Bridged tricyclic carbamoylpyridone compounds and uses thereof

Abstract

Disclosed is a compound for use in the treatment or prevention of human immunodeficiency virus (HIV) infection. The compound has the following formula (I): TIFF2023543059000115.tif3458, including stereoisomers and pharmaceutically acceptable salts thereof. Methods related to the preparation and use of the disclosed compounds, as well as pharmaceutical compositions containing such compounds, are also disclosed. In some embodiments, the disclosure provides a kit comprising a compound of Formula I or a pharmaceutically acceptable salt thereof and instructions for use. In some embodiments, the disclosure provides a method of treating an HIV infection in a human having or at risk of having such an infection, comprising administering to the human a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims priority to U.S. Provisional Patent Application No. 63 / 085,704, filed September 30, 2020, which is incorporated herein in its entirety for all purposes.

[0002] FIELD OF THE INVENTION FIELD OF THE DISCLOSURE The present disclosure relates generally to certain tricyclic compounds, pharmaceutical compositions containing such compounds, and methods of making and using such compounds and pharmaceutical compositions. [Background technology]

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

[0004] The goal of antiretroviral therapy is to achieve viral suppression in HIV-infected patients. Current treatment guidelines published by the United States Department of Health and Human Services suggest that achieving viral suppression requires the use of combination therapy, i.e., the use of several drugs from at least two or more drug classes (Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. Available at https: / / files.aidsinfo.nih.gov / contentfiles / lvguidelines / AdultandAdolescentGL.pdf, accessed February 20, 2020). Furthermore, treatment decisions for HIV-infected patients are complicated when patients require treatment for other medical conditions. Because standard treatment requires the use of multiple different drugs to suppress HIV and treat other conditions the patient may experience, the potential for drug interactions is a criterion for selecting a drug regimen. Therefore, there is a need for antiretroviral therapy with a reduced potential for drug interactions.

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

[0006] [Non-Patent Document 1] Palella, et al. N. Engl. J Med. (1998) 338:853-860 [Non-patent document 2] Richman, DDNature (2001) 410:995-1001 [Non-patent document 3] 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 [Non-patent document 4] Tang,et al.Drugs(2012)72(9)e1-e25 [Non-Patent Document 5] Hurt, et al.HIV / AIDS CID(2014)58,423-431 Summary of the Invention [Means for solving the problem]

[0007] In some embodiments, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is C 6~10 aryl or 5- to 10-membered heteroaryl, C 6~10 The aryl or 5- to 10-membered heteroaryl is 1 to 4 R A1 and each R A1 independently, halo, C 1~6 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkyl-OC 1~4 is alkyl, R 2 is H, C 1~6 Alkyl or C 1~4 is haloalkyl, R 3 is halo or -OR 3a and R 3a -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 3~6 cycloalkyl, or R 3a and R 2 , R 5a , and R 6a any one of these, taken together with the carbon to which they are attached, forms a 4- to 6-membered heterocycle containing 1 or 2 heteroatoms independently selected from N, O, and S; R 3b -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 1~4 Alkylene-OC 1~4 is alkyl, R 4a -C 1~6 Alkyl or -C 1~4 is haloalkyl, R 4bH, halo, -C 1~6 Alkyl or -C 1~4 is haloalkyl, W 1 is a bond or -CR 5a R 5b - and R 5a and R 5b are independently H, C 1~6 Alkyl, C 1~4 haloalkyl or halo; or R 5a and R 3a together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 5b But H, C 1~6 Alkyl, C 1~4 haloalkyl or halo, W 2 But, -CR 6a R 6b -or-CR 7a =CR 7b - and R 6a and R 6b are independently H, C 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkylene-OC 1~4 alkyl, or R 6a and R 3a together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 6b But H, C 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkylene-OC 1~4 is alkyl, R 7a and R 7b are independently H, halo, and C 1~4Haloalkyl, or C 1~6 alkyl, or R 7a and R 7b However, together with the carbon to which they are attached, they form 1 to 4 R A2 C optionally replaced with 5~10 Form an aryl, and each R A2 are independently halo, cyano, or C 1~4 It is alkyl.

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

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

[0010] In some embodiments, the present disclosure provides a method of treating an HIV infection in a human having or at risk of having such an infection, comprising administering to the human a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

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

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

[0013] In some embodiments, the present disclosure provides the use of a compound of formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating HIV infection.

[0014] In some embodiments, the disclosure provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating an HIV infection in a human having or at risk of having such infection. DETAILED DESCRIPTION OF THE INVENTION

[0015] In the following description, certain specific details are set forth to provide a thorough understanding of the various embodiments disclosed herein. However, those skilled in the art will understand that the embodiments disclosed herein may be practiced without these details. The following description of several embodiments is made with the understanding that the disclosure should be considered as an illustration of the claimed subject matter and is not intended to limit the scope of the appended claims to the specific embodiments illustrated. Headings used throughout this disclosure are provided for convenience only and should not be construed in any way as limiting the scope of the claims. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading. I. Definition

[0016] Unless the context requires otherwise, throughout this specification and claims, the word "comprise" and variations thereof, such as "comprises" or "comprising," are to be interpreted in an open and inclusive sense, i.e., "including but not limited to."

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

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

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

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

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

[0022] "Alkyl" is saturated and has 1 to 12 carbon atoms (C 1~12 alkyl), and in certain embodiments, have 1 to 8 carbon atoms (C 1~8 alkyl), having 1 to 6 carbon atoms (C 1~6 alkyl), having 1 to 4 carbon atoms (C 1~4 alkyl), or having 1 to 3 carbon atoms (C 1~3 Alkyl) refers to a straight or branched chain hydrocarbon radical consisting of carbon and hydrogen atoms attached to the rest of the molecule by a single bond, such as methyl, ethyl, n-propyl, 1-methylethyl (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 or straight-chain, or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For example, an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkylene radicals include, but are not limited to, methylene (-CH-), 1,1-ethyl (-CH(CH)-), 1,2-ethyl (-CHCH-), 1,1-propyl (-CH(CHCH)-), 1,2-propyl (-CHCH(CH)-), 1,3-propyl (-CHCHCHCH-), 1,4-butyl (-CHCHCHCHCH-), and the like.

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

[0025] "Cyano" refers to a carbonitrile group (-CN).

[0026] "Cycloalkyl" refers to saturated or partially saturated cyclic alkyl groups having single or multiple rings, including fused, bridged, and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl groups (i.e., cyclic groups having at least one double bond). As used herein, cycloalkyl refers to groups having 3 to 20 ring carbon atoms (i.e., C 3~20 cycloalkyl) and having 3 to 12 ring carbon atoms (i.e., C3~12 cycloalkyl) and having 3 to 10 ring carbon atoms (i.e., C 3~10 cycloalkyl) and having 3 to 8 ring carbon atoms (i.e., C 3~8 cycloalkyl), or having 3 to 6 ring carbon atoms (i.e., C 3~6 Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

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

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

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

[0030] "Heterocycle" refers to a non-aromatic radical or ring having 3 to 15 atoms, of which 1 to 6 atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur and attached to the remainder of the molecule by single bonds. In certain embodiments, a "heterocyclyl" has 3 to 10 atoms, of which 1 to 4 atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or 3 to 7 atoms, of which 1 to 2 atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen, carbon, or sulfur atom in a heterocyclyl may be optionally oxidized, and the nitrogen atom may be optionally quaternized. As used herein, heterocycle refers to a saturated or partially saturated ring. Examples of such heterocycles 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. The term includes groups having a single ring or multiple rings, including fused, bridged, and spiro ring systems.

[0031] The embodiments disclosed herein are also meant to encompass all pharmaceutically acceptable compounds of Formula I that are isotopically labeled by replacing one or more atoms with atoms having a different atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, for example, 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31 P, 32 P,35 S, 18 F, 36 Cl, 123 I, and 125 In certain embodiments, these radiolabeled compounds are useful for determining or measuring the efficacy of compounds, for example, by characterizing the site or mode of action or binding affinity to a pharmacologically important site of action. Certain isotopically labeled compounds of Formula I, Ia, Ib, Ic, Id, or II, for example, those incorporating a radioactive isotope, are useful in drug and / or substrate tissue distribution studies. The radioactive isotope tritium, i.e., 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose because of their ease of incorporation and facile means of detection.

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

[0033] Substitution with positron-emitting isotopes, e.g. 11 C. 18 F, 15 O, and 13 N may be useful in Positron Emission Topography (PET) studies to examine substrate receptor occupancy. Isotopically labeled compounds of Formula I, Ia, Ib, Ic, Id, or II can be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the Examples below, using the appropriate isotopically labeled reagent in place of the previously used non-labeled reagent.

[0034] The methods, compositions, kits, and articles of manufacture provided herein employ or include compounds (e.g., compounds of Formula I, Ia, Ib, Ic, Id, or II) or pharmaceutically acceptable salts thereof, wherein 1 to n hydrogen atoms bonded to a carbon atom (where n is the number of hydrogen atoms in the molecule) may be replaced by deuterium atoms or D. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds have increased resistance to metabolism and are therefore useful for increasing the half-life of the compound or its pharmaceutically acceptable salt when administered to a mammal. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends Pharmacol. Sci., 5(12):524-527 (1984). Such compounds can be synthesized by means known in the art, for example, by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

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

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

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

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

[0039] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include alkali metal (e.g., sodium), alkaline earth metal (e.g., magnesium), ammonium, and NX4 salts. + (Wherein, X is C 1~4Pharmaceutically acceptable salts of a nitrogen atom or amino group include, for example, salts derived from appropriate bases such as acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, butyric acid, camphoric acid, cinnamic acid, citric acid, digluconic acid, glutamic acid, glycolic acid, glycerophosphoric acid, formic acid, hexanoic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, hydroxymaleic acid, malonic acid, malic acid, mandelic acid, isethionic acid, lactobionic acid, nicotinic acid, oxalic acid, pamoic acid, pectic acid, phenylacetic acid, 3-phenylpropionic acid, ... Pharmaceutically acceptable salts of hydroxy compounds include salts of organic carboxylic acids such as propionic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, sulfanilic acid, tartaric acid, undecanoic acid, and succinic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, mesitylenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and 2-naphthalenesulfonic acid; and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and sulfamic acid. + and NX4 + (X is H or C 1~4 The anions of the compounds include those in combination with suitable cations such as alkyl groups.

[0040] For therapeutic use, salts of the active ingredients of the compounds disclosed herein are typically pharmaceutically acceptable, i.e., salts derived from physiologically acceptable acids or bases. However, salts of acids or bases that are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of a compound of Formula I or another compound of an embodiment disclosed herein. All salts, whether derived from a physiologically acceptable acid or base, are within the scope of the embodiments disclosed herein.

[0041] Metal salts are typically prepared by reacting a metal hydroxide with a compound according to an embodiment disclosed herein. Examples of metal salts prepared in this manner include Li + , Na + , and K +A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.

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

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

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

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

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

[0047] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)-, or for amino acids, as (D)- or (L)-. The present disclosure is meant to encompass all such possible isomers, as well as their racemic, scalemic, and optically pure forms. Optically active (+)- and (−), (R)- and (S)-, or (D)- and (L)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using methods such as chromatography and fractional crystallization. Techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, these compounds are intended to include both E and Z geometric isomers, as well as all tautomeric forms.

[0048] "Stereoisomer" refers to a compound composed of the same atoms connected by the same bonds but with different, non-interchangeable three-dimensional structures. The present disclosure contemplates various stereoisomers and mixtures thereof, including "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another. In any of the embodiments disclosed herein, the compounds disclosed herein may be in the form of their stereoisomers.

[0049] "Partially unsaturated" refers to a cyclic group that contains at least one double bond but is not aromatic. II. Compounds

[0050] In some embodiments, the present disclosure provides a compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein: R 1 is C 6~10 aryl or 5- to 10-membered heteroaryl, C 6~10 The aryl or 5- to 10-membered heteroaryl is 1 to 4 R A1 and each R A1 independently, halo, C 1~6 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkyl-OC 1~4 is alkyl, R 2 is H, C 1~6 Alkyl or C 1~4 is haloalkyl, R 3 is halo or -OR 3a and R 3a -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 3~6 cycloalkyl, or R 3a and R 2 , R 5a , and R 6a any one of these, taken together with the carbon to which they are attached, forms a 4- to 6-membered heterocycle containing 1 or 2 heteroatoms independently selected from N, O, and S; R 3b -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 1~4 Alkylene-OC 1~4 is alkyl, R 4a -C 1~6 Alkyl or -C 1~4 is haloalkyl, R 4b H, halo, -C 1~6 Alkyl or -C 1~4is haloalkyl, W 1 is a bond or -CR 5a R 5b - and R 5a and R 5b are independently H, C 1~6 Alkyl, C 1~4 haloalkyl or halo; or R 5a and R 3a together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 5b But H, C 1~6 Alkyl, C 1~4 haloalkyl or halo, W 2 But, -CR 6a R 6b -or-CR 7a =CR 7b - and R 6a and R 6b are independently H, C 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkylene-OC 1~4 alkyl, or R 6a and R 3a together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 6b But H, C 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkylene-OC 1~4 is alkyl, R 7a and R 7b are independently H, halo, and C 1~4 Haloalkyl, or C 1~6 alkyl, or R 7a and R 7b However, together with the carbon to which they are attached, they form 1 to 4 R A2 C optionally replaced with 5~10 Form an aryl, and each R A2 are independently halo, cyano, or C 1~4 It is alkyl.

[0051] It is desirable to find a compound or its pharmaceutically acceptable salt that has good stability, i.e., physical stability, chemical stability, and / or metabolic stability. Increasing the overall stability of a compound can provide increased circulation time in the body. Less degradation allows a stable compound to be administered at a lower dose and still maintain efficacy. Also, less degradation means less concern about by-products from compound degradation. Higher drug stability means more drug is available to target cells without being metabolized.

[0052] It is further desirable to find a compound or its pharmaceutically acceptable salt with an improved pharmacokinetic and / or pharmacodynamic profile and a long half-life.It is advantageous for a drug to have a moderate or low clearance and a long half-life, because this can lead to good bioavailability and high systemic exposure.Reducing clearance and increasing the half-life of a compound can reduce the daily dose required for efficacy, thus resulting in a better efficacy and safety profile.Therefore, an improved pharmacokinetic and / or pharmacodynamic profile and a long half-life can provide better patient compliance.

[0053] As shown below, compounds of formula I provided herein contain (i) at least one oxygen attached at the "a" position or a halogen substitution at the "a" position (R 3 is halo or -OR 3a and (ii) at least one alkyl or haloalkyl substituent at the "b" position (R 4a -C 1~6Alkyl or -C 1~4 haloalkyl): [ka] It is characterized by:

[0054] Advantageously, certain compounds of Formula I provided herein exhibit improved stability, for example, compared to structurally related compounds lacking (i) at least one oxygen atom attached at the "a" position or a halogen substitution at the "a" position, and (ii) at least one alkyl or haloalkyl substituent at the "b" position. In some embodiments, compounds of Formula I provided herein exhibit improved metabolic stability, for example, compared to structurally related compounds lacking (i) at least one oxygen atom attached at the "a" position or a halogen substitution at the "a" position, and (ii) at least one alkyl or haloalkyl substituent at the "b" position. In some embodiments, the improved metabolic stability of compounds of Formula I provided herein results in reduced intrinsic clearance, for example, reduced intrinsic clearance in a human liver microsomal (HLM) assay.

[0055] In some embodiments, the compound of Formula I provided herein is a compound of Formula Ia: [ka]

[0056] In some embodiments, the compound of Formula I provided herein is a compound of Formula Ib: [ka]

[0057] In some embodiments, the compound of Formula I provided herein is a compound of Formula Ic: [ka]

[0058] In some embodiments, the compound of Formula I provided herein is a compound of Formula Id: [ka]

[0059] In some embodiments of the compound of Formula I, Ia, Ib, Ic, or Id, or a pharmaceutically acceptable salt thereof, R 1 is C 6~10 aryl or 5- to 10-membered heteroaryl, C 6~10 The aryl or 5- to 10-membered heteroaryl is 1 to 4 R A1 and each R A1 independently, halo, C 1~6 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkyl-OC 1~4 In some embodiments, R 1 is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, and the phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine may have one, two, three, or four R A1 and each R A1 independently, halo, C 1~6 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkyl-OC 1~4 In some embodiments, R 1 is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, one, two, three, or four R A1 and each R A1 independently, halo, C 1~4 Alkyl, C 1~4 Haloalkyl or -OC 1~4 In some embodiments, R 1 is one, two, three, or four RA1 phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine optionally substituted with A1 independently, halo, C 1~4 Alkyl or -OC 1~4 In some embodiments, R 1 is one, two, three, or four R A1 phenyl, pyridyl, pyridazine, pyrazine optionally substituted with A1 are independently halo or C 1~4 In some embodiments, R 1 is one, two, three, or four R A1 phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine optionally substituted with A1 are independently halo or -OC 1~4 In some embodiments, R 1 is one, two, three, or four R A1 phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine substituted with A1 is independently halogen. In some embodiments, R 1 is two or three R A1 phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine substituted with A1 is independently halogen. In some embodiments, R 1 is two or three R A1 phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine substituted with A1 is independently selected from chloro and fluoro.

[0060] In some embodiments of the compound of Formula I, Ia, Ib, Ic, or Id, or a pharmaceutically acceptable salt thereof, R 1 is phenyl or pyridyl, and the phenyl or pyridyl is selected from the group consisting of 1, 2, 3, or 4 R A1 and each R A1 independently, halo, C 1~6 Alkyl, C1~4 Haloalkyl, cyano, -OC 1~4 Alkyl or -C 1~4 Alkyl-OC 1~4 In some embodiments, R 1 is phenyl or pyridyl, and the phenyl or pyridyl is selected from the group consisting of 1, 2, 3, or 4 R A1 and each R A1 independently, halo, C 1~4 Alkyl, C 1~4 Haloalkyl or -OC 1~4 In some embodiments, R 1 is phenyl or pyridyl, and the phenyl or pyridyl is selected from the group consisting of 1, 2, 3, or 4 R A1 and each R A1 independently, halo, C 1~4 Alkyl or -OC 1~4 In some embodiments, R 1 is phenyl or pyridyl, and the phenyl or pyridyl is selected from the group consisting of 1, 2, 3, or 4 R A1 and each R A1 are independently halo or C 1~4 In some embodiments, R 1 is phenyl or pyridyl, and the phenyl or pyridyl is selected from the group consisting of 1, 2, 3, or 4 R A1 and each R A1 are independently halo or -OC 1~4 In some embodiments, R 1 is phenyl or pyridyl, and the phenyl or pyridyl is selected from the group consisting of 1, 2, 3, or 4 R A1 Each R is replaced by A1 is independently halogen. In some embodiments, R 1 is phenyl or pyridyl, and the phenyl or pyridyl is A1 Each R is replaced by A1 is independently halogen. In some embodiments, R 1is phenyl or pyridine, and the phenyl or pyridine has two or three R A1 Each R is replaced by A1 is independently selected from chloro and fluoro.

[0061] In some embodiments of the compound of Formula I, Ia, Ib, Ic, or Id, or a pharmaceutically acceptable salt thereof, R 1 is pyridyl, and pyridyl is a group having one, two, three, or four R A1 and each R A1 independently, halo, C 1~6 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl or -C 1~4 Alkyl-OC 1~4 In some embodiments, R 1 is pyridyl, and pyridyl is a group having one, two, three, or four R A1 and each R A1 independently, halo, C 1~4 Alkyl, C 1~4 Haloalkyl or -OC 1~4 In some embodiments, R 1 is pyridyl, and pyridyl is a group having one, two, three, or four R A1 and each R A1 independently, halo, C 1~4 Alkyl or -OC 1~4 In some embodiments, R 1 is pyridyl, and pyridyl is a group having one, two, three, or four R A1 and each R A1 are independently halo or C 1~4 In some embodiments, R 1 is pyridyl, and pyridyl is a group having one, two, three, or four R A1 and each R A1 are independently halo or -OC 1~4 In some embodiments, R 1is pyridyl, and pyridyl is a group having one, two, three, or four R A1 Each R is replaced by A1 is independently halogen. In some embodiments, R 1 is pyridyl, and pyridyl is a group having two or three R A1 Each R is replaced by A1 is independently halogen. In some embodiments, R 1 is pyridyl, and pyridyl is a group having two or three R A1 Each R is replaced by A1 is independently selected from chloro and fluoro.

[0062] In some embodiments of the compound of Formula I, Ia, Ib, Ic, or Id, or a pharmaceutically acceptable salt thereof, R 1 is phenyl, and phenyl may have one, two, three, or four R A1 and each R A1 independently, halo, C 1~6 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl or -C 1~4 Alkyl-OC 1~4 In some embodiments, R 1 is phenyl, and phenyl may have one, two, three, or four R A1 and each R A1 independently, halo, C 1~4 Alkyl, C 1~4 Haloalkyl or -OC 1~4 In some embodiments, R 1 is phenyl, and phenyl may have one, two, three, or four R A1 and each R A1 independently, halo, C 1~4 Alkyl or -OC 1~4 In some embodiments, R 1 is phenyl, and phenyl may have one, two, three, or four R A1 and each R A1are independently halo or C 1~4 In some embodiments, R 1 is phenyl, and phenyl may have one, two, three, or four R A1 and each R A1 are independently halo or -OC 1~4 In some embodiments, R 1 is phenyl, and phenyl may have one, two, three, or four R A1 Each R is replaced by A1 is independently halogen. In some embodiments, R 1 is phenyl, and the phenyl is selected from two or three R A1 Each R is replaced by A1 is independently halogen. In some embodiments, R 1 is phenyl, and the phenyl is selected from two or three R A1 Each R is replaced by A1 is independently selected from chloro and fluoro.

[0063] In some embodiments of the compound of Formula I, Ia, Ib, Ic, or Id, or a pharmaceutically acceptable salt thereof, R 1 teeth, [ka] is selected from the group consisting of:

[0064] In some embodiments, the compound of Formula I, Ia, Ib, Ic, or Id is a compound of Formula II: [ka] wherein n is 0, 1, 2, 3, or 4; and each R A1 independently, halo, C 1~6 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkyl-OC 1~4 It is alkyl.

[0065] In some embodiments of the compound of Formula II, n is 2, 3, or 4, and each R A1 independently, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, cyano, or -OC 1~4 In some embodiments, n is 2, 3, or 4, and each R A1 independently, halo, C 1~4 Alkyl, C 1~4 Haloalkyl or -OC 1~4 In some embodiments, n is 2, 3, or 4, and each R A1 independently, halo, C 1~4 Alkyl or -OC 1~4 In some embodiments, n is 2, 3, or 4, and each R A1 are independently halo or C 1~4 In some embodiments, n is 2, 3, or 4, and each R A1 are independently halo or -OC 1~4 In some embodiments, n is 2, 3, or 4, and each R A1 is independently halogen. In some embodiments, n is 2, 3, or 4, and each R A1 is independently selected from chloro and fluoro.

[0066] In some embodiments of the compound of Formula II, n is 2 or 3, and each R A1 independently, halo, C 1~4 Alkyl, C 1~4 Haloalkyl, cyano, or -OC 1~4 In some embodiments, n is 2 or 3, and each R A1 independently, halo, C 1~4 Alkyl, C 1~4 Haloalkyl or -OC 1~4 In some embodiments, n is 2 or 3, and each R A1 independently, halo, C 1~4 Alkyl or -OC 1~4In some embodiments, n is 2 or 3, and each R A1 are independently halo or C 1~4 In some embodiments, R is 2 or 3, and each R A1 are independently halo or -OC 1~4 In some embodiments, n is 2 or 3, and each R A1 is independently halogen. In some embodiments, n is 2 or 3 and each R A1 is independently selected from chloro and fluoro.

[0067] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 2 is H, C 1~6 Alkyl or C 1~4 In some embodiments, R 2 is H or C 1~6 In some embodiments, R 2 is H or C 1~4 In some embodiments, R 2 is C 1~6 Alkyl or C 1~4 In some embodiments, R2 is C1-3 alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is H.

[0068] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3 is halo. In some embodiments, R 3 is chloro.

[0069] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3 is OR 3a and R 3a -H, -C1~6 Alkyl, -C 1~4 Haloalkyl, or -C 3~6 is cycloalkyl, and R 3b -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 1~4 Alkylene-OC 1~4 In some embodiments, R 3a -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 3~6 is cycloalkyl, and R 3b -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 1~4 Alkylene-OC 1~4 In some embodiments, R 3a -C 1~6 Alkyl or -C 1~4 haloalkyl, and R 3b -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 1~4 Alkylene-OC 1~4 In some embodiments, R 3a -C 1~6 alkyl, and R 3b -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 1~4 Alkylene-OC 1~4 In some embodiments, R 3a is methyl or ethyl, and R 3b -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 1~4 Alkylene-OC 1~4 In some embodiments, R 3a is methyl and R 3b -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 1~4 Alkylene-OC 1~4It is alkyl.

[0070] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3 is OR 3a and R 3a -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 3~6 is cycloalkyl, and R 3b -H, -C 1~6 Alkyl or -C 1~4 In some embodiments, R 3a -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 3~6 is cycloalkyl, and R 3b -H, -C 1~6 Alkyl or -C 1~4 In some embodiments, R 3a -C 1~6 Alkyl or -C 1~4 haloalkyl, and R 3b -H, -C 1~6 Alkyl or -C 1~4 In some embodiments, R 3a -C 1~6 alkyl, and R 3b -H, -C 1~6 Alkyl or -C 1~4 In some embodiments, R 3a is methyl or ethyl, and R 3b -H, -C 1~6 Alkyl or -C 1~4 In some embodiments, R 3a is methyl and R 3b -H, -C 1~6 Alkyl or -C 1~4 It is haloalkyl.

[0071] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3 is OR 3a and R 3a -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 3~6 is cycloalkyl, and R 3b is H or -C 1~6 In some embodiments, R 3a -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 3~6 Cycloalkane and R 3b is H or -C 1~6 In some embodiments, R 3a -C 1~6 Alkyl or -C 1~4 HaloArchi is R 3b is H or -C 1~6 In some embodiments, R 3a -C 1~6 alkyl, and R 3b is H or -C 1~6 In some embodiments, R 3a is methyl or ethyl, and R 3b is H or -C 1~6 In some embodiments, R 3a is methyl and R 3b is H or -C 1~6 It is alkyl.

[0072] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3 is OR 3a and R 3a -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 3~6 Cycloalkane and R 3b is H or -C 1~3 In some embodiments, R3a -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 3~6 Cycloalkane and R 3b is H or -C 1~3 In some embodiments, R 3a -C 1~6 Alkyl or -C 1~4 HaloArchi is R 3b is H or -C 1~3 In some embodiments, R 3a -C 1~6 alkyl, and R 3b is H or -C 1~3 In some embodiments, R 3a is methyl or ethyl, and R 3b is H or -C 1~6 In some embodiments, R 3a is methyl and R 3b is H or -C 1~3 It is alkyl.

[0073] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3 is OR 3a and R 3a -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 3~6 Cycloalkane and R 3b is H or methyl. In some embodiments, R 3a -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 3~6 Cycloalkane and R 3b is H or methyl. In some embodiments, R 3a -C 1~6 Alkyl or -C 1~4 HaloArchi is R 3b is H or methyl. In some embodiments, R 3a -C 1~6Alki and R 3b is H or methyl. In some embodiments, R 3a is methyl or ethyl, and R 3b is H or methyl. In some embodiments, R 3a is methyl and R 3b is H or methyl.

[0074] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3 is OR 3a and R 3a -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 3~6 is cycloalkyl, and R 3b is H. In some embodiments, R 3a -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 3~6 is cycloalkyl, and R 3b is H. In some embodiments, R 3a -C 1~6 Alkyl or -C 1~4 haloalkyl, and R 3b is H. In some embodiments, R 3a -C 1~6 alkyl, and R 3b is H. In some embodiments, R 3a is methyl or ethyl, and R 3b is H. In some embodiments, R 3a is methyl and R 3b is H.

[0075] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3a and R 2 , R 5a and R 6aany one of R, ... 3b -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 1~4 Alkylene-OC 1~4 In some embodiments, R 3a and R 2 , R 5a and R 6a any one of R, ... 3b -H, -C 1~6 Alkyl or -C 1~4 In some embodiments, R 3a and R 2 , R 5a and R 6a any one of R, ... 3b is H or -C 1~6 In some embodiments, R 3a and R 2 , R 5a and R 6a any one of R, ... 3b is H or -C 1~3 In some embodiments, R 3a and R 2 , R 5a and R 6a any one of R, ... 3b is H or methyl. In some embodiments, R 3a and R2 , R 5a and R 6a any one of R, ... 3b is H.

[0076] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3a and R 2 , R 5a and R 6a any one of R together with the carbon to which it is attached forms a 4- to 6-membered heterocycle containing one oxygen atom; 3b -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 1~4 Alkylene-OC 1~4 In some embodiments, R 3a and R 2 , R 5a and R 6a any one of R together with the carbon to which it is attached forms a 4- to 6-membered heterocycle containing one oxygen atom; 3b -H, -C 1~6 Alkyl or -C 1~4 In some embodiments, R 3a and R 2 , R 5a and R 6a any one of R together with the carbon to which it is attached forms a 4- to 6-membered heterocycle containing one oxygen atom; 3b is H or -C 1~6 In some embodiments, R 3a and R 2 , R 5a and R 6a any one of R together with the carbon to which it is attached forms a 4- to 6-membered heterocycle containing one oxygen atom; 3b is H or -C 1~3 In some embodiments, R3a and R 2 , R 5a and R 6a any one of R together with the carbon to which it is attached forms a 4- to 6-membered heterocycle containing one oxygen atom; 3b is H or methyl. In some embodiments, R 3a and R 2 , R 5a and R 6a any one of R together with the carbon to which it is attached forms a 4- to 6-membered heterocycle containing one oxygen atom; 3b is H.

[0077] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3a and R 2 together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 3b -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 1~4 Alkylene-OC 1~4 In some embodiments, R 3a and R 2 together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 3b -H, -C 1~6 Alkyl or -C 1~4 In some embodiments, R 3a and R 2 together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 3b is H or -C 1~6 In some embodiments, R 3a and R 2together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 3b is H or -C 1~3 In some embodiments, R 3a and R 2 together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 3b is H or methyl. In some embodiments, R 3a and R 2 together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 3b is H.

[0078] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3a and R 2 together with the carbon to which they are attached form a 4- to 6-membered heterocycle containing one oxygen atom, and R 3b -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 1~4 Alkylene-OC 1~4 In some embodiments, R 3a and R 2 together with the carbon to which they are attached form a 4- to 6-membered heterocycle containing one oxygen atom, and R 3b -H, -C 1~6 Alkyl or -C 1~4 In some embodiments, R 3a and R 2 together with the carbon to which they are attached form a 4- to 6-membered heterocycle containing one oxygen atom, and R 3b is H or -C 1~6 In some embodiments, R 3a and R 2together with the carbon to which they are attached form a 4- to 6-membered heterocycle containing one oxygen atom, and R 3b is H or -C 1~3 In some embodiments, R 3a and R 2 together with the carbon to which they are attached form a 4- to 6-membered heterocycle containing one oxygen atom, and R 3b is H or methyl. In some embodiments, R 3a and R 2 together with the carbon to which they are attached form a 4- to 6-membered heterocycle containing one oxygen atom, and R 3b is H.

[0079] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, R 3a and R 5a together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 3b -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 1~4 Alkylene-OC 1~4 In some embodiments, R 3a and R 5a together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 3b -H, -C 1~6 Alkyl or -C 1~4 In some embodiments, R 3a and R 5a together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 3b is H or -C 1~6 In some embodiments, R 3a and R 5atogether with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 3b is H or -C 1~3 In some embodiments, R 3a and R 5a together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 3b is H methyl. In some embodiments, R 3a and R 5a together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 3b is H.

[0080] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3a and R 5a together with the carbon to which they are attached form a 4- to 6-membered heterocycle containing one oxygen atom, and R 3b -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 1~4 Alkylene-OC 1~4 In some embodiments, R 3a and R 5a together with the carbon to which they are attached form a 4- to 6-membered heterocycle containing one oxygen atom, and R 3b -H, -C 1~6 Alkyl or -C 1~4 In some embodiments, R 3a and R 5a together with the carbon to which they are attached form a 4- to 6-membered heterocycle containing one oxygen atom, and R 3b is H or -C 1~6 In some embodiments, R 3a and R 5atogether with the carbon to which they are attached form a 4- to 6-membered heterocycle containing one oxygen atom, and R 3b is H or -C 1~3 In some embodiments, R 3a and R 5a together with the carbon to which they are attached form a 4- to 6-membered heterocycle containing one oxygen atom, and R 3b is H or methyl. In some embodiments, R 3a and R 5a together with the carbon to which they are attached form a 4- to 6-membered heterocycle containing one oxygen atom, and R 3b is H.

[0081] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3a and R 6a together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 3b -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 1~4 Alkylene-OC 1~4 In some embodiments, R 3a and R 6a together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 3b -H, -C 1~6 Alkyl or -C 1~4 In some embodiments, R 3a and R 6a together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 3b is H or -C 1~6 In some embodiments, R 3a and R 6atogether with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 3b is H or -C 1~3 In some embodiments, R 3a and R 6a together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 3b is H or methyl. In some embodiments, R 3a and R 6a together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 3b is H.

[0082] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3a and R 6a together with the carbon to which they are attached form a 4- to 6-membered heterocycle containing one oxygen atom, and R 3b -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 1~4 Alkylene-OC 1~4 In some embodiments, R 3a and R 6a together with the carbon to which they are attached form a 4- to 6-membered heterocycle containing one oxygen atom, and R 3b -H, -C 1~6 Alkyl or -C 1~4 In some embodiments, R 3a and R 6a together with the carbon to which they are attached form a 4- to 6-membered heterocycle containing one oxygen atom, and R 3b is H or -C 1~6 In some embodiments, R 3a and R 6atogether with the carbon to which they are attached form a 4- to 6-membered heterocycle containing one oxygen atom, and R 3b is H or -C 1~3 In some embodiments, R 3a and R 6a together with the carbon to which they are attached form a 4- to 6-membered heterocycle containing one oxygen atom, and R 3b is H or methyl. In some embodiments, R 3a and R 6a together with the carbon to which they are attached form a 4- to 6-membered heterocycle containing one oxygen atom, and R 3b is H.

[0083] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 4a -C 1~6 Alkyl or -C 1~4 In some embodiments, R 4a -C 1~3 In some embodiments, R 4a is methyl. In some embodiments, R 4a -C 1~4 It is haloalkyl.

[0084] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 4b H, halo, -C 1~6 Alkyl or -C 1~4 In some embodiments, R 4b -H, -C 1~3 Alkyl or -C 1~4 In some embodiments, R 4b is H or C 1~3 In some embodiments, R 4b -C 1~3 Alkyl or -C 1~4 In some embodiments, R 4b -C1~3 In some embodiments, R 4b -C 1~4 In some embodiments, R 4b is H.

[0085] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 4a -C 1~6 Alkyl or -C 1~4 haloalkyl, and R 4b H, halo, -C 1~6 Alkyl or -C 1~4 In some embodiments, R 4a -C 1~6 Alkyl or -C 1~4 haloalkyl, and R 4b is H or C 1~3 In some embodiments, R 4a -C 1~6 Alkyl or -C 1~4 haloalkyl, and R 4b -C 1~3 Alkyl or -C 1~4 In some embodiments, R 4a -C 1~6 Alkyl or -C 1~4 haloalkyl, and R 4b -C 1~3 In some embodiments, R 4a -C 1~6 Alkyl or -C 1~4 haloalkyl, and R 4b -C 1~4 In some embodiments, R 4a -C 1~6 Alkyl or -C 1~4 haloalkyl, and R 4b is H.

[0086] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R4a -C 1~3 alkyl, and R 4b H, halo, -C 1~6 Alkyl or -C 1~4 In some embodiments, R 4a -C 1~3 alkyl, and R 4b -H, -C 1~3 Alkyl or -C 1~4 In some embodiments, R 4a -C 1~3 alkyl, and R 4b is H or C 1~3 In some embodiments, R 4a -C 1~3 alkyl, and R 4b -C 1~3 Alkyl or -C 1~4 In some embodiments, R 4a -C 1~3 alkyl, and R 4b -C 1~3 In some embodiments, R 4a -C 1~3 alkyl, and R 4b -C 1~4 In some embodiments, R 4a -C 1~3 alkyl, and R 4b is H.

[0087] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 4a is methyl and R 4b H, halo, -C 1~6 Alkyl or -C 1~4 In some embodiments, R 4a is methyl and R 4b -H, -C 1~3 Alkyl or -C 1~4 In some embodiments, R 4a is methyl and R4b is H or C 1~3 In some embodiments, R 4a is methyl and R 4b -C 1~3 Alkyl or -C 1~4 In some embodiments, R 4a is methyl and R 4b -C 1~3 In some embodiments, R 4a is methyl and R 4b -C 1~4 In some embodiments, R 4a is methyl and R 4b is H.

[0088] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 4a -C 1~4 haloalkyl, and R 4b H, halo, -C 1~6 Alkyl or -C 1~4 In some embodiments, R 4a -C 1~4 haloalkyl, and R 4b -H, -C 1~3 Alkyl or -C 1~4 In some embodiments, R 4a -C 1~4 haloalkyl, and R 4b is H or C 1~3 In some embodiments, R 4a -C 1~4 haloalkyl, and R 4b -C 1~3 Alkyl or -C 1~4 In some embodiments, R 4a -C 1~4 haloalkyl, and R 4b -C 1~3 In some embodiments, R 4a -C1~4 haloalkyl, and R 4b -C 1~4 In some embodiments, R 4a -C 1~4 haloalkyl, and R 4b is H.

[0089] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, W 1 is a bond.

[0090] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, W 1 -CR 5a R 5b - and R 5a and R 5b are independently H, C 1~6 Alkyl, C 1~4 haloalkyl, or halo. In some embodiments, R 5a is H, C 1~6 Alkyl, C 1~4 haloalkyl or halo, R 5b is H, C 1~6 In some embodiments, R 5a is H, C 1~6 Alkyl, C 1~4 haloalkyl or halo, R 5b is H or C 1~6 In some embodiments, R 5a is H, C 1~6 Alkyl, C 1~4 haloalkyl or halo, R 5b is C 1~6 In some embodiments, R 5a is H, C 1~6 Alkyl, C 1~4 haloalkyl or halo, R 5b is H.

[0091] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, W 1 -CR 5a R 5b - and R 5a is H, C 1~6 Alkyl or C 1~4 haloalkyl, and R 5b is H, C 1~6 Alkyl, C 1~4 haloalkyl, or halo. In some embodiments, R 5a is H, C 1~6 Alkyl or C 1~4 haloalkyl, and R 5b is H, C 1~6 In some embodiments, R 5a is H, C 1~6 Alkyl or C 1~4 haloalkyl, and R 5b is H or C 1~6 In some embodiments, R 5a is H, C 1~6 Alkyl or C 1~4 haloalkyl, and R 5b is C 1~6 In some embodiments, R 5a is H, C 1~6 Alkyl or C 1~4 haloalkyl, and R 5b is H.

[0092] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, W 1 -CR 5a R 5b - and R 5a is H or C 1~6 alkyl, and R 5b is H, C 1~6 Alkyl, C 1~4 haloalkyl, or halo. In some embodiments, R 5a is H or C 1~6 alkyl, and R 5b is H, C1~6 In some embodiments, R 5a is H or C 1~6 alkyl, and R 5b is H or C 1~6 In some embodiments, R 5a is H or C 1~6 It is Rukill and R 5b is C 1~6 In some embodiments, R 5a is H or C 1~6 It is Rukill and R 5b is H.

[0093] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, W 1 -CR 5a R 5b - and R 5a is C 1~6 alkyl, and R 5b is H, C 1~6 Alkyl, C 1~4 haloalkyl, or halo. In some embodiments, R 5a is C 1~6 alkyl, and R 5b is H, C 1~6 In some embodiments, R 5a is C 1~6 alkyl, and R 5b is H or C 1~6 In some embodiments, R 5a is C 1~6 alkyl, and R 5b is C 1~6 In some embodiments, R 5a is C 1~6 alkyl, and R 5b is H.

[0094] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, W 1 -CR 5a R5b - and R 5a is H and R 5b is H, C 1~6 Alkyl, C 1~4 haloalkyl, or halo. In some embodiments, R 5a is H and R 5b is H, C 1~6 In some embodiments, R 5a is H and R 5b is H or C 1~6 In some embodiments, R 5a is H and R 5b is C 1~6 In some embodiments, R 5a is H and R 5b is H.

[0095] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, W 2 -CR 6a R 6b - and R 6a and R 6b are independently H, C 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkylene-OC 1~4 In some embodiments, R 6a and R 6b are independently H, C 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, or -OC 1~4 In some embodiments, R 6a and R 6b are independently H, C 1~6 Alkyl, C 1~4 haloalkyl, halo, hydroxyl, or cyano. In some embodiments, R 6a and R 6b are independently H, C 1~6 Alkyl, C1~4 haloalkyl, halo, or hydroxyl. In some embodiments, R 6a and R 6b are independently H, C 1~6 Alkyl, C 1~4 haloalkyl, or halo. In some embodiments, R 6a and R 6b are independently H, C 1~6 Alkyl or C 1~4 In some embodiments, R 6a and R 6b are independently H or C 1~6 In some embodiments, R 6a and R 6b are both H.

[0096] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, W 2 -CR 6a R 6b - and R 6a is H and R 6b is H, C 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkylene-OC 1~4 In some embodiments, R 6a is H and R 6b is H, C 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, or -OC 1~4 In some embodiments, R 6a is H and R 6b is H, C 1~6 Alkyl, C 1~4 haloalkyl, halo, hydroxyl, or cyano. In some embodiments, R 6a is H and R 6b is H, C 1~6 Alkyl, C 1~4haloalkyl, halo, or hydroxyl. In some embodiments, R 6a is H and R 6b is H, C 1~6 Alkyl, C 1~4 haloalkyl, or halo. In some embodiments, R 6a is H and R 6b is H, C 1~6 Alkyl or C 1~4 In some embodiments, R 6a is H and R 6b is H or C 1~6 In some embodiments, R 6a is H and R 6b is H.

[0097] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, W 2 -CR 6a R 6b - and R 6a and R 3a together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 6b is H, C 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkylene-OC 1~4 In some embodiments, R 6a and R 3a together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 6b is H, C 1~6 Alkyl, C 1~4 haloalkyl, halo. In some embodiments, R 6a and R 3atogether with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S; R 6b is H.

[0098] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, W 2 -CR 6a R 6b - and R 6a and R 3a together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one heteroatom selected from N, O, and S; R 6b is H, C 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkylene-OC 1~4 In some embodiments, R 6a and R 3a together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one heteroatom selected from N, O, and S; R 6b is H, C 1~6 Alkyl, C 1~4 haloalkyl, halo. In some embodiments, R 6a and R 3a together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one heteroatom selected from N, O, and S; R 6b is H.

[0099] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, W 2 -CR 7a =CR 7b - and R 7a and R 7b are independently H, halo, and C 1~4 Haloalkyl, or C 1~6 alkyl, and R 7a and R7b together with the carbon to which they are attached, form 1 to 4 R A2 C optionally replaced with 5~10 Form an aryl, and each R A2 are independently halo, cyano, or C 1~4 In some embodiments, W is alkyl. 2 -CR 7a =CR 7b - and R 7a and R 7b are independently H, halo, and C 1~4 Haloalkyl, or C 1~6 In some embodiments, W is alkyl. 2 -CR 7a =CR 7b - and R 7a and R 7b are independently H, halo, or C 1~6 In some embodiments, W is alkyl. 2 -CR 7a =CR 7b - and R 7a and R 7b are independently H or C 1~6 In some embodiments, W is alkyl. 2 -CR 7a =CR 7b - and R 7a and R 7b are both H.

[0100] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, W 2 -CR 7a =CR 7b - and R 7a and R 7b together with the carbon atoms to which they are attached, form 1 to 4 R A2 C optionally replaced with 5~10 Form an aryl, and each R A2 are independently halo, cyano, or C 1~4 In some embodiments, R 7a and R 7btogether with the carbon atoms to which they are attached, form 1 to 4 R A2 wherein each R A4 are independently halo, cyano, or C 1~4 In some embodiments, R 7a and R 7b together with the carbon atom to which they are attached form an unsubstituted fused phenyl.

[0101] In some embodiments of the compound of Formula I, Ia, Ib, Ic, or Id, or a pharmaceutically acceptable salt thereof, R 1 is C 6~10 aryl, C 6~10 Aryl is 1 to 4 R A1 and each R A1 independently, halo, C 1~6 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkyl-OC 1~4 is alkyl, R 2 is H, C 1~6 Alkyl or C 1~4 is haloalkyl, R 3 is halo or -OR 3a and R 3a -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 3~6 is cycloalkyl, R 3b -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 1~4 Alkylene-OC 1~4 is alkyl, R 4a -C 1~6 Alkyl or -C 1~4 is haloalkyl, R 4b H, halo, -C 1~6 Alkyl or -C1~4 is haloalkyl, W 1 is a bond or -CR 5a R 5b - and R 5a and R 5b are independently H, C 1~6 Alkyl, C 1~4 haloalkyl or halo, W 2 But, -CR 6a R 6b -or-CR 7a =CR 7b - and R 6a and R 6b are independently H, C 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkylene-OC 1~4 is alkyl, R 7a and R 7b are independently H, halo, and C 1~4 Haloalkyl, or C 1~6 It is alkyl.

[0102] In some embodiments of the compound of Formula I, Ia, Ib, Ic, or Id, or a pharmaceutically acceptable salt thereof, R 1 is C 6~10 aryl, C 6~10 Aryl is 1 to 4 R A1 and each R A1 independently, halo, C 1~6 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkyl-OC 1~4 is alkyl, R 2 is H, C 1~6 Alkyl or C 1~4 is haloalkyl, R 3 -OR3a and R 3a -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 3~6 is cycloalkyl, R 3b -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 1~4 Alkylene-OC 1~4 is alkyl, R 4a -C 1~6 Alkyl or -C 1~4 is haloalkyl, R 4b H, halo, -C 1~6 Alkyl or -C 1~4 is haloalkyl, W 1 is a bond or -CR 5a R 5b - and R 5a and R 5b are independently H, C 1~6 Alkyl, C 1~4 haloalkyl or halo, W 2 But, -CR 6a R 6b -or-CR 7a =CR 7b - and R 6a and R 6b are independently H, C 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkylene-OC 1~4 is alkyl, R 7a and R 7b are independently H, halo, and C 1~4 Haloalkyl, or C 1~6 It is alkyl.

[0103] In some embodiments of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 1 is two, three, or four R A1 and each R A1 independently, halo, C 1~6 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkyl-OC 1~4 is alkyl, R 2 is H, C 1~6 Alkyl or C 1~4 is haloalkyl, R 3 -OR 3a and R 3a -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 3~6 is cycloalkyl, R 3b -H, -C 1~6 Alkyl, -C 1~4 Haloalkyl, or -C 1~4 Alkylene-OC 1~4 is alkyl, R 4a -C 1~6 Alkyl or -C 1~4 is haloalkyl, R 4b H, halo, -C 1~6 Alkyl or -C 1~4 is haloalkyl, W 1 is a bond or -CR 5a R 5b - and R 5a and R 5b are independently H, C 1~6 Alkyl, C 1~4 haloalkyl or halo, W 2 But, -CR 6a R 6b -or-CR 7a =CR7b - and R 6a and R 6b are independently H, C 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl or C 1~4 Alkylene-OC 1~4 is alkyl, R 7a and R 7b are independently H, halo, and C 1~4 Haloalkyl, or C 1~6 It is alkyl.

[0104] In some embodiments, the compound of formula I, Ia, Ib, Ic, Id, or II is [ka] is selected from the group consisting of:

[0105] In some embodiments, the compound of formula I, Ia, Ib, Ic, Id, or II is [ka] [ka] [ka] is selected from the group consisting of:

[0106] In some embodiments, the compound of Formula I, Ia, or II is [ka] is selected from the group consisting of:

[0107] In some embodiments, the compound of Formula I, Ic, or II is [ka] [ka] [ka] is selected from the group consisting of:

[0108] In some embodiments, the compound of formula I, Id, or II is [ka] is selected from the group consisting of:

[0109] In some embodiments, the compound of formula I is [ka] is.

[0110] In some embodiments, the compound of formula I is [ka] is.

[0111] In some embodiments, the compound of formula I is [ka] is.

[0112] In some embodiments, the compound of formula I is [ka] is.

[0113] In some embodiments, the compound of formula I is [ka] is.

[0114] In some embodiments, the compound of formula I is [ka] is.

[0115] In some embodiments, the compound of formula I is [ka] is.

[0116] In some embodiments, the compound of formula I is [ka] is.

[0117] In some embodiments, the compound of formula I is [ka] is.

[0118] In some embodiments, the compound of formula I is [ka] is. III. Compositions and Kits

[0119] The compounds provided herein are typically administered in the form of pharmaceutical compositions. Accordingly, pharmaceutical compositions comprising one or more of the compounds provided herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients are also provided herein. The compounds provided herein may be the sole active ingredient or one of the active ingredients of the pharmaceutical composition. Suitable pharmaceutically acceptable vehicles include, for example, inert solid diluents and fillers, diluents including sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical arts. For example, see Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0120] In one aspect, provided herein is a pharmaceutical composition comprising a compound provided herein (e.g., a compound of Formula I, Ia, Ib, Ic, Id, or II), 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.

[0121] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical compositions further comprise a therapeutically effective amount of one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents, or pharmaceutically acceptable salts thereof.

[0122] The pharmaceutical compositions may be administered in either a single dose or multiple doses. The pharmaceutical compositions may be administered by a variety of methods, including, for example, rectal, oral, intranasal, and transdermal routes. In some embodiments, the pharmaceutical compositions may be administered by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0123] One mode of administration is parenterally, e.g., by injection. Forms into which the pharmaceutical compositions described in this disclosure can be incorporated for administration by injection include, for example, aqueous or oily suspensions, or emulsions with sesame oil, corn oil, cottonseed oil, or peanut oil, or elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0124] Oral administration may be another route for administering the compounds provided herein. Administration may be, for example, via capsules or enteric-coated tablets. When preparing pharmaceutical compositions containing at least one compound provided herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, the active ingredient (such as a compound provided herein) is typically diluted with an excipient and / or enclosed within a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, the excipient may be in the form of a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the pharmaceutical composition may be in the form of a tablet, pill, powder, lozenge, sachet, cachet, elixir, suspension, emulsion, solution, syrup, aerosol (as a solid or in a liquid medium), for example, an ointment containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile-packaged powders.

[0125] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, microcrystalline cellulose, sterile water, syrup, and methylcellulose, or any combination thereof. The pharmaceutical composition may further include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners and flavoring agents; or any combination thereof.

[0126] Pharmaceutical compositions containing at least one compound described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof can be formulated to provide rapid, sustained, or delayed release of the active ingredient (such as the compounds provided herein) after administration to a subject using procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and solution-based systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled-release systems are provided in U.S. Patent Nos. 3,845,770, 4,326,525, 4,902,514, and 5,616,345. Another formulation for use in the methods of the present disclosure employs transdermal delivery devices ("patches"). Such transdermal patches can be used to provide continuous or discontinuous infusion of the compounds provided herein in controlled amounts. The construction and use of transdermal patches to deliver pharmaceutical agents is well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0127] To prepare solid compositions such as tablets, the primary active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof. When these preformulation compositions are referred to as homogeneous, the active ingredient may be dispersed evenly throughout the composition, so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0128] Tablets or pills of the compounds described herein may be coated or otherwise formulated to provide a dosage form that provides the advantage of prolonged action or to protect against the acidic conditions of the stomach. For example, the tablet or pill may comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components may be separated by an enteric layer that resists disintegration in the stomach and allows the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, including many polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0129] Pharmaceutical compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, as well as powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described above. In some embodiments, compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be atomized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from a device that delivers the formulation in an appropriate manner.

[0130] In one aspect, provided herein are kits that include a compound provided herein (e.g., a compound of Formula I, Ia, Ib, Ic, Id, or II), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and suitable packaging. In some embodiments, the kit further includes instructions for use. In some embodiments, the kit includes a compound provided herein (e.g., a compound of Formula I, Ia, Ib, Ic, Id, or II), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a label and / or instructions for use of the compound in treating an indication, including a disease or condition described herein.

[0131] In some embodiments, the kit further comprises one or more (e.g., 1, 2, 3, 4, 1 or 2, 1 to 3, or 1 to 4) additional therapeutic agents, or pharmaceutically acceptable salts thereof.

[0132] In one aspect, provided herein is an article of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, in a suitable container, hi some embodiments, the container may be a vial, jar, ampoule, pre-filled syringe, or infusion bag. IV. Method

[0133] In one embodiment, a method of treating an HIV (e.g., HIV-1 and / or HIV-2) infection in a human having or at risk of having such infection is provided, comprising administering a therapeutically effective amount of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof.

[0134] In some embodiments, the method further comprises administering to the human a therapeutically effective amount of one, two, three, or four additional therapeutic agents. In certain embodiments, the additional therapeutic agent is an anti-HIV agent. In certain embodiments, the additional therapeutic agent is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latency 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, N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, or a pharmaceutically acceptable salt thereof.

[0135] In another embodiment, there is provided the use of a compound of Formula I, Ia, Ib, Ic, Id or II or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, Ia, Ib, Ic, Id or II 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.

[0136] In another embodiment, there is provided a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, for use in medical therapy.

[0137] In another embodiment, there is provided a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, for use in the treatment of HIV infection.

[0138] In another embodiment, there is provided a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, for use in a method of treating an HIV infection in a human having, having, or at risk of having said infection.

[0139] In another embodiment, there is provided a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, for use in a method of treating an HIV infection in a human having or at risk of having said infection, the method further comprising administering to the human one, two, three, or four additional therapeutic agents.

[0140] In another embodiment, there is provided a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, for use in a method of treating an HIV infection in a human having or at risk of having such 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 latency reactivator, a capsid polymerization inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof. In one embodiment, the one, two, three, or four additional therapeutic agents are selected from an HIV protease inhibitor, an HIV non-nucleoside inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, a latent infection reactivator, an HIV capsid inhibitor, an HIV bNAb, a TLR7 agonist, and combinations thereof.

[0141] In another embodiment, there is provided a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, for use in a method of treating an HIV infection in a human having or at risk of having said infection, the method further comprising administering therapeutically effective amounts of tenofovir disoproxil and emtricitabine to the human.

[0142] In another embodiment, there is provided a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, for use in a method of treating an HIV infection in a human having or at risk of having such infection, the method further comprising administering therapeutically effective amounts of tenofovir alafenamide and emtricitabine to the human.

[0143] In another embodiment, there is provided a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, for use in a method of treating an HIV infection in a human having or at risk of having such infection, the method further comprising administering a therapeutically effective amount of tenofovir disoproxil to the human.

[0144] In another embodiment, there is provided a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, for use in a method of treating an HIV infection in a human having or at risk of having such infection, the method further comprising administering a therapeutically effective amount of tenofovir alafenamide to the human.

[0145] In another embodiment, methods of using a compound of Formula I, Ia, Ib, Ic, Id, or II in therapy are provided. In particular, methods are provided for treating HIV viral growth, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human), comprising administering to the mammal a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof.

[0146] In another embodiment, there is provided a composition comprising a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for use in a method of treating HIV viral growth, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human).

[0147] In one embodiment, a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, is provided for use in the prevention of HIV infection.

[0148] For example, in one embodiment, there is provided a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, for use in pre-exposure prophylaxis (PrEP), i.e., before an individual is exposed to the HIV virus, to prevent an HIV infection from becoming established when the individual is exposed to the virus, and / or to prevent the virus from establishing a permanent infection, and / or to prevent symptoms of the disease from appearing, and / or to prevent the virus from reaching detectable levels in the blood.

[0149] In another embodiment, disclosed is a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating an HIV infection in a human having or at risk of having such infection.

[0150] In another embodiment, the use of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, as a research tool is disclosed.

[0151] In another embodiment, an article of manufacture comprising a composition effective for treating HIV infection, and packaging material comprising a label indicating that the composition can be used to treat infection by HIV, is disclosed. Exemplary compositions comprise a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof.

[0152] In yet another embodiment, a method of inhibiting HIV replication is disclosed, comprising exposing the virus to an effective amount of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a salt thereof, under conditions such that HIV replication is inhibited.

[0153] In another embodiment, the use of a compound of Formula I, Ia, Ib, Ic, Id, or II to inhibit the activity of the HIV integrase enzyme is disclosed.

[0154] In another embodiment, the use of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a salt thereof, for inhibiting the replication of HIV is disclosed. V. Administration

[0155] The compounds of the present disclosure (also referred to herein as active ingredients) can be administered by any route appropriate to the condition being treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural), etc. It will be understood that the preferred route may vary depending, for example, on the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0156] The compounds of the present disclosure can be administered to an individual according to an effective dosing regimen for any desired period or duration, such as at least about 1 month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or more, in some embodiments, the compounds are administered on a daily or intermittent schedule for the duration of the individual's life.

[0157] The specific dose 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, dosages may be expressed as milligrams of a compound described herein per kilogram of subject body weight (mg / kg). Doses of about 0.1 to 150 mg / kg may be appropriate. In some embodiments, doses of about 0.1 and 100 mg / kg may be appropriate. In other embodiments, doses of 0.5 to 60 mg / kg may be appropriate. Normalizing by subject body weight is particularly useful when adjusting dosages between subjects of widely different sizes, such as occurs when using drugs in both pediatric and adult humans, or when converting effective dosages in non-human subjects, such as dogs, to dosages suitable for human subjects.

[0158] A daily dose may also be described as the total amount of a compound described herein administered per administration or per day. The daily dose of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof, may be about 1 mg to 4,000 mg, about 2,000 to 4,000 mg / day, about 1 to 2,000 mg / day, about 1 to 1,000 mg / day, about 10 to 500 mg / day, about 20 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 15 to 150 mg / day.

[0159] The dosage or frequency of administration of a compound of the present disclosure may be adjusted over the course of treatment, based on the judgment of the administering physician.

[0160] The compounds of the present disclosure can be administered to an individual (e.g., a human) in a therapeutically effective amount. In some embodiments, the compounds are administered once daily.

[0161] The compounds provided herein can be administered by any useful route and means, such as oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of a compound can include from about 0.00001 mg / kg body weight per day to about 10 mg / kg body weight per day, e.g., from about 0.0001 mg / kg body weight per day to about 10 mg / kg body weight per day, or from about 0.001 mg / kg body weight per day to about 1 mg / kg body weight per day, or from about 0.01 mg / kg body weight per day to about 1 mg / kg body weight per day, or from about 0.05 mg / kg body weight per day to about 0.5 mg / kg body weight per day. In some embodiments, a therapeutically effective amount of a compound provided herein can include from about 0.3 mg to about 30 mg per day, or from about 30 mg to about 300 mg per day, or from about 0.3 μg to about 30 mg per day, or from about 30 μg to about 300 μg per day.

[0162] The compounds of the present disclosure can be combined with one or more additional therapeutic agents at any dosage of the compound of the present disclosure (e.g., 1 mg to 1000 mg of compound). Therapeutically effective amounts may include from about 0.1 mg per dose to about 1000 mg per dose, such as from about 50 mg per dose to about 500 mg per dose, or from about 100 mg per dose to about 400 mg per dose, or from about 150 mg per dose to about 350 mg per dose, or from about 200 mg per dose to about 300 mg per dose, or from about 0.01 mg per dose to about 1000 mg per dose, or from about 0.01 mg per dose to about 100 mg per dose, or from about 0.1 mg per dose to about 100 mg per dose, or from about 1 mg per dose to about 100 mg per dose, or from about 1 mg per dose to about 10 mg per dose, or from about 1 mg per dose to about 1000 mg per dose. Other therapeutically effective amounts of a compound of Formula I, Ia, Ib, Ic, Id, or II are about 1 mg per dose, or about 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, or about 100 mg per dose. Other therapeutically effective amounts of compounds of the present disclosure are about 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, or about 1000 mg per dose.

[0163] In some embodiments, the method includes administering an initial daily dose of about 1 to 500 mg of a compound of formula (I) to a subject, and increasing the dose incrementally until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose can be increased daily, daily, twice weekly, weekly, every two weeks, every three weeks, or monthly.

[0164] When administered orally, the total daily dosage for a human subject may 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 may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 200, 300, 400, 500, 600, 700, or 800 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 300, 400, 500, or 600 mg / day administered in a single dose.

[0165] In some embodiments, the total daily dosage for a human subject may be about 100 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 150 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 200 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 250 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 300 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 350 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 400 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 450 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 500 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 550 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 600 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 650 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 700 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 750 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 800 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 850 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 900 mg / day administered in a single dose. In some embodiments, the total daily dosage for a human subject may be about 950 mg / day administered in a single dose.In some embodiments, the total daily dosage for a human subject may be about 1000 mg / day administered in a single dose.

[0166] A single dose can be administered hourly, daily, weekly, or monthly. For example, a single dose can be administered once every 1, 2, 3, 4, 6, 8, 12, 16 hours, or once every 24 hours. A single dose can also be administered once every 1, 2, 3, 4, 5, 6 days, or once every 7 days. A single dose can also be administered once every 1, 2, 3 weeks, or once every 4 weeks. In some embodiments, a single dose can be administered once weekly. A single dose can also be administered once monthly. In some embodiments, a compound disclosed herein is administered once daily in the methods disclosed herein. In some embodiments, a compound disclosed herein is administered twice daily in the methods disclosed herein.

[0167] The frequency of administration of the compounds of the present disclosure will be determined by the needs of the individual patient and can be, for example, once daily or twice daily or more. Administration of the compounds will continue for as long as necessary to treat HBV infection, HIV infection, cancer, a hyperproliferative disease, or any other indication described herein. For example, the compounds can be administered to a human infected with HBV for a period of 20 to 180 days, or for example, for a period of 20 to 90 days, or for example, for a period of 30 to 60 days.

[0168] Administration can be intermittent, with the patient receiving a daily dose of a compound of the present disclosure for a period of several days or more, followed by a period of several days or more during which the patient does not receive a daily dose of the compound. For example, the patient can receive a dose of the compound every other day or three times per week. As a further example, the patient can receive a dose of the compound daily for a period of 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive a dose of the compound, followed by a subsequent period (e.g., 1 to 14 days) during which the patient again receives a daily dose of the compound. The alternating periods of compound administration followed by non-compound administration can be repeated as clinically needed to treat the patient.

[0169] The compounds of the present disclosure or pharmaceutical compositions thereof may be administered once, twice, three times, or four times daily using any suitable method described above. Administration or treatment with the compound may also continue for several days; for example, treatment will typically continue for at least 7, 14, or 28 days per treatment cycle. Treatment cycles are well known in cancer chemotherapy and frequently alternate with rest periods of about 1 to 28 days, typically about 7 days or about 14 days, between cycles. Treatment cycles may also be continuous in other embodiments. VI. Combination Therapy

[0170] In certain embodiments, methods are provided for treating or preventing an HIV infection in a human having or at risk of having such an infection, comprising administering to the human a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with therapeutically effective amounts of one or more (e.g., 1, 2, 3, 1 or 2, or 1 to 3) additional therapeutic agents. In one embodiment, methods are provided for treating an HIV infection in a human having or at risk of having such an infection, comprising administering to the human a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with therapeutically effective amounts of one or more (e.g., 1, 2, 3, 1 or 2, or 1 to 3) additional therapeutic agents.

[0171] In one embodiment, a pharmaceutical composition is provided that includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, 1 or 2, or 1-3) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0172] In certain embodiments, the present disclosure provides a method for treating an HIV infection, comprising administering to a subject in need thereof a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more additional therapeutic agents suitable for treating an HIV infection.

[0173] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents and / or may be selected from different classes of therapeutic agents. Administration of HIV combination therapy

[0174] In certain embodiments, the compounds disclosed herein are administered together with one or more additional therapeutic agents. Co-administration of the compounds disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of the compounds disclosed herein and one or more additional therapeutic agents, so that therapeutically effective amounts of both the compounds disclosed herein and one or more additional therapeutic agents are present in the patient's body. When administered sequentially, the combination may be administered in two or more doses.

[0175] Co-administration includes administration of a unit dose of a compound disclosed herein before or after administration of a unit dose of one or more additional therapeutic agents. For example, a compound disclosed herein may be administered within seconds, minutes, or hours of administration of one or more additional therapeutic agents. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by a unit dose of one or more additional therapeutic agents. Alternatively, in other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed within seconds or minutes by a unit dose of a compound disclosed herein. In other embodiments, a unit dose of a compound disclosed herein is administered first, followed several hours (e.g., 1-12 hours) later by a unit dose of one or more additional therapeutic agents. In yet other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed several hours (e.g., 1-12 hours) later by a unit dose of a compound disclosed herein.

[0176] In certain embodiments, the compounds disclosed herein are combined with one or more additional therapeutic agents in a unit dosage form for simultaneous administration to a subject, e.g., as a solid dosage form for oral administration.

[0177] In certain embodiments, a compound of Formula I, Ia, Ib, Ic, Id, or II is formulated as a tablet that may optionally include one or more other compounds useful in the treatment of HIV. In certain embodiments, the tablet may include another active ingredient for treating HIV, such as an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleoside inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, a pharmacokinetic enhancer, and combinations thereof.

[0178] In one embodiment, such tablets are suitable for once-daily administration. HIV combination therapy

[0179] In the above embodiments, the additional therapeutic agent may be an anti-HIV agent, such as an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an HIV 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 nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), a cellular therapy (such as chimeric antigen receptor T cells, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapies, etc.), a latent infection reactivator, a compound targeting the HIV capsid, an immune system therapeutic, a phosphatidylinositol 3-kinase (PI3K) inhibitor, an HIV antibody, a bispecific antibody and an "antibody-like" therapeutic protein, an HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MKI) kinase-3, MLK-3 inhibitors, HIV-1 splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, CD4 modulators, CD4 antagonists, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, CCR5 chemokine antagonists, CCR5 gene modulators, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIVPOL protein inhibitors, hyaluronidase inhibitors, Nef antagonists, Nef inhibitors, protease activated receptor-1 antagonists, TNFα ligand inhibitors, PDE4 inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy agents, HIV vaccines, and combinations thereof.

[0180] In some embodiments, the additional therapeutic agent is selected from the group consisting of HIV combination medications, other HIV therapeutic agents, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reactivators, capsid inhibitors, immune system therapeutics, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and "antibody-like" therapeutic proteins, and combinations thereof. HIV combination drugs

[0181] Examples of combination medications include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); BIKTARVY® (bictegravir, emtricitabine, tenofovir alafenamide); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tetracycline, ... Nofovir disoproxil fumarate and emtricitabine; TDF+FTC; DESCOVY® (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 CIMDU™ (lamivudine and tenofovir disoproxil fumarate); tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR® (zidovudine and lamivudine; AZT+3TC ); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (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 and levonorgestrel, dolutegravir and lamivudine, dolutegravir and emtricitabine and tenofovir alafenamide, elsulfavirine and emtricitabine These include licitabine + 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; Other HIV drugs

[0182] Examples of other drugs for treating HIV include acemannan, alisporivir, astodrimer, BanLec, CC-11050, deferiprone, Gamimune, Griffithsin, metenkefalin, naltrexone, Prolastin, REP9, RPI-MN, Vorapaxar, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy drugs, MK-8527, BlockAide, PSC-RANTES, ABX-464, and AG-11 05, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-2048, MK-4250, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576. HIV protease inhibitors

[0183] Examples of HIV protease inhibitors include amprenavir, atazanavir, brecanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, DG-17, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, and TMC-310911. HIV reverse transcriptase inhibitors

[0184] Examples of HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, and elsulfavirine (VM-1500).

[0185] Examples of HIV nucleoside or nucleotide inhibitors of reverse transcriptase include adefovir, adefovir dipivoxil, azuvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, VIDEX®, and VIDEX These include EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, didanosine, elvucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, tidoxilfodivudine, islatravir, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, lobafovir etalafenamid (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, and KP-1461. HIV integrase inhibitors

[0186] Examples of HIV integrase inhibitors include elvitegravir, curcumin, curcumin derivatives, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tyrphostin, derivatives of tyrphostin, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir These include le, AVX-15567, BMS-986197, cabotegravir (long-acting injectable), diketoquinoline 4-one derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, VM-3500, and cabotegravir.

[0187] Examples of HIV non-catalytic or allosteric integrase inhibitors (NCINIs) include CX-05045, CX-05168, and CX-14442. HIV entry inhibitors

[0188] Examples of HIV entry (fusion) inhibitors include cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 binding inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors.

[0189] Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (PRO-140), adaptavir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu).

[0190] Examples of gp41 inhibitors include albuvirtide, enfuvirtide, BMS-986197, enfuvirtide biobetter, enfuvirtide biosimilar, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide.

[0191] Examples of CD4 binding inhibitors include ibalizumab and CDA analogs.

[0192] Examples of gp120 inhibitors include Radha-108 (receptor) 3B3-PE38, BanLec, bentonite-based nanopharmaceuticals, fostemsavir tromethamine, IQP-0831, and BMS-663068.

[0193] Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu). HIV maturation inhibitors

[0194] Examples of HIV maturation inhibitors include BMS-955176, BMS-986197, GSK-3640254, and GSK-2838232. Latent infection reactivator

[0195] Examples of latent infection reactivators include histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as Velcade and ixazomib citrate, protein kinase C (PKC) activators, Smyd2 inhibitors, 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.

[0196] Examples of HDAC inhibitors include romidepsin, vorinostat, and panobinostat.

[0197] Examples of PKC activators include indolactams, prostratin, ingenol B, and DAG-lactone. Capsid inhibitors

[0198] Examples of capsid inhibitors include capsid polymerization inhibitors or capsid-disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors, such as azodicarbonamide, HIV p24 capsid protein inhibitors, GS-6207, AVI-621, AVI-101, AVI-201, AVI-301, and the AVI-CAN1-15 series. In some embodiments, the compounds disclosed herein are used in combination with lenacapavir. immune system therapy

[0199] Examples of immune system therapeutics include toll-like receptor modulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed death-ligand 1 (Pd-L1) modulators; IL-15 modulators, DermaVir; interleukin-7; Plaquenil (hydroxychloroquine); Proleukin (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivatives mycophenolate mofetil (MMF); ribavirin; the polymer polyethyleneimine (polymer polyethyleneimine, PEI); gepon; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15 / Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255, NKTR-262, NKTR-214, normferon, pegylated interferon alpha-2a, pegylated interferon alpha-2b, recombinant interleukin-15, Xmab-24306, RPI-MN, STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103.

[0200] Examples of TLR agonists: vesatolimod (GS-9620), GS-986, IR-103, lefitolimod, tilsotolimod, lintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, tellulatorimod, RO-7020531. Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0201] Examples of PI3K inhibitors include idelalisib, alpelisib, bupalisib, CAI orotate, copanlisib, duvelisib, gedatricib, neratinib, panulisib, perifosine, pictilisib, pilalalisib, pukitinib mesylate, rigosertib, rigosertib sodium, sonoliside, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, D Examples include S-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765, and ZSTK-474. Alpha-4 / beta-7 antagonists

[0202] 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

[0203] Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include DARTs®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bispecific antibodies, trispecific antibodies, multivalent antibodies, bnAB (broadly neutralizing HIV-1 antibody), BMS-936559, TMB-360, and HIV These include antibodies targeting gp120 or gp41, antibody recruiting molecules targeting HIV, anti-CD63 monoclonal antibodies, CD3 bispecific antibodies, CD16 bispecific antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, CCR5 bispecific antibodies, anti-Nef single domain antibodies, anti-Rev antibodies, camel-derived anti-CD18 antibodies, camel-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAb (PGT-121), ibalizumab, Immuglo, and MB-66.

[0204] 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, PGT1 45, 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, N60 P22, NIH45-46, PG9, PG16, 8ANC195, 2Dm2m, 4Dm2m, 6Dm2m, VRC-01, VRC-01-LS, PGDM1400, A32 , 7B2, 10E8, 10E8VLS, 3810109, 10E8v4, 10E8.4 / iMab, VRC-01 / PGDM-1400 / 10E8v4, IMC-HIV, i Examples of HIV bispecific antibodies include Mabm36, 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.

[0205] Examples of in vivo delivered bnABs include AAV8-VRC07; mRNA encoding the anti-HIV antibody VRC01. Pharmacokinetic enhancers

[0206] Examples of pharmacokinetic enhancers include cobicistat and ritonavir. Additional medications

[0207] Examples of additional therapeutic agents include those described in WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO 2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO 2014 / 100323 (Gilead Sciences), U.S. Patent Application Publication No. 2013 / 0165489 (University of

[0023] Examples of compounds disclosed in U.S. Patent Application Publication No. 2014 / 0221378 (Japan Tobacco), U.S. Patent Application Publication No. 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), U.S. Patent Application Publication No. 2014 / 0221356 (Gilead Sciences), U.S. Patent Application Publication No. 2010 / 0143301 (Gilead Sciences), and WO 2013 / 091096 (Boehringer Ingelheim). HIV vaccine

[0208] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines using viral vectors such as arenaviruses, lymphocytic choriomeningitis virus (LCMV), Pichinde virus, modified vaccinia Ankara virus (MVA), adenovirus, adeno-associated virus (AAV), vesicular stomatitis virus (VSV), and chimpanzee adenovirus (ChAd), DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, BG505 SOSIP.664 gp140, rgp120 (AIDSVAX), ALVAC HIV, (vCP1521) / AIDSVAX B / E(gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad4-Env145NFL, Ad5-ENVA-48, HB-500, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, Vacc-CRX, VVX-004, VAC-3S, multiclad DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol env A / B / C vaccine, Pennvax-G, Pennvax-GP / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSP ISA-51, polyICLC-adjuvanted vaccine, TatImmune, GTU-multiHIV (FIT-06), gp140[delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4(Ad4-env Clade C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag / pol / nef / nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.HIV + MVA mosaic vaccine + gp140, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particle vaccines, such as pseudovirion vaccines, CombiVICHvac, LFn-p24 B / C fusion vaccines, GTU-based DNA vaccines, HIV gag / pol / nef / env DNA vaccines, anti-TAT HIV vaccines, conjugate polypeptide vaccines, dendritic cell vaccines, gag-based DNA vaccines, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), Ii-key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multiclad Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x + romidepsin, mutant gp120 polypeptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA.HTI, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP + VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980;eOD-GT8 60mer vaccine, PD-201401, env(A,B,C,A / E) / gag(C) DNA vaccine, gp120(A,B,C,A / E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine (GLA-SE adjuvant), HIV p24gag prime-boost plasmid DNA vaccine, arenavirus vector-based immunotherapies (Vaxwave, TheraT), MVA-BN HIV-1 vaccine regimen, MVA.tHIVconsv4, MVA.tHIVconsv3, UBI HIV These include gp120, mRNA-based prophylactic vaccines, TBL-1203HI, VRC-HIVRGP096-00-VP, VAX-3S, and HIV MAG DNA vaccines. HIV combination therapy

[0209] In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are selected from the group consisting of ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate, and emtricitabine); TDF+FTC; DESCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir Fovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir, and lamivudine); dolutegravir, abacavir sulfate, and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT + 3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC + 3TC); TR IZIVIR® (abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolastin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate;in combination with one, two, three, four, or more additional therapeutic agents selected from interferon; didanosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; aldesleukin; zalcitabine; tipranavir; amprenavir; delavirdine; delavirdine mesylate; Radha-108 (Receptor); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazides; lamivudine, nevirapine, and zidovudine; abacavir, and abacavir sulfate;

[0210] Those skilled in the art will appreciate that the additional therapeutic agents listed above may fall into more than one of the classes listed above, and the particular classes are not intended to limit the functionality of the compounds listed in those classes.

[0211] In certain embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV protease inhibitor compound. In additional embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In some embodiments, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, a compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0212] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0213] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0214] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent selected from the group consisting of emtricitabine and lamivudine.

[0215] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with a first additional therapeutic agent selected from the group consisting of tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, and tenofovir alafenamide hemifumarate, and a second additional therapeutic agent, wherein the second additional therapeutic agent is emtricitabine.

[0216] A compound disclosed herein (e.g., any compound of Formula I, Ia, Ib, Ic, Id, or II) may be combined with one or more additional therapeutic agents, at any dosage of a compound of Formula I, Ia, Ib, Ic, Id, or II (e.g., 1 mg to 500 mg of the compound).

[0217] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5-10, 5-15, 5-20, 5-25, 25-30, 20-30, 15-30, or 10-30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide and 200 mg of emtricitabine. A compound disclosed herein (e.g., a compound of Formula I) may be combined with a pharmaceutical agent provided herein at any dosage of the compound (e.g., 1 mg to 500 mg of the compound), as if each dosage combination were specifically and individually listed.

[0218] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200-250, 200-300, 200-350, 250-350, 250-400, 350-400, 300-400, or 250-400 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 300 mg of tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, or tenofovir disoproxil and 200 mg of emtricitabine. A compound disclosed herein (e.g., a compound of Formula I) may be combined with an agent provided herein at any dosage of the compound (e.g., 1 mg to 500 mg of the compound), as if each combination of dosages were specifically and individually recited.

[0219] In one embodiment, a kit is provided that includes a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., 1, 2, 3, 1 or 2, or 1 to 3) additional therapeutic agents. Combined birth control (contraceptive) therapy

[0220] Therapeutic agents used for birth control (contraception) include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, ethynodiol, etonogestrel, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norregestromin, norethindrone, nortinodrel, norgestimate, ormeloxifene, segestrel acetate, ulipristal acetate, and any combination thereof. Gene Therapy and Cell Therapy

[0221] Gene and cell therapies include genetic modifications to silence genes; genetic approaches to directly kill infected cells; infusion of immune cells designed to either replace a large portion of a patient's own immune system to enhance the immune response against infected cells, or activate the patient's own immune system to kill infected cells, or to find and kill infected cells; and genetic approaches to modify cellular activity to further alter the endogenous immune responsiveness to infection.

[0222] An example of a dendritic cell therapy is AGS-004.

[0223] Examples of CCR5 gene editing drugs, such as SB-728T.

[0224] Examples of CCR5 gene inhibitors, such as Cal-1.

[0225] CD4-positive T cells expressing C34-CCR5 / C34-CXCR4.

[0226] AGT-103 transduced autologous T cell therapy.

[0227] AAV-eCD4-Ig gene therapy. Gene Editor

[0228] 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.

[0229] An example of an HIV-targeting CRISPR / Cas9 system includes EBT-101. CAR-T cell therapy

[0230] A population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HIV antigen-binding domain. The HIV antigen includes an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4-binding site on gp120, a CD4-inducible binding site on gp120, an N-glycan on gp120, V2 of gp120, or a membrane-proximal region on gp41. The immune effector cells are T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, or a combination thereof. The cells can be autologous or allogeneic.

[0231] Examples of HIV CAR-T include VC-CAR-T, an anti-CD4 CAR cell therapy, and autologous hematopoietic stem cells genetically engineered to express the CD4 CAR and C46 peptide. TCR-T cell therapy

[0232] TCR-T cells are genetically engineered to target HIV-derived peptides displayed on the surface of virus-infected cells. [Example]

[0233] VII. Working Examples Exemplary chemicals of the present disclosure are provided in the specific examples below. Those skilled in the art will understand that to obtain the various compounds described herein, starting materials can be suitably selected so that the ultimately desired substituents are carried through the reaction scheme, with or without protection as necessary, to obtain the desired product. Alternatively, it may be necessary or desirable to use, in place of the ultimately desired substituent, a suitable group that can be carried through the reaction scheme and appropriately replaced with the desired substituent. Furthermore, those skilled in the art will understand that the transformations shown in the following schemes can be performed in any order that is compatible with the functionality of the particular pendant groups.

[0234] The examples provided herein describe the synthesis of the compounds disclosed herein, as well as the intermediates used to prepare the compounds. It is understood that the individual steps described herein can be combined. It is also understood that separate batches of compounds can be combined and then carried forward to the next synthetic step.

[0235] In the following description of the examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the present disclosure. Other embodiments may be utilized, and logical and other changes may be made without departing from the scope of the present disclosure. Accordingly, the following description is not intended to limit the scope of the present disclosure. Intermediate A: (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Synthesis of (3S,7S)-7-methyl-2,3,4,7-tetrahydro-1H-azepin-3-amine:

[0236] Trifluoroacetic acid (20 mL) was added to benzyl (3S,7S)-3-(((benzyloxy)carbonyl)amino)-7-methyl-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (6.2 g, 15.7 mmol) and the reaction was heated to 100° C. for 4 hours. The reaction mixture was concentrated and the crude material was used directly in the next step. Synthesis of (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0237] Methanol (300 mL) and water (30 mL) were added to methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate (6.75 g, 15.7 mmol) and (3S,7S)-7-methyl-2,3,4,7-tetrahydro-1H-azepin-3-amine (crude reaction product from previous step). At room temperature, NaHCO (13.2 g, 157 mmol) was added to the reaction mixture. The reaction was stirred at room temperature overnight and then heated to 60° C. for 5 hours. The reaction mixture was concentrated, followed by the addition of ethyl acetate and washing with saturated ammonium chloride solution. The organic layer was concentrated and purified by silica chromatography (eluting with 0-10% MeOH / DCM) to give (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. MS (m / z) 524.11 [M+H] + . Synthesis of (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0238] Selenium dioxide (17.4 g, 157 mmol) was added to (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (product from the previous step, 15.7 mmol) in dioxane (160 mL). The reaction was then heated to 105° C. overnight. The reaction mixture was cooled, and the solid was filtered off. The filtrate was extracted with ethyl acetate and saturated ammonium chloride solution. The organic layer was concentrated and purified by silica chromatography (eluting with 40–100% ethyl acetate / hexanes) to give (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. MS (m / z) 538.095 [M+H] + . Intermediate B: (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka]

[0239] This intermediate was prepared according to the procedure for making (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Intermediate A), except that methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate was used in the second step. MS (m / z): 520.200 [M+H] + ). Example 1: (3S,6S,7R)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Preparation of (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0240] To a solution of (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Intermediate A) (122 mg, 0.227 mmol) in methanol (5 mL) was added cerium(III) chloride heptahydrate (85 mg, 0.227 mmol). Sodium borohydride (2.1 mg, 0.057 mmol) was then slowly added to the mixture at 0 °C. After 5 min, the reaction was quenched by adding saturated NaHCO solution and extracted with DCM. The organic phase was separated and concentrated. The residue was then dissolved in DCM and washed with brine. The organic phase was dried over MgSO4, filtered, concentrated and used further without purification. Preparation of (3S,6S,7R)-12-(benzyloxy)-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0241] To a solution of (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (16 mg, 0.030 mmol) in DMF (1 mL) was added sodium hydride (1.8 mg, 0.045 mmol, 60%) and iodomethane (2.8 μL, 0.045 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched by adding saturated NaHCO3 and extracted with EtOAc. The organic phase was separated, dried over MgSO4, filtered, and concentrated, and the resulting product was used in the next step without further purification. Preparation of (3S,6S,7R)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0242] To a solution of (3S,6S,7R)-12-(benzyloxy)-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (15 mg, 0.018 mmol) in ethanol (1 mL) was added palladium on carbon (10 mg). The reaction was stirred under a H balloon for 30 minutes. The reaction was filtered through Celite. The filtrate was concentrated, and the residue was purified by reverse-phase HPLC chromatography (eluting with 5-100% acetonitrile / water containing 0.1% TFA) to give the title product. MS (m / z) 466.2 [M+H] + . 1H NMR(400MHz, methanol-d4)δ 8.34(s,1H),6.98-6.85(m,2H),4.74(s,1H),4.68(s,2H),4.66-4.58(m,1H),3.80-3.69(m,2H),3.55(d,J=11.8 Hz,1H),3.46(s,3H),2.18-1.99(m,3H),1.61-1.49(m,1H),1.28(d,J=6.7Hz,3H),1.00(dt,J=14.9,11.6Hz,1H). Example 2: (3S,6S,7R)-6,12-dihydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide

[0243] To a solution of (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (10 mg, 0.018 mmol) in ethanol (1 mL) was added palladium on carbon (10 mg). The reaction was stirred under a H balloon for 30 minutes. The reaction was filtered through Celite. The filtrate was concentrated, and the residue was purified by reverse-phase HPLC chromatography (eluting with 5-100% acetonitrile / water containing 0.1% TFA) to give the title product. MS (m / z) 452.3 [M+H] + . 1 H NMR(400MHz, methanol-d4)δ 8.40(s,1H),6.98-6.86(m,2H),4.68(s,2H),4.67-4.60(m,1H),4.56(s,1H),4.02-3.90(m,1H),3.75(s,2H),2.07(dt,J=14.5,7. 1Hz,1H), 1.81(ddd,J=14.8,7.6,3.8Hz,1H),1.59(dt,J=15.0,11.3Hz,1H),1.28(d,J=6.7Hz,3H),1.19(dt,J=14.8,11.7Hz,1H). Example 3: (3S,6S,7R)—N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka]

[0244] Instead of (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Intermediate A), (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide was used. (3S,6S,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide was prepared in the same manner as in Example 1, except that d-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Intermediate B) was used. MS (m / z) 448.2 [M+H] + . 1 H NMR(400MHz, methanol-d4)δ 8.37(s,1H),7.45(q,J=7.8Hz,1H),7.09-6.88(m,2H),4.65(s,4H),3.75(s,2H),3.56(d,J=11.1Hz,1H),3. 46(s,3H),2.18-1.98(m,2H),1.54(dd,J=25.7,11.4Hz,1H),1.29(d,J=6.6Hz,3H),1.01(q,J=12.1Hz,1H). Example 4: (3S,6R,7R)-12-Hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Preparation of (3S,6R,7R)-12-(benzyloxy)-3-methyl-1,11-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-6-yl benzoate:

[0245] To a solution of (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (29 mg, 0.054 mmol) in Me-THF (3 mL) was added benzoic acid (16 mg, 0.134 mmol), triphenylphosphine (35 mg, 0.134 mmol), and diisopropyl azodicarboxylate (27.2 mg, 0.134 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with EtOAc, washed with saturated NaHCO3, and the organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (0-100% EtOAc / hexanes) to give the title product (30 mg). Preparation of (3S,6R,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0246] A reaction mixture of (3S,6R,7R)-12-(benzyloxy)-3-methyl-1,11-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-6-ylbenzoate (30 mg, 0.047 mmol), LiOH·HO (5.6 mg, 0.233 mmol) in MeOH (2 mL) and HO (0.5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was washed with brine and extracted with EtOAc. The organic phase was separated, dried over MgSO, filtered, concentrated, and used in the next step without purification. Preparation of (3S,6R,7R)-12-(benzyloxy)-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0247] To a solution of (3S,6R,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (20 mg, 0.037 mmol) in DMF (1 mL) was added sodium hydride (1.8 mg, 0.045 mmol, 60%) and iodomethane (3.5 μL, 0.056 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched by the addition of saturated NaHCO3, extracted with EtOAc, and the organic phase was separated, dried over MgSO4, filtered, concentrated, and carried on to the next step without purification. Preparation of (3S,6R,7R)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0248] A reaction mixture of (3S,6R,7R)-12-(benzyloxy)-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide in DCM (1 mL) and TFA (1 mL) was stirred at room temperature for 3 hours. The reaction mixture was concentrated. The residue was purified by reverse-phase HPLC chromatography (eluting with 5-100% acetonitrile / water containing 0.1% TFA) to give the title compound. MS (m / z) 464.1 [M+H] + . 1 H NMR(400MHz, methanol-d4)δ 8.45(s,1H),6.98-6.85(m,2H),5.77(dt,J=11.8,2.8Hz,1H),5.56(ddd,J=11.9,2.7,1.7Hz,1H),5.33(dq,J=7.6,2.8Hz,1H),4.69( s,2H),4.59(s,1H),4.27(dq,J=5.7,3.0Hz,1H),4.11(d,J=13.7Hz,1H),3.65(d,J=14.4Hz,1H),3.32(s,3H),1.39(d,J=7.2Hz,3H). Example 5: (3S,6R,7R)-6,12-dihydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka]

[0249] To a solution of (3S,6R,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (10 mg, 0.018 mmol) in ethanol (1 mL) was added palladium on carbon (10 mg). The reaction was stirred under a H balloon for 30 minutes. The reaction was filtered through Celite. The filtrate was concentrated, and the residue was purified by reverse-phase HPLC chromatography (eluting with 5-100% acetonitrile / water containing 0.1% TFA) to give the title product. MS (m / z) 452.2 [M+H] + . 1 H NMR(400MHz, methanol-d4)δ 8.46(s,1H),6.99-6.85(m,2H),4.68(s,2H),4.58(dt,J=10.7,6.5Hz,1H),4.40(s,1H),4.04(d,J=3.9Hz,1H),3.81(d,J=14. 8Hz,1H), 3.69(d,J=14.7Hz,1H),2.01(dd,J=14.5,11.3Hz,1H),1.95-1.79(m,2H),1.38-1.30(m,1H),1.29(d,J=6.6Hz,3H). Example 6: (3S,6R,7R)-12-Hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka]

[0250] To a solution of (3S,6R,7R)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Example 4) (18 mg, 0.039 mmol) in EtOH (2 mL) was added Pd(OH) / C (10 mg). A H balloon was attached and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through Celite, the filtrate was concentrated, and the residue was purified by reverse-phase chromatography (eluting with 5-100% acetonitrile / water containing 0.1% TFA) to give the title product. MS (m / z) 466.2 [M+H] + . 1 H NMR(400MHz, methanol-d4)δ 8.37(s,1H),7.45(q,J=7.8Hz,1H),7.09-6.88(m,2H),4.65(s,4H),3.75(s,2H),3.56(d,J=11.1Hz,1H),3. 46(s,3H),2.18-1.98(m,2H),1.54(dd,J=25.7,11.4Hz,1H),1.29(d,J=6.6Hz,3H),1.01(q,J=12.1Hz,1H). 1H NMR (400MHz, methanol-d4)δ 8.51(s,1H),6.98-6.85(m,2H),4.68(s,2H),4.66-4.50(m,2H),3.75(d,J=14.9Hz,1H),3.72-3.60(m,2H),3. 48(s,3H),2.09(dt,J=15.0,4.6Hz,1H),1.86(td,J=9.6,2.7Hz,2H),1.28(d,J=6.7Hz,3H),1.24-1.15(m,1H). Example 7: (3S,6R,7R)—N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka]

[0251] Instead of (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide, (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (see Example 3), (3S,6R,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide was prepared in a manner similar to that used to prepare (3S,6R,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Example 4), except that: MS (m / z) 446.2 [M+H] + . 1 H NMR(400MHz, methanol-d4)δ 8.47(s,1H),7.45(td,J=8.4,6.3Hz,1H),7.03-6.90(m,2H),5.77(dt,J= 11.8,2.8Hz,1H),5.56(ddd,J=11.8,2.7,1.7Hz,1H),5.34(dq,J=7.4,2. 8Hz,1H),4.67-4.56(m,3H),4.29(dq,J=5.6,2.9Hz,1H),4.11(dd,J=14. 4,3.0Hz,1H),3.65(d,J=14.2Hz,1H),3.34(s,3H),1.39(d,J=7.3Hz,3H). Example 8: (3S,6R,7R)-6,12-dihydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka]

[0252] To a solution of (3S,6R,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Example 7) (20 mg, 0.045 mmol) in EtOH (2 mL) was added Pd(OH) / C (7 mg). A H balloon was attached and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through Celite, the filtrate was concentrated, and the residue was purified by reverse-phase chromatography (eluting with 5-100% acetonitrile / water containing 0.1% TFA) to give the title product. MS (m / z) 448.3 [M+H] + . 1 H NMR(400MHz, methanol-d4)δ 8.53(s,1H),7.50-7.40(m,1H),6.97(dddd,J=12.6,11.1,8.9,2.6Hz,2H),4.65(s,2H),4.62-4.52(m,2H),3 .80-3.59(m,3H),3.48(s,3H),2.10(dt,J=15.1,4.6Hz,1H),1.85(tt,J=9.4,5.2Hz,2H),1.36-1.16(m,4H). Example 9: (3S,6S,7R)—N-(3-chloro-2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Preparation of ethyl (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxylate:

[0253] A reaction mixture of (3S,7S)-7-methyl-2,3,4,7-tetrahydro-1H-azepin-3-amine (0.39 g, 3.1 mmol), (diethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (1.07 g, 3.09 mmol), and sodium bicarbonate (2.6 g, 30.9 mmol) in MeOH (10 mL) and water (2 mL) was stirred at room temperature overnight. The reaction mixture was stirred at 60 °C for 8 h. The reaction mixture was cooled and concentrated. The residue was washed with water and extracted with EtOAc. The organic phase was separated, dried over MgSO, filtered, concentrated, and purified by silica gel chromatography eluting with 0-100% hexanes / EtOAc to give the title compound. Preparation of (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxylic acid:

[0254] A reaction mixture of ethyl (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxylate (1.02 g, 2.5 mmol) and sodium hydroxide (2N, 3.75 mL) in MeOH (5 mL) was stirred at 60° C. for 1 hour. The reaction mixture was cooled and concentrated. The residue was dissolved in water, the pH was adjusted to 4 with HCl, and extracted with EtOAc. The organic phase was separated, dried over MgSO, filtered, concentrated, and used in the next reaction without further purification. Preparation of (3S,7S)-12-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0255] To a solution of (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxylic acid (0.88 g, 2.31 mmol) in DCM (10 mL) were added diisopropylethylamine (1.61 mL, 9.25 mmol) and 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (0.88 g, 2.31 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was washed with saturated NaHCO.sub.3, extracted with EtOAc, and the organic phase was separated, dried over MgSO.sub.4, filtered, concentrated, and purified by silica gel chromatography eluting with 0-100% hexanes / EtOAc to give the title compound. Preparation of (3S,7R)-12-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0256] A reaction mixture of (3S,7S)-12-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (0.48 g, 0.89 mmol) and selenium dioxide (0.986 g, 8.9 mmol) in dioxane was stirred at 100 °C overnight. The reaction mixture was cooled and filtered to remove solids. The filtrate was diluted with EtOAc and washed with saturated NaHCO. The organic phase was dried over MgSO, filtered, concentrated, and purified by silica gel chromatography eluting with 0-100% hexanes / EtOAc to provide the title compound. Preparation of (3S,6S,7R)-N-(3-chloro-2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0257] Instead of (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Intermediate A), (3S,7R)-12-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro (3S,6S,7R)-N-(3-chloro-2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide was prepared in a manner similar to that used in Example 1, except that tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide was used. MS (m / z) 482.4 [M+H] + . 1 H NMR(400MHz, methanol-d4)δ 8.35(s,1H),7.40(td,J=8.4,6.0Hz,1H),7.11(td,J=8.7,1.9Hz,1H),4.74(s,1H),4.71-4.57(m,3H),3.83-3.67(m,2H),3.61-3 .50(m,1H),3.46(s,3H),2.18-1.98(m,3H),1.54(dt,J=14.4,11.2Hz,1H),1.28(d,J=6.7Hz,3H),1.01(dt,J=14.9,11.7Hz,1H). Example 10: (3S,6R,7R)—N-(3-chloro-2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka]

[0258] Instead of (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide, (3S,6S,7R)-12-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-6-hydroxy-3-methyl-1,11-dioxo-1,6,7, (3S,6R,7R)-N-(3-chloro-2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide was prepared in a manner similar to that used in Example 4, except that 11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide was used. MS (m / z) 480.2 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d3) δ 10.38 (s, 1H), 8.35 (s, 1H), 7.39 (q, J = 8.1 Hz, 1H), 7.18-7.04 (m, 1H), 5.72 (dq, J = 8.7, 2.8 Hz, 1H), 5.63-5.48 (m, 1H), 5.30 (s, 1H), 4.73-4.60 (m, 3H), 4.46 (s, 1H), 4.27 (s, 1H), 4.01 (dd, J = 14.4, 2.9 Hz, 1H), 3.58 (d, J = 14.4 Hz, 1H), 3.29 (d, J = 4.3 Hz, 3H), 1.34 (d, J = 7.3 Hz, 3H). Example 11 (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Synthesis of (3S,6S,7R)-6,12-dihydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0259] (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (132 mg, 0.246 mmol) was dissolved in anhydrous THF (3.0 mL), and the resulting mixture was cooled to -20 °C. To this stirred, cold mixture was added a 3.0 M ethereal solution of methylmagnesium bromide (0.41 mL, 1.23 mmol). After stirring for 20 min, the reaction was quenched with saturated NH4Cl. The reaction was extracted with EtOAc, and the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting product was purified by normal phase chromatography (4 g silica gel, 0–100% EtOAc / hexanes). LCMS-ESI+(m / z):C 29 H 26 Calculated H+ value for F3N3O5: theoretical value: 553.18, measured value: 553.95. Synthesis of (1R,10S,13S)-6,13-dihydroxy-10,13-dimethyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide:

[0260] (3S,6S,7R)-6,12-dihydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (20.0 mg, 0.0361 mmol) was dissolved in MeOH (15.0 mL) at room temperature and treated with 7 mg of 20% Pd(OH)2 / C (50 wt% water). The mixture was degassed and flushed with hydrogen three times, after which it was hydrogenated under a hydrogen balloon overnight. The reaction was then degassed, flushed with nitrogen, filtered through a pad of Celite, and concentrated. The resulting residue was redissolved in DMF, filtered, and purified by reverse-phase HPLC. LCMS-ESI+ (m / z): C 22 H 22 Calculated H+ value for F3N3O5: theoretical value 465.15, measured value: 466.24. 1 H NMR(400MHz,DMSO-d6)δ 10.95(s,1H),10.46(t,J=5.8Hz,1H),8.31(s,1H),7.21(t,J=8.6Hz,2H),4.93(s,1H),4.62-4.41(m,3H),4.26(s ,1H),3.66(d,J=2.5Hz,2H),1.91-1.81(m,1H),1.41(dd,J=14.6,7.7Hz,2H),1.34(s,3H),1.17(d,J=6.6Hz,4H). Example 12: [(3S,6S,7R)—N-(2,4-difluorobenzyl)-6,12-dihydroxy-3,6-dimethyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide]

[0261] This compound was prepared by following the same procedure as in the synthesis of Example 11, except that (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide was used instead of (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide in Step 1. The stereochemistry was not confirmed. LCMS-ESI+ (m / z): H+ calculated for C22H23F2N3O5, theory: 447.16, found: 448.22. 1 H NMR(400MHz,DMSO-d6)δ 10.98(s,1H),10.46(t,J=6.0Hz,1H),8.34(s,1H),7.40(td,J=8.7,6.7Hz,1H),7.2 5(ddd,J=10.6,9.3,2.6Hz,1H),7.12-7.03(m,1H),5.03-4.83(m,1H),4.56(d,J=5. 9Hz,2H),4.47(dt,J=12.2,6.5Hz,1H),4.28(s,1H),3.67(d,J=3.2Hz,2H),1.87(dt ,J=14.3,7.1Hz,1H),1.42(dd,J=14.4,7.7Hz,2H),1.35(s,3H),1.25-1.12(m,4H). Example 13: Preparation of (3S,6R,7R)-6-chloro-N-(2,4-difluorobenzyl)-12-hydroxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Preparation of (3S,6R,7R)-12-(benzyloxy)-6-chloro-N-(2,4-difluorobenzyl)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0262] To a solution of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (110 mg, 0.211 mmol) in DCM (27 mL) under N was added triethylamine (1.18 mL, 8.44 mmol) and thionyl chloride (0.615 mL, 8.44 mmol). After 5 min, the reaction was quenched by the addition of saturated NaHCO solution and extracted with DCM. The combined organic layers were washed with brine, dried over NaSO, filtered, concentrated, and purified by flash column chromatography on silica gel using DCM / MeOH (1:0 → 95:5 → 8:2 gradient) as the solvent system to afford (3S,6R,7R)-12-(benzyloxy)-6-chloro-N-(2,4-difluorobenzyl)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide as a red / brown solid (111 mg, 98%). Preparation of (3S,6R,7R)-6-chloro-N-(2,4-difluorobenzyl)-12-hydroxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0263] A solution of (3S,6R,7R)-12-(benzyloxy)-6-chloro-N-(2,4-difluorobenzyl)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (63 mg, 0.116 mmol) in toluene / TFA (1:1) (10 mL) was stirred at room temperature for 2.75 h. The reaction was quenched with saturated aqueous sodium bicarbonate until the pH was greater than 7. EtOAc was added, and the layers were separated. The aqueous layer was washed with EtOAc. The combined organic layers were then washed with brine, dried over Na2SO4, filtered, concentrated, and purified by reverse-phase HPLC chromatography (eluting with 5 to 100% acetonitrile in water with 0.1% TFA) to give the title product (34 mg, 65%). MS(m / z) 450.100[M+H] + . 1H NMR(400MHz,MeOD)δ 8.50(s,1H),7.46-7.40(m,1H),6.99-6.91(m,2H),5.76(dt,J=11.9,3.1Hz,1H),5.55(dt,J=11.9,2.3Hz,1H),5.35-5. 33(m,1H),5.13(s,1H),4.98(s,1H),4.63(s,2H),4.20(d,J=14.5Hz,1H),3.73(d,J=14.5Hz,1H),1.39(d,J=7.3Hz,3H). Example 14: (3S,6S,7R)-6,12-dihydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka]

[0264] Instead of (3S,6R,7R)-12-(benzyloxy)-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide, (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11 (3S,6S,7R)-6,12-dihydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide was prepared in a manner similar to that of Example 4, except that N-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (prepared according to Example 1) was used. MS (m / z) 449.1 [M+H] + . 1H NMR(400MHz,MeOD)δ 8.45(s,1H),6.91(t,J=8.4Hz,2H),5.85(ddd,J=11.9,6.1,2.3Hz,1H),5.63(dd,J=11.9,2.7Hz,1H),5.33(d,J=7.4Hz ,1H),4.70(d,J=7.8Hz,2H),4.4(m,1H),4.05-3.87(m,1H),3.73(d,J=14.6Hz,1H),3.03(m,2H),1.39(d,J=7.3Hz,3H). Example 15: Preparation of (1R,10S,13S)-6,13-dihydroxy-10,13-dimethyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide [ka]

[0265] (1R,10S)-6-Hydroxy-10-methyl-5,8,13-trioxo-N-[(2,4,6-trifluorophenyl)methyl]-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide (15 mg, 0.0335 mmol) was dissolved in THF (0.5 mL) and cooled to −78° C. To this stirred, cold mixture was added dropwise 3.0 M MeMgBr in diethyl ether (0.056 mL, 0.168 mmol). The resulting mixture was stirred at −78° C. for 5 minutes and then warmed to 0° C. for 5 minutes. The reaction was quenched with acetic acid, filtered, and purified by reverse-phase preparative HPLC. LCMS-ESI+ (m / z): H+ calculated for C22H20F3N3O5, theoretical: 463.14, found: 464.02. 1H NMR (400 MHz, DMSO-d6) δ 10.46(t,J=5.8Hz,1H),8.36(s,1H),7.25-7.23(m,1H),7.22-7.19(m,2H),5.54(dd,J=11.9,2.3Hz,1H),5.39(dd,J=11.8,2.6Hz,1H),5. 18-5.08(m,1H),4.68(s,1H),4.59-4.55(m,3H),3.86(dd,J=14.7,2.6Hz,1H),3.63(d,J=14.2Hz,1H),1.38(s,3H),1.27(d,J=7.3Hz,3H). Example 16: (3S,6S,7R)—N-(2,4-difluorobenzyl)-6,12-dihydroxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Synthesis of (3S,6S,7R)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0266] (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (10 mg, 0.019 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 (4.08 mg, 0.0038 mmol) was added. The mixture was sparged under a hydrogen atmosphere (1 atm, balloon), 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 compound. MS(m / z): 434.113 [M+H]+. 1 H NMR(400MHz, methanol-d4)δ 8.43(s,1H),7.56-7.31(m,1H),7.03-6.91(m,2H),4.70-4.55(m,4H),3.95(dt,J=11.8,4.4Hz,1H),3.76(d,J=1.8Hz,2H),2. 14-2.01(m,1H),1.82(ddd,J=14.7,7.6,3.8Hz,1H),1.59(dt,J=15.0,11.3Hz,1H),1.28(d,J=6.7Hz,3H),1.27-1.13(m,1H). Example 17: Preparation of (1R,10S,13S)—N-[(2,4-difluorophenyl)methyl]-6,13-dihydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide [ka] Step 1: Synthesis of (1R,10S,13S)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-13-hydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide:

[0267] The compound was prepared according to step 1 of the synthesis of Example 11, except that in step 1, (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide was used instead of (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. LCMS-ESI+ (m / z): H+ calculated for C29H27F2N3O5, theory: 535.19, found: 535.94. Step 2: Synthesis of (1R,10S,13S)-N-[(2,4-difluorophenyl)methyl]-6,13-dihydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide:

[0268] (1R,10S,13S)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-13-hydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide (13.0 mg, 0.0243 mmol) from step 1 was treated with a mixture of DCM (0.2 mL) and TFA (0.2 mL) at room temperature for 4 hours. The reaction was concentrated, redissolved in DMF, filtered, and purified by reverse-phase preparative HPLC. LCMS-ESI+ (m / z): H+ calculated for CHFNO5, theory: 445.14, found: 446.04. 1H NMR (400 MHz, acetone-d6) δ 10.51(s,1H),8.38(s,1H),7.49(q,J=8.3Hz,1H),7.08-6.95(m,2H),6.25 (s,1H),5.74(dd,J=11.9,2.5Hz,1H),5.53(dd,J=11.8,2.5Hz,1H),5.35-5 .23(m,1H),4.79-4.69(m,2H),4.63(d,J=6.0Hz,2H),4.12(dd,J=14.7,2. 7Hz, 1H), 3.85 (dd, J = 14.6, 1.8Hz, 1H), 1.60 (s, 3H), 1.39 (d, J = 7.3Hz, 3H). Example 18: (3S,6S,7R)-12-Hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Preparation of (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0269] To a solution of (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Intermediate A) (122 mg, 0.227 mmol) in methanol (5 mL) was added cerium(III) chloride heptahydrate (85 mg, 0.227 mmol). Sodium borohydride (2.1 mg, 0.057 mmol) was then slowly added to the mixture at 0 °C. After 5 min, the reaction was quenched by adding saturated NaHCO solution and extracted with DCM. The organic phase was separated and concentrated. The residue was then dissolved in DCM and washed with brine. The organic phase was dried over MgSO4, filtered, concentrated and used further without purification. Preparation of (3S,6S,7R)-12-(benzyloxy)-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0270] To a solution of (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (16 mg, 0.030 mmol) in DMF (1 mL) was added sodium hydride (1.8 mg, 0.045 mmol, 60%) and iodomethane (2.8 μL, 0.045 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction was quenched by adding saturated NaHCO3 and extracted with EtOAc. The organic phase was separated, dried over MgSO4, filtered, and concentrated. The resulting product was used in the next step without further purification. Preparation of (3S,6S,7R)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0271] A reaction mixture of (3S,6S,7R)-12-(benzyloxy)-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (16 mg, 0.029 mmol) in TFA (1 mL) and DCM (1 mL) was stirred at room temperature for 3 h. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC chromatography (eluting with 5-100% acetonitrile / water containing 0.1% TFA) to give the title product. MS (m / z) 464.16 [M+H] + . 1 H NMR(400MHz, methanol-d4)δ 8.47(s,1H),6.98-6.85(m,2H),6.00(ddd,J=11.6,6.6,2.6Hz,1H),5.75(dd,J=11.6,2.0Hz,1H),5.27(qt,J=7.4,2.4Hz,1H),5.00(d,J= 7.3Hz,1H),4.69(s,2H),4.29(t,J=7.0Hz,1H),3.96(dd,J=14.6,2.5Hz,1H),3.66(d,J=14.5Hz,1H),3.12(s,3H),1.39(d,J=7.4Hz,3H). Example 19: (3S,6S,7R)—N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka]

[0272] Instead of (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide, (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3 (3S,6S,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide was prepared in the same manner as in Example 18, except that N-10-carboxamide was used instead of N-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. MS (m / z) 446.22 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.50(s,1H),7.45(td,J=8.4,6.3Hz,1H),7.04-6.90(m,2H),6.00(ddd,J=11 .6,6.6,2.6Hz,1H),5.76(dd,J=11.7,2.0Hz,1H),5.28(tdt,J=7.4,4.7,2.4H z,1H),5.00(d,J=6.9Hz,1H),4.65(s,2H),4.29(t,J=7.0Hz,1H),3.97(dd,J= 14.6,2.4Hz,1H),3.66(d,J=14.5Hz,1H),3.13(s,3H),1.39(d,J=7.3Hz,3H). Example 20: (3S,6S,7R)—N-(2,4-difluorobenzyl)-6,12-dihydroxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka]

[0273] (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (10 mg, 0.19 mmol), prepared according to Example 3, was dissolved in 1 mL of toluene and 1 mL of TFA. The mixture was stirred at room temperature for 1 hour and concentrated to dryness. The residue was purified by RP-HPLC to give the title compound. MS (m / z): 432.124 [M+H]+. 1 H NMR(400MHz,DMSO-d6)δ 10.49-10.39(m,2H),8.42(s,1H),7.41(td,J=8.7,6.6Hz,1H),7.25(ddd,J=10.5,9 .3,2.6Hz,1H),7.07(td,J=8.5,2.6Hz,1H),5.67(ddd,J=11.9,5.6,2.1Hz,1H),5.57 -5.48(m,2H),5.20-5.12(m,1H),4.93(d,J=7.3Hz,1H),4.58(dd,J=13.2,6.2Hz,3H ),3.83(dd,J=14.8,2.4Hz,1H),3.68(dd,J=14.7,2.0Hz,1H),1.28(d,J=7.3Hz,3H). Example 21: (3S,6S,7R)—N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-6-d-10-carboxamide [ka]

[0274] The use of sodium borohydride instead of sodium borohydride and (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide with (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11 (3S,6S,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-6-d-10-carboxamide was prepared in the same manner as in Example 18, except that 3S,6S,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-6-d-10-carboxamide was used. MS (m / z) 447.2 [M+H] + . 1 H NMR(400MHz, methanol-d4)δ 8.50(s,1H),7.45(td,J=8.4,6.4Hz,1H),7.04-6.90(m,2H),6.00(dd,J=11.6,2.7Hz,1H),5.76(dd,J=11.6,2.0Hz,1H),5.28(dddd,J=9.9 ,7.6,4.9,2.5Hz,1H),5.00(s,1H),4.65(s,2H),3.96(dd,J=14.6,2.7Hz,1H),3.66(d,J=14.4Hz,1H),3.12(s,3H),1.39(d,J=7.3Hz,3H). Example 22: (3S,6S,7R)-6-(difluoromethoxy)-12-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Step 1: Synthesis of (3S,6S,7R)-12-(benzyloxy)-6-(difluoromethoxy)-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0275] (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (60 mg, 0.11 mmol) was dissolved in 1 mL of acetonitrile, and copper iodide (4.24 mg, 0.022 mmol) was added. The mixture was heated to 50°C, and a solution of 2-fluorosulfonyl-2,2-difluoroacetic acid (0.017 mL, 0.17 mmol) in 1 mL of acetonitrile was added dropwise. The reaction mixture was heated at 50°C for 10 minutes. It was then cooled to 0°C, and ethyl acetate was added, followed by washing with saturated aqueous sodium bicarbonate and brine. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated to dryness. The residue was purified by RP-HPLC to give the title product. MS(m / z): 590.200 [M+H]+. Step 2: Synthesis of (3S,6S,7R)-6-(difluoromethoxy)-12-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0276] (3S,6S,7R)-12-(benzyloxy)-6-(difluoromethoxy)-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (10 mg) was dissolved in 0.5 mL of toluene and 0.5 mL of TFA and stirred at room temperature for 1.5 h, then the solvent was removed and purified by RP-HPLC to give the title product. MS (m / z): 500.100 [M+H]+. 1H NMR (400MHz, methanol-d4)δ 10.54(s,1H),8.46(s,1H),6.92(t,J=8.4Hz,2H),6.25(t,J=73.1Hz,1H),5.95-5.86(m,1H),5.79(dd,J=11.8,2.3Hz,1H),5.35(d,J=7.5 Hz,1H),5.27(t,J=7.0Hz,1H),5.10(d,J=7.5Hz,1H),4.68(s,3H),3.98(d,J=14.5Hz,1H),3.74(d,J=14.6Hz,1H),1.41(d,J=7.3Hz,3H). Example 23: (3S,6S,7R)-12-Hydroxy-6-methoxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Synthesis of (3S,6S,7R)-12-(benzyloxy)-6-methoxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0277] (3S,6S,7R)-6,12-dihydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (product of Step 1 of Example 11, 25 mg, 0.045 mmol) was dissolved in anhydrous DMF (0.90 mL), and the resulting mixture was cooled to 0 °C. To this stirred, cooled mixture was added 60% sodium hydride in mineral oil (2.6 mg, 0.068 mmol), followed by iodomethane (10 mg, 0.068 mmol). After stirring for 5 minutes, the reaction was quenched with 10% aqueous citric acid. The mixture was extracted with EtOAc, and the organic layer was washed with water, then saturated aqueous sodium bicarbonate, then brine, dried over magnesium sulfate, filtered, and concentrated. Flash column chromatography (silica gel, EtOAc / hexanes) afforded the product (stereochemical assignment is tentative). H NMR (400 MHz, chloroform-d) δ 10.47 (s, 1H), 8.35 (s, 1H), 7.59-7.53 (m, 2H), 7.37-7.27 (m, 3H), 6.66 (dd, J = 8.8, 7.5 Hz, 2H), 5.63 (dd, J = 11.6, 1.8 Hz, 1H), 5.52-5.41 (m, 2H), 5.39-5.29 (m, 1H), 5. 21(d,J=10.3Hz,1H),4.66(d,J=5.4Hz,2H),4.11(s,1H),3.78(dd,J=14.5,2.9Hz, 1H),3.27(dd,J=14.5,1.3Hz,1H),3.00(s,3H),1.45(s,3H),1.29(d,J=7.4Hz,3H). LCMS-ESI+(m / z):C 30 H 28 Calculated H+ value for F3N3O5: theoretical value: 568.21, measured value: 568.19. Synthesis of (3S,6S,7R)-12-hydroxy-6-methoxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0278] (3S,6S,7R)-12-(benzyloxy)-6-methoxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (20.0 mg, 0.035 mmol) was dissolved in EtOH (1.0 mL) at room temperature and treated with 1.2 mg of 20% Pd(OH)2 / C (50 wt% water). The mixture was degassed and flushed with hydrogen three times, then stirred under a hydrogen atmosphere for 45 minutes. The reaction was then degassed, flushed with nitrogen, filtered through a pad of Celite, and concentrated. The resulting residue was purified by flash column chromatography (silica gel, dichloromethane / methanol) to give the product (stereochemical assignment is tentative). 1H NMR (400MHz, chloroform-d)δ 10.48(s,1H),6.65(dd,J=8.8,7.5Hz,2H),4.75-4.58(m,3H),3.67(dd,J=15.3,3.0Hz,1H),3.44(d,J=15.2Hz,1H),3.12(s,3 H),2.13-2.01(m,1H),1.91(dd,J=14.8,7.7Hz,1H),1.41(s,3H),1.36-1.28(m,1H),1.26(d,J=6.7Hz,3H),1.24-1.06(m,2H). LCMS-ESI+(m / z):C 23 H 24 Calculated H+ value for F3N3O5: theoretical value 480.18, measured value: 480.30. Example 24: Synthesis of (3S,6S,7R)-12-hydroxy-6-methoxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka]

[0279] (3S,6S,7R)-12-(benzyloxy)-6-methoxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (16 mg, 0.028 mmol from Step 1 of Example 23) was dissolved in 1:1 toluene:trifluoroacetic acid (1.16 mL). The resulting solution was stirred at 20° C. for 8 hours and then allowed to stand at 0° C. for 12 hours. The solution was diluted with acetonitrile and concentrated in vacuo, and the crude material was purified by flash column chromatography (silica gel, dichloromethane / methanol) to give the product (stereochemical assignment is tentative). 1H NMR (400MHz, chloroform-d)δ 10.36(s,1H),8.32(s,1H),6.65(dd,J=8.7,7.5Hz,2H),5.64(dd,J=11.6,1.8Hz,1H),5.53(dd,J=11.6,2.7Hz,1H),5.29-5.20(m,1H),4. 77-4.55(m,2H),4.23(s,1H),3.93(dd,J=14.3,3.0Hz,1H),3.54(dd,J=14.3,1.3Hz,1H),2.97(s,3H),1.45(s,3H),1.36(d,J=7.4Hz,3H). LCMS-ESI+(m / z):C 23 H 22 Calculated H+ value for F3N3O5: theoretical value 478.16, measured value: 478.25. Example 25: Preparation of (3S,6S,7R)-6-ethoxy-12-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Synthesis of (3S,6S,7R)-12-(benzyloxy)-6-ethoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0280] (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (24 mg, 0.04 mmol) was dissolved in 2 mL of anhydrous DMF, cooled to 0 °C, and NaH (1.5 equiv.) was added, followed by EtI (1.2 equiv.). After 10 min, the reaction was complete. The reaction was quenched by adding one drop of water. The crude reaction was purified by preparative HPLC eluting with 10–60% acetonitrile (0.1% TFA) in water (0.1% TFA) to give (3S,6S,7R)-12-(benzyloxy)-6-ethoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. MS (m / z) 568.24 [M+H] + . Synthesis of (3S,6S,7R)-6-ethoxy-12-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0281] At room temperature, (3S,6S,7R)-12-(benzyloxy)-6-ethoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (5 mg) was dissolved in toluene (0.5 mL) and TFA (0.5 mL) was added. The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by preparative HPLC eluting with 10-60% acetonitrile (0.1% TFA) in water (0.1% TFA). The combined fractions were lyophilized to give the title compound. MS (m / z) 478.32 [M+H] +. 1H NMR (400MHz, acetonitrile-d3) δ 8.44 (d, J = 22.1 Hz, 1H), 7.00-6.81 (m, 1H), 6.73 (t, J = 8.5 Hz, 1H), 6.02-5.84 (m, 1H), 5.79-5.60 (m, 1H), 5.24 (d, J = 7.9 Hz, 1H), 5.03 (dd, J = 42.6, 7.4 Hz, 1H), 4.82 (dd, J = 15.0, 6 .8Hz,1H),4.70-4.58(m,1H),4.52(d,J=12.9Hz,1H),4.44-4.29(m,1H),3.81(t,J=12.5 Hz,1H),3.70-3.54(m,1H),3.41(p,J=6.9Hz,1H),1.43-1.24(m,3H),0.92-0.68(m,3H). Example 26: Preparation of (3S,6S,7R)-6-ethoxy-12-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka]

[0282] (3S,6S,7R)-12-(benzyloxy)-6-ethoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (7 mg) was dissolved in 2 mL of ethanol and 2 mL of ethyl acetate. 2 mg of 10% Pd / C was added, and a hydrogen balloon was applied. After 2 hours, the catalyst was filtered off through Celite. The filtrate was concentrated. The crude reaction was purified by preparative HPLC eluting with 10–60% acetonitrile (0.1% TFA) in water (0.1% TFA) to give (3S,6S,7R)-6-ethoxy-12-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. MS (m / z) 480.27 [M+H]+ 1H NMR (400 MHz, acetonitrile-d3) δ 8.46-8.26 (m, 1H), 6.87 (t, J = 8.5 Hz, 1H), 6.69 (t, J = 8.5 Hz, 1H), 4.97-4.38 (m, 4H), 3.86-3.49 (m, 5H), 1.87 (m, 2H), 1.44 (d, J = 17.7 Hz, 2H), 1.25-1.08 (m, 3H), 1.08-0.82 (m, 3H). Example 27: (3S,6S,7R)-6-(difluoromethoxy)-12-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka]

[0283] Instead of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide, (3S,6S,7R)-12-(benzyloxy)-6-(difluoromethoxy)-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,1 Prepared in a similar manner to (3S,6S,7R)—N-(2,4-difluorobenzyl)-6,12-dihydroxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Example 16), except that 1-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (prepared according to Example 22) was used. MS (m / z): 502.137 [M+H]. 1H NMR (400MHz, methanol-d4)δ 10.56(s,1H),8.35(s,1H),6.92(t,J=8.4Hz,2H),6.58(t,J=73.8Hz,1H),4.79-4.44(m,5H),3.81(s,2H),2 .14(dt,J=14.7,7.2Hz,1H),2.02-1.81(m,1H),1.74-1.60(m,1H),1.45-1.30(m,1H),1.29(d,J=6.7Hz,3H). Example 28: Preparation of (3S,6S,7R)-6-ethyl-6,12-dihydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Synthesis of (3S,6S,7R)-12-(benzyloxy)-6-ethyl-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0284] (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (43 mg, 0.08 mmol) was dissolved in 2 mL of anhydrous THF. The mixture was cooled to 0 °C, and EtMgBr (3.4 M, 3 equiv., 0.07 mL) was added. The reaction was maintained at 0 °C for 1 hour. The reaction was quenched by the addition of one drop of water. The reaction crude was filtered and purified by preparative HPLC eluting with 10-60% acetonitrile (0.1% TFA) in water (0.1% TFA) to give (3S,6S,7R)-12-(benzyloxy)-6-ethyl-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. MS (m / z) 568.21 [M+H] + . Synthesis of (3S,6S,7R)-6-ethyl-6,12-dihydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0285] At room temperature, (3S,6S,7R)-12-(benzyloxy)-6-ethyl-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (3 mg) was dissolved in 2 mL of ethanol and 2 mL of ethyl acetate. Then, 2 mg of 10% Pd / C was added, and a hydrogen balloon was applied. After 2 hours, the catalyst was filtered off through Celite. The filtrate was concentrated. The crude reaction product was purified by preparative HPLC eluting with 10-60% acetonitrile (0.1% TFA) in water (0.1% TFA) to give the title compound. MS (m / z) 480.20 [M+H] + 1H NMR (400 MHz, acetonitrile-d3) δ 10.44 (s, 1H), 8.27 (s, 1H), 6.87 (t, J = 8.6 Hz, 2H), 6.69 (d, J = 7.5 Hz, 1H), 4.79-4.51 (m, 2H), 4.06 (m, 1H), 3.76-3.48 (m, 3H), 1.90-1.74 (m, 2H), 1.65 (td, J = 14.8, 7.5 Hz, 2H), 1.49-1.32 (m, 1H), 1.32-1.09 (m, 4H), 0.96 (t, J = 7.2 Hz, 3H). Example 29: Synthesis of (1R,10S,13S)-6,13-dihydroxy-10-methyl-5,8-dioxo-13-(trideuteriomethyl)-N-[(2,4,6-trifluorophenyl)methyl]-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide [ka]

[0286] To a cold solution of (1R,10S)-6-benzyloxy-10-methyl-5,8,13-trioxo-N-[(2,4,6-trifluorophenyl)methyl]-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide (50 mg, 0.093 mmol) in THF (1.0 mL) at 0 °C was added 1.0 M CD3MgI (0.279 mmol, 0.279 mL) in diethyl ether. The reaction was stirred at 0 °C for 30 minutes before it was quenched with ice and methanol. The reaction was then concentrated, redissolved in DMF, filtered, and purified by reverse-phase preparative HPLC. LCMS-ESI+ (m / z): H+ calculated for C22H17D3F3N3O5, theoretical: 466.15, found: 467.35. 1H NMR (400 MHz, DMSO-d6) δ 10.46(t,J=5.8Hz,1H),8.36(s,1H),7.21(t,J=8.6Hz,2H),5.54(dd,J=11 .8,2.3Hz,1H),5.39(dd,J=11.8,2.6Hz,1H),5.32(s,1H),5.13(dt,J=7.3 ,2.6Hz,1H),4.67(d,J=2.3Hz,1H),4.59(dt,J=11.3,6.0Hz,2H),3.86(dd ,J=14.8,2.6Hz,1H),3.63(dd,J=14.8,1.9Hz,1H),1.27(d,J=7.3Hz,3H). Example 30: Synthesis of (1R,10S,13S)—N-[(2,4-difluorophenyl)methyl]-6,13-dihydroxy-10-methyl-5,8-dioxo-13-(trideuteriomethyl)-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide: [ka]

[0287] The title compound was prepared according to the same method as the synthesis of Example 29, except that (1R,10S)-6-benzyloxy-10-methyl-5,8,13-trioxo-N-[(2,4,6-trifluorophenyl)methyl]-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide was used instead of (1R,10S)-6-benzyloxy-10-methyl-5,8,13-trioxo-N-[(2,4,6-trifluorophenyl)methyl]-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide. LCMS-ESI+(m / z): H+ calculated value of C22H18D3F2N3O5, theoretical value: 448.16, measured value: 449.23. 1H NMR (400MHz, DMSO-d6)δ 10.44(t,J=5.9Hz,1H),8.38(s,1H),7.42(td,J=8.7,6.6Hz,1H),7.25(ddd,J=11.9,9 .3,2.6Hz,1H),7.08(td,J=8.5,2.7Hz,1H),5.54(dd,J=11.9,2.3Hz,1H),5.40(dd,J=1 1.9,2.6Hz,2H),5.13(dt,J=7.1,2.3Hz,1H),4.70(d,J=2.2Hz,1H),4.56(d,J=5.9Hz, 2H), 3.87(dd,J=14.7,2.7Hz,1H),3.65(dd,J=14.7,1.9Hz,1H),1.28(d,J=7.3Hz,3H). Example 31: Synthesis of (1R,10S,13S)—N-[(2,4-difluorophenyl)methyl]-6,13-dihydroxy-10-methyl-5,8-dioxo-13-(trideuteriomethyl)-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide: [ka] Step 1: Synthesis of (1R,10S)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-methyl-5,8,13-trioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide:

[0288] To a solution of (1R,10S)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-methyl-5,8,13-trioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide (215 mg, 0.41 mmol) in EtOH (50 mL) at room temperature was added 20% Pd(OH)2 / C (50 mg, 50 wt % water). The resulting suspension was degassed and flushed with nitrogen three times, then degassed and flushed with hydrogen three times before hydrogenating under a hydrogen balloon for 3 hours. The reaction was then degassed, flushed with nitrogen, and filtered through a pad of Celite. The filtrate was concentrated and dried on a vacuum line. The residue was then dissolved in DMF (4.0 mL) and treated with potassium carbonate (171 mg, 1.24 mmol) and benzyl bromide (212 mg, 1.24 mmol) at room temperature overnight. The reaction was then diluted with EtOAc, washed with water, then brine, dried over sodium sulfate, filtered, concentrated, and purified by normal phase chromatography. Step 2: Synthesis of (1R,10S,13S)-N-[(2,4-difluorophenyl)methyl]-6,13-dihydroxy-10-methyl-5,8-dioxo-13-(trideuteriomethyl)-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide:

[0289] The compound was prepared according to the synthesis of Example 29, except that (1R,10S)-6-benzyloxy-10-methyl-5,8,13-trioxo-N-[(2,4,6-trifluorophenyl)methyl]-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide was used instead of (1R,10S)-6-benzyloxy-10-methyl-5,8,13-trioxo-N-[(2,4-difluorophenyl)methyl]-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide. LCMS-ESI+ (m / z): H+ calculated for C22H20D3F2N3O5, theoretical: 450.18, found: 451.28. 1H NMR (400 MHz, DMSO-d6) δ 10.98(s,1H),10.46(t,J=6.0Hz,1H),8.34(s,1H),7.40(td,J=8.7,6.6Hz,1H) ,7.25(ddd,J=10.5,9.3,2.6Hz,1H),7.07(td,J=8.5,2.6Hz,1H),4.93(s,1H),4 .56(d,J=5.9Hz,2H),4.47(dt,J=10.4,6.5Hz,1H),4.28(s,1H),3.67(t,J=2.5 Hz,2H),1.87(dt,J=14.4,7.0Hz,1H),1.52-1.34(m,2H),1.17(t,J=7.6Hz,4H). Example 32: Synthesis of (3S,6R,7R)-6,12-dihydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: [ka] Synthesis of (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0290] To (1R,10S,13S)-6,13-dihydroxy-10,13-dimethyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide (Example 11, 165 mg, 0.355 mmol) was added DMF (7.0 mL), followed by potassium carbonate and then benzyl bromide. The mixture was stirred at 20° C. for 4 h. The reaction was extracted with EtOAc, and the organic layer was washed with water, then brine, dried over magnesium sulfate, filtered, and concentrated. Flash column chromatography (silica gel, EtOAc / hexanes) gave the product (stereochemical assignment is tentative). 1H NMR (400 MHz, chloroform-d) δ 10.40(t,J=5.6Hz,1H),8.46(s,1H),7.59-7.49(m,2H),7.39-7.27(m,3H),6.62(dd,J=8.8,7.4Hz,2H),5.2 8(d,J=10.3Hz,1H),5.15(d,J=10.3Hz,1H),4.78(dt,J=10.5,6.7Hz,1H),4.57(dd,J=14.5,5.7Hz,1H),4.4 9(dd,J=14.5,5.4Hz,1H),4.38(s,1H),4.03(s,1H),3.26(dd,J=15.3,3.0Hz,1H),3.06(dd,J=15. 0,1.5Hz,1H),1.98(dt,J=13.4,6.8Hz,1H),1.62-1.47(m,2H),1.39(s,3H),1.15(d,J=6.7Hz,3H). LCMS-ESI+(m / z):C 23 H 22 Calculated H+ value for F3N3O5: theoretical value 556.21, measured value: 556.20. Synthesis of (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0291] (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (82 mg, 0.148 mmol) was dissolved in toluene (4.1 mL), and then martensulfurane (506 mg, 0.75 mmol) was added. The mixture was stirred at 20° C. for 1 hour. The reaction mixture was directly purified by flash column chromatography (silica gel, EtOAc / hexane) to give the product. 1H NMR (400 MHz, chloroform-d) δ 10.43(t,J=5.8Hz,1H),8.47(s,1H),7.64-7.53(m,2H),7.42-7.30(m,3H),6.68(dd,J=8.7,7.5Hz,2H), 5.56(d,J=10.2Hz,1H),5.31(s,1H),5.21-5.11(m,2H),4.86(dp,J=10.2,6.7Hz,1H),4.68(d,J=5.7Hz,2 H),4.60(s,1H),3.52(dd,J=14.9,2.6Hz,1H),3.44(dd,J=14.9,1.9Hz,1H),2.36(dd,J=14.9,7.3Hz,1H ),2.22(dt,J=14.2,7.0Hz,1H),2.02-1.92(m,1H),1.35(dt,J=14.5,10.8Hz,1H),1.22(d,J=6.8Hz,3H). LCMS-ESI+(m / z):C 29 H 26 Calculated H+ value for F3N3O4: theoretical value 538.20, measured value: 538.16. Synthesis of (2R,3'S,7'R)-12'-(benzyloxy)-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,7'H-spiro[oxirane-2,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide:

[0292] (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (30 mg, 0.0558 mmol) was dissolved in dichloromethane (3.0 mL), and then 3-chloroperoxybenzoic acid (88 mg, 0.391 mmol) was added. The mixture was stirred at 45° C. in a metal heating block for 48 hours. The reaction mixture was diluted with additional dichloromethane, and the organic phase was washed with 2N aqueous sodium hydroxide solution followed by brine. The combined aqueous phase was extracted with additional dichloromethane. The combined organic phase was dried over magnesium sulfate, filtered, and concentrated. Flash column chromatography (silica gel, EtOAc / hexanes) afforded the product (stereochemical assignment is tentative). 1H NMR (400 MHz, chloroform-d) δ 10.33 (s, 1H), 8.33 (s, 1H), 7.61-7.51 (m, 2H), 7.32 (dd, J = 12.1, 7.2 Hz, 3H), 6.67 (t, J = 8.1 Hz, 2H), 5.54 (d, J = 10.2 Hz, 1H), 5.17 (d, J = 10.2 Hz, 1H), 4.90 (dt, J = 10.7, 6.6 Hz, 1H), 4.66 (dd, J = 5.6, 3.1 Hz, 2H). H),3.64(dd,J=14.9,1.8Hz,1H),3.52(s,1H),3.44(dd,J=15.1,2.5Hz,1H),3.21(d,J=3.7Hz,1H),2 .79(d,J=3.7Hz,1H),2.07-1.98(m,1H),1.79(ddd,J=39.5,15.0,11.6Hz,2H),1.24(d,J=6.8Hz,3H). LCMS-ESI+(m / z):C 29 H 26 Calculated H+ value for F3N3O5: theoretical value 554.19, measured value: 554.21. Synthesis of (3S,6R,7R)-6,12-dihydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0293] ((2R,3'S,7'R)-12'-(benzyloxy)-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,7'H-spiro[oxirane-2,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (4 mg, 0.007 mmol) was dissolved in ethanol (0.5 mL), and then ammonium formate (23 mg, 0.36 mmol) was added, followed by 10% palladium on carbon (1.54 mg, 0.0015 mmol). The mixture was stirred at 70 °C in a metal heating block for 12 h. The reaction mixture was 1:1 Dilution with DMF:water, filtration, and purification by reverse-phase HPLC (acetonitrile / water, 0.1% trifluoroacetic acid) gave the product (stereochemical assignment is tentative). 1H NMR (400 MHz, DMSO-d6) δ 11.00(s,1H),10.45-10.33(m,1H),8.35(s,1H),7.21(t,J=8.8Hz,2H) ,5.16(s,1H),4.56(d,J=5.5Hz,2H),4.48(s,1H),4.27(s,1H),3.70(d, J=14.9Hz,1H),3.60(d,J=14.7Hz,1H),1.87-1.75(m,2H),1.75-1.65(m,1H),1.52(dd,J=16.0,6.6Hz,1H),1.16(d,J=7.0Hz,3H),1.02(s,3H). LCMS-ESI+(m / z):C 22 H 22 Calculated H+ value for F3N3O5: theoretical value 466.16, measured value: 466.27. Example 33: Synthesis of (1R,10S,13R)-N-[(2,4-difluorophenyl)methyl]-6,13-dihydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide: [ka] Step 1: Synthesis of (1R,10S)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-13-hydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide:

[0294] (1R,10S)-6-Benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-methyl-5,8,13-trioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide (200 mg, 0.384 mmol) was dissolved in THF (4.0 mL) and cooled to 0 °C. To this cold mixture was added dropwise 3.0 M MeMgBr in EtO (0.38 mL, 1.15 mmol). The reaction was stirred at 0 °C for 20 minutes and then quenched with ice-water. The mixture was then diluted with EtOAc, washed with saturated ammonium chloride, washed with brine, dried over sodium sulfate, filtered, concentrated, and purified by normal phase chromatography. LCMS-ESI+ (m / z): H+ calculated for C29H29F2N3O5, theoretical: 537.21, found: 538.17. Step 2: Synthesis of (1S,10S)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-methyl-13-methylene-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide:

[0295] (1R,10S)-6-Benzyloxy-N-[(2,4-difluorophenyl)methyl]-13-hydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide (81 mg, 0.151 mmol) was dissolved in toluene (3.0 mL) at room temperature and treated with Martinsulfurane dehydrating reagent (507 mg, 0.753 mmol) for 20 minutes. The reaction was concentrated and purified by normal phase chromatography. LCMS-ESI+ (m / z): H+ calculated for CHFNO, calculated: 519.20, found: 520.22. Step 3: Synthesis of (1R,10S,13R)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-methyl-5,8-dioxo-spiro[2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-13,2′-oxirane]-4-carboxamide:

[0296] (1S,10S)-6-Benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-methyl-13-methylene-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide (57 mg, 0.11 mmol) was dissolved in DCE (2.0 mL) and treated with MCPBA (56.8 mg, 0.329 mmol) at 60 °C for 3 h. The reaction was cooled to room temperature, diluted with DCM, mixed with a 1:1 mixture of 1N sodium thiosulfate and saturated sodium bicarbonate, and stirred vigorously for 10 min. The layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered, concentrated, and purified by normal phase chromatography. LCMS-ESI+(m / z): H+ calculated for C29H27F2N3O5, theoretical: 535.19, found: 536.17. Step 4: Synthesis of (1R,10S,13R)-N-[(2,4-difluorophenyl)methyl]-6,13-dihydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide:

[0297] (1R,10S,13R)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-methyl-5,8-dioxo-spiro[2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-13,2'-oxirane]-4-carboxamide (10 mg, 0.0187 mmol) was dissolved in EtOH (0.5 mL) and treated with ammonium formate (59 mg, 0.934 mmol) and 10% Pd / C (3.97 mg). The resulting mixture was degassed and flushed with nitrogen three times, then heated under nitrogen at 70 °C for 3 h. The reaction was then cooled to room temperature, filtered, concentrated, redissolved in DMF, filtered, and purified by reverse-phase preparative HPLC. LCMS-ESI+ (m / z): H+ calculated for C22H23F2N3O5, theoretical: 447.16, found: 448.256. 1H NMR (400 MHz, DMSO-d6) δ 11.04(s,1H),10.37(t,J=6.0Hz,1H),8.38(s,1H),7.41(td,J=8.6,6.5 Hz,1H),7.34-7.18(m,1H),7.08(td,J=8.6,2.7Hz,1H),5.16(s,1H),4. 52(dt,J=22.6,6.3Hz,3H),4.30(s,1H),3.75-3.61(m,2H),1.92-1.64( m,2H),1.53(dd,J=15.3,6.7Hz,1H),1.17(d,J=6.7Hz,4H),1.03(s,3H). Example 34: (3S,6S,7R)—N-(2,4-difluorobenzyl)-12-hydroxy-6-(methoxy-d3)-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Preparation of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(methoxy-d3)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0298] The use of iodomethane-d3 instead of iodomethane and (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide were also noted. (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide was prepared similarly to (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide in Example 18, except that: Preparation of (3S,6S,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-6-(methoxy-d3)-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0299] To a solution of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(methoxy-d3)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (35 mg, 0.065 mmol) in EtOH (3 mL) was added Pd / C (10 mg). The reaction mixture was stirred at room temperature under a H2 balloon. After completion of the reaction, the reaction mixture was filtered through Celite, the filtrate was concentrated, and the residue was purified by reverse-phase chromatography (eluting with 5-100% acetonitrile / water containing 0.1% TFA) to give the title compound. MS (m / z) 451.2 [M+H] + . 1 H NMR(400MHz, methanol-d4)δ 8.36(s,1H),7.45(q,J=8.3Hz,1H),7.04-6.85(m,2H),4.80-4.53(m,4H),3.94-3.64(m,2H),3.55(d,J=11.7H) z,1H),2.19-1.96(m,2H),1.54(dt,J=14.5,11.2Hz,1H),1.28(d,J=6.7Hz,3H),1.01(dt,J=14.8,11.6Hz,1H). Example 35: Synthesis of (1R,10R,13S)—N-[(2,4-difluorophenyl)methyl]-6,13-dihydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide: [ka] Step 1: Synthesis of methyl (3S,7R)-3-amino-7-methyl-1,2,4,7-tetrahydroazepine-3-carboxylate: 2,2,2-trifluoroacetic acid:

[0300] O1-Benzyl O3-methyl (3S,7R)-3-(benzyloxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1,3-dicarboxylate (1.2 g, 2.65 mmol) was mixed with TFA (10.0 mL). The resulting mixture was sealed and heated at 100 °C for 4 h. The reaction was cooled to room temperature, concentrated, and the residue was co-evaporated four times with EtOAc to give the desired product, which was used directly in the next step. LCMS-ESI+ (m / z): H+ calculated for C9H16N2O2, theoretical: 184.12, found: 185.01. Step 2: Synthesis of (1S,10R)-6-benzyloxy-4-[(2,4-difluorophenyl)methylcarbamoyl]-10-methyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-1-carboxylic acid:

[0301] The residue from the previous step (2.36 g, 5.72 mmol) and methyl 3-benzyloxy-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyran-2-carboxylate (1.08 g, 2.52 mmol) were suspended in a mixture of THF (6.0 mL), ethanol (1.0 mL), and triethylamine (5.36 g, 53 mmol). The resulting mixture was heated at 40 °C overnight. The reaction was cooled to room temperature. The residue was partitioned between EtOAc and water, and the organic layer was washed with 10% citric acid, water, brine, dried over sodium sulfate, filtered, concentrated, and purified by normal phase chromatography. LCMS-ESI+ (m / z): H+ calculated for CHFNO, calculated: 549.17, found: 550.10. Step 3: Synthesis of (1R,10R)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-methyl-5,8,13-trioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide:

[0302] (1S,10R)-6-Benzyloxy-4-[(2,4-difluorophenyl)methylcarbamoyl]-10-methyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-1-carboxylic acid (470 mg, 0.855 mmol) was dissolved in 1,4-dioxane (8.0 mL) and treated with selenium dioxide (753 mg, 6.84 mmol) at 100 °C for 8 h. The reaction was cooled to room temperature, filtered, concentrated, and purified by normal phase chromatography. LCMS-ESI+ (m / z): H+ calculated for CHFNO, calculated: 519.16, found: 520.04. Step 4: Synthesis of (1R,10R,13S)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-13-hydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide:

[0303] The compound was prepared according to step 1 of the preparation of Example 17, except that (1R,10S)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-methyl-5,8,13-trioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide was used instead of (1R,10R)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-methyl-5,8,13-trioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide. LCMS-ESI+ (m / z): H+ calculated for C29H27F2N3O5, theoretical: 535.19, found: 536.13. Stereochemistry at C13 was not confirmed. Step 5: Synthesis of (1R,10R,13S)—N-[(2,4-difluorophenyl)methyl]-6,13-dihydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide:

[0304] (1R,10R,13S)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-13-hydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide (40 mg, 0.0747 mmol) was dissolved in EtOH (10 mL) at room temperature. To this mixture was added 10% Pd / C (30 mg) and ammonium formate (235 mg, 3.73 mmol). The resulting mixture was degassed and flushed with nitrogen, and then heated at 70 °C for 1 h. The reaction was cooled to room temperature, filtered, concentrated, and purified by reverse-phase preparative HPLC. The stereochemistry at C13 was not confirmed. LCMS-ESI+ (m / z): H+ calculated for C22H23F2N3O5, theoretical: 447.16, found: 448.23. 1H NMR (400 MHz, acetone-d6) δ 11.11(s,1H),10.55(s,1H),8.32(s,1H),7.53-7.44(m,1H),7.08-6.96(m,2H) ),4.62(t,J=4.5Hz,2H),4.53-4.46(m,1H),4.08(dd,J=15.2,2.1Hz,1H),3.83 (dd,J=15.1,2.5Hz,1H),3.73(dt,J=14.5,7.0Hz,1H),2.18(q,J=5.6,5.0Hz, 1H),2.05-1.89(m,3H),1.87-1.77(m,1H),1.74(d,J=7.1Hz,3H),1.55(s,3H). Intermediate C: (3S,7S)-12-(benzyloxy)-3-methyl-1,4,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,4,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka]

[0305] (3S,7S)-12-(benzyloxy)-3-methyl-1,4,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,4,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Intermediate C) was synthesized in a similar manner to Intermediate A and isolated as a further product from the same reaction conditions. 1H NMR (400 MHz, chloroform-d) δ 10.41(t,J=5.8Hz,1H),8.66(s,1H),7.58-7.46(m,2H),7.41-7.27(m,3H),6.7 6-6.56(m,2H),6.31(d,J=12.4Hz,1H),6.11(d,J=12.2Hz,1H),5.50(d,J=10.2H) z,1H),5.28(q,J=7.0Hz,1H),5.15(d,J=10.2Hz,1H),4.98(s,1H),4.66(d,J=5. 7Hz,2H), 3.75(d,J=15.0Hz,1H),3.50(d,J=14.9Hz,1H),1.46(d,J=7.0Hz,3H). LCMS-ESI+(m / z):C 28 H 22 Calculated H+ value for F3N3O5: theoretical value 538.16, measured value: 538.10. Example 36: Preparation of (3S,6R,7R)-4,4-difluoro-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Step 1: Synthesis of (3S,6R,7R)-12-(benzyloxy)-6-methoxy-3-methyl-1,4,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0306] To (3S,7S)-12-(benzyloxy)-3-methyl-1,4,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,4,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Intermediate C, 50 mg, 0.093 mmol) was added triethylamine hydrochloride (12.8 mg, 0.093 mmol), followed by methanol (2.0 mL), followed by water (0.5 mL), followed by triethylamine (30 μL, 0.214 mmol), followed by potassium cyanide (6.0 mg, 0.093 mmol). The reaction was stirred at 60° C. in a metal heating block for 1 hour. The reaction was partitioned between EtOAc and 10% aqueous sodium carbonate. The organic phase was washed with saturated aqueous ammonium chloride and then brine. The aqueous NaCO phase was extracted with additional ethyl acetate. The combined organic phases were dried over MgSO, filtered, and concentrated in vacuo. Flash column chromatography (silica gel, EtOAc / hexanes) afforded the product (stereochemical assignment is tentative). H NMR (400 MHz, chloroform-d) δ 10.27 (t, J = 6.0 Hz, 1H), 8.52 (s, 1H), 7.61-7.48 (m, 2H), 7.46-7.29 (m, 3H), 6.67 (dd, J = 8.7, 7.5 Hz, 2H), 5.57 (d, J = 10.3 Hz, 1H), 5.16 (d, J = 10.3 Hz, 1H), 5.10 (d, J = 7.0 Hz, 1H), 4.67 (dd, J = 5.7, 3.6 Hz). ,2H),4.24(s,1H),3.80(t,J=4.1Hz,1H),3.55(dt,J=15.3,1.8Hz,1H),3.48(s,3H),3.45(dd,J=1 5.2,1.8Hz,1H),2.91(dd,J=13.6,5.7Hz,1H),2.70(dd,J=13.5,1.6Hz,1H),1.36(d,J=7.0Hz,3H). LCMS-ESI+(m / z):C 29 H 26 Calculated H+ value for F3N3O6: theoretical value 570.18, measured value: 570.13. Step 2: Synthesis of (3S,6R,7R)-12-(benzyloxy)-4,4-difluoro-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0307] To (1R,10S,13S)-6,13-dihydroxy-10,13-dimethyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide (50 mg, 0.355 mmol) was added DCM (0.88 mL), followed by a 2.7 M solution of Deoxo-Fluor in toluene (3.25 mL, 8.8 mmol). The mixture was stirred at 20° C. for 60 h. The reaction was quenched by slow addition to ice-cold 10% aqueous potassium carbonate solution and then extracted with EtOAc. The organic layer was washed with saturated aqueous ammonium chloride, then brine, dried over magnesium sulfate, filtered, and concentrated. Flash column chromatography (silica gel, EtOAc / hexanes) gave the product (stereochemical assignment is tentative). LCMS-ESI+ (m / z): C 29 H 26 Calculated H+ value for F5N3O5: theoretical value 592.19, measured value: 592.11. Step 3: Synthesis of (3S,6R,7R)-4,4-difluoro-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0308] (3S,6R,7R)-12-(benzyloxy)-4,4-difluoro-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (30 mg) was dissolved in 1:1 toluene:trifluoroacetic acid (2.2 mL). The resulting solution was stirred at 60° C. for 30 minutes. The solution was diluted with acetonitrile and concentrated in vacuo, and the resulting crude material was purified by reverse-phase preparative HPLC (acetonitrile / water, 0.1% trifluoroacetic acid). The crude residue was further washed with a minimal amount of dichloromethane to afford the product (stereochemical assignment is tentative). 1H NMR (400MHz, acetonitrile-d3)δ 10.29(s,1H),8.39(s,1H),6.88(dd,J=9.2,8.1Hz,2H),4.95(dt,J=13.8,7.0Hz,1H),4.63(d,J=5.9Hz,2H),4.49(d,J=2.9Hz,1H),3.91(d d,J=15.4,2.6Hz,1H),3.75-3.61(m,2H),3.38(s,3H),2.58(ddd,J=27.6,15.6,8.5Hz,1H),2.36-2.21(m,1H),1.39(dd,J=7.2,2.8Hz,3H). LCMS-ESI+(m / z):C 22 H 20 Calculated H+ value for F5N3O5: theoretical value 502.14, measured value: 502.24. Example 37: (3S,4S,6R,7R)-4-fluoro-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Step 1: Synthesis of (3S,4R,6R,7R)-12-(benzyloxy)-4-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0309] A mixture of (3S,6R,7R)-12-(benzyloxy)-6-methoxy-3-methyl-1,4,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (770.8 mg, 1.35 mmol) prepared according to Example 36 in methanol (30 mL) was stirred at 0 °C, and NaBH (57.7 mg, 1.53 mmol) was added. After 3 minutes, the insoluble material was dissolved with THF (approximately 10 mL). The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (approximately 50 mL), saturated NaHCO (approximately 25 mL), and water (approximately 25 mL). After separation of the two layers, the aqueous fraction was extracted with ethyl acetate (approximately 50 mL). The two organic fractions were washed with brine, combined, dried (MgSO), and concentrated. The residue was purified by column chromatography on silica gel (80 g column) eluting with 0–10% methanol in CHCl to give (3S,4R,6R,7R)-12-(benzyloxy)-4-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. ES / MS m / z: calculated for C H F N O (M+H), theoretical 572.20; found: 572.20. Step 2: Synthesis of (3S,4S,6R,7R)-12-(benzyloxy)-4-fluoro-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0310] A solution of (3S,4R,6R,7R)-12-(benzyloxy)-4-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (811.2 mg, 1.42 mmol) in CHCl (14 mL) was stirred at 0° C. while adding a 2.7 M solution of Deoxo-Fluor (bis(2-methoxyethyl)aminosulfur trifluoride) in toluene (1.39 mL, 3.75 mmol). After 30 min, the reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled and stirred at 0° C. while adding saturated NaHCO (approximately 40 mL). After adding water (approximately 40 mL), the product was extracted with ethyl acetate (approximately 70 mL × 2). The extract was washed with brine (approximately 70 mL × 1), and the combined organic fractions were dried (MgSO). The residue was purified by column chromatography on silica gel (80 g column) eluting with 50–100% ethyl acetate in hexane to give (3S,4S,6R,7R)-12-(benzyloxy)-4-fluoro-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: ES / MS m / z: calculated for CHFNO (M+H): 574.20, found: 574.30.

[0311] Step 3: Synthesis of (3S,4S,6R,7R)-4-fluoro-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0312] (3S,4S,6R,7R)-12-(benzyloxy)-4-fluoro-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (556.5 mg, 0.970 mmol) was dissolved in toluene (0.25 mL) and trifluoroacetic acid (10 mL). The resulting mixture was stirred at room temperature for 1 hour and at 60°C for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (approximately 25 mL) and then washed with saturated NaHCO (approximately 25 mL). The two layers were separated, and the aqueous fraction was extracted with ethyl acetate (approximately 25 mL). The organic fractions were washed with brine, combined, dried (MgSO), and concentrated. The residue was purified by column chromatography on silica gel (50 g column) eluting with 0-10% methanol / CH2Cl2 to give the product.The impure product was purified again using column chromatography on silica gel (40 g column) eluting with 0-10% methanol in ethyl acetate to give (3S,4S,6R,7R)-4-fluoro-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: 1H NMR (400 MHz, acetonitrile-d3) δ 10.62(s,1H),10.31(t,J=6.0Hz,1H),8.37(s,1H),6.84(t,J=8.5Hz,2H ),5.01-4.70(m,2H),4.60(d,J=5.9Hz,2H),4.48(q,J=2.4Hz,1H),3.91 19F NMR(376MHz,acetonitrile-d3)δ -111.21(ddd,J=15.3,9.1,6.1Hz),-113.91(t,J=7.0Hz),-193.86(ddd,J=46.9,31.9,16.7Hz);ES / MS m / z: C22H22F4N3O5 (M+H) calculated value: 484.15, measured value: 484.20. Example 38: (3S,4R,6R,7R)-4-fluoro-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Step 1: Synthesis of (3S,4S,6R,7R)-12-(benzyloxy)-6-methoxy-3-methyl-1,11-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-4-ylbenzoate:

[0313] To (3S,4R,6R,7R)-12-(benzyloxy)-4-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (prepared according to Example 37, 45 mg, 0.079 mmol) was added 2-methyltetrahydrofuran (1.6 mL), followed by triphenylphosphine (54 mg, 0.205 mmol), followed by benzoic acid (25 mg, 0.205 mmol), followed by diisopropyl azodicarboxylate (41 mg, 0.205 mmol). The reaction was stirred at 20° C. for 1.5 hours. The reaction was then diluted with dichloromethane and concentrated in vacuo. Flash column chromatography (silica gel, EtOAc / hexanes) gave the product (stereochemical assignment is tentative). LCMS-ESI+(m / z): C 36 H 32 Calculated H+ value for F3N3O7: theoretical value 676.23, measured value: 676.13. Step 2: Synthesis of (3S,4S,6R,7R)-12-(benzyloxy)-4-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0314] To (3S,4S,6R,7R)-12-(benzyloxy)-6-methoxy-3-methyl-1,11-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-4-ylbenzoate (65 mg, 0.0962 mmol) was added methanol (2 mL), then THF (2 mL), then water (0.5 mL), then lithium hydroxide monohydrate (40 mg, 0.962 mmol). The reaction was stirred at 20° C. for 1.5 hours. The reaction was then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic layer was further washed with brine, dried over MgSO4, and concentrated in vacuo. Flash column chromatography (silica gel, EtOAc / hexanes) afforded the product (stereochemical assignment is tentative). 1H NMR (400 MHz, chloroform-d) δ 10.35 (t, J = 5.8 Hz, 1H), 8.46 (s, 1H), 7.57-7.48 (m, 2H), 7.34 (d, J = 6.6 Hz, 3H), 6.72-6.61 (m, 2H), 5.50 (d, J = 10.3 Hz, 1H), 5.13 (d, J = 10.3 Hz, 1H), 4.74-4.59 (m, 2H), 4.53-4.43 (m, 1H), 4.12 (d,J=7.0Hz,1H),3.86(t,J=9.3Hz,1H),3.64-3.57(m,1H),3.45(s,3H),3.45-3.38(m,1H),3. 36-3.27(m,1H),2.18-2.10(m,1H),1.76(ddd,J=15.4,10.6,1.5Hz,1H),1.34(d,J=6.8Hz,3H). LCMS-ESI+(m / z):C 29 H 28 Calculated H+ value for F3N3O6: theoretical value 572.20, measured value: 572.16. Step 3: Synthesis of (3S,4R,6R,7R)-12-(benzyloxy)-4-fluoro-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0315] To (3S,4S,6R,7R)-12-(benzyloxy)-4-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (13 mg, 0.0227 mmol) was added DCM (1.3 mL), followed by a 2.7 M solution of Deoxo-Fluor in toluene (0.020 mL, 0.0546 mmol). The mixture was stirred at 20°C for 1.5 hours. The reaction was quenched by slow addition to ice-cold 10% aqueous potassium carbonate solution and then extracted with EtOAc. The organic layer was washed with saturated aqueous ammonium chloride, then brine, dried over magnesium sulfate, filtered, and concentrated. Preparative thin-layer chromatography (silica gel, EtOAc) gave the product (stereochemical assignment is tentative). 1H NMR (400 MHz, chloroform-d) δ 10.35 (t, J = 5.7 Hz, 1H), 8.50 (s, 1H), 7.61-7.46 (m, 2H), 7.44-7.27 (m, 3H), 6.67 (dd, J = 8.7, 7.5 Hz, 2H), 5.54 (d, J = 10.3 Hz, 1H), 5.13 (d, J = 10.3 Hz, 1H), 4.93-4.85 (m, 1H), 4.67 (d, J = 5.6 Hz, 2H), 4.28 ( d,J=2.2Hz,1H),3.87(dd,J=15.0,2.1Hz,1H),3.70(s,1H),3.45(s,3H),3.42-3.36(m,1H),2.63(d t,J=15.9,6.3Hz,1H),1.78-1.68(m,1H),1.63(dd,J=15.8,2.8Hz,1H),1.34(dd,J=6.8,2.6Hz,3H). LCMS-ESI+(m / z):C 29 H 27 Calculated H+ value for F4N3O5: theoretical value 574.20, measured value: 574.14. Step 4: Synthesis of (3S,4R,6R,7R)-4-fluoro-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0316] (3S,4R,6R,7R)-12-(benzyloxy)-4-fluoro-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (7 mg) was dissolved in 1:1 toluene:trifluoroacetic acid (0.48 mL). The resulting solution was stirred at 60° C. for 30 minutes. The solution was diluted with acetonitrile and concentrated in vacuo, and the resulting crude was purified by reverse-phase preparative HPLC (acetonitrile / water, 0.1% trifluoroacetic acid) to give the product (stereochemical assignment is tentative). 1H NMR (400MHz, acetonitrile-d3)δ 10.31(s,1H),8.37(s,1H),6.85(dd,J=9.1,8.0Hz,2H),5.00-4.73(m,2H),4.60(d,J=5.7Hz,2H),4.48(d,J=2.5Hz,1H),3.91(dd,J=15.1,2. 3Hz,1H), 3.65(d,J=8.1Hz,1H),3.63(s,1H),3.37(s,3H),2.53(ddd,J=15.3,8.2,6.4Hz,1H),1.86-1.66(m,1H),1.33(dd,J=7.1,2.7Hz,3H). LCMS-ESI+(m / z):C 22 H 21 Calculated H+ value for F4N3O5: theoretical value 484.15, measured value: 484.23. Example 39: (3S,4R,6S,7R)-4-fluoro-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Step 1: Synthesis of ((3S,4S,6S,7R)-12-(benzyloxy)-4-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0317] To (3S,6S,7R)-12-(benzyloxy)-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (50 mg, 0.0903 mmol, from Step 2 of Example 1) was added isopropanol (2.5 mL), followed by phenylsilane (20 mg, 0.181 mmol), followed by benzoic acid (25 mg, 0.205 mmol), followed by tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (1.6 mg, 0.0027 mmol). The reaction was cycled between vacuum and oxygen three times, then vigorously stirred under oxygen at 20° C. for 45 minutes, after which additional tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (0.5 mg, 0.0009 mmol) was added. The reaction was vigorously stirred under oxygen at 20° C. for 45 minutes. 1N aqueous sodium thiosulfate solution was then added, and the phases were mixed for 60 minutes. The reaction was then extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Flash column chromatography (silica gel, EtOAc / hexanes) provided the product as the major diastereomer (stereochemical assignment is tentative). 1H NMR (400 MHz, chloroform-d) δ 10.43(s,1H),8.48(s,1H),7.66-7.50(m,2H),7.46-7.27(m,3H),6.66(t,J=8 .1Hz,2H),5.42(d,J=10.3Hz,1H),5.14(d,J=10.3Hz,1H),4.72-4.59(m,2H),4 .54(q,J=7.2Hz,1H),4.40(s,1H),3.52-3.28(m,3H),3.41(s,3H),3.12(d,J= 15.3Hz, 1H), 2.06 (d, J=13.2Hz, 1H), 1.72-1.57 (m, 1H), 1.33 (d, J=6.7Hz, 3H). LCMS-ESI+(m / z):C 29 H 28 Calculated H+ value for F3N3O6: theoretical value 572.20, measured value: 572.02. Steps 2-3: Synthesis of (3S,4R,6S,7R)-4-fluoro-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0318] In a manner similar to Example 38, (3S,4R,6S,7R)-4-fluoro-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide was synthesized starting from (3S,4S,6S,7R)-12-(benzyloxy)-4-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. 1H NMR (400MHz, acetonitrile-d3) δ 10.33(s,1H),8.27(s,1H),6.84(t,J=8.5Hz,2H),5.03(ddd,J=48.0,7.1,4.9 Hz,1H),4.79-4.63(m,2H),4.60(d,J=5.8Hz,2H),3.90(ddd,J=11.8,5.1,3.7H z,1H),3.74(dt,J=15.1,2.6Hz,1H),3.61(d,J=15.2Hz,1H),3.42(s,3H),2.51 (ddd,J=15.3,7.3,3.6Hz,1H),1.45-1.35(m,1H),1.33(dd,J=7.1,2.3Hz,3H). LCMS-ESI+(m / z):C 22 H 21 Calculated H+ value for F4N3O5: theoretical value 484.15, measured value: 484.11. Example 40: (3S,4S,6S,7R)-4-fluoro-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Step 1: Synthesis of (3S,4R,6S,7R)-12-(benzyloxy)-4-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0319] To a mixture of intermediate C (706.9 mg, 1.32 mmol) in methanol (10 mL) was added 0.5 M sodium methoxide (3 mL, 1.5 mmol) at room temperature. The reaction mixture was stirred at 50 °C. After 2 h, the reaction mixture was stirred at 0 °C and 4 N HCl in dioxane (0.375 mL, 1.5 mmol) was added: ES / MS m / z: calculated for C29H27F3N3O6 (M+H): 570.19, found: 570.30.

[0320] The solution was stirred at 0 °C while NaBH (157 mg, 4.15 mmol) was added. After 30 min at 0 °C, the reaction mixture was concentrated, the residue was dissolved in saturated NaHCO, and the product was extracted with ethyl acetate (×2). The organic extracts were washed with brine (×1), and the organic fractions were combined, dried (MgSO), and concentrated. The residue was purified by column chromatography on silica gel (80 g column) eluting with 0–5% methanol in CHCl and preparative HPLC (column, Gemini 5 μm C18 110A, LC column 100 × 30 mm) eluting with 23–90% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 min. The combined fractions were neutralized by adding saturated NaHCO (approximately 1 mL), and the solution was concentrated to remove most of the acetonitrile. The resulting aqueous mixture was extracted with EA (approximately 25 mL × 2), and the extracts were washed with brine (× 1), combined, dried (MgSO4), and concentrated to give (3S,4R,6S,7R)-12-(benzyloxy)-4-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. ES / MS m / z: calculated for CHFNO (M+H): 572.20, found: 572.27. Step 2: Synthesis of (3S,4S,6S,7R)-12-(benzyloxy)-4-fluoro-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0321] A solution of (3S,4R,6S,7R)-12-(benzyloxy)-4-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (81.8 mg, 0.143 mmol) in CHCl (2 mL) was stirred at 0 °C while adding a 2.7 M solution of bis(2-methoxyethyl)aminosulfur trifluoride in toluene (0.14 mL, 0.378 mmol). After 30 min, saturated NaHCO (10 mL) was added, and the reaction mixture was stirred at room temperature for 2.5 h and cooled to 0 °C. After adding water (20 mL), the product was extracted with ethyl acetate (25 mL × 2). The combined extracts were dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (using a 12 g column) eluting with 20–100% EA in hexanes to give (3S,4S,6S,7R)-12-(benzyloxy)-4-fluoro-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: ES / MS m / z: calculated for CHFNO (M+H): 574.20, found: 574.30. Step 3: Synthesis of (3S,4S,6S,7R)-4-fluoro-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0322] (3S,4S,6S,7R)-12-(benzyloxy)-4-fluoro-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (50.3 mg, 0.0877 mmol) was dissolved in toluene (0.02 mL) and trifluoroacetic acid (2 mL). After stirring at room temperature for 1 h, the reaction mixture was completely concentrated, and the residue was purified by preparative HPLC (two injections; Gemini 5 μm C18 110A, LC column 100 × 30 mm) eluting with 20–65% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 min. The combined fractions were neutralized by the addition of saturated NaHCO (approximately 1 mL) and then concentrated to remove most of the acetonitrile. The concentrated solution was extracted with ethyl acetate (approximately 20 mL × 2). The extracted fractions were washed with brine (× 1), combined, dried (MgSO), concentrated, and dried in vacuo to give (3S,4S,6S,7R)-4-fluoro-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide.1H NMR (400MHz, chloroform-d) δ 10.39(s,1H),10.19(s,1H),8.44(s,1H),6.74-6.59(m,2H),4.97(dt,J=46.8 ,6.4Hz,1H),4.82(dp,J=19.9,6.8Hz,1H),4.74-4.59(m,2H),4.39(d,J=2.4H z,1H),4.02(dd,J=14.7,2.1Hz,1H),3.73-3.58(m,2H),3.45(s,3H),2.68(dd d,J=16.0,7.5,5.1Hz,1H),1.73-1.55(m,1H),1.41(dd,J=7.1,2.6Hz,3H);19F NMR (376 MHz, acetonitrile-d3) δ -111.29 (q, J = 7.8, 7.3 Hz), -113.92 (t, J = 7.1 Hz), -200.03--200.69 (m); ES / MS m / z: calculated for C22H22F4N3O5 (M+H): 484.15, found: 484.20. Example 41: (3R,6S,7R)—N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12-hydroxy-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Steps 1-2: Synthesis of (3R,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0323] Following the procedure for making intermediate B, except using Benzyl(3S,7R)-3-(((benzyloxy)carbonyl)amino)-7-(((tert-butyldimethylsilyl)oxy)methyl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxyl in the first step, (3R,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide was prepared. ES / MS m / z: calculated for CHFNO (M+H): 522.18, found: 522.20. Steps 3-4: Synthesis of (3R,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0324] To a solution of (3R,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (2971.9 mg, 5.70 mmol) and imidazole (601.0 mg, 8.83 mmol) in CHCl (45 mL) was added tert-butyldimethylsilyl chloride (1039.7 mg, 6.90 mmol) at room temperature, and the resulting solution was stirred at room temperature. After 16 h, the reaction mixture was diluted with CHCl and washed with water (×1), and the two layers were separated. The aqueous fraction was extracted with ethyl acetate (×1), and the organic fractions were combined, dried (MgSO), and concentrated. The residue was purified by column chromatography on silica gel (120 g column) eluting with 0 to 100% ethyl acetate in hexanes to give (3R,7S)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. ES / MS m / z: calculated for CHFNOSi (M+H): 636.27, found: 636.30.

[0325] (3R,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide was prepared by following the procedure for making intermediate B, except that (3R,7S)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide was used. ES / MS m / z: calculated for C34H38F2N3O6Si (M+H): 650.25, found: 650.30. Steps 5-6: Synthesis of (3R,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0326] A mixture of (3R,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (1420.6 mg, 2.19 mmol) and 10% palladium on carbon (151.3 mg) in ethanol (30 mL) was stirred at room temperature under an atmosphere of H. After 2 h, the reaction mixture was filtered, and the filtrate was concentrated and dried in vacuo for 30 min. ES / MS m / z: calculated for CHFNOSi (M + EtOH + H): 608.26, found: 608.30.

[0327] The above residue and potassium carbonate (614.5 mg, 4.45 mmol) in DMF (13 mL) were stirred at room temperature, and benzyl bromide (0.35 mL, 2.94 mmol) was added. After stirring at room temperature overnight, the reaction mixture was diluted with water (approximately 30 mL), and the product was extracted with ethyl acetate (×2). The extracts were washed with water (×1), then combined, dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel (40 g column) eluting with 0–10% methanol in CHCl to give (3R,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: ES / MS m / z: calculated for CHFNOSi (M+H0+H): 670.28, found: 670.30; calculated for CHFNOSi (M+MeOH+H): 684.29, found: 684.40. Steps 7-8: Synthesis of (3R,6S,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0328] A solution of (3R,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (1234.0 mg, 1.89 mmol) in methanol (18 mL) was stirred at 0 °C while NaBH (156.2 mg, 4.13 mmol) was added. After 1 h at 0 °C, the reaction mixture was concentrated, and the residue was dissolved in water and then extracted with EtOAc (×2). The combined extracts were dried (MgSO) and concentrated. The residue was purified by column chromatography on silica gel (80 g column) eluting with 0–10% methanol in CHCl to give (3R,6S,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-6-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. ES / MS m / z: calculated for CHFNOSi (M+H): 654.28, found: 654.30.

[0329] A solution of the above product (221.3 mg, 0.338 mmol) in DMF (2.25 mL) was stirred at 0 °C while 60% sodium hydride dispersion (19.1 mg, 0.498 mmol) was added. After 20 min at 0 °C, a solution of iodomethane (0.021 mL, 0.337 mmol) was added. After 1 h at 0 °C, additional iodomethane (0.021 mL, 0.337 mmol) was added to the reaction mixture. After approximately 1 h at 0 °C, the reaction mixture was diluted with saturated NH4Cl, and the product was extracted with ethyl acetate (×2). After washing the extract with water (×1), the organic fractions were combined, dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel (120 g column) eluting with 0–10% methanol in CHCl2. The product-containing fractions were combined and concentrated, and the residue was purified again by column chromatography on silica gel (24 g column) eluting with 20–100% ethyl acetate in hexanes to give a mixture of the reactant and (3R,6S,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. ES / MS m / z: calculated for CHFNOSi (M+H): 668.30, found: 668.30. Step 9: Synthesis of (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0330] The above (3R,6S,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (333 mg, 0.494 mmol) was dissolved in 4 N HCl in dioxane (3 mL) in a 0° C. bath and stirred at 0° C. for 30 minutes. The reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel (24 g column) eluting with 0–15% methanol in CHCl to give (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. ES / MS m / z: calculated for CHFNO (M+H): 554.21, found: 554.30. Steps 10-11 Synthesis of (3R,6S,7R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12-hydroxy-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0331] A solution of (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (50.3 mg, 0.0909 mmol) in CHCl (2.5 mL) was stirred at 0° C. while adding (diethylamino)sulfur trifluoride (0.05 mL, 0.378 mmol). After 30 min, the reaction mixture was stirred at room temperature overnight. The reaction mixture was stirred at 0° C., and saturated NaHCO (5 mL) was added. The mixture was diluted with water (20 mL), and the product was extracted with CHCl (2 × 20 mL). The combined extracts were dried (MgSO4) and concentrated to give crude product (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. ES / MS m / z: calculated for C29H29F3N3O5 (M+H): 556.21, found: 556.30.

[0332] The fluorinated crude product was dissolved in trifluoroacetic acid (3 mL) and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC (column: Gemini 5 um C18 110A, LC column 100 x 30 mm) eluting with 15-70% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 minutes to give (3R,6S,7R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12-hydroxy-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 10.49(t,J=5.9Hz,1H),9.63(s,2H),8.44(s,1H),7.36(td,J=8.6,6.6Hz,1H),6.87-6. 74(m,2H),4.84-4.67(m,1H),4.67-4.62(m,3H),4.62-4.50(m,1H),4.48(dd,J=5.7,2. 8 Hz, 1H), 3.86 (dd, J = 15.5, 3.1 Hz, 1H), 3.74 (dt, J = 15.5, 1.3 Hz, 1H), 3.50-3.42 (m, 1H), 3.41 (s, 3H), 2.20-2.01 (m, 2H), 1.98-1.79 (m, 1H), 1.14 (dt, J = 13.9, 11.6 Hz, 1H); 19F NMR (376 MHz, chloroform-d) δ -76.43, -111.94 (p, J = 7.8 Hz), -114.64-114.87 (m); ES / MS m / z: calculated for C22H23F3N3O5 (M + H): 466.16, found: 466.20. Example 42: (3R,6S,7R)—N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Steps 1-2: Synthesis of (3R,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0333] Following the procedure for making intermediate B, except using benzyl (3S,7R)-3-(((benzyloxy)carbonyl)amino)-7-methyl-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate in the first step, (3R,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide was prepared. ES / MS m / z: calculated for CHFNO (M+H): 520.17, found: 520.20.

[0334] Step 3: Synthesis of (3R,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0335] A mixture of (3R,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (0.637 mmol) and 10% palladium on carbon (70 mg) in ethanol (10 mL) was stirred at room temperature under an H atmosphere for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated and dried in vacuo for 30 minutes.

[0336] The residue and potassium carbonate (179.0 mg, 1.3 mmol) in DMF (3.8 mL) were stirred at room temperature upon the addition of benzyl bromide (0.1 mg, 0.841 mmol). After overnight, the reaction mixture was diluted with water (30 mL) and the product was extracted with ethyl acetate (×2). The extracts were washed with water (×1), then combined, dried (MgSO), and concentrated. The residue was purified by column chromatography on silica gel (40 g column) eluting with 20–100% ethyl acetate in hexane to give (3R,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. ES / MS m / z: calculated for C28H26F2N3O5 (M+H): 522.18, found: 522.20. Step 4: Synthesis of (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-methoxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0337] A solution of (3R,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (125.1 mg, 0.24 mmol) in methanol (3 mL) was stirred at 0 °C while adding NaBH (28.9 mg, 0.764 mmol). After 1 h at 0 °C, the reaction mixture was concentrated, and the residue was dissolved in water (approximately 30 mL) and then extracted with ethyl acetate (20 mL × 2). The combined extracts were dried (MgSO) and concentrated. The residue was purified by column chromatography on silica gel (24 g column) eluting with 0–20% methanol in CHCl to give (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: ES / MS m / z: calculated for CHFNO (M+H): 524.20, found: 524.30.

[0338] A solution of the above alcohol (73.2 mg, 0.140 mmol) in DMF (1.5 mL) was stirred at 0 °C while 60% sodium hydride dispersion (10.5 mg, 0.274 mmol) was added. After 20 min at 0 °C, a solution of iodomethane (0.0104 mL, 0.168 mmol), 0.21 mL, 0.337 mmol) was added. After 1 h at 0 °C, the reaction mixture was diluted with saturated NaHCO solution, and the product was extracted with ethyl acetate (x2), and the combined extracts were dried (MgSO) and concentrated. The residue was purified by preparative HPLC (Gemini 5 um C18 110A, LC column 100 × 30 mm) eluting with 20–100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 30 min to give (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-methoxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. ES / MS m / z: calculated for CHFNO (M+H): 538.22, found: 538.30. Step 5: Synthesis of (3R,6S,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0339] (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-methoxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (3.1 mg, 5.77 μmol) was dissolved in trifluoroacetic acid (1 mL) and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated and the residue was purified by preparative HPLC (column, Gemini 5 um C18 110A, LC column 100 × 30 mm) eluting with 15–70% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 min to give (3R,6S,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. 1H NMR (400MHz, acetonitrile-d3)δ 10.41(s,1H),8.29(s,1H),7.41(q,J=8.2Hz,1H),7.04-6.85(m,2H),4.63(d,J=5.7Hz,1H),4.60-4.51(m,2H),3.87(dd,J=15.0,2.1Hz,1H) ,3.76(td,J=5.9,2.9Hz,1H),3.57(h,J=7.0Hz,1H),3.45(dd,J=15.0,2.1Hz,1H),3.24(s,3H),1.92-1.74(m,3H),1.67(d,J=7.2Hz,4H);19F NMR (376 MHz, acetonitrile-d3) δ -77.29, -114.23 (p, J = 7.4 Hz), -116.68 (q, J = 8.8, 8.2 Hz); ES / MS m / z: calculated for C22H24F2N3O5 (M+H): 448.17, found: 448.22. Example 43: Preparation of (3S,6S,7R)—N-(2,4-difluorobenzyl)-6,12-dihydroxy-3,7-dimethyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka]

[0340] (3S,6S,7R)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-3-methyl-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate, except that benzyl (3S,7S)-3-(((benzyloxy)carbonyl)amino)-3,7-dimethyl-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate was used instead of benzyl (3S,7S)-3-(((benzyloxy)carbonyl)amino)-7-methyl-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate. In a similar manner to that of N-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (Example 16), (3S,6S,7R)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-3,7-dimethyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide was prepared. MS (m / z) 448.27 [M+H] + . 1H NMR (400MHz, chloroform-d)δ 10.64-10.42(m,1H),8.59(s,2H),7.47-7.32(m,1H),6.96-6.58(m,2H),4.99-4.32(m,2H),3.96(d,J=4.7Hz, 1H),3.62(d,J=14.9Hz,1H),3.38(dd,J=14.9,2.0Hz,2H),2.14-1.76(m,4H),1.57(s,3H),1.45-1.07(m,3H). Example 44: (3S,6S,7R)-6-(fluoromethyl)-6,12-dihydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka] Step 1: Synthesis of (3S,6S,7R)-12-(benzyloxy)-6-(fluoromethyl)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0341] To a stirred solution of (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (220 mg, 0.409 mmol) in a dry mixture of THF:EtO (12 mL, 1:1, v / v) cooled at −78 °C, fluoroiodomethane (164 mg, 2.5 equiv.) was added. A solution of MeLi-LiBr complex (1.5 M in EtO, 2 equiv.) was then added dropwise. After stirring at −78 °C for 5 min, the reaction mixture was quenched with saturated aqueous NH4Cl (1 mL). The mixture was poured into water (50 mL) and extracted with EtOAc. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was subjected to flash chromatography to give (3S,6S,7R)-12-(benzyloxy)-6-(fluoromethyl)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. MS (m / z) 572.157 [M+H] + . Step 2: Synthesis of (3S,6S,7R)-6-(fluoromethyl)-6,12-dihydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0342] (3S,6S,7R)-12-(benzyloxy)-6-(fluoromethyl)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (5.8 mg, 0.0102 mmol) was dissolved in MeOH (5.0 mL) at room temperature and treated with 2 mg of 20% Pd(OH)2 / C (50 wt% water). The mixture was degassed and flushed with hydrogen three times, after which it was hydrogenated under a hydrogen balloon overnight. The reaction was then degassed, flushed with nitrogen, filtered through a pad of Celite, concentrated, and the resulting residue was redissolved in DMF, filtered, and purified by reverse-phase HPLC. MS (m / z) 484.227 [M+H] + . 1H NMR (400MHz, chloroform-d)δ 11.12(s,1H),10.22(t,J=5.7Hz,1H),8.35(s,1H),6.65(dd,J=8.7,7.5Hz,2H),4.81-4.60(m,4H),4.60-4.49(m,1H),4.45(dd,J=14. 5,5.1Hz,1H),4.26(s,1H),3.79-3.62(m,2H),2.15-2.05(m,1H),2.00-1.92(m,1H),1.80(s,1H),1.65(s,1H),1.29(d,J=6.8Hz,3H). Example 45: Preparation of (3S,4S,7R,8R)-N-(2,4-difluorobenzyl)-13-hydroxy-3-methyl-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8:4,7-dimethanopyrido[1,2-d][1,4,7]oxadiazecine-11-carboxamide [ka] Step 1: Preparation of (3S,4S,7R)-12-(benzyloxy)-4-cyano-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide

[0343] To a solution of (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (512 mg, 0.985 mmol, 1 equiv.) in THF / MeOH (1:1) (18 mL) was added tetrabutylammonium cyanide (397 mg, 1.48 mmol, 1.5 equiv.), and the resulting solution was stirred at room temperature for 2 days. EtOAc (20 mL) was added, and the resulting mixture was washed with saturated aqueous sodium carbonate and brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by flash column chromatography on silica gel using a gradient of MeOH (0 to 10%) in DCM to give the desired product as a mixture of the parent ketone and the ketone hydrate and hemiketal with methanol. The stereochemistry α to the cyano group was assigned by 2D NMR spectroscopy using nuclear Overhauser effect correlation of the diol product obtained after step 3. Step 2: Preparation of (3S,4S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-4-formyl-3-methyl-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0344] A solution of (3S,4S,7R)-12-(benzyloxy)-4-cyano-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (179 mg, 0.317 mmol, 1 equiv.) in DCM (5 mL) was cooled to 0 °C under N. Bis(cyclopentadienyl)zirconium(IV) chloride hydride (Schwartz's reagent, 425 mg, 0.159 mmol, 5 equiv.) was added, and the resulting mixture was stirred at 0 °C for 1 h and then at room temperature for 15 min. Water was added, and the mixture was extracted three times with DCM. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was filtered through a plug of silica and any Zr species were removed using a gradient of MeOH (0 to 20%) in DCM to give the desired product as a mixture of the parent carbonyl as well as the carbonyl hydrate, the hemiketal with MeOH, and the over-reduction product, which was used directly in Step 3 below. Step 3: Preparation of (3S,4S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-4-(hydroxymethyl)-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0345] To a solution of the product mixture from step 2 (above) (169 mg, 0.298 mmol, 1 equiv.) in THF / MeOH (1:1) (12 mL) at 0 °C, sodium borohydride (22.5 mg, 0.596 mmol, 2 equiv.) was added, and the resulting mixture was stirred at room temperature for 10 minutes and then concentrated in vacuo. Water was added, and the pH was adjusted to approximately 5 by the addition of dilute acetic acid. The mixture was extracted twice with DCM, and the combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was purified by reverse-phase preparative high-performance liquid chromatography using a gradient of MeCN (40% to 80% with 0.1% TFA) in HO to give the desired product. Step 4: Preparation of (3S,4S,6S,7R)-12-(benzyloxy)-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide:

[0346] To a solution of (3S,4S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-4-(hydroxymethyl)-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (15 mg, 0.027 mmol, 1 equiv.) in DMF (1.0 mL) was added tert-butylchlorodimethylsilane (22.7 mg, 0.135 mmol, 5 equiv.) and imidazole (10 mg, 0.149 mmol, 5.5 equiv.), and the resulting mixture was stirred at 60° C. for 30 min. The reaction mixture was partitioned between water and EtOAc, and the layers were separated. The aqueous layer was extracted twice with EtOAc, and the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was used directly in step 5 without further purification. Step 5: Preparation of (3S,4S,7R,8R)-N-(2,4-difluorobenzyl)-13-hydroxy-3-methyl-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8:4,7-dimethanopyrido[1,2-d][1,4,7]oxadiazecine-11-carboxamide

[0347] To a solution of the crude residue from Step 5 (estimated to be 0.0271 mmol, 1 equiv.) in DCM (6 mL) was added triethylamine (22.7 μL, 0.163 mmol, 6 equiv.) and MsCl (6.29 μL, 0.0813 mmol, 3 equiv.) under a N atmosphere, and the resulting solution was stirred at room temperature for 5 minutes. Tetrabutylammonium fluoride (1.0 M in THF, 0.569 mL, 0.569 mmol, 21 equiv.) was added directly to the reaction, and the resulting solution was stirred at 45° C. in a sealed vial for 2 days. The reaction mixture was concentrated in vacuo and partitioned between water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The resulting residue was dissolved in TFA / toluene (1:1) (2 mL) and stirred at room temperature for 4 hours. The reaction mixture was concentrated in vacuo and purified by reverse-phase preparative high-performance liquid chromatography using a gradient of MeCN (10% to 90% with 0.1% TFA) in HO and normal-phase silica gel column chromatography using a gradient of MeOH (0% to 20%) in DCM to give the desired compound. MS (m / z) 446.200 [M+H] +1 H NMR(400MHz,CD3CN)δ 10.63(s,1H),10.32(s,1H),8.43(s,1H),7.40(td,J=8.8,6.5Hz,1H),7.00-6.88(m,2H), 4.65(p,J=6.9Hz,1H),4.57(d,J=6.0Hz,2H),4.54-4.47(m,1H),4.31(dt,J=4.9,2.3Hz,1 H),4.23(dd,J=9.9,1.5Hz,1H),3.85(dd,J=10.0,7.5Hz,1H),3.60-3.38(m,2H),2.71(q, J=6.2Hz,1H),2.02(dt,J=14.7,7.4Hz,1H),1.59(d,J=14.7Hz,1H),1.28(d,J=7.1Hz,3H). Example 46: (3S,6S,7R)—N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-6-d-10-carboxamide [ka]

[0348] Step 1: Preparation of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-6-d-10-carboxamide:

[0349] To a solution of (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (100 mg, 0.192 mmol) in MeOH (5 mL) was added cerium(III) chloride heptahydrate (717 mg, 0.192 mmol). Sodium borodeuteride (4 mg, 0.096 mol) was then slowly added to the mixture. The reaction mixture was stirred at 0 °C. After completion of the reaction, the reaction was quenched by adding saturated NaHCO3, extracted with DCM, and the organic phase was separated and dried over MgSO4. The separated organic phase was then filtered, concentrated, and used in the next step without purification. Step 2: Preparation of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-6-d-10-carboxamide:

[0350] To a solution of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-6-d-10-carboxamide (90 mg, 0.172 mmol) in DMF (3 mL) was added sodium hydride (8.3 mg, 0.21 mmol, 60%) and iodomethane (12.9 μL, 0.21 mmol). The reaction mixture was stirred at 0° C. for 0.5 h. The reaction was quenched by adding saturated NaHCO and extracted with EtOAc. The organic phase was separated, dried over MgSO, filtered, concentrated, and the resulting product was used in the next step without further purification. Step 3: Preparation of (3S,6S,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-6-d-10-carboxamide

[0351] To a solution of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-6-d-10-carboxamide (60 mg, 0.112 mmol) in EtOH (3 mL) was added Pd / C (38 mg). The reaction mixture was stirred at room temperature under a H2 balloon. After completion of the reaction, the reaction mixture was filtered through Celite. The filtrate was concentrated, and the residue was purified by reverse-phase HPLC eluting with 4-100% ACN in water containing 0.1% TFA to give the title compound. MS (m / z) 449.2 [M+H] +. 1H NMR (400MHz, methanol-d4)δ 8.36(s,1H),7.44(td,J=8.4,6.3Hz,1H),7.03-6.90(m,2H),4.89(s,1H),4.73(s,1H),4.69-4.57(m,3H),3.83-3.68(m, 2H),3.46(s,3H),2.18-1.97(m,2H),1.54(dt,J=14.6,11.3Hz,1H),1.28(d,J=6.7Hz,3H),1.00(dd,J=14.7,11.6Hz,1H). Example 47: HIV MT-4 antiviral and cytotoxicity assays Antiviral assay in MT-4 cells

[0352] Compounds were tested in a high-throughput 384-well assay format for their ability to inhibit HIV-1 (IIIB) replication in MT-4 cells. Compounds were serially diluted (1:3) in DMSO onto 384-well polypropylene plates and further diluted 200-fold into complete RPMI medium (10% FBS, 1% P / S) using a Biotek Micro Flow and Labcyte ECHO acoustic dispenser. Each plate contained up to eight test compounds, with a negative (no drug control) and a 5 μM AZT positive control. MT-4 cells were pre-infected with either 10 μL of RPMI (mock-infected) or a fresh 1:250 dilution of HIV-1 IIIB concentrated virus stock. Infected and uninfected MT-4 cells were further diluted in complete RPMI medium and added to each plate using a Micro Flow dispenser. After 5 days of incubation in a humidified, temperature-controlled incubator (37°C), Cell Titer Glo (Promega) was added to the assay plates, and chemiluminescence was read using an Envision plate reader. 50 Values ​​were defined as the compound concentration that reduced the luminescence signal by 50% and were calculated using a sigmoidal dose-response model to generate a curve fit. Cytotoxicity assay in MT-4 cells

[0353] The assay was performed as described above, except that uninfected MT-4 cells were added to each well containing test compound, and 10 μM puromycin was added to the last row of each assay plate to assess the basal level of cytotoxicity. Example 48: HIV MT-4 Serum Shift Antiviral Reporter Assay

[0354] To quantify protein binding to human serum, compounds were serially diluted (1:3) in DMSO and acoustically transferred onto a 384-well assay plate using a Labcyte ECHO robot. Each plate contained up to eight test compounds, including negative and positive controls (DMSO and 5 μM AZT, respectively). Assay plates were prepared in duplicate and tested in either CCM (cell culture medium) or HS / CCM (human serum / cell culture medium). MT-4 cells were first pre-infected with the pLai RLuc reporter virus for 2 h at 37°C, then further diluted in CCM (RPMI medium, 10% FBS, 1% P / S) or HS / CCM (RPMI medium, 10% FBS, 50% HS, 1% P / S) and then added to each plate using a Biotek Micro Flow dispenser. After 72 hours of incubation in a humidified, temperature-controlled incubator (37°C), Renilla Glo (Promega) was added to all assay plates, and chemiluminescent readings were performed using an Envision plate reader. 50 The EC value was defined as the compound concentration that reduced the luminescence signal by 50% and was calculated using a sigmoidal dose-response model to generate a curve fit. To determine the amount of protein binding, the EC 50 Magnification shift (or EC 50 Shift) to EC 50 (HS / CCM) / EC 50 (CCM) was calculated by dividing

[0355] Compounds of the present disclosure exhibit antiviral activity in this assay, as shown below in Table 1. Accordingly, compounds of the embodiments disclosed herein may be useful in inhibiting HIV viral proliferation, treating AIDS, or delaying the onset of AIDS or ARC symptoms. Example 49: High-throughput microsome stability assay

[0356] The metabolic stability of compounds was assessed using a human or rat liver microsome assay (Corning). In this assay, 10 nL of compound at a concentration of 1 mM in 100% DMSO was dispensed into a 384-well polypropylene plate using an Echo550 acoustic liquid dispenser (Labcyte®). Each plate contained 384 wells, each containing a single test compound.

[0357] A 2 mg / ml solution of human (Corning® Gentest™ Human Mixed Pooled Microsomes) or rat (Corning® Gentest™ Rat [Sprague-Dawley] Pooled Liver Microsomes) liver microsomes in 100 mM K2HPO4 / KH2PO4 (pH 7.4) containing 0.0225 mg / ml alamethicin from Trichoderma viride (Sigma-Aldrich) was incubated on ice for 15 minutes. After a 15-minute incubation at room temperature, 5 μL of this solution was added to each well and supplemented with 5 μL of NADPH regeneration solution (Corning® Gentest™ UGT Reaction Mix) containing 100 mM K2HPO4 / KH2PO4 (pH 7.4), 2.6 mM NADP+, 6.6 mM glucose-6-phosphate, 6.6 mM MgCl2, 0.8 U / mL glucose-6-phosphate dehydrogenase, 0.1 mM sodium citrate, and 6.8 mM uridine diphosphate-glucuronic acid cofactors. The final concentration of analyte compound at the start of the reaction was 1 μM. Reactions were incubated at 37°C, and time points of 0, 5, 15, 30, 40, 50, 60, and 70 minutes were collected for further analysis. Background data were collected using a reaction without analyte compound.

[0358] Upon collection of the reaction time points, the samples were quenched with 30 μL of a solution of 72% acetonitrile, 8% methanol, 0.1% formic acid, 19.9% ​​water, and internal standard (IS). 10 μL of the quenched reaction was diluted with 40 μL of deionized water, and the reaction plate was centrifuged at 4,000 rcf for 30 minutes at 4°C to obtain the assay plate.

[0359] The assay plate was analyzed using a C4 Type A solid cartridge with solid extraction coupled to a quadrupole time-of-flight mass spectrometer using an Agilent QToF 6530 RapidFire 360 ​​system. Analysis was performed in either positive or negative ionization mode. The mobile phase contained 0.1% formic acid in water to load the analytes onto the solid extraction cartridge and 0.1% formic acid in acetonitrile to elute into the mass spectrometer in positive ionization mode, or 0.1% acetic acid in water for loading and 0.1% acetic acid in acetonitrile for extraction in negative ionization mode. The peak area ratios of the integrated counts for each compound versus the IS were plotted as a semi-logarithmic log-time chart. The initial linear portion of the decay was fitted to a linear regression equation to derive the compound decay half-life.

[0360] Pharmacological parameters for analyte compound metabolism were calculated using the following equations: [Table 1] During the ceremony, Calculation of in vitro intrinsic clearance

number

[0361] Concentration refers to protein concentration in the reaction (mg / mL). [Table 2] Calculation of in vivo intrinsic clearance

[0362] This determines the in vitro intrinsic clearance, up to that expected for the total mass of liver tissue (but not limited by blood flow), which depends on liver size (species dependent) and, if necessary, microsomal protein yield (assumed to be species independent).

number

[0363] Hepatic clearance depends on the interrelationship between intrinsic clearance and hepatic blood flow and can be predicted from in vitro data using a variety of approaches.

number

[0364] This is a simple predicted clearance expressed as a percentage of hepatic blood flow. E=CL / Q H * 100%

[0365] The intrinsic clearance of the compounds of the present invention as well as reference compounds A to F was calculated according to the procedure described above. The results for these compounds are shown in Table 2 below. As can be seen, the compounds of the present invention are 1.5 to 3.6 times more stable than reference compounds A to F. [Table 6] [Table 7-1] [Table 7-2] [Table 7-3]

[0366] All references, including publications, patents, and patent documents, are incorporated herein by reference, as if individually incorporated by reference. This disclosure refers to various embodiments and techniques. However, it should be understood that many variations and modifications can be made while remaining within the spirit and scope of the disclosure. The description is to be considered as exemplary of the claimed subject matter, with the understanding that it is not intended to limit the scope of the appended claims to the specific embodiments illustrated.

Claims

1. A compound of formula I, 【Chemistry 1】 During the ceremony, R １ But, C ６～１０ aryl or 5- to 10-membered heteroaryl, ６～１０ Aryl or 5- to 10-membered heteroaryl is selected from 1 to 4 R Ａ１ and each R Ａ１ But independently, Halo, C １～６ Alkyl, C １～４ Haloalkyl, cyano, —O—C １～４ Alkyl, or C １～４ Alkyl-O-C １～４ is alkyl, R ２ But, H, C １～６ Alkyl, or C １～４ is haloalkyl, R ３ is halo or -OR ３ａ and R ３ａ But H, -C １～６ Alkyl, -C １～４ Haloalkyl, or -C ３～６ cycloalkyl, or R ３ａ and R ６ａ together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing 1 or 2 heteroatoms of O; R ３ｂ But H, -C １～６ Alkyl, -C １～４ Haloalkyl, or -C １～４ Alkylene -O-C １～４ is alkyl, R ４ａ But, -C １～６ Alkyl or -C １～４ is haloalkyl, R ４ｂ H, halo, -C １～６ Alkyl, or -C １～４ is haloalkyl, W １ is a bond or -CR ５ａ R ５ｂ - and R ５ａ and R ５ｂ However, independently, H, C １～６ Alkyl, C １～４ haloalkyl or halo; W ２ But -CR ６ａ R ６ｂ -or- CR ７ａ =CR ７ｂ - and R ６ａ and R ６ｂ However, independently, H, C １～６ Alkyl, C １～４ Haloalkyl, halo, hydroxyl, cyano, -O-C １～４ Alkyl, or C １～４ Alkylene -O-C １～４ is alkyl, or R ６ａ and R ３ａ together with the carbons to which they are attached form a 4- to 6-membered heterocycle containing one or two heteroatoms of O; R ６ｂ But, H, C １～６ Alkyl, C １～４ Haloalkyl, halo, hydroxyl, cyano, -O-C １～４ Alkyl, or C １～４ Alkylene -O-C １～４ is alkyl, R ７ａ and R ７ｂ However, independently, H, halo, C １～４ Haloalkyl, or C １～６ or a pharma- ceutically acceptable salt thereof, wherein:

2. 2. The compound of claim 1, wherein the compound is a compound of formula Ia: or a pharma- ceutically acceptable salt thereof: 【Chemistry 2】

3. 2. The compound of claim 1, wherein the compound is a compound of formula Ib: or a pharma- ceutically acceptable salt thereof: 【Chemistry 3】

4. 2. The compound of claim 1, wherein the compound is a compound of formula Ic: or a pharma- ceutically acceptable salt thereof: 【Chemistry 4】

5. 2. The compound of claim 1, wherein the compound is a compound of formula Id: or a pharma- ceutically acceptable salt thereof: 【Chemistry 5】

6. R １ is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, and the phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine has one, two, three, or four R Ａ１ and each R Ａ１ But independently, Halo, C １～６ Alkyl, C １～４ Haloalkyl, cyano, —O—C １～４ Alkyl, or -C １～４ Alkyl-O-C １～４ The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

7. R １ is phenyl or pyridyl, and said phenyl or pyridyl is selected from the group consisting of 1, 2, 3, or 4 R Ａ１ and each R Ａ１ But independently, Halo, C １～６ Alkyl, C １～４ Haloalkyl, cyano, —O—C １～４ Alkyl, or -C １～４ Alkyl-O-C １～４ The compound according to any one of claims 1 to 6, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

8. R １ is phenyl or pyridyl, and said phenyl or pyridyl is selected from the group consisting of 1, 2, 3, or 4 R Ａ１ and each R Ａ１ The compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, wherein is independently a halogen.

9. R １ is phenyl or pyridyl, and the phenyl or pyridyl is selected from the group consisting of two or three R Ａ１ and each R Ａ１ or a pharma- ceutically acceptable salt thereof, according to any one of claims 1 to 8, wherein is independently selected from chloro and fluoro.

10. R １ is pyridyl, said pyridyl being selected from the group consisting of 1, 2, 3, or 4 R Ａ１ and each R Ａ１ But independently, Halo, C １～６ Alkyl, C １～４ Haloalkyl, cyano, —O—C １～４ Alkyl, or -C １～４ Alkyl-O-C １～４ The compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

11. R １ is pyridyl, said pyridyl being selected from the group consisting of 1, 2, 3, or 4 R Ａ１ and each R Ａ１ The compound according to any one of claims 1 to 8 and 10, or a pharma- ceutically acceptable salt thereof, wherein is independently a halogen.

12. R １ is pyridyl, and the pyridyl is a group having two or three R Ａ１ and each R Ａ１ or a pharma- ceutically acceptable salt thereof, according to any one of claims 1 to 11, wherein is independently selected from chloro and fluoro.

13. R １ 1, 2, 3, or 4 R Ａ１ and each R Ａ１ But independently, Halo, C １～４ Alkyl, C １～４ Haloalkyl, or -O-C １～４ The compound according to any one of claims 1 to 7, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

14. R １ 1, 2, 3, or 4 R Ａ１ and each R Ａ１ The compound according to any one of claims 1 to 7 and 13, or a pharma- ceutically acceptable salt thereof, wherein is independently a halogen.

15. R １ But, two or three R Ａ１ and each R Ａ１ or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 1 to 7, 13, and 14, wherein is independently selected from chloro and fluoro.

16. R １ but, 【Chemistry 6】 The compound according to any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

17. The compound has the formula II: 【Chemistry 7】 wherein n is 2, 3, or 4; Ａ１ But independently, Halo, C １～６ Alkyl, C １～４ Haloalkyl, cyano, —O—C １～４ Alkyl, or C １～４ Alkyl-O-C １～４ 16. The compound according to any one of claims 1 to 8 and 13 to 15, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

18. Each R Ａ１ But independently, Halo, C １～６ Alkyl, C １～４ Haloalkyl, cyano, or -O-C １～４ 18. The compound according to any one of claims 1 to 17, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

19. Each R Ａ１ or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 1 to 18, wherein:

20. Each R Ａ１ is independently chloro or fluoro, or a pharma- ceutically acceptable salt thereof.

21. R ２ is H or C １～６ 21. The compound according to any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, which is alkyl.

22. R ２ is H or C １～４ 21. The compound of any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

23. R ２ But, C １～６ Alkyl or C １～４ 21. The compound of any one of claims 1 to 20, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

24. R ２ or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 1 to 22, wherein

25. R ３ or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 1 to 24, wherein: is halo.

26. R ３ or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 1 to 25, wherein is chloro.

27. R ３ But, OR ３ａ 25. The compound according to any one of claims 1 to 24, wherein:

28. R ４ａ But, -C １～４ 28. The compound of any one of claims 1 to 27, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

29. R ４ａ But, -C １～３ 28. The compound according to any one of claims 1 to 27, or a pharma- ceutically acceptable salt thereof, which is alkyl.

30. R ４ａ 30. The compound according to any one of claims 1 to 27 and 29, or a pharma- ceutically acceptable salt thereof, wherein is methyl.

31. R ４ｂ But H, -C １～４ Haloalkyl, or -C １～３ 31. The compound according to any one of claims 1 to 30, or a pharma- ceutically acceptable salt thereof, which is alkyl.

32. R ４ｂ or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 1 to 31, wherein

33. R ３ａ But, -C １～６ Alkyl, -C １～４ Haloalkyl, or -C ３～６ is cycloalkyl, R ３ｂ But H, -C １～６ Alkyl, -C １～４ Haloalkyl, or -C １～４ Alkylene -O-C １～４ A compound according to any one of claims 27 to 32, when not dependent on claims 1 to 24 and claims 25 or 26, which is alkyl, or a pharma- ceutically acceptable salt thereof.

34. R ３ａ But, -C １～６ Alkyl or -C １～４ A compound according to any one of claims 27 to 33, when not dependent on claims 1 to 24 and claims 25 or 26, which is haloalkyl, or a pharma- ceutically acceptable salt thereof.

35. R ３ａ But, -C １～６ A compound according to any one of claims 27 to 34, when not dependent on claims 1 to 24 and claims 25 or 26, which is alkyl, or a pharma- ceutically acceptable salt thereof.

36. R ３ａ The compound according to any one of claims 27 to 35, when not dependent on claims 1 to 24 and claims 25 or 26, wherein is methyl or ethyl, or a pharma- ceutically acceptable salt thereof.

37. R ３ａ The compound according to any one of claims 27 to 36, when not dependent on claims 1 to 24 and claims 25 or 26, wherein is methyl, or a pharma- ceutically acceptable salt thereof.

38. R ３ａ and R ６ａ are taken together with the carbons to which they are attached to form a 4-6 membered heterocycle containing 1 or 2 heteroatoms of O, or a pharma- ceutically acceptable salt thereof.

39. R ３ａ and R ６ａ are taken together with the carbons to which they are attached to form a 4-6 membered heterocycle containing one oxygen atom, or a pharma- ceutically acceptable salt thereof.

40. R ３ｂ But H, -C １～６ Alkyl, -C １～４ 40. The compound of any one of claims 1 to 39, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

41. R ３ｂ is H or -C １～６ 41. The compound according to any one of claims 1 to 40, or a pharma- ceutically acceptable salt thereof, which is alkyl.

42. R ３ｂ is H or -C １～３ 42. The compound of any one of claims 1 to 41, or a pharma- ceutically acceptable salt thereof, which is alkyl.

43. R ３ｂ or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 1 to 42, wherein:

44. R ３ｂ or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 1 to 43, wherein:

45. W １ The compound according to any one of claims 1 to 44, or a pharma- ceutically acceptable salt thereof, wherein is a bond.

46. W １ But -CR ５ａ R ５ｂ 45. The compound according to any one of claims 1 to 44, wherein:

47. R ５ａ But, H, C １～６ Alkyl, C １～４ haloalkyl or halo, R ５ｂ or a pharma- ceutically acceptable salt thereof.

47. The compound of any one of claims 1 to 46, wherein: is H or halo; or a pharma- ceutically acceptable salt thereof.

48. R ５ａ is H or halo, R ５ｂ or a pharma- ceutically acceptable salt thereof.

48. The compound of any one of claims 1 to 47, wherein: is H or halo; or a pharma- ceutically acceptable salt thereof.

49. R ５ａ But, H, C １～６ Alkyl, C １～４ haloalkyl or halo, R ５ｂ or a pharma- ceutically acceptable salt thereof.

48. The compound according to any one of claims 1 to 47, wherein:

50. R ５ａ is H, and R ５ｂ or a pharma- ceutically acceptable salt thereof.

51. W ２ But -CR ６ａ R ６ｂ 51. The compound according to any one of claims 1 to 50, or a pharma- ceutically acceptable salt thereof, wherein:

52. R ６ａ is H, and R ６ｂ But, H, C １～６ Alkyl, C １～４ Haloalkyl, halo, hydroxyl, cyano, -O-C １～４ Alkyl, or C １～４ Alkylene -O-C １～４ 52. The compound of any one of claims 1 to 51, or a pharma- ceutically acceptable salt thereof, which is alkyl.

53. R ６ａ is H, and R ６ｂ or a pharma- ceutically acceptable salt thereof.

54. W ２ But -CR ７ａ =CR ７ｂ 54. The compound according to any one of claims 1 to 53, or a pharma- ceutically acceptable salt thereof, wherein

55. R ７ａ and R ７ｂ However, independently, H, halo, C １～４ Haloalkyl, or C １～６ 55. The compound according to any one of claims 1 to 50 and 54, or a pharma- ceutically acceptable salt thereof, wherein:

56. R ７ａ is H, and R ７ｂ or a pharma- ceutically acceptable salt thereof.

57. A compound of formula Ic, 【Chemistry 1】 During the ceremony, R １ is phenyl or pyridyl, and said phenyl or pyridyl is selected from the group consisting of 1, 2, 3, or 4 R Ａ１ where each R Ａ１ are independently halogen; R ２ is H or C １～６ is alkyl, R ３ａ But H, -C １～６ Alkyl, -C １～４ Haloalkyl, or -C ３～６ is cycloalkyl, R ３ｂ But H, -C １～６ Alkyl, -C １～４ Haloalkyl, or -C １～４ Alkylene -O-C １～４ is alkyl, R ４ａ But, -C １～３ is alkyl, R ４ｂ is H, W １ But -CR ５ａ R ５ｂ - and R ５ａ and R ５ｂ However, independently, H, C １～６ Alkyl, C １～４ haloalkyl or halo; W ２ But -CR ６ａ R ６ｂ - and R ６ａ and R ６ｂ However, independently, H, C １～６ Alkyl, C １～４ Haloalkyl, halo, hydroxyl, cyano, -O-C １～４ Alkyl, or C １～４ Alkylene -O-C １～４ is alkyl, A compound or a pharma- ceutically acceptable salt thereof.

58. R １ is phenyl or pyridyl, wherein said phenyl or pyridyl is selected from the group consisting of two or three R Ａ１ and each R Ａ１ 58. The compound of claim 57, or a pharma- ceutically acceptable salt thereof, wherein is independently selected from chloro and fluoro.

59. R １ 1, 2, 3, or 4 R Ａ１ where each R Ａ１ 58. The compound of claim 57, or a pharma- ceutically acceptable salt thereof, wherein is independently a halogen.

60. R １ But, two or three R Ａ１ and each R Ａ１ or a pharma- ceutically acceptable salt thereof.

59. The compound of any one of claims 57 to 59, wherein is independently selected from chloro and fluoro.

61. R １ but, 【Chemistry 6】 61. The compound according to any one of claims 57 to 60, or a pharma- ceutically acceptable salt thereof, selected from the group consisting of:

62. Each R Ａ１ is independently chloro or fluoro; or a pharma- ceutically acceptable salt thereof.

63. R ２ or a pharma- ceutically acceptable salt thereof.

64. R ３ａ But, -C １～６ Alkyl or -C １～４ 64. The compound of any one of claims 57 to 63, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

65. R ３ａ But, -C １～６ 65. The compound of any one of claims 57 to 64, or a pharma- ceutically acceptable salt thereof, which is alkyl.

66. R ３ａ or a pharma- ceutically acceptable salt thereof. The compound according to any one of claims 57 to 65, wherein is methyl or ethyl.

67. R ３ｂ But H, -C １～６ Alkyl, -C １～４ 67. The compound of any one of claims 57 to 66, or a pharma- ceutically acceptable salt thereof, which is haloalkyl.

68. R ３ｂ is H or -C １～６ 68. The compound of any one of claims 57 to 67, or a pharma- ceutically acceptable salt thereof, which is alkyl.

69. R ３ｂ is H or -C １～３ 69. The compound of any one of claims 57 to 68, or a pharma- ceutically acceptable salt thereof, which is alkyl.

70. R ３ｂ or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 57 to 69, wherein is H or methyl.

71. R ３ｂ or a pharma- ceutically acceptable salt thereof.

72. R ５ａ But, H, C １～６ Alkyl, C １～４ haloalkyl or halo, R ５ｂ or a pharma- ceutically acceptable salt thereof. The compound of any one of claims 57 to 71, wherein is H or halo.

73. R ５ａ is H or halo, R ５ｂ or a pharma- ceutically acceptable salt thereof.

73. The compound of any one of claims 57 to 72, wherein is H or halo; or a pharma- ceutically acceptable salt thereof.

74. R ６ａ is H, and R ６ｂ But, H, C １～６ Alkyl, C １～４ Haloalkyl, halo, hydroxyl, cyano, -O-C １～４ Alkyl, or C １～４ Alkylene -O-C １～４ 74. The compound of any one of claims 57 to 73, or a pharma- ceutically acceptable salt thereof, which is alkyl.

75. R ６ａ is H, and R ６ｂ or a pharma- ceutically acceptable salt thereof.

76. 【Catalog 8】 or a pharma- ceutically acceptable salt thereof.

77. 【Chemical 9】 【Chemistry 10】 【Chemistry 11】 or a pharma- ceutically acceptable salt thereof.

78. 【Catalog 12】 or a pharma- ceutically acceptable salt thereof.

79. 【Catalog 13】 【Chemistry 14】 【Chemistry 15】 or a pharma- ceutically acceptable salt thereof.

80. 【Catalog 16】 or a pharma- ceutically acceptable salt thereof.

81. formula: 【Chemistry 17】 or a pharma- ceutically acceptable salt thereof.

82. formula: 【Chemistry 18】 or a pharma- ceutically acceptable salt thereof.

83. formula: 【Chemistry 19】 or a pharma- ceutically acceptable salt thereof.

84. formula: 【Chemistry 20】 or a pharma- ceutically acceptable salt thereof.

85. formula: 【Chemistry 21】 or a pharma- ceutically acceptable salt thereof.

86. formula: 【Chemical 22】 or a pharma- ceutically acceptable salt thereof.

87. formula: 【Chemistry 23】 or a pharma- ceutically acceptable salt thereof.

88. formula: 【Chemistry 24】 or a pharma- ceutically acceptable salt thereof.

89. formula: 【Chemistry 25】 or a pharma- ceutically acceptable salt thereof.

90. formula: 【Chemistry 26】 or a pharma- ceutically acceptable salt thereof.

91. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 90 or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable excipient.

92. 92. The pharmaceutical composition of claim 91, further comprising one, two, three, or four additional therapeutic agents.

93. 93. The pharmaceutical composition of claim 92, wherein the additional therapeutic agent is an anti-HIV agent.

94. 94. The pharmaceutical composition of claim 92 or 93, wherein the additional therapeutic agent is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latent infection reactivator, a capsid polymerization inhibitor, a maturation inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof.

95. 95. The pharmaceutical composition of any one of claims 92-94, wherein the additional therapeutic agent is abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl)-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, or a pharma- ceutically acceptable salt thereof.

96. The pharmaceutical composition according to any one of claims 91 to 95, wherein the pharmaceutical composition is for oral or parenteral administration.

97. 91. A kit comprising a compound according to any one of claims 1 to 90, or a pharma- ceutically acceptable salt thereof, and instructions for use.

98. 98. The kit of claim 97, further comprising one, two, three, or four additional therapeutic agents.

99. 99. The kit of claim 98, wherein the additional therapeutic agent is an anti-HIV agent.

100. The kit of claim 98 or 99, wherein the additional therapeutic agent is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latent infection reactivator, a capsid polymerization inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof.

101. 101. The kit of any one of claims 98-100, wherein the additional therapeutic agent is abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl)-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, or a pharma- ceutically acceptable salt thereof.

102. A composition comprising a compound according to any one of claims 1 to 90 or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 91 to 96, for treating an HIV infection in a human having or at risk of having said infection.

103. 103. The composition of claim 102, wherein the composition is administered in combination with one, two, three, or four additional therapeutic agents.

104. The composition of claim 103, wherein the additional therapeutic agent is an anti-HIV agent.

105. The composition of claim 103 or 104, wherein the additional therapeutic agent is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latent infection reactivator, a capsid polymerization inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof.

106. 106. The composition of any one of claims 103-105, wherein the additional therapeutic agent is abacavir, tenofovir alafenamide, tenofovir disoproxil, lenacapavir, or a pharma- ceutically acceptable salt thereof.

107. The composition of any one of claims 102 to 106, wherein the composition is administered orally, intravenously, subcutaneously, or intramuscularly.

108. A composition comprising a compound according to any one of claims 1 to 90, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 91 to 96, for use in medical treatment.

109. A composition comprising a compound according to any one of claims 1 to 90, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 91 to 96, for use in the treatment of HIV infection.

110. 110. The composition of claim 109, wherein the composition is used in combination with one, two, three, or four additional therapeutic agents.

111. The composition of claim 110, wherein the additional therapeutic agent is an anti-HIV agent.

112. The composition of claim 110 or 111, wherein the additional therapeutic agent is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latent infection reactivator, a capsid polymerization inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof.

113. 113. The composition of any one of claims 110-112, wherein the additional therapeutic agent is abacavir, tenofovir alafenamide, tenofovir disoproxil, lenacapavir, or a pharma- ceutically acceptable salt thereof.

114. The composition of any one of claims 110 to 113, wherein the composition is for oral, intravenous, subcutaneous, or intramuscular administration.

115. 97. Use of a compound according to any one of claims 1 to 90, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 91 to 96, in the manufacture of a medicament for treating an HIV infection in a human having or at risk of having said infection.

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