hydrogen.

[0341] Technical solution 75. A compound of any one of technical solutions 47-72, wherein X is -NZ 3 -

[0342] Technical solution 76. A compound of any one of technical solutions 47-72, wherein X is -NH-.

[0343] Technical solution 77. A compound of any one of technical solutions 47-55 or 57-72, wherein X is -CHZ 3 -

[0344] Technical solution 78. A compound of any one of technical solutions 47-55 or 57-72, wherein X is -CH2-.

[0345] Technical solution 79. A compound of any one of technical solutions 47-49, 51, 54 or 57-78, wherein Z 4 For the bond or -CH2-.

[0346] Technical solution 80. A compound of any one of technical solutions 47-49, 51, 54 or 57-78, wherein Z 4 It is -CH2-.

[0347] Technical solution 81. A compound of any one of technical solutions 47-49, 51, 54 or 57-78, wherein Z 4 For key.

[0348] Technical solution 82. A compound of any one of technical solutions 47-49 or 57-81, wherein Y 1 and Y 2 Each can be independently hydrogen, methyl, or trifluoromethyl.

[0349] Technical solution 83. A compound of any one of technical solutions 47-82, wherein R 1 It is a phenyl group.

[0350] Technical solution 84. A compound of any one of technical solutions 47-82, wherein R 1 It is pyridyl.

[0351] Technical solution 85. A compound of any one of technical solutions 47-84, wherein R 1 It is replaced by at least one halogen.

[0352] Technical solution 86. A compound of any one of technical solutions 47-84, wherein R 1 It was replaced by a halogen.

[0353] Technical solution 87. The compound of technical solution 86, wherein R 1 It is 4-fluorophenyl or 2-fluorophenyl.

[0354] Technical solution 88. A compound of any one of technical solutions 47-84, wherein R 1 It was replaced by two halogens.

[0355] Technical solution 89. The compound of technical solution 88, wherein R 1 It is 2,4-difluorophenyl, 2,3-difluorophenyl, 2,6-difluorophenyl, 3-fluoro-4-chlorophenyl, 3,4-difluorophenyl, 2-fluoro-4-chlorophenyl, or 3,5-difluorophenyl.

[0356] Compounds of technical solution 90 and technical solution 89, wherein R 1 It is 2,4-difluorophenyl.

[0357] Technical solution 91. A compound of any one of technical solutions 47-84, wherein R 1 It was replaced by three halogens.

[0358] Technical solution 92. The compound of technical solution 91, wherein R 1 It is 2,4,6-trifluorophenyl or 2,3,4-trifluorophenyl.

[0359] Technical solution 93. The compound of technical solution 92, wherein R 1 It is 2,4,6-trifluorophenyl.

[0360] Compounds of technical solution 94 and technical solution 85, wherein R1 It is 3-trifluoromethyl-4-fluorophenyl or 2-cyclopropoxy-4-fluorophenyl.

[0361] Technical Solution 95. A pharmaceutical composition comprising a compound or stereoisomer thereof or a pharmaceutically acceptable salt and a pharmaceutically acceptable carrier, diluent or excipient of any one of Technical Solutions 47-94.

[0362] Technical solution 96. The pharmaceutical composition of technical solution 95 further includes one or more additional therapeutic agents.

[0363] Technical Solution 97. The pharmaceutical composition of Technical Solution 96, wherein one or more additional therapeutic agents are anti-HIV agents.

[0364] Technical Solution 98. The pharmaceutical composition of Technical Solution 97, wherein the one or more additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, and combinations thereof.

[0365] Technical Solution 99. A method for treating HIV infection in a person who is infected or at risk of infection, comprising administering to the person a therapeutically effective amount of a compound of any one of Technical Solutions 47-94 or a pharmaceutical composition of Technical Solution 95.

[0366] The method of technical solution 100 and technical solution 99 further includes administering a therapeutically effective amount of one or more other therapeutic agents to the person.

[0367] Technical solution 101. The method of technical solution 100, wherein the one or more additional therapeutic agents are anti-HIV agents.

[0368] Technical Solution 102. The method of Technical Solution 101, wherein the one or more additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, and other drugs for treating HIV, and combinations thereof.

[0369] The use of any compound of any one of technical solutions 47-94 or the pharmaceutical composition of technical solution 95 for treating HIV infection in a person who is infected or at risk of being infected.

[0370] Technical solution 104. The use of technical solution 103 further includes administering a therapeutically effective amount of one or more other therapeutic agents to the person.

[0371] Technical solution 105. Use of technical solution 104, wherein the one or more additional therapeutic agents are anti-HIV agents.

[0372] Technical solution 106. Use of technical solution 105, wherein the one or more additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside inhibitors of reverse transcriptase, HIV nucleotide inhibitors of reverse transcriptase, and other drugs for treating HIV, and combinations thereof.

[0373] Technical solution 107. The compound or its pharmaceutically acceptable salt as described in any one of technical solutions 47-94, for use in medical treatment.

[0374] Technical Solution 108. The compound or its pharmaceutically acceptable salt as described in any one of Technical Solutions 47-94, for the therapeutic treatment of HIV infection.

[0375] The following embodiments are provided for illustrative purposes and not for limitation. Example

[0376] General synthesis scheme

[0377] Schemes 1-3 are provided as further embodiments of the present invention, and examples illustrate general methods for preparing compounds having formula (I) and for preparing other compounds having formula (I).

[0378] Option 1

[0379]

[0380] A1 can be converted to amide A2 using a suitable amine and coupling agent such as HATU or EDCI. A2 can be converted to A3 using a strong acid such as methanesulfonic acid. A3 can be converted to A5 or A4 by heating with a suitable cyclic diamine or cyclic amino alcohol, followed by demethylation with a reagent such as magnesium bromide.

[0381] Alternatively, A1 can be converted to A6 by treatment with a strong acid such as methanesulfonic acid. A6 can then be condensed with a suitable cyclic diamine or cyclic amino alcohol, followed by methyl deprotection with a reagent such as magnesium bromide to form A7 or A8, respectively. A7 or A8 can be converted to amides A5 and A4 by treatment with a suitable amine and coupling agent such as HATU or EDCI, followed by methyl deprotection with a reagent such as magnesium bromide. Scheme 2

[0382]

[0383] B1 (as described in WO2012 / 018065) ​​is condensed with a diamine under reflux to give B2. B2 is hydrolyzed and coupled to an amine by an amide formation method, and product B3 is obtained when the benzyl protecting group is removed.

[0384] Representative compounds

[0385] Example 1

[0386] Preparation of Compound 1

[0387] N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0388]

[0389] Step 1

[0390] Will

[0391] 1-(2,2-Dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1-A, 0.300 g, 0.95 mmol), prepared as described in WO2011 / 119566A1, was evaporated once from anhydrous toluene, suspended in acetonitrile (4 mL), and treated with N,N-diisopropylethylamine (DIPEA) (0.329 mL, 1.90 mmol), 2,4-difluoroaniline (0.125 mL, 1.05 mmol), and HATU (0.433 g, 1.14 mmol). The reaction mixture was stirred for 10 minutes and concentrated. The residue was purified by rapid chromatography on silica gel (10 to 60% ethyl acetate: dichloromethane) to give compound methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid, 1-B. 1 H-NMR (400MHz, DMSO-d6) δ10.28(t,J=6.0Hz,1H),8.46(s,1H),7.42(dd,J=15.4,8.6Hz,1H),7.2 4(m,1H),7.06(m,1H),4.52(m,3H),4.22(d,J=4.4Hz,2H),3.92(s,3H),3.80(s,3H),3.29(d,6H). LCMS-ESI + (m / z):C 20 H 23 [M+H] of F2N2O7 + Theoretical value: 441.15; Measured value: 441.2.

[0392] Step 2

[0393] Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate (1-B, 0.106 g, 0.24 mmol) in acetonitrile (0.9 mL) and acetic acid (0.1 mL) was treated with methanesulfonic acid (0.005 mL, 0.072 mmol), sealed with a yellow cap, and heated to 70 °C. After 16 hours, the mixture was cooled to give a crude solution of methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyacetic acid)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylate 1-C. LCMS-ESI + (m / z):C 18 H 19 [M+H] of F2N2O7 + Theoretical value: 413.12; Measured value: 413.1.

[0394] Steps 3 and 4

[0395] Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid (1-C, 0.65 mL of the crude mixture from the preceding steps, 0.17 mmol) was treated with acetonitrile (0.65 mL) and cis-3-aminocyclopentanol (0.06 mL). The reaction mixture was sealed and heated to 90 °C. After 30 minutes, the reaction mixture was cooled and magnesium bromide (0.063 g, 0.34 mmol) was added. The mixture was resealed and heated to 50 °C. After 10 minutes, the reaction mixture was partitioned between dichloromethane and hydrochloric acid (0.2 Maq). The organic layer was removed, and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Preparation-HPLC purification (30–70% acetonitrile:water, 0.1% TFA) gave compound 1 as a racemic mixture. 1H-NMR (400MHz, DMSO-d6) δ12.45(brs,1H),10.35(t,J=5.8Hz,1H),8.45(s,1H),7.37(dd,J=15.4,8.6 Hz,1H),7.23(dt,J=2.5,9.9Hz,1H),7.05(dt,J=2.2,8.7Hz,1H),5.43(dd,J=9.6,4.0Hz,1H),5.09(br s,1H),4.68(dd,J=13.2,4.0Hz,1H),4.59(br s,1H),4.53(m,2H),4.02(dd,J=12.6,9.4Hz),1.93(br s, 4H), 1.83 (d, J = 12.0Hz), 1.57 (dt, J = 12.2, 3.2Hz). LCMS-ESI + (m / z):C 21 H 20 [M+H] of F2N3O5 + Theoretical value: 432.14; Measured value: 432.2.

[0396] Examples 2 and 3

[0397] Preparation of compounds 2 and 3

[0398] (2R,5S,13aR)-N-(2,4-difluorophenylmethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-Formamide (2) and (2S,5R,13aS)-N-(2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -1

[0399] 0-Formamide (3)

[0400]

[0401] Compound 1 (16 mg) was separated by chiral HPLC using Chiralpak AS-H with 100% ethanol as the eluent, yielding compounds 2 and 3 in enantiomer-enriched forms. For compound 2: LCMS-ESI + (m / z):[M+H) + Theoretical value: C 21 H 20F2N3O5: 432.14; Measured value: 432.2, chiral HPLC retention time = 4.50 min (Chiralpak AS-H, 150 x 4.6 mm, 1 mL / min EtOH). For compound 3: LCMS-ESI + (m / z):[M+H) + Theoretical value: C 21 H 20 F2N3O5: 432.14; Measured value: 432.2, chiral HPLC retention time = 6.84 min (Chiralpak AS-H, 150 x 4.6 mm, 1 mL / min EtOH). 1 H-NMR(400MHz,DMSO-d6)δ12.45(br s,1H),10.35(t,J=5.8Hz,1H),8.44(s,1H),7.37(dd,J=15.2,8.4Hz,1H),7 .23(m,1H),7.05(dt,J=1.8Hz,8.7Hz,1H),5.44(dd,J=9.6,4.0Hz),5.09(br s,1H),4.68(dd,J=12.8,4.0Hz,1H),4.59(br s,1H),4.53(m,2H),4.02(dd,J=12.6,9.4Hz,1H),1.93(br s, 4H), 1.83 (d, J = 12.4Hz, 1H), 1.57 (m, 1H).

[0402] Alternatively, compound 3 can be prepared as follows:

[0403]

[0404] Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid (1-C, 1.2 mmol in 5 mL of 9:1 acetonitrile:acetic acid containing 0.026 mL of methanesulfonic acid) was treated with acetonitrile (5.0 mL) and cis-3-aminocyclopentanol (0.24 g, 2.4 mmol). The reaction mixture was sealed and heated to 90 °C. After 30 minutes, the reaction mixture was cooled, treated with potassium carbonate (0.332 g, 2.4 mmol), sealed, and heated again to 90 °C. After 15 minutes, the mixture was cooled and partitioned between dichloromethane and hydrochloric acid (0.2 M aqueous solution). The organic layer was removed, and the aqueous solution was extracted again with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by rapid chromatography (0-8% ethanol in dichloromethane (containing 11% saturated ammonium hydroxide aqueous solution)) to give intermediate 1-D.LCMS-ESI.+ (m / z):C 22 H 22 [M+H] of F2N3O5 + Theoretical value: 446.15; Measured value: 446.2.

[0405] Intermediate 1-D (270 mg) was separated on a 50 mm Chiralpak AD-H column using a chiral SFC with 50% (1:1 methanol:acetonitrile) in supercritical carbon dioxide as the eluent, yielding enantiomer-enriched intermediates 3-A (first elution peak) and 3-B (second elution peak). For 3-A: LCMS-ESI + (m / z):[M+H) + Theoretical value: C 22 H 22 F2N3O5: 446.15; Measured value: 446.2. For 3-B:LCMS-ESI + (m / z):[M+H) + Theoretical value: C 22 H 22 F2N3O5: 446.15; Measured value: 446.2.

[0406] Intermediate 3-A (0.110 g, 0.247 mmol) in acetonitrile (5 mL) was treated in portions with magnesium bromide (0.091 g, 0.494 mmol), sealed, and heated to 50 °C. After 10 min, the mixture was cooled and partitioned between dichloromethane and hydrochloric acid (0.2 M aqueous solution). The organic layer was separated, and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Preparative HPLC purification (30–70% acetonitrile:water, 0.1% TFA) yielded compound 3 in an enantiomer-enriched form. Chiral HPLC retention time = 6.51 min (Chiralpak AS-H, 150x, measured: 432.2). 1 H-NMR (44.6mm, 1mL / minEtOH). LCMS-ESI + (m / z):C 21 H 20 [M+H] of F2N3O5 +Theoretical value: 432.14; 00MHz, DMSO-d6) δ12.45 (br s,1H),10.35(t,J=5.8Hz,1H),8.44(s,1H),7.37(dd,J=15.2,8.4Hz,1H),7.23(m,1H),7.05(dt,J =1.8Hz,8.7Hz,1H),5.44(dd,J=9.6,4.0Hz),5.09(brs,1H),4.68(dd,J=12.8,4.0Hz,1H),4.59(br s,1H),4.53(m,2H),4.02(dd,J=12.6,9.4Hz,1H),1.93(br s, 4H), 1.83 (d, J = 12.4Hz, 1H), 1.57 (m, 1H).

[0407] Example 4

[0408] Preparation of compound 4

[0409] (1S,4R)-N-(2,4-difluorophenylmethyl)-7-hydroxy-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-1,4-bridged methylenepyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

[0410]

[0411] First, acetonitrile was used, followed by treatment of methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid (1-C, 0.12 mmol in 0.53 mL of 9:1 acetonitrile:acetic acid containing 0.002 mL of methanesulfonic acid) with (R)-pyrrolidine-3-amine (0.032 mL, 0.36 mmol). The reaction mixture was capped and heated to 90 °C for 5.5 h. After cooling, the mixture was partitioned between dichloromethane and sodium bicarbonate (1 M aqueous solution). The organic layer was separated, and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was dissolved in acetonitrile (1 mL), treated with magnesium bromide (0.022 g, 0.12 mmol), capped, and heated to 50 °C for 10 min. After cooling, the mixture was partitioned between dichloromethane and ammonium chloride (saturated). The organic layer was separated, and the aqueous layer was extracted again with dichloromethane. The aqueous layer was adjusted to pH 1 with HCl (aq) and extracted again with dichloromethane. The aqueous layer was adjusted to pH 3 with NaOH (aq) and extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Preparative HPLC purification (10–55% acetonitrile:water, 0.1% TFA) yielded compound 4.1 H-NMR (400MHz, CD3OD-d4) δ8.42(s,1H),7.42,(q,J=7.7Hz,1H),6.99-6.90(m,2H),5.07(br s,1H),4.73(br d,J=10.8Hz,1H),4.62(s,2H),4.51(br d,J=12.8Hz,1H),4.07(t,J=11.8Hz,1H),3.4-3.0(m,3H),2.76(br d,J=8.8Hz,1H),2.15-2.0(m,1H),1.9-1.8(m,1H). LCMS-ESI + (m / z):C 20 H 19 [M+H] of F2N4O4 + Theoretical value: 417.14; Measured value: 417.2.

[0412] Example 5

[0413] Preparation of compound 5

[0414] (4R,12aS)-N-(1-(2,4-difluorophenyl)cyclopropyl)-7-hydroxy-4-methyl-6,8-dioxo

[0415] -3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazin-9-carboxamide

[0416]

[0417]

[0418] Step 1

[0419] Intermediate 5-A (4R,12aS)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-8-carboxylic acid was prepared by replacing (S)-2-aminoprop-1-ol with (R)-3-aminobut-1-ol. The entire contents of WO2011 / 119566 are incorporated herein by reference. At ambient temperature, a suspension of intermediates 5-A (24.8 mg, 0.080 mmol), 1-(2,4-difluorophenyl)cyclopropylamine HCl salt (5-B, 21.9 mg, 0.107 mmol), and HATU (48 mg, 0.126 mmol) in CH₂Cl₂ (2 mL) was stirred, while N,N-diisopropylethylamine (DIPEA) (0.1 mL, 0.574 mmol) was added. After 30 minutes, the reaction mixture was diluted with ethyl acetate, followed by washing with 10% citric acid aqueous solution (x1) and saturated NaHCO₃ aqueous solution (x1). After extraction of the aqueous fraction with ethyl acetate (x1), the organic fractions were combined, dried (MgSO₄), and concentrated. The residue was purified by combiflash (12 g column) with hexane, ethyl acetate, and 20% methanol in ethyl acetate to give (4R,12aS)-N-(1-(2,4-difluorophenyl)cyclopropyl)-7-methoxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazin-9-carboxamide, intermediate 5-C. LCMS-ESI + (m / z):C 23 H 24 [M+H] of F2N3O5 + Theoretical value: 460.17; Measured value: 460.2.

[0420] Step 2

[0421] The suspension of intermediate 5-C (39 mg, 0.080 mmol) and magnesium bromide (42 mg, 0.2282 mmol) in acetonitrile (2 mL) was stirred at 50 °C. After 1 hour, the reaction mixture was stirred in a bath at 0 °C with the addition of 1 N HCl (2 mL). After diluting the resulting mixture with water (~20 mL), the product was extracted with dichloromethane (x3), dried (MgSO4), and the combined extracts were concentrated. The residue was purified by preparative HPLC to give (4R,12aS)-N-(1-(2,4-difluorophenyl)cyclopropyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazin-9-carboxamide, compound 5, as a TFA salt. 1 ¹H-NMR (400MHz, CDCl₃) δ 10.72 (br s, 1H), 8.37 (s, 1H), 7.57 (d, J = 7.9 Hz, 1H), 6.71–6.81 (m, 2H), 5.23 (dd, J = 5.6 and 4.4 Hz, 1H), 4.98 (brquint, J = ~6.5 Hz, 1H), 4.26 (dd, J = 13.6 and 4.4 Hz, 1H), 4.12 (dd, J = 13.6 and 5.6 Hz, 1H), 4.00–4.06 (m, 2H), 2.16–2.25 (m, 1H), 1.55 (br dd, J = 13.8 and 1.8 Hz, 1H), 1.40 (d, J = 6.8 Hz, 3H), 1.22–1.31 (m, 4H). 19 F NMR (376.1MHz, CDCl3) δ-76.38 (s, 3F), -111.69~-111.645 (m, 2F). LCMS-ESI + (m / z):C 22 H 22 [M+H] of F2N3O5 + Theoretical value: 446.15; Measured value: 446.2.

[0422] Example 6

[0423] Preparation of compound 6

[0424] (1R,4S)-N-(2,4-difluorophenylmethyl)-7-hydroxy-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-1,4-bridged methylenepyrido[1',2':4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide

[0425]

[0426] Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid (1-C, 0.100 g, 0.243 mmol), (S)-pyrrolidine-3-amine (0.043 mL, 0.485 mmol), and potassium carbonate (0.067 g, 0.485 mmol) were suspended in acetonitrile (1.9 mL) and acetic acid (0.1 mL) and heated to 90 °C for 1.5 h. After cooling, the mixture was treated with magnesium bromide (0.090 g) and heated to 50 °C for 30 min. After cooling, the mixture was partitioned between dichloromethane and 0.2 M HCl. The organic layer was separated, and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. The compound 6 was prepared by HP LC purification (25-50% acetonitrile:water, 0.1% TFA). 1 H-NMR (400MHz, DMSO-d6) δ10.33(t,J=6.0Hz,1H),8.44(s,1H),7.48-7.32(m,1H),7.31-7.15(m,1H),7.14-6.97(m,1H),4.86(d,J=2.9Hz ,1H),4.62-4.54(m,1H),4.52(d,J=5.9Hz,1H),4.01(d,J=13.0Hz,1H),2.99-2.76(m,3H),1.96-1.81(m,1H),1.71-1.53(m,1H).LCMS-ESI + (m / z):C 20 H 19 [M+H] of F2N4O4 + Theoretical value: 417.14; Measured value: 417.2.

[0427] Example 7

[0428] Preparation of compound 7

[0429] (2S,6R)-N-(2,4-difluorophenylmethyl)-9-hydroxy-8,10-dioxo-3,4,5,6,8,10,14,14a-octahydro-2H-2,6-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazocine-11-carboxamide

[0430]

[0431] Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid (1-C, 0.050 g, 0.121 mmol), (1S,3R)-3-aminocyclohexanol (0.028 g, 0.243 mmol), and potassium carbonate (0.034 g, 0.243 mmol) were suspended in acetonitrile (0.95 mL) and heated to 90 °C for 0.5 h. After cooling, acetic acid (0.050 mL) was added, and the mixture was reheated to 90 °C for 2 h. After cooling, the mixture was treated with magnesium bromide (0.044 g) and heated to 50 °C for 1 h. After cooling, a second portion of magnesium bromide (0.044 g) was added, and the mixture was reheated to 50 °C for 15 min. After cooling, the mixture was partitioned between dichloromethane and 0.2 M HCl. The organic layer was separated, and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated. Preparative HPLC purification (40–80% acetonitrile:water, 0.1% TFA) gave compound 7. 1 H-NMR (400MHz, DMSO-d6) δ12.40 (s, 1H), 10.36 (t, J = 6.1Hz, 1H), 8.45 (s, 1H), 7.4 8-7.29(m,1H),7.31-7.13(m,1H),7.13-6.97(m,1H),5.56(dd,J=10.0,4.1Hz,1H ),4.70(dd,J=12.7,4.1Hz,1H),4.52(d,J=5.5Hz,2H),4.40-4.29(m,2H),4.06(d d,J=12.5,10.2Hz,1H),2.46-2.36(m,1H),1.98-1.63(m,4H),1.57-1.30(m,3H). LCMS-ESI + (m / z):C 22 H 22 [M+H] of F2N3O5 + Theoretical value: 446.15; Measured value: 446.2.

[0432] Example 8

[0433] Preparation of compound 8

[0434] (2R,6S)-N-(2,4-difluorophenylmethyl)-9-hydroxy-8,10-dioxo-3,4,5,6,8,10,14,14a-octahydro-2H-2,6-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazocine-11-carboxamide

[0435]

[0436] Compound 8 was prepared by using a method similar to that of compound 7, but instead of (1S,3R)-3-aminocyclohexanol. 1 H-NMR(400MHz,DMSO-d6)δ12.40(s,1H),10.36(t,J=6.1Hz,1H),8.45(s,1H),7.48-7.30 (m,1H),7.23(td,J=10.6,2.7Hz,1H),7.05(td,J=8.3,2.3Hz,1H),5.56(dd,J=10.1,4.1 Hz,1H),4.70(dd,J=12.8,3.9Hz,1H),4.52(d,J=5.6Hz,2H),4.39-4.27(m,2H),4.06(dd ,J=12.6,10.0Hz,1H),2.47-2.35(m,1H),2.00-1.64(m,4H),1.58-1.30(m,3H).LCMS-ESI + (m / z):C 22 H 22 [M+H] of F2N3O5 + Theoretical value: 446.15; Measured value: 446.2.

[0437] Examples 9 and 10

[0438] Preparation of compounds 9 and 10

[0439] (2S,5R,13aS)-N-((R)-1-(4-fluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-Formamide 9 and (2R,5S,13aR)-N-((R)-1-(4-fluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazine

[0440] [2,1-b][1,3]oxazaza -10-Formamide 10

[0441]

[0442]

[0443] Step 1

[0444] 1-(2,2-Dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1-A, 0.500 g, 1.59 mmol) was suspended in acetonitrile (6 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.550 mL, 3.17 mmol), (R)-1-(4-fluorophenyl)ethylamine (0.242 mg, 1.74 mmol), and HATU (0.661 g, 1.74 mmol). The reaction mixture was stirred for 2 hours and partitioned between ethyl acetate and water. The organic layer was separated and washed with HCl (10% aq) and sodium bicarbonate (1M aq), dried over sodium sulfate, filtered, and concentrated to give crude (R)-1-(2,2-dimethoxyethyl)-5-(1-(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester, which was used in the next step without purification: LCMS-ESI + (m / z):[M+H) + Theoretical value: C 21 H 26 FN2O7: 437.17; Measured value: 437.1.

[0445] Step 2

[0446] Methyl (R)-1-(2,2-dimethoxyethyl)-5-(1-(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid was suspended in acetonitrile (5.7 mL) and acetic acid (0.6 mL) and treated with methanesulfonic acid (0.031 mL, 0.477 mmol). The mixture was capped and heated to 75 °C. After 7 hours, the mixture was cooled and used in the next step without purification: LCMS-ESI + (m / z):[M+H) + Theoretical value: C 19 H 22 FN2O7: 409.14; Measured value: 409.0.

[0447] Step 3

[0448] Methyl (R)-1-(2,2-dihydroxyethyl)-5-(1-(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid (3.6 mL from the crude mixture of step 2, 0.8 mmol) was diluted with acetonitrile (3.6 mL) and treated with cis-3-aminocyclopentanol, HCl salt (0.219 g, 1.6 mmol), and potassium carbonate (0.276 g, 2.0 mmol). The mixture was capped and heated to 90 °C. After 20 minutes, the reaction mixture was cooled and partitioned between dichloromethane and HCl (0.2 Maq). The layers were separated, and the aqueous layer was extracted again with dichloromethane. The combined organic layers were treated with a small amount of acetonitrile, dried over sodium sulfate, filtered, and concentrated.

[0449] The residue was suspended in acetonitrile (4 mL) and treated with magnesium bromide (0.177 g). The mixture was capped and heated to 50 °C. After 10 minutes, the reaction mixture was cooled and partitioned between dichloromethane and HCl (0.2 Maq). The organic layer was separated, and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. The residue was purified by rapid chromatography on silica gel (0–8% ethanol: DCM) to give the desired mixture of diastereomers 9 and 10.

[0450] Compounds 9 and 10 were obtained in enantiomer-enriched form by chiral HPLC separation of the mixture using Chiralpak AD-H and 100% ethanol as eluent.

[0451] For compound 9: LCMS-ESI + (m / z):C 22 H 23 [M+H] of FN3O5 + Theoretical value: 428.16; Measured value: 428.1. Chiral HPLC retention time = 10.177 min (Chiralpak AD-H, 150 x 4.6 mm, 1 mL / min EtOH). 1H-NMR(400MHz,DMSO-d6)δ12.45(s,1H),10.45(d,J=7.7Hz,1H),8.40(s,1H),7.3 7(dd,J=8.6,5.6Hz,2H),7.15(t,J=8.9Hz,2H),5.44(dd,J=9.5,4.2Hz,1H),5.17- 5.04(m,2H),4.73-4.62(m,1H),4.59(s,1H),4.00(dd,J=12.7,9.5Hz,1H),1.93(s ,4H),1.83(d,J=11.8Hz,1H),1.56(dt,J=12.1,3.4Hz,1H),1.44(d,J=6.9Hz,3H).

[0452] For compound 10: LCMS-ESI + (m / z):C 22 H 23 [M+H] of FN3O5 + Theoretical value: 428.16; Measured value: 428.1. Chiral HPLC retention time = 14.061 min (Chiralpak AD-H, 150 x 4.6 mm, 1 mL / min EtOH). 1 H-NMR (400MHz, DMSO-d6) δ12.44(s,1H),10.46(d,J=7.8Hz,1H),8.41(s,1H),7.37(d d,J=8.6,5.6Hz,2H),7.15(t,J=8.9Hz,2H),5.42(dd,J=9.6,4.1Hz,1H),5.18-5.02( m,2H),4.67(dd,J=12.8,4.2Hz,1H),4.59(s,1H),4.02(dd,J=12.7,9.6Hz,1H),1.93 (s, 4H), 1.83 (d, J = 12.0Hz, 1H), 1.57 (dt, J = 13.0, 3.5Hz, 1H), 1.44 (d, J = 6.9Hz, 3H).

[0453] Example 11

[0454] Preparation of compound 11

[0455] (2S,5R,13aS)-N-((R)-1-(2,4-difluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0456]

[0457] Step 1

[0458] 1-(2,2-Dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1-A, 0.315 g, 1.00 mmol) was suspended in acetonitrile (4 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.348 mL, 2.00 mmol), (R)-1-(2,4-difluorophenyl)ethylamine HCl salt (0.213 mg, 1.10 mmol), and HATU (0.418 g, 1.10 mmol). The reaction mixture was stirred for 1 hour and partitioned between dichloromethane and HCl (10% aq). The organic layer was separated and washed with sodium bicarbonate (1 Maq), dried over sodium sulfate, filtered, and concentrated to give crude (R)-5-(1-(2,4-difluorophenyl)ethylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester, which was used in the next step without purification. LCMS-ESI + (m / z):C 21 H 25 [M+H] of F2N2O7 + Theoretical value: 455.16; Measured value: 455.1.

[0459] Step 2

[0460] Methyl (R)-5-(1-(2,4-difluorophenyl)ethylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid was suspended in acetonitrile (3.6 mL) and acetic acid (0.4 mL) and treated with methanesulfonic acid (0.020 mL). The mixture was capped and heated to 75 °C. After 16 hours, the crude mixture was cooled and used in the next step without purification. LCMS-ESI + (m / z):[M+H) + Theoretical value: C 19 H 21 F2N2O7: 427.13; Measured value: 427.1.

[0461] Step 3

[0462] Methyl (R)-5-(1-(2,4-difluorophenyl)ethylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid (half of the crude mixture from step 2, about 0.5 mmol) was diluted with acetonitrile (2.5 mL) and treated with (1S,3R)-3-aminocyclopentanol (0.110 g, 1.09 mmol) and potassium carbonate (0.069 g, 0.50 mmol). The mixture was capped and heated to 90 °C. After 15 minutes, the reaction mixture was cooled and magnesium bromide (0.184 g) was added. The reaction mixture was heated to 50 °C. After 10 minutes, the mixture was cooled and treated with another portion of magnesium bromide (0.184 g). The reaction mixture was reheated to 50 °C and stirred for 10 minutes. After cooling, the mixture was partitioned between dichloromethane and HCl (0.2 Maq). The layers were separated, and the aqueous layer was extracted again with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated. Preparative HPLC purification (30-60% acetonitrile:water, 0.1% TFA) yielded the desired compound 11. LCMS-ESI + (m / z):C 22 H 22 [M+H] of F2N3O5 + Theoretical value: 446.15; Measured value: 446.1. 1 H-NMR (400MHz, DMSO-d6) δ12.46(s,1H),10.53(d,J=7.5Hz,1H),8.38(s,1H),7.39(q,J=8.5 Hz,1H),7.29-7.12(m,1H),7.13-6.93(m,1H),5.44(dd,J=9.8,4.2Hz,1H),5.28(p,J=7.3,6. 8Hz,1H),5.09(s,1H),4.66(dd,J=13.2,4.3Hz,1H),4.59(s,1H),3.99(dd,J=13.1,9.6Hz,1 H), 1.93 (s, 4H), 1.83 (d, J = 12.4Hz, 1H), 1.56 (dt, J = 12.5, 2.9Hz, 1H), 1.45 (d, J = 6.9Hz, 3H).

[0463] Example 12

[0464] Preparation of compound 12

[0465] (2R,5S,13aR)-N-((R)-1-(2,4-difluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0466]

[0467] Compound 12 was prepared by using a method similar to that of compound 11, but instead of (1S,3R)-3-aminocyclopentanol. 1 H-NMR (400MHz, DMSO-d6) δ12.43(s,1H),10.52(d,J=8.2Hz,1H),8.38(s,1H),7.39(q,J=8 .4Hz,1H),7.28-7.12(m,1H),7.11-6.97(m,1H),5.41(dd,J=10.0,4.0Hz,1H),5.35-5.20( m,1H),5.08(s,1H),4.65(dd,J=13.1,3.8Hz,1H),4.58(s,1H),4.01(dd,J=12.8,9.5Hz,1H ),1.92(s,4H),1.83(d,J=11.5Hz,1H),1.61-1.51(m,1H),1.44(d,J=6.9Hz,3H).LCMS-ESI + (m / z):C 22 H 22 [M+H] of F2N3O5 + Theoretical value: 446.15; Measured value: 446.1.

[0468] Example 13

[0469] Preparation of compound 13

[0470] (2S,5R,13aS)-N-((S)-1-(2,4-difluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0471]

[0472] Compound 13 was prepared using a method similar to that of Compound 11, but with ((S)-1-(2,4-difluorophenyl)ethylamine instead of (R)-1-(2,4-difluorophenyl)ethylamine, and with only a single portion of magnesium bromide (0.184 g). 1 H-NMR (400MHz, DMSO-d6) δ12.44(s,1H),10.53(d,J=7.8Hz,1H),8.39(s,1H),7.39(q,J=8.5 Hz,1H),7.32-7.14(m,1H),7.05(t,J=9.1Hz,1H),5.42(dd,J=9.5,4.2Hz,1H),5.29(p,J=6. 9Hz,1H),5.09(s,1H),4.65(dd,J=12.9,4.3Hz,1H),4.59(s,1H),4.02(dd,J=12.6,9.8Hz,1 H),1.92(s,4H),1.83(d,J=12.1Hz,1H),1.61-1.52(m,1H),1.44(d,J=6.9Hz,3H).LCMS-ESI + (m / z):C 22 H 22 [M+H] of F2N3O5 + Theoretical value: 446.15; Measured value: 446.2.

[0473] Example 14

[0474] Preparation of compound 14

[0475] (2R,5S,13aR)-N-((S)-1-(2,4-difluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0476]

[0477] Compound 14 was prepared using a method similar to that of Compound 11, but with ((S)-1-(2,4-difluorophenyl)ethylamine instead of (R)-1-(2,4-difluorophenyl)ethylamine, and with (1R,3S)-3-aminocyclopentanol instead of (1S,3R)-3-aminocyclopentanol. 1H-NMR (400MHz, DMSO-d6) δ12.46(s,1H),10.53(d,J=7.6Hz,1H),8.38(s,1H),7.39(q,J=8.6Hz ,1H),7.28-7.14(m,1H),7.05(t,J=8.5Hz,1H),5.44(dd,J=9.8,3.8Hz,1H),5.28(p,J=8.0Hz, 1H),5.09(s,1H),4.66(dd,J=12.9,4.0Hz,1H),4.59(s,1H),3.99(dd,J=12.5,9.6Hz,1H),1.9 3(s,4H),1.83(d,J=12.6Hz,1H),1.56(dt,J=13.0,3.3Hz,1H),1.45(d,J=6.9Hz,3H).LCMS-ESI + (m / z):C 22 H 22 [M+H] of F2N3O5 + Theoretical value: 446.15; Measured value: 446.1.

[0478] Example 15

[0479] Preparation of compound 15

[0480] (2S,5R,13aS)-N-(4-fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0481]

[0482]

[0483] Step 1

[0484] 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (1-A, 3.15 g, 10.0 mmol) suspended in acetonitrile (36 mL) and acetic acid (4 mL) was treated with methanesulfonic acid (0.195 mL). The mixture was heated to 75 °C. After 7 hours, the crude mixture was cooled and stored at -10 °C for three days. The crude mixture was then reheated to 75 °C for 2 hours, cooled, and used in the next step without purification. LCMS-ESI + (m / z):C 19 H 21[M+H] of F2N2O7 + Theoretical value: 288.07; Measured value: 288.1.

[0485] Step 2

[0486] Crude 1-(2,2-dihydroxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (16.8 mL from the crude mixture of step 1, approximately 4 mmol) was mixed with (1S,3R)-3-aminocyclopentanol (0.809 g, 8 mmol), diluted with acetonitrile (16.8 mL), and treated with potassium carbonate (0.553 g, 4 mmol). The reaction mixture was heated to 85 °C, stirred for 15 min, cooled to ambient temperature, and stirred again for 16 h. HCl (50 mL, 0.2 Maq) was added, and the clear yellow solution was extracted three times with dichloromethane. The combined organic layers were dried over sodium sulfate, filtered, and concentrated to a yellow solid. The crude substance was precipitated from dichloromethane / hexane to give the desired intermediate 15-B as a light beige powder. 1 H-NMR(400MHz,DMSO-d6)δ8.72(s,1H),5.42(dd,J=9.6,4.1Hz,1H),5.09(s,1H),4.72(dd,J=13.0,3.7Hz,1H), 4.57(s,1H),4.09(dd,J=12.5,9.6Hz,1H),3.83(s,3H),1.92(s,3H),1.78(m,2H),1.62-1.47(m,1H).LCMS-ESI + (m / z):C 15 H 17 [M+H] of N2O6 + Theoretical value: 321.11; Measured value: 321.2.

[0487] Step 3

[0488] Intermediate 15-B (0.040 g, 0.125 mmol) and (4-fluorophenyl)methylamine (0.017 g, 0.137 mmol) were suspended in acetonitrile (1 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.033 mL, 0.187 mmol) and HATU (0.052 g, 0.137 mmol). After stirring for 30 min, the reaction mixture was treated with magnesium bromide (0.046 g, 0.25 mmol) and heated to 50 °C. After 10 min, the reaction mixture was cooled and treated with HCl (2 mL, 10% aq). After a few minutes, the precipitate was filtered and washed with HCl (10% aq) and water. The precipitate was purified by HPLC (20–65% acetonitrile:water, 0.1% TFA) to give the desired compound 15. 1 H-NMR(400MHz,DMSO-d6)δ12.44(s,1H),10.36(t,J=6.0Hz,1H),8.46(s,1H),7 .37-7.28(m,2H),7.19-7.09(m,2H),5.43(dd,J=9.6,4.0Hz,1H),5.08(s,1H), 4.68(dd,J=12.8,4.1Hz,1H),4.59(s,1H),4.58-4.42(m,3H),4.02(dd,J=12.7 ,9.6Hz,1H),1.92(s,5H),1.83(d,J=12.2Hz,1H),1.56(dt,J=12.0,3.4Hz,1H). LCMS-ESI + (m / z):C 21 H 21 [M+H] of FN3O5 + Theoretical value: 414.15; Measured value: 414.2.

[0489] Example 16

[0490] Preparation of compound 16

[0491] (2S,5R,13aS)-N-(2,3-difluorophenylmethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0492]

[0493] Compound 16 was prepared using a method similar to that of Compound 15, but with (2,3-difluorophenyl)methylamine instead of (4-fluorophenyl)methylamine. 1H-NMR(400MHz,DMSO-d6)δ12.46(s,1H),10.41(t,J=6.1Hz,1H),8.45(s,1H),7 .43-7.25(m,1H),7.25-7.05(m,2H),5.44(dd,J=9.5,3.9Hz,1H),5.09(s,1H), 4.68(dd,J=12.8,4.0Hz,1H),4.65-4.53(m,3H),4.02(dd,J=12.7,9.8Hz,1H), 3.56(s,1H),1.93(s,4H),1.83(d,J=11.9Hz,1H),1.57(dt,J=11.5,3.0Hz,1H). LCMS-ESI + (m / z):C 21 H 20 [M+H] of F2N3O5 + Theoretical value: 432.14; Measured value: 432.2.

[0494] Example 17

[0495] Preparation of compound 17

[0496] (2S,5R,13aS)-N-(4-chloro-2-fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0497]

[0498] Compound 17 was prepared using a method similar to that of Compound 15, but with (4-chloro-2-fluorophenyl)methylamine instead of (4-fluorophenyl)methylamine. 1 H-NMR(400MHz,DMSO-d6)δ12.46(s,1H),10.45-10.29(m,1H),8.44(s,1H),7.42(dd,J= 10.0,2.0Hz,1H),7.33(t,J=8.1Hz,1H),7.26(dd,J=8.4,1.8Hz,1H),5.50-5.38(m,1H), 5.09(s,1H),4.68(dd,J=13.0,4.0Hz,1H),4.59(s,1H),4.54(m,2H),4.02(dd,J=12.8, 9.7Hz,1H),1.93(s,4H),1.83(d,J=12.0Hz,1H),1.57(dt,J=11.9,3.4Hz,1H).LCMS-ESI+ (m / z):C 21 H 20 [M+H] of ClFN3O5 + Theoretical value: 448.11; Measured value: 448.2.

[0499] Example 18

[0500] Preparation of compound 18

[0501] (2S,5R,13aS)-N-(3,4-difluorophenylmethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0502]

[0503] Compound 18 was prepared using a method similar to that of Compound 15, but with (3,4-difluorophenyl)methylamine instead of (4-fluorophenyl)methylamine. 1 H-NMR(400MHz,DMSO-d6)δ12.46(s,1H),10.51-10.27(m,1H),8.46(s,1H),7. 50-7.23(m,2H),7.23-7.03(m,1H),5.44(dd,J=9.5,3.6Hz,1H),5.09(s,1H),4 .75-4.63(m,1H),4.60(s,1H),4.57-4.44(m,2H),4.02(dd,J=12.6,9.8Hz,1H ),1.93(s,4H),1.83(d,J=12.0Hz,1H),1.57(dt,J=12.0,3.4Hz,1H).LCMS-ESI + (m / z):C 21 H 20 [M+H] of F2N3O5 + Theoretical value: 432.14; Measured value: 432.2.

[0504] Example 19

[0505] Preparation of compound 19

[0506] (1R,5S)-N-(2,4-difluorophenylmethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-1,5-bridged methylenepyrido[1',2':4,5]pyrazino[1,2-a][1,3]diaza -10-formamide

[0507]

[0508] Steps 1 and 2

[0509] Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid (1-C, 97.5 mg, 0.236 mmol) was treated with acetonitrile (1.9 mL), acetic acid (0.1 mL), potassium carbonate (145 mg, 1.05 mmol), and (S)-piperidine-3-amine dihydrochloride (82 mg, 0.472 mmol). The reaction mixture was sealed and heated to 90 °C. After 60 minutes, the reaction mixture was cooled and partitioned between brine and dichloromethane. The aqueous phase was extracted three times into dichloromethane, and the combined organic phases were mixed, dried over MgSO4, filtered, and concentrated. The crude product was dissolved in acetonitrile (2 mL), and magnesium bromide (89.1 mg, 0.48 mmol) was added. The mixture was resealed and heated to 50 °C. After 80 minutes, the reaction mixture was quenched with ~5 mL of 0.2 M HCl (aq), the pH was adjusted to ~10, diluted with brine, and extracted three times into DCM. HPLC (acetonitrile:water, 0.1% TFA) yielded compound 19. 1 H-NMR (400MHz, chloroform-d) δ10.43(t,J=5.9Hz,1H),8.43(s,1H),7.39-7.30(m,1H),6 .81(q,J=8.1Hz,2H),4.89(dd,J=11.6,3.8Hz,1H),4.69(s,1H),4.64(d,J=5.8H z,2H),4.26(dd,J=12.6,3.8Hz,1H),3.91(t,J=12.1Hz,1H),3.20-3.10(m,2H), 3.06(s,2H),2.14-2.02(m,1H),1.96-1.81(m,2H),1.81-1.70(m,1H).LCMS-ESI + (m / z):C 21 H 20 [M+H] of F2N4O4 + Theoretical value: 431.15; Measured value: 431.2.

[0510] Example 20

[0511] Preparation of compound 20

[0512] (1S,5R)-N-(2,4-difluorophenylmethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-1,5-bridged methylenepyrido[1',2':4,5]pyrazino[1,2-a][1,3]diaza -10-formamide

[0513]

[0514] Steps 1 and 2

[0515] Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid (1-C, 103.3 mg, 0.25 mmol) was treated with (1.9 mL), acetic acid (0.1 mL), potassium carbonate (159.8 mg, 1.16 mmol), and (R)-piperidine-3-amine dihydrochloride (90 mg, 0.52 mmol). The reaction mixture was sealed and heated to 90 °C. After 40 minutes, the reaction mixture was partitioned between brine and dichloromethane. The aqueous phase was extracted three times into dichloromethane, and the combined organic phases were mixed, dried over MgSO4, filtered, and concentrated. The crude product was dissolved in acetonitrile (2 mL), and magnesium bromide (96.5 mg, 0.52 mmol) was added. The mixture was resealed and heated to 50 °C. After 80 minutes, the reaction mixture was quenched with ~5 mL of 0.2 M HCl (aq), the pH was adjusted to ~10, diluted with brine, and extracted three times into DCM. HPLC (acetonitrile:water, 0.1% TFA) yielded compound 20. 1 H-NMR (400MHz, DMSO-d6) δ10.35(t,J=6.0Hz,1H),8.48(s,1H),7.45-7.33(m,1H),7.29-7.18(m,1H),7.05(td,J=8.5,2.4Hz,1H),5.06(dd,J =11.4,3.5Hz,1H),4.56-4.47(m,3H),4.44(s,1H),4.05(t,J=11.8Hz,1H),3.07-2.89(m,4H),1.85-1.73(m,3H),1.54-1.46(m,1H).LCMS-ESI + (m / z):C 21 H 20 [M+H] of F2N4O4 + Theoretical value: 431.15; Measured value: 431.2.

[0516] Example 21

[0517] Preparation of compound 21

[0518] (2S,5R,13aS)-N-((S)-1-(4-fluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0519]

[0520] Steps 1 and 2

[0521] (S)-1-(2,2-dihydroxyethyl)-5-(1-(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester (21-A, 1 mL, in a 0.23 M solution in acetonitrile:acetic acid at a ratio of 19:1, prepared according to (R)-1-(2,2-dihydroxyethyl)-5-(1-(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid methyl ester 9-A from Example 9, using (S)-1-(4-fluorophenyl)ethylamine instead of (R)-1-(4-fluorophenyl)ethylamine. The reaction mixture was sealed and heated to 90°C. After 60 minutes, the reaction mixture was cooled and partitioned between brine and dichloromethane. The aqueous phase was extracted three times into dichloromethane, and the combined organic phases were mixed, dried over MgSO4, filtered, and concentrated. The crude product was dissolved in acetonitrile (2 mL), and magnesium bromide (74 mg, 0.4 mmol) was added. The mixture was resealed and heated to 50 °C. After 100 minutes, the reaction mixture was quenched with 0.2 M HCl (aq), diluted with brine, and extracted three times into DCM. HPLC purification (acetonitrile:water, 0.1% TFA) gave compound 21. 1H-NMR(400MHz,DMSO-d6)δ12.42(br s,1H),10.45(d,J=7.9Hz,1H),8.40(s,1H),7.36(dd,J=8.6,5.5Hz,2H),7 .14(t,J=8.9Hz,2H),5.42(dd,J=9.6,4.2Hz,1H),5.15-5.04(m,2H),4.72 -4.55(m,2H),4.02(dd,J=12.7,9.7Hz,1H),1.97-1.89(m,4H),1.82(d,J= 12.2Hz,1H),1.56(dt,J=11.9,3.3Hz,1H),1.43(d,J=6.9Hz,3H).LCMS-ESI + (m / z):C 22 H 22 [M+H] of FN3O5 + Theoretical value: 428.16; Measured value: 428.1.

[0522] Example 22

[0523] Preparation of compound 22

[0524] (2R,5S,13aR)-N-((S)-1-(4-fluorophenyl)ethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0525]

[0526] Steps 1 and 2

[0527] Methyl (S)-1-(2,2-dihydroxyethyl)-5-(1-(4-fluorophenyl)ethylcarbamoyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid (21-A, 1 mL, in 0.23 M solution in 19:1 acetonitrile:acetic acid) was treated with (1R,3S)-3-aminocyclopentanol (52 mg, 0.51 mmol) and potassium carbonate (31 mg, 0.22 mmol). The reaction mixture was sealed and heated to 90 °C. After 60 min, the reaction mixture was cooled and partitioned between brine and dichloromethane. The aqueous phase was extracted three times into dichloromethane, and the combined organic phases were mixed, dried over MgSO4, filtered, and concentrated. The crude product was dissolved in acetonitrile (2 mL) and magnesium bromide (91 mg, 0.49 mmol) was added. The reaction mixture was sealed and heated to 50 °C. After 100 minutes, the reaction mixture was quenched with 0.2 M HCl (aq), diluted with brine, and extracted three times into DCM. HPLC purification (acetonitrile:water, 0.1% TFA) gave compound 22. 1 H-NMR(400MHz,DMSO-d6)δ12.44(br s,1H),10.45(d,J=7.7Hz,1H),8.39(s,1H),7.36(dd,J=8.5,5.6Hz,2H),7.1 4(t,J=8.9Hz,2H),5.43(dd,J=9.6,4.0Hz,1H),5.15-5.06(m,2H),4.66(dd, J=12.8,3.9Hz,1H),4.58(s,1H),3.99(dd,J=12.6,9.5Hz,1H),1.93(s,4H), 1.82(d,J=12.0Hz,1H), 1.56(dt,J=12.0,3.0Hz,1H), 1.44(d,J=6.9Hz,3H). LCMS-ESI + (m / z):C 22 H 22 [M+H] of FN3O5 + Theoretical value: 428.16; Measured value: 428.1.

[0528] Example 23

[0529] Preparation of compound 23

[0530] (2S,5R,13aS)-N-(2-fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0531]

[0532] Steps 1 and 2

[0533] 15-B (41 mg, 0.13 mmol) was treated with acetonitrile (1 mL), (2-fluorophenyl)methylamine (17 mg, 0.14 mmol), HATU (67 mg, 0.18 mmol), and N,N-diisopropylethylamine (DIPEA) (24 mg, 0.19 mmol). The reaction mixture was stirred at room temperature for 1 hour, and magnesium bromide (47 mg, 0.26 mmol) was added. The mixture was sealed and heated to 50 °C. After 60 minutes, the reaction mixture was quenched with 0.2 M HCl (aq), diluted with brine, and extracted three times into DCM. HPLC purification (acetonitrile:water, 0.1% TFA) gave compound 23. 1 H-NMR (400MHz, chloroform-d) δ10.42(s,1H),8.34(s,1H),7.36(t,J=7.9Hz,1H),7.24-7.17(m,1H),7.12-6.97(m,2H),5.40-5.32(m,1H),5.29(t,J= 3.5Hz,1H),4.67(s,3H),4.28-4.20(m,1H),4.06-3.95(m,1H),2.20-1.96(m,4H),1.95-1.84(m,1H),1.59(dt,J=12.4,3.3Hz,1H).LCMS-ESI + (m / z):C 21 H 20 [M+H] of FN3O5 + Theoretical value: 414.15; Measured value: 414.2.

[0534] Example 24

[0535] Preparation of compound 24

[0536] (2S,5R,13aS)-N-(3,5-difluorophenylmethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0537]

[0538] Steps 1 and 2

[0539] 15-B (44 mg, 0.14 mmol) was treated with acetonitrile (1 mL), (3,5-difluorophenyl)methylamine (32 mg, 0.23 mmol), HATU (54 mg, 0.14 mmol), and N,N-diisopropylethylamine (37 mg, 0.29 mmol). The reaction mixture was stirred at room temperature for 1 hour, and magnesium bromide (57 mg, 0.31 mmol) was added. The mixture was sealed and heated to 50 °C. After 60 minutes, the reaction mixture was quenched with 0.2 M HCl (aq), diluted with brine, and extracted three times into DCM. HPLC purification (acetonitrile:water, 0.1% TFA) gave compound 24. 1 H-NMR (400MHz, chloroform-d) δ10.39(s,1H),8.42(s,1H),6.82(d,J=7.9Hz,2H),6.65(t,J=8.8Hz,1H),5.38(d,J=7.7Hz,1H),5.28(s,1H) ,4.78-4.41(m,3H),4.32(d,J=12.1Hz,1H),4.02(t,J=10.9Hz,1H),2.30-1.97(m,4H),1.97-1.81(m,1H),1.59(d,J=12.3Hz,1H). LCMS-ESI + (m / z):C 21 H 19 [M+H] of F2N3O5 + Theoretical value: 432.14; Measured value: 432.2.

[0540] Example 25

[0541] Preparation of compound 25

[0542] (2S,5R,13aS)-N-(4-fluoro-3-(trifluoromethyl)benzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0543]

[0544]

[0545] Steps 1 and 2

[0546] 15-B (43 mg, 0.13 mmol) was treated with acetonitrile (1 mL), (4-fluoro-3-(trifluoromethyl)phenyl)methylamine (29 mg, 0.15 mmol), HATU (62 mg, 0.16 mmol), and N,N-diisopropylethylamine (26 mg, 0.20 mmol). The reaction mixture was stirred at room temperature for 1 hour, and magnesium bromide (62 mg, 0.34 mmol) was added. The mixture was sealed and heated to 50 °C. After 60 minutes, the reaction mixture was quenched with 0.2 M HCl (aq), diluted with brine, and extracted three times into DCM. HPLC purification (acetonitrile:water, 0.1% TFA) gave compound 25. 1 H-NMR (400MHz, chloroform-d) δ10.44(s,1H),8.29(s,1H),7.56-7.38(m,2H),7.06(t,J=9.2Hz,1H),5.30(dd,J=9.3,3.5Hz,1H),5.21(s,1H),4.65-4.45 LCMS-ESI + (m / z):C 22 H 19 [M+H] of F4N3O5 + Theoretical value: 482.14; Measured value: 482.2.

[0547] Example 26

[0548] Preparation of compound 26

[0549] (2S,5R,13aS)-N-(4-chloro-3-fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0550]

[0551] Steps 1 and 2

[0552] 15-B (41 mg, 0.13 mmol) was treated with acetonitrile (1 mL), (4-chloro-3-fluorophenyl)methylamine (40 mg, 0.25 mmol), HATU (60 mg, 0.16 mmol), and N,N-diisopropylethylamine (28 mg, 0.22 mmol). The reaction mixture was stirred at room temperature for 1 hour, and magnesium bromide (48 mg, 0.26 mmol) was added. The mixture was sealed and heated to 50 °C. After 60 minutes, the reaction mixture was quenched with 0.2 M HCl (aq), diluted with brine, and extracted three times into DCM. HPLC purification (acetonitrile:water, 0.1% TFA) gave compound 26. 1 H-NMR (400MHz, chloroform-d) δ10.41(s,1H),8.30(s,1H),7.24(t,J=6.1Hz,1H),7.13-6.90(m,2H),5.30(dd,J=9.1,3.2Hz,1H),5.22(s,1H),4.61 LCMS-ESI + (m / z):C 21 H 19 [M+H] of ClFN3O5 + Theoretical value: 448.11; Measured value: 448.2.

[0553] Example 27

[0554] Preparation of compound 27

[0555] (2S,5R)-N-(1-(2,4-difluorophenyl)cyclopropyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0556]

[0557] Step 1

[0558] The suspension of compounds 1-A (1.004 g, 3.19 mmol), amine 27-A (688 mg, 3.35 mmol), and HATU (1.453 g, 3.82 mmol) in CH₂Cl₂ (20 mL) was stirred in a 0 °C bath while N,N-diisopropylethylamine (DIPEA) (2 mL, 11.48 mmol) was added. After 1 hour at 0 °C, the reaction mixture was concentrated into a slurry, diluted with ethyl acetate, and washed with water (×2). After extraction of the aqueous fraction with ethyl acetate (×1), the organic fractions were combined, dried (Na₂SO₄), and concentrated. The residue was purified using a CombiFlash (120 g column) with hexane-ethyl acetate as the eluent. The major peaks were combined and concentrated to give product 27-B at 1.082 (73%). After combining the minor peaks and concentrating, the concentrated residue was dissolved in CH₂Cl₂ and some insoluble substances were filtered off. The filtrate was concentrated to yield an additional 361 mg (24%) of product 27-B. LCMS-ESI + (m / z):C 22 H 25 [M+H] of F2N2O7 + Theoretical value: 467.16; Measured value: 467.1.

[0559] Steps 2 and 3

[0560] Compound 27-B (81 mg, 0.174 mmol) was dissolved in a mixture of acetonitrile (22 mL), AcOH (2 mL), and methanesulfonic acid (0.14 mL, 2.16 mmol) (1 mL) at room temperature, and the solution was stirred at 65 °C for 20 hours.

[0561] After cooling the resulting solution to room temperature, amino alcohol 27-D (50 mg, racemic, 0.363 mmol), K₂CO₃ (50 mg, 0.362 mmol), and acetonitrile (2 mL) were added. The mixture was stirred in a 65 °C bath for 1 hour. After cooling the reaction mixture to room temperature, it was acidified with 1 N HCl (~2 mL), diluted with water (~8 mL), and extracted with CH₂Cl₂ (x 3). The combined extracts were dried (Na₂SO₄), concentrated, and purified by CombiFlash to give 67 mg (82%) of compound 27-E. 1H-NMR (400MHz, CDCl3) δ10.53(s,1H),8.25(s,1H),7.60(td,J=8.5,6.5Hz, 1H),6.85-6.57(m,2H),5.33(br,1H),5.26(dd,J=9.6,3.9Hz,1H),4.60(t,J =3.0Hz,1H),4.18-4.06(m,1H),4.01(s,3H),3.92(dd,J=12.7,9.6Hz,1H), 2.11-1.91(m,4H),1.88-1.71(m,1H),1.60-1.49(m,1H),1.31-1.10(m,4H). 19 F-NMR (376.1MHz, CDCl3) δ-111.80 (q, J=8.8Hz, 1F), -112.05 (p, J=7.9Hz, 1F). LCMS-ESI + (m / z):C 24 H 24 [M+H] of F2N3O5 + Theoretical value: 472.17; Measured value: 472.1.

[0562] Step 4

[0563] The mixture of compound 27-E (67 mg, 0.142 mmol) and MgBr2 (66 mg, 0.358 mmol) in MeCN (3 mL) was stirred at 50 °C for 30 min and cooled to 0 °C, followed by treatment with 1 N HCl (3 mL). After diluting the mixture with water (~30 mL), the product was extracted with CH2Cl2 (×3), and the combined extracts were dried (Na2SO4) and concentrated. The product was purified by HPLC and lyophilized to give product 27 as a 1:1 mixture with trifluoroacetic acid. 1 H-NMR (400MHz, CDCl3) δ10.70(s,1H),8.35(s,1H),7.57(q,J=8.2Hz,1H),6.91-6.56(m,2H),5.31(dt,J=14.3,4.0Hz,2H),4.68(s,1H),4.22(dd ,J=13.2,3.9Hz,1H),3.99(dd,J=12.8,9.3Hz,1H),2.28-1.96(m,5H),1 .88(ddt,J=12.1,8.6,3.7Hz,1H),1.71-1.49(m,1H),1.38-1.11(m,4H). 19F-NMR (376.1MHz, CDCl3) δ-76.37 (s, 3F), -111.6~-111.75 (m, 2F). LCMS-ESI + (m / z):C 23 H 22 [M+H] of F2N3O5 + Theoretical value: 458.15; Measured value: 458.1.

[0564] Example 28

[0565] Preparation of compound 28

[0566] (2S,6R)-N-(1-(2,4-difluorophenyl)cyclopropyl)-9-hydroxy-8,10-dioxo-3,4,5,6,8,10,14,14a-octahydro-2H-2,6-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazocine-11-carboxamide

[0567]

[0568] Steps 1 and 2

[0569] Compound 27-B (87 mg, 0.187 mmol) was dissolved in a mixture of acetonitrile (22 mL), AcOH (2 mL), and methanesulfonic acid (0.14 mL, 2.16 mmol) (2 mL) at room temperature, and the solution was stirred at 65 °C for 20 hours.

[0570] After cooling the resulting solution to room temperature, amino alcohol 28-A (44 mg, racemic, 0.382 mmol) and acetonitrile (2 mL) were added. The mixture was stirred in a 65°C bath for 30 minutes, followed by the addition of K₂CO₃ (41 mg, 0.297 mmol), and the mixture was stirred at 65°C for 21 hours. The reaction mixture was cooled to room temperature, acidified with 1N HCl (~2 mL), diluted with water (~8 mL), and extracted with CH₂Cl₂ (×3). The combined extracts were dried (Na₂SO₄), concentrated, purified by preparative HPLC, and the fraction containing the product was lyophilized. After dissolving the residue in ethyl acetate, the solution was washed with saturated NaHCO₃ (×1), dried (Na₂SO₄), and concentrated to give 18 mg (20%) of compound 28-B as a 1:1 mixture with trifluoroacetic acid. 1H-NMR (400MHz, CDCl3) δ10.54(s,1H),8.26(s,1H),7.63(td,J=8.6,6.6Hz,1H),6.76(dddd, J=21.9,11.2,8.7,2.3Hz,2H),5.39(dd,J=9.6,3.7Hz,1H),4.53-4.36(m,2H),4.09(dd,J=12 .8,3.7Hz,1H),4.03(s,3H),3.99(dd,J=12.7,9.7Hz,1H),2.41-2.20(m,2H),1.84(dtd,J=19 .7,9.3,8.8,4.4Hz,2H),1.74(dd,J=14.6,2.5Hz,1H),1.62-1.35(m,2H),1.34-1.14(m,5H). 19 F-NMR (376.1MHz, CDCl3) δ-111.75 (q, J=8.9Hz, 1F), -112.01 (p, J=7.9Hz, 1F). LCMS-ESI + (m / z):C 25 H 26 [M+H] of F2N3O5 + Theoretical value: 486.18; Measured value: 486.2.

[0571] Step 3

[0572] As described in step 4 of the synthesis of compound 27-E, compound 28-B (18 mg, 0.037 mmol) was treated with MgBr2 to obtain compound 28. 1 H-NMR (400MHz, CDCl3) δ10.66 (s, 1H), 8.29 (s, 1H), 7.59 (td, J = 8.5, 6.6Hz, 1H), 6.89-6 .60(m,2H),5.51(dd,J=9.9,4.0Hz,1H),4.55(s,1H),4.48(t,J=4.2Hz,1H),4.21(dd,J= 12.9,4.1Hz,1H),3.99(dd,J=12.8,9.8Hz,1H),2.56-2.35(m,1H),2.14(dd,J=16.1,5.9 Hz,1H),1.96-1.74(m,3H),1.66-1.37(m,3H),1.28(d,J=4.4Hz,2H),1.26-1.19(m,2H). 19 F-NMR(376.1MHz, CDCl3)δ-76.41(s,3F,-111.79(m,2F). LCMS-ESI+ (m / z):C 24 H 23 [M+H] of F2N3O5 + Theoretical value: 472.17; Measured value: 472.1.

[0573] Example 29

[0574] Preparation of compound 29

[0575] (2R,6S)-N-(1-(2,4-difluorophenyl)cyclopropyl)-9-hydroxy-8,10-dioxo-3,4,5,6,8,10,14,14a-octahydro-2H-2,6-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazocine-11-carboxamide

[0576]

[0577]

[0578] Steps 1 and 2

[0579] Compound 29-B (13 mg, 14%) was prepared from compound 27-B (87 mg, 0.187 mmol) and amino alcohol 29-A (45 mg, 0.391 mmol) using the method described in step 1, similar to the synthesis of compound 28-B. 1 H-NMR (400MHz, CDCl3) δ10.54(s,1H),8.26(s,1H),7.63(td,J=8.6,6.6Hz,1H),6.76(dddd, J=21.9,11.2,8.7,2.3Hz,2H),5.39(dd,J=9.6,3.7Hz,1H),4.53-4.36(m,2H),4.09(dd,J=12 .8,3.7Hz,1H),4.03(s,3H),3.99(dd,J=12.7,9.7Hz,1H),2.41-2.20(m,2H),1.84(dtd,J=19 .7,9.3,8.8,4.4Hz,2H),1.74(dd,J=14.6,2.5Hz,1H),1.62-1.35(m,2H),1.34-1.14(m,5H). 19 F-NMR (376.1MHz, CDCl3) δ-111.75 (q, J=8.9Hz, 1F), -112.01 (p, J=7.9Hz, 1F). LCMS-ESI + (m / z):C 25 H 26[M+H] of F2N3O5 + Theoretical value: 486.18; Measured value: 486.2.

[0580] Step 3

[0581] Compound 29 was prepared from compound 29-B using a method similar to that described in step 2 of the synthesis of compound 16. 1 H-NMR (400MHz, CDCl3) δ10.66 (s, 1H), 8.29 (s, 1H), 7.59 (td, J = 8.5, 6.6Hz, 1H), 6.89-6 .60(m,2H),5.51(dd,J=9.9,4.0Hz,1H),4.55(s,1H),4.48(t,J=4.2Hz,1H),4.21(dd,J= 12.9,4.1Hz,1H),3.99(dd,J=12.8,9.8Hz,1H),2.56-2.35(m,1H),2.14(dd,J=16.1,5.9 Hz,1H),1.96-1.74(m,3H),1.66-1.37(m,3H),1.28(d,J=4.4Hz,2H),1.26-1.19(m,2H). 19 F-NMR(376.1MHz, CDCl3)δ-76.41(s,3F,-111.79(m,2F). LCMS-ESI + (m / z):C 24 H 23 [M+H] of F2N3O5 + Theoretical value: 472.17; Measured value: 472.1.

[0582] Example 30

[0583] Preparation of compound 30

[0584] (2S,5R,13aS)-N-(1-(2,4-difluorophenyl)cyclopropyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0585]

[0586] Steps 1 and 2

[0587] Compound 27-B (150 mg, 0.322 mmol) was dissolved in acetonitrile (2 mL), AcOH (0.2 mL), and methanesulfonic acid (0.007 mL, 0.108 mmol) at room temperature, and the solution was stirred at 65 °C for 20 hours. After cooling the solution to room temperature, amino alcohol 30-A (72.1 mg, chiral, 0.713 mmol), K₂CO₃ (89.4 mg, 0.647 mmol), and acetonitrile (2 mL) were added. The mixture was stirred in a 65 °C bath for 0.5 hours. After cooling the reaction mixture to room temperature, it was acidified with 1N HCl (~3 mL), diluted with water (~12 mL), and extracted with CH₂Cl₂ (×3). The combined extracts were dried (Na₂SO₄), concentrated, and purified by CombiFlash to give 128 mg (84%) of compound 30-B. 1 H-NMR (400MHz, CDCl3) δ10.52(s,1H),8.24(s,1H),7.61(td,J=8.6,6.6Hz,1H) ,6.85-6.65(m,2H),5.33(t,J=4.1Hz,1H),5.25(dd,J=9.5,3.9Hz,1H),4.61(d, J=3.4Hz,1H),4.18-4.08(m,1H),4.02(s,3H),3.99-3.87(m,1H),2.12-1.91(m ,4H),1.85-1.69(m,1H),1.55(ddd,J=12.3,4.1,2.8Hz,1H),1.31-1.14(m,4H). 19 F-NMR (376.1MHz, CDCl3) δ-111.79 (q, J=8.8Hz, 1F), -112.05 (p, J=7.9Hz, 1F).LCMS-ESI + (m / z):C 24 H 24 [M+H] of F2N3O5 + Theoretical value: 472.17; Measured value: 472.2.

[0588] Step 3

[0589] The mixture of compound 30-B (128 mg, 0.272 mmol) and MgBr2 (130 mg, 0.706 mmol) in MeCN (5 mL) was stirred at 50 °C for 30 min and cooled to 0 °C, followed by treatment with 1 N HCl (4 mL). After diluting the mixture with water, the product was extracted with CH2Cl2 (×3), and the combined extracts were dried (Na2SO4) and concentrated. The product was purified by CombiFlash to give product 30. 1 H-NMR (400MHz, CDCl3) δ12.27(s,1H),10.52(s,1H),8.16(s,1H),7.61(td ,J=8.6,6.6Hz,1H),6.96-6.54(m,2H),5.36-5.23(m,2H),4.66(t,J=3.1H z,1H),4.18-4.06(m,1H),3.94(dd,J=12.8,9.4Hz,1H),2.20-1.95(m,4H) ,1.89(td,J=11.4,9.8,6.7Hz,1H),1.70-1.54(m,1H),1.32-1.15(m,4H). 19 F-NMR (376.1MHz, CDCl3) δ-111.87 (q, J=8.9Hz, 1F), -112.21 (p, J=7.9Hz, 1F). LCMS-ESI + (m / z):C 23 H 22 [M+H] of F2N3O5 + Theoretical value: 458.15; Measured value: 458.2.

[0590] Example 31

[0591] Preparation of compound 31

[0592] (2R,5S)-N-(1-(2,4-difluorophenyl)cyclopropyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0593]

[0594]

[0595] Steps 1 and 2

[0596] Compound 31-B (123 mg, 81%) was prepared from compound 27-B (150 mg, 0.322 mmol) and amino alcohol 31-A (70.3 mg, 0.695 mmol) using a method similar to that described in steps 1 and 2 of the synthesis of compound 30-B. 1 H-NMR (400MHz, CDCl3) δ10.52(s,1H),8.24(s,1H),7.62(td,J=8.6,6.6Hz,1H),6 .91-6.63(m,2H),5.33(t,J=4.1Hz,1H),5.25(dd,J=9.5,3.9Hz,1H),4.61(d,J=3. 4Hz,1H),4.14-4.07(m,1H),4.03(s,3H),3.93(dd,J=12.7,9.5Hz,1H),2.12-1.91 (m,4H),1.85-1.69(m,1H),1.55(ddd,J=12.3,4.1,2.8Hz,1H),1.31-1.14(m,4H). 19 F-NMR (376.1MHz, CDCl3) δ-111.79 (q, J=9.2, 8.7Hz, 1F), -112.03 (h, J=8.1, 7.5Hz, 1F). LCMS-ESI + (m / z):C 24 H 24 [M+H] of F2N3O5 + Theoretical value: 472.17; Measured value: 472.1.

[0597] Step 3

[0598] Compound 31 is prepared from compound 31-B using a method similar to that described in step 3 of the synthesis of compound 30. 1 H-NMR (400MHz, CDCl3) δ12.26(s,1H),10.49(s,1H),8.13(s,1H),7.58(td,J=8 .6,6.5Hz,1H),6.90-6.56(m,2H),5.32(dd,J=9.4,4.1Hz,1H),5.27-5.22(m,1 H),4.64(t,J=3.1Hz,1H),4.11(dd,J=12.8,4.0Hz,1H),4.01-3.79(m,1H),2.2 8-1.95(m,4H),1.95-1.80(m,1H),1.71(m,1H),1.56(m,1H),1.42-1.08(m,4H). 19F-NMR (376.1MHz, CDCl3) δ-111.95 (q, J=8.9Hz, 1F), -112.22 (p, J=7.9Hz, 1F).LCMS-ESI + (m / z):C 23 H 22 [M+H] of F2N3O5 + Theoretical value: 458.15; Measured value: 458.1.

[0599] Example 32

[0600] Preparation of compound 32

[0601] (2S,5R)-N-(1-(2,4-difluorophenyl)cyclobutyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0602]

[0603] At room temperature, a solution of compound 32-A (22.2 mg, 0.069 mmol), compound 32-B (18.7 mg, 0.102 mmol), and HATU (43 mg, 0.113 mmol) in CH₂Cl₂ (2 mL) was stirred while N,N-diisopropylethylamine (DIPEA) (0.075 mL, 0.431 mmol) was added. After 30 minutes, the reaction mixture was diluted with ethyl acetate and washed with water (x²). After extraction of the aqueous fraction with EA (x¹), the organic fractions were combined, dried, concentrated, and dried under vacuum.

[0604] The mixture of the crude product and MgBr2 (35 mg, 0.190 mmol) in MeCN (2 mL) was stirred in a 50 °C bath for 1 hour and cooled to 0 °C, followed by treatment with 1 N HCl (~1 mL). The resulting solution was diluted with water and extracted with CH2Cl2 (×3). The combined extracts were dried (Na2SO4) and concentrated. The product was purified by preparative HPLC and lyophilized to give compound 32. 1H-NMR (400MHz, CDCl3) δ10.87 (s, 1H), ~ 9.3 (br, 1H), 8.35 (s, 1H), 7.50 (td, J = 8.7 ,6.3Hz,1H),6.89-6.78(m,1H),6.72(ddd,J=11.2,8.9,2.6Hz,1H),5.48-5.12(m, 2H),4.72-4.60(m,1H),4.22(dd,J=13.0,4.1Hz,1H),3.98(dd,J=12.9,9.4Hz,1H) ,2.68(m,4H),2.33-1.98(m,6H),1.90(m,2H),1.60(ddd,J=12.4,4.1,2.7Hz,1H). 19 F-NMR (376.1MHz, CD3CN) δ -76.39 (s, 3F), -110.50 (q, J = 9.2Hz, 1F), -112.65 (p, J = 7.8Hz, 1F). LCMS-ESI + (m / z):C 24 H 24 [M+H] of F2N3O5 + Theoretical value: 472.17; Measured value: 472.0.

[0605] Example 33

[0606] Preparation of compound 33

[0607] (2S,5R)-N-(1-(2,4-difluorophenyl)cyclopentyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0608]

[0609] As described in the synthesis of compound 32, compound 33 was obtained from compound 32-A and compound 33-A. 1H-NMR (400MHz, CDCl3) δ10.70(s,1H),~9.5(br,1H),8.41(s,1H),7.43(td,J=8.9,6.4 Hz,1H),6.85-6.76(m,1H),6.72(ddd,J=11.5,8.8,2.6Hz,1H),5.48-5.18(m,2H),4.6 8(t,J=3.2Hz,1H),4.26(dd,J=13.0,4.1Hz,1H),4.00(dd,J=13.0,9.4Hz,1H),2.72-2 .45(m,2H),2.22-1.96(m,6H),1.96-1.75(m,5H),1.60(ddd,J=12.5,4.1,2.7Hz,1H). 19 F-NMR(376.1MHz,CD3CN)δ-76.41(s,3F),-107.86(q,J=9.4Hz,1F),-113.13(p,J=8.0Hz,1F).LCMS-ESI + (m / z):C 25 H 26 [M+H] of F2N3O5 + Theoretical value: 486.18; Measured value: 485.9.

[0610] Example 34

[0611] Preparation of compound 34

[0612] (2S,5R)-N-(1-(2,4-difluorophenyl)cyclohexyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0613]

[0614] As described in the synthesis of compound 32, compound 34 was obtained from compound 32-A and compound 34-A. 1H-NMR (400MHz, CDCl3) δ10.83 (s, 1H), ~ 9.6 (br, 1H), 8.44 (s, 1H), 7.37 (td, J = 9.0, 6.4Hz, 1H), 6 .97-6.76(m,1H),6.69(ddd,J=11.9,8.8,2.7Hz,1H),5.48-5.18(m,2H),4.68(t,J=3.0Hz,1H), 4.28(dd,J=13.1,4.1Hz,1H),4.03(dd,J=13.0,9.4Hz,1H),2.60(d,J=13.1Hz,2H),2.29-1.96( m,4H),1.95-1.77(m,4H),1.77-1.65(m,4H),1.61(ddd,J=12.5,4.1,2.7Hz,1H),1.30(br,1H). 19 F-NMR(376.1MHz,CD3CN)δ-76.41(s,3F),-107.86(q,J=9.4Hz,1F),-113.13(p,J=8.0Hz,1F).LCMS-ESI + (m / z):C 26 H 28 [M+H] of F2N3O5 + Theoretical value: 500.20; Measured value: 500.0.

[0615] Example 35

[0616] Preparation of compound 35

[0617] (2S,5R)-N-(4-(2,4-difluorophenyl)tetrahydro-2H-pyran-4-yl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0618]

[0619] As described in the synthesis of compound 32, compound 35 was obtained from compound 32-A and compound 35-A. 1H-NMR (400MHz, CDCl3) δ10.95(s,1H),8.33(s,1H),~7.6(br,1H),7.38(td,J=9.0,6.3Hz,1 H),6.85(td,J=8.4,2.6Hz,1H),6.73(ddd,J=11.7,8.6,2.6Hz,1H),5.32(dt,J=14.4,4.0Hz ,2H),4.68(t,J=3.1Hz,1H),4.24(dd,J=13.0,3.9Hz,1H),4.11-3.81(m,5H),2.60(d,J=13 .7Hz,2H),2.33-2.17(m,2H),2.18-1.97(m,4H),1.87(m,1H),1.61(dt,J=12.5,3.3Hz,1H). 19 F-NMR(376.1MHz,CD3CN)δ-76.40(s,3F),-108.78(q,J=10.3,9.8Hz,1F),-112.63(p,J=8.0Hz,1F).LCMS-ESI + (m / z):C 25 H 26 [M+H] of F2N3O6 + Theoretical value: 502.18; Measured value: 502.0.

[0620] Example 36

[0621] Preparation of compound 36

[0622] (2S,5R)-N-((S)-1-(2,4-difluorophenyl)-2,2,2-trifluoroethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0623]

[0624] As described in the synthesis of compound 32, compound 36 was obtained from compound 32-A and compound 36-A. 1H-NMR (400MHz, CDCl3) δ11.31 (d, J = 9.4Hz, 1H), 8.41 (s, 1H), 7.65-7.44 (m, 1H), 6.95 (ddd ,J=9.6,5.6,2.0Hz,1H),6.92-6.79(m,1H),6.15(h,J=7.4Hz,1H),~6(br,1H),5.41(dd,J= 9.5,4.0Hz,1H),5.31(t,J=4.0Hz,1H),4.70(s,1H),4.34(dd,J=12.8,3.9Hz,1H),4.05(d d,J=12.9,9.4Hz,1H),2.26-1.99(m,4H),1.99-1.87(m,1H),1.62(dt,J=12.6,3.4Hz,1H). 19 F-NMR(376.1MHz, CDCl3)δ-75.23(t,J=6.9Hz,3F),-76.33(s,3F),-108.31(m,1F),-112.30(p,J=8.0Hz,1F).LCMS-ESI + (m / z):C 22 H 19 [M+H] of F5N3O5 + Theoretical value: 500.12; Measured value: 500.1.

[0625] Example 37

[0626] Preparation of compounds 37

[0627] (3S,11aR)-N-(1-(2,4-difluorophenyl)cyclopropyl)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydrooxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

[0628]

[0629] Step 1

[0630] Methyl 5-(1-(2,4-difluorophenyl)cyclopropylcarbamoyl)-1-(2,2-dimethoxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid (27-B, 0.150 g, 0.32 mmol) in acetonitrile (1.5 mL) and acetic acid (0.2 mL) was treated with methanesulfonic acid (0.05 mL), sealed with a yellow cap, and heated to 70 °C. After 16 hours, the mixture was cooled to give a crude solution of methyl 5-(1-(2,4-difluorophenyl)cyclopropylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid 27-C. LCMS-ESI + (m / z):C 18 H 19 [M+H] of F2N2O7 + Theoretical value: 439; Measured value: 439.

[0631] Steps 2 and 3

[0632] Methyl 5-(1-(2,4-difluorophenyl)cyclopropylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid (27-C, 0.32 mmol, from the crude mixture in the preceding steps) was dissolved in acetonitrile (1.5 mL) and acetic acid (0.2 mL). (S)-2-aminoprop-1-ol (0.048 g, 0.64 mmol) and K₂CO₃ (0.088 g, 0.64 mmol) were added to the reaction mixture. The reaction mixture was sealed and heated to 70 °C. After 3 hours, the reaction mixture was cooled and magnesium bromide (0.081 g, 0.44 mmol) was added. The mixture was resealed and heated to 50 °C. After 10 minutes, the reaction mixture was cooled to 0 °C and 1N hydrochloric acid (0.5 mL) was added. The reaction mixture was then diluted with MeOH (2 mL). After filtration, the crude substance was purified by preparative-HPLC (30-70% acetonitrile: water, 0.1% TFA) to obtain compound 37 as a TFA salt. 1 H-NMR (400MHz, methanol-d4) δ8.31(s,1H),7.62(td,J=9.2,8.7,6.5Hz,1H),7.02-6.78(m,2H),5.53-5.20(m,1H),4.68(dd,J=12.3,4.2H z,1H),4.40(dq,J=19.1,6.7Hz,2H),3.98(dd,J=12.2,10.0Hz,1H),3.71(dd,J=8.3,6.3Hz,1H),1.41(d,J=6.1Hz,3H),1.22(s,4H).19 F-NMR (376MHz, methanol-d4) δ -113.66–113.95 (m, 1F), -113.94–114.29 (m, 1F). LCMS-ESI + (m / z):C 21 H 20 [M+H] of F2N3O5 + Theoretical value: 432; Measured value: 432.

[0633] Example 38

[0634] Preparation of compound 38

[0635] (1S,4R,12aR)-N-(2,4-difluorophenylmethyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0636]

[0637]

[0638] Step 1

[0639] A solution of compound 38-A (1562 mg, 5.799 mmol) (see Example 41b in WO 97 / 05139) in 10 mL of THF was stirred at -78 °C, while 2.0 M LiBH4 in 3.2 mL of THF was added, and the mixture was stirred at room temperature. After 3 hours, another 2.0 M LiBH4 in 3.2 mL of THF was added, and the solution was stirred at room temperature for 17.5 hours. After diluting the reaction mixture with ethyl acetate and slowly adding water, the two phases were separated, and the aqueous fraction was extracted with ethyl acetate (×1). The two organic fractions were washed with water (×1), combined, dried (Na2SO4), and concentrated. The residue was purified by CombiFlash (40 g column) using hexane-ethyl acetate as the eluent to give compound 38-B. 1 ¹H-NMR (400MHz, chloroform-d) δ 4.11 (s, 1H), 3.65–3.52 (m, 2H), 3.45 (m, 1H), 2.32 (d, J = 4.1 Hz, 1H), 2.20 (s, 1H), 1.75–1.64 (m, 2H), 1.61 (m, 2H), 1.49–1.41 (m, 1H), 1.47 (s, 9H), 1.28–1.23 (d, J = 10 Hz, 1H). LCMS-ESI +(m / z):C 12 H 22 NO3's [M+H] + Theoretical value: 228.16; Measured value: 227.7.

[0640] Step 2

[0641] A solution of compound 38-B (589 mg, 2.591 mmol) and NEt3 (0.47 mL, 3.369 mmol) in CH2Cl2 (6 mL) was stirred at 0 °C while MsCl (0.22 mL, 2.842 mmol) was added. After 1 hour at room temperature, the mixture was diluted with ethyl acetate and then diluted with water (×2). The aqueous fraction was extracted with ethyl acetate (×1), and the organic fractions were combined, dried (Na2SO4), and concentrated. The residue was purified by CombiFlash (40 g column) using hexane-ethyl acetate as the eluent to give compound 38-C. 1 H-NMR (400MHz, chloroform-d) δ4.39-4.28(m,1H),4.16(s,0.4H),4.06(s,0.6H),3.98 (dd,J=10.0,8.7Hz,0.6H),3.86(t,J=9.6Hz,0.4H),3.51(dd,J=9.3,3.7Hz,0 .6H),3.43(dd,J=9.3,3.6Hz,0.4H),3.02(s,3H),2.59(m,1H),1.82-1.58(m, 4H), 1.51-1.44 (m, 9H), 1.41 (d, J = 14.8Hz, 1H), 1.31 (s, 0.6H), 1.29 (s, 0.4H).

[0642] Step 3

[0643] Sodium azide (819 mg, 12.6 mmol) was added to a solution of compound 38-C (769 mg, 2.518 mmol) in DMF (5 mL). The reaction mixture was stirred at 50 °C for 15 h, at 80 °C for 5 h, and at 100 °C for 19 h. The reaction mixture was diluted with 5% LiCl solution, and the product was extracted with ethyl acetate (×2). After washing the organic fractions with water (×1), the two organic fractions were combined, dried (Na2SO4), and concentrated. The residue was purified by CombiFlash (40 g column) using hexane-ethyl acetate as the eluent to give compound 38-D. 1H-NMR (400MHz, chloroform-d) δ4.16 (s, 0.4H), 4.06 (s, 0.6H), 3.61 (dd, J = 12.2, 3.6Hz, 0.6H), 3 .51(dd,J=12.1,3.2Hz,0.4H),3.38(dd,J=9.4,3.4Hz,0.6H),3.26(dd,J=9.8,3.3Hz,0 .4H),3.06(dd,J=12.2,9.4Hz,0.6H),3.01-2.92(m,0.4H),2.48(d,J=5.2Hz,1H),1.82 -1.57(m,4H),1.46(d,J=3.0Hz,9H),1.42(m,1H),1.28(m,0.6H),1.27-1.23(m,0.4H).

[0644] Step 4

[0645] 10% Pd / C (52 mg) was added to a solution of compound 38-D (507 mg, 2.009 mmol) in ethyl acetate (10 mL) and EtOH (10 mL). The reaction mixture was stirred for 1.5 hours under a H2 atmosphere. The mixture was filtered through diatomaceous earth and the filtrate was concentrated to give crude compound 38-E. LCMS-ESI + (m / z):C 12 H 23 [M+H] of N2O2 + Theoretical value: 227.18; Measured value: 226.8.

[0646] Step 5

[0647] At room temperature, a mixture of crude compound 38-E (206 mg, 0.910 mmol), compound 38-F (330 mg, 0.953 mmol), and NaHCO3 (154 mg, 1.833 mmol) in water (3 mL) and EtOH (3 mL) was stirred for 20 hours. After diluting the reaction mixture with water and extracting with ethyl acetate (×2), the extracts were washed with water (×1), combined, dried (Na2SO4), and concentrated to give the crude pyridine product.

[0648] The crude residue (388 mg) was dissolved in CH₂Cl₂ (4 mL) and 4N HCl in dioxane (4 mL). After 1.5 hours, another 4N HCl in dioxane (4 mL) was added, and the mixture was stirred at room temperature for 1 hour. The mixture was dried to dryness, co-evaporated with toluene (×1), and dried under vacuum for 30 minutes.

[0649] The crude residue and 1,8-diazabicycloundecyl-7-ene (DBU) (1.06 mL, 7.088 mmol) were stirred in toluene (10 mL) in a 110 °C bath. After 30 min, the mixture was concentrated and purified by using a CombiFlash 40 g column with ethyl acetate-20% MeOH / ethyl acetate as eluent to give compound 38-G. 1 ¹H-NMR (400MHz, chloroform-d) δ 8.03 (s, 1H), 7.68–7.58 (m, 2H), 7.36–7.27 (m, 3H), 5.53 (d, J = 9.9 Hz, 1H), 5.11 (d, J = 9.9 Hz, 1H), 4.93 (s, 1H), 4.43–4.30 (m, 2H), 3.89 (dd, J = 12.2, 3.3 Hz) ,1H),3.73(t,J=12.0Hz,1H),3.59(dd,J=11.9,3.3Hz,1H),2.53(d,J=2.8Hz,1H),1.87- 1.67(m,4H),1.55(d,J=10.0Hz,1H),1.51-1.45(m,1H),1.38(t,J=7.1Hz,3H).LCMS-ESI + (m / z):C 23 H 25 [M+H] of N2O5 + Theoretical value: 409.18; Measured value: 409.2.

[0650] Step 6

[0651] At room temperature, a mixture of compound 38-G (232 mg, 0.568 mmol) in THF (3 mL) and MeOH (3 mL) was stirred while 1N KOH (3 mL) was added. After 1 hour, the reaction mixture was neutralized with 1N HCl (~3.1 mL), concentrated, and the residue was concentrated with toluene (×3). After drying the residue under vacuum for 30 minutes, a suspension of the crude residue, 2,4-difluorobenzylamine (86 mg, 0.601 mmol), and HATU (266 mg, 0.700 mmol) in CH2Cl2 (4 mL) and DMF (4 mL) was stirred at 0 °C while N,N-diisopropylethylamine (DIPEA) (0.7 mL, 4.019 mmol) was added. After 45 minutes, additional 2,4-difluorobenzylamine (86 mg, 0.559 mmol), HATU (266 mg, 0.700 mmol), and N,N-diisopropylethylamine (DIPEA) (0.7 mL, 4.019 mmol) were added at room temperature. After 1.25 hours, the mixture was concentrated to remove most of the CH2Cl2, diluted with ethyl acetate, and washed with 5% LiCl (×2). After extraction of the aqueous fraction with ethyl acetate (×1), the organic fractions were combined, dried (Na2SO4), and concentrated. The residue was purified by CombiFlash (40 g column) using ethyl acetate-20% MeOH / ethyl acetate as the eluent to give compound 38-H. 1 ¹H-NMR (400MHz, chloroform-d) δ 10.48 (t, J = 6.0Hz, 1H), 8.33 (s, 1H), 7.62–7.51 (m, 2H), 7.40–7.27 (m, 4H), 6.87–6.75 (m, 2H), 5.39 (d, J = 10.0Hz, 1H), 5.15 (d, J = 10.0Hz, 1H), 4.92 ( s,1H),4.68-4.53(m,2H),3.97(dd,J=12.5,3.4Hz,1H),3.77(t,J=12.2Hz,1H),3.55 (dd,J=12.1,3.3Hz,1H),2.53(d,J=3.1Hz,1H),1.88-1.62(m,4H),1.59-1.42(m,2H). 19 F-NMR (376MHz, chloroform-d) δ -112.17 (q, J = 7.6Hz, 1F), -114.79 (q, J = 8.6Hz, 1F). LCMS-ESI + (m / z): [M+H] of C28H26F2N3O4 + Theoretical value: 506.19; Measured value: 506.2.

[0652] Step 7

[0653] Compound 38-H (240 mg, 0.475 mmol) was dissolved in TFA (3 mL) for 30 minutes at room temperature, and the solution was concentrated. The residue was purified using a CombiFlash (40 g column) with CH2Cl2-20% MeOH in CH2Cl2 as the eluent. After concentrating the collected product fraction, the residue was milled in MeCN (~2 mL) at 0 °C for 15 minutes, the solid was filtered and washed with MeCN. The collected solid was dried under vacuum to give compound 38.

[0654] The filtrate was concentrated, and the residue was dissolved in MeCN (~1 mL) and water (~1 mL) by heating. The solution was slowly cooled to room temperature and then cooled in an ice bath for 15 minutes. The solid was filtered and washed with MeCN and dried under vacuum to give the other compound 38. 1 ¹H-NMR (400MHz, chloroform-d) δ 11.68 (s, 1H), 10.42 (s, 1H), 8.27 (s, 1H), 7.41–7.31 (m, 1H), 6.86–6.73 (m, 2H), 4.90 (d, J = 2.5 Hz, 1H), 4.71–4.53 (m, 2H), 4.07 (d, J = 10.6 Hz, 1H), 3.90–3.67 (m, 2H), 2.68 (s, 1H), 2.01 (s, 1H), 1.97–1.80 (m, 3H), 1.80–1.62 (m, 2H). 19 F-NMR (376MHz, chloroform-d) δ -112.28 (m, 1F), -114.74 (m, 1F). LCMS-ESI + (m / z):C 21 H 19 [M+H] of F2N3O4 + Theoretical value: 416.14; Measured value: 416.3.

[0655] Examples 39 and 40

[0656] Preparation of compounds 39 and 40

[0657] (2R,3S,5R,13aS)-N-(2,4-difluorophenylmethyl)-8-hydroxy-3-methyl-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-Formamide 39 and (2S,3R,5S,13aR)-N-(2,4-difluorophenylmethyl)-8-hydroxy-3-methyl-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-Formamide 40

[0658]

[0659] Step 1

[0660] Cuprous cyanide (290 mg, 3.27 mmol) was suspended in 3.3 mL of THF and cooled to -78 °C. A 1.6 M solution of MeLi (4.1 mL, 6.56 mmol) in diethyl ether was added dropwise, and the reaction solution was warmed to room temperature over 2 hours, then cooled to -78 °C. (1R,3R,5S)-6-oxobicyclo[3.1.0]hexane-3-ylcarbamate tert-butyl ester (330 mg, 1.66 mmol) was added dropwise to 3.3 mL of THF, followed by the addition of boron trifluoride diethyl ether (0.25 mL, 1.99 mmol). The mixture was warmed to -30 °C over 30 minutes and stirred between -35 °C and -25 °C for 1 hour. The reaction solution was then heated to room temperature and quenched with a saturated mixture of NH3(aq) / NH4(aq), extracted with EtOAc, washed with brine, dried over MgSO4, filtered, concentrated, and purified by SGC (0-10% EtOH / DCM) to obtain racemic (1S,3S,4S)-3-hydroxy-4-methylcyclopentylcarbamate tert-butyl ester. 1 H-NMR (400MHz, chloroform-d) δ5.16(s,1H),3.98(s,1H),3.74(q,J=4.3Hz,1H),3.65(q,J=7.0Hz,1H),2.23(dt,J=14.0,7.0Hz,1H),1 .98(dt,J=13.3,7.0Hz,1H),1.89-1.79(m,1H),1.58-1.44(m,1H),1.38(s,9H),1.18(t,J=7.0Hz,1H),0.91(d,J=7.0Hz,3H).

[0661] Step 2

[0662] 3 mL of HCl / dioxane (4 M, 12 mmol) was added to a solution of racemic (1S,3S,4S)-3-hydroxy-4-methylcyclopentylcarbamate tert-butyl ester (182 mg, 0.85 mmol). The reaction mixture was stirred for 2 hours at room temperature, concentrated, and chased twice with toluene to give racemic (1S,2S,4S)-4-amino-2-methylcyclopentanol.

[0663] Step 3

[0664] Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid (1-C, 310 mg, 0.75 mmol), racemic (1S,2S,4S)-4-amino-2-methylcyclopentanol (115 mg, 0.76 mmol), and potassium carbonate (232 mg, 1.68 mmol) were dissolved in 3.8 mL of acetonitrile / 0.2 mL of acetic acid and stirred at 90 °C for 2 hours. The reaction mixture was then partitioned between DCM and brine. The aqueous phase was extracted into DCM, and the combined organic phases were dried over MgSO4, filtered, concentrated, and purified by SGC (0-10% EtOH / DCM) to give intermediate 39-A.

[0665] Step 4

[0666] Intermediate 39-A (190 mg) was separated by chiral preparative HPLC on a Lux Cellulose-2 column using a 9:1 ACN:MeOH eluent, yielding enantiomer-enriched intermediates 39-B (first elution peak) and 40-A (second elution peak). For intermediate 39-B (absolute stereochemistry confirmed by X-ray crystallography), the chiral HPLC retention time was 3.98 min (Lux Cellulose-2 IC, 150 x 4.6 mm, 2 mL / min 9:1 ACN:MeOH). For intermediate 40-A (absolute stereochemistry confirmed by X-ray crystallography), the chiral HPLC retention time was 6.35 min (Lux Cellulose-2 IC, 150 x 4.6 mm, 2 mL / min 9:1 ACN:MeOH).

[0667] Step 5a

[0668] Magnesium bromide (68 mg, 0.37 mmol) was added to intermediate 39-B (83 mg, 0.18 mmol) in 2 mL of acetonitrile. The reaction mixture was stirred at 50 °C for 1 hour, acidified with 10% HCl aqueous solution, partitioned between aqueous solution and dichloromethane, and the aqueous phase was extracted into dichloromethane. The combined organic phases were dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (0-10% EtOH / DCM) to give compound 39. 1 H-NMR (400MHz, chloroform-d) δ12.32(s,1H),10.36(s,1H),8.29(s,1H),7.44-7.33(m,1H),6.88-6.76(m,2H),5.37(dd,J= 9.5,4.1Hz,1H),5.28(t,J=5.3Hz,1H),4.63(d,J=5.9Hz,2H),4.23(d,J=23.0Hz,2H),3.99(dd,J=12.7,9.5Hz,1H) ,3.72(q,J=7.0Hz,1H),2.51(dq,J=13.7,6.8,6.1Hz,1H),2.15(ddd,J=14.7,8.3,2.3Hz,1H),1.94(d,J=12.7Hz,1 H), 1.77 (ddd, J=12.7, 4.0, 2.9Hz, 1H), 1.61 (dt, J=14.6, 5.2Hz, 2H), 1.24 (t, J=7.0Hz, 1H), 1.09 (d, J=7.2Hz, 3H). LCMS-ESI + (m / z):C 22 H 22 [M+H] of F2N3O5 + Theoretical value: 446.15; Measured value: 446.2.

[0669] Step 5b

[0670] Magnesium bromide (59 mg, 0.32 mmol) was added to a solution of intermediate 40-A (70 mg, 0.15 mmol) in 2 mL of acetonitrile. The reaction mixture was stirred at 50 °C for 1 hour, acidified with 10% aqueous HCl, partitioned between aqueous solution and dichloromethane, and the aqueous phase was extracted into dichloromethane. The combined organic phases were dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (0-10% EtOH / DCM) to give compound 40. 1H-NMR (400MHz, chloroform-d) δ12.32(s,1H),10.36(s,1H),8.29(s,1H),7.44-7.33(m,1H),6.88-6.76(m,2H),5.37(dd,J= 9.5,4.1Hz,1H),5.28(t,J=5.3Hz,1H),4.63(d,J=5.9Hz,2H),4.23(d,J=23.0Hz,2H),3.99(dd,J=12.7,9.5Hz,1H) ,3.72(q,J=7.0Hz,1H),2.51(dq,J=13.7,6.8,6.1Hz,1H),2.15(ddd,J=14.7,8.3,2.3Hz,1H),1.94(d,J=12.7Hz,1 H), 1.77 (ddd, J=12.7, 4.0, 2.9Hz, 1H), 1.61 (dt, J=14.6, 5.2Hz, 2H), 1.24 (t, J=7.0Hz, 1H), 1.09 (d, J=7.2Hz, 3H). LCMS-ESI + (m / z):C 22 H 22 [M+H] of F2N3O5 + Theoretical value: 446.15; Measured value: 446.2.

[0671] Example 41

[0672] Preparation of compound 41

[0673] (1R,4S,12aR)-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0674]

[0675] Step 1

[0676] A solution of 41-A (2020 mg, 7.463 mmol) (prepared using the same method as 38-A) in 14 mL THF was stirred at 0 °C while 2.0 M LiBH4 in 7.5 mL, 15 mmol THF was added. After stirring the resulting mixture at room temperature for 21 hours, it was cooled at 0 °C, diluted with EA, and then slowly quenched with water. After separation of the two phases, the aqueous fraction was extracted with EA (x1), and the two organic fractions were washed with water (x1), combined, dried (Na2SO4), and concentrated. The residue was purified using a CombiFlash (120 g column) with hexane-EA as the eluent to give 41-B. LCMS-ESI + (m / z):C8H 14 NO3 [M-C4H8+H] + Theoretical value: 172.10; Measured value: 171.95.

[0677] Step 2

[0678] To a 100-mL round-bottom flask, charge reactants 41-B (1.6 g, 7.05 mmol) and triethylamine (0.94 g, 9.3 mmol) in DCM (20 mL). Add methanesulfonyl chloride (0.91 g, 8.0 mmol) to the reaction mixture. Then, stir the reaction mixture at room temperature for 3 hours. Dilute the mixture with EA (100 mL) and wash with water (2x). Extract the aqueous fraction with EA (1x), combine the organic fractions, dry (Na2SO4), and concentrate. Purify the residue using a CombiFlash (120 g column, column used) with hexane-EA as the eluent to give 41-C. LCMS-ESI + (m / z):[M+H) + Theoretical value: C 18 H 19 F2N2O7:306; Measured value: 306.

[0679] Step 3

[0680] The reactants 41-C (2.1 g, 6.9 mmol) and sodium azide (2.3 g, 34.5 mmol) in DMF (10 mL) were charged into a 100 mL round-bottom flask. The reaction mixture was then stirred overnight at 100 °C. The mixture was diluted with EA (100 mL) and washed with water (2x). The aqueous fraction was extracted with EA (1x), and the organic fractions were combined, dried (Na₂SO₄), and concentrated. The residue was purified to 41-D using a CombiFlash column (120 g column used) with hexane-EA as the eluent. LCMS-ESI + (m / z):C 18 H 19 [M+H] of F2N2O7 + Theoretical value: 253; Measured value: 253.

[0681] Step 4

[0682] Pd / C (130 mg) was added to a solution of reactant 41-D (1.3 g) in EA (20 mL) and EtOH (20 mL) (purged with N2). The mixture was stirred under H2 for 3 hours. The mixture was filtered through diatomaceous earth and the filtrate was concentrated to give compound 41-E. LCMS-ESI + (m / z):C 18 H 19 [M+H] of F2N2O7 + Theoretical value: 227; Measured value: 227.

[0683] Step 5

[0684] In a 100-mL round-bottom flask, 41-E (1.05 g, 4.62 mmol) and reactant 38-F (1.6 g, 4.62 mmol) in ethanol (20 mL) were added. Sodium bicarbonate (0.77 g, 9.2 mmol) in water (20 mL) was added to the reaction mixture. The mixture was then stirred overnight at room temperature. The mixture was diluted with EA (100 mL) and washed with water (2x). The aqueous fraction was extracted with EA (1x), and the organic fractions were combined, dried (Na₂SO₄), and concentrated. The crude product (2.4 g) was used in the next step without further purification. LCMS-ESI + (m / z):C 18 H 19 [M+H] of F2N2O7 + Theoretical value: 556; Measured value: 556.

[0685] The crude product from the preceding reaction was charged into a 100-mL round-bottom flask in 4N HCl / dioxane (24.7 mL). The reaction mixture was then stirred for 1 hour at room temperature. After concentration, the intermediate (2.1 g) in toluene (30 mL) and DBU (3.27 g, 21.5 mmol) were heated to 110 °C and stirred for 1 hour. After concentration, the residue was purified by CombiFlash (120 g column) using hexane-ethyl acetate as eluent to give 41-F. LCMS-ESI + (m / z):C 18 H 19 [M+H] of F2N2O7 + Theoretical value: 409; Measured value: 409.

[0686] Step 6

[0687] Reactant 41-F (0.5 g, 1.22 mmol) in THF (5 mL) and MeOH (5 mL) was placed in a 100 mL round-bottom flask. 1 N KOH (3.7 mL) was added to the reaction mixture. The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1 N HCl (3.7 mL), concentrated to remove most of the organic solvent, and extracted with EtOAc (2X). The organic layers were combined, dried (Na₂SO₄), and concentrated to give compound 41-G.

[0688] Step 7

[0689] To a 100-mL round-bottom flask, reactants 41-G (0.14 g, 0.37 mmol), (2,4,6-trifluorophenyl)methylamine (0.12 g, 0.73 mmol), N,N-diisopropylethylamine (DIPEA) (0.24 g, 1.84 mmol), and HATU (0.28 g, 0.74 mmol) dissolved in DCM (5 mL) were added. The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA (100 mL), washed with saturated NaHCO3 (2x) and saturated NH4Cl (2x), and dried over Na2SO4. After concentration, the crude compound was purified by column chromatography on silica gel with hexane-EtOAc to give compound 41-H. LCMS-ESI + (m / z):C 18 H 19 [M+H] of F2N2O7 + Theoretical value: 524.5; Measured value: 524.5.

[0690] Step 8

[0691] The reactant 41-H (0.13 g, 0.25 mmol) in 2 mL of TFA was added to a 50 mL round-bottom flask. The reaction mixture was stirred for 30 minutes at room temperature. After concentration, the crude substance was purified by column chromatography on silica gel with EtOAc-MeOH to give compound 41. 1 H-NMR (400MHz, chloroform-d) δ11.61(s,1H),10.70-10.01(m,1H),8.26(s,1H),6.65(t,J=8.1Hz,2H),4.88(s,1H),4. 65(dd,J=6.1,2.4Hz,2H),4.07(d,J=10.9Hz,1H),3.93-3.58(m,2H),2.67(d,J=3.1Hz,1H),2.08-1.41(m,7H). 19 F-NMR (376MHz, chloroform-d) δ -109.22 (d, J = 11.6Hz, 1F), -111.04–-112.79 (m, 2F). LCMS-ESI + (m / z):C 21 H 20 [M+H] of F2N3O5 + Theoretical value: 434; Measured value: 434.

[0692] Example 42

[0693] Preparation of compound 42

[0694] (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0695]

[0696] Step 1

[0697] 1-(2,2-dimethoxyethyl)-5-methoxy-6-(methoxycarbonyl)-4-oxo-1,4-dihydropyridine-3-carboxylic acid (3.15 g, 10 mmol) in acetonitrile (36 mL) and acetic acid (4 mL) was treated with methanesulfonic acid (0.195 mL, 3 mmol) and placed in a bath at 75 °C. The reaction mixture was stirred for 7 hours, cooled, and stored at -10 °C for 3 days, then heated to 75 °C for an additional 2 hours. The substance was cooled and proceeded to the next step as a crude product.

[0698] Step 2

[0699] The crude reaction mixture from step 1 (20 mL, 4.9 mmol) was transferred to a flask containing (1R,3S)-3-aminocyclopentanol (0.809 g, 8 mmol). The mixture was diluted with acetonitrile (16.8 mL), treated with potassium carbonate (0.553 g, 4 mmol), and heated to 85 °C. After 2 hours, the reaction mixture was cooled to ambient temperature and stirred overnight. 0.2 M HCl (50 mL) was added, and the resulting clear yellow solution was extracted with dichloromethane (2 x 150 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to 1.49 g of a pale orange solid. Recrystallization from dichloromethane:hexane gave the desired intermediate 42A:LCMS-ESI. + (m / z):C 15 H 17 [M+H] of N2O6 + Theoretical value: 321.11; Measured value: 321.3.

[0700] Step 3

[0701] Intermediate 42-A (0.225 g, 0.702 mmol) and (2,4,6-trifluorophenyl)methylamine (0.125 g, 0.773 mmol) were suspended in acetonitrile (4 mL) and treated with N,N-diisopropylethylamine (DIPEA) (0.183 mmol, 1.05 mmol). (Dimethylamino)-N,N-dimethyl(3H-[1,2,3]triazolo[4,5-b]pyridin-3-yloxy)methaniminium hexafluorophosphate (HATU, 0.294 g, 0.774 mmol) was added to this suspension. After 1.5 hours, the crude reaction mixture was proceeded to the next step. LCMS-ESI + (m / z):[M+H) + Theoretical value: C 22 H 21 F3N3O5: 464.14; Measured value: 464.2.

[0702] Step 4

[0703] MgBr2 (0.258 g, 1.40 mmol) was added to the crude reaction mixture from the previous step. The reaction mixture was stirred at 50 °C for 10 min, acidified with 10% HCl aqueous solution, and extracted twice with dichloromethane. The combined organic phases were dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (EtOH / dichloromethane), followed by HPLC (ACN / H2O containing 0.1% TFA modifier) ​​to give compound 42. 1 H-NMR (400MHz, DMSO-d6) δ12.43(s,1H),10.34(t,J=5.7Hz,1H),8.42(s,1H),7.19(t,J=8.7Hz,2H),5.43(dd,J=9.5,4.1Hz,1H),5.08(s,1H),4.66(dd ,J=12.9,4.0Hz,1H),4.59(s,1H),4.56-4.45(m,2H),4.01(dd,J=12.7,9.7 Hz, 1H), 1.93 (s, 4H), 1.83 (d, J = 12.0Hz, 1H), 1.56 (dt, J = 12.0, 3.4Hz, 1H). LCMS-ESI + (m / z):C 21 H 19 [M+H] of F3N3O5 + Theoretical value: 450.13; Measured value: 450.2.

[0704] Example 43

[0705] Preparation of compound 43

[0706] (12aR)-N-((R)-1-(2,4-difluorophenyl)ethyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0707]

[0708] Step 1

[0709] Reactants 41-G (0.14 g, 0.37 mmol), (R)-1-(2,4-difluorophenyl)ethylamine (0.12 g, 0.74 mmol), N,N-diisopropylethylamine (0.24 g, 1.84 mmol), and HATU (0.28 g, 0.74 mmol) were charged into a 100-mL round-bottom flask and dissolved in DCM (5 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA (100 mL), washed with saturated NaHCO3 (2x) and saturated NH4Cl (2x), and dried over Na2SO4. After concentration, the crude compound was purified by column chromatography on silica gel with hexane-EtOAc to give compound 43-A. LCMS-ESI + (m / z):C 18 H 19 [M+H] of F2N2O7 + Theoretical value: 520; Measured value: 520.

[0710] Step 2

[0711] Reactant 43-A (0.14 g, 0.27 mmol) in 2 mL of TFA was added to a 50 mL round-bottom flask. The reaction mixture was stirred for 30 minutes at room temperature. After concentration, the crude substance was purified by column chromatography on silica gel with EtOAc-MeOH to give compound 43. 1 ¹H-NMR (400MHz, chloroform-d) δ 11.65 (s, 1H), 10.57 (s, 1H), 8.22 (s, 1H), 7.31 (m, 1H), 6.99–6.62 (m, 2H), 5.64–5.32 (m, 1H), 4.90 (d, J = 2.7 Hz, 1H), 4.04 (d, J = 11.5 Hz, 1H), 3.93–3.63 (m, 2H), 2.67 (s, 1H), 2.08–1.40 (m, 9H). 19 F-NMR (376MHz, chloroform-d) δ -113.09 (m, 1F), -115.01 (m, 1F). LCMS-ESI + (m / z):C 21 H 20 [M+H] of F2N3O5 + Theoretical value: 430; Measured value: 430.

[0712] Example 44

[0713] Preparation of compound 44

[0714] (13aS)-8-hydroxy-7,9-dioxo-N-(2,3,4-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0715]

[0716] Step 1

[0717] Compound 15-B (40 mg, 0.12 mmol) was dissolved in 1 mL of acetonitrile and treated with 2,3,4-trifluorobenzylmethylamine (29 mg, 0.18 mmol), HATU (53 mg, 0.14 mmol), and N,N-diisopropylethylamine (DIPEA) (20 mg, 0.16 mmol) for 2 hours at room temperature. Subsequent LCMS analysis showed that compound 15-B was completely consumed and intermediate 44-A was formed. The reaction mixture was then proceeded to the next step.

[0718] Step 2

[0719] MgBr2 (63 mg, 0.34 mmol) was added to the crude reaction solution from the previous step. The reaction mixture was stirred at 50 °C for 1 hour, acidified with 10% HCl aqueous solution, partitioned between the aqueous solution and dichloromethane, and the aqueous phase was extracted into dichloromethane. The combined organic phases were dried over MgSO4, filtered, concentrated, and purified by HPLC (ACN / H2O containing 0.1% TFA modifier) ​​to give compound 44. 1 H-NMR (400MHz, DMSO-d6) δ12.45(s,1H),10.38(t,J=6.0Hz,1H),8.43(s,1H),7.27(q,J=9.2Hz,1H),7.16(q,J=8.5Hz,1H),5.42(dd,J=9.5, 4.0Hz,1H),5.08(s,1H),4.76-4.47(m,4H),4.01(dd,J=12.8,9.7Hz,1H),1.92(s,4H),1.82(d,J=12.1Hz,1H),1.55(dt,J=12.2,2.9Hz,1H). LCMS-ESI + (m / z):C 21 H 19 [M+H] of F3N3O5 + Theoretical value: 450.13; Measured value: 450.2.

[0720] Example 45

[0721] Preparation of compound 45

[0722] (13aS)-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0723]

[0724]

[0725] Step 1

[0726] Compound 15-B (38 mg, 0.12 mmol) was dissolved in 1 mL of acetonitrile and treated with 2,4,6-trifluorobenzylmethylamine (34 mg, 0.21 mmol), HATU (50 mg, 0.13 mmol), and N,N-diisopropylethylamine (DIPEA) (23 mg, 0.18 mmol) for 2 hours at room temperature. Subsequent LCMS analysis showed that compound 15-B was completely consumed and intermediate 45-A was formed. The reaction mixture was then proceeded to the next step.

[0727] Step 2

[0728] MgBr2 (55 mg, 0.30 mmol) was added to the crude reaction solution from the previous step. The reaction mixture was stirred at 50 °C for 1 hour, acidified with 10% HCl aqueous solution, partitioned between aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO4, filtered, concentrated, and purified by HPLC (ACN / H2O containing 0.1% TFA modifier) ​​to give compound 45. 1 H-NMR (400MHz, DMSO-d6) δ12.37(s,1H),10.37-10.25(m,1H),8.37(s,1H),7.14(t,J=8.7Hz,2H),5.37(dd,J=9.5,4.0Hz,1H),5 .02(s,1H),4.66-4.40(m,4H),3.95(dd,J=12.8,9.6Hz,1H),1.87(s,4H),1.77(d,J=11.9Hz,1H),1.50(dt,J=11.8,3.2Hz,1H). LCMS-ESI + (m / z):C 21 H 19[M+H] of F3N3O5 + Theoretical value: 450.13; Measured value: 450.2.

[0729] Example 46

[0730] Preparation of compound 46

[0731] (13aS)-N-(2,6-difluorophenylmethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0732]

[0733] Step 1

[0734] Compound 15-B (38 mg, 0.12 mmol) was dissolved in 1 mL of acetonitrile and treated with 2,6-difluoroanisole (19 mg, 0.14 mmol), HATU (56 mg, 0.15 mmol), and N,N-diisopropylethylamine (DIPEA) (20 mg, 0.15 mmol) for 90 minutes at room temperature. Subsequent LCMS analysis showed complete consumption of compound A and formation of intermediate 46-A. The reaction mixture was then proceeded to the next step.

[0735] Step 2

[0736] MgBr2 (50 mg, 0.27 mmol) was added to the crude reaction solution from the previous step. The reaction mixture was stirred at 50 °C for 1 hour, acidified with 10% HCl aqueous solution, partitioned between the aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO4, filtered, concentrated, and purified by HPLC (ACN / H2O containing 0.1% TFA modifier) ​​to give compound 46. 1 H-NMR (400MHz, DMSO-d6) δ12.37(s,1H),10.33-10.26(m,1H),8.37(s,1H),7.39-7.29(m,1H),7.05(t,J=7.9Hz,2H),5.37(dd,J=9.5,4.1 Hz,1H),5.02(s,1H),4.66-4.45(m,4H),3.95(dd,J=12.7,9.6Hz,1H),1.87(s,4H),1.77(d,J=12.0Hz,1H),1.50(dt,J=12.2,3.5Hz,1H). LCMS-ESI+ (m / z):C 21 H 20 [M+H] of F2N3O5 + Theoretical value: 432.14; Measured value: 432.2.

[0737] Example 47

[0738] Preparation of compound 47

[0739] (1R,4S,12aR)-N-(2,4-difluorophenylmethyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0740]

[0741] Step 1

[0742] Crude acid 41-G (0.45 g, 1.18 mmol), 2,4-difluorobenzylmethylamine (0.35 g, 2.44 mmol), N,N-diisopropylethylamine (DIPEA) (0.79 g, 6.11 mmol), and HATU (0.93 g, 2.44 mmol) were dissolved in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EA (100 mL), washed with saturated NaHCO3 (2x) and saturated NH4Cl (2x), and dried over Na2SO4. After concentration, the crude substance was purified by column chromatography on silica gel with hexane-EtOAc to give compound 47-A. LCMS-ESI + (m / z):C 18 H 19 [M+H] of F2N2O7 + Theoretical value: 506; Measured value: 506.

[0743] Step 2

[0744] Reactant 47-A (0.5 g, 0.99 mmol) in 6 mL of TFA was added to a 50 mL round-bottom flask. The reaction mixture was stirred for 30 minutes at room temperature. After concentration, the crude compound was purified by column chromatography on silica gel with EtOAc-MeOH to give compound 47. 1¹H NMR (400MHz, chloroform-d) δ 11.70 (s, 1H), 10.44 (s, 1H), 8.29 (s, 1H), 7.60–7.29 (m, 1H), 6.95–6.58 (m, 2H), 4.10 (s, 1H), 4.02–3.54 (m, 3H), 2.68 (d, J = 3.1 Hz, 1H), 2.00–1.40 (m, 8H). 19 F NMR (376MHz, chloroform-d) δ -112.31 (d, J = 8.0Hz, 1F), -114.77 (d, J = 8.4Hz, 1F). LCMS-ESI + (m / z):C 21 H 20 [M+H] of F2N3O5 + Theoretical value: 416; Measured value: 416.

[0745] Example 48

[0746] Preparation of compound 48

[0747] (1S,4R,12aS)-N-(2,4-difluorophenylmethyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0748]

[0749] Similar to 55-H in Example 55, 48-B was prepared by replacing 55-A with 48-A. Compound 48 was prepared by replacing 38-B with 48-B as described in Compound 38 of Example 38, thus obtaining Compound 48. 1 ¹H-NMR (400MHz, chloroform-d) δ 11.79 (s, 1H), 10.44 (m, 1H), 8.33 (s, 1H), 7.42–7.31 (m, 1H), 6.86–6.74 (m, 2H), 4.74 (s, 1H), 4.63 (d, J = 5.8 Hz, 2H), 4.19 (m, 1H), 4.07–4.03 (m, 2H), 2.83 (s, 1H), 1.92–1.68 (m, 6H). 19 F NMR (376MHz, chloroform-d) δ -112.3 (m, 1F), -114.8 (m, 1F). LCMS-ESI + (m / z):C 21 H 20 [M+H] of F2N3O4 + Theoretical value: 416.14; Measured value: 416.07.

[0750] Example 49

[0751] Preparation of compounds 49

[0752] (2S,5R,13aS)-8-hydroxy-7,9-dioxo-N-((3-(trifluoromethyl)pyridin-2-yl)methyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0753]

[0754] Step 1

[0755] Compound 15-B (44 mg, 0.11 mmol) was dissolved in 1 mL of acetonitrile and treated with (3-(trifluoromethyl)pyridin-2-yl)methylamine (38 mg, 0.18 mmol, HCl salt), HATU (69 mg, 0.18 mmol), and N,N-diisopropylethylamine (DIPEA) (0.07 mL, 0.40 mmol). The mixture was stirred at room temperature for 1 hour. Subsequent LCMS analysis showed that compound 15-B was completely consumed and intermediate 49-A was formed. The reaction mixture was then proceeded to the next step.

[0756] Step 2

[0757] MgBr2 (51 mg, 0.28 mmol) was added to the crude reaction solution from the preceding steps. The reaction mixture was stirred at 50 °C for 90 minutes, acidified with 10% HCl aqueous solution, partitioned between aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO4, filtered, concentrated, and ground with methanol, followed by grinding with diethyl ether, to give compound 49. 1H-NMR (400MHz, DMSO-d6) δ12.42 (s, 1H), 10.80-10.70 (m, 1H), 8.83 (d, J = 5.0Hz, 1H), 8.44(s,1H),8.19(d,J=8.6Hz,1H),7.56(dd,J=7.7,5.2Hz,1H),5.43(dd,J=9.5,4.0 Hz,1H),5.08(s,1H),4.86-4.80(m,2H),4.67(dd,J=12.9,4.0Hz,1H),4.59(s,1H),4 .02(dd,J=12.6,9.8Hz,1H),1.93(s,4H),1.82(d,J=12.1Hz,1H),1.60-1.52(m,1H). LCMS-ESI + (m / z):C 21 H 20 [M+H] of F3N4O5 + Theoretical value: 465.14; Measured value: 465.2.

[0758] Examples 50 and 51

[0759] Preparation of compounds 50 and 51

[0760] N-(2,4-difluorobenzyl)-9-hydroxy-8,10-dioxo-2,3,5,6,8,10,14,14a-octahydro-2,6-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,6,3]dioxazocine-11-formamide 50 and 51

[0761]

[0762] Step 1

[0763] Methyl 5-(2,4-difluorobenzylcarbamoyl)-1-(2,2-dihydroxyethyl)-3-methoxy-4-oxo-1,4-dihydropyridine-2-carboxylic acid (1-C, 392 mg, 0.95 mmol) (Example 87), racemic cis-5-aminotetrahydro-2H-pyran-3-ol (WO 2012 / 145569 Bennett, BL et al., submitted April 20, 2012) (112 mg, 0.95 mmol), and potassium carbonate (134 mg, 0.97 mmol) were dissolved in 3.8 mL acetonitrile / 0.2 mL acetic acid and stirred at 90 °C for 90 min. The reaction mixture was then partitioned between DCM and brine. The aqueous phase was extracted with DCM, and the combined organic phases were dried over MgSO4, filtered, concentrated, and purified by SGC (0-10% EtOH / DCM) to give intermediate 50-A.

[0764] Step 2

[0765] Intermediate 50-A (40 mg) was separated by chiral SFC on a Chiralpak IC column using 10% DMF in supercritical carbon dioxide as the eluent, yielding enantiomer-enriched intermediates 50-B (first elution peak) and 51-A (second elution peak). For intermediate 50-B (absolute stereochemistry unknown), the chiral HPLC retention time was 11.48 min (Chiralpak IC, 150 x 4.6 mm, 1 mL / min MeOH). For intermediate 51-A (absolute stereochemistry unknown), the chiral HPLC retention time was 14.35 min (Chiralpak IC, 150 x 4.6 mm, 1 mL / min MeOH).

[0766] Step 3a

[0767] Magnesium bromide (12 mg, 0.06 mmol) was added to a solution of intermediate 50-B (10.5 mg, 0.02 mmol, absolute stereochemistry unknown) in 1 mL of acetonitrile. The reaction mixture was stirred at 50 °C for 1 hour, acidified with 10% aqueous HCl, partitioned between aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO4, filtered, concentrated, and purified by HPLC (ACN / H2O with 0.1% TFA modifier) ​​to give compound 50. 1H-NMR (400MHz, chloroform-d) δ10.47(t,J=5.8Hz,1H),8.42(s,1H),7.35(q,J=8.6,8. 2Hz, 1H), 6.81 (q, J=8.7, 8.0Hz, 2H), 6.41 (dd, J=10.0, 3.6Hz, 1H), 4.79 (s, 1H) ,4.65(s,2H),4.36-4.26(m,2H),4.20-4.08(m,2H),3.98(dd,J=12.4,10.2Hz ,1H),3.88(t,J=11.8Hz,2H),2.27(dt,J=13.3,3.1Hz,1H),2.15-2.06(m,1H). LCMS-ESI + (m / z):C 21 H 20 [M+H] of F2N3O6 + Theoretical value: 448.40; Measured value: 448.2.

[0768] Step 3b

[0769] Magnesium bromide (13 mg, 0.07 mmol) was added to a solution of intermediate 51-A (13.2 mg, 0.03 mmol, absolute stereochemistry unknown) in 1 mL of acetonitrile. The reaction mixture was stirred at 50 °C for 1 hour, acidified with 10% aqueous HCl, partitioned between aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO4, filtered, concentrated, and purified by HPLC (ACN / H2O with 0.1% TFA modifier) ​​to give compound 51. 1 H-NMR (400MHz, chloroform-d) δ10.47(t,J=5.8Hz,1H),8.42(s,1H),7.35(q,J=8.6,8. 2Hz, 1H), 6.81 (q, J=8.7, 8.0Hz, 2H), 6.41 (dd, J=10.0, 3.6Hz, 1H), 4.79 (s, 1H) ,4.65(s,2H),4.36-4.26(m,2H),4.20-4.08(m,2H),3.98(dd,J=12.4,10.2Hz ,1H),3.88(t,J=11.8Hz,2H),2.27(dt,J=13.3,3.1Hz,1H),2.15-2.06(m,1H). LCMS-ESI + (m / z):C 21 H 20 [M+H] of F2N3O6 + Theoretical value: 448.40; Measured value: 448.2.

[0770] Example 52

[0771] Preparation of compound 52

[0772] (2S,5R,13aS)-N-(2-cyclopropoxy-4-fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0773]

[0774] Step 1

[0775] A solution of cyclopropanol (1.9 g, 29 mmol) in 20 mL of dioxane was added dropwise to a solution of sodium hydride (60% dispersion in mineral oil, 1.04 g, 26 mmol) in 80 mL of dioxane at 0 °C. The reaction mixture was heated to room temperature, and 2,4-difluorobenzonitrile (3.48 g, 25 mmol) was added in portions, with the reaction temperature raised to 95 °C. After stirring for 18 hours, the reaction solution was cooled to room temperature, diluted with ethyl acetate, washed twice with water and twice with brine, dried over MgSO4, filtered, and concentrated on a silica gel. Purification by silica gel chromatography (0–10% EtOAc / hexane) gave 2-cyclopropoxy-4-fluorobenzonitrile. 1 H-NMR (400MHz, chloroform-d) δ7.52 (dd, J = 8.6, 6.2 Hz, 1H), 7.05 (dd, J = 10.5, 2.3 Hz, 1H), 6.73 (td, J = 8.2, 2.3 Hz, 1H), 3.87-3.76 (m, 1H), 0.87 (m, 4H).

[0776] Step 2

[0777] 2-Cyclopropoxy-4-fluorobenzonitrile in 14 mL of diethyl ether was added dropwise to a 0°C suspension of lithium aluminum hydride in THF (1 M, 15 mL, 15 mmol). The reaction solution was stirred for 3 hours, gradually warmed to room temperature, then cooled to 0°C. Another 8 mL of lithium aluminum hydride in THF (1 M, 8 mmol) was added, and the mixture was stirred for another 90 minutes. The reaction was then continued by adding 0.9 mL of water and 0.9 mL of 15% NaOH. (aq) The reaction was quenched with 2.7 mL of water. The reactants were filtered through diatomaceous earth, washed with ether, dried over MgSO4, and concentrated to obtain 2-cyclopropoxy-4-fluorobenzylamine of sufficient purity as crude material. 1¹H-NMR (400MHz, chloroform-d) δ 7.17–7.08 (m, 1H), 6.96 (dd, J = 10.9, 2.4 Hz, 1H), 6.61 (td, J = 8.3, 2.5 Hz, 1H), 3.78–3.66 (m, 3H), 0.89–0.72 (m, 4H).

[0778] Step 3

[0779] Compound 15-B (46 mg, 0.14 mmol) was dissolved in 1 mL of acetonitrile and treated with 2-cyclopropoxy-4-fluorobenzylmethylamine (32 mg, 0.18 mmol), HATU (62 mg, 0.16 mmol), and N,N-diisopropylethylamine (DIPEA) (0.04 mL, 0.22 mmol). The mixture was stirred at room temperature for 2 hours, after which LCMS analysis showed that compound 15-B was completely consumed and intermediate 52-A was formed. The reaction mixture was then proceeded to the next step.

[0780] Step 4

[0781] MgBr2 (56 mg, 0.30 mmol) was added to the crude reaction solution from the previous step. The reaction mixture was stirred at 50 °C for 90 minutes, acidified with 10% HCl aqueous solution, partitioned between aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO4, filtered, concentrated, and purified by HPLC (ACN / H2O containing 0.1% TFA modifier) ​​to give compound 52. 1 H-NMR (400MHz, DMSO-d6) δ12.44(s,1H),10.21(t,J=5.8Hz,1H),8.41(s,1H),7.22-7.15(m,1H),7.12 (dd,J=11.2,2.5Hz,1H),6.72(td,J=8.5,2.5Hz,1H),5.42(dd,J=9.6,4.1Hz,1H),5.07(s,1H),4.66(d d,J=12.8,4.1Hz,1H),4.58(s,1H),4.34(dd,J=5.6,2.4Hz,2H),4.04-3.91(m,2H),1.92(s,4H),1.82( d, J=11.9Hz, 1H), 1.55 (dt, J=12.4, 3.5Hz, 1H), 0.80 (q, J=6.3, 5.7Hz, 2H), 0.72 (q, J=6.0, 4.9Hz, 2H). LCMS-ESI + (m / z):C 24 H 25 [M+H] of FN3O6+ Theoretical value: 470.17; Measured value: 470.1.

[0782] Example 53

[0783] Preparation of compound 53

[0784] (2R,5S,13aR)-N-(2-cyclopropoxy-4-fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0785]

[0786] Step 1

[0787] Compound 42-A (46 mg, 0.14 mmol) was dissolved in 1 mL of acetonitrile and treated with 2-cyclopropoxy-4-fluorobenzylmethylamine (33 mg, 0.18 mmol), HATU (61 mg, 0.16 mmol), and N,N-diisopropylethylamine (DIPEA) (0.04 mL, 0.24 mmol). The mixture was stirred at room temperature for 2 hours, after which LCMS analysis showed that compound 42-A was completely consumed and intermediate 53-A was formed. The reaction mixture was then proceeded to the next step.

[0788] Step 2

[0789] MgBr2 (55 mg, 0.30 mmol) was added to the crude reaction solution from the previous step. The reaction mixture was stirred at 50 °C for 90 minutes, acidified with 10% HCl aqueous solution, partitioned between aqueous solution and dichloromethane, and the aqueous phase was extracted with dichloromethane. The combined organic phases were dried over MgSO4, filtered, concentrated, and purified by HPLC (ACN / H2O containing 0.1% TFA modifier) ​​to give compound 53. 1H-NMR (400MHz, DMSO-d6) δ12.44(s,1H),10.21(t,J=5.8Hz,1H),8.41(s,1H),7.22-7.15(m,1H),7.12 (dd,J=11.2,2.5Hz,1H),6.72(td,J=8.5,2.5Hz,1H),5.42(dd,J=9.6,4.1Hz,1H),5.07(s,1H),4.66(d d,J=12.8,4.1Hz,1H),4.58(s,1H),4.34(dd,J=5.6,2.4Hz,2H),4.04-3.91(m,2H),1.92(s,4H),1.82( d, J=11.9Hz, 1H), 1.55 (dt, J=12.4, 3.5Hz, 1H), 0.80 (q, J=6.3, 5.7Hz, 2H), 0.72 (q, J=6.0, 4.9Hz, 2H). LCMS-ESI + (m / z):C 24 H 25 [M+H] of FN3O6 + Theoretical value: 470.17; Measured value: 470.1.

[0790] Example 54

[0791] Preparation of compound 54

[0792] (2R,5S)-N-((S)-1-(2,4-difluorophenyl)-2,2,2-trifluoroethyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0793]

[0794] Step 1

[0795] 54-A (0.02 g, 0.06 mmol), (S)-1-(2,4-difluorophenyl)-2,2,2-trifluoroethylamine (0.019 g, 0.09 mmol), N,N-diisopropylethylamine (DIPEA) (0.048 g, 0.38 mmol), and HATU (0.036 g, 0.09 mmol) were placed in DCM (2 mL) and added to a 50 mL round-bottom flask. The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated and dissolved in EtOAc (50 mL), washed with saturated NaHCO3 (2x) and saturated NH4Cl, and dried over Na2SO4. After concentration, the crude substance was purified by column chromatography on silica gel using hexane-EtOAc to give 54-B. LCMS-ESI + (m / z):C 18 H 19 [M+H] of F2N2O7 + Theoretical value: 514; Measured value: 514.

[0796] Step 2

[0797] Reactant 54-B (0.03 g, 0.058 mmol) and magnesium bromide (0.03 g, 0.15 mmol) were placed in acetonitrile (2 mL) and added to a 50 mL round-bottom flask. The reaction mixture was heated to 50 °C. After 10 minutes, the reaction mixture was cooled to 0 °C and 1 N hydrochloric acid (0.5 mL) was added. The reaction mixture was then diluted with MeOH (2 mL). After filtration, the crude substance was purified by preparative HPLC (30–70% acetonitrile:water, 0.1% TFA) to give compound 54as TFA salt. 1 H-NMR (400MHz, chloroform-d) δ11.28(d,J=9.4Hz,1H),8.39(s,1H),7.54(q,J=7.8Hz,1H),7.12-6.76(m,2H),6.40-5.98(m,1H),5.57-5.18(m,2H),4. 68(s,1H),4.29(dd,J=13.1,4.0Hz,1H),4.05(dd,J=12.9,9.3Hz,1H),2.39-1.94(m,4H),1.86(t,J=10.5Hz,1H),1.60(dt,J=12.6,3.4Hz,1H). 19 F-NMR (376MHz, chloroform-d) δ -75.30 (t, J = 6.8Hz, 3F), -108.33 (dd, J = 8.6, 6.3Hz, 1F), -111.56–113.23 (m, 1F). LCMS-ESI +(m / z):C 21 H 20 [M+H] of F2N3O5 + Theoretical value: 500; Measured value: 500.

[0798] Example 55

[0799] Preparation of compound 55

[0800] (1R,4S,12aS)-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0801]

[0802]

[0803] Step 1

[0804] A mixture of compound 55-A (40.60 g, 150 mmol) and Pd(OH)₂ / C (12 g) in EtOH (400 mL) was stirred overnight at room temperature under a H₂ atmosphere. The reaction mixture was filtered and treated with HCl / EtOH (400 mL). The mixture was then stirred at room temperature for 2 hours. The reaction mixture was concentrated to give compound 55-B, which was used in the next step without purification. LCMS-ESI + (m / z):[M+H) + Theoretical value: C9H 16 NO:170.1; Measured value: 170.2.

[0805] Step 2

[0806] At 0 °C, benzyl bromide (76.50 g, 0.45 mol) was added to a solution of compound 55-B (92.25 g, 0.45 mol) and K₂CO₃ (186.30 g, 1.35 mol) in CH₃CN (1 L). The mixture was stirred overnight at room temperature. The reaction mixture was filtered, concentrated, and the residue was purified by silica gel chromatography to give compound 55-C.

[0807] Step 3

[0808] Under a nitrogen atmosphere and at -78°C, n-BuLi (200 mL, 0.50 mol) was added to a mixture of diisopropylamine (50 g, 0.50 mol) in THF (400 mL). After 0.5 hours, the reaction mixture was warmed to 20°C and stirred for 0.5 hours. The mixture was then cooled to -78°C, and under a nitrogen atmosphere, a solution of compound 55-C (64.75 g, 0.25 mol) in THF (600 mL) was added. The mixture was stirred for 4 hours and quenched with a saturated NH4Cl solution. The mixture was extracted with EtOAc, the organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography to give compound 55-D.

[0809] Step 4

[0810] The mixture of compound 55-D (129.50 g 0.50 mol) in 4N HCl (1.30 L) was refluxed for 4 hours. The mixture was concentrated. The residue was purified by HPLC to give compound 55-E.

[0811] Step 5

[0812] At room temperature and under a H2 atmosphere, a mixture of compound 55-E (47 g, 176 mmol) and Pd(OH)2 / C (9 g) in EtOH (400 mL) was stirred overnight. The reaction mixture was concentrated to give compound 55-F, which was used in the next step without purification. 1 H-NMR (400MHz, CDCl3) δ4.22 (s, 1H), 4.06 (s, 1H), 2.98-2.95 (d, J = 11.2Hz, 1H), 1.96-1.9 3(d,J=11.2Hz,1H),1.86-1.82(m,2H),1.76-1.74(d,J=9.2Hz,2H),1.49(s,1H).LCMS-ESI + (m / z):C7H 12 NO2's [M+H] + Theoretical value: 142.1; Measured value: 142.1.

[0813] Step 6

[0814] At 0 °C, Boc₂O (39.60 g, 181 mmol) was added to a mixture of compound 55-F (29.20 g, 165 mmol) and 2N NaOH solution (330 mL, 0.66 mol) in dioxane (120 mL). The reaction mixture was stirred overnight at room temperature. The mixture was adjusted to pH 5–6 with 3N HCl and extracted with DCM. The organic layer was dried over Na₂SO₄, filtered, and concentrated to give 55-G. 1 H-NMR (400MHz, CDCl3) δ4.40(s,1H),4.26(s,1H),2.89(s,1H),1.76-1.74(s,1H),1.69-1.59(m,4H),1.50(s,1H),1.47(s,9H).LCMS-ESI + (m / z):C 12 H 19 [M+Na] of NNaO4 + Theoretical value: 264.1; Measured value: 264.1.

[0815] Step 7

[0816] The BH3-DMS THF complex (2N, 8.23 ​​mmol, 4.1 mL in THF) was slowly added to a mixture of compound 55-G (500 mg, 2.07 mmol) frozen to 0 °C in 10 mL of THF. Gas escape occurred. The internal temperature was monitored to ensure no significant exothermic reaction. The reaction was allowed to proceed to room temperature overnight. By LC / MS, with the remaining starting material, another 2 mL of the BH3-DMS THF complex was added, and the mixture was stirred for another 3 hours. The mixture was then cooled to 0 °C and slowly quenched with methanol (gas escape occurred). The internal temperature was monitored to ensure the exothermic reaction was less than 25 °C. The mixture was concentrated and then purified by silica gel chromatography (20–40% EtOAc / hexane) to give 55-H.

[0817] Step 8

[0818] Compound 55 was prepared as described in Example 41, with 55-H replacing 41-B, to obtain compound 55. 1H-NMR (400MHz, DMSO-d6) δ11.81(s,1H),10.40(t,J=5.8Hz,1H),8.39(s,1H),7.19(t,J=8.6Hz,2H),4.59-4.48 (m,4H),4.16(t,J=12.2Hz,1H),4.03(d,J=12.2Hz,1H),2.69(s,1H),1.75(d,J=10.1Hz,1H),1.69-1.55(m,5H). 19 F NMR(376MHz,DMSO-d6)δ-109.3(m,1F),-112.5(m,1F).LCMS-ESI + (m / z):C 21 H 19 [M+H] of F3N3O4 + Theoretical value: 434.13; Measured value: 434.32.

[0819] Example 56

[0820] Preparation of compound 56

[0821] (1R,2S,4R,12aR)-2-fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorophenylmethyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0822]

[0823] Step 1

[0824] A solution of 56-A (5 g, 19.43 mmol) in tetrahydrofuran (65 mL) was cooled in an ice bath while 0.5 M of 9-boronadicyclo[3.3.1]nonane (48.58 mL) was added dropwise. The reaction mixture was heated to room temperature. After 18 hours, the reaction was cooled to 0 °C and a mixture of 2 M sodium hydroxide (34 mL) and hydrogen peroxide (9.34 mL, 97.15 mmol) was added dropwise. After 2 hours at 0 °C, the reaction was heated to room temperature and stirred for 1 hour. The mixture was diluted with EtOAc and washed with water. The aqueous fraction was extracted with EtOAc, and the combined organic fractions were dried (Na2SO4) and concentrated. The residue was purified by silica column chromatography (50–70% EtOAc / hexane) to give 56-B (3.05 g, 57%). LCMS-ESI + (m / z):C 16 H 21 NO3's [M+H]+ Theoretical value: 275.34; Measured value: 276.122.

[0825] Step 2

[0826] To a solution of 56-B (1.45 g, 5.27 mmol) in N,N-dimethylformamide (12 mL), tert-butylchlorodiphenylsilane (1.51 mL, 5.79 mmol) and imidazole (1.08 g, 15.8 mmol) were added. After 18 hours, the mixture was diluted with water, extracted into EtOAc (2x), and the organic fractions were combined, dried (Na2SO4), and concentrated. The residue was purified by silica column chromatography (10–20% EtOAc / hexane) to give 56-C (2.6 g, 96.1%). LCMS-ESI + (m / z):C 32 H 39 [M+H] of NO3Si + Theoretical value: 513.74; Measured value: 514.625.

[0827] Step 3

[0828] 10% PdOH / C (0.52 g, 3.7 mmol) was added to a solution of 56-C (3.27 g, 6.36 mmol) in EtOH (26 mL) and acetic acid (3 mL), and the suspension was shaken at 50 atm for 20 hours in a Parr apparatus. After filtration through diatomaceous earth, the filter cake was washed with EtOH, and the filtrate was concentrated under vacuum. The residue was dissolved in ethanol (26 mL) and acetic acid (3 mL, 52.4 mmol), treated with 10% PdOH / C (0.52 g, 3.7 mmol), and shaken at 50 atm for 20 hours in a Parr apparatus. After filtration through diatomaceous earth, the filter cake was washed with EtOH, and the filtrate was concentrated to dryness under vacuum to give a crude deprotected product (2.07 g, 79.4%). LCMS-ESI + (m / z):C 24 H 31 [M+H] of NO3Si + Theoretical value: 409.59; Measured value: 410.485.

[0829] N,N-diisopropylethylamine (DIPEA) (2.14 mL, 12.27 mmol) was added to the crude residue (2 g, 4.88 mmol) in THF (20 mL) and 97% di-tert-butyl dicarbonate (2.14 g, 9.79 mmol). After 20 hours, the reaction mixture was diluted with water, extracted into EtOAc (2x), and the two organic fractions were washed with water, combined, dried (Na2SO4), and concentrated. The residue was purified by silica column chromatography (10–20% EtOAc / hexane) to give 56-D (2.13 g, 86.14%). LCMS-ESI + (m / z):C 30 H 41 [M+H] of NO5Si + Theoretical value: 523.74; Measured value: 523.922.

[0830] Step 4

[0831] A solution of 56-D (2.07 g, 4.06 mmol) in 20 mL THF was stirred in an ice bath while 2.0 M LiBH4 in 4.07 mL THF was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with ethyl acetate and slowly treated with water. The two phases were separated, and the aqueous fraction was extracted again with ethyl acetate. The two organic fractions were washed with water, combined, dried (Na₂SO₄), and concentrated. The residue was purified by silica column chromatography (20–40% EOAc / hexane) to give 56-E (1.59 g, 81.3%). LCMS-ESI + (m / z):C 28 H 39 [M+H] of NO4Si + Theoretical value: 481.7; Measured value: 482.337.

[0832] Step 5

[0833] A mixture of 56-E (1.58 g, 3.28 mmol), phthalimide (0.79 g, 5.38 mmol), and triphenylphosphine (1.93 g, 7.37 mmol) in THF (90 mL) was cooled in an ice bath. 95% diisopropyl azodiacetic acid (1.46 mL, 7.42 mmol) was added. The mixture was then heated to room temperature and stirred for 20 hours. The reaction mixture was then concentrated, and the residue was dissolved in diethyl ether, cooled in an ice bath, and stirred for 1.5 hours. The solid was filtered off, and the filtrate was concentrated. The residue was purified by silica column chromatography (10–30% EtOAc / hexane) to give a protected amino compound (1.86 g, 92.8%).

[0834] A solution of amino compound 56-F (1.85 g, 3.03 mmol) and hydrazine hydrate (0.6 mL, 12.39 mmol) in ethanol (19 mL) was stirred under protection at 70 °C for 2 hours. The reaction mixture was cooled in an ice bath, ether (10 mL) was added, and the mixture was stirred for 30 minutes. The solid formed was filtered off, and the filtrate was concentrated to dryness under vacuum.

[0835] Step 6

[0836] A mixture of crude amino compound 56-F (991 mg, 2.06 mmol), compound 38-F (Example 38) (714 mg, 2.06 mmol), and NaHCO3 (347 mg, 4.12 mmol) in water (15 mL) and EtOH (15 mL) was stirred for 20 hours. The reaction mixture was concentrated under vacuum, and the residue was partitioned between water and EtOAc. The aqueous layer was re-extracted with EtOAc, and the combined organic layers were dried (Na2SO4) and concentrated. The residue (1.5 g) was dissolved in CH2Cl2 (5 mL) and 4N HCl was added to dioxane (18.6 mL). After 1.5 hours, the mixture was concentrated to dryness, co-evaporated with toluene, and dried under vacuum.

[0837] The crude residue (1.38 g) and DBU (1.4 mL, 9.38 mmol) were stirred in toluene (25 mL) at 110 °C. After 35 min, the mixture was concentrated and the residue was purified by silica column chromatography (5-15% MeOH / EtOAc) to give 56-G (450 mg, 72.3%). LCMS-ESI + (m / z):C 39 H 42 [M+H] of N2O6Si + Theoretical value: 662.85; Measured value: 663.766.

[0838] Step 7

[0839] At room temperature, a mixture of 56-G (890 mg, 1.34 mmol) in MeOH (14 mL) and THF (14 mL) was stirred while 1 M KOH (7.09 mL) was added. After 30 minutes, the reaction mixture was neutralized with 1 N HCl, extracted into EtOAc (2x), and the combined organic extracts were dried (Na2SO4) and concentrated.

[0840] At room temperature, the suspension of the crude residue (850 mg), 2,4,6-trifluorobenzylmethylamine (248 mg, 1.54 mmol), and HATU (662 mg, 1.74 mmol) in dichloromethane (5 mL) was stirred while N,N-diisopropylethylamine (DIPEA) (1.63 mL, 9.37 mmol) was added. After 1 hour, additional 2,4,6-difluorobenzylmethylamine (32 mg, 0.2 mmol), HATU (153 mg, 0.4 mmol), and N,N-diisopropylethylamine (DIPEA) (0.12 mL, 0.67 mmol) were added. After 30 minutes, the mixture was diluted with water, extracted into EtOAc (3x), the combined organic phases were dried (Na2SO4), concentrated, and the residue was purified by silica column chromatography (50–75% EtOAc / hexane) to give 56-H (919 mg, 88.23%). LCMS-ESI + (m / z):C 44 H 42 [M+H] of F3N3O5Si + Theoretical value: 777.9; Measured value: 778.409.

[0841] Step 8

[0842] A solution of 56-H (915 mg, 1.18 mmol) in THF (5 mL) was stirred in an ice bath. Simultaneously, 1.0 M tetrabutylammonium fluoride was added dropwise to THF (1.18 mL). The resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under vacuum, the residue was diluted with EtOAc, washed with water, dried (Na₂SO₄), concentrated, and purified by silica column chromatography (50-75% EtOAc / hexane, then 5% MeOH / EtOAc). The resulting substance (248 mg, 0.46 mmol) was dissolved in dichloromethane (2 mL) cooled to -78 °C, while diethylaminosulfurtrifluoride (0.07 mL, 0.55 mmol) was added dropwise. The reaction was heated to room temperature and stirred for 1 hour. The reactants were cooled in an ice bath and quenched with saturated NaHCO₃. The two phases were separated, and the aqueous fraction was extracted with CH₂Cl₂. The two organic fractions were combined, dried (Na2SO4), and concentrated. The residue was purified by silica column chromatography (1% MeOH / EtOAc) to give 56-J (75 mg) (LCMS-ESI). + (m / z):C 28 H 23 [M+H] of F4N3O4 +Theoretical value: 541.49; measured value: 542.320) and 56-I (30mg) (LCMS-ESI) + (m / z):[M+H) + Theoretical value: C 28 H 22 F3N3O4: 521.49; Measured value: 522.05).

[0843] Step 9

[0844] Compound 56-J (75 mg, 139 mmol) was dissolved in TFA (1 mL), stirred at room temperature for 10 minutes, and the solution was concentrated. The residue was purified by reversed-phase HPLC (Gemini, 15 to 43% ACN / H2O + 0.1% TFA) to give compound 56. 1 H-NMR (400MHz, DMSO-d6) δ10.67(s,1H),7.80(s,1H),7.17(t,J=8.6Hz,2H),5.45-5.18(m,1H),4.70-4.39(m,3H),4.2 3(d,J=11.5Hz,1H),4.11-3.85(m,2H),2.85(dd,J=4.2,2.0Hz,1H),2.34-2.13(m,1H),1.81(s,1H),1.55-1.33(m,2H). 19 F-NMR(376MHz, DMSO-d6)δ-74.20(m),-106.95--116.45(m),-190.65--194.54(m).

[0845] Example 57

[0846] Preparation of compound 57

[0847] (1R,4R,12aR)-2,2-difluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorophenylmethyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0848]

[0849]

[0850] Step 1

[0851] A solution of 57-A (1.45 g, 5.34 mmol) in dichloromethane (30 mL) was cooled in an ice bath while Dess Martin periodide (4.53 g, 10.69 mmol) was added in portions, and the reaction was stirred at room temperature for 18 hours. The reaction was quenched with water, the precipitate was filtered off, and a saturated solution of Na₂S₂O₃ was added. The mixture was stirred until the biphasic solution reversed, then saturated NaHCO₃ was added, and the aqueous layer was extracted with CH₂Cl₂. The combined organic fractions were dried (Na₂SO₄) and concentrated. The residue was purified by silica column chromatography (30–50% EtOAc / hexane) to give 57-B (1.13 g, 78.2%). LCMS-ESI + (m / z):C 13 H 19 NO5 [M+H] + Theoretical value: 269.29; Measured value: 269.722.

[0852] Step 2

[0853] A solution of 57-B (0.5 g, 1.86 mmol) in dichloromethane (10 mL) was cooled to -78 °C, while diethylaminosulfur trifluoride (0.52 mL, 3.91 mmol) was added dropwise. The reaction mixture was heated to room temperature and stirred for 18 hours. The reactants were cooled in an ice bath and quenched with saturated NaHCO3. The two phases were separated, and the aqueous fraction was extracted with CH2Cl2. The two organic fractions were combined, dried (Na2SO4), and concentrated. The residue was purified by silica column chromatography (20–50% EtOAc / hexane) to give 57-C (518 mg, 95.39%). 1 ¹H-NMR (400MHz, chloroform-d) δ 4.43 (s, 1H), 4.36–4.27 (m, 1H), 4.22 (s, 1H), 3.75 (s, 3H), 2.95 (t, J = 8.1 Hz, 1H), 2.30–1.98 (m, 2H), 1.85–1.71 (m, 1H), 1.44 (m, 9H).

[0854] Step 3

[0855] A solution of 57-C (935 mg, 3.21 mmol) in 10 mL of THF was stirred in an ice bath while 2.0 M LiBH4 in 3.22 mL of THF was added, and the mixture was stirred at room temperature for 18 hours. The reaction mixture was then diluted with ethyl acetate, and water was slowly added. The two phases were separated, and the aqueous fraction was extracted with ethyl acetate. The two organic fractions were washed with water, combined, dried (Na₂SO₄), and concentrated. The residue was purified by silica column chromatography (20–40% EtOAc / hexane) to give 57-D (724 mg, 85.67%). 1 ¹H-NMR (400MHz, chloroform-d) δ 4.30–3.48 (m, 5H), 2.75–2.56 (m, 1H), 2.24–1.90 (m, 3H), 1.86–1.65 (m, 1H), 1.47 (s, 9H).

[0856] Step 4

[0857] A mixture of 57-D (720 mg, 2.74 mmol), phthalimide (402 mg, 2.73 mmol), and triphenylphosphine (1.61 g, 6.15 mmol) in THF (45 mL) was cooled in an ice bath. 95% diisopropyl azodiacetic acid (1.22 mL, 6.19 mmol) was added. The mixture was then heated to room temperature and stirred for 20 hours. The reaction mixture was then concentrated, and the residue was dissolved in diethyl ether, cooled in an ice bath, and stirred for 1.5 hours. After filtering out the solids, the filtrate was concentrated. The residue was purified by silica column chromatography (40–60% EtOAc / hexane) to give the phthalimide adduct (1.07 g, 99.7%). LCMS-ESI + (m / z):[M+H) + Theoretical value: C 20 H 22 F2N2O4: 392.4; Measured value: 393.204.

[0858] A solution of phthalimide adduct (1.07 g, 2.73 mmol) and hydrazine hydrate (0.54 mL, 11.15 mmol) in ethanol (10 mL) was stirred at 70 °C for 2 hours. The reaction mixture was cooled in an ice bath, and diethyl ether (10 mL) was added. The mixture was stirred for 30 minutes. The solid formed was filtered off, and the filtrate was concentrated under vacuum to give crude 57-E.

[0859] Step 5

[0860] A mixture of crude 57-E (709 mg, 2.7 mmol), compound 38-F (Example 38) (936 mg, 2.7 mmol), and NaHCO3 (454 mg, 5.41 mmol) in water (15 mL) and EtOH (15 mL) was stirred for 20 hours. The reaction mixture was concentrated under vacuum, and the residue was partitioned between water and EtOAc. The aqueous layer was re-extracted with EtOAc, and the combined organic layers were dried (Na2SO4) and concentrated. The residue (1.5 g) was dissolved in CH2Cl2 (7 mL), and 4NHCl was added to dioxane (26.9 mL). After 1.5 hours, the mixture was concentrated to dryness, co-evaporated with toluene, and dried under vacuum. The crude residue (1.3 g) and DBU (2 mL, 13.4 mmol) in toluene (25 mL) were stirred at 110 °C. After 35 minutes, the mixture was concentrated, and the residue was purified by silica column chromatography (5-15% MeOH / EtOAc) to give 57-F (426 mg, 36.17%). LCMS-ESI + (m / z):C 23 H 22 [M+H] of F2N2O5 + Theoretical value: 444.43; Measured value: 445.280.

[0861] Step 6

[0862] At room temperature, a mixture of compound 57-F (426 mg, 0.96 mmol) in MeOH (7 mL) and THF (7 mL) was stirred while 1 M KOH (5.06 mL) was added. After 30 minutes, the reaction mixture was neutralized with 1 N HCl, extracted into EtOAc (2x), and the combined organic extracts were dried (Na2SO4) and concentrated to crude 57-G.

[0863] Step 7

[0864] At room temperature, a suspension of the crude residue 57-G (189 mg), 2,4,6-trifluorobenzylmethylamine (95 mg, 0.59 mmol), and HATU (276 mg, 0.73 mmol) in dichloromethane (3 mL) was stirred while N,N-diisopropylethylamine (DIPEA) (0.59 mL, 3.4 mmol) was added. After 1 hour, the mixture was diluted with water and extracted into EtOAc (3x). The combined organic phases were dried (Na₂SO₄) and concentrated to 57-H. LCMS-ESI + (m / z):C 28 H 22 [M+H] of F5N3O4+ Theoretical value: 559.48; Measured value: 560.24.

[0865] Step 8

[0866] Compound 57-H (150 mg, 0.27 mmol) was dissolved in TFA (2 mL), stirred at room temperature for 10 min, and the solution was concentrated. The residue was purified by reversed-phase HPLC (Gemini, 15 to 60% ACN / H2O + 0.2% TFA) to give compound 57 (85 mg, 67.5%). LCMS-ESI + (m / z):[M+H) + Theoretical value: C 21 H 16 F5N3O4: 469.36; Measured value: 470.229. 1 H-NMR (400MHz, DMSO-d6) δ10.41(t,J=5.6Hz,1H),8.20(s,1H),7.12(t,J=8.7Hz,2H),4.79(s,1H),4.48(m,3 H), 4.10 (m, 2H), 3.02 (d, J = 5.7Hz, 1H), 2.33 (m, 1H), 2.22-1.97 (m, 2H), 1.85 (d, J = 11.0Hz, 1H), 1.21 (s, 1H). 19 F NMR (376MHz, DMSO-d6) δ-69.88,-71.77,-74.09,-88.33(dd,J=222.6,23.8Hz),-109.15--109.60(m),-110.04,-112.44(t,J=7.6Hz).

[0867] Example 58

[0868] Preparation of compound 58

[0869] (1R,4R,12aR)-N-(3-chloro-2,4-difluorobenzyl)-2,2-difluoro-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0870]

[0871] Step 1

[0872] At room temperature, a suspension of crude residue 57-G (120 mg), 3-chloro,2,4-difluorobenzylamine (67 mg, 0.38 mmol), and HATU (175 mg, 0.46 mmol) in dichloromethane (3 mL) was stirred while N,N-diisopropylethylamine (DIPEA) (0.38 mL, 0.28 mmol) was added. After 1 hour, the mixture was diluted with water and extracted into EtOAc (3x). The combined organic phases were dried (Na₂SO₄) and concentrated to give 58-A. LCMS-ESI + (m / z):C 28 H 22 [M+H] of ClF4N3O4 + Theoretical value: 575.94; Measured value: 576.394.

[0873] Step 2

[0874] Compound 58-A (166 mg) was dissolved in TFA (2 mL), stirred at room temperature for 10 min, and the solution was concentrated. The residue was purified by reversed-phase HPLC (Gemini, 15 to 70% ACN / H2O + 0.1% TFA) to give compound 57 (60 mg, 42.8%). LCMS-ESI + (m / z):C 21 H 16 [M+H] of ClF4N3O4 + Theoretical value: 485.82; Measured value: 486.135. 1 H-NMR (400MHz, DMSO-d6) δ10.77(t,J=6.0Hz,1H),7.77(s,1H),7.28(m,2H),4.77(s,1H),4.64-4.40(m,2H),4.27(d ,J=9.1Hz,1H),3.93(m,2H),2.95(d,J=5.8Hz,1H),2.51(s,1H),2.42-2.17(m,1H),2.14-1.89(m,2H),1.77(m,1H). 19 F-NMR (376MHz, DMSO-d6) δ -87.63, -88.23, -108.67, -109.27, -116.42 (t, J = 7.0Hz), -118.48 (d, J = 7.8Hz).

[0875] Example 59

[0876] Preparation of compound 59

[0877] (1R,2R,4R,12aR)-2-fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0878]

[0879]

[0880] Step 1

[0881] A solution of 57-B (1.9 g, 7.06 mmol) in methanol (35 mL) was stirred at 0 °C while sodium borohydride (667 mg, 17.64 mmol) was added in portions, and the resulting mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled in an ice bath, quenched by adding water, and concentrated. The residue was partitioned between water and EtOAc. The aqueous layer was re-extracted with EtOAc, and the combined organic layers were dried (Na₂SO₄) and concentrated. The residue was purified by silica column chromatography (30–60% EtOAc / hexane) to give 59-A (1.49 g). 1 ¹H-NMR (400MHz, chloroform-d) δ 4.57 (s, 1H), 4.52–4.42 (m, 2H), 4.28 (s, 1H), 4.14 (s, 1H), 3.72 (d, J = 2.1 Hz, 3H), 2.74 (s, 1H), 2.08–1.87 (m, 2H), 1.43 (d, J = 23.1 Hz, 10H) and 57-A (96 mg): 1 ¹H-NMR (400MHz, chloroform-d) δ 4.65–4.40 (m, 2H), 4.34–4.02 (m, 1H), 3.73 (d, J = 2.3 Hz, 3H), 2.74 (t, J = 5.3 Hz, 1H), 2.12–1.55 (m, 3H), 1.52–1.18 (m, 11H).

[0882] Step 2

[0883] To a solution of 59-A (686 mg, 2.53 mmol) in N,N-dimethylformamide (5 mL), tert-butylchlorodiphenylsilane (0.723 mL, 2.78 mmol) and imidazole (516 mg, 7.56 mmol) were added. After 18 hours, the mixture was diluted with water, extracted into EtOAc (2x), the organic fractions were combined, dried (Na2SO4), and concentrated. The residue was purified by silica column chromatography (10-20% EtOAc / hexane) to give 59-C. LCMS-ESI + (m / z):C 29 H 39 [M+H] of NO5Si + Theoretical value: 509.71; Measured value: 510.793.

[0884] Step 3

[0885] A solution of 59-C (1.23 g, 2.41 mmol) in 13 mL THF was stirred in an ice bath while 2.0 M LiBH4 in 2.42 mL, 4.84 mmol THF was added, and the mixture was stirred at room temperature for 18 hours. After diluting the reaction mixture with ethyl acetate, water was slowly added to separate the two phases, and the aqueous fraction was extracted with ethyl acetate. The two organic fractions were washed with water, combined, dried (Na2SO4), and concentrated. The residue was purified by silica column chromatography (20–40% EtOAC / hexane) to give 59-D. LCMS-ESI + (m / z):C 28 H 39 [M+H] of NO4Si + Theoretical value: 481.7; Measured value: 482.741.

[0886] Step 4

[0887] A mixture of 59-D (963 mg, 2.0 mmol), phthalimide (482 mg, 3.28 mmol), and triphenylphosphine (1.18 g, 4.49 mmol) in THF (50 mL) was cooled in an ice bath. Diisopropyl azodicarboxylate, 95% (0.89 mL, 4.52 mmol), was added. The mixture was then heated to room temperature and stirred for 20 hours. The reaction mixture was then concentrated, and the residue was dissolved in diethyl ether, cooled in an ice bath, and stirred for 1.5 hours. The solid was then filtered off, and the filtrate was concentrated. The residue was purified by silica column chromatography (10–30% EtOAc / hexane) to give the phthalimide adduct. LCMS-ESI + (m / z):C 36 H42 [M+H] of N2O5Si + Theoretical value: 610.81; Measured value: 611.935.

[0888] A solution of phthalimide adduct (1.2 g, 1.97 mmol) and hydrazine hydrate (0.4 mL, 8.03 mmol) in ethanol (12 mL) was stirred at 70 °C for 2 hours. The reaction mixture was cooled in an ice bath, and ether (10 mL) was added, followed by stirring for 30 minutes. The resulting solid was filtered off, and the filtrate was concentrated to dryness under vacuum to give 59-E. LCMS-ESI + (m / z):C 28 H 40 [M+H] of N2O3Si + Theoretical value: 480.71; Measured value: 481.356.

[0889] Step 5

[0890] The mixture of crude 59-E (770 mg, 1.60 mmol), compound 38-F (Example 38) (555 mg, 1.60 mmol), and NaHCO3 (269 mg, 3.20 mmol) in water (12 mL) and EtOH (12 mL) was stirred for 20 hours. The reaction mixture was concentrated under vacuum, and the residue was partitioned between water and EtOAc. The aqueous layer was re-extracted with EtOAc, the combined organic layers were dried (Na2SO4), and concentrated.

[0891] The residue (1.29 g) was dissolved in CH₂Cl₂ (4 mL) and 4 N HCl was added to dioxane (15.6 mL). After 1.5 hours, the mixture was concentrated to dryness, co-evaporated with toluene, and dried under vacuum. LCMS-ESI + (m / z):C 41 H 48 [M+H] of N2O7Si + Theoretical value: 708.91; Measured value: 709.782.

[0892] The crude residue (1.09 mg) and DBU (1.17 mL, 7.8 mmol) were stirred in toluene (20 mL) at 110 °C. After 35 min, the mixture was concentrated, and the residue was purified by silica column chromatography (5-15% MeOH / EtOAc) to give 59-F. LCMS-ESI + (m / z):C 39 H 42 [M+H] of N2O6Si +Theoretical value: 662.85; Measured value: 663.677.

[0893] Step 6

[0894] At room temperature, a mixture of 59-F (680 mg, 1.03 mmol) in MeOH (10 mL) and THF (10 mL) was stirred, and 1 M KOH (5.42 mL) was added. After 30 minutes, the reaction mixture was neutralized with 1 N HCl, extracted into EtOAc (2x), and the combined organic extracts were dried (Na₂SO₄) and concentrated. LCMS-ESI + (m / z):C 37 H 38 [M+H] of N2O6Si + Theoretical value: 634.79; Measured value: 635.466.

[0895] At room temperature, a suspension of the crude residue (650 mg), 2,4,6-trifluorobenzylmethylamine (214 mg, 1.33 mmol), and HATU (623 mg, 1.64 mmol) in dichloromethane (6 mL) was stirred while N,N-diisopropylethylamine (DIPEA) (1.34 mL, 7.68 mmol) was added. After 2 hours, the mixture was diluted with water, extracted into EtOAc (3x), the combined organic phases were dried (Na2SO4), concentrated, and the residue was purified by silica column chromatography (50-75% EtOAc / hexane) to give 59-G.LCMS-ESI. + (m / z):C 44 H 42 [M+H] of F3N3O5Si + Theoretical value: 777.9; Measured value: 778.566.

[0896] Step 7

[0897] A solution of 59-G (648 mg, 0.83 mmol) in 10 mL of THF was stirred in an ice bath while 1.0 M tetrabutylammonium fluoride was added dropwise to 0.83 mL of THF. The mixture was stirred at room temperature for 30 minutes. Another 1.0 M tetrabutylammonium fluoride was added dropwise to 0.1 mL of THF. After 30 minutes, the reaction mixture was concentrated under vacuum, and the residue was diluted with EtOAc, washed with water, dried (Na₂SO₄), concentrated, and purified by silica column chromatography (5% MeOH / EtOAc). A solution of the residue (290 mg, 0.54 mmol) in 3 mL of dichloromethane was cooled to -78 °C while diethylaminosulfur trifluoride (0.09 mL, 0.65 mmol) was added dropwise. The reaction was then heated to room temperature and stirred for 2.5 hours. The reactants were cooled in an ice bath, quenched with saturated NaHCO3, and the two phases were separated. The aqueous fraction was extracted with CH2Cl2. The two organic fractions were combined, dried (Na2SO4), and concentrated. The residue was purified by silica column chromatography (1% MeOH / EtOAc) to give 59-H. LCMS-ESI + (m / z):C 28 H 23 [M+H] of F4N3O4 + Theoretical value: 541.49; Measured value: 542.320.

[0898] Step 8

[0899] Compound 59-H (103 mg, 0.19 mmol) was dissolved in 1.4 mL of TFA at room temperature for 15 minutes, and the solution was concentrated. The residue was suspended in DMF, filtered, and the precipitate was washed with water and dried under vacuum to give compound 59. LCMS-ESI + (m / z):C 21 H 17 [M+H] of F4N3O4 + Theoretical value: 451.37, measured value: 452.226. 1 H-NMR (400MHz, DMSO-d6) δ11.53(s,1H),10.35(t,J=5.8Hz,1H),8.34(s,1H),7.18(t,J=8.6Hz,2H),5.15-4.88(m,1H),4.73(d,J=3. 3Hz,1H),4.49(m,3H),4.04(t,J=12.4Hz,1H),3.65(dd,J=12.4,3.7Hz,1H),2.95-2.76(m,1H),2.26-2.03(m,1H),1.96-1.64(m,3H).19 F-NMR (376MHz, DMSO-d6) δ -73.93, -74.74 (d, J = 28.8Hz), -109.31 (m), -112.51 (m), -165.65 (m).

[0900] Example 60

[0901] Preparation of compound 60

[0902] (1R,4S,12aR)-N-(2,3-dichlorophenylmethyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0903]

[0904] Step 1

[0905] To a solution of dimethyl 3-methoxy-4-oxo-4H-pyran-2,5-dicarboxylate (5.5 g, 23 mmol) in MeOH (100 mL), 41-E (Example 41) (5 g, 22 mmol) and sodium bicarbonate (3.6 g, 43 mmol) were added. The solution was stirred at room temperature for 1.5 hours. 4M HCl (in dioxane, 55 mL, 221 mmol) was added, and the solution was heated to 50 °C for 2 hours. The reaction was cooled to room temperature and concentrated under vacuum. The resulting oil was dissolved in sodium bicarbonate and washed with EtOAc. The aqueous layer was then extracted with CH2Cl2 (4x). The combined CH2Cl2 extracts were dried over Na2SO4 and concentrated to give 60-A. LCMS-ESI + (m / z):C 16 H 19 [M+H] of N2O5 + Theoretical value: 319.13; Measured value: 319.20.

[0906] Step 2

[0907] Add 2M, 15.7mL, 31.4mmol of KOH aqueous solution to a suspension of 60-A (3.7g, 11.6mmol) in MeOH (12mL) and THF (23mL). Stir the resulting solution at room temperature for 10 minutes. Remove volatiles under vacuum and acidify the resulting aqueous layer with 1N HCl. Filter the resulting white solid, wash with water, and dry under vacuum to give 60-B. 1¹H-NMR (400MHz, chloroform-d) δ 8.36 (s, 1H), 5.01 (d, J = 2.7 Hz, 1H), 4.12 (s, 4H), 3.90 (t, J = 12.2 Hz, 1H), 3.78 (dd, J = 12.1, 3.1 Hz, 1H), 2.69 (s, 1H), 1.95–1.71 (m, 4H), 1.70–1.54 (m, 2H). LCMS-ESI + (m / z):C 15 H 17 [M+H] of N2O5 + Theoretical value: 305.11; Measured value: 305.15.

[0908] Step 3

[0909] To a solution of 60-B (0.10 g, 0.33 mmol) in CH₂Cl₂ (3.5 mL), (2,3-dichlorophenyl)methylamine (0.12 g, 0.70 mmol), HATU (0.25 g, 0.66 mmol), and N,N-diisopropylethylamine (DIPEA) (0.29 mL, 1.64 mmol) were added. The solution was stirred at room temperature until the reaction was determined to be complete by LC / MS. The reaction mixture was diluted with CH₂Cl₂ and washed with 1N HCl. The aqueous layer was extracted with CH₂Cl₂, and the combined organic layers were dried over Na₂SO₄ and then dried under vacuum. The crude material was dissolved in hot DMF and allowed to precipitate upon cooling. The precipitate was obtained by filtration. LC / MS-ESI + (m / z):C 22 H 22 [M+H] of Cl2N3O4 + Theoretical value: 462.10; Measured value: 462.14.

[0910] Step 4

[0911] Magnesium bromide (0.089 g, 0.48 mmol) was added to a slurry of 60-C (0.11 g, 0.24 mmol) in acetonitrile (4.5 mL). The reaction mixture was heated to 45 °C for 2.5 h and then cooled to room temperature. The slurry was diluted with CH₂Cl₂ and washed with 1 N HCl and brine. The aqueous layer was extracted with CH₂Cl₂ (2x), and the combined organic layers were dried over Na₂SO₄ and then dried under vacuum. The crude solid was ground with methanol and filtered to give 60. 1H-NMR(400MHz,DMSO-d6)δ11.72(s,1H),10.50(t,1H),8.34(s,1H),7.55(dd,1H),7.40-7.24(m,2H),4.67(s,1 H),4.61(d,2H),4.45(dd,1H),3.95(t,1H),3.84-3.73(m,1H),1.86-1.67(m,3H),1.66-1.40(m,4H).LCMS-ESI + (m / z):C 21 H 20 [M+H] of Cl2N3O4 + Theoretical value: 448.08; Measured value: 448.18.

[0912] Example 61

[0913] Preparation of compound 61

[0914] (1R,4S,12aS)-N-(3-chloro-2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0915]

[0916]

[0917] Similar to Example 60, 41-E was prepared by replacing 41-E with (1S,3S,4R)-3-(aminomethyl)-2-azabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (prepared in Example 55) and (2,3-dichlorophenyl)methylamine with (3-chloro-2,4-difluorophenyl)methylamine. 1 H-NMR(400MHz,DMSO-d6)δ11.85(s,1H),10.45(t,1H),8.40(s,1H),7.37(td,1H),7.27(td, 1H),4.63-4.46(m,4H),4.17(t,1H),4.04(dt,1H),1.76(d,1H),1.73-1.54(m,5H).LCMS-ESI + (m / z):C 21 H 19 [M+H] of ClF2N3O4 + Theoretical value: 450.10; Measured value: 450.15.

[0918] Example 62

[0919] Preparation of Compounds 62

[0920] '(2R,5S,13aR)-N-(4-fluoro-2-(trifluoromethyl)benzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0921]

[0922] Compound 62 was prepared using a method similar to that of compound 42, but with (4-fluoro-2-(trifluoromethyl)phenyl)methylamine instead of (2,4,6-trifluorophenyl)methylamine. 1 H-NMR (400MHz, chloroform-d) δ10.50(s,1H),8.38(s,1H),7.57(dd,1H),7.36(dd,1H),7.19(td,1H),5.40-5.28(m,2H),4. 79(t,2H),4.69(s,1H),4.25(dd,1H),4.03(dd,1H),2.17-1.98(m,4H),1.96-1.84(m,1H),1.61(dt,1H).LCMS-ESI + (m / z):C 22 H 20 [M+H] of F4N3O5 + Theoretical value: 482.13; Measured value: 482.145.

[0923] Example 63

[0924] Preparation of compound 63

[0925] (2R,5S,13aR)-N-(2-chloro-4-fluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0926]

[0927] Compound 63 was prepared by using (2-chloro-4-fluorophenyl)methylamine instead of (2,4,6-trifluorophenylphenyl)methylamine, similar to the method used for compound 42. 1H-NMR (400MHz, chloroform-d) δ10.48(s,1H),8.45(s,1H),7.39(dd,1H),7.12(dd,1H),6.93(td,1H),5.37(d,1H),5.31( t,1H),4.68(s,3H),4.29(d,1H),4.04(t,1H),2.21-2.01(m,4H),1.97-1.82(m,1H),1.67-1.56(m,1H).LCMS-ESI + (m / z):C 21 H 20 [M+H] of ClFN3O5 + Theoretical value: 448.10; Measured value: 448.143.

[0928] Example 64

[0929] Preparation of compound 64

[0930] (2R,5S,13aR)-8-hydroxy-7,9-dioxo-N-(2,4,5-trifluorobenzyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]

[0931] Oxy-nitrogen -10-formamide

[0932]

[0933] Compound 64 was prepared by using (2,4,5-trifluorophenyl)methylamine instead of (2,4,6-trifluorophenyl)methylamine in a manner similar to that used for compound 42. 1 H-NMR (400MHz, chloroform-d) δ10.42(s,1H),8.42(s,1H),7.19(ddd,1H),6.91(td,1H),5.38(dd,1H),5.31(t,1H),4.69(s ,1H),4.61(d,2H),4.29(dd,1H),4.05(dd,1H),2.18-2.02(m,4H),1.96-1.84(m,1H),1.66-1.56(m,1H).LCMS-ESI + (m / z):C 21 H 19 [M+H] of F3N3O5 + Theoretical value: 450.12; Measured value: 450.119.

[0934] Example 65

[0935] Preparation of compound 65

[0936] (2R,5S,13aR)-N-(5-chloro-2,4-difluorobenzyl)-8-hydroxy-7,9-dioxo-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[0937]

[0938] Compound 65 was prepared by using (5-chloro-2,4-difluorophenyl)methylamine instead of (2,4,6-trifluorophenyl)methylamine, similar to the method used for compound 42. 1 H-NMR (400MHz, chloroform-d) δ10.47(t,1H),8.41(s,1H),7.40(dd,1H),6.90(t,1H),5.37(dd,1H),5.31(t,1H),4.69 (s,1H),4.62(d,2H),4.28(d,1H),4.04(dd,1H),2.17-2.02(m,4H),1.94-1.86(m,1H),1.61(dt,1H).LCMS-ESI + (m / z):C 21 H 19 [M+H] of ClF2N3O5 + Theoretical value: 466.09; Measured value: 466.107.

[0939] Example 66

[0940] Preparation of compound 66

[0941] (1R,4S,12aR)-N-(3,4-difluorophenylmethyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylene dipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0942]

[0943] Compound 66 was prepared using a method similar to that of compound 60, but with (3,4-difluorophenyl)methylamine instead of (2,3-dichlorophenyl)methylamine. 1¹H-NMR (400MHz, chloroform-d) δ 10.59 (s, 1H), 7.24–7.16 (m, 2H), 7.14–7.04 (m, 2H), 4.91 (s, 1H), 4.58 (d, 3H), 3.94–3.82 (m, 1H), 3.79 (d, 1H), 1.99–1.81 (m, 4H), 1.76 (d, 1H), 1.70–1.60 (m, 3H). LCMS-ESI + (m / z):C 21 H 20 [M+H] of F2N3O4 + Theoretical value: 416.13; Measured value: 416.415.

[0944] Example 67

[0945] Preparation of compound 67

[0946] (1R,4S,12aR)-N-(4-fluoro-2-(trifluoromethyl)benzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0947] 67

[0949] Compound 67 was prepared by using (4-fluoro-2-(trifluoromethyl)phenyl)methylamine instead of (2,3-dichlorophenyl)methylamine, similar to the method used for compound 60. 1 H-NMR (400MHz, chloroform-d) δ11.72(s,1H),10.55(s,1H),8.29(s,1H),7.61(s,1H),7.36(dd,1H),7.18(td,1 H),4.91(s,1H),4.80(d,3H),4.11(s,1H),1.99-1.80(m,4H),1.76(d,1H),1.71-1.47(m,3H).LCMS-ESI + (m / z):C 22 H 20 [M+H] of F4N3O4 + Theoretical value: 466.13; Measured value: 466.297.

[0950] Example 68

[0951] Preparation of compound 68

[0952] (1R,4S,12aR)-N-(2-chloro-4-fluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0953]

[0954] Compound 68 was prepared by using (2-chloro-4-fluorophenyl)methylamine instead of (2,3-dichlorophenyl)methylamine in a manner similar to that used for compound 60. 1 H-NMR (400MHz, chloroform-d) δ11.68(s,1H),10.52(s,1H),8.27(s,1H),7.44-7.37(m,1H),7.11(dd,1H),6.93(td,1H),4.90( s,1H),4.68(d,2H),4.16-4.01(m,1H),3.88-3.70(m,2H),2.00-1.79(m,4H),1.75(d,1H),1.70-1.57(m,2H).LCMS-ESI + (m / z):C 21 H 20 [M+H] of ClFN3O4 + Theoretical value: 432.10; Measured value: 432.214.

[0955] Example 69

[0956] Preparation of compound 69

[0957] (1R,4S,12aR)-N-(3-chloro-2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0958]

[0959] Compound 69 was prepared by using (3-chloro-2,4-difluorophenyl)methylamine instead of (2,3-dichlorophenyl)methylamine in a manner similar to that of compound 60. 1¹H-NMR (400MHz, chloroform-d) δ 11.71 (s, 1H), 10.48 (s, 1H), 8.26 (s, 1H), 7.27 (s, 1H), 6.92 (td, 1H), 4.90 (s, 1H), 4.66 (d, 2H), 4.08 (s, 1H), 3.91–3.69 (m, 2H), 2.01–1.79 (m, 3H), 1.75 (d, 1H), 1.71–1.44 (m, 2H). LCMS-ESI + (m / z):C 21 H 19 [M+H] of ClF2N3O4 + Theoretical value: 450.10; Measured value: 450.27.

[0960] Example 70

[0961] Preparation of compound 70

[0962] (1R,4S,12aR)-N-(2-fluoro-3-methylbenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0963]

[0964] Compound 70 was prepared by using (2-fluoro-3-methylphenyl)methylamine instead of (2,3-dichlorophenyl)methylamine in a manner similar to that used for compound 60. 1 ¹H-NMR (400MHz, chloroform-d) δ 11.62 (s, 1H), 10.39 (s, 1H), 8.30 (s, 1H), 7.19 (t, 1H), 7.07 (t, 1H), 6.96 (t, 1H), 4.89 (d, 1H), 4.67 (d, 2H), 4.08 (s, 1H), 3.88–3.67 (m, 2H), 2.26 (d, 3H), 1.97–1.79 (m, 3H), 1.78–1.39 (m, 3H). LCMS-ESI + (m / z):C 22 H 23 [M+H] of FN3O4 + Theoretical value: 412.16; Measured value: 412.26.

[0965] Example 71

[0966] Preparation of compound 71

[0967] (1R,4S,12aR)-N-(3,6-dichloro-2-fluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0968]

[0969] Compound 71 was prepared by using (3,6-dichloro-2-fluorophenyl)methylamine instead of (2,3-dichlorophenyl)methylamine in a manner similar to that of compound 60. 1 ¹H-NMR (400MHz, chloroform-d) δ 11.62 (s, 1H), 10.47 (t, 1H), 8.29 (s, 1H), 7.13 (dd, 1H), 4.88 (s, 1H), 4.85–4.73 (m, 2H), 4.09 (d, 1H), 3.88–3.68 (m, 2H), 1.99–1.53 (m, 8H). LCMS-ESI + (m / z):C 21 H 19 [M+H] of Cl2FN3O4 + Theoretical value: 466.07; Measured value: 466.257.

[0970] Example 72

[0971] Preparation of compound 72

[0972] (1R,4S,12aR)-N-(3-chlorophenylmethyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0973]

[0974] Compound 72 was prepared by using (3-chlorophenyl)methylamine instead of (2,3-dichlorophenyl)methylamine in a manner similar to that used for compound 60. 1 H-NMR(400MHz,DMSO-d6)δ11.75(s,1H),10.44(t,1H),8.38(s,1H),7.42-7.22(m,4H),4.68(s,1H),4.54(d,2H),4 .48(dd,1H),3.97(t,1H),3.81(dd,1H),2.58(s,1H),1.87-1.69(m,3H),1.68-1.51(m,2H),1.46(d,1H).LCMS-ESI + (m / z):C21 H 21 [M+H] of ClN3O4 + Theoretical value: 414.11; Measured value: 414.21.

[0975] Example 73

[0976] Preparation of compound 73

[0977] (1R,4S,12aR)-N-(3-chloro-2,6-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0978]

[0979] Compound 73 was prepared by using (3-chloro-2,6-difluorophenyl)methylamine instead of (2,3-dichlorophenyl)methylamine in a manner similar to that of compound 60. 1 H-NMR(400MHz,DMSO-d6)δ11.71(s,1H),10.46(t,1H),8.34(s,1H),7.60(td,1H),7.19(td,1H),4.67(s,1H),4.62(d,2 H),4.44(dd,1H),3.95(t,1H),3.78(dd,1H),2.57(s,1H),1.86-1.68(m,3H),1.67-1.49(m,2H),1.45(d,1H).LCMS-ESI + (m / z):C 21 H 19 [M+H] of ClF2N3O4 + Theoretical value: 450.10; Measured value: 450.16.

[0980] Example 74

[0981] Preparation of compound 74

[0982] (1R,4S,12aR)-N-(2-fluoro-3-(trifluoromethyl)benzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0983]

[0984] Compound 74 was prepared by using (2-fluoro-3-(trifluoromethyl)phenyl)methylamine instead of (2,3-dichlorophenyl)methylamine in a manner similar to that used for compound 60. 1 H-NMR(400MHz,DMSO-d6)δ11.76(s,1H),10.48(t,1H),8.36(s,1H),7.68(q,2H),7.38(t,1H),4.68(s,1H),4.65(d,2H ),4.47(dd,1H),3.96(t,1H),3.80(dd,1H),2.57(s,1H),1.88-1.69(m,3H),1.67-1.50(m,2H),1.45(d,1H).LCMS-ESI + (m / z):C 22 H 20 [M+H] of F4N3O4 + Theoretical value: 466.13; Measured value: 466.142.

[0985] Example 75

[0986] Preparation of compound 75

[0987] (1R,4S,12aR)-N-(3-chloro-4-fluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0988]

[0989] Compound 75 was prepared by using (3-chloro-4-fluorophenyl)methylamine instead of (2,3-dichlorophenyl)methylamine in a manner similar to that used for compound 60. 1 H-NMR(400MHz,DMSO-d6)δ11.75(s,1H),10.43(t,1H),8.38(s,1H),7.51(dd,1H),7.42-7.28(m,2H),4.68(s,1H),4.51(d ,2H),4.47(dd,1H),3.97(t,1H),3.80(dd,1H),2.58(s,1H),1.86-1.68(m,3H),1.68-1.52(m,2H),1.46(d,1H).LCMS-ESI + (m / z):C 21 H 20 [M+H] of ClFN3O4 + Theoretical value: 432.10; Measured value: 432.159.

[0990] Example 76

[0991] Preparation of compound 76

[0992] (1R,4S,12aR)-N-((3,5-difluoropyridin-2-yl)methyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0993]

[0994] Compound 76 was prepared by using (3,5-difluoropyridin-2-yl)methylamine instead of (2,3-difluoropyridinylphenyl)methylamine, similar to the method used for compound 60. 1 ¹H-NMR (400MHz, chloroform-d) δ 10.80 (s, 1H), 8.81 (s, 1H), 8.33 (d, 1H), 7.20 (td, 1H), 4.90 (s, 1H), 4.82 (s, 2H), 4.28 (d, 1H), 3.92–3.75 (m, 2H), 3.48 (s, 2H), 1.98–1.80 (m, 3H), 1.77 (d, 1H), 1.71–1.58 (m, 2H). LCMS-ESI + (m / z):C 20 H 19 [M+H] of F2N4O4 + Theoretical value: 417.13; Measured value: 417.189.

[0995] Example 77

[0996] Preparation of compound 77

[0997] (1R,4S,12aR)-7-hydroxy-6,8-dioxo-N-((R)-1-(2,4,6-trifluorophenyl)ethyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[0998]

[0999] Step 1

[1000] A 50-mL round-bottom flask was loaded with 77-A (0.15 g, 0.39 mmol), (R)-1-(2,4,6-trifluorophenyl)ethylamine (0.14 g, 0.78 mmol), N,N-diisopropylethylamine (DIPEA) (0.25 g, 1.97 mmol), and HATU (0.29 g, 0.79 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and dissolved in EtOAc (50 mL), washed with saturated NaHCO3 (2x) and saturated NH4Cl, and dried over Na2SO4. After concentration, the crude substance was purified by column chromatography on silica gel using hexane-EtOAc to give 77-B as a white solid. LCMS-ESI + (m / z):[M+H) + , Measured value: 538.

[1001] Step 2

[1002] 77-B (0.20 g, 0.27 mmol) in 2 mL of TFA was loaded into a 50 mL round-bottom flask. The reaction mixture was stirred for 30 minutes at room temperature. The solution was concentrated, and the residue was purified by column chromatography on silica gel with EtOAc-20% MeOH as the eluent to give compound 77. 1 ¹H-NMR (400MHz, chloroform-d) δ 10.67 (d, J = 8.2 Hz, 1H), 8.22 (s, 1H), 6.61 (t, J = 8.4 Hz, 2H), 5.60 (dd, J = 8.1, 6.9 Hz, 1H), 4.85 (s, 1H), 3.82 (t, J = 12.2 Hz, 1H), 3.71 (dd, J = 12.4, 3.4 Hz, 1H), 2.75–2.55 (m, 3H), 1.97–1.57 (m, 9H). 19 F-NMR (376MHz, chloroform-d) δ -109.65′–-111.29(m), -111.76–-113.09(m). LCMS-ESI + (m / z):[M+H) + Measured value: 448.

[1003] Example 78

[1004] Preparation of compound 78

[1005] (2R,13aR)-8-hydroxy-7,9-dioxo-N-((R)-1-(2,4,6-trifluorophenyl)ethyl)-2,3,4,5,7,9,13,13a-octahydro-2,5-bridged methylenepyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxaza -10-formamide

[1006]

[1007]

[1008] Step 1

[1009] A 50-mL round-bottom flask was loaded with 78-A (0.30 g, 0.94 mmol), (R)-1-(2,4,6-trifluorophenyl)ethylamine (0.39 g, 1.87 mmol), N,N-diisopropylethylamine (DIPEA) (0.61 g, 4.87 mmol), and HATU (0.71 g, 1.87 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and dissolved in EtOAc (50 mL), washed with saturated NaHCO3 (2x) and saturated NH4Cl, and dried over Na2SO4. After concentration, the crude substance was purified by column chromatography on silica gel using hexane-EtOAc to give 78-B as a white solid. LCMS-ESI + (m / z):[M+H) + ; Measured value: 478.

[1010] Step 2

[1011] 78-B (0.4 g, 0.84 mmol) and magnesium bromide (0.4 g, 2.2 mmol) were placed in acetonitrile (5 mL) in a 50 mL round-bottom flask. The reaction mixture was heated to 50 °C. After 10 minutes, the reaction mixture was cooled to 0 °C, and 1 N hydrochloric acid (4 mL) was added. Further water (~5 mL) was added, the solid was filtered, washed with water, and dried to give compound 78. 1H-NMR (400MHz, chloroform-d) δ12.30(s,1H),10.59(d,J=8.3Hz,1H),8.21(s,1H),6.60(t,J=8.4Hz,2H),5.59(t,J=7.4Hz,1H),5.37(dd,J=9.4,4.1Hz, 1H),5.31-5.09(m,1H),4.64(t,J=3.0Hz,1H),4.20(dd,J=12.9,4.1Hz, 2H), 3.96 (dd, J=12.8, 9.4Hz, 2H), 2.21-1.85 (m, 4H), 1.71-1.43 (m, 3H). 19 F-NMR (376MHz, chloroform-d) δ -110.37 (tt, J = 8.7, 6.1Hz), -112.19 (t, J = 7.2Hz). LCMS-ESI + (m / z):[M+H) + Measured value: 464.

[1012] Example 79

[1013] Preparation of compound 79

[1014] (1R,4S,12aR)-7-hydroxy-6,8-dioxo-N-(2,4,5-trifluorobenzyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[1015]

[1016] Step 1

[1017] A 50-mL round-bottom flask was loaded with 79-A (0.12 g, 0.32 mmol), (2,4,5-trifluorophenyl)methylamine (0.10 g, 0.63 mmol), N,N-diisopropylethylamine (DIPEA) (0.20 g, 1.58 mmol), and HATU (0.24 g, 0.63 mmol) in DCM (10 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and dissolved in EtOAc (50 mL), washed with saturated NaHCO3 (2x) and saturated NH4Cl, and dried over Na2SO4. After concentration, the crude substance was purified by column chromatography on silica gel using hexane-EtOAc to give 79-B as a white solid. LCMS-ESI + (m / z):[M+H) + ; Measured value: 524.

[1018] Step 2

[1019] 79-B (0.15 g, 0.29 mmol) in 2 mL of TFA was loaded into a 50 mL round-bottom flask. The reaction mixture was stirred at room temperature for 30 minutes. The solution was concentrated, and the residue was purified by column chromatography on silica gel with EtOAc-20% MeOH as the eluent to give compound 79. 1 H-NMR (400MHz, chloroform-d) δ11.70(s,1H),10.65-10.18(m,1H),8.27(s,1H),7.26(m,1H),6.90(td,J=9.7,6.4Hz,1H),4 .89(s,1H),4.60(d,J=6.0Hz,2H),4.09(dd,J=11.4,2.6Hz,1H),3.96-3.66(m,2H),2.68(s,1H),2.15-1.43(m,6H). 19 F-NMR (376MHz, chloroform-d) δ 120.53–120.85 (m), -134.68–136.79 (m), -142.26–144.11 (m). LCMS-ESI + (m / z):[M+H) + Measured value: 434.

[1020] Example 80

[1021] Preparation of compound 80

[1022] (1R,4S,12aR)-N-(5-chloro-2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[1023]

[1024] Step 1

[1025] A 50-mL round-bottom flask was filled with 80-A (0.12 g, 0.32 mmol), (5-chloro-2,4-difluorophenyl)methylamine (0.11 g, 0.63 mmol), N,N-diisopropylethylamine (DIPEA) (0.20 g, 1.58 mmol), and HATU (0.24 g, 0.63 mmol) in DCM (10 mL). The reaction mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated and dissolved in EtOAc (50 mL), washed with saturated NaHCO3 (2x) and saturated NH4Cl, and dried over Na2SO4. After concentration, the crude substance was purified by column chromatography on silica gel using hexane-EtOAc to give 80-B as a white solid. LCMS-ESI + (m / z):[M+H) + ; Measured value: 541.

[1026] Step 2

[1027] 80-B (0.14 g, 0.26 mmol) in 2 mL of TFA was loaded into a 50 mL round-bottom flask. The reaction mixture was stirred at room temperature for 30 minutes. The solution was concentrated, and the residue was purified by column chromatography on silica gel with EtOAc-20% MeOH as the eluent to give compound 80. 1 ¹H-NMR (400MHz, chloroform-d) δ 10.46 (s, 1H), 8.27 (s, 1H), 7.40 (t, J = 7.8 Hz, 1H), 6.89 (t, J = 9.1 Hz, 1H), 4.90 (s, 1H), 4.78–4.48 (m, 2H), 4.08 (dd, J = 11.3, 2.5 Hz, 1H), 3.95–3.63 (m, 2H), 2.68 (s, 1H), 2.22–1.51 (m, 7H). 19 F-NMR (376MHz, chloroform-d) δ -113.37 (q, J = 8.1Hz), -116.37 (q, J = 8.0Hz). LCMS-ESI + (m / z):[M+H) + Measured value: 451.

[1028] Example 81

[1029] Preparation of compound 81

[1030] (1R,3S,4S,12aS)-3-fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorophenylmethyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[1031]

[1032]

[1033] Step 1

[1034] 81-A (1.0 g, 3.7 mmol) in 10 mL of DCM was placed in a 100 mL round-bottom flask. The reaction mixture was cooled to 0 °C. Diethylaminosulfur trifluoride (DAST) (0.58 mL, 4.1 mmol) was slowly added. The reaction mixture was then stirred at room temperature for 1 hour. The mixture was cooled back to 0 °C. The reaction was quenched dropwise with saturated NaHCO3 (5 mL). The reaction mixture was then diluted with EtOAc (100 mL), washed with saturated NaHCO3 and brine, and dried over Na2SO4. After concentration, the residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 81-B. LCMS-ESI + (m / z):[M+H) + Measured value: 274.

[1035] Step 2

[1036] 0.8 g (3.0 mmol) of 81-B in 10 mL of THF was added to a 100 mL round-bottom flask. The reaction mixture was stirred at -78 °C. 2.0 M LiBH4 in 3.2 mL (6.4 mmol) of THF was slowly added. The reaction mixture was then heated and stirred at room temperature for 3 hours. The reaction mixture was then diluted with 100 mL of EtOAc and slowly treated with water (to release H2). After phase separation, the aqueous fraction was extracted with EtOAc, and the two organic fractions were combined, washed with water, and dried over Na2SO4. After concentration, the residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 81-C. LCMS-ESI + (m / z):[M+H) + Measured value: 246.

[1037] Step 3

[1038] 81-C (0.57 g, 2.3 mmol), triphenylphosphine (1.3 g, 5.1 mmol), and phthalimide (0.55 g, 3.7 mmol) in THF (15 mL) were charged into a 100 mL round-bottom flask. The reaction mixture was then cooled to 0 °C while stirring. Diisopropyl azodicarboxylate (DIAD) (1.0 mL, 5.1 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. After concentration, the residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 81-D. LCMS-ESI + (m / z):[M+H) + Measured value: 375.

[1039] Step 4

[1040] Hydrazine monohydrate (0.6 mL) was added to a solution of 81-D (0.8 g, 2.1 mmol) in EtOH (40 mL). The reaction mixture was heated to 70 °C and stirred for 3 hours. After filtering to remove the solids, the filtrate was concentrated to give 81-E. LCMS-ESI + (m / z):[M+H) + Measured value: 245.

[1041] Step 5

[1042] To a 100-mL round-bottom flask, add 0.49 g (2.0 mmol) of 81-E and 0.7 g (2.0 mmol) in ethanol (7 mL). Add sodium bicarbonate (0.34 g, 4.0 mmol) in water (7 mL). Stir the reaction mixture overnight at room temperature. Dilute the mixture with EtOAc (50 mL) and wash with water (2x). Extract the aqueous fraction with EtOAc (1x), combine the organic fractions, dry (Na₂SO₄), and concentrate. The crude 81-G is used in the next step without further purification. LCMS-ESI + (m / z):[M+H) + Measured value: 573.

[1043] Step 6

[1044] 1.1 g (1.9 mmol) of 81-G was added to a 100 mL round-bottom flask in 11 mL of 4N HCl / dioxane. The reaction mixture was then stirred for 1 hour at room temperature. After concentration, 1.0 g of the intermediate was obtained. This intermediate and DBU (1.3 g, 8.8 mmol) were dissolved in 10 mL of toluene. The reaction mixture was heated to 110 °C and stirred for 1 hour. After concentration, the residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 81-H. LCMS-ESI + (m / z):[M+H) + Measured value: 413.

[1045] Step 7

[1046] 81-H (0.56 g, 1.4 mmol) in THF (5 mL) and MeOH (5 mL) was placed in a 100 mL round-bottom flask. 1N KOH (4 mL) was added to the reaction mixture. The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1N HCl (4 mL). After concentration, the residue was co-evaporated with toluene (3 x). Half of the crude acid, 2,4,6-trifluorobenzylmethylamine (0.2 g, 1.3 mmol), N,N-diisopropylethylamine (DIPEA) (0.41 g, 3.1 mmol), and HATU (0.48 g, 1.25 mmol) were dissolved in DMF (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (100 mL), washed with saturated NaHCO3 (2 x) and saturated NH4Cl (2 x), and dried over Na2SO4. After concentration, the crude substance was purified by column chromatography on silica gel with hexane-EtOAc to obtain 81-I. LCMS-ESI + (m / z):[M+H) + Measured value: 542.

[1047] Step 8

[1048] The reactant 81-I (0.31 g, 0.58 mmol) in 3 mL of TFA was added to a 50 mL round-bottom flask. The reaction mixture was stirred for 30 minutes at room temperature. After concentration, the crude substance was purified by column chromatography on silica gel with EtOAc-MeOH to give compound 81. 1H-NMR (400MHz, chloroform-d) δ10.29(s,1H),8.31(s,1H),6.65(dd,J=8.7,7.5Hz,2H),5.05-4.75(m,2H),4.65(d,J=5.6Hz,2H),4.11(d,J=12.2Hz ,1H),3.83(t,J=12.3Hz,1H),3.56(dd,J=12.3,3.3Hz,1H),2.77(s,1H),2.25-1.97(m,2H),1.95(d,J=11.0Hz,2H),1.77(d,J=11.2Hz,1H). 19 F-NMR (376MHz, chloroform-d) δ -108.98 (t, J = 8.2Hz), -112.03 (t, J = 7.2Hz), -168.00. LCMS-ESI + (m / z): Measured value: 452.

[1049] Example 82

[1050] Preparation of compound 82

[1051] (1S,3R,4R,12aR)-3-fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorophenylmethyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[1052]

[1053]

[1054] Step 1

[1055] 82-A (0.6 g, 2.1 mmol) in DCM (6 mL) was placed in a 100 mL round-bottom flask. The reaction mixture was cooled to 0 °C. DAST (0.35 mL, 3.0 mmol) was slowly added. The reaction mixture was then stirred at room temperature for 1 hour. The mixture was cooled back to 0 °C. The reaction was quenched dropwise with saturated NaHCO3 (5 mL). The reaction mixture was then diluted with EtOAc (100 mL), washed with saturated NaHCO3 and brine, and dried over Na2SO4. After concentration, the residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 82-B. LCMS-ESI + (m / z):[M+H) + Measured value: 274.

[1056] Step 2

[1057] 0.4 g (1.5 mmol) of 82-B in 10 mL of THF was placed in a 100 mL round-bottom flask. The reaction mixture was stirred at -78 °C. 2.0 M LiBH4 in 1.6 mL (3.2 mmol) of THF was slowly added. The reaction mixture was then heated and stirred at room temperature for 3 hours. The reaction mixture was then diluted with 100 mL of EtOAc, and water was slowly added (H2 was released). After phase separation, the aqueous fraction was extracted with EtOAc, and the two organic fractions were combined, washed with water, and dried over Na2SO4. After concentration, the residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 82-C. LCMS-ESI + (m / z):[M+H) + Measured value: 246.

[1058] Step 3

[1059] 82-C (0.25 g, 1.0 mmol), triphenylphosphine (0.59 g, 2.2 mmol), and phthalimide (0.24 g, 1.6 mmol) in 10 mL THF were charged into a 100 mL round-bottom flask. The reaction mixture was then cooled to 0 °C while stirring. DIAD (0.44 mL, 2.2 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. After concentration, the residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 82-D. LCMS-ESI + (m / z):[M+H) + Measured value: 375.

[1060] Step 4

[1061] Hydrazine monohydrate (0.3 mL) was added to a solution of 82-D (0.35 g, 0.9 mmol) in EtOH (20 mL). The reaction mixture was heated to 70 °C and stirred for 3 hours. After filtering to remove the solids, the filtrate was concentrated to give 82-E. LCMS-ESI + (m / z):[M+H) + Measured value: 245.

[1062] Step 5

[1063] In a 100-mL round-bottom flask, add 0.21 g (0.87 mmol) of 82-E and 0.3 g (0.87 mmol) in ethanol (7 mL). Add sodium bicarbonate (0.15 g, 1.7 mmol) in water (7 mL). Then, stir the reaction mixture overnight at room temperature. Dilute the mixture with EtOAc (50 mL) and wash with water (2x). Extract the aqueous fraction with EtOAc, combine the organic fractions, dry (Na₂SO₄), and concentrate. The crude 82-G is used in the next step and requires further purification. LCMS-ESI + (m / z):[M+H) + Measured value: 573.

[1064] Step 6

[1065] 0.49 g (0.86 mmol) of 82-G in 5 mL of 4N HCl / dioxane was added to a 100 mL round-bottom flask. The reaction mixture was then stirred for 1 hour at room temperature. After concentration, 0.4 g of the intermediate was obtained. This intermediate and DBU (0.6 g, 4.0 mmol) were dissolved in 10 mL of toluene. The reaction mixture was heated to 110 °C and stirred for 1 hour. After concentration, the residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 82-H. LCMS-ESI + (m / z):[M+H) + Measured value: 413.

[1066] Step 7

[1067] 0.2 g (0.49 mmol) of 82-H in 5 mL of THF and 5 mL of MeOH was added to a 100 mL round-bottom flask. The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1 N HCl (1.5 mL). After concentration, the residue was co-evaporated with toluene (3 x). Half of the crude acid, 0.15 g (0.95 mmol) of 2,4,6-trifluorobenzylmethylamine, 0.31 g (2.4 mmol) of N,N-diisopropylethylamine (DIPEA) and 0.36 g (0.95 mmol) of HATU were dissolved in 10 mL of DCM. The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with 100 mL of EtOAc, washed with saturated NaHCO3 (2 x) and saturated NH4Cl (2 x), and dried over Na2SO4. After concentration, the crude substance was purified by column chromatography on silica gel with hexane-EtOAc to obtain 82-I. LCMS-ESI +(m / z):[M+H) + Measured value: 542.

[1068] Step 8

[1069] The reactant 82-I (0.22 g, 0.41 mmol) in 3 mL of TFA was added to a 50 mL round-bottom flask. The reaction mixture was stirred for 30 minutes at room temperature. After concentration, the crude substance was purified by column chromatography on silica gel with EtOAc-MeOH to give compound 82. 1 ¹H-NMR (400MHz, chloroform-d) δ 10.25 (s, 1H), 8.28 (s, 1H), 6.65 (s, 2H), 5.15–4.77 (m, 2H), 4.65 (s, 2H), 4.32–3.41 (m, 2H), 2.78 (s, 1H), 1.86 (dd, J = 144.8, 72.3 Hz, 6H). 19 F-NMR (376MHz, chloroform-d) δ -108.98 (t, J = 8.2Hz), -112.03 (t, J = 7.2Hz), -168.00. LCMS-ESI + (m / z): Measured value: 452.

[1070] Example 83

[1071] Preparation of compound 83

[1072] (1S,4R,12aS)-3,3-difluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorophenylmethyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[1073]

[1074]

[1075] Step 1

[1076] 83-A (1.0 g, 3.7 mmol) in 20 mL of DCM was loaded into a 100 mL round-bottom flask. The reaction mixture was cooled to 0 °C. Dess-Martin periodide (1.8 g, 4.2 mmol) was slowly added. The reaction mixture was then stirred at room temperature for 3 hours. After concentration, the residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 83-B. LCMS-ESI + (m / z):[M+H) +Measured value: 270.

[1077] Step 2

[1078] 83-B (0.85 g, 3.2 mmol) in 15 mL of DCM was placed in a 100 mL round-bottom flask. The reaction mixture was cooled to 0 °C. DAST (1.5 mL, 11.3 mmol) was slowly added. The reaction mixture was then stirred overnight at room temperature. The mixture was cooled back to 0 °C. The reaction was quenched dropwise with saturated NaHCO3 (5 mL). The reaction mixture was then diluted with 100 mL of EtOAc, washed with saturated NaHCO3 and brine, and dried over Na2SO4. After concentration, the residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 83-C. LCMS-ESI + (m / z):[M+H) + Measured value: 292.

[1079] Step 3

[1080] 0.44 g (1.5 mmol) of 83-C in 6 mL of THF was placed in a 100 mL round-bottom flask. The reaction mixture was stirred at -78 °C. 2.0 M LiBH4 in 1.6 mL (3.2 mmol) of THF was slowly added. The reaction mixture was then heated and stirred at room temperature for 3 hours. The reaction mixture was then diluted with 100 mL of EtOAc, and water was slowly added (releasing H2). After phase separation, the aqueous fraction was extracted with EtOAc, and the two organic fractions were combined, washed with water, and dried over Na2SO4. After concentration, the residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 83-D. LCMS-ESI + (m / z):[M+H) + Measured value: 264.

[1081] Step 4

[1082] 83-D (0.17 g, 0.65 mmol), triphenylphosphine (0.37 g, 1.4 mmol), and phthalimide (0.15 g, 1.0 mmol) in 10 mL THF were charged into a 100 mL round-bottom flask. The reaction mixture was then cooled to 0 °C while stirring. DIAD (0.28 mL, 1.4 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. After concentration, the residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 83-E. LCMS-ESI+ (m / z):[M+H) + Measured value: 393.

[1083] Step 5

[1084] Hydrazine monohydrate (0.3 mL) was added to a solution of 83-E (0.25 g, 0.64 mmol) in EtOH (20 mL). The reaction mixture was heated to 70 °C and stirred for 3 hours. After filtering to remove the solids, the filtrate was concentrated to give 83-F. LCMS-ESI + (m / z):[M+H) + Measured value: 263.

[1085] Step 6

[1086] In a 100-mL round-bottom flask, add 0.18 g (0.69 mmol) of 83-F and 0.324 g (0.69 mmol) in ethanol (7 mL). Add sodium bicarbonate (0.12 g, 1.4 mmol) in water (7 mL). Then, stir the reaction mixture overnight at room temperature. Dilute the mixture with EtOAc (50 mL) and wash with water. Extract the aqueous fraction with EtOAc, combine the organic fractions, dry (Na₂SO₄), and concentrate. The crude 83-H is used in the next step and requires further purification. LCMS-ESI + (m / z):[M+H) + Measured value: 591.

[1087] Step 7

[1088] 0.4 g (0.68 mmol) of 83-H was added to a 100 mL round-bottom flask in 3.8 mL of 4N HCl / dioxane. The reaction mixture was then stirred for 1 hour at room temperature. After concentration, 0.35 g of the intermediate was obtained. This intermediate and DBU (0.51 g, 3.3 mmol) were dissolved in 10 mL of toluene. The reaction mixture was heated to 110 °C and stirred for 1 hour. After concentration, the residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 83-I. LCMS-ESI + (m / z):[M+H) + Measured value: 431.

[1089] Step 8

[1090] 83-I (0.2 g, 0.47 mmol) in THF (5 mL) and MeOH (5 mL) was placed in a 100 mL round-bottom flask. 1N KOH (1.4 mL) was added to the reaction mixture. The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1N HCl (1.4 mL). After concentration, the residue was co-evaporated with toluene (3x). Half of the crude acid, 2,4,6-trifluorobenzylmethylamine (0.14 g, 0.91 mmol), N,N-diisopropylethylamine (DIPEA) (0.29 g, 2.2 mmol), and HATU (0.35 g, 0.91 mmol) were dissolved in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (100 mL), washed with saturated NaHCO3 (2x), saturated NH4Cl (2x), and dried over Na2SO4. After concentration, the crude substance was purified by column chromatography on silica gel with hexane-EtOAc to obtain 83-J. LCMS-ESI + (m / z):[M+H) + Measured value: 560.

[1091] Step 9

[1092] The reactant 83-J (0.18 g, 0.32 mmol) in 3 mL of TFA was added to a 50 mL round-bottom flask. The reaction mixture was stirred for 30 minutes at room temperature. After concentration, the crude substance was purified by column chromatography on silica gel with EtOAc-MeOH to give compound 83 as a white solid. 1 ¹H-NMR (400MHz, chloroform-d) δ 10.29 (d, J = 6.1 Hz, 1H), 8.34 (s, 1H), 6.65 (dd, J = 8.7, 7.5 Hz, 2H), 4.83 (s, 1H), 4.72–4.58 (m, 2H), 4.36–4.10 (m, 2H), 4.05 (t, J = 11.5 Hz, 1H), 2.97 (d, J = 4.4 Hz, 1H), 2.49–2.08 (m, 3H), 2.12–1.94 (m, 2H). 19 F-NMR (376MHz, chloroform-d) δ -92.32 (ddd, J = 225.6, 22.5, 9.1Hz), -107.64–109.54 (m), -112.05 (t, J = 7.0Hz), -114.67 (d, J = 226.7Hz). LCMS-ESI + (m / z): Measured value: 470.

[1093] Example 84

[1094] Preparation of compound 84

[1095] (1S,2R,4S,12aR)-7-hydroxy-2-methyl-6,8-dioxo-N-(2,4,6-trifluorophenylmethyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[1096]

[1097]

[1098] Step 1

[1099] 84-A (1.6 g, 5.9 mmol) in 20 mL of DCM was loaded into a 100 mL round-bottom flask. The reaction mixture was cooled to 0 °C. Dess-Martin periodide (4.9 g, 11.7 mmol) was slowly added. The reaction mixture was then stirred at room temperature for 3 hours. After concentration, the residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 84-B. LCMS-ESI + (m / z):[M+H) + Measured value: 270.

[1100] Step 2

[1101] 84-B (1.3 g, 4.8 mmol) in 30 mL THF was placed in a 100 mL round-bottom flask. The reaction mixture was cooled to 0 °C. Tebbe reagent (0.5 M in toluene, 19.4 mL, 9.7 mmol) was slowly added. The reaction mixture was then stirred at room temperature for 2 hours. The mixture was cooled back to 0 °C. The reaction was quenched dropwise with saturated NaHCO3 (5 mL). The reaction mixture was stirred again at room temperature for 15 minutes and filtered through diatomaceous earth. The filter cake was washed with DCM (2x). The combined filtrates were concentrated under vacuum, and the residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 84-C. LCMS-ESI + (m / z):[M+H) + Measured value: 268.

[1102] Step 3

[1103] Pd / C (0.18 g) was added to a solution of 84-C (0.9 g, 3.4 mmol) in EtOH (20 mL) (purged with N2). The mixture was stirred for 3 hours under H2. The mixture was filtered through diatomaceous earth and the filtrate was concentrated to obtain 84-D. LCMS-ESI + (m / z):[M+H) + Measured value: 270.

[1104] Step 4

[1105] 0.9 g (3.3 mmol) of 84-D in 6 mL of THF was placed in a 100 mL round-bottom flask. The reaction mixture was stirred at -78 °C. 2.0 M LiBH4 in 13.2 mL (26.4 mmol) of THF was slowly added. The reaction mixture was then heated and stirred at room temperature for 3 hours. The reaction mixture was then diluted with 100 mL of EtOAc, and water was slowly added (releasing H2). After phase separation, the aqueous fraction was extracted with EtOAc, and the two organic fractions were combined, washed with water, and dried over Na2SO4. After concentration, the residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 84-E. LCMS-ESI + (m / z):[M+H) + Measured value: 242.

[1106] Step 5

[1107] 84-E (0.4 g, 1.66 mmol), triphenylphosphine (0.96 g, 3.6 mmol), and phthalimide (0.39 g, 2.7 mmol) in 15 mL of THF were charged into a 100 mL round-bottom flask. The reaction mixture was then cooled to 0 °C while stirring. DIAD (0.7 mL, 3.6 mmol) was slowly added to the reaction mixture. The reaction mixture was stirred overnight at room temperature. After concentration, the residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 84-F. LCMS-ESI + (m / z):[M+H) + Measured value: 371.

[1108] Step 6

[1109] Hydrazine monohydrate (0.3 mL) was added to a solution of 84-F (0.55 g, 1.5 mmol) in EtOH (20 mL). The reaction mixture was heated to 70 °C and stirred for 3 hours. After filtering to remove the solids, the filtrate was concentrated to give 84-G. LCMS-ESI+ (m / z):[M+H) + Measured value: 241.

[1110] Step 7

[1111] In a 100-mL round-bottom flask, add 0.35 g (1.4 mmol) of 84-G and 0.5 g (1.4 mmol) in 10 mL of ethanol. Slowly add 0.24 g (2.8 mmol) of sodium bicarbonate in 10 mL of water to the reaction mixture. Then, stir the reaction mixture overnight at room temperature. Dilute the mixture with 50 mL of EtOAc and wash with water (2x). Extract the aqueous fraction with EtOAc, combine the organic fractions, dry (Na2SO4), and concentrate. The crude 84-I is used in the next step and requires further purification. LCMS-ESI + (m / z):[M+H) + Measured value: 583.

[1112] Step 8

[1113] 84-I (0.84 g, 1.4 mmol) in 4N HCl / dioxane (8.2 mL) was added to a 100 mL round-bottom flask. The reaction mixture was then stirred for 1 hour at room temperature. After concentration, 0.74 g of the intermediate was obtained. This intermediate and DBU (1.1 g, 7.2 mmol) were dissolved in toluene (10 mL). The reaction mixture was heated to 110 °C and stirred for 1 hour. After concentration, the residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 84-J. LCMS-ESI + (m / z):[M+H) + Measured value: 409.

[1114] Step 9

[1115] 84-J (0.4 g, 0.98 mmol) in THF (5 mL) and MeOH (5 mL) was placed in a 100 mL round-bottom flask. 1N KOH (3.0 mL) was added to the reaction mixture. The reaction mixture was then stirred at room temperature for 1 hour. The reaction mixture was acidified by adding 1N HCl (3.0 mL). After concentration, the residue was co-evaporated with toluene (3x). Half of the crude acid, 2,4,6-trifluorobenzylmethylamine (0.32 g, 1.96 mmol), N,N-diisopropylethylamine (DIPEA) (0.63 g, 4.9 mmol), and HATU (0.74 g, 1.96 mmol) were dissolved in DCM (10 mL). The reaction mixture was stirred at room temperature for 2 hours. The mixture was diluted with EtOAc (100 mL), washed with saturated NaHCO3 (2x), saturated NH4Cl (2x), and dried over Na2SO4. After concentration, the crude substance was purified by column chromatography on silica gel with hexane-EtOAc to obtain 84-K. LCMS-ESI + (m / z):[M+H) + Measured value: 538.

[1116] Step 10

[1117] 0.5 g (0.93 mmol) of 84-K in 6 mL of TFA was added to a 50 mL round-bottom flask. The reaction mixture was stirred for 30 minutes at room temperature. After concentration, the crude compound was purified by column chromatography on silica gel with EtOAc-MeOH to give compound 84. 1 ¹H-NMR (400MHz, chloroform-d) δ 10.37 (s, 1H), 8.28 (s, 1H), 6.65 (t, J = 8.1 Hz, 2H), 4.80 (s, 1H), 4.77–4.52 (m, 3H), 4.08 (d, J = 13.1 Hz, 1H), 3.88 (d, J = 12.3 Hz, 1H), 2.47 (d, J = 3.2 Hz, 1H), 2.35 (s, 1H), 2.16 (ddd, J = 14.3, 11.2, 3.6 Hz, 1H), 1.93–1.57 (m, 3H), 1.29–1.19 (m, 1H), 1.17 (d, J = 7.0 Hz, 3H). 19 F-NMR (376MHz, chloroform-d) δ -109.24, -111.98. LCMS-ESI + (m / z): Measured value: 448.

[1118] Example 85

[1119] Preparation of compound 85

[1120] (6aS,7R,11S)-1-hydroxy-2,13-dioxo-N-(2,4,6-trifluorobenzyl)-6,6a,7,8,9,10,11,13-octahydro-2H-7,11-bridged methylenepyrido[1',2':4,5]pyrazino[1,2-a]aza -3-Formamide

[1121]

[1122] Step 1

[1123] At room temperature, a solution of 85-A (1100 mg, 3.855 mmol) in DMSO (6 mL) and water (0.75 mL) was stirred while N-iodosuccinimide (885 mg, 3.934 mmol) was added. After 2 hours, additional N-iodosuccinimide (88 mg, 0.391 mmol) was added, and the resulting mixture was stirred at room temperature for 1.5 hours. The dark brown reaction mixture was diluted with EtOAc and washed with a mixture of 10% aq. Na₂S₂O₃ and aq. NaHCO₃ solutions (~1:4 mixture), followed by washing with water (containing some brine). After extraction of the aqueous fraction with EtOAc, the organic fractions were combined, dried (Na₂SO₄), and concentrated. The residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 85-B. 1 H-NMR (400MHz, CDCl3) δ7.51-7.44(m,2H),7.33-7.17(m,3H),4.22-4.05(m,2H),4.02-3.8 6(m,2H),3.77(d,J=5.3Hz,1H),3.54-3.44(m,1H),3.27(t,J=4.5Hz,1H),2.75-2.66(m,1H ),2.30(dddd,J=14.8,13.1,7.2,5.8Hz,1H),2.14(dddd,J=14.8,13.0,6.1,2.1Hz,1H),1. 97(d,J=8.9Hz,1H),1.58-1.46(m,1H),1.45-1.34(m,4H),1.24(t,J=7.1Hz,3H).LCMS-ESI + (m / z):C 18 H 25 INO3's [M+H] + Theoretical value: 430.1; Measured value: 430.0.

[1124] Step 2

[1125] A solution of 85-B (993 mg, 2.313 mmol), AIBN (305 mg, 1.857 mmol), and tributyltin hydride (1392 mg, 4.799 mmol) in toluene (15 mL) was stirred at 100 °C. After 2 hours, the reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with water and brine. After extraction of the aqueous fraction with EtOAc, the organic fractions were combined, dried (Na₂SO₄), and concentrated. The residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 85-C. 1 H-NMR(400MHz, CDCl3)δ7.57-7.49(m,2H),7.32-7.23(m,2H),7.23-7.15(m,1H),4.24-4.02(m,2H),3 .97(q,J=6.7Hz,1H),3.83(d,J=5.1Hz,1H),3.48(t,J=4.6Hz,1H),3.19-3.04(m,1H),2.58(p,J=4.0H z,1H),2.30(dddd,J=14.7,13.1,7.0,4.5Hz,1H),1.98(d,J=11.2Hz,1H),1.64(tdd,J=13.3,6.2,2.6 Hz,1H),1.49-1.33(m,3H),1.37(d,J=6.7Hz,3H),1.32-1.26(m,1H),1.23(t,J=7.2Hz,3H).LCMS-ESI + (m / z):C 18 H 26 NO3's [M+H] + Theoretical value: 304.2; Measured value: 304.1.

[1126] Step 3

[1127] Under a H2 atmosphere, a mixture of 85-C (725 mg, 2.39 mmol) and 20% Pd(OH)2 / C (351 mg) in EtOH (25 mL) and 4N HCl in dioxane (0.9 mL) was stirred. After 2 hours, the reaction mixture was filtered and the filtrate was concentrated. LCMS-ESI + (m / z):[M+H) + Theoretical value: C 10 H 18NO3: 200.13; Measured: 200.1. After co-evaporation of the residue with toluene (x2), the residue and Boc2O (720 mg, 3.299 mmol) were stirred in THF (15 mL) at room temperature, while N,N-diisopropylethylamine (DIPEA) (1.2 mL, 6.889 mmol) was added. After 1 hour, the reaction mixture was diluted with water and extracted with EtOAc (x2). After washing the organic extracts with water, the combined extracts were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography using hexane-EtOAc as the eluent to give 85-D as a mixture of rotational isomers. 1 H-NMR (400MHz, CDCl3) δ4.42-3.97(m,5H),2.62(d,J=5.6Hz,1H),2.45-2.26(m,1H),2.25-2.15(m,1H),1.80(td,J=13.7,6 .7Hz,1H),1.66(dd,J=12.3,6.6Hz,2H),1.55-1.70(m,2H),1.47(s,2H),1.42(s,7H),1.28(dt,J=9.5,7.1Hz,3H).LCMS-ESI + (m / z):C 15 H 26 NO5 [M+H] + Theoretical value: 300.2; Measured value: 299.7.

[1128] Step 4

[1129] At 0 °C, phenyl chlorothiocarbamate (0.3 mL, 2.169 mmol) was added to a solution of 85-D (568 mg, 1.897 mmol) and pyridine (0.25 mL, 3.091 mmol) in THF (5 mL), which quickly produced an insoluble substance. After ~30 min at 0 °C, additional pyridine (0.3 mL, 3.709 mmol) and phenyl chlorothiocarbamate (0.3 mL, 2.169 mmol) were added. After 1.5 h at 0 °C and 1 h at room temperature, the mixture was concentrated, and the residue was dissolved in EtOAc and water. After separation of the two layers, the organic fraction was washed with ~0.1 N HCl, saturated aqueous NaHCO3 solution, and brine. After extraction of the aqueous fraction with EtOAc, the combined organic fractions were dried (Na2SO4) and concentrated. The residue was purified by rapid chromatography using EtOAc / hexane as the eluent to give 85-E. 1H-NMR (400MHz, CDCl3) δ7.47-7.37(m,2H),7.30(t,J=6.9Hz,1H),7.11(dd,J=8.0, 4.0Hz,2H),5.54(dt,J=9.0,4.9Hz,1H),4.50(dt,J=9.8,5.3Hz,1H),4.35(dd,J=21 .4,5.0Hz,1H),4.30-4.14(m,2H),2.71(s,1H),2.54(s,1H),2.14-2.00(m,1H),1. 82(m,3H),1.54(m,1H),1.48(s,4.5H),1.45(s,4.5H),1.30(dt,J=9.4,7.1Hz,3H). LCMS-ESI + (m / z):C 22 H 30 NO6S's [M+H] + Theoretical value: 436.2; Measured value: 435.8.

[1130] Step 5

[1131] A mixture of 85-E (602 mg, 1.382 mmol), AIBN (182 mg, 1.108 mmol), and tributyltin hydride (608 mg, 2.096 mmol) in toluene (8 mL) was stirred at 100 °C. After 1 hour, the reaction mixture was concentrated, and the residue was dissolved in EtOAc, followed by washing with water and brine. After extraction of the aqueous fraction with EtOAc, the combined organic fractions were dried (Na₂SO₄) and concentrated. The residue was purified by rapid chromatography using EtOAc / hexane as the eluent to give 85-F as a mixture of rotational isomers. 1 H-NMR (400MHz, CDCl3) δ4.37-4.06(m,4H),2.69-2.53(m,1H),2.11(m,1H),1.97(m,0.65H), 1.93-1.80(m,1.35H),1.54(s,5H),1.46(s,3.15H),1.42(s,5.85H),1.27(m,3H).LCMS-ESI + (m / z):C 11 H 18 NO4 [M-C4H8+H] + Theoretical value: 228.1; Measured value: 227.9.

[1132] Step 6

[1133] 85-F (420 mg) was further purified by stirring the purified 85-F in 1.5 mL of THF at 0 °C, while 2.0 M LiBH4 in 1.5 mL of THF was added. After 5 minutes, the mixture was stirred at room temperature for 17 hours, and another 2.0 M LiBH4 in 1.5 mL of THF was added at room temperature. After 23 hours at room temperature, another 2.0 M LiBH4 in 3 mL of THF was added, and the mixture was stirred for approximately 72 hours. The reaction mixture was stirred at 0 °C while water was slowly added and further diluted with water. The product was extracted with EtOAc (×2). The extracts were washed with water, combined, dried (Na2SO4), and concentrated. The residue was rapidly purified by chromatography using hexane-EtOAc as the eluent to give 85-G. 1 H-NMR (400MHz, CDCl3) δ4.12(t,J=5.3Hz,1H),3.99(dd,J=12.0,7.9Hz,1H),3.85(dd,J=8.0,4.7Hz,1H),3.73(dd,J=1 1.9,1.4Hz,1H),2.28(d,J=4.6Hz,1H),1.90-1.73(m,2H),1.68-1.45(m,6H),1.47(s,9H),1.43-1.33(m,1H).LCMS-ESI + (m / z):C9H 16 NO3 [M-C4H8+H] + Theoretical value: 186.1; Measured value: 186.0.

[1134] Step 7

[1135] A solution of 85-G (198 mg, 0.820 mmol), phthalimide (200 mg, 1.359 mmol), and PPh3 (488 mg, 1.861 mmol) in THF (10 mL) was stirred in a 0 °C bath while DIAD (0.36 mL, 1.828 mmol) was added. After 30 minutes at 0 °C, the mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated, and the residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give a mixture of 85-H, which are rotational isomers. 1H-NMR (400MHz, CDCl3) δ7.82 (dd, J=5.4, 3.1Hz, 2H), 7.69 (dd, J=5.4, 3.1Hz, 2H), 4.46 (s, 1H), 4.19 (m, 2H), 3.95 (s, 1H) ,2.31-2.14(m,1H),2.05(d,J=16.5Hz,1H),1.84(m,2H),1.79-1.70(m,1H),1.66(m,1H),1.61-1.30(m,12H).LCMS-ESI + (m / z):[M+H) + Theoretical value: C 21 H 27 N₂O₄: 371.2; Measured value: 370.8.

[1136] Step 8

[1137] At room temperature, hydrazine hydrate (0.145 mL, 3.083 mmol) was added to a solution of 85-H (270 mg, 0.729 mmol) in EtOH (12 mL), and the solution was stirred at 70 °C. After 1.5 h, the mixture was cooled to 0 °C, diluted with ether (30 mL), and then stirred at 0 °C for 1 h. The mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2 and filtered to remove some insoluble substances. The resulting filtrate was concentrated. At room temperature, the residue was mixed with 85-I (257 mg, 0.742 mmol) and NaHCO3 (131 mg, 1.559 mmol) in water (3 mL) and EtOH (3 mL). After 1 h, the mixture was diluted with water and extracted with EtOAc (x2). After washing the extract with water, the organic extracts were combined, dried (Na2SO4), and concentrated. 4NHCl in dioxane (6 mL) was added to a solution of the residue in CH₂Cl₂ (2 mL). After 1.5 hours at room temperature, the solution was concentrated and co-evaporated with toluene. The mixture of the residue and DBU (0.6 mL, 4.012 mmol) in toluene (5 mL) was stirred in a 100 °C bath. After 1 hour, additional DBU (0.3 mL, 2.006 mmol) was added, and the mixture was stirred again at 100 °C for 1 hour. After concentrating the mixture, the residue was purified by rapid chromatography using EtOAc-20% MeOH / EtOAc as the eluent to give 85-J. 1H-NMR (400MHz, CDCl3) δ8.08(s,1H),7.71-7.62(m,2H),7.36-7.29(m,2H),7.29-7.23(m,1H),5.44(d ,J=9.8Hz,1H),5.10(d,J=9.8Hz,1H),4.44-4.28(m,3H),4.23(t,J=13.0Hz,1H),3.99(ddt,J=10.2,6. 3,3.6Hz,2H),2.44-2.36(m,1H),2.29(dt,J=11.6,5.3Hz,1H),1.84(dt,J=10.8,5.3Hz,2H),1.77-1.6 1(m,3H),1.57(d,J=11.7Hz,1H),1.48(ddd,J=20.9,12.3,5.5Hz,1H),1.38(t,J=7.1Hz,3H).LCMS-ESI + (m / z):C 24 H 27 [M+H] of N2O5 + Theoretical value: 423.2; Measured value: 423.3.

[1138] Step 9

[1139] At room temperature, a mixture of 85-J (214 mg, 0.507 mmol) in THF (4 mL) and MeOH (4 mL) was stirred while 1N KOH (1.1 mL) was added. After 30 minutes, the reaction mixture was concentrated to ~1 mL, acidified with 1N HCl (~1.2 mL), diluted with brine, and then extracted with CH2Cl2 (20 mL x 2). The combined extracts were dried over Na2SO4 and concentrated to give crude acid. LCMS-ESI + (m / z):C 22 H 23 [M+H] of N2O5 + Theoretical value: 395.2; Measured value: 395.3.

[1140] At room temperature, a mixture of crude acid (199 mg, 0.505 mmol), 2,4,6-trifluorobenzylmethylamine (130 mg, 0.807 mmol), and HATU (304 mg, 0.800 mmol) in CH₂Cl₂ (6 mL) was stirred while N,N-diisopropylethylamine (DIPEA) (0.62 mL, 3.559 mmol) was added. After 30 minutes, the reaction mixture was concentrated, and the residue was dissolved in EtOAc and washed with saturated aqueous NH₄Cl (x2), saturated aqueous NaHCO₃ (x2), and brine. After extraction of the aqueous fraction with EtOAc, the two organic fractions were combined, dried (Na₂SO₄), and concentrated. The residue was purified by flash chromatography using EtOAc-20% MeOH / EA as the eluent to give 85-K. 1 H-NMR (400MHz, CDCl3) δ10.40(t,J=5.7Hz,1H),8.42(s,1H),7.68-7.54(m,2H),7.33(ddd,J=7.7,6.3,1.5Hz,2H),7.30-7.2 6(m,1H),6.74-6.60(m,2H),5.37(d,J=10.0Hz,1H),5.17(d,J=10.0Hz,1H),4.76-4.57(m,2H),4.46(dd,J=6.0,4.3Hz,1H), 4.34(t,J=12.4Hz,1H),4.07(dd,J=12.4,3.6Hz,1H),3.91(dt,J=12.4,3.9Hz,1H),2.52-2.44(m,1H),2.32(dd,J=11.8,6.2 Hz,1H),1.92(dt,J=10.7,5.4Hz,1H),1.83-1.70(m,3H),1.67(d,J=11.7Hz,1H),1.52(dddt,J=25.5,17.0,11.8,5.3Hz,2H). 19 F-NMR(376MHz, CDCl3)δ-109.15(dq,J=15.0,7.5,7.1Hz,1F),-111.85(t,J=6.8Hz,2F).LCMS-ESI + (m / z):C 29 H 27 [M+H] of F3N3O4 + Theoretical value: 538.2; Measured value: 538.3.

[1141] Step 10

[1142] 85-K (187 mg, 0.348 mmol) was dissolved in trifluoroacetic acid (3 mL) at room temperature and stirred at room temperature. After 1 hour, the solution was concentrated, and the residue was dissolved in CH2Cl2. After washing the solution with 0.1 N HCl, the aqueous fraction was extracted with CH2Cl2 (x2). The organic fractions were combined, dried (Na2SO4), and concentrated. The residue was purified by rapid chromatography using CH2Cl2-20% MeOH in CH2Cl2 as the eluent to give 150 mg (96%) of compound 85. Compound 85 was further purified by recrystallization from methanol (10 mL) to give compound 85. 1 H-NMR (400MHz, CDCl3) δ12.09(s,1H),10.39(t,J=5.7Hz,1H),8.36(s,1H),6.74-6.48(m,2H),4.64(d,J=5.7Hz,2H),4.59(dd,J=6.1,4.4Hz,1H) ,4.36-4.18(m,2H),4.12(dt,J=12.4,4.1Hz,1H),2.68-2.47(m,1H),2.2 5-2.10(m,1H),2.10-1.98(m,1H),1.98-1.66(m,4H),1.66-1.48(m,2H). 19 F-NMR (376MHz, CDCl3) δ-109.23 (ddd, J=15.1, 8.6, 6.0Hz, 1F), -112.02 (t, J=6.9Hz, 2F). LCMS-ESI + (m / z):C 22 H 21 [M+H] of F3N3O4 + Theoretical value: 448.2; Measured value: 448.3.

[1143] Example 86

[1144] Preparation of compound 86

[1145] (1R,3S,4R,12aS)-7-hydroxy-3-methyl-6,8-dioxo-N-(2,4,6-trifluorophenylmethyl)-1,2,3,4,6,8,12,12a-octahydro-1,4-bridged methylenedipyrido[1,2-a:1',2'-d]pyrazine-9-carboxamide

[1146]

[1147]

[1148] Step 1

[1149] At room temperature, a solution of 86-A (10.160 g, 39.48 mmol) in DMSO (52 mL) and water (6.5 mL) was stirred while N-iodosuccinimide (8.888 g, 39.50 mmol) was added. After 30 minutes, the dark brown reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3 solution, 10% Na2S2O3 solution, and brine. After extraction of the aqueous fraction with EtOAc, the organic fractions were combined, dried (Na2SO4), and concentrated. The residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 86-B as a white solid. 1 H-NMR (400MHz, CDCl3) δ7.33-7.19(m,5H),4.25-4.12(m,1H),3.79(q,J=1. 6Hz,1H),3.72(q,J=6.5Hz,1H),3.51(s,1H),3.47(s,3H),3.31(dd,J=3.9,1 .6Hz,1H),2.76-2.69(m,1H),2.13(ddd,J=14.3,7.8,1.7Hz,1H),2.08-1.97 (m,1H),1.91(dtd,J=14.1,4.0,1.5Hz,1H),1.42(d,J=6.5Hz,3H).LCMS-ESI + (m / z):C 16 H 21 INO3's [M+H] + Theoretical value: 402.1; Measured value: 402.0.

[1150] Step 2

[1151] A solution of 86-B (12.468 g, 31.07 mmol), azobisisobutyronitrile (AIBN) (4.082 g, 24.86 mmol), and tributyltin hydride (18.047 g, 62.22 mmol) in toluene (150 mL) was stirred at 100 °C. After 30 minutes, the reaction mixture was cooled to room temperature, diluted with EtOAc, and washed with water and brine. The aqueous fraction was extracted with EtOAc, and the organic fractions were combined, dried (Na₂SO₄), and concentrated. The residue was purified twice by rapid chromatography using hexane-EtOAc as the eluent to give 86-C. 1H-NMR (400MHz, CDCl3) δ7.39-7.31(m,2H),7.31-7.24(m,2H),7.24-7.17(m, 1H),4.11(s,1H),3.72(s,1H),3.49(s,3H),3.33(d,J=3.4Hz,1H),3.27(d,J =6.4Hz,1H),2.65-2.51(m,1H),1.92(ddd,J=13.6,6.8,2.4Hz,1H),1.69-1. 50(m,2H),1.47(d,J=10.1Hz,1H),1.41(d,J=6.6Hz,3H),1.21-1.07(m,1H). LCMS-ESI + (m / z):C 16 H 22 NO3's [M+H] + Theoretical value: 276.2; Measured value: 276.1.

[1152] Step 3

[1153] Under a H2 atmosphere, a mixture of 86-C (4.187 g, 15.21 mmol), 20% Pd(OH)2 / C (1.022 g) in EtOH (100 mL), and 4N HCl in dioxane (5.7 mL) was stirred. After 1.5 hours, the reaction mixture was filtered, and the filtrate was concentrated. After co-evaporation of the residue with toluene, the residue was used in the next step. LCMS-ESI + (m / z):C8H 14 NO3's [M+H] + Theoretical value: 172.1; Measured value: 172.1.

[1154] After co-evaporating the residue with toluene, the residue and Boc₂O (5.712 g, 26.17 mmol) were stirred in THF (45 mL) at room temperature, while N,N-diisopropylethylamine (DIPEA) (8 mL, 45.93 mmol) was added. After 30 minutes, the reaction mixture was diluted with water and extracted with EtOAc (x²). After washing the organic extract with water, the combined extracts were dried (Na₂SO₄) and concentrated. The residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 86-D. 1 1H NMR spectroscopy shows a mixture of rotational isomers. 1H-NMR (400MHz, CDCl3) δ4.20(d,J=7.6Hz,1H),4.19-4.10(m,2H),4.08(d,J=3.5Hz,1H),3.72(s,3H),2.74(d,J=5.6Hz,1H),1.97 (ddd,J=13.6,6.9,2.8Hz,1H),1.88-1.78(m,1H),1.79-1.50(m,1H),1.46(s,3H),1.38(s,6H),1.31(d,J=13.3Hz,1H).LCMS-ESI + (m / z):C 13 H 22 NO5 [M+H] + Theoretical value: 272.2; Measured value: 271.6.

[1155] Step 4

[1156] A solution of 86-D (1659 mg, 6.115 mmol) in 35 mL CH₂Cl₂ was stirred in a bath at 0 °C while Dess-Martin periodide (5.183 g, 12.22 mmol) was added in portions. After 5 minutes, the mixture was stirred at room temperature. After 2 hours, the reaction mixture was cooled in an ice bath, quenched with water, and filtered. The filtrate was washed with saturated NaHCO₃, dried (Na₂SO₄), and concentrated. The residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 86-E. 1 HNMR chromatograms showed two rotational isomers. 1 H-NMR (400MHz, CDCl3) δ4.43 (d, J = 3.8Hz, 0.5H), 4.39 (s, 1H), 4.26 (s, 0.5H), 3.75 (s, 3H),3.10(s,1H),2.24(d,J=4.5Hz,0.5H),2.19(d,J=4.4Hz,0.5H),2.12(d,J=4.4Hz,0 .5H),2.07(d,J=4.2Hz,0.5H),2.01(dd,J=4.5,2.2Hz,0.5H),1.98(dt,J=4.3,1.9Hz,0 .5H),1.80(s,0.5H),1.77(s,0.5H),1.46(s,4.5H),1.40(d,J=2.8Hz,4.5H).LCMS-ESI + (m / z):C9H 12 NO5 [M-C4H8+H] + Theoretical value: 214.1; Measured value: 213.8.

[1157] Step 5

[1158] A solution of 86-E (528 mg, 1.961 mmol) in 12 mL of THF was stirred at 0 °C while a 0.5 M Tebbe reagent solution in 7.9 mL, 3.95 mmol of toluene was added dropwise. After the addition, the brown solution was slowly heated to room temperature and stirred at room temperature for 2.5 hours. The reaction mixture was stirred in a 0 °C bath while the reaction was quenched by carefully adding a saturated aqueous solution of NaHCO3. After diluting the mixture with CH2Cl2 and stirring at room temperature for 15 minutes, the resulting mixture was filtered through a diatomaceous earth mat, and the filter cake was washed with CH2Cl2. After separating the two fractions in the filtrate, the aqueous fraction was extracted with CH2Cl2, the organic fractions were combined, dried (Na2SO4), and concentrated. The residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 86-F. 1 1H NMR spectroscopy revealed two rotational isomers. 1 H-NMR (400MHz, CDCl3) δ5.13(s,0.6H),5.04(s,0.4H),4.82-4.71(m,1H),4.55(s,0.6H),4.43(s,0.4H),4.29(d,J=3.7Hz,0.4H),4.24(d,J=3 .7Hz,0.6H),3.71(s,3H),2.84(s,1H),2.14(m,2H),1.75(s,0.6H),1.7 4-1.70(s,0.4H),1.55(m,1H),1.45(s,3.6H),1.37(s,5.4H).LCMS-ESI + (m / z):C 14 H 22 NO4 [M+H] + Theoretical value: 268.2; Measured value: 267.6.

[1159] Step 6

[1160] The mixture of 86-F (333 mg, 1.246 mmol) and 20% Pd(OH)2 / C (53 mg) in EtOH (5 mL) was stirred under a H2 atmosphere. After 30 minutes, the mixture was filtered and the filtrate was concentrated to obtain 86-G. 1 1H NMR spectroscopy revealed two rotational isomers. 1H-NMR(400MHz, CDCl3)δ4.20(m,1H),4.08(m,1H),3.71(two s,3H),2.68(m,1H),2.06(m,1H),1.80-1.63(m,2H),1.63-1.51(m,1H),1.44(s,4H),1.38(s,5H),1.13(m,3H),0.92(m,1H).LCMS-ESI + (m / z):C 14 H 24 NO4 [M+H] + Theoretical value: 270.2; Measured value: 269.7.

[1161] Step 7

[1162] A solution of 86-G (336 mg, 1.482 mmol) in 5 mL of THF was stirred at 0 °C, while 2.0 M LiBH4 in 1.5 mL of THF was added. After 5 minutes, the mixture was stirred at room temperature. After 2 hours, another 2.0 M LiBH4 in 1.5 mL of THF was added. After 21 hours, another 2.0 M LiBH4 in 3 mL of THF was added. After 3 hours at room temperature, the solution was heated at 35 °C for 18 hours. The reaction mixture was cooled to 0 °C and carefully quenched with water. After extraction of the mixture with EtOAc (x2), the two organic fractions were washed with water, combined, dried (Na2SO4), and concentrated. The residue was purified by rapid chromatography using hexane-EtOAc to give 86-H. 1 H-NMR (400MHz, CDCl3) δ4.95-4.09(br,1H),4.05(s,1H),3.82(dd,J=11.5,7.7Hz ,1H),3.76-3.69(m,1H),3.66(d,J=11.5Hz,1H),2.45(d,J=4.1Hz,1H),2.03(dqd d,J=11.4,7.0,4.5,2.6Hz,1H),1.77-1.57(m,2H),1.48(dd,J=10.1,1.8Hz,1H), 1.45(s,9H),1.00(d,J=6.9Hz,3H),0.93(ddd,J=13.2,4.7,2.6Hz,1H).LCMS-ESI + (m / z):C 13 H 24 NO3's [M+H] + Theoretical value: 242.2; Measured value: 241.7.

[1163] Step 8

[1164] A solution of 86-H (218 mg, 0.903 mmol), phthalimide (218 mg, 1.482 mmol), and PPh3 (535 mg, 2.040 mmol) in THF (10 mL) was stirred in a bath at 0 °C, while DIAD (0.40 mL, 2.032 mmol) was added. After 10 minutes at 0 °C, the mixture was stirred at room temperature for 19 hours. The reaction mixture was concentrated, and the residue was purified by rapid chromatography using hexane-EtOAc as the eluent to give 86-I. 1 H NMR revealed two rotational isomers. 1 H-NMR (400MHz, CDCl3) δ7.82(dt,J=7.3,3.6Hz,2H),7.70(d,J=5.3Hz,2H),4.53-4.26(m,1H),4.26-3.89(m,2H),3.89- 3.65(m,1H),2.28(m,1H),2.04(m,1H),1.82-1.65(m,2H),1.66-1.43(m,7H),1.38(s,4H),1.19-1.01(m,3H).LCMS-ESI + (m / z):C 21 H 27 [M+H] of N2O4 + Theoretical value: 371.2; Measured value: 370.8.

[1165] Step 9

[1166] At room temperature, hydrazine hydrate (0.17 mL, 3.494 mmol) was added to a solution of 86-I (319 mg, 0.861 mmol) in EtOH (12 mL), and the solution was stirred in a bath at 70 °C. After 1.5 hours, the mixture was cooled to 0 °C and diluted with diethyl ether (25 mL), then stirred at 0 °C for 1 hour. The mixture was filtered, and the filtrate was concentrated. The residue was dissolved in CH2Cl2 and filtered to remove some insoluble substances. The filtrate was concentrated to obtain crude amine. LCMS-ESI + (m / z):C 13 H 25 [M+H] of N2O2 + Theoretical value: 241.2; Measured value: 240.9.

[1167] After co-evaporating the crude amine with toluene, a mixture of crude amine 85-I (300 mg, 0.866 mmol) and NaHCO3 (150 mg, 1.845 mmol) in water (3 mL) and EtOH (3 mL) was stirred at room temperature. After 2 hours, the mixture was diluted with water and extracted with EtOAc (x2). After washing the extract with water, the organic extracts were combined, dried (Na2SO4), and concentrated. 4N HCl in dioxane (6 mL) was added to a solution of the residue in CH2Cl2 (2 mL). After 1.5 hours at room temperature, the solution was concentrated and co-evaporated with toluene. At 100 °C, a mixture of the residue and DBU (0.65 mL, 4.347 mmol) in toluene (6 mL) was stirred. After 1 hour, additional DBU (0.65 mL, 4.347 mmol) was added, and the mixture was stirred again at 100 °C. One hour later, additional DBU (0.65 mL, 4.347 mmol) was added, and the mixture was stirred at 100 °C for another 2.5 hours. The mixture was diluted with CH₂Cl₂ and washed with water containing 3 mL of 1N HCl. The organic fraction was dried (Na₂SO₄) and concentrated. The residue was rapidly purified by chromatography using EtOAc-20% MeOH / EtOAc as the eluent to give 86-J. 1 H-NMR (400MHz, CDCl3) δ8.09 (s, 1H), 7.70-7.62 (m, 2H), 7.37-7.27 (m, 3H), 5.48 (d, J = 9.9Hz, 1H), 5.16(d,J=9.9Hz,1H),4.53(s,1H),4.38(m,2H),4.11(m,1H),3.97(dd,J=12.2,3.0Hz,1H),3.88( dt,J=12.2,3.0Hz,1H),2.63(d,J=4.2Hz,1H),2.28(qd,J=7.2,3.1Hz,1H),2.00-1.88(m,1H),1.8 0-1.56(m,2H),1.39(t,J=7.1Hz,3H),1.07(d,J=6.9Hz,3H),1.04(dd,J=5.0,2.5Hz,1H).LCMS-ESI + (m / z):C 24 H 27 [M+H] of N2O5 + Theoretical value: 423.2; Measured value: 423.2.

[1168] Step 10

[1169] At room temperature, a mixture of 86-J (83 mg, 0.196 mmol) in THF (2 mL) and EtOH (2 mL) was stirred while 1 N KOH (0.4 mL) was added. After 30 minutes, the reaction mixture was diluted with water and washed with CH₂Cl₂. After acidifying the aqueous fraction with 1 N HCl (0.45 mL), the product was extracted with CH₂Cl₂ (x2). The combined extracts were dried (Na₂SO₄) and concentrated to give crude acid. LCMS-ESI + (m / z):[M+H) + Theoretical value: C 22 H 23 N2O5: 395.2; Measured value: 395.2.

[1170] At room temperature, a mixture of crude acid (69 mg, 0.175 mmol), 2,4,6-trifluorobenzylmethylamine (42 mg, 0.261 mmol), and HATU (106 mg, 0.279 mmol) in CH₂Cl₂ (3 mL) was stirred while N,N-diisopropylethylamine (DIPEA) (0.25 mL, 1.435 mmol) was added. After 30 minutes, the reaction mixture was concentrated, and the residue was dissolved in EtOAc and washed with saturated aqueous NH₄Cl (x2), saturated aqueous NaHCO₃ (x2), and brine. After extraction of the aqueous fraction with EtOAc, the two organic fractions were combined, dried (Na₂SO₄), and concentrated. The residue was purified by rapid chromatography using EtOAc-20% MeOH / EtOAc as the eluent to give 86-K. 1 H-NMR (400MHz, CDCl3) δ10.40(t,J=5.7Hz,1H),8.40(s,1H),7.66-7.51(m,2H),7.36-7.29(m,2H),7.29-7.23(m, 1H),6.71-6.61(m,2H),5.36(d,J=10.0Hz,1H),5.18(d,J=10.0Hz,1H),4.73-4.58(m,2H),4.53(s,1H),4.22-4.1 1(m,1H),4.03(dd,J=12.4,3.1Hz,1H),3.81(dt,J=12.3,3.1Hz,1H),2.68-2.59(m,1H),2.29(dddd,J=11.4,7.1, 4.7, 2.4Hz, 1H), 1.94 (ddd, J=13.5, 11.2, 4.6Hz, 1H), 1.88-1.67 (m, 2H), 1.06 (d, J=7.0Hz, 3H), 1.03-1.09 (m, 1H). 19F-NMR (376MHz, CDCl3) δ-109.14 (ddd, J=15.2, 8.7, 6.2Hz, 1F), -111.86 (t, J=7.0Hz, 2F). LCMS-ESI + (m / z):C 29 H 27 [M+H] of F3N3O4 + Theoretical value: 538.2; Measured value: 538.1.

[1171] Step 11

[1172] 86-K (61 mg, 0.113 mmol) was dissolved in trifluoroacetic acid (2 mL) at room temperature. After 1 hour, the solution was concentrated, and the residue was dissolved in CH₂Cl₂. After washing the solution with 0.1 N HCl, the aqueous fraction was extracted with CH₂Cl₂ (x²). The organic fractions were combined, dried (Na₂SO₄), and concentrated...

Claims

1. A compound having the formula (II-B) or (II-C) below, or a stereoisomer thereof or a pharmaceutically acceptable salt thereof, (II-B), (II-C), Where L is -C(R) a )2-、-C(R a )2C(R a )2-、-C(R a )2C(R a )2C(R a )2-, or -C(R a )2C(R a )2C(R a )2C(R a )2-; R 1 A phenyl group substituted with one to three halogens; and Each R a Independently hydrogen, halogen, hydroxyl or C 1-4 alkyl.