Substituted pyridotriazine compounds and uses thereof

Abstract

To provide methods for treating diseases.SOLUTION: The present disclosure relates generally to certain tricyclic compounds, pharmaceutical compositions comprising the compounds, and methods of making the compounds and pharmaceutical compositions. The compounds of the disclosure are useful in treating or preventing human immunodeficiency virus (HIV) infection. As elaborated and specifically demonstrated herein, it is surprising that the present invention yields significant effects, which could not have been easily predicted by those skilled in the art on the basis of the prior art.SELECTED DRAWING: None

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application Nos. 63 / 139,237, filed January 19, 2021, and 63 / 190,461, filed May 19, 2021, each of which is incorporated herein in its entirety for all purposes.

[0002] The present disclosure relates generally to certain 2,3-dihydro-1H-pyrido[2,1-f][1,2,4]triazine compounds, pharmaceutical compositions containing such compounds, and methods of making and using such compounds and pharmaceutical compositions. [Background technology]

[0003] Human immunodeficiency virus infection and related diseases are major public health problems worldwide. Human immunodeficiency virus encodes three enzymes required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are widely used and have shown utility, especially when used 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, DD Nature (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 suggest 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, treatment decisions for HIV-infected patients are complicated when patients require treatment for other medical conditions. Because standard treatment requires the use of multiple different drugs to suppress HIV as well as to treat other conditions a patient may experience, the potential for drug interactions is a criterion for selecting a drug regimen. Therefore, there is a need for antiretroviral therapy with a reduced potential for drug interactions.

[0005] In addition, the HIV virus is known to mutate in infected subjects (Tang, et al. Drugs (2012) 72 (9) e1-e25). Because the HIV virus is prone to mutation, there is a need for anti-HIV drugs that are effective against the various known HIV variants (Hurt, et al. HIV / AIDS CID (2014) 58, 423-431). For certain patients, for example, those with poor or limited access to medical care, adherence to a daily oral treatment or prophylactic regimen can be difficult. Drugs that offer favorable pharmaceutical properties (e.g., improved efficacy, long-acting pharmacokinetics, low solubility, low clearance, and / or other properties) are suitable for less frequent administration and provide better Provides patient compliance. Such improvements in turn result in optimizing drug exposure and limiting the emergence 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 Summary of the Invention [Means for solving the problem]

[0007] In some embodiments, the compound of formula I is [ka] During the ceremony, Ar is C6~C 10 aryl or 6-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S; C6-C 10the aryl or 6- to 10-membered heteroaryl is optionally substituted by 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 6-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S; C1-C6 alkyl, C1-C6 alkyloxy, C6-C 10 the 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; R 4 and R 5 are linked together to form a 3- to 6-membered carbocyclic or 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; -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 - in which R 9 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyloxy; R 10 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyloxy; R 9 and R 10 taken together with the carbons to which they are attached form phenyl or a 5- to 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the phenyl or 5- to 6-membered heteroaromatic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy; R 11A , R 11B , R 12A , R 12B , R 13A , and R 13B are each independently H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl; R 11A , R 12A , R 13A , and R 13B are each independently H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl, and R 11B and R 12B taken together with the carbons to which they are attached form a 3- to 6-membered carbocyclic ring, which 3- to 6-membered carbocyclic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy; 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 (i)R 4 Halogen, cyano, C1-C6 alkyl, C1-C6 alkyloxy, C6-C 10 aryl or 6-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; C1-C6 alkyl, C1-C6 alkyloxy, C6-C 10 the 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; R 5 H, halogen, cyano, C1-C6 alkyl, C1-C6 alkyloxy, C6-C 10 aryl or 6-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; C1-C6 alkyl, C1-C6 alkyloxy, C6-C 10 the 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; (ii)R 4 and R 5 are linked together to form a 3- to 6-membered carbocyclic or 4- to 6-membered heterocyclic ring containing one heteroatom; or (iii)R 8A is C1-C3 alkyl or benzyl, or (iv)R 6 Disclosed herein are compounds, or pharmaceutically acceptable salts thereof, wherein is halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl.

[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 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 disclosure provides a method of treating HIV infection in a human having or at risk of having the infection, comprising administering to a subject a therapeutically effective amount of a compound of formula I, or a pharmaceutical composition thereof to said human.

[0011] In some embodiments, the present 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 human having or at risk of having the infection.

[0012] In some embodiments, the present disclosure provides a compound of Formula I, a pharmaceutically acceptable salt thereof, or any pharmaceutical composition thereof, for use in medical therapy.

[0013] In some embodiments, the present disclosure provides a compound of formula I, a pharmaceutically acceptable salt thereof, or any pharmaceutical composition thereof, for use in treating 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 treating HIV infection in a human having or at risk of having the infection. DETAILED DESCRIPTION OF THE INVENTION

[0015] In the following description, certain specific details are set forth to provide a thorough understanding of the various embodiments disclosed herein. However, those skilled in the art will understand that the embodiments disclosed herein may be practiced without these details. The following description of several embodiments is made with the understanding that the disclosure should be considered as an illustration of the claimed subject matter and is not intended to limit the scope of the appended claims to the specific embodiments illustrated. Headings used throughout this disclosure are provided for convenience only and should not be construed in any way as limiting the scope of 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, throughout this specification and claims, the word "comprise" and variations thereof, such as "comprises," i.e., " "Comprising" is to be interpreted in an open and inclusive sense, i.e. "including but not limited to."

[0017] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment disclosed herein. Thus, the appearances 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, the particular features, structures, or characteristics may be combined in any suitable 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 the =O substituent.

[0021] "C u~v " or "(C u ~C v A prefix such as "C" indicates that the following group has u to v carbon atoms. 1~6 "Alkyl" or "C1-C6 alkyl" indicates that the alkyl group has from 1 to 6 carbon atoms.

[0022] "Alkyl" is saturated and has 1 to 12 carbon atoms (C 1~12 alkyl), and in certain embodiments, have 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 straight or branched chain hydrocarbon radical consisting of carbon and hydrogen atoms attached to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (t-butyl), n-pentyl, hexyl, 3-methylhexyl, 2-methylhexyl, and the like.

[0023] "Alkylene" refers to a saturated branched or straight-chain, or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of 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 (-CH-), 1,1-ethyl (-CH(CH)-), 1,2-ethyl (-CHCH-), 1,1-propyl (-CH(CHCH)-), 1,2-propyl (-CHCH(CH)-), 1,3-propyl (-CHCHCHCH-), 1,4-butyl (-CHCHCHCHCH-), and the like.

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

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

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

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

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

[0029] "Heteroaryl" or "heteroaromatic ring" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, each having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl contains 5 to 20 ring atoms (5-20-membered heteroaromatic ring), 5 to 12 ring atoms (5-12-membered heteroaromatic ring), 5 to 10 ring atoms (5-10-membered heteroaromatic ring), or 5 to 6 ring atoms (5-6-membered heteroaromatic ring), and includes 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, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not encompass and does not overlap with aryl, as defined above.

[0030] "Heterocyclyl" or "heterocyclic ring" refers to a non-aromatic radical or ring having 3 to 15 atoms, of which 1 to 6 atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur and are attached to the remainder of the molecule by single bonds. In certain embodiments, a "heterocyclyl" has 3 to 10 atoms, of which 1 to 4 atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or 3 to 7 atoms, of which 1 to 2 atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen, carbon, or sulfur atom in a heterocyclyl can be optionally oxidized, and the nitrogen atom can be optionally quaternized. As used herein, "heterocyclyl" or "heterocyclic ring" refers to a saturated ring unless otherwise indicated; 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, dioxolanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuran, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0031] The embodiments disclosed herein are also meant to encompass all pharmaceutically acceptable compounds of Formula I that are isotopically labeled by replacing one or more atoms with atoms having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as, for example, 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 In certain embodiments, these radiolabeled compounds are useful for determining or measuring the efficacy of compounds, for example, by characterizing the site or mode of action or binding affinity to 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, i.e., 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose because of their ease of incorporation and facile means of detection.

[0032] In certain embodiments, deuterium, i.e., 2 Substitution with heavier isotopes, such as H, may offer certain therapeutic advantages due to greater metabolic stability, such as increased in vivo half-life or reduced required dosage. Thus, in some situations, heavier isotopes may be preferred.

[0033] Substitution with positron-emitting isotopes, e.g. 11 C. 18 F, 15 O, and 13 N is the substrate acceptor They may be useful in Positron Emission Topography (PET) studies to examine volume occupancy. Isotopically labeled compounds of Formula 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 set forth below, using appropriate isotopically labeled reagents in place of conventionally used non-labeled reagents.

[0034] The methods, compositions, kits, and articles of manufacture provided herein employ or include compounds (e.g., compounds of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb) or pharmaceutically acceptable salts thereof, in which 1 to n hydrogen atoms bonded to a carbon atom can be replaced by deuterium atoms, i.e., D, where 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 are useful for increasing the half-life of a compound or a pharmaceutically acceptable salt thereof when administered to a mammal because they have increased resistance to metabolism. See, e.g., 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 have been replaced with deuterium.

[0035] The embodiments disclosed herein are also meant to encompass in vivo metabolic products of the disclosed compounds. Such products may result, for example, from the oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily by enzymatic processes. Accordingly, the embodiments disclosed herein include compounds produced by a process comprising administering a compound according to embodiments disclosed herein to a mammal for a period of time sufficient to yield a metabolic product thereof. Such products are typically identified by administering a detectable dose of a radiolabeled compound according to embodiments disclosed herein to an animal, such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur, and isolating the conversion product from urine, blood, or other biological sample.

[0036] "Mammal" includes both humans and non-domestic animals such as domestic animals, eg, laboratory animals and household pets (eg, cats, dogs, pigs, rabbits, sheep, goats, horses, hares) and wildlife.

[0037] The term "optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances where the event or circumstance occurs and instances where the event or circumstance does not occur. For example, "optionally substituted heterocyclyl" means that the heterocyclyl radical may be substituted or unsubstituted, and that the description includes both substituted and unsubstituted heterocyclyl radicals.

[0038] A "pharmaceutically acceptable excipient" includes, but is not limited to, any carrier, excipient, glidant, sweetener, diluent, preservative, dye / colorant, flavoring, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonicity agent, solvent, emulsifier, or other pharmacologically inactive substance that can be combined with and formulated with a pharmacologically active ingredient of a pharmaceutical composition, is compatible with the other ingredients of the formulation, and is suitable for use in humans or veterinary animals without undue toxicity, irritation, allergic response, etc.

[0039] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include alkali metal (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and NX4 + (Wherein, X is C 1~4Pharmaceutically acceptable salts of a nitrogen atom or an amino group include, for example, salts derived from acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, butyric acid, camphoric acid, cinnamic acid, citric acid, digluconic acid, glutamic acid, glycolic acid, glycerophosphoric acid, 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, pectic acid, phenylacetic acid, 3-phenylpropionic acid, ... Pharmaceutically acceptable salts of hydroxy compounds include salts of organic carboxylic acids such as propionic 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 inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and sulfamic acid. + and NX4 + (X is H or C 1~4 The anions of the compounds include the anions of the compounds in combination with suitable cations such as 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 acids or bases that are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a compound of Formula I or another compound of an embodiment disclosed herein. All salts, whether derived from a physiologically acceptable acid or base, 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 an embodiment disclosed herein. Examples of metal salts prepared in this manner include Li + , Na + , and K +A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.

[0042] Additionally, salts can be formed from the acid addition of certain organic and inorganic acids, such as HCl, HBr, HSO, HPO, or organic sulfonic acids, to a basic center, typically an amine. Finally, it should be understood that the compositions herein include the non-ionized and zwitterionic forms of the compounds disclosed herein.

[0043] A "pharmaceutical composition" refers to a formulation of a compound of the embodiments disclosed herein with a vehicle generally accepted in the art for delivering biologically active compounds to mammals, e.g., humans. Such vehicles include all pharmaceutically acceptable excipients.

[0044] An "effective amount" or "therapeutically effective amount" refers to an amount of a compound according to embodiments disclosed herein that, when administered to a patient in need thereof, is sufficient to effect treatment of a disease state, condition, or disorder disclosed herein. Such an amount would be sufficient to elicit the biological or medical response in a tissue system or patient that is desired by a researcher or clinician. The amount of a compound according to embodiments disclosed herein that constitutes a therapeutically effective amount will vary depending on factors such as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type and severity of the disease state or disorder being treated, drugs used in combination with or concomitantly with the compound of embodiments disclosed herein, and the patient's age, weight, general health, sex, and diet. Such a therapeutically effective amount can be determined by one of ordinary skill in the art having regard to their own knowledge, the state of the art, and this disclosure.

[0045] As used herein, the terms "treating" and "treatment" are intended to mean administering a compound or composition according to the present embodiments disclosed herein to reduce or eliminate one or more symptoms of HIV infection and / or to reduce the viral load in a patient. In certain embodiments, the terms "treating" and "treatment" also encompass administering a compound or composition according to the present embodiments disclosed herein after an individual has been exposed to the virus but before symptoms of the disease appear and / or before the virus is detectable in the blood to prevent symptoms of the disease from appearing and / or the virus from reaching detectable levels in the blood, and administering a compound or composition according to the present embodiments disclosed herein to a mother before birth and to her child within the first few days of life to prevent perinatal transmission of HIV from mother to infant. The terms "treating" and "treatment" also encompass administering a compound or composition according to the embodiments disclosed herein before an individual is exposed to a virus to prevent an HIV infection from becoming established if the individual is exposed to the virus, and / or to bar the virus from establishing a permanent infection, and / or to prevent symptoms of the disease from appearing, and / or to prevent the virus from reaching detectable levels in the blood (also known as pre-exposure prophylaxis (PrEP)). The terms "treating" and "treatment" also encompass administering a compound or composition according to the embodiments disclosed herein both before and after an individual is exposed to the virus.

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

[0047] As used herein, the term "antiviral agent" is intended to mean an agent (compound or biological) that is effective in inhibiting the formation and / or replication of a virus in humans, including, but not limited to, an agent that interferes with either the host or viral mechanisms 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 an agent that is capable of reducing or eliminating the ability of HIV to replicate in host cells, whether in vitro, ex vivo, or in vivo.

[0049] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined with respect to absolute stereochemistry as (R)- or (S)-, or for amino acids as (D)- or (L)-. The present disclosure is meant to encompass 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 resolved using methods such as chromatography and fractional crystallization. Techniques for the preparation / isolation of individual enantiomers include suitable optically pure precursors. or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, these compounds are intended to include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0050] "Stereoisomer" refers to a compound composed of the same atoms connected by the same bonds but having different, non-interchangeable three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, including "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another. 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 rest of the molecule in any position and in any orientation to produce a stable compound. For example, in a compound of Formula I: [ka] In the formula, -XY- is [ka] Compounds of formula [ka] -CR 13A R 13B -CR 9 =CR 10 Similarly, compounds of formula I, in which -XY- is defined as [ka] Compounds of formula [ka] -CR 11A R 11B -CR 12A R 12B -A compound. II. Compounds

[0053] A compound of formula I, [ka] During the ceremony, Ar is C6~C 10 aryl or 6-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from the group consisting of N, O, and S; C6-C 10 the aryl or 6- to 10-membered heteroaryl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkyloxy; R1 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 6-10 membered heteroaryl containing 1, 2 or 3 heteroatoms selected from N, O and S; C1-C6 alkyl, C1-C6 alkyloxy, C6-C 10 the 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; R 4 and R 5 are linked together to form a 3- to 6-membered carbocyclic or 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 each 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 - in which R 9is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyloxy; R 10 is H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyloxy; R 9 and R 10 taken together with the carbons to which they are attached form phenyl or a 5- to 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the phenyl or 5- to 6-membered heteroaromatic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy; R 11A , R 11B , R 12A , R 12B , R 13A , and R 13B are each independently H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl; R 11A , R 12A , R 13A , and R 13B are each independently H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl, and R 11B and R 12B taken together with the carbons to which they are attached form a 3- to 6-membered carbocyclic ring, which 3- to 6-membered carbocyclic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy; 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 (i)R 4 Halogen, cyano, C1-C6 alkyl, C1-C6 alkyloxy, C6-C 10 aryl or 6-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; C1-C6 alkyl, C1-C6 alkyloxy, C6-C 10 the 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; R 5 H, halogen, cyano, C1-C6 alkyl, C1-C6 alkyloxy, C6-C 10 aryl or 6-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; C1-C6 alkyl, C1-C6 alkyloxy, C6-C 10 the 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; (ii)R 4 and R 5 are linked together to form a 3- to 6-membered carbocyclic or 4- to 6-membered heterocyclic ring containing one heteroatom; or (iii)R 8A is C1-C3 alkyl or benzyl, or (iv)R 6 Disclosed herein are compounds, or pharmaceutically acceptable salts thereof, wherein is halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl.

[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 Formula I, Formula Ia, and Formula Ib, Ar is a C-C 10 aryl or 6-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and C6-C 10 The aryl or 6- to 10-membered heteroaryl is optionally substituted with 1 to 4 halogens. In some embodiments, Ar is a C6-C 10 aryl or 6-10 membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; C6-C 10 The aryl or 6- to 10-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from Cl and F.

[0057] In some embodiments of the compounds of Formula I, Formula Ia, and Formula Ib, Ar is a C-C 10 aryl or 6-10 membered heteroaryl containing one heteroatom selected from N, O, and S, and C6-C 10 The aryl 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. In some embodiments, Ar is a C6-C 10 aryl or 6-10 membered heteroaryl containing one heteroatom selected from N, O, and S, and C6-C 10 The aryl 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, and C1-C6 alkyloxy. 10aryl or 6-10 membered heteroaryl containing one heteroatom selected from N, O, and S, and C6-C 10 The aryl or 6- to 10-membered heteroaryl is optionally substituted with 1 to 4 halogens. In some embodiments, Ar is a C6-C 10 aryl or 6-10 membered heteroaryl containing one heteroatom selected from N, O, and S, and C6-C 10 The aryl or 6- to 10-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from Cl and F.

[0058] In some embodiments of the compounds of Formula I, Formula Ia, and Formula Ib, Ar is phenyl 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. In some embodiments, Ar is phenyl optionally substituted with 1-4 substituents independently selected from the group consisting of halogen, C1-C6 alkyl, and C1-C6 alkyloxy. In some embodiments, Ar is phenyl optionally substituted with 1-4 halogen. In some embodiments, Ar is phenyl optionally substituted with 1-3 substituents independently selected from Cl and F.

[0059] In some embodiments of the compounds of Formula I, Formula Ia, and Formula Ib, Ar is phenyl optionally substituted with 1, 2, 3, or 4 substituents independently selected from halogen and C1-C6 alkyloxy. In some embodiments, Ar is phenyl substituted with 1, 2, 3, or 4 substituents independently selected from halo and C1-C4 alkyloxy. In some embodiments, Ar is phenyl substituted with 1, 2, 3, or 4 substituents independently selected from Cl and F.

[0060] In some embodiments of the compounds of Formula I, Formula Ia, and Formula 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 are independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkyloxy.

[0061] In some embodiments of the compounds of Formula I, Formula Ia, and Formula 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 Formula I, Formula Ia, and Formula Ib, Ar is [ka] and n is 1, 2, 3, or 4, and each R A is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkyloxy. In some embodiments of the compounds of Formula I, Formula Ia, and Formula Ib, Ar is [ka] and n is 1, 2, 3, or 4, and each R A is independently halogen, C1-C6 alkyl, and C1-C6 alkyloxy. In some embodiments of the compounds of Formula I, Formula Ia, and Formula Ib, Ar is [ka] and n is 1, 2, 3, or 4, and each R A is independently halogen and C1-C6 alkyloxy. In some embodiments, Ar is [ka] and n is 1, 2, 3, or 4, and each R A is independently halogen and C1-C4 alkyloxy. In some embodiments, Ar is [ka] where n is 1, 2, or 3, and each R A is independently fluoro or chloro.

[0063] In some embodiments of the compounds of Formula I, Formula Ia, and Formula Ib, Ar is [ka] and n is 1, 2, 3, or 4, and each R A is independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkyloxy. In some embodiments of the compounds of Formula I, Formula Ia, and Formula Ib, Ar is [ka] and n is 1, 2, 3, or 4, and each R A is independently halogen, C1-C6 alkyl, and C1-C6 alkyloxy. In some embodiments of the compounds of Formula I, Formula Ia, and Formula Ib, Ar is [ka] and n is 1, 2, 3, or 4, and each R A is independently halogen and C1-C6 alkyloxy. In some embodiments, Ar is [ka] and n is 1, 2, 3, or 4, and each R A is independently halogen and C1-C4 alkyloxy. In some embodiments, Ar is [ka] where n is 1, 2, or 3, and each R A is independently fluoro or chloro.

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

[0065] In some embodiments, the compounds of Formula I, Formula Ia, and Formula Ib disclosed herein have Formula II: [ka] wherein n is 0, 1, 2, 3, or 4; and each R A are independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkyloxy.

[0066] In some embodiments, the compounds of Formula I, Formula Ia, Formula Ib, and Formula II disclosed herein have Formula IIa: [ka] wherein n is 0, 1, 2, 3, or 4; and each R A are independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkyloxy.

[0067] In some embodiments, the compounds of Formula I, Formula Ib, and Formula II disclosed herein have Formula IIb: [ka] wherein n is 0, 1, 2, 3, or 4; and each R A are independently halogen, C1-C6 alkyl, C1-C6 haloalkyl, and C1-C6 alkyloxy.

[0068] In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, and IIb, - XY-CR 13A CR 13B -CR 9 =CR 10 -, wherein R 9 , R 10 , R 13A , and R 13B are each independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyloxy, or R 13A and R 13B are each independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyloxy, and R 9 and R 10 together with the carbons to which they are attached form phenyl or a 5- to 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the phenyl or 5- to 6-membered heteroaromatic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy.

[0069] In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, and IIb, -XY- is -CR 9 =CR 10 wherein each R 9 and R 10 are independently H, halogen, C1-C6 alkyl, C1-C6 haloalkyl, or C1-C6 alkyloxy, or R 9 and R 10 together with the carbons to which they are attached form phenyl or a 5- to 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the phenyl or 5- to 6-membered heteroaromatic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy.

[0070] In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, and IIb, -XY- is -CH2-CR 9 =CR 10 -, wherein R 9 and R 10 are taken together with the carbons to which they are attached to form a phenyl or a 5-6 membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the phenyl or 5-6 membered heteroaromatic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy. In some embodiments, -XY- is -CH2-CR 9 =CR 10 -, wherein R 9 and R 10 together with the carbons to which they are attached form a 5- to 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and the 5- to 6-membered heteroaromatic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy.

[0071] In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, and IIb, -XY- is -CR 9 =CR 10 -, wherein R 9 and R 10 are taken together with the carbons to which they are attached to form a phenyl or a 5-6 membered heterocyclic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, wherein the phenyl or 5-6 membered heteroaromatic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy. 9 =CR10 -, wherein R 9 and R 10 together with the carbons to which they are attached form a 5- to 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and the 5- to 6-membered heteroaromatic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy.

[0072] In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, and IIb, - XY-, -CH2-CR 9 =CR 10 - and R 9 and R 10 together with the carbons to which they are attached form a 5- to 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and the 5- to 6-membered heteroaromatic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy.

[0073] In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, and IIb, -XY- is -CR 9 =CR 10 -, wherein R 9 and R 10 together with the carbons to which they are attached form a 5- to 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, and the 5- to 6-membered heteroaromatic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy.

[0074] In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, and IIb, -XY- is -CH2-CR9 =CR 10 -, wherein R 9 and R 10 together with the carbons to which they are attached form a 5- to 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N and O, and the 5- to 6-membered heteroaromatic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy.

[0075] In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, and IIb, -XY- is -CR 9 =CR 10 -, wherein R 9 and R 10 together with the carbons to which they are attached form a 5- to 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N and O, and the 5- to 6-membered heteroaromatic ring is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy.

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

[0077] In some embodiments of the compound 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 are independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkyloxy.

[0078] In some embodiments of the compounds of Formula I, Ia, II, IIa, and III, the compounds have the formula IIIa: [ka] During the ceremony, m is 0, 1, 2, or 3; Each R B are independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkyloxy.

[0079] In some embodiments of the compounds of Formula I, Ib, II, IIb, and III, the compounds have the formula IIIb: [ka] During the ceremony, m is 0, 1, 2, or 3; Each R B are independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, or C1-C3 alkyloxy.

[0080] In some embodiments of compounds of Formula 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 some embodiments, m is 1. In some embodiments, m is 2. In an embodiment, m is 3.

[0081] In some embodiments of compounds of Formula III, IIIa, and IIIb, each R B are independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy. B is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl. B is independently halogen or C1-C3 alkyl. In some embodiments, each R B are independently halogen.

[0082] In some embodiments of compounds of Formula III, IIIa, and IIIb, m is 0, 1, or 2, and each R B is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy. In some embodiments, m is 0, 1, or 2, and each R B is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments, m is 0, 1, or 2, and each R B is independently halogen or C1-C3 alkyl. In some embodiments, m is 0, 1, or 2, and each R B are independently halogen.

[0083] In some embodiments of compounds of Formula III, IIIa, and IIIb, m is 0 or 1 and each R Bis independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy. In some embodiments, m is 0 or 1, and each R B is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments, m is 0 or 1, and each R B is independently halogen or C1-C3 alkyl. In some embodiments, m is 0 or 1, and each R B are independently halogen.

[0084] In some embodiments of compounds of Formula III, IIIa, and IIIb, m is 1 or 2, and each R B is independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy. In some embodiments, m is 1 or 2, and each R B is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments, m is 1 or 2, and each R B is independently halogen or C1-C3 alkyl. In some embodiments, m is 1 or 2, and each R B are independently halogen.

[0085] In some embodiments of compounds of Formula III, IIIa, and IIIb, m is 1 and R B is halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy. In some embodiments, m and R B is halogen, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments, m is 1 and R B is halogen or C1-C3 alkyl. In some embodiments, m is 1 and R B is a halogen.

[0086] In some embodiments of compounds of Formula III, IIIa, and IIIb, m is 2 and each R Bis independently halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy. In some embodiments, m is 2 and each R B is independently halogen, C1-C3 alkyl, or C1-C3 haloalkyl. In some embodiments, m is 2 and each R B is independently halogen or C1-C3 alkyl. In some embodiments, m is 2 and each R B are independently halogen.

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

[0088] In some embodiments of the compounds of Formula I, Ia, II, IIa, and IV, the compounds have the formula IVa: [ka] In the formula, z is 0 or 1.

[0089] In some embodiments of the compounds of Formula I, Ib, II, IIb, and IV, the compounds have the formula IVb: [ka] In the formula, z is 0 or 1.

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

[0091] In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, and IIb, -XY- is -CR 11A R 11B -CR 12A R 12B wherein each R 11A , R 11B , R 12A , and R 12B are independently H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl, or each R 11A and R 12A are independently H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl, and R 11B and R 12B taken together with the carbons to which they are attached form a 3- to 6-membered carbocyclic ring, which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy.

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

[0093] In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, and IIb, -XY- is -CR 11A R 11B -CR 12A R 12B wherein each R 11A and R 12A are independently H, halogen, C1-C6 alkyl, C1-C6 alkyloxy, or C1-C6 haloalkyl, and R 11B and R 12B taken together with the carbons to which they are attached form a 3- to 6-membered carbocyclic ring, which is optionally substituted with 1, 2, or 3 substituents independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 haloalkyl, and C1-C3 alkyloxy.

[0094] In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, and IIb, the compounds have the formula V: [ka] In the formula, z' is 1 or 2.

[0095] In some embodiments of the compounds of Formula I, Ia, II, IIa, and V, the compounds have the formula Va: [ka] In the formula, z' is 1 or 2.

[0096] In some embodiments of the compounds of Formula I, Ib, II, IIb, and V, the compounds have the formula Vb: [ka] In the formula, z' is 1 or 2.

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

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

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

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

[0101] In some embodiments of the compounds of Formula 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 C1-C3 alkyl or phenyl, and R 2 is H. In some embodiments, R 1 and R 2 are both H. In some embodiments, R 1 is a C1-C3 alkyl, and R 2 is H. In some embodiments, R 1 is phenyl and R 2 is H.

[0102] In some embodiments of the compounds of Formula 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 C1-C3 alkyl. In some embodiments, R 1 is H and R 2 is C1-C3 alkyl. In some embodiments, R 1 is H or C1-C3 alkyl, and R 2 is C1-C3 alkyl. In some embodiments, R 1 is C1-C3 alkyl or phenyl, and R 2 is C1-C3 alkyl. In some embodiments, R 1 is H and R 2 is C1-C3 alkyl. In some embodiments, each R 1 and R 2 is independently C1-C3 alkyl. In some embodiments, R 1 is phenyl and R 2 is C1-C3 alkyl. In some embodiments, each R 1 and R 2 are independently H or C1-C3 alkyl.

[0103] In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb described herein, each R 4 and R 5 is independently H or C1-C6 alkyl, where C1-C6 alkyl is optionally substituted with 1, 2, or 3 groups independently selected from halogen, C1-C3 alkyloxy, or C1-C3 haloalkyloxy. 4 is H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1, 2, or 3 groups independently selected from halogen, C1-C3 alkyloxy, or C1-C3 haloalkyloxy; R 5 is H or C1-C6 alkyl. In some embodiments, R 4 is H or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1, 2, or 3 groups independently selected from halogen, C1-C3 alkyloxy, or C1-C3 haloalkyloxy; R 5 But it's H.

[0104] In some embodiments of the compounds of formula IV, IVa, and IVb described herein, R 4 is halogen or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1, 2, or 3 groups independently selected from halogen, C1-C3 alkyloxy, or C1-C3 haloalkyloxy; R 5 is H, halogen, or C1-C6 alkyl, and the C1-C6 alkyl is optionally selected from halogen, C1-C3 alkyloxy, and C1-C3 haloalkyloxy; or 3 groups. In some embodiments, R 4is halogen or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1, 2, or 3 groups independently selected from halogen, C1-C3 alkyloxy, or C1-C3 haloalkyloxy; R 5 is H, halogen, or C1-C6 alkyl. In some embodiments, R 4 is halogen or C1-C6 alkyl, wherein the C1-C6 alkyl is optionally substituted with 1, 2, or 3 groups independently selected from halogen, C1-C3 alkyloxy, or C1-C3 haloalkyloxy; R 5 But it's 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 is independently H, Me, OMe, or CHF. In some embodiments, R 4 is H, Me, OMe, or CHF, and R 5 is H.

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

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

[0108] In some embodiments of the compounds of Formula 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. 6 is H, halogen, or C1-C6 alkyl. In some embodiments, R 6 is halogen or C1-C6 alkyl. In some embodiments, R 6 is C1-C6 alkyl. In some embodiments, R 6 is H.

[0109] In some embodiments of the compounds of Formula 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. 7 is H, halogen, or C1-C6 alkyl. In some embodiments, R 7 is halogen or C1-C6 alkyl. In some embodiments, R 7 is C1-C6 alkyl. In some embodiments, R 7 is H.

[0110] In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is [ka] [ka] is selected from the group consisting of:

[0111] In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is [ka] [ka] is selected from the group consisting of:

[0112] In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is [ka] [ka] is selected from the group consisting of:

[0113] In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0114] In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is [ka] [ka] [ka] is selected from the group consisting of:

[0115] In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0116] In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is [ka] [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0117] In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is [ka] [ka] [ka] [ka] is selected from the group consisting of:

[0118] In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is [ka] [ka] [ka] is selected from the group consisting of:

[0119] In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is [ka] [ka] is selected from the group consisting of:

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

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

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

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

[0124] In some embodiments, the compounds of formula I, Ia, Ib, II, IIa, IIb, III, III The compound of formula (Illa), IIIb, IV, IVa, IVb, V, Va, or Vb is [ka] is.

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

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

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

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

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

[0130] In some embodiments, the compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb is [ka] is. 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 pharmaceutically acceptable salts, isomers, or mixtures thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients are also provided herein. The compounds provided herein may be the sole active ingredient or may be one of the active ingredients of the pharmaceutical composition. Suitable pharmaceutically acceptable vehicles include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical arts. For example, see Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0132] In one aspect, provided herein is a pharmaceutical composition 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 compositions provided herein further comprise one or more (e.g., 1; 2; 3; 4; 1 or 2; 1 to 3; or 1 to 4) additional therapeutic agents, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of one or more (e.g., 1; 2; 3; 4; 1 or 2; 1 to 3; or 1 to 4) additional therapeutic agents, or pharmaceutically acceptable salts thereof.

[0134] The pharmaceutical compositions may be administered in either a single dose or multiple doses. The pharmaceutical compositions may be administered by a variety of methods, including, for example, rectal, oral, intranasal, and transdermal routes. In some embodiments, the pharmaceutical compositions may be administered by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0135] One mode of administration is parenterally, 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 with 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, via capsules or enteric-coated tablets. When preparing pharmaceutical compositions containing at least one compound provided herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, the active ingredient (such as a compound provided herein) is typically diluted with an excipient and / or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, the excipient may be in the form of a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the pharmaceutical composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), for example, an ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile-packaged powders.

[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; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners, and flavoring agents; or any combination thereof.

[0138] Pharmaceutical compositions containing 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 a compound provided herein) after administration to a subject using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and solution-based systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are found in U.S. Patent Nos. 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 transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of a compound provided herein in controlled amounts. The construction and use of transdermal patches to deliver pharmaceutical agents is 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, pulsatile, 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 mixture of the compound described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof. Solid preformulation compositions may be formed containing the mixture. These preformulation compositions are referred to as homogeneous because the active ingredient may be dispersed evenly throughout the composition, such that the composition may be readily subdivided into uniformly effective unit dosage forms, such as tablets, pills, and capsules.

[0140] Tablets or pills of the compounds described herein can be coated or otherwise compounded to provide a dosage form offering the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, the tablets or pills can comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer, which serves to resist disintegration in the stomach and allow the inner component to pass intact into the duodenum or be delayed in release. A variety of materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0141] Pharmaceutical compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous 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 by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be atomized by use of an inert gas. The atomized solution may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing device. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0142] In one aspect, provided herein are kits that include 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 includes instructions for use. In some embodiments, the kit includes 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 use of the compound in treating an indication, including a disease or condition described herein.

[0143] In some embodiments, the kit further comprises one or more (e.g., 1; 2; 3; 4; 1 or 2; 1 to 3; or 1 to 4) additional therapeutic agents, or pharmaceutically acceptable salts thereof.

[0144] In one aspect, provided herein is an article of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, in a suitable container, hi some embodiments, the container can be a vial, jar, ampoule, pre-filled syringe, or infusion bag. IV. Method

[0145] In one embodiment, a method of treating HIV (e.g., HIV-1 and / or HIV-2) infection in a human having or at risk of having such infection comprises administering 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 salt thereof. and administering to the human 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.

[0146] In some embodiments, the method further comprises administering to the human a therapeutically effective amount of one, two, three, or four additional therapeutic agents. In certain embodiments, the additional therapeutic agent is an anti-HIV agent. In certain embodiments, the additional therapeutic agent is 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, an HIV bNAb (broadly neutralizing HIV antibody), a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof. In one embodiment, the additional therapeutic agent is abacavir, tenofovir alafenamide, tenofovir disoproxil, lenacapavir, or a pharmaceutically acceptable salt 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, there is provided 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, for treating HIV (e.g., HIV-1 and / or HIV-2) infection in a human having or at risk of having that infection.

[0148] In another embodiment, there is provided 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, for use in medical therapy.

[0149] In another embodiment, there is provided 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, for use in the treatment of HIV infection.

[0150] In another embodiment, there is provided 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, for use in a method of treating HIV infection in a human having or at risk of having such infection.

[0151] In another embodiment, a compound of Formula I, Ia, Ib, II, IIa, IIb, IIc, IId, IIe, IIf, IIg, IIh, IIi, IIj ... and 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, wherein the method further comprises administering to the human one, two, three, or four additional therapeutic agents.

[0152] In another embodiment, there is provided 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, for use in a method of treating HIV infection in a human having or at risk of having such infection, the method comprising administering to a human a therapeutic agent selected from the group consisting of 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, an HIV further comprising administering to the human one, two, three, or four additional therapeutic agents selected from the group consisting of a bNAb, a TLR7 agonist, a pharmacokinetic enhancer, another agent for treating HIV, or a combination thereof. In one embodiment, the one, two, three, or four additional therapeutic agents are selected from an HIV protease inhibitor, an HIV non-nucleoside inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, a latency reactivator, an HIV capsid inhibitor, an HIV bNAb, a TLR7 agonist, and a combination thereof.

[0153] In another embodiment, there is provided 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, for use in a method of treating HIV infection in a human having or at risk of having the infection, the method further comprising administering therapeutically effective amounts of tenofovir disoproxil and emtricitabine to the human.

[0154] In another embodiment, there is provided 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, for use in a method of treating HIV infection in a human having or at risk of having the infection, the method further comprising administering therapeutically effective amounts of tenofovir alafenamide and emtricitabine to the human.

[0155] In another embodiment, there is provided 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, for use in a method of treating HIV infection in a human having or at risk of having the infection, the method further comprising administering a therapeutically effective amount of tenofovir disoproxil to the human.

[0156] In another embodiment, in a human having or at risk of having HIV infection and 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, for use in a method for treating an infection in a human, the method further comprising administering a therapeutically effective amount of tenofovir alafenamide to the human.

[0157] In another embodiment, methods of using a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb in therapy are provided. In particular, methods are provided for treating HIV viral growth, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human), comprising administering to the mammal 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.

[0158] In another embodiment, there is provided a composition 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 growth of the HIV virus, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human).

[0159] In one embodiment, there is provided 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, for use in the prevention of HIV infection.

[0160] For example, in one embodiment, there is provided 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, for use in pre-exposure prophylaxis (PrEP), i.e., for use before an individual is exposed to the HIV virus, to prevent an HIV infection from becoming established when the individual is exposed to the virus, and / or to hinder the virus from establishing a permanent infection, and / or to prevent symptoms of the disease from appearing, and / or to prevent the virus from reaching detectable levels in the blood.

[0161] In another embodiment, disclosed is 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, for the manufacture of a medicament for treating HIV infection in a human having or at risk of having the infection.

[0162] 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, as a research tool is disclosed.

[0163] In another embodiment, an article of manufacture comprising a composition effective to treat HIV infection, and Packaging materials are disclosed that include a label indicating that the composition can be used to treat infection by HIV. Exemplary compositions include 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.

[0164] In yet another embodiment, a method of inhibiting HIV replication is disclosed, the method comprising 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 such that HIV replication is inhibited.

[0165] 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 to inhibit the activity of the HIV integrase enzyme is disclosed.

[0166] 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 salt thereof, to inhibit the replication of HIV is disclosed. V. Administration

[0167] The compounds of the present disclosure (also referred to herein as active ingredients) can be administered by any route appropriate to the ill health condition being treated. Suitable 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 depending, for example, on the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0168] The compounds of the present disclosure can be administered to an individual according to an effective dosing regimen for any desired period or duration, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more, in some embodiments, the compounds are administered on a daily or intermittent schedule for the duration of the individual's life.

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

[0170] The daily dose may also be described as the total amount of a compound described herein administered per administration 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 tautomer thereof, may be about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day.

[0171] The dosage or frequency of administration of a compound of the present disclosure may be adjusted over the course of treatment, based on the judgment of the administering physician.

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

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

[0174] The compounds of the present disclosure can be combined with one or more additional therapeutic agents at any dosage of the compound of the present disclosure (e.g., 1 mg to 1000 mg of compound). Therapeutically effective amounts can include from about 0.1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or from about 100 mg per dose to about 400 mg per dose, or from about 150 mg per dose to about 350 mg per dose, or from about 200 mg per dose to about 300 mg per dose, or from about 0.01 mg per dose to about 1000 mg per dose, or from about 0.01 mg per dose to about 100 mg per dose, or from about 0.1 mg per dose to about 100 mg per dose, or from about 1 mg per dose to about 100 mg per dose, or from about 1 mg per dose to about 10 mg per dose, or from about 1 mg per dose to about 1000 mg per dose. Other therapeutically effective amounts of a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are about 1 mg per dose, or about 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 about 100 mg per dose. Other therapeutically effective amounts of compounds of the present disclosure are about 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 about 1000 mg per dose.

[0175] In some embodiments, the methods described herein include administering to a subject an initial daily dose of about 1-500 mg of a compound of formula (I) described herein, and increasing the dose incrementally until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose can be increased daily, every other day, twice a week, once a week, once every two weeks, once every three weeks, or once a month.

[0176] When administered orally, the total daily dosage for a human subject can be about 1 mg to 1,000 mg, about 10 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 100 to 150 mg / day. In some embodiments, the total daily dosage for a human subject can be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject can be about 200, 300, 400, 500, or 1000 mg / day administered in a single dose. , 600, 700, or 800 mg / day. In some embodiments, the total daily dosage for a human subject can be about 300, 400, 500, or 600 mg / day administered in a single dose.

[0177] In some embodiments, the total daily dosage for a human subject may be about 100 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 150 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 200 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 250 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 300 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 350 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 400 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 450 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 500 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 550 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 600 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 650 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 700 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 750 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 800 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 850 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 900 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 950 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject can be about 1000 mg / day administered in 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, 16 hours, or once every 24 hours. A single dose can also be administered once every 1, 2, 3, 4, 5, 6 days, or once every 7 days. A single dose can also be administered once every 1, 2, 3 weeks, or once every 4 weeks. In some embodiments, a single dose can be administered once weekly. A single dose can also be administered once monthly. In some embodiments, a compound disclosed herein is administered once daily in a method disclosed herein. In some embodiments, a compound disclosed herein is administered twice daily in a method disclosed herein.

[0179] In some embodiments, a compound disclosed herein is administered once every 10 days. In some embodiments, a compound disclosed herein is administered once every 15 days. In some embodiments, a compound disclosed herein is administered once every 20 days. In some embodiments, a compound disclosed herein is administered once every 10-15 days. In some embodiments, a compound disclosed herein is administered once every 15-20 days. In some embodiments, a compound disclosed herein is administered once every 10-20 days. In some embodiments, a compound disclosed herein is administered once every month. In some embodiments, a compound disclosed herein is administered once every two months. In some embodiments, a compound disclosed herein is administered once every three months. In some embodiments, a compound disclosed herein is administered once every four months. 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 every year.

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

[0181] Administration can be intermittent, with the patient receiving a daily dose of a compound of the present disclosure for a period of several days or more, followed by a period of several days or more during which the patient does not receive a daily dose of the compound. For example, the patient can receive a dose of the compound every other day or three times per week. As a further example, the patient can receive a 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 dose of the compound, followed by a subsequent period (e.g., 1 to 14 days) during which the patient again receives a daily dose of the compound. The alternating periods of compound administration followed by non-compound administration can be repeated as clinically needed to treat the patient.

[0182] The compounds of the present disclosure or pharmaceutical compositions thereof can be administered once, twice, three times, or four times daily using any suitable method described above. Administration or treatment with the compound can also continue for several days; for example, treatment typically lasts for at least 7, 14, or 28 days per treatment cycle. Treatment cycles are well known in cancer chemotherapy and frequently alternate with rest periods of about 1 to 28 days, typically about 7 days or about 14 days, between cycles. Treatment cycles can also be continuous in other embodiments. VI. Combination Therapy

[0183] In certain embodiments, methods are provided for treating or preventing HIV infection in a human having or at risk of having the infection, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one; two; three; one or two; or one to three) additional therapeutic agents. In one embodiment, methods are provided for treating HIV infection in a human having or at risk of having the infection, comprising administering to the human a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one; two; three; one or two; or one to three) additional therapeutic agents.

[0184] In one embodiment, a pharmaceutical composition is provided that includes 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, in a pharmaceutically acceptable carrier, diluent, or excipient.

[0185] In certain embodiments, the present disclosure provides a method for treating an HIV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating an HIV infection.

[0186] In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents and / or can 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.The 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 therapeutically effective amounts of both the compounds disclosed herein and one or more additional therapeutic agents are present in the patient's body.When administered sequentially, the combination can be administered in two or more doses.

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

[0189] In certain embodiments, the compounds disclosed herein are combined with one or more additional therapeutic agents in a unit dosage form for simultaneous administration to a subject, e.g., 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 in 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 site (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 above embodiments, the additional therapeutic agent can be an anti-HIV agent, such as 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 integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV synthesis inhibitor, an HIV integrase inhibitor, an HIV protease inhibitor, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV synthesis inhibitor, an HIV integrase ... Maturation inhibitors, immunomodulators, immunotherapeutics, antibody-drug conjugates, gene modifiers, gene editing agents (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN, etc.), cell therapy (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 therapy, 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 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 splice inhibitors splicing 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, retrocyclin modulators, CDK-9 inhibitors, CCR5 chemokine antagonists, CCR5 gene modulators, dendritic ICAM-3 grabbing nonintegrin 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 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

[0193] In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV combination medications, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune system therapies, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof. HIV combination drugs

[0194] Examples of combination medications include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); BIKTARVY® (bictegravir, emtricitabine, tenofovir alafenamide); 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® (TDF+FTC); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); SYMTUZA® (darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat); SYMFIT™ (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 Trademarks) (ALUVIA®, lopinavir and ritonavir), TRIUMEQ® (dolutegravir, abacavir, and lamivudine); TRIZIVIR® (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 rilpivirine Rupivirine hydrochloride; dolutegravir, abacavir sulfate, and lamivudine; lamivudine, nevirapine, and zidovudine; raltegravir and lamivudine; doravirine, lamivudine, and tenofovir disoproxil fumarate; doravirine, lamivudine, and tenofovir disoproxil; dapivirine and levonorgestrel, dolutegravir and lamivudine, dolutegravir and emtricitabine and tenofovir alafenamide, elsulfavirine and emtricitabine and tenofovir disoproxil Roxyl, 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] Examples of other drugs for treating HIV include acemannan, alisporivir, astodrimer, BanLec, CC-11050, deferiprone, Gamimune, Griffithsin, metenkefalin, 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 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, brecanavir, 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 HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, A CC-007, AIC-292, KM-023, PC-1005, and elsulfavirine (VM-1500).

[0198] Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase 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 EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, tidoxilfodivudine, islatravir, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, lobafovir etalafenamid (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, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, and bictegravir. vir, AVX-15567, BMS-986197, cabotegravir (long-acting injectable), 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, stilbene disulfonic acid, T-169, VM-3500, and cabotegravir.

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

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

[0202] Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (PRO-140), adaptavir (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, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide.

[0204] Examples of CD4 binding inhibitors include ibalizumab and CDA analogs.

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

[0206] Examples of CXCR4 inhibitors include plerixafor, 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. agent, BET-bromodomain 4 (BRD4) inhibitor, ionomycin, These include PMA, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), IL-15 modulating 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 indolactams, prostratin, ingenol B, and DAG-lactone. Capsid inhibitors

[0211] Examples of capsid inhibitors include capsid polymerization inhibitors or capsid-disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors, such as azodicarbamate. 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 immune system therapies 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, 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 derivatives; 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, These include NKTR-214, Normferon, pegylated interferon alfa-2a, pegylated interferon alfa-2b, recombinant interleukin-15, Xmab-24306, RPI-MN, STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103.

[0213] Examples of TLR agonists: vesatolimod (GS-9620), GS-986, IR-103, lefitolimod, tilsotolimod, lintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, tellulatorimod, RO-7020531. Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0214] Examples of PI3K inhibitors include idelalisib, alpelisib, bupallisib, CAI orotate, copanlisib, duvelisib, gedatrisib, neratinib, panulisib, perifosine, pictilisib, pilalalisib, pukitinib mesylate, rigosertib, rigosertib sodium, sonoliside, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, 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 antagonists

[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, multivalent antibodies, bnAB (broadly neutralizing HIV-1 antibody), BMS-936559, TMB-360, and HIV These include antibodies targeting gp120 or gp41, antibody recruiting 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-targeting antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAb (PGT-121), ibalizumab, Immuglo, and MB-66.

[0217] Examples of drugs targeting HIV in such a way include bavituximab, 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 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, TMB-bispecific.

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

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

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

[0221] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, arenavirus vaccines, and lymphocytic choriomeningitis virus (LCVM). Viruses such as LCMV, Pichinde virus, modified vaccinia Ankara virus (MVA), adenovirus, adeno-associated virus (AAV), vesicular stomatitis virus (VSV), and chimpanzee adenovirus (ChAd) Live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, BG505 SOSIP.664 gp140, rgp120 (AIDSVAX), ALVAC HIV, (vCP1521) / AIDSVAX B / E(gp120) (RV144), monomeric 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, multiclad 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-adjuvanted 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 vaccines, GTU-based DNA vaccines, HIV gag / pol / nef / env DNA vaccines, anti-TAT HIV vaccine, conjugate polypeptide vaccine, dendritic cell vaccine, gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), Ii-key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multiclad 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 Env These include HIV-1 vaccine (GLA-SE adjuvant), HIV p24gag prime-boost plasmid DNA vaccine, arenavirus vector-based immunotherapy (Vaxwave, TheraT), MVA-BN HIV-1 vaccine regimen, MVA.tHIVconsv4, MVA.tHIVconsv3, UBI HIV gp120, mRNA-based prophylactic vaccine, 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 pharmaceutically acceptable salts thereof are selected from the group consisting of 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® ( ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; T RIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® Registered Trademarks) (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; Prolastin; Fosamprenavir; Fosamprenavir calcium; Efavirenz; Etravirine; Nelfinavir; Nelfinavir mesylate Salt;Interferon;Didanosine;Stavudine;Indinavir;Indinavir sulfate;Tenofovir and lamivudine;Zidovudine;Nevirapine;Saquinavir;Saquinavir mesylate;Aldesleukin;Zalcitabine;Tipranavir;Amprenavir;Delavirdine;Delavirdine mesylate;Radha-108 (Receptor);Lamivudine and tenofovir disoproxil fumarate;Efavirenz, lamivudine, and tenofovir disoproxil fumarate;Phosphazides;Lamivudine, nevirapine, and zidovudine;in combination with one, two, three, four or more additional therapeutic agents selected from abacavir and abacavir sulfate;

[0223] Those skilled in the art will appreciate that the additional therapeutic agents listed above may fall into more than one of the classes listed above. The particular classes are not intended to limit the functionality of the compounds listed in those classes.

[0224] In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV protease inhibitor compound. In additional embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0225] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is 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, are , tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0227] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is 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, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is 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, wherein the second additional therapeutic agent is emtricitabine.

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

[0230] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30, or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. A compound disclosed herein (e.g., a compound of Formula I) can be combined with a drug provided herein at any dosage of the compound (e.g., 1 mg to 500 mg of the compound), as if each dosage combination were specifically and individually listed.

[0231] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is 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, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is 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) can be administered in combination with the compounds provided herein. The drugs may be combined in any dosage of the compound (eg, 1 mg to 500 mg of compound), as long as each combination of dosages is specifically and individually listed.

[0232] In one embodiment, a kit is provided that includes 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 to 3) additional therapeutic agents. Combined birth control (contraceptive) therapy

[0233] Therapeutic agents used for birth control (contraception) include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, ethynodiol, etonogestrel, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norregestromin, norethindrone, nortinodrel, norgestimate, ormeloxifene, segestrel acetate, ulipristal acetate, and any combination thereof. Gene Therapy and Cell Therapy

[0234] Gene and cell therapies include genetic modifications to silence genes; genetic approaches to directly kill infected cells; infusion of immune cells designed to either replace a large portion of a patient's own immune system to enhance the immune response against infected cells, or activate the patient's own immune system to kill infected cells, or to find and kill infected cells; and genetic approaches to modify cellular activity to further alter the endogenous immune responsiveness to infection.

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

[0236] Examples of CCR5 gene editing drugs, such as SB-728T.

[0237] Examples of CCR5 gene inhibitors, such as 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 a CRISPR / Cas9 system, a zinc finger nuclease system, a TALEN system, a homing endonuclease system, and a meganuclease system.

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

[0243] engineered to express a chimeric antigen receptor (CAR) and a population of immune effector cells, wherein the CAR comprises an HIV antigen-binding domain. The HIV antigen includes an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, a CD4-inducible binding site on gp120, an N-glycan on gp120, V2 of gp120, or a membrane proximal region on gp41. The immune effector cells are T cells or NK cells. In some embodiments, the 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, an anti-CD4 CAR cell therapy, and autologous hematopoietic stem cells genetically engineered to express the CD4 CAR and C46 peptide. TCR-T cell therapy

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

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

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

[0248] In the following description of the examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the present disclosure. Other embodiments may be utilized, and logical and other changes may be made without departing from the scope of the present disclosure. Accordingly, the following description is not intended to limit the scope of the present disclosure. Examples 1 to 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 WO 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 dione (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 h. The reaction mixture was stirred overnight without refilling the cold bath. The reaction mixture was then diluted with EtOAc and treated with NH4Cl / water. The organic phase was separated and concentrated. The residue was purified by silica gel chromatography using 0-100% EtOAc in heptane, followed by 10% MeOH in EtOAc, to give a mixture of two regioisomers of the product (2-a and 2-b). MS (m / z): 392.1 [M+H]. These two regioisomers were not separated and were carried on 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 min. Additional m-CPBA (77%) (114 mg, 0.51 mmol) and NIS (114 mg, 0.51 mmol) were added sequentially. The reaction mixture was again heated at 80 °C for 30 min. The reaction mixture was then diluted with EtOAc and treated with NaHCO3 / water and Na2SO3 (10%) in water. The organic phase was separated and concentrated. The residue was purified on a silica gel column using 0-100% EtOAc / heptane to give the product as a mixture of two regioisomers (3-a and 3-b) (60 mg). MS (m / z): 518.06 [M+H]. These two regioisomers were not separated and were carried on 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 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) was added 2,4,6-trifluorobenzylamine (50 mg, 0.309 mmol), DIPEA (40 mg, 0.309 mmol), and Pd(PPh) (3.57 mg, 0.00309 mmol). CO (g) was bubbled through the reaction mixture for 10 minutes. The reaction mixture was then heated at 80 °C under a CO atmosphere for 17 hours. 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 brine. The organic phase was then dried over Na2SO4 and concentrated. The residue was purified on a silica gel column using 0-100% EtOAc in hexane to give the desired product. This mixture of four isomers was subjected to SFC separation (ADH 50 IPA-NH3) to give the four isomers in descending order of 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) 6 mg. 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) 7 mg.MS (m / z): 579.03 [M+H], and 4 mg 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). 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 in one portion. The reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated to dryness. The residue was taken up in MeOH and purified by reverse-phase preparative HPLC using 0-100% CH3CN in water with 0.1% TFA to give the desired product. Lyophilization afforded the product as the TFA salt. 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 [g] Preparation of pyrido[1,2-b][1,2,5]triazonine-3-carboxamide (C2):

[0254] The synthesis of the title product was carried out in a similar manner to (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-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 synthesis of the title product was carried out in a similar manner to (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-a). The product was obtained as the TFA salt. MS (m / z): 489.18 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d3) δ 10.13 (s, 1H), 8.52 (s, 1H), 7.32 (dd, J = 8.4, 5.8 Hz, 1H), 7.23-7.08 (m, 1H), 7.08-6.97 (m, 1H), 6.88 (t, J = 8.5 Hz, 2H), 5.56 (d, J = 16.7 Hz, 1H), 4.83-4.69 (m, 2H), 4.64 (d, J = 5.7 Hz, 2H), 4.58-4.49 (m, 2H), 4.13 (d, J = 13.3 Hz, 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 synthesis of the title product was carried out in a similar manner to (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-a). The product was obtained as the TFA salt. MS (m / z): 489.19 [M+H] + . 1 H 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) was added tert-butyl N-allyl-N-amino-carbamate (0.77 g, 4.47 mmol) and sodium bicarbonate (3.76 g, 44.7 mmol). The resulting mixture was stirred at room temperature overnight. Water (15.0 mL) was added to the reaction, and the mixture was stirred for 10 minutes. The suspension was filtered, and then the filter cake was partitioned between ethyl acetate and water. The aqueous layer was extracted with EtOAc (x2), and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to give the desired product, which was carried on directly to the next step. LCMS-ESI+ (m / z): C 30 H 30 Calculated H+ value for F3N3O7: theoretical value 601.20, measured value: 601.99. 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). To this mixture was added lithium hydroxide monohydrate (1.28 g, 30.6 mmol). The resulting mixture was heated to 60° C. with stirring for 3 hours. The reaction was allowed to stand at room temperature. The residue was diluted with EtOAc and acidified with 1N aqueous HCl to pH 4, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated.

[0259] The residue was then 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). (2S)-But-3-en-2-amine HCl (315 mg, 4.43 mmol) was then added. The newly formed mixture was stirred at room temperature overnight. The reaction was then diluted with DCM, washed with saturated aqueous NH4Cl, brine, dried over sodium sulfate, filtered, and concentrated. The residue was mixed with silica gel, concentrated to dryness, and purified by combiflash® (24 g silica gel, 0% to 100% EtOAc / hexanes). The desired fractions were combined and concentrated to give 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 Calculated H for F3N4O6, theory: 640.25, found: 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): calculated H for C28H27F3N4O4, theory: 540.20, found: 541.02) were obtained.

[0260] Compound 6 was then converted to compound 7 by treating a solution of 6 (1.0 g) in DCM (10.0 mL) with 4 N HCl in 1,4-dioxane (10.0 mL, 40.0 mmol) at room temperature for 1 h. The reaction was concentrated and co-evaporated with 3× EtOAc. The residue was then dissolved in MeOH (20 mL), NaHCO (solid) was added, stirred for 15 min, filtered, and the filtrate was concentrated and re-purified by combiflash® to give 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 in a mixture of ACN (3.5 mL) and DCE (3.5 mL) at room temperature. To this mixture was added paraformaldehyde (58.4 mg, 0.647 mmol). The resulting mixture was heated to 88 °C. To this hot mixture was added acetic acid (0.35 mL) dropwise, followed by TFA (0.15 mL). The reaction was capped and heated for an additional 30 minutes. The reaction was cooled to room temperature, diluted with EtOAc, and basified with saturated NaHCO3 to pH 7. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by combiflash® (12 g silica gel, 0–100% EtOAc, dry loading) to give 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): H+ calculated for CHFNO, theory: 552.20, found: 552.93. The debenzylated form (8) was also isolated. LCMS-ESI+ (m / z): H+ calculated for CHFNO, theory: 462.15, found: 463.02.

[0262] Compound 8 was converted back to compound 9 by treating compound 8 (120 mg, 0.26 mmol) in DMF (2.6 mL) with benzyl bromide (46.6 mg, 0.272 mmol) and cesium carbonate (101 mg, 0.31 mmol) at room temperature overnight. The reaction was diluted with EtOAc, washed with water, brine, dried over sodium sulfate, filtered, mixed with silica gel, concentrated to dryness, and purified by combiflash® (4 g silica gel, 0-100% EtOAc / hexanes) to give 9. LCMS-ESI+ (m / z): H+ calculated for CHFNO, calculated: 552.20, found: 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 to this mixture was added Hoveyda-Grubbs II catalyst (36.9 mg, 0.059 mmol). The resulting mixture was sparged with nitrogen for 5 minutes, then capped and heated at 70 °C overnight. The reaction was then cooled to room temperature, concentrated, and purified by normal phase chromatography (12 g silica gel, 0-100% EtOAc / hexanes). LCMS-ESI+ (m / z): H+ calculated for C27H23F3N4O4, theory: 524.17, found: 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 was concentrated, redissolved in DMF, filtered, and purified by reverse-phase preparative HPLC. LCMS-ESI+ (m / z): H+ calculated for C20H17F3N4O4, theoretical: 434.12, found: 435.19. 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] A reactor was charged with tert-butyl N-aminocarbamate (390 mg, 2.95 mmol), NaHCO3 (451 mg, 5.4 mmol) in MeOH / water (9 ml / 6 ml), 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 to 60°C overnight. The reaction 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 reaction 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] To the above residue in MeOH (6 ml) was added a 2.5N solution of LiOH (2 ml) at room temperature. After 2 hours at room temperature, the reaction mixture 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 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)pyridin-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) was added 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) at room temperature. After stirring overnight at room temperature, the reaction was diluted with ethyl acetate (100 ml) and washed with brine. The organic layer was dried over MgSO4 and concentrated in vacuo. 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 = 5.7 Hz, 1H), 8.58 (s, 1H), 8.50 (s, 1H), 7.37 (dq, J = 4.1, 3.0, 2.4 Hz, 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) was added TFA (0.5 ml) 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 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 to 100 °C for 2 hours, 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 DMF (12 ml), 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 DMF (10 ml) was added via syringe pump at 0° C. over 2 hours. 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 reaction 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) was added TFA (1 mL) 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 give the TFA salt of the title 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-tetrahydrofuran 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)(pent-4-en-2-yl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (7A):

[0272] 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)-pent-4-en-2-ol (805 mg, 9.35 mmol), and triphenylphosphine (3.27 g, 12.5 mmol) in 7 mL of THF was added diisopropyl azodicarboxylate (2.45 mL, 12.5 mmol). The resulting reaction mixture was stirred at room temperature for 30 minutes and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc / hexane to give the title product. MS (m / z) 630.10 [M+H]+. Step 2: Synthesis of (R)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(pent-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)(pent-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 at room temperature overnight. It was diluted with EtOAc and acidified with 1 N HCl to pH 4, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give the title product. MS (m / z): 616.20 [M+H]+. Step 3: Synthesis of tert-butyl (3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)((R)-pent-4-en-2-yl)carbamate (7C):

[0274] (R)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(penta To a reaction mixture of (4-en-2-yl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid (7B, 2.1 g, 3.41 mmol), (2S)-but-3-en-2-amine, hydrochloride (477 mg, 4.43 mmol), EDCI.HCl (977 mg, 5.12 mmol), and HOAt (696 mg, 5.12 mmol) in DCM (34 mL) was added N,N-diisopropylethylamine (2.38 mL, 13.6 mmol). The reaction mixture was stirred at room temperature for 30 minutes, diluted with DCM, washed with saturated NH4Cl and brine, dried over sodium sulfate, filtered, and concentrated. The residue was chromatographed on silica gel eluting with EtOAc / hexane to give the title 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]triazecine-1-carboxylate (7D):

[0275] A solution of tert-butyl (3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)((R)-pent-4-en-2-yl)carbamate (7C, 1.0 g, 1.5 mmol) and Grubbs catalyst second generation (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 80° C. oil bath for 5 hours. The reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel eluting with EtOAc in hexane to give the title 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]triazecin-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]triazecine-1-carboxylate (7D, 170 mg, 0.265 mmol) was dissolved in DCM (5 mL) and treated with 4 N HCl in 1,4-dioxane (3 mL) at room temperature for 3 h. Then, additional 4 N HCl in 1,4-dioxane (2 mL) was added and stirred at room temperature for 2 h. After concentration to dryness, the residue was dissolved in EtOAc and washed with saturated NaHCO and brine. The organic layer was dried over MgSO, filtered, concentrated to dryness, and then dried under high vacuum to give the title 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]triazecin-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 g) and paraformaldehyde (6.1 mg, 2.2 equivalents based on MW: 30 g) were mixed with acetonitrile (1.25 mL) and DCE (1.25 mL) at room temperature, capped, and immediately placed on a hot plate preheated to 88 °C. To this was added dropwise AcOH (0.25 mL, 10% in acetonitrile). , followed by the dropwise addition of TFA (0.25 mL, 10% in DCE). The resulting reaction mixture was then continued to heat for 30 min. It was cooled to room temperature and poured into a well-stirred biphasic mixture of EtOAc-NaHCO3 (aq). The organic phase was separated. The aqueous layer was extracted once with EtOAc. The combined organic phases were washed with brine, dried over Na2SO4, and filtered. The residue was concentrated to dryness and purified by RP-HPLC to give the title 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]triazecin-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, to which 2 mL of TFA was added. The mixture was stirred at room temperature for 40 minutes. The solvent was removed and purified by RP-HPLC to give the title 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 EtOAc and sparged under an argon atmosphere. Palladium on carbon (10 wt%, 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 pad of Celite®. The Celite® was washed with absolute ethanol, the filtrate was concentrated to dryness, and the residue was purified by RP-HPLC to give the title product. MS(m / z): 465.200[M+H]+. 1 H NMR (400 MHz, acetonitrile-d3) δ 10.37 (s, 1H), 8.32 (s, 1H), 6.94-6.81 (m, 2H), 4.87 (d, J = 14.3 Hz, 1H), 4.71-4.59 (m, 3H), 4.39 (tt, J = 11.5, 6.6 Hz, 1H), 2.95 (dq, J = 8.6, 6.3 Hz, 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 a method similar to that described 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. MS (m / z) 519.24 [M+H]+. 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]triazecin-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]triazecin-11-carboxamide (C11) [ka]

[0281] Using methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylate instead of methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate in step 1, and using allylamine hydrochloride instead of (2S)-but-3-en-2-amine hydrochloride in step 3, (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 (9A) was prepared in a similar manner to (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): 521.20 [M+H]+.

[0282] It was separated into its individual diastereomers (10B and 11A) 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 h. After concentration, purification by RP-HPLC eluting with ACN / water (0.1% TFA) gave the title 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]triazecin-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-hydroxy ci-2-methyl-8,10-dioxo-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C11): MS (m / z): 431.20 [M+H]+. 1H NMR (400 MHz, acetonitrile-d3) δ 10.41 (s, 1H), 8.44 (s, 1H), 7.44 (q, J = 8.8, 8.3 Hz, 1H), 6.97 (tt, J = 10.8, 3.1 Hz, 2H), 5.79-5.64 (m, 2H), 4.98-4.88 (m, 2H), 4.69-4.58 (m, 3H), 3.61 (t, J = 6.7 Hz, 1H), 3.53 (dd, J = 18.0, 4.0 Hz, 1H), 2.42 (dd, J = 15.4, 7.1 Hz, 1H), 2.16-2.03 (m, 1H), 1.29 (d, J = 7.1 Hz, 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 a similar manner to (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), except that (2R)-pent-4-en-2-ol was used instead of (2S)-pent-4-en-2-ol in step 1 and (2R)-but-3-en-2-amine hydrochloride was used instead of (2S)-but-3-en-2-amine hydrochloride in step 3. MS (m / z): 431.20 [M+H]+. 1 H NMR (400 MHz, 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 = 7.5 Hz, 1H), 4.84-4.53 (m, 4H), 3.58 (q, J = 6.9 Hz, 1H), 2.39 (dd, J = 15.2, 7.2 Hz, 1H), 2.12-2.00 (m, 1H), 1.29 (t, J = 7.3 Hz, 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-carboxamide Compound 13 was prepared in a similar manner to (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) in Example 8, using (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]triazecin-11-carboxamide (11) instead of triazecin-11 (7F). 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) Compound 14 was prepared in a similar manner to (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) in Example 8 using hydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide. MS (m / z): 465.20 [M+H]+. 1 H NMR (400 MHz, acetonitrile-d3) δ 10.37 (s, 1H), 8.32 (s, 1H), 6.94-6.81 (m, 2H), 4.87 (d, J = 14.3 Hz, 1H), 4.74-4.58 (m, 3H), 4.39 (ddd, J = 11.8, 6.7, 4.8 Hz, 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, 10.1 Hz, 1H), 1.30 (q, J = 12.0 Hz, 1H), 1.13 (dd, J = 14.5, 6.5 Hz, 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-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (7F) instead of (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 Compound 15 was prepared in a similar manner to Example 8 using -2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (10), producing (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]triazecin-11-carboxamide (C8). 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, allylamine hydrochloride was used instead of (2S)-but-3-en-2-amine hydrochloride to give (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 a similar manner to (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] It was separated into its individual diastereomers (peak 1 and peak 2) by RP-HPLC eluting with acetonitrile and water (with 0.1% TFA). Peak 2 (23 mg, 0.043 mmol) was taken, dissolved in 0.5 mL of toluene and 0.5 mL of TFA, and stirred at room temperature for 1 h. After concentration, it was purified by RP-HPLC eluting with ACN / water (0.1% TFA) to give the title 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] (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 (7F) instead of (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). Compound 17 was prepared in a similar manner to (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) in Example 8 using 1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (16). 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)-but-3-en-2-amine, hydrochloride was used instead of (2S)-but-3-en-2-amine, hydrochloride to give (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]trimethyl- Azecin-11-carboxamide (18A) was prepared in a similar manner to (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): 553.30 [M+H]+.

[0293] It was separated into its individual diastereomers (top and bottom spots) by silica gel chromatography eluting with EtOAc / hexane. The bottom spot (15 mg, 0.027 mmol) was taken, dissolved in 0.5 mL of toluene and 0.5 mL of TFA, and stirred at room temperature for 1 h. After concentration, it was purified by RP-HPLC eluting with ACN / water (0.1% TFA) to give the title 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]triazecin-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]triazecin-11-carboxamide (C20) [ka]

[0294] (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 (19A) was prepared in a similar manner to (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 (7 in Example 7), using (2R)-pent-4-en-2-ol instead of (2S)-pent-4-en-2-ol in step 1. MS(m / z): 463.20 [M+H]+.

[0295] It was separated into its individual diastereomers (peak 1 and peak 2) by preparative SFC chromatography on an AZ-column using methanol as a co-solvent.

[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]triazecin-11-carboxamide (19): MS (m / z): 463.20 [M+H]+. 1 H NMR (400 MHz, 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, 1.6 Hz, 1H), 5.27 (d, J = 8.0 Hz, 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]triazecin-11-carboxamide (20): MS (m / z): 463.20 [M+H]+. 1 H NMR (400 MHz, acetonitrile-d3) δ 10.44 (s, 1H), 8.39 (s, 1H), 6.87 (t, J = 8.5 Hz, 2H), 5.69 (d, J = 12.1 Hz, 1H), 5.59 (dd, J = 18.9, 9.5 Hz, 1H), 4.93 (d, J = 14.2 Hz, 1H), 4.76-4.42 (m, 3H), 4.06 (s, 1H), 3.55 (s, 1H), 2.60 (s, 1H), 2.07 (t, J = 7.4 Hz, 1H), 1.81 (d, J = 7.4 Hz, 3H), 1.29 (d, J = 7.1 Hz, 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-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) Prepared in a manner similar to that used in Example 8 to prepare (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) using dro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C19). MS (m / z): 465.20 [M+H]+. 1 H NMR (400 MHz, acetonitrile-d3) δ 10.40 (s, 1H), 8.29 (s, 1H), 6.91-6.83 (m, 2H), 4.84 (d, J = 14.4 Hz, 1H), 4.77 (d, J = 14.5 Hz, 1H), 4.69-4.51 (m, 3H), 3.57 (q, J = 7.1 Hz, 1H), 1.96-1.83 (m, 2H), 1.80-1.54 (m, 3H), 1.39 (dd, J = 13.0, 6.2 Hz, 1H), 1.18 (dd, J = 7.0, 2.3 Hz, 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-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) Prepared in a manner similar to that used in Example 8 to prepare (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) using dro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C18). MS (m / z): 465.20 [M+H]+. 1 H NMR (400 MHz, acetonitrile-d3) δ 10.41 (s, 1H), 8.28 (s, 1H), 6.87 (t, J = 8.5 Hz, 2H), 4.84 (d, J = 14.4 Hz, 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] (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]triazecin-11-carboxamide (7F) instead of (2R,6S,Z)-9-(benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro- Compound 23 was prepared in a similar manner to (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) in Example 8 using 2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide (C20). 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 equiv) was mixed with MeOH (300 mL) and HO (60.0 mL). BocNHNH (19.5 g, 147 mmol, 1.10 equiv) and NaHCO (22.5 g, 268 mmol, 10.4 mL, 2.00 equiv) were added at room temperature. The reaction mixture was then stirred at 55 °C for 16 h. The reaction mixture was placed under vacuum to remove most of the MeOH. The resulting residue was diluted with HO (200 mL), and the crude product was extracted with EtOAc (1500 mL). The organic layer was washed with brine (500 mL), dried over NaSO, and concentrated in vacuo. The resulting slurry was purified by silica gel chromatography using petroleum ether:ethyl acetate=5:1 to give the product: MS(m / z): 562.5 [M+H]+. Step 2: Preparation of methyl 3-(benzyloxy)-1-(but-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. But-3-en-2-ol (963 mg, 13.4 mmol) and Ph3P (3.5 g, 13.4 mmol) were added sequentially. DIAD (2.7 g, 13.4 mmol) was then added dropwise over 5 minutes. The resulting reaction 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% EtOAc / Hex to give the product. MS(m / z): 616.0 [M+H]+. Step 3: Preparation of 3-(benzyloxy)-1-(but-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)carbonyl) 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. with stirring for 3.5 h. Additional LiOH (5 M) (2 mL) was added. The reaction mixture was then stirred at 40° C. for 17 h. The reaction mixture was carefully concentrated to remove MeOH. The residue was diluted, rinsed with some water, and acidified to pH=3 with 1N HCl. EtOAc (200 mL) was added for extraction. The organic phase was separated. The aqueous layer was extracted with additional EtOAc (100 mL). The combined organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated to give the product. MS (m / z): 602.0 [M+H]+. Step 4: Preparation of tert-butyl (3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)(but-3-en-2-yl)carbamate [ka]

[0304] 3-(Benzyloxy)-1-(but-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)-but-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 EtOAc (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 brine (50 mL). The final organic phase was concentrated to remove the solvent. The residue was purified on a silica gel column using 0-100% EtOAc / Hex to give the product. MS m / z): 655.0 [M+H]+. Step 5: Preparation of 3-(benzyloxy)-N2-((S)-but-3-en-2-yl)-1-(but-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)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)(but-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 between EtOAc (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 give the product. MS (m / z): 555.3 [M+H]+. Step 6: Preparation of 5-(benzyloxy)-3-((S)-but-3-en-2-yl)-1-(but-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)-but-3-en-2-yl)-1-(but-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 heating bath. AcOH (0.9 mL) and TFA (0.9 mL) were then added sequentially 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. The resulting crude material was then 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 h. The reaction mixture was then diluted with EtOAc (100 mL) and then treated with NaHCO3 (sat. aq.) (100 mL) and water (100 mL). The organic layer was separated and washed with water (50 mL) and brine (50 mL). The solvent was removed in vacuo. The residual crude product was purified on a silica gel column using 0-100% EtOAc / Hex to give the 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)-but-3-en-2-yl)-1-(but-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 bubbled through the reaction solution for 5 minutes. HG-M720 catalyst (103.4 mg, 0.164 mmol) was then added with stirring. Argon purging was continued for 10 minutes. The reaction mixture was then heated with stirring under an argon atmosphere 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% EtOAc / Hex to afford three diastereomers, which could be separated. (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), 334 mg, MS m / 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-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide (B), 96 mg. MS m / 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 nopyrido[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 taken up in MeOH and purified by reverse-phase preparative HPLC using 0-100% CH3CN in water with 0.1% TFA to give the desired product. Lyophilization afforded the product as the mono-TFA salt. 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 taken up in MeOH and purified by reverse-phase preparative HPLC using 0-100% CH3CN in water with 0.1% TFA to give the desired product. Lyophilization afforded the product as the mono-TFA salt. 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, 2.1 Hz, 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% EtOAc in hexane to give the product as neural form. 8 mg. MS (m / z): 449.2 [M+H]+. H NMR (400 MHz, acetonitrile-d) δ 10.30 (s, 1H), 8.40 (s, 1H), 6.97-6.77 (m, 2H), 5.80 (ddd, J = 11.7, 2.7, 1.9 Hz, 1H), 5.45 (ddd, J = 11.7, 4.2, 2.4 Hz, 1H), 4.81-4.69 (m, 2H), 4.65-4.59 (m, 2H), 4.32 (dtt, J = 7.5, 5.0, 2.5 Hz, 1H), 4.01 (ddq, J = 7.0, 4.8, 2.4 Hz, 1H), 1.79 (d, J = 7.5 Hz, 3H), 1.40 (d, J = 7.0 Hz, 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. Hydrogenolysis was carried out at room temperature using a H balloon for 7 h. The reaction mixture was filtered through Celite. The filtrate was collected and concentrated to dryness. The residue was taken up in MeOH and reversed using 0-100% CHCN in water with 0.1% TFA. Purification by phase preparative HPLC gave the desired product. Lyophilization afforded the product as the mono-TFA salt. 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. Hydrogenolysis was carried out at room temperature using a H₂ balloon for 7 h. The reaction mixture was filtered through Celite. The filtrate was collected and concentrated to dryness. The residue was taken up in MeOH and purified by reverse-phase preparative HPLC using 0-100% CH₃CN in water with 0.1% TFA to give the desired product. Lyophilization afforded the product as the mono-TFA salt. 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 HO (30.0 mL). BocNHNH (5 g, 37.8 mmol) and NaHCO (5.87 g, 69.9 mmol) were added at room temperature. The reaction mixture was then stirred at 55 °C for 16 h. The reaction mixture was placed under vacuum to remove most of the MeOH. The resulting residue was diluted with HO (200 mL), and the crude product was extracted with EtOAc (500 mL). The organic layer was washed with brine (500 mL), dried over NaSO, and concentrated in vacuo. The resulting slurry was purified by silica gel chromatography using hexane:ethyl acetate = 5:1 to give 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. But-3-en-2-ol (2.37 g, 32.8 mmol) and Ph3P (8.6 g, 32.8 mmol) were added sequentially. DIAD (6.64 g, 32.8 mmol) was then added dropwise over 5 minutes. The resulting reaction mixture was a slightly orange solution. It was allowed to stir at 0° C. for 5 minutes. The cooling bath was removed. The reaction mixture was allowed to stir at room temperature for 17 hours. The reaction mixture was concentrated to dryness. The residue was purified on a silica gel column with 0-100% EtOAc / Hex to give 10 g of product. MS m / z: 598.04 [M+H]. Step 3: Preparation of 3-(benzyloxy)-1-(but-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. with stirring for 17 hours. The reaction mixture was carefully concentrated to remove MeOH. The residue was diluted, rinsed with some water, and acidified to pH=3 with 1N HCl. A solid appeared. EtOAc (200 mL) was added to extract. The organic phase was separated. The aqueous layer was extracted with additional EtOAc (100 mL). The combined organic phase was washed with water and brine. It was dried over Na2SO4, filtered and concentrated to give 9g of the acid product. MS (m / z): 584.30 [M+H]. Step 4: Preparation of tert-butyl (3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4-difluorobenzyl)carbamoyl)pyridin-1(4H)-yl)(but-3-en-2-yl)carbamate [ka]

[0316] 3-(Benzyloxy)-1-(but-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) was added and the reaction mixture was cooled in an ice-water bath. HATU (6.52 g, 17.14 mmol) was added in one portion. The reaction mixture was then warmed to room temperature with stirring for 1 hour. (S)-But-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 EtOAc (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 brine (50 mL). The final organic phase was concentrated to remove the solvent. The residue was pure enough for the next step. 4 g. MS (m / z): 637.03 [M+H]. Step 5: 3-(benzyloxy)-N2-((S)-but-3-en-2-yl)-1 Preparation of -(but-3-en-2-ylamino)-4-oxo-N5-(2,4-difluorobenzyl)-1,4-dihydropyridine-2,5-dicarboxamide [ka]

[0317] tert-Butyl (3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-4-oxo-5-((2,4-difluorobenzyl)carbamoyl)pyridin-1(4H)-yl)(but-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 between EtOAc (100 mL) and NaHCO3 (saturated aqueous solution, 100 mL). The organic layer was separated, washed with brine, and dried over Na2SO4. Removal of the solvent gave product 3g. MS (m / z): 537.17 [M+H]. Step 6: Preparation of 5-(benzyloxy)-3-((S)-but-3-en-2-yl)-1-(but-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)-but-3-en-2-yl)-1-(but-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 heating bath. AcOH (1.15 mL) and TFA (1.15 mL) were then added sequentially 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. The resulting crude material was then 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 h. The reaction mixture was then diluted with EtOAc (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 brine (50 mL). The solvent was removed in vacuo. The remaining crude product The product was purified on a silica gel column using 0-100% EtOAc / Hex to give product 1g. 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)-but-3-en-2-yl)-1-(but-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 bubbled through the reaction solution for 5 minutes. HG-M720 catalyst (146.4 mg, 0.233 mmol) was then added with stirring. Argon purging was continued for 10 minutes. The reaction mixture was then heated with stirring under an argon atmosphere 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% EtOAc / Hex to give 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 ( A solution of 230 mg (0.188 mmol) of 2-chloro-2-methyl-4-propanol (H2O, 230 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 taken up in MeOH and purified by reverse-phase preparative HPLC using 0-100% CH3CN in water with 0.1% TFA to give the desired product. Lyophilization afforded the product as the mono-TFA salt. 150 mg. MS (m / z): 431.2 [M+H]. H NMR (400 MHz, acetonitrile-d) δ 10.21 (s, 1H), 8.39 (s, 1H), 7.44 (td, J = 8.8, 6.5 Hz, 1H), 7.21-6.84 (m, 2H), 5.66 (dt, J = 11.4, 2.4 Hz, 1H), 5.46-5.32 (m, 2H), 5.02 (d, J = 14.4 Hz, 1H), 4.67-4.50 (m, 3H), 3.84 (qq, J = 6.6, 3.0 Hz, 1H), 1.35 (dd, J = 7.1, 4.1 Hz, 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 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 taken up in MeOH and purified by reverse-phase preparative HPLC using 0-100% CH3CN in water with 0.1% TFA to give the desired product. Lyophilization afforded the product as the mono-TFA salt. 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-difluorobenzene) in EtOH (9 mL) solution (I)-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 evacuated and backfilled with argon (five cycles), then treated with 10% Pd / C (25 mg), evacuated and backfilled with argon (five cycles), followed by backfilling with hydrogen (five 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 redissolved in EtOH (22 mL) and treated with 10% Pd / C (50 mg) and hydrogen as described above. After 4 h, 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) and lyophilized to give the title compound as the trifluoroacetate salt (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, Part 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-water bath. 4-Methylmorpholine N-oxide (50% in water, 0.1 mL, 2 equiv.) was slowly added to the reaction solution. 2.5% osmium tetroxide (0.01 mL, 4% equiv.) was then added. The mixture was stirred at 0° C. and allowed to warm to room temperature for 2 days. The reaction was quenched by adding 10% aqueous sodium sulfite solution. The reaction mixture was extracted using (1:1) EtOAc:n-BnOH. The organic layer was concentrated and purified via silica column (eluting with 0-10% MeOH / DCM) to give (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 ( (non-polar, 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, major product). 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-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide Preparation of (1S,2R,3R,4S,5S)-8-(benzyl)-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 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 cooled to 0 °C in an ice-water bath. Sodium hydride (60%, 11 mg, 2.2 equiv.) was added to the reaction solution. After 10 min, methyl iodide (100x diluted with DCM, 1 mL, 1.3 equiv.) was added. The mixture was stirred at 0 °C for 30 min. LC-MS showed the bis-Me product and two mono-Me products, as well as some starting material. The reaction was quenched by adding saturated aqueous sodium bicarbonate. The reaction mixture was extracted with ethyl acetate. The organic layer was concentrated and purified via preparative HPLC eluting with 10 to 100% acetonitrile (0.1% TFA) in water (0.1% TFA) to give (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, major 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 (non-polar, minor mono-Me product MS (m / z) 587.3 [M+H] + ) 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 was stirred at room temperature for 2 hours. The reaction was concentrated and purified via preparative HPLC eluting with 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to give 7.2 mg of the title compound. MS (m / z) 511.3 [M+H] + 1H NMR (400 MHz, 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 = 14.8 Hz, 2H), 4.26-4.12 (m, 1H), 3.81 (d, J = 7.6 Hz, 1H), 3.61 (d, J = 3.1 Hz, 1H), 3.47 (d, J = 8.8 Hz, 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-trifluorobenzyl)- Preparation of (fluorobenzyl)-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 purged with argon. Phenylsilane (2 equivalents) and Shenvi's catalyst (tris[(Z)-1-tert-butyl-4,4-dimethyl-3-oxo-pent-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 showed the product was still the starting material. The reaction was quenched by adding 10% aqueous sodium thiosulfate. The reaction mixture was extracted using ethyl acetate. The organic layer was concentrated and purified via silica column (eluting with 0-10% MeOH / DCM) to give (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]). + NMR HMBC, COSY, and NOE studies confirmed the structure), 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 was stirred at room temperature for 2 hours. The reaction was concentrated and purified via preparative HPLC eluting with 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to give the title 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 cooled to 0 °C in an ice-water bath. Sodium hydride (60%, 1.4 mg, 2 equiv.) was added to the reaction solution. After 10 min, methyl iodide (100x diluted with DCM, 0.11 mL, 1 equiv.) was added. The mixture was stirred at 0 °C for 30 min. LC-MS showed the bis-Me product, with the major product being the mono-Me product. The reaction was quenched by adding saturated sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate. The organic layer was concentrated and purified via preparative HPLC eluting with 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to give the title 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]triazol- Zonin-10-carboxamide (4 mg) was dissolved in toluene (0.2 mL) and trifluoroacetic acid (0.4 mL) was added. The reaction was stirred at room temperature for 2 hours. The reaction was concentrated and purified via preparative HPLC eluting with 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to give 1.6 mg of the title 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 cooled to 0 °C in an ice-water 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 the formation of fluorinated and eliminated products. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate. The organic layer was concentrated, and purification via normal-phase silica column and preparative HPLC was attempted, but no separation was 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-water bath. 4-Methylmorpholine N-oxide (50% in water, 0.017 mL, 1.5 equiv.) was slowly added to the above reaction solution. Then, 2.5% osmium tetroxide (0.023 mL, 4% equiv.) was added. The mixture was stirred at 0°C and allowed to warm to room temperature for 2 days. The reaction was quenched by adding 10% aqueous sodium sulfite solution. The reaction mixture was extracted using ethyl acetate. The organic layer was concentrated, and 10% in water (0.1% TFA) was added. Purification by preparative HPLC eluting with ∼100% acetonitrile (0.1% TFA) and collecting the non-polar product gave (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 (non-polar). 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 was stirred at room temperature for 2 hours. The reaction was concentrated and purified via preparative HPLC eluting with 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to give the title compound. MS (m / z) 469.2 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d3) δ 10.26 (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, 2.0 Hz, 3H), 1.35 (dd, J = 7.2, 2.9 Hz, 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 DCM (3 mL) and cooled to 0 °C in an ice-water bath. Dess-Martin periodinane (194 mg, 2 equiv.) was added to the reaction solution. The mixture was stirred at 0 °C and allowed to warm to room temperature for 2 h. The reaction was quenched by adding 10% aqueous sodium thiosulfate solution. The reaction mixture was extracted with ethyl acetate. The organic layer was concentrated and purified via silica column (eluting with 0-10% MeOH / DCM) to give (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 DCM (5 mL) and cooled to 0 °C in an ice-water bath. Bis(2-methoxyethyl)aminosulfur trifluoride (50% in toluene, 2.7 M, 0.147 mL, 2 equiv.) was added to the reaction solution. The mixture was stirred at 0 °C and allowed to warm to room temperature overnight. The reaction was quenched by adding saturated aqueous sodium bicarbonate solution. The reaction mixture was extracted with ethyl acetate. Concentrate the organic layer and elute it on a silica column (eluting with 0-10% MeOH / DCM). ) to give (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] + . 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):

[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 was stirred at room temperature for 2 hours. The reaction was concentrated and purified via preparative HPLC eluting with 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to give the title 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 cooled to 0° C. in an ice-water bath. Dess-Martin periodinane (11 mg, 2 equivalents) was added to the reaction solution. The mixture was stirred at 0° C. and allowed to warm to room temperature for 2 hours. The reaction was quenched by adding 10% aqueous sodium thiosulfate solution. The reaction mixture was extracted with ethyl acetate. The organic layer was concentrated and purified via silica column (eluting with 0-10% MeOH / DCM) to give (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 DCM (2 mL) and cooled to 0 °C in an ice-water bath. Bis(2-methoxyethyl)aminosulfur trifluoride (50% in toluene, 2.7 M, 0.018 mL, 2 equiv.) was added to the reaction solution. The mixture was stirred at 0 °C and allowed to warm to room temperature for 3 h. LC-MS showed the formation of the elimination product and the di-F product. The reaction was quenched by adding saturated aqueous sodium bicarbonate. The reaction mixture was extracted with ethyl acetate. The organic layer was concentrated and purified via preparative HPLC eluting with 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to give (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 was stirred at room temperature for 2 hours. The reaction was concentrated and purified via preparative HPLC eluting with 10-100% acetonitrile (0.1% TFA) in water (0.1% TFA) to give the title compound. MS (m / z) 467.2 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d3) δ 10.20 (s, 1H), 8.43 (s, 1H), 6.87 (t, J = 8.5 Hz, 2H), 5.70-5.48 (m, 1H), 5.32-5.17 (m, 1H), 5.00 (d, J = 14.8 Hz, 1H), 4.78-4.57 (m, 3H), 4.22-4.08 (m, 1H), 1.52 (dd, J = 6.9, 3.0 Hz, 3H), 1.37 (d, J = 7.2 Hz, 3H). Example 37: (1S,2R,5S)-N-(2,4-difluorobenzyl)-8-hydroxybenzoate Preparation of 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) was added PtO (2 mg, 0.009 mmol). The reaction was stirred at room temperature under a H balloon for 2 h. The reaction mixture was filtered through Celite, the filtrate was concentrated, and the residue was purified by reverse-phase HPLC eluting with 5–100% acetonitrile in water to give 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. To this was added 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). The reaction was stirred at room temperature for 2 days. 10% aqueous sodium sulfite solution (3 mL) was added to the reaction and stirred for 15 minutes. It 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 give the title product. Both hydroxy 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]triazecin-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) in dichloromethane (2 mL) was cooled to 0 °C under argon. To this was added deoxo-fluoro (50% in toluene, 0.02 mL, 0.054 mmol). 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 the dropwise addition of saturated aqueous sodium bicarbonate. The resulting mixture was stirred for 20 minutes, and additional saturated aqueous sodium bicarbonate was added until effervescence ceased. The organic phase was separated, dried over magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified by RP-HPLC eluting with acetonitrile / water (with 0.1% TFA) to give (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 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 (with 0.1% TFA) to give the title 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-methanopyrido[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-water 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 was quenched with saturated aqueous ammonium chloride solution and extracted three times with ethyl acetate. The combined organic extracts were washed with 5% aqueous lithium chloride and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate to give the title 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]triazecin-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]triazecin-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]triazecin-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 eluting with acetonitrile / water (with 0.1% TFA) to give the title 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) (prop-2-yn-1-yl)carbamate:

[0345] To a stirred solution of prop-2-yn-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) were added portionwise at room temperature, followed by stirring at room temperature for 4 hours. After completion of the reaction, 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 give the crude compound, which was purified by silica gel column chromatography eluting with ethyl acetate in hexane to give the title product as a colorless liquid. MS (m / z): 256.31 [M+H]+ Step 2: Synthesis of tert-butyl (R,Z)-(tert-butoxycarbonyl)(5-hydroxyhex-2-en-1-yl)carbamate:

[0346] To a stirred solution of tert-butyl (tert-butoxycarbonyl)(prop-2-yn-1-yl)carbamate (100 g, 390.6 mmol) in THF (1 L) was added n-BuLi (1.6 M in hexane, 244.14 mL, 390.6 mmol) dropwise over 30 minutes at −78° C. To this was added BF etherate (119.7 g, 390.6 mmol), 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. Upon 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, dried over Na2SO4 and evaporated to give the crude product, which was purified by silica gel column chromatography eluting with ethyl acetate in hexane to give tert-butyl (R)-(tert-butoxycarbonyl)(5-hydroxyhex-2-yn-1-yl)carbamate as a colorless liquid. 20 g (63.89 mmol) of the product was taken and loaded into a Parr apparatus, and 400 ml of ethyl acetate was added. Lindlar's catalyst (4.4 g) was added under an inert atmosphere, followed by quinoline, and hydrogenated at 30 Psi and room temperature for 16 hours. Upon completion, the reaction mixture was filtered through a pad of Celite. The Celite pad was washed with ethyl acetate. The filtrate was washed with 1N HCl and concentrated under reduced pressure to give the crude product, which was purified by silica gel column chromatography eluting with ethyl acetate in hexane to give the title product. MS (m / z): 316.29 [M+H]+. Step 3: Synthesis of (R,Z)-6-aminohex-4-en-2-ol hydrochloride:

[0347] A solution of tert-butyl (R,Z)-(tert-butoxycarbonyl)(5-hydroxyhex-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, and the crude was washed with diethyl ether, filtered, and dried under vacuum to give the title product. MS (m / z): 116.3 [M+H]+. Step 4: Synthesis of tert-butyl (R,Z)-(5-hydroxyhex-2-en-1-yl)carbamate:

[0348] To a stirred solution of (R,Z)-6-aminohex-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 eluting with ethyl acetate in hexane to give the title product. 1 H NMR (400 MHz, chloroform-d) δ 5.59 (dq, J = 10.4, 5.4 Hz, 2H), 4.67 (s, 1H), 3.94-3.78 (m, 2H), 3.71 (dd, J = 15.0, 5.0 Hz, 1H), 2.44-2.18 (m, 2H), 1.46 (s, 9H), 1.25 (d, J = 6.3 Hz, 3H). Step 5: Synthesis of methyl (S,Z)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(6-((tert-butoxycarbonyl)amino)hex-4-en-2-yl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylate (26E):

[0349] Methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate and (2S)-pent-4-en-2-ol were replaced with methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylate. Prepared in a similar manner to methyl (R)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(pent-4-en-2-yl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (7A) using hydropyridine-2-carboxylate and tert-butyl (R,Z)-(5-hydroxyhex-2-en-1-yl)carbamate. MS (m / z): 741.400 [M+H]+. Step 6: Synthesis of (S,Z)-1-((6-aminohex-4-en-2-yl)amino)-3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid hydrochloride (26F):

[0350] Methyl (S,Z)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(6-((tert-butoxycarbonyl)amino)hex-4-en-2-yl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carbamoyl) in 140 ml of THF / MeOH / H2O (3 / 2 / 1) To a solution of the carboxylate (5.4 g, 7.29 mmol) was added lithium hydroxide (698 mg, 29.2 mmol). The reaction mixture was stirred at 60° C. for 2 hours. LCMS showed high conversion to the carboxylic acid. The reaction mixture was diluted with ethyl acetate and acidified with 1 N HCl to pH 4. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give (S,Z)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(6-((tert-butoxycarbonyl)amino)hex-4-en-2-yl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid, which was dissolved in 50 mL of DCM, treated with 4 N HCl in 1,4-dioxane (7.3 mL) at room temperature overnight, and concentrated to dryness. Drying under high vacuum gave the title 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-aminohex-4-en-2-yl)amino)-3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid hydrochloride (5.29 g, 8.8 mmol) was dissolved in 500 ml of DCM. · 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 brine. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with EtOAc / hexane to give the title 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) instead of (S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-2,3,6,7,8, (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]triazecine-11-carboxamide (7F) was prepared in a similar manner using 10-hexahydro-1H-pyrido[1,2-b][1,2,5]triazecine-11-carboxamide. 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]triazecin-11-carboxamide (C40):

[0353] (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 (7F) Prepared in a similar manner to (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) 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]triazecin-11-carboxamide. MS (m / z): 433.200 [M+H]+. 1H NMR (400 MHz, 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 = 14.1 Hz, 1H), 4.80 (d, J = 14.2 Hz, 1H), 4.59 (d, J = 5.9 Hz, 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) instead of (1S,2S,Z)-9-(benzyloxy)-N-(2,4-difluorobenzyl)-2-methyl-8,10-dioxo-3,6, Prepared in a similar manner to (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) using 8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecin-11-carboxamide. 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] (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 (7F) Prepared in a similar manner to (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) 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]triazecin-11-carboxamide. MS (m / z): 433.200 [M+H]+. 1H NMR (400 MHz, acetonitrile-d3) δ 10.38 (s, 1H), 8.35 (s, 1H), 7.44 (td, J = 9.2, 8.8, 6.5 Hz, 1H), 7.03-6.91 (m, 2H), 4.86 (d, J = 14.5 Hz, 1H), 4.78 (d, J = 14.5 Hz, 1H), 4.60 (d, J = 5.8 Hz, 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 (7F) was replaced with (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. Prepared in a similar 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-11 carboxamide (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] 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, using methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate instead of methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate. MS (m / z) 530.200 [M+H] + . Synthesis of tert-butyl (S)-(3-(benzyloxy)-2-(but-3-en-2-ylcarbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridin-1(4H)-yl)carbamate:

[0358] A 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)-but-3-en-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 brine. The organic layer was dried over MgSO and concentrated in vacuo. The residue was purified by silica gel column chromatography. MS(m / z) 583.300[M+H]+. Synthesis of tert-butyl (3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridin-1(4H)-yl)((S)-1-hydroxybut-3-en-2-yl)carbamate:

[0359] tert-Butyl (S)-(3-(benzyloxy)-2-(but-3-en-2-ylcarbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridin-1(4H)-yl)carbamate (430 mg, 0.738 mmol) and tetrabutylammonium bromide (476 mg, 1.48 mmol) were added to a round-bottom flask, followed by acetonitrile (20 mL, degassed by bubbling argon through immediately before use), 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 monoxide (0.149 ml, 1.85 mmol) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and purified by column chromatography eluting with ethyl acetate / hexane to give the title product. MS (m / z) 653.300 [M+H] + . Synthesis of (S)-2-((3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridin-1(4H)-yl)(tert-butoxycarbonyl)amino)but-3-en-1-yl acetate:

[0360] tert-Butyl (3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridin-1(4H)-yl)((S)-1-hydroxybut-3-en-2-yl)carbamate (280 mg, 0.429 mmol) was dissolved in 14 ml of pyridine. To it was added DMAP (105 mg, 0.858 mmol) and acetic anhydride (0.40 ml, 4.29 mmol). The reaction was heated to 60° C. for 2 hours, cooled to room temperature, and concentrated to dryness. The reaction mixture was partitioned between ethyl acetate and 1N HCl, and the organic phase was washed with additional 1N HCl, followed by saturated aqueous NaHCO and brine. The organic phase was dried over MgSO, filtered, and concentrated in vacuo. Purification by silica gel column chromatography eluting with ethyl acetate in hexane gave the title product. MS (m / z) 695.400 [M+H] + . Synthesis of (S)-2-((3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridin-1(4H)-yl)amino)but-3-en-1-yl acetate:

[0361] (S)-2-((3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxopyridin-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 hydrogen chloride, a 4.0 M solution in 1,4-dioxane (0.73 ml, 2.9 mmol) was added thereto. The mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and dried under high vacuum to give the title product. MS (m / z) 595.300 [M+H] + . Synthesis of (S)-2-(5-(benzyloxy)-3-((S)-but-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]triazin-1-yl)but-3-en-1-yl acetate:

[0362] (S)-2-((3-(benzyloxy)-2-(((S)-but-3-en-2-yl)carbamoyl)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo instead of 3-(benzyloxy)-N2-((S)-but-3-en-2-yl)-1-(but-3-en-2-ylamino)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1,4-dihydropyridine-2,5-dicarboxamide Prepared in a similar manner to Example 24, 5-(benzyloxy)-3-((S)-but-3-en-2-yl)-1-(but-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, using pyridin-1(4H)-yl)amino)but-3-en-1-yl acetate. MS (m / z) 607.300 [M+H] + . Synthesis of methyl ((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)acetate:

[0363] 5-(benzyloxy)-3-((S)-but-3-en-2-yl)-1-(but-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 instead of (S)-2-(5-(benzyloxy)-3-((S)-but-3-en-2-yl)-7-((2,4-difluorobenzyl)carbamoyl)-4,6-dioxo Prepared in a similar manner to Example 24 (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 using 2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazin-1-yl)but-3-en-1-yl acetate. 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] Methyl ((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)acetate (46 mg, 0.79 mmol) was dissolved in 2 ml of methanol. To it was added potassium carbonate (22 mg, 0.16 mmol). The reaction was stirred at room temperature for 10 minutes and then partitioned between ethyl acetate and water. The organic layer was separated, washed with brine, dried over MgSO4, and concentrated to dryness to give the title 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 at 0 °C under argon. To this was added deoxo-fluro (50% in toluene, 0.031 mL, 0.084 mmol). The resulting mixture was stirred at 0 °C for 2 h. The reaction mixture was diluted with DCM, cooled in an ice / water bath, and quenched by the dropwise addition of saturated aqueous NaHCO3. The resulting mixture was stirred for 20 min, and additional saturated aqueous NaHCO3 was added and stirred for 10 min until effervescence ceased. 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 EtOAc / hexane to give the title 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 eluting with acetonitrile / water (with 0.1% TFA) to give the title 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 sparged under an argon atmosphere. Palladium on carbon (10 wt%, wet) E101 NE / W (2 mg) was added, and the mixture was placed under a hydrogen atmosphere (1 atm, balloon). The mixture was vigorously stirred for 1 hour and then sparged under an argon atmosphere. It was filtered through a pad of Celite®. The Celite® was washed with absolute ethanol and the filtrate was concentrated to dryness. The residue was purified by RP-HPLC to give the title 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] 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 equiv.) in methanol (200 mL) and water (100 mL), prepared according to Example 24, Step 3, was added lithium hydroxide monohydrate (5.979 g, 142 mmol, 8 equiv.). The reaction mixture was heated to 50° C. for 18 hours, diluted with water, and acidified with 1 N HCl (aq.). The slurry was extracted with EtOAc (2x) and the combined organic phases were washed with brine, dried over Na2SO4, filtered and concentrated to give 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-(but-3-en-2-ylcarbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-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 equiv.), (S)-but-3-en-2-amine hydrochloride (1.769 g, 16.4 mmol, 1.5 equiv.), and HOBt (2.221 g, 16.4 mmol, 1.5 equiv.) in CHCl (120 mL) at 0° C. was added DIPEA (9.54 mL, 54.8 mmol, 5 equiv.) and EDCI (3.151 g, 16.4 mmol, 1.5 equiv.). The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was quenched with water and 1 M HCl and extracted with CHCl (3×). The combined organic phases were dried over NaSO, filtered, and concentrated. The crude residue was purified by column chromatography (0–100% EtOAc / hexanes) and concentrated to give tert-butyl (S)-(3-(benzyloxy)-2-(but-3-en-2-ylcarbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)carbamate. MS (m / z) 600.90 [M+H] + . Step 3: Synthesis of tert-butyl (S)-5-(benzyloxy)-3-(but-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] To a suspension of tert-butyl (S)-(3-(benzyloxy)-2-(but-3-en-2-ylcarbamoyl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)pyridin-1(4H)-yl)carbamate (2.20 g, 3.66 mmol, 1 equiv.) and cesium carbonate (4.77 g, 14.7 mmol, 4 equiv.) in MeCN (55 mL) was added diiodomethane (0.59 mL, 7.33 mmol, 2 equiv.). The reaction mixture was heated to 70° C. for 8 h and quenched with NH4Cl (aq.). The mixture was extracted with EtOAc (2×), and the combined organic phases were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0–100% EtOAc / hexanes) to give tert-butyl (S)-5-(benzyloxy)-3-(but-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-(but-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-(but-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 equiv.) in methanol (55 mL) was added 2 N aqueous NaOH (2.45 mL, 4.90 mmol, 1.5 equiv.). The reaction mixture was heated to 40 °C for 1 h, quenched with 10% citric acid solution, and diluted with CHCl. ​​The phases were separated, and the aqueous phase was extracted with CHCl. ​​The combined organic phases were dried over NaSO, filtered, and concentrated. The residue was suspended in 1:1 EtOAc / hexanes, and the precipitate was collected by filtration to give (S)-5-(benzyloxy)-3-(but-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)-but-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] To a solution of (S)-5-(benzyloxy)-3-(but-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 equiv.) in acetonitrile (5 mL) was added Pd( OAc) (0.0027 g, 0.012 mmol, 0.05 equiv), 1,3-bis(diphenylphosphino)propane (dppp) (0.0049 g, 0.012 mmol, 0.05 equiv), trimethylamine (0.050 mL, 0.356 mmol, 1.5 equiv), and methoxyallene (0.100 mL, 1.19 mmol, 5 equiv) were added. The reaction mixture was heated to 100 °C for 20 min. Water and brine were added, and the aqueous phase was extracted with EtOAc (2x). The combined organic phases were dried over NaSO, filtered, and concentrated. The residue was purified by column chromatography (0–100% EtOAc / hexanes) to give 5-(benzyloxy)-3-((S)-but-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)-but-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 equiv.) in 1,2-dichloroethane (5 mL) was added Hoveyda-Grubbs II catalyst (0.024 g, 0.038 mmol, 0.2 equiv.). The reaction mixture was heated to 70 °C for 24 h and concentrated. The residue was purified by preparative HPLC (column, Gemini 10μ C18) eluting with 5–100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 min. The combined fractions were frozen. Drying gave (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. (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] 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 equiv.) in DMF (2 mL) was added lithium chloride (0.0348 g, 0.821 mmol, 10 equiv.). The reaction mixture was heated to 100° C. for 1 h and filtered. The filtrate was purified by preparative HPLC (Gemini 10μ C18 110A, AXI / ; 250 × 21.2 mm column) eluting with 5–100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 min. The combined fractions were lyophilized to give (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- prepared according to Example 46 in methanol (1 mL) 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 equiv.) was added platinum(IV) oxide (0.0003 g, 0.0014 equiv. 0.1 equiv.). The reaction mixture was evacuated, backfilled with hydrogen gas (2x), sparged with hydrogen gas for 5 min, and left stirring under a hydrogen balloon atmosphere for 1 h. The reaction mixture was filtered, concentrated, and purified by preparative HPLC (Gemini 10μ C18 110A, AXI / ; 250 × 21.2 mm column) eluting with 5–100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 min. The combined fractions were lyophilized to give (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-(but-3-en-2-yl)-1-(2-methylbut-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-(but-3-en-2-yl)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pi (prepared according to Example 46) in THF (3 mL) and DMF (0.15 mL). To a solution of pyrido[2,1-f][1,2,4]triazine-7-carboxamide (0.150 g, 0.293 mmol, 1 equiv.), (S)-5-(benzyloxy)-3-(but-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 equiv.) was added methyl (2-methylbut-3-en-2-yl)carbonate (0.0633 g, 0.439 mmol, 1.5 equiv.). The reaction mixture was heated to 60 °C for 2 h and concentrated. The residue was purified by column chromatography (0–100% EtOAc / hexanes), and the pure fractions were collected and concentrated to give (S)-5-(benzyloxy)-3-(but-3-en-2-yl)-1-(2-methylbut-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 equiv.) in 1,2-dichloroethane (1 mL) was added Hoveyda-Grubbs II catalyst (0.004 g, 0.006 mmol, 0.2 equiv.). The reaction mixture was sparged with Ar(g) for 10 min and heated to 75 °C for 18 h. The mixture was concentrated and purified by column chromatography (0–100% EtOAc / hexanes) to give (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 equiv.) was dissolved in 1:1 TFA / toluene (2 mL) and stirred at room temperature for 5 h. The reaction mixture was concentrated, dissolved in MeCN, filtered, and purified by preparative HPLC (Gemini 10μ C18 110A, AXI / ; 250 × 21.2 mm column) eluting with 5–100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 min. The combined fractions were lyophilized to give (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-oxo-pyridine-2-carboxylate:

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

[0380] Methyl 3-benzyloxy-1-[tert-butoxycarbonyl(1-methylallyl)amino]-5-[(2,4-difluorophenyl)methylcarbamoyl]-4-oxo-pyridine-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 to 60° C. for 6 hours. The reaction was then cooled to room temperature and concentrated. The residue was diluted with EtOAc and acidified to pH 4 with 1N HCl. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give a pale pinkish solid. The resulting product was used directly in the next step. LCMS-ESI+ (m / z): H+ calculated for C30H31F2N3O7, theoretical: 583.21, found: 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 was added (2R)-2-aminobut-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). The newly formed mixture was stirred for 1 h. The reaction was then diluted with DCM, washed with 10% citric acid, brine, dried over sodium sulfate, filtered, concentrated, and used directly in the next step. LCMS-ESI+ (m / z): H+ calculated for C34H38F2N4O7, theoretical: 652.27, found: 653.03. Step 4: Synthesis of 3-benzyloxy-N5-[(2,4-difluorophenyl)methyl]-N2-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallylamino)-4-oxo-pyridine-2,5-dicarboxamide:

[0382] tert-Butyl N-[3-benzyloxy-5-[(2,4-difluorophenyl)methylcarbamoyl]-2-[[(1R)-1-(hydroxymethyl)allyl]carbamoyl]-4-oxo-1-pyridyl]-N-(1-methylallyl)carbamate (7.8 g, 12 mmol) was dissolved in DCM (70 mL) at room temperature and treated with 4N HCl in 1,4-dioxane (70 mL) at room temperature for 1 hour. The reaction was concentrated, diluted with EtOAc, and slowly basified with saturated sodium bicarbonate until no more foaming occurred. Solid sodium bicarbonate was then added to saturate the aqueous layer. Extraction with EtOAc followed by washing the organic layer with brine, drying over sodium sulfate, filtering, and concentrating gave a brownish oil. The resulting product was used directly in the next step. LCMS-ESI+(m / z): H+ calculated for C29H30F2N4O5, theoretical: 552.22, found: 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-oxo-pyridine-2,5-dicarboxamide (1.57 g, 2.84 mmol) was dispensed into a mixture of DCE (5.3 mL) and acetonitrile (5.3 mL) at room temperature, 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 added in one portion. The reaction was sealed and stirred for 1 hour. The reaction was then cooled to room temperature, concentrated, redissolved in EtOAc, washed with saturated sodium bicarbonate, brine, dried over sodium sulfate, filtered, and concentrated to give a brownish oil. The residue was then 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 was then heated at 70 °C for 2 h, after which it was cooled to room temperature and partitioned between EtOAc 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): H+ calculated for C30H30F2N4O5, theory: 564.22, found: 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 the addition, the reaction was removed from the cold bath and stirred at ambient temperature overnight. The reaction was then cooled to 0 °C and quenched with saturated sodium bicarbonate. Additional sodium bicarbonate powder was added to saturate the mixture. The reaction was extracted with DCM, washed with brine, dried over sodium sulfate, filtered, concentrated, and purified by normal phase chromatography. LCMS-ESI+(m / z): H+ calculated for C30H29F3N4O4, theoretical: 566.21, found: 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 sparged with argon for an additional 5 minutes, then sealed and heated at 80° C. under a nitrogen balloon overnight. The reaction 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=10.5 Hz, 1H), 5.11 (d, J=14.6 Hz, 1H), 4.79-4.65 (m, 1H), 4.65-4.62 (m, 2H), 4.62-4.46 (m, 1H), 4.26 (d, J=14.6 Hz, 1H), 3.77 (tp, J=6.6, 3.3 Hz, 1H), 1.41 (d, J=6.6 Hz, 3H). LCMS-ESI+ (m / z): H+ calculated for CHFNO4, theory: 538.18, found: 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 was concentrated, redissolved in DMF, and purified by reverse-phase preparative HPLC. The absolute configuration at C13 was not confirmed. 1 H NMR (400 MHz, acetonitrile-d3) δ 10.15 (s, 1H), 8.39 (s, 1H), 7.44 (td, J = 9.2, 8.8, 6.5 Hz, 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 for 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, and the reaction was degassed and flushed with nitrogen three times, then degassed and flushed with hydrogen three times before hydrogenating under a hydrogen balloon for 1 hour. The reaction 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 (400 MHz, acetonitrile-d3) δ 10.33 (s, 1H), 8.45 (s, 1H), 7.44 (td, J = 9.2, 8.8, 6.5 Hz, 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, 3.5 Hz, 2H), 1.32 (d, J = 7.2 Hz, 3H). LCMS-ESI+ (m / z): H+ calculated for C21H21F3N4O4, theory: 450.15, found: 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] To methyl 3-benzyloxy-1-(tert-butoxycarbonylamino)-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyridine-2-carboxylate (10 g, 17.8 mmol) in THF (200 ml) at 0° C. was added but-3-en-2-ol (1.93 g, 26.7 mmol), followed by 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 allowed to warm to room temperature. The reaction was stirred at room temperature overnight. The solvent was removed under vacuum, and the resulting crud material was purified by silica gel column to give the title 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] To 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) in MeOH (80 ml) was added aqueous LiOH (2.5 N) (43 ml, 107 mmol). The reaction mixture was heated to 70 °C overnight. The reaction mixture was carefully concentrated to remove MeOH. The residue was diluted, rinsed with some water, and acidified to pH = 3 with 1 N HCl. EtOAc was added for extraction. The organic phase was separated. The aqueous layer was extracted with more EtOAc. The combined organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated to give the title compound. The crude material was carried on 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 ( To [(1-methylallyl)amino]-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyridine-2-carboxylic acid (11.2 g, 18.6 mmol) was added DIEA (16.2 ml, 93.1 mmol), followed by HATU (9.2 g, 24.2 mmol). After stirring the reaction mixture at room temperature for 1 hour, (2R)-2-aminobut-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 EtOAc and washed with aqueous LiCl. The aqueous layer was extracted with EtOAc (1×). The combined organic phases were washed with water (1×). The organic phase was dried over MgSO4 and concentrated to give the crude product, which was purified by silica gel chromatography to give the title 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. LCMS indicated the reaction was complete. Therefore, the reaction mixture was then concentrated to dryness. The residue was then partitioned between EtOAc and aqueous NaHCO3. The aqueous layer was extracted with EtOAc. The combined organic phase was washed with water, dried over Na2SO4, filtered, and concentrated to give the title compound. MS (m / z) 571.06 [M+H] + . Synthesis of 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, added bromomethylbenzene.

[0392] To 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 a 20 ml microwave reaction mixture in CAN (5 ml) and DCE (5 ml) was added paraformaldehyde (93.1 mg, 3.04 mmol), AcOH (0.5 mL), followed by TFA (0.5 mL). After the addition, the mixture was capped and heated at 89 °C overnight. LCMS indicated a complete reaction. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3. The organic phase was dried over MgSO4, and the solvent was removed in vacuo to give the crude material of the title compound, which was carried on crude 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]triazin-3-yl]but-3-enyl]acetate:

[0393] To 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 added bromomethylbenzene (XX-5) (2.08 g, 12.2 mmol), followed by potassium carbonate (2.93 g, 21.2 mmol). The reaction mixture was stirred at 60 °C overnight. Lcms indicated a complete reaction. The reaction mixture was diluted with EtOAc and washed with saturated aqueous NaHCO3. The organic phase was washed with MgSO4. After drying, the solvent was removed in vacuo to give 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] To 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]triazin-3-yl]but-3-enyl]acetate (7.61 g, 12.2 mmol) in MeOH (100 ml) was added NaOH (1N) (63 ml, 63.3 mmol). The mixture was stirred at room temperature for 30 minutes. LCMS showed the reaction was complete. The solvent was removed in vacuo, and the resulting residue was diluted in EtOAc and washed with H2O. The organic layer was dried over MgSO4 and concentrated in vacuo. The resulting crude material was purified by silica gel column to give the title 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] To 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 added deoxofluor-1H-fluoren-1-ol (5.21 ml, 14.1 mmol) in toluene (2.7 N) at 0 °C. The mixture was then slowly warmed to room temperature and stirred overnight. The reaction mixture was added to ice-cold NaHCO3 and then extracted with DCM. The DCM phase was dried over MgSO4, and the crude product was purified on a silica gel column to give the title 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 by vacuum, and then refilled with N2 (3x) at room temperature. Catalyst HG-II was then added to the solution, which was then flushed with argon using a vent needle at 80 °C for 1.5 hours. The vent needle was then removed, and the reaction was stirred overnight at 80 °C using an argon balloon. LCMS indicated a complete reaction, and the solvent was removed under vacuum. The resulting residue was purified using a silica gel column to give the title 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-(furan) in toluene (2 ml) To (2,4,6-trifluoromethyl)-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 (80 mg, 0.144 mmol) was added TFA (2 ml), and the reaction mixture was stirred at room temperature overnight. LCMS indicated a complete reaction. The solvent was removed in vacuo, and the resulting material was purified by preparative HPLC to give the title 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), followed by the addition of Pd / C (10% by weight) (7.8 mg, 0.09 mmol). The mixture was then evacuated and refilled with H three times. The reaction was stirred under H for 2 hours. LCMS indicated 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 provide the title 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 in isopropyl alcohol (5 mL) was purged with argon. To the solution was added 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 10% sodium thiosulfate solution, and the mixture was extracted with EtOAc. The organic phase was separated, dried over MgSO4, filtered, concentrated, and the residue was purified by silica gel chromatography eluting with 0-100% hexanes / EtOAc to give the title 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] 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 (20 mg, 0.037 mmol) in DCM (2 mL) was added a solution of dexofluorin in toluene (50%, 0.041 mL, 0.11 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 15 min and quenched by the addition of saturated NaHCO solution. The mixture was extracted with DCM, and the organic phase was separated, dried over MgSO, filtered, concentrated, and purified by silica gel chromatography (eluting with 0–100% hexanes / EtOAc) to give the title 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) was added TFA (1 mL). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC eluting with 5-100% acetonitrile in water to give the title 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]triazonin-4-yl benzoate:

[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, was added benzoic acid (24.5 mg, 0.201 mmol), diisopropyl azodicarboxylate (40.6 mg, 0.201 mmol), and triphenylphosphine (53 mg, 0.201 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, and extracted with EtOAc. The organic phase was dried over MgSO4, filtered, and concentrated to 0-100% The residue was purified by silica gel chromatography eluting with xanthenes / EtOAc to give the title 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] 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]triazonin-4-ylbenzoate (15 mg, 0.023 mmol) in MeOH (2 mL) and water (0.5 mL) was added LiOH·HO (2.80 mg, 0.117 mmol). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was washed with saturated NaHCO, extracted with EtOAc, dried over MgSO, 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 similarly to 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] 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) was added Dess-Martin periodinane (94.5 mg, 0.223 mmol) at 0 °C. The reaction mixture was then stirred at room temperature for 3 hours. The reaction mixture was quenched by adding 1N NaSO, and the mixture was washed with saturated NaHCO and extracted with DCM. The organic phase was separated, dried over MgSO4, filtered, concentrated, and the residue was purified by silica gel chromatography eluting with 0-100% hexanes / EtOAc to give the title 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] To 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 DCM (2.0 mL) at 0 °C was added a solution of dexofluoride in toluene (50%, 0.072 mL, 0.20 mmol). The reaction was stirred overnight at room temperature. To the reaction mixture was added additional dexofluoride in toluene (50%, 0.072 mL, 0.20 mmol) and stirred at room temperature. After 1 day, to the mixture was added additional deoxofluor solution in toluene (50%, 0.072 mL, 0.20 mmol). The reaction mixture was stirred at room temperature for approximately 2 weeks. The reaction was quenched by the addition of saturated NaHCO3 and extracted with DCM. The organic phase was separated, dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography eluting with 0-100% hexanes / EtOAc to give the title compound. MS (m / z) 559.09 [M+H]+. Step 3: 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:

[0407] A solution 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 (13 mg, 0.023 mmol) in DCM (1 mL) and TFA (1 mL) was stirred at room temperature overnight. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC eluting with 5-100% acetonitrile / water to give the title compound. MS (m / z) 469.26 [M+H] +. 1H NMR (400MHz, chloroform-d) δ10.23(t,J=5.7Hz,1H),8.56(s,1H),7.38(td,J=8.7,6.4Hz,1H),6.90-6.78(m,2H),5.06(dp,J=14.1,7.1 Hz,1H),4.83-4.56(m,4H),3.37(tt,J=7.9,5.1Hz,1H),2.42-2.21(m,2H),1.52(dd,J=7.0,1.7Hz,3H),1.44(dd,J=7.3,2.6Hz,3H). Example 55: Preparation of (1S,2R,5S)-4-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 (C55) [ka]

[0408] (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 instead of (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 was used to obtain (1S,2R,5S)-8-(benzyloxy)-4-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, except that (1S,2R,5S)-4-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 was a by-product of the fluorination reaction. (Iodobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazonine-10-carboxamide was prepared in a manner similar to that used to prepare Example 54. MS (m / z) 467.17 [M+H] + . 1H NMR (400MHz, methanol-d4) δ10.47(s,1H),8.45(s,1H),6.92(t,J=8.4Hz,2H),5.53(d,J=7.7Hz,1H),5.33-5.14(m,2H),4.79 (d,J=14.6Hz,1H),4.69(t,J=3.5Hz,2H),3.92(dq,J=6.9,3.5Hz,1H),1.49(dd,J=7.3,1.8Hz,3H),1.44(d,J=6.8Hz,3H). Example 56: Preparation of (1S,2R,4R,5S)-4-(difluoromethyl)-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 (C56) [ka] Step 1: Preparation of (1S,2R,5S,E)-8-(benzyloxy)-4-(methoxymethylene)-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:

[0409] To a solution 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 (120 mg, 0.22 mmol) in methanol (1.5 mL) were added 1-diazo-1-dimethoxyphosphoryl-propan-2-one (96 mg, 0.5 mmol) and potassium tert-butoxide (85 mg, 0.76 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 45 minutes. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO, extracted with EtOAc, and the organic phase was separated, dried over MgSO, filtered, concentrated, and purified on a silica gel column eluted with 0-100% hexane / EtOAc to give the title compound. MS (m / z) 583.06 [M+H]. Step 2: Preparation of (1S,2R,5S)-8-(benzyloxy)-4-formyl-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:

[0410] (1S,2R,5S,E)-8-(benzyloxy)-4-(methoxymethylene)-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 (30 mg, 0.051 mmol) was treated with THF (1.5 mL) and 1 N HCl (1.5 mL) in a microwave vial. The vial was then sealed and heated to 55 °C for 1 day. The reaction was quenched with saturated sodium bicarbonate solution and extracted into EtOAc. The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 0-100% EtOAc / hexanes. MS(m / z) 569.07[M+H]+. Step 3: Preparation of (1S,2R,4R,5S)-8-(benzyloxy)-4-(difluoromethyl)-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:

[0411] To a solution of (1S,2R,5S)-8-(benzyloxy)-4-formyl-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, 0.026 mmol) in DCM (2.0 mL) was added toluene (50%, 23 mg, 0.053 mmol) at 0...

Claims

1. Formula I: 【Chemical 1】 or a pharmaceutically acceptable salt thereof, wherein Ar is C ６ ~C １０ aryl, or a 6- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S; ６ ~C １０ The aryl or 6- to 10-membered heteroaryl is optionally selected from the group consisting of halogen, C １ ~C ６ Alkyl, C １ ~C ６ Haloalkyl, and C １ ~C ６ substituted with 1 to 4 substituents independently selected from the group consisting of alkyloxy; R １ But H, C １ ~C ３ alkyl or phenyl; R ２ is H or C １ ~C ３ is alkyl; R ３ is H or C １ ~C ３ is alkyl; R ４ and R ５ are each independently H, halogen, cyano, C １ ~C ６ Alkyl, C １ ~C ６ Alkyloxy, C ６ ~C １０ aryl or a 6- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, １ ~C ６ Alkyl, C １ ~C ６ Alkyloxy, C ６ ~C １０ The aryl or 6- to 10-membered heteroaryl is optionally selected from the group consisting of halogen, C １ ~C ３ Alkyloxy, or C １ ~C ３ substituted with 1, 2, or 3 groups independently selected from haloalkyloxy; R ４ and R ５ are joined together to form a 3- to 6-membered carbocyclic or 4- to 6-membered heterocyclic ring containing one heteroatom selected from N, O, and S; R ６ H, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkyloxy or C １ ~C ６ haloalkyl; R ７ H, halogen, C １ ~C ６ Alkyl, C １ ~C ６ Alkyloxy, or C １ ~C ６ haloalkyl; R ８Ａ and R ８Ｂ However, independently, H, C １ ~C ３ alkyl or benzyl; and -XY- is -(CR １３Ａ R １３Ｂ ) ｐ -CR ９ =CR １０ - where: R ９ and R １０ together with the carbons to which they are attached form a phenyl or a 5- to 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S; wherein said phenyl or said 5- to 6-membered heteroaromatic ring optionally contains halogen, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, and C １ ~C ３ substituted with 1, 2, or 3 substituents independently selected from the group consisting of alkyloxy; and R １３Ａ , and R １３Ｂ are each independently H, halogen, or C １ ~C ６ Alkyl, C １ ~C ６ alkyloxy; or C １ ~C ６ haloalkyl; and p is 0 or 1; The compound or a pharmaceutically acceptable salt thereof.

2. The compound has formula Ia: 【Chemistry 2-1】 or a compound of The compound has the formula Ib: 【Chemistry 2-2】 is a compound of 2. The compound of claim 1 or a pharmaceutically acceptable salt thereof.

3. Ar is C ６ ~C １０ aryl, or a 6- to 10-membered heteroaryl containing one heteroatom selected from N, O, and S; ６ ~C １０ The aryl or 6- to 10-membered heteroaryl is optionally selected from the group consisting of halogen, C １ ~C ６ Alkyl, and C １ ~C ６ 3. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, which is substituted with 1 to 4 substituents independently selected from the group consisting of alkyloxy.

4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Ar is C6-C10 aryl or a 6- to 10-membered heteroaryl containing one heteroatom selected from N, O, and S; and wherein the C6-C10 aryl or 6- to 10-membered heteroaryl is optionally substituted with 1 to 4 halogens.

5. A compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, wherein Ar is a C6-C10 aryl or a 6- to 10-membered heteroaryl containing one heteroatom selected from N, O, and S; and wherein the C6-C10 aryl or 6- to 10-membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from Cl and F.

6. Ar is a group represented by the following formula: 【Chemistry 3-1】 is a group of wherein Z is N or CR A ; n is 0, 1, 2, 3, or 4; and each RA is independently halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkyloxy, optionally where Z is CH or N.

4. The compound of claim 3 or a pharmaceutically acceptable salt thereof.

7. Ar is 【Chemistry 3-2】 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein: n is 1, 2, 3, or 4; and each R A is independently selected from halogen and C 1 -C 6 alkyloxy.

8. Ar is 【Chemistry 3-2】 4. The compound of claim 3, wherein: n is 1, 2, 3, or 4; and each R A is independently halo or —O—C 1-4 alkyl, or a pharmaceutically acceptable salt thereof.

9. Ar is 【Chemistry 3-3】 4. The compound of claim 3, wherein:

10. Ar is 【Chemistry 3-4】 4. The compound of claim 3, or a pharmaceutically acceptable salt thereof, wherein n is 1, 2, or 3, and each RA is independently fluoro or chloro.

11. The compound has the formula II: 【Chemistry 4-1】 and where: n is 0, 1, 2, 3, or 4; and Each R Ａ are independently halogen, C １ ~C ６ Alkyl, and C １ ~C ６ alkyloxy, The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof.

12. The compound of formula IIa: 【Chemistry 4-2】 and where: n is 0, 1, 2, 3, or 4; and each R A is independently halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkyloxy; 12. The compound of claim 11 or a pharmaceutically acceptable salt thereof.

13. The compound of formula IIb: 【Chemistry 4-3】 and where: n is 0, 1, 2, 3, or 4; and each R A is independently halogen, C 1 -C 6 alkyl, and C 1 -C 6 alkyloxy; 12. The compound of claim 11 or a pharmaceutically acceptable salt thereof.

14. (a) -XY- is -CR １３Ａ R １３Ｂ -CR ９ =CR １０ - is; or (b) -XY- is -CH ２ -CR ９ =CR １０ - is; or (c) -XY- is -CR ９ =CR １０ -is, The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof.

15. R ９ and R １０ together with the carbons to which they are attached form a phenyl or a 5- to 6-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms independently selected from N and O; wherein said phenyl or said 5- to 6-membered heteroaromatic ring optionally contains halogen, C １ ~C ３ Alkyl, C １ ~C ３ Haloalkyl, and C １ ~C ３ substituted by 1, 2, or 3 substituents independently selected from the group consisting of alkyloxy; 15. The compound according to any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof.

16. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 together with the carbons to which they are attached form a phenyl, wherein said phenyl is optionally substituted with one, two, or three substituents independently selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and C 1 -C 3 alkyloxy.

17. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 together with the carbons to which they are attached form a phenyl, wherein the phenyl is optionally substituted with one substituent selected from the group consisting of halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, and C 1 -C 3 alkyloxy.

18. The compound of any one of claims 1 to 14, or a pharmaceutically acceptable salt thereof, wherein R 9 and R 10 together with the carbon to which they are attached form a phenyl, wherein said phenyl is optionally substituted with one halogen.

19. The compound has the formula III: 【Chemistry 7-1】 having where: m is 0, 1, 2, or 3; and Each R Ｂ are independently halogen, C １ ~C ３ Alkyl, C １ ~C ３ haloalkyl, or C １ ~C ３ alkyloxy, The compound according to any one of claims 11 to 13, or a pharmaceutically acceptable salt thereof.

20. The compound of claim 1, wherein the compound has the formula IIIa: 【Chemistry 7-2】 having where: m is 0, 1, 2, or 3; and each R B is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 1 -C 3 alkyloxy; 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof.

21. The compound of claim 20, wherein the compound has the formula IIIb: 【Chemistry 7-3】 having where: m is 0, 1, 2, or 3; and each R B is independently halogen, C 1 -C 3 alkyl, C 1 -C 3 haloalkyl, or C 1 -C 3 alkyloxy; 20. The compound of claim 19, or a pharmaceutically acceptable salt thereof.

22. The compound of claim 21, wherein the compound has formula IV: 【Chemistry 7-4】 having where z is 0 or 1. The compound according to any one of claims 11 to 13, or a pharmaceutically acceptable salt thereof.

23. The compound of claim 22, wherein the compound has formula IVa: 【Chemistry 7-5】 having where z is 0 or 1.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof.

24. The compound of claim 23, wherein the compound has formula IVb: 【Chemistry 7-6】 having wherein z is 0 or 1.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof.

25. R ８Ｂ The compound according to any one of claims 1 to 24, or a pharmaceutically acceptable salt thereof, wherein is H.

26. The compound according to any one of claims 1 to 25, wherein R 8A is H, or a pharmaceutically acceptable salt thereof.

27. The compound according to any one of claims 1 to 26, wherein R 3 is H, or a pharmaceutically acceptable salt thereof.

28. The compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are both H.

29. Each R ４ and R ５ are independently H or C １ ~C ６ alkyl, wherein said C １ ~C ６ The alkyl may optionally be selected from the group consisting of halogen, C １ ~C ３ Alkyloxy, or C １ ~C ３ 29. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, substituted by 1, 2, or 3 groups independently selected from haloalkyloxy.

30. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R 4 is H or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1, 2, or 3 groups independently selected from halogen, C 1 -C 3 alkyloxy, or C 1 -C 3 haloalkyloxy; and R 5 is H or C 1 -C 6 alkyl.

31. The compound of any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R 4 is H or C 1 -C 6 alkyl, wherein the C 1 -C 6 alkyl is optionally substituted with 1, 2, or 3 groups independently selected from halogen, C 1 -C 3 alkyloxy, or C 1 -C 3 haloalkyloxy; and R 5 is H.

32. The compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are independently H, Me, OMe, or —CH 2 F.

33. A compound according to any one of claims 1 to 28, or a pharmaceutically acceptable salt thereof, wherein R 4 and R 5 are linked together to form a 4- to 6-membered heterocyclic ring containing one heteroatom selected from N, O, and S.

34. R ６ H, halogen, C １ ~C ６ Alkyl, or C １ ~C ６ 34. The compound of any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

35. The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R 6 is H, C 1 -C 6 alkyl, or C 1 -C 6 haloalkyl.

36. The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R 6 is H, methyl, or CH 2 F.

37. The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R 6 is H, halogen, or C 1 -C 6 alkyl.

38. The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R 6 is halogen or C 1 -C 6 alkyl.

39. The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R 6 is C 1 -C 6 alkyl.

40. The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R 6 is methyl.

41. The compound according to any one of claims 1 to 33, or a pharmaceutically acceptable salt thereof, wherein R 6 is H.

42. R ７ H, halogen, C １ ~C ６ Alkyl, or C １ ~C ６ 42. The compound of any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, which is haloalkyl.

43. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein R 7 is H, halogen, or C 1 -C 6 alkyl.

44. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein R 7 is halogen or C 1 -C 6 alkyl.

45. The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein R 7 is C 1 -C 6 alkyl.

46. ​​The compound according to any one of claims 1 to 41, or a pharmaceutically acceptable salt thereof, wherein R 7 is H.

47. R １３Ａ , and R １３Ｂ are each independently H, halogen, or C １ ~C ６ Alkyl, or C １ ~C ６ 47. The compound of any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, which is alkyloxy.

48. The compound according to any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, wherein R 13A and R 13B are each independently H, halogen, or C 1 -C 6 alkyloxy.

49. The compound according to any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, wherein R 13A and R 13B are each independently H, halogen, or methoxy.

50. The compound of any one of claims 1 to 46, or a pharmaceutically acceptable salt thereof, wherein R 13A and R 13B are each independently H, fluoro, or methoxy.

51. The compound is 【Chemistry 13】 2. The compound of claim 1, wherein:

52. The compound is selected from the group consisting of: 【Chemistry 14-1】 【Chemistry 14-2】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

53. The compound is selected from the group consisting of: 【Chemistry 15】 2. The compound of claim 1, selected from the group consisting of: or a pharmaceutically acceptable salt thereof.

54. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 53 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, Optionally, further comprising an additional therapeutic agent; Optionally, wherein said additional therapeutic agent is: (a) an anti-HIV agent; or (b) 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 latency reactivator, a capsid polymerization inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, or a combination thereof; or (c) lenacapavir, islatravir, or a pharmaceutically acceptable salt thereof; or (d) abacavir, tenofovir alafenamide, tenofovir disoproxil, lenacapavir, GS-5894, islatravir, or a pharmaceutically acceptable salt thereof A pharmaceutical composition comprising:

55. A composition comprising a compound according to any one of claims 1 to 53 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 54 for use in medical therapy.

56. A composition comprising a compound according to any one of claims 1 to 53 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition according to claim 54 for use in the treatment of HIV infection.

57. 57. The composition or pharmaceutical composition for use according to claim 56, wherein said composition or pharmaceutical composition is for use with a therapeutically effective amount of an additional therapeutic agent, Optionally, wherein said additional therapeutic agent is: (a) an anti-HIV agent; or (b) 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 latency reactivator, a capsid polymerization inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, or a combination thereof; or (c) lenacapavir, islatravir, or a pharmaceutically acceptable salt thereof; or (d) abacavir, tenofovir alafenamide, tenofovir disoproxil, lenacapavir, GS-5894, islatravir, or a pharmaceutically acceptable salt thereof 2. A composition or pharmaceutical composition for use, wherein

58. 58. The composition or pharmaceutical composition for use according to any one of claims 56 to 57, wherein said composition or pharmaceutical composition is for use by oral, intravenous, subcutaneous or intramuscular administration.

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