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 the benefit of U.S. Provisional Patent Application No. 63 / 139,237, filed on January 19, 2021, and U.S. Provisional Patent Application No. 63 / 190,461, filed on May 19, 2021, each of which is hereby incorporated by reference in its entirety for all purposes.

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

Background Art

[0003] Human immunodeficiency virus (HIV) infection and related diseases are major public health problems worldwide. The HIV virus encodes three enzymes required for viral replication: reverse transcriptase, protease, and integrase. Drugs targeting reverse transcriptase and protease are widely used and have shown utility, especially when used in combination. However, 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, D.D. Nature (2001) 410:995 - 1001). Therefore, new agents that inhibit HIV replication are needed.

[0004] The goal of antiretroviral therapy is to achieve viral suppression in patients infected with HIV. 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, that is, the use of several drugs from at least two or more drug classes (available at 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. https: / / files.aidsinfo.nih.gov / contentfiles / lvguidelines / AdultandAdolescentGL.pdf. Accessed February 20, 2020). In addition, when patients require treatment for other medical conditions, the decision-making regarding the treatment of HIV-infected patients is complicated. Standard treatment requires the use of multiple different drugs to suppress HIV as well as to treat other conditions that the patient may experience, so 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). Since the HIV virus has a tendency to mutate, there is a need for anti-HIV drugs that are effective against various known HIV variants (Hurt, et al. HIV / AIDS CID (2014) 58, 423-431). For a particular patient, for example, a patient with difficult or limited access to healthcare, it can be difficult to adhere to a daily oral treatment or prevention regimen. Drugs that provide favorable pharmaceutical properties (e.g., improved efficacy, long-acting pharmacokinetics, low solubility, low clearance, and / or other properties) are suitable for less frequent dosing and provide better patient compliance. Such improvements in turn result in optimization of drug exposure and limitation of the emergence of drug resistance.

Prior Art Documents

Non-Patent Documents

[0006]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

Means for Solving the Problems

[0007] In some embodiments, a compound of formula I,

Chemical Formula

[0008] In some embodiments, the 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, the method comprising administering to the human a therapeutically effective amount of a compound of Formula I, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

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

[0012] In some embodiments, the 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 the treatment of HIV infection.

[0014] 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 in the manufacture of a medicament for treating HIV infection in a human having or at risk of having the infection.

BRIEF DESCRIPTION OF THE DRAWINGS

[0015] In the following description, specific details are set forth in order to provide a thorough understanding of the various embodiments disclosed herein. However, one of ordinary skill in the art will understand that the embodiments disclosed herein may be practiced without these details. The following description of some embodiments is to be understood as being provided by way of illustration of the subject matter claimed and is not intended to limit the claimed subject matter to the specific embodiments illustrated. Headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading. I. DEFINITIONS

[0016] Unless the context requires otherwise, throughout this specification and the claims, the word “comprise” and variations thereof, such as “comprises” and “comprising,” are to be construed in an open, inclusive sense, that is, as “including, but not limited to.” is to be construed in an open and inclusive sense, that is, as “including, but not limited to.”

[0017] References to "one embodiment" or "an embodiment" throughout this specification mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment disclosed herein. Thus, appearances of the phrases "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Further, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0018] "Amino" refers to -NH 2 radical.

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

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

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

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

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

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

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

[0026] "Cycloalkyl" or "carbocyclic ring" refers to a saturated or partially saturated cyclic alkyl group having a monocyclic or fused ring system, a bridged ring system, and a polycyclic ring including a spiro ring system. The term "cycloalkyl" includes a cycloalkenyl group (i.e., a cyclic group having at least one double bond). As used herein, cycloalkyl has 3 to 20 carbocyclic atoms (i.e., C 3~20 cycloalkyl), has 3 to 12 carbocyclic atoms (i.e., C 3~12 cycloalkyl), has 3 to 10 carbocyclic atoms (i.e., C 3~10 cycloalkyl), has 3 to 8 carbocyclic atoms (i.e., C 3~8 cycloalkyl), or has 3 to 6 carbocyclic atoms (i.e., C 3~6 cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. "Halocycloalkyl" refers to cycloalkyl substituted by 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 substituted by one or more halogen radicals as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, etc.

[0029] "Heteroaryl" or "heteroaromatic ring" refers to an aromatic group having a monocyclic, polycyclic, or fused polycyclic ring having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl contains 5 to 20 ring atoms (5- to 20-membered heteroaromatic ring), contains 5 to 12 ring atoms (5- to 12-membered heteroaromatic ring), contains 5 to 10 ring atoms (5- to 10-membered heteroaromatic ring), or contains 5 to 6 ring atoms (5- to 6-membered heteroaromatic ring), and contains 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 include aryl as previously defined and does not overlap with aryl.

[0030] "Heterocyclyl" or "heterocyclic ring" refers to a non-aromatic radical or ring having 3 to 15 atoms, wherein 1 to 6 atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and are bonded to the remainder of the molecule by single bonds, a non-aromatic group or ring. In certain embodiments, "heterocyclyl" has 3 to 10 atoms, or 1 to 2 atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, wherein 1 to 4 atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen, carbon, or sulfur atoms in heterocyclyl can optionally be oxidized, and the nitrogen atoms can optionally be 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 a partially saturated ring when so designated. 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 also mean that all pharmaceutically acceptable compounds of formula I that are isotopically labeled by replacing one or more atoms with atoms having different atomic masses or mass numbers are included. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, each 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O,17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I are included. In certain embodiments, these radiolabeled compounds are useful for determining or measuring the effectiveness of a compound, for example, by characterizing the site or mode of action or the binding affinity for a pharmacologically important site of action. Certain isotopically labeled compounds of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, for example, those incorporating a radioisotope, are useful in drug and / or substrate tissue distribution studies. The radioisotope tritium, i.e., 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose in view of the ease of their incorporation and the ready means of detection.

[0032] In certain embodiments, substitution with a heavier isotope such as deuterium, i.e., 2 H, can provide certain therapeutic advantages due to greater metabolic stability. For example, the in vivo half-life can be increased or the required dosage can be decreased. Thus, in some situations, a heavier isotope may be preferred.

[0033] Substitution with a positron-emitting isotope, for example, 11 C, 18 F, 15 O, and 13 N is for positron emission tomography (PET) to examine substrate receptor occupancy It may be useful in the research. The 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 using appropriate isotopically labeled reagents instead of the conventionally used unlabeled reagents by a process similar to those described in the examples shown below.

[0034] The methods, compositions, kits, and articles of manufacture provided herein use or include a compound (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 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 enhance resistance to metabolism. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds can be synthesized by means known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0035] The embodiments disclosed herein are also meant to include the in vivo metabolites of the compounds of the present disclosure. Such products can result, for example, mainly from enzymatic processes such as oxidation, reduction, hydrolysis, amidation, esterification, etc. of the administered compounds. Thus, the embodiments disclosed herein include compounds produced by a process that includes administering a compound according to an embodiment disclosed herein to a mammal for a period of time sufficient to obtain its metabolites. Such products are typically identified by administering a radiolabeled compound according to an embodiment disclosed herein to an animal such as a rat, mouse, guinea pig, monkey, or human at a detectable dose, allowing sufficient time for metabolism to occur, and isolating the conversion product from urine, blood, or other biological samples.

[0036] "Mammal" includes both humans and non-domestic animals such as livestock, for example, laboratory animals and household pets (e.g., cats, dogs, pigs, rabbits, sheep, goats, horses, rabbits) and wild animals.

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

[0038] "Pharmaceutically acceptable excipients" include any carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavoring agent, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifying agent, or other pharmacologically inactive substances that are formulated in combination with the pharmacologically active components of a pharmaceutical composition, are compatible with the other components of the formulation, and are suitable for use in humans or livestock without undue toxicity, irritation, allergic reaction, etc., but are not limited thereto.

[0039] Examples of the "pharmaceutically acceptable salts" of the compounds disclosed in this specification include salts derived from suitable bases such as alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and NX 4 + (wherein X is C 1~4 alkyl). Pharmaceutically acceptable salts of nitrogen atoms or amino groups include, for example, 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, pectinic acid, phenylacetic acid, 3-phenylpropionic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, sulfanilic acid, tartaric acid, undecanoic acid, and succinic acid, etc. organic carboxylic acids, methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, mesitylenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and 2-naphthalenesulfonic acid, etc. organic sulfonic acids, and salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and sulfamic acid. Pharmaceutically acceptable salts of compounds with hydroxy groups include anions of the said compounds combined with suitable cations such as Na + and NX 4 + (X is independently selected from H or C 1~4 alkyl group).

[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 non-pharmaceutically acceptable acids or bases may also find use, for example, in the preparation or purification of a compound of formula I or another compound of the embodiments disclosed herein. All salts, whether or not derived from physiologically acceptable acids or bases, 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 the embodiments disclosed herein. Examples of metal salts prepared in this manner are salts containing Li + , Na + , and K + . By adding a suitable metal compound, a less soluble metal salt can be precipitated from a solution of a more soluble salt.

[0042] In addition, salts can be formed by adding certain organic and inorganic acids, such as HCl, HBr, H 2 SO 4 , H 3 PO 4 , or an organic sulfonic acid, to a basic center, typically an amine. Finally, it should be understood that the compositions herein include the compounds disclosed herein in their unionized and zwitterionic forms.

[0043] A "pharmaceutical composition" refers to a formulation of a compound of the embodiments disclosed herein with a medium generally accepted in the art for delivering a biologically active compound to a mammal, such as a human. Such media include all pharmaceutically acceptable excipients.

[0044] "Effective amount" or "therapeutically effective amount" refers to an amount of a compound according to the embodiments disclosed herein that, when administered to a patient in need thereof, is sufficient to effect treatment of a medical condition, state, or disorder disclosed herein. Such amount will be sufficient to elicit the biological or medical response of the tissue system or patient as required by a researcher or clinician. The amount of the compound according to the embodiments disclosed herein that constitutes a therapeutically effective amount will vary depending on the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type and severity of the medical condition or disorder being treated, the drugs used in combination with or concurrently with the compound of the embodiments disclosed herein, and factors such as the age, weight, general health, gender, and diet of the patient. Such therapeutically effective amount can be determined by one of ordinary skill in the art in view of their 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 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 refer to administering a compound or composition according to the embodiments disclosed herein to prevent the appearance of symptoms of the disease and / or to prevent the virus from reaching a detectable level in the blood after an individual has been exposed to the virus but before the symptoms of the disease appear and / or before the virus is detected in the blood, and administering a compound or composition according to the embodiments disclosed herein to a mother before delivery and to a child within a few days after birth to prevent perinatal transmission of HIV from the mother to the infant. The terms "treating" and "treatment" also include administering a compound or composition according to the embodiments disclosed herein before an individual is exposed to the virus to prevent the establishment of HIV infection if the individual is exposed to the virus and / or to prevent the virus from establishing a permanent infection and / or to prevent the appearance of symptoms of the disease and / or to prevent the virus from reaching a detectable level in the blood (also referred to as pre-exposure prophylaxis (PrEP)). The terms "treating" and "treatment" also include administering a compound or composition according to the embodiments disclosed herein both before and after an individual is exposed to the virus. are included. The terms "treating" and "treatment" also include 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 "prevent" and "prevention" refer to administering a compound, composition, or pharmaceutically acceptable salt according to the present disclosure before or after a human is exposed to a virus, but before the symptoms of the disease appear and / or before the virus is detected in the blood. This term also refers to preventing the appearance of symptoms of the disease and / or preventing the virus from reaching detectable levels in the blood. This term includes both pre-exposure prophylaxis (PrEP), as well as post-exposure prophylaxis (PEP) and both event driven or "on demand" prevention. These terms also refer to preventing perinatal transmission of HIV from mother to infant by administering to the mother before birth and to the infant within a few days after birth. This term also refers to preventing HIV infection by blood transfusion.

[0047] As used herein, the term "antiviral agent" is intended to mean an agent (compound or biological agent) effective to inhibit the formation and / or replication of a virus in a human, including but not limited to agents that interfere with the mechanism of action of either the host or the virus required for virus formation and / or replication in a human.

[0048] As used herein, the term "HIV replication inhibitor" is intended to mean an agent capable of reducing or eliminating the ability of HIV to replicate in host cells, regardless of 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, can give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- with respect to absolute stereochemistry or as (D)- or (L)- with respect to amino acids. This disclosure means that all such possible isomers are included, as well as their racemic, scalemic, and optically pure forms. The optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using a chiral synthon or chiral reagent or can be resolved using methods such as chromatography and fractional crystallization. Techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of a racemic compound (or racemization of a salt or derivative thereof) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain an olefinic double bond or other geometrically asymmetric center and are not otherwise specified, these compounds are intended to include both E and Z geometric isomers. Similarly, all tautomeric forms are also intended to be included. A "stereoisomer" refers to a compound that is composed of the same atoms bonded by the same bonds but has a different three-dimensional structure that is not interchangeable. This disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers," which refer to two stereoisomers that are mirror images of each other and whose molecules cannot be superimposed on each other. In any of the embodiments disclosed herein, the compounds disclosed herein can be in the form of their stereoisomers.

[0050] "Partially unsaturated" refers to a cyclic group that contains at least one double bond but is not aromatic.

[0051]

[0052] ​The substituents and polyvalent groups can be attached to the remainder of the molecule at any position and in any orientation to form stable compounds. For example, a compound of formula I,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0053] A compound of formula I,

Chemical formula

[0054] In some embodiments, the compound of Formula I provided herein has Formula Ia.

Chemical formula

[0055] In some embodiments, the compound of Formula I provided herein has Formula Ib.

Chemical formula

[0056] In some embodiments of the compounds of Formula I, Formula Ia, and Formula Ib, Ar is C 6 ~C 10 aryl, or 6- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and C 6 ~C 10 aryl or 6- to 10-membered heteroaryl is optionally substituted with 1 to 4 halogens. In some embodiments, Ar is C 6 ~C 10 aryl, or 6- to 10-membered heteroaryl containing 1, 2, or 3 heteroatoms selected from N, O, and S, and C 6 ~C 10 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 C 6 ~C 10Aryl, or a 6- to 10-membered heteroaryl containing one heteroatom selected from N, O, and S, C 6 ~C 10 Aryl or 6- to 10-membered heteroaryl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C 1 ~C 6 Alkyl, C 1 ~C 6 Haloalkyl, and C 1 ~C 6 Alkoxy. In some embodiments, Ar is C 6 ~C 10 Aryl, or a 6- to 10-membered heteroaryl containing one heteroatom selected from N, O, and S, C 6 ~C 10 Aryl or 6- to 10-membered heteroaryl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halogen, C 1 ~C 6 Alkyl, and C 1 ~C 6 Alkoxy. In some embodiments, Ar is C 6 ~C 10 Aryl, or a 6- to 10-membered heteroaryl containing one heteroatom selected from N, O, and S, C 6 ~C 10 Aryl or 6- to 10-membered heteroaryl is optionally substituted with 1 to 4 halogens. In some embodiments, Ar is C 6 ~C 10 Aryl, or a 6- to 10-membered heteroaryl containing one heteroatom selected from N, O, and S, C 6 ~C 10 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 halogen, C 1 ~C 6 Alkyl, C 1 ~C6 Haloalkyl, and C 1 ~C 6 phenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of alkyloxy. In some embodiments, Ar is halogen, C 1 ~C 6 alkyl, and C 1 ~C 6 phenyl optionally substituted by 1 to 4 substituents independently selected from the group consisting of alkyloxy. In some embodiments, Ar is phenyl optionally substituted by 1 to 4 halogens. In some embodiments, Ar is phenyl optionally substituted by 1 to 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 1 ~C 6 phenyl optionally substituted by 1, 2, 3, or 4 substituents independently selected from halogen and C 1 ~C 4 phenyl substituted by 1, 2, 3, or 4 substituents independently selected from halo and C

[0060] In some embodiments of the compounds of Formula I, Formula Ia, and Formula Ib, Ar is

Chemical formula

[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 [Chemical formula] and n is 1, 2, 3, or 4, and each R A is independently halogen, C 1 ~C 6 is alkyl, C 1 ~C 6 is haloalkyl, and C 1 ~C 6 is alkyloxy. In some embodiments of the compounds of Formula I, Formula Ia, and Formula Ib, Ar is [Chemical formula] and n is 1, 2, 3, or 4, and each R A is independently halogen, C 1 ~C 6 is alkyl and C 1 ~C 6 is alkyloxy. In some embodiments of the compounds of Formula I, Formula Ia, and Formula Ib, Ar is [Chemical formula] and n is 1, 2, 3, or 4, and each R A is independently halogen and C 1 ~C 6 is alkyloxy. In some embodiments, Ar is [Chemical formula] and n is 1, 2, 3, or 4, and each RA is independently halogen and C 1 ~C 4 alkyloxy. In some embodiments, Ar is

Chem.

[0063] In some embodiments of the compounds of Formula I, Formula Ia, and Formula Ib, Ar is

Chem.

Chem.

Chem.

Chem.

Chemical formula

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

Chemical formula

[0065] In some embodiments, the compounds of Formula I, Formula Ia, and Formula Ib disclosed herein have Formula II,

Chemical formula

[0066] In some embodiments, the compounds of Formula I, Formula Ia, Formula Ib, and Formula II disclosed herein have Formula IIa,

Chemical formula

[0067] In some embodiments, the compounds of Formula I, Formula Ib, and Formula II disclosed herein have Formula IIb,

Chemical formula

[0068] In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, and IIb, - X-Y- is -CR 13A CR 13B -CR 9 =CR 10 -, wherein R 9 , R 10 , R 13A , and R 13B are each independently H, halogen, C 1 ~C 6 alkyl, C 1 ~C 6 haloalkyl, or C 1 ~C 6 alkyloxy, or R 13A and R 13B are each independently H, halogen, C 1 ~C 6 alkyl, C 1 ~C 6 haloalkyl, or C 1 ~C 6 alkyloxy, and R 9 and R 10 together with the carbon 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, and the phenyl or 5- to 6-membered heteroaromatic ring is optionally substituted with halogen, C1 ~C 3 alkyl, C 1 ~C 3 haloalkyl, and C 1 ~C 3 is substituted by one, two, or three substituents independently selected from the group consisting of alkyloxy.

[0069] In some embodiments of the compounds of Formulas I, Ia, Ib, II, IIa, and IIb, -X-Y- is -CR 9 =CR 10 -, wherein each R 9 and R 10 is independently H, halogen, C 1 ~C 6 alkyl, C 1 ~C 6 haloalkyl, or C 1 ~C 6 alkyloxy, or R 9 and R 10 together with the carbon to which they are attached form phenyl or a 5- to 6-membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from N, O, and S, and the phenyl or 5- to 6-membered heteroaromatic ring is optionally substituted by 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.

[0070] In some embodiments of the compounds of Formulas I, Ia, Ib, II, IIa, and IIb, -X-Y- is -CH 2 -CR 9 =CR 10 -, wherein R 9 and R 10together with the carbon to which they are attached, form a phenyl or a 5- to 6-membered heterocyclic ring containing one, two, or three heteroatoms independently selected from N, O, and S, and the phenyl or 5- to 6-membered heteroaromatic ring 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. In some embodiments, -X-Y- is -CH 2 -CR 9 =CR 10 -, wherein R 9 and R 10 together with the carbon to which they are attached, form a 5- to 6-membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from N, O, and S, and the 5- to 6-membered heteroaromatic ring 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.

[0071] In some embodiments of the compounds of Formulas I, Ia, Ib, II, IIa, and IIb, -X-Y- is -CR 9 =CR 10 -, wherein R 9 and R 10 together with the carbon to which they are attached, form a phenyl or a 5- to 6-membered heterocyclic ring containing one, two, or three heteroatoms independently selected from N, O, and S, and the phenyl or 5- to 6-membered heteroaromatic ring 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 3It is substituted by one, two, or three substituents independently selected from the group consisting of alkyloxy. In some embodiments, -X-Y- is -CR 9 =CR 10 -, wherein R 9 and R 10 together with the carbon to which they are attached form a 5- to 6-membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from N, O, and S, and the 5- to 6-membered heteroaromatic ring is optionally substituted by 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.

[0072] In some embodiments of the compounds of Formulas I, Ia, Ib, II, IIa, and IIb, - X-Y- is -CH 2 -CR 9 =CR 10 -, R 9 and R 10 together with the carbon to which they are attached form a 5- to 6-membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from N, O, and S, and the 5- to 6-membered heteroaromatic ring is optionally substituted by 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.

[0073] In some embodiments of the compounds of Formulas I, Ia, Ib, II, IIa, and IIb, -X-Y- is -CR 9 =CR 10 -, wherein R 9 and R 10together with the carbon to which they are attached, form a 5- to 6-membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from N, O, and S, and the 5- to 6-membered heteroaromatic ring 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.

[0074] In some embodiments of the compounds of Formulas I, Ia, Ib, II, IIa, and IIb, -X-Y- is -CH 2 -CR 9 =CR 10 -, wherein R 9 and R 10 together with the carbon to which they are attached, form a 5- to 6-membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from N and O, and the 5- to 6-membered heteroaromatic ring 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.

[0075] In some embodiments of the compounds of Formulas I, Ia, Ib, II, IIa, and IIb, -X-Y- is -CR 9 =CR 10 -, wherein R 9 and R 10 together with the carbon to which they are attached, form a 5- to 6-membered heteroaromatic ring containing one, two, or three heteroatoms independently selected from N and O, and the 5- to 6-membered heteroaromatic ring 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 C1 ~C 3 It is substituted by one, two, or three substituents independently selected from the group consisting of alkyloxy.

[0076] In some embodiments of the compounds of Formulas I, Ia, Ib, II, IIa, and IIb, R 11A , R 11B , R 12A , R 12B , R 13A , and R 13B are each independently H, halogen, C 1 ~C 6 alkyl, or C 1 ~C 6 alkyloxy. In some embodiments, R 11A , R 11B , R 12A , R 12B , R 13A , and R 13B are each independently H, halogen, or C 1 ~C 6 alkyloxy. In some embodiments, R 11A , R 11B , R 12A , R 12B , R 13A , and R 13B are each independently H, halogen, or methoxy. In some embodiments, R 11A , R 11B , R 12A , R 12B , R 13A , and R 13B are each independently H, fluoro, or methoxy.

[0077] In some embodiments of the compounds of Formulas I, Ia, Ib, II, IIa, or IIb, it has Formula III,

Chemical formula

[0078] In some embodiments of the compounds of Formulas I, Ia, II, IIa, and III, they have Formula IIIa,

Chemical formula

[0079] In some embodiments of the compounds of Formulas I, Ib, II, IIb, and III, they have Formula IIIb,

Chemical formula

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

[0081] In some embodiments of the compounds of Formulas III, IIIa, and IIIb, each R B is, independently, halogen, C 1 ~C 3 alkyl, C 1 ~C 3 haloalkyl, and C 1 ~C 3 alkyloxy. In some embodiments, each R B is, independently, halogen, C 1 ~C 3 alkyl, or C 1 ~C 3 haloalkyl. In some embodiments, each R B is, independently, halogen or C 1 ~C 3 alkyl. In some embodiments, each R B is, independently, halogen.

[0082] In some embodiments of the compounds of Formulas III, IIIa, and IIIb, m is 0, 1, or 2, and each R B is, independently, halogen, C 1 ~C 3 alkyl, C 1 ~C 3 haloalkyl, and C 1 ~C 3 alkyloxy. In some embodiments, m is 0, 1, or 2, and each R B is, independently, halogen, C 1 ~C 3 alkyl or C 1 ~C 3 haloalkyl. In some embodiments, m is 0, 1, or 2, and each R B is, independently, halogen or C 1 ~C 3 alkyl. In some embodiments, m is 0, 1, or 2, and each R B is, independently, halogen.

[0083] In some embodiments of the compounds of Formulas III, IIIa, and IIIb, m is 0 or 1, and each R B is independently halogen, C 1 ~C 3 alkyl, C 1 ~C 3 haloalkyl, and C 1 ~C 3 alkyloxy. In some embodiments, m is 0 or 1, and each R B is independently halogen, C 1 ~C 3 alkyl or C 1 ~C 3 haloalkyl. In some embodiments, m is 0 or 1, and each R B is independently halogen or C 1 ~C 3 alkyl. In some embodiments, m is 0 or 1, and each R B is independently halogen.

[0084] In some embodiments of the compounds of Formulas III, IIIa, and IIIb, m is 1 or 2, and each R B is independently halogen, C 1 ~C 3 alkyl, C 1 ~C 3 haloalkyl, and C 1 ~C 3 alkyloxy. In some embodiments, m is 1 or 2, and each R B is independently halogen, C 1 ~C 3 alkyl or C 1 ~C 3 haloalkyl. In some embodiments, m is 1 or 2, and each R B is independently halogen or C 1 ~C 3 alkyl. In some embodiments, m is 1 or 2, and each R B is independently halogen.

[0085] In some embodiments of the compounds of Formulas III, IIIa, and IIIb, m is 1, and R B is halogen, C 1 ~C 3 alkyl, C 1 ~C 3 haloalkyl, and C 1 ~C 3 alkyloxy. In some embodiments, m and R B are halogen, C 1 ~C 3 alkyl, or C 1 ~C 3 haloalkyl. In some embodiments, m is 1, and R B is halogen or C 1 ~C 3 alkyl. In some embodiments, m is 1, and R B is halogen.

[0086] In some embodiments of the compounds of Formulas III, IIIa, and IIIb, m is 2, and each R B is independently halogen, C 1 ~C 3 alkyl, C 1 ~C 3 haloalkyl, and C 1 ~C 3 alkyloxy. In some embodiments, m is 2, and each R B is independently halogen, C 1 ~C 3 alkyl or C 1 ~C 3 haloalkyl. In some embodiments, m is 2, and each R B is independently halogen or C 1 ~C 3 alkyl. In some embodiments, m is 2, and each R B is independently halogen.

[0087] In some embodiments of the compounds of Formulas I, Ia, Ib, II, IIa, or IIb, they have Formula IV,

Chemical Formula

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

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

[0090] In some embodiments of the compounds of Formulas I, Ia, Ib, II, IIa, and IIb, -X-Y- is -CR 9 =CR 10 -, where each R 9 and R 10 is independently H, halogen, C 1 ~C 6 alkyl, C 1 ~C 6 haloalkyl, or C 1 ~C 6 alkyloxy. In some embodiments, -X-Y- is -CR 9 =CR 10 -, where each R 9 and R 10 is independently H, halogen, C 1 ~C 6 alkyl, or C 1 ~C 6 haloalkyl. In some embodiments, -X-Y- is -CR 9 =CR 10 -, where each R 9 and R 10 is independently H, halogen, or C 1 ~C 6is alkyl. In some embodiments, -X-Y- is -CR 9 =CR 10 -, wherein each R 9 and R 10 is independently H or halogen. In some embodiments, -X-Y- is -CR 9 =CR 10 -, wherein each R 9 and R 10 is independently H or F.

[0091] In some embodiments of the compounds of Formulas I, Ia, Ib, II, IIa, and IIb, -X-Y- is -CR 11A R 11B -CR 12A R 12B -, wherein each R 11A , R 11B , R 12A , and R 12B is independently H, halogen, C 1 ~C 6 alkyl, C 1 ~C 6 alkyloxy, or C 1 ~C 6 haloalkyl, or each R 11A and R 12A is independently H, halogen, C 1 ~C 6 alkyl, C 1 ~C 6 alkyloxy, or C 1 ~C 6 haloalkyl, and R 11B and R 12B together with the carbon to which they are attached form a 3- to 6-membered carbocyclic ring, and the 3- to 6-membered carbocyclic ring 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.

[0092] In some embodiments of the compounds of Formula I, Ia, Ib, II, IIa, and IIb, -X-Y- is -CR 11A R 11B -CR 12A R 12B -, wherein each R 11A , R 11B , R 12A , and R 12B is independently H, halogen, C 1 ~C 6 alkyl, C 1 ~C 6 alkyloxy, or C 1 ~C 6 haloalkyl. In some embodiments, -X-Y- is -CR 11A R 11B -CR 12A R 12B -, wherein each R 11A , R 11B , R 12A , and R 12B is independently H, halogen, C 1 ~C 6 alkyl or C 1 ~C 6 haloalkyl. In some embodiments, -X-Y- 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 C 1 ~C 6 alkyl. In some embodiments, -X-Y- 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, -X-Y- is -CR 11A R 11B -CR 12A R 12B- and in the formula, each R 11A , R 11B , R 12A , and R 12B is independently H or F. In some embodiments, -X-Y- is -CR 11A R 11B -CR 12A R 12B - and in the formula, each R 11A , R 11B , R 12A , and R 12B is H.

[0093] In some embodiments of the compounds of Formulas I, Ia, Ib, II, IIa, and IIb, -X-Y- is -CR 11A R 11B -CR 12A R 12B - and in the formula, each R 11A and R 12A is independently H, halogen, C 1 ~C 6 alkyl, C 1 ~C 6 alkyloxy, or C 1 ~C 6 haloalkyl, and R 11B and R 12B together with the carbon to which they are attached form a 3- to 6-membered carbocyclic ring, and the 3- to 6-membered carbocyclic ring 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.

[0094] In some embodiments of the compounds of Formulas I, Ia, Ib, II, IIa, and IIb, it has Formula V,

Chemical formula

[0095] In some embodiments of the compounds of Formulas I, Ia, II, IIa, and V, they have Formula Va, [Chemical Formula] wherein z’ is 1 or 2.

[0096] In some embodiments of the compounds of Formulas I, Ib, II, IIb, and V, they have Formula Vb, [Chemical Formula] wherein z’ is 1 or 2.

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

[0098] In some embodiments of the compounds of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, and Vb described herein, R 8A is H, and R 8B is H, C 1 ~C 3 alkyl, or benzyl. In some embodiments, R 8A is H, and R 8B is H or C 1 ~C 3 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 C 1 ~C 3 alkyl, or benzyl. In some embodiments, R 8A is H, and R 8B is C 1 ~C 3 alkyl. In some embodiments, R 8A is H, and R 8B is benzyl. In some embodiments, R 8Aand 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 C 1 ~C 3 alkyl, and R 8B is H, C 1 ~C 3 alkyl, or benzyl. In some embodiments, R 8A is C 1 ~C 3 alkyl, and R 8B is H or C 1 ~C 3 alkyl. In some embodiments, R 8A is C 1 ~C 3 alkyl, and R 8B is H or benzyl. In some embodiments, R 8A is C 1 ~C 3 alkyl, and R 8B is C 1 ~C 3 alkyl or benzyl. In some embodiments, R 8A is C 1 ~C 3 alkyl, and R 8B is H. In some embodiments, R 8A is C 1 ~C 3 alkyl, and R 8B is benzyl. In some embodiments, R 8A and R 8B are independently C 1 ~C 3 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 8Ais benzyl, and R 8B is H, C 1 ~C 3 alkyl, or benzyl. In some embodiments, R 8A is benzyl, and R 8B is H or C 1 ~C 3 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 C 1 ~C 3 alkyl, or benzyl. In some embodiments, R 8A is benzyl, and R 8B is C 1 ~C 3 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, C 1 ~C 3 alkyl, or phenyl, and R 2 is H. In some embodiments, R 1 is H or phenyl, and R 2 is H. In some embodiments, R 1 is H or C 1 ~C 3 alkyl, and R 2 is H. In some embodiments, R 1 is C 1 ~C 3 alkyl or phenyl, and R 2 is H. In some embodiments, R 1 and R2 Both are H. In some embodiments, R 1 is C 1 ~C 3 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, C 1 ~C 3 alkyl, or phenyl, and R 2 is C 1 ~C 3 alkyl. In some embodiments, R 1 is H, and R 2 is C 1 ~C 3 alkyl. In some embodiments, R 1 is H or C 1 ~C 3 alkyl, and R 2 is C 1 ~C 3 alkyl. In some embodiments, R 1 is C 1 ~C 3 alkyl or phenyl, and R 2 is C 1 ~C 3 alkyl. In some embodiments, R 1 is H, and R 2 is C 1 ~C 3 alkyl. In some embodiments, each R 1 and R 2 is independently C 1 ~C 3 alkyl. In some embodiments, R 1 is phenyl, and R 2 is C 1 ~C 3is alkyl. In some embodiments, each R 1 and R 2 is independently H or C 1 ~C 3 alkyl.

[0103] In some embodiments of the compounds of Formulas I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, and IVb described herein, each R 4 and R 5 is independently H or C 1 ~C 6 alkyl, and C 1 ~C 6 alkyl is optionally substituted with one, two, or three groups independently selected from halogen, C 1 ~C 3 alkyloxy, or C 1 ~C 3 haloalkyloxy. In some embodiments, R 4 is H or C 1 ~C 6 alkyl, and C 1 ~C 6 alkyl is optionally substituted with one, two, or three 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. In some embodiments, R 4 is H or C 1 ~C 6 alkyl, and C 1 ~C 6 alkyl is optionally substituted with one, two, or three groups independently selected from halogen, C 1 ~C 3 alkyloxy, or C 1 ~C 3 haloalkyloxy, and R 5 is H.

[0104] In some embodiments of the compounds of Formulas IV, IVa, and IVb described herein, R 4 is halogen or C 1 ~C 6 alkyl, and C 1 ~C 6 alkyl is optionally substituted with one, two, or three groups independently selected from halogen, C 1 ~C 3 alkyloxy, or C 1 ~C 3 haloalkyloxy, and R 5 is H, halogen, or C 1 ~C 6 alkyl, and C 1 ~C 6 alkyl is optionally substituted with one, two 1 ~C 3 alkyloxy, or C 1 ~C 3 haloalkyloxy, or three groups independently selected therefrom. In some embodiments, R is halogen or C 4 ~C 1 ~C 6 alkyl, and C 1 ~C 6 alkyl is optionally substituted with one, two, or three groups independently selected from halogen, C 1 ~C 3 alkyloxy, or C 1 ~C 3 haloalkyloxy, and R 5 is H, halogen, or C 1 ~C 6 alkyl. In some embodiments, R 4 is halogen or C 1 ~C 6 alkyl, and C 1 ~C 6 alkyl is optionally substituted with one, two, or three groups independently selected from halogen, C 1 ~C 3 alkyloxy, or C 1 ~C 3is substituted by one, two, or three groups independently selected from haloalkyloxy, and R 5 is H.

[0105] In some embodiments of the compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, or IVb described herein, each R 4 and R 5 is independently H, Me, OMe, or CH 2 F. In some embodiments, R 4 is H, Me, OMe, or CH 2 F, 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- to 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, C 1 ~C 6 alkyl, or C 1 ~C 6 haloalkyl. In some embodiments, R 6 is H, halogen, or C 1 ~C 6 alkyl. In some embodiments, R6 is halogen or C 1 ~C 6 alkyl. In some embodiments, R 6 is C 1 ~C 6 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, C 1 ~C 6 alkyl, or C 1 ~C 6 haloalkyl. In some embodiments, R 7 is H, halogen, or C 1 ~C 6 alkyl. In some embodiments, R 7 is halogen or C 1 ~C 6 alkyl. In some embodiments, R 7 is C 1 ~C 6 alkyl. In some embodiments, R 7 is H.

[0110] In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are

Chemical formula

Chemical formula

[0111] In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are

Chemical formula

Chem.

[0112] In some embodiments, the compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are

Chem.

Chem.

[0113] In some embodiments, the compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are

Chem.

Chem.

Chem.

Chem.

Chem.

[0114] In some embodiments, the compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are

Chem.

Chem.

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

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

[0117] In some embodiments, the compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are [Chemical formula] [Chemical formula] [Chemical formula] [Chemical formula] 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 [Chemical formula] [Chemical formula] [Chemical formula] 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 [Chemical formula] [Chemical formula] 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 [Chemical formula] is.

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

Chemical formula

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

Chemical formula

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

Chemical formula

[0124] In some embodiments, the compounds of Formula I, Ia, Ib, II, IIa, IIb, III, III a, IIIb, IV, IVa, IVb, V, Va, or Vb are

Chemical formula

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

Chemical formula

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

Chem.

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

Chem.

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

Chem.

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

Chem.

[0130] In some embodiments, the compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb are

Chem.

[0131] The compounds provided herein are typically administered in the form of pharmaceutical compositions. Accordingly, provided herein are pharmaceutical compositions comprising one or more of the compounds provided herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients. The compounds provided herein can be the sole active ingredient or can be one of the active ingredients of a pharmaceutical composition. Suitable pharmaceutically acceptable vehicles can include, for example, inert solid diluents and fillers, diluents comprising sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizing agents, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, for example, Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (see G.S. Banker & C.T. Rhodes, Eds.).

[0132] In one aspect, provided herein are pharmaceutical compositions 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 a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises 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 a pharmaceutically acceptable salt thereof.

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

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

[0136] Oral administration can be another route for administration of the compounds provided herein. The administration can be, for example, by capsules or enteric-coated tablets. When manufacturing a pharmaceutical composition comprising at least one compound provided herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, the active ingredient (such as the compound provided herein) is usually diluted by an excipient and / or encapsulated in a carrier which can be in the form of a capsule, sachet, paper, or other container. When the excipient functions as a diluent, the excipient can 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 can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solvents, 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 can further include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweetening agents, as well as flavoring agents; or any combination thereof.

[0138] A pharmaceutical composition comprising at least one compound or a pharmaceutically acceptable salt, isomer, or mixture thereof described herein can be formulated to provide rapid release, sustained release, or delayed release of the active ingredient (such as the compounds provided herein) after administration to a subject by using procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and solubilized systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are shown in U.S. Pat. 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 a transdermal delivery device (“patch”). Such transdermal patches can be used to provide a controlled amount of continuous or discontinuous infusion of the compounds provided herein. The construction and use of transdermal patches for delivering pharmaceuticals are well known in the art. See, for example, U.S. Pat. Nos. 5,023,252, 4,992,445, and 5,001,139. Such patches can be constructed for continuous, pulsed, or on-demand delivery of a pharmaceutical agent.

[0139] To prepare solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical excipient to obtain a homogeneous mixture of the compounds or a pharmaceutically acceptable salt, isomer, or mixture thereof described herein Solid preformulation compositions containing the mixture can be formed. When these preformulation compositions are referred to as homogeneous, the active ingredient can be uniformly dispersed throughout the composition, so that the composition can be easily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0140] Tablets or pills of the compounds described herein can be coated or otherwise formulated to provide a dosage form that provides the advantage of long - acting action or to protect from the acidic conditions of the stomach. For example, a tablet or pill can comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope that overlies and encapsulates the former. The two components can be separated by an enteric layer that resists disintegration in the stomach and functions to allow the inner component to pass intact into the duodenum or to delay release. A variety of materials can be used for such enteric layers or enteric coatings, such materials 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 can include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, as well as powders. The liquid or solid compositions can contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, the composition is administered by the oral or nasal respiratory route for local or systemic effects. In other embodiments, the composition in a pharmaceutically acceptable solvent can be atomized by the use of an inert gas. The atomized solution can be inhaled directly from the nebulizer or the nebulizer can be attached to a face mask tent or an intermittent positive pressure breathing simulator. The composition of solution, suspension, or powder can be preferably administered orally or nasally from a device that delivers the formulation in a suitable manner.

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

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

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

[0145] In one embodiment, provided is a method of treating an HIV (e.g., HIV-1 and / or HIV-2) infection in a human having or at risk of having the infection, the method comprising administering to the human 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, 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. A method is provided that comprises administering to the human 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, 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.

[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 particular embodiments, the additional therapeutic agent is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitor, an HIV nucleoside or nucleotide reverse transcriptase inhibitor, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gpl20 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, islatravir. In some embodiments, the additional therapeutic agent is lenacapavir. In some embodiments, the additional therapeutic agent is islatravir.

[0147] In another embodiment, provided 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, 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 an HIV (e.g., HIV-1 and / or HIV-2) infection in a human having or at risk of having such infection.

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

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

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

[0151] In another embodiment, a compound of formula I, Ia, Ib, II, IIa, II Compounds of b, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or pharmaceutically acceptable salts thereof are provided, and the method further comprises administering to the human one, two, three, or four additional therapeutic agents.

[0152] In another embodiment, provided are compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of compounds of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or pharmaceutically acceptable salts thereof for use in a method of treating an infection in a human having or at risk of having an HIV infection, the method further comprising administering to the human one, two, three, or four additional therapeutic agents 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 bNAb, a TLR7 agonist, a pharmacokinetic enhancer, other agents for treating HIV, or combinations 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 latent infection reactivator, an HIV capsid inhibitor, an HIV bNAb, a TLR7 agonist, and combinations thereof.

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

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

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

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

[0157] In another embodiment, there is provided a method of using a compound of formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb in therapy. In particular, 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), the method 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, is provided.

[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, 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 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, is provided for use in preventing HIV infection.

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

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

[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 a packaging material including a label indicating that the composition can be used to treat an infection by HIV is disclosed. 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 the replication of HIV is disclosed. The method includes 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 in which the replication of HIV 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 health disorder 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 can vary, for example, depending 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 over a 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 compound is administered daily or on an intermittent schedule over the lifetime of the individual.

[0169] The specific dosage level of the compounds 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 being treated. For example, the dosage can be expressed as milligrams of the compound described herein per kilogram of body weight of the subject (mg / kg). Dosages of about 0.1 to 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments, dosages of 0.5 to 60 mg / kg may be appropriate. Normalizing by the body weight of the subject is particularly useful when adjusting dosages between subjects of widely different sizes, such as 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 dosage can also be described as the total amount of the compound described herein administered per administration or per day. The daily dosage of a compound of Formula I, Ia, Ib, II, IIa, IIb, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, can 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 dosing frequency of the compounds of the present disclosure can 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 compound is administered once a day.

[0173] The compounds provided herein can be administered by any useful route and means, such as oral or parenteral (e.g., intravenous) administration. The therapeutically effective amount of the compound can include from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, such as from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or for example from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or for example 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, the therapeutically effective amount of the compounds 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 compounds of the present disclosure (e.g., 1 mg to 1000 mg of the 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 for example from about 100 mg per dose to about 400 mg per dose, or for example from about 150 mg per dose to about 350 mg per dose, or for example from about 200 mg per dose to about 300 mg per dose, or for example from about 0.01 mg per dose to about 1000 mg per dose, or for example from about 0.01 mg per dose to about 100 mg per dose, or for example from about 0.1 mg per dose to about 100 mg per dose, or for example from about 1 mg per dose to about 100 mg per dose, or for example from about 1 mg per dose to about 10 mg per dose, or for example from about 1 mg per dose to about 1000 mg per dose. Other therapeutically effective amounts of the compounds 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 the 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 from about 1 to 500 mg of the compound p herein and increasing the dose incrementally until clinical effectiveness 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 1,000 mg / day administered as a single dose. In some embodiments, the total daily dosage for a human subject can be about 200, 300, 400, 500 , 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 as a single dose.

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

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

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

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

[0181] Administration can be intermittent, involving a period of several days or more during which the patient receives a daily dose of the compound of the present disclosure, 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 a week. As a further example, the patient receives 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 can again receive a daily dose of the compound. The alternating periods of administration of the compound, followed by non - administration of the compound, can be repeated as clinically necessary to treat the patient.

[0182] The compounds or pharmaceutical compositions thereof of the present disclosure can be administered once, twice, three times, or four times a day using any of the above suitable modes. Also, the administration or treatment with the compound can be continued for several days. For example, usually, the treatment will continue for at least 7 days, 14 days, or 28 days for one treatment cycle. Treatment cycles are well known in cancer chemotherapy and frequently alternate with a rest period of about 1 to 28 days, generally about 7 days or about 14 days between cycles. The treatment cycles can also be continuous in other embodiments. VI. Combination Therapy

[0183] In certain embodiments, there is provided a method for treating or preventing HIV infection in a human having or at risk of having such 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, there is provided a method for treating HIV infection in a human having or at risk of having such 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, there is provided a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, 1 or 2, or 1 to 3) additional therapeutic agents and a pharmaceutically acceptable carrier, diluent, or excipient.

[0185] In certain embodiments, the present disclosure provides a method for treating 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 HIV infection.

[0186] In certain embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are combined with two additional therapeutic agents. In other embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are combined with three additional therapeutic agents. In further embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are 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 combination HIV therapy

[0187] In certain specific embodiments, the compounds disclosed herein are administered together with one or more additional therapeutic agents. Co - administration of the compounds disclosed herein and one or more additional therapeutic agents generally refers to simultaneously or sequentially administering the compounds disclosed herein and one or more additional therapeutic agents such that a therapeutically effective amount of both the compounds disclosed herein and the one or more additional therapeutic agents are present in the patient's body. When administered sequentially, the combination can be administered in more than two administrations.

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

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

[0190] In certain embodiments, a compound of formula I is formulated as a tablet that can optionally contain one or more other compounds useful for the treatment of HIV. In some embodiments, the tablet can contain other active ingredients for treating HIV, 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, a pharmacokinetic enhancer, and combinations thereof.

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

[0192] In the above-described embodiments, the additional therapeutic agent can be an anti-HIV agent. 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 maturation inhibitor, an immunomodulatory agent, an immunotherapeutic agent, an antibody-drug conjugate, a gene modifier, a gene editing agent (such as CRISPR / Cas9, zinc finger nuclease, homing nuclease, synthetic nuclease, TALEN, etc.), cell therapy (chimeric antigen receptor T cells, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapy, etc.), a latent infection reactivator, a compound targeting the HIV capsid, an immune system therapy, a phosphatidylinositol 3-kinase (PI3K) inhibitor, an HIV antibody, a bispecific antibody and an "antibody-like" therapeutic protein, an HIV p17 matrix protein inhibitor, an IL-13 antagonist, a peptidyl-prolyl cis-trans isomerase A modulator, a protein disulfide isomerase inhibitor, a complement C5a receptor antagonist, a DNA methyltransferase inhibitor, an HIV vif gene modulator, a Vif dimerization antagonist, an HIV-1 viral infectivity factor inhibitor, a TAT protein inhibitor, an HIV-1 Nef modulator, an Hck tyrosine kinase modulator, a mixed lineage kinase-3 (MLK-3) inhibitor, an HIV-1 splice Sing inhibitor, Rev protein inhibitor, integrin antagonist, nucleoprotein inhibitor, splicing factor modulator, COMM domain-containing protein 1 modulator, CD4 modulator, CD4 antagonist, HIV ribonuclease H inhibitor, retrocyclin modulator, CDK-9 inhibitor, CCR5 chemokine antagonist, CCR5 gene modulator, dendritic ICAM-3-grabbing non-integrin 1 inhibitor, HIV GAG protein inhibitor, HIV POL protein inhibitor, hyaluronidase inhibitor, Nef antagonist, Nef inhibitor, protease-activated receptor-1 antagonist, TNF alpha ligand inhibitor, PDE4 inhibitor, complement factor H modulator, ubiquitin ligase inhibitor, deoxycytidine kinase inhibitor, cyclin-dependent kinase inhibitor, proprotein convertase PC9 stimulator, ATP-dependent RNA helicase DDX3X inhibitor, reverse transcriptase priming complex inhibitor, G6PD and NADH-oxidase inhibitor, pharmacokinetic enhancer, HIV gene therapy, HIV vaccine, and combinations thereof.

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

[0194] Examples of combination drugs 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); DESCCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); SYMTUZA® (darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat); SYMFITM (efavirenz, lamivudine, and tenofovir disoproxil fumarate); CIMDUTM (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® (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 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 + levonorgestrel, dolutegravir + lamivudine, dolutegravir + emtricitabine + tenofovir alafenamide, elsulfavirine + emtricitabine + tenofovir disoproxil, 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 are included. Other HIV drugs

[0195] Examples of other drugs for treating HIV include acemannan, alisporivir, astodrimer, BanLec, CC-11050, deferiprone, Gamimune, griffithsin, metenkephalin, 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, AG-1105, 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 inhibitor

[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 inhibitor

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

[0198] Examples of reverse transcriptase HIV nucleoside or nucleotide inhibitors include adefovir, adefovir dipivoxil, azidothymidine, 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, hosalbuvir tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, tidoxil fozidibine, islatravir, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, lobafovir et alafenamide (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, cholic acid, cholic acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tilorone, tilorone derivatives, quercetin, quercetin derivatives, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, BMS-986197, cabotegravir (long-acting injection), diketoquinoline 4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbenedisulfonic acid, T-169, VM-3500, and cabotegravir.

[0200] Examples of HIV non-catalytic site or allosteric integrase inhibitors (NCINIs) 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 apraviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (PRO-140), adapterivir (RAP-101), nelfinavir (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 albuviridine, 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 CADA analogs.

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

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

[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 berkeleyide and ixazomib citrate, protein kinase C (PKC) activators, Smyd2 inhibitors agents, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, 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 indolactam, prostratin, ingenol B, and DAG-lactone. Capsid inhibitor

[0211] Examples of capsid inhibitors include capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (nucleocapsid p7, NCp7) inhibitors, such as azodicarboxamide mid, HIV p24 capsid protein inhibitors, GS-6207, AVI-621, AVI-101, AVI-201, AVI-301, and 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 (programmed cell death protein 1, Pd-1) modulators; programmed death-ligand 1 (programmed death-ligand 1, Pd-L1) modulators; IL-15 modulators, Derma Vir; interleukin-7; plakenyl (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; PEGylated interferon alpha; interferon gamma; hydroxyurea; mycophenolate mofetil (mycophenolate mofetil, MPA) and its ester derivative mycophenolate mofetil (mycophenolate mofetil, MMF); ribavirin; polymer polyethyleneimine (polymer polyethyleneimine , PEI); gpon; 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, NKTR-214, normferon, peginterferon alpha-2a, peginterferon alpha-2b, recombinant interleukin-15, Xmab-24306, RPI-MN, STING modulator, RIG-I modulator, NOD2 modulator, SB-9200, and IR-103.

[0213] Examples of TLR agonists: besatolimod (GS-9620), GS-986, IR-103, refitremod, chilosotrimod, lintatrimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motrimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, tellurtrimod, RO-7020531. Phosphatidylinositol 3-kinase (PI3K) inhibitor

[0214] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI orotate, copanlisib, duvelisib, gedatolisib, neratinib, panolisib, perifosine, pictilisib, piraralisib, pucitinib mesylate, rigosertib, rigosertib sodium, sonolisib, 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 antagonist

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

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

[0217] Examples of those 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, PGT-151, 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 such as 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 the compounds disclosed 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), US 2013 / 0165489 (University of Pennsylvania), US 2014 / 0221378 (Japan Tobacco), US 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), US 2014 / 0221356 (Gilead Sciences), US 2010 / 0143301 (Gilead Sciences), and WO 2013 / 091096 (Boehringer Ingelheim). HIV vaccine

[0221] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, arenaviruses, lymphocytic choriomeningitis virus (lymphocyticchoriomeningitis Viruses such as virus, LCMV), picornavirus, modified vaccinia Ankara virus (MVA), adenovirus, adeno-associated virus (AAV), vesicular stomatitis virus (VSV), and chimpanzee adenovirus (ChAd) Live vector vaccines using vectors, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, BG505 SOSIP.664 gp140, rgp120 (AIDSVAX), ALVAC HIV, (vCP1521) / AIDSVAX B / E (gp120) (RV144), 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, multiclade DNA recombinant adenovirus-5 (recombinant adenovir 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, poly ICLC 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, e.g., pseudovirion vaccines, CombiVICHvac, LFn-p24 B / C fusion vaccine, 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), I i-key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multi-clade 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-based vaccine, PD-201401, env(A, B, C, A / E) / gag(C) DNA vaccine, gp120(A,B,C,A / E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs 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 are included. HIV combination therapy

[0222] In certain embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCCOVY( Registered Trademark)(Tenofovir Alafenamide and Emtricitabine); ODEFSEY (Registered Trademark) (Tenofovir Alafenamide, Emtricitabine, and Rilpivirine); GENVOYA (Registered Trademark) (Tenofovir Alafenamide, Emtricitabine, Cobicistat, and Elvitegravir); Adofovir; Adofovir Dipivoxil; Cobicistat; Emtricitabine; Tenofovir; Tenofovir Disoproxil; Tenofovir Disoproxil Fumarate; Tenofovir Alafenamide; Tenofovir Alafenamide Hemifumarate; TRIUMEQ (Registered Trademark) (Dolutegravir, Abacavir, and Lamivudine); Dolutegravir, Abacavir Sulfate, and Lamivudine; Raltegravir; Raltegravir and Lamivudine; Maraviroc; Enfuvirtide; ALUVIA (Registered Trademark) (KALETRA (Registered Trademark); Lopinavir and Ritonavir); COMBIVIR (Registered Trademark) (Zidovudine and Lamivudine; AZT + 3TC); EPZICOM (Registered Trademark) (LIVEXA (Registered Trademark); Abacavir Sulfate and Lamivudine; ABC + 3TC); TRIZIVIR (Registered Trademark) (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; Prolactin; Fosamprenavir; Fosamprenavir Calcium Efavirenz; Etravirine; Nelfinavir; Nelfinavir Mesylate; Interferon; Didanosine; Stavudine; Indinavir; Indinavir Sulfate; Tenofovir and Lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir Mesylate; Aldesleukin; Zalcitabine; Tipranavir; Amprenavir; Delavirdine; Delavirdine Mesylate; Radha-108 (Receptol); Lamivudine and Tenofovir Disoproxil Fumarate; Efavirenz, Lamivudine, and Tenofovir Disoproxil Fumarate; Phosphatide; Lamivudine, Nevirapine, and Zidovudine;It is combined with one, two, three, four or more additional therapeutic agents selected from abacavir and abacavir sulfate.;

[0223] It will be understood by those skilled in the art that the additional therapeutic agents listed above may be included in two or more of the classes listed above. The specific classes are not intended to limit the functionality of these compounds listed in those classes.

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

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

[0226] In certain embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are , is combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

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

[0228] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, 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 and any dosage of a compound of Formula I (e.g., 1 mg to 500 mg of the compound).

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

[0231] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 200 - 400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 200 - 250, 200 - 300, 200 - 350, 250 - 350, 250 - 400, 350 - 400, 300 - 400, or 250 - 400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil, and 200 mg of emtricitabine. The compounds disclosed herein (e.g., compounds of Formula I) can be combined at any dose of the compound (e.g., 1 mg - 500 mg of the compound) as if each combination of doses of the agents provided herein were specifically and individually listed. In one embodiment, a kit is provided that comprises the compounds disclosed herein, or pharmaceutically acceptable salts thereof, in combination with one or more (e.g., one; two; three; one or two; or one to three) additional therapeutic agents.

[0232] Contraceptive combination therapy

[0233] ​Therapeutic agents used for fertility regulation (contraception) include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, ethinodiol, etonogestrel, levonorgestrel, levonorgestrel, linestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, noregestromin, norethindrone, nortestosterone, norgestimate, ormeloxifene, segesterone acetate, ulipristal acetate, and any combination thereof. Gene Therapy and Cell Therapy

[0234] Gene therapy and cell therapy include gene modification for gene silencing; genetic approaches for directly killing infected cells; replacing most of the patient's own immune system to enhance the immune response against infected cells, or activating the patient's own immune system to kill infected cells, or injecting immune cells designed to find and kill infected cells; genetic approaches for modifying cell activity to further alter the endogenous immune responsiveness to infection.

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

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

[0237] Examples of CCR5 gene inhibitors, such as Cal-1.

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

[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 chimeric antigen receptor (CAR) The population of immune effector cells obtained by injecting CARs into the host, wherein the CAR comprises an HIV antigen binding domain. The HIV antigen comprises an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, a CD4-induced binding site on gp120, an N-glycan on gp120, V2 of gp120, 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, an autologous hematopoietic stem cell 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. EXAMPLES

[0246] VII. Examples Exemplary chemical substances of the present disclosure are provided in the following specific examples. Those skilled in the art will understand that, in order to obtain the various compounds described herein, the starting materials can be suitably selected such that the ultimately desired substituents are carried through reaction schemes with or without protection as necessary to obtain the desired product. Alternatively, it may be necessary or desirable to use suitable groups that are carried through the reaction scheme and can be replaced with the desired substituents as necessary. Furthermore, those skilled in the art will understand that the transformations shown in the following schemes can be carried out 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 should be understood that the individual steps described herein can be combined. It should also be understood that separate batches of the compounds can be combined and 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 can be utilized and logical changes and other changes can 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 1-4: (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]triazocin-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]triazocin-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]triazocin-3-carboxamide (C3) (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]triazocin-3-carboxamide (C4) Preparation

Chemical Structure

[0249] 5-(Benzyloxy)-2,3-dihydro-1H-pyrido[2,1-f][1,2,4]triazine-4,6-dione (1) was prepared according to the published procedure for "Intermediate A" in International Publication No. WO 2019 / 160883 (A1). Step 1: Preparation of 1-(benzyloxy)-10-fluoro-7,12-dihydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazine-2,14-dione (2-a) and 1-(benzyloxy)-9-fluoro-7,12-dihydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazine-2,14- 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 in DMF (5 ml), and the mixture was cooled to 0 °C. NaOt-Bu (159 mg, 1.66 mmol) was added over 1 hour. The reaction mixture was stirred overnight without a replenished cold bath. Then, the reaction mixture was diluted with EtOAc, and NH 4It was treated with Cl / water. The organic phase was separated and concentrated. The residue was purified by silica gel chromatography using 0 - 100% EtOAc in heptane, and then 10% MeOH in EtOAc to obtain a mixture of two positional isomers (2 - a and 2 - b) of the product. MS (m / z): 392.1 [M + H]. These two positional isomers were not separated and 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]triazocin - 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]triazocin - 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]triazocin - 2,14 - dione (2 - a) and 1 - (benzyloxy) - 9 - fluoro - 7,12 - dihydro - 6,13 - methanobenzo[g]pyrido[1,2 - b][1,2,5]triazocin - 2,14 - dione (2 - b) (50 mg, 0.128 mmol) was mixed with MeOH (0.8 ml) at room temperature. m - CPBA (77%) (114 mg, 0.51 mmol) and NIS (114 mg, 0.51 mmol) were added sequentially. The reaction vial was sealed and heated from room temperature to 80 °C for 30 minutes. Additional m - CPBA (77%) (114 mg, 0.51 mmol) and NIS (114 mg, 0.51 mmol) were added sequentially. The reaction mixture was heated again at 80 °C for 30 minutes. Then, the reaction mixture was diluted with EtOAc and treated with NaHCO 3 / water and Na 2 S 2 O 3 (10%). The organic phase was separated and concentrated. The residue was purified on a silica gel column using 0 - 100% EtOAc / heptane to obtain 60 mg of a mixture of two positional isomers (3 - a and 3 - b) of the product. MS (m / z): 518.06 [M + H]. These two positional isomers were not separated and 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]triazocin-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]triazocin-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]triazocin-3-carboxamide (4-c) (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]triazocin-3-carboxamide (4-d) Preparation

[0252] A solution of a mixture of 1-(benzyloxy)-10-fluoro-3-iodo-7, 12-dihydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazocin-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]triazocin-2,14-dione (3-b) (32 mg, 0.062 mmol) in DMSO (2 ml) was added to 2,4,6-trifluorobenzylamine (50 mg, 0.309 mmol), DIPEA (40 mg, 0.309 mmol), and Pd(PPh 3 ) 4(3.57 mg, 0.00309 mmol) was added. The reaction mixture was bubbled with CO(g) for 10 minutes. Then, the reaction mixture was heated at 80 °C for 17 hours under a CO atmosphere. The reaction mixture was cooled to room temperature and diluted with ethyl acetate. The resulting mixture was treated with 0.05 N HCl. The organic phase was separated and treated with saturated sodium bicarbonate solution and brine. Then, the organic phase was dried over Na 2 SO 4 and concentrated. The residue was purified by silica gel column using 0 - 100% EtOAc in hexane to obtain the desired product. The mixture of these four isomers was subjected to SFC separation method (ADH 50 IPA - NH 3 ) to obtain four isomers in the order of increasing 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]triazocin-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]triazocin-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]triazocin-3-carboxamide (4-c) 7 mg. MS (m / z): 579.03 [M+H], and (6S)-1-(Benzyloxy)-9-fluoro-2,14-dioxo-N-(2,4,6-trifluorobenzyl)-2,7,12,14-tetrahydro-6,13-methanobenzo[g]pyrido[1,2-b][1,2,5]triazocin-3-carboxamide (4-d) 4 mg. 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]triazocin-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]triazocin-3-carboxamide (4-a) (10 mg, 0.0173 mmol) was dissolved in toluene (0.5 ml) at room temperature. TFA (0.5 ml) was added all at once. The reaction mixture was stirred at room temperature for 17 h. The reaction mixture was concentrated to dryness. The residue was taken up in MeOH and purified by reverse-phase preparative HPLC using 0 - 100% CH 3 CN in water with 0.1% TFA to give the desired product. The product was obtained as the TFA salt by lyophilization. MS (m / z): 489.26 [M + H] + . 1 H NMR (400 MHz, acetonitrile-d3) δ 10.13 (s, 1H), 8.52 (s, 1H), 7.41 - 7.22 (m, 1H), 7.13 (d, J = 9.3 Hz, 1H), 7.04 (t, J = 8.6 Hz, 1H), 6.88 (t, J = 8.6 Hz, 2H), 5.56 (d, J = 16.7 Hz, 1H), 4.87 - 4.69 (m, 2H), 4.64 (d, J = 5.7 Hz, 2H), 4.55 (d, J = 15.3 Hz, 2H), 4.13 (d, J = 13.2 Hz, 1H) (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]triazocin-3-carboxamide (C2) preparation:

[0254] The synthesis of the title product was carried out in the same manner as (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]triazocin-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]triazocin-3-carboxamide (4-a). The product was obtained as the TFA salt. MS (m / z): 489.14 [M+H] + 。 1 H NMR (400 MHz, acetonitrile-d3) δ 10.14 (s, 1H), 8.54 (d, J = 17.3 Hz, 1H), 7.36 (dd, J = 8.4, 5.7 Hz, 1H), 7.23 - 6.98 (m, 2H), 6.88 (t, J = 8.5 Hz, 2H), 5.51 (d, J = 16.5 Hz, 1H), 4.81 (p, J = 14.7, 14.0 Hz, 2H), 4.64 (d, J = 5.4 Hz, 2H), 4.56 (dd, J = 15.0, 10.4 Hz, 2H), 4.20 (d, J = 13.6 Hz, 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]triazocin-3-carboxamide (C3).

[0255] (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]triazocin-3-carboxamide (4-a) was replaced with (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]triazocin-3-carboxamide (4-c) as the starting material, and the synthesis of the title product was carried out in the same manner as (C1). 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]triazocin-3-carboxamide (C4):

[0256] (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]triazocin-3-carboxamide (4-a) was replaced with (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]triazocin-3-carboxamide (4-d) as the starting material, and the synthesis of the title product was carried out in the same manner as (C1). 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 = 14.2 Hz, 1H), 7.36 (dd, J = 8.5, 5.7 Hz, 1H), 7.28 - 7.01 (m, 2H), 6.88 (t, J = 8.6 Hz, 2H), 5.51 (d, J = 16.3 Hz, 1H), 4.79 (q, J = 14.5 Hz, 2H), 4.71 - 4.60 (m, 2H), 4.56 (dd, J = 15.0, 10.3 Hz, 2H), 4.20 (d, J = 13.6 Hz, 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):

Chemical formula

[0257] 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 to 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 the filter cake was then partitioned between ethyl acetate and water. The aqueous layer was extracted with EtOAc (x2), the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated to afford the desired product, which was sent directly to the next step. LCMS-ESI+(m / z): C 30 H 30 F 3 N 3 O 7 Calculated H+ for C, 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 for 3 hours with stirring. The reaction was allowed to cool to room temperature Cooled and concentrated. The residue was diluted with EtOAc, acidified to pH ~4 with 1N aqueous HCl, the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated.

[0259] Subsequently, the residue was dissolved in DCM (17.0 mL) at room temperature and treated with EDCI.HCl (975 mg, 5.11 mmol), followed by HOAt (695 mg, 5.11 mmol) and DIEA (1.76 g, 13.6 mmol). Then, (2S)-but-3-en-2-amine HCl (315 mg, 4.43 mmol) was added. The newly formed mixture was stirred at room temperature overnight. The reaction was then diluted with DCM, washed with saturated NH 4 Cl aqueous solution, brine, dried over sodium sulfate, filtered, concentrated, the residue was mixed with silica gel, concentrated to dryness, and purified by combiflash® (24 g silica gel, 0% - 100% EtOAc / hexane). The desired fractions were combined, 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 F 3 N 4 O 6 calculated H+ value, theoretical value: 640.25, measured value: 641.05) and 1-(allylamino)-3-benzyloxy-N2-[(1S)-1-methylallyl]-4-oxo-N5-[(2,4,6-trifluorophenyl)methyl]pyridine-2,5-dicarboxamide (7) (LCMS-ESI+(m / z): calculated H+ value for C28H27F3N4O4, theoretical value: 540.20, measured value: 541.02) were obtained.

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

[0261] 1-(Allylamino)-3-benzyloxy-N2-[(1S)-1-methylallyl]-4-oxo-N5-[(2,4,6-trifluorophenyl)methyl]pyridine-2,5-dicarboxamide (7) (350 mg, 0.647 mmol) was dissolved at room temperature in a mixture of ACN (3.5 mL) and DCE (3.5 mL). Paraformaldehyde (58.4 mg, 0.647 mmol) was added to this mixture. The resulting mixture was heated to 88 °C. Acetic acid (0.35 mL) was added dropwise to this hot mixture, followed by dropwise addition of TFA (0.15 mL). The reaction vessel was capped and heated for an additional 30 minutes. The reaction was cooled to room temperature, diluted with EtOAc, and saturated NaHCO 3It was basified to a pH of about 7. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by combiflash® (12 g of silica gel, 0 - 100% EtOAc, dry packing) to obtain the desired 1-allyl-5-benzyloxy-3-[(1S)-1-methylallyl]-4,6-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide (9) LCMS-ESI+ (m / z): calculated value of H+ for C29H27F3N4O4, theoretical value: 552.20, measured value: 552.93. The debenzylated form (8) was also isolated. LCMS-ESI+ (m / z): calculated value of H+ for C22H21F3N4O4, theoretical value: 462.15, measured value: 463.02.

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

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

[0264] Compound 10 (8 mg, 0.015 mmol) was dissolved in DCM (1.0 mL) at room temperature and treated with TFA (1.0 mL) at room temperature for 3 hours. The reaction was concentrated, redissolved in DMF, filtered, and purified by reverse-phase preparative HPLC. LCMS-ESI+(m / z): Calculated for H+ of C20H17F3N4O4, theoretical value: 434.12, measured value: 435.19. 1H NMR (400 MHz, DMSO-d6) δ 10.34 (t, J = 5.8 Hz, 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, 3.3 Hz, 1H), 5.34 - 5.22 (m, 1H), 4.92 (d, J = 14.4 Hz, 1H), 4.72 (d, J = 14.4 Hz, 1H), 4.65 - 4.50 (m, 3H), 4.27 - 4.17 (m, 1H), 3.70 - 3.62 (m, 1H), 1.29 (d, J = 7.3 Hz, 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]triazocin-10-carboxamide (C6):

Chemical Structure

[0265] To the reactor were charged tert-butyl N-aminocarbamate (390 mg, 2.95 mmol) and NaHCO 3 (451 mg, 5.4 mmol) in MeOH / water (9 ml / 6 ml), and then methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate (1200 mg, 2.68 mmol) was added. The reaction mixture was heated at 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 2.5 N solution of LiOH (2 ml) at room temperature. After 2 hours at room temperature, the reaction was acidified with 2 N 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] 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 with 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 mixture was diluted with ethyl acetate (100 ml) and washed with brine. The organic layer was dried over MgSO 4 and concentrated under vacuum. The resulting residue was purified by column chromatography. MS (m / z) 547.029 [M+H] + . 1H NMR (400 MHz, 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, 7.5 Hz, 3H), 5.84 (s, 1H), 5.33 (d, J = 4.5 Hz, 3H), 4.68 (d, J = 5.7 Hz, 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: TFA (0.5 ml) was added 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) at room temperature. After stirring for 2 hours at room temperature, the solvent and excess TFA were removed under vacuum. The resulting residue was used in the next step reaction without purification. MS (m / z) 447.075 [M+H] + . Step 5: Synthesis of 2-benzyl-5-(benzyloxy)-4,6-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,6-tetrahydro-1H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide:

[0269] To a solution of 1-amino-3-(benzyloxy)-4-oxo-N5-(2,4,6-trifluorobenzyl)-1,4-dihydropyridine-2,5-dicarboxamide (165 mg, 0.37 mmol) in DMF (2 ml) were added AcOH (2 ml) and 2-phenylacetaldehyde (44 mg, 0.37 mmol) at room temperature. After heating at 100 °C for 2 h, 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]triazocin-10-carboxamide:

[0270] Solid KOH (106 mg, 1.9 mmol) was suspended in DMF (12 ml), and a mixed solution 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 dropwise thereto at 0 °C over 2 h by a syringe pump. The reaction mixture was extracted with ethyl acetate (100 ml). The organic layer was concentrated under vacuum. The residue was used in the next step reaction without purification. MS (m / z) 601.033 [M+H] + 。 Step 7: Synthesis of 7:13-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]triazocin-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]triazocin-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 obtain the TFA salt of the title compound. MS (m / z) 513.253 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 10.37 (d, J = 5.9 Hz, 1H), 9.13 (s, 1H), 8.57 (s, 1H), 7.28 (s, 5H), 7.11 (d, J = 7.0 Hz, 1H), 6.69 (t, J = 8.3 Hz, 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: Preparation 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]triazecine-11-carboxamide (C7)

Chemical Structure

[0272] Methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (3.5 g, 6.23 mmol), (2S)-penta-4-en-2-ol (805 mg, 9.35 mmol) and triphenylphosphine (3.27 g, 12.5 mmol) in 7 mL of THF were added with 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 subjected to silica gel chromatography eluting with EtOAc / hexane to afford the title product. MS (m / z) 630.10 [M+H]+. Step 2: Synthesis of (R)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(penta-4-en-2-yl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid (7B):

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

[0274] (R)-3-(Benzyloxy)-1-((tert-butoxycarbonyl)(penta -4-en-2-yl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid (7B, 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) were added to the reaction mixture 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 NH 4 Cl and brine, dried over sodium sulfate, filtered, and concentrated. The residue was subjected to silica gel chromatography 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)-penta-4-en-2-yl)carbamate (7C, 1.0 g, 1.5 mmol) and Grubbs catalyst 2nd 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]triazecine-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 (3 ml) in 1,4-dioxane at room temperature for 3 hours. Subsequently, an additional 4 N HCl (2 mL) in 1,4-dioxane was added and stirred at room temperature for 2 hours. After concentration in vacuo, the residue was dissolved in EtOAc and washed with saturated NaHCO 3 and brine. The organic layer was dried over MgSO 4 and filtered, concentrated in vacuo, and then dried under high vacuum to afford 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]triazecine-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]triazecine-11-carboxamide (7E, 50 mg, 0.093) and paraformaldehyde (6.1 mg, 2.2 equivalents based on MW: 30) were mixed with acetonitrile (1.25 mL) and DCE (1.25 mL) at room temperature, capped, and immediately placed on a hot plate preheated to 88 °C. To this, AcOH (0.25 mL, 10% in acetonitrile) was added dropwise , followed by dropwise addition of TFA (0.25 mL, 10% in DCE). The resulting reaction mixture was then heated for an additional 30 minutes. It was cooled to room temperature and poured into a biphasic mixture of EtOAc - NaHCO 3 (aqueous solution). The organic phase was separated. The aqueous layer was extracted once with EtOAc. The combined organic phases were washed with brine, dried over Na 2 SO 4 , and filtered. The residue was concentrated to dryness and purified by RP - HPLC to obtain 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]triazecine-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]triazecine-11-carboxamide (7F, 30 mg, 0.054 mmol) was dissolved in 2 mL of toluene, and 2 mL of TFA was added thereto. The mixture was stirred at room temperature for 40 minutes. The solvent was removed and the product was purified by RP - HPLC to obtain the title compound. The structure was confirmed by X - ray crystallographic analysis. MS (m / z): 463.20 [M + H]+. 11H NMR (400 MHz, acetonitrile-d3) δ 10.42 (s, 1H), 8.42 (s, 1H), 6.94 - 6.81 (m, 2H), 5.75 - 5.60 (m, 2H), 5.20 (q, J = 7.1, 6.7 Hz, 1H), 4.82 - 4.56 (m, 4H), 3.59 (p, J = 6.9 Hz, 1H), 2.39 (dd, J = 15.5, 7.3 Hz, 1H), 2.06 (ddd, J = 16.7, 7.9, 5.5 Hz, 1H), 1.29 (t, J = 7.3 Hz, 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]triazecine-11-carboxamide (C8): [Chemical formula]

[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]triazecine-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 stirred vigorously 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 and the filtrate was concentrated to dryness. The residue was purified by RP-HPLC to give the title product. MS (m / z): 465.200 [M + H]+. 11H 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 = 12.0 Hz, 1H), 1.13 (dd, J = 14.3, 6.5 Hz, 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]triazocin]-10’-carboxamide (C9). [Chemical formula]

[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]triazocin]-10’-carboxamide was prepared in the same manner as in Example 84, except that 5,5-dimethyltetrahydrofuran-3-carbaldehyde was used instead of tetrahydrofuran-3-carbaldehyde in Step 1 and only one product was isolated from the ring-closing metathesis reaction in Step 9. MS (m / z) 519.24 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 8.79 (s, 1H), 6.91 (t, J = 8.4 Hz, 2H), 6.01 (dd, J = 11.9, 2.3 Hz, 1H), 5.49 (dd, J = 12.0, 2.8 Hz, 1H), 5.19 (d, J = 14.7 Hz, 1H), 5.01 (d, J = 14.7 Hz, 1H), 4.67 (s, 2H), 4.37 (dt, J = 7.5, 2.6 Hz, 1H), 3.73 - 3.61 (m, 2H), 2.52 (dd, J = 13.5, 1.6 Hz, 1H), 2.07 - 1.94 (m, 1H), 1.87 (d, J = 7.4 Hz, 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]triazocin-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]triazocin-11-carboxamide (C11): [Chemical formula]

[0281] In Step 1, methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylate was used instead of methyl 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate, and in Step 3, allylamine, hydrochloride was used instead of (2S)-but-3-en-2-amine, hydrochloride to prepare (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]triazecine-11-carboxamide (9A) 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]triazecine-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 co-solvent. The separated diastereomers were dissolved in 1 mL of toluene and 1 mL of TFA and stirred at room temperature for 1 hour. After concentration, it was purified by RP-HPLC eluting with ACN / water (0.1% TFA) to obtain 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]triazecine-11-carboxamide (C10): MS (m / z): 431.20 [M+H]+. 11H NMR (400 MHz, acetonitrile-d3) δ 10.37 (s, 1H), 8.35 (s, 1H), 7.44 (d, J = 7.4 Hz, 1H), 6.96 (d, J = 9.8 Hz, 2H), 5.83 (q, J = 9.7, 8.6 Hz, 1H), 5.66 - 5.58 (m, 1H), 5.15 (d, J = 13.8 Hz, 1H), 4.94 (d, J = 17.8 Hz, 1H), 4.68 - 4.57 (m, 3H), 3.55 - 3.38 (m, 2H), 2.25 (dt, J = 16.7, 8.5 Hz, 1H), 1.97 - 1.86 (m, 1H), 1.15 (d, J = 6.9 Hz, 3H).

[0284] Peak 2: (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]triazecine-11-carboxamide (C11): MS (m / z): 431.20 [M+H]+. 1 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]triazecine-11-carboxamide (C12)

Chemical Structure

[0285] In step 1, (2R)-penta-4-en-2-ol was used instead of (2S)-penta-4-en-2-ol, and in step 3, (2R)-but-3-en-2-amine, hydrochloride was used instead of (2S)-but-3-en-2-amine, hydrochloride to prepare Compound 12 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]triazecine-11-carboxamide (C7 in Example 7). MS (m / z): 431.20 [M+H]+. 1 1H 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]triazecine-11-carboxamide (C13):

Chemical Structure

[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]triazecine-11-carboxylic Instead of samid (7F), 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]triazecine-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]triazecine-11-carboxamide (11). MS (m / z): 433.20 [M+H]+. 1 H NMR (400 MHz, acetonitrile-d 3 ) δ 10.39 (s, 1H), 8.34 (s, 1H), 7.57 - 7.20 (m, 1H), 7.03 - 6.91 (m, 2H), 4.86 (d, J = 14.3 Hz, 1H), 4.78 (d, J = 14.6 Hz, 1H), 4.60 (d, J = 5.6 Hz, 2H), 4.14 (dd, J = 13.4, 5.9 Hz, 1H), 3.39 - 2.97 (m, 2H), 1.97 - 1.87 (m, 2H), 1.75 (d, J = 6.5 Hz, 1H), 1.63 (dt, J = 16.9, 9.1 Hz, 1H), 1.55 - 1.20 (m, 2H), 1.17 (d, J = 6.5 Hz, 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]triazecine-11-carboxamide (C14):

Chemical Structure

[0287] Instead of using (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]triazecine-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]triazecine-11-carboxamide (C8) in Example 8 using (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]triazecine-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]triazecine-11-carboxamide (C15):

Chemical Structure

[0288] (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]triazecine-11-carboxamide (7F) was replaced with (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]triazecine-11-carboxamide (10), and Compound 15 was prepared in a similar manner to (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]triazecine-11-carboxamide (C8) in Example 8. MS (m / z): 433.20 [M+H]+. 1 H NMR (400 MHz, acetonitrile-d3) δ 11.50 (s, 1H), 10.41 (s, 1H), 8.32 (d, J = 16.7 Hz, 1H), 7.49 - 7.38 (m, 1H), 6.97 (ddt, J = 13.4, 8.5, 3.0 Hz, 2H), 5.13 (d, J = 14.1 Hz, 1H), 4.80 (t, J = 14.9 Hz, 1H), 4.60 (d, J = 6.0 Hz, 2H), 4.22 (dt, J = 13.8, 4.6 Hz, 1H), 3.57 (p, J = 7.2 Hz, 1H), 3.02 (ddd, J = 14.0, 10.1, 4.2 Hz, 1H), 1.96 (d, J = 2.5 Hz, 3H), 1.70 - 1.55 (m, 1H), 1.53 - 1.16 (m, 2H), 1.13 (d, J = 7.0 Hz, 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]triazecine-11-carboxamide (C16):

Chemical Structure

[0289] In Step 3, instead of using (2S)-but-3-en-2-amine, hydrochloride, allylamine, hydrochloride was used to prepare (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]triazecine-11- carboxamide (16A) 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]triazecine-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 hour. After concentration, it was purified by RP-HPLC eluting with ACN / water (0.1% TFA) to obtain the title compound. MS (m / z): 449.10 [M+H]+. 1 1H NMR (400 MHz, acetonitrile-d 3 ) δ 10.41 (s, 1H), 8.42 (s, 1H), 6.87 (t, J = 8.7 Hz, 2H), 5.72 (q, J = 11.7, 9.1 Hz, 2H), 4.92 (d, J = 15.7 Hz, 2H), 4.64 (d, J = 14.6 Hz, 3H), 3.82 - 3.11 (m, 2H), 2.46 - 2.35 (m, 1H), 2.08 (dt, J = 13.7, 6.3 Hz, 1H), 1.28 (d, J = 7.2 Hz, 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]triazecine-11-carboxamide (C17): [Chemistry]

[0291] (2R,6S,Z)-9-(Benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide (7F) was replaced with (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]triazecine-11-carboxamide (16), and 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]triazecine-11-carboxamide (C8) in Example 8. MS (m / z): 451.20 [M+H]+. 1 H NMR (400 MHz, acetonitrile-d3) δ 10.38 (s, 1H), 8.33 (s, 1H), 6.94 - 6.81 (m, 2H), 4.85 (d, J = 14.4 Hz, 1H), 4.76 (d, J = 14.5 Hz, 1H), 4.62 (d, J = 5.6 Hz, 2H), 4.14 (dt, J = 14.0, 7.0 Hz, 1H), 3.06 (dt, J = 13.8, 4.4 Hz, 2H), 1.93 (d, J = 14.4 Hz, 3H), 1.75 (t, J = 8.3 Hz, 1H), 1.63 (dt, J = 16.9, 8.9 Hz, 1H), 1.44 (q, J = 10.1 Hz, 1H), 1.16 (d, J = 6.5 Hz, 3H). Example 18: Preparation of (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]triazecine-11 -carboxamide (C18): [Chemistry]

[0292] In Step 3, instead of using (2S)-but-3-en-2-amine, hydrochloride, (2R)-but-3-en-2-amine, hydrochloride was used to prepare (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]triazecine-11-carboxamide (18A) in the same manner as (1S,2R,6S)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide (7F in Example 7). MS (m / z): 553.30 [M+H]+.

[0293] It was separated into its individual diastereomers (upper spot and lower spot) by silica gel chromatography eluting with EtOAc / hexane. The lower 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 hour. After concentration, it was purified by RP-HPLC eluting with ACN / H2O (0.1% TFA) to give the title compound (18). MS (m / z): 463.20 [M+H]+. 1 1H NMR (400 MHz, acetonitrile-d 3 ) δ 10.38 (s, 1H), 8.34 (s, 1H), 6.94 - 6.81 (m, 2H), 5.85 - 5.72 (m, 1H), 5.53 (dt, J = 11.6, 1.6 Hz, 1H), 5.27 (d, J = 7.9 Hz, 1H), 4.96 (d, J = 13.7 Hz, 1H), 4.73 (d, J = 13.7 Hz, 1H), 4.62 (d, J = 5.7 Hz, 2H), 3.48 - 3.35 (m, 1H), 2.29 - 2.15 (m, 1H), 1.96 - 1.87 (m, 1H), 1.27 (d, J = 7.4 Hz, 3H), 1.12 (d, J = 7.0 Hz, 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]triazecine-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]triazecine-11-carboxamide (C20): [Chemical Structure]

[0294] In Step 1, (2R)-penta-4-en-2-ol was used instead of (2S)-penta-4-en-2-ol to prepare (2S,6S,Z)-9-hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide (19A) in a manner similar 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]triazecine-11-carboxamide (7 in Example 7). 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]triazecine-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 = 13.7 Hz, 1H), 4.72 (d, J = 13.6 Hz, 1H), 4.62 (d, J = 5.7 Hz, 2H), 3.48 - 3.35 (m, 1H), 2.29 - 2.15 (m, 1H), 1.97 - 1.85 (m, 1H), 1.27 (d, J = 7.4 Hz, 3H), 1.12 (d, J = 7.0 Hz, 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]triazecine-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]triazecine-11-carboxamide (C21):

Chemical Structure

[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]triazecine-11-carboxamide (C19) was used 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]triazecine-11-carboxamide (7F), and it 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]triazecine-11-carboxamide (C8) in Example 8. MS (m / z): 465.20 [M+H]+. 1 1H 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]triazecine-11-carboxamide (C22):

Chemical formula

[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]triazecine-11-carboxamide (C18) was used 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]triazecine-11-carboxamide (7F) and 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]triazecine-11-carboxamide (C8) in Example 8. MS (m / z): 465.20 [M+H]+. 1 1H NMR (400 MHz, acetonitrile-d 3 ) 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 = 14.4 Hz, 1H), 4.65 - 4.52 (m, 3H), 3.55 (q, J = 7.0 Hz, 1H), 1.95 - 1.84 (m, 1H), 1.79 - 1.54 (m, 3H), 1.44 - 1.34 (m, 1H), 1.18 (dd, J = 6.9, 2.5 Hz, 7H). Preparation of Example 23 (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]triazecine-11-carboxamide (C23):

Chemical formula

[0300] (2R,6S,Z)-9-(Benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide (7F) was replaced with (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]triazecine-11-carboxamide (C20) to prepare Compound 23 in the same manner as (1S,2R,6S)-9-Hydroxy-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl)-3,4,5,6,8,10-hexahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-11-carboxamide (C8) in Example 8. MS (m / z): 465.20 [M+H]+. 1 1H NMR (400 MHz, DMSO-d 6 ) δ 11.10 (s, 1H), 10.41 (t, J = 5.8 Hz, 1H), 8.28 (s, 1H), 7.21 (t, J = 8.6 Hz, 2H), 6.53 (s, 0H), 5.00 (d, J = 14.4 Hz, 1H), 4.88 (d, J = 14.6 Hz, 1H), 4.60 (dd, J = 14.6, 6.0 Hz, 1H), 4.51 (dd, J = 14.6, 5.7 Hz, 1H), 3.53 - 3.50 (m, 2H), 2.11 - 1.96 (m, 1H), 1.76 (q, J = 12.1 Hz, 1H), 1.70 - 1.61 (m, 2H), 1.53 (d, J = 6.9 Hz, 5H), 1.32 (d, J = 7.1 Hz, 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]triazocin-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.

Chemical Structure

[0301] Methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate (60.0 g, 134 mmol, 1.00 equivalent) was mixed with MeOH (300 mL) and H 2 O (60.0 mL). BocNHNH 2 (19.5 g, 147 mmol, 1.10 equivalents) and NaHCO 3 (22.5 g, 268 mmol, 10.4 mL, 2.00 equivalents) were added at room temperature. Then, the reaction mixture was stirred at 55 °C for 16 hours. The reaction mixture was placed under vacuum to remove most of the MeOH. The resulting residue was diluted with H 2 O (200 mL), and the crude product was extracted with EtOAc (1500 mL). The organic layer was washed with brine (500 mL), dried over Na 2 SO 4 and concentrated in vacuo. The resulting slurry was purified by silica gel chromatography using petroleum ether:ethyl acetate = 5:1 to obtain 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. [Chemistry]

[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 Ph 3 P (3.5 g, 13.4 mmol) were added sequentially. Then, DIAD (2.7 g, 13.4 mmol) was added dropwise over 5 minutes. The resulting reaction mixture was stirred at 0 °C for 5 minutes. The cold bath was removed. The reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated to dryness. The residue was purified on a silica gel column using 0 - 100% 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. [Chemistry]

[0303] 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 (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 Ph 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 cooler was attached and the reaction mixture was heated to 73 °C for 3.5 hours with stirring. Further LiOH (5 M) (2 mL) was added. Then, the reaction mixture was stirred at 40 °C 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 1 N HCl. EtOAc (200 mL) was added for extraction. The organic phase was separated. The aqueous layer was extracted with further EtOAc (100 ml). The combined organic phases were washed with water and brine, and dried over Na 2 SO 4 and 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

Chemical formula

[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 NaHCO 3(Saturated aqueous solution, 100 mL) and water (100 mL) were used for treatment. 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 obtain 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.

Chemical formula

[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. Then, the reaction mixture was concentrated to dryness. The residue was partitioned between EtOAc (100 mL) and NaHCO 3 (Saturated aqueous solution, 100 mL). The organic layer was separated, washed with brine, and dried over Na 2 SO 4 . The solvent was removed to obtain 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.

Chemical formula

[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 hot bath at 88 °C. Then, AcOH (0.9 mL) and TFA (0.9 mL) were sequentially added into the preheated reaction mixture within 5 minutes. Then, the resulting reaction mixture was sealed and heated with stirring for 30 minutes. Then, the resulting reaction mixture was concentrated to dryness to remove all solvents and acids. Then, the resulting crude material was dissolved in DMF (17 mL). K 2 CO 3 (2.76 g, 20 mmol) and benzyl bromide (2.56 g, 15 mmol) were sequentially added. Then, the reaction mixture was heated at 100 °C for 3 hours. Then the reaction mixture was diluted with EtOAc (100 mL), and then treated with NaHCO 3 (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 residual crude product was purified on a silica gel column using 0 - 100% EtOAc / Hex to obtain the product. MS (m / z): 567.2 [M+H]+. Step 7: Preparation of (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]triazocin-10-carboxamide (A), (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]triazocin-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]triazocin-10-carboxamide (C)

Chemical formula

[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. Then, HG-M720 catalyst (103.4 mg, 0.164 mmol) was added with stirring. The purge with argon was continued for 10 minutes. Then, the reaction mixture was heated with stirring under an argon atmosphere for 48 hours. Then, the resulting reaction mixture was concentrated to dryness. The crude material was purified on a silica gel column using 0 - 100% EtOAc / Hex to obtain 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]triazocin-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]triazocin-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]triazocin-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 (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]triazocin-10-carboxamide (C24):

Chem.

[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]triazocin-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 h. 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% CH 3 CN in water with 0.1% TFA to give the desired product. The product was obtained as the mono-TFA salt by lyophilization. 50 mg. MS (m / z): 449.2 [M + H]. 1H NMR (400 MHz, acetonitrile-d3) δ 10.21 (t, J = 5.9 Hz, 1H), 8.38 (s, 1H), 6.87 (t, J = 8.5 Hz, 2H), 5.65 (dt, J = 11.4, 2.4 Hz, 1H), 5.47 - 5.27 (m, 2H), 5.01 (d, J = 14.4 Hz, 1H), 4.62 (d, J = 5.8 Hz, 2H), 4.57 (d, J = 14.3 Hz, 1H), 3.82 (tp, J = 6.6, 3.3 Hz, 1H), 1.35 (d, J = 2.0 Hz, 3H), 1.33 (d, J = 2.6 Hz, 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]triazocin-10-carboxamide (C25)

Chem.

[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]triazocin-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 h. 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% CH 3 CN in water with 0.1% TFA to give the desired product. The product was obtained as the mono-TFA salt by lyophilization. 34 mg. MS (m / z): 449.2 [M+H]+. 1H NMR (400 MHz, 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 = 14.4 Hz, 1H), 4.72 (d, J = 14.4 Hz, 1H), 4.66-4.53 (m, 3H), 1.35 (d, J = 7.2 Hz, 3H), 1.01 (d, J = 7.4 Hz, 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]triazocin-10-carboxamide (C26)

Chem.

[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]triazocin-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 obtain the product in neural form. 8 mg. MS (m / z): 449.2 [M + H]+. 1H NMR (400 MHz, acetonitrile-d3) δ 10.30 (s, 1H), 8.40 (s, 1H), 6.97 - 6.77 (m, 2H), 5.80 (ddd, J = 11.7, 2.7, 1.9 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]triazocin-10-carboxamide (C27): [Chemical formula]

[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]triazocin-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 under H 2It was carried out at room temperature for 7 hours using a balloon. 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% CH in water with 0.1% TFA to obtain the desired product. The product was obtained as the mono-TFA salt by lyophilization. 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). 3 reverse using phase preparative HPLC to obtain the desired product. The product was obtained as the mono-TFA salt by lyophilization. 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]triazocin-10-carboxamide (C28):

Chemical Structure

[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]triazocin-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 for 7 hours using a balloon. 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% CH in water with 0.1% TFA to obtain the desired product. The product was obtained as the mono-TFA salt by lyophilization. 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). 2 It was carried out at room temperature for 7 hours using a balloon. 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% CH in water with 0.1% TFA to obtain the desired product. The product was obtained as the mono-TFA salt by lyophilization. 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). 3Purified by reverse-phase preparative HPLC using CN to obtain the desired product. The product was obtained as the mono-TFA salt by lyophilization. 7 mg. MS (m / z): 451.3 [M+H]+. 1H NMR (400 MHz, acetonitrile-d3) δ 10.36 (s, 1H), 8.34 (s, 1H), 6.98 - 6.77 (m, 2H), 4.76 - 4.59 (m, 5H), 3.41 (dd, J = 11.6, 6.3 Hz, 1H), 2.20 (dt, J = 14.2, 6.8 Hz, 1H), 1.80 - 1.49 (m, 2H), 1.26 (d, J = 6.7 Hz, 3H), 1.30 - 1.17 (m, 1H), 1.08 (d, J = 6.9 Hz, 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]triazocin-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

Chemical formula

[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 H 2 O (30.0 mL). BocNHNH 2 (5 g, 37.8 mmol) and NaHCO 3 (5.87 g, 69.9 mmol) were added at room temperature. Then, the reaction mixture was 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 H 2 O (200 mL), and the crude product was extracted with EtOAc (500 mL). The organic layer was washed with brine (500 mL), and Na 2 SO 4It was dried and concentrated in vacuo. The resulting slurry was purified by silica gel chromatography using hexane:ethyl acetate = 5:1 to obtain 18 g of the 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

Chemical formula

[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 Ph 3 P (8.6 g, 32.8 mmol) were added sequentially. Then, DIAD (6.64 g, 32.8 mmol) was added dropwise over 5 minutes. The resulting reaction mixture was a slightly orange solution. It was stirred at 0 °C for 5 minutes. The cold bath was removed. The reaction mixture was stirred at room temperature for 17 hours. The reaction mixture was concentrated to dryness. The residue was purified on a silica gel column using 0 - 100% EtOAc / Hex to obtain 10 g of the 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

Chemical formula

[0315] Methyl 3-(benzyloxy)-1-(but-3-en-2-yl(tert-butoxycarbonyl)amino)-4-oxo-5-((2,4-difluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (12.5 g, 20.9 mmol) was mixed with MeOH (200 mL) and water (100 mL) at room temperature. LiOH (5 M in water) (33.5 mL, 167 mmol) was added. An air condenser was attached and the reaction mixture was heated to 63 °C for 17 h with stirring. 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. A solid appeared. EtOAc (200 mL) was added for extraction. The organic phase was separated. The aqueous layer was extracted with further EtOAc (100 mL). The combined organic phases were washed with water and brine. It was dried over Na 2 SO 4 and filtered, and concentrated to give 9 g 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

Chemical formula

[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) and the reaction mixture were cooled in an ice-water bath. HATU (6.52 g, 17.14 mmol) was added all at once. The reaction mixture was then warmed to room temperature with stirring for 1 h. Then, (S)-but-3-en-2-amine hydrochloride (2.3 g, 21.4 mmol) was added. The resulting reaction mixture was stirred at room temperature for 17 h. The reaction mixture was diluted with EtOAc (200 mL), and then treated with NaHCO 3 (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: Preparation of 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

Chemical Structure

[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 h. Then, the reaction mixture was concentrated to dryness. The residue was partitioned between EtOAc (100 mL) and NaHCO 3 (saturated aqueous solution, 100 mL). The organic layer was separated, washed with brine, and Na 2SO 4 [It was dried with 4 . The solvent was removed to obtain 3 g of the product. 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 [ [

Chemical formula

[0318] [

[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 hot bath at 88 °C. Then, AcOH (1.15 mL) and TFA (1.15 mL) were sequentially added to the preheated reaction mixture within 5 minutes. Then, the resulting reaction mixture was sealed and heated with stirring for 30 minutes. Then, the resulting reaction mixture was concentrated to dryness to remove all solvents and acids. Then, the resulting crude material was dissolved in DMF (17 mL). K 2 [ 2 CO 3 [ 3 (10 g, 72.4 mmol) and benzyl bromide (6.63 g, 38.8 mmol) were sequentially added. Then, the reaction mixture was heated at 100 °C for 3 hours. Then, the reaction mixture was diluted with EtOAc (100 mL), and then treated with NaHCO 3 [ 3 (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 residual crude product [ was purified on a silica gel column using 0-100% EtOAc / Hex to obtain 1 g of the product. MS (m / z): 549.2 [M+H]. [ ​​Process 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]triazocin-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]triazocin-10-carboxamide

Chemical formula

[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. Then, HG-M720 catalyst (146.4 mg, 0.233 mmol) was added with stirring. Purging with argon was continued for 10 minutes. Then, the reaction mixture was heated with stirring under an argon atmosphere for 48 hours. Then, the resulting reaction mixture was concentrated to dryness. The crude material was purified on a silica gel column using 0 - 100% EtOAc / Hex to obtain two products as a single diastereomer. (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]triazocin-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]triazocin-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]triazocin-10-carboxamide:

Chemical Structure

[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]triazocin-10-carboxamide( 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 h. 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% CH 3 CN in water with 0.1% TFA to give the desired product. The product was obtained as the mono-TFA salt by lyophilization. 150 mg. MS (m / z): 431.2 [M + H]. 1H NMR (400 MHz, acetonitrile-d3) 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]triazocin-10-carboxamide (C30)

Chemical Structure

[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]triazocin-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 h. 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% CH 3 CN in water with 0.1% TFA to give the desired product. The product was obtained as the mono-TFA salt by lyophilization. 5 mg. MS (m / z): 431.2 [M+H]. 1H NMR (400 MHz, acetonitrile-d3) δ 10.27 (s, 1H), 8.45 (s, 1H), 7.44 (td, J = 8.8, 6.5 Hz, 1H), 6.97 (dddd, J = 10.7, 5.2, 4.3, 2.5 Hz, 2H), 5.62 (ddd, J = 12.2, 3.3, 2.1 Hz, 1H), 5.46-5.31 (m, 2H), 4.94 (d, J = 14.4 Hz, 1H), 4.73 (d, J = 14.4 Hz, 1H), 4.61 (d, J = 6.1 Hz, 3H), 1.36 (d, J = 7.2 Hz, 3H), 1.03 (d, J = 7.4 Hz, 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]triazocin-10-carboxamide (C31)

Chem.

[0322] In an EtOH (9 mL) solution of (1S,2S,5S)-N-(2,4-difluorobenzy (R)-8-Hydroxy-2,5-dimethyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazocin-10-carboxamide (Example 30, 0.291 mmol, 125 mg) was discharged, the argon was refilled (5 cycles), then it was treated with 10% Pd / C (25 mg), further discharged, the argon was refilled (5 cycles), and then hydrogen was refilled (5 cycles). The reaction mixture was stirred overnight at room temperature under a hydrogen balloon, then filtered through celite, washed with EtOH, and concentrated. The obtained residue was dissolved again in EtOH (22 mL) and treated with 10% Pd / C (50 mg) and hydrogen as described above. After 4 hours, the reaction mixture was filtered through celite, washed with EtOH, concentrated, and then purified by preparative HPLC (10 - 100% MeCN in water with 0.1% TFA) and lyophilized to obtain the title compound as the trifluoroacetate salt (62 mg, 39% yield). MS (m / z) 433.25 [M + H]+. 1 H NMR (400 MHz, methanol-d4) δ 8.43 (s, 1H), 7.43 (td, J = 8.5, 6.4 Hz, 1H), 7.02 - 6.88 (m, 2H), 4.85 - 4.76 (m, 2H), 4.69 (dt, J = 10.6, 6.7 Hz, 1H), 4.63 (s, 2H), 3.55 - 3.44 (m, 1H), 2.22 (dt, J = 14.2, 6.8 Hz, 1H), 1.75 (dt, J = 15.0, 11.3 Hz, 1H), 1.66 (dd, J = 15.7, 6.9 Hz, 1H), 1.30 (d, J = 6.7 Hz, 3H), 1.36 - 1.20 (m, 1H), 1.11 (d, J = 6.8 Hz, 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]triazocin-10-carboxamide: (C32)

Chemical Structure

[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]triazocin-10-carboxamide (Example 24, Step 7, A) (140 mg, 0.26 mmol) was dissolved in a mixture of acetone (8 mL) and water, and then cooled to 0 °C in an ice-water bath. 4-Methylmorpholine N-oxide (50% in water, 0.1 mL, 2 equivalents) was slowly added into the above reaction solution. Then, 2.5% osmium tetroxide (0.01 mL, 4% equivalents) was added. The mixture was stirred at 0 °C and warmed 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 through a silica column (eluting with 0 - 10% MeOH / DCM) to obtain (1S,2R,3S,4R,5S)-8-(benzyloxy)-3,4-dihydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazocin-10-carboxamide ( Nonpolar, by-product) and (1S,2R,3R,4S,5S)-8-(benzyloxy)-3,4-dihydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazocin-10-carboxamide (Polar, main product). MS (m / z) 573.3 [M+H] + . [Chemical Structure] (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]triazocin-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]triazocin-10-carboxamide, and Preparation of (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]triazocin-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]triazocin-10-carboxamide (77 mg, 0.134 mmol) was dissolved in DMF (3 mL), and then cooled to 0 °C in an ice-water bath. Sodium hydride (60%, 11 mg, 2.2 equiv) was added to the above reaction solution. After 10 minutes, methyl iodide (diluted 100-fold with DCM, 1 mL, 1.3 equiv) was added. The mixture was stirred at 0 °C for 30 minutes. 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 an extract using 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,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]triazocin-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]triazocin-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]triazocin-10-carboxamide (non-polar, minor mono-Me product MS (m / z) 587.3 [M+H] + ) was obtained (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]triazocin-10-carboxamide (C32) Preparation:

Chemical formula

[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]triazocin-10-carboxamide (15 mg) was dissolved in toluene (0.5 mL), and trifluoroacetic acid (1 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by preparative HPLC 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]triazocin-10-carboxamide (C33):

Chemical formula

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

[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]triazocin-10-carboxamide (4 mg) was dissolved in toluene (0.2 mL), and trifluoroacetic acid (0.4 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by preparative HPLC eluting with 10 - 100% acetonitrile (0.1% TFA) in water (0.1% TFA) to obtain the title compound. MS (m / z) 467.2 [M+H] + . 1H NMR (400 MHz, acetonitrile-d3) δ 10.35 (s, 1H), 8.40 (s, 1H), 6.87 (t, J = 8.5 Hz, 2H), 4.71 - 4.43 (m, 4H), 4.36 (p, J = 6.8 Hz, 1H), 3.88 (dd, J = 9.2, 6.0 Hz, 1H), 3.49 (m, 1H), 1.87 - 1.69 (m, 1H), 1.51 - 1.19 (m, 7H). (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]triazocin-10-carboxamide Preparation:

[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]triazocin-10-carboxamide (10 mg, 0.018 mmol) was dissolved in DMF (1 mL), and then cooled to 0 °C in an ice-water bath. Sodium hydride (60%, 1.4 mg, 2 equivalents) was added to the above reaction solution. After 10 minutes, methyl iodide (diluted 100-fold with DCM, 0.11 mL, 1 equivalent) was added. The mixture was stirred at 0 °C for 30 minutes. LC-MS indicated the bis-Me product, and the main product was the mono-Me product. The reaction was quenched by adding saturated sodium bicarbonate solution. The reaction mixture was extracted using 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 obtain 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]triazocin-10-carboxamide (C33):

Chemical Structure

[0329] (1S,2R,4R,5S)-8-(benzyloxy)-4-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]tri Zonine-10-carboxamide (4 mg) was dissolved in toluene (0.2 mL), and trifluoroacetic acid (0.4 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified via preparative HPLC eluting with 10 - 100% acetonitrile (0.1% TFA) in water (0.1% TFA) to afford 1.6 mg of the labeled compound. MS (m / z) 481.2 [M+H] + 。 1 H NMR (400 MHz, acetonitrile-d3) δ 10.33 (s, 1H), 8.42 (d, J = 8.2 Hz, 1H), 6.87 (t, J = 8.5 Hz, 2H), 4.76 - 4.46 (m, 4H), 3.45 (dd, J = 9.0, 5.4 Hz, 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]triazocin-10-carboxamide (C34):

Chem.

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

Chem.

[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]triazocin-10-carboxamide (8 mg) was dissolved in toluene (0.2 mL), and trifluoroacetic acid (0.4 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by preparative HPLC eluting with 10 - 100% acetonitrile (0.1% TFA) in water (0.1% TFA) to obtain the title compound. MS (m / z) 469.2 [M + H] + 。 1 1H 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]triazocin-10-carboxamide (C35)

Chem.

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

[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]triazocin-10-carboxamide (110 mg, 0.2 mmol) was dissolved in DCM (5 mL), and then 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 above reaction solution. The mixture was stirred at 0 °C and warmed to room temperature overnight. 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 through a silica column (eluting with 0 - 10% MeOH / DCM ) to obtain (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]triazocin-10-carboxamide. MS (m / z) 577.2 [M+H] + . (1S,2R,5S)-4,4-Difluoro-8-hydroxy-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazocin-10-carboxamide (Preparation of 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]triazocin-10-carboxamide (25 mg) was dissolved in toluene (0.5 mL), and trifluoroacetic acid (2 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified via preparative HPLC eluting with 10 - 100% acetonitrile (0.1% TFA) in water (0.1% TFA) to afford the title compound. MS (m / z) 487.2 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 10.47 (s, 1H), 10.29 (t, J = 5.8 Hz, 1H), 8.24 (s, 1H), 7.31 - 7.16 (m, 2H), 5.76 (s, 1H), 5.07 (d, J = 15.2 Hz, 1H), 4.91 (dq, J = 15.0, 7.2 Hz, 1H), 4.76 (d, J = 15.2 Hz, 1H), 4.57 (d, J = 5.8 Hz, 2H), 3.21 (t, J = 8.3 Hz, 1H), 2.83 (ddd, J = 32.9, 16.3, 10.1 Hz, 2H), 1.33 (dd, J = 7.0, 3.1 Hz, 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]triazocin-10-carboxamide: (C36)

Chemical Structure

[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]triazocin-10-carboxamide (16 mg, 0.028 mmol) was dissolved in DCM (1 mL), and then cooled to 0 °C in an ice-water bath. Dess-Martin periodinane (11 mg, 2 equivalents) was added into the above reaction solution. The mixture was stirred at 0 °C and warmed to room temperature for 2 hours. The reaction was quenched by adding 10% aqueous sodium thiosulfate solution. The reaction mixture was extracted using ethyl acetate. The organic layer was concentrated and purified through a silica column (eluting with 0 - 10% MeOH / DCM) to obtain (1S,2R,5S)-8-(benzyloxy)-2,5-dimethyl-3,7,9-trioxo-N-(2,4,6-trifluorobenzyl)-2,3,4,5,7,9-hexahydro-1,6-methanopyrido[1,2-b][1,2,5]triazocin-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]triazocin-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]triazocin-10-carboxamide (12 mg, 0.2 mmol) was dissolved in DCM (2 mL), and then cooled to 0 °C in an ice-water bath. Bis(2-methoxyethyl)aminosulfur trifluoride (50% in toluene, 2.7 M, 0.018 mL, 2 eq) was added into the above reaction solution. The mixture was stirred at 0 °C and warmed to room temperature for 3 h. LC-MS showed the elimination product and the di-F product. 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 purified via preparative HPLC eluting with 10 - 100% acetonitrile (0.1% TFA) in water (0.1% TFA) to obtain (1S,2R,5S)-8-(benzyloxy)-3-fluoro-2,5-dimethyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazocin-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]triazocin-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]triazocin-10-carboxamide (6 mg) was dissolved in toluene (0.2 mL), and trifluoroacetic acid (0.5 mL) was added. The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated and purified by preparative HPLC 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: Preparation of (1S,2R,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]triazocin-10-carboxamide (C37)

Chemical formula

[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]triazocin-10-carboxamide (10.2 mg, 0.023 mmol) in EtOH (5 mL), PtO 2 (2 mg, 0.009 mmol) was added. The reaction mixture was hydrogenated 2Under the balloon, it was stirred at room temperature for 2 hours. The reaction mixture was filtered through celite, the filtrate was concentrated, and the residue was purified by reverse-phase HPLC eluting with 5 - 100% acetonitrile in water to obtain the desired product. MS (m / z): 433.11 [M + H] + 。 1 H NMR (400 MHz, methanol-d4) δ 8.50 (s, 1H), 7.51 - 7.38 (m, 1H), 6.97 (q, J = 10.0, 9.5 Hz, 2H), 4.78 (d, J = 14.3 Hz, 1H), 4.65 (s, 4H), 3.57 (s, 1H), 2.05 (dd, J = 15.0, 7.6 Hz, 1H), 1.82 (dd, J = 15.1, 9.4 Hz, 1H), 1.62 (d, J = 12.2 Hz, 2H), 1.40 (d, J = 7.0 Hz, 3H), 1.33 (d, J = 6.7 Hz, 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]triazecine-11-carboxamide (C38):

Chemical formula

[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]triazecine-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 it were 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 mixture was stirred at room temperature for 2 days. An aqueous solution of 10% sodium sulfite (3 mL) was added to the reaction mixture 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: Synthesis 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]triazecine-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]triazecine-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 h. 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 min and further saturated aqueous sodium bicarbonate was added until effervescence ceased. The organic phase was separated, dried over magnesium sulfate and the solvent 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]triazecine-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 h. The solvent was removed under reduced pressure and the residue 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 (400 MHz, acetonitrile-d3) δ 10.32 (s, 1H), 8.33 (s, 1H), 7.43 (q, J = 9.1, 8.4 Hz, 1H), 7.00 - 6.95 (m, 2H), 4.82 (s, 2H), 4.69 (s, 0H), 4.60 (d, J = 6.0 Hz, 2H), 4.37 (dq, J = 8.5, 4.4 Hz, 1H), 4.19 (dd, J = 14.2, 7.9 Hz, 1H), 3.45 (t, J = 7.3 Hz, 1H), 3.39 - 3.31 (m, 1H), 2.29 - 2.06 (m, 2H), 1.20 (d, J = 6.5 Hz, 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]triazecine-11-carboxamide (C39): [Chemical formula] Step 1: Synthesis of (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]triazecine-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 ,7-methanopyrido[1,2-b][1,2,5]triazecine-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]triazecine-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 wt% in oil) was added and the mixture was stirred at 0 °C for 30 minutes. Iodomethane (0.0056 ml, 0.09 mmol) was added thereto, the mixture was stirred at 0 °C for 10 minutes, the reaction was quenched with a saturated aqueous ammonium chloride solution, and it was extracted 3 times with ethyl acetate. The combined organic extracts were washed with a 5% aqueous lithium chloride solution and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with ethyl acetate to obtain 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]triazecine-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]triazecine-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]triazecine-11-carboxamide (C39):

Chemical formula

[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]triazecine-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-d 3)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, 3.6 Hz, 2H), 3.46 - 3.37 (m, 0H), 3.41 (s, 3H), 3.33 (s, 3H), 3.32 (d, J = 13.2 Hz, 1H), 3.19 (d, J = 33.1 Hz, 1H), 3.20 - 3.08 (m, 1H), 2.18 (s, 1H), 1.94 (d, J = 2.5 Hz, 0H), 1.89 - 1.74 (m, 0H), 1.18 (d, J = 6.5 Hz, 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]triazecine-11-carboxamide (C40): [Chemical Structure] 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) was added portionwise at room temperature, followed by DMAP (221.9 g, 181.65 mmol), and then the mixture was stirred at room temperature for 4 h. 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 and dried over Na 2 SO 4 and evaporated under reduced pressure to obtain 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 hexanes, 244.14 ml, 390.6 mmol) dropwise at -78 °C over 30 min. 3 Etherate (119.7 g, 390.6 mmol) was added dropwise, followed by a solution of (R)-2-methyloxirane (21.51 g, 390.6 mmol) in THF (0.5 L). The reaction mixture was stirred at this temperature for 4 h. After completion, the reaction mixture was quenched with saturated ammonium chloride solution and water. The reaction mixture was extracted with ethyl acetate. The combined organic layers were washed with saturated NaHCO 3 and washed with water, and 2 SO 4 The mixture was dried 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) was taken and charged in a Parr apparatus and 400 ml ethyl acetate was added. Lindlar catalyst (4.4 g) was added under inert atmosphere followed by quinoline and hydrogenated at 30 Psi at room temperature for 16 hours. After 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 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 product was washed with diethyl ether, filtered, and dried under vacuum to obtain 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 obtain 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)-penta-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 and tert-butyl (R,Z)-(5-hydroxyhex-2-en-1-yl)carbamate, and methyl (R)-3-(benzyloxy)-1-((tert-butoxycarbonyl)(penta-4-en-2-yl)amino)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (7A) was prepared in a similar manner. 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] 140 ml of THF / MeOH / H 2 O (3 / 2 / 1) 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-car To a solution of boxylate (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 indicated high conversion to the carboxylic acid. The reaction mixture was diluted with ethyl acetate and acidified to pH ~4 with 1N HCl. 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 and treated with 4N HCl in 1,4-dioxane (7.3 mL) overnight at room temperature and concentrated to dryness. Dried under high vacuum to give 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]triazecine-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. To it were added EDCI · 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). 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]triazecine-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]triazecine-11-carboxamide:

[0352] (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 (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]triazecine-11-carboxamide instead 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]triazecine-11-carboxamide (7E). 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]triazecine-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]triazecine-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]triazecine-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]triazecine-11-carboxamide was used 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]triazecine-11-carboxamide (7F) and 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]triazecine-11-carboxamide (C8). MS (m / z): 433.200 [M+H]+. 1 1H NMR (400 MHz, acetonitrile-d 3)δ11.45(s,1H),10.40(s,1H),8.29(s,1H),7.49-7.38(m,1H),7.04-6.91(m,2H),5.12(d,J=14.1Hz,1H),4.80(d,J=14.2Hz,1H),4.59(d,J=5.9Hz,2H),4.21(dt,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]triazecine-11-carboxamide (C41): [Chemical formula]

[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]triazecine-11-carboxamide (7F) was replaced with (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]triazecine-11-carboxamide and 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]triazecine-11-carboxamide (C7). MS (m / z): 431.200 [M+H]+. 1 H NMR (400 MHz, acetonitrile-d 3)δ 10.37 (s, 1H), 8.35 (s, 1H), 7.50 - 7.39 (m, 1H), 6.97 (ddt, J = 12.9, 8.4, 3.0 Hz, 2H), 5.89 - 5.77 (m, 1H), 5.62 (ddt, J = 11.8, 4.3, 1.8 Hz, 1H), 5.14 (d, J = 13.8 Hz, 1H), 4.94 (d, J = 18.1 Hz, 1H), 4.68 - 4.57 (m, 3H), 3.55 - 3.38 (m, 2H), 2.26 (dt, J = 16.1, 8.4 Hz, 1H), 1.97 - 1.86 (m, 1H), 1.15 (d, J = 7.0 Hz, 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]triazecine-11-carboxamide (C42):

Chemical Structure

[0355] (2R,6S,Z)-9-(Benzyloxy)-2,6-dimethyl-8,10-dioxo-N-(2,4,6-trifluorobenzyl) 3,6,8,10-tetrahydro-2H-1,7-methanopyrido[1,2-b][1,2,5]triazecine-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]triazecine-11-carboxamide and 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]triazecine-11-carboxamide (C8). MS (m / z): 433.200 [M+H]+. 11H 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, 5.2 Hz, 1H), 3.14 - 3.02 (m, 2H), 1.96 - 1.91 (m, 1H), 1.77 (dd, J = 16.7, 7.1 Hz, 1H), 1.71 - 1.57 (m, 1H), 1.45 (q, J = 10.3 Hz, 2H), 1.17 (d, J = 6.5 Hz, 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]triazecine-11-carboxamide (C43): [Chemical formula]

[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]triazecine-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]triazecine-11-carboxamide and 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]triazecine-11-carboxamide (C7). MS (m / z): 431.200 [M + H]+. 1 1H NMR (400 MHz, acetonitrile-d3 ) δ 10.41 (s, 1H), 8.44 (s, 1H), 7.44 (td, J = 8.8, 6.5 Hz, 1H), 6.97 (ddt, J = 10.8, 8.2, 3.0 Hz, 2H), 5.79 - 5.63 (m, 2H), 5.00 - 4.88 (m, 2H), 4.69 - 4.57 (m, 3H), 3.61 (p, J = 6.8 Hz, 1H), 3.58 - 3.48 (m, 1H), 2.42 (dd, J = 15.5, 7.1 Hz, 1H), 2.10 (ddd, J = 14.7, 8.4, 5.5 Hz, 1H), 1.29 (d, J = 7.1 Hz, 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]triazocin-10-carboxamide (C44):

Chemical formula

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

[0358] The reaction mixture of 3-(benzyloxy)-1-((tert-butoxycarbonyl)amino)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-1,4-dihydropyridine-2-carboxylic acid (200 mg, 0.378 mmol), (2S)-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 4 and concentrated under vacuum. The residue was purified by silica gel column chromatography. MS (m / z) 583.300 [M+H]+. Synthesis of tert-butyl (3-(benzyloxy)-2-(((S)-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] (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 synthesis: + 。 (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 synthesis:

[0360] (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 synthesis: 3 Aqueous solution, and brine. The organic phase was washed with MgSO 4It was dried, filtered, and concentrated in vacuo. It was purified by silica gel column chromatography eluting with ethyl acetate in hexane to obtain the title product. MS (m / z) 695.400 [M+H] + . (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 synthesis:

[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)but-3- (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 (202 mg, 0.29 mmol) was dissolved in 4 ml of DCM, and thereto was added hydrogen chloride, 4.0 M solution in 1,4-dioxane (0.73 ml, 2.9 mmol). It was stirred at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and dried under high vacuum to obtain the title product. MS (m / z) 595.300 [M+H] + . (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 synthesis:

[0362] 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, (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 was used and prepared in a similar manner to 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 in Example 24. 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]triazocin-2-yl)acetate:

[0363] Instead 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, (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 was used and prepared in a similar manner to (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]triazocin-10-carboxamide in Example 24. MS (m / z) 579.300 [M+H] + 。 Synthesis of (2S,5S)-8-(benzyloxy)-N-(2,4-difluorobenzyl)-2-(hydroxymethyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazocin-10-carboxamide:

[0364] ((2S,5S)-8-(Benzyloxy)-10-((2,4-difluorobenzyl)carbamoyl)-5-methyl-7,9-dioxo-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazin-2-yl)methyl acetate (46 mg, 0.79 mmol) was dissolved in 2 ml of methanol. Potassium carbonate (22 mg, 0.16 mmol) was added thereto. The reaction mixture 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 MgSO 4 and concentrated to dryness to obtain 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 -1,6-methanopyrido[1,2-b][1,2,5]triazocin-10-carboxamide synthesis:

[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]triazocin-10-carboxamide (xxH, 15 mg, 0.028 mmol) in DCM (2 mL) was cooled to 0 °C under argon. Deoxo-fluoro (50% in toluene, 0.031 ml, 0.084 mmol) was added thereto. 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 dropwise addition of saturated NaHCO 3 aqueous solution. The resulting mixture was stirred for 20 min, additional saturated NaHCO 3 aqueous solution was added, and the mixture was stirred for 10 min until foaming ceased. The organic layer was separated, dried over Na 2 SO 4 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] + . (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]triazocin-10-carboxamide (C44) synthesis:

[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]triazocin-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 (400 MHz, acetonitrile-d 3 ) δ 10.19 (s, 1H), 8.47 (s, 1H), 7.44 (td, J = 9.2, 8.7, 6.4 Hz, 1H), 6.97 (ddt, J = 11.1, 8.5, 3.0 Hz, 2H), 5.83 (dt, J = 11.8, 2.7 Hz, 1H), 5.39 (ddt, J = 14.5, 12.0, 2.9 Hz, 2H), 4.96 (d, J = 14.4 Hz, 1H), 4.70 - 4.57 (m, 4H), 4.52 (d, J = 5.5 Hz, 1H), 4.10 (ddq, J = 20.0, 5.7, 2.9 Hz, 1H), 1.36 (d, J = 7.3 Hz, 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]triazocin-10-carboxamide (C45): [Chemical formula]

[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]triazocin-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 sparged under a hydrogen atmosphere (1 atm, balloon) and sparged. The mixture was stirred vigorously for 1 hour and then sparged under an argon atmosphere. It was filtered through a pad of Celite®. 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 1H NMR (400 MHz, acetonitrile-d3) δ 10.31 (s, 1H), 8.41 (s, 1H), 7.44 (td, J = 9.2, 8.7, 6.3 Hz, 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, 4.1 Hz, 1H), 1.77 - 1.57 (m, 2H), 1.26 (d, J = 6.8 Hz, 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]triazocin-10-carboxamide (C46):

Chemical formula

[0368] 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 eq.) prepared according to Example 24, Step 3, in a suspension in methanol (200 mL) and water (100 mL), lithium hydroxide monohydrate (5.979 g, 142 mmol, 8 eq.) was added. The reaction mixture was heated at 50 °C for 18 h, diluted with water, and acidified with 1 N HCl (aqueous solution). The slurry was extracted with EtOAc (2×), the combined organic phases were washed with brine, dried over Na 2 SO 4 , filtered, and concentrated to afford 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 eq.), (S)-but-3-en-2-amine hydrochloride (1.769 g, 16.4 mmol, 1.5 eq.), and HOBt (2.221 g, 16.4 mmol, 1.5 eq.) in CH 2 Cl 2 (120 mL) at 0 °C, DIPEA (9.54 mL, 54.8 mmol, 5 eq.) and EDCI (3.151 g, 16.4 mmol, 1.5 eq.) were added. The reaction mixture was warmed to room temperature and stirred for 18 h. The reaction mixture was quenched with water and 1 M HCl, and CH 2 Cl 2Extracted with (3×). The combined organic phases were dried over Na 2 SO 4 , filtered, and concentrated. The crude residue was purified by column chromatography (0 - 100% EtOAc / hexane) 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 at 70 °C for 8 h and quenched with NH 4 Cl (aqueous solution). The mixture was extracted with EtOAc (2×), the combined organic phases were dried over Na 2 SO 4 , filtered, and concentrated. The residue was purified by column chromatography (0 - 100% EtOAc / hexane) 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 2N aqueous NaOH solution (2.45 mL, 4.90 mmol, 1.5 equiv). The reaction mixture was heated at 40 °C for 1 h, quenched with 10% citric acid solution, and diluted with CH 2 Cl 2 The phases were separated and the aqueous phase was extracted with CH 2 Cl 2 The combined organic phases were dried over Na 2 SO 4 filtered, and concentrated. The residue was suspended in 1:1 EtOAc / hexane 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] 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 treated with Pd(OAc) 2 (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). The reaction mixture was heated at 100 °C for 20 min. Water and brine were added, and the aqueous phase was extracted with EtOAc (2×). The combined organic phases were dried over Na 2 SO 4 and filtered, and concentrated. The residue was purified by column chromatography (0–100% EtOAc / hexanes) to afford 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]triazocin-10-carboxamide:

[0373] 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 to Hoveyda-Grubbs II catalyst (0.024 g, 0.038 mmol, 0.2 equiv). The reaction mixture was heated at 70 °C for 24 h and concentrated. The residue was purified by preparative HPLC eluting with 5 - 100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 min (column, Gemini 10μ C18 110A, AXI / ; 250×21.2 mm). The combined fractions were frozen dried to give (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]triazocin-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]triazocin-10-carboxamide (C46):

[0374] 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]triazocin-10-carboxamide (0.0455 g, 0.0821 mmol, 1 equiv) in DMF (2 mL) was added with lithium chloride (0.0348 g, 0.821 mmol, 10 equiv). The reaction mixture was heated at 100 °C for 1 h and filtered. The filtrate was purified by preparative HPLC eluting with 5 - 100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 min (column, Gemini 10μ C18 110A, AXI / ; 250×21.2 mm). 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]triazocin-10-carboxamide. MS (m / z) 465.02 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.31 (t, J = 5.8 Hz, 1H), 8.21 (s, 1H), 7.20 (t, J = 8.6 Hz, 2H), 5.76 (dt, J = 12.1, 2.3 Hz, 1H), 5.55 (dt, J = 12.0, 2.4 Hz, 1H), 5.29 - 5.17 (m, 2H), 5.06 (d, J = 14.6 Hz, 1H), 4.75 (d, J = 14.6 Hz, 1H), 4.57 (d, J = 5.8 Hz, 2H), 3.39 (s, 3H), 1.28 (d, J = 7.2 Hz, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -109.25 (ddd, J = 15.5, 9.3, 6.2 Hz), -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]triazocin-10-carboxamide (C47): [Chemical formula] Engineering 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]triazocin-10-carboxamide):

[0375] (1R,2R,5S)-8- prepared according to Example 46 in methanol (1 mL) (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]triazocin-10-carboxamide (0.008 g, 0.0144 mmol, 1 equivalent) solution, platinum(IV) oxide (0.0003 g, 0.0014 equivalent, 0.1 equivalent) was added. The reaction mixture was evacuated, refilled with hydrogen gas (2×), sparged with hydrogen gas for 5 minutes, and stirred for 1 hour under a hydrogen balloon atmosphere. The reaction mixture was filtered, concentrated, and purified by preparative HPLC eluting with 5 - 100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 minutes (column, Gemini 10μ C18 110A, AXI / ; 250×21.2 mm). 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]triazocin-10-carboxamide. MS (m / z) 467.07 [M+H] + . 1 1H NMR (400 MHz, DMSO-d 6)δ 10.37 (t, J = 5.9 Hz, 1H), 8.25 (s, 1H), 7.20 (t, J = 8.6 Hz, 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 = 6.7 Hz, 3H). 19 19F NMR (376 MHz, DMSO-d 6 )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]triazocin-10-carboxamide (C48):

Chemical Structure

[0376] In THF (3 mL) and DMF (0.15 mL), (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 prepared according to Example 46 (0.150 g, 0.293 mmol, 1 equivalent), (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(PPh 3 ) 4To a solution of [[ID=]], methyl (2-methylbut-3-en-2-yl) carbonate (0.0633 g, 0.439 mmol, 1.5 equiv) was added. The reaction mixture was heated at 60 °C for 2 h and concentrated. The residue was purified by column chromatography (0 - 100% EtOAc / hexane) to afford pure fractions which were 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]triazocin-10-carboxamide:

[0377] To a solution of [[ID=]] (0.019 g, 0.033 mmol, 1 equiv) in 1,2-dichloroethane (1 mL), Hoveyda-Grubbs II catalyst (0.004 g, 0.006 mmol, 0.2 equiv) was added. The reaction mixture was sparged with Ar(g) for 10 min and heated at 75 °C for 18 h. The mixture was concentrated and purified by column chromatography (0 - 100% EtOAc / hexane) to afford (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]triazocin-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]triazocin-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]triazocin-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 eluting with 5 - 100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 min (column, Gemini 10μ C18 110A, AXI / ; 250×21.2 mm). 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]triazocin-10-carboxamide. MS (m / z) 463.10 [M+H] + 。 1 H NMR (400 MHz, DMSO-d 6 ) δ 10.33 (t, J = 5.7 Hz, 1H), 8.25 (s, 1H), 7.23 - 7.17 (m, 2H), 5.41 (td, J = 11.8, 11.3, 2.9 Hz, 1H), 5.33 (dd, J = 12.4, 2.0 Hz, 1H), 5.29 - 5.18 (m, 1H), 5.06 - 4.98 (m, 1H), 4.72 (d, J = 14.5 Hz, 1H), 4.56 (d, J = 5.6 Hz, 2H), 1.49 (s, 3H), 1.28 (d, J = 7.2 Hz, 3H), 0.93 (s, 3H). 19 F NMR (376 MHz, DMSO-d 6 ) δ -109.19 (ddd, J = 15.6, 9.3, 6.3 Hz), -112.52 (q, J = 7. 3, 5.9 Hz). 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) [Chemical formula] 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, 3-buten-2-ol (1.59 g, 22.1 mmol) and triphenylphosphine (5.79 g, 22.1 mmol) were added. Then, diisopropyl azodicarboxylate (4.46 g, 22.1 mmol) was added dropwise. The resulting mixture was stirred at 0 °C for 5 minutes, then removed from the cold bath and stirred at room temperature for 2 hours. The reaction mixture was mixed with silica gel, concentrated and purified by normal phase chromatography. LCMS-ESI+(m / z): Calculated value of H+ for C31H33F2N3O7, theoretical value: 597.23, measured value: 597.88. Step 2: Synthesis of 3-benzyloxy-1-[tert-butoxycarbonyl(1-methylallyl)amino]-5-[(2,4-difluorophenyl)methylcarbamoyl]-4-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 at 60 °C for 6 hours. Then, the reaction was cooled to room temperature, concentrated, the residue was diluted with EtOAc, 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 Used. LCMS-ESI+(m / z): Calculated for H+ of 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, (2R)-2-aminobut-3-en-1-ol (1.57 g, 18.0 mmol) was added, 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 hour. Then, the reaction was diluted with DCM, washed with 10% citric acid and brine, dried over sodium sulfate, filtered, and concentrated, and used directly in the next step. LCMS-ESI+(m / z): Calculated for H+ of 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 4 N HCl in 1,4-dioxane (70 mL) for 1 h at room temperature. The reaction mixture was concentrated, diluted with EtOAc, basified slowly with saturated sodium bicarbonate until effervescence ceased, and then solid sodium bicarbonate was added to saturate the aqueous layer. It was extracted with EtOAc, the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to give a brownish oil. The product obtained was used directly in the next step. LCMS-ESI+(m / z): calculated for H+ of C29H30F2N4O5, theoretical value: 552.22, measured value: 553.09. Step 5: Synthesis of 5-benzyloxy-N-[(2,4-difluorophenyl)methyl]-3-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide:

[0383] 3-Benzyloxy-N5-[(2,4-difluorophenyl)methyl]-N2-[(1R)-1-(hydroxymethyl)allyl]-1-(1-methylallylamino)-4-oxo-pyridine-2,5-dicarboxamide (1.57 g, 2.84 mmol) was dispensed at room temperature into a mixture of DCE (5.3 mL) and acetonitrile (5.3 mL), and paraformaldehyde (224 mg) was added. The resulting mixture was then heated to 88 °C, and a mixture of AcOH (0.79 mL) and TFA (0.79 mL) was added rapidly all at once. 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 and 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 hours, 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): calculated for H+ of C30H30F2N4O5, theoretical: 564.22, found: 565.02. Step 6: Synthesis 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:

[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 mixture was removed from the cold bath and stirred overnight at ambient temperature. The reaction mixture was then cooled to 0 °C and quenched with saturated sodium bicarbonate. Additional sodium bicarbonate powder was added to saturate the mixture. The reaction mixture was extracted with DCM, washed with brine, dried over sodium sulfate, filtered, concentrated, and purified by normal phase chromatography. LCMS-ESI+(m / z): calculated for H+ of C30H29F3N4O4, theoretical value: 566.21, observed value: 566.99. Step 7: Synthesis of (1S,10R,13R)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-(fluoromethyl)-13-methyl-5,8-dioxo-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide:

[0385] A solution of 5-benzyloxy-N-[(2,4-difluorophenyl)methyl]-3-[(1R)-1-(fluoromethyl)allyl]-1-(1-methylallyl)-4,6-dioxo-2H-pyrido[2,1-f][1,2,4]triazine-7-carboxamide (370 mg, 0.65 mmol) in DCE (9 mL) at room temperature was sparged with argon. Hoveyda-Grubbs II catalyst HG-M720 (41 mg, 0.065 mmol) was added. The mixture was sparged with argon for an additional 5 minutes and then sealed and heated at 80 °C overnight under a nitrogen balloon. The reaction mixture was then cooled to room temperature, concentrated, and purified by normal phase chromatography. 11H NMR (400 MHz, CDCl3) δ 10.38 (t, J = 6.0 Hz, 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, 2.3 Hz, 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): Calculated for H+ of C28H25F3N4O4, theoretical value: 538.18, measured value: 539.09. Step 8: Synthesis of (1S,10R,13R)-N-[(2,4-difluorophenyl)methyl]-10-(fluoromethyl)-6-hydroxy-13-methyl-5,8-dioxo-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide:

[0386] (1S,10R,13R)-6-Benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-(fluoromethyl)-13-methyl-5,8-dioxo-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide (20 mg, 0.037 mmol) was treated with a mixture of DCM (1.5 mL) and TFA (1.5 mL) at room temperature for 2 hours. The reaction was concentrated, redissolved in DMF, and purified by reverse-phase preparative HPLC. The absolute configuration at C13 was not confirmed. 1 1H 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, 2.3 Hz, 1H), 5.66 - 5.59 (m, 1H), 5.54 - 5.41 (m, 1H), 5.13 (d, J = 14.5 Hz, 1H), 4.80 - 4.55 (m, 5H), 3.87 (dp, J = 10.1, 3.4 Hz, 1H), 1.37 (d, J = 6.7 Hz, 3H). LCMS-ESI+ (m / z): Calculated H+ 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, the reaction mixture was degassed, flushed with nitrogen three times, then degassed again and flushed with hydrogen three times, and then hydrogenated under a hydrogen balloon for 1 hour. The reaction mixture was then degassed, flushed with nitrogen, filtered through celite, concentrated, and purified by reverse-phase preparative HPLC. The absolute configuration at C13 was not confirmed. 1 H NMR (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): Calculated H+ value for C21H21F3N4O4, Theoretical value: 450.15, Measured value: 451.12. Example 50: Preparation of (1S,2R,5R)-5-(fluoromethyl)-8-hydroxy-2-methyl-7,9-dioxo-N-(2,4,6-trifluorobenzyl)-2,5,7,9-tetrahydro-1,6-methanopyrido[1,2-b][1,2,5]triazocin-10-carboxamide (C50)

Chem.

Chem.

[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 Ph 3 P (7.0 g, 26.7 mmol). Then, DIAD (5.4 g, 26.7 mmol) was added dropwise over 5 minutes. The resulting reaction mixture was stirred at 0 °C for 5 minutes and then warmed to room temperature. The reaction was stirred at room temperature overnight. The solvent was removed under vacuum, and the resulting crude material was purified by silica gel column to obtain 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] 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 to an aqueous solution of LiOH (2.5 N) (43 ml, 107 mmol). The reaction mixture was heated at 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 additional EtOAc. The combined organic phases were washed with water and brine, dried over Na 2 SO 4 and 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] To 3-benzyloxy-1-[tert-butoxycarbonyl( 1-methylallyl)amino]-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyridine-2-carboxylic acid (11.2 g, 18.6 mmol) in DMF (50 ml) was added DIEA (16.2 ml, 93.1 mmol), followed by HATU (9.2 g, 24.2 mmol). The reaction mixture was stirred at room temperature for 1 h, then (2R)-2-aminobut-3-en-1-ol, hydrochloride (2.9 g, 24.2 mmol) was added to the reaction mixture. After 2 h, the reaction mixture was diluted with EtOAc and washed with an aqueous solution of LiCl. The aqueous layer was extracted with EtOAc (1×). The combined organic phases were washed with water (1×). The organic phase was dried over MgSO 4 and concentrated to give a 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 h. LCMS indicated that the reaction was complete. Therefore, the reaction mixture was then concentrated to dryness. The residue was then partitioned between EtOAc and an aqueous solution of NaHCO 3 3. The aqueous layer was extracted with EtOAc. The combined organic phases were 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, bromomethylbenzene was added.

[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 CAN (5 mL) and DCE (5 mL) in a 20 mL microwave reaction vial, paraformaldehyde (93.1 mg, 3.04 mmol) and AcOH (0.5 mL) were added, followed by TFA (0.5 mL). After addition, the vial 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 under vacuum to obtain the crude material of the title compound, and the crude product was carried on 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, bromomethylbenzene (XX-5) (2.08 g, 12.2 mmol) was added, 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 dried over MgSO4 and the solvent was removed under vacuum to obtain the crude material. MS (m / z) 625 [M+H] + . Synthesis of 5 - Benzyloxy - 3 - [(1R)-1-(hydroxymethyl)allyl]-1-(1 - methylallyl)-4,6 - dioxo - N - [(2,4,6 - trifluorophenyl)methyl]-2H - pyrido[2,1 - f][1,2,4]triazine - 7 - carboxamide:

[0394] To the 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 indicated that the reaction was complete. The solvent was removed under vacuum, and the resulting residue was diluted in EtOAc and washed with H 2 O. The organic layer was dried over MgSO 4 and concentrated under vacuum. The obtained 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] At 0 °C, Deoxo - Fluor in toluene (2.7 N) (5.21 ml, 14.1 mmol) was added 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). Then the mixture was slowly warmed to room temperature and stirred overnight. The reaction mixture was added to ice - cold NaHCO 3 and then extracted with DCM. The DCM phase was dried over MgSO 4It was dried and the crude product was purified by a silica gel column to obtain the title compound. MS (m / z) 585.03 [M+H] + 。 (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 synthesis:

[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 (3×) at room temperature. Then, catalyst HG-II was added into the solution, and it was flushed with argon for 1.5 hours using an aeration needle at 80 °C. Thereafter, the aeration needle was removed, and the reaction mixture was stirred overnight at 80 °C using an argon balloon. LCMS indicated a complete reaction. The solvent was removed under vacuum, and the obtained residue was purified by a silica gel column to obtain the title compound (XX-9). MS (m / z) 556.94 [M+H] + 。 (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]triazocin-10-carboxamide (C50) synthesis:

[0397] (1S,10R,13R)-6-Benzyloxy-10-(f (1S,10R,13R)-6-Benzyloxy-10-(fluoromethyl)-13-methyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-1,2,9-triazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide (from Example 50) (520 mg, 0.93 mmol) was dissolved in EtOH (100 ml), and then Pd / C (10 wt%) (7.8 mg, 0.09 mmol) was added. The mixture was then evacuated and H + . 1 H NMR (400 MHz, chloroform-d) δ 10.19 (s, 1H), 8.57 (s, 1H), 6.75 - 6.68 (m, 3H), 5.88 (dt, J = 11.4, 2.3 Hz, 1H), 5.65 (dt, J = 11.4, 3.5 Hz, 1H), 5.49 (dd, J = 32.6, 3.1 Hz, 1H), 5.26 (d, J = 14.6 Hz, 1H), 4.84 (dd, J = 9.9, 3.3 Hz, 1H), 4.77 - 4.66 (m, 3H), 4.67 - 4.55 (m, 2H), 3.80 (dq, J = 6.7, 3.4 Hz, 1H), 1.43 (d, J = 6.7 Hz, 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]triazocin-10-carboxamide (C51) [Chemical formula]

[0398] (1S,2R,5R)-5-(Fluoromethyl)-8-hydroxy-2-methyl-7,9-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 treated with TFA (2 ml), and the reaction mixture was stirred at room temperature overnight. LCMS indicated complete reaction. The solvent was removed under vacuum, and the resulting material was purified by preparative HPLC to afford the title compound (51). MS (m / z) 467 [M + H]2 It was refilled three times at [conditions]. The reactants were H 2 and stirred for 2 hours under [conditions]. LCMS indicated a complete reaction. The reaction mixture was filtered through celite to remove Pd / C, and the solvent was removed under vacuum. The obtained crude material was purified by preparative HPLC to obtain the title compound (XX). MS (m / z) 469.11 [M+H] + 1H NMR (400 MHz, Chloroform-d) δ 10.37 (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 = 7.1 Hz, 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]triazocin-10-carboxamide (C52):

Chemical formula

[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]triazocin-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 for 1 day under an oxygen balloon. 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 MgSO 4 and filtered, concentrated, and the residue was purified by silica gel chromatography eluting with 0 - 100% hexane / 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]triazocin-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]triazocin-10-carboxamide (20 mg, 0.037 mmol) in DCM (2 mL) was added a solution of deoxofluor in toluene (50%, 0.041 mL, 0.11 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 15 minutes and the reaction was quenched by adding saturated NaHCO 3 solution. The mixture was extracted with DCM, the organic phase was separated, dried over MgSO 4It was dried, filtered, concentrated, and purified by silica gel chromatography (eluting with 0 - 100% hexane / EtOAc) to obtain 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]triazocin-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]triazocin-10-carboxamide (13 mg, 0.024 mmol) in DCM (1 mL) was added TFA (1 mL). The reaction mixture 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 obtain the title compound. MS (m / z) 451.12 [M...

Claims

[Claim 1] The invention described in the specification.

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