Substituted pyridotriazine compounds and their use

Abstract

Provided is a compound useful for treating or preventing human immunodeficiency virus infection. [Solution] Provided are a compound of formula I, and the like. TIFF2026143754000260.tif38123 Ar: C6~C 10 aryl, and the like. R 1 , R 8A , R 8B : H, C1~C3 alkyl, and the like. R 2 , R 3 : H, C1~C3 alkyl. R 4 ~R 7 : H, halogen, and the like. -X-Y-: (CR 13A R 13B )p-CR 9 =CR 10 and the like (R 13A , R 13B , R 9 , R 10 : H, halogen, and the like. p: 0, 1).)

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 139,237, filed on 19 January 2021, and U.S. Provisional Patent Application No. 63 / 190,461, filed on 19 May 2021, each of which is incorporated herein by reference in whole for all purposes.

[0002] This disclosure generally relates to a particular 2,3-dihydro-1H-pyrido[2,1-f][1,2,4]triazine compound, a pharmaceutical composition containing the compound, and methods for preparing and using the compound and the pharmaceutical composition. [Background technology]

[0003] Human immunodeficiency virus (HIV) infection and related diseases are a major public health problem worldwide. HIV encodes three enzymes necessary for viral replication: reverse transcriptase, protease, and integrase. While drugs targeting reverse transcriptase and protease are widely used and have shown efficacy, particularly in combination, their effectiveness can be limited by toxicity and the development of resistant strains (Palella, et al. N.Engl.J Med. (1998) 338:853-860, Richman, DDNature (2001) 410:995-1001). Therefore, new drugs that inhibit HIV replication are needed.

[0004] The goal of antiretroviral therapy is to achieve viral suppression in HIV-infected patients. Current treatment guidelines published by the United States Department of Health and Human Services indicate that achieving viral suppression requires the use of combination therapy, i.e., the use of 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 Adults and Adolescents Living with HIV.Department of Health and Human Services.Available at https: / / files.aidsinfo.nih.gov / contentfiles / lvguidelines / AdultandAdolescentGL.pdf, accessed February 20, 2020). In addition, decisions regarding the treatment of HIV-infected patients are complicated when patients require treatment for other medical conditions. Standard treatment requires the use of multiple different drugs to suppress HIV and to treat other conditions the patient may experience, so the possibility of drug interactions is a criterion for selecting drug regimens. Therefore, antiretroviral therapies with a reduced likelihood of drug interactions are needed.

[0005] In addition, the HIV virus is known to mutate in infected individuals (Tang, et al. Drugs (2012) 72(9) e1-e25). Because the HIV virus tends to mutate, there is a need for anti-HIV drugs that are effective against various known HIV variants (Hurt, et al. HIV / AIDS CID (2014) 58, 423-431). For certain patients, for example, those with limited or difficult access to healthcare, adhering to daily oral therapy or prophylactic regimens can be challenging. Drugs that offer desirable pharmaceutical properties (e.g., improved potency, long-acting pharmacokinetics, low solubility, low clearance, and / or other properties) are suitable for less frequent administration and offer better results. This provides patient compliance. Such improvements, in turn, lead to optimized drug exposure and limited development of drug resistance. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Palella, et al. N. Engl. J Med. (1998) 338:853-860, [Non-Patent Document 2] Richman, DDNature (2001) 410:995-1001 [Non-Patent Document 3] Tang,et al.Drugs(2012)72(9)e1-e25 [Non-Patent Document 4] Hurt, et al.HIV / AIDS CID(2014)58,423-431 [Overview of the project] [Means for solving the problem]

[0007] In some embodiments, the compound is of formula I, [ka] During the ceremony, Ar, C6~C 10 A 6-10 membered heteroaryl compound containing aryl, or one, two, or three heteroatoms selected from the group consisting of N, O, and S, and C6-C 10Aryl or 6- to 10-membered heteroaryl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkyloxy, R 1 is H, C1-C3 alkyl, or phenyl, R 2 is H or C1-C3 alkyl, R 3 is H or C1-C3 alkyl, R 4 and R 5 are each independently H, halogen, cyano, C1-C6 alkyl, C1-C6 alkyloxy, C6-C 10 aryl, or 6- to 10-membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S, wherein C1-C6 alkyl, C1-C6 alkyloxy, C6-C 10 aryl, or 6- to 10-membered heteroaryl is optionally substituted with 1, 2, or 3 groups independently selected from halogen, C1-C3 alkyloxy, or C1-C3 haloalkyloxy, or R 4 and R 5 are linked together to form a 3- to 6-membered carbocyclic ring or a 4- to 6-membered heterocyclic ring containing one heteroatom selected from N, O, and S, R 6 is H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl, R 7 is H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl, R 8A and R 8B are independently H, C1-C3 alkyl, or benzyl, -X-Y- is -(CR 13A R 13B ) p -CR 9 =CR 10 -,-, or -(CR 13A R 13B ) q -CR 11A R 11B -CR 12A R 12B - and in the formula, R 9 However, it is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyloxy, R 10 However, it is either H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyloxy, R 9 and R 10 However, together with the carbon atoms to which they are bonded, they form a 5-6 membered heteroaromatic ring containing phenyl or one, two, or three heteroatoms independently selected from N, O, and S, and the phenyl or 5-6 membered heteroaromatic ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys. R 11A , R 11B , R 12A , R 12B , R 13A , and R 13B However, each is independently H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl, or R 11A , R 12A , R 13A , and R 13B However, each is independently H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl, and R 11B and R 12B However, together with the carbon atoms to which they are bonded, they form a 3-6 membered carbocyclic ring, and this 3-6 membered carbocyclic ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys. p is 0 or 1, q is 0 or 1, -XY is-(CR 13A R 13B ) q -CR 11A R 11B -CR 12A R 12B -If that is the case, (i)R 4 However, halogen, cyano, C1-C6 alkyl, C1-C6 alkyloxy, C6-C 10 A 6-10 membered heteroaryl compound containing an aryl group or one, two, or three heteroatoms selected from N, O, and S, and comprising C1-C6 alkyl, C1-C6 alkyloxy, and C6-C 10 An aryl or 6-10 membered heteroaryl is optionally substituted with one, two, or three groups independently selected from halogens, C1-C3 alkyloxys, or C1-C3 haloalkyloxys, R 5 However, H, halogen, cyano, C1-C6 alkyl, C1-C6 alkyloxy, C6-C 10 A 6-10 membered heteroaryl compound containing an aryl group or one, two, or three heteroatoms selected from N, O, and S, and comprising C1-C6 alkyl, C1-C6 alkyloxy, and C6-C 10 An aryl or 6-10 membered heteroaryl is optionally substituted with one, two, or three groups independently selected from halogens, C1-C3 alkyloxys, or C1-C3 haloalkyloxys, or (ii)R 4 and R 5 However, they link together to form a 3-6 membered carboncyclic ring or a 4-6 membered heterocyclic ring having one heteroatom, or (iii)R 8A However, it is either C1-C3 alkyl or benzyl, or (iv)R 6 Compounds, or pharmaceutically acceptable salts thereof, that are halogens, C1-C6 alkyls, C1-C6 alkyloxys, or C1-C6 haloalkyls are disclosed herein.

[0008] In some embodiments, the present disclosure provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0009] In some embodiments, the present disclosure provides a kit comprising a compound of formula I, or a pharmaceutically acceptable salt thereof, and instructions for use.

[0010] In some embodiments, the present disclosure relates to a method for treating HIV infection in a person who has or is at risk of having HIV infection, comprising a therapeutically effective amount of a compound of formula I, and The present invention provides a method comprising administering to a person a pharmaceutically acceptable salt of or a pharmaceutical composition thereof.

[0011] In some embodiments, the Disclosure provides the use of a compound of Formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for treating HIV infection in a person who has or is at risk of having HIV infection.

[0012] In some embodiments, the present disclosure provides compounds of formula I, pharmaceutically acceptable salts thereof, or any pharmaceutical compositions thereof for use in medical therapy.

[0013] In some embodiments, the present disclosure provides compounds of formula I, pharmaceutically acceptable salts thereof, or any pharmaceutical compositions thereof for use in the treatment of HIV infection.

[0014] In some embodiments, the Disclosure provides the use of a compound of Formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of HIV infection in a person who has or is at risk of having HIV infection. [Modes for carrying out the invention]

[0015] The following description includes certain specific details in order to provide a complete understanding of the various embodiments disclosed herein. However, those skilled in the art will understand that the embodiments disclosed herein can be carried out without these details. The following descriptions of some embodiments are made with the understanding that this disclosure should be considered as illustrative of the subject matter described in the claims and is not intended to limit the appended claims to the specific embodiments described herein. The headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the claims. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading. I. Definition

[0016] Unless otherwise required by context, the word “comprise” and its variations, such as “comprises,” throughout this specification and the claims, shall not be used. The term "comprising" should be interpreted in an open and inclusive sense, meaning "includes, but is not limited to."

[0017] Throughout this specification, any reference to “one embodiment” or “embodiment” means that a particular feature, structure, or characteristic described in relation to an embodiment is included in at least one embodiment disclosed herein. Therefore, occurrences of the phrase “in one embodiment” or “in an embodiment” in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, a particular feature, structure, or characteristic may be combined in any preferred manner in one or more embodiments.

[0018] "Amino" refers to the -NH2 radical.

[0019] "Hydroxy" or "hydroxyl" refers to the -OH radical.

[0020] "Oxo" refers to an =O substituent.

[0021] "C u~v " or "(C u ~C v Prefixes such as ")" indicate that the following group has u to v carbon atoms. For example, "C 1~6 "Alkyl" or "C1-C6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0022] "Alkyl" is saturated and has 1 to 12 carbon atoms (C 1~12 Alkyl), and in certain embodiments, having 1 to 8 carbon atoms (C 1~8 Alkyl) or having 1 to 6 carbon atoms (C 1~6 Alkyl, or having 1 to 4 carbon atoms (C 1~4 Alkyl refers to a linear or branched hydrocarbon radical consisting of carbon and hydrogen atoms bonded to the rest of the molecule by a single bond. Examples include methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (t-butyl), n-pentyl, hexyl, 3-methylhexyl, and 2-methylhexyl.

[0023] "Alkylene" refers to a saturated branched, linear, or cyclic hydrocarbon radical having two monovalent radical centers, obtained by removing two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For example, an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkylene radicals include, but are not limited to, methylene (-CH2-), 1,1-ethyl (-CH(CH3)-), 1,2-ethyl (-CH2CH2-), 1,1-propyl (-CH(CH2CH3)-), 1,2-propyl (-CH2CH(CH3)-), 1,3-propyl (-CH2CH2CH2-), and 1,4-butyl (-CH2CH2CH2CH2-).

[0024] "Aryl" or "aromatic ring" refers to an aromatic carbon ring having a monocyclic (e.g., monocyclic) or polycyclic (e.g., bicyclic or tricyclic) system including a condensed system. As used herein, aryl has 6 to 20 carbon ring atoms (i.e., C 6~20 (aryl), having 6 to 12 carbocyclic atoms (i.e., C 6~12 aryl), or having 6 to 10 carbon ring atoms (i.e., C 6~10 (aryl). Non-restrictive examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not in any way encompass, and does not overlap with, the heteroaryls defined below.

[0025] "Cyano" or "carbonitrile" refers to the -CN group.

[0026] "Cycloalkyl" or "carbocyclic ring" refers to saturated or partially saturated cyclic alkyl groups having polycyclic systems, including monocyclic or fused ring systems, bridging ring systems, and spirocyclic systems. The term "cycloalkyl" includes a cycloalkenyl group (i.e., a cyclic group having at least one double bond). As used herein, a cycloalkyl has 3 to 20 carbocyclic atoms (i.e., C 3~20 Cycloalkyl), having 3 to 12 carbocyclic atoms (i.e., C 3~12 Cycloalkyl), having 3 to 10 carbon ring atoms (i.e., C 3~10 Cycloalkyl), having 3 to 8 carbon ring atoms (i.e., C 3~8 (Cycloalkyl), or having 3 to 6 carbon ring atoms (i.e., C 3~6 (Cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. "Halocycloalkyl" refers to a cycloalkyl group substituted with one or more halogens.

[0027] "Halo" or "halogen" refers to bromo, chloro, fluoro, or iodine.

[0028] "Haloalkyl" refers to an alkyl group defined above that is substituted with one or more halo radicals as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl.

[0029] A "heteroaryl" or "heteroaromatic ring" refers to an aromatic group having a monocyclic, polycyclic, or fused polycyclic ring having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, a heteroaryl may contain 5 to 20 ring atoms (5 to 20-membered heteroaromatic ring), 5 to 12 ring atoms (5 to 12-membered heteroaromatic ring), 5 to 10 ring atoms (5 to 10-membered heteroaromatic ring), or 5 to 6 ring atoms (5 to 6-membered heteroaromatic ring), and may contain 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, prinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. A heteroaryl does not include aryl as defined above, and does not overlap with aryl.

[0030] A “heterocyclyl” or “heterocyclic ring” refers to a non-aromatic radical or ring having 3 to 15 atoms, wherein 1 to 6 atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and are bonded to the rest of the molecule by single bonds. In certain embodiments, a “heterocyclyl” has 3 to 10 atoms, where 1 to 4 atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or 3 to 7 atoms, where 1 to 2 atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Nitrogen, carbon, or sulfur atoms in a heterocyclyl may be optionally oxidized, and nitrogen atoms may be optionally quaternized. As used herein, “heterocyclyl” or “heterocyclic ring” refers to a saturated ring unless otherwise indicated, and for example, in some embodiments, “heterocyclyl” or “heterocyclic ring” refers to a saturated ring, or, where specified, a partially saturated ring. Examples of such heterocyclyls include, but are not limited to, dioxolanil, imidazolidinil, isothiazolidinil, isoxazolidinil, morpholinil, 2-oxopiperazinil, 2-oxopiperidinil, 2-oxopyrrolidinil, oxazolidinil, piperidinil, piperazinil, 4-piperidonil, pyrrolidinil, pyrazolidinil, thiazolidinil, tetrahydrofuran, trithianil, tetrahydropyranil, thiomorpholinil, thiamorpholinil, 1-oxo-thiomorpholinil, and 1,1-dioxo-thiomorpholinil.

[0031] The embodiments disclosed herein also encompass all pharmaceutically acceptable compounds of formula I that are isotope-labeled by replacing one or more atoms with atoms having different atomic masses or mass numbers. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, respectively. 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. In certain embodiments, these radiolabeled compounds are useful for determining or measuring the efficacy of a compound, for example, by characterizing the site or mode of action, or binding affinity for a pharmacologically important site of action. Certain isotopically-labeled compounds of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, namely 3 H, and carbon-14, namely 14 C, are particularly useful for this purpose in view of their ease of incorporation and simple means of detection.

[0032] In certain embodiments, substitution with heavier isotopes such as deuterium, namely 2 H, may afford certain therapeutic advantages resulting from greater metabolic stability. For example, in vivo half-life may increase or the required dosage may be reduced. Accordingly, heavier isotopes may be preferred in some circumstances.

[0033] Substitution with positron-emitting isotopes, for example, 11 C, 18 F, 15 O, and 13 N can be used to examine substrate recep tor occupancy using Positron Emission Tomography (PET) These may be useful in research. Isotope-labeled compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb can be prepared by techniques known to those skilled in the art, or by processes similar to those described in the examples below, using appropriate isotope-labeling reagents instead of conventionally used unlabeled reagents.

[0034] The methods, compositions, kits, and articles provided herein use or include compounds (e.g., compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb) or pharmaceutically acceptable salts thereof, where 1 to n hydrogen atoms bonded to a carbon atom may be replaced by deuterium atoms, i.e., D, and n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds enhance resistance to metabolism and are therefore useful in increasing the half-life of compounds or pharmaceutically acceptable salts thereof when administered to mammals. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds can be synthesized by means known in the art, for example, by using starting materials in which one or more hydrogen atoms are replaced with deuterium.

[0035] The embodiments disclosed herein also encompass in vivo metabolites of the compounds disclosed herein. Such products may arise, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily by enzymatic processes. Accordingly, the embodiments disclosed herein include compounds produced by processes, which involve administering the compounds according to the embodiments disclosed herein to mammals for a period of time sufficient to obtain their metabolites. Such products are typically identified by administering the radiolabeled compounds according to the embodiments disclosed herein to animals such as rats, mice, guinea pigs, monkeys, or humans in a detectable dose, allowing sufficient time for metabolism to occur, and then isolating the conversion products from urine, blood, or other biological samples.

[0036] "Mammals" include both humans and non-domesticated animals such as livestock, e.g., laboratory animals and household pets (e.g., cats, dogs, pigs, rabbits, sheep, goats, horses, etc.) and wild animals.

[0037] The terms "optional" or "optionally" mean that the event or situation described thereafter may or may not occur, and that the description includes both the cases in which the event or situation occurs and the cases in which it does not occur. For example, "optionally substituted heterocyclyl" means that the heterocyclyl radical may or may not be substituted, and that the description includes both substituted and unsubstituted heterocyclyl radicals.

[0038] "Pharmacologically acceptable excipients" include, but are not limited to, any carrier, excipient, flow enhancer, sweetener, diluent, preservative, dye / colorant, flavoring agent, surfactant, humectant, dispersant, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or other pharmacologically inactive substances formulated in combination with the pharmacologically active components of a pharmaceutical composition, which are compatible with the other components of the formulation and suitable for use in humans or livestock without excessive toxicity, irritation, allergic reactions, etc.

[0039] Examples of “pharmaceutically acceptable salts” of the compounds disclosed herein include alkali metals (e.g.) For example, sodium, alkaline earth metals (e.g., magnesium), ammonium, and NX4 + (In the formula, X is C) 1~4 Examples of pharmaceutically acceptable salts of nitrogen atoms or amino groups include salts derived from appropriate bases such as alkyl groups. Examples of pharmaceutically acceptable salts of nitrogen atoms or amino groups include acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, butyric acid, camphoric acid, cinnamic acid, citric acid, digluconic acid, glutamic acid, glycolic acid, glycerophosphate, formic acid, hexanoic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, hydroxymaleic acid, malonic acid, malic acid, mandelic acid, isethionic acid, lactobionic acid, nicotinic acid, oxalic acid, pamoic acid, pectinic acid, phenylacetic acid, 3-phenylpropyl sulfate This includes organic carboxylic acids such as ropionic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, sulfanilic acid, tartaric acid, undecanoic acid, and succinic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, mesitylenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and 2-naphthalenesulfonic acid; and salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and sulfamic acid. Pharmacopoecitable salts of hydroxyl group compounds include Na + and NX4 + (X is H or C 1~4 This includes anions of the compound combined with suitable cations (selected independently of alkyl groups).

[0040] For therapeutic use, salts of the active ingredients of the compounds disclosed herein are typically pharmaceutically acceptable, i.e., salts derived from physiologically acceptable acids or bases. However, salts of pharmaceutically unacceptable acids or bases may also find uses, for example, in the preparation or purification of the compounds of formula I or other compounds of the embodiments disclosed herein. All salts, whether derived from physiologically acceptable acids or bases or not, are within the scope of the embodiments disclosed herein.

[0041] Metal salts are typically prepared by reacting a metal hydroxide with a compound according to embodiments disclosed herein. An example of a metal salt prepared in this manner is Li + na + , and K + It is a salt containing [a specific compound]. By adding a suitable metal compound, a less soluble metal salt can be precipitated from a solution of a more soluble salt.

[0042] In addition, salts may be formed by acid addition of certain organic and inorganic acids, such as HCl, HBr, H2SO4, H3PO4, or organic sulfonic acids, to a base center, typically an amine. Finally, it should be understood that the compositions herein include the compounds disclosed herein in non-ionized and zwitterionic forms.

[0043] "Pharmaceutical composition" refers to a formulation of the compounds of the embodiments disclosed herein and a medium commonly accepted in the art for delivering the biologically active compounds to mammals, such as humans. Such a medium may include all pharmaceutically acceptable excipients.

[0044] "Effective dose" or "therapeutic dose" means the amount of a compound according to the embodiments disclosed herein that, when administered to a patient in need, is sufficient to produce treatment for the disease, condition, or disorder disclosed herein. Such a dose would be sufficient to induce a tissue system or a patient's biological or medical response as required by the researcher or clinician. The amount of a compound according to the embodiments disclosed herein that constitutes a therapeutic dose will vary depending on 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 or disorder being treated, any drugs used in combination with or concurrently with the compound according to the embodiments disclosed herein, and factors such as the patient's age, weight, overall health, sex, and diet. Such a therapeutic dose can be determined by a person skilled in the art, taking into account their knowledge, the latest technology, and this disclosure.

[0045] As used herein, the terms “to treat” and “to cure” are intended to mean administering a compound or composition according to these embodiments to alleviate or eliminate one or more symptoms of HIV infection and / or to reduce the viral load in a patient. In certain embodiments, the terms “to treat” and “to cure” also include administering a compound or composition according to these embodiments to prevent the onset of symptoms of the disease and / or to prevent the virus from reaching a detectable level in the blood, after an individual has been exposed to the virus but before symptoms of the disease appear and / or before the virus is detected in the blood, and administering a compound or composition according to these embodiments to prevent perinatal transmission of HIV from mother to infant by administering it to a mother before childbirth and to a child within a few days of birth. The terms “to treat” and “treatment” also encompass administering a compound or composition according to these embodiments disclosed herein to an individual before exposure to the virus (also known as pre-exposure prophylaxis, PrEP) in order to prevent HIV infection from becoming established in the event that the individual has been exposed to the virus, and / or to prevent the virus from establishing a permanent infection, and / or to prevent the symptoms of the disease from appearing, and / or to prevent the virus from reaching a detectable level in the blood. The terms “to treat” and “treatment” also encompass administering the compounds or compositions according to these embodiments disclosed herein to an individual both before and after exposure to the virus.

[0046] As used herein, the terms “prevent” and “prevent” mean administering a compound, composition, or pharmaceutically acceptable salt of the Disclosure to a person before or after exposure to a virus, but before symptoms of the disease appear and / or before the virus is detected in the blood. The terms also mean preventing symptoms of the disease from appearing and / or preventing the virus from reaching a detectable level in the blood. The terms include pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP). This includes both event-driven and "on-demand" prophylaxis. These terms also refer to preventing perinatal transmission of HIV from mother to infant by administering the drug to the mother before birth and to the child within a few days of birth. This term also refers to preventing HIV infection through blood transfusions.

[0047] As used herein, the term “antiviral agent” is intended to mean any agent (compound or biological preparation) that is effective in inhibiting the formation and / or replication of a virus in humans, including but not limited to agents that interfere with the host or viral mechanism of action necessary for the formation and / or replication of a virus in humans.

[0048] As used herein, the term “HIV replication inhibitor” is intended to mean any agent that can reduce or eliminate the replication capacity of HIV in host cells, whether in vitro, ex vivo, or otherwise.

[0049] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts, may contain one or more chiral centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- with respect to absolute stereochemistry, or as (D)- or (L)- with respect to amino acids. This disclosure includes all such possible isomers, as well as their racemic, scalemic, and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or separated using methods such as chromatography and fractional crystallization. Techniques for the preparation / isolation of individual enantiomers include suitable optically pure precursors. Chiral synthesis from, or racemization of racemic compounds (or salts or derivatives) using, for example, high-pressure chiral liquid chromatography (HPLC). This includes the division of compounds. When the compounds described herein contain an olefinic double bond or other geometrically asymmetric center, and unless otherwise specified, these compounds are intended to include both E and Z geometric isomers. Similarly, all tautomer forms are also intended to be included.

[0050] A “stereoisomer” refers to a compound that has the same atoms bonded together by the same bonds but has different three-dimensional structures that are not interchangeable. This disclosure intends various stereoisomers and mixtures thereof, and includes “enantiomers,” which refer to two stereoisomers whose molecules are mirror images of each other and cannot be superimposed. In any of the embodiments disclosed herein, the compounds disclosed herein may be in the form of their stereoisomers.

[0051] "Partially unsaturated" refers to a cyclic group that contains at least one double bond but is not aromatic.

[0052] Substituents and polyvalent groups can be attached to the remainder of the molecule at any position and orientation to form a stable compound. For example, in a compound of formula I, [ka] In the formula, -XY- is in the formula [ka] Compounds and formulas [ka] Contains the compound -CR 13A R 13B -CR 9 =CR 10 A compound defined as -. Similarly, a compound of formula I, where -XY- is a compound of formula I. [ka] Compounds and formulas [ka] Contains the compound -CR 11A R 11B -CR 12A R 12B - a compound. II. Compounds

[0053] A compound of formula I, [ka] During the ceremony, Ar, C6~C 10 A 6-10 membered heteroaryl compound containing aryl, or one, two, or three heteroatoms selected from the group consisting of N, O, and S, and C6-C 10 An aryl or 6-10 membered heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogens, C1-C6 alkyls, C1-C6 haloalkyls, and C1-C6 alkyloxys. R1 However, it is H, C1-C3 alkyl, or phenyl. R 2 However, it is H or C1-C3 alkyl, R 3 However, it is H or C1-C3 alkyl, R 4 and R 5 However, each is independent of H, halogen, cyano, C1-C6 alkyl, C1-C6 alkyloxy, and C6-C 10 A 6-10 membered heteroaryl compound containing an aryl or one, two, or three heteroatoms selected from N, O, and S, and comprising C1-C6 alkyl, C1-C6 alkyloxy, and C6-C 10 An aryl or 6-10 membered heteroaryl is optionally substituted with one, two, or three groups independently selected from halogens, C1-C3 alkyloxys, or C1-C3 haloalkyloxys, or R 4 and R 5 However, they link together to form a 3-6 membered carbocyclic ring or a 4-6 membered heterocyclic ring containing one heteroatom selected from N, O, and S. R 6 However, it is H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl, R 7 However, it is H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl, R 8A and R 8B However, each is independently H, C1-C3 alkyl, or benzyl. -XY- is -(CR 13A R 13B ) p -CR 9 =CR 10 -or-(CR 13A R 13B ) q -CR 11A R 11B -CR 12A R 12B - and in the formula, R 9However, it is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyloxy, R 10 However, it is either H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyloxy, R 9 and R 10 However, together with the carbon atoms to which they are bonded, they form a 5-6 membered heteroaromatic ring containing phenyl or one, two, or three heteroatoms independently selected from N, O, and S, and the phenyl or 5-6 membered heteroaromatic ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys. R 11A , R 11B , R 12A , R 12B , R 13A , and R 13B However, each is independently H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl, or R 11A , R 12A , R 13A , and R 13B However, each is independently H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl, and R 11B and R 12B However, together with the carbon atoms to which they are bonded, they form a 3-6 membered carbocyclic ring, and this 3-6 membered carbocyclic ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys. p is 0 or 1, q is 0 or 1, -XY is-(CR 13A R 13B ) q -CR 11A R 11B -CR 12A R 12B-If that is the case, (i)R 4 However, halogen, cyano, C1-C6 alkyl, C1-C6 alkyloxy, C6-C 10 A 6-10 membered heteroaryl compound containing an aryl group or one, two, or three heteroatoms selected from N, O, and S, and comprising C1-C6 alkyl, C1-C6 alkyloxy, and C6-C 10 An aryl or 6-10 membered heteroaryl is optionally substituted with one, two, or three groups independently selected from halogens, C1-C3 alkyloxys, or C1-C3 haloalkyloxys, R 5 However, H, halogen, cyano, C1-C6 alkyl, C1-C6 alkyloxy, C6-C 10 A 6-10 membered heteroaryl compound containing an aryl group or one, two, or three heteroatoms selected from N, O, and S, and comprising C1-C6 alkyl, C1-C6 alkyloxy, and C6-C 10 An aryl or 6-10 membered heteroaryl is optionally substituted with one, two, or three groups independently selected from halogens, C1-C3 alkyloxys, or C1-C3 haloalkyloxys, or (ii)R 4 and R 5 However, they link together to form a 3-6 membered carboncyclic ring or a 4-6 membered heterocyclic ring having one heteroatom, or (iii)R 8A However, it is either C1-C3 alkyl or benzyl, or (iv)R 6 Compounds, or pharmaceutically acceptable salts thereof, that are halogens, C1-C6 alkyls, C1-C6 alkyloxys, or C1-C6 haloalkyls are disclosed herein.

[0054] In some embodiments, the compounds of formula I provided herein have formula Ia. [ka]

[0055] In some embodiments, the compounds of formula I provided herein have formula Ib. [ka]

[0056] In some embodiments of the compounds of formulas I, Ia, and Ib, Ar is C6-C 10 A 6-10 membered heteroaryl compound containing aryl, or one, two, or three heteroatoms selected from N, O, and S, and C6-C 10 An aryl or 6-10 member heteroaryl is optionally substituted with 1-4 halogens. In some embodiments, Ar is C6-C 10 A 6-10 membered heteroaryl compound containing an aryl group or one, two, or three heteroatoms selected from N, O, and S, and C6-C 10 An aryl or 6-10 membered heteroaryl is optionally substituted with 1-3 substituents independently selected from Cl and F.

[0057] In some embodiments of the compounds of formulas I, Ia, and Ib, Ar is C6-C 10 A 6-10 membered heteroaryl containing an aryl or one heteroatom selected from N, O, and S, and C6-C 10 An aryl or 6-10 member heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogens, C1-C6 alkyls, C1-C6 haloalkyls, and C1-C6 alkyloxys. In some embodiments, Ar is C6-C 10 A 6-10 membered heteroaryl containing an aryl or one heteroatom selected from N, O, and S, and C6-C 10 An aryl or 6-10 membered heteroaryl is optionally substituted with 1-4 substituents independently selected from the group consisting of halogens, C1-C6 alkyls, and C1-C6 alkyloxys. In some embodiments, Ar is C6-C 10A 6-10 membered heteroaryl containing an aryl or one heteroatom selected from N, O, and S, and C6-C 10 An aryl or 6-10 member heteroaryl is optionally substituted with 1-4 halogens. In some embodiments, Ar is C6-C 10 A 6-10 membered heteroaryl containing an aryl or one heteroatom selected from N, O, and S, and C6-C 10 An aryl or 6-10 membered heteroaryl is optionally substituted with 1-3 substituents independently selected from Cl and F.

[0058] In some embodiments of the compounds of formulas I, Ia, and Ib, Ar is a phenyl compound optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogens, C1-C6 alkyls, C1-C6 haloalkyls, and C1-C6 alkyloxys. In some embodiments, Ar is a phenyl molecule optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogens, C1-C6 alkyls, and C1-C6 alkyloxys. In some embodiments, Ar is a phenyl molecule optionally substituted with 1 to 4 halogens. In some embodiments, Ar is a phenyl molecule optionally substituted with 1 to 3 substituents independently selected from Cl and F.

[0059] In some embodiments of the compounds of formulas I, Ia, and Ib, Ar is a phenyl compound optionally substituted with one, two, three, or four substituents independently selected from halogens and C1-C6 alkyloxys. In some embodiments, Ar is a phenyl compound substituted with one, two, three, or four substituents independently selected from halos and C1-C4 alkyloxys. In some embodiments, Ar is a phenyl compound substituted with one, two, three, or four substituents independently selected from Cl and F.

[0060] In some embodiments of the compounds of formulas I, Ia, and Ib, Ar is [ka] And, In the formula, Z is N or CR A And, n is 0, 1, 2, 3, or 4, R A However, these are independently halogens, C1-C6 alkyls, C1-C6 haloalkyls, and C1-C6 alkyloxys.

[0061] In some embodiments of the compounds of formulas I, Ia, and Ib, Z is CH or N. In some embodiments, Z is CH. In some embodiments, Z is N.

[0062] In some embodiments of the compounds of formulas I, Ia, and Ib, Ar is [ka] n is 1, 2, 3, or 4, and each R A These are independently halogens, C1-C6 alkyls, C1-C6 haloalkyls, and C1-C6 alkyloxys. In some embodiments of the compounds of formulas I, Ia, and Ib, Ar is [ka] n is 1, 2, 3, or 4, and each R A These are independently halogens, C1-C6 alkyls, and C1-C6 alkyloxys. In some embodiments of the compounds of formulas I, Ia, and Ib, Ar is [ka] n is 1, 2, 3, or 4, and each R A These are, independently, halogens and C1-C6 alkyloxys. In some embodiments, Ar is [ka] n is 1, 2, 3, or 4, and each R A These are, independently, halogens and C1-C4 alkyloxys. In some embodiments, Ar is [ka] n is 1, 2, or 3, and each R A These are independently fluoro or chloro.

[0063] In some embodiments of the compounds of formulas I, Ia, and Ib, Ar is [ka] n is 1, 2, 3, or 4, and each R A These are independently halogens, C1-C6 alkyls, C1-C6 haloalkyls, and C1-C6 alkyloxys. In some embodiments of the compounds of formulas I, Ia, and Ib, Ar is [ka] n is 1, 2, 3, or 4, and each R A These are independently halogens, C1-C6 alkyls, and C1-C6 alkyloxys. In some embodiments of the compounds of formulas I, Ia, and Ib, Ar is [ka] n is 1, 2, 3, or 4, and each R A These are, independently, halogens and C1-C6 alkyloxys. In some embodiments, Ar is [ka] n is 1, 2, 3, or 4, and each R A These are, independently, halogens and C1-C4 alkyloxys. In some embodiments, Ar is [ka] n is 1, 2, or 3, and each R A These are independently fluoro or chloro.

[0064] In some embodiments of the compounds of formulas I, Ia, and Ib, Ar is [ka] That is the case.

[0065] In some embodiments, the compounds of formula I, formula Ia, and formula Ib disclosed herein have formula II, [ka] In the formula, n is 0, 1, 2, 3, or 4, and each R A However, these are independently halogens, C1-C6 alkyls, C1-C6 haloalkyls, and C1-C6 alkyloxys.

[0066] In some embodiments, the compounds of formulas I, Ia, Ib, and II disclosed herein have formula IIa, [ka] In the formula, n is 0, 1, 2, 3, or 4, and each R A However, these are independently halogens, C1-C6 alkyls, C1-C6 haloalkyls, and C1-C6 alkyloxys.

[0067] In some embodiments, the compounds of formula I, formula Ib, and formula II disclosed herein have formula IIb, [ka] In the formula, n is 0, 1, 2, 3, or 4, and each R A However, these are independently halogens, C1-C6 alkyls, C1-C6 haloalkyls, and C1-C6 alkyloxys.

[0068] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, and IIb, - XY- is -CR 13A CR 13B -CR 9 =CR 10 - and in the formula, R 9 , R 10 , R 13A , and R 13B However, each is independently either H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyloxy, or R 13A and R 13B However, each is independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyloxy, and R 9 and R 10 However, together with the carbon atoms to which they are bonded, they form a 5-6 membered heteroaromatic ring containing phenyl or one, two, or three heteroatoms independently selected from N, O, and S, and the phenyl or 5-6 membered heteroaromatic ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys.

[0069] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, and IIb, -XY- is -CR 9 =CR 10 - and in the formula, each R 9 and R 10 However, independently, these are H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyloxy, or R 9 and R 10 However, together with the carbon atoms to which they are bonded, they form a 5-6 membered heteroaromatic ring containing phenyl or one, two, or three heteroatoms independently selected from N, O, and S, and the phenyl or 5-6 membered heteroaromatic ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys.

[0070] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, and IIb, -XY- is -CH2-CR 9 =CR 10 - and in the formula, R 9 and R 10 However, together with the carbon to which they are bonded, they form a 5-6 membered heterocyclic ring containing phenyl or one, two, or three heteroatoms independently selected from N, O, and S, and the phenyl or 5-6 membered heteroaromatic ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys. In some embodiments, -XY- is -CH2-CR 9 =CR 10 - and in the formula, R 9 and R 10 However, together with the carbon atoms to which they are bonded, they form a 5-6 membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from N, O, and S, and the 5-6 membered heteroaromatic ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys.

[0071] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, and IIb, -XY- is -CR 9 =CR 10 - and in the formula, R 9 and R 10 However, together with the carbon to which they are bonded, they form a 5-6 membered heterocyclic ring containing phenyl or one, two, or three heteroatoms independently selected from N, O, and S, and the phenyl or 5-6 membered heteroaromatic ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys. In some embodiments, -XY- is -CR 9 =CR10 - and in the formula, R 9 and R 10 However, together with the carbon atoms to which they are bonded, they form a 5-6 membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from N, O, and S, and the 5-6 membered heteroaromatic ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys.

[0072] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, and IIb, - XY- is -CH2-CR 9 =CR 10 - and R 9 and R 10 However, together with the carbon atoms to which they are bonded, they form a 5-6 membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from N, O, and S, and the 5-6 membered heteroaromatic ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys.

[0073] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, and IIb, -XY- is -CR 9 =CR 10 - and in the formula, R 9 and R 10 However, together with the carbon atoms to which they are bonded, they form a 5-6 membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from N, O, and S, and the 5-6 membered heteroaromatic ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys.

[0074] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, and IIb, -XY- is -CH2-CR9 =CR 10 - and in the formula, R 9 and R 10 However, together with the carbon atoms to which they are bonded, they form a 5-6 membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from N and O, and the 5-6 membered heteroaromatic ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys.

[0075] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, and IIb, -XY- is -CR 9 =CR 10 - and in the formula, R 9 and R 10 However, together with the carbon atoms to which they are bonded, they form a 5-6 membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from N and O, and the 5-6 membered heteroaromatic ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys.

[0076] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, and IIb, R 11A , R 11B , R 12A , R 12B , R 13A , and R 13B However, each is independently H, halogen, C1-C6 alkyl, or C1-C6 alkyloxy. In some embodiments, R 11A , R 11B , R 12A , R 12B , R 13A , and R 13B However, each is independently H, a halogen, or a C1-C6 alkyloxy. In some embodiments, R 11A , R 11B , R 12A , R 12B , R13A , and R 13B However, each is independently H, halogen, or methoxy. In some embodiments, R 11A , R 11B , R 12A , R 12B , R 13A , and R 13B However, each is independently H, fluoro, or methoxy.

[0077] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, the compound has formula III, [ka] During the ceremony, m is 0, 1, 2, or 3, Each R B However, they are independently halogens, C1-C3 alkyls, C1-C3 haloalkyls, or C1-C3 alkyloxys.

[0078] Compounds of formulas I, Ia, II, IIa, and III have formula IIIa in some embodiments. [ka] During the ceremony, m is 0, 1, 2, or 3, Each R B However, they are independently halogens, C1-C3 alkyls, C1-C3 haloalkyls, or C1-C3 alkyloxys.

[0079] In some embodiments of the compounds of formulas I, Ib, II, IIb, and III, formula IIIb is present, [ka] During the ceremony, m is 0, 1, 2, or 3, Each R B However, they are independently halogens, C1-C3 alkyls, C1-C3 haloalkyls, or C1-C3 alkyloxys.

[0080] In some embodiments of the compounds of formulas III, IIIa, and IIIb, m is 0, 1, or 2. In some embodiments, m is 0 or 1. In some embodiments, m is 1 or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2. In some embodiments, m is 0. In the application form, m is 3.

[0081] In some embodiments of the compounds of formulas III, IIIa, and IIIb, each R B These are independently halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys. In some embodiments, each R B R is independently a halogen, a C1-C3 alkyl, or a C1-C3 haloalkyl. In some embodiments, each R B R is independently a halogen or a C1-C3 alkyl. In some embodiments, each R B However, it is a halogen element on its own.

[0082] In some embodiments of the compounds of formulas III, IIIa, and IIIb, m is 0, 1, or 2, and each R B These are independently halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys. In some embodiments, m is 0, 1, or 2, and each R B m is independently a halogen, a C1-C3 alkyl, or a C1-C3 haloalkyl. In some embodiments, m is 0, 1, or 2, and each R B m is independently a halogen or a C1-C3 alkyl. In some embodiments, m is 0, 1, or 2, and each R B It is, independently, a halogen.

[0083] In some embodiments of the compounds of formulas III, IIIa, and IIIb, m is 0 or 1, and each R BThese are independently halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys. In some embodiments, m is 0 or 1, and each R B These are independently a halogen, a C1-C3 alkyl, or a C1-C3 haloalkyl. In some embodiments, m is 0 or 1, and each R B m is independently a halogen or a C1-C3 alkyl. In some embodiments, m is 0 or 1, and each R B It is, independently, a halogen.

[0084] In some embodiments of the compounds of formulas III, IIIa, and IIIb, m is 1 or 2, and each R B These are independently halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys. In some embodiments, m is 1 or 2, and each R B m is independently a halogen, a C1-C3 alkyl, or a C1-C3 haloalkyl. In some embodiments, m is 1 or 2, and each R B m is independently a halogen or a C1-C3 alkyl. In some embodiments, m is 1 or 2, and each R B It is, independently, a halogen.

[0085] In some embodiments of the compounds of formulas III, IIIa, and IIIb, m is 1, and R B These are halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys. In some embodiments, m is R B is a halogen, a C1-C3 alkyl, or a C1-C3 haloalkyl. In some embodiments, m is 1 and R B is a halogen or a C1-C3 alkyl. In some embodiments, m is 1 and R B It is a halogen.

[0086] In some embodiments of the compounds of formulas III, IIIa, and IIIb, m is 2, and each R BThese are independently halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys. In some embodiments, m is 2, and each R B These are independently halogens, C1-C3 alkyls, or C1-C3 haloalkyls. In some embodiments, m is 2, and each R B These are independently halogens or C1-C3 alkyls. In some embodiments, m is 2, and each R B It is, independently, a halogen.

[0087] In some embodiments of compounds of formula I, Ia, Ib, II, IIa, or IIb, the compound has formula IV, [ka] In the equation, z is either 0 or 1.

[0088] Compounds of formulas I, Ia, II, IIa, and IV, in some embodiments, have formula IVa, [ka] In the equation, z is either 0 or 1.

[0089] In some embodiments of the compounds of formulas I, Ib, II, IIb, and IV, the compound has formula IVb, [ka] In the equation, z is either 0 or 1.

[0090] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, and IIb, -XY- is -CR 9 =CR 10 - and in the formula, each R 9 and R 10 However, these are independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyloxy. In some embodiments, -XY- is -CR 9 =CR 10 - and in the formula, each R9 and R 10 However, independently, these are H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, -XY- is -CR 9 =CR 10 - and in the formula, each R 9 and R 10 However, these are independently H, halogen, or C1-C6 alkyl. In some embodiments, -XY- is -CR 9 =CR 10 - and in the formula, each R 9 and R 10 However, independently, it is H or halogen. In some embodiments, -XY- is -CR 9 =CR 10 - and in the formula, each R 9 and R 10 However, independently, it is either H or F.

[0091] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, and IIb, -XY- is -CR 11A R 11B -CR 12A R 12B - and in the formula, each R 11A , R 11B , R 12A , and R 12B However, independently, these are H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl, or each R 11A and R 12A However, independently, these are H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl, and R 11B and R 12B However, together with the carbon atoms to which they are bonded, they form a 3- to 6-membered carbocyclic ring, and this 3- to 6-membered carbocyclic ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys.

[0092] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, and IIb, -XY- is -CR 11A R 11B -CR 12A R 12B - and in the formula, each R 11A , R 11B , R 12A , and R 12B However, these are independently H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl. In some embodiments, -XY- is -CR 11A R 11B -CR 12A R 12B - and in the formula, each R 11A , R 11B , R 12A , and R 12B However, independently, these are H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, -XY- is -CR 11A R 11B -CR 12A R 12B - and in the formula, each R 11A , R 11B , R 12A , and R 12B However, these are independently H, halogen, or C1-C6 alkyl. In some embodiments, -XY- is -CR 11A R 11B -CR 12A R 12B - and in the formula, each R 11A , R 11B , R 12A , and R 12B However, independently, it is H or halogen. In some embodiments, -XY- is -CR 11A R 11B -CR 12A R 12B - and in the formula, each R 11A , R 11B , R 12A , and R 12B However, independently, it is H or F. In some embodiments, -XY- is -CR 11A R 11B -CR 12A R12B - and in the formula, each R 11A , R 11B , R 12A , and R 12B However, it is H.

[0093] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, and IIb, -XY- is -CR 11A R 11B -CR 12A R 12B - and in the formula, each R 11A and R 12A However, independently, these are H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl, and R 11B and R 12B However, together with the carbon atoms to which they are bonded, they form a 3- to 6-membered carbocyclic ring, and this 3- to 6-membered carbocyclic ring is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogens, C1-C3 alkyls, C1-C3 haloalkyls, and C1-C3 alkyloxys.

[0094] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, and IIb, the compound has formula V, [ka] In the equation, z' is either 1 or 2.

[0095] In some embodiments of the compounds of formulas I, Ia, II, IIa, and V, the compound has formula Va, [ka] In the equation, z' is either 1 or 2.

[0096] In some embodiments of the compounds of formulas I, Ib, II, IIb, and V, the compound has formula Vb, [ka] In the equation, z' is either 1 or 2.

[0097] In some embodiments of the compounds of formulas V, Va, and Vb described herein, z' is 1. In some embodiments, z' is 2.

[0098] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, and Vb described herein, R 8A H is R 8B is H, C1-C3 alkyl, or benzyl. In some embodiments, R 8A H is R 8B is H or C1-C3 alkyl. In some embodiments, R 8A H is R 8B is H or benzyl. In some embodiments, R 8A H is R 8B is a C1-C3 alkyl or benzyl. In some embodiments, R 8A H is R 8B is a C1-C3 alkyl group. In some embodiments, R 8A H is R 8B is benzyl. In some embodiments, R 8A and R 8B Both are H.

[0099] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, and Vb described herein, R 8A It is a C1-C3 alkyl group, and R 8B is H, C1-C3 alkyl, or benzyl. In some embodiments, R 8A It is a C1-C3 alkyl group, and R 8B is H or C1-C3 alkyl. In some embodiments, R 8A It is a C1-C3 alkyl group, and R 8B is H or benzyl. In some embodiments, R 8A It is a C1-C3 alkyl group, and R8B is C1-C3 alkyl or benzyl. In some embodiments, R 8A It is a C1-C3 alkyl group, and R 8B is H. In some embodiments, R 8A It is a C1-C3 alkyl group, and R 8B is benzyl. In some embodiments, R 8A and R 8B These are independently C1-C3 alkyl groups.

[0100] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, and Vb described herein, R 8A It is benzyl, and R 8B is H, C1-C3 alkyl, or benzyl. In some embodiments, R 8A It is benzyl, and R 8B is H or C1-C3 alkyl. In some embodiments, R 8A It is benzyl, and R 8B is H or benzyl. In some embodiments, R 8A It is benzyl, and R 8B is a C1-C3 alkyl or benzyl. In some embodiments, R 8A It is benzyl, and R 8B is a C1-C3 alkyl group. In some embodiments, R 8A It is benzyl, and R 8B is H. In some embodiments, R 8A and R 8B Both are benzyl.

[0101] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, and Vb described herein, R 1 is H, C1-C3 alkyl, or phenyl, and R 2 is H. In some embodiments, R 1is H or phenyl, and R 2 is H. In some embodiments, R 1 is H or C1-C3 alkyl, and R 2 is H. In some embodiments, R 1 is a C1-C3 alkyl or phenyl, and R 2 is H. In some embodiments, R 1 and R 2 Both are H. In some embodiments, R 1 It is a C1-C3 alkyl group, and R 2 is H. In some embodiments, R 1 It is phenyl, and R 2 H is H.

[0102] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, and Vb described herein, R 1 is H, C1-C3 alkyl, or phenyl, and R 2 is a C1-C3 alkyl group. In some embodiments, R 1 H is R 2 is a C1-C3 alkyl group. In some embodiments, R 1 is H or C1-C3 alkyl, and R 2 is a C1-C3 alkyl group. In some embodiments, R 1 is a C1-C3 alkyl or phenyl, and R 2 is a C1-C3 alkyl group. In some embodiments, R 1 H is R 2 is a C1-C3 alkyl group. In some embodiments, each R 1 and R 2 R is independently a C1-C3 alkyl group. In some embodiments, R 1 It is phenyl, and R 2 is a C1-C3 alkyl group. In some embodiments, each R 1 and R 2 These are independently H or C1-C3 alkyl groups.

[0103] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb described herein, each R 4 and R 5 R is independently H or C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with one, two, or three groups independently selected from halogen, C1-C3 alkyloxy, or C1-C3 haloalkyloxy. In some embodiments, R 4 R is H or C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with one, two, or three groups independently selected from halogen, C1-C3 alkyloxy, or C1-C3 haloalkyloxy, 5 However, it is H or C1-C6 alkyl. In some embodiments, R 4 R is H or C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted with one, two, or three groups independently selected from halogen, C1-C3 alkyloxy, or C1-C3 haloalkyloxy, 5 However, it is H.

[0104] In some embodiments of the compounds of formulas IV, IVa, and IVb described herein, R 4 R is a halogen or a C1-C6 alkyl group, and the C1-C6 alkyl group is optionally substituted with one, two, or three groups independently selected from halogens, C1-C3 alkyloxy groups, or C1-C3 haloalkyloxy groups, 5 However, the C1-C6 alkyl group is either H, a halogen, or a C1-C6 alkyl group, and the C1-C6 alkyl group is optionally selected independently from halogen, C1-C3 alkyloxy, or C1-C3 haloalkyloxy, with one or two such groups. , or substituted with three groups. In some embodiments, R 4R is a halogen or a C1-C6 alkyl group, and the C1-C6 alkyl group is optionally substituted with one, two, or three groups independently selected from halogens, C1-C3 alkyloxy groups, or C1-C3 haloalkyloxy groups, 5 However, it is H, a halogen, or a C1-C6 alkyl. In some embodiments, R 4 R is a halogen or a C1-C6 alkyl group, and the C1-C6 alkyl group is optionally substituted with one, two, or three groups independently selected from halogens, C1-C3 alkyloxy groups, or C1-C3 haloalkyloxy groups, 5 However, it is H.

[0105] In some embodiments of the compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb described herein, each R 4 and R 5 These are independently H, Me, OMe, or CH2F. In some embodiments, R 4 is H, Me, OMe, or CH2F, and R 5 H is H.

[0106] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, and Vb described herein, R 4 and R 5 These elements link together to form a 4- to 6-membered heterocyclic ring containing one heteroatom selected from N, O, and S.

[0107] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, and Vb described herein, R 4 and R 5 These link together to form a 3- to 6-membered carbon-cyclic ring.

[0108] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, and Vb described herein, R 6 is H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R 6 is H, halogen, or C1-C6 alkyl. In some embodiments, R 6 is a halogen or a C1-C6 alkyl group. In some embodiments, R 6 is a C1-C6 alkyl group. In some embodiments, R 6 H is H.

[0109] In some embodiments of the compounds of formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb described herein, R 7 is H, halogen, C1-C6 alkyl, or C1-C6 haloalkyl. In some embodiments, R 7 is H, halogen, or C1-C6 alkyl. In some embodiments, R 7 is a halogen or a C1-C6 alkyl group. In some embodiments, R 7 is a C1-C6 alkyl group. In some embodiments, R 7 H is H.

[0110] In some embodiments, compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] [ka] It is selected from the group consisting of the following.

[0111] In some embodiments, compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] [ka] It is selected from the group consisting of the following.

[0112] In some embodiments, compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] [ka] It is selected from the group consisting of the following.

[0113] In some embodiments, compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] [ka] [ka] [ka] [ka] It is selected from the group consisting of the following.

[0114] In some embodiments, compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] [ka] [ka] It is selected from the group consisting of the following.

[0115] In some embodiments, compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] [ka] [ka] [ka] [ka] It is selected from the group consisting of the following.

[0116] In some embodiments, compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] [ka] [ka] [ka] [ka] It is selected from the group consisting of the following.

[0117] In some embodiments, compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] [ka] [ka] [ka] It is selected from the group consisting of the following.

[0118] In some embodiments, compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] [ka] [ka] It is selected from the group consisting of the following.

[0119] In some embodiments, compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] [ka] It is selected from the group consisting of the following.

[0120] In some embodiments, compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] That is the case.

[0121] In some embodiments, compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] That is the case.

[0122] In some embodiments, compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] That is the case.

[0123] In some embodiments, compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] That is the case.

[0124] In some embodiments, formulas I, Ia, Ib, II, IIa, IIb, III, III Compounds a, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] That is the case.

[0125] In some embodiments, compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] That is the case.

[0126] In some embodiments, compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] That is the case.

[0127] In some embodiments, compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] That is the case.

[0128] In some embodiments, compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] That is the case.

[0129] In some embodiments, compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] That is the case.

[0130] In some embodiments, compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [ka] That is the case. III. Compositions and Kits

[0131] The compounds provided herein are typically administered in the form of pharmaceutical compositions. Accordingly, pharmaceutical compositions comprising one or more of the compounds provided herein, or their pharmaceutically acceptable salts, isomers, or mixtures, and one or more pharmaceutically acceptable vehicles selected from carriers, auxiliaries, and excipients are also provided herein. The compounds provided herein may be the sole active ingredient or one of the active ingredients of a pharmaceutical composition. Suitable pharmaceutically acceptable vehicles include, for example, inert solid diluents and fillers, diluents containing sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared in ways well known in the pharmaceutical field. For example, see Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (see GS Banker & C.T. Rhodes, Eds.).

[0132] In one embodiment, a pharmaceutical composition is provided herein comprising a compound provided herein (e.g., a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0133] In some embodiments, the pharmaceutical composition provided herein further comprises one or more (e.g., one; two; three; four; one or two; one to three; or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition further comprises one or more (e.g., one; two; three; four; one or two; one to three; or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof in a therapeutically effective amount.

[0134] The pharmaceutical composition may be administered in single or multiple doses. The pharmaceutical composition may be administered by various methods, including, for example, rectally, orally, intranasally, and transdermally. In some embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0135] One mode of administration is parenteral, for example, by injection. Forms into which the pharmaceutical compositions described herein can be incorporated for administration by injection include, for example, aqueous or oily suspensions, or emulsions having sesame oil, corn oil, cottonseed oil, or peanut oil, or elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0136] Oral administration may be another route for administering the compounds provided herein. Administration may be, for example, by capsule or enteric-coated tablet. When preparing a pharmaceutical composition comprising at least one of the compounds provided herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, the active ingredient (such as the compounds provided herein) is usually diluted with an excipient and / or encapsulated in a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient functions as a diluent, the excipient may be in the form of a solid, semi-solid, or liquid material acting as a vehicle, carrier, or medium for the active ingredient. Thus, the pharmaceutical composition may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), ointments, soft and hard gelatin capsules, sterile injectable solvents, and sterile packaged powders, for example, containing up to 10% by weight of the active compound.

[0137] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, microcrystalline cellulose, sterile water, syrup, and methylcellulose, or any combination thereof. The pharmaceutical composition may further include lubricants such as talc, magnesium stearate, and mineral oil; humectants; emulsifiers and suspending agents; preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweeteners and flavoring agents; or any combination thereof.

[0138] Pharmaceutical compositions comprising at least one compound described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof can be formulated to provide rapid, sustained, or delayed release of the active ingredient (such as the compounds provided herein) after administration to a subject by using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and solution systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are shown in U.S. Patents 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the methods of the present disclosure employs a transdermal delivery device ("patch"). Such transdermal patches may be used to provide continuous or discontinuous infusions of the compounds provided herein in controlled amounts. The construction and use of transdermal patches for drug delivery are well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches may be constructed for continuous, pulsed, or on-demand delivery of pharmaceutical agents.

[0139] To prepare solid compositions such as tablets, the main active ingredient is mixed with a pharmaceutical excipient to form a homogeneous compound described herein or its pharmaceutically acceptable salts, isomers, or mixtures. A solid preformulation composition containing the mixture can be formed. When these preformulation compositions are referred to as homogeneous, the active ingredient can be uniformly dispersed throughout the composition, and as a result, the composition can be easily subdivided into uniformly effective unit dosage forms such as tablets, pills, and capsules.

[0140] Tablets or pills of the compounds described herein may be coated or otherwise formulated to provide a dosage form that offers the benefit of long-term action or to protect from the acidic conditions of the stomach. For example, a tablet or pill may contain an inner dose component and an outer dose component, the latter in the form of an envelope covering the former. The two components may be separated by an enteric coating, which functions to resist disintegration in the stomach and to allow the inner component to pass through the duodenum intact or to delay its release. A variety of materials may be used for such enteric coatings or layers, including many high molecular weight acids and mixtures of high molecular weight acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0141] Pharmaceutical compositions for inhalation or inhalation may include solutions and suspensions in pharmaceutically acceptable aqueous solvents or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, compositions are administered orally or via nasal respiration for topical or systemic effects. In other embodiments, compositions in pharmaceutically acceptable solvents may be atomized using an inert gas. The atomized solution may be inhaled directly from a spray device, or the spray device may be attached to a face mask tent or an intermittent positive pressure breathing simulator. The compositions of solutions, suspensions, or powders may be administered preferably orally or nasally from a device that delivers the formulation in an appropriate manner.

[0142] In one embodiment, a kit is provided herein comprising a compound provided herein (e.g., a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and suitable packaging. In some embodiments, the kit further comprises instructions for use. In some embodiments, the kit comprises a compound provided herein (e.g., a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a label and / or instructions for the use of the compound in the treatment of indications including diseases or conditions described herein.

[0143] In some embodiments, the kit further comprises one or more (e.g., one; two; three; four; one or two; one to three; or one to four) additional therapeutic agents or pharmaceutically acceptable salts thereof.

[0144] In one embodiment, a manufactured article comprising a compound described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof in a suitable container is provided herein. In some embodiments, the container may be a vial, a wide-mouthed bottle, an ampoule, a pre-filled syringe, or an infusion bag. IV. Method

[0145] In one embodiment, a method for treating HIV (e.g., HIV-1 and / or HIV-2) infection in a person who has or is at risk of having said infection, comprising a therapeutically effective amount of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable compound thereof. A method is provided which involves administering to a person a pharmaceutical composition of a salt of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof.

[0146] In some embodiments, the method further comprises administering to the person a therapeutically effective dose of one, two, three, or four additional therapeutic agents. In certain embodiments, the additional therapeutic agents are anti-HIV agents. In certain embodiments, the additional therapeutic agents are HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, latent infection reactivators, capsid polymerization inhibitors, HIV bNAb (broadly neutralizing HIV antibody), TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. In one embodiment, the additional therapeutic agent is abacavir, tenofovir alafenamide, tenofovir disoproxil, lenacapapvir, or pharmaceutically acceptable salts thereof. In one embodiment, the additional therapeutic agent is abacavir, tenofovir alafenamide, tenofovir disoproxil, lenacapavir, GS-5894, islatravir, or a pharmaceutically acceptable salt thereof. In some embodiments, the additional therapeutic agent is lenacapavir or islatravir. In some embodiments, the additional therapeutic agent is lenacapavir. In some embodiments, the additional therapeutic agent is islatravir.

[0147] In another embodiment, the use of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, is provided for treating HIV (e.g., HIV-1 and / or HIV-2) infection in a person who has or is at risk of having such infection.

[0148] In another embodiment, a pharmaceutical composition is provided of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in medical therapy.

[0149] In another embodiment, a pharmaceutical composition is provided of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in the treatment of HIV infection.

[0150] In another embodiment, a pharmaceutical composition of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, is provided for use in a method of treating HIV infection in a person who has or is at risk of having HIV infection.

[0151] In another embodiment, formulas I, Ia, Ib, II, IIa, II are used for a method of treating HIV infection in a person who has or is at risk of having HIV infection. A pharmaceutical composition is provided of a compound of formula b, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, or a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, the method further comprising administering one, two, three, or four additional therapeutic agents to a person.

[0152] In another embodiment, a pharmaceutical composition of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or pharmaceutically acceptable salts thereof, is provided for use in a method of treating HIV infection in a person who has or is at risk of having HIV infection, the method being an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latent infection reactivator, a capsid polymerization inhibitor, or an HIV The present invention further comprises administering to the person one, two, three, or four additional therapeutic agents selected from the group consisting of bNAbs, TLR7 agonists, pharmacokinetic enhancers, other agents for treating HIV, or combinations thereof. In one embodiment, the one, two, three, or four additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, latent infection reactivators, HIV capsid inhibitors, HIV bNAbs, TLR7 agonists, and combinations thereof.

[0153] In another embodiment, a pharmaceutical composition of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, is provided for use in a method of treating HIV infection in a person who has or is at risk of having HIV infection, the method further comprising administering a therapeutically effective amount of tenofovir disoproxil and emtricitabine to the person.

[0154] In another embodiment, a pharmaceutical composition of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, is provided for use in a method of treating HIV infection in a person who has or is at risk of having HIV infection, the method further comprising administering a therapeutically effective amount of tenofovir alafenamide and emtricitabine to the person.

[0155] In another embodiment, a pharmaceutical composition of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, is provided for use in a method of treating HIV infection in a person who has or is at risk of having HIV infection, the method further comprising administering a therapeutically effective amount of tenofovir disoproxil to the person.

[0156] In another embodiment, a person who has or is at risk of having HIV infection... A pharmaceutical composition of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in a method of treating the infection, the method further comprising administering a therapeutically effective amount of tenofovir alafenamide to a human.

[0157] In another embodiment, a method is provided for using compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb in a therapy. In particular, a method is provided for treating the replication of the HIV virus, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human), comprising administering a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient to the mammal.

[0158] In another embodiment, a composition is provided comprising a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for use in a method of treating the replication of the HIV virus in a mammal (e.g., a human), treating AIDS, or delaying the onset of AIDS or ARC symptoms.

[0159] In one embodiment, a pharmaceutical composition is provided of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in preventing HIV infection.

[0160] For example, in one embodiment, a pharmaceutical composition is provided of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in pre-exposure prophylaxis (PrEP), i.e., for use before an individual is exposed to the HIV virus, in order to prevent HIV infection from becoming established in an individual who has been exposed to the virus, and / or to prevent the virus from establishing a permanent infection, and / or to prevent the symptoms of the disease from appearing, and / or to prevent the virus from reaching a detectable level in the blood.

[0161] In another embodiment, the use of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or pharmaceutically acceptable salts thereof, is disclosed for the manufacture of a medicament for the treatment of HIV infection in a person who has or is at risk of having HIV infection.

[0162] In another embodiment, the use of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or pharmaceutically acceptable salts thereof, as research tools is disclosed.

[0163] In another embodiment, a manufactured article comprising a composition effective for treating HIV infection, and A packaging material is disclosed that includes a label indicating that the composition can be used to treat HIV infection. Exemplary compositions include compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or pharmaceutically acceptable salts thereof.

[0164] In yet another embodiment, a method for inhibiting HIV replication is disclosed. This method involves exposing the virus to an effective amount of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a salt thereof, under conditions that inhibit HIV replication.

[0165] In another embodiment, the use of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb to inhibit the activity of the HIV integrase enzyme is disclosed.

[0166] In another embodiment, the use of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or salts thereof, for inhibiting HIV replication is disclosed. v. Administration

[0167] The compounds disclosed herein (also referred to herein as active ingredients) can be administered by any route appropriate to the malaise being treated. Preferred routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be understood that the preferred route may vary, for example, depending on the recipient's condition. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0168] The compounds of this disclosure may be administered to an individual according to an effective administration plan for a desired period or duration, such as at least about one month, at least about two months, at least about three months, at least about six months, or at least about twelve months or more. In some embodiments, the compounds are administered daily or on an intermittent schedule over the lifespan of the individual.

[0169] The specific dose levels of the compounds of this disclosure for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, overall health, sex, diet, administration time, route of administration, and excretion rate, drug combinations, and the severity of the particular disease in the subject receiving treatment. For example, the dose may be expressed as milligrams (mg / kg) of the compound described herein per kilogram of body weight of the subject. Doses of about 0.1 to 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments, doses of 0.5 to 60 mg / kg may be appropriate. Normalization by body weight of the subject is particularly useful when adjusting doses between subjects of widely different sizes, such as when using drugs in both children and adults, or when converting effective doses in non-human subjects such as dogs to doses suitable for human subjects.

[0170] The daily dose may also be expressed as the total amount of the compound described herein administered per single dose or per day. The daily dose of a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, may be approximately 1 mg to 4,000 mg, approximately 2,000 to 4,000 mg / day, approximately 1 to 2,000 mg / day, approximately 1 to 1,000 mg / day, approximately 10 to 500 mg / day, approximately 20 to 500 mg / day, approximately 50 to 300 mg / day, approximately 75 to 200 mg / day, or approximately 15 to 150 mg / day.

[0171] The dosage or frequency of administration of the compounds disclosed herein may be adjusted throughout the course of treatment at the discretion of the administering physician.

[0172] The compounds of this disclosure may be administered to an individual (e.g., a human) in a therapeutically effective dose. In some embodiments, the compounds are administered once daily.

[0173] The compounds provided herein may be administered by any useful route and means, such as oral or parenteral (e.g., intravenous) administration. The therapeutically effective dose of the compounds may include about 0.00001 mg / kg body weight to about 10 mg / kg body weight per day, for example, about 0.0001 mg / kg body weight to about 10 mg / kg body weight per day, or for example, about 0.001 mg / kg body weight to about 1 mg / kg body weight per day, or for example, about 0.01 mg / kg body weight to about 1 mg / kg body weight per day, or about 0.05 mg / kg body weight to about 0.5 mg / kg body weight per day. In some embodiments, the therapeutically effective dose of the compounds provided herein may include about 0.3 mg to about 30 mg per day, or about 30 mg to about 300 mg per day, or about 0.3 μg to about 30 mg per day, or about 30 μg to about 300 μg per day.

[0174] The compounds of this disclosure can be combined with one or more additional therapeutic agents at any dose of the compounds of this disclosure (e.g., 1 mg to 1000 mg of the compounds). The therapeutically effective dose may include approximately 0.1 mg to approximately 1000 mg per dose, for example, approximately 50 mg to approximately 500 mg per dose, or for example, approximately 100 mg to approximately 400 mg per dose, or for example, approximately 150 mg to approximately 350 mg per dose, or for example, approximately 200 mg to approximately 300 mg per dose, or for example, approximately 0.01 mg to approximately 1000 mg per dose, or for example, approximately 0.01 mg to approximately 100 mg per dose, or for example, approximately 0.1 mg to approximately 100 mg per dose, or for example, approximately 1 mg to approximately 100 mg per dose, or for example, approximately 1 mg to approximately 100 mg per dose. Other effective therapeutic doses of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are approximately 1 mg per dose, or approximately 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or approximately 100 mg per dose. Other therapeutically effective doses of the compounds disclosed herein are approximately 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or approximately 1000 mg per dose.

[0175] In some embodiments, the methods described herein include administering a target compound p of this specification to an initial daily dose of about 1 to 500 mg, and increasing the dose incrementally until clinical efficacy is achieved. The dose can be increased using increments of about 5, 10, 25, 50, or 100 mg. The dose can be increased daily, every other day, twice a week, once a week, every two weeks, every three weeks, or once a month.

[0176] When administered orally, the total daily dose for human subjects may be approximately 1 mg to 1,000 mg, approximately 10 to 500 mg / day, approximately 50 to 300 mg / day, approximately 75 to 200 mg / day, or approximately 100 to 150 mg / day. In some embodiments, the total daily dose for human subjects may be approximately 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1,000 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 200, 300, 400, 500 mg / day administered as a single dose. The dose may be 600, 700, or 800 mg / day. In some embodiments, the total daily dose for human subjects may be approximately 300, 400, 500, or 600 mg / day administered as a single dose.

[0177] In some embodiments, the total daily dose for human subjects may be approximately 100 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 150 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 200 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 250 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 300 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 350 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 400 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 450 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 500 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 550 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 600 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 650 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 700 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 750 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 800 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 850 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 900 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 950 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 1000 mg / day administered as a single dose.

[0178] A single dose can be administered hourly, daily, weekly, or monthly. For example, a single dose can be administered once every 1, 2, 3, 4, 6, 8, 12, or 16 hours, or once every 24 hours. A single dose can also be administered once every 1, 2, 3, 4, 5, or 6 days, or once every 7 days. A single dose can also be administered once every 1, 2, or 3 weeks, or once every 4 weeks. In some embodiments, a single dose may be administered once weekly. A single dose may also be administered once monthly. In some embodiments, the compounds disclosed herein are administered once daily in the manner disclosed herein. In some embodiments, the compounds disclosed herein are administered twice daily in the manner disclosed herein.

[0179] In some embodiments, the compounds disclosed herein are administered once every 10 days. In some embodiments, the compounds disclosed herein are administered once every 15 days. In some embodiments, the compounds disclosed herein are administered once every 20 days. In some embodiments, the compounds disclosed herein are administered once every 10 to 15 days. In some embodiments, the compounds disclosed herein are administered once every 15 to 20 days. In some embodiments, the compounds disclosed herein are administered once every 10 to 20 days. In some embodiments, the compounds disclosed herein are administered once a month. In some embodiments, the compounds disclosed herein are administered once every two months. In some embodiments, the compounds disclosed herein are administered once every three months. In some embodiments, the compounds disclosed herein... It is administered once every four months. In some embodiments, the compounds disclosed herein are administered once every five months. In some embodiments, the compounds disclosed herein are administered once every six months. In some embodiments, the compounds disclosed herein are administered once every eight months. In some embodiments, the compounds disclosed herein are administered once every ten months. In some embodiments, the compounds disclosed herein are administered once a year.

[0180] The frequency of administration of the compounds disclosed herein is determined by the needs of the individual patient and may be, for example, once daily, twice daily, or more. Administration of the compounds is continued for as long as necessary to treat HBV infection, HIV infection, cancer, hyperproliferative disorders, or any other indication described herein. For example, the compounds may be administered to a person infected with HBV for a period of 20 to 180 days, or for example, 20 to 90 days, or for example, 30 to 60 days.

[0181] Administration may be intermittent, involving periods of several days or more during which the patient receives a daily dose of the compound, followed by periods of several days or more during which the patient does not receive a daily dose of the compound. For example, a patient may receive a certain dose of the compound every other day or three times per week. As another example, a patient may receive a certain dose of the compound daily for a period of 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive a certain dose of the compound, and then for a subsequent period (e.g., 1 to 14 days) during which the patient may again receive a daily dose of the compound. Alternating periods of administration and subsequent non-administration of the compound may be repeated as clinically necessary to treat the patient.

[0182] The compounds or pharmaceutical compositions thereof of this disclosure may be administered once, twice, three times, or four times daily using any preferred form described above. Administration or treatment with the compounds may also be continued for several days; for example, treatment will typically last for at least 7, 14, or 28 days for one treatment cycle. Treatment cycles are well known in cancer chemotherapy and frequently alternate with rest periods of approximately 1 to 28 days, generally about 7 or 14 days. Treatment cycles may also be continuous in other embodiments. VI. Combination Therapy

[0183] In one particular embodiment, a method is provided for treating or preventing HIV infection in a person who has or is at risk of having HIV infection, comprising administering to that person a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with one or more (e.g., one; two; three; one or two; or one to three) additional therapeutic agents.

[0184] In one embodiment, a pharmaceutical composition is provided comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, 1 or 2, or 1-3) additional therapeutic agents, a pharmaceutically acceptable carrier, diluent, or excipient.

[0185] In certain embodiments, the Disclosure provides a method for treating HIV infection, comprising administering to a subject in need of such treatment a therapeutically effective amount of one or more additional therapeutic agents suitable for treating HIV infection, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating HIV infection.

[0186] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with one, 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 further embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class and / or may be selected from different classes of therapeutic agents. Administration of HIV combination therapy

[0187] In certain embodiments, the compounds disclosed herein are administered together 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 so that both therapeutically effective amounts of the compounds disclosed herein and one or more additional therapeutic agents are present in the patient's body. When administered sequentially, the combination may be administered in two or more doses.

[0188] Co-administration involves administering a unit dose of the compound disclosed herein before or after the administration of a unit dose of one or more additional therapeutic agents. For example, the compound disclosed herein may be administered within seconds, minutes, or hours of the administration of one or more additional therapeutic agents. In some embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents within seconds or minutes. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein within seconds or minutes. In yet another embodiment, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one or more additional therapeutic agents several hours later (e.g., 1 to 12 hours). In yet another embodiment, a unit dose of one or more additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein several hours later (e.g., 1 to 12 hours).

[0189] In certain embodiments, the compounds disclosed herein are combined with one or more additional therapeutic agents in a unit dosage form for co-administration to a subject, for example, as a solid dosage form for oral administration.

[0190] In certain embodiments, the compound of formula I is formulated as a tablet that may optionally contain one or more other compounds useful for the treatment of HIV. In certain embodiments, the tablet may contain another active ingredient for treating HIV, such as an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleoside inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic (or allosteric) integrase inhibitor, a pharmacokinetic enhancer, and combinations thereof.

[0191] In one embodiment, such tablets are suitable for once-daily administration. HIV combination therapy

[0192] In the embodiments described above, additional therapeutic agents may be anti-HIV agents. These include HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry inhibitors, and HIV inhibitors. Mature inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editing agents (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), cell therapies (chimeric antigen receptor T cells, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapy, etc.), latent infection reactivators, compounds targeting HIV capsid, immune system therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, dual Specific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 virus infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed-lineage kinase-3 (MLK-3) inhibitors, HIV-1 splices HIV inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, CD4 modulators, CD4 antagonists, HIV ribonuclease H inhibitors, retrocycline modulators, CDK-9 inhibitors, CCR5 chemokine antagonists, CCR5 gene modulators, dendritic ICAM-3 grabbing non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, hyaluronidase inhibitors, Nef antagonists, Nef inhibitors, protease-activated receptor-1 antagonists, TNF-alpha ligand inhibitors, PDE4 inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulants, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapies, HIV vaccines, and combinations thereof.

[0193] In some embodiments, additional therapeutic agents are selected from the group consisting of HIV combination drugs, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latent infection reactivators, capsid inhibitors, immunotherapy, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and “antibody-like” therapeutic proteins, as well as combinations thereof. HIV combination drugs

[0194] Examples of concomitant medications include ATRIPLA(registered trademark) (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); BIKTARVY(registered trademark) (bictegravir, emtricitabine, tenofovir alafenamide); COMPLERA(registered trademark) (EVIPLERA(registered trademark); rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD(registered trademark) (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA(registered trademark) (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY(registered trademark) (Tenofovir alafenamide and emtricitabine); ODEFSEY (Registered Trademark) (Tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA (Registered Trademark) (Tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); SYMTUZA (Registered Trademark) (Darunavir, tenofovir alafenamide hemi fumarate, emtricitabine, and cobicistat); SYMFITM (Efavirenz, lamivudine, and tenofovir disoproxil fumarate); CIMDU™ (Lamivudine and tenofovir disoproxil fumarate); Tenofovir and lamivudine; Tenofovir alafenamide and emtricitabine Tenofovir alafenamide hemifumarate and emtricitabine; Tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; Tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR® (Zidovudine and Lamivudine; AZT+3TC); EPZICOM® (LIVEXA®); Abacavir sulfate and Lamivudine; ABC+3TC); KALETRA (Registered Trademark) (ALUVIA (Registered Trademark), lopinavir and ritonavir), TRIUMEQ (Registered Trademark) (dolutegravir, abacavir and lamivudine); TRIZIVIR (Registered Trademark) (abacavir sulfate, zidovudine and lamivudine; ABC+AZT+3TC); atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and ri Lupivrine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dapivrine + levonorgestrel, dolutegravir + lamivudine, dolutegravir + emtricitabine + tenofovir alafenamide, elsulfavirine + emtricitabine + tenofovir disop Examples include Roxil, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, and zidovudine. Other HIV drugs

[0195] Other examples of drugs used to treat HIV include acemannan, arispolivir, astodrimer, BanLec, CC-11050, deferipron, gamimune, griffiscin, methenkephalin, naltrexone, prolastin, REP9, RPI-MN, Vorapaxar, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy, MK-8527, BlockAide, PSC-RANTES, ABX-464, and AG-11. Examples include 05, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-2048, MK-4250, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576. HIV protease inhibitors

[0196] Examples of HIV protease inhibitors include amprenavir, atazanavir, brekanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, and TMC-310911. HIV reverse transcriptase inhibitors

[0197] Examples of reverse transcriptase HIV non-nucleoside or non-nucleotide inhibitors include dapivine, delavirdin, delavirdin mesylate, doravirine, efavirenz, etravirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, A Examples include CC-007, AIC-292, KM-023, PC-1005, and el-sulfavirine (VM-1500).

[0198] Examples of reverse transcriptase HIV nucleoside or nucleotide inhibitors include adefovir, adefovir dipivoxil, azuvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX® and VIDEX Examples include EC (registered trademark) (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, sensabudine, didanosine, erbucitabine, festinavir, fosaluvudine tidoxil, CMX-157, dapivine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotinate, tidoxilfodivudine, islatravir, lamivudine, phosphazide, stabudine, zalcitabine, zidovudine, lobafovir etalafenamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, and KP-1461. HIV integrase inhibitors

[0199] Examples of HIV integrase inhibitors include elvitegravir, curcumin, curcumin derivatives, chicolinic acid, chicolinic acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tilphostine, tilphostine derivatives, quercetin, quercetin derivatives, raltegravir, dolutegravir, JTK-351, and Bictegravir. Examples include vir, AVX-15567, BMS-986197, cabotegravir (long-acting injection), diketoquinoline 4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbendesulfonic acid, T-169, VM-3500, and cabotegravir.

[0200] Examples of HIV non-catalytic or allosteric integrase inhibitors (NCINIs) include CX-05045, CX-05168, and CX-14442. HIV entry inhibitors

[0201] Examples of HIV entry (fusion) inhibitors include cenicliviroc, CCR5 inhibitors, gp41 inhibitors, CD4 binding inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors.

[0202] Examples of CCR5 inhibitors include aplaviroc, bicriviroc, maraviroc, senicliviroc, leronrimab (PRO-140), adaptervir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu).

[0203] Examples of gp41 inhibitors include albuvirtide, enfvirtide, BMS-986197, enfvirtide biobetter, enfvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and shifvirtide.

[0204] Examples of CD4 binding inhibitors include ivalizumab and CADA analogs.

[0205] Examples of gp120 inhibitors include Radha-108 (Receptol) 3B3-PE38, BanLec, bentonite-based nanopharmaceuticals, fostemsavir tromethamine, IQP-0831, and BMS-663068.

[0206] Examples of CXCR4 inhibitors include prelixafor, ALT-1188, N15 peptide, and vMIP (Haimipu). HIV maturation inhibitors

[0207] Examples of HIV maturation inhibitors include BMS-955176, BMS-986197, GSK-3640254, and GSK-2838232. Latent infection reactivator

[0208] Examples of latent infection reactivators include histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as Velcade, and ixazomib citrate, protein kinase C (PKC) activators, and Smyd2 inhibitors. Drugs, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, Examples include PMA, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), IL-15 modulated antibodies, JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors, such as largazole analogs, APH-0812, and GSK-343.

[0209] Examples of HDAC inhibitors include romidepsin, vorinostat, and panobinostat.

[0210] Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG-lactone. Capsid inhibitors

[0211] Examples of capsid inhibitors include capsid polymerization inhibitors or capsid disruption compounds, HIV nucleocapsid p7 (NCp7) inhibitors, such as azodicarbons. Examples include Mido, HIV p24 capsid protein inhibitors, GS-6207, AVI-621, AVI-101, AVI-201, AVI-301, and the AVI-CAN1-15 series. immune system therapy

[0212] Examples of immunotherapy include Toll-like receptor modulators such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13; programmed cell death protein 1 (Pd-1) modulators; programmed death ligand 1 (Pd-L1) modulators; IL-15 modulators; and Derma Vir; Interleukin-7; Plaquenil (hydroxychloroquine); Proleukin (aldesleukin, IL-2); Interferon Alpha; Interferon Alpha-2b; Interferon Alpha-n3; PEGylated Interferon Alpha; Interferon Gamma; Hydroxyurea; Mycophenolate Mofetil (MPA) and its ester derivative Mycophenolate Mofetil (MMF); Ribavirin; Polymer Polyethyleneimine ,PEI);gepon;IL-12;WF-10;VGV-1;MOR-22;BMS-936559;CYT-107, Interleukin-15 / Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255, NKTR-262, Examples include NKTR-214, Normferon, Peginterferon Alpha-2a, Peginterferon Alpha-2b, Recombinant Interleukin-15, Xmab-24306, RPI-MN, STING modulator, RIG-I modulator, NOD2 modulator, SB-9200, and IR-103.

[0213] Examples of TLR agonists: Besatrimod (GS-9620), GS-986, IR-103, Refitrimod, Chilsotrimod, Lintatrimod, DSP-0509, AL-034, G-100, Kobitrimod, AST-008, Motrimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, Tellatrimod, RO-7020531. Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0214] Examples of PI3K inhibitors include idelalisib, alpelisib, buparisib, CAI orotinate, copanlisib, duvelisib, gedatricib, neratinib, panulisib, perifosin, pictilisib, piraralisib, pukitinib mesylate, rigosertib, rigosertib sodium, sonolicid, taselicib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, Examples include DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765, and ZSTK-474. Alpha-4 / Beta-7 Antagonist

[0215] Examples of integrin alpha-4 / beta-7 antagonists include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast-methyl, and vedolizumab. HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins

[0216] Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bispecific antibodies, trispecific antibodies, polyvalent antibodies, bnAB (broadly neutralizing HIV-1 antibody), BMS-936559, TMB-360, and HIV Examples include antibodies targeting gp120 or gp41, antibody mobilization molecules targeting HIV, anti-CD63 monoclonal antibodies, CD3 bispecific antibodies, CD16 bispecific antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, CCR5 bispecific antibodies, anti-Nef single-domain antibodies, anti-Rev antibodies, camel-derived anti-CD18 antibodies, camel-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeted antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAb (PGT-121), ivalizumab, Immuglo, and MB-66.

[0217] Examples of drugs that target HIV in this way include babituximab, UB-421, C2F5, 2G12, C4E10, C2F5+C2G12+C4E10, 8ANC195, 3BNC117, 3BNC117-LS, 3BNC60, D1D2, 10-1074, 10-1074-LS, GS-9722, DH411-2, BG18, PGT145, PGT121, PGT122, and PGT-1. 51, PGT-133, PGT-135, PGT-128, MDX010 (ipilimumab), DH511, DH511-2, N6, N6LS, N49P6, N49P7, N49P7.1, N49P9, N49P11, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH45-46, PG9, PG16, 8ANC195, 2Dm2m, 4Dm2m, 6Dm2 Examples of HIV bispecific antibodies include m, VRC-01, VRC-01-LS, PGDM1400, A32, 7B2, 10E8, 10E8VLS, 3810109, 10E8v4, 10E8.4 / iMab, VRC-01 / PGDM-1400 / 10E8v4, IMC-HIV, iMabm36, 10E8v4 / PGT121-VRC01, eCD4-Ig, IOMA, CAP256-VRC26.25, DRVIA7, SAR-441236, VRC-07-523, VRC07-523LS, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, and VRC07. Examples of HIV bispecific antibodies include MGD014 and TMB-bispecific.

[0218] Examples of in vivo delivered bnABs such as AAV8-VRC07; mRNA encoding the anti-HIV antibody VRC01. Pharmacokinetic enhancers

[0219] Examples of pharmacokinetic enhancers include cobicistat and ritonavir. Additional treatments

[0220] Examples of additional therapeutic agents include International Publication No. 2004 / 096286 (Gilead Sciences), International Publication No. 2006 / 015261 (Gilead Sciences), International Publication No. 2006 / 110157 (Gilead Sciences), International Publication No. 2012 / 003497 (Gilead Sciences), International Publication No. 2012 / 003498 (Gilead Sciences), International Publication No. 2012 / 145728 (Gilead Sciences), International Publication No. 2013 / 006738 (Gilead Sciences), International Publication No. 2013 / 159064 (Gilead Sciences), International Publication No. 2014 / 100323 (Gilead Sciences), and U.S. Patent Application Publication No. 2013 / 0165489 (University of Pennsylvania), U.S. Patent Application Publication No. 2014 / 0221378 (Japan Tobacco), U.S. Patent Application Publication No. 2014 / 0221380 (Japan Tobacco), International Publication No. 2009 / 062285 (Boehringer Ingelheim), International Publication No. 2010 / 130034 (Boehringer Ingelheim), International Publication No. 2013 / 006792 (Pharma Examples of compounds disclosed in U.S. Patent Publication No. 2014 / 0221356 (Gilead Sciences), U.S. Patent Publication No. 2010 / 0143301 (Gilead Sciences), and International Publication No. 2013 / 091096 (Boehringer Ingelheim) include those disclosed in Resources, U.S. Patent Publication No. 2014 / 0221356 (Gilead Sciences), U.S. Patent Publication No. 2010 / 0143301 (Gilead Sciences), and International Publication No. 2013 / 091096 (Boehringer Ingelheim). HIV vaccine

[0221] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, arenaviruses, and lymphocytic choriomeningitis virus. Viruses such as LCMV, pitindevirus, modified vaccinia ankara virus (MVA), adenovirus, adeno-associated virus (AAV), vesicularstomatitis virus (VSV), and chimpanzee adenovirus (ChAd). Live vector vaccines using vectors, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, BG505 SOSIP.664 gp140, rgp120 (AIDSVAX), ALVAC HIV, (vCP1521) / AIDSVAX B / E (gp120) (RV144), monomer gp120 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad4-Env145NFL, Ad5-ENVA-48, HB-500, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, Vacc-CRX, VVX-004, VAC-3S, multi-clad DNA recombinant adenovirus-5 (recombinant adenovirus) us-5, rAd5), rAd5 gag-pol env A / B / C vaccine, Pennvax-G, Pennvax-GP / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSP ISA-51, polyICLC adjuvant vaccine, TatImmune, GTU-multiHIV(FIT-06), gp140[Delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4(Ad4-env Clade C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag / pol / nef / nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.HIV + MVA mosaic vaccine + gp140, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particle vaccines, such as pseudovirion vaccines, CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccine, conjugate polypeptide vaccine, dendritic cell vaccine, gag DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), I i-key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multi-clad Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x + romidepsin, variant gp120 polypeptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA.HTI, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP+VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980; eOD-GT8 60mer vaccine, PD-201401, env(A,B,C,A / E) / gag(C)DNA vaccine, gp120(A,B,C,A / E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs Examples include HIV-1 vaccines (GLA-SE adjuvant), HIV p24gag prime boost plasmid DNA vaccine, arenavirus vector immunotherapy (Vaxwave, TheraT), MVA-BN HIV-1 vaccine regimen, MVA.tHIVconsv4, MVA.tHIVconsv3, UBI HIV gp120, mRNA-based prophylactic vaccines, TBL-1203HI, VRC-HIVRGP096-00-VP, VAX-3S, and HIV MAG DNA vaccine. HIV combination therapy

[0222] In certain embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCOVY (Registered Trademark) (Tenofovir alafenamide and emtricitabine); ODEFSEY (Registered Trademark) (Tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA (Registered Trademark) (Tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); Adefovir; Adefovir dipivoxil; Cobicistat; Emtricitabine; Tenofovir; Tenofovir disoproxil; Tenofovir disoproxil fumarate; Tenofovir alafenamide; Tenofovir alafenamide hemifumarate; T RIUMEQ(registered trademark) (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA(registered trademark) (KALETRA(registered trademark); lopinavir and ritonavir); COMBIVIR(registered trademark) (zidovudine and lamivudine; AZT+3TC); EPZICOM(registered trademark) (LIVEXA(registered trademark); abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR(registered trademark) (Registered Trademark) (Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Rilpivirine; Rilpivirine hydrochloride; Atazanavir sulfate and cobicistat; Atazanavir and cobicistat; Darunavir and cobicistat; Atazanavir; Atazanavir sulfate; Dolutegravir; Elvitegravir; Ritonavir; Atazanavir sulfate and ritonavir; Darunavir; Lamivudine; Prolastine; Hosanprenavir; Hosanprenavir calcium efavirenz; Etravirine; Nelfinavir; Nelfinavir mesin Luates; interferon; didanosine; stabudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirudine; delavirudine mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphatide; lamivudine, nevirapine, and zidovudine;It is combined with one, two, three, or four or more additional therapeutic agents selected from abacavir and abacavir sulfate.

[0223] Those skilled in the art will understand that the additional therapeutic agents listed above may belong to two or more of the classes listed above. No particular class is intended to limit the functionality of these compounds listed within those classes.

[0224] In certain embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with HIV nucleoside or nucleotide inhibitors and HIV non-nucleoside inhibitors of reverse transcriptase. In other specific embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with HIV nucleoside or nucleotide inhibitors and HIV protease inhibitors of reverse transcriptase. In additional embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with HIV nucleoside or nucleotide inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, and pharmacokinetic enhancers. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with at least one HIV nucleoside inhibitor, an integrase inhibitor, and a pharmacokinetic enhancer of reverse transcriptase. In other embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0225] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0226] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, It is used in combination with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0227] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

[0228] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, the second additional therapeutic agent being emtricitabine.

[0229] The compounds disclosed herein (e.g., any compound of formula I) may be combined with one or more additional therapeutic agents in any dosage of the compound of formula I (e.g., 1 mg to 500 mg of the compound).

[0230] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 5 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 5 to 10, 5 to 15, 5 to 20, 5 to 25, 25 to 30, 20 to 30, 15 to 30, or 10 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. The compounds disclosed herein (e.g., compounds of formula I) can be combined with the agents provided herein at any dosage of the compound (e.g., 1 mg to 500 mg of the compound), as each dosage combination is specifically and individually enumerated.

[0231] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 200–400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 200–250, 200–300, 200–350, 250–350, 250–400, 350–400, 300–400, or 250–400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. The compounds disclosed herein (e.g., compounds of formula I) are provided herein. Just as each combination of drug and dosage is specifically and individually listed, any dosage of compound (for example, 1 mg to 500 mg of a compound) can be used in combination.

[0232] In one embodiment, a kit is provided comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with one or more (e.g., one; two; three; one or two; or one to three) additional therapeutic agents. Combination therapy for contraception

[0233] Therapeutic agents used for contraception include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinylestradiol, etinodiol, etonogestrel, levonorgestrel, levonorgestrel, linestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norlegestromine, norethindrone, nortinodrel, norgestimate, olmeloxifen, segestersone acetate, ulipristal acetate, and any combination thereof. Gene therapy and cell therapy

[0234] Gene therapy and cell therapy include gene modification to silence genes; genetic approaches to directly kill infected cells; injection of immune cells designed to replace a large portion of the patient's own immune system to enhance the immune response to infected cells, or to activate the patient's own immune system to kill infected cells, or to locate and kill infected cells; and genetic approaches to modify cell activity to further alter the endogenous immune response to infection.

[0235] An example of dendritic cell therapy is AGS-004.

[0236] An example of a CCR5 gene editing drug is SB-728T.

[0237] An example of a CCR5 gene inhibitor is Cal-1.

[0238] CD4-positive T cells expressing C34-CCR5 / C34-CXCR4.

[0239] AGT-103 transduced autologous T cell therapy.

[0240] AAV-eCD4-Ig gene therapy. Gene editing agents

[0241] The genome editing system is selected from the group consisting of CRISPR / Cas9 systems, zinc finger nuclease systems, TALEN systems, homing endonuclease systems, and meganuclease systems.

[0242] An example of an HIV-targeted CRISPR / Cas9 system is EBT-101. CAR-T cell therapy

[0243] It is engineered to express a chimeric antigen receptor (CAR). A population of immune effector cells, where CAR includes an HIV antigen-binding domain. The HIV antigen includes the HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, a CD4 induction binding site on gp120, an N-glycan on gp120, V2 of gp120, and a membrane proximal region on gp41. The immune effector cells are T cells or NK cells. In some embodiments, T cells are CD4+ T cells, CD8 +T cells, or a combination thereof. The cells can be autologous or allogeneic.

[0244] Examples of HIV CAR-T include VC-CAR-T, anti-CD4 CAR-T cell therapy, and autologous hematopoietic stem cells genetically engineered to express CD4 CAR and C46 peptide. TCR-T cell therapy

[0245] TCR-T cells are genetically engineered to target HIV-derived peptides presented on the surface of virus-infected cells. [Examples]

[0246] VII. Examples The exemplary chemicals of this disclosure are provided in the following specific examples. Those skilled in the art will understand that, in order to obtain the various compounds described herein, the starting materials may be suitably selected such that the ultimately desired substituents are supported through a reaction scheme with or without protection as necessary to obtain the desired product. Alternatively, it may be necessary or desirable to use a suitable group that is supported through the reaction scheme and can be replaced with the desired substituent as necessary, instead of the ultimately desired substituent. Furthermore, those skilled in the art will understand that the transformations shown in the following schemes may be carried out in any order that is suitable for the functionality of the particular pendant group.

[0247] The examples provided herein describe the synthesis of the compounds disclosed herein, as well as the intermediates used to prepare the compounds. It should be understood that the individual steps described herein can be combined. It should also be understood that separate batches of the compounds can be combined and carried over to the next synthesis step.

[0248] The following description of embodiments describes specific embodiments. These embodiments are described in sufficient detail to enable those skilled in the art to carry out certain embodiments of the Disclosure. Other embodiments may be utilized, and logical and other modifications may be made without departing from the scope of the Disclosure. Therefore, the following description is not intended to limit the scope of the Disclosure. Examples 1-4: (6R)-10-Fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(C1) (6R)-9-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(C2) (6S)-10-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(C3) Preparation of (6S)-9-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide (C4) [ka]

[0249] 5-(benzyloxy)-2,3-dihydro-1H-pyrido[2,1-f][1,2,4]triazine-4,6-dione(1) was prepared according to the published procedure for “Intermediate A” in International Publication No. 2019 / 160883(A1). Step 1: 1-(benzyloxy)-10-fluoro-7,12-dihydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-2,14-dione(2-a) and 1-(benzyloxy)-9-fluoro-7,12-dihydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-2,14- Preparation of Zion(2-b)

[0250] 5-(benzyloxy)-2,3-dihydro-1H-pyrido[2,1-f][1,2,4]triazine-4,6-dione(1) (200 mg, 0.737 mmol) and 1,2-bis(bromomethyl)-4-fluorobenzene (229 mg, 0.811 mmol) were mixed with DMF (5 ml), and the mixture was cooled to 0°C. NaOt-Bu (159 mg, 1.66 mmol) was added over 1 hour. The reaction mixture was stirred overnight without a refilled cold bath. The reaction mixture was then diluted with ethyl acetate and treated with NH4Cl / water. The organic phase was separated and concentrated. The residue was purified by silica gel chromatography using 0-100% ethyl acetate in heptane, followed by 10% MeOH in ethyl acetate, to obtain a mixture of two positional isomers of the product (2-a and 2-b). MS (m / z): 392.1 [M+H]. These two positional isomers were not separated and were carried over to the next step. Step 2: Preparation of 1-(benzyloxy)-10-fluoro-3-iodo-7,12-dihydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-2,14-dione(3-a) and 1-(benzyloxy)-9-fluoro-3-iodo-7,12-dihydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-2,14-dione(3-b).

[0251] A mixture of 1-(benzyloxy)-10-fluoro-7,12-dihydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-2,14-dione(2-a) and 1-(benzyloxy)-9-fluoro-7,12-dihydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-2,14-dione(2-b) (50 mg, 0.128 mmol) was mixed with MeOH (0.8 ml) at room temperature. m-CPBA (77%) (114 mg, 0.51 mmol) and NIS (114 mg, 0.51 mmol) were added sequentially. The reaction vial was sealed and heated from room temperature to 80°C for 30 minutes. Additional m-CPBA (77%) (114 mg, 0.51 mmol) and NIS (114 mg, 0.51 mmol) were added sequentially. The reaction mixture was heated again at 80°C for 30 minutes. The reaction mixture was then diluted with  and treated in water with NaHCO3 / water and Na2S2O3 (10%). The organic phase was separated and concentrated. The residue was purified on a silica gel column using 0-100%  / heptane to obtain 60 mg of the product as a mixture of two positional isomers (3-a and 3-b). MS (m / z): 518.06 [M+H]. These two positional isomers were not separated and proceeded to the next step. Step 3: (6R)-1-(benzyloxy)-10-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-a) (6R)-1-(benzyloxy)-9-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-b) (6S)-1-(benzyloxy)-10-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-c) Preparation of (6S)-1-(benzyloxy)-9-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-d).

[0252] 1-(benzyloxy)-10-fluoro-3-iodo-7 in DMSO (2 ml) To a solution of a mixture of 12-dihydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-2,14-dione(3-a) and 1-(benzyloxy)-9-fluoro-3-iodo-7,12-dihydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-2,14-dione(3-b) (32 mg, 0.062 mmol), 2,4,6-trifluorobenzylamine (50 mg, 0.309 mmol), DIPEA (40 mg, 0.309 mmol), and Pd(PPh3)4 (3.57 mg, 0.00309 mmol) were added. The reaction mixture was bubbling with CO(g) for 10 minutes. The reaction mixture was then heated at 80°C for 17 hours under a CO atmosphere. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was treated with 0.05 N HCl. The organic phase was separated and treated with saturated sodium bicarbonate solution and saline solution. The organic phase was then dried over Na2SO4 and concentrated. The residue was purified by silica gel column using 0-100% RINKAN in hexane to obtain the desired product. A mixture of these four isomers was subjected to SFC separation (ADH 50 IPA-NH3) to obtain the four isomers in order of shortest retention time: (6R)-1-(benzyloxy)-10-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-a) 10 mg. MS(m / z): 579.08[M+H], (6R)-1-(benzyloxy)-9-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-b) 6mg. MS(m / z): 579.08[M+H], (6S)-1-(benzyloxy)-10-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-c) 7mg.MS(m / z): 579.03[M+H], and (6S)-1-(benzyloxy)-9-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-d)4mg. MS(m / z): 579.02[M+H]. Step 4: Preparation of (6R)-10-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(C1).

[0253] (6R)-1-(benzyloxy)-10-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide (4-a) (10 mg, 0.0173 mmol) was dissolved in toluene (0.5 ml) at room temperature. TFA (0.5 ml) was added all at once. The reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated to dryness. The residue was incorporated into MeOH and purified by reverse-phase preparative HPLC using 0-100% CH3CN in water containing 0.1% TFA to obtain the desired product. The product was obtained as a TFA salt by lyophilization. MS(m / z):489.26[M+H] + . 1 H NMR (400MHz, acetonitrile-d3) δ10.13(s,1H),8.52(s,1H),7.41-7.22(m,1H),7.13(d,J=9.3Hz,1H),7.04(t,J=8.6Hz,1H),6.88(t ,J=8.6Hz,2H),5.56(d,J=16.7Hz,1H),4.87-4.69(m,2H),4.64(d,J=5.7Hz,2H),4.55(d,J=15.3Hz,2H),4.13(d,J=13.2Hz,1H) (6R)-9-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo Preparation of [g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide (C2):

[0254] The product was synthesized in the same manner as in (C1), except that (6R)-9-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-b) was used as the starting material instead of (6R)-1-(benzyloxy)-10-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-b) (4-b) instead of (6R)-9-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-b) (4-b) (4-a). The product was obtained as the TFA salt. MS(m / z):489.14[M+H] + . 1 H NMR(400MHz,acetonitrile-d3)δ10.14(s,1H),8.54(d,J=17.3Hz,1H),7.36(dd,J=8.4,5.7Hz,1H),7.23-6.98(m,2H),6.88(t,J=8.5Hz,2H ),5.51(d,J=16.5Hz,1H),4.81(p,J=14.7,14.0Hz,2H),4.64(d,J=5.4Hz,2H),4.56(dd,J=15.0,10.4Hz,2H),4.20(d,J=13.6Hz,1H). Preparation of (6S)-10-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(C3).

[0255] The product was synthesized in the same manner as in (C1), except that (6S)-10-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-c) was used as the starting material instead of (6R)-1-(benzyloxy)-10-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-c) instead of (6R)-1-(benzyloxy)-10-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-c) as the starting material. The product was obtained as the TFA salt. MS(m / z):489.18[M+H] + . 1 ¹H NMR (400MHz, acetonitrile-d3) δ 10.13 (s, 1H), 8.52 (s, 1H), 7.32 (dd, J=8.4, 5.8Hz, 1H), 7.23-7.08 (m, 1H), 7.08-6.97 (m, 1H), 6.88 (t, J=8.5Hz, 2H), 5.56 (d, J=16.7Hz, 1H), 4.83-4.69 (m, 2H), 4.64 (d, J=5.7Hz, 2H), 4.58-4.49 (m, 2H), 4.13 (d, J=13.3Hz, 1H). Preparation of (6S)-9-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(C4):

[0256] The product was synthesized in the same manner as in (C1), except that (6S)-9-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-d) was used as the starting material instead of (6R)-1-(benzyloxy)-10-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-d) instead of (6R)-9-fluoro-1-hydroxy-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazonine-3-carboxamide(4-d) as the starting material. The product was obtained as the TFA salt. MS(m / z):489.19[M+H] + . 1 ¹H NMR (400 MHz, acetonitrile-d3) δ 10.14 (s, 1H),8.53(d,J=14.2Hz,1H),7.36(dd,J=8.5,5.7Hz,1H),7.28-7.01(m,2H),6.88(t,J=8.6Hz,2H),5.51(d,J= 16.3Hz,1H),4.79(q,J=14.5Hz,2H),4.71-4.60(m,2H),4.56(dd,J=15.0,10.3Hz,2H),4.20(d,J=13.6Hz,1H). Example 5: Preparation of (10S)-6-hydroxy-10-methyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide (C5): [ka] Step 1: Synthesis of methyl 1-(allyl(tert-butoxycarbonyl)amino)-3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (5):

[0257] To a suspension of methyl 3-benzyloxy-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyran-2-carboxylate (2.0 g, 4.47 mmol) in a mixture of MeOH (48.0 mL) and water (8.0 mL), tert-butyl N-allyl-N-amino-carbamate (0.77 g, 4.47 mmol) and sodium bicarbonate (3.76 g, 44.7 mmol) were added. The resulting mixture was stirred overnight at room temperature. Water (15.0 mL) was added to the reaction mixture, and the mixture was stirred for 10 minutes. The suspension was filtered, and the filter cake was then partitioned into ethyl acetate and water. The aqueous layer was extracted with RINKAN (x2), the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain the desired product, which was sent directly to the next step. LCMS-ESI+(m / z):C 30 H 30 The calculated H+ value for F3N3O7 is 601.20 (theoretical value) and 601.99 (measured value). Step 2: Synthesis of tert-butyl N-allyl-N-[3-benzyloxy-2-[[(1S)-1-methylallyl]carbamoyl]-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]-1-pyridyl]carbamate (443-int-2) and 1-(allylamino)-3-benzyloxy-N2-[(1S)-1-methylallyl]-4-oxo-N5-[(2,4,6-trifluorophenyl)methyl]pyridine-2,5-dicarboxamide (6):

[0258] Methyl 1-(allyl(tert-butoxycarbonyl)amino)-3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (5, 2.3 g, 3.82 mmol) was dissolved in a mixture of MeOH (24.0 mL), THF (12.0 mL), and water (12.0 mL). Lithium hydroxide monohydrate (1.28 g, 30.6 mmol) was added to this mixture. The resulting mixture was heated at 60°C for 3 hours with stirring. The reaction product was left at room temperature. The solution was cooled and concentrated. The residue was diluted with dimethyl sulfate, acidified to approximately pH 4 with a 1N HCl aqueous solution, the organic layer was washed with saline solution, dried over sodium sulfate, filtered, and concentrated.

[0259] Next, the residue was dissolved in DCM (17.0 mL) at room temperature and treated with EDCI.HCl (975 mg, 5.11 mmol), followed by HOAt (695 mg, 5.11 mmol) and DIEA (1.76 g, 13.6 mmol). Then, (2S)-buta-3-en-2-amine HCl (315 mg, 4.43 mmol) was added. The newly formed mixture was stirred overnight at room temperature. The reaction product was then diluted with DCM, washed with saturated NH4Cl aqueous solution and brine, dried over sodium sulfate, filtered, concentrated, the residue was mixed with silica gel, concentrated to dryness, and purified with combiflash® (24 g silica gel, 0%~100% toluene / hexane). Combine the desired fractions and concentrate to obtain tert-butyl N-allyl-N-[3-benzyloxy-2-[[(1S)-1-methylallyl]carbamoyl]-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]-1-pyridyl]carbamate(6)(LCMS-ESI+(m / z):C 33 H 35 The calculated H+ values ​​for F3N4O6 (theoretical value: 640.25, measured value: 641.05) and 1-(allylamino)-3-benzyloxy-N2-[(1S)-1-methylallyl]-4-oxo-N5-[(2,4,6-trifluorophenyl)methyl]pyridine-2,5-dicarboxamide (7) (LCMS-ESI+(m / z):C28H27F3N4O4, calculated H+ values: theoretical value: 540.20, measured value: 541.02) were obtained.

[0260] Next, a solution of compound 6 (1.0 g) in DCM (10.0 mL) was treated with 4N HCl in 1,4-dioxane (10.0 mL, 40.0 mmol) at room temperature for 1 hour to convert compound 6 to compound 7. The reaction product was concentrated and co-evaporated with HCl × 3. The residue was then dissolved in MeOH (20 mL), NaHCO3 (solid) was added, the mixture was stirred for 15 minutes, filtered, the filtrate was concentrated, and the mixture was re-purified with combiflash® to obtain compound 7. Step 3: Synthesis of 1-allyl-5-hydroxy-3-[(1S)-1-methylallyl]-4,6-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide (8) and 1-allyl-5-benzyloxy-3-[(1S)-1-methylallyl]-4,6-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide (9):

[0261] 1-(allylamino)-3-benzyloxy-N2-[(1S)-1-methylallyl]-4-oxo-N5-[(2,4,6-trifluorophenyl)methyl]pyridine-2,5-dicarboxamide (7) (350 mg, 0.647 mmol) was dissolved at room temperature in a mixture of ACN (3.5 mL) and DCE (3.5 mL). Paraformaldehyde (58.4 mg, 0.647 mmol) was added to this mixture. The resulting mixture was heated to 88°C. Acetic acid (0.35 mL) was added dropwise to the hot mixture, followed by TFA (0.15 mL). The reaction mixture was covered and heated for a further 30 minutes. The reaction mixture was cooled to room temperature, diluted with ethyl acetate, and basicized to approximately pH 7 with saturated NaHCO3. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified using combiflash® (12g silica gel, 0-100% siRNA, dry packing) to obtain the desired 1-allyl-5-benzyloxy-3-[(1S)-1-methylallyl]-4,6-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide (9) LCMS-ESI+(m / z):C29H27F3N4O4. The calculated H+ values ​​were theoretical: 552.20, experimental: 552.93. The debenzylated form (8) was also isolated. The calculated H+ values ​​were theoretical: 462.15, experimental: 463.02.

[0262] Compound 8 (120 mg, 0.26 mmol) in DMF (2.6 mL) was converted back to compound 9 by treating it overnight at room temperature with benzyl bromide (46.6 mg, 0.272 mmol) and cesium carbonate (101 mg, 0.31 mmol). The reaction mixture was diluted with siRNA, washed with water and brine, dried over sodium sulfate, filtered, mixed with silica gel, concentrated to dryness, and purified with combiflash® (4 g silica gel, 0-100% siRNA / hexane) to obtain compound 9. LCMS-ESI+(m / z): Calculated H+ value of C29H27F3N4O4, theoretical value: 552.20, experimental value: 552.92. Step 4: Synthesis of (10S)-6-benzyloxy-10-methyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide (10):

[0263] Compound 9 (130 mg, 0.23 mmol) was dissolved in DCM (29 mL), and Hoveyda-Grubbs II catalyst (36.9 mg, 0.059 mmol) was added to this mixture. The resulting mixture was sparged with nitrogen for 5 minutes, then covered and heated overnight at 70°C. The reaction product was then cooled to room temperature, concentrated, and purified by normal-phase chromatography (12 g silica gel, 0-100% toluene / hexane). LCMS-ESI+(m / z): Calculated H+ value of C27H23F3N4O4, theoretical value: 524.17, experimental value: 524.91. Step 5: Synthesis of (10S)-6-hydroxy-10-methyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide (C5):

[0264] Compound 10 (8 mg, 0.015 mmol) was dissolved in DCM (1.0 mL) at room temperature and treated with TFA (1.0 mL) at room temperature for 3 hours. The reaction product was concentrated, redissolved in DMF, filtered, and purified by reverse-phase preparative HPLC. LCMS-ESI+(m / z):Calculated H+ value of C20H17F3N4O4, theoretical value: 434.12, experimental value: 435.19. 1H NMR(400MHz,DMSO-d6)δ10.34(t,J=5.8Hz,1H),8.32(s,1H),7.26-7.17(m,2H),5.75-5.66(m,1H),5.46(ddt,J=12.0,6.2,3.3Hz,1H),5.34- 5.22(m,1H),4.92(d,J=14.4Hz,1H),4.72(d,J=14.4Hz,1H),4.65-4.50(m,3H),4.27-4.17(m,1H),3.70-3.62(m,1H),1.29(d,J=7.3Hz,3H). Example 6: Preparation of 13-benzyl-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C6): [ka] Step 1: Synthesis of methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate:

[0265] In a reactor, tert-butyl N-aminocarbamate (390 mg, 2.95 mmol) and NaHCO3 (451 mg, 5.4 mmol) in MeOH / water (9 ml / 6 ml) were added, followed by the addition of methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate (1200 mg, 2.68 mmol). The reaction mixture was heated at 60°C overnight. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (100 ml). The organic layer was concentrated under vacuum. The residue was used in the next step without purification. MS (m / z) 562.064 [M+H] + . Step 2: Synthesis of 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid:

[0266] A 2.5N solution of LiOH (2 ml) was added to the above residue in MeOH (6 ml) at room temperature. After 2 hours at room temperature, the reaction product was acidified with 2N HCl and extracted with ethyl acetate (100 ml). The organic layer was concentrated under vacuum. The residue was used in the next step of the reaction without purification. MS (m / z) 547.96 [M+H] + . Step 3: Synthesis of tert-butyl(3-(benzyloxy)-2-carbamoyl-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridine-1(4H)-yl)carbamate:

[0267] To a solution of 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid (1720 mg, 3.14 mmol) in DMF (12 ml), EDC (1205 mg, 6.28 mmol), HOBt (722 mg, 4.7 mmol), DIPEA (4060 mg, 31.4 mmol), and ammonium chloride (1680 mg, 31.4 mmol) were added at room temperature. After stirring overnight at room temperature, the reaction mixture was diluted with ethyl acetate (100 ml) and washed with brine. The organic layer was dried over MgSO4 and concentrated under vacuum. The resulting residue was purified by column chromatography. MS (m / z) 547.029 [M+H] + ¹H NMR (400MHz, chloroform-d) δ 10.12 (t, J=5.7Hz, 1H), 8.58 (s, 1H), 8.50 (s, 1H), 7.37 (dq, J=4.1, 3.0, 2.4Hz, 5H), 6.70 (d d,J=8.7,7.5Hz,3H),5.84(s,1H),5.33(d,J=4.5Hz,3H),4.68(d,J=5.7Hz,2H),1.45(s,9H).

[0268] Step 4: Synthesis of 1-amino-3-(benzyloxy)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1,4-dihydropyridine-2,5-dicarboxamide: To a solution of 1-amino-3-(benzyloxy)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1,4-dihydropyridine-2,5-dicarboxamide (200 mg, 0.366 mmol) in DCM (6 ml), TFA (0.5 ml) was added at room temperature. After stirring at room temperature for 2 hours, the solvent and excess TFA were removed under vacuum. The resulting residue was used in the next step of the reaction without purification. MS (m / z) 447.075 [M+H] + . Step 5: Synthesis of 2-benzyl-5-(benzyloxy)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide:

[0269] To a solution of 1-amino-3-(benzyloxy)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1,4-dihydropyridine-2,5-dicarboxamide (165 mg, 0.37 mmol) in DMF (2 ml), AcOH (2 ml) and 2-phenylacetaldehyde (44 mg, 0.37 mmol) were added at room temperature. After heating at 100 °C for 2 hours, the DMF and excess AcOH were removed under vacuum. The remaining residue was purified by column chromatography. MS (m / z) 549.065 [M+H] + . Step 6: Synthesis of 13-benzyl-8-(benzyloxy)-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0270] Solid KOH (106 mg, 1.9 mmol) was suspended in 12 ml of DMF, and a mixture of 2-benzyl-5-(benzyloxy)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide (129 mg, 0.235 mmol) and 1,4-dibromobutane (56 mg, 0.26 mmol) in 10 ml of DMF was added over 2 hours at 0°C using a syringe pump. The reaction mixture was extracted with ethyl acetate (100 ml). The organic layer was concentrated under vacuum. The residue was used in the next step without purification. MS (m / z) 601.033 [M+H] + . Step 7: Synthesis of 13-benzyl-8-hydroxy-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C6):

[0271] To a solution of crude 13-benzyl-8-(benzyloxy)-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (129 mg, 0.225 mmol) in toluene (5 ml), TFA (1 ml) was added at room temperature. After stirring overnight at room temperature, the solvent and excess TFA were removed. The resulting residue was purified by preparative HPLC to obtain the TFA salt of the indicated compound. MS (m / z) 513.253 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ10.37(d,J=5.9Hz,1H),9.13(s,1H),8.57(s,1H),7.28(s,5H),7.11(d,J=7.0Hz ,1H),6.69(t,J=8.3Hz,2H),4.90-4.60(m,2H),4.56-4.22(m,2H),3.58-3.24(m,2H),3.06-2.74(m,2H). Example 7: (1S,2R,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydroxy Preparation of dro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C7) [ka] Step 1: Synthesis of methyl(R)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(penta-4-en-2-yl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (7A):

[0272] Diisopropyl azodicarboxylate (2.45 mL, 12.5 mmol) was added to a reaction mixture of methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (3.5 g, 6.23 mmol), (2S)-penta-4-en-2-ol (805 mg, 9.35 mmol), and triphenylphosphine (3.27 g, 12.5 mmol) in 7 mL of THF. The resulting reaction mixture was stirred at room temperature for 30 minutes and concentrated under vacuum. The residue was subjected to chromatography on silica gel eluted with siRNA / hexane to obtain the labeled product. MS (m / z) 630.10 [M+H]+. Step 2: Synthesis of (R)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(penta-4-en-2-yl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid (7B):

[0273] Methyl(R)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(penta-4-en-2-yl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (7A, 3.17 g, 5.04 mmol) was dissolved in MeOH (20 mL), THF (30 mL), and water (10 mL). Lithium hydroxide monohydrate (1.05 g, 25.2 mmol) was added. The reaction mixture was stirred overnight at room temperature. It was diluted with ethyl acetate, acidified to approximately pH 4 with 1 N HCl, the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain the labeled product. MS (m / z): 616.20 [M+H]+. Step 3: Synthesis of tert-butyl(3-(benzyloxy)-2-(((S)-buta-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridine-1(4H)-yl)((R)-penta-4-en-2-yl)carbamate(7C):

[0274] (R)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(penta N,N-diisopropylethylamine (2.38 mL, 13.6 mmol) was added to a reaction mixture in DCM (34 mL) of (2S)-buta-3-en-2-amine hydrochloride (477 mg, 4.43 mmol), EDCI.HCl (977 mg, 5.12 mmol), and HOAt (696 mg, 5.12 mmol). The reaction mixture was stirred at room temperature for 30 minutes, diluted in DCM, washed with saturated NH4Cl and saline, dried over sodium sulfate, filtered, and concentrated. The residue was subjected to chromatography on silica gel eluted with siRNA to obtain the labeled product. MS(m / z):669.83[M+H]+. Step 4: Synthesis of (2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-11-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,6,7,8,10-hexahydro-1H-pyrido[1,2-b][1,2,5]triazesin-1-carboxylate (7D):

[0275] A solution of tert-butyl(3-(benzyloxy)-2-(((S)-buta-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridine-1(4H)-yl)((R)-penta-4-en-2-yl)carbamate (7C, 1.0 g, 1.5 mmol) and a second-generation Grubbs catalyst (63.5 mg, 0.075 mmol) in 500 ml of toluene was purged with Ar gas for 30 minutes. The resulting solution was heated in an oil bath at 80°C for 5 hours. The reaction mixture was concentrated, and the residue was purified by column chromatography using silica gel eluted with ethyl in hexane to obtain the labeled product. MS (m / z): 641.29 [M+H]+. Step 5: Synthesis of (2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,6,7,8,10-hexahydro-1H-pyrido[1,2-b][1,2,5]triazesin-11-carboxamide(7E):

[0276] tert-butyl(2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-11-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,6,7,8,10-hexahydro-1H-pyrido[1,2-b][1,2,5]triazecin-1-carboxylate (7D, 170 mg, 0.265 mmol) was dissolved in DCM (5 ml) and treated with 4N HCl (3 ml) in 1,4-dioxane at room temperature for 3 hours. Then, an additional 4N HCl (2 mL) in 1,4-dioxane was added and the mixture was stirred at room temperature for 2 hours. After concentration to dryness, the residue was dissolved in ELISA and washed with saturated NaHCO3 and brine. The organic layer was dried over MgSO4, filtered, concentrated to dryness, and then dried under high vacuum to obtain the labeled product. MS(m / z): 541.24[M+H]+. Step 6: Synthesis of (1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide(7F):

[0277] In an 8 mL sample vial, (2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,6,7,8,10-hexahydro-1H-pyrido[1,2-b][1,2,5]triazecin-11-carboxamide (7E, 50 mg, 0.093) and paraformaldehyde (6.1 mg, 2.2 equivalents based on MW:30) were mixed with acetonitrile (1.25 mL) and DCE (1.25 mL) at room temperature, the vial was capped, and immediately placed on a hot plate preheated to 88°C. AcOH (0.25 mL, 10% in acetonitrile) was added dropwise to it. Next, TFA (0.25 mL, 10% in DCE) was added dropwise. The resulting reaction mixture was then heated for 30 minutes. After cooling to room temperature, it was poured into a well-stirred two-phase mixture of siRNA-NaHCO3 (aqueous solution). The organic phase was separated. The aqueous layer was extracted once with siRNA. The combined organic phases were washed with saline solution, dried over Na2SO4, and filtered. The residue was concentrated to dryness and purified by RP-HPLC to obtain the labeled product. MS (m / z): 553.17 [M+H]+. Step 7: Synthesis of (1S,2R,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (C7):

[0278] (1S,2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (7F, 30 mg, 0.054 mmol) was dissolved in 2 mL of toluene, and 2 mL of TFA was added. The mixture was stirred at room temperature for 40 minutes. The solvent was removed, and the compound was purified by RP-HPLC to obtain the marked compound. The structure was confirmed by X-ray crystallography. MS(m / z):463.20[M+H]+. 1 H NMR (400MHz, acetonitrile-d3) δ10.42(s,1H),8.42(s,1H),6.94-6.81(m,2H),5.75-5.60(m,2H),5.20(q,J=7.1,6.7Hz,1H),4.82 -4.56(m,4H),3.59(p,J=6.9Hz,1H),2.39(dd,J=15.5,7.3Hz,1H),2.06(ddd,J=16.7,7.9,5.5Hz,1H),1.29(t,J=7.3Hz,6H). Example 8: Preparation of (1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C8): [ka]

[0279] (1S,2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (7F, 35 mg, 0.063 mmol) was dissolved in 3 mL of ethanol and 3 mL of ELISA and sparged under an argon atmosphere. Palladium carbon (10% by weight, wet) (13.5 mg) was added, and the mixture was sparged under a hydrogen atmosphere (1 atm, balloon). The mixture was vigorously stirred for 2 hours and then sparged under an argon atmosphere. It was filtered through a Celite® pad. The Celite® was washed with anhydrous ethanol, the filtrate was concentrated to dryness, and the residue was purified by RP-HPLC to obtain the labeled product. MS(m / z):465.200[M+H]+. 1 ¹H NMR (400MHz, acetonitrile-d3) δ 10.37 (s, 1H), 8.32 (s, 1H), 6.94-6.81 (m, 2H), 4.87 (d, J=14.3Hz, 1H), 4.71-4.59 (m, 3H), 4.39 (tt, J=11.5, 6.6Hz, 1H), 2.95 (dq, J=8.6, 6.3Hz, 1H), 2.10-1.97 (m, 2H), 1.87-1 .72(m,2H),1.63-1.49(m,1H),1.30(q,J=12.0Hz,1H),1.13(dd,J=14.3,6.5Hz,6H). Example 9: Preparation of (1'S,5'S)-8'-hydroxy-5,5,5'-trimethyl-7',9'-dioxo-N-(2,4,6-trifluorobenzyl)-4,5,7',9'-tetrahydro-2H,5'H-spiro[furan-3,2'-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10'-carboxamide (C9). [ka]

[0280] (1'S,5'S)-8'-hydroxy-5,5,5'-trimethyl-7',9'-dioxo-N-(2,4,6-trifluorobenzyl)-4,5,7',9'-tetrahydro-2H,5'H-spiro[furan-3,2'-[1,6]methanopyrido[1,2-b][1,2,5]triazonine]-10'-carboxamide was prepared using the same method as in Example 84, except that 5,5-dimethyltetrahydrofuran-3-carbaldehyde was used instead of tetrahydrofuran-3-carbaldehyde in step 1, and only one product was isolated from the ring-closing metathesis reaction in step 9. 1H NMR (400MHz, methanol-d4) δ8.79(s,1H),6.91(t,J=8.4Hz,2H),6.01(dd,J=11.9,2. 3Hz,1H),5.49(dd,J=12.0,2.8Hz,1H),5.19(d,J=14.7Hz,1H),5.01(d,J=14.7Hz, 1H),4.67(s,2H),4.37(dt,J=7.5,2.6Hz,1H),3.73-3.61(m,2H),2.52(dd,J=13. 5,1.6Hz,1H),2.07-1.94(m,1H),1.87(d,J=7.4Hz,3H),1.56(s,3H),1.34(s,3H). Examples 10 and 11: Preparation of (1R,2R,Z)-N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (C10) and (1S,2R,Z)-N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (C11): [ka]

[0281] In step 1, methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate is used instead of methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylate, and in step 3, allylamine hydrochloride is used instead of (2S)-buta-3-en-2-amine hydrochloride, (2R, Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (9A) was prepared in the same manner as (1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (7F in Example 7). MS(m / z): 521.20[M+H]+.

[0282] The individual diastereomers (10B and 11A) were separated by preparative SFC chromatography on an IA column using ethanol as a cosolvent. The separated diastereomers were dissolved in 1 mL of toluene and 1 mL of TFA and stirred at room temperature for 1 hour. After concentration, the mixture was purified by RP-HPLC eluting with ACN / water (0.1% TFA) to obtain the labeled compounds C10 and C11.

[0283] Peak 1: (1R,2R,Z)-N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide(C10):MS(m / z):431.20[M+H]+. 1 H NMR (400MHz, acetonitrile-d3) δ10.37(s,1H),8.35(s,1H),7.44(d,J=7.4Hz,1H ),6.96(d,J=9.8Hz,2H),5.83(q,J=9.7,8.6Hz,1H),5.66-5.58(m,1H),5.15 (d,J=13.8Hz,1H),4.94(d,J=17.8Hz,1H),4.68-4.57(m,3H),3.55-3.38(m, 2H), 2.25(dt,J=16.7,8.5Hz,1H),1.97-1.86(m,1H),1.15(d,J=6.9Hz,3H).

[0284] Peak 2: (1S,2R,Z)-N-(2,4-difluorobenzyl)-9-hydrox C-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide(C11):MS(m / z):431.20[M+H]+. 1¹H NMR (400MHz, acetonitrile-d3) δ 10.41 (s, 1H), 8.44 (s, 1H), 7.44 (q, J=8.8, 8.3Hz, 1H), 6.97 (tt, J=10.8, 3.1Hz, 2H), 5.79-5.64 (m, 2H), 4.98-4.88 (m, 2H), 4.69-4.58 (m, 3H), 3.61 (t, J=6.7Hz, 1H), 3.53 (dd, J=18.0, 4.0Hz, 1H), 2.42 (dd, J=15.4, 7.1Hz, 1H), 2.16-2.03 (m, 1H), 1.29 (d, J=7.1Hz, 3H). Example 12: Preparation of (1R,2S,6R,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C12) [ka]

[0285] Compound 12 was prepared in the same manner as (1S,2R,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C7 in Example 7), by using (2R)-penta-4-en-2-ol instead of (2S)-penta-4-en-2-ol in step 1, and (2R)-penta-3-en-2-amine hydrochloride instead of (2S)-penta-3-en-2-amine hydrochloride in step 3. MS(m / z):431.20[M+H]+. 1 ¹H NMR (400MHz, acetonitrile-d3): δ 10.43 (s, 1H), 8.42 (s, 1H), 6.94-6.81 (m, 2H), 5.75-5.60 (m, 2H), 5.20 (q, J=7.5Hz, 1H), 4.84-4.53 (m, 4H), 3.58 (q, J=6.9Hz, 1H), 2.39 (dd, J=15.2, 7.2Hz, 1H), 2.12-2.00 (m, 1H), 1.29 (t, J=7.3Hz, 6H). Example 13: Preparation of (1S,2R)-N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C13): [ka]

[0286] (2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carbocyanide Compound 13 was prepared in the same manner as (1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (C8) in Example 8, using (1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (C8). MS(m / z):433.20[M+H]+. 1 H NMR (400MHz, acetonitrile-d3) δ10.39(s,1H),8.34(s,1H),7.57-7.20(m,1H),7.03-6 .91(m,2H),4.86(d,J=14.3Hz,1H),4.78(d,J=14.6Hz,1H),4.60(d,J=5.6Hz,2H) ,4.14(dd,J=13.4,5.9Hz,1H),3.39-2.97(m,2H),1.97-1.87(m,2H),1.75(d,J=6 .5Hz,1H),1.63(dt,J=16.9,9.1Hz,1H),1.55-1.20(m,2H),1.17(d,J=6.5Hz,3H). Example 14: Preparation of (1R,2S,6R)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C14): [ka]

[0287] (1R,2S,6R,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide(7F) is replaced with (1R,2S,6R,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide(7F) Compound 14 was prepared using hydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide in the same manner as (1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (C8) in Example 8. MS(m / z):465.20[M+H]+. 1 H NMR (400MHz, acetonitrile-d3) δ 10.37 (s, 1H), 8.32 (s, 1H), 6.94-6.81 (m, 2H), 4.87 (d, J=14.3Hz, 1H), 4.74-4.58 (m, 3H), 4.39 (ddd, J=11.8, 6.7, 4.8Hz, 1H), 3.01-2.89 (m, 1H), 2.07-1.97 (m, 1H), 1.87-1.72 (m, 2H), 1.56 (dt, J=16.6, 10.1Hz, 1H), 1.30 (q, J=12.0Hz, 1H), 1.13 (dd, J=14.5, 6.5Hz, 6H). Example 15: Preparation of (1R,2R)-N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C15): [ka]

[0288] (1R,2R,Z)-N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide(7F) is replaced with (1R,2R,Z)-N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro Compound 15 was prepared using -2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (10) in the same manner as (1R,2R,Z)-N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (C8) in Example 8. MS(m / z):433.20[M+H]+. 1 H NMR (400MHz, acetonitrile-d3) δ11.50(s,1H),10.41(s,1H),8.32(d,J=16.7Hz,1H),7.49-7.38(m, 1H),6.97(ddt,J=13.4,8.5,3.0Hz,2H),5.13(d,J=14.1Hz,1H),4.80(t,J=14.9Hz,1H),4.60( d,J=6.0Hz,2H),4.22(dt,J=13.8,4.6Hz,1H),3.57(p,J=7.2Hz,1H),3.02(ddd,J=14.0,10.1, 4.2Hz,1H), 1.96(d,J=2.5Hz,3H),1.70-1.55(m,1H),1.53-1.16(m,2H),1.13(d,J=7.0Hz,3H). Example 16: Preparation of (1S,2R,Z)-9-hydroxy-2-methyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C16): [ka]

[0289] In step 3, instead of (2S)-buta-3-en-2-amine hydrochloride, allylamine hydrochloride is used, (2R,Z)-9-(benzyloxy)-2-methyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11- Carboxamide (16A) was prepared in the same manner as (1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (7F in Example 7). MS(m / z): 539.20[M+H]+.

[0290] The individual diastereomers (peaks 1 and 2) were separated by RP-HPLC elution with acetonitrile and water (containing 0.1% TFA). Peak 2 (23 mg, 0.043 mmol) was taken and dissolved in 0.5 mL of toluene and 0.5 mL of TFA, and stirred at room temperature for 1 hour. After concentration, the solution was purified by RP-HPLC elution with ACN / water (0.1% TFA) to obtain the labeled compound. MS (m / z): 449.10 [M+H]+. 1H NMR (400MHz, acetonitrile-d3) δ10.41(s,1H),8.42(s,1H),6.87(t,J=8.7Hz,2H),5.72(q,J=11.7,9.1Hz,2H),4.92(d,J=15.7 Hz,2H),4.64(d,J=14.6Hz,3H),3.82-3.11(m,2H),2.46-2.35(m,1H),2.08(dt,J=13.7,6.3Hz,1H),1.28(d,J=7.2Hz,3H). Example 17: Preparation of (1S,2R)-9-hydroxy-2-methyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C17): [ka]

[0291] (2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide(7F) is replaced with (1S,2R,Z)-9-hydroxy-2-methyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H- Compound 17 was prepared using 1,7-methanopyride[1,2-b][1,2,5]triazesin-11-carboxamide (16) in the same manner as (1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyride[1,2-b][1,2,5]triazesin-11-carboxamide (C8) in Example 8. MS(m / z):451.20[M+H]+. 1H NMR (400MHz, acetonitrile-d3) δ10.38(s,1H),8.33(s,1H),6.94-6.81(m,2H),4.85(d ,J=14.4Hz,1H),4.76(d,J=14.5Hz,1H),4.62(d,J=5.6Hz,2H),4.14(dt,J=14.0,7 .0Hz,1H),3.06(dt,J=13.8,4.4Hz,2H),1.93(d,J=14.4Hz,3H),1.75(t,J=8.3Hz ,1H),1.63(dt,J=16.9,8.9Hz,1H),1.44(q,J=10.1Hz,1H),1.16(d,J=6.5Hz,3H). Example 18: (1S,2R,6R,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11 - Preparation of carboxamide (C18): [ka]

[0292] In step 3, (2R)-buta-3-en-2-amine, hydrochloride is used instead of (2S)-buta-3-en-2-amine, hydrochloride to obtain (2R,6R,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]tri Azesin-11-carboxamide (18A) was prepared in the same manner as (1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (7F in Example 7). MS(m / z): 553.30[M+H]+.

[0293] The individual diastereomers (upper and lower spots) were separated by silica gel chromatography eluted with toluene / hexane. The lower spot (15 mg, 0.027 mmol) was taken and dissolved in 0.5 mL of toluene and 0.5 mL of TFA, and stirred at room temperature for 1 hour. After concentration, it was purified by RP-HPLC eluting with ACN / water (0.1% TFA) to obtain the labeled compound (18). MS (m / z): 463.20 [M+H]+. 1 H NMR (400MHz, acetonitrile-d3) δ10.38(s,1H),8.34(s,1H),6.94-6.81(m,2H),5.85 -5.72(m,1H),5.53(dt,J=11.6,1.6Hz,1H),5.27(d,J=7.9Hz,1H),4.96(d,J=13 .7Hz,1H),4.73(d,J=13.7Hz,1H),4.62(d,J=5.7Hz,2H),3.48-3.35(m,1H),2.2 9-2.15(m,1H),1.96-1.87(m,1H),1.27(d,J=7.4Hz,3H),1.12(d,J=7.0Hz,3H). Examples 19 and 20: Preparation of (1R,2S,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (C19) and (1S,2S,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (C20): [ka]

[0294] In step 1, (2R)-penta-4-en-2-ol was used instead of (2S)-penta-4-en-2-ol to prepare (2S,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (19A) in the same manner as (1S,2R,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (7 in Example 7). MS(m / z):463.20[M+H]+.

[0295] These were then separated into their individual diastereomers (peaks 1 and 2) by preparative SFC chromatography on an AZ column using methanol as a cosolvent.

[0296] Peak 1: (1R,2S,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide(19):MS(m / z):463.20[M+H]+. 1 ¹H NMR (400MHz, acetonitrile-d3) δ 11.45 (s, 1H), 10.38 (s, 1H), 8.33 (s, 1H), 6.94-6.81 (m, 2H), 5.85-5.72 (m, 1H), 5.53 (dt, J=11.5, 1.6Hz, 1H), 5.27 (d, J=8.0Hz, 1H), 4.96 ( d,J=13.7Hz,1H),4.72(d,J=13.6Hz,1H),4.62(d,J=5.7Hz,2H),3.48-3.35(m,1H), 2.29-2.15(m,1H),1.97-1.85(m,1H),1.27(d,J=7.4Hz,3H),1.12(d,J=7.0Hz,3H).

[0297] Peak 2: (1S,2S,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide(20):MS(m / z):463.20[M+H]+. 1 ¹H NMR (400MHz, acetonitrile-d3) δ 10.44 (s, 1H), 8.39 (s, 1H), 6.87 (t, J=8.5Hz, 2H), 5.69 (d, J=12.1Hz, 1H), 5.59 (dd, J=18.9, 9.5Hz, 1H), 4.93 (d, J=14.2Hz, 1H), 4.76-4.42 (m, 3H), 4.06 (s, 1H), 3.55 (s, 1H), 2.60 (s, 1H), 2.07 (t, J=7.4Hz, 1H), 1.81 (d, J=7.4Hz, 3H), 1.29 (d, J=7.1Hz, 3H). Example 21: Preparation of (1R,2S,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C21): [ka]

[0298] (1R,2S,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide(7F) is replaced with (1R,2S,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide(7F) Using dro-2H-1,7-methanopyrid[1,2-b][1,2,5]triazesin-11-carboxamide (C19), it was prepared in the same manner as (1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrid[1,2-b][1,2,5]triazesin-11-carboxamide (C8) in Example 8. MS(m / z):465.20[M+H]+. 1 ¹H NMR (400MHz, acetonitrile-d3) δ 10.40 (s, 1H), 8.29 (s, 1H), 6.91-6.83 (m, 2H), 4.84 (d, J=14.4Hz, 1H), 4.77 (d, J=14.5Hz, 1H), 4.69-4.51 (m, 3H), 3.57 (q, J=7.1Hz, 1H), 1.96-1.83 (m, 2H), 1.80-1.54 (m, 3H), 1.39 (dd, J=13.0, 6.2Hz, 1H), 1.18 (dd, J=7.0, 2.3Hz, 6H). Example 22: Preparation of (1S,2R,6R)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C22): [ka]

[0299] (1S,2R,6R,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide(7F) is replaced with (1S,2R,6R,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide(7F) Using dro-2H-1,7-methanopyrid[1,2-b][1,2,5]triazesin-11-carboxamide (C18), it was prepared in the same manner as (1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrid[1,2-b][1,2,5]triazesin-11-carboxamide (C8) in Example 8. MS(m / z):465.20[M+H]+. 1 ¹H NMR (400MHz, acetonitrile-d3) δ 10.41 (s, 1H), 8.28 (s, 1H), 6.87 (t, J=8.5Hz, 2H), 4.84 (d, J=14.4Hz, 1H), 4.77(d,J=14.4Hz,1H),4.65-4.52(m,3H),3.55(q,J=7.0Hz,1H),1.95-1.8 4(m,1H),1.79-1.54(m,3H),1.44-1.34(m,1H),1.18(dd,J=6.9,2.5Hz,7H). Example 23: Preparation of (1S,2S,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C23): [ka]

[0300] (2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide(7F) is replaced with (1S,2S,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro- Compound 23 was prepared using 2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (C20) in the same manner as (1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (C8) in Example 8. MS(m / z):465.20[M+H]+. 1 H NMR(400MHz,DMSO-d6)δ11.10(s,1H),10.41(t,J=5.8Hz,1H),8.28(s,1H),7.21(t,J= 8.6Hz,2H),6.53(s,0H),5.00(d,J=14.4Hz,1H),4.88(d,J=14.6Hz,1H),4.60(dd,J=1 4.6,6.0Hz,1H),4.51(dd,J=14.6,5.7Hz,1H),3.53-3.50(m,2H),2.11-1.96(m,1H),1 .76(q,J=12.1Hz,1H),1.70-1.61(m,2H),1.53(d,J=6.9Hz,5H),1.32(d,J=7.1Hz,3H). Example 24. Preparation of (1S,2R,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C24): Step 1: Preparation of methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate. [ka]

[0301] Methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate (60.0 g, 134 mmol, 1.00 equivalent) was mixed with MeOH (300 mL) and H2O (60.0 mL). BocNHNH2 (19.5 g, 147 mmol, 1.10 equivalent) and NaHCO3 (22.5 g, 268 mmol, 10.4 mL, 2.00 equivalent) were added at room temperature. The reaction mixture was then stirred at 55°C for 16 hours. The reaction mixture was placed under vacuum to remove most of the MeOH. The resulting residue was diluted with H2O (200 mL), and the crude product was extracted with ELISA (1500 mL). The organic layer was washed with saline (500 mL), dried over Na2SO4, and concentrated under vacuum. The obtained slurry was purified by silica gel chromatography using petroleum ether:ethyl acetate in a 5:1 ratio to obtain the product. MS(m / z): 562.5[M+H]+. Step 2: Preparation of methyl 3-(benzyloxy)-1-(buta-3-en-2-yl(tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate. [ka]

[0302] Methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (5 g, 8.9 mmol) was dissolved in THF (100 mL) at room temperature. The solution was cooled to 0°C under argon. Buta-3-en-2-ol (963 mg, 13.4 mmol) and Ph3P (3.5 g, 13.4 mmol) were added sequentially. Then, DIAD (2.7 g, 13.4 mmol) was added dropwise over 5 minutes. The resulting reaction mixture was stirred at 0°C for 5 minutes. The cold bath was removed. The reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated to dryness. The residue was purified on a silica gel column using 0-100% Âx to obtain the product. MS(m / z):616.0[M+H]+. Step 3: Preparation of 3-(benzyloxy)-1-(buta-3-en-2-yl(tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid. [ka]

[0303] Methyl 3-(benzyloxy)-1-(but-3-en-2-yl(tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl) Rubamoyl)-1,4-dihydropyridine-2-carboxylate (5.4 g, 8.9 mmol) was mixed with MeOH (125 mL) and water (100 mL) at room temperature. LiOH (5 M in water) (11 mL) was added. An air condenser was attached, and the reaction mixture was heated to 73 °C for 3.5 hours with stirring. Further LiOH (5 M) (2 mL) was added. The reaction mixture was then stirred at 40 °C for 17 hours. The reaction mixture was carefully concentrated to remove the MeOH. The residue was diluted, rinsed with some water, and acidified to pH=3 with 1 N HCl. ELISA (200 mL) was added for extraction. The organic phase was separated. The aqueous layer was extracted with further ELISA (100 mL). The combined organic phase was washed with water and saline, dried over Na₂SO₄, filtered, and concentrated to obtain the product. MS (m / z): 602.0 [M + H]+. Step 4: Preparation of tert-butyl(3-(benzyloxy)-2-(((S)-buta-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridine-1(4H)-yl)(buta-3-en-2-yl)carbamate [ka]

[0304] 3-(benzyloxy)-1-(buta-3-en-2-yl(tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid (4.75 g, 7.9 mmol) was dissolved in DMF (20 mL) at room temperature. DIEA (6.1 g, 47.4 mmol) was added. Then, (S)-buta-3-en-2-amine hydrochloride (1.27 g, 11.8 mmol) and HATU (4.5 g, 11.8 mmol) were added sequentially. The resulting reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with ELISA (100 mL) and then treated with NaHCO3 (saturated aqueous solution, 100 mL) and water (100 mL). The organic phase was separated and washed with water (50 mL) and saline solution (50 mL). The final organic phase was concentrated and the solvent was removed. The residue was purified on a silica gel column using 0-100% Âx / Hex to obtain the product. MSm / z): 655.0[M+H]+. Step 5: Preparation of 3-(benzyloxy)-N2-((S)-buta-3-en-2-yl)-1-(buta-3-en-2-ylamino)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1,4-dihydropyridine-2,5-dicarboxamide. [ka]

[0305] tert-butyl(3-(benzyloxy)-2-(((S)-buta-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridine-1(4H)-yl)(buta-3-en-2-yl)carbamate (4.42 g, 6.75 mmol) was dissolved in DCM (10 mL) at room temperature. HCl (4 M in dioxane) (10 mL) was added. The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was then concentrated to dryness. The residue was partitioned into  (100 mL) and NaHCO3 (saturated aqueous solution, 100 mL). The organic layer was separated, washed with brine, and dried over Na2SO4. The solvent was removed to obtain the product. MS (m / z): 555.3 [M+H]+. Step 6: Preparation of 5-(benzyloxy)-3-((S)-buta-3-en-2-yl)-1-(buta-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide. [ka]

[0306] 3-(benzyloxy)-N2-((S)-buta-3-en-2-yl)-1-(buta-3-en-2-ylamino)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1,4-dihydropyridine-2,5-dicarboxamide (1.845 g, 3.33 mmol) was dissolved in acetonitrile (18.45 mL) and dichloroethane (18.45 mL) at room temperature. Paraformaldehyde (200 mg, 6.66 mmol) was added. The resulting mixture was placed on a preheated 88°C hot bath. AcOH (0.9 mL) and TFA (0.9 mL) were then sequentially added to the preheated reaction mixture within 5 minutes. The resulting reaction mixture was then sealed and heated with stirring for 30 minutes. The resulting reaction mixture was then concentrated to dryness to remove all solvent and acid. Next, the obtained crude material was dissolved in DMF (17 mL). K2CO3 (2.76 g, 20 mmol) and benzyl bromide (2.56 g, 15 mmol) were added sequentially. The reaction mixture was then heated at 100 °C for 3 hours. The reaction mixture was then diluted with  (100 mL), and subsequently treated with NaHCO3 (saturated aqueous solution) (100 mL) and water (100 mL). The organic layer was separated and washed with water (50 mL) and saline solution (50 mL). The solvent was removed under vacuum. The residual crude product was purified on a silica gel column using 0-100%  / Hex to obtain the final product. MS (m / z): 567.2 [M+H]+. Step 7: (1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(A), (1S,2S,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl) Preparation of -2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (B) and (1R,2S,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C) [ka]

[0307] 5-(benzyloxy)-3-((S)-buta-3-en-2-yl)-1-(buta-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide (931 mg, 1.64 mmol) was dissolved in dichloroethane (88 mL) at room temperature. Argon was bubbling through the reaction solution for 5 minutes. Then, HG-M720 catalyst (103.4 mg, 0.164 mmol) was added with stirring. Argon purging was continued for 10 minutes. The reaction mixture was then heated under an argon atmosphere with stirring for 48 hours. The resulting reaction mixture was then concentrated to dryness. The crude material was purified on a silica gel column using 0-100% siRNA / Hex to obtain and separate three diastereomers. (1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrid[1,2-b][1,2,5]triazonine-10-carboxamide (A), 334 mg. MSm / z: 539.2 [M+H], and (1S,2S,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrid[1,2-b][1,2,5]triazonine-10-carboxamide (B), 96 mg. MSm / z: 539.2[M+H], and (1R,2S,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C), 16 mg, MS(m / z): 539.2[M+H]. The absolute configurations of these two compounds have not yet been determined. (1S,2R,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-meth Preparation of nopiride[1,2-b][1,2,5]triazonine-10-carboxamide (C24): [ka]

[0308] (1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (110 mg, 0.188 mmol) was dissolved in toluene (1 mL) at room temperature. TFA (1 mL) was carefully added with stirring. The resulting reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was then concentrated to dryness. The residue was incorporated into MeOH and purified by reverse-phase preparative HPLC using 0-100% CH3CN in water with 0.1% TFA to obtain the desired product. The product was obtained as a mono-TFA salt by lyophilization. 50 mg. MS (m / z): 449.2 [M+H]. 1H NMR (400MHz, acetonitrile-d3) δ10.21(t,J=5.9Hz,1H),8.38(s,1H),6.87(t,J=8.5Hz,2H),5.65(dt,J=11.4,2.4Hz,1H),5.47-5.27(m,2H),5.0 1(d,J=14.4Hz,1H),4.62(d,J=5.8Hz,2H),4.57(d,J=14.3Hz,1H),3.82(tp,J=6.6,3.3Hz,1H),1.35(d,J=2.0Hz,3H),1.33(d,J=2.6Hz,3H). Example 25: Preparation of (1S,2S,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C25) [ka]

[0309] (1S,2S,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (78 mg, 0.145 mmol) was dissolved in toluene (1 mL) at room temperature. TFA (1 mL) was carefully added with stirring. The resulting reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was then concentrated to dryness. The residue was incorporated into MeOH and purified by reverse-phase preparative HPLC using 0-100% CH3CN in water with 0.1% TFA to obtain the desired product. The product was obtained as a mono-TFA salt by lyophilization. 34 mg. MS (m / z): 449.2 [M+H]+. ¹H NMR (400MHz, acetonitrile-d3) δ 10.28 (s, ¹H), 8.44 (s, ¹H), 7.11-6.61 (m, ²H), 5.61 (ddd, J=12.3, 3.3, 2.1Hz, ¹H), 5.50-5.27 ( m,2H),4.93(d,J=14.4Hz,1H),4.72(d,J=14.4Hz,1H),4.66-4.53(m,3H),1.35(d,J=7.2Hz,3H),1.01(d,J=7.4Hz,3H). Example 26: Preparation of (1R,2S,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C26) [ka]

[0310] (1R,2S,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (16 mg, mmol) was dissolved in toluene (1 mL) at room temperature. TFA (1 mL) was carefully added with stirring. The resulting reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was then concentrated to dryness. The residue was purified with 0-100% ethylethanol in hexane to obtain the product in neural form. 8 mg. MS (m / z): 449.2 [M+H]+. ¹H NMR (400MHz, acetonitrile-d3): δ 10.30 (s, ¹H), 8.40 (s, ¹H), 6.97-6.77 (m, ²H), 5.80 (ddd, J=11.7, 2.7, 1.9Hz, ¹H), 5.45 (ddd, J=11.7, 4.2, 2.4Hz, ¹H), 4.81-4.69 (m, ²H), 4.65-4.59 (m, ²H), 4.32 (dtt, J=7.5, 5.0, 2.5Hz, ¹H), 4.01 (ddq, J=7.0, 4.8, 2.4Hz, ¹H), 1.79 (d, J=7.5Hz, ³H), 1.40 (d, J=7.0Hz, ³H). Example 27: Preparation of (1S,2R,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C27): [ka]

[0311] (1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (92.8 mg, 0.172 mmol) was dissolved in MeOH (10 mL). Pd-C (10%) (23 mg) was added. Hydrolysis was carried out at room temperature for 7 hours using an H2 balloon. The reaction mixture was filtered through Celite. The filtrate was collected and concentrated to dryness. The residue was incorporated into MeOH and subjected to reverse filtration using 0-100% CH3CN in water containing 0.1% TFA. The desired product was obtained by purification using phase separation HPLC. The product was obtained as mono-TFA salt by freeze-drying. 34 mg. MS (m / z): 451.3 [M+H]. ¹H NMR (400 MHz, acetonitrile-d3) δ 10.37 (s, ¹H), 8.43 (s, ¹H), 7.02-6.78 (m, ²H), 4.71-4.45 (m, ₅H), 3.51 (dq, J=7.2, 3.6 Hz, ¹H), 2.02 (ddd, J=8.2, 6.1, 3.3 Hz, ¹H), 1.78-1.66 (m, ¹H), 1.55 (dt, J=8.6, 3.3 Hz, ²H), 1.31 (d, J=7.2 Hz, ³H), 1.27 (d, J=6.8 Hz, ³H). Example 28: Preparation of (1S,2S,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C28): [ka]

[0312] (1S,2S,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (18 mg, 0.172 mmol) was dissolved in MeOH (8 mL). Pd-C (10%) (10 mg) was added. Hydrolysis was carried out at room temperature for 7 hours using an H2 balloon. The reaction mixture was filtered through Celite. The filtrate was collected and concentrated to dryness. The residue was incorporated into MeOH and purified by reverse-phase preparative HPLC using 0-100% CH3CN in water containing 0.1% TFA to obtain the desired product. The product was obtained as a mono-TFA salt by lyophilization. 7 mg. MS (m / z): 451.3 [M+H]+. 1H NMR (400MHz, acetonitrile-d3) δ10.36(s,1H),8.34(s,1H),6.98-6.77(m,2H),4.76-4.59(m,5H),3.41(dd,J=11.6,6.3Hz, 1H),2.20(dt,J=14.2,6.8Hz,1H),1.80-1.49(m,2H),1.26(d,J=6.7Hz,3H),1.30-1.17(m,1H),1.08(d,J=6.9Hz,3H). Example 29: Preparation of (1S,2R,5S)-N-(2,4-difluorobenzyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C29) Step 1: Preparation of methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylate [ka]

[0313] Methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate (15 g, 34.9 mmol) was mixed with MeOH (100 mL) and H2O (30.0 mL). BocNHNH2 (5 g, 37.8 mmol) and NaHCO3 (5.87 g, 69.9 mmol) were added at room temperature. The reaction mixture was then stirred at 55°C for 16 hours. The reaction mixture was placed under vacuum to remove most of the MeOH. The resulting residue was diluted with H2O (200 mL), and the crude product was extracted with ELISA (500 mL). The organic layer was washed with saline (500 mL), dried over Na2SO4, and concentrated under vacuum. The resulting slurry was purified by silica gel chromatography using hexane:ethyl acetate = 5:1 to obtain 18 g of product as a white solid. MS (m / z): 543.95 [M+H]. Step 2: Preparation of methyl 3-(benzyloxy)-1-(but-3-en-2-yl(tert-butoxycarbonyl)amino)-4-oxo-5-((2,4-difluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate [ka]

[0314] Methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4-difluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (10.5 g, 19.3 mmol) was dissolved in THF (200 mL) at room temperature. The solution was cooled to 0°C under argon. Buta-3-en-2-ol (2.37 g, 32.8 mmol) and Ph3P (8.6 g, 32.8 mmol) were added sequentially. Then DIAD (6.64 g, 32.8 mmol) was added dropwise over 5 minutes. The resulting reaction mixture was a slightly orange solution. It was stirred at 0°C for 5 minutes. The cold bath was removed. The reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated to dryness. The residue was purified on a silica gel column using 0-100% Â / Hex to obtain 10 g of product. MSm / z: 598.04 [M+H]. Step 3: Preparation of 3-(benzyloxy)-1-(buta-3-en-2-yl(tert-butoxycarbonyl)amino)-4-oxo-5-((2,4-difluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid [ka]

[0315] Methyl 3-(benzyloxy)-1-(but-3-en-2-yl(tert-butoxycarbonyl)amino)-4-oxo-5-((2,4-difluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (12.5 g, 20.9 mmol) was mixed with MeOH (200 mL) and water (100 mL) at room temperature. LiOH (5 M in water) (33.5 mL, 167 mmol) was added. An air condenser was attached, and the reaction mixture was heated to 63 °C for 17 hours with stirring. The reaction mixture was carefully concentrated to remove the MeOH. The residue was diluted, rinsed with some water, and acidified to pH=3 with 1 N HCl. A solid appeared. ELISA (200 mL) was added for extraction. The organic phase was separated. The aqueous layer was extracted with a further ELISA (100 mL). The combined organic phase was washed with water and saline. The solution was dried with Na2SO4, filtered, and concentrated to obtain 9 g of the acid product. MS(m / z): 584.30[M+H]. Step 4: Preparation of tert-butyl(3-(benzyloxy)-2-(((S)-buta-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4-difluorobenzyl)carbamoyl)pyridine-1(4H)-yl)(buta-3-en-2-yl)carbamate [ka]

[0316] 3-(benzyloxy)-1-(buta-3-en-2-yl(tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid (5 g, 8.56 mmol) was dissolved in DMF (40 mL) at room temperature. DIEA (5.52 g, 42.8 mmol) and the reaction mixture were cooled in an ice bath. HATU (6.52 g, 17.14 mmol) was added all at once. The reaction mixture was then warmed to room temperature with stirring for 1 hour. (S)-buta-3-en-2-amine hydrochloride (2.3 g, 21.4 mmol) was then added. The resulting reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was diluted with ELISA (200 mL) and then treated with NaHCO3 (saturated aqueous solution, 100 mL) and water (100 mL). The organic phase was separated and washed with water (50 mL) and saline solution (50 mL). The final organic phase was concentrated to remove the solvent. The residue was sufficiently pure for the next step. 4 g. MS (m / z): 637.03 [M+H]. Process 5: 3-(benzyloxy)-N2-((S)-buta-3-en-2-yl)-1 Preparation of (buta-3-en-2-ylamino)-4-oxo-N5-(2,4-difluorobenzyl)-1,4-dihydropyridine-2,5-dicarbosamide [ka]

[0317] tert-butyl(3-(benzyloxy)-2-(((S)-buta-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4-difluorobenzyl)carbamoyl)pyridine-1(4H)-yl)(buta-3-en-2-yl)carbamate (4 g, 6.29 mmol) was dissolved in DCM (10 mL) at room temperature. HCl (4 M in dioxane) (10 mL) was added. The reaction mixture was stirred at room temperature for 6 hours. The reaction mixture was then concentrated to dryness. The residue was partitioned into ELISA (100 mL) and NaHCO3 (saturated aqueous solution, 100 mL). The organic layer was separated, washed with brine, and dried over Na2SO4. The solvent was removed to obtain 3 g of product. MS (m / z): 537.17 [M+H]. Step 6: Preparation of 5-(benzyloxy)-3-((S)-buta-3-en-2-yl)-1-(buta-3-en-2-yl)-4,6-dioxo-N-(2,4-difluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide [ka]

[0318] 3-(benzyloxy)-N2-((S)-buta-3-en-2-yl)-1-(buta-3-en-2-ylamino)-4-oxo-N5-(2,4-difluorobenzyl)-1,4-dihydropyridine-2,5-dicarboxamide (2.52 g, 4.7 mmol) was dissolved in acetonitrile (25 mL) and dichloroethane (25 mL) at room temperature. Paraformaldehyde (278 mg, 9.25 mmol) was added. The resulting slurry was placed on a preheated 88°C hot bath. AcOH (1.15 mL) and TFA (1.15 mL) were then sequentially added to the preheated reaction mixture within 5 minutes. The resulting reaction mixture was then sealed and heated with stirring for 30 minutes. The resulting reaction mixture was then concentrated to dryness to remove all solvent and acid. Next, the obtained crude material was dissolved in DMF (17 mL). K2CO3 (10 g, 72.4 mmol) and benzyl bromide (6.63 g, 38.8 mmol) were added sequentially. The reaction mixture was then heated at 100 °C for 3 hours. The reaction mixture was then diluted with toluene (100 mL), and then treated with NaHCO3 (saturated aqueous solution) (100 mL) and water (100 mL). The organic layer was separated and washed with water (50 mL) and saline solution (50 mL). The solvent was removed under vacuum. Residual crude material The product was purified on a silica gel column using 0-100% Â / Hex to obtain 1 g of the product. MS (m / z): 549.2 [M+H]. Step 7: Preparation of (1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4-difluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide and (1S,2S,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4-difluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide [ka]

[0319] 5-(benzyloxy)-3-((S)-buta-3-en-2-yl)-1-(buta-3-en-2-yl)-4,6-dioxo-N-(2,4-difluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide (753 mg, 1.37 mmol) was dissolved in dichloroethane (83 mL) at room temperature. Argon was bubbling through the reaction solution for 5 minutes. Then, HG-M720 catalyst (146.4 mg, 0.233 mmol) was added with stirring. The argon purging was continued for 10 minutes. The reaction mixture was then heated under an argon atmosphere with stirring for 48 hours. The resulting reaction mixture was then concentrated to dryness. The crude material was purified on a silica gel column using 0-100% siRNA / Hex to obtain two products as single diastereomers. (1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4-difluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide, 230 mg. MS(m / z): 521.2[M+H], and (1S,2S,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4-difluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide, 15 mg. MS(m / z): 521.2[M+H]. The absolute configurations of these two compounds have not yet been determined. Step 8: Preparation of (1S,2R,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4-difluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide: [ka]

[0320] (1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide( 230 mg (0.188 mmol) was dissolved in toluene (1 mL) at room temperature. TFA (1 mL) was carefully added while stirring. The resulting reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was then concentrated to dryness. The residue was incorporated into MeOH and purified by reverse-phase preparative HPLC using 0-100% CH3CN in water containing 0.1% TFA to obtain the desired product. The product was obtained as mono-TFA salt by lyophilization. 150 mg. MS (m / z): 431.2 [M+H]. ¹H NMR (400MHz, acetonitrile-d3): δ 10.21 (s, ¹H), 8.39 (s, ¹H), 7.44 (td, J=8.8, 6.5Hz, ¹H), 7.21-6.84 (m, ²H), 5.66 (dt, J=11.4, 2.4Hz, ¹H), 5.46-5.32 (m, ²H), 5.02 (d, J=14.4Hz, ¹H), 4.67-4.50 (m, ³H), 3.84 (qq, J=6.6, 3.0Hz, ¹H), 1.35 (dd, J=7.1, 4.1Hz, ⁶H). Example 30: Preparation of (1S,2S,5S)-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4-difluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C30) [ka]

[0321] (1S,2S,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4-difluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (15 mg, 0.0288 mmol) was dissolved in toluene (1 mL) at room temperature. TFA (1 mL) was carefully added while stirring. The resulting reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was then concentrated to dryness. The residue was incorporated into MeOH and purified by reverse-phase preparative HPLC using 0-100% CH3CN in water with 0.1% TFA to obtain the desired product. The product was obtained as a mono-TFA salt by lyophilization. 5 mg. MS (m / z): 431.2 [M+H]. 1H NMR (400MHz, acetonitrile-d3) δ10.27(s,1H),8.45(s,1H),7.44(td,J=8.8,6.5Hz,1H),6.97(dddd,J=10.7,5.2,4.3,2.5Hz,2H),5.62(ddd,J=12.2,3.3 ,2.1Hz,1H),5.46-5.31(m,2H),4.94(d,J=14.4Hz,1H),4.73(d,J=14.4Hz ,1H),4.61(d,J=6.1Hz,3H),1.36(d,J=7.2Hz,3H),1.03(d,J=7.4Hz,3H). Example 31: Preparation of (1S,2S,5S)-N-(2,4-difluorobenzyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C31) [ka]

[0322] (1S,2S,5S)-N-(2,4-difluorobenzyl) in EtOH (9 mL) solution (L)-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (Example 30, 0.291 mmol, 125 mg) was discharged, argon was refilled (5 cycles), then treated with 10% Pd / C (25 mg), discharged again, argon was refilled (5 cycles), and then hydrogen was refilled (5 cycles). The reaction mixture was stirred overnight at room temperature under a hydrogen balloon, then filtered through Celite, washed with EtOH, and concentrated. The resulting residue was again dissolved in EtOH (22 mL) and treated with 10% Pd / C (50 mg) and hydrogen as described above. After 4 hours, the reaction mixture was filtered through Celite, washed with EtOH, concentrated, and then purified by preparative HPLC (10-100% MeCN in water with 0.1% TFA). The mixture was then lyophilized to obtain the marked compound as trifluoroacetate (62 mg, 39% yield). MS(m / z) 433.25[M+H]+. 1 H NMR(400MHz, methanol-d4)δ8.43(s,1H),7.43(td,J=8.5,6.4Hz,1H),7.02-6.88(m ,2H),4.85-4.76(m,2H),4.69(dt,J=10.6,6.7Hz,1H),4.63(s,2H),3.55-3.44(m ,1H),2.22(dt,J=14.2,6.8Hz,1H),1.75(dt,J=15.0,11.3Hz,1H),1.66(dd,J=1 5.7,6.9Hz,1H),1.30(d,J=6.7Hz,3H),1.36-1.20(m,1H),1.11(d,J=6.8Hz,3H). Example 32: Preparation of (1S,2R,3R,4S,5S)-8-hydroxy-3,4-dimethoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide: (C32) [ka] Preparation of (1S,2R,3R,4S,5S)-8-(benzyloxy)-3,4-dihydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0323] In a 50 mL flask, (1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (Example 24, Step 7, A) (140 mg, 0.26 mmol) was dissolved in a mixture of acetone (8 mL) and water, and then cooled to 0°C in an ice bath. 4-methylmorpholine N-oxide (50% in water, 0.1 mL, 2 equivalents) was slowly added to the reaction solution. Then, 2.5% osmium tetroxide (0.01 mL, 4% equivalent) was added. The mixture was stirred at 0°C and warmed at room temperature for 2 days. The reaction product was quenched by adding a 10% sodium sulfite aqueous solution. The reaction mixture was extracted using (1:1) HCl:n-BnOH. The organic layer was concentrated and purified via silica column (eluted with 0-10% MeOH / DCM) to obtain (1S,2R,3S,4R,5S)-8-(benzyloxy)-3,4-dihydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide( Nonpolar (by-product) and (1S,2R,3R,4S,5S)-8-(benzyloxy)-3,4-dihydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (polar, main product) were obtained. MS(m / z) 573.3[M+H] + . [ka] (1S,2R,3R,4S,5S)-8-(benzyloxy)-3,4-dimethoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide, (1S,2R,3R,4S,5S)-8-(benzyloxy)-3-hydroxy-4-methoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluoro Preparation of benzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide and (1S,2R,3R,4S,5S)-8-(benzyloxy)-4-hydroxy-3-methoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0324] In a 50 mL flask, (1S,2R,3R,4S,5S)-8-(benzyloxy)-3,4-dihydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (77 mg, 0.134 mmol) was dissolved in DMF (3 mL), and then cooled to 0°C in an ice bath. Sodium hydride (60%, 11 mg, 2.2 equivalents) was added to the reaction solution. After 10 minutes, methyl iodide (diluted 100-fold in DCM, 1 mL, 1.3 equivalents) was added. The mixture was stirred at 0°C for 30 minutes. LC-MS revealed the bis-Me product, two mono-Me products, and some starting materials. The reaction was quenched by adding saturated sodium bicarbonate aqueous solution. The reaction mixture was an extract using ethyl acetate. The organic layer was concentrated and purified by preparative HPLC eluting with 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to obtain (1S,2R,3R,4S,5S)-8-(benzyloxy)-3,4-dimethoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide MS(m / z)601.3[M+H] + , and (1S,2R,3R,4S,5S)-8-(benzyloxy)-3-hydroxy-4-methoxy-2,5-dimethyl-7, 9-Dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (polar, main mono-Me product MS(m / z) 587.3[M+H] +, and (1S,2R,3R,4S,5S)-8-(benzyloxy)-4-hydroxy-3-methoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (nonpolar, by-mono-Me product MS(m / z) 587.3[M+H] + ) obtained Preparation of (1S,2R,3R,4S,5S)-8-hydroxy-3,4-dimethoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C32): [ka]

[0325] (1S,2R,3R,4S,5S)-8-(benzyloxy)-3,4-dimethoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (15 mg) was dissolved in toluene (0.5 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by preparative HPLC elution with 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to obtain 7.2 mg of the labeled compound. MS (m / z) 511.3 [M+H] + ¹H NMR (400MHz, acetonitrile-d3) δ 10.40 (s, ¹H), 8.45 (s, ¹H), 6.99-6.80 (m, ²H), 4.70-4.59 (m, ²H), 4.52 (t, J=14.8Hz, ²H), 4.26-4.12 (m, ¹H), 3.81 (d, J=7.6Hz, ¹H), 3.61 (d, J=3.1Hz, ¹H), 3.47 (d, J=8.8Hz, ¹H), 3.36 (s, ³H), 3.09 (s, ³H), 1.48-1.25 (m, ⁶H). Example 33: Preparation of (1S,2R,4R,5S)-8-hydroxy-4-methoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C33): [ka] (1S,2R,4R,5S)-8-(benzyloxy)-4-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide and (1S,2R,3S,5S)-8-(benzyloxy)-3-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trif Preparation of ruolobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0326] In a 100 mL flask, (1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (Example 24, Step 7, A) (384 mg, 0.71 mmol) was dissolved in isopropanol (15 mL), and the mixture was purged with argon. Phenylsilane (2 equivalents) and Shenvi's catalyst (tris[(Z)-1-tert-butyl-4,4-dimethyl-3-oxo-penta-1-enoxy]manganese) (3%) were added to the reaction solution. A poxygen balloon was applied. The reaction mixture was stirred at room temperature for 1 day. LC-MS still showed the product, which was the starting material. The reaction product was quenched by adding a 10% sodium thiosulfate aqueous solution. The reaction mixture was extracted using ethyl acetate. The organic layer was concentrated and purified via silica column (eluted with 0-10% MeOH / DCM) to obtain (1S,2R,4R,5S)-8-(benzyloxy)-4-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (polar product, MS(m / z) 573.3[M+H]). + (Structure confirmed by NMR HMBC, COSY, NOE studies), and (1S,2R,3S,5S)-8-(benzyloxy)-3-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (nonpolar, MS(m / z) 573.3[M+H] + ) was obtained. [ka] Preparation of (1S,2R,4R,5S)-4,8-dihydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide: [ka]

[0327] (1S,2R,4R,5S)-8-(benzyloxy)-4-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (4 mg) was dissolved in toluene (0.2 mL), and trifluoroacetic acid (0.4 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by preparative HPLC elution with 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to obtain the marked compound. MS (m / z) 467.2 [M+H] + . 1H NMR (400MHz, acetonitrile-d3) δ10.35(s,1H),8.40(s,1H),6.87(t,J=8.5Hz,2H),4.71-4.43(m,4H),4. 36(p,J=6.8Hz,1H),3.88(dd,J=9.2,6.0Hz,1H),3.49(m,1H),1.87-1.69(m,1H),1.51-1.19(m,7H). Preparation of (1S,2R,4R,5S)-8-(benzyloxy)-4-methoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0328] In a 50 mL flask, (1S,2R,4R,5S)-8-(benzyloxy)-4-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (10 mg, 0.018 mmol) was dissolved in DMF (1 mL) and then cooled to 0°C in an ice bath. Sodium hydride (60%, 1.4 mg, 2 equivalents) was added to the reaction solution. After 10 minutes, methyl iodide (diluted 100-fold in DCM, 0.11 mL, 1 equivalent) was added. The mixture was stirred at 0°C for 30 minutes. LC-MS showed bis-Me products, with the main product being mono-Me products. The reaction was quenched by adding a saturated sodium bicarbonate solution. The reaction mixture was extracted using ethyl acetate. The organic layer was concentrated and purified by preparative HPLC elution with 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to obtain the indicated compound. MS (m / z) 571.3 [M+H] + . Preparation of (1S,2R,4R,5S)-8-hydroxy-4-methoxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C33): [ka]

[0329] (1S,2R,4R,5S)-8-(benzyloxy)-4-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]tri 4 mg of zonin-10-carboxamide was dissolved in toluene (0.2 mL), and trifluoroacetic acid (0.4 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by preparative HPLC elution with 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to obtain 1.6 mg of the labeled compound. MS (m / z) 481.2 [M+H] + . 1 H NMR (400MHz, acetonitrile-d3) δ10.33(s,1H),8.42(d,J=8.2Hz,1H),6.87(t,J=8.5Hz,2H),4.76- 4.46(m,4H),3.45(dd,J=9.0,5.4Hz,2H),3.30(s,3H),1.90-1.74(m,2H),1.55-1.21(m,7H). Example 34: Preparation of (1S,2R,4S,5S)-4-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C34): [ka] Preparation of (1S,2R,4S,5S)-8-(benzyloxy)-4-fluoro-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0330] In a 50 mL flask, (1S,2R,4R,5S)-8-(benzyloxy)-4-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (28 mg, 0.05 mmol) was dissolved in DCM (1.5 mL) and then cooled to 0°C in an ice bath. Bis(2-methoxyethyl)aminosulfur trifluoride (50% in toluene, 2.7 M, 0.037 mL, 2 equivalents) was added to the reaction solution. The mixture was stirred at 0°C for 30 minutes. LC-MS showed fluorination and elimination products. The reaction products were quenched by adding saturated sodium bicarbonate aqueous solution. The reaction mixture was extracted using ethyl acetate. The organic layer was concentrated and purified by normal-phase silica column and preparative HPLC, but separation was not achieved. The mixture was dissolved in a mixture of acetone (4 mL) and water (0.5 mL) and cooled to 0°C in an ice bath. 4-Methylmorpholine N-oxide (50% in water, 0.017 mL, 1.5 equivalents) was slowly added to the reaction solution. Then, 2.5% osmium tetroxide (0.023 mL, 4% equivalents) was added. The mixture was stirred at 0°C and warmed at room temperature for 2 days. The reaction product was quenched by adding 10% sodium sulfite aqueous solution. The reaction mixture was extracted using ethyl acetate. The organic layer was concentrated and diluted in water (0.1% TFA) for 10 minutes. The compound was purified by preparative HPLC elution with ~100% acetonitrile (0.1% TFA), followed by purification via a nonpolar product. The nonpolar product was recovered to obtain (1S,2R,4S,5S)-8-(benzyloxy)-4-fluoro-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (nonpolar). MS(m / z) 559.3[M+H] + . Preparation of (1S,2R,4S,5S)-4-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C34): [ka]

[0331] (1S,2R,4S,5S)-8-(benzyloxy)-4-fluoro-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (8 mg) was dissolved in toluene (0.2 mL), and trifluoroacetic acid (0.4 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by preparative HPLC elution with 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to obtain the marked compound. MS (m / z) 469.2 [M+H] + . 1 ¹H NMR (400MHz, acetonitrile-d3) δ10.26(s,1H),8.41(s,1H),7.01-6.75(m,2H),5.11-4.92(m,1H),4.91-4.81(m,2H),4.66-4.59(m,2H),3.49-3.34(m,1H),2.39-2.23(m,1H),1.95-1.79(m,1H),1.51,1.30(m,1H),1.45(dd,J=7.1,2.0Hz,3H),1.35(dd,J=7.2,2.9Hz,3H). Example 35: Preparation of (1S,2R,5S)-4,4-difluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide: (C35) [ka] Preparation of (1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-4,7,9-trioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0332] In a 50 mL flask, (1S,2R,4R,5S)-8-(benzyloxy)-4-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (127 mg, 0.228 mmol) was dissolved in 3 mL of DCM, and then cooled to 0°C in an ice bath. Dess-Martin periodinane (194 mg, 2 equivalents) was added to the reaction solution. The mixture was stirred at 0°C and warmed to room temperature for 2 hours. The reaction product was quenched by adding a 10% sodium thiosulfate aqueous solution. The reaction mixture was extracted using ethyl acetate. The organic layer was concentrated and purified via silica column chromatography (eluted with 0-10% MeOH / DCM) to obtain (1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-4,7,9-trioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (93 mg). MS (m / z) 555.3 [M+H] + . Preparation of (1S,2R,5S)-8-(benzyloxy)-4,4-difluoro-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0333] In a 50 mL flask, (1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-4,7,9-trioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (110 mg, 0.2 mmol) was dissolved in 5 mL of DCM, and then cooled to 0°C in an ice bath. Bis(2-methoxyethyl)aminosulfur trifluoride (50% in toluene, 2.7 M, 0.147 mL, 2 equivalents) was added to the reaction solution. The mixture was stirred at 0°C and warmed overnight at room temperature. The reaction product was quenched by adding saturated sodium bicarbonate aqueous solution. The reaction reaction was extracted using ethyl acetate. The organic layer is concentrated and eluted using a silica column (0-10% MeOH / DCM). Purified via (1S,2R,5S)-8-(benzyloxy)-4,4-difluoro-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide. MS(m / z) 577.2[M+H] + . (1S,2R,5S)-4,4-difluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide(C35 preparation:

[0334] (1S,2R,5S)-8-(benzyloxy)-4,4-difluoro-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (25 mg) was dissolved in toluene (0.5 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by preparative HPLC elution with 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to obtain the marked compound. MS (m / z) 487.2 [M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.47(s,1H),10.29(t,J=5.8Hz,1H),8.24(s,1H) ,7.31-7.16(m,2H),5.76(s,1H),5.07(d,J=15.2Hz,1H),4.91(dq,J=15.0 ,7.2Hz,1H),4.76(d,J=15.2Hz,1H),4.57(d,J=5.8Hz,2H),3.21(t,J=8.3 Hz,1H),2.83(ddd,J=32.9,16.3,10.1Hz,2H),1.33(dd,J=7.0,3.1Hz,6H). Example 36: Preparation of (1S,2R,5S)-3-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide: (C36) [ka] Preparation of (1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-3,7,9-trioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0335] In a 25 mL flask, (1S,2R,3S,5S)-8-(benzyloxy)-3- Hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (16 mg, 0.028 mmol) was dissolved in DCM (1 mL) and then cooled to 0°C in an ice bath. Dess-Martin periodinane (11 mg, 2 equivalents) was added to the reaction solution. The mixture was stirred at 0°C and warmed to room temperature for 2 hours. The reaction product was quenched by adding a 10% sodium thiosulfate aqueous solution. The reaction mixture was extracted using ethyl acetate. The organic layer was concentrated and purified via silica column (eluted with 0-10% MeOH / DCM) to obtain (1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-3,7,9-trioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide. MS(m / z) 555.3[M+H] + . Preparation of (1S,2R,5S)-8-(benzyloxy)-3-fluoro-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0336] In a 50 mL flask, (1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-3,7,9-trioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (12 mg, 0.2 mmol) was dissolved in 2 mL of DCM, and then cooled to 0°C in an ice bath. Bis(2-methoxyethyl)aminosulfur trifluoride (50% in toluene, 2.7 M, 0.018 mL, 2 equivalents) was added to the reaction solution. The mixture was stirred at 0°C and warmed to room temperature for 3 hours. LC-MS showed the elimination product and the di-F product. The reaction product was quenched by adding saturated sodium bicarbonate aqueous solution. The reaction reaction was extracted using ethyl acetate. The organic layer was concentrated and purified by preparative HPLC elution with 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to obtain (1S,2R,5S)-8-(benzyloxy)-3-fluoro-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide. MS(m / z) 557.3[M+H] + . Preparation of (1S,2R,5S)-3-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C36):

[0337] (1S,2R,5S)-8-(benzyloxy)-3-fluoro-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (6 mg) was dissolved in toluene (0.2 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by preparative HPLC elution with 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to obtain the marked compound. MS (m / z) 467.2 [M+H] + . 1 ¹H NMR (400MHz, acetonitrile-d3): δ 10.20 (s, 1H), 8.43 (s, 1H), 6.87 (t, J=8.5Hz, 2H), 5.70-5.48 (m, 1H), 5.32-5.17 (m, 1H), 5.00 (d, J=14.8Hz, 1H), 4.78-4.57 (m, 3H), 4.22-4.08 (m, 1H), 1.52 (dd, J=6.9, 3.0Hz, 3H), 1.37 (d, J=7.2Hz, 3H). Example 37: (1S,2R,5S)-N-(2,4-difluorobenzyl)-8-Hyd Preparation of roxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C37) [ka]

[0338] To a solution of (1S,2R,5S)-N-(2,4-difluorobenzyl)-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (10.2 mg, 0.023 mmol) in EtOH (5 mL), PtO2 (2 mg, 0.009 mmol) was added. The reaction mixture was stirred under an H2 balloon at room temperature for 2 hours. The reaction mixture was filtered through Celite, the filtrate was concentrated, and the residue was purified by reverse-phase HPLC with elution in 5-100% acetonitrile water to obtain the desired product. MS (m / z): 433.11 [M+H] + . 1 H NMR (400MHz, methanol-d4) δ8.50(s,1H),7.51-7.38(m,1H),6.97(q,J=10.0,9.5Hz,2H),4.78(d,J=14.3Hz,1H),4.65(s,4H),3.57(s,1 H),2.05(dd,J=15.0,7.6Hz,1H),1.82(dd,J=15.1,9.4Hz,1H),1.62(d,J=12.2Hz,2H),1.40(d,J=7.0Hz,3H),1.33(d,J=6.7Hz,3H). Example 38: Preparation of (1S,2R,4R,5S)-N-(2,4-difluorobenzyl)-4,5-difluoro-9-hydroxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C38): [ka] Step 1: Synthesis of (1S,2R,4S,5R)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-4,5-dihydroxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (15A):

[0339] (1S,2R,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (11A, 190 mg, 0.36 mmol) in 3 mL of acetone and 0.45 mL of water was cooled to 0°C. 4-methylmorpholine n-oxide (50% in water, 0.076 ml, 0.36 mmol) and osmium tetroxide (2.5% in t-BuOH, 0.15 ml, 0.0014 mmol) were added to the mixture. The reaction mixture was stirred at room temperature for 2 days. 3 mL of 10% sodium sulfite aqueous solution was added to the reaction mixture and stirred for 15 minutes. The mixture was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried over magnesium sulfate, filtered, and concentrated to dryness. The residue was purified by silica gel chromatography eluting with methanol in dichloromethane to obtain the labeled product. Both hydroxyl stereocenters were arbitrarily assigned. MS (m / z) 555.300 [M+H] + . Step 2: (1S,2R,4R,5S)-N-(2,4-difluorobenzyl)-4,5 Synthesis of -difluoro-9-hydroxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (C38):

[0340] (1S,2R,4S,5R)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-4,5-dihydroxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (10 mg, 0.018 mmol) was cooled to 0°C under argon. Deoxo-fluoro (50% in toluene, 0.02 ml, 0.054 mmol) was added to it. The resulting mixture was stirred at 0°C for 3 hours. The reaction mixture was diluted with dichloromethane, cooled in an ice / water bath, and quenched by dropwise addition of saturated sodium bicarbonate aqueous solution. The resulting mixture was stirred for 20 minutes, and further saturated sodium bicarbonate aqueous solution was added until foaming subsided. The organic phase was separated, dried on magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by RP-HPLC eluting with acetonitrile / water (containing 0.1% TFA) to obtain (1S,2R,4R,5S)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-4,5-difluoro-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide, which was dissolved in 0.5 ml of toluene and 0.5 ml of TFA. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by RP-HPLC eluting with acetonitrile / water (containing 0.1% TFA) to obtain the labeled product. MS(m / z) 469.200[M+H] + . 1 H NMR(400MHz,acetonitrile-d3)δ10.32(s,1H),8.33(s,1H),7.43(q,J=9.1,8.4Hz,1H),7.00-6.95(m,2H),4.82(s,2H),4.69(s,0H),4.60(d,J=6.0Hz, 2H),4.37(dq,J=8.5,4.4Hz,1H),4.19(dd,J=14.2,7.9Hz,1H),3.45(t,J =7.3Hz,1H),3.39-3.31(m,1H),2.29-2.06(m,2H),1.20(d,J=6.5Hz,3H). Example 39: Preparation of (1S,2R,4S,5R)-N-(2,4-difluorobenzyl)-9-hydroxy-4,5-dimethoxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C39): [ka] Step 1: (1S,2R,4S,5R)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-5-hydroxy-4-methoxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide and (1S,2R,4S,5R)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-4,5-dimethoxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1 Synthesis of 7-methanopyride[1,2-b][1,2,5]triazecin-11-carboxamide:

[0341] (1S,2R,4S,5R)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-4,5-dihydroxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (40 mg, 0.072 mmol) was dissolved in 2 ml of dry DMF and cooled to 0°C using an ice bath. Sodium hydride (3.8 mg, 0.094 mmol, 60% by weight in oil) was added, and the mixture was stirred at 0°C for 30 minutes. Iodomethane (0.0056 ml, 0.09 mmol) was added, and the mixture was stirred at 0°C for 10 minutes. The reaction product was quenched with saturated ammonium chloride aqueous solution and extracted three times with ethyl acetate. The combined organic extracts were washed with a 5% lithium chloride aqueous solution and saline solution, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate to obtain the labeled product.

[0342] (1S,2R,4S,5R)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-5-hydroxy-4-methoxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide:(m / z):569.300[M+H]+.

[0343] (1S,2R,4S,5R)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-4,5-dimethoxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide:(m / z):583.300[M+H]+. Step 2: Synthesis of (1S,2R,4S,5R)-N-(2,4-difluorobenzyl)-9-hydroxy-4,5-dimethoxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (C39): [ka]

[0344] (1S,2R,4S,5R)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-4,5-dimethoxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (10 mg, 0.017 mmol) was dissolved in 0.5 ml of toluene and 0.5 ml of TFA and stirred at room temperature for 20 minutes. The solvent was removed under reduced pressure, and the residue was purified by RP-HPLC by elution with acetonitrile / water (containing 0.1% TFA) to obtain the labeled product. MS (m / z) 493.200 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d3) δ 10.37 (s, 1H), 8.32 (s, 1H), 7.49-7.38 (m, 1H), 6.97 (ddt, J=14.4, 8.4, 3.0 Hz, 2H), 4.81 (d, J=15.0 Hz, 1H), 4.59 (d, J=6.2 Hz, 3H), 3.79 (dd, J=7.0,3.6Hz,2H),3.46-3.37(m,0H),3.41(s,3H),3.33(s,3H),3.32(d,J=13.2Hz, 1H),3.19(d,J=33.1Hz,1H),3.20-3.08(m,1H),2.18(s,1H),1.94(d,J=2.5Hz,0H), 1.89-1.74(m,0H),1.18(d,J=6.5Hz,3H). Example 40: Preparation of (1S,2S)-N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C40): [ka] Step 1: Synthesis of tert-butyl(tert-butoxycarbonyl)(propa-2-in-1-yl)carbamate:

[0345] To a stirred solution of propa-2-in-1-amine (100 g, 181.65 mmol) in acetonitrile (2 L), di-tert-butyl dicarbonate (991 g, 4541 mmol), followed by DMAP (221.9 g, 181.65 mmol), was gradually added at room temperature, and the mixture was stirred at room temperature for 4 hours. After the reaction was complete, the reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, and evaporated under reduced pressure to obtain the crude compound. This was purified by silica gel column chromatography eluting with ethyl acetate in hexane to obtain the labeled product as a colorless liquid. MS (m / z): 256.31 [M+H]+. Step 2: Synthesis of tert-butyl(R,Z)-(tert-butoxycarbonyl)(5-hydroxyhexa-2-en-1-yl)carbamate:

[0346] To a stirred solution of tert-butyl(tert-butoxycarbonyl)(propa-2-in-1-yl)carbamate (100 g, 390.6 mmol) in THF (1 L), n-BuLi (1.6 M in hexane, 244.14 ml, 390.6 mmol) was added dropwise at -78°C for 30 minutes. To this, BF3 etherate (119.7 g, 390.6 mmol) was added dropwise, followed by a solution of (R)-2-methyloxirane (21.51 g, 390.6 mmol) in THF (0.5 L). The reaction mixture was stirred at this temperature for 4 hours. After completion, the reaction mixture was quenched with saturated ammonium chloride solution and water. The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated NaHCO3 and water, the Na2SO4 was dried and evaporated to obtain the crude product, which was purified by silica gel column chromatography eluting with ethyl acetate in hexane to obtain tert-butyl(R)-(tert-butoxycarbonyl)(5-hydroxyhexa-2-in-1-yl)carbamate as a colorless liquid. The following was obtained: 20 g (63.89 mmol) was taken and loaded into a parr apparatus, and 400 ml of ethyl acetate was added. Lindler catalyst (4.4 g) was added under an inert atmosphere, followed by quinoline, and hydrogenation was carried out at 30 Psi at room temperature for 16 hours. After completion, the reaction mixture was filtered through a Celite pad. The Celite pad was washed with ethyl acetate. The filtrate was washed with 1 N HCl and concentrated under reduced pressure to obtain the crude product, which was purified by silica gel column chromatography eluting with ethyl acetate in hexane to obtain the labeled product. MS (m / z): 316.29 [M+H]+. Step 3: Synthesis of (R,Z)-6-aminohexa-4-en-2-ol hydrochloride:

[0347] A solution of tert-butyl(R,Z)-(tert-butoxycarbonyl)(5-hydroxyhexa-2-en-1-yl)carbamate (14 g, 44.44 mmol) and 4 M HCl in dioxane (210 ml) was stirred at room temperature for 1 hour. After completion, the reaction mixture was concentrated under reduced pressure, the crude product was washed with diethyl ether, filtered, and dried under vacuum to obtain the labeled product. MS (m / z): 116.3 [M+H]+. Step 4: Synthesis of tert-butyl(R,Z)-(5-hydroxyhexa-2-en-1-yl)carbamate:

[0348] To a stirred solution of (R,Z)-6-aminohexa-4-en-2-ol hydrochloride (2 g, 13.2 mmol) in 30 ml of DCM, di-tert-butyl dicarbonate (4.3 g, 19.8 mmol) was added, followed by triethylamine (5.52 ml, 39.6 mmol) at room temperature. The reaction mixture was stirred overnight and concentrated to dryness. The crude compound was purified by silica gel column chromatography eluted with ethyl acetate in hexane to obtain the labeled product. 1 ¹H NMR (400MHz, chloroform-d): δ 5.59 (dq, J=10.4, 5.4Hz, 2H), 4.67 (s, 1H), 3.94-3.78 (m, 2H), 3.71 (dd, J=15.0, 5.0Hz, 1H), 2.44-2.18 (m, 2H), 1.46 (s, 9H), 1.25 (d, J=6.3Hz, 3H). Step 5: Synthesis of methyl(S,Z)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(6-((tert-butoxycarbonyl)amino)hexa-4-en-2-yl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylate (26E):

[0349] Instead of methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate and (2S)-penta-4-en-2-ol, use methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-di Hydropyridine-2-carboxylate and tert-butyl(R,Z)-(5-hydroxyhexa-2-en-1-yl)carbamate were used to prepare the same preparation as for methyl(R)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(penta-4-en-2-yl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (7A). MS(m / z):741.400[M+H]+. Step 6: Synthesis of (S,Z)-1-((6-aminohexa-4-en-2-yl)amino)-3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylate hydrochloride (26F):

[0350] Methyl(S,Z)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(6-((tert-butoxycarbonyl)amino)hexa-4-en-2-yl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-cal in 140 ml of THF / MeOH / H2O(3 / 2 / 1) Lithium hydroxide (698 mg, 29.2 mmol) was added to a solution of 5.4 g, 7.29 mmol of benzoate. The reaction mixture was stirred at 60°C for 2 hours. LC-MS showed a high conversion to carboxylic acid. The reaction mixture was diluted with ethyl acetate and acidified to approximately pH 4 with 1 N HCl. The organic layer was washed with saline solution, dried over sodium sulfate, filtered, and concentrated to obtain (S,Z)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(6-((tert-butoxycarbonyl)amino)hexa-4-en-2-yl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid. This was dissolved in 50 ml of DCM and treated overnight at room temperature with 4 N HCl in 1,4-dioxane (7.3 mL) to concentrate to dryness. High vacuum drying was performed to obtain the labeled product. MS(m / z): 527.300[M+H]+. Step 7: Synthesis of (S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-2,3,6,7,8,10-hexahydro-1H-pyrido[1,2-b][1,2,5]triazecin-11-carboxamide:

[0351] (S,Z)-1-((6-aminohexa-4-en-2-yl)amino)-3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylate hydrochloride (5.29 g, 8.8 mmol) was dissolved in 500 ml of DCM. EDCI was then added to it. · HCl (2.5 g, 13.2 mmol), HOAt (1.8 g, 13.2 mmol), followed by N,N-diisopropylethylamine (7.69 ml, 44.1 mmol) were added. The reaction mixture was stirred at room temperature for 10 minutes and washed with water and saline solution. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with toluene / hexane to obtain the marked compound. MS (m / z): 509.300 [M+H]+. Step 8: Synthesis of (1R,2S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide(26H) and (1S,2S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide:

[0352] (2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,6,7,8,10-hexahydro-1H-pyrido[1,2-b][1,2,5]triazecin-11-carboxamide(7E) is replaced with (S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-2,3,6,7,8, Using 10-hexahydro-1H-pyrido[1,2-b][1,2,5]triazesin-11-carboxamide, it was prepared in the same manner as (1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (7F). After silica gel chromatography eluting with ethyl acetate in hexane, two products were obtained. Peak 1: (1R,2S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide:MS(m / z):521.300[M+H]+. Peak 2: (1S,2S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide:MS(m / z):521.300[M+H]+. Step 9: Synthesis of (1S,2S)-N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide (C40):

[0353] (2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide(7F) is replaced with (1S,2S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6,8,10 It was prepared using tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide in the same manner as (1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11carboxamide (C8). MS(m / z): 433.200[M+H]+. 1¹H NMR (400MHz, acetonitrile-d3) δ 11.45 (s, 1H), 10.40 (s, 1H), 8.29 (s, 1H), 7.49-7.38 (m, 1H), 7.04-6.91 (m, 2H), 5.12 (d, J=14.1Hz, 1H), 4.80 (d, J=14.2Hz, 1H), 4.59 (d, J=5.9Hz, 2H), 4.21 (d t,J=13.8,4.7Hz,1H),3.57(p,J=7.2Hz,1H),3.02(ddd,J=14.1,10.1,4.2Hz,1H),1.97(p,J =2.5Hz,3H),1.84-1.70(m,1H),1.71-1.54(m,2H),1.50-1.25(m,1H),1.12(d,J=7.0Hz,3H). Example 41: Preparation of (1S,2S,Z)-N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C41): [ka]

[0354] (1S,2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide(7F) is replaced with (1S,2S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6, It was prepared using 8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide in the same manner as (2R,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11carboxamide (C7). MS(m / z): 431.200[M+H]+. 1H NMR (400MHz, acetonitrile-d3) δ10.37(s,1H),8.35(s,1H),7.50-7.39(m,1H),6.97(ddt,J=12.9,8.4,3.0Hz,2H),5 .89-5.77(m,1H),5.62(ddt,J=11.8,4.3,1.8Hz,1H),5.14(d,J=13.8Hz,1H),4.94(d,J=18.1Hz,1H),4.68-4.57 (m,3H),3.55-3.38(m,2H),2.26(dt,J=16.1,8.4Hz,1H),1.97-1.86(m,1H),1.15(d,J=7.0Hz,3H). Example 42: Preparation of (1R,2S)-N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C42): [ka]

[0355] (2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide(7F) is replaced with (1R,2S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6,8,10 It was prepared using tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11-carboxamide in the same manner as (1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazesin-11carboxamide (C8). MS(m / z): 433.200[M+H]+. 1¹H NMR (400MHz, acetonitrile-d3) δ 10.38 (s, 1H), 8.35 (s, 1H), 7.44 (td, J=9.2, 8.8, 6.5Hz, 1H), 7.03-6.91 (m, 2H), 4.86 (d, J=14.5Hz, 1H), 4.78 (d, J=14.5Hz, 1H), 4.60 (d, J=5.8Hz, 2H),4.15(ddd,J=14.1,7.4,5.2Hz,1H),3.14-3.02(m,2H),1.96-1.91(m,1H),1.77(dd ,J=16.7,7.1Hz,1H),1.71-1.57(m,1H),1.45(q,J=10.3Hz,2H),1.17(d,J=6.5Hz,3H). Example 43: Preparation of (1R,2S,Z)-N-(2,4-difluorobenzyl)-9-hydroxy-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C43): [ka]

[0356] (2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide is used instead of (2R,6S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (7F). Prepared in the same manner as 8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11carboxamide(C7). MS(m / z):431.200[M+H]+. 1H NMR (400MHz, acetonitrile-d3) δ10.41(s,1H),8.44(s,1H),7.44(td,J=8.8,6.5H z,1H),6.97(ddt,J=10.8,8.2,3.0Hz,2H),5.79-5.63(m,2H),5.00-4.88(m, 2H),4.69-4.57(m,3H),3.61(p,J=6.8Hz,1H),3.58-3.48(m,1H),2.42(dd,J =15.5,7.1Hz,1H),2.10(ddd,J=14.7,8.4,5.5Hz,1H),1.29(d,J=7.1Hz,3H). Example 44: Preparation of (2S,5S)-N-(2,4-difluorobenzyl)-2-(fluoromethyl)-8-hydroxy-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C44): [ka] Synthesis of 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid:

[0357] Instead of methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate, it was prepared in a similar manner to 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid (12) in Example 6. MS(m / z)530.200[M+H] + . Synthesis of tert-butyl(S)-(3-(benzyloxy)-2-(buta-3-en-2-ylcarbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridine-1(4H)-yl)carbamate:

[0358] The reaction mixture of 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid (200 mg, 0.378 mmol), (2S)-buta-3-ene-2-amine hydrochloride (61 mg, 0.567 mmol), HATU (172 mg, 0.453 mmol), and HOAt (61.7 mg, 0.453 mmol) in 10 ml of DMF was cooled to 0°C. DIPEA (0.2 ml, 1.13 mmol) was added dropwise. The reaction mixture was stirred for 10 minutes and then poured into water. It was extracted three times with ethyl acetate. The combined organic layers were washed with 5% aqueous lithium chloride solution and saline solution. The organic layers were dried over MgSO4 and concentrated under vacuum. The residue was purified by silica gel column chromatography. MS(m / z)583.300[M+H]+. Synthesis of tert-butyl(3-(benzyloxy)-2-(((S)-buta-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridine-1(4H)-yl)((S)-1-hydroxybuta-3-en-2-yl)carbamate:

[0359] 430 mg, 0.738 mmol of tert-butyl(S)-(3-(benzyloxy)-2-(buta-3-en-2-ylcarbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridine-1(4H)-yl)carbamate and 476 mg, 1.48 mmol of tetrabutylammonium bromide were placed in a round-bottom flask. Then, 20 ml of acetonitrile (degassed by bubbling with argon immediately before use) was added, followed by (R,R)-DACH naphthyltrost ligand (58.4 mg, 0.0738 mmol) and tris(dibenzylideneacetone)dipalladium-chloroform adduct (22.9 mg, 0.0221 mmol). The solution was stirred under argon at room temperature for 20 minutes. Butadiene monooxide (0.149 ml, 1.85 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum and purified by column chromatography eluting with ethyl acetate in hexane to obtain the labeled product. MS (m / z) 653.300 [M+H] + . Synthesis of (S)-2-((3-(benzyloxy)-2-(((S)-buta-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridine-1(4H)-yl)(tert-butoxycarbonyl)amino)buta-3-en-1-yl acetate:

[0360] 280 mg, 0.429 mmol of tert-butyl(3-(benzyloxy)-2-(((S)-buta-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridine-1(4H)-yl)((S)-1-hydroxybuta-3-en-2-yl)carbamate was dissolved in 14 ml of pyridine. 105 mg, 0.858 mmol of DMAP and 0.40 ml, 4.29 mmol of acetic anhydride were added. The reaction mixture was heated at 60°C for 2 hours, cooled to room temperature, and concentrated to dryness. The reaction mixture was partitioned into ethyl acetate and 1N HCl, and the organic phase was washed with further 1N HCl, then saturated aqueous NaHCO3, and finally brine. The organic phase was dried over MgSO4, filtered, and concentrated under vacuum. The product was purified by silica gel column chromatography eluting with ethyl acetate in hexane to obtain the labeled product. MS (m / z) 695.400 [M+H] + . Synthesis of (S)-2-((3-(benzyloxy)-2-(((S)-buta-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridine-1(4H)-yl)amino)buta-3-en-1-yl acetate:

[0361] (S)-2-((3-(benzyloxy)-2-(((S)-buta-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridine-1(4H)-yl)(tert-butoxycarbonyl)amino)buta-3- En-1-yl acetate (202 mg, 0.29 mmol) was dissolved in 4 ml of DCM, and a 4.0 M solution of hydrogen chloride in 1,4-dioxane (0.73 ml, 2.9 mmol) was added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum and dried under high vacuum to obtain the labeled product. MS (m / z) 595.300 [M+H] + . Synthesis of (S)-2-(5-(benzyloxy)-3-((S)-buta-3-en-2-yl)-7-((2,4-difluorobenzyl)carbamoyl)-4,6-dioxo-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-1-yl)buta-3-en-1-yl acetate:

[0362] Instead of 3-(benzyloxy)-N2-((S)-buta-3-en-2-yl)-1-(buta-3-en-2-ylamino)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1,4-dihydropyridine-2,5-dicarboxamide, use (S)-2-((3-(benzyloxy)-2-(((S)-buta-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo Using pyridine-1(4H)-yl)amino)buta-3-en-1-yl acetate, it was prepared in the same manner as 5-(benzyloxy)-3-((S)-buta-3-en-2-yl)-1-(buta-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide in Example 24. MS(m / z) 607.300[M+H] + . Synthesis of ((2S,5S)-8-(benzyloxy)-10-((2,4-difluorobenzyl)carbamoyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-2-yl)methyl acetate:

[0363] 5-(benzyloxy)-3-((S)-buta-3-en-2-yl)-1-(buta-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide can be replaced with (S)-2-(5-(benzyloxy)-3-((S)-buta-3-en-2-yl)-7-((2,4-difluorobenzyl)carbamoyl)-4,6-dioxo -2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-1-yl)buta-3-en-1-yl acetate was used to prepare the same preparation as for (1R,2R,5S)-8-(benzyloxy)-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide in Example 24. MS(m / z) 579.300[M+H] + . Synthesis of (2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-(hydroxymethyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0364] ((2S,5S)-8-(benzyloxy)-10-((2,4-difluorobenzyl)carbamoyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonin-2-yl)methyl acetate (46 mg, 0.79 mmol) was dissolved in 2 ml of methanol. Potassium carbonate (22 mg, 0.16 mmol) was added to the mixture. The reaction mixture was stirred at room temperature for 10 minutes, then partitioned into ethyl acetate and water. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated to dryness to obtain the labeled product. MS (m / z) 537.300 [M+H] + . (2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-(fluoromethyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro Synthesis of -1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0365] (2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-(hydroxymethyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (xxH, 15 mg, 0.028 mmol) in DCM (2 mL) was cooled under argon at 0°C. Deoxo-fluoro (50% in toluene, 0.031 ml, 0.084 mmol) was added to it. The resulting mixture was stirred at 0°C for 2 hours. The reaction mixture was diluted with DCM, cooled in an ice / water bath, and quenched by dropwise addition of saturated NaHCO3 aqueous solution. The resulting mixture was stirred for 20 minutes, and further saturated NaHCO3 aqueous solution was added, stirring for 10 minutes until foaming subsided. The organic layer was separated, dried over Na2SO4, and the solvent was removed under reduced pressure. The residue was purified by silica gel chromatography eluting with HCl / hexane to obtain the indicated compound. MS(m / z) 539.200[M+H] + . Synthesis of (2S,5S)-N-(2,4-difluorobenzyl)-2-(fluoromethyl)-8-hydroxy-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C44):

[0366] (2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-(fluoromethyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (11 mg, 0.02 mmol) was dissolved in 0.5 ml of toluene and 0.5 ml of TFA and stirred at room temperature for 3 hours. The solvent was removed under reduced pressure, and the residue was purified by RP-HPLC by elution with acetonitrile / water (containing 0.1% TFA) to obtain the labeled product. MS (m / z) 449.200 [M+H] + . 1 H NMR (400MHz, acetonitrile-d3) δ10.19(s,1H),8.47(s,1H),7.44(td,J=9.2,8.7,6. 4Hz,1H),6.97(ddt,J=11.1,8.5,3.0Hz,2H),5.83(dt,J=11.8,2.7Hz,1H),5.3 9(ddt,J=14.5,12.0,2.9Hz,2H),4.96(d,J=14.4Hz,1H),4.70-4.57(m,4H),4. 52(d,J=5.5Hz,1H),4.10(ddq,J=20.0,5.7,2.9Hz,1H),1.36(d,J=7.3Hz,3H). Example 45: Preparation of (1S,2S,5S)-N-(2,4-difluorobenzyl)-2-(fluoromethyl)-8-hydroxy-5-methyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C45): [ka]

[0367] (1S,2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-(fluoromethyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (10 mg, 0.19 mmol) was dissolved in 3 mL of ethanol and 3 mL of ethyl acetate and spurged under an argon atmosphere. Palladium carbon (10% by weight, wet) E101 NE / W (2 mg) was added, and the mixture was subjected to a hydrogen atmosphere (1 atm, balloon). The mixture was sparged. The mixture was vigorously stirred for 1 hour, then sparged under an argon atmosphere. It was filtered through a Celite® pad. The Celite® was washed with anhydrous ethanol, and the filtrate was concentrated to dryness. The residue was purified by RP-HPLC to obtain the labeled product. MS (m / z) 451.200 [M+H] + . 1 H NMR (400MHz, acetonitrile-d3) δ10.31(s,1H),8.41(s,1H),7.44(td,J=9.2,8.7,6.3Hz,1H),7.03-6.91(m,2H),5.05-4.26(m ,7H),3.62-3.51(m,1H),2.13-2.00(m,1H),1.84(ddd,J=15.6,8.0,4.1Hz,1H),1.77-1.57(m,2H),1.26(d,J=6.8Hz,3H). Example 46: Preparation of (1R,2R,5S)-8-hydroxy-2-methoxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C46): [ka] Step 1: 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino) Synthesis of -4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid:

[0368] In Example 24, lithium hydroxide monohydrate (5.979 g, 142 mmol, 8 equivalents) was added to a suspension of methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (10.0 g, 17.8 mmol, 1 equivalent) in methanol (200 mL) and water (100 mL), prepared according to Step 3. The reaction mixture was heated at 50°C for 18 hours, diluted with water, and acidified with 1N HCl (aqueous solution). The slurry was extracted with ELISA (2×), the combined organic phase was washed with saline solution, dried over Na₂SO₄, filtered, and concentrated to obtain 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid. MS(m / z) 547.82[M+H] + . Step 2: Synthesis of tert-butyl(S)-(3-(benzyloxy)-2-(buta-3-en-2-ylcarbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridine-1(4H)-yl)carbamate:

[0369] To a solution of 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid (6.00 g, 11.0 mmol, 1 equivalent), (S)-buta-3-ene-2-amine hydrochloride (1.769 g, 16.4 mmol, 1.5 equivalents), and HOBt (2.221 g, 16.4 mmol, 1.5 equivalents) in CH2Cl2 (120 mL) at 0°C, DIPEA (9.54 mL, 54.8 mmol, 5 equivalents) and EDCI (3.151 g, 16.4 mmol, 1.5 equivalents) were added. The reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction mixture was quenched with water and 1 M HCl and extracted with CH2Cl2(3×). The combined organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by column chromatography (0-100% Âxane / hexane) and concentrated to obtain tert-butyl(S)-(3-(benzyloxy)-2-(buta-3-en-2-ylcarbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridine-1(4H)-yl)carbamate. MS(m / z) 600.90[M+H] + . Step 3: Synthesis of tert-butyl(S)-5-(benzyloxy)-3-(buta-3-en-2-yl)-4,6-dioxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-1-carboxylate:

[0370] Diiodomethane (0.59 mL, 7.33 mmol, 2 equivalents) was added to a suspension of tert-butyl(S)-(3-(benzyloxy)-2-(buta-3-en-2-ylcarbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridine-1(4H)-yl)carbamate (2.20 g, 3.66 mmol, 1 equivalent) and cesium carbonate (4.77 g, 14.7 mmol, 4 equivalents) in MeCN (55 mL). The reaction mixture was heated at 70 °C for 8 hours and quenched with NH4Cl (aqueous solution). The mixture was extracted with ELISA (2×), the combined organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0-100% ethyl acetate / hexane) to obtain tert-butyl(S)-5-(benzyloxy)-3-(buta-3-en-2-yl)-4,6-dioxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-1-carboxylate. MS(m / z) 612.79[M+H] + . Step 4: (S)-5-(benzyloxy)-3-(buta-3-en-2-yl)-4, Synthesis of 6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide:

[0371] To a solution of tert-butyl(S)-5-(benzyloxy)-3-(buta-3-en-2-yl)-4,6-dioxo-7-((2,4,6-trifluorobenzyl)carbamoyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-1-carboxylate (2.00 g, 3.26 mmol, 1 equivalent) in methanol (55 mL), 2.45 mL, 4.90 mmol, 1.5 equivalents were added. The reaction mixture was heated at 40°C for 1 hour, quenched with 10% citric acid solution, and diluted with CH2Cl2. The phases were separated, and the aqueous phase was extracted with CH2Cl2. The combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was suspended in a 1:1 ELISA / hexane solution, and the precipitate was collected by filtration to obtain (S)-5-(benzyloxy)-3-(buta-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide. MS(m / z) 512.96[M+H] + . Step 5: Synthesis of 5-(benzyloxy)-3-((S)-buta-3-en-2-yl)-1-(1-methoxyallyl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide:

[0372] In a solution of (S)-5-(benzyloxy)-3-(buta-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide (0.122 g, 0.237 mmol, 1 equivalent) in acetonitrile (5 mL), Pd( OAc)2 (0.0027 g, 0.012 mmol, 0.05 equivalents), 1,3-bis(diphenylphosphin)propane (dppp) (0.0049 g, 0.012 mmol, 0.05 equivalents), trimethylamine (0.050 mL, 0.356 mmol, 1.5 equivalents), and methoxyalene (0.100 mL, 1.19 mmol, 5 equivalents) were added. The reaction mixture was heated at 100°C for 20 minutes. Water and saline solution were added, and the aqueous phase was extracted with SiO(2×). The combined organic phase was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography (0-100% ethyl acetate / hexane) to obtain 5-(benzyloxy)-3-((S)-buta-3-en-2-yl)-1-(1-methoxyallyl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide. MS(m / z) 583.00[M+H] + . Step 6: Synthesis of (1R,2R,5S)-8-(benzyloxy)-2-methoxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0373] To a solution of 5-(benzyloxy)-3-((S)-buta-3-en-2-yl)-1-(1-methoxyallyl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide (0.112 g, 0.192 mmol, 1 equivalent) in 1,2-dichloroethane (5 mL), Hoveyda-Grubbs II catalyst (0.024 g, 0.038 mmol, 0.2 equivalents) was added. The reaction mixture was heated at 70°C for 24 hours and concentrated. The residue was eluted by preparative HPLC (column: Gemini 10 μm C18) using 5-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 minutes. The sample was purified using 110A, AXI (250×21.2mm). The combined fraction was frozen. By drying, (1R,2R,5S)-8-(benzyloxy)-2-methoxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide was obtained. (MS(m / z) 554.98). Step 7: Synthesis of (1R,2R,5S)-8-hydroxy-2-methoxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C46):

[0374] Lithium chloride (0.0348 g, 0.821 mmol, 10 equivalents) was added to a solution of (1R,2R,5S)-8-(benzyloxy)-2-methoxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (0.0455 g, 0.0821 mmol, 1 equivalent) in DMF (2 mL). The reaction mixture was heated at 100°C for 1 hour and filtered. The filtrate was purified by preparative HPLC (column: Gemini 10μ C18 110A, AXI / ; 250×21.2mm) by eluting 5-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 minutes. The combined fraction was freeze-dried to obtain (1R,2R,5S)-8-hydroxy-2-methoxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide. MS(m / z) 465.02[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.31(t,J=5.8Hz,1H),8.21(s,1H),7.20(t,J=8.6Hz,2H),5.76(dt,J=12.1,2.3Hz,1H),5.55(dt,J=12.0,2. 4Hz,1H),5.29-5.17(m,2H),5.06(d,J=14.6Hz,1H),4.75(d,J=14.6Hz,1H),4.57(d,J=5.8Hz,2H),3.39(s,3H),1.28(d,J=7.2Hz,3H). 19 F NMR (376MHz, DMSO-d6) δ -109.25 (ddd, J=15.5, 9.3, 6.2Hz), -112.45--112.69 (m). Example 47: Preparation of (1R,2R,5S)-8-hydroxy-2-methoxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C47): [ka] Step 1: Synthesis of (1R,2R,5S)-8-hydroxy-2-methoxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide):

[0375] (1R,2R,5S)-8- in methanol (1 mL), prepared according to Example 46. To a solution of (benzyloxy)-2-methoxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (0.008 g, 0.0144 mmol, 1 equivalent), platinum(IV) oxide (0.0003 g, 0.0014 equivalents, 0.1 equivalents) was added. The reaction mixture was drained, refilled with hydrogen gas (2×), sparged with hydrogen gas for 5 minutes, and stirred for 1 hour under a hydrogen balloon atmosphere. The reaction mixture was filtered, concentrated, and purified by preparative HPLC (column: Gemini 10μ C18 110A, AXI / ; 250×21.2mm) by eluting 5–100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 minutes. The combined fraction was lyophilized to obtain (1R,2R,5S)-8-hydroxy-2-methoxy-5-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide. MS(m / z) 467.07[M+H] + . 1 H NMR(400MHz,DMSO-d6)δ10.37(t,J=5.9Hz,1H),8.25(s,1H),7.20(t,J=8.6Hz,2H),4.69-4.59(m,2H),4.59-4.49 (m,2H),4.45(s,1H),4.44-4.35(m,1H),3.53(s,3H),1.91-1.72(m,3H),1.34-1.22(m,1H),1.17(d,J=6.7Hz,3H).19 F NMR (376MHz, DMSO-d6) δ -109.32 (ddd, J = 15.5, 9.4, 6.4 Hz), -112.55 (t, J = 7.2 Hz). Example 48: Preparation of (1S,5S)-8-hydroxy-2,2,5-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C48): [ka] Step 1: Synthesis of (S)-5-(benzyloxy)-3-(buta-3-en-2-yl)-1-(2-methylbuta-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide:

[0376] (S)-5-(benzyloxy)-3-(buta-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-p Methyl (2-methylbuta-3-en-2-yl) carbonate (0.0633 g, 0.439 mmol, 1.5 equivalents) was added to a solution of lido[2,1-f][1,2,4]triazine-7-carboxamide (0.150 g, 0.293 mmol, 1 equivalent), (S)-5-(benzyloxy)-3-(buta-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide, and Pd(PPh3)4 (0.0338 g, 0.029 mmol, 0.1 equivalent). The reaction mixture was heated at 60°C for 2 hours and concentrated. The residue was purified by column chromatography (0-100% siRNA / hexane), the pure fraction was recovered and concentrated to obtain (S)-5-(benzyloxy)-3-(buta-3-en-2-yl)-1-(2-methylbuta-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide. MS(m / z) 581.02[M+H] + . Step 2: Synthesis of (1S,5S)-8-(benzyloxy)-2,2,5-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0377] To a solution of (0.019 g, 0.033 mmol, 1 equivalent) of Hoveyda-Grubbs II catalyst (0.004 g, 0.006 mmol, 0.2 equivalents) in 1 mL of 1,2-dichloroethane, Hoveyda-Grubbs II catalyst (0.004 g, 0.006 mmol, 0.2 equivalents) was added. The reaction mixture was sparged with Ar (g) for 10 minutes and heated at 75°C for 18 hours. The mixture was concentrated and purified by column chromatography (0-100% siRNA / hexane) to obtain (1S,5S)-8-(benzyloxy)-2,2,5-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide. MS (m / z) 553.00 [M+H] + . Step 3: Synthesis of (1S,5S)-8-hydroxy-2,2,5-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C49):

[0378] (1S,5S)-8-(benzyloxy)-2,2,5-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (0.011 g, 0.020 mmol, 1 equivalent) was dissolved in 1:1 TFA / toluene (2 mL) and stirred at room temperature for 5 hours. The reaction mixture was concentrated, dissolved in MeCN, filtered, and purified by preparative HPLC (column: Gemini 10 μC C18 110A, AXI / ; 250 × 21.2 mm) by eluting 5-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 minutes. The combined fraction was freeze-dried to obtain (1S,5S)-8-hydroxy-2,2,5-trimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide. MS(m / z) 463.10[M+H] + . 1H NMR(400MHz,DMSO-d6)δ10.33(t,J=5.7Hz,1H),8.25(s,1H),7.23-7.17(m,2H),5.41(td,J=11.8,11.3,2.9Hz,1H),5.33(dd,J=12.4,2.0Hz ,1H),5.29-5.18(m,1H),5.06-4.98(m,1H),4.72(d,J=14.5Hz,1H),4.56(d,J=5.6Hz,2H),1.49(s,3H),1.28(d,J=7.2Hz,3H),0.93(s,3H). 19 F NMR(376MHz,DMSO-d6)δ-109.19(ddd,J=15.6,9.3,6.3Hz),-112.52(q,J=7. (3.5.9Hz). Example 49: Preparation of (1S,10R,13R)-N-[(2,4-difluorophenyl)methyl]-10-(fluoromethyl)-6-hydroxy-13-methyl-5,8-dioxo-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide (C49a) and (1S,10R,13R)-N-[(2,4-difluorophenyl)methyl]-10-(fluoromethyl)-6-hydroxy-13-methyl-5,8-dioxo-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide (C49b) [ka] Step 1: Synthesis of methyl 3-benzyloxy-1-[tert-butoxycarbonyl(1-methylallyl)amino]-5-[(2,4-difluorophenyl)methylcarbamoyl]-4-oxopyridine-2-carboxylate:

[0379] To a mixture of methyl 3-benzyloxy-1-(tert-butoxycarbonylamino)-5-[(2,4-difluorophenyl)methylcarbamoyl]-4-oxopyridine-2-carboxylate (8 g, 14.7 mmol) in 75 mL of THF at 0°C, buta-3-en-2-ol (1.59 g, 22.1 mmol) and triphenylphosphine (5.79 g, 22.1 mmol) were added. Then, diisopropyl azodicarboxylate (4.46 g, 22.1 mmol) was added dropwise. The resulting mixture was stirred at 0°C for 5 minutes, then removed from the cold bath and stirred at room temperature for 2 hours. The reaction product was mixed with silica gel, concentrated, and purified by normal-phase chromatography. LCMS-ESI+(m / z):Calculated H+ value for C31H33F2N3O7, theoretical value: 597.23, measured value: 597.88. Step 2: Synthesis of 3-benzyloxy-1-[tert-butoxycarbonyl(1-methylallyl)amino]-5-[(2,4-difluorophenyl)methylcarbamoyl]-4-oxopyridine-2-carboxylic acid:

[0380] Methyl 3-benzyloxy-1-[tert-butoxycarbonyl(1-methylallyl)amino]-5-[(2,4-difluorophenyl)methylcarbamoyl]-4-oxopyridine-2-carboxylate (10 g, 16.7 mmol) was dissolved in a mixture of MeOH (96 mL), THF (48 mL), and water (48 mL). Lithium hydroxide monohydrate (4.2 g, 41.96 mmol) was added. The resulting mixture was heated at 60°C for 6 hours. The reaction mixture was then cooled to room temperature, concentrated, the residue was diluted with ELISA, acidified to approximately pH 4 with 1N HCl, the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain a pale pink solid. The obtained product was directly used in the next step. Used. LCMS-ESI+(m / z):Calculated H+ value for C30H31F2N3O7, theoretical value: 583.21, measured value: 583.87. Step 3: Synthesis of tert-butyl N-[3-benzyloxy-5-[(2,4-difluorophenyl)methylcarbamoyl]-2-[[(1R)-1-(hydroxymethyl)allyl]carbamoyl]-4-oxo-1-pyridyl]-N-(1-methylallyl)carbamate:

[0381] The residue from the previous step (7 g, 12.0 mmol) was dissolved in DCM (60 mL) at room temperature. To this stirred mixture, (2R)-2-aminobuta-3-en-1-ol (1.57 g, 18.0 mmol), followed by EDCI.HCl (4.12 g, 21.6 mmol), HOAt (2.94 g, 21.6 mmol), and DIEA (6.2 g, 48 mmol) were added. The newly formed mixture was stirred for 1 hour. The reaction product was then diluted with DCM, washed with 10% citric acid and brine, dried over sodium sulfate, filtered, concentrated, and used directly in the next step. LCMS-ESI+(m / z):Calculated H+ value of C34H38F2N4O7, theoretical value: 652.27, measured value: 653.03. Step 4: Synthesis of 3-benzyloxy-N5-[(2,4-difluorophenyl)methyl]-N2-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallylamino)-4-oxopyridine-2,5-dicarboxamide:

[0382] 7.8 g, 12 mmol of tert-butyl N-[3-benzyloxy-5-[(2,4-difluorophenyl)methylcarbamoyl]-2-[[(1R)-1-(hydroxymethyl)allyl]carbamoyl]-4-oxo-1-pyridyl]-N-(1-methylallyl)carbamate was dissolved in 70 mL of DCM at room temperature and treated with 4N HCl in 70 mL of 1,4-dioxane at room temperature for 1 hour. The reaction mixture was concentrated, diluted with ethyl acetate, and slowly basicized with saturated sodium bicarbonate until no more foaming occurred. Then, solid sodium bicarbonate was added to saturate the aqueous layer. The mixture was extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated to obtain a brownish oily substance. The obtained product was used directly in the next step. LCMS-ESI+(m / z): Calculated H+ value for C29H30F2N4O5, theoretical value: 552.22, measured value: 553.09. Step 5: Synthesis of 5-benzyloxy-N-[(2,4-difluorophenyl)methyl]-3-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide:

[0383] 3-Benzyloxy-N5-[(2,4-difluorophenyl)methyl]-N2-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallylamino)-4-oxopyridine-2,5-dicarboxamide (1.57 g, 2.84 mmol) was dispensed at room temperature into a mixture of DCE (5.3 mL) and acetonitrile (5.3 mL), and paraformaldehyde (224 mg) was added. The resulting mixture was then heated to 88°C, and a mixture of AcOH (0.79 mL) and TFA (0.79 mL) was rapidly added in one go. The reaction mixture was sealed and stirred for 1 hour. The reaction mixture was then cooled to room temperature, concentrated, redissolved in toluene, washed with saturated sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated to obtain a brownish oily substance. Next, the residue was dissolved in DMF (5 mL) and treated with potassium carbonate (392 mg, 2.84 mmol) and benzyl bromide (485 mg, 2.84 mmol). The reaction mixture was then heated at 70°C for 2 hours, cooled to room temperature, and partitioned into toluene and water. The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated, and purified by normal-phase chromatography. LCMS-ESI+(m / z): Calculated H+ value of C30H30F2N4O5, theoretical value: 564.22, experimental value: 565.02. Step 6: 5-benzyloxy-N-[(2,4-difluorophenyl)methyl]-3- Synthesis of [(1R)-1-(fluoromethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide:

[0384] 5-Benzyloxy-N-[(2,4-difluorophenyl)methyl]-3-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide (851 mg, 1.51 mmol) was dissolved in DCM (12.0 mL) at 0°C. Bis(2-methoxyethyl)aminosulfur trifluoride (1.33 g, 6.03 mmol) was added. After addition, the reaction mixture was removed from the cold bath and stirred overnight at ambient temperature. The reaction mixture was then cooled to 0°C and quenched with saturated sodium bicarbonate. Additional sodium bicarbonate powder was added to saturate the mixture. The reaction mixture was extracted with DCM, washed with saline solution, dried over sodium sulfate, filtered, concentrated, and purified by normal-phase chromatography. LCMS-ESI+(m / z):Calculated H+ value for C30H29F3N4O4, theoretical value: 566.21, measured value: 566.99. Step 7: Synthesis of (1S,10R,13R)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-(fluoromethyl)-13-methyl-5,8-dioxo-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide:

[0385] A solution of 5-benzyloxy-N-[(2,4-difluorophenyl)methyl]-3-[(1R)-1-(fluoromethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide (370 mg, 0.65 mmol) in DCE (9 mL) at room temperature was sparged with argon. Hoveyda-Grubbs II catalyst HG-M720 (41 mg, 0.065 mmol) was added. The mixture was further sparged with argon for 5 minutes, then sealed and heated overnight at 80°C under a nitrogen balloon. The reaction product was then cooled to room temperature, concentrated, and purified by normal-phase chromatography. 1H NMR(400MHz,CDCl3)δ10.38(t,J=6.0Hz,1H),8.54(s,1H),7.55-7.47(m,2H),7.44-7. 29(m,4H),6.89-6.76(m,2H),5.83(dt,J=10.8,2.3Hz,1H),5.62-5.45(m,3H),5.25(d ,J=10.5Hz,1H),5.11(d,J=14.6Hz,1H),4.79-4.65(m,1H),4.65-4.62(m,2H),4.62-4.46(m,1H),4.26(d,J=14.6Hz,1H),3.77(tp,J=6.6,3.3Hz,1H),1.41(d,J=6.6Hz,3H). LCMS-ESI+(m / z):Calculated H+ value of C28H25F3N4O4, theoretical value: 538.18, measured value: 539.09. Step 8: Synthesis of (1S,10R,13R)-N-[(2,4-difluorophenyl)methyl]-10-(fluoromethyl)-6-hydroxy-13-methyl-5,8-dioxo-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide:

[0386] (1S,10R,13R)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-(fluoromethyl)-13-methyl-5,8-dioxo-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide (20 mg, 0.037 mmol) was treated with a mixture of DCM (1.5 mL) and TFA (1.5 mL) at room temperature for 2 hours. The reaction product was concentrated, redissolved in DMF, and purified by reverse-phase preparative HPLC. The absolute configuration at C13 was not confirmed. 1 ¹H NMR (400MHz, acetonitrile-d3) δ 10.15 (s, 1H), 8.39 (s, 1H), 7.44 (td, J=9.2, 8.8, 6.5Hz, 1H), 7.09 -6.88(m,2H),5.81(dt,J=11.5,2.3Hz,1H),5.66-5.59(m,1H),5.54-5.41(m,1H),5.13( d,J=14.5Hz,1H),4.80-4.55(m,5H),3.87(dp,J=10.1,3.4Hz,1H),1.37(d,J=6.7Hz,3H). LCMS-ESI+(m / z): H+ calculated value of C21H19F3N4O4, theoretical value: 448.14, measured value: 449.10. Step 9: Synthesis of (1S,10R,13R)-N-[(2,4-difluorophenyl)methyl]-10-(fluoromethyl)-6-hydroxy-13-methyl-5,8-dioxo-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide:

[0387] (1S,10R,13R)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-(fluoromethyl)-13-methyl-5,8-dioxo-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide (20 mg, 0.037 mmol) was dissolved in EtOH (20 mL) at room temperature. 10% Pd / C (4 mg) was added, the reaction mixture was degassed, flushed three times with nitrogen, then degassed again, flushed three times with hydrogen, and then hydrogenated under a hydrogen balloon for 1 hour. The reaction mixture was then degassed, flushed with nitrogen, filtered through Celite, concentrated, and purified by reverse-phase preparative HPLC. The absolute configuration at C13 was not confirmed. 1 H NMR (400MHz, acetonitrile-d3): δ 10.33 (s, 1H), 8.45 (s, 1H), 7.44 (td, J=9.2, 8.8, 6.5Hz, 1H), 7.06-6.86 (m, 2H), 4.79-4.39 (m, 7H), 3.63-3.58 (m, 1H), 1.95-1.82 (m, 2H), 1.62 (dt, J=7.1, 3.5Hz, 2H), 1.32 (d, J=7.2Hz, 3H). LCMS-ESI+ (m / z): Calculated H+ value of C21H21F3N4O4, theoretical value: 450.15, measured value: 451.12. Example 50: Preparation of (1S,2R,5R)-5-(fluoromethyl)-8-hydroxy-2-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C50) [ka] [ka] Synthesis of methyl 3-benzyloxy-1-[tert-butoxycarbonyl(1-methylallyl)amino]-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyridine-2-carboxylate:

[0388] Methyl 3-benzyloxy-1-(tert-butoxycarbonylamino)-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyridine-2-carboxylate (10 g, 17.8 mmol) was added to methyl 3-benzyloxy-1-(tert-butoxycarbonylamino)-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyridine-2-carboxylate (10 g, 17.8 mmol) in 200 ml of THF at 0°C, followed by the addition of buta-3-en-2-ol (1.93 g, 26.7 mmol), and then Ph3P (7.0 g, 26.7 mmol). DIAD (5.4 g, 26.7 mmol) was then added dropwise over 5 minutes. The resulting reaction mixture was stirred at 0°C for 5 minutes, and then warmed to room temperature. The reaction mixture was stirred overnight at room temperature. The solvent was removed under vacuum, and the resulting clad material was purified by silica gel column chromatography to obtain the marked compound. MS (m / z) 615.99 [M+H] + . Synthesis of 3-benzyloxy-1-[tert-butoxycarbonyl(1-methylallyl)amino]-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyridine-2-carboxylic acid:

[0389] Methyl 3-benzyloxy-1-[tert-butoxycarbonyl(1-methylallyl)amino]-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyridine-2-carboxylate (11 g, 17.9 mmol) was added to 2.5 N aqueous LiOH solution (43 ml, 107 mmol). The reaction mixture was heated overnight at 70°C. The reaction mixture was carefully concentrated to remove the MeOH. The residue was diluted, rinsed with some water, and acidified to pH=3 with 1 N HCl. ELISA was added for extraction. The organic phase was separated. The aqueous layer was further extracted with ELISA. The combined organic phase was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated to obtain the marked compound. The crude material was proceeded to the next step. MS (m / z) 601.84 [M+H] + . Synthesis of tert-butyl N-[3-benzyloxy-2-[[(1R)-1-(hydroxymethyl)allyl]carbamoyl]-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]-1-pyridyl]-N-(1-methylallyl)carbamate:

[0390] 3-benzyloxy-1-[tert-butoxycarbonyl( 50ml) in DMF 1-methylallyl)amino]-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyridine-2-carboxylic acid (11.2 g, 18.6 mmol) was mixed with DIEA (16.2 ml, 93.1 mmol), followed by HATU (9.2 g, 24.2 mmol). The reaction mixture was stirred at room temperature for 1 hour, after which (2R)-2-aminobuta-3-en-1-ol hydrochloride (2.9 g, 24.2 mmol) was added to the reaction mixture. After 2 hours, the reaction mixture was diluted with SiO2 and washed with an aqueous solution of LiCl. The aqueous layer was extracted with SiO2 (1×). The combined organic phase was washed with water (1×). The organic phase was dried over MgSO4 and concentrated to obtain the crude product, which was purified by silica gel chromatography to obtain the marked compound. MS (m / z) 670.86 [M+H] + . Synthesis of 3-benzyloxy-N2-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallylamino)-4-oxo-N5-[(2,4,6-trifluorophenyl)methyl]pyridine-2,5-dicarboxamide:

[0391] tert-butyl N-[3-benzyloxy-2-[[(1R)-1-(hydroxymethyl)allyl]carbamoyl]-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]-1-pyridyl]-N-(1-methylallyl)carbamate (XX-3) (10 g, 14.9 mmol) was dissolved in DCM (50 ml) at room temperature. HCl (4 M in dioxane) (11.2 mL, 44.7 mmol) was added. The reaction mixture was stirred at room temperature for 24 hours. LC-MS indicated that the reaction was complete. Therefore, the reaction mixture was then concentrated to dryness. The residue was then partitioned into HCl and aqueous NaHCO3. The aqueous layer was extracted with HCl. The combined organic phases were washed with water, dried over Na2SO4, filtered, and concentrated to obtain the marked compound. MS (m / z) 571.06 [M+H] + . 5-hydroxy-3-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide (2g, 4.06 mmol) was synthesized in DMF, and bromomethylbenzene was added.

[0392] 3-benzyloxy-N2-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallylamino)-4-oxo-N5-[(2,4,6-trifluorophenyl)methyl]pyridine-2,5-dicarboxamide (XX-4) (0.89 g, 1.56 mmol) in 20 ml of microwave-reacted virus in CAN (5 ml) and DCE (5 ml) was mixed with paraformaldehyde (93.1 mg, 3.04 mmol) and AcOH (0.5 mL), followed by the addition of TFA (0.5 ml). After the addition, the virus was capped and heated overnight at 89 °C. LC-MS showed a complete reaction. The reaction mixture was diluted with ELISA and washed with saturated NaHCO3 aqueous solution. The organic phase was dried over MgSO4, and the solvent was removed under vacuum to obtain the crude material of the labeled compound, which was then used to proceed to the next step. MS (m / z) 535.1 [M+H] + . Synthesis of [(2R)-2-[5-benzyloxy-1-(1-methylallyl)-4,6-dioxo-7-[(2,4,6-trifluorophenyl)methylcarbamoyl]-2H-pyrido[2,1-f][1,2,4]triazine-3-yl]buta-3-enyl]acetate:

[0393] 5-hydroxy-3-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide (2 g, 4.06 mmol) in DMF was mixed with bromomethylbenzene (XX-5) (2.08 g, 12.2 mmol), followed by potassium carbonate (2.93 g, 21.2 mmol). The reaction mixture was stirred overnight at 60°C. Lcms showed a complete reaction. The reaction mixture was diluted with ELISA and washed with saturated NaHCO3 aqueous solution. The organic phase was then treated with MgSO4. The material was dried and the solvent removed under vacuum to obtain the crude material. MS(m / z)625[M+H] + . Synthesis of 5-benzyloxy-3-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide:

[0394] Crude [(2R)-2-[5-benzyloxy-1-(1-methylallyl)-4,6-dioxo-7-[(2,4,6-trifluorophenyl)methylcarbamoyl]-2H-pyrido[2,1-f][1,2,4]triazine-3-yl]buta-3-enyl]acetate (7.61 g, 12.2 mmol) was added to MeOH (100 ml) with NaOH (1N) (63 ml, 63.3 mmol). The mixture was stirred at room temperature for 30 minutes. LC-MS indicated that the reaction was complete. The solvent was removed under vacuum, and the resulting residue was diluted in SiO2 and washed with H2O. The organic layer was dried over MgSO4 and concentrated under vacuum. The resulting crude material was purified by silica gel column chromatography to obtain the marked compound. MS (m / z) 583.01 [M+H] + . Synthesis of 5-benzyloxy-3-[(1R)-1-(fluoromethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide:

[0395] At 0°C, 5-benzyloxy-3-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide (XX-7) (0.82 g, 1.41 mmol) in DCM (8 ml) was mixed with deoxofluor in toluene (2.7 N) (5.21 ml, 14.1 mmol). The mixture was then slowly warmed to room temperature and stirred overnight. The reaction mixture was added to ice-cold NaHCO3 and extracted with DCM. The DCM phase was dried over MgSO4, and the crude product was purified by silica gel column chromatography to obtain the marked compound. MS (m / z) 585.03 [M+H] + . Synthesis of (1S,10R,13R)-6-benzyloxy-10-(fluoromethyl)-13-methyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide:

[0396] 5-benzyloxy-3-[(1R)-1-(fluoromethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide (XX-9) (0.41 g, 0.7 mmol) was dissolved in DEC (25 ml), degassed under vacuum, and then repacked with N2 (3×) at room temperature. Catalyst HG-II was then added to the solution, and the mixture was flushed with argon using a venting needle at 80°C for 1.5 hours. After removing the venting needle, the reaction mixture was stirred overnight at 80°C using an argon balloon. LC-MS showed a complete reaction, the solvent was removed under vacuum, and the resulting residue was purified by silica gel column to obtain the marked compound (XX-9). MS (m / z) 556.94 [M+H] + . Synthesis of (1S,2R,5R)-5-(fluoromethyl)-8-hydroxy-2-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C50):

[0397] (1S,10R,13R)-6-benzyloxy-10-(f) in toluene (2 ml) To 80 mg, 0.144 mmol of tetrazomethyl)-13-methyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide, TFA (2 ml) was added, and the reaction mixture was stirred overnight at room temperature. LC-MS showed a complete reaction. The solvent was removed under vacuum, and the resulting material was purified by preparative HPLC to obtain the indicated compound (51). MS (m / z) 467 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ10.19(s,1H),8.57(s,1H),6.75-6.68(m,3H),5.8 8(dt,J=11.4,2.3Hz,1H),5.65(dt,J=11.4,3.5Hz,1H),5.49(dd,J=32.6,3. 1Hz,1H),5.26(d,J=14.6Hz,1H),4.84(dd,J=9.9,3.3Hz,1H),4.77-4.66(m ,3H),4.67-4.55(m,2H),3.80(dq,J=6.7,3.4Hz,1H),1.43(d,J=6.7Hz,3H). Example 51: Preparation of (1S,2R,5R)-5-(fluoromethyl)-8-hydroxy-2-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C51) [ka]

[0398] (1S,10R,13R)-6-benzyloxy-10-(fluoromethyl)-13-methyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide (from Example 50) (520 mg, 0.93 mmol) was dissolved in EtOH (100 ml), and then Pd / C (10 wt%) (7.8 mg, 0.09 mmol) was added. The mixture was then vacuumed and repacked three times with H2. The reaction was stirred under H2 for 2 hours. LC-MS showed a complete reaction. The reaction mixture was filtered through Celite to remove Pd / C, and the solvent was removed under vacuum. The resulting crude material was purified by preparative HPLC to obtain the labeled compound (XX). MS (m / z) 469.11 [M+H] + 1H NMR(400MHz,Chloroform-d)δ10.37(s,1H),8.61(s,1H),6.82-6.59(m,2H),4.79-4.44(m,7H),3 .64-3.39(m,1H),2.35-2.27(m,1H),2.14-1.86(m,1H),1.71-1.61(m,2H),1.38(d,J=7.1Hz,3H). Example 52: Preparation of (1S,2R,4S,5S)-N-(2,4-difluorobenzyl)-4-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C52): [ka] Step 1: Preparation of (1S,2R,4R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0399] A solution of (1S,2R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (455 mg, 0.85 mmol) prepared according to Example 29 was purged with argon to the added solution of phenylsilane (189 mg, 1.75 mmol) and tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (16 mg, 0.026 mmol). The reaction mixture was stirred at room temperature under an oxygen balloon for 1 day. The reaction was then quenched by adding a 10% sodium thiosulfate solution, and the mixture was extracted with ethyl acetate. The organic phase was separated, dried over MgSO4, filtered, concentrated, and the residue was purified by silica gel chromatography eluted with 0-100% hexane / toluene to obtain the indicated product. MS(m / z) 539.03[M+H]+. Step 2: Preparation of (1S,2R,4S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-fluoro-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0400] A solution of (1S,2R,4R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (20 mg, 0.037 mmol) in DCM (2 mL) was added at 0°C to a deoxofluorine solution in toluene (50%, 0.041 mL, 0.11 mmol). The reaction mixture was stirred at 0°C for 15 minutes, and the reaction product was quenched by adding a saturated NaHCO3 solution. The mixture was extracted with DCM, the organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (eluted with 0-100% hexane / ELISA) to obtain the labeled compound. MS(m / z)540.92[M+H]+. Step 3: Preparation of (1S,2R,4S,5S)-N-(2,4-difluorobenzyl)-4-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0401] To a solution of (1S,2R,4S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-fluoro-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (13 mg, 0.024 mmol) in DCM (1 mL), TFA (1 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC eluting with 5-100% acetonitrile in water to obtain the marked compound. MS (m / z) 451.12 [M+H] +. 1H NMR(400MHz, methanol-d4)δ8.50(s,1H),7.45(td,J=8.5,6.4Hz,1H),7.04-6.90(m,2H),5.13-5.03(m,1H),5.03-4.91(m,2H),4.73(d,J=15.0Hz, 1H),4.65(s,2H),3.50-3.41(m,1H),2.42(dt,J=15.8,7.7Hz,1H),2.01-1.84(m,1H),1.52(dd,J=7.1,1.7Hz,3H),1.41(dd,J=7.1,2.7Hz,3H). Example 53: Preparation of (1S,2R,4R,5S)-N-(2,4-difluorobenzyl)-4-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C53) [ka] Step 1: Preparation of (1S,2R,4S,5S)-8-(benzyloxy)-10-((2,4-difluorobenzyl)carbamoyl)-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-4-ylbenzoate:

[0402] To a solution of (1S,2R,4R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (36.0 mg, 0.067 mmol) in THF (2 mL) prepared according to Example 52, benzoic acid (24.5 mg, 0.201 mmol), diisopropyl azodicarboxylate (40.6 mg, 0.201 mmol), and triphenylphosphine (53 mg, 0.201 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with ethyl acetate, washed with saturated NaHCO3, and extracted with ethyl acetate. The organic phase is dried with MgSO4, filtered, concentrated, and then converted to 0-100%. The residue was purified by silica gel chromatography eluted with xane / ethyl acetate to obtain the indicated product. MS(m / z)643.02[M+H]+. Step 2: Preparation of (1S,2R,4S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0403] LiOH·H2O (2.80 mg, 0.117 mmol) was added to a solution of (1S,2R,4S,5S)-8-(benzyloxy)-10-((2,4-difluorobenzyl)carbamoyl)-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-4-ylbenzoate (15 mg, 0.023 mmol) in MeOH (2 mL) and water (0.5 mL). The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated. The residue was washed with saturated NaHCO3, extracted with ethyl acetate, dried over MgSO4, filtered, concentrated, and used in the next step without purification. Steps 3-4: Preparation of (1S,2R,4R,5S)-N-(2,4-difluorobenzyl)-4-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0404] (1S,2R,4S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-fluoro-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide instead of (1S,2R,4R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-fluoro-2,5-dimethyl-7,9-dioxo-2,3, (1S,2R,4R,5S)-N-(2,4-difluorobenzyl)-4-fluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide was prepared in the same manner as in Example 52, except that 4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide was used. MS(m / z)451.11[M+H] + . 1H NMR (400MHz, methanol-d4) δ8.50(s,1H),7.46(dd,J=8.7,6.4Hz,1H),7.04-6.90(m,2H),5.13-5.03(m,1H),5.03-4.91(m,2H),4.72(d,J=15.0Hz,1 H),4.65(s,2H),3.46(d,J=8.4Hz,1H),2.42(dt,J=15.7,7.9Hz,1H),2.00-1.84(m,2H),1.52(dd,J=7.0,1.7Hz,3H),1.41(dd,J=7.0,2.7Hz,3H). Example 54: Preparation of (1S,2R,5S)-N-(2,4-difluorobenzyl)-4,4-difluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (C54) [ka] Step 1: Preparation of (1S,2R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5-dimethyl-4,7,9-trioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0405] Dess-Martin periodinane (94.5 mg, 0.223 mmol) was added at 0°C to a solution of (1S,2R,4R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (60 mg, 0.11 mmol) in DCM (2.0 mL). The reaction mixture was then stirred at room temperature for 3 hours. The reaction mixture was quenched by adding 1N NaS2SO3, washed with saturated NaHCO3, and extracted with DCM. The organic phase was separated, dried over MgSO4, filtered, concentrated, and the residue was purified by silica gel chromatography eluted with 0-100% hexane / toluene to obtain the indicated compound. MS(m / z) 537.09[M+H]+. Step 2: Preparation of (1S,2R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-4,4-difluoro-2,5-dimethyl-7,9-dioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide:

[0406] A solution of (1S,2R,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2,5-dimethyl-4,7,9-trioxo-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (35 mg, 0.065 mmol) in 2.0 mL of DCM at 0°C was mixed with a 50% deoxofluorine solution in toluene (0.072 mL, 0.20 mmol). The reaction mixture was stirred overnight at room temperature. Further deoxofluorine solutions in toluene (50% deoxofluorine solution in 0.072 mL, 0.20 mmol) were added to the reaction mixture and stirred at room temperature....

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