Bridged tricyclic carbamoyl pyridinone compounds and uses thereof

Abstract

Disclosed are compounds useful for the treatment or prevention of human immunodeficiency virus (HIV) infection. These compounds have the following formula (I): (I) including stereoisomers and pharmaceutically acceptable salts thereof. Also disclosed are methods related to the preparation and use of the disclosed compounds and pharmaceutical compositions comprising such compounds.

Description

[0001] Cross-references

[0002] This application claims priority to U.S. Provisional Application No. 63 / 085,704, filed on September 30, 2020, which is incorporated herein by reference in its entirety for all purposes. Technical Field

[0003] This disclosure relates in its entirety to certain bridged tricyclic compounds, pharmaceutical compositions comprising said compounds, and methods for preparing and using said compounds and pharmaceutical compositions. Background Technology

[0004] Human immunodeficiency virus (HIV) infection and related diseases are a major public health problem worldwide. HIV 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 effectiveness, especially when used in combination, toxicity and the development of drug-resistant strains may limit their usefulness (Palella et al., N. Engl. J Med. (1998) 338:853-860; Richman, DDNature (2001) 410:995-1001). Therefore, new agents to inhibit HIV replication are needed.

[0005] One goal of antiretroviral therapy is to achieve viral suppression in patients with HIV infection. Current treatment guidelines from the U.S. Department of Health and Human Services state that achieving viral suppression requires the use of combination therapy, i.e., several drugs from at least two or more drug classes (Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. https: / / files.aidsinfo.nih.gov / contentfiles / lvguidelines / AdultandAdolescentGL.pdf. Accessed February 20, 2020). Furthermore, decisions regarding the treatment of HIV-infected patients are complex when they require treatment for other medical conditions. Because the standard of care requires the use of multiple different drugs to suppress HIV, as well as to treat other conditions the patient may be experiencing, the possibility of drug interactions is a criterion for selecting a drug regimen. Therefore, there is a need for antiretroviral therapies with a reduced likelihood of drug interactions.

[0006] In addition, HIV is known to mutate in infected subjects (Tang et al., Drugs (2012) 72(9)e1-e25). Due to the mutability of HIV, there is a need for anti-HIV drugs that are effective against a range of known HIV variants (Hurt et al., HIV / AIDS CID (2014) 58, 423-431).

[0007] For some patients, such as those with limited or difficulty accessing healthcare, adherence to daily oral treatment or preventative regimens can be challenging. Medications offering favorable pharmaceutical properties (e.g., improved potency, long-acting pharmacokinetics, low solubility, low clearance, and / or other properties) can reduce dosing frequency and provide better patient compliance. Such improvements can, in turn, optimize drug exposure and limit the development of resistance. Summary of the Invention

[0008] In some embodiments, this disclosure provides a compound of formula I:

[0009]

[0010] Or its pharmaceutically acceptable salt, wherein

[0011] R1 C for C 6-10 aryl or 5- to 10-membered heteroaryl, wherein C 6-10 aryl or 5- to 10-membered heteroaryl optionally substituted with one to four R A1 substituents, wherein each R A1 is independently halo, C 1-6 alkyl, C 1-4 haloalkyl, cyano, -O-C 1-4 alkyl or C 1-4 haloalkyl; 1-4 alkyl;

[0012] R 2 is H, C 1-6 alkyl or C 1-4 haloalkyl;

[0013] R 3 is halo or -OR 3a , wherein R 3a is H, -C 1-6 alkyl, -C 1-4 haloalkyl or -C 3-6 cycloalkyl; or

[0014] R 3a and R 2 , R 5a and R 6a , together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O and S;

[0015] R 3b is H, -C 1-6 alkyl, -C 1-4 haloalkyl or -C 1-4 alkylene-O-C 1-4 alkyl;

[0016] R 4a is -C 1-6 alkyl or -C 1-4 haloalkyl;

[0017] R 4b is H, halo, -C 1-6 alkyl or -C 1-4 haloalkyl;

[0018] W 1 is a bond or -CR 5a R 5b -;

[0019] R 5a and R 5b are independently H, C 1-6 alkyl, C1-4 Halogenated alkyl or halogenated; or

[0020] R 5a and R 3a Together with the carbon atoms to which they are attached, they form 4- to 6-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 5b For H, C 1-6 Alkyl, C 1-4 Haloalkyl or halogenated groups;

[0021] W 2 For -CR 6a R 6b -or-CR 7a =CR 7b -;

[0022] R 6a and R 6b H and C independently 1-6 Alkyl, C 1-4 Halogenated alkyl, halogenated, hydroxyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkylene-OC 1-4 Alkyl; or

[0023] R 6a and R 3a Together with the carbon atoms to which they are attached, they form 4- to 6-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 6b For H, C 1-6 Alkyl, C 1-4 Halogenated alkyl, halogenated, hydroxyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkylene-OC 1-4 alkyl;

[0024] R 7a and R 7b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; or

[0025] R 7a and R 7b Together with the carbon to which they are attached, they form optionally one to four R A2 Replacement C 5-10 Aryl, where each R A2 Independently a halogenated, cyanoated, or C group 1-4 alkyl.

[0026] 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.

[0027] In some embodiments, the present disclosure provides a kit comprising a compound of Formula I, or a pharmaceutically acceptable salt thereof, and instructions for use.

[0028] In some embodiments, the present disclosure provides a method of treating an HIV infection in a human having or at risk of having an HIV 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.

[0029] 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 an HIV infection.

[0030] 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 therapy.

[0031] 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 treating an HIV infection.

[0032] 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, in the manufacture of a medicament for treating an HIV infection in a human having or at risk of having an HIV infection. DETAILED DESCRIPTION

[0033] In the following description, certain specific details are set forth in order to provide a thorough understanding of various embodiments disclosed herein. However, one skilled in the art will understand that the embodiments disclosed herein can be practiced without these details. In other instances, well-known structures have not been described in detail in order to avoid obscuring the understanding of this description. The following description is presented for the purpose of illustrating certain embodiments disclosed herein and is not intended to limit the scope of claims appended hereto. The use of headings throughout this disclosure is provided for convenience only and should not be construed to limit the claims in any way. Embodiments illustrated under any heading can be combined with embodiments illustrated under any other heading.

[0034] I. Definitions

[0035] The words "comprise," "comprising," "include," "including," and "includes" when used in this disclosure and claims are to be interpreted as specifying the presence of the state, material, or act, but not to the exclusion of the presence of one or more other either additional or

[0036] References throughout this specification to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the disclosure. The appearances of the phrase "in one embodiment" or "in an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics can be combined in any suitable manner in one or more embodiments.

[0037] "Amino" refers to the -NH2 group.

[0038] "Hydroxy" refers to the -OH group.

[0039] "Oxo" refers to the =0 substituent.

[0040] Prefixes such as "C u-v " or (C u -C v ) indicate that the group following has u to v carbon atoms. For example, "C 1-6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0041] "Alkyl" refers to a straight or branched hydrocarbon group that is saturated, having from one to twelve carbon atoms (C 1-12 alkyl), in certain embodiments, from one to eight carbon atoms (C 1-8 alkyl), from one to six carbon atoms (C 1-6 alkyl), from one to four carbon atoms (C 1-4 alkyl), or from one to three carbon atoms (C 1-3 alkyl), and which is attached to the rest of the molecule by a single bond, such as, for example, methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), n-pentyl, hexyl, 3-methylhexyl, 2-methylhexyl, and the like.

[0042] “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 can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkylene groups include, but are not limited to, methylene (-CH2-), 1,1-ethyl (-CH(CH3)-), 1,2-ethyl (-CH2CH2-), 1,1-propyl (-CH(CH2CH3)-), 1,2-propyl (-CH2CH(CH3)-), 1,3-propyl (-CH2CH2CH2-), 1,4-butyl (-CH2CH2CH2CH2-), and the like.

[0043] “Aryl” refers to an aromatic carbocyclic radical having a single ring (e.g., phenyl) or multiple rings (e.g., biphenyl, terphenyl, or naphthyl) including fused rings. As used herein, an aryl group has 6 to 20 ring carbon atoms (i.e., C 6-20 Aryl), 6 to 12 carbon ring atoms (i.e., C 6-12 Aryl), or 6 to 10 carbon ring atoms (i.e., C 6-10 Aryl). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass heteroaryl groups as defined below or overlap therewith in any way.

[0044] “Cyano” refers to a nitrile group (-CN).

[0045] “Cycloalkyl” refers to a saturated or partially saturated cyclic alkyl radical having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl radicals (i.e., cyclic radicals having at least one double bond). As used herein, a cycloalkyl group has 3 to 20 ring carbon atoms (i.e., C 3-20 Cycloalkyl), 3 to 12 ring carbon atoms (i.e., C 3-12 Cycloalkyl), 3 to 10 ring carbon atoms (i.e., C 3-10 Cycloalkyl), 3 to 8 ring carbon atoms (i.e., C 3-8 Cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C 3-6 Cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0046] “Halo” or “halogen” refers to bromo, chloro, fluoro, or iodo.

[0047] “Haloalkyl” refers to an alkyl radical as defined above substituted with 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.

[0048] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings, or multiple condensed rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 5 to 20 ring atoms (5- to 20-membered heteroaromatic ring), 5 to 12 ring atoms (5- to 12-membered heteroaromatic ring), 5 to 10 ring atoms (5- to 10-membered heteroaromatic ring), or 5 to 6 ring atoms (5- to 6-membered heteroaromatic ring); and 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 aryl as defined above or overlap therewith.

[0049] "Heterocycle" refers to a non-aromatic group or ring having three to fifteen atoms, wherein one to six atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur and attached to the rest of the molecule by single bonds. In certain embodiments, "heterocyclyl" has three to ten atoms, wherein one to four atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or has three to seven atoms, wherein one to two atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen, carbon, or sulfur atoms in a heterocyclyl group can optionally be oxidized; the nitrogen atoms can optionally be 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, tetrahydrofuranyl, 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 rings, bridged rings, and spiro ring systems.

[0050] The embodiments disclosed herein are also intended to encompass all pharmaceutically acceptable compounds of Formula I that are isotopically-labeled by having one or more atoms replaced by an atom 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, phosphorous, fluorine, chlorine, and iodine, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35S、 18 F、 36 Cl、 123 I and 125 I. In certain embodiments, these radiolabeled compounds are useful in helping to determine or measure the effectiveness of a compound by characterizing, for example, the site or pattern of action or binding affinity to a site of pharmacological interest. Certain isotopically-labeled compounds of Formula I, Ia, Ib, Ic, Id, or II, for example those into which radioactive isotopes are 3 H) and carbon-14 (i.e., 14 C), are particularly preferred for their ease of

[0051] In certain embodiments, substitution with heavier isotopes such as deuterium (i.e., 2 H) can afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements. Thus, in some cases, heavier isotopes can be preferred.

[0052] Substitution with positron emitting isotopes such as 11 C, 18 F, 15 O, and 13 N can be useful in positron emission tomography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of Formula I, Ia, Ib, Ic, Id, or II can generally be prepared by techniques known to those skilled in the art, or by processes analogous to those described below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

[0053] The methods, compositions, kits, and articles of manufacture provided herein use or include a compound (e.g., a compound of Formula I, Ia, Ib, Ic, Id, or II) or a pharmaceutically acceptable salt thereof, wherein one to n hydrogen atoms attached to a carbon atom can be replaced with a deuterium atom or D, wherein n is the number of hydrogen atoms in the molecule. As is known in the art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. Such compounds will increase resistance to metabolism, and thus can be useful to increase the half-life of the compound or a pharmaceutically acceptable salt thereof 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 employing starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0054] The embodiments disclosed herein are also intended to encompass in vivo metabolic products of the disclosed compounds. Such products can result for example from oxidative, reductive, hydrolytic, amidation, esterification, and the like, of the administered compound, primarily due to enzymatic processes. Thus, the embodiments disclosed herein include compounds produced by a process comprising administration of a compound according to the 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 radiolabeled compound according to the embodiments disclosed herein to an animal, such as a rat, mouse, guinea pig, monkey, or to a human, allowing an adequate period of time for metabolism to occur, and determining the presence of the metabolic product(s) in a urine, a blood, or other biological sample.

[0055] “Mammal” includes humans, as well as domestic and captive animals (such as laboratory animals and household pets (e.g., cats, dogs, pigs, cows, sheep, goats, horses, rabbits)) and non-domestic animals (such as wild animals, etc.).

[0056] “Optional” or “optionally” means that the subsequently described event or circumstance can or can not occur, and that the description includes instances where the event or circumstance occurs and instances where it does not. For example, “optionally substituted alkyl” means that the alkyl can or can not be substituted and that the description includes substituted alkyl and un-substituted alkyl.

[0057] “Pharmaceutically acceptable excipient” includes, but is not limited to, any adjuvant, carrier, excipient, glidant, sweetening, diluting, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or other pharmacologically inactive substance that is combined with a pharmacologically active ingredient of a pharmaceutical composition and is compatible with the other ingredients of the formulation and is suitable for use in humans or domestic animals without undue toxicity, irritation, allergic response, and the like.

[0058] Examples of “pharmaceutically acceptable salts” of the compounds disclosed herein include salts derived from appropriate bases, such as alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium and NX4 + (where X is C 1-4pharmaceutically acceptable salt of a nitrogen atom or an amino group includes, for example, a salt of an organic carboxylic acid 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, pectinic acid, phenylacetic acid, 3-phenylpropionic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, sulfanilic acid, tartaric acid, undecanoic acid, and succinic acid; an organic sulfonic acid such as methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, mesitylenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and 2-naphthalenesulfonic acid; and an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and sulfamic acid. A pharmaceutically acceptable salt of a hydroxyl group of a compound includes the anion of the compound with a suitable cation such as Na + and NX4 + wherein X is independently selected from H or C 1-4 alkyl groups.

[0059] For therapeutic use, salts of the active ingredient of the compounds disclosed herein will typically be pharmaceutically acceptable salts, i.e., salts derived from pharmaceutically acceptable acids or bases. However, salts of acids or bases that are non-pharmaceutically acceptable can also find use, for example, in the preparation or purification of a compound of Formula I or another compound of the embodiments disclosed herein. All salts, whether derived from a pharmaceutically acceptable acid or base, are within the scope of the embodiments disclosed herein.

[0060] Metal salts are typically prepared by reacting a metal hydroxide with a compound according to the embodiments disclosed herein. Examples of metal salts prepared in this way are salts containing Li + , Na + , and K + . Less soluble metal salts can be precipitated from solutions of more soluble salts by the addition of a suitable metal compound.

[0061] Additionally, salts can be formed from acid addition of certain organic and inorganic acids (e.g., HC1, HBr, H2S04, H3P04, or organic sulfonic acids) to basic centers, typically amines. Finally, it should be understood that the compositions herein include the compounds disclosed herein in un-ionized as well as zwitterionic form.

[0062] A “pharmaceutical composition” refers to a formulation of a compound of the embodiments disclosed herein and a medium generally accepted for the delivery of biologically active compounds to mammals, e.g., humans. Such a medium includes all pharmaceutically acceptable excipients.

[0063] "Effective amount" or "therapeutically effective amount" refers to the amount of a compound according to the embodiments disclosed herein that, when administered to a patient in need, is sufficient to effect treatment of the disease state, condition, or disorder disclosed herein. Such amount would be enough to elicit the biological or medical response of a tissue system, or patient, that is being sought by the researcher, clinician or medical practitioner. The amount of a compound according to the embodiments disclosed herein that constitutes a therapeutically effective amount will vary depending on factors such as the compound and its bioactivity, the composition being administered, the time of administration, the route of administration, the rate of excretion of the compound, the duration of treatment, the type of disease state or disorder being treated and its severity, drugs used in combination or coincidental with the compounds of the embodiments disclosed herein, and the age, body weight, general health, sex, and diet of the patient. This therapeutically effective amount can be determined in a manner known per se by the person of ordinary skill in the art taking into account his own expert knowledge and the present disclosure.

[0064] The term "treatment" as used herein is intended to mean the administration of a compound or composition according to the embodiments of the application disclosed herein to alleviate or eliminate one or more symptoms of HIV infection and / or to reduce the viral load of a patient. In certain embodiments, the term "treatment" also encompasses the administration of a compound or composition according to the embodiments of the application disclosed herein after an individual has been exposed to the virus, but prior to the appearance of symptoms of the disease and / or prior to the detection of the virus in the blood, to prevent the appearance of symptoms of the disease and / or to prevent the virus from reaching detectable levels in the blood, as well as the administration of a compound or composition according to the embodiments of the application disclosed herein to prevent perinatal transmission of HIV from mother to infant by administration to the mother prior to delivery and to the child within the first days of life. The term "treatment" also encompasses the administration of a compound or composition according to the embodiments of the application disclosed herein prior to an individual's exposure to the virus (also known as pre-exposure prophylaxis or PrEP) to prevent HIV infection from taking hold when the individual is exposed to the virus and / or to prevent the virus from establishing a permanent infection and / or to prevent the appearance of symptoms of the disease and / or to prevent the virus from reaching detectable levels in the blood. The term "treatment" also encompasses the administration of a compound or composition according to the embodiments of the application disclosed herein both prior to and after an individual's exposure to the virus.

[0065] As used herein, the term "prevent" refers to the administration of a compound, composition, or pharmaceutically salt according to the present disclosure prior to or after exposure to the virus but before the appearance of symptoms of the disease and / or before the virus is detected in the blood. The term also refers to preventing the appearance of symptoms of the disease and / or preventing the virus from reaching detectable levels in the blood. The term includes pre-exposure prophylaxis (PrEP) as well as post-exposure prophylaxis (PEP) and event-driven or "on-demand" prophylaxis. The term also refers to preventing perinatal transmission of HIV from mother to infant by administration to the mother prior to delivery and to the child within the first days of life. The term also refers to preventing transmission of HIV through blood transfusion.

[0066] The compounds of the embodiments disclosed herein or their pharmaceutically acceptable salts can contain one or more asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined, in terms of absolute stereochemistry, as (R)- or (S)- or as (D)- or (L)- for amino acids. The present disclosure is intended to include all such possible isomers, as well as, their racemic, scalemic, and optically pure form. Opticaliy active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using, for example, chromatography and fractional crystallization. Techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor (or scalemic) or resoiving the racmate (or scalemate of a salt or derivative) using, for example, chiral high pressure liquid chromatography. When the compounds described herein contain olefinic double bonds or other geometrical asymmetric centers, and unless indicated otherwise, the compounds are intended to include E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0067] "stereoisomers" refers to compounds which are mirror images of one another and which are not superimposable on one another. In any of the embodiments disclosed herein, the compounds disclosed herein can be in the form of a stereoisomer thereof.

[0068] "Partially saturated" refers to cyclic groups containing at least one double bond but which are not aromatic.

[0069] II. Compounds

[0070] In some embodiments, the present disclosure provides a compound of Formula I:

[0071]

[0072] or a pharmaceutically acceptable salt thereof, wherein

[0073] R1 C 6-10 Aryl or 5 to 10-membered heteroaryl, of which C 6-10 Aryl or 5 to 10 heteroaryl groups are optionally surrounded by one to four R groups. A1 Replace, where each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Halogenated alkyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkyl-OC 1-4 alkyl;

[0074] R 2 For H, C 1-6 Alkyl or C 1-4 Halogenated alkyl groups;

[0075] R 3 Halogenated or -OR 3a , where R 3a H, -C 1-6 Alkyl, -C 1-4 Halogenated alkyl or -C 3-6 cycloalkyl; or

[0076] R 3a and R 2 R 5a and R 6a Each of them, together with the carbon to which they are attached, forms a 4- to 6-membered heterocycle containing one or two independent heteroatoms selected from N, O, and S;

[0077] R 3b H, -C 1-6 Alkyl, -C 1-4 Halogenated alkyl or -C 1-4 Alkylene-OC 1-4 alkyl;

[0078] R 4a -C 1-6 Alkyl or -C 1-4 Halogenated alkyl groups;

[0079] R 4b H, halogen, -C 1-6 Alkyl or -C 1-4 Halogenated alkyl groups;

[0080] W 1 For key or -CR 5a R 5b -;

[0081] R 5a and R 5b Independently for H and C 1-6 Alkyl, C1-4 Halogenated alkyl or halogenated; or

[0082] R 5a and R 3a Together with the carbon atoms to which they are attached, they form 4- to 6-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 5b For H, C 1-6 Alkyl, C 1-4 Haloalkyl or halogenated groups;

[0083] W 2 For -CR 6a R 6b -or-CR 7a =CR 7b -;

[0084] R 6a and R 6b Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl, halogenated, hydroxyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkylene-OC 1-4 Alkyl; or

[0085] R 6a and R 3a Together with the carbon atoms to which they are attached, they form 4- to 6-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 6b For H, C 1-6 Alkyl, C 1-4 Halogenated alkyl, halogenated, hydroxyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkylene-OC 1-4 Alkyl; and

[0086] R 7a and R 7b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl; or

[0087] R 7a and R 7b Together with the carbon to which they are attached, they form optionally one to four R A2 Replacement C 5-10 Aryl, where each R A2 Independently a halogenated, cyanoated, or C group 1-4 alkyl.

[0088] It is desirable to find compounds, or pharmaceutically acceptable salts thereof, that have good stability, i.e., physical, chemical stability, and / or metabolic stability. Increased overall stability of a compound can provide for an increase in the time of circulation in the body. Stable compounds can be administered at lower doses and still maintain efficacy due to less degradation. Also, there are fewer problems with byproducts resulting from degradation of the compound due to less degradation. Higher stability of a drug means more drug is available to the target cell without being metabolized.

[0089] It is further desirable to find compounds, or pharmaceutically acceptable salts thereof, that have improved pharmacokinetic and / or pharmacodynamic properties and long half-life. It is advantageous for a drug to have a moderate or low clearance and a long half-life, as this can lead to good bioavailability and high systemic exposure. Reducing the clearance and / or increasing the half-life time of a compound can reduce the daily dose needed for efficacy, and thus result in better efficacy and safety profiles. Thus, improved pharmacokinetic and / or pharmacodynamic properties and long half-life can provide for better patient compliance.

[0090] As shown below, the compounds of Formula I provided herein are characterized by (i) at least one oxygen attachment or halogen substitution (R 3 is halo or -OR 3a ) and (ii) at least one alkyl or haloalkyl substituent (R 4a is -C 1-6 alkyl or -C 1-4 haloalkyl) at the “b” position:

[0091]

[0092] Advantageously, certain compounds of Formula I provided herein exhibit improved properties, e.g., improved stability compared to structurally related compounds lacking (i) at least one oxygen attachment or halogen substitution at the “a” position and (ii) at least one alkyl or haloalkyl substituent at the “b” position. In some embodiments, the compounds of Formula I provided herein exhibit improved metabolic stability compared to structurally related compounds lacking (i) at least one oxygen attachment or 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 the compounds of Formula I provided herein results in their reduced intrinsic clearance, e.g., due to their reduced intrinsic clearance in human liver microsomes assay (HLM).

[0093] In some embodiments, the compounds of Formula I provided herein are compounds of Formula la:

[0094]

[0095] In some embodiments, the compound of Formula I provided herein is a compound of Formula Ib:

[0096]

[0097] In some embodiments, the compound of Formula I provided herein is a compound of Formula Ic:

[0098]

[0099] In some embodiments, the compound of Formula I provided herein is a compound of Formula Id:

[0100]

[0101] In some embodiments of the compound of Formula I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof, R 1 is C 6-10 aryl or 5- to 10-membered heteroaryl, wherein the C 6-10 aryl or 5- to 10-membered heteroaryl is optionally substituted with one to four R A1 , wherein each R A1 is 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 alkyl. In some embodiments, R 1 is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, wherein the phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine is optionally substituted with one, two, three, or four R A1 , wherein each R A1 is 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 alkyl. In some embodiments, R 1 is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine optionally substituted with one, two, three, or four R A1 , wherein each R A1 is independently halo, C 1-4 alkyl, C 1-4 haloalkyl, or -O-C 1-4 alkyl. In some embodiments, R 1 is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine optionally substituted with one, two, three, or four R A1 , wherein each R A1 is independently halo, C1-4 Alkyl or -OC 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, wherein each R A1 Independently a halogenated or C 1-4 Alkyl group. In some embodiments, R 1 To be optionally controlled by one, two, three or four R A1 Substituted phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, wherein each R A1 Independently a halogenated or -OC group 1-4 Alkyl group. In some embodiments, R 1 For being one, two, three or four R A1 Substituted phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, wherein each R A1 Independently halogenated. In some implementations, R 1 For two or three R A1 Substituted phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, wherein each R A1 Independently halogenated. In some implementations, R 1 For two or three R A1 Substituted phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, wherein each R A1 It is independently selected from chlorine and fluorine.

[0102] In embodiments of compounds of formula I, Ia, Ib, Ic, or Id, or their pharmaceutically acceptable salts, R 1 It is phenyl or pyridyl, wherein the phenyl or pyridyl group is optionally surrounded by one, two, three or four R groups. A1 Replace, where each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Halogenated alkyl, cyano, -OC 1-4 Alkyl or -C 1-4 Alkyl-OC 1-4 Alkyl group. In some embodiments, R 1 It is phenyl or pyridyl, wherein the phenyl or pyridyl group is optionally surrounded by one, two, three or four R groups. A1 Replace, where each R A1 Independently halogenated, C 1-4 Alkyl, C 1-4 Halogenated alkyl or -OC 1-4 Alkyl group. In some embodiments, R 1 It is phenyl or pyridyl, wherein the phenyl or pyridyl group is optionally surrounded by one, two, three or four R groups.A1 Replace, where each R A1 Independently halogenated, C 1-4 Alkyl or -OC 1-4 Alkyl group. In some embodiments, R 1 It is phenyl or pyridyl, wherein the phenyl or pyridyl group is optionally surrounded by one, two, three or four R groups. A1 Replace, where each R A1 Independently a halogenated or C 1-4 Alkyl group. In some embodiments, R 1 It is phenyl or pyridyl, wherein the phenyl or pyridyl group is optionally surrounded by one, two, three or four R groups. A1 Replace, where each R A1 Independently a halogenated or -OC group 1-4 Alkyl group. In some embodiments, R 1 It is phenyl or pyridyl, wherein the phenyl or pyridyl group is surrounded by one, two, three or four R groups. A1 Replace, where each R A1 Independently halogenated. In some implementations, R 1 It is phenyl or pyridyl, wherein the phenyl or pyridyl group is formed by two or three R groups. A1 Replace, where each R A1 Independently halogenated. In some implementations, R 1 It is phenyl or pyridyl, wherein the phenyl or pyridyl group is formed by two or three R groups. A1 Replace, where each R A1 It is independently selected from chlorine and fluorine.

[0103] In embodiments of compounds of formula I, Ia, Ib, Ic, or Id, or their pharmaceutically acceptable salts, R 1 It is a pyridinyl group, wherein the pyridinyl group is optionally surrounded by one, two, three or four R groups. A1 Replace, where each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Halogenated alkyl, cyano, -OC 1-4 Alkyl or -C 1-4 Alkyl-OC 1-4 Alkyl group. In some embodiments, R 1 It is a pyridinyl group, wherein the pyridinyl group is optionally surrounded by one, two, three or four R groups. A1 Replace, where each R A1 Independently halogenated, C 1-4 Alkyl, C 1-4 Halogenated alkyl or -OC 1-4 Alkyl group. In some embodiments, R 1is pyridyl, wherein the pyridyl is optionally substituted with one, two, three, or four R A1 each R A1 is independently halo, C 1-4 alkyl, or -O-C 1-4 alkyl. In some embodiments, R 1 is phenyl, wherein the phenyl is optionally substituted with one, two, three, or four R A1 each R A1 is independently halo or C 1-4 alkyl. In some embodiments, R 1 is pyridyl, wherein the pyridyl is optionally substituted with one, two, three, or four R A1 each R A1 is independently halo or -O-C 1-4 alkyl. In some embodiments, R 1 is pyridyl, wherein the pyridyl is substituted with one, two, three, or four R A1 each R A1 is independently halo. In some embodiments, R 1 is pyridyl, wherein the pyridyl is substituted with two or three R A1 each R A1 is independently halo. In some embodiments, R 1 is pyridyl, wherein the pyridyl is substituted with two or three R A1 each R A1 is independently selected from chlorine and fluorine.

[0104] In embodiments of the compound of Formula I, Ia, Ib, Ic, or Id, or a pharmaceutically acceptable salt thereof, R 1 is phenyl, wherein the phenyl is optionally substituted with one, two, three, or four R A1 each R A1 is 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 alkyl. In some embodiments, R 1 is phenyl, wherein the phenyl is optionally substituted with one, two, three, or four R A1 each R A1 is independently halo, C 1-4 alkyl, C 1-4 haloalkyl, or -O-C 1-4 alkyl. In some embodiments, R 1It is a phenyl group, wherein the phenyl group is optionally surrounded by one, two, three or four R groups. A1 Replace, where each R A1 Independently halogenated, C 1-4 Alkyl or -OC 1-4 Alkyl group. In some embodiments, R 1 It is a phenyl group, wherein the phenyl group is optionally surrounded by one, two, three or four R groups. A1 Replace, where each R A1 Independently a halogenated or C 1-4 Alkyl group. In some embodiments, R 1 It is a phenyl group, wherein the phenyl group is optionally surrounded by one, two, three or four R groups. A1 Replace, where each R A1 Independently a halogenated or -OC group 1-4 Alkyl group. In some embodiments, R 1 It is a phenyl group, wherein the phenyl group is reacted with one, two, three or four R groups. A1 Replace, where each R A1 Independently halogenated. In some implementations, R 1 It is a phenyl group, wherein the phenyl group is reacted with two or three R groups. A1 Replace, where each R A1 Independently halogenated. In some implementations, R 1 It is a phenyl group, wherein the phenyl group is reacted with two or three R groups. A1 Replace, where each R A1 It is independently selected from chlorine and fluorine.

[0105] In some embodiments of compounds of formula I, Ia, Ib, Ic, or Id, or pharmaceutically acceptable salts thereof, R 1 Choose from the following groups:

[0106]

[0107] In some embodiments, the compounds of formula I, Ia, Ib, Ic, or Id are compounds of formula II:

[0108]

[0109] Where n is 0, 1, 2, 3, or 4; and each R A1 Independently halogenated, C 1-6 Alkyl, C 1-4 Halogenated alkyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkyl-OC 1-4 alkyl.

[0110] 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 -O-C 1-4 alkyl. In some embodiments, n is 2, 3, or 4, and each R A1 independently halo, C 1-4 alkyl, C 1-4 haloalkyl, or -O-C 1-4 alkyl. In some embodiments, n is 2, 3, or 4, and each R A1 independently halo, C 1-4 alkyl, or -O-C 1-4 alkyl. In some embodiments, n is 2, 3, or 4, and each R A1 independently halo or C 1-4 alkyl. In some embodiments, n is 2, 3, or 4, and each R A1 independently halo or -O-C 1-4 alkyl. In some embodiments, n is 2, 3, or 4, and each R A1 independently halo. In some embodiments, n is 2, 3, or 4, and each R A1 is independently selected from chlorine and fluorine.

[0111] 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 -O-C 1-4 alkyl. In some embodiments, n is 2 or 3, and each R A1 independently halo, C 1-4 alkyl, C 1-4 haloalkyl, or -O-C 1-4 alkyl. In some embodiments, n is 2 or 3, and each R A1 independently halo, C 1-4 alkyl, or -O-C 1-4 alkyl. In some embodiments, n is 2 or 3, and each R A1 independently halo or C 1-4 alkyl. In some embodiments, n is 2 or 3, and each R A1 independently halo or -O-C 1-4 alkyl. In some embodiments, n is 2 or 3, and each R A1 independently halo. In some embodiments, n is 2 or 3, and each R A1 is independently selected from chlorine and fluorine.

[0112] In some embodiments of the 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 haloalkyl. In some embodiments, R 2 is H or C 1-6 alkyl. In some embodiments, R 2 is H or C 1-4 haloalkyl. In some embodiments, R 2 is C 1-6 alkyl, or C 1-4 haloalkyl. In some embodiments, R2is C1-3alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is H.

[0113] In some embodiments of the 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.

[0114] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3 is OR 3a , wherein R 3a is H, -C 1-6 alkyl, -C 1-4 haloalkyl, or -C 3-6 cycloalkyl, and R 3b is H, -C 1-6 alkyl, -C 1-4 haloalkyl, or -C 1-4 alkylene-O-C 1-4 alkyl. In some embodiments, R 3a is -C 1-6 alkyl, -C 1-4 haloalkyl, or -C 3-6 cycloalkyl; and R 3b is H, -C 1-6 alkyl, -C 1-4 haloalkyl, or -C 1-4 alkylene-O-C 1-4 alkyl. In some embodiments, R 3a is -C 1-6 alkyl, or -C 1-4 haloalkyl; and R 3b is H, -C 1-6 alkyl, -C1-4 haloalkyl or -C 1-4 alkylene-O-C 1-4 alkyl. In some embodiments, R 3a is -C 1-6 alkyl; and R 3b is H, -C 1-6 alkyl, -C 1-4 haloalkyl or -C 1-4 alkylene-O-C 1-4 alkyl. In some embodiments, R 3a is methyl or ethyl; and R 3b is H, -C 1-6 alkyl, -C 1-4 haloalkyl or -C 1-4 alkylene-O-C 1-4 alkyl. In some embodiments, R 3a is methyl; and R 3b is H, -C 1-6 alkyl, -C 1-4 haloalkyl or -C 1-4 alkylene-O-C 1-4 alkyl.

[0115] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3 is OR 3a , wherein R 3a is H, -C 1-6 alkyl, -C 1-4 haloalkyl or -C 3-6 cycloalkyl, and R 3b is H, -C 1-6 alkyl or -C 1-4 haloalkyl. In some embodiments, R 3a is -C 1-6 alkyl, -C 1-4 haloalkyl or -C 3-6 cycloalkyl, and R 3b is H, -C 1-6 alkyl or -C 1-4 haloalkyl. In some embodiments, R 3a is -C 1-6 alkyl or -C 1-4 haloalkyl, and R 3b is H, -C 1-6 alkyl or -C 1-4 haloalkyl. In some embodiments, R 3a is -C 1-6 alkyl, and R 3b is H, -C 1-6Alkyl or -C 1-4 Halogenated alkyl groups. In some embodiments, R 3a It is methyl or ethyl, and R 3b H, -C 1-6 Alkyl or -C 1-4 Halogenated alkyl groups. In some embodiments, R 3a It is methyl, and R 3b H, -C 1-6 Alkyl or -C 1-4 Halogenated alkyl groups.

[0116] In some embodiments of compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, R 3 OR 3a , where R 3a H, -C 1-6 Alkyl, -C 1-4 Halogenated alkyl or -C 3-6 Cycloalkyl, and R 3b H or -C 1-6 Alkyl group. In some embodiments, R 3a -C 1-6 Alkyl, -C 1-4 Halogenated alkyl or -C 3-6 cycloalkyl and R 3b H or -C 1-6 Alkyl group. In some embodiments, R 3a -C 1-6 Alkyl or -C 1-4 Halogenated alkyl groups, and R 3b H or -C 1-6 Alkyl group. In some embodiments, R 3a -C 1-6 Alkyl; and R 3b H or -C 1-6 Alkyl group. In some embodiments, R 3a It is methyl or ethyl, and R 3b H or -C 1-6 Alkyl group. In some embodiments, R 3a It is methyl, and R 3b H or -C 1-6 alkyl.

[0117] In some embodiments of compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, R 3 OR 3a , where R 3a H, -C 1-6 Alkyl, -C 1-4 Halogenated alkyl or -C 3-6cycloalkyl, and R 3b is H or -C 1-3 alkyl. In some embodiments, R 3a is -C 1-6 alkyl, -C 1-4 haloalkyl, or -C 3-6 cycloalkyl, and R 3b is H or -C 1-3 alkyl. In some embodiments, R 3a is -C 1-6 alkyl, or -C 1-4 haloalkyl, and R 3b is H or -C 1-3 alkyl. In some embodiments, R 3a is -C 1-6 alkyl, and R 3b is H or -C 1-3 alkyl. In some embodiments, R 3a is methyl or ethyl, and R 3b is H or -C 1-6 alkyl. In some embodiments, R 3a is methyl, and R 3b is H or -C 1-3 alkyl.

[0118] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3 is OR 3a , wherein R 3a is H, -C 1-6 alkyl, -C 1-4 haloalkyl, or -C 3-6 cycloalkyl, and R 3b is H or methyl. In some embodiments, R 3a is -C 1-6 alkyl, -C 1-4 haloalkyl, or -C 3-6 cycloalkyl, and R 3b is H or methyl. In some embodiments, R 3a is -C 1-6 alkyl, or -C 1-4 haloalkyl, and R 3b is H or methyl. In some embodiments, R 3a is -C 1-6 alkyl, 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 R3b It is H or methyl.

[0119] In some embodiments of compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, R 3 OR 3a , where R 3a H, -C 1-6 Alkyl, -C 1-4 Halogenated alkyl or -C 3-6 Cycloalkyl, and R 3b For H. In some implementations, R 3a -C 1-6 Alkyl, -C 1-4 Halogenated alkyl or -C 3-6 cycloalkyl and R 3b For H. In some implementations, R 3a -C 1-6 Alkyl or -C 1-4 Halogenated alkyl groups, and R 3b For H. In some implementations, R 3a -C 1-6 Alkyl, and R 3b For H. In some implementations, R 3a It is methyl or ethyl, and R 3b For H. In some implementations, R 3a It is methyl, and R 3b For H.

[0120] In some embodiments of compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, R 3a and R 2 R 5a and R 6a Each of these elements, together with the carbon atom to which it is attached, forms a 4- to 6-membered heterocycle containing one or two independent heteroatoms selected from N, O, and S; and R 3b H, -C 1-6 Alkyl, -C 1-4 Halogenated alkyl or -C 1-4 Alkylene-OC 1-4 Alkyl group. In some embodiments, R 3a and R 2 R 5a and R 6a Each of these elements, together with the carbon atom to which it is attached, forms a 4- to 6-membered heterocycle containing one or two independent heteroatoms selected from N, O, and S; and R 3b H, -C 1-6 Alkyl or -C 1-4 Halogenated alkyl groups. In some embodiments, R3a and R 2 R 5a and R 6a Each of these elements, together with the carbon atom to which it is attached, forms a 4- to 6-membered heterocycle containing one or two independent heteroatoms selected from N, O, and S; and R 3b H or -C 1-6 Alkyl group. In some embodiments, R 3a and R 2 R 5a and R 6a Each of these elements, together with the carbon atom to which it is attached, forms a 4- to 6-membered heterocycle containing one or two independent heteroatoms selected from N, O, and S; and R 3b H or -C 1-3 Alkyl group. In some embodiments, R 3a and R 2 R 5a and R 6a Each of these elements, together with the carbon atom to which it is attached, forms a 4- to 6-membered heterocycle containing one or two independent heteroatoms selected from N, O, and S; and R 3b It is H or methyl. In some embodiments, R 3a and R 2 R 5a and R 6a Each of these elements, together with the carbon atom to which it is attached, forms a 4- to 6-membered heterocycle containing one or two independent heteroatoms selected from N, O, and S; and R 3b For H.

[0121] In some embodiments of compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, R 3a and R 2 R 5a and R 6a Each of these elements, together with the carbon atom to which it is attached, forms a 4- to 6-membered heterocycle containing one oxygen atom; and R 3b H, -C 1-6 Alkyl, -C 1-4 Halogenated alkyl or -C 1-4 Alkylene-OC 1-4 Alkyl group. In some embodiments, R 3a and R 2 R 5a and R 6a Each of these elements, together with the carbon atom to which it is attached, forms a 4- to 6-membered heterocycle containing one oxygen atom; and R 3b H, -C 1-6 Alkyl or -C 1-4 Halogenated alkyl groups. In some embodiments, R 3a and R2 R 5a and R 6a Each of these elements, together with the carbon atom to which it is attached, forms a 4- to 6-membered heterocycle containing one oxygen atom; and R 3b H or -C 1-6 Alkyl group. In some embodiments, R 3a and R 2 R 5a and R 6a Each of these elements, together with the carbon atom to which it is attached, forms a 4- to 6-membered heterocycle containing one oxygen atom; and R 3b H or -C 1-3 Alkyl group. In some embodiments, R 3a and R 2 R 5a and R 6a Each of these elements, together with the carbon atom to which it is attached, forms a 4- to 6-membered heterocycle containing one oxygen atom; and R 3b It is H or methyl. In some embodiments, R 3a and R 2 R 5a and R 6a Each of these elements, together with the carbon atom to which it is attached, forms a 4- to 6-membered heterocycle containing one oxygen atom; and R 3b For H.

[0122] In some embodiments of compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, R 3a and R 2 Together with the carbon atoms to which they are attached, they form 4- to 6-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 3b H, -C 1-6 Alkyl, -C 1-4 Halogenated alkyl or -C 1-4 Alkylene-OC 1-4 Alkyl group. In some embodiments, R 3a and R 2 Together with the carbon atoms to which they are attached, they form 4- to 6-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 3b H, -C 1-6 Alkyl or -C 1-4 Halogenated alkyl groups. In some embodiments, R 3a and R 2 Together with the carbon atoms to which they are attached, they form 4- to 6-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 3b H or -C 1-6 Alkyl group. In some embodiments, R 3a and R2 with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R 3b is H or -C 1-3 alkyl. In some embodiments, R 3a and R 2 with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R 3b is H or methyl. In some embodiments, R 3a and R 2 with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R 3b is H.

[0123] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3a and R 2 with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom; and R 3b is H, -C 1-6 alkyl, -C 1-4 haloalkyl, or -C 1-4 alkylene-O-C 1-4 alkyl. In some embodiments, R 3a and R 2 with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom; and R 3b is H, -C 1-6 alkyl, or -C 1-4 haloalkyl. In some embodiments, R 3a and R 2 with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom; and R 3b is H or -C 1-6 alkyl. In some embodiments, R 3a and R 2 with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom; and R 3b is H or -C 1-3 alkyl. In some embodiments, R 3a and R 2 with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom; and R 3b is H or methyl. In some embodiments, R 3a and R 2 with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom; and R 3bH.

[0124] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, R 3a and R 5a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R 3b is H, -C 1-6 alkyl, -C 1-4 haloalkyl, or -C 1-4 alkylene-O-C 1-4 alkyl. In some embodiments, R 3a and R 5a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R 3b is H, -C 1-6 alkyl, or -C 1-4 haloalkyl. In some embodiments, R 3a and R 5a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R 3b is H or -C 1-6 alkyl. In some embodiments, R 3a and R 5a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R 3b is H or -C 1-3 alkyl. In some embodiments, R 3a and R 5a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; 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 heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R 3b is H.

[0125] In some embodiments of the 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 heterocyclic ring containing one oxygen atom; and R 3b is H, -C 1-6 alkyl, -C 1-4 haloalkyl, or -C 1-4 alkylene-O-C1-4 Alkyl group. In some embodiments, R 3a and R 5a Together with the carbon atoms to which they are attached, they form 4- to 6-membered heterocycles containing one oxygen atom; and R 3b H, -C 1-6 Alkyl or -C 1-4 Halogenated alkyl groups. In some embodiments, R 3a and R 5a Together with the carbon atoms to which they are attached, they form 4- to 6-membered heterocycles containing one oxygen atom; and R 3b H or -C 1-6 Alkyl group. In some embodiments, R 3a and R 5a Together with the carbon atoms to which they are attached, they form 4- to 6-membered heterocycles containing one oxygen atom; and R 3b H or -C 1-3 Alkyl group. In some embodiments, R 3a and R 5a Together with the carbon atoms to which they are attached, they form 4- to 6-membered heterocycles containing one oxygen atom; and R 3b It is H or methyl. In some embodiments, R 3a and R 5a Together with the carbon atoms to which they are attached, they form 4- to 6-membered heterocycles containing one oxygen atom; and R 3b For H.

[0126] In some embodiments of compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, R 3a and R 6a Together with the carbon atoms to which they are attached, they form 4- to 6-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 3b H, -C 1-6 Alkyl, -C 1-4 Halogenated alkyl or -C 1-4 Alkylene-OC 1-4 Alkyl group. In some embodiments, R 3a and R 6a Together with the carbon atoms to which they are attached, they form 4- to 6-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 3b H, -C 1-6 Alkyl or -C 1-4 Halogenated alkyl groups. In some embodiments, R 3a and R 6a Together with the carbon atoms to which they are attached, they form 4- to 6-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 3b H or -C 1-6alkyl. In some embodiments, R 3a and R 6a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R 3b is H or -C 1-3 alkyl. In some embodiments, R 3a and R 6a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R 3b is H or -C 3a alkyl. In some embodiments, R 6a and R 3b together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R 3a is H.

[0127] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 6a and R 3b together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom; and R 1-6 is H, -C 1-4 alkyl, -C 1-4 haloalkyl, or -C 1-4 alkylene-O-C 3a alkyl. In some embodiments, R 6a and R 3b together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom; and R 1-6 is H, -C 1-4 alkyl, or -C 3a haloalkyl. In some embodiments, R 6a and R 3b together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom; and R 1-6 is H or -C 3a alkyl. In some embodiments, R 6a and R 3b together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom; and R 1-3 is H or -C 3a alkyl. In some embodiments, R 6a and R 3b together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom; and R 3a is H or -C 6awith the carbon to which they are attached forms a 4- to 6-membered heterocyclic ring containing one oxygen atom; and R 3b is H.

[0128] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 4a is -C 1-6 alkyl or -C 1-4 haloalkyl. In some embodiments, R 4a is -C 1-3 alkyl. In some embodiments, R 4a is methyl. In some embodiments, R 4a is -C 1-4 haloalkyl.

[0129] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 4b is H, halo, -C 1-6 alkyl or -C 1-4 haloalkyl. In some embodiments, R 4b is H, -C 1-3 alkyl or -C 1-4 haloalkyl. In some embodiments, R 4b is H or C 1-3 alkyl. In some embodiments, R 4b is -C 1-3 alkyl or -C 1-4 haloalkyl. In some embodiments, R 4b is -C 1-3 alkyl. In some embodiments, R 4b is -C 1-4 haloalkyl. In some embodiments, R 4b is H.

[0130] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 4a is -C 1-6 alkyl or -C 1-4 haloalkyl, and R 4b is H, halo, -C 1-6 alkyl or -C 1-4 haloalkyl. In some embodiments, R 4a is -C 1-6 alkyl or -C 1-4 haloalkyl, and R 4b is H or C 1-3 alkyl. In some embodiments, R 4a is -C 1-6alkyl or -C 1-4 haloalkyl, and R 4b is -C 1-3 alkyl or -C 1-4 haloalkyl. In some embodiments, R 4a is -C 1-6 alkyl or -C 1-4 haloalkyl, and R 4b is -C 1-3 alkyl. In some embodiments, R 4a is -C 1-6 alkyl or -C 1-4 haloalkyl, and R 4b is -C 1-4 haloalkyl. In some embodiments, R 4a is -C 1-6 alkyl or -C 1-4 haloalkyl, and R 4b is H.

[0131] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 4a is -C 1-3 alkyl, and R 4b is H, halo, -C 1-6 alkyl or -C 1-4 haloalkyl. In some embodiments, R 4a is -C 1-3 alkyl, and R 4b is H, -C 1-3 alkyl or -C 1-4 haloalkyl. In some embodiments, R 4a is -C 1-3 alkyl, and R 4b is H or C 1-3 alkyl. In some embodiments, R 4a is -C 1-3 alkyl, and R 4b is -C 1-3 alkyl or -C 1-4 haloalkyl. In some embodiments, R 4a is -C 1-3 alkyl, and R 4b is -C 1-3 alkyl. In some embodiments, R 4a is -C 1-3 alkyl, and R 4b is -C 1-4 haloalkyl. In some embodiments, R 4a is -C 1-3 alkyl, and R 4bH.

[0132] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 4a is methyl, and R 4b is H, halo, -C 1-6 alkyl, or -C 1-4 haloalkyl. In some embodiments, R 4a is methyl, and R 4b is H, -C 1-3 alkyl, or -C 1-4 haloalkyl. In some embodiments, R 4a is methyl, and R 4b is H or C 1-3 alkyl. In some embodiments, R 4a is methyl, and R 4b is -C 1-3 alkyl, or -C 1-4 haloalkyl. In some embodiments, R 4a is methyl, and R 4b is -C 1-3 alkyl. In some embodiments, R 4a is methyl, and R 4b is -C 1-4 haloalkyl. In some embodiments, R 4a is methyl, and R 4b is H.

[0133] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 4a is -C 1-4 haloalkyl, and R 4b is H, halo, -C 1-6 alkyl, or -C 1-4 haloalkyl. In some embodiments, R 4a is -C 1-4 haloalkyl, and R 4b is H, -C 1-3 alkyl, or -C 1-4 haloalkyl. In some embodiments, R 4a is -C 1-4 haloalkyl, and R 4b is H or C 1-3 alkyl. In some embodiments, R 4a is -C 1-4 haloalkyl, and R 4b is -C 1-3 alkyl, or -C 1-4 haloalkyl. In some embodiments, R4a -C 1-4 haloalkyl, and R 4b -C 1-3 alkyl. In some embodiments, R 4a -C 1-4 haloalkyl, and R 4b -C 1-4 haloalkyl. In some embodiments, R 4a -C 1-4 haloalkyl, and R 4b H.

[0134] 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.

[0135] 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 -, wherein 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, and R 5b is H, C 1-6 alkyl, or halo. In some embodiments, R 5a is H, C 1-6 alkyl, C 1-4 haloalkyl, or halo, and R 5b is H or C 1-6 alkyl. In some embodiments, R 5a is H, C 1-6 alkyl, C 1-4 haloalkyl, or halo, and R 5b C 1-6 alkyl. In some embodiments, R 5a is H, C 1-6 alkyl, C 1-4 haloalkyl, or halo, and R 5b H.

[0136] 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 -, wherein R 5aH, C 1-6 alkyl, C 1-4 haloalkyl, and R 5b H, C 1-6 alkyl, C 1-4 haloalkyl or halo. In some embodiments, R 5a H, C 1-6 alkyl or C 1-4 haloalkyl, and R 5b H, C 1-6 alkyl or halo. In some embodiments, R 5a H, C 1-6 alkyl or C 1-4 haloalkyl, and R 5b H or C 1-6 alkyl. In some embodiments, R 5a H, C 1-6 alkyl or C 1-4 haloalkyl, and R 5b C 1-6 alkyl. In some embodiments, R 5a H, C 1-6 alkyl or C 1-4 haloalkyl, and R 5b H.

[0137] In some embodiments of the compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, W 1 -CR 5a R 5b -, wherein R 5a H or C 1-6 alkyl, and R 5b H, C 1-6 alkyl, C 1-4 haloalkyl or halo. In some embodiments, R 5a H or C 1-6 alkyl, and R 5b H, C 1-6 alkyl or halo. In some embodiments, R 5a H or C 1-6 alkyl, and R 5b H or C 1-6 alkyl. In some embodiments, R 5a H or C 1-6 alkyl, and R 5b C 1-6 alkyl. In some embodiments, R 5a H or C 1-6 alkyl, and R 5b H.

[0138] In some embodiments of the compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, W 1 is -CR 5a R 5b - wherein 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 alkyl, or halo. In some embodiments, R 5a is C 1-6 alkyl, and R 5b is H or C 1-6 alkyl. In some embodiments, R 5a is C 1-6 alkyl, and R 5b is C 1-6 alkyl. In some embodiments, R 5a is C 1-6 alkyl, and R 5b is H.

[0139] In some embodiments of the compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, W 1 is -CR 5a R 5b - wherein 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 alkyl, or halo. In some embodiments, R 5a is H, and R 5b is H or C 1-6 alkyl. In some embodiments, R 5a is H, and R 5b is C 1-6 alkyl. In some embodiments, R 5a is H, and R 5b is H.

[0140] In some embodiments of the compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, W 2 is -CR6a R 6b - wherein R 6a and R 6b are 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 alkyl. In some embodiments, R 6a and R 6b are independently H, C 1-6 alkyl, C 1-4 haloalkyl, halo, hydroxyl, cyano, or -O-C 1-4 alkyl. 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, C 1-4 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 haloalkyl. In some embodiments, R 6a and R 6b are independently H or C 1-6 alkyl. In some embodiments, R 6a and R 6b are both H.

[0141] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, W 2 is -CR 6a R 6b - wherein R 6a is H, and R 6b is 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 alkyl. In some embodiments, R 6a is H, and R6b H, C 1-6 alkyl, C 1-4 haloalkyl, halo, hydroxyl, cyano, or -O-C 1-4 alkyl. In some embodiments, R 6a is H, and R 6b H, C 1-6 alkyl, C 1-4 haloalkyl, halo, hydroxyl, or cyano. In some embodiments, R 6a is H, and R 6b H, C 1-6 alkyl, C 1-4 haloalkyl, halo, or hydroxyl. In some embodiments, R 6a is H, and R 6b H, C 1-6 alkyl, C 1-4 haloalkyl, or halo. In some embodiments, R 6a is H, and R 6b H, C 1-6 alkyl, or C 1-4 haloalkyl. In some embodiments, R 6a is H, and R 6b H, or C 1-6 alkyl. In some embodiments, R 6a is H, and R 6b H.

[0142] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, W 2 is -CR 6a R 6b -, R 6a and R 3a any one of R 6b 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 alkyl. In some embodiments, R 6a and R 3a any one of R 6b H, C 1-6 alkyl, C 1-4 haloalkyl, halo. In some embodiments, R 6a and R3a Together with the carbon atoms to which they are attached, they form 4- to 6-membered heterocycles containing one or two independent heteroatoms selected from N, O, and S; and R 6b For H.

[0143] In some embodiments of compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, W 2 For -CR 6a R 6b -, R 6a and R 3a Each of these atoms, together with the carbon atom to which it is attached, forms a 4- to 6-membered heterocycle containing a heteroatom selected from N, O, and S; and R 6b For H, C 1-6 Alkyl, C 1-4 Halogenated alkyl, halogenated, hydroxyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkylene-OC 1-4 Alkyl group. In some embodiments, R 6a and R 3a Together with the carbon atoms to which they are attached, they form 4- to 6-membered heterocycles containing a heteroatom selected from N, O, and S; and R 6b For H, C 1-6 Alkyl, C 1-4 Halogenated alkyl groups, halogenated groups. In some embodiments, R 6a and R 3a Together with the carbon atoms to which they are attached, they form 4- to 6-membered heterocycles containing a heteroatom selected from N, O, and S; and R 6b For H.

[0144] In some embodiments of compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, W 2 For -CR 7a =CR 7b , where R 7a and R 7b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 Alkyl, or R 7a and R 7b Together with the carbon to which they are attached, they form optionally one to four R A2 Replacement C 5-10 Aryl, where each R A2 Independently a halogenated, cyanoated, or C group 1-4 Alkyl group. In some embodiments, W 2 For -CR 7a =CR 7b -, where R 7a and R7b independently H, halo, C 1-4 haloalkyl or C 1-6 alkyl. In some embodiments, W 2 is -CR 7a =CR 7b -, wherein R 7a and R 7b are independently H, halo, or C 1-6 alkyl. In some embodiments, W 2 is -CR 7a =CR 7b -, wherein R 7a and R 7b are independently H or C 1-6 alkyl. In some embodiments, W 2 is -CR 7a =CR 7b -, wherein R 7a and R 7b are both H.

[0145] In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, W 2 is -CR 7a =CR 7b -, wherein R 7a and R 7b , together with the carbon atom to which they are attached, form a C A2 aryl group optionally substituted with one to four R 5-10 , wherein each R A2 is independently halo, cyano, or C 1-4 alkyl. In some embodiments, R 7a and R 7b , together with the carbon atom to which they are attached, form a fused phenyl group optionally substituted with one to four R A2 , wherein each R A4 is independently halo, cyano, or C 1-4 alkyl. In some embodiments, R 7a and R 7b , together with the carbon atom to which they are attached, form an unsubstituted fused phenyl group.

[0146] In some embodiments, the compound of Formula I, Ia, Ib, Ic, or Id, or a pharmaceutically acceptable salt thereof,

[0147] R 1 is C 6-10 aryl, wherein the C 6-10 aryl is optionally substituted with one to four R A1 , wherein each R A1independently halogen, C 1-6 alkyl, C 1-4 haloalkyl, cyano, -O-C 1-4 alkyl or C 1-4 alkyl-O-C 1-4 alkyl;

[0148] R 2 is H, C 1-6 alkyl or C 1-4 haloalkyl;

[0149] R 3 is halogen or -OR 3a wherein R 3a is H, -C 1-6 alkyl, -C 1-4 haloalkyl or -C 3-6 cycloalkyl;

[0150] R 3b is H, -C 1-6 alkyl, -C 1-4 haloalkyl or -C 1-4 alkylene-O-C 1-4 alkyl;

[0151] R 4a is -C 1-6 alkyl or -C 1-4 haloalkyl;

[0152] R 4b is H, halogen, -C 1-6 alkyl or -C 1-4 haloalkyl;

[0153] W 1 is a bond or -CR 5a R 5b -;

[0154] R 5a and R 5b are independently H, C 1-6 alkyl, C 1-4 haloalkyl or halogen;

[0155] W 2 is -CR 6a R 6b - or -CR 7a =CR 7b -;

[0156] R 6a and R 6b are independently H, C 1-6 alkyl, C 1-4 haloalkyl, halogen, hydroxyl, cyano, -O-C1-4 alkyl or C 1-4 alkylene-O-C 1-4 alkyl; and

[0157] R 7a and R 7b are independently H, halo, C 1-4 haloalkyl or C 1-6 alkyl.

[0158] In some embodiments, the compound of Formula I, la, lb, Ic, or Id, or a pharmaceutically acceptable salt thereof,

[0159] R 1 is C 6-10 aryl, wherein the C 6-10 aryl is optionally substituted with one to four R A1 , wherein each R A1 is 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 alkyl;

[0160] R 2 is H, C 1-6 alkyl or C 1-4 haloalkyl;

[0161] R 3 is -OR 3a , wherein R 3a is H, -C 1-6 alkyl, -C 1-4 haloalkyl or -C 3-6 cycloalkyl;

[0162] R 3b is H, -C 1-6 alkyl, -C 1-4 haloalkyl or -C 1-4 alkylene-O-C 1-4 alkyl;

[0163] R 4a is -C 1-6 alkyl or -C 1-4 haloalkyl;

[0164] R 4b is H, halo, -C 1-6 alkyl or -C 1-4 haloalkyl;

[0165] W 1 is a bond or -CR 5a R5b -;

[0166] R 5a and R 5b are independently H, C 1-6 alkyl, C 1-4 haloalkyl or halo;

[0167] W 2 is -CR 6a R 6b - or -CR 7a =CR 7b -;

[0168] R 6a and R 6b are 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 alkyl; and

[0169] R 7a and R 7b are independently H, halo, C 1-4 haloalkyl or C 1-6 alkyl.

[0170] In some embodiments, the compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof,

[0171] R 1 is phenyl substituted with two, three, or four R A1 , wherein each R A1 is 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 alkyl;

[0172] R 2 is H, C 1-6 alkyl or C 1-4 haloalkyl;

[0173] R 3 is -OR 3a , wherein R 3a is H, -C 1-6 alkyl, -C 1-4 haloalkyl or -C 3-6 cycloalkyl;

[0174] R 3b is H, -C1-6 Alkyl, -C 1-4 Halogenated alkyl or -C 1-4 Alkylene-OC 1-4 alkyl;

[0175] R 4a -C 1-6 Alkyl or -C 1-4 Halogenated alkyl groups;

[0176] R 4b H, halogen, -C 1-6 Alkyl or -C 1-4 Halogenated alkyl groups;

[0177] W 1 For key or -CR 5a R 5b -;

[0178] R 5a and R 5b Independently for H and C 1-6 Alkyl, C 1-4 Haloalkyl or halogenated groups;

[0179] W 2 For -CR 6a R 6b -or-CR 7a =CR 7b -;

[0180] R 6a and R 6b Independently for H and C 1-6 Alkyl, C 1-4 Halogenated alkyl, halogenated, hydroxyl, cyano, -OC 1-4 Alkyl or C 1-4 Alkylene-OC 1-4 Alkyl; and

[0181] R 7a and R 7b Independently H, halogen, C 1-4 Halogenated alkyl or C 1-6 alkyl.

[0182] In some embodiments, the compounds of formula I, Ia, Ib, Ic, Id, or II are selected from the group consisting of:

[0183]

[0184] In some embodiments, the compounds of formula I, Ia, Ib, Ic, Id, or II are selected from the group consisting of:

[0185]

[0186]

[0187]

[0188] In some embodiments, the compound of Formula I, la, or II is selected from the group consisting of:

[0189]

[0190]

[0191] In some embodiments, the compound of Formula I, Ic, or II is selected from the group consisting of:

[0192]

[0193]

[0194]

[0195] In some embodiments, the compound of Formula I, Id, or II is selected from the group consisting of:

[0196]

[0197] In some embodiments, the compound of Formula I is In some embodiments, the compound of Formula I is In some embodiments, the compound of Formula I is In some embodiments, the compound of Formula I is In some embodiments, the compound of Formula I is In some embodiments, the compound of Formula I is In some embodiments, the compound of Formula I is In some embodiments, the compound of Formula I is In some embodiments, the compound of Formula I is

[0198] In some embodiments, the compound of Formula I is

[0199] III. Compositions and Kits

[0200] The compounds provided herein are typically administered in the form of pharmaceutical compositions. Accordingly, also provided herein are pharmaceutical compositions comprising one or more compounds provided herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof, and one or more pharmaceutically acceptable vehicles, adjuvants, and excipients. The compounds provided herein can be the sole active ingredient or one of the active ingredients of the pharmaceutical composition. Suitable pharmaceutically acceptable vehicles can include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G. S. Banker and C. T. Rhodes, Eds.).

[0201] In one aspect, provided herein are pharmaceutical compositions comprising a compound provided herein (i.e., a compound of Formula I, la, lb, 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.

[0202] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition further comprises a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

[0203] The pharmaceutical compositions can be administered in single or multiple doses. The pharmaceutical compositions can be administered by various methods including, for example, rectal, buccal, intranasal, and transdermal routes. In some embodiments, the pharmaceutical compositions can be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0204] One mode of administration is parenteral, e.g., by injection. Forms in which the pharmaceutical compositions described herein can be incorporated for administration by injection include, for example, aqueous or oil suspensions or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0205] Oral administration can be another route for administering the compounds provided herein. Administration can be via, for example, a capsule or enteric-coated tablet. In making the pharmaceutical compositions that include at least one of the compounds provided herein, or a pharmaceutically acceptable salt, isomer, or a mixture thereof, the active ingredient, such as a compound provided herein, is typically diluted by an excipient and / or enclosed within such a carrier that can be in the form of a capsule, sachet, paper, or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material that acts as a vehicle, carrier or medium for the active ingredient. Thus, the pharmaceutical compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0206] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose or any combination thereof. The pharmaceutical composition can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propylhydroxybenzoates; sweetening agents; and flavoring agents; or any combination thereof.

[0207] Pharmaceutical compositions that include at least one of the compounds described herein, or a pharmaceutically acceptable salt, isomer, or a mixture thereof, can be formulated so as to provide quick, sustained, or delayed release of the active ingredient (such as a compound provided herein) after administration to a subject by employing procedures known in the art. Controlled release pharmaceutical delivery systems for oral administration include osmotic pump systems and dissolution systems containing polymer-coated reservoirs or a drug-polymer matrix formulation. Examples of controlled release systems are given in U.S. Patents 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation employed in the methods of the present disclosure employs transdermal delivery devices (“patches”). Such transdermal patches can provide controlled delivery of a compound provided herein for a sustained or intermittent period. The construction and use of transdermal patches for the delivery of agents is well known. See, e.g., U.S. Patents 5,023,252; 4,992,445; and 5,001,139. Such patches can be constructed to deliver agents continuously or intermittently in periodic bursts.

[0208] To prepare solid compositions such as tablets, the principal active ingredient can 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 a mixture thereof. When referring to these preformulation compositions as homogeneous, the active ingredient can be dispersed essentially uniformly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0209] Tablets or pills of the compounds described herein can be coated or otherwise compounded with factors that provide a dosage form having prolonged action or to protect against the acidic conditions of the stomach. For example, the tablet or pill can comprise an inner dosage component and an outer dosage component. The outer component can be in the form of an envelope which encloses the inner component. The two components can be adjoined by an enteric layer which serves to resist disintegration in the stomach and permits 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, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.

[0210] Pharmaceutical compositions for inhalation or insufflation can include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents, or mixtures thereof, and powders. Liquid or solid compositions can 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 can be nebulized by use of inert gases for delivery of the composition in the pharmaceutically acceptable solvent. Solution or suspension can be inhaled directly from a nebulizer or the nebulizer can be attached to a face mask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions can be administered preferably orally or nasally from devices which deliver the formulation in an appropriate manner.

[0211] In one aspect, provided herein is a kit comprising a compound provided herein (i.e., a compound of Formula I, la, lb, Ic, Id, or II), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and suitable packaging. In some embodiments, the kit further comprises instructions for use. In some embodiments, the kit comprises a compound provided herein (i.e., a compound of Formula I, la, lb, Ic, Id, or II), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a label and / or instructions for using the compound to treat an indication described herein, including a disease or disorder.

[0212] In some embodiments, the kit further comprises one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

[0213] In one aspect, provided herein is an article of manufacture comprising a compound described herein, or a pharmaceutically acceptable salt, isomer, or a mixture thereof, in a suitable container. In some embodiments, the container can be a vial, jar, ampule, pre-filled syringe, or intravenous bag.

[0214] IV. Methods

[0215] In one embodiment, provided is a method of treating an HIV infection in a human having, or at risk of having, an HIV (e.g., HIV-1 and / or HIV-2) infection, the method comprising administering to the human 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.

[0216] 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 one or more additional therapeutic agents is an anti-HIV agent. In specific embodiments, the one or more additional therapeutic agents is an HIV protease inhibitor, an HIV reverse transcriptase non-nucleoside or non-nucleotide inhibitor, an HIV reverse transcriptase nucleoside or nucleotide inhibitor, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latency reversing agent, 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 one or more additional therapeutic agents is abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-l-(3-(4-chloro-3-(methylsulfonamido)-l-(2,2,2-trifluoroethyl)-lH-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)acetamide, or a pharmaceutically acceptable salt thereof.

[0217] In another embodiment, provided is 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 infection in a human having, or at risk of having, an HIV (e.g., HIV-1 and / or HIV-2) infection.

[0218] In another embodiment, there is provided a compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, for use in medical therapy.

[0219] In another embodiment, there is provided a compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, for use in the treatment of an HIV infection.

[0220] In another embodiment, there is provided a compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, la, lb, 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, an HIV infection.

[0221] In another embodiment, there is provided a compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, la, lb, 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, an HIV infection, wherein the method further comprises administering to the human one, two, three, or four additional therapeutic agents.

[0222] In another embodiment, there is provided a compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, la, lb, 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, an HIV infection, wherein the method further comprises administering to the human one, two, three, or four additional therapeutic agents selected from the group consisting of: an HIV protease inhibitor, a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gpl20 inhibitor, a CCR5 inhibitor, a latency reversing agent, 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, a non-nucleoside inhibitor of HIV reverse transcriptase, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, a latency reversing agent, an HIV capsid inhibitor, an HIV bNAb, a TLR7 agonist, and a combination thereof.

[0223] In another embodiment, a compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, is used in a method of treating an HIV infection in a human having or at risk of having an HIV infection, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir disoproxil and emtricitabine.

[0224] In another embodiment, a compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, is used in a method of treating an HIV infection in a human having or at risk of having an HIV infection, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir disoproxil and emtricitabine.

[0225] In another embodiment, a compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, is used in a method of treating an HIV infection in a human having or at risk of having an HIV infection, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir disoproxil.

[0226] In another embodiment, a compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, is used in a method of treating an HIV infection in a human having or at risk of having an HIV infection, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir disoproxil.

[0227] In another embodiment, a method of using a compound of Formula I, la, lb, Ic, Id, or II in therapy is provided. Specifically, a method of treating HIV viral proliferation, treating AIDS, or delaying the onset of symptoms of AIDS or ARC in a mammal (e.g., a human) is provided, the method comprising administering to the mammal a compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0228] In another embodiment, 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 is provided for use in a method of treating HIV viral proliferation, treating AIDS, or delaying the onset of symptoms of AIDS or ARC in a mammal (e.g., a human).

[0229] 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 preventing HIV infection.

[0230] For example, 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 pre-exposure prophylaxis (PrEP), i.e., preventing the virus from taking hold and / or preventing the virus from establishing a permanent infection and / or preventing the appearance of symptoms of the disease and / or preventing the virus from reaching detectable levels in the blood of an individual prior to the individual being exposed to the HIV virus.

[0231] In another embodiment, the use of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating HIV infection in a human having or at risk of having HIV infection is disclosed.

[0232] 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.

[0233] In another embodiment, an article of manufacture is disclosed, the article of manufacture comprising a composition effective to treat HIV infection; and packaging material comprising a label that indicates the composition can be used to treat an infection caused by HIV. An exemplary composition comprises a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof.

[0234] In another embodiment, a method of inhibiting HIV replication is disclosed. The method comprises exposing a virus to an effective amount of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a salt thereof, under conditions that inhibit HIV replication.

[0235] In another embodiment, the use of a compound of Formula I, Ia, Ib, Ic, Id, or II to inhibit the activity of HIV integrase is disclosed.

[0236] In another embodiment, the use of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a salt thereof, to inhibit HIV replication is disclosed.

[0237] V. Administration

[0238] The compounds of the present disclosure, also referred to herein as active ingredients, can be administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), transdermal, vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural) and the like. It will be appreciated that the preferred route can vary with for example the condition of the recipient. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be dosed orally.

[0239] The compounds of the present disclosure can be administered to an individual for a period of time or duration necessary to achieve the desired period of time, 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, according to an effective dosing regimen. In some embodiments, the compounds are administered on a daily or intermittent schedule for the lifetime of the individual.

[0240] The specific dose level of the compounds of the present disclosure for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion of the subject being treated, drug combinations, and the severity of the particular disease undergoing therapy. For example, dosages can be expressed in milligrams of a compound described herein per kilogram of body weight of the subject (mg / kg). Dosages between about 0.1 mg / kg and 150 mg / kg can be appropriate. In some embodiments, dosages between about 0.1 mg / kg and 100 mg / kg can be appropriate. In other embodiments, dosages between 0.5 mg / kg and 60 mg / kg can be appropriate. Normalization to body weight is particularly useful in adjusting dosages between subjects that differ greatly in size, such as when using a drug in children and adults, or when converting an effective dosage for a non-human subject, such as a dog, to a dosage appropriate for a human subject.

[0241] A daily dose can also be described as the total amount of a compound described herein administered per dose or per day. A daily dose of a compound of Formula I, la, lb, Ic, Id, or II, or a pharmaceutically acceptable salt or pharmaceutically acceptable tautomer thereof can be between about 1 mg and 4,000 mg, between about 2,000 mg / day to 4,000 mg / day, between about 1 mg / day to 2,000 mg / day, between about 1 mg / day to 1,000 mg / day, between about 10 mg / day to 500 mg / day, between about 20 mg / day to 500 mg / day, between about 50 mg / day to 300 mg / day, between about 75 mg / day to 200 mg / day, or between about 15 mg / day to 150 mg / day.

[0242] The dosage or frequency of administration of the compounds of the present disclosure can be adjusted in the course of treatment according to the judgment of the administering physician.

[0243] The compounds of the present disclosure can be administered to an individual (e.g., a human) in a therapeutically effective amount. In some embodiments, the compound is administered once per day.

[0244] The compounds provided herein can be administered by any useful route and means, such as by oral or parenteral (e.g., intravenous) administration. A therapeutically effective amount of a compound can include about 0.00001 mg / kg body weight / day to about 10 mg / kg body weight / day, such as about 0.0001 mg / kg body weight / day to about 10 mg / kg body weight / day, or such as about 0.001 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as about 0.01 mg / kg body weight / day to about 1 mg / kg body weight / day, or such as about 0.05 mg / kg body weight / day to about 0.5 mg / kg body weight / day. In some embodiments, a therapeutically effective amount of a compound provided herein includes about 0.3 mg / day to about 30 mg / day, or about 30 mg / day to about 300 mg / day, or about 0.3 pg / day to about 30 mg / day, or about 30 pg / day to about 300 pg / day per day.

[0245] The compounds disclosed herein may be combined with one or more additional therapeutic agents at any dose of the disclosed compounds (e.g., 1 mg to 1000 mg of the compound). Therapeuticly effective doses may include about 0.1 mg / dose to about 1000 mg / dose, such as about 50 mg / dose to about 500 mg / dose, or such as about 100 mg / dose to about 400 mg / dose, or such as about 150 mg / dose to about 350 mg / dose, or such as about 200 mg / dose to about 300 mg / dose, or such as about 0.01 mg / dose to about 100 mg / dose, or such as about 0.01 mg / dose to about 100 mg / dose, or such as about 0.1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 100 mg / dose, or such as about 1 mg / dose to about 1000 mg / dose. Other therapeutically effective doses of compounds of formula I, Ia, Ib, Ic, Id, or II are about 1 mg / dose, or about 2 mg / dose, 3 mg / dose, 4 mg / dose, 5 mg / dose, 6 mg / dose, 7 mg / dose, 8 mg / dose, 9 mg / dose, 10 mg / dose, 15 mg / dose, 20 mg / dose, 25 mg / dose, 30 mg / dose, 35 mg / dose, 40 mg / dose, 45 mg / dose, 50 mg / dose, 55 mg / dose, 60 mg / dose, 65 mg / dose, 70 mg / dose, 75 mg / dose, 80 mg / dose, 85 mg / dose, 90 mg / dose, 95 mg / dose, or about 100 mg / dose. Other therapeutically effective doses of the compounds disclosed herein are approximately 100 mg / dose, 125 mg / dose, 150 mg / dose, 175 mg / dose, 200 mg / dose, 225 mg / dose, 250 mg / dose, 275 mg / dose, 300 mg / dose, 325 mg / dose, 350 mg / dose, 375 mg / dose, 400 mg / dose, 425 mg / dose, 450 mg / dose, 475 mg / dose, 500 mg / dose, 525 mg / dose. mg / dose, 550mg / dose, 575mg / dose, 600mg / dose, 625mg / dose, 650mg / dose, 675mg / dose, 700mg / dose, 725mg / dose, 750mg / dose, 775mg / dose, 800mg / dose, 825mg / dose, 850mg / dose, 875mg / dose, 900mg / dose, 925mg / dose, 950mg / dose, 975mg / dose or approximately 1000mg / dose.

[0246] In some embodiments, the method described herein involves administering an initial daily dose of about 1 mg to 500 mg of the compound described herein to a subject, and gradually increasing the dose until clinical efficacy is achieved. Increments of about 5 mg, 10 mg, 25 mg, 50 mg, or 100 mg may be used to increase the dose. The dose may be increased daily, every other day, twice a week, once a week, once every two weeks, once every three weeks, or once a month.

[0247] When administered orally, the total daily dose to a human subject can be between about 1 mg and 1,000 mg, between about 10 mg / day to 500 mg / day, between about 50 mg / day to 300 mg / day, between about 75 mg / day to 200 mg / day, or between about 100 mg / day to 150 mg / day. In some embodiments, the total daily dose to a human subject can be about 100 mg / day, 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, 800 mg / day, 900 mg / day, or 1000 mg / day administered in a single dose. In some embodiments, the total daily dose to a human subject can be about 200 mg / day, 300 mg / day, 400 mg / day, 500 mg / day, 600 mg / day, 700 mg / day, or 800 mg / day administered in a single dose. In some embodiments, the total daily dose to a human subject can be about 300 mg / day, 400 mg / day, 500 mg / day, or 600 mg / day administered in a single dose.

[0248] In some embodiments, the total daily dose for a human subject can be about 100 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 150 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 200 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 250 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 300 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 350 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 400 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 450 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 500 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 550 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 600 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 650 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 700 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 750 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 800 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 850 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 900 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 950 mg / day administered in a single dose. In some embodiments, the total daily dose for a human subject can be about 1000 mg / day administered in a single dose.

[0249] A single dose can be administered every hour, every day, every week, or every month. For example, a single dose can be administered once every 1 hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 12 hours, 16 hours, or once every 24 hours. A single dose can also be administered once every 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or once every 7 days. A single dose can also be administered once every 1 week, 2 weeks, 3 weeks, or once every 4 weeks. In certain embodiments, a single dose can be administered once a week. A single dose can also be administered once a month. In some embodiments, a compound disclosed herein is administered once a day in a method disclosed herein. In some embodiments, a compound disclosed herein is administered twice a day in a method disclosed herein.

[0250] The frequency of dosage of the compounds of the present disclosure will be determined by the needs of the individual patient and can be, for example, once per day or two or more times per day. Administration of the compound is continued for as long as necessary to treat the HBV infection, HIV infection, cancer, hyperproliferative disease, or any other indication described herein. For example, a person infected with HBV can be administered the compound for a period of 20 days to 180 days, or for example, 20 days to 90 days, or for example, 30 days to 60 days.

[0251] 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 in which the patient does not receive the daily dose of the compound. For example, a patient can receive a dose of a compound every other day or three times per week. Again by way of example, a patient can receive a dose of a compound every day for a period of 1 day to 14 days, followed by a period of 7 days to 21 days in which the patient does not receive a dose of the compound, followed by another period (e.g., 1 day to 14 days) in which the patient again receives a daily dose of the compound. The alternating periods of administration and non-administration of the compound can be repeated as clinically indicated to treat the patient.

[0252] A compound of the present disclosure, or a pharmaceutical composition thereof, can be administered once, twice, three times, or four times per day using any of the above-mentioned appropriate modes. Also, administration or treatment with a compound can continue for several days; for example, for one treatment cycle, treatment will generally continue for at least 7 days, 14 days, or 28 days. Treatment cycles are well known in cancer chemotherapy, often alternating with rest periods of about 1 day to 28 days, often about 7 days or about 14 days, between cycles. In other embodiments, the treatment cycles can also be continuous.

[0253] VI. Combination Therapy

[0254] In certain embodiments, a method is provided for treating or preventing an HIV infection in a person having or at risk of having an HIV infection, the method comprising administering to the person a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In one embodiment, a method is provided for treating an HIV infection in a person having or at risk of having an HIV infection, the method comprising administering to the person a therapeutically effective amount of a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

[0255] In one embodiment, a pharmaceutical composition is provided comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0256] In certain embodiments, the present disclosure provides a method for treating an HIV infection comprising administering to a patient 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.

[0257] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one, two, three, four or more additional therapeutic agents. In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two additional therapeutic agents. In other embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with three additional therapeutic agents. In further embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with four additional therapeutic agents. The one, two, three, four or more additional therapeutic agents can be different therapeutic agents selected from the same class of therapeutic agents, and / or they can be selected from different classes of therapeutic agents.

[0258] Administration of HIV Combination Therapy

[0259] In certain embodiments, a compound disclosed herein is administered with one or more additional therapeutic agents. Co-administration of a compound disclosed herein and one or more additional therapeutic agents generally means that a therapeutically effective amount of both the compound disclosed herein and the one or more additional therapeutic agents are present in the patient's body at the same time. When administered sequentially, the combination can be administered in two or more administrations.

[0260] Co-administration includes administration of a unit dose of a compound disclosed herein prior to or subsequent to administration of a unit dose of one or more additional therapeutic agents. For example, a compound disclosed herein can be administered within seconds, minutes, or hours of administration of one or more additional therapeutic agents. In some embodiments, a unit dose of a compound disclosed herein is administered first, followed within seconds or minutes by administration of a unit dose of one or more additional therapeutic agents. Alternatively, a unit dose of one or more additional therapeutic agents is administered first, followed within seconds or minutes by administration of a unit dose of a compound disclosed herein. In other embodiments, a unit dose of a compound disclosed herein is administered first, followed by administration of a unit dose of one or more additional therapeutic agents after a number of hours (e.g., 1 to 12 hours). In further embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed by administration of a unit dose of a compound disclosed herein after a number of hours (e.g., 1 to 12 hours).

[0261] In certain embodiments, a compound disclosed herein is combined with one or more additional therapeutic agents in a single dosage form for simultaneous administration to a patient, e.g., as a solid dosage form for oral administration.

[0262] In certain embodiments, a compound of Formula I, Ia, Ib, Ic, Id, or II is formulated into a tablet, which can optionally contain one or more other compounds useful in the treatment of HIV. In certain embodiments, the tablet can contain another active ingredient for the treatment of HIV, such as an HIV protease inhibitor, an HIV reverse transcriptase non-nucleoside or non-nucleotide inhibitor, an HIV reverse transcriptase nucleoside or nucleotide inhibitor, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, a pharmacokinetic enhancer, and combinations thereof.

[0263] In certain embodiments, such tablets are adapted for once-a-day dosing.

[0264] HIV Combination Therapy

[0265] In the above embodiments, the additional therapeutic agent can be an anti-HIV agent. HIV protease inhibitors, HIV reverse transcriptase non-nucleoside or non-nucleotide inhibitors, HIV reverse transcriptase nucleoside or nucleotide inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutics, antibody-drug conjugates, gene modifying agents, gene editors such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, cell therapies such as chimeric antigen receptor T cells CAR-T and engineered T cell receptor TCR-T, autologous T cell therapies, latency reversing agents, compounds targeting the HIV capsid, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and “antibody-like” therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptideyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV-1 viral infectivity factor inhibitors, TAT protein inhibitors, HIV-1 Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV-1 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, defensin modulators, CDK-9 inhibitors, CCR5 chemokine antagonists, CCR5 gene modulators, dendritic ICAM-3 grabbing nonintegrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, hyaluronidase inhibitors, Nef antagonists, Nef inhibitors, proteinase activated receptor-1 antagonists, TNF alpha ligand inhibitors, PDE4 inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase initiation complex inhibitors, G6PD and NADH oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapies, HIV vaccines, and combinations thereof.

[0266] In some embodiments, the additional therapeutic agent is selected from the group consisting of combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversing agents, capsid inhibitors, immune-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and“antibody-like” therapeutic proteins, and combinations thereof.

[0267] HIV Combination Drugs

[0268] Examples of combination drugs include (Atripla® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine)); (Eviplera® (bictegravir, emtricitabine, and tenofovir alafenamide)); (Atripla® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine)); (Eviplera® (bictegravir, emtricitabine, and tenofovir alafenamide)); (Eviplera® (bictegravir, emtricitabine, and tenofovir alafenamide)); (Atripla® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine)); (Eviplera® (bictegravir, emtricitabine, and tenofovir alafenamide)); (Eviplera® (bictegravir, emtricitabine, and tenofovir alafenamide)); (Eviplera® (bictegravir, emtricitabine, and tenofovir alafenamide)); (Eviplera® (bictegravir, emtricitabine, and tenofovir alafenamide)); (Atripla® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine)); (Atripla® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine)); (Atripla® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine)); (Atripla® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine)); (Atripla® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine)); (Atripla® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine)); (abcamavir 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 fumarate; dapivirine + levonorgestrel, dolutegravir + lamivudine, dolutegravir + emtricitabine + tenofovir alafenamide, efavirenz + emtricitabine + tenofovir disoproxil fumarate, 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, zidovudine, and lamivudine.

[0269] Other HIV Drugs

[0270] Examples of other drugs for treating HIV include acemannan, ala- boceprevir, atorolimumab, BanLec, CC-11050, deferiprone, Gamimune, Gammagard, Methafurane, naltrexone, Prolastin, REP 9, RPI-MN, Vorapaxar, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy, MK-8527, BlockAide, PSC-RANTES, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-2048, MK-4250, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576.

[0271] HIV Protease Inhibitors

[0272] 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.

[0273] HIV Reverse Transcriptase Inhibitors

[0274] Examples of HIV reverse transcriptase non-nucleoside or non-nucleotide inhibitors include dapivirine, delavirdine, delavirdine mesylate, doravirine, efavirenz, etravirine, lentinan, MK-8583, nevirapine, rilpivirine, TMC-278LA, ACC-007, AIC-292, KM-023, PC-1005, and islatravir (VM-1500).

[0275] Examples of HIV reverse transcriptase nucleoside or nucleotide inhibitors include adefovir, adefovir dipivoxil, azidothymidine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, and VIDEX (ddl), abacavir, abacavir sulfate, alovudine, alitaskin, censavudine, didanosine, elvucitabine, fozivudine tidoxil, CMX-157, dapivirine, doravirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, islatravir, lamivudine, phosphazide, stavudine, zalcitabine, zidovudine, rofavir-ethamiramide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500, and KP-1461.

[0276] HIV Integrase Inhibitors

[0277] Examples of HIV integrase inhibitors include Elvitegravir, Curcumin, a derivative of curcumin, chicoric acid, a derivative of chicoric acid, 3,5-dicaffeoylquinic acid, a derivative of 3,5-dicaffeoylquinic acid, aurothioglucose, a derivative of aurothioglucose, caffeic acid phenethyl ester, a derivative of caffeic acid phenethyl ester, a tyrosine kinase inhibitor, a derivative of a tyrosine kinase inhibitor, quercetin, a derivative of quercetin, Raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, BMS-986197, cabotegravir (long-acting injectable), diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, VM-3500, and cabotegravir.

[0278] Examples of HIV non-catalytic site or allosteric integrase inhibitors (NCINI) include CX-05045, CX-05168, and CX-14442.

[0279] HIV Entry Inhibitors

[0280] Examples of HIV entry (fusion) inhibitors include Cenicriviroc, CCR5 inhibitors, gp41 inhibitors, CD4 attachment inhibitors, DS-003 (BMS-599793), gp120 inhibitors, and CXCR4 inhibitors.

[0281] Examples of CCR5 inhibitors include aplaviroc, vicriviroc, maraviroc, cenicriviroc, leronlimab (PRO-140), adatansvir (RAP-101), nelfibrio (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, and vMIP (Haimipu).

[0282] Examples of gp41 inhibitors include ibalizumab, enfuvirtide, BMS-986197, bio- improved drugs of enfuvirtide, bio-generic drugs of enfuvirtide, HIV-1 fusion inhibitors (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, PIE-12 trimer, and sifuvirtide.

[0283] Examples of CD4 attachment inhibitors include ibalizumab and CADA analogs.

[0284] Examples of gp120 inhibitors include Radha-108 (receptor alcohol) 3B3-PE38, BanLec, bentonite-based nanomedicine, fosters simeprevir, IQP-0831, and BMS-663068.

[0285] Examples of CXCR4 inhibitors include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0286] HIV Maturation Inhibitors

[0287] Examples of HIV maturation inhibitors include BMS-955176, BMS-986197, GSK-3640254, and GSK-2838232.

[0288] Latency Reversing Agents

[0289] Examples of latency reversing agents 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 (suberoylanilide hydroxamic acid or suberoyl, aniline, and hydroxamic acid), IL-15 modulating antibodies, JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors (such as Lagunavir and GSK-343), and APH-0812 and GSK-343.

[0290] Examples of HDAC inhibitors include romidepsin, vorinostat, and panobinostat.

[0291] Examples of PKC activators include indolactam, prostratin, ingenol B, and DAG-lactones.

[0292] Capsid Inhibitors

[0293] 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 (lenacapavir), 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.

[0294] Immune-Based Therapies

[0295] Examples of immune-based therapies include toll-like receptor modulators such as tlr1, tlr2, tlr3, tlr4, tlr5, tlr6, tlr7, tlr8, tlr9, tlr10, tlr11, tlr12, and tlr13; programmed cell death protein 1 (Pd-1) modulators; programmed death ligand 1 (Pd-L1) modulators; IL-15 modulators; 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 derivative mycophenolate mofetil (MMF); ribavirin; the polymer polyethylenimine (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, Novilumab, peginterferon alfa-2a, peginterferon alfa-2b, recombinant interleukin-15, Xmab-24306, RPI-MN, STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103.

[0296] Examples of TLR agonists: Vesatolimod (GS-9620), GS-986, IR-103, Resiquimod, Tilsotolimod, Rintatlimod, DSP-0509, AL-034, G-100, Cobitolimod, AST-008, Motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, Telratolimod. RO-7020531.

[0297] Phosphatidylinositol 3-kinase (PI3K) Inhibitors

[0298] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, CAI, copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, plafibrocin, rigosertib, rigosertib sodium, sonolisib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-2269577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV-1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765, and ZSTK-474.

[0299] a-4 / b-7 Antagonists

[0300] Examples of integrin alpha-4 / beta-7 antagonists include PTG-100, TRK-170, atorulimab, etrolizumab, carotegrast methyl, and vedolizumab.

[0301] HIV Antibodies, Bispecific Antibodies, and "Antibody-like" Therapeutic Proteins

[0302] Examples of HIV antibodies, bispecific antibodies, and “antibody-like” therapeutic proteins include Fab derivatives, bispecific antibodies, trispecific antibodies, multivalent antibodies, bnAB (broadly neutralizing HIV-1 antibodies), BMS-936559, TMB-360, and those antibodies targeting HIV 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, camelid-derived anti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeting antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAb (PGT-121), ibalizumab, Immuglo, MB-66.

[0303] Examples of those antibodies targeting HIV in this manner include bavituximab, UB-421, C2F5, 2G12, C4E10, C2F5+C2G12+C4E10, 8ANC195, 3BNC117, 3BNC117-LS, 3BNC60, D1D2, 10-1074, 10-1074-LS, GS-9722, DH411-2, BG18, PGT145, PGT121, PGT122, PGT-151, PGT-133, PGT-135, PGT-128, MDX010 (ipilimumab), DH511, DH511-2, N6, N6LS, N49P6, N49P7, N49P7.1, N49P9, N49P11, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH 45-46, 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, iMabm36, 10E8v4 / PGT121-VRC01, eCD4-Ig, IOMA, CAP256-VRC26.25, DR VI A7, 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 antibodies.

[0304] Examples of bnABs delivered in vivo such as AAV8-VRC07, mRNA encoding anti-HIV antibody VRC01.

[0305] Pharmacokinetic Enhancers

[0306] Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

[0307] Additional Therapeutic Agents

[0308] Examples of additional therapeutic agents include compounds disclosed in WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO 2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO 2014 / 100323 (Gilead Sciences), US 2013 / 0165489 (University of Pennsylvania), US 2014 / 0221378 (Japan Tobacco), US 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences), and WO 2013 / 091096 (Boehringer Ingelheim).

[0309] HIV Vaccines

[0310] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines using viral vectors such as arenavirus, 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, WNX-004, VAC-3S, multistage 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, poly ICLC adjuvanted vaccine, TatImmune, GTU-multiHIV (FIT-06), gp140[deltav2.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-Ad5gag / 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 pseudo-virus vaccines), CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, Anti-TAT HIV vaccine, conjugated polypeptide vaccine, dendritic cell vaccine, gag-based DNA vaccine, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), Ii-key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multistage Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x+ romidepsin, variant gp120 polypeptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA.HTI, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP+VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980; eOD-GT8 60mer-based vaccine, PD-201401, env (A, B, C, A / E) / gag (C) DNA vaccine, gp120 (A, B, C, A / E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV-1 vaccine (GLA-SE adjuvant), HIV p24 gag prime-boost plasmid DNA vaccine, arenavirus vector-based immunotherapy (Vaxwave, TheraT), MVA-BN HIV-1 vaccine regimen, MVA.tHIVconsv4, MVA.tHIVconsv3, UBI HIV gp120, mRNA-based prophylactic vaccine, TBL-1203HI, VRC-HIVRGP096-00-VP, VAX-3S, HIV MAG DNA vaccine.

[0311] HIV Combination Therapy

[0312] In one specific embodiment, the compound disclosed herein or a pharmaceutically acceptable salt thereof is combined with one, two, three, four or more additional therapeutic agents selected from the following: (Efavirenz, tenofovir disoproxil fumarate and emtricitabine); ( Rilpivirine, tenofovir disoproxil fumarate, and emtricitabine; (Ertiravir, Cobistat, Tenofovir disoproxil fumarate and Emtricitabine); (Tenofovir dipivoxil fumarate and emtricitabine; TDF+FTC); (tenofovir alafenamide and emtricitabine); (Tenofovir alafenamide, emtricitabine, and rilpivirine); (Tenofovir alafenamide, emtricitabine, cobistatin and ertiravir); Adefovir; Adefovir dipyridamole; Cobistatin; Emtricitabine; Tenofovir; Tenofovir disoproxil fumarate; Tenofovir disoproxil fumarate; Tenofovir alafenamide hemifumarate; (Durutexvir, Abacavir and Lamivudine); Durutvir, Abacavir Sulfate and Lamivudine; Rettagvir; Rettagvir and Lamivudine; Maraviro; Enfuvirtide; ( Lopinavir and ritonavir); (Zidovudine and Lamivudine; AZT+3TC); ( Abacavir sulfate and lamivudine; ABC+3TC); (Abacavir sulfate, zidovudine, and lamivudine; ABC+AZT+3TC); Rilpivirine; Rilpivirine hydrochloride; Atazanavir sulfate and cobistat; Atazanavir and cobistat; Derreravir and cobistat; Atazanavir; Atazanavir sulfate; Dulutevir; Ertirapvir; Ritonavir; Atazanavir sulfate and Ritonavir; Derreravir; Lamivudine; Prandine; Fosanavir; Fosanavir calcium efavirenz; Etravirine; Nefernavir; Nefernavir mesylate; Interferon; Didanoxin; Stavudine; Indinavir; Indinavir sulfate; Tenofovir and Lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir mesylate; Aldehyde interleukin; Zacitabine; Telanavir; Ampravir; Delavudine; Delavudine mesylate; Radha-108 (receptor alcohol); Lamivudine and Tenofovir disoproxil fumarate; Efaviraxyl, Lamivudine and Tenofovir disoproxil fumarate; Aziphosphonate; Lamivudine, Nevirapine and Zidovudine; Abacavir; and Abacavir sulfate.

[0313] Those skilled in the art will understand that the additional therapeutic agents listed above can be included in more than one of the categories listed above. The specific categories are not intended to limit the function of those compounds listed in those categories.

[0314] In one embodiment, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV reverse transcriptase nucleoside or nucleotide inhibitor and an HIV reverse transcriptase non-nucleoside inhibitor. In another embodiment, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV reverse transcriptase nucleoside or nucleotide inhibitor and an HIV protease inhibitor compound. In a further embodiment, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with an HIV reverse transcriptase nucleoside or nucleotide inhibitor, an HIV reverse transcriptase non-nucleoside inhibitor, and a pharmacokinetic enhancer. In certain embodiments, the 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, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0315] In one embodiment, the 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.

[0316] In one embodiment, the compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0317] In one embodiment, the 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.

[0318] In one embodiment, the 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 selected from the group consisting of emtricitabine and lamivudine.

[0319] A compound as disclosed herein (e.g., any compound of Formula I, la, lb, Ic, Id, or II) can be combined with one or more additional therapeutic agents in any dosage amount of the compound of Formula I, la, lb, Ic, Id, or II (e.g., 1 mg to 500 mg of the compound).

[0320] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 5 mg to 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 mg to 10 mg, 5 mg to 15 mg, 5 mg to 20 mg, 5 mg to 25 mg, 25 mg to 30 mg, 20 mg to 30 mg, 15 mg to 30 mg, or 10 mg to 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 as disclosed herein (e.g., a compound of Formula I) can be combined with an agent provided herein in any dosage amount of the compound (e.g., 1 mg to 500 mg of the compound) as each combination of dosage amounts is specifically and individually listed.

[0321] In certain embodiments, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with 200 mg to 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 mg to 250, 200 mg to 300, 200 mg to 350, 250 mg to 350, 250 mg to 400, 350 mg to 400, 300 mg to 400, or 250 mg to 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 as disclosed herein (e.g., a compound of Formula I) can be combined with an agent provided herein at any dose of the compound (e.g., 1 mg to 500 mg of the compound), as each combination of doses is specifically and individually listed.

[0322] In one embodiment, a kit is provided comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

[0323] Combination Therapy for Contraceptives (Birth Control)

[0324] Therapeutic agents for fertility agents (contraceptives) include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinylestradiol, norelgestromin, etonogestrel, levomefomin, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norethisterone, norgestimate, ormeloxifene, segesterone acetate, ulipristal acetate, and any combination thereof.

[0325] Gene Therapy and Cell Therapy

[0326] Gene therapy and cell therapy include genetic modification to silence genes; gene methods to directly kill infected cells; infusion of immune cells designed to replace much of the patient's own immune system to enhance the immune response to infected cells, or to activate the patient's own immune system to kill infected cells, or to find and kill infected cells; genetic methods to modify the activity of cells to further alter the endogenous immune response to infection.

[0327] Examples of dendritic cell therapy include AGS-004.

[0328] Examples of CCR5 gene editing drugs include such as SB-728T.

[0329] Examples of CCR5 gene inhibitors include such as Cal-1.

[0330] CD4 positive T cells expressing C34-CCR5 / C34-CXCR4.

[0331] AGT-103 transduced autologous T cell therapy.

[0332] AAV-eCD4-Ig gene therapy.

[0333] Gene Editing Agents

[0334] 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.

[0335] Examples of HIV targeting CRISPR / Cas9 systems include EBT-101.

[0336] CAR-T Cell Therapy

[0337] The immune effector cell population is 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 portion thereof, gpl20 or portion thereof, a CD4 binding site on gpl20, a CD4 induced binding site on gpl20, an N-glycan on gpl20, V2 of gpl20, a membrane proximal region on gp41. The immune effector cell is a T cell or an NK cell. In some embodiments, the T cell is a CD4+ T cell, a CD8+ T cell, or a combination thereof. The cell can be autologous or allogeneic.

[0338] Examples of HIV CAR-Ts include VC-CAR-T, anti-CD4 CART cell therapy, autologous hematopoietic stem cells genetically engineered to express a CD4 CAR and C46 peptide.

[0339] TCR-T Cell Therapy

[0340] The TCR-T cell is engineered to target a HIV-derived peptide present on the surface of a virally infected cell.

[0341] VII. Examples

[0342] Exemplary chemical entities of the present disclosure are provided in the following specific examples. Those skilled in the art will recognize that, in order to obtain the various compounds herein, starting materials can be appropriately selected such that the final desired substituents will be in place of a suitable group that can be reacted using a reaction scheme, and optionally displaced with the desired substituent. Alternatively, it can be necessary or desirable to employ a suitable group in the place of the final desired substituent, which suitable group can be reacted using a reaction scheme and optionally displaced with the desired substituent. Further, those skilled in the art will recognize that the transformations shown in the following schemes can be performed in any order that is compatible with the functionality of the particular side groups.

[0343] The examples provided herein describe the synthesis of the compounds disclosed herein as well as intermediates used to prepare these compounds. It will be appreciated that individual steps described herein can be combined. It will also be appreciated that individual batches of compounds can be combined prior to proceeding to the next step of the synthesis.

[0344] In the following example description, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of this disclosure. Other embodiments can be utilized and logical and other changes can be made without departing from the scope of the disclosure. The following description is, therefore, not to be taken in a limiting sense.

[0345] Intermediate A: (3S,7R)-12-(benzyloxy)-3-methyl-l,6,l l-trioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazonine-10- carboxamide Intermediate B: (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-l,6,l l- trioxo-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazonine-10-carboxamide Example 1: (3S,6S,7R)-12-hydroxy-6-methoxy-3-methyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazonine-10- carboxamide

[0346]

[0347] Synthesis of (3S,7S)-7-methyl-2,3,4,7-tetrahydro-lH-azepine-3-carboxylic acid:

[0348] Trifluoroacetic acid (20 mL) was added to (3S,7S)-3-(((benzyloxy)carbonyl)amino)-7- methyl-2,3,4,7-tetrahydro-lH-azepine-l-carboxylic acid benzyl ester (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 product was used directly in the next step.

[0349] Synthesis of (3S,7S)-12-(benzyloxy)-3-methyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7, l l-tetrahydro-3H-2,7-bridged methylenepyrido[l,2- a][l,4]diazocin-10-carboxamide:

[0350] ​​Methanol (300 mL) and water (30 mL) were added to methyl 3-(benzyloxy)-4-oxo-5-((2,4,6- trifluorobenzyl)carbamoyl)-4H-pyrran-2-carboxylate (6.75 g, 15.7 mmol) and (3S,7S)-7- methyl-2,3,4,7-tetrahydro-lH-azepine-3,5-dicarboxylic acid 1-tert-butyl ester 2-methyl ester (5.00 g, 15.7 mmol) and (S)-l-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (3.30 g, 17.4 mmol) in DMF (100 mL). The reaction was stirred at room temperature overnight. The reaction mixture was concentrated and the residue was purified by silica gel chromatography eluting with 0-10% MeOH / DCM to give methyl (3S,7S)-12-(benzyloxy)-3-methyl-l, l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrrolo[l,2-a][l,4]diazepine-10- carboxylate. MS (m / z) 524.11 [M+H] NaHCO3(13.2 g, 157 mmol) was added to the reaction mixture at room temperature. The reaction was stirred at room temperature overnight, then heated to 60 °C for 5 hours. The reaction mixture was concentrated, then ethyl acetate was added, washed with saturated ammonium chloride solution. The organic layer was concentrated and purified by silica gel chromatography eluting with 0-10% MeOH / DCM to give (3S,7S)-12-(benzyloxy)-3-methyl-l, l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrrolo[l,2-a][l,4]diazepine-10- carboxylate. MS (m / z) 524.11 [M+H] + .

[0351] Synthesis of (3S,7R)-12-(benzyloxy)-3-methyl-l,6,l l-trioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrrolo[l,2-a][l,4]diazepine-10- carboxylate:

[0352] Selenium dioxide (17.4 g, 157 mmol) was added to a solution of (3S,7S)-12-(benzyloxy)-3- methyl-l, l l-dioxo-N-(2,4,6-trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7- methanopyrrolo[l,2-a][l,4]diazepine-10-carboxylate (product of 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 solids were filtered off from the solids. The filtrate was extracted using ethyl acetate and saturated ammonium chloride solution. The organic layer was concentrated and purified by silica gel chromatography eluting with 40-100% ethyl acetate / hexanes to give (3S,7R)-12-(benzyloxy)-3-methyl-l,6,l l-trioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrrolo[l,2-a][l,4]diazepine-10- carboxylate. MS (m / z) 538.095 [M+H] + .

[0353] Example 2: (3S,6S,7R)-6,12-dihydroxy-3-methyl-l,l l-dioxo-N-(2,4,6-trifluorobenzyl)- 1,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazonine-10-carboxamide Example 3: (3S,6S,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-l,l l- dioxo-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazonine-10-carboxamide

[0354]

[0355] This intermediate was prepared according to the procedure for the preparation of (3S,7R)-12-(benzyloxy)-3-methyl-l,6,l l-trioxo-N-(2,4,6-trifluorobenzyl)- 1,6,7,11-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10-carboxamide (Intermediate A), except that in Step 2, 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4- oxo-4H-pyran-2-carboxylic acid methyl ester was used. MS (m / z) 520.2 [M+H] + .

[0356] Example 4: (3S,6R,7R)-12-hydroxy-6-methoxy-3-methyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazonine-10- carboxamide Example 5: (3S,6R,7R)-6,12-dihydroxy-3-methyl-l,l l-dioxo-N-(2,4,6-trifluorobenzyl)- 1,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazonine-10-carboxamide ​

[0357]

[0358] Preparation of (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-l, l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,11-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide:

[0359] To a solution of (3S,7R)-12-(benzyloxy)-3-methyl-l,6,l l-trioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,11-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide (Intermediate A) (122 mg, 0.227 mmol) in methanol (5 mL) was added cesium chloride (III) heptahydrate (85 mg, 0.227 mmol). Then to the mixture was slowly added sodium borohydride (2.1 mg, 0.057 mmol) at 0 °C. After 5 min, the reaction was quenched by the addition of saturated NaHC03solution 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 MgS04, filtered, concentrated and used further without purification.

[0360] Preparation of (3S,6S,7R)-12-(benzyloxy)-6-methoxy-3-methyl-l, l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,11-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide:

[0361] 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]diazocin-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 uL, 0.045 mmol). The reaction mixture was stirred at room temperature for half an hour. The reaction was quenched by the addition of saturated NaHC03, extracted with EtOAc, the organic phase was separated, dried over MgS04, filtered, concentrated and the resulting product was used in the next step without further purification.

[0362] 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]diazocin- 10-carboxamide:

[0363] 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]diazocin-10- carboxamide (15 mg, 0.018 mmol) in ethanol (1 mL) was added palladium on carbon (10 mg). The reaction was stirred under a H2balloon for half an hour. The reaction mixture was filtered through celite. The filtrate was concentrated and the residue was purified by reverse phase HPLC chromatography (eluting with 5-100% acetonitrile in water (containing 0.1% TFA)) to give the title product. MS (m / z) 466.2 [M+H] + . 1 H NMR (400 MHz, 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 = 6.7 Hz, 3H), 1.00 (dt, J = 14.9, 11.6 Hz, 1H).

[0364] ​ ​

[0365] To a solution of (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-l, l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7, l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide (10 mg, 0.018 mmol) in ethanol (1 mL) was added palladium on carbon (10 mg). The reaction was stirred under a H2 balloon for half an hour. The reaction mixture was filtered through celite. The filtrate was concentrated and the residue was purified by reverse phase HPLC chromatography eluting with 5% - 100% acetonitrile in water with 0.1% TFA to give the title product. MS (m / z) 452.3 [M+H] + . 1 H NMR (400 MHz, 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, 7.1 Hz, 1H), 1.81 (ddd, J = 14.8, 7.6, 3.8 Hz, 1H), 1.59 (dt, J = 15.0, 11.3 Hz, 1H), 1.28 (d, J = 6.7 Hz, 3H), 1.19 (dt, J = 14.8, 11.7 Hz, 1H).

[0366] ​ ​

[0367]

[0368] (3S,6S,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-l, l l-dioxo- 1,4,5,6,7, l l-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocine-10-carboxamide was prepared in analogy to Example 1, except that (3S,7R)-12-(benzyloxy)-N-(2,4- difluorobenzyl)-3-methyl-l,6,l l-trioxo-l,6,7,l l-tetrahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocine-10-carboxamide (Intermediate B) was used instead of (3S,7R)-12-(benzyloxy)-3-methyl-l,6,l l-trioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocine-10- carboxamide (Intermediate A). MS (m / z) 448.2 [M+H] + .1 H NMR (400 MHz, Methanol-d4) d 8.37 (s, 1H), 7.45 (q, J = 7.8 Hz, 1H), 7.09 - 6.88 (m, 2H), 4.65 (s, 4H), 3.75 (s, 2H), 3.56 (d, J = 11.1 Hz, 1H), 3.46 (s, 3H), 2.18 - 1.98 (m, 2H), 1.54 (dd, J = 25.7, 11.4 Hz, 1H), 1.29 (d, J = 6.6 Hz, 3H), 1.01 (q, J = 12.1 Hz, 1H).

[0369] ​ ​

[0370]

[0371] Preparation of (3S,6R,7R)-12-(benzyloxy)-3-methyl-l, l l-dioxo-10-((2,4,6- trifluorobenzyl)carbamoyl)-l,6,7, l l-tetrahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-6-yl benzoate:

[0372] To a solution of (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-l, l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7, l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-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 oxalate (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 NaHC03, the organic phase was separated, dried over MgS04, filtered, concentrated and purified by silica gel column chromatography (0% - 100% EtOAc / hexanes) to give the title compound (30 mg).

[0373] Preparation of (3S,6R,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-l, l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7, l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide:

[0374] A reaction mixture of (3S,6R,7R)-12-(benzyloxy)-3-methyl-l,l l-dioxo-10- ((2,4,6-trifluorobenzyl)carbamoyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-6-yl benzoate (30 mg, 0.047 mmol), LiOH.H20 (5.6 mg, 0.233 mmol) in MeOH (2 mL) and H20 (0.5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated. The residue was washed with brine, extracted with EtOAc, the organic phase was separated, dried over MgS04, filtered, concentrated and used in the next step without purification.

[0375] Preparation of (3S,6R,7R)-12-(benzyloxy)-6-methoxy-3-methyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocine-10- carboxamide:

[0376] To a solution of (3S,6R,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocine-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 uL, 0.056 mmol). The reaction mixture was stirred at room temperature for half an hour. The reaction was quenched by the addition of saturated NaHC03, extracted with EtOAc, the organic phase was separated, dried over MgS04, filtered, concentrated and used in the next step without purification.

[0377] Preparation of (3S,6R,7R)-12-hydroxy-6-methoxy-3-methyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocine-10- carboxamide:

[0378] 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]diazocin-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 in water with 0.1% TFA to give the title compound. MS (m / z) 464.1 [M+H] + . 1 H NMR (400 MHz, Methanol-d4) δ 8.45 (s, 1H), 6.98 - 6.85 (m, 2H), 5.77 (dt, J = 11.8, 2.8 Hz, 1H), 5.56 (ddd, J = 11.9, 2.7, 1.7 Hz, 1H), 5.33 (dq, J = 7.6, 2.8 Hz, 1H), 4.69 (s, 2H), 4.59 (s, 1H), 4.27 (dq, J = 5.7, 3.0 Hz, 1H), 4.11 (d, J = 13.7 Hz, 1H), 3.65 (d, J = 14.4 Hz, 1H), 3.32 (s, 3H), 1.39 (d, J = 7.2 Hz, 3H).

[0379] ​ 1,4,5,6,7,1 1 -hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide

[0380]

[0381] 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]diazocin-10- carboxamide (10 mg, 0.018 mmol) in ethanol (1 mL) was added palladium on carbon (10 mg). The reaction was stirred under a H2 balloon for half an hour. The reaction mixture was filtered through celite. The filtrate was concentrated and the residue was purified by reverse phase HPLC chromatography eluting with 5-100% acetonitrile in water with 0.1% TFA to give the title product. MS (m / z) 452.2 [M+H] + . 1H NMR (400 MHz, Methanol-d4) δ 8.46 (s, 1H), 6.99 - 6.85 (m, 2H), 4.68 (s, 2H), 4.58 (dt, J = 10.7, 6.5 Hz, 1H), 4.40 (s, 1H), 4.04 (d, J = 3.9 Hz, 1H), 3.81 (d, J = 14.8 Hz, 1H), 3.69 (d, J = 14.7 Hz, 1H), 2.01 (dd, J = 14.5, 11.3 Hz, 1H), 1.95 - 1.79 (m, 2H), 1.38 - 1.30 (m, 1H), 1.29 (d, J = 6.6 Hz, 3H).

[0382] Example 6: (3S,6R,7R)-12-hydroxy-6-methoxy-3-methyl-1,1 1 -dioxo-N-(2,4,6-trifluoro benzyl)-1,4,5,6,7,1 1 -hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carbox amide

[0383]

[0384] To a solution of (3S,6R,7R)-12-hydroxy-6-methoxy-3-methyl-l,l l- dioxo-N-(2,4,6-trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7- methanobenzo[l,2-a][l,4]diazocin-10-carboxamide (Example 4) (18 mg, 0.039 mmol) in EtOH (2 mL) was added Pd(OH)2 / C (10 mg). The reaction mixture was stirred at room temperature for half an hour with a H2balloon attached. 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 in water with 0.1% TFA to give the title product. MS (m / z) 466.2 [M+H] + . 1H NMR (400 MHz, Methanol-d4) δ 8.37 (s, 1H), 7.45 (q, J = 7.8 Hz, 1H), 7.09 - 6.88 (m, 2H), 4.65 (s, 4H), 3.75 (s, 2H), 3.56 (d, J = 11.1 Hz, 1H), 3.46 (s, 3H), 2.18 - 1.98 (m, 2H), 1.54 (dd, J = 25.7, 11.4 Hz, 1H), 1.29 (d, J = 6.6 Hz, 3H), 1.01 (q, J = 12.1 Hz, 1H).1H NMR (400 MHz, 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 = 14.9 Hz, 1H), 3.72 - 3.60 (m, 2H), 3.48 (s, 3H), 2.09 (dt, J = 15.0, 4.6 Hz, 1H), 1.86 (td, J = 9.6, 2.7 Hz, 2H), 1.28 (d, J = 6.7 Hz, 3H), 1.24 - 1.15 (m, 1H).

[0385] Example 7: (3S,6R,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,1 1 -dio xo-1,6,7,1 1 -tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide

[0386]

[0387] (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]diazocin-10- carboxamide was prepared in a similar manner to that for preparing (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]diazocin-10-carboxamide (Example 4), except that (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]diazocin-10- carboxamide (see Example 3) was used 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]diazocin-10-carboxamide. MS (m / z) 446.2 [M+H] +. 1 H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 7.45 (td, J = 8.4, 6.3 Hz, 1H), 7.03 - 6.90 (m, 2H), 5.77 (dt, J = 11.8, 2.8 Hz, 1H), 5.56 (ddd, J = 11.8, 2.7, 1.7 Hz, 1H), 5.34 (dq, J = 7.4, 2.8 Hz, 1H), 4.67 - 4.56 (m, 3H), 4.29 (dq, J = 5.6, 2.9 Hz, 1H), 4.11 (dd, J = 14.4, 3.0 Hz, 1H), 3.65 (d, J = 14.2 Hz, 1H), 3.34 (s, 3H), 1.39 (d, J = 7.3 Hz, 3H).

[0388] Example 8: (3S,6R,7R)-6,12-dihydroxy-3-methyl-1,1 1 -dioxo-N-(2,4,6-trifluorobenzyl) 1,4,5,6,7,1 1 -hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide

[0389]

[0390] To a solution of (3S,6R,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-bridged methylenepyrido[l,2- a][l,4]diazocin-10-carboxamide (Example 7) (20 mg, 0.045 mmol) in EtOH (2 mL) was added Pd(OH)2 / C (7 mg). The reaction mixture was stirred at room temperature for half an hour with a H2 balloon attached. 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 in water (with 0.1% TFA) to give the title product. MS (m / z) 448.3 [M+H] + . 1 H NMR (400 MHz, Methanol-d4) δ 8.53 (s, 1H), 7.50 - 7.40 (m, 1H), 6.97 (dddd, J = 12.6, 11.1, 8.9, 2.6 Hz, 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, 4.6 Hz, 1H), 1.85 (tt, J = 9.4, 5.2 Hz, 2H), 1.36 - 1.16 (m, 4H).

[0391] Example 9: (3S,6S,7R)-N-(3-chloro-2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl- 1,1 1 -dioxo-1,6,7,1 1 -tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide Example 10: (3S,6R,7R)-N-(3-chloro-2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methy

[0392]

[0393] 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]diazocin-10-carboxylic acid ethyl ester:

[0394] A reaction mixture of (3S,7S)-7-methyl-2,3,4,7-tetrahydro-1H-azepine-3,4-dicarboxylic acid 1-tert-butyl ester, 2-tert-butyl ester (0.39 g, 1.2 mmol), 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylic acid diethyl ester (0.62 g, 1.7 mmol), and sodium bicarbonate (1.6 g, 19.2 mmol) in MeOH (10 mL) and water (2 mL) was stirred at room temperature overnight. The reaction mixture was then stirred at 60 °C for 8 hours. The reaction mixture was cooled and concentrated. The residue was washed with water, extracted with EtOAc. The organic phase was separated, dried over MgSO4, filtered, concentrated and purified by silica gel chromatography (eluting with 0% - 100% hexanes / EtOAc) to give the title compound. -3-amine (0.39 g, 3.1 mmol), 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylic acid diethyl ester (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 then stirred at 60 °C for 8 hours. The reaction mixture was cooled and concentrated. The residue was washed with water, extracted with EtOAc. The organic phase was separated, dried over MgSO4, filtered, concentrated and purified by silica gel chromatography (eluting with 0% - 100% hexanes / EtOAc) to give the title compound.

[0395] 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]diazocin-10-carboxylic acid ethyl ester:

[0396] A reaction mixture of (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-1,6,7,11- tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxylic acid ethyl ester (1.02 g, 2.5 mmol) and sodium hydroxide (2 N, 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 using HCl, extracted with EtOAc. The organic phase was separated, dried over MgSO4, filtered, concentrated and used in the next reaction without further purification.

[0397] 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]diazocin-10- carboxamide:

[0398] 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]diazocin-10-carboxylic acid (0.88 g, 2.31 mmol) in DCM (10 mL) at 0 °C was 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). The reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was washed with saturated NaHCO3, extracted with EtOAc, the organic phase was separated, dried over MgSO4, filtered, concentrated and purified by silica gel chromatography (eluting with 0% - 100% hexanes / EtOAc) to give the title compound.

[0399] 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]diazocine-10-carboxamide:

[0400] 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]diazocine-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, washed with saturated NaHCO3. The organic phase was dried over MgSO4, filtered, concentrated and purified by silica gel chromatography (eluting with 0% - 100% hexanes / EtOAc) to give the title compound.

[0401] 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]diazocine-10-carboxamide:

[0402] (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]diazocin-10- carboxamide was prepared in a similar manner to that described in the preparation of Example 1, except that (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]diazocin-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]diazocin-10-carboxamide (Intermediate A). MS (m / z) 482.4 [M+H] + . 1 H NMR (400 MHz, Methanol-d4) δ 8.35 (s, 1H), 7.40 (td, J = 8.4, 6.0 Hz, 1H), 7.11 (td, J = 8.7, 1.9 Hz, 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, 11.2 Hz, 1H), 1.28 (d, J = 6.7 Hz, 3H), 1.01 (dt, J = 14.9, 11.7 Hz, 1H).

[0403] l-1,1 1 -dioxo-1,6,7,1 1 -tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide Example 11. (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-1,1 1 -dioxo-N-(2,4,6-trifluoro benzyl)-1,6,7,1 1 -tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide

[0404]

[0405] (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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide was prepared using a method similar to that used in Example 4, except that (3S,6R,7R)-12-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-6-hydroxy-3 3-Methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide substituted with (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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide. MS (m / z) 480.2 [M+H] + . 1 H NMR (400MHz, acetonitrile-d3) δ10.38(s,1H),8.35(s,1H),7.39(q,J=8.1Hz,1H),7. 18-7.04(m,1H),5.72(dq,J=8.7,2.8Hz,1H),5.63-5.48(m,1H),5.30(s,1 H),4.73-4.60(m,3H),4.46(s,1H),4.27(s,1H),4.01(dd,J=14.4,2.9Hz, 1H), 3.58 (d, J = 14.4Hz, 1H), 3.29 (d, J = 4.3Hz, 3H), 1.34 (d, J = 7.3Hz, 3H).

[0406] Example 12: [(3S,6S,7R)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-3,6-dimethyl-1,1 1 -dioxo-1,4, 5,6,7,1 1 -hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide] Example 13: Preparation of (3S,6R,7R)-6-chloro-N-(2,4-difluorobenzyl)-12-hydroxy-3-methy

[0407]

[0408] 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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-10-carboxamide:

[0409] (3S,7R)-12-(benzyloxy)-3-methyl-l,6,l l-trioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-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 stirring, cooled mixture was added methylmagnesium bromide, 3.0 M in ether (0.41 mL, 1.23 mmol). After stirring for 20 min, the reaction was quenched with saturated NH4Cl. The mixture was extracted with EtOAc, 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 H+calc for C3N3O5: 553.18, found: 553.95.

[0410] Synthesis of (3S,6S,7R)-6,12-dihydroxy-3,6-dimethyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-10-carboxamide:

[0411] (3S,6S,7R)-6,12-dihydroxy-3,6-dimethyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-10-carboxamide (20.0 mg, 0.0361 mmol) was dissolved in MeOH (15.0 mL) and treated with 7 mg 20% Pd(OH)2 / C (50 wt% water). The mixture was degassed and purged with hydrogen gas 3 times, then hydrogenated under a hydrogen balloon overnight. The reaction was then degassed and purged with nitrogen, filtered through a celite pad, concentrated, the resulting residue was re-dissolved in DMF, filtered and purified by reverse phase HPLC. LCMS-ESI+(m / z): C 22 H 22 H+calc for C3N3O5: 553.18, found: 553.95. 1H NMR (400 MHz, DMSO-d6) δ 10.95 (s, 1H), 10.46 (t, J = 5.8 Hz, 1H), 8.31 (s, 1H), 7.21 (t, J = 8.6 Hz, 2H), 4.93 (s, 1H), 4.62 - 4.41 (m, 3H), 4.26 (s, 1H), 3.66 (d, J = 2.5 Hz, 2H), 1.91 - 1.81 (m, 1H), 1.41 (dd, J = 14.6, 7.7 Hz, 2H), 1.34 (s, 3H), 1.17 (d, J = 6.6 Hz, 4H).

[0412] l-1,1 1 -dioxo-1,6,7,1 1 -tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide Example 14: (3S,6S,7R)-6,12-dihydroxy-3-methyl-1,1 1 -dioxo-N-(2,4,6-trifluorobenzyl ​

[0413] This compound was prepared in the same sequence as 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]diazocin-10-carboxamide was used in place 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]diazocin-10-carboxamide in Step 1. Stereochemistry was not confirmed. LCMS-ESI+(m / z): H+calc'd for C22H23F2N3O5, 447.16; found, 448.22. 1 H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.46 (t, J = 6.0 Hz, 1H), 8.34 (s, 1H), 7.40 (td, J = 8.7, 6.7 Hz, 1H), 7.25 (ddd, J = 10.6, 9.3, 2.6 Hz, 1H), 7.12 - 7.03 (m, 1H), 5.03 - 4.83 (m, 1H), 4.56 (d, J = 5.9 Hz, 2H), 4.47 (dt, J = 12.2, 6.5 Hz, 1H), 4.28 (s, 1H), 3.67 (d, J = 3.2 Hz, 2H), 1.87 (dt, J = 14.3, 7.1 Hz, 1H), 1.42 (dd, J = 14.4, 7.7 Hz, 2H), 1.35 (s, 3H), 1.25 - 1.12 (m, 4H).

[0414] ​ ​

[0415]

[0416] 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]diazocin- 10-carboxamide:

[0417] 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]diazocin-10- carboxamide (110 mg, 0.211 mmol) in DCM (27 mL) was added triethylamine (1.18 mL, 8.44 mmol) and thionyl chloride (0.615 mL, 8.44 mmol) under N2. After 5 min, the reaction was quenched by the addition of saturated NaHCO3solution and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated and purified by flash silica gel column chromatography using DCM / MeOH as the solvent system (1:0 -> 95:5 -> 8:2 gradient) to give (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]diazocin-10- carboxamide as a red / brown solid (111 mg, 98%).

[0418] 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]diazocin-10-carboxamide:

[0419] 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-bridged methylenepyrido[1,2- a][1,4]diazacyclononene-10-carboxamide (63 mg, 0.116 mmol) in toluene / TFA (1 :1 ) (10 mL) was stirred at room temperature for 2.75 hours. 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 Na2S04, filtered, concentrated and purified by reverse phase HPLC chromatography eluting with 5%-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 (400 MHz, MeOD) d 8.50 (s, 1H), 7.46-7.40 (m, 1H), 6.99-6.91 (m, 2H), 5.76 (dt, J = 11.9, 3.1 Hz, 1H), 5.55 (dt, J = 11.9, 2.3 Hz, 1H), 5.35-5.33 (m, 1H), 5.13 (s, 1H), 4.98 (s, 1H), 4.63 (s, 2H), 4.20 (d, J = 14.5 Hz, 1H), 3.73 (d, J = 14.5 Hz, 1H), 1.39 (d, J = 7.3 Hz, 3H).

[0420] ​ (3S,6S,7R)-6-(difluoromethoxy)-12-hydroxy-3-methyl-1,1 1 -dioxo-N-(2,4,6-trifluoro- benzyl)-1,6,7,1 1 -tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide

[0421]

[0422] (3S,6S,7R)-6,12-dihydroxy-3-methyl-l, 11-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,11-tetrahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-10-carboxamide was prepared in a similar manner as Example 4, except (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-l, 11-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,11-tetrahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-10-carboxamide (prepared according to Example 1) was used in place of (3S,6S,7R)-12-(benzyloxy)-6-methoxy-3-methyl-l, 11-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,11-tetrahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-10-carboxamide. MS (m / z) 449.1 [M+H] + .1H NMR (400 MHz, MeOD) δ 8.45 (s, 1H), 6.91 (t, J = 8.4 Hz, 2H), 5.85 (ddd, J = 11.9, 6.1, 2.3 Hz, 1H), 5.63 (dd, J = 11.9, 2.7 Hz, 1H), 5.33 (d, J = 7.4 Hz, 1H), 4.70 (d, J = 7.8 Hz, 2H), 4.4 (m, 1H), 4.05 - 3.87 (m, 1H), 3.73 (d, J = 14.6 Hz, 1H), 3.03 (m, 2H), 1.39 (d, J = 7.3 Hz, 3H).

[0423] Example 15: Preparation of (1 R,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-3,6,1 1 -trien-4- carboxamide Example 15: Preparation of (1 R,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-3,6,1 1 -trien-4- carboxamide

[0424]

[0425] (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 stirring cooled mixture was added dropwise 3.0 M MeMgBr in ether (0.056 mL, 0.168 mmol). The resulting mixture was stirred at -78 °C for 5 minutes 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+calcd for C22H20F3N3O5: 463.14, found: 464.02.1H NMR (400 MHz, DMSO-d6) δ 10.46 (t, J = 5.8 Hz, 1H), 8.36 (s, 1H), 7.25 - 7.23 (m, 1H), 7.22 - 7.19 (m, 2H), 5.54 (dd, J = 11.9, 2.3 Hz, 1H), 5.39 (dd, J = 11.8, 2.6 Hz, 1H), 5.18 - 5.08 (m, 1H), 4.68 (s, 1H), 4.59 - 4.55 (m, 3H), 3.86 (dd, J = 14.7, 2.6 Hz, 1H), 3.63 (d, J = 14.2 Hz, 1H), 1.38 (s, 3H), 1.27 (d, J = 7.3 Hz, 3H).

[0426] Example 16: Preparation of (3S,6S,7R)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-3- methyl-1,1 1 -dioxo-1,6,7,1 1 -tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10- carboxamide Example 15: Preparation of (1 R,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-3,6,1 1 -trien-4- carboxamide

[0427]

[0428] 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]diazocin-10-carboxamide:

[0429] (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide (10 mg, 0.019 mmol) was dissolved in 3 mL of ethanol and 3 mL of ethyl acetate and bubbled under an argon atmosphere. Carbon-supported palladium (10 wt%, wet) E101 NE / W (4.08 mg, 0.0038 mmol) was added. The mixture was bubbled under a hydrogen atmosphere (1 atm, balloon) with vigorous stirring for two hours, followed by bubbling under an argon atmosphere. Pad filtration. Wash with anhydrous ethanol. 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) δ8.43(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=1.8 Hz,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).

[0430] Example 17: (1R,10S,13S)-N-[(2,4-difluorophenyl)methyl]-6,13-dihydroxy-10,13-di Example 15: Preparation of (1 R,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-3,6,1 1 -trien-4- carboxamide Example 15: Preparation of (1 R,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-3,6,1 1 -trien-4- carboxamide

[0431]

[0432] 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]tetradecade-3,6,11-triene-4-carboxamide:

[0433] This compound was prepared according to the procedure of Step 1 for 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]diazocin-10- carboxamide was used in Step 1 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]diazocin-10-carboxamide. LCMS-ESI+(m / z): H+calc'd for C29H27F2N3O5, 535.19, found: 535.94.

[0434] 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:

[0435] (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 from Step 1 (13.0 mg, 0.0243 mmol) was treated with a mixture of DCM (0.2 mL) and TFA (0.2 mL) at room temperature for 4 h. The reaction was concentrated, re-dissolved in DMF, filtered and purified by reverse phase preparative HPLC. LCMS-ESI+(m / z): H+calc'd for C22H21F2N3O5, 445.14, found: 446.04.1H NMR (400 MHz, Acetone-d6) δ 10.51 (s, 1H), 8.38 (s, 1H), 7.49 (q, J = 8.3 Hz, 1H), 7.08 - 6.95 (m, 2H), 6.25 (s, 1H), 5.74 (dd, J = 11.9, 2.5 Hz, 1H), 5.53 (dd, J = 11.8, 2.5 Hz, 1H), 5.35 - 5.23 (m, 1H), 4.79 - 4.69 (m, 2H), 4.63 (d, J = 6.0 Hz, 2H), 4.12 (dd, J = 14.7, 2.7 Hz, 1H), 3.85 (dd, J = 14.6, 1.8 Hz, 1H), 1.60 (s, 3H), 1.39 (d, J = 7.3 Hz, 3H).

[0436] Example 15: Preparation of (1 R,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-3,6,1 1 -trien-4- carboxamideExample 15: Preparation of (1 R,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-3,6,1 1 -trien-4- carboxamide

[0437]

[0438] 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]diazocin-10- carboxamide:

[0439] 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]diazocin-10- carboxamide (Intermediate A) (122 mg, 0.227 mmol) in methanol (5 mL) was added cesium chloride (III) heptahydrate (85 mg, 0.227 mmol). To the mixture was then slowly added sodium borohydride (2.1 mg, 0.057 mmol) at 0 °C. After 5 minutes, the reaction was quenched by the addition of saturated NaHCO3solution 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.

[0440] 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]diazocin-10- carboxamide:

[0441] 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]diazocin-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 uL, 0.045 mmol). The reaction mixture was stirred at room temperature for half an hour. The reaction was quenched by the addition of saturated NaHCO3, extracted with EtOAc, the organic phase was separated, dried over MgSO4, filtered, concentrated and the resulting product was used in the next step without further purification.

[0442] Preparation of (3S,6S,7R)-12-hydroxy-6-methoxy-3-methyl-l, 11-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,11-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- formamide:

[0443] A reaction mixture of (3S,6S,7R)-12-(benzyloxy)-6-methoxy-3-methyl-l, 11-dioxo-N- (2,4,6-trifluorobenzyl)-l,6,7,11-tetrahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-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 in water (with 0.1% TFA) to afford the title product. MS (m / z) 464.16 [M+H] + . 1 H NMR (400 MHz, Methanol-d4) δ 8.47 (s, 1H), 6.98 - 6.85 (m, 2H), 6.00 (ddd, J = 11.6, 6.6, 2.6 Hz, 1H), 5.75 (dd, J = 11.6, 2.0 Hz, 1H), 5.27 (qt, J = 7.4, 2.4 Hz, 1H), 5.00 (d, J = 7.3 Hz, 1H), 4.69 (s, 2H), 4.29 (t, J = 7.0 Hz, 1H), 3.96 (dd, J = 14.6, 2.5 Hz, 1H), 3.66 (d, J = 14.5 Hz, 1H), 3.12 (s, 3H), 1.39 (d, J = 7.4 Hz, 3H).

[0444] Example 15: Preparation of (1 R,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-3,6,1 1 -trien-4- carboxamide Example 15: Preparation of (1 R,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-3,6,1 1 -trien-4- carboxamide

[0445]

[0446] Prepared similarly to Example 18 for (3S,6S,7R)-N-(2,4-difluorobenzyl)-12- hydroxy-6-methoxy-3-methyl-l, 11-dioxo-l, 6, 7, 11-tetrahydro-3H-2, 7- methanopyrido[l,2-a][l,4]diazocin-10-carboxamide, except (3S,7R)-12- (benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-l,6,11-trioxo-l,6,7,11- tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10-carboxamide was used instead of (3S,7R)-12-(benzyloxy)-3-methyl-l,6,11-trioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,11-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin- 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, 6.3 Hz, 1H), 7.04 - 6.90 (m, 2H), 6.00 (ddd, J = 11.6, 6.6, 2.6 Hz, 1H), 5.76 (dd, J = 11.7, 2.0 Hz, 1H), 5.28 (tdt, J = 7.4, 4.7, 2.4 Hz, 1H), 5.00 (d, J = 6.9 Hz, 1H), 4.65 (s, 2H), 4.29 (t, J = 7.0 Hz, 1H), 3.97 (dd, J = 14.6, 2.4 Hz, 1H), 3.66 (d, J = 14.5 Hz, 1H), 3.13 (s, 3H), 1.39 (d, J = 7.3 Hz, 3H).

[0447] Example 15: Preparation of (1 R,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-3,6,1 1 -trien-4- carboxamide ​

[0448]

[0449] (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-l, 11- dioxo-l,6,7,11-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide prepared according to Example 3 (10 mg, 0.19 mmol) was dissolved in 1 mL of toluene and 1 mL of TFA. It 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]+. 1H NMR (400 MHz, DMSO-d6) δ 10.49 - 10.39 (m, 2H), 8.42 (s, 1H), 7.41 (td, J = 8.7, 6.6 Hz, 1H), 7.25 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.07 (td, J = 8.5, 2.6 Hz, 1H), 5.67 (ddd, J = 11.9, 5.6, 2.1 Hz, 1H), 5.57 - 5.48 (m, 2H), 5.20 - 5.12 (m, 1H), 4.93 (d, J = 7.3 Hz, 1H), 4.58 (dd, J = 13.2, 6.2 Hz, 3H), 3.83 (dd, J = 14.8, 2.4 Hz, 1H), 3.68 (dd, J = 14.7, 2.0 Hz, 1H), 1.28 (d, J = 7.3 Hz, 3H).

[0450] ​ ​ ​

[0451]

[0452] Prepared in analogy to Example 18 (3S,6S,7R)-N-(2,4-difluorobenzyl)-12- hydroxy-6-methoxy-3-methyl-l, l l-dioxo-l,6,7, l l-tetrahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-6-d-10-carboxamide, except sodium borodeuteride was used instead of sodium borohydride and (3S,7R)-12-(benzyloxy)-N-(2,4- difluorobenzyl)-3-methyl-l,6,l l-trioxo-l,6,7, l l-tetrahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-10-carboxamide was used instead of (3S,7R)- 12-(benzyloxy)-3-methyl-l,6,l l-trioxo-N-(2,4,6-trifluorobenzyl)-l,6,7, l l- tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10-carboxamide. MS (m / z) 447.2 [M+H] + . 1H NMR (400 MHz, Methanol-d4) δ 8.50 (s, 1H), 7.45 (td, J = 8.4, 6.4 Hz, 1H), 7.04 - 6.90 (m, 2H), 6.00 (dd, J = 11.6, 2.7 Hz, 1H), 5.76 (dd, J = 11.6, 2.0 Hz, 1H), 5.28 (dddd, J = 9.9, 7.6, 4.9, 2.5 Hz, 1H), 5.00 (s, 1H), 4.65 (s, 2H), 3.96 (dd, J = 14.6, 2.7 Hz, 1H), 3.66 (d, J = 14.4 Hz, 1H), 3.12 (s, 3H), 1.39 (d, J = 7.3 Hz, 3H).

[0453] ​ ​ ​

[0454]

[0455] 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]diazocin-10-carboxamide:

[0456] (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]diazocin-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, ethyl acetate was added, washed 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]+.

[0457] 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]diazocin-10-carboxamide:

[0458] (3S,6S,7R)-12-(benzyloxy)-6-(difluoromethoxy)-3-methyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7, 11 -tetrahydro-3H-2,7-methanopyrido[ 1,2 -a] [ 1,4] diazacyclonon e- 10-carboxamide (10 mg) was dissolved in 0.5 ml of toluene and 0.5 ml of TFA, stirred at room temperature for 1.5 hours, then the solvent was removed, and purified by RP-HPLC to give the title product. MS (m / z): 500.100 [M+H]+. 1H NMR (400 MHz, Methanol-d4) δ 10.54 (s, 1H), 8.46 (s, 1H), 6.92 (t, J = 8.4 Hz, 2H), 6.25 (t, J = 73.1 Hz, 1H), 5.95 - 5.86 (m, 1H), 5.79 (dd, J = 11.8, 2.3 Hz, 1H), 5.35 (d, J = 7.5 Hz, 1H), 5.27 (t, J = 7.0 Hz, 1H), 5.10 (d, J = 7.5 Hz, 1H), 4.68 (s, 3H), 3.98 (d, J = 14.5 Hz, 1H), 3.74 (d, J = 14.6 Hz, 1H), 1.41 (d, J = 7.3 Hz, 3H).

[0459] ​ ​ ​

[0460]

[0461] Synthesis of (3S,6S,7R)-12-(benzyloxy)-6-methoxy-3,6-dimethyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7, 11 -tetrahydro-3H-2,7-methanopyrido[ 1,2 -a] [ 1,4] diazacyclonon e- 10-carboxamide:

[0462] (3S,6S,7R)-6,12-dihydroxy-3,6-dimethyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-10-carboxamide (product from Step 1 of Example 11, 25 mg, 0.045 mmol) was dissolved in dry DMF (0.90 mL) and the resulting mixture was cooled to 0 °C. To this stirring, cooled mixture was added a 60% suspension of 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 sequentially with water, saturated aqueous sodium bicarbonate, and brine, dried over magnesium sulfate, filtered, and concentrated. Flash column chromatography (silica gel, EtOAc / hexanes) afforded the product (stereochemical assignment tentative).1H 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 = 10.3 Hz, 1H), 4.66 (d, J = 5.4 Hz, 2H), 4.11 (s, 1H), 3.78 (dd, J = 14.5, 2.9 Hz, 1H), 3.27 (dd, J = 14.5, 1.3 Hz, 1H), 3.00 (s, 3H), 1.45 (s, 3H), 1.29 (d, J = 7.4 Hz, 3H). LCMS-ESI+ (m / z): C 30 H 28 H+calc for F3N3O5: 568.21, found: 568.19.

[0463] Synthesis of (3S,6S,7R)-12-hydroxy-6-methoxy-3,6-dimethyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-10-carboxamide:

[0464] (3S,6S,7R)-12-(benzyloxy)-6-methoxy-3,6-dimethyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7, l l-tetrahydro-3H-2,7-bridged methylenepyrido[l,2- a][l,4]diazacyclononene-10-carboxamide (20.0 mg, 0.035 mmol) was dissolved in EtOH (1.0 mL) at room temperature and treated with 1.2 mg 20% Pd(OH)2 / C (50 wt% water). The mixture was degassed and purged with hydrogen gas 3 times, then stirred under a hydrogen atmosphere for 45 minutes. The reaction was then degassed and purged with nitrogen, filtered through a pad of celite, concentrated, and the resulting residue purified by flash column chromatography (silica gel, dichloromethane / methanol) to give the product (stereochemistry assignment tentative).1H NMR (400 MHz, chloroform-d) δ 10.48 (s, 1H), 6.65 (dd, J = 8.8, 7.5 Hz, 2H), 4.75 - 4.58 (m, 3H), 3.67 (dd, J = 15.3, 3.0 Hz, 1H), 3.44 (d, J = 15.2 Hz, 1H), 3.12 (s, 3H), 2.13 - 2.01 (m, 1H), 1.91 (dd, J = 14.8, 7.7 Hz, 1H), 1.41 (s, 3H), 1.36 - 1.28 (m, 1H), 1.26 (d, J = 6.7 Hz, 3H), 1.24 - 1.06 (m, 2H). LCMS-ESI+(m / z): C 23 H 24 H+calc for F3N3O5: 480.18, found: 480.30.

[0465] Example 24: Synthesis of (3S,6S,7R)-12-hydroxy-6-methoxy-3,6-dimethyl-l,l l- dioxo-N-(2,4,6-trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-10-carboxamide Example 24: Synthesis of (3S,6S,7R)-12-hydroxy-6-methoxy-3,6-dimethyl-l,l l- dioxo-N-(2,4,6-trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-10-carboxamide Example 25: Preparation of (3S,6S,7R)-6-ethoxy-12-hydroxy-3-methyl-l,l l-dioxo-N- (2,4,6-trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide

[0466]

[0467] (3S,6S,7R)-12-(benzyloxy)-6-methoxy-3,6-dimethyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7, 11 -tetrahydro-3H-2,7-methanopyrido[ 1,2 -a] [ 1,4] diazacyclononedece-10-carboxamide (from Example 23, Step 1, 16 mg, 0.028 mmol) was dissolved in 1:1 toluene:trifluoroacetic acid (1.16 mL). The resulting solution was stirred at 20 °C for 8 hours, then allowed to stand at 0 °C for 12 hours. The solution was diluted with acetonitrile and concentrated in vacuo, and the resulting crude product was purified with flash column chromatography (silica gel, dichloromethane / methanol) to give the product (stereochemical assignment tentative). ¾ NMR (400 MHz, chloroform-d) δ 10.36 (s, 1H), 8.32 (s, 1H), 6.65 (dd, J = 8.7, 7.5 Hz, 2H), 5.64 (dd, J = 11.6, 1.8 Hz, 1H), 5.53 (dd, J = 11.6, 2.7 Hz, 1H), 5.29 - 5.20 (m, 1H), 4.77 - 4.55 (m, 2H), 4.23 (s, 1H), 3.93 (dd, J = 14.3, 3.0 Hz, 1H), 3.54 (dd, J = 14.3, 1.3 Hz, 1H), 2.97 (s, 3H), 1.45 (s, 3H), 1.36 (d, J = 7.4 Hz, 3H). LCMS-ESI+(m / z): C 23 H 22 H+calc for F3N3O5: 478.16, found: 478.25.

[0468] Example 25: Preparation of (3S,6S,7R)-6-ethoxy-12-hydroxy-3-methyl-l,l l-dioxo-N- (2,4,6-trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide Example 26: Preparation of (3S,6S,7R)-6-ethoxy-12-hydroxy-3-methyl-l,l l-dioxo-N- (2,4,6-trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide Example 27: Synthesis of (3S,6S,7R)-6-(difluoromethoxy)-12-hydroxy-3-methyl-l,l l- dioxo-N-(2,4,6-trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4] diazocin-10-carboxamide

[0469]

[0470] Synthesis of (3S,6S,7R)-12-(benzyloxy)-6-ethoxy-3-methyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7, 11 -tetrahydro-3H-2,7-methanopyrido[ 1,2 -a] [ 1,4] diazacyclononedece-10-carboxamide:

[0471] (3S,6S,7R)-12-(benzyloxy)-6-ethoxy-3-methyl-1,1 l-dioxo-N-(2,4,6- trifluorobenzyl)-1,6,7,1 l-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin- 10-carboxamide (5 mg) was dissolved in toluene (0.5 mL) at room temperature, TFA (0.5 mL) was added. The reaction was stirred at room temperature for one 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] + .

[0472] Synthesis of (3S,6S,7R)-6-ethoxy-12-hydroxy-3-methyl-1,1 l-dioxo-N-(2,4,6- trifluorobenzyl)-1,6,7,1 l-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin- 10-carboxamide:

[0473] (3S,6S,7R)-12-(benzyloxy)-6-ethoxy-3-methyl-1,1 l-dioxo-N-(2,4,6- trifluorobenzyl)-1,6,7,1 l-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin- 10-carboxamide (5 mg) was dissolved in toluene (0.5 mL) at room temperature, TFA (0.5 mL) was added. The reaction was stirred at room temperature for one 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 =12.5Hz,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).

[0474] Example 28: Preparation of (3S,6S,7R)-6-ethyl-6,12-dihydroxy-3-methyl-l,l l-dioxo-N- (2,4,6-trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide Example 29: Synthesis of (lR,10S,13S)-6,13-dihydroxy-10-methyl-5,8-dioxo-13- (trideuteromethyl)-N-[(2,4,6-trifluorophenyl)methyl]-2,9-diazatricyclo[7.4.1.02,7]tetradeca- 3,6,l l-triene-4-carboxamide Example 30: Synthesis of (lR,10S,13S)-N-[(2,4-difluorophenyl)methyl]-6,13- dihydroxy-10-methyl-5,8-dioxo-13-(trideuteromethyl)-2,9-diazatricyclo[7.4.1.02,7]tetra- deca-3,6,l l-triene-4-carboxamide

[0475]

[0476] (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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonene-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 through diatomaceous earth. The filtrate was concentrated. The crude reactant was purified by preparative HPLC, eluting with an aqueous solution of 10%-60% acetonitrile (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-bridged methylenepyrido[1,2-a][1,4]diazacyclic nonen-10-carboxamide. MS (m / z) 480.27 [M+H] + ¹H NMR (400MHz, 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).

[0477] Example 31: Synthesis of (lR,10S,13S)-N-[(2,4-difluorophenyl)methyl]-6,13- dihydroxy-10-methyl-5,8-dioxo-13-(trideuteromethyl)-2,9-diazatricyclo[7.4.1.02,7]tetra- deca-3,6-diene-4-carboxamide Example 32: Synthesis of (3S,6R,7R)-6,12-dihydroxy-3,6-dimethyl-l,l l-dioxo-N- (2,4,6-trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide ​

[0478]

[0479] Prepared in a similar manner to (3S,6S,7R)-N-(2,4-difluorobenzyl)-6,12- dihydroxy-3-methyl-l, l l-dioxo-l,4,5,6,7, l l-hexahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-10-carboxamide (Example 16) except using (3S,6S,7R)-12-(benzyloxy)-6-(difluoromethoxy)-3-methyl-l, l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7, l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin- 10-carboxamide (prepared according to Example 22) instead of (3S,6S,7R)- 12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-l, l l-dioxo- 1,6,7, l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10-carboxamide. MS (m / z): 502.137 [M+H]+. ¾ NMR (400 MHz, Methanol-d4) δ 10.56 (s, 1H), 8.35 (s, 1H), 6.92 (t, J = 8.4 Hz, 2H), 6.58 (t, J = 73.8 Hz, 1H), 4.79 - 4.44 (m, 5H), 3.81 (s, 2H), 2.14 (dt, J = 14.7, 7.2 Hz, 1H), 2.02 - 1.81 (m, 1H), 1.74 - 1.60 (m, 1H), 1.45 - 1.30 (m, 1H), 1.29 (d, J = 6.7 Hz, 3H).

[0480] ​ ​ ​

[0481]

[0482] Synthesis of (3S,6S,7R)-12-(benzyloxy)-6-ethyl-6-hydroxy-3-methyl-l, l l-dioxo-N- (2,4,6-trifluorobenzyl)-l,6,7, l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin- 10-carboxamide:

[0483] Dissolved (3S,7R)-12-(benzyloxy)-3-methyl-l,6,l l-trioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin- 10-carboxamide (43 mg, 0.08 mmol) in 2 mL of anhydrous THF. Cool the mixture to 0 °C and add EtMgBr (3.4 M, 3 eq, 0.07 mL). Keep the reaction at 0 °C for one hour. Add one drop of water to quench the reaction. Filter the reaction crude and purify 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-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin- 10-carboxamide. MS (m / z) 568.21 [M+H] + .

[0484] Synthesis of (3S,6S,7R)-6-ethyl-6,12-dihydroxy-3-methyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin- 10-carboxamide:

[0485] Dissolved (3S,6S,7R)-12-(benzyloxy)-6-ethyl-6-hydroxy-3-methyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin- 10-carboxamide (3 mg) in 2 mL of ethanol and 2 mL of ethyl acetate at room temperature. Then added 2 mg of 10% Pd / C and applied a balloon of hydrogen. After 2 hours, filtered off the catalyst through celite. Concentrated the filtrate. Purified the reaction crude 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).

[0486] ​ ​ ​

[0487]

[0488] To a cooled 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 in ether (0.279 mmol, 0.279 mL). The reaction was stirred at 0 °C for 30 min, then quenched with ice and methanol. The reaction was then concentrated, re-dissolved in DMF, filtered and purified by reverse phase preparative HPLC. LCMS-ESI+(m / z): H+calcd for C22H17D3F3N3O5: 466.15, found: 467.35.1H NMR (400 MHz, DMSO-d6) δ 10.46 (t, J = 5.8 Hz, 1H), 8.36 (s, 1H), 7.21 (t, J = 8.6 Hz, 2H), 5.54 (dd, J = 11.8, 2.3 Hz, 1H), 5.39 (dd, J = 11.8, 2.6 Hz, 1H), 5.32 (s, 1H), 5.13 (dt, J = 7.3, 2.6 Hz, 1H), 4.67 (d, J = 2.3 Hz, 1H), 4.59 (dt, J = 11.3, 6.0 Hz, 2H), 3.86 (dd, J = 14.8, 2.6 Hz, 1H), 3.63 (dd, J = 14.8, 1.9 Hz, 1H), 1.27 (d, J = 7.3 Hz, 3H).

[0489] ​ ​ ​

[0490]

[0491] The title compound was prepared in the same manner as the synthesis of Example 29, except (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,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+calcd for C22H18D3F2N3O5: 448.16, found: 449.23.1H NMR (400 MHz, DMSO-d6) δ 10.44 (t, J = 5.9 Hz, 1H), 8.38 (s, 1H), 7.42 (td, J = 8.7, 6.6 Hz, 1H), 7.25 (ddd, J = 11.9, 9.3, 2.6 Hz, 1H), 7.08 (td, J = 8.5, 2.7 Hz, 1H), 5.54 (dd, J = 11.9, 2.3 Hz, 1H), 5.40 (dd, J = 11.9, 2.6 Hz, 2H), 5.13 (dt, J = 7.1, 2.3 Hz, 1H), 4.70 (d, J = 2.2 Hz, 1H), 4.56 (d, J = 5.9 Hz, 2H), 3.87 (dd, J = 14.7, 2.7 Hz, 1H), 3.65 (dd, J = 14.7, 1.9 Hz, 1H), 1.28 (d, J = 7.3 Hz, 3H).

[0492] ​ ​

[0493]

[0494] 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:

[0495] 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, purged with nitrogen three times, then degassed and purged with hydrogen three times, then hydrogenated under a hydrogen balloon for 3 hours. The reaction was then degassed, purged with nitrogen, and filtered through a pad of celite. The filtrate was concentrated and dried through 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, brine, dried over sodium sulfate, filtered, and concentrated, purified by normal phase chromatography.

[0496] Step 2: Synthesis of (1R,10S,13S)-N-[(2,4-difluorophenyl)methyl]-6,13- dihydroxy-10-methyl-5,8-dioxo-13-(trideuteromethyl)-2,9-diazatricyclo[7.4.1.02,7] tetradeca-3,6-diene-4-carboxamide:

[0497] This compound was prepared according to the synthesis of Example 29, with the exception 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-diene-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+calcd for C22H20D3F2N3O5: 450.18, found: 451.28.1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.46 (t, J = 6.0 Hz, 1H), 8.34 (s, 1H), 7.40 (td, J = 8.7, 6.6 Hz, 1H), 7.25 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.07 (td, J = 8.5, 2.6 Hz, 1H), 4.93 (s, 1H), 4.56 (d, J = 5.9 Hz, 2H), 4.47 (dt, J = 10.4, 6.5 Hz, 1H), 4.28 (s, 1H), 3.67 (t, J = 2.5 Hz, 2H), 1.87 (dt, J = 14.4, 7.0 Hz, 1H), 1.52 - 1.34 (m, 2H), 1.17 (t, J = 7.6 Hz, 4H).

[0498] ​ 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 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

[0499]

[0500] Synthesis of (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-l,l l- dioxo-N-(2,4,6-trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-10-carboxamide:

[0501] 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, benzyl bromide. The mixture was stirred at 20 °C for 4 h. The reaction was extracted with EtOAc, the organic layer was washed with water, brine successively, dried over magnesium sulfate, filtered and concentrated. Flash column chromatography (silica gel, EtOAc / hexanes) afforded the product (stereochemistry assignment tentative).1H NMR (400 MHz, Chloroform-d) δ 10.40 (t, J = 5.6 Hz, 1H), 8.46 (s, 1H), 7.59 - 7.49 (m, 2H), 7.39 - 7.27 (m, 3H), 6.62 (dd, J = 8.8, 7.4 Hz, 2H), 5.28 (d, J = 10.3 Hz, 1H), 5.15 (d, J = 10.3 Hz, 1H), 4.78 (dt, J = 10.5, 6.7 Hz, 1H), 4.57 (dd, J = 14.5, 5.7 Hz, 1H), 4.49 (dd, J = 14.5, 5.4 Hz, 1H), 4.38 (s, 1H), 4.03 (s, 1H), 3.26 (dd, J = 15.3, 3.0 Hz, 1H), 3.06 (dd, J = 15.0, 1.5 Hz, 1H), 1.98 (dt, J = 13.4, 6.8 Hz, 1H), 1.62 - 1.47 (m, 2H), 1.39 (s, 3H), 1.15 (d, J = 6.7 Hz, 3H). LCMS-ESI+ (m / z): C 23 H 22 H+calc for F3N3O5: 556.21, found: 556.20.

[0502] 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]diazepine- 10-carboxamide:

[0503] (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-bridged methylenepyrido[l,2- a] [ 1,4] diazacyclonon e- 10 -carboxamide (82 mg, 0.148 mmol) was dissolved in toluene (4.1 mL) followed by addition of Martin sulfane (506 mg, 0.75 mmol). The mixture was stirred at 20 °C for 1 h. The reaction mixture was purified directly by flash column chromatography (silica gel, EtOAc / hexanes) to give the product.1H NMR (400 MHz, Chloroform-d) δ 10.43 (t, J = 5.8 Hz, 1H), 8.47 (s, 1H), 7.64 - 7.53 (m, 2H), 7.42 - 7.30 (m, 3H), 6.68 (dd, J = 8.7, 7.5 Hz, 2H), 5.56 (d, J = 10.2 Hz, 1H), 5.31 (s, 1H), 5.21 - 5.11 (m, 2H), 4.86 (dp, J = 10.2, 6.7 Hz, 1H), 4.68 (d, J = 5.7 Hz, 2H), 4.60 (s, 1H), 3.52 (dd, J = 14.9, 2.6 Hz, 1H), 3.44 (dd, J = 14.9, 1.9 Hz, 1H), 2.36 (dd, J = 14.9, 7.3 Hz, 1H), 2.22 (dt, J = 14.2, 7.0 Hz, 1H), 2.02 - 1.92 (m, 1H), 1.35 (dt, J = 14.5, 10.8 Hz, 1H), 1.22 (d, J = 6.8 Hz, 3H). LCMS-ESI+(m / z): C 29 H 26 H+calc for F3N3O4: 538.20, found: 538.16.

[0504] Synthesis of (2R,3'S,7'R)-12'-(benzyloxy)-3'-methyl-l',l l'-dioxo-N-(2,4,6- trifluorobenzyl)-l',4',5',l l'-tetrahydro-3'H,7'H-spiro[oxirane-2,6'-[2,7] bridged

[0505] (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-l, l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-10-carboxamide (30 mg, 0.0558 mmol) was dissolved in dichloromethane (3.0 mL) and 3-chloroperbenzoic 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 more dichloromethane and the organic phase was washed with 2 N aqueous sodium hydroxide solution, then brine. The combined aqueous phases were extracted with additional dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated. Flash column chromatography (silica gel, EtOAc / hexanes) gave the product (stereochemical assignment 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), 3.64 (dd, J = 14.9, 1.8 Hz, 1H), 3.52 (s, 1H), 3.44 (dd, J = 15.1, 2.5 Hz, 1H), 3.21 (d, J = 3.7 Hz, 1H), 2.79 (d, J = 3.7 Hz, 1H), 2.07 - 1.98 (m, 1H), 1.79 (ddd, J = 39.5, 15.0, 11.6 Hz, 2H), 1.24 (d, J = 6.8 Hz, 3H). LCMS-ESI+(m / z): C 29 H 26 H+calc for F3N3O5: 554.19, found: 554.21.

[0506] Synthesis of (3S,6R,7R)-6,12-dihydroxy-3,6-dimethyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-10-carboxamide:

[0507] (2R,3'S,7'R)-12'-(benzyloxy)-3'-methyl-l',ll'-dioxo-N-(2,4,6- trifluorobenzyl)-l',4',5',ll'-tetrahydro-3'H,7'H-spiro[oxirane-2,6'- [2,7]bridged methylenepyrano[1,2-a][1,4]diazacyclononene]-10'-carboxamide (4 mg, 0.007 mmol) was dissolved in ethanol (0.5 mL) followed by the addition of ammonium formate (23 mg, 0.36 mmol) followed by 10% palladium on carbon (1.54 mg, 0.0015 mmol). The mixture was stirred in a metal heating block at 70 °C for 12 hours. The reaction mixture was diluted with 1 :1 DMF:water, filtered, and purified by reverse phase HPLC (acetonitrile / water, 0.1% trifluoroacetic acid) to give the product (stereochemical assignment 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 = 8.8 Hz, 2H), 5.16 (s, 1H), 4.56 (d, J = 5.5 Hz, 2H), 4.48 (s, 1H), 4.27 (s, 1H), 3.70 (d, J = 14.9 Hz, 1H), 3.60 (d, J = 14.7 Hz, 1H), 1.87-1.75 (m, 2H), 1.75-1.65 (m, 1H), 1.52 (dd, J = 16.0, 6.6 Hz, 1H), 1.16 (d, J = 7.0 Hz, 3H), 1.02 (s, 3H). LCMS-ESI+(m / z): C 22 H 22 H+calc for F3N3O5: 466.16, found: 466.27.

[0508] Synthesis 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]diazocin-10-carboxamide Synthesis 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]diazocin-10-carboxamide

[0509]

[0510] 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:

[0511] (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 cooled mixture was added dropwise 3.0 M MeMgBr in Et20 (0.38 mL, 1.15 mmol). The reaction was stirred at 0 °C for 20 minutes, then quenched with ice water. The mixture was then diluted with EtOAc, washed with saturated ammonium chloride, brine, dried over sodium sulfate, filtered and concentrated, purified by normal phase chromatography. LCMS-ESI+(m / z): H+calc of C29H29F2N3O5 537.21 found 538.17.

[0512] 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:

[0513] (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 Martin's sulfum 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+calc of C29H27F2N3O4 519.20 found 520.22.

[0514] 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:

[0515] (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 hours. The reaction was cooled to room temperature, diluted with DCM, mixed with a 1 : 1 mixture of 1 N sodium thiosulfate and saturated sodium bicarbonate, and stirred vigorously for 10 minutes. The layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated, and purified by normal phase chromatography. LCMS-ESI+(m / z): H+calcd for C29H27F2N3O5: 535.19, found: 536.17.

[0516] 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:

[0517] (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-formamide (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 purged with nitrogen three times, then heated at 70 °C under nitrogen for 3 hours. The reaction was then cooled to room temperature, filtered and concentrated, redissolved in DMF, filtered and purified by reverse phase preparative HPLC. LCMS-ESI+(m / z): H+calcd for C22H23F2N3O5: 447.16, found: 448.256.1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 10.37 (t, J = 6.0 Hz, 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, 2.7 Hz, 1H), 5.16 (s, 1H), 4.52 (dt, J = 22.6, 6.3 Hz, 3H), 4.30 (s, 1H), 3.75 - 3.61 (m, 2H), 1.92 - 1.64 (m, 2H), 1.53 (dd, J = 15.3, 6.7 Hz, 1H), 1.17 (d, J = 6.7 Hz, 4H), 1.03 (s, 3H).

[0518] Synthesis 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]diazocin-10-carboxamide Synthesis 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]diazocin-10-carboxamide Synthesis 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]diazocin-10-carboxamide

[0519]

[0520] 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-bridgemethylenepyrido[1,2- a][1,4]diazacyclononene-10-carboxamide:

[0521] 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]diazocin- 10-carboxamide:

[0522] 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]diazocin- 10-carboxamide:

[0523] 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]diazocin-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 the reaction was complete, 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 in water with 0.1% TFA) to give the title compound. MS (m / z) 451.2 [M+H] + . 1H NMR (400MHz, methanol-d4) δ8.36(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=11.7Hz,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).

[0524] Synthesis 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]diazocin-10-carboxamide Synthesis 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]diazocin-10-carboxamide

[0525]

[0526] Step 1: (3S,7R)-3-amino-7-methyl-1,2,4,7-tetrahydrozaza Synthesis of methyl 3-carboxylate and 2,2,2-trifluoroacetic acid:

[0527] (3S,7R)-3-(benzyloxycarbonylamino)-7-methyl-4,7-dihydro-2H-aza 1,3-Dicarboxylic acid O1-benzyl O3-methyl ester (1.2 g, 2.65 mmol) was mixed with (10.0 mL). The resulting mixture was sealed and heated at 100 °C for 4 hours. The reaction was cooled to room temperature and concentrated. The residue was co-evaporated with EtOAc four times to obtain the desired product, which was used directly in the next step. LCMS-ESI+ (m / z): Theoretical calculated value of H+ in C9H16N2O2: 184.12, measured value: 185.01.

[0528] 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]tetradecano-3,6,11-trien-1-carboxylic acid:

[0529] The residue from the previous step (2.36 g, 5.72 mmol) and 3-benzyloxy-4-oxo-5- [(2,4,6-trifluorophenyl)methylaminocarbonyl]pyran-2-carboxylic acid methyl ester (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, 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+calc'd for C29H25F2N3O6, 549.17, found, 550.10.

[0530] 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:

[0531] (1S,10R)-6-benzyloxy-4-[(2,4-difluorophenyl)methylaminocarbonyl]-10-methyl-5,8- dio xo-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 hours. The reaction was cooled to room temperature, filtered, and concentrated, and purified by normal phase chromatography. LCMS-ESI+(m / z): H+calc'd for C29H23F2N3O6, 519.16, found, 520.04.

[0532] 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:

[0533] This compound was prepared according to the preparation procedure of Example 17, Step 1, 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,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. LCMS-ESI+(m / z): H+calc'd for C29H27F2N3O5, 535.19, found, 536.13. Stereochemistry at C13 was not confirmed.

[0534] 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:

[0535] (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 purged with nitrogen, then it was heated at 70 °C for 1 hour. 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+calcd for C22H23F2N3O5: 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 = 4.5 Hz, 2H), 4.53 - 4.46 (m, 1H), 4.08 (dd, J = 15.2, 2.1 Hz, 1H), 3.83 (dd, J = 15.1, 2.5 Hz, 1H), 3.73 (dt, J = 14.5, 7.0 Hz, 1H), 2.18 (q, J = 5.6, 5.0 Hz, 1H), 2.05 - 1.89 (m, 3H), 1.87 - 1.77 (m, 1H), 1.74 (d, J = 7.1 Hz, 3H), 1.55 (s, 3H).

[0536] Synthesis 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]diazocin-10-carboxamide ​

[0537]

[0538] (3S,7S)-12-(benzyloxy)-3-methyl-l,4,l l-trioxo-N-(2,4,6-trifluorobenzyl)- 1,4,7, 11 -tetrahydro-3H-2,7-methanopyrido[ 1,2-a] [ 1,4]diazocin-10-carboxamide (Intermediate C) was synthesized in the same manner as Intermediate A and isolated as an additional product under the same reaction conditions. 1H NMR (400 MHz, Chloroform-d) δ 10.41 (t, J = 5.8 Hz, 1H), 8.66 (s, 1H), 7.58 - 7.46 (m, 2H), 7.41 - 7.27 (m, 3H), 6.76 - 6.56 (m, 2H), 6.31 (d, J = 12.4 Hz, 1H), 6.11 (d, J = 12.2 Hz, 1H), 5.50 (d, J = 10.2 Hz, 1H), 5.28 (q, J = 7.0 Hz, 1H), 5.15 (d, J = 10.2 Hz, 1H), 4.98 (s, 1H), 4.66 (d, J = 5.7 Hz, 2H), 3.75 (d, J = 15.0 Hz, 1H), 3.50 (d, J = 14.9 Hz, 1H), 1.46 (d, J = 7.0 Hz, 3H). LCMS-ESI+ (m / z): C 28 H 22 H+calc for F3N3O5: 538.16, found: 538.10.

[0539] ​ ​ ​

[0540]

[0541] Step 1: Synthesis of (3S,6R,7R)-12-(benzyloxy)-6-methoxy-3-methyl-l,4,l l- trioxo-N-(2,4,6-trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-10-carboxamide:

[0542] To (3S,7S)-12-(benzyloxy)-3-methyl-l,4,l l-trioxo-N-(2,4,6- trifluorobenzyl)-l,4,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin- 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), water (0.5 mL), triethylamine (30 μL, 0.214 mmol), potassium cyanide (6.0 mg, 0.093 mmol) in that order. The reaction was stirred at 60 °C in a metal heating block for 1 hour. The reaction was partitioned between EtOAc, 10% aqueous sodium carbonate solution. The organic phase was washed with saturated aqueous ammonium chloride solution, then brine. The aqueous Na2CO3 phase was extracted with more ethyl acetate. The combined organic phases were dried over MgSO4, filtered, and concentrated in vacuo. Flash column chromatography (silica gel, EtOAc / hexanes) gave the product (stereochemical assignment tentative).1H 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 = 4.1 Hz, 1H), 3.55 (dt, J = 15.3, 1.8 Hz, 1H), 3.48 (s, 3H), 3.45 (dd, J = 15.2, 1.8 Hz, 1H), 2.91 (dd, J = 13.6, 5.7 Hz, 1H), 2.70 (dd, J = 13.5, 1.6 Hz, 1H), 1.36 (d, J = 7.0 Hz, 3H). LCMS-ESI+ (m / z): C 29 H 26 H+calc for F3N3O6: 570.18, found: 570.13.

[0543] Step 2: Synthesis of (3S,6R,7R)-12-(benzyloxy)-4,4-difluoro-6-methoxy-3- methyl-l, l l-dioxo-N-(2,4,6-trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocine-10-carboxamide:

[0544] 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- formamide (50 mg, 0.355 mmol) was added DCM (0.88 mL) followed by 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 solution then brine, dried over magnesium sulfate, filtered and concentrated. Flash column chromatography (silica gel, EtOAc / hexanes) afforded the product (stereochemical assignment tentative). LCMS-ESI+(m / z): C 29 H 26 H+calc for F5N3O5: 592.19, found: 592.11.

[0545] 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]diazocin-10-carboxamide:

[0546] (3S,6R,7R)-12-(benzyloxy)-4,4-difluoro-6-methoxy-3-methyl-l, 11-dioxo-N-(2,4,6- trifluorobenzyl)-l,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin- 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. This solution was diluted with acetonitrile and concentrated in vacuo, and the resulting crude product 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 give the product (stereochemical assignment tentative).1H NMR (400 MHz, Acetonitrile-d3) δ 10.29 (s, 1H), 8.39 (s, 1H), 6.88 (dd, J = 9.2, 8.1 Hz, 2H), 4.95 (dt, J = 13.8, 7.0 Hz, 1H), 4.63 (d, J = 5.9 Hz, 2H), 4.49 (d, J = 2.9 Hz, 1H), 3.91 (dd, J = 15.4, 2.6 Hz, 1H), 3.75 - 3.61 (m, 2H), 3.38 (s, 3H), 2.58 (ddd, J = 27.6, 15.6, 8.5 Hz, 1H), 2.36 - 2.21 (m, 1H), 1.39 (dd, J = 7.2, 2.8 Hz, 3H). LCMS-ESI+(m / z): C 22 H 20 H+calc for F5N3O5: 502.14, found: 502.24.

[0547] ​ ​ ​

[0548]

[0549] Step 1: Synthesis of (3S,4R,6R,7R)-12-(benzyloxy)-4-hydroxy-6-methoxy-3-methyl- 1, 11-dioxo-N-(2,4,6-trifluorobenzyl)-l,4,5,6,7,11-hexahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-10-carboxamide:

[0550] A mixture of (3S,6R,7R)-12-(benzyloxy)-6-methoxy-3-methyl-l,4,l l- trioxo-N-(2,4,6-trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-10-carboxamide prepared according to Example 36 (770.8 mg, 1.35 mmol) in methanol (30 mL) was stirred at 0 °C and NaBH4(57.7 mg, 1.53 mmol) was added. After 3 min, the insoluble material was dissolved with THF (~10 mL). The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (~50 mL) and saturated NaHCO3(~25 mL) and water (~25 mL). After the two layers were separated, the aqueous portion was extracted with ethyl acetate (~50 mL). The two organic fractions were washed with brine, combined, dried (MgSO4) and concentrated. The residue was purified by silica gel column chromatography (80 g column) eluting with 0% to 10% methanol in CH2Cl2to give (3S,4R,6R,7R)-12-(benzyloxy)-4-hydroxy-6-methoxy-3-methyl-l,l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-10-carboxamide. ES / MS m / z: Calcd. for C29H29F3N3O6(M+H): 572.20, found: 572.20.

[0551] Step 2: Synthesis of (3S,4S,6R,7R)-12-(benzyloxy)-4-fluoro-6-methoxy-3-methyl- 1, 11-dioxo-N-(2,4,6-trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-10-carboxamide:

[0552] 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]diazocin-10-carboxamide (811.2 mg, 1.42 mmol) in CH2Cl2(14 mL) was stirred at 0 °C while 2.7 M Deoxo-Fluor (bis(2-methoxyethyl)aminosulfur trifluoride) in toluene (1.39 mL, 3.75 mmol) was added. After 30 min, the reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled and stirred at 0 °C while saturated NaHCO3(~40 mL) was added. After the addition of water (~40 mL), the product was extracted with ethyl acetate (~70 mL x 2). After the extracts were washed with brine (~70 mL x 1), the combined organic fractions were dried (MgSO4). The residue was purified by silica gel column chromatography (80 g column) eluted with 50% to 100% ethyl acetate in hexanes 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]diazocin-10- carboxamide: ES / MS m / z: Calcd. for C29H28F4N3O5 (M+H), 574.20; found, 574.30.

[0553] 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]diazocin-10-carboxamide:

[0554] (3S,4S,6R,7R)-12-(benzyloxy)-4-fluoro-6-methoxy-3-methyl-l, l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin- 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 (~25 mL) and then washed with saturated NaHC03(~25 mL). After the two layers were separated, the aqueous portion was extracted with ethyl acetate (~25 mL). The organic fractions were combined, washed with brine, dried (MgS04) and concentrated. The residue was purified by silica gel column chromatography (50 g column) eluting with 0% to 10% methanol in CH2CI2to give the product. Impure product was purified again using silica gel column chromatography (40 g column) eluting with 0% to 10% methanol in ethyl acetate to give (3S,4S,6R,7R)-4-fluoro-12-hydroxy-6-methoxy-3-methyl-l, l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide:1H NMR (400 MHz, Acetoni tr-d3) δ 10.62 (s, 1H), 10.31 (t, J = 6.0 Hz, 1H), 8.37 (s, 1H), 6.84 (t, J = 8.5 Hz, 2H), 5.01 - 4.70 (m, 2H), 4.60 (d, J = 5.9 Hz, 2H), 4.48 (q, J = 2.4 Hz, 1H), 3.91 (dd, J = 15.1, 2.3 Hz, 1H), 3.73 - 3.57 (m, 2H), 3.37 (s, 3H), 2.53 (ddd, J = 15.3, 8.4, 6.5 Hz, 1H), 1.85 - 1.65 (m, 1H), 1.33 (dd, J = 7.1, 2.7 Hz, 3H);19F NMR (376 MHz, Acetoni tr-d3) δ -111.21 (ddd, J = 15.3, 9.1, 6.1 Hz), -113.91 (t, J = 7.0 Hz), -193.86 (ddd, J = 46.9, 31.9, 16.7 Hz); ES / MS m / z: Calculated for C22H22F4N3O5 (M+H): 484.15, found: 484.20.

[0555] ​ ​ ​

[0556]

[0557] 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]diazocin-4-yl benzoate:

[0558] 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]diazocin-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), benzoic acid (25 mg, 0.205 mmol), diisopropyl azodicarboxylate (41 mg, 0.205 mmol) sequentially. The reaction was stirred at 20 °C for 1.5 h. The reaction was then diluted with dichloromethane and concentrated in vacuo. Flash column chromatography (silica gel, EtOAc / hexanes) afforded the product (stereochemistry assignment tentative). LCMS-ESI+(m / z): C 36 H 32 H+calc for F3N3O7: 676.23, found: 676.13.

[0559] 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]diazocin-10-carboxamide:

[0560] To (3S,4S,6R,7R)-12-(benzyloxy)-6-methoxy-3-methyl-l,l l-dioxo-10-((2,4,6- trifluorobenzyl)carbamoyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-4-yl benzoate (65 mg, 0.0962 mmol) was added methanol (2 mL), THF (2 mL), water (0.5 mL), lithium hydroxide monohydrate (40 mg, 0.962 mmol) sequentially. The reaction was stirred at 20 °C for 1.5 h. The reaction was then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate solution. The organic phase was washed with brine, dried over MgS04, filtered, and concentrated in vacuo. Flash column chromatography (silica gel, EtOAc / hexanes) afforded the product (stereochemical assignment 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 = 7.0 Hz, 1H), 3.86 (t, J = 9.3 Hz, 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, 1.5 Hz, 1H), 1.34 (d, J = 6.8 Hz, 3H). LCMS-ESI+ (m / z): C 29 H 28 H+calc for F3N3O6: 572.20, found: 572.16.

[0561] Step 3: Synthesis of (3S,4R,6R,7R)-12-(benzyloxy)-4-fluoro-6-methoxy-3-methyl- 1, 11-dioxo-N-(2,4,6-trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-10-carboxamide:

[0562] 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]diazocin-10-carboxamide (13 mg, 0.0227 mmol) was added DCM (1.3 mL) followed by 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 h. The reaction was quenched by slow addition to ice-cold 10% aqueous potassium carbonate solution, then extracted with EtOAc. The organic layer was washed with saturated aqueous ammonium chloride solution, then brine, dried over magnesium sulfate, filtered and concentrated. Preparative thin layer chromatography (silica gel, EtOAc) gave the product (stereochemical assignment 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 = 2.2 Hz, 1H), 3.87 (dd, J = 15.0, 2.1 Hz, 1H), 3.70 (s, 1H), 3.45 (s, 3H), 3.42 - 3.36 (m, 1H), 2.63 (dt, J = 15.9, 6.3 Hz, 1H), 1.78 - 1.68 (m, 1H), 1.63 (dd, J = 15.8, 2.8 Hz, 1H), 1.34 (dd, J = 6.8, 2.6 Hz, 3H). LCMS-ESI+ (m / z): C 29 H 27 H+calc for F4N3O5: 574.20, found: 574.14.

[0563] 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]diazocin-10-carboxamide:

[0564] (3S,4R,6R,7R)-12-(benzyloxy)-4-fluoro-6-methoxy-3-methyl-l, l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin- 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. This solution was diluted with acetonitrile and concentrated in vacuo, and the resulting crude product was purified by reverse phase preparative HPLC (acetonitrile / water, 0.1% trifluoroacetic acid) to give the product (stereochemical assignment tentative).1H NMR (400 MHz, Acetonitrile-d3) δ 10.31 (s, 1H), 8.37 (s, 1H), 6.85 (dd, J = 9.1, 8.0 Hz, 2H), 5.00 - 4.73 (m, 2H), 4.60 (d, J = 5.7 Hz, 2H), 4.48 (d, J = 2.5 Hz, 1H), 3.91 (dd, J = 15.1, 2.3 Hz, 1H), 3.65 (d, J = 8.1 Hz, 1H), 3.63 (s, 1H), 3.37 (s, 3H), 2.53 (ddd, J = 15.3, 8.2, 6.4 Hz, 1H), 1.86 - 1.66 (m, 1H), 1.33 (dd, J = 7.1, 2.7 Hz, 3H). LCMS-ESI+(m / z): C 22 H 21 H+calc for F4N3O5: 484.15, found: 484.23.

[0565] ​ ​ ​

[0566]

[0567] Step 1: Synthesis of (3S,4S,6S,7R)-12-(benzyloxy)-4-hydroxy-6-methoxy-3-methyl- 1, 11-dioxo-N-(2,4,6-trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-10-carboxamide:

[0568] 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]diazocin-10- carboxamide (from Step 2 of Example 1, 50 mg, 0.0903 mmol) was added isopropanol (2.5 mL) followed by phenylsilane (20 mg, 0.181 mmol), benzoic acid (25 mg, 0.205 mmol), tris(2,2,6,6-tetramethyl-3,5-heptanedione)manganese(III) (1.6 mg, 0.0027 mmol) sequentially. The reaction was cycled between vacuum and oxygen three times, then stirred vigorously under oxygen at 20 °C for 45 minutes, then more tris(2,2,6,6-tetramethyl-3,5-heptanedione)manganese(III) (0.5 mg, 0.0009 mmol) was added. The reaction was stirred vigorously under oxygen at 20 °C for 45 minutes. Then 1 N aqueous sodium thiosulfate was 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, concentrated in vacuo. Flash column chromatography (silica gel, EtOAc / hexanes) gave the product as the major diastereomer (stereochemical assignment 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 = 8.1 Hz, 2H), 5.42 (d, J = 10.3 Hz, 1H), 5.14 (d, J = 10.3 Hz, 1H), 4.72 - 4.59 (m, 2H), 4.54 (q, J = 7.2 Hz, 1H), 4.40 (s, 1H), 3.52 - 3.28 (m, 3H), 3.41 (s, 3H), 3.12 (d, J = 15.3 Hz, 1H), 2.06 (d, J = 13.2 Hz, 1H), 1.72 - 1.57 (m, 1H), 1.33 (d, J = 6.7 Hz, 3H). LCMS-ESI+ (m / z): C 29 H 28 H+calc for F3N3O6: 572.20, found: 572.02.

[0569] Step 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]diazocin-10-carboxamide:

[0570] (3S,4R,6S,7R)-4-fluoro-12-hydroxy-6-methoxy-3-methyl-l, l l-dioxo-N-(2,4,6- trifluorophenyl)-l,4,5,6,7, l l-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin- 10-carboxamide was synthesized in a similar manner as Example 38, starting from (3S,4S,6S,7R)-12-(benzyloxy)-4-hydroxy-6-methoxy-3-methyl-l, l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,4,5,6,7, l l-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide. ¾ NMR (400 MHz, Acetonitrile-d3) d 10.33 (s, 1H), 8.27 (s, 1H), 6.84 (t, J = 8.5 Hz, 2H), 5.03 (ddd, J = 48.0, 7.1, 4.9 Hz, 1H), 4.79 - 4.63 (m, 2H), 4.60 (d, J = 5.8 Hz, 2H), 3.90 (ddd, J = 11.8, 5.1, 3.7 Hz, 1H), 3.74 (dt, J = 15.1, 2.6 Hz, 1H), 3.61 (d, J = 15.2 Hz, 1H), 3.42 (s, 3H), 2.51 (ddd, J = 15.3, 7.3, 3.6 Hz, 1H), 1.45 - 1.35 (m, 1H), 1.33 (dd, J = 7.1, 2.3 Hz, 3H). LCMS-ESI+(m / z): C 22 H 21 H+calc for F4N3O5: 484.15, found: 484.11.

[0571] 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]diazocin-10-carboxamide 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]diazocin-10-carboxamide 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]diazocin-10-carboxamide

[0572]

[0573] Step 1: Synthesis of (3S,4R,6S,7R)-12-(benzyloxy)-4-hydroxy-6-methoxy-3- methyl-l, l l-dioxo-N-(2,4,6-trifluorobenzyl)-l,4,5,6,7, l l-hexahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-10-carboxamide:

[0574] To a mixture of Intermediate C (706.9 mg, 1.32 mmol) in methanol (10 mL) at room temperature was added 0.5 M sodium methoxide in methanol (3 mL, 1.5 mmol). The reaction mixture was stirred at 50 °C. After 2 hours, the reaction mixture was stirred at 0 °C and 4 N HC1 in dioxane (0.375 mL, 1.5 mmol) was added: ES / MS m / z: Calcd. for C29H27F3N3O6 (M+H): 570.19, found: 570.30.

[0575] The above solution was stirred at 0 °C while NaBH4(157 mg, 4.15 mmol) was added. After 30 minutes at 0 °C, the reaction mixture was concentrated and the residue was dissolved in saturated NaHC03, then the product was extracted with ethyl acetate (x 2). After washing the organic extracts with brine (x 1), the organic fractions were combined, dried (MgS04) and concentrated. The residue was purified by repeated silica gel column chromatography (80 g column) (eluting with 0% - 5% methanol in CH2C12) and preparative HPLC (column, Gemini 5um C18 110A, LC Column 100 x 30 mm) (eluting with 23% - 90% acetonitrile (0.1% TFA) in water (0.1% TFA) for 20 minutes). After neutralizing the combined fractions by adding saturated NaHC03(~ 1 mL), the solution was concentrated to remove most of the acetonitrile. The resulting aqueous mixture was extracted with EA (~ 25 mL x 2) and the extracts were washed with brine (x 1), combined, dried (MgS04) 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]diazocin-10-carboxamide. ES / MS m / z: Calcd. for C29H29F3N3O6 (M+H): 572.20, found: 572.27.

[0576] 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]diazocin-10-carboxamide:

[0577] 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]diazocin-10-carboxamide (81.8 mg, 0.143 mmol) in CH2Cl2(2 mL) was stirred at 0 °C while 2.7 M bis(2-methoxyethyl)aminosulfur trifluoride in toluene (0.14 mL, 0.378 mmol) was added. After 30 min, the reaction mixture was stirred at room temperature for 2.5 h and cooled to 0 °C while saturated NaHCO3(10 mL) was added. After addition of water (20 mL), the product was extracted with ethyl acetate (25 mL x 2). After the combined extracts were dried (MgSO4) and concentrated. The residue was purified by silica gel column chromatography (using a 12 g column) eluted 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]diazocin-10- carboxamide: ES / MS m / z: Calcd. for C29H28F4N3O5(M+H): 574.20, found: 574.30.

[0578] 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]diazocin-10-carboxamide:

[0579] (3S,4S,6S,7R)-12-(benzyloxy)-4-fluoro-6-methoxy-3-methyl-l, l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin- 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 concentrated completely, and the residue was purified by preparative HPLC (2 injections; column, Gemini 5um C18 110A, LC Column 100 x 30 mm) eluting with 20% - 65% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 min. The combined fractions were neutralized by addition of saturated NaHC03(~1 mL), then concentrated to remove most of the acetonitrile. The concentrated solution was extracted with ethyl acetate (~20 mL x 2). The extracted fractions were washed with brine (x 1), combined, dried (MgS04), concentrated and dried in vacuum to give (3S,4S,6S,7R)-4-fluoro-12-hydroxy-6-methoxy-3-methyl-l, l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide. ¾ NMR (400 MHz, 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, 6.4 Hz, 1H), 4.82 (dp, J = 19.9, 6.8 Hz, 1H), 4.74 - 4.59 (m, 2H), 4.39 (d, J = 2.4 Hz, 1H), 4.02 (dd, J = 14.7, 2.1 Hz, 1H), 3.73 - 3.58 (m, 2H), 3.45 (s, 3H), 2.68 (ddd, J = 16.0, 7.5, 5.1 Hz, 1H), 1.73 - 1.55 (m, 1H), 1.41 (dd, J = 7.1, 2.6 Hz, 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.

[0580] Example 43: (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]diazocin- 10-carboxamide 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]diazocin-10-carboxamide Example 45: (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-methanopyrido[1,2-d][1,4,7]oxadia- zepine-11-carboxamide

[0581]

[0582] Step 1-2: Synthesis of (3R,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3- (hydroxymethyl)-l, l l-dioxo-l,6,7, l l-tetrahydro-3H-2,7-methanopyrido[l,2- a] [ 1,4] diazacyclonon e- 10 -carboxamide:

[0583] (3R,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-l, l l-dioxo- 1,6,7, l l-tetrahydro-3H-2,7-methanopyrido[l,2-a] [ 1,4] diazacyclonon e- 10 - carboxamide was prepared following the procedure for the preparation of Intermediate B, except that (3S,7R)-3-(((benzyloxy)carbonyl)amino)-7-(((tert- butyldimethylsilyl)oxy)methyl)-2,3,4,7-tetrahydro-lH-azepine- 1 -carboxylate was used in Step 1. ES / MS m / z: calcd for C28H26F2N3O5 (M + H): 522.18, found: 522.20. -1 -carboxylate. ES / MS m / z: calcd for C28H26F2N3O5 (M + H): 522.18, found: 522.20.

[0584] Step 3-4: Synthesis of (3R,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-l,6,l l-trioxo-l,6,7, l l-tetrahydro-3H-2,7- methanopyrido[l,2-a] [ 1,4] diazacyclonon e- 10 -carboxamide:

[0585] 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]diazocin-10-carboxamide (2971.9 mg, 5.70 mmol) and imidazole (601.0 mg, 8.83 mmol) in CH2Cl2(45 mL) at room temperature was added tert- butyldimethylsilyl chloride (1039.7 mg, 6.90 mmol), and the resulting solution was stirred at room temperature. After 16 h, the reaction mixture was diluted with CH2Cl2, washed with water (x 1), and the two layers were separated. After the aqueous fraction was extracted with ethyl acetate (x 1), the organic fractions were combined, dried (MgSO4), and concentrated. The residue was purified by silica gel column chromatography (120 g column) eluted 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]diazocin-10-carboxamide. ES / MS m / z: calc. for C34H40F2N3O5Si (M+H): 636.27, found: 636.30.

[0586] (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]diazocin-10-carboxamide was prepared following the procedure of Intermediate B, with the exception that (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]diazocin-10-carboxamide was used. ES / MS m / z: calc. for C34H38F2N3O6Si (M+H): 650.25, found: 650.30.

[0587] Step 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]diazocin-10-carboxamide:

[0588] A mixture of (3R,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)- N-(2,4-difluorobenzyl)-l,6,l l-trioxo-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-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 H2. After 2 hours, the reaction mixture was filtered and the filtrate was concentrated and dried under vacuum for 30 minutes. ES / MS m / z:

[0589] C29H40F2N3O7Si (M+EtOH+H) calculated 608.26, found 608.30.

[0590] The above residue and a solution of potassium carbonate (614.5 mg, 4.45 mmol) in DMF (13 mL) were stirred at room temperature while adding benzyl bromide (0.35 mL, 2.94 mmol). After stirring at room temperature overnight, the reaction mixture was diluted with water (~30 mL) and the product was extracted with ethyl acetate (x 2). After washing the extracts with water (x 1), they were combined, dried (MgS04) and concentrated. The residue was purified by silica gel column chromatography (40 g column) eluting with 0% to 10% methanol in CH2Cl2to give (3R,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4- difluorobenzyl)-l,6,l l-trioxo-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-10-carboxamide: ES / MS m / z: C34H42F2N3O7Si (M+H20+H) calculated 670.28, found 670.30; C35H44F2N3O7Si (M+MeOH+H) calculated 684.29, found 684.40.

[0591] Step 7-8: Synthesis of (3R,6S,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-6-methoxy-l, l l-dioxo-l,4,5,6,7,l l- hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10-carboxamide:

[0592] 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-methano- pyrido[1,2-a][1,4]diazocin-10-carboxamide (1234.0 mg, 1.89 mmol) in methanol (18 mL) was stirred at 0 °C while NaBH4(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 (x 2). The combined extracts were dried (MgS04) and concentrated. The residue was purified by silica gel column chromatography (80 g column) eluting with 0-10% methanol in CH2CI2to 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]diazocin-10-carboxamide. ES / MS m / z: Calcd. for C34H42F2N3O6Si (M+H): 654.28, found: 654.30.

[0593] A solution of the above product (221.3 mg, 0.338 mmol) in DMF (2.25 mL) was stirred at 0 °C while adding a 60% dispersion of sodium hydride (19.1 mg, 0.498 mmol). After 20 minutes at 0 °C, a solution of iodomethane (0.021 mL, 0.337 mmol) was added. After 1 hour at 0 °C, additional iodomethane (0.021 mL, 0.337 mmol) was added to the reaction mixture. After ~1 hour at 0 °C, the reaction mixture was diluted with saturated NH4Cl and the product was extracted with ethyl acetate (x 2). After washing the extracts with water (x 1), the organic fractions were combined, dried (MgSO4) and concentrated. The residue was purified by silica gel column chromatography (120 g column) eluting with 0% - 10% methanol in CH2Cl2. Fractions containing product were combined and concentrated, and the residue was purified again by silica gel column chromatography (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]diazocin-10-carboxamide. ES / MS m / z: Calcd. for C35H44F2N3O6Si (M+H): 668.30, found: 668.30.

[0594] 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]diazocin-10-carboxamide:

[0595] (3R,6S,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4- difluorobenzyl)-6-methoxy-l, l l-dioxo-l,4,5,6,7, l l-hexahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-10-carboxamide (333 mg, 0.494 mmol) was dissolved in 4 N HCI in dioxane (3 mL) in a 0 °C bath and stirred at 0 °C for 30 min. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (24 g column) eluted with 0% to 15% methanol in CH2CI2to give (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-6- methoxy-l, l l-dioxo-l,4,5,6,7, l l-hexahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-10-carboxamide. ES / MS m / z: calcd for C28H28F2N3O6(M+H): 554.21, found: 554.30.

[0596] Step 10-11: Synthesis of (3R,6S,7R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12- hydroxy-6-methoxy-l, l l-dioxo-l,4,5,6,7, l l-hexahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-10-carboxamide:

[0597] A solution of (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3- (hydroxymethyl)-6-methoxy-l, l l-dioxo-l,4,5,6,7, l l-hexahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-10-carboxamide (50.3 mg, 0.0909 mmol) in CH2Cl2(2.5 mL) was stirred at 0 °C while (diethylamino)sulfur trifluoride (0.05 mL, 0.378 mmol) was added. After 30 min, the reaction mixture was stirred at room temperature overnight. The reaction mixture was stirred at 0 °C and saturated NaHCO3(5 mL) was added. After the mixture was diluted with water (20 mL), the product was extracted with CH2Cl2(2 x 20 mL). The combined extracts were dried (MgSO4) and concentrated to give crude (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3- (fluoromethyl)-6-methoxy-l, l l-dioxo-l,4,5,6,7, l l-hexahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-10-carboxamide. ES / MS m / z: calcd for C29H29F3N3O5(M+H), 556.21; found, 556.30.

[0598] 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 5um 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]diazocin-10-carboxamide.1H NMR (400 MHz, Chloroform-d) δ 10.49 (t, J = 5.9 Hz, 1H), 9.63 (s, 2H), 8.44 (s, 1H), 7.36 (td, J = 8.6, 6.6 Hz, 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.

[0599] 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] diazocin-6-d-10-carboxamide Example 47: HIV MT-4 antiviral and cytotoxicity assay

[0600]

[0601] Step 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]diazocin-10-carboxamide:

[0602] (3R,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl- 1,6,1 1 -trioxo- 1,6,7, 1 1 -tetrahydro-3H-2,7-methanopyrido[ 1,2-a][ 1,4]diazocin-10-carboxamide was prepared following the procedure for the preparation of Intermediate B, with the exception that (3S,7R)-3-(((benzyloxy)carbonyl)amino)-7-methyl-2,3,4,7-tetrahydro- 1 H-azepine -1 -carboxylic acid benzyl ester. ES / MS m / z: [M+H] calcd for C28H24F2N3O5, 520.17; found, 520.20.

[0603] Step 3: Synthesis of (3R,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl- 1,6,1 1 -trioxo- 1,4,5,6,7, 1 1 -hexahydro-3H-2,7-methanopyrido[ 1,2-a][ 1,4]diazocin-10-carboxamide:

[0604] A mixture of (3R,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl- 1,6,1 1 -trioxo- 1,6,7, 1 1 -tetrahydro-3H-2,7-methanopyrido[ 1,2-a][ 1,4]diazocin-10-carboxamide (0.637 mmol) and 10% palladium on carbon (70 mg) in ethanol (10 mL) was stirred at room temperature under an atmosphere of H2for 4 hours. The reaction mixture was filtered and the filtrate was concentrated and dried under vacuum for 30 minutes.

[0605] A solution of the residue and potassium carbonate (179.0 mg, 1.3 mmol) in DMF (3.8 mL) was stirred at room temperature while benzyl bromide (0.1 mg, 0.841 mmol) was added. After overnight, the reaction mixture was diluted with water (30 mL) and the product was extracted with ethyl acetate (x 2). After washing the extracts with water (x 1), they were combined, dried (MgS04) and concentrated. The residue was purified by silica gel column chromatography (40 g column) eluted with 20% to 100% ethyl acetate in hexanes to give (3R,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl- 1,6,1 1 -trioxo- 1,4,5,6,7, 1 1 -hexahydro-3H-2,7-methanopyrido[ 1,2-a][ 1,4]diazocin-10-carboxamide. ES / MS m / z: [M+H] calcd for C28H26F2N3O5, 522.18; found, 522.20.

[0606] Step 4: Synthesis of (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6- methoxy-3-methyl-l, 11-dioxo-l, 4, 5, 6, 7, 11-hexahydro-3H-2, 7- methanopyrido[l,2-a][l,4]diazocin-10-carboxamide:

[0607] A solution of (3R,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl- 1,6,11-trioxo-l,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-10-carboxamide (125.1 mg, 0.24 mmol) in methanol (3 mL) was stirred at 0 °C while NaBH4(28.9 mg, 0.764 mmol) was added. After 1 h at 0 °C, the reaction mixture was concentrated and the residue was dissolved in water (~30 mL) and then extracted with ethyl acetate (20 mL x 2). The combined extracts were dried (MgS04) and concentrated. The residue was purified by silica gel column chromatography (24 g column) eluted with 0% to 20% methanol in CH2Cl2to give (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3- methyl-l, 11-dioxo-l, 4, 5, 6, 7, 11-hexahydro-3H-2, 7-methanopyrido[l,2- a][l,4]diazocin-10-carboxamide: ES / MS m / z: Calcd. for C28H28F2N3O5(M+H): 524.20, found: 524.30.

[0608] A solution of the above alcohol (73.2 mg, 0.140 mmol) in DMF (1.5 mL) was stirred at 0 °C while adding a 60% sodium hydride dispersion (10.5 mg, 0.274 mmol). After 20 minutes at 0 °C, iodomethane solution (0.0104 mL, 0.168 mmol) (0.21 mL, 0.337 mmol) was added. After 1 hour at 0 °C, the reaction mixture was diluted with saturated NaHCO3solution after which the product was extracted with ethyl acetate (x 2) and the combined extracts were dried (MgSO4) and concentrated. The residue was purified by preparative HPLC (column, Gemini 5um C18 110A, LC Column 100 x 30 mm) eluting with 20% - 100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 30 minutes 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]diazocin-10-carboxamide. ES / MS m / z: Calculated for C29H30F2N3O5 (M+H): 538.22, found: 538.30.

[0609] 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]diazocin-10-carboxamide:

[0610] (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]diazocin- 10-carboxamide (3.1 mg, 5.77 umol) 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 5um 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)-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]diazocin- 10-carboxamide.1H NMR (400 MHz, Acetonitrile-d3) δ 10.41 (s, 1H), 8.29 (s, 1H), 7.41 (q, J = 8.2 Hz, 1H), 7.04 - 6.85 (m, 2H), 4.63 (d, J = 5.7 Hz, 1H), 4.60 - 4.51 (m, 2H), 3.87 (dd, J = 15.0, 2.1 Hz, 1H), 3.76 (td, J = 5.9, 2.9 Hz, 1H), 3.57 (h, J = 7.0 Hz, 1H), 3.45 (dd, J = 15.0, 2.1 Hz, 1H), 3.24 (s, 3H), 1.92 - 1.74 (m, 3H), 1.67 (d, J = 7.2 Hz, 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.

[0611] Antiviral assay in MT-4 cells Cytotoxicity assay in MT-4 cells Example 48: HIV MT-4 serum shift antiviral reporter assay

[0612]

[0613] (3S,6S,7R)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-3,7-dimethyl-l, 11-dioxo- 1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide was 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]diazocin-10-carboxamide (Example 16), except (3S,7S)- 3-(((benzyloxy)carbonyl)amino)-3,7-dimethyl-2,3,4,7-tetrahydro-1H-azepine-1- carboxylate was used instead of (3S,7S)-3-(((benzyloxy)carbonyl)amino)-7- methyl-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate -1-carboxylate instead of (3S,7S)-3-(((benzyloxy)carbonyl)amino)-7-methyl- 2,3,4,7-tetrahydro-1H-azepine-1-carboxylate -1-carboxylate instead of (3S,7S)-3-(((benzyloxy)carbonyl)amino)-7-methyl- 2,3,4,7-tetrahydro-1H-azepine-1-carboxylate + 1H NMR (400 MHz, 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=4.7 Hz, 1H), 3.62 (d, J=14.9 Hz, 1H), 3.38 (dd, J=14.9, 2.0 Hz, 2H), 2.14 - 1.76 (m, 4H), 1.57 (s, 3H), 1.45 - 1.07 (m, 3H).

[0614] Example 49: High throughput microsomal stability assay System Concentration

[0615]

[0616] 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]diazocin-10-carboxamide:

[0617] To a stirred solution of (3S,7R)-12-(benzyloxy)-3-methyl-l,6,l l-trioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide (220 mg, 0.409 mmol) in a dry mixture of THF:Et20 (12 ml, 1:1, v / v) cooled at -78 °C was added iodoform (164 mg, 2.5 eq). Then, a solution of MeLi-LiBr complex (1.5 M in Et20, 2 eq) was added dropwise. After 5 min stirring at -78 °C, the reaction mixture was quenched with a saturated aqueous NH4C1 solution (1 ml). The mixture was poured into water (50 ml) and extracted with EtOAc. The organic layer was dried over MgS04, filtered and concentrated in vacuo. Flash chromatography was performed on the crude product to give (3S,6S,7R)-12-(benzyloxy)-6-(fluoromethyl)-6-hydroxy-3-methyl-l, l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide. MS (m / z) 572.157 [M+H] + .

[0618] Step 2: Synthesis of (3S,6S,7R)-6-(fluoromethyl)-6,12-dihydroxy-3-methyl-l, l l-dioxo-N- (2,4,6-trifluorobenzyl)-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin- 10-carboxamide:

[0619] (3S,6S,7R)-12-(benzyloxy)-6-(fluoromethyl)-6-hydroxy-3-methyl-l, l l-dioxo-N-(2,4,6- trifluorobenzyl)-l,6,7,l l-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide (5.8 mg, 0.0102 mmol) was dissolved in MeOH (5.0 mL) and treated with 2 mg of 20% Pd(OH)2 / C (50 wt% water) at room temperature. The mixture was degassed and purged with hydrogen gas 3 times, then hydrogenated under a hydrogen balloon overnight. The reaction was then degassed and purged with nitrogen, filtered through a celite pad, concentrated, the resulting residue was re-dissolved in DMF, filtered and purified by reverse phase HPLC. MS (m / z) 484.227 [M+H] +1H NMR (400 MHz, Chloroform-d) δ 11.12 (s, 1H), 10.22 (t, J = 5.7 Hz, 1H), 8.35 (s, 1H), 6.65 (dd, J = 8.7, 7.5 Hz, 2H), 4.81 - 4.60 (m, 4H), 4.60 - 4.49 (m, 1H), 4.45 (dd, J = 14.5, 5.1 Hz, 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 = 6.8 Hz, 3H).

[0620] "mixed cofactor" liver microsomes (+UDPGA + NADPH) 1.0 mg protein / mL Calculation of intrinsic clearance in vivo Calculation of predicted clearance

[0621]

[0622] Step 1: Preparation of (3S,4S,7R)-12-(benzyloxy)-4-cyano-N-(2,4-difluorobenzyl)-3- methyl-1,6,1 1-trioxo-1,4,5,6,7,1 1-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin- 10-carboxamide:

[0623] To a solution of (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,1 1- trioxo-1,6,7,1 1-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-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 silica gel flash column chromatography using a gradient of MeOH in DCM (0 to 10%) to give the desired product as a mixture of the ketone and the ketol and hemiketal with methanol. The stereochemistry of the cyano alpha position was determined by 2D NMR spectroscopy using the Nuclear Overhauser Effect correlation of the diol product obtained after Step 3.

[0624] Step 2: Preparation of (3S,4S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-4- formyl-3-methyl-l,6,l l-trioxo-l,4,5,6,7,l l-hexahydro-3H-2,7-methano pyrido[l,2- a][l,4]diazocin-10-carboxamide:

[0625] A solution of (3S,4S,7R)-12-(benzyloxy)-4-cyano-N-(2,4-difluorobenzyl)-3- methyl-l,6,l l-trioxo-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2- a][l,4]diazocin-10-carboxamide (179 mg, 0.317 mmol, 1 equiv) in DCM (5 mL) was cooled to 0 °C under N2. Bis(cyclopentadienyl)zirconium(IV) chloride (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 with DCM 3 times. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was filtered through a plug of silica using a gradient of DCM solutions of MeOH (0 to 20%) to remove any Zr species to give the desired product as a mixture of the parent carbonyl and carbonyl hydrate, hemiketal with MeOH and over-reduced product. This mixture was used directly in the following Step 3.

[0626] Step 3: Preparation of (3S,4S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6- hydroxy-4-(hydroxymethyl)-3-methyl-l,l l-dioxo-l,4,5,6,7,l l-hexahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-10-carboxamide:

[0627] To a solution of the product mixture of Step 2 (above) (169 mg, 0.298 mmol, 1 equiv) in THF / MeOH (1:1) (12 mL) at 0 °C was added sodium borohydride (22.5 mg, 0.596 mmol, 2 equiv) and the resulting mixture was stirred at room temperature for 10 min and then concentrated in vacuo. Water was added and the pH was adjusted to 5 by the addition of dilute acetic acid. The mixture was extracted with DCM twice 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 in H2O (40% to 80% with 0.1% TFA) to give the desired product.

[0628] Step 4: Preparation of (3S,4S,6S,7R)-12-(benzyloxy)-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-l, l l-dioxo-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2- a] [ 1,4] diazepine-10-carboxamide:

[0629] To a solution of (3S,4S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-4- (hydroxymethyl)-3-methyl-l, l l-dioxo-l,4,5,6,7,l l-hexahydro-3H-2,7-methanopyrido[l,2- a] [ 1,4] diazepine-10-carboxamide (15 mg, 0.027 mmol, 1 equiv) in DMF (1.0 mL) was added tert-butyldimethylsilyl chloride (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.

[0630] Step 5: Preparation of (3S,4S,7R,8R)-N-(2,4-difluorobenzyl)-13-hydroxy-3-methyl-l,12- dioxo-l,4,5,7,8,12-hexahydro-3H-2,8:4,7-methanopyrido[l,2-d][l,4,7]oxadiazepine- 11 -carboxamide:

[0631] ​To a solution of the crude residue from Step 5 (assumed to be 0.0271 mmol, 1 equiv) in DCM (6 mL) under N2atmosphere was added triethylamine (22.7 uL, 0.163 mmol, 6 equiv) and MsCl (6.29 uL, 0.0813 mmol, 3 equiv) 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 H2O in MeCN (10% to 90% with 0.1% TFA) and normal-phase silica gel column chromatography using a gradient of DCM in MeOH (0 to 20%) to afford the desired compound. MS (m / z) 446.200 [M+H] +1 H NMR (400 MHz, CD3CN) δ 10.63 (s, 1H), 10.32 (s, 1H), 8.43 (s, 1H), 7.40 (td, J = 8.8, 6.5 Hz, 1H), 7.00 - 6.88 (m, 2H), 4.65 (p, J = 6.9 Hz, 1H), 4.57 (d, J = 6.0 Hz, 2H), 4.54 - 4.47 (m, 1H), 4.31 (dt, J = 4.9, 2.3 Hz, 1H), 4.23 (dd, J = 9.9, 1.5 Hz, 1H), 3.85 (dd, J = 10.0, 7.5 Hz, 1H), 3.60 - 3.38 (m, 2H), 2.71 (q, J = 6.2 Hz, 1H), 2.02 (dt, J = 14.7, 7.4 Hz, 1H), 1.59 (d, J = 14.7 Hz, 1H), 1.28 (d, J = 7.1 Hz, 3H).

[0632] Species Liver blood flow L / h / kg

[0633]

[0634] Step 1: Preparation of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6- hydroxy-3-methyl-l, l l-dioxo-l,6,7, l l-tetrahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-6-d-10-carboxamide:

[0635] To a solution of (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl- 1,6,11-trioxo-l,6,7,11-tetrahydro-3H-2,7-methanopyrido[l,2-a][l,4]diazocin-10- carboxamide (100 mg, 0.192 mmol) in MeOH (5 mL) was added cesium (III) chloride heptahydrate (717 mg, 0.192 mmol). To the mixture was then slowly added sodium borohydride (4 mg, 0.096 mol). The reaction mixture was stirred at 0 °C. Upon completion of the reaction, the reaction was quenched by the addition of saturated NaHC03, extracted with DCM, the organic phase was separated and dried over MgS04. The separated organic phase was then filtered, concentrated, and used directly in the next step without purification.

[0636] Step 2: Preparation of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6- methoxy-3-methyl-l, l l-dioxo-l,6,7, l l-tetrahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-6-d-10-carboxamide:

[0637] To a solution of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6- hydroxy-3-methyl-l, l l-dioxo-l,6,7, l l-tetrahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-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 uL, 0.21 mmol). The reaction mixture was stirred at 0 °C for 0.5 h. The reaction was quenched by the addition of saturated NaHC03, extracted with EtOAc, the organic phase was separated, dried over MgS04, filtered, concentrated, and the resulting product was used in the next step without further purification.

[0638] Step 3: Preparation of (3S,6S,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-6- methoxy-3-methyl-l, l l-dioxo-l,6,7, l l-tetrahydro-3H-2,7- methanopyrido[l,2-a][l,4]diazocin-6-d-10-carboxamide:

[0639] 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-bridged methylenepyrido[1,2-a][1,4]diazocin-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 with a H2 balloon attached. After the reaction was complete, 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 with 0.1% TFA to give the title compound. MS (m / z) 449.2 [M+H] + .1H NMR (400 MHz, Methanol-d4) δ 8.36 (s, 1H), 7.44 (td, J = 8.4, 6.3 Hz, 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, 11.3 Hz, 1H), 1.28 (d, J = 6.7 Hz, 3H), 1.00 (dd, J = 14.7, 11.6 Hz, 1H).

[0640] Human Calculation of liver extraction

[0641] Table 1

[0642] Compounds were tested for their ability to inhibit HIV-1 (IIIB) replication in MT-4 cells in a high throughput 384-well assay format. Compounds were serially diluted (1 :3) in DMSO on 384-well polypropylene plates and further diluted 200-fold into complete RPMI media (10% FBS, 1% P / S) using a Biotek Micro Flow and Labcyte ECHO acoustic dispenser. Each plate contained up to 8 test compounds with a negative (no drug control) and 5 μΜ AZT positive control. MT-4 cells were pre-infected with 10 μΐ^ of either RPMI (mock infected) or fresh 1 :250 dilution of HIV-1 IIIB concentrated virus stock. Infected and uninfected MT-4 cells were further diluted in complete RPMI media and added to each plate using the Micro Flow dispenser. After incubation in a humidified and temperature controlled incubator (37°C) for 5 days, Cell Titer Glo (Promega) was added to the assay plates and the Envision plate reader read the chemiluminescence. EC 50 values were defined as the concentration of compound that caused a 50% reduction in luminescent signal and were calculated using a sigmoidal dose response model to generate curve fits.

[0643] Table 2

[0644] The assay was performed as above except that uninfected MT-4 cells were added to each well containing test compound. In addition, 10 δ μΜ puromycin was added to the last column of each assay plate to assess the basal level of cytotoxicity.

[0645] ​

[0646] To quantify the amount of protein bound to human serum, compounds were serially diluted (1 :3) in DMSO and acousticly transferred via a Labcyte ECHO robot onto 384-well assay plates. Each plate contained up to 8 test compounds, including negative and positive controls (DMSO, 5 mM AZT, respectively). Assay plates were prepared in duplicate and tested in CCM (cell culture medium) or HS / CCM (human serum / cell culture medium). MT-4 cells were first pre-infected with pLai RLuc reporter virus for 2 hours 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) before being added to each plate using a Biotek Micro Flow dispenser. After 72 hours of incubation in a humidified and temperature-controlled incubator (37°C), Renilla Glo (Promega) was added to all assay plates and the chemiluminescence was read by an Envision plate reader. EC 50 values were defined as the concentration of compound that caused a 50% reduction in luminescent signal and were calculated using a sigmoidal dose response model to generate curve fits. To determine the amount of protein binding, the EC 50 (HS / CCM) / EC 50 (CCM) was divided to calculate the EC 50 fold change (or EC 50 change).

[0647] Compounds of the present disclosure showed antiviral activity in this assay, as shown in Table 1 below. Accordingly, the compounds of the embodiments disclosed herein can be used to treat the proliferation of the HIV virus, to treat AIDS, or to delay the onset of symptoms of AIDS or ARC.

[0648] ​

[0649] Metabolic stability of compounds was assessed using a human or rat liver microsomal assay (Corning). In this assay, Echo 550 acoustic liquid dispenser 10 nL of compound at 1 mM concentration in 100% DMSO was dispensed into 384 wells of a polypropylene plate. Each plate contained 384 wells with a single test compound in each well.

[0650] Human liver microsomes (Gentest Gentest TM mixed-pooled microsomes) or rat liver microsomes (Gentest Gentest TMRat [Sprague-Dawley] pooled liver microsomes) were incubated with 0.0225 mg / ml Alkaline from Trichoderma viride (Sigma-Aldrich) in a solution of 100 mM K2H2PO4 / KH2PO4at a concentration of 2 mg / ml (pH 7.4) on ice for 15 minutes. After incubation at room temperature for 15 minutes, 5 uL of this solution was added to each well; and 5 uL of NADPH cofactor regeneration solution was added Gentest TM UGT reaction mixture) containing 100 mM K2H2PO4 / 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, 6.8 mM uridine diphosphate-glucuronide. The final concentration of the analyte compound at the start of the reaction was 1 uM. The reactions were incubated at 37 °C and collected at time points of 0 minutes, 5 minutes, 15 minutes, 30 minutes, 40 minutes, 50 minutes, 60 minutes, and 70 minutes for further analysis. Background data was collected using reactions without the analyte compound.

[0651] At the reaction collection time points, the samples were quenched with 30 uL of a solution of 72% acetonitrile, 8% methanol, 0.1% formic acid, 19.9% water, and an internal standard (IS). After diluting 10 uL of the quenched reaction into 40 uL of deionized water, the reaction plate was spun in a centrifuge at 4,000 rcf for 30 minutes at 4 °C to obtain an assay plate.

[0652] The assay plate was analyzed using an Agilent QToF 6530 RapidFire 360 system equipped with a C4 A type solid phase extraction column using a quadrupole time-of-flight mass spectrometer coupled with solid phase extraction. Analysis was performed in either positive or negative ionization mode. The mobile phase contained a solution of 0.1% formic acid in water for loading the analyte onto the solid state extraction column and a solution of 0.1% formic acid in acetonitrile for elution into the mass spectrometer in positive ionization mode, or a solution of 0.1% acetic acid in water for loading and a solution of 0.1% acetic acid in acetonitrile for extraction in negative ionization mode. The ratio of the integrated counts of each compound to the peak area of the IS was plotted as a semi-log plot of log versus time. The initial linear portion of the decay was fitted to a linear regression equation to derive the half-life of the decay of the compound.

[0653] The pharmacological parameters of the metabolism of the analyte compound were calculated using the following formula:

[0654]

[0655] where:

[0656] Calculation of intrinsic clearance in vitro

[0657]

[0658] Concentration refers to the concentration of protein in the reaction (mg / mL).

[0659] ​ ​ ​ ​

[0660] ​

[0661] This extends the intrinsic clearance in vitro to a value predicted for the entire liver tissue mass (but not limited by blood flow). This value depends on the size of the liver (depending on the species) and, as appropriate, on the yield of microsomal protein (assumed to be independent of the species).

[0662]

[0663]

[0664]

[0665] ​

[0666] The liver clearance will depend on the interplay between intrinsic clearance and liver blood flow and can be predicted from in vitro data using a variety of methods.

[0667]

[0668] ​ ​ ​ ​ 1.3

[0669] ​

[0670] This is the predicted clearance expressed as a fraction of liver blood flow.

[0671] E = CL / Q H * 100%

[0672] The intrinsic clearance of the compounds of the application as well as reference compounds A-F was calculated according to the procedure described above. The results for these compounds are shown in Table 2 below. It can be seen that the stability of the compounds of the application is 1.5 to 3.6 times that of the reference compounds A-F.

[0673] ​

[0674]

[0675]

[0676] ​

[0677]

[0678]

[0679]

[0680] All references, including publications, patents, and patent documents, are incorporated by reference herein, as though individually incorporated by reference. The present disclosure provides a reference for various embodiments and techniques. However, it is to be understood that numerous changes and modifications can be made and still remain within the spirit and scope of the present disclosure. Descriptions of exemplary embodiments are provided to illustrate the subject matter of the claimed subject matter and are not intended to restrict the scope of claims to the exemplary embodiments.

Claims

1. A compound of Formula I: or a pharmaceutically acceptable salt thereof, wherein with the proviso that the compound of Formula I is not R 1 is phenyl, wherein said phenyl is optionally substituted with one to four R A1 , wherein each R A1 is independently halo; R 2 is H or C 1-6 alkyl; R 3 is halo or -OR 3a wherein R 3a is H, -C 1-6 alkyl or -C 1-4 haloalkyl; or R 3a and R 6a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one O heteroatom; R 3b H, -C 1-6 alkyl or -C 1-4 haloalkyl; R 4a -C 1-6 alkyl or -C 1-4 haloalkyl; R 4b is H; W 1 is a bond or -CR 5a R 5b -; R 5a and R 5b are independently H or halo; W 2 -CH2-; or -CR 6a R 6b -CH2-; or -CR 7a =CR 7b -; R 6a and R 6b are independently H; or R 6a and R 3a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one O heteroatom; and R 6b is H; and R 7a and R 7b is H; 2. A compound of Formula la: or a pharmaceutically acceptable salt thereof, wherein 3. A compound of Formula lb: or a pharmaceutically acceptable salt thereof, wherein 4. A compound of Formula lc: or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, wherein said phenyl is optionally substituted with one to four R A1 , wherein each R A1 is independently halo; R 2 is H or C 1-6 alkyl; R 3a H, -C 1-6 alkyl or -C 1-4 haloalkyl; or R 3a and R 6a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one O heteroatom; R 3b is H, -C 1-6 alkyl or -C 1-4 haloalkyl; R 4a -C 1-6 alkyl or -C 1-4 haloalkyl; R 4b is H; W 1 is a bond or -CR 5a R 5b -; R 5a and R 5b are independently H or halo; W 2 is -CR 6a R 6b - or -CR 7a =CR 7b -; R 6a and R 6b are independently H; or R 6a and R 3a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one O heteroatom; and R 6b is H; and R 7a and R 7b is H.

5. A compound of Formula Id: or a pharmaceutically acceptable salt thereof, wherein 33. A compound of Formula lc: or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, wherein said phenyl is optionally substituted with one to four R A1 , wherein each R A1 is independently halo; R 2 is H or C 1-6 alkyl; R 3a is H, -C 1-6 alkyl or -C 1-4 haloalkyl; or R 3a and R 6a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one O heteroatom; R 3b H, -C 1-6 alkyl or -C 1-4 haloalkyl; R 4a -C 1-6 alkyl or -C 1-4 haloalkyl; R 4b is H; W 1 is a bond or -CR 5a R 5b -; R 5a and R 5b are independently H or halo; W 2 is -CR 6a R 6b - or -CR 7a =CR 7b -; R 6a and R 6b are independently H; or R 6a and R 3a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one O heteroatom; and R 6b is H; and R 7a and R 7b is H.

46. A compound selected from the group consisting of 47. A compound selected from the group consisting of R 1 is phenyl, wherein said phenyl is optionally substituted with one to four R A1 , wherein each R A1 is independently halo; R 2 is H or C 1-6 alkyl; R 3a H, -C 1-6 alkyl or -C 1-4 haloalkyl; or R 3a and R 6a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one O heteroatom; R 3b H, -C 1-6 alkyl or -C 1-4 haloalkyl; R 4a -C 1-6 alkyl or -C 1-4 haloalkyl; R 4b is H; W 1 is a bond or -CR 5a R 5b -; R 5a and R 5b are independently H or halo; W 2 -CR 6a R 6b - or -CR 7a =CR 7b -; R 6a and R 6b are independently H; or R 6a and R 3a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one O heteroatom; and R 6b is H; and R 7a and R 7b is H.

48. A compound selected from the group consisting of 49. A compound selected from the group consisting of: R 1 is phenyl, wherein said phenyl is optionally substituted with one to four R A1 , wherein each R A1 is independently halo; R 2 is H or C 1-6 alkyl; R 3a H, -C 1-6 alkyl or -C 1-4 haloalkyl; or R 3a and R 6a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one O heteroatom; R 3b H, -C 1-6 alkyl or -C 1-4 haloalkyl; R 4a -C 1-6 alkyl or -C 1-4 haloalkyl; R 4b is H; W 1 is a bond or -CR 5a R 5b -; R 5a and R 5b are independently H or halo; W 2 is -CR 6a R 6b - or -CR 7a =CR 7b -; R 6a and R 6b are independently H; or R 6a and R 3a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one O heteroatom; and R 6b is H; and R 7a and R 7b is H.

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl substituted with two or three R A1 , wherein each R A1 is independently selected from chlorine and fluorine.

7. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 1 is selected from the group consisting of:

8. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, wherein the phenyl is substituted with two to four R A1 , wherein each R A1 is independently halo.

9. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein each R A1 is independently chloro or fluoro.

10. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-5, wherein R 2 is H.

11. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 3 is halo.

12. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-5, wherein R 3 is chloro.

13. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 3 is OR 3a .

14. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 4a is -C 1-4 haloalkyl.

15. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 4a is -C 1-3 alkyl.

16. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 4a is methyl.

17. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 3a is -C 1-6 alkyl or -C 1-4 haloalkyl.

18. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 3a is -C 1-6 alkyl.

19. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 3a is methyl or ethyl.

20. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 3a is methyl.

21. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 3a and R 6a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom.

22. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 3b is H, -C 1-6 alkyl, -C 1-4 haloalkyl.

23. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 3b is H or -C 1-6 alkyl.

24. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 3b is H or -C 1-3 alkyl.

25. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-5, wherein R 3b is H or methyl.

26. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 3b is H.

27. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein W 1 is a bond.

28. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein W 1 is -CR 5a R 5b - 29. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein R 5a is H or halo, and R 5b is H.

30. The compound or pharmaceutically acceptable salt thereof of any one of claims 1-5, wherein R 5a is H and R 5b is H.

31. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein W 2 is -CR 6a R 6b - 32. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt thereof, wherein W 2 is -CR 7a =CR 7b -.

50. A compound selected from the group consisting of:

51. A compound of the formula: R 1 is phenyl, wherein said phenyl is optionally substituted by one, two, three or four R A1 substituted, wherein each R A1 independently is halo; R 2 is H or C 1-6 alkyl; R 3a H, -C 1-6 alkyl or -C 1-4 haloalkyl; R 3b H, -C 1-6 alkyl or -C 1-4 haloalkyl; R 4a -C 1-3 alkyl; R 4b is H; W 1 -CR 5a R 5b -; R 5a and R 5b are independently H or halo; W 2 -CH2-; and 6a R 6b -; and R 6a and R 6b are independently H.

34. The compound of claim 33, or a pharmaceutically acceptable salt thereof, wherein R 1 is phenyl, wherein the phenyl is substituted with two or three R A1 , wherein each R A1 is independently selected from chlorine and fluorine.

35. The compound or pharmaceutically acceptable salt thereof of claim 33 or 34, wherein R 1 is selected from the group consisting of:

36. The compound or pharmaceutically acceptable salt thereof of claim 33 or 34, wherein each R A1 is independently chloro or fluoro.

37. The compound or pharmaceutically acceptable salt thereof of claim 33 or 34, wherein R 2 is H.

38. The compound or pharmaceutically acceptable salt thereof of claim 33 or 34, wherein R 3a is -C 1-6 alkyl or -C 1-4 haloalkyl.

39. The compound or pharmaceutically acceptable salt thereof of claim 33 or 34, wherein R 3a is -C 1-6 alkyl.

40. The compound or pharmaceutically acceptable salt thereof of claim 33 or 34, wherein R 3a is methyl or ethyl.

41. The compound or pharmaceutically acceptable salt thereof of claim 33 or 34, wherein R 3b is H, -C 1-6 alkyl, -C 1-4 haloalkyl.

42. The compound or pharmaceutically acceptable salt thereof of claim 33 or 34, wherein R 3b is H or -C 1-6 alkyl.

43. The compound of claim 33 or 34, or a pharmaceutically acceptable salt thereof, wherein R 3b is H or -C 1-3 alkyl.

44. The compound or pharmaceutically acceptable salt thereof of claim 33 or 34, wherein R 3b is H or methyl.

45. The compound or pharmaceutically acceptable salt thereof of claim 33 or 34, wherein R 3b is H.

52. A compound of the formula: or a pharmaceutically acceptable salt thereof.

53. A compound of the formula: or a pharmaceutically acceptable salt thereof.

54. A compound of the formula: or a pharmaceutically acceptable salt thereof.

55. A compound of the formula: or a pharmaceutically acceptable salt thereof.

56. A compound of the formula: or a pharmaceutically acceptable salt thereof.

57. A compound of the formula: or a pharmaceutically acceptable salt thereof.

58. A compound of the formula: or a pharmaceutically acceptable salt thereof.

59. A compound of the formula: or a pharmaceutically acceptable salt thereof.

60. A compound of the formula: or a pharmaceutically acceptable salt thereof.

61. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1-60, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. or a pharmaceutically acceptable salt thereof.

62. The pharmaceutical composition of claim 61, further comprising one, two, three, or four additional therapeutic agents. or a pharmaceutically acceptable salt thereof.

63. The pharmaceutical composition of claim 62, wherein the one or more additional therapeutic agents is an anti-HIV agent. or a pharmaceutically acceptable salt thereof.

64. The pharmaceutical composition of claim 62 or 63, wherein the one or more additional therapeutic agents is an HIV protease inhibitor, a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latency reversing agent, a capsid polymerization inhibitor, a maturation inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, another drug that treats HIV, or a combination thereof. or a pharmaceutically acceptable salt thereof. ​ or a pharmaceutically acceptable salt thereof. ​ or a pharmaceutically acceptable salt thereof. ​ ​ ​ ​ 65. The pharmaceutical composition of claim 62 or 63, wherein the one or more additional therapeutic agents is abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-l-(3-(4-chloro-3-(methylsulfonamido)-l-(2,2,2-trifluoroethyl)-lH-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)acetamide, or a pharmaceutically acceptable salt thereof.

66. The pharmaceutical composition of claim 61, wherein the pharmaceutical composition is for oral or parenteral administration.

67. A kit comprising the compound of any one of claims 1-60, or a pharmaceutically acceptable salt thereof, and instructions for use.

68. The kit of claim 67, further comprising one, two, three, or four additional therapeutic agents.

69. The kit of claim 68, wherein the one or more additional therapeutic agents is an anti-HIV agent.

70. The kit of claim 68 or 69, wherein the one or more additional therapeutic agents is an HIV protease inhibitor, an HIV reverse transcriptase non-nucleoside or non-nucleotide inhibitor, an HIV reverse transcriptase nucleoside or nucleotide inhibitor, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latency reversing agent, a capsid polymerization inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof.

71. The kit of claim 68 or 69, wherein the one or more additional therapeutic agents is abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-l-(3-(4-chloro-3-(methylsulfonamido)-l-(2,2,2-trifluoroethyl)-lH-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-lH-cyclopropa[3,4]cyclopenta[l,2-c]pyrazol-l-yl)acetamide, or a pharmaceutically acceptable salt thereof.

72. Use of a compound of any one of claims 1-60, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of any one of claims 61-66, in the manufacture of a medicament for treating an HIV infection in a human having or at risk of having an HIV infection.

73. The use of claim 72, wherein the compound or pharmaceutically acceptable salt thereof according to any one of claims 1-60 is combined with one, two, three, or four additional therapeutic agents.

74. The use of claim 73, wherein the one or more additional therapeutic agents is an anti-HIV agent.

75. The use of claim 73 or 74, wherein the one or more additional therapeutic agents is an HIV protease inhibitor, a non-nucleoside or non-nucleotide inhibitor of HIV reverse transcriptase, a nucleoside or nucleotide inhibitor of HIV reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latency reversing agent, a capsid polymerization inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, another drug that treats HIV, or a combination thereof.

76. The use of claim 73 or 74, wherein the one or more additional therapeutic agents is abacavir, tenofovir alafenamide, tenofovir disoproxil, lenacapavir, or a pharmaceutically acceptable salt thereof.

77. The use of claim 72, wherein the medicament is suitable for oral, intravenous, subcutaneous, or intramuscular administration.

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