BRIDGED TRICYCLIC CARBAMOYLPYRIDONE COMPOUNDS AND USES THEREOF

Compounds for use in treating or preventing human immunodeficiency virus (HIV) infection are disclosed. The compounds have the following Formula (I):   including stereoisomers and pharmaceutically acceptable salts thereof. Methods associated with the preparation and use of the disclosed compounds, as well as pharmaceutical compositions comprising such compounds are also disclosed.

FIELD

This disclosure relates generally to certain bridged tricyclic compounds, pharmaceutical compositions comprising said compounds, and methods of making and using said compounds and pharmaceutical compositions.

BACKGROUND

Human immunodeficiency virus infection and related diseases are a major public health problem worldwide. Human immunodeficiency virus encodes three enzymes which are required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are in wide use and have shown effectiveness, particularly when employed in combination, toxicity and development of resistant strains may limit their usefulness (Palella, et al.N. Engl. J Med. (1998) 338:853-860; Richman, D. D.Nature(2001) 410:995-1001). Accordingly, there is a need for new agents that inhibit the replication of HIV.

A goal of antiretroviral therapy is to achieve viral suppression in the HIV infected patient. Current treatment guidelines published by the United States Department of Health and Human Services provide that achievement of viral suppression requires the use of combination therapies, 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. Available at https://files.aidsinfo.nih.gov/contentfiles/lvguidelines/AdultandAdolescentGL.pdf. Accessed Feb. 20, 2020). In addition, decisions regarding the treatment of HIV infected patients are complicated when the patient requires 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 potential for drug interaction is a criterion for selection of a drug regimen. As such, there is a need for antiretroviral therapies having a decreased potential for drug interactions.

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

For certain patients, for example, those with difficult or limited access to health care, adherence to daily oral treatment or prophylactic regimens can be challenging. Drugs that offer favorable pharmaceutical properties (for example, improved potency, long-acting pharmacokinetics, low solubility, low clearance, and/or other properties) are amenable to less frequent administration and provide for better patient compliance. Such improvements can, in turn, optimize drug exposure and limit the emergence of drug resistance.

SUMMARY

In some embodiments, the disclosure provides a compound of Formula I:

or a pharmaceutically acceptable salt thereof, wherein

R3aand any one of R2, R5a, and R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S;

W1is a bond or —CR5aR5b—;R5aand R5bare independently H, C1-6alkyl, C1-4haloalkyl, or halo; orR5aand R3atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R5bis H, C1-6alkyl, C1-4haloalkyl, or halo;

W2is —CR6aR6b- or —CR7a═CR7b—;R6aand R6bare independently H, C1-6alkyl, C1-4haloalkyl, halo, hydroxyl, cyano, —O—C1-4alkyl, or C1-4alkylene-O—C1-4alkyl; orR6and R3atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R6bis H, C1-6alkyl, C1-4haloalkyl, halo, hydroxyl, cyano, —O—C1-4alkyl, or C1-4alkylene-O—C1-4alkyl;R7aand R7bare independently H, halo, C1-4haloalkyl, or C1-6alkyl; orR7aand R7btogether with the carbons to which they are attached form a C5-10aryl optionally substituted with one to four RA2, wherein each RA2is independently halo, cyano, or C1-4alkyl.

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

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

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

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

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

In some embodiments, the disclosure provides a compound of Formula I, or pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for use in treating an HIV infection.

In some embodiments, the disclosure provides use of a compound of Formula I, or 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 the infection.

DETAILED DESCRIPTION

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 may be practiced without these details. The description below of several embodiments is made with the understanding that the present disclosure is to be considered as an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout this disclosure are provided for convenience only and are not to be construed to limit the claims in any way. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

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

“Amino” refers to the —NH2radical.

“Hydroxy” or “hydroxyl” refers to the —OH radical.

“Oxo” refers to the ═O substituent.

A prefix such as “Cu-v” or (Cu-Cv) indicates that the following group has from u to v carbon atoms. For example, “C1-6alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.

“Alkyl” refers to a straight or branched chain hydrocarbon radical consisting of carbon and hydrogen atoms, which is saturated, having from one to twelve carbon atoms (C1-12alkyl), in certain embodiments one to eight carbon atoms (C1-8alkyl), one to six carbon atoms (C1-6alkyl), one to four carbon atoms (C1-4alkyl), or one to three carbon atoms (C1-3alkyl), and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (iso-propyl), n-butyl, 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (t-butyl), n-pentyl, hexyl, 3-methylhexyl, 2-methylhexyl, and the like.

“Alkylene” refers to a saturated, branched or straight chain or cyclic hydrocarbon radical having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkane. For example, an alkylene group can have 1 to 20 carbon atoms, 1 to 10 carbon atoms, or 1 to 6 carbon atoms. Typical alkylene radicals include, but are not limited to, methylene (—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.

“Aryl” refers to an aromatic carbocyclic group having a single ring (e.g. monocyclic) or multiple rings (e.g. bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-20aryl), 6 to 12 carbon ring atoms (i.e., C6-12aryl), or 6 to 10 carbon ring atoms (i.e., C6-10aryl). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below.

“Cyano” refers to the carbonitrile group (—CN).

“Cycloalkyl” refers to a saturated or partially saturated cyclic alkyl group having a single ring or multiple rings including fused, bridged, and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e. the cyclic group having at least one double bond). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-20cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-12cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-10cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-8cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-6cycloalkyl). Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

“Haloalkyl” refers to an alkyl group, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

“Heteroaryl” refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, with one or more ring heteroatoms 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 or overlap with aryl as defined above.

“Heterocyclic ring” refers to a non-aromatic radical or ring having from three to fifteen atoms wherein from 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 a single bond. In certain embodiments, “heterocyclyl” has from three to ten atoms, wherein from one to four atoms are heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur, or from three to seven atoms, wherein from one to two atoms are heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The nitrogen, carbon or sulfur atoms in the heterocyclyl may be optionally oxidized; the nitrogen atom may be optionally quaternized. As used herein, heterocyclic ring refers to rings that are saturated or partially saturated. Examples of such heterocyclic ring 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, bridged, and spiro ring systems.

The embodiments disclosed herein are also meant to encompass all pharmaceutically acceptable compounds of Formula I being 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 as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36Cl,123I, and125I, respectively. In certain embodiments, these radiolabeled compounds are useful to help determine or measure the effectiveness of the compounds, by characterizing, for example, the site or mode of action, or binding affinity to pharmacologically important site of action. Certain isotopically-labeled compounds of Formula I, Ia, Ib, Ic, Id, or II, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e.,3H, and carbon-14, i.e.,14C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

In certain embodiments, substitution with heavier isotopes such as deuterium, i.e.,2H, may afford certain therapeutic advantages resulting from greater metabolic stability. For example, in vivo half-life may increase or dosage requirements may be reduced. Thus, heavier isotopes may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as11C,18F,15O, and13N, can be useful in Positron Emission Topography (PET) studies for examining substrate receptor occupancy. Isotopically-labeled compounds of Formula I, Ia, Ib, Ic, Id or II can be prepared by techniques known to those skilled in the art or by processes analogous to those described in the Examples as set out below using an appropriate isotopically-labeled reagent in place of the non-labeled reagent previously employed.

The methods, compositions, kits and articles of manufacture provided herein use or include compounds (e.g., a compound of Formula I, Ia, Ib, Ic, Id, or II) or pharmaceutically acceptable salts thereof, in which from 1 to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or D, in which n is the number of hydrogen atoms in the molecule. As known in the art, the deuterium atom is a non-radioactive isotope of the hydrogen atom. Such compounds increase resistance to metabolism, and thus are useful for increasing the half-life of compounds or pharmaceutically acceptable salts 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.

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

“Mammal” includes humans and both domestic animals such as laboratory animals and household pets (e.g., cats, dogs, swine, cattle, sheep, goats, horses, rabbits), and non-domestic animals such as wildlife and the like.

“Optional” or “optionally” means that the subsequently described event or circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted alkyl” means that the alkyl radical may or may not be substituted and that the description includes both substituted alkyl radicals and alkyl radicals having no substitution.

“Pharmaceutically acceptable excipient” includes without limitation any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye/colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifier, or other pharmacologically inactive substance that is formulated in combination with a pharmacologically active ingredient of a pharmaceutical composition and is compatible with the other ingredients of the formulation and suitable for use in humans or domestic animals without undue toxicity, irritation, allergic response, and the like.

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

Metal salts typically are prepared by reacting the metal hydroxide with a compound according to the embodiments disclosed herein. Examples of metal salts which are prepared in this way are salts containing Li+, Na+, and K+. A less soluble metal salt can be precipitated from the solution of a more soluble salt by addition of the suitable metal compound.

In addition, salts may be formed from acid addition of certain organic and inorganic acids, e.g., HCl, HBr, H2SO4, H3PO4or organic sulfonic acids, to basic centers, typically amines. Finally, it is to be understood that the compositions herein comprise compounds disclosed herein in their un-ionized, as well as zwitterionic form.

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

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

The terms “treating” and “treatment” as used herein are intended to mean the administration of a compound or composition according to the present embodiments disclosed herein to alleviate or eliminate one or more symptoms of HIV infection and/or to reduce viral load in a patient. In certain embodiments, the terms “treating” and “treatment” also encompass the administration of a compound or composition according to the present embodiments disclosed herein post-exposure of the individual to the virus but before 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, and the administration of a compound or composition according to the present embodiments disclosed herein to prevent perinatal transmission of HIV from mother to baby, by administration to the mother before giving birth and to the child within the first days of life. The terms “treating” and “treatment” also encompass the administration of a compound or composition according to the present embodiments disclosed herein before the exposure of the individual to the virus (also called pre-exposure prophylaxis or PrEP), to prevent HIV infection from taking hold if the individual is exposed to the virus and/or to keep 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 terms “treating” and “treatment” also encompass the administration of a compound or composition according to the present embodiments disclosed herein both before and after the exposure of the individual to the virus.

As used herein, the terms “preventing” and “prevention” refer to the administration of a compound, composition, or pharmaceutically salt according to the present disclosure pre- or post-exposure of the human to the virus but before the appearance of symptoms of the disease, and/or prior to the detection of the virus in the blood. The terms also refer to prevention of the appearance of symptoms of the disease and/or to prevent the virus from reaching detectible levels in the blood. The terms include both pre-exposure prophylaxis (PrEP), as well as post-exposure prophylaxis (PEP) and event driven or “on demand” prophylaxis. The terms also refer to prevention of perinatal transmission of HIV from mother to baby, by administration to the mother before giving birth and to the child within the first days of life. The terms also refer to prevention of transmission of HIV through blood transfusion.

A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present disclosure contemplates various stereoisomers and mixtures thereof and includes “enantiomers”, which refers to two stereoisomers whose molecules are non-superimposable mirror images of one another. In any of the embodiments disclosed herein, compounds disclosed herein may be in the form of a stereoisomer thereof.

“Partially saturated” refers to a cyclic group which contains at least one double bond but is not aromatic.

or a pharmaceutically acceptable salt thereof, wherein

R3aand any one of R2, R5a, and R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S;

W1is a bond or —CR5aR5b—;R5aand R5bare independently H, C1-6alkyl, C1-4haloalkyl, or halo; orR5aand R3atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R5bis H, C1-6alkyl, C1-4haloalkyl, or halo; W2is —CR6aR6b- or —CR7a═CR7b—;R6aand R6bare independently H, C1-6alkyl, C1-4haloalkyl, halo, hydroxyl, cyano, —O—C1-4alkyl, or C1-4alkylene-O—C1-4alkyl; orR6aand R3atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R6bis H, C1-6alkyl, C1-4haloalkyl, halo, hydroxyl, cyano, —O—C1-4alkyl, or C1-4alkylene-O—C1-4alkyl; andR7aand R7bare independently H, halo, C1-4haloalkyl, or C1-6alkyl; orR7aand R7btogether with the carbons to which they are attached form a C5-10aryl optionally substituted with one to four RA2, wherein each RA2is independently halo, cyano, or C1-4alkyl.

It is a desirable to discover compounds, or pharmaceutically acceptable salts thereof, that have good stability, i.e. physical, chemical stability, and/or metabolic stability. An increase in overall stability of a compound can provide an increase in circulation time in the body. With less degradation, a stable compound can be administered in lower doses and still maintain efficacy. Also, with less degradation there are less concerns about by-products from degradation of the compound. Higher stability of the drug means that more drug is available for target cells without being metabolized.

It is further desirable to discover compounds, or pharmaceutically acceptable salts thereof, that have improved pharmacokinetic and/or pharmacodynamic profiles 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 a good bioavailability and high systemic exposure. Reducing the clearance and/or increasing half-life time of a compound could reduce the daily dose required for efficacy and therefore give a better efficacy and safety profile. Thus, improved pharmacokinetic and/or pharmacodynamic profiles and long half-life can provide for better patient compliance.

As shown below, the compounds of Formula I provided herein are characterized by (i) at least one oxygen linked or halogen substitution at the “a” position (R3is halo or —OR3a) and (ii) at least one alkyl or haloalkyl substituent the “b” position (R4ais —C1-6alkyl or —C1-4haloalkyl):

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

In some embodiments, the compound of Formula I provided herein is a compound of Formula Ia:

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

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

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

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, or Id, or the pharmaceutically acceptable salt thereof, R1is phenyl or pyridyl, wherein the phenyl or pyridyl is optionally substituted with one, two, three, or four RA1, wherein each RA1is independently halo, C1-6alkyl, C1-4haloalkyl, cyano, —O—C1-4alkyl, or —C1-4alkyl-O—C1-4alkyl. In some embodiments, R1is phenyl or pyridyl, wherein the phenyl or pyridyl is optionally substituted with one, two, three, or four RA1, wherein each RA1is independently halo, C1-4alkyl, C1-4haloalkyl, or —O—C1-4alkyl. In some embodiments, R1is phenyl or pyridyl, wherein the phenyl or pyridyl is optionally substituted with one, two, three, or four RA1, wherein each RA1is independently halo, C1-4alkyl, or —O—C1-4alkyl. In some embodiments, R1is phenyl or pyridyl, wherein the phenyl or pyridyl is optionally substituted with one, two, three, or four RA1, wherein each RA1is independently halo or C1-4alkyl. In some embodiments, R1is phenyl or pyridyl, wherein the phenyl or pyridyl is optionally substituted with one, two, three, or four RA1, wherein each RA1is independently halo or —O—C1-4alkyl. In some embodiments, R1is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with one, two, three, or four RA1, wherein each RA1is independently a halogen. In some embodiments, R1is phenyl or pyridyl, wherein the phenyl or pyridyl is substituted with two or three RA1, wherein each RA1is independently a halogen. In some embodiments, R1is phenyl or pyridyl, wherein the phenyl of pyridyl is substituted with two or three RA1, wherein each RA1is independently selected from chloro and fluoro.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, or Id, or the pharmaceutically acceptable salt thereof, R1is pyridyl, wherein the pyridyl is optionally substituted with one, two, three, or four RA1, wherein each RA1is independently halo, C1-6alkyl, C1-4haloalkyl, cyano, —O—C1-4alkyl, or —C1-4alkyl-O—C1-4alkyl. In some embodiments, R1is pyridyl, wherein the pyridyl is optionally substituted with one, two, three, or four RA1, wherein each RA1is independently halo, C1-4alkyl, C1-4haloalkyl, or —O—C1-4alkyl. In some embodiments, R1is pyridyl, wherein the pyridyl is optionally substituted with one, two, three, or four RA1wherein each RA1is independently halo, C1-4alkyl, or —O—C1-4alkyl. In some embodiments, R1is pyridyl, wherein the pyridyl is optionally substituted with one, two, three, or four RA1, wherein each RA1is independently halo or C1-4alkyl. In some embodiments, R1is pyridyl, wherein the pyridyl is optionally substituted with one, two, three, or four RA1, wherein each RA1is independently halo or —O—C1-4alkyl. In some embodiments, R1is pyridyl, wherein the pyridyl is substituted with one, two, three, or four RA1, wherein each RA1is independently a halogen. In some embodiments, R1is pyridyl, wherein the pyridyl is substituted with two or three RA1wherein each RA1is independently a halogen. In some embodiments, R1is pyridyl, wherein the pyridyl is substituted with two or three RA1, wherein each RA1is independently selected from chloro and fluoro.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, or Id, or the pharmaceutically acceptable salt thereof, R1is phenyl, wherein the phenyl is optionally substituted with one, two, three, or four RA1, wherein each RA1is independently halo, C1-6alkyl, C1-4haloalkyl, cyano, —O—C1-4alkyl, or —C1-4alkyl-O—C1-4alkyl. In some embodiments, R1is phenyl, wherein the phenyl is optionally substituted with one, two, three, or four RA1, wherein each RA1is independently halo, C1-4alkyl, C1-4haloalkyl, or —O—C1-4alkyl. In some embodiments, R1is phenyl, wherein the phenyl is optionally substituted with one, two, three, or four RA1wherein each RA1is independently halo, C1-4alkyl, or —O—C1-4alkyl. In some embodiments, R1is phenyl, wherein the phenyl is optionally substituted with one, two, three, or four RA1, wherein each RA1is independently halo or C1-4alkyl. In some embodiments, R1is phenyl, wherein the phenyl is optionally substituted with one, two, three, or four RA1, wherein each RA1is independently halo or —O—C1-4alkyl. In some embodiments, R1is phenyl, wherein the phenyl is substituted with one, two, three, or four RA1, wherein each RA1is independently a halogen. In some embodiments, R1is phenyl, wherein the phenyl is substituted with two or three RA1wherein each RA1is independently a halogen. In some embodiments, R1is phenyl, wherein the phenyl is substituted with two or three RA1, wherein each RA1is independently selected from chloro and fluoro.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, or Id, or the pharmaceutically acceptable salt thereof, R1is selected from the group consisting of:

In some embodiments, the compound of Formula I, Ia, Ib, Ic, or Id is a compound of Formula II:

In some embodiments of the compound of Formula II, n is 2, 3, or 4 and each RA1is independently halo, C1-4alkyl, C1-4haloalkyl, cyano, or —O—C1-4alkyl. In some embodiments, n is 2, 3, or 4 and each RA1is independently halo, C1-4alkyl, C1-4haloalkyl, or —O—C1-4alkyl. In some embodiments, n is 2, 3, or 4, and each RA1is independently halo, C1-4alkyl, or —O—C1-4alkyl. In some embodiments, n is 2, 3, or 4, and each RA1is independently halo or C1-4alkyl. In some embodiments, n is 2, 3, or 4, and each RA1is independently halo or —O—C1-4alkyl. In some embodiments, n is 2, 3, or 4, and each RA1is independently a halogen. In some embodiments, n is 2, 3, or 4, and each RA1is independently selected from chloro and fluoro.

In some embodiments of the compound of Formula II, n is 2 or 3 and each RA1is independently halo, C1-4alkyl, C1-4haloalkyl, cyano, or —O—C1-4alkyl. In some embodiments, n is 2 or 3 and each RA1is independently halo, C1-4alkyl, C1-4haloalkyl, or —O—C1-4alkyl. In some embodiments, n is 2 or 3, and each RA1is independently halo, C1-4alkyl, or —O—C1-4alkyl. In some embodiments, n is 2 or 3, and each RA1is independently halo or C1-4alkyl. In some embodiments, n is 2 or 3, and each RA1is independently halo or —O—C1-4alkyl. In some embodiments, n is 2 or 3, and each RA1is independently a halogen. In some embodiments, n is 2 or 3, and each RA1is independently selected from chloro and fluoro.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof, R2is H, C1-6alkyl, or C1-4haloalkyl. In some embodiments, R2is H or C1-6alkyl. In some embodiments, R2is H or C1-4haloalkyl. In some embodiments, R2is C1-6alkyl or C1-4haloalkyl. In some embodiments, R2is a C1-3alkyl. In some embodiments, R2is methyl. In some embodiments R2is H.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof, R3is halo. In some embodiments, R3is chloro.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof, R3is OR3a, wherein R3ais H, —C1-6alkyl, —C1-4haloalkyl, or —C3-6cycloalkyl and R3bis H or —C1-6alkyl. In some embodiments, R3ais —C1-6alkyl, —C1-4haloalkyl, or —C3-6cycloalkyl and R3bis H or —C1-6alkyl. In some embodiments, R3ais —C1-6alkyl or —C1-4haloalkyl and R3bis H or —C1-6alkyl. In some embodiments, R3ais —C1-6alkyl; and R3bis H or —C1-6alkyl. In some embodiments, R3ais methyl or ethyl and R3bis H or —C1-6alkyl. In some embodiments, R3ais methyl and R3bis H or —C1-6alkyl.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof, R3is OR3a, wherein R3ais H, —C1-6alkyl, —C1-4haloalkyl, or —C3-6cycloalkyl and R3bis H or —C1-3alkyl. In some embodiments, R3ais —C1-6alkyl, —C1-4haloalkyl, or —C3-6cycloalkyl and R3bis H or —C1-3alkyl. In some embodiments, R3ais —C1-6alkyl or —C1-4haloalkyl and R3bis H or —C1-3alkyl. In some embodiments, R3ais —C1-6alkyl and R3bis H or —C1-3alkyl. In some embodiments, R3ais methyl or ethyl and R3bis H or —C1-6alkyl. In some embodiments, R3ais methyl and R3bis H or —C1-3alkyl.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof, R3is OR3a, wherein R3ais H, —C1-6alkyl, —C1-4haloalkyl, or —C3-6cycloalkyl and R3bis H or methyl. In some embodiments, R3ais —C1-6alkyl, —C1-4haloalkyl, or —C3-6cycloalkyl and R3bis H or methyl. In some embodiments, R3ais —C1-6alkyl or —C1-4haloalkyl and R3bis H or methyl. In some embodiments, R3ais —C1-6alkyl and R3bis H or methyl. In some embodiments, R3ais methyl or ethyl and R3bis H or methyl. In some embodiments, R3ais methyl and R3bis H or methyl.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof, R3aand any one of R2, R5aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H, —C1-6alkyl, —C1-4haloalkyl, or —C1-4alkylene-O—C1-4alkyl. In some embodiments, R3aand any one of R2, R5aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H, —C1-6alkyl, or —C1-4haloalkyl. In some embodiments, R3aand any one of R2, R5aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H or —C1-6alkyl. In some embodiments, R3aand any one of R2, R5aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H or —C1-3alkyl. In some embodiments, R3aand any one of R2, R5aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H or methyl. In some embodiments, R3aand any one of R2, R5aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof, R3aand any one of R2, R5aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H, —C1-6alkyl, —C1-4haloalkyl, or —C1-4alkylene-O—C1-4alkyl. In some embodiments, R3aand any one of R2, R5aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H, —C1-6alkyl, or —C1-4haloalkyl. In some embodiments, R3aand any one of R2, R5aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H or —C1-6alkyl. In some embodiments, R3aand any one of R2, R5aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H or —C1-3alkyl. In some embodiments, R3aand any one of R2, R5aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H or methyl. In some embodiments, R3aand any one of R2, R5aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof, R3aand R2together with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H, —C1-6alkyl, —C1-4haloalkyl, or —C1-4alkylene-O—C1-4alkyl. In some embodiments, R3aand R2together with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H, —C1-6alkyl, or —C1-4haloalkyl. In some embodiments, R3aand R2together with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H or —C1-6alkyl. In some embodiments, R3aand R2together with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H or —C1-3alkyl. In some embodiments, R3aand R2together with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H or methyl. In some embodiments, R3aand R2together with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof, R3aand R2together with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H, —C1-6alkyl, —C1-4haloalkyl, or —C1-4alkylene-O—C1-4alkyl. In some embodiments, R3aand R2together with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H, —C1-6alkyl, or —C1-4haloalkyl. In some embodiments, R3aand R2together with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H or —C1-6alkyl. In some embodiments, R3aand R2together with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H or —C1-3alkyl. In some embodiments, R3aand R2together with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H or methyl. In some embodiments, R3aand R2together with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, R3aand R5atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H, —C1-6alkyl, —C1-4haloalkyl, or —C1-4alkylene-O—C1-4alkyl. In some embodiments, R3aand R5atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H, —C1-6alkyl, or —C1-4haloalkyl. In some embodiments, R3aand R5atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H or —C1-6alkyl. In some embodiments, R3aand R5atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H or —C1-3alkyl. In some embodiments, R3aand R5atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H methyl. In some embodiments, R3aand R5atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof, R3aand R5atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H, —C1-6alkyl, —C1-4haloalkyl, or —C1-4alkylene-O—C1-4alkyl. In some embodiments, R3aand R5atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H, —C1-6alkyl, or —C1-4haloalkyl. In some embodiments, R3aand R5atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H or —C1-6alkyl. In some embodiments, R3aand R5atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H or —C1-3alkyl. In some embodiments, R3aand R5atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H or methyl. In some embodiments, R3aand R5atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof, R3aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H, —C1-6alkyl, —C1-4haloalkyl, or —C1-4alkylene-O—C1-4alkyl. In some embodiments, R3aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H, —C1-6alkyl, or —C1-4haloalkyl. In some embodiments, R3aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H or —C1-6alkyl. In some embodiments, R3aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H or —C1-3alkyl. In some embodiments, R3aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H or methyl. In some embodiments, R3aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R3bis H.

In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof, R3aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H, —C1-6alkyl, —C1-4haloalkyl, or —C1-4alkylene-O—C1-4alkyl. In some embodiments, R3aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H, —C1-6alkyl, or —C1-4haloalkyl. In some embodiments, R3aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H or —C1-6alkyl. In some embodiments, R3aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H or —C1-3alkyl. In some embodiments, R3aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H or methyl. In some embodiments, R3aand R6atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one oxygen atom; and R3bis H.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof, R4ais —C1-6alkyl or —C1-4haloalkyl. In some embodiments, R4ais —C1-3alkyl. In some embodiments, R4ais methyl. In some embodiments, R4ais —C1-4haloalkyl.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof, R4ais methyl and R4bis H, halo, —C1-6alkyl, or —C1-4haloalkyl. In some embodiments, R4ais methyl and R4bis H, —C1-3alkyl, or —C1-4haloalkyl. In some embodiments, R4ais methyl and R4bis H or C1-3alkyl. In some embodiments, R4ais methyl and R4bis —C1-3alkyl or —C1-4haloalkyl. In some embodiments, R4ais methyl and R4bis —C1-3alkyl. In some embodiments, R4ais methyl and R4bis —C1-4haloalkyl. In some embodiments, R4ais methyl and R4bis H.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof, W1is a bond.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof, W1is —CR5aR5b—, wherein R5ais H or C1-6alkyl and R5bis H, C1-6alkyl, C1-4haloalkyl, or halo. In some embodiments, R5ais H or C1-6alkyl and R5bis H, C1-6alkyl, or halo. In some embodiments, R5ais H or C1-6alkyl and R5bis H or C1-6alkyl. In some embodiments, R5ais H or C1-6alkyl and R5bis C1-6alkyl. In some embodiments, R5ais H or C1-6alkyl and R5bis H.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof, W1is —CR5aR5b—, wherein R5ais H and R5bis H, C1-6alkyl, C1-4haloalkyl, or halo. In some embodiments, R5ais H and R5bis H, C1-6alkyl, or halo. In some embodiments, R5ais H and R5bis H or C1-6alkyl. In some embodiments, R5ais H and R5bis C1-6alkyl. In some embodiments, R5ais H and R5bis H.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof W2is —CR6aR6b—, R6aand R3atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R6bis H, C1-6alkyl, C1-4haloalkyl, halo, hydroxyl, cyano, —O—C1-4alkyl, or C1-4alkylene-O—C1-4alkyl. In some embodiments, R6aand R3atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R6bis H, C1-6alkyl, C1-4haloalkyl, halo. In some embodiments, R6aand R3atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S; and R6bis H.

In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof W2is —CR6aR6b—, R6aand R3atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one heteroatom selected from N, O, and S; and R6bis H, C1-6alkyl, C1-4haloalkyl, halo, hydroxyl, cyano, —O—C1-4alkyl, or C1-4alkylene-O—C1-4alkyl. In some embodiments, R6aand R3atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one heteroatom selected from N, O, and S; and R6bis H, C1-6alkyl, C1-4haloalkyl, halo. In some embodiments, R6aand R3atogether with the carbons to which they are attached from a 4 to 6 membered heterocyclic ring containing one heteroatom selected from N, O, and S; and R6bis H.

In some embodiments of the compound of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof, W2is —CR7a═CR7b—, wherein R7aand R7btogether with the carbon atoms to which they are attached form a C5-10aryl optionally substituted with one to four RA2, wherein each RA2is independently halo, cyano, or C1-4alkyl. In some embodiments, R7aand R7btogether with the carbon atoms to which they are attached form a fused phenyl optionally substituted with one to four RA2, wherein each RA4is independently halo, cyano, or C1-4alkyl. In some embodiments, R7aand R7btogether with the carbon atoms to which they are attached form an unsubstituted fused phenyl.

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

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

In some embodiments, the compound of Formula I, Ia, Ib, Ic, Id, or II, or the pharmaceutically acceptable salt thereof,

In some embodiments, the compound of Formula I, Ia, Ib, Ic, Id or II, is selected form the group consisting of:

In some embodiments, the compound of Formula I, Ia, Ib, Ic, Id or II, is selected form the group consisting of:

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

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

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

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

In some embodiments, the compound of Formula I is

III. Compositions and Kits

Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that comprise one or more of the compounds provided herein or pharmaceutically acceptable salts, isomer, or a mixture thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. The compounds provided herein may be the sole active ingredient or one of the active ingredients of the pharmaceutical compositions. Suitable pharmaceutically acceptable vehicles may 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 & C. T. Rhodes, Eds.).

In one aspect, provided herein are pharmaceutical compositions comprising a compound provided herein (e.g., a compound of Formula I, Ia, Ib, Ic, Id, or II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical compositions comprise a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

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 compositions further comprise a therapeutically effective amount of the 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.

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

One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may 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 a sterile aqueous solution, and similar pharmaceutical vehicles.

Oral administration may be another route for administration of the compounds provided herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound provided herein or pharmaceutically acceptable salts, isomer, or a mixture thereof, the active ingredient (such as a compound provided herein) is usually 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, which 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.

The pharmaceutical compositions that include at least one compound described herein or pharmaceutically acceptable salts, 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 the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Pat. Nos. 3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods of the present disclosure employs transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds provided herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

In one aspect, provided herein are kits that comprise a compound provided herein (e.g., a compound of Formula I, Ia, Ib, Ic, Id, or II), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and suitable packaging. In some embodiments, the kit further comprises instructions for use. In some embodiments, the kit comprises a compound provided herein (e.g., a compound of Formula I, Ia, Ib, Ic, Id, or II), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a label and/or instructions for use of the compounds in the treatment of the indications, including the diseases or conditions, described herein.

In some embodiments, the kits 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 one aspect, provided herein are articles of manufacture that comprise a compound described herein or pharmaceutically acceptable salts, isomer, or a mixture thereof in a suitable container. In some embodiments, the container may be a vial, jar, ampoule, preloaded syringe, or intravenous bag.

In one embodiment, methods of treating an HIV (e.g., HIV-1 and/or HIV-2) infection in a human having or at risk of having the infection 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, are provided.

In some embodiments, the methods further comprise administering to the human a therapeutically effective amount of one, two, three, or four additional therapeutic agents. In certain embodiments, the additional therapeutic agent or agents are anti-HIV agents. In particular embodiments, the additional therapeutic agent or agents are HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsid polymerization inhibitors, HIV bNAbs (broadly neutralizing HIV antibodies), TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. In one embodiment, the additional therapeutic agent or agents are abacavir, tenofovir alafenamide, tenofovir disoproxil, N—((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, or a pharmaceutically acceptable salt thereof.

In another embodiment, a use of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, for treating an HIV (e.g., HIV-1 and/or HIV-2) infection in a human having or at risk of having the infection is provided.

In another 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, for use in medical therapy is provided.

In another embodiment, a compound of Formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salt thereof, for use in treating an HIV infection is provided.

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

In another 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 for use in a method of treating an HIV infection in a human having or at risk of having the infection, is provided wherein said method further comprises administering to the human one, two, three, or four additional therapeutic agents.

In another 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 for use in a method of treating an HIV infection in a human having or at risk of having the infection, is provided wherein said method further comprises administering to the human one, two, three, or four additional therapeutic agents selected from the group consisting of HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversing agents, capsid polymerization inhibitors, HIV bNAbs, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. In one embodiment, the one, two, three, or four additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, latency reversing agents, HIV capsid inhibitors, HIV bNAbs, TLR7 agonists, and combinations thereof.

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

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

In another 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 for use in a method of treating an HIV infection in a human having or at risk of having the infection, is provided wherein said method further comprises administering to the human a therapeutically effective amount of tenofovir disoproxil.

In another 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 for use in a method of treating an HIV infection in a human having or at risk of having the infection, is provided wherein said method further comprises administering to the human a therapeutically effective amount of tenofovir alafenamide.

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

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

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.

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., before the exposure of the individual to the HIV virus to prevent HIV infection from taking hold if the individual is exposed to the virus and/or to keep 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.

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

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.

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

In still another embodiment, a method of inhibiting the replication of HIV is disclosed. The method comprises exposing the virus to an effective amount of the compound of Formula I, Ia, Ib, Ic, Id, or II, or a salt thereof, under conditions where replication of HIV is inhibited.

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

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

The compounds of the present disclosure (also referred to herein as the 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 may 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.

A compound of the present disclosure may be administered to an individual in accordance with an effective dosing regimen for a desired period of time or duration, such as at least about one month, at least about 2 months, at least about 3 months, at least about 6 months, or at least about 12 months or longer. In some embodiments, the compound is administered on a daily or intermittent schedule for the duration of the individual's life.

The specific dose level of a compound 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, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject's body weight (mg/kg). Dosages of between about 0.1 and 150 mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate. Normalizing according to the subject's body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject.

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

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

The compounds of the present disclosure may be administered to an individual (e.g., a human) in a therapeutically effective amount. In some embodiments, the compound is administered once daily.

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

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

In some embodiments, the methods described herein comprise administering to the subject an initial daily dose of about 1 to 500 mg of a compound p herein and increasing the dose by increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dosage can be increased daily, every other day, twice per week, once per week, once every two weeks, once every three weeks, or once a month.

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

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

The frequency of dosage of the compound of the present disclosure will be determined by the needs of the individual patient and can be, for example, once per day or twice, or more times, per day. Administration of the compound continues for as long as necessary to treat the HBV infection, HIV infection, cancer, hyper-proliferative disease, or any other indication described herein. For example, a compound can be administered to a human being infected with HBV for a period of from 20 days to 180 days or, for example, for a period of from 20 days to 90 days or, for example, for a period of from 30 days to 60 days.

Administration can be intermittent, with a period of several or more days during which a patient receives a daily dose of the compound of the present disclosure followed by a period of several or more days during which a patient does not receive a daily dose of the compound. For example, a patient can receive a dose of the compound every other day, or three times per week. Again by way of example, a patient can receive a dose of the compound each day for a period of from 1 to 14 days, followed by a period of 7 to 21 days during which the patient does not receive a dose of the compound, followed by a subsequent period (e.g., from 1 to 14 days) during which the patient again receives a daily dose of the compound. Alternating periods of administration of the compound, followed by non-administration of the compound, can be repeated as clinically required to treat the patient.

The compounds of the present disclosure or the pharmaceutical compositions thereof may be administered once, twice, three, or four times daily, using any suitable mode described above. Also, administration or treatment with the compounds may be continued for a number of days; for example, commonly treatment would continue for at least 7 days, 14 days, or 28 days, for one cycle of treatment. Treatment cycles are well known in cancer chemotherapy, and are frequently alternated with resting periods of about 1 to 28 days, commonly about 7 days or about 14 days, between cycles. The treatment cycles, in other embodiments, may also be continuous.

VI. Combination Therapy

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

In one embodiment, pharmaceutical compositions 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 are provided.

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 which are suitable for treating an HIV infection.

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.

Administration of HIV Combination Therapy

In certain embodiments, a compound disclosed herein is administered with one or more additional therapeutic agents. Co-administration of a compound disclosed herein with one or more additional therapeutic agents generally refers to simultaneous or sequential administration of a compound disclosed herein and one or more additional therapeutic agents, such that therapeutically effective amounts of the compound disclosed herein and the one or more additional therapeutic agents are both present in the body of the patient. When administered sequentially, the combination may be administered in two or more administrations.

Co-administration includes administration of unit dosages of the compounds disclosed herein before or after administration of unit dosages of one or more additional therapeutic agents. For example, the compound disclosed herein may be administered within seconds, minutes, or hours of the administration of the 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 by administration of a unit dose of a compound disclosed herein within seconds or minutes. In other embodiments, a unit dose of a compound disclosed herein is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of one or more additional therapeutic agents. In yet other embodiments, a unit dose of one or more additional therapeutic agents is administered first, followed, after a period of hours (e.g., 1-12 hours), by administration of a unit dose of a compound disclosed herein.

In certain embodiments, a compound disclosed herein is combined with one or more additional therapeutic agents in a unitary dosage form for simultaneous administration to a patient, for example as a solid dosage form for oral administration.

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

In certain embodiments, such tablets are suitable for once daily dosing.

HIV Combination Therapy

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.

HIV Combination Drugs

Other HIV Drugs

HIV Protease Inhibitors

HIV Reverse Transcriptase Inhibitors

HIV Integrase Inhibitors

HIV Entry Inhibitors

Examples of CD4 attachment inhibitors include ibalizumab and CADA analogs.

HIV Maturation Inhibitors

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

Latency Reversing Agents

Examples of HDAC inhibitors include romidepsin, vorinostat, and panobinostat.

Capsid Inhibitors

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 (lenacapvir), AVI-621, AVI-101, AVI-201, AVI-301, and AVI-CAN1-15 series. In some embodiments, the compounds disclosed herein are used in combination with lenacapvir.

Example of in vivo delivered bnABs such as AAV8-VRC07; mRNA encoding anti-HIV antibody VRC01.

Examples of pharmacokinetic enhancers include cobicistat and ritonavir.

Additional Therapeutic Agents

HIV Vaccines

HIV Combination Therapy

It will be appreciated by one of skill in the art that the additional therapeutic agents listed above may be included in more than one of the classes listed above. The particular classes are not intended to limit the functionality of those compounds listed in those classes.

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

In a particular embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

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

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

A compound as disclosed herein (e.g., any compound of Formula I, Ia, Ib, Ic, Id, or II) may be combined with one or more additional therapeutic agents in any dosage amount of the compound of Formula I, Ia, Ib, Ic, Id, or II (e.g., from 1 mg to 500 mg of compound).

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

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

In one embodiment, kits 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 are provided.

Birth Control (Contraceptive) Combination Therapy

Gene Therapy and Cell Therapy

Gene Therapy and Cell Therapy including the genetic modification to silence a gene; genetic approaches to directly kill the infected cells; the infusion of immune cells designed to replace most of the patient's own immune system to enhance the immune response to infected cells, or activate the patient's own immune system to kill infected cells, or find and kill the infected cells; genetic approaches to modify cellular activity to further alter endogenous immune responsiveness against the infection.

Examples of dendritic cell therapy include AGS-004.

Example of CCR5 gene editing drugs such as SB-728T.

Example of CCR5 gene inhibitors such as Cal-1.

Gene Editors

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 endonucleases system, and a meganuclease system.

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

CAR-T Cell Therapy

A population of immune effector cells engineered to express a chimeric antigen receptor (CAR), wherein the CAR comprises an HIV antigen-binding domain. The HIV antigen include an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, the CD4-induced binding site on gp120, N glycan on gp120, the V2 of gp120, the 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. Cells can be autologous or allogeneic.

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

TCR-T Cell Therapy

TCR-T cells are engineered to target HIV derived peptides present on the surface of virus-infected cells.

Exemplary chemical entities of the present disclosure are provided in the specific examples that follow. Those skilled in the art will recognize that, to obtain the various compounds herein, starting materials may be suitably selected so that the ultimately desired substituents will be carried through the reaction scheme with or without protection as appropriate to yield the desired product. Alternatively, it may be necessary or desirable to employ, in the place of the ultimately desired substituent, a suitable group that may be carried through the reaction scheme and replaced as appropriate with the desired substituent. Furthermore, one of skill in the art will recognize that the transformations shown in the schemes below may be performed in any order that is compatible with the functionality of the particular pendant groups.

The Examples provided herein describe the synthesis of compounds disclosed herein as well as intermediates used to prepare the compounds. It is to be understood that individual steps described herein may be combined. It is also to be understood that separate batches of a compound may be combined and then carried forth in the next synthetic step.

In the following description of the Examples, specific embodiments are described. These embodiments are described in sufficient detail to enable those skilled in the art to practice certain embodiments of the present disclosure. Other embodiments may be utilized and logical and other changes may be made without departing from the scope of the disclosure. The following description is, therefore, not intended to limit the scope of the present disclosure.

Synthesis of (3S,7S)-7-methyl-2,3,4,7-tetrahydro-1H-azepin-3-amine

Trifluoacetic acid (20 mL) was added to benzyl (3S,7S)-3-(((benzyloxy)carbonyl)amino)-7-methyl-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate (6.2 g, 15.7 mmol) and the reaction was heated to 100° C. for 4 hours. The reaction mixture was concentrated down and the crude was used directly in next step.

Methanol (300 mL) and water (30 mL) were added to methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate (6.75 g, 15.7 mmol) and (3S,7S)-7-methyl-2,3,4,7-tetrahydro-1H-azepin-3-amine (the reaction crude from the previous step). At room temperature, NaHCO3(13.2 g, 157 mmol) was added to the reaction mixture. The reaction was stirred at. room temperature overnight, then heat to 60° C. for 5 hours. The reaction mixture was concentrated down, then added ethyl acetate, washed with saturated ammonium chloride solution. The organic layer was concentrated an d purified via silica chromatograph (eluting with 0-10% MeOH/DCM) to give (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide. MS (m/z) 524.11 [M+H]+.

Synthesis of (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

Selenium dioxide (17.4 g, 157 mmol.) was added to (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (product of previous step, 15.7 mmol) in dioxane (160 mL). Then the reaction was heated to 105° C. overnight. The reaction mixture was cooled down and the solid was filtered off the solid. The filtrate was extracted using ethyl acetate and saturated ammonium chloride solution. The organic layer was concentrated and purified via silica chromatograph (eluting with 40-100% Ethyl acetate/hexane) to give (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide. MS (m/z) 538.095 [M+H]+.

This intermediate was prepared by following the procedure of making (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (intermediate A), except that methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate was used in the 2ndstep. MS (m/z) 520.200 [M+H]+.

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]diazonine-10-carboxamide (intermediate A) (122 mg, 0.227 mmol) in methanol (5 mL) was added cerium (III) chloride heptahydrate (85 mg, 0.227 mmol). Then to the mixture was added sodium borohydride (2.1 mg, 0.057 mmol) slowly at 0° C. After 5 min, the reaction was quenched by adding sat. NaHCO3solution and extracted with DCM. The organic phase was separated and concentrated down. The residue was then dissolved in DCM, washed with brine. The organic phase was dried over MgSO4, filtered, concentrated down and further used without purification.

Preparation of (3S,6S,7R)-12-(benzyloxy)-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

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]diazonine-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 adding sat. NaHCO3, extracted with EtOAc, the organic phase was separated, dried over MgSO4, filtered, concentrated down and to the resulting product was used in next step without further purification.

Preparation of (3S,6S,7R)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

Preparation of (3S,6R,7R)-12-(benzyloxy)-3-methyl-1,11-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-6-yl benzoate

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]diazonine-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 axodicarboxylate (27.2 mg, 0.134 mmol). The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc, washed with sat. NaHCO3, the organic phase was separated, dried over MgSO4, filtered, concentrated down and purified by silica gel column chromatography (0-100% EtOAc/hexane) to give the title product (30 mg).

Preparation of (3S,6R,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

The reaction mixture of (3S,6R,7R)-12-(benzyloxy)-3-methyl-1,11-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-6-yl benzoate (30 mg, 0.047 mmol), LiOH.H2O (5.6 mg, 0.233 mmol) in MeOH (2 mL) and H2O (0.5 mL) was stirred at room temperature overnight. The reaction mixture was concentrated down. The residue was washed with brine, extracted with EtOAc, the organic phase was separated, dried over MgSO4, filtered, concentrated down and used in next step without purification.

Preparation of (3S,6R,7R)-12-(benzyloxy)-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

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]diazonine-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 adding sat. NaHCO3, extracted with EtOAc, the organic phase was separated, dried over MgSO4, filtered, concentrated down and go to next step without purification.

Preparation of (3S,6R,7R)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

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]diazonine-10-carboxylic acid

A reaction mixture of (3S,7S)-7-methyl-2,3,4,7-tetrahydro-1H-azepin-3-amine (0.39 g, 3.1 mmol), (diethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (1.07 g, 3.09 mmol) and sodium bicarbonate (2.6 g, 30.9 mmol) in MeOH (10 mL) and water (2 mL) was stirred at rt overnight. Then the reaction mixture was stirred at 60° C. for 8 h. The reaction mixture was cooled and concentrated down. The residue was washed with water, extracted with EtOAc. The organic phase was separated, dried over MgSO4, filtered, concentrated down and purified by silica gel chromatography, eluting by 0-100% hexane/EtOAc to give title compound.

Preparation of (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxylic acid

A reaction mixture of ethyl (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxylate (1.02 g, 2.5 mmol) and sodium hydroxide (2N, 3.75 mL) in MeOH (5 mL) was stirred at 60° C. for 1 h. The reaction mixture is cooled and concentrated down. The residue was dissolved in water, using HCl to adjust the pH to 4, extracted with EtOAc. The organic phase was separated, dried over MgSO4, filtered, concentrated down and used in next reaction without further purification

Preparation of (3S,7S)-12-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

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]diazonine-10-carboxylic acid (0.88 g, 2.31 mmol) in DCM (10 mL) was added diisopropylethylamine (1.61 mL, 9.25 mmol) and 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU) (0.88 g, 2.31 mmol) at 0° C. The reaction mixture was stirred at 0° C. for 2 h. The reaction mixture was washed with sat. NaHCO3, extracted with EtOAc, the organic phase was separated, dried over MgSO4, filtered, concentrated down and purified by silica gel chromatography, eluting by 0-100% hexane/EtOAc to give titled compound.

Preparation of (3S,7R)-12-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

The 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]diazonine-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 down and filtered to remove solid. The filtrate was diluted with EtOAc, washed with sat. NaHCO3. The organic phase was dried over MgSO4, filtered, concentrated down and purified by silica gel chromatography, eluting with 0-100% hexane/EtOAc to give titled compound.

Preparation of (3S,6S,7R)—N-(3-chloro-2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

Synthesis of (3S,6S,7R)-6,12-dihydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

(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]diazonine-10-carboxamide (132 mg, 0.246 mmol) was dissolved in anhydrous THF (3.0 mL) and the resulting mixture was cooled to −20° C. To this stirred cold mixture was added 3.0 M ether solution of methyl magnesium bromide (0.41 mL, 1.23 mmol). After stirring for 20 minutes, 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): calcd H+ for C29H26F3N3O5, Theoretical: 553.18, Found: 553.95. Synthesis of (1R,10S,13S)-6,13-dihydroxy-10,13-dimethyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide:

Example 13: Preparation of (3S,6R,7R)-6-chloro-N-(2,4-difluorobenzyl)-12-hydroxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

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]diazonine-10-carboxamide

To a solution (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]diazonine-10-carboxamide (110 mg, 0.211 mmol) in DCM (27 mL) under N2was added triethylamine (1.18 mL, 8.44 mmol) and thionyl chloride (0.615 mL, 8.44 mmol). After 5 min, the reaction was quenched by adding sat. NaHCO3solution and extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, concentrated down and purified by flash column chromatography on silica gel using DCM/MeOH as a solvent system (1:0->95:5->8:2 gradient) to afford (3S,6R,7R)-12-(benzyloxy)-6-chloro-N-(2,4-difluorobenzyl)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide as a red/brown solid (111 mg, 98%).

Example 15: Preparation of (1R,10S,13S)-6,13-dihydroxy-10,13-dimethyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide

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]diazonine-10-carboxamide

Example 17: Preparation of (1R,10S,13S)—N-[(2,4-difluorophenyl)methyl]-6,13-dihydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide

Step 1: Synthesis of (1R,10S,13S)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-13-hydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide

The compound was prepared by following step 1 for the synthesis of Example 11, except in step 1, (3 S,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]diazonine-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]diazonine-10-carboxamide. LCMS-ESI+(m/z): calcd H+ for C29H27F2N3O5, Theoretical: 535.19, Found: 535.94.

Step 2: Synthesis of (1R,10S,13S)—N-[(2,4-difluorophenyl)methyl]-6,13-dihydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide

Preparation of (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

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]diazonine-10-carboxamide (intermediate A) (122 mg, 0.227 mmol) in methanol (5 mL) was added cerium (III) chloride heptahydrate (85 mg, 0.227 mmol). Then to the mixture was added sodium borohydride (2.1 mg, 0.057 mmol) slowly at 0° C. After 5 min, the reaction was quenched by adding saturated NaHCO3solution and extracted with DCM. The organic phase was separated and concentrated down. The residue was then dissolved in DCM, washed with brine. The organic phase was dried over MgSO4, filtered, concentrated down and further used without purification.

Preparation of (3 S,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]diazonine-10-carboxamide

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]diazonine-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 adding saturated NaHCO3, extracted with EtOAc, the organic phase was separated, dried over MgSO4, filtered, concentrated down and the resulting product was used in next step without further purification.

Preparation of (3S,6S,7R)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

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]diazonine-10-carboxamide

(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]diazonine-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 for 10 minutes at 50° C. Then cooled to 0° C., ethyl acetate was added, washed with saturated sodium bicarbonate aqueous solution and brine. The organic layer was separated, dried over magnesium sulfate, filtered and concentrated to dryness. the residue was purified by RP-HPLC to afford the title product. MS (m/z): 590.200 [M+H]+.

Step 2: Synthesis of (3S,6S,7R)-6-(difluoromethoxy)-12-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

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

Synthesis of (3S,6S,7R)-12-hydroxy-6-methoxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

Example 24: Synthesis of (3S,6S,7R)-12-hydroxy-6-methoxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

Example 25: Preparation of (3S,6S,7R)-6-ethoxy-12-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

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

Dissolve (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]diazonine-10-carboxamide (24 mg, 0.04 mmol) in 2 mL anhydrous DMF, cool to 0° C., NaH (1.5 eq.) was added, followed by EtI (1.2 eq.). After 10 minutes, the reaction was complete. A drop of water was added to quench the reaction. The crude reaction was purified via preparative HPLC, eluting 10-60% acetonitrile (0.1% TFA) in water (0.1% TFA) to give (3S,6S,7R)-12-(benzyloxy)-6-ethoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide. MS (m/z) 568.24 [M+H]+.

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

Example 26: Preparation of (3S,6S,7R)-6-ethoxy-12-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

Example 28: Preparation of (3S,6S,7R)-6-ethyl-6,12-dihydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

Synthesis of (3S,6S,7R)-12-(benzyloxy)-6-ethyl-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

Dissolved (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]diazonine-10-carboxamide (43 mg, 0.08 mmol) is 2 mL anhydrous THF. The mixture was cooled to 0° C. and EtMgBr (3.4 M, 3 eq., 0.07 mL) was added. The reaction was kept at 0° C. for one hour. A drop of water was added to quench the reaction. The reaction crude was filtered and purified via preparative HPLC, eluting 10-60% acetonitrile (0.1% TFA) in water (0.1% TFA) to give (3S,6S,7R)-12-(benzyloxy)-6-ethyl-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide. MS (m/z) 568.21 [M+H]+.

Synthesis of (3S,6S,7R)-6-ethyl-6,12-dihydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

Example 29: Synthesis of (1R,10S,13S)-6,13-dihydroxy-10-methyl-5,8-dioxo-13-(trideuteriomethyl)-N-[(2,4,6-trifluorophenyl)methyl]-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide

Example 30: Synthesis of (1R,10S,13S)—N-[(2,4-difluorophenyl)methyl]-6,13-dihydroxy-10-methyl-5,8-dioxo-13-(trideuteriomethyl)-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide

Example 31: Synthesis of (1R,10S,13S)—N-[(2,4-difluorophenyl)methyl]-6,13-dihydroxy-10-methyl-5,8-dioxo-13-(trideuteriomethyl)-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide

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

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, flushed with nitrogen three times, then it was degassed and flushed with hydrogen three times before it was hydrogenated under hydrogen balloon for 3 hours. The reaction was then degassed and flushed with nitrogen and filtered through a pad of Celite. The filtrate was concentrated, and dried over the 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 for overnight. The reaction was then diluted with EtOAc, washed with water, then brine, dried over sodium sulfate, filtered and concentrated, purified by normal phase chromatography.

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

Example 32: Synthesis of (3S,6R,7R)-6,12-dihydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

Synthesis of (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

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]diazonine-10-carboxamide

Synthesis of (2R,3′S,7′R)-12′-(benzyloxy)-3′-methyl-1′,11′-dioxo-N-(2,4,6-trifluorobenzyl)-1′,4′,5′,11′-tetrahydro-3′H,7′H-spiro[oxirane-2,6′-[2,7]methanopyrido[1,2-a][1,4]diazonine]-10′-carboxamide

Example 33: Synthesis of (1R,10S,13R)—N-[(2,4-difluorophenyl)methyl]-6,13-dihydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide

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

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

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

(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 1:1 mixture of 1 N sodium thiosulfate and saturated sodium bicarbonate, stirred vigorously for 10 minutes. Layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered and concentrated, purified by normal phase chromatography. LCMS-ESI+(m/z): calcd H+ for C29H27F2N3O5, Theoretical: 535.19, Found: 536.17.

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

Preparation of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(methoxy-d3)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

(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]diazonine-10-carboxamide was made similar to (3 S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide in Example 18, except that iodomethane-d3 was used instead of iodomethane and 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]diazonine-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]diazonine-10-carboxamide.

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]diazonine-10-carboxamide

Example 35: Synthesis of (1R,10R,13S)—N-[(2,4-difluorophenyl)methyl]-6,13-dihydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide

Step 1: Synthesis of methyl (3S,7R)-3-amino-7-methyl-1,2,4,7-tetrahydroazepine-3-carboxylate; 2,2,2-trifluoroacetic acid

O1-benzyl O3-methyl (3S,7R)-3-(benzyloxycarbonylamino)-7-methyl-4,7-dihydro-2H-azepine-1,3-dicarboxylate (1.2 g, 2.65 mmol) was mixed with TFA (10.0 mL). The resulting mixture was sealed and heated at 100° C. for 4 hours. The reaction was cooled to room temperature and concentrated, the residue was coevaporated with EtOAc for 4 times to give desired product, which was used directly in next step. LCMS-ESI+(m/z): calcd H+ for C9H16N2O2, Theoretical: 184.12, Found: 185.01.

Step 2: Synthesis of (1S,10R)-6-benzyloxy-4-[(2,4-difluorophenyl)methylcarbamoyl]-10-methyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-1-carboxylic acid

The residue from previous step (2.36 g, 5.72 mmol) and methyl 3-benzyloxy-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyran-2-carboxylate (1.08 g, 2.52 mmol) was 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. for overnight. The reaction was cooled to room temperature. The residue was partitioned between EtOAc and water, 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): calcd H+ for C29H25F2N3O6, Theoretical: 549.17, Found: 550.10.

Step 3: Synthesis of (1R,10R)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-methyl-5,8,13-trioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide

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

The compound was prepared following Step 1 of the preparation of Example 17 except (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 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): calcd H+ for C29H27F2N3O5, Theoretical: 535.19, Found: 536.13. Stereochemistry at C13 not confirmed.

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

Example 36: 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]diazonine-10-carboxamide

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

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

To ((1R,10S,13S)-6,13-dihydroxy-10,13-dimethyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide (50 mg, 0.355 mmol) was added DCM (0.88 mL), then 2.7 M solution in toluene of Deoxo-Fluor (3.25 mL, 8.8 mmol). The mixture was stirred at 20° C. for 60 hr. The reaction was quenched by slow addition into ice-cold 10% aqueous potassium carbonate, then extracted with EtOAc. The organic layer was washed with saturated aqueous ammonium chloride, then brine, dried over magnesium sulfate, filtered and concentrated. Flash column chromatography (silica gel, EtOAc/Hexane) yielded the product (stereochemistry assignment tentative). LCMS-ESI+(m/z): calcd H+ for C29H26F5N3O5, Theoretical: 592.19, Found: 592.11.

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

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

A mixture of (3S,6R,7R)-12-(benzyloxy)-6-methoxy-3-methyl-1,4,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (770.8 mg, 1.35 mmol), prepared according to Example 36, in methanol (30 mL) was stirred at 0° C. and NaBH4 (57.7 mg, 1.53 mmol) was added. After 3 min, THF (˜10 mL) was to dissolve the insoluble material. 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 separation of two layers, the aqueous fraction 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 column chromatography on silica gel (80 g column) eluting 0-10% methanol in CH2Cl2 to get (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]diazonine-10-carboxamide. ES/MS m/z: calculated for C29H29F3N3O6 (M+H): 572.20, found: 572.20.

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

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]diazonine-10-carboxamide (811.2 mg, 1.42 mmol) in CH2Cl2 (14 mL) was stirred at 0° C. as 2.7 M Deoxo-Fluor (bis(2-methoxyethyl)aminosulfur trifluoride) solution 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. as saturated NaHCO3 (˜40 mL) was added. After water was added (˜40 mL). the product was extracted with ethyl acetate (˜70 mL×2). After the extracts were washed with brine (˜70 mL×1), the combined organic fractions were dried (MgSO4). The residue was purified by column chromatography on silica gel (80 g column) eluting 50-100% ethyl acetate in hexane to get (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]diazonine-10-carboxamide: ES/MS m/z: calculated for C29H28F4N3O5 (M+H): 574.20, found: 574.30.

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]diazonine-10-carboxamide

Step 1: Synthesis of (3S,4S,6R,7R)-12-(benzyloxy)-6-methoxy-3-methyl-1,11-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-4-yl benzoate

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]diazonine-10-carboxamide

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

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]diazonine-10-carboxamide

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

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

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

The above solution was stirred at 0° C. as NaBH4 (157 mg, 4.15 mmol) was added. After 30 min at 0° C., the reaction mixture was concentrated, and the residue was dissolved in saturated NaHCO3 before the product was extracted with ethyl acetate (×2). After the organic extracts were washed with brine (×1), the organic fractions were combined, dried (MgSO4), and concentrated. The residue was purified by repeated column chromatography on silica gel (80 g column) eluting 0-5% methanol in CH2Cl2, and preparative HPLC (column, Gemini 5 um C18 110A, LC column 100×30 mm) eluting 23-90% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 min. After the combined fractions were neutralized by adding saturated NaHCO3 (˜1 mL), the solution was concentrated to remove most of acetonitrile. The resulting aqueous mixture was extracted with EA (˜25 mL×2), and the extracts were washed with brine (×1) combined, dried (MgSO4), and concentrated to get (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]diazonine-10-carboxamide. ES/MS m/z: calculated for C29H29F3N3O6 (M+H): 572.20, found: 572.27.

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

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]diazonine-10-carboxamide (81.8 mg, 0.143 mmol) in CH2Cl2 (2 mL) was stirred at 0° C. as 2.7 M bis(2-methoxyethyl)aminosulfur trifluoride solution 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. as saturated NaHCO3 (10 mL) was added. After water was added (20 mL). The product was extracted with ethyl acetate (25 mL×2). After the extracts were combined, it was dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (12 g column used) eluting 20-100% EA in hexane to get (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]diazonine-10-carboxamide: ES/MS m/z: calculated for C29H28F4N3O5 (M+H): 574.20, found: 574.30.

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

Steps 1-2: Synthesis of (3R,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

Steps 3-4: Synthesis of (3R,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

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]diazonine-10-carboxamide (2971.9 mg, 5.70 mmol) and imidazole (601.0 mg, 8.83 mmol) in CH2Cl2 (45 mL) was added tert-butyldimethylsilyl chloride (1039.7 mg, 6.90 mmol) at room temperature and the resulting solution was stirred at rt. After 16 h, the reaction mixture was diluted with CH2Cl2, washed with water (×1), and the two layers were separated. After the aqueous fraction was extracted with ethyl acetate (×1), the organic fractions were combined, dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel (120 g column) eluting 0-100% ethyl acetate in hexane to get (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]diazonine-10-carboxamide. ES/MS m/z: calculated for C34H40F2N3O5Si (M+H): 636.27, found: 636.30.

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

Steps 5-6: Synthesis of (3R,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

A mixture of (3R,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (1420.6 mg, 2.19 mmol) and 10% palladium on carbon (151.3 mg) in ethanol (30 mL) was stirred under H2 atmosphere at rt. After 2 h, the reaction mixture was filtered, and the filtrate was concentrated and dried in vacuum for 30 min. ES/MS m/z: calculated for C29H40F2N3O7Si (M+EtOH+H): 608.26, found: 608.30.

The above residue and potassium carbonate (614.5 mg, 4.45 mmol) in DMF (13 mL) was stirred at room temperature when benzyl bromide (0.35 mL, 2.94 mmol) was added. After stirring at room temperature overnight, the reaction mixture was diluted with water (˜30 mL) and the product was extracted with ethyl acetate (×2). After the extracts were washed with water (×1), combined, dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel (40 g column) eluting 0-10% methanol in CH2Cl2 to get (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]diazonine-10-carboxamide: ES/MS m/z: calculated for C34H42F2N3O7Si (M+H2O+H): 670.28, found: 670.30; calculated for C35H44F2N3O7Si (M+MeOH+H): 684.29, found: 684.40.

Steps 7-8: Synthesis of (3R,6S,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

A solution of (3R,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (1234.0 mg, 1.89 mmol) in methanol (18 mL) was stirred at 0° C. as 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 before extraction with EtOAc (×2). The combined extracts were dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel (80 g column) eluting 0-10% methanol in CH2Cl2 to get (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]diazonine-10-carboxamide. ES/MS m/z: calculated for C34H42F2N3O6Si (M+H): 654.28, found: 654.30.

A solution of the above product (221.3 mg, 0.338 mmol) in DMF (2.25 mL) was stirred at 0° C. as 60% sodium hydride dispersion (19.1 mg, 0.498 mmol) was added. After 20 min at 0° C., a solution of iodomethane (0.021 mL, 0.337 mmol) was added. After 1 h at 0° C., additional iodomethane (0.021 mL, 0.337 mmol) to the reaction mixture. After ˜1 h at 0° C., the reaction mixture was diluted with saturated NH4C1 and the product was extracted with ethyl acetate (×2). After the extracts were washed with water (×1), the organic fractions were combined, dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel (120 g column) eluting 0-10% methanol in CH2Cl2. The fractions containing product were combined and concentrated and the residue was purified again by column chromatography on silica gel (24 g column) eluting 20-100% ethyl acetate in hexane to get a mixture 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]diazonine-10-carboxamide. ES/MS m/z: calculated for C35H44F2N3O6Si (M+H): 668.30, found: 668.30.

Step 9: Synthesis of (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

(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]diazonine-10-carboxamide (333 mg, 0.494 mmol) from above was dissolved in 4 N HCl in dioxane (3 mL) in 0° C. bath and stirred at 0° C. for 30 min. The reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel (24 g column) eluting 0-15% methanol in CH2Cl2 to get (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]diazonine-10-carboxamide. ES/MS m/z: calculated for C28H28F2N3O6 (M+H): 554.21, found: 554.30.

Steps 10-11: Synthesis of (3R,6S,7R)—N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12-hydroxy-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

A solution of (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (50.3 mg, 0.0909 mmol) in CH2Cl2 (2.5 mL) was stirred at 0° C. as (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 added saturated NaHCO3 (5 mL). After the mixture was diluted with water (20 mL), the product was extracted with CH2Cl2 (2×20 mL). The combined extracts were dried (MgSO4), and concentrated to get the crude product, (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide. ES/MS m/z: calculated for C29H29F3N3O5 (M+H): 556.21, found: 556.30.

Steps 1-2: Synthesis of (3R,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

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

A mixture of (3R,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (0.637 mmol) and 10% palladium on carbon (70 mg) in ethanol (10 mL) was stirred under H2 atmosphere at room temperature for 4 h. The reaction mixture was filtered, and the filtrate was concentrated and dried in vacuum for 30 min.

The residue and potassium carbonate (179.0 mg, 1.3 mmol) in DMF (3.8 mL) was stirred at room temperature when 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 (×2). After the extracts were washed with water (×1), combined, dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel (40 g column) eluting 20-100% ethyl acetate in hexane to get (3R,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide. ES/MS m/z: calculated for C28H26F2N3O5 (M+H): 522.18, found: 522.20.

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

A solution of (3R,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (125.1 mg, 0.24 mmol) in methanol (3 mL) was stirred at 0° C. as 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) before extraction with ethyl acetate (20 mL×2). The combined extracts were dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel (24 g column) eluting 0-20% methanol in CH2Cl2 to get (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide: ES/MS m/z: calculated for C28H28F2N3O5 (M+H): 524.20, found: 524.30.

A solution of the above alcohol (73.2 mg, 0.140 mmol) in DMF (1.5 mL) was stirred at 0° C. as 60% sodium hydride dispersion (10.5 mg, 0.274 mmol) was added After 20 min at 0° C., a solution of iodomethane (0.0104 mL 0.168 mmol), 0.21 mL, 0.337 mmol) was added. After 1 h at 0° C., After the reaction mixture was diluted with saturated NaHCO3 solution, the product was extracted with ethyl acetate (×2), and the combined extracts were dried (MgSO4) and concentrated. The residue was purified by preparative HPLC (column, Gemini Sum C18 110A, LC column 100×30 mm) eluting 20-100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 30 min to get (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]diazonine-10-carboxamide. ES/MS m/z: calculated for C29H30F2N3O5 (M+H): 538.22, found: 538.30.

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

Example 43: Preparation of (3S,6S,7R)—N-(2,4-difluorobenzyl)-6,12-dihydroxy-3,7-dimethyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

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]diazonine-10-carboxamide

To a stirred solution of (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (220 mg, 0.409 mmol) in dry mixture of THF:Et2O (12 ml, 1:1, v/v) cooled at −78° C., fluoroiodomethane (164 mg, 2.5 eq.) was added. Then, a solution of MeLi—LiBr complex (1.5 M, in Et2O, 2 eq.) was added dropwise. After stirring for 5 min at −78° C., the reaction mixture was quenched with saturated aqueous NH4Cl (1 ml). The mixture was poured into water (50 ml) and extracted with EtOAc. The organic layer was dried with MgSO4, filtered and concentrated under vacuum. Flash chromatography on the crude afforded (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]diazonine-10-carboxamide. MS (m/z) 572.157[M+H]+.

Step 2: Synthesis of (3S,6S,7R)-6-(fluoromethyl)-6,12-dihydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

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

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

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

A solution of (3S,4S,7R)-12-(benzyloxy)-4-cyano-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide (179 mg, 0.317 mmol, 1 Eq) in DCM (5 mL) was cooled to 0° C. under N2. Bis(cyclopentadienyl)zirconium(IV) chloride hydride (Schwartz's reagent, 425 mg, 0.159 mmol, 5 Eq.) was added and the resulting mixture was stirred for 1 h at 0° C. and then 15 minutes at rt. Water was added and the mixture was extracted 3× with DCM. The combined organic layers were dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was filtered through a plug of silica to remove any Zr species using a gradient of MeOH in DCM (0 to 20%) to afford the desired product as a mixture of the parent carbonyl as well as carbonyl hydrates, hemiketals with MeOH and overreduction products. The mixture was use directly in Step 3 below.

Step 3: Preparation of (3S,4S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-4-(hydroxymethyl)-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

To a solution of the product mixture from Step 2 (above) (169 mg, 0.298 mmol, 1 Eq) in THF/MeOH (1:1) (12 mL) at 0° C. was added sodium borohydride (22.5 mg, 0.596 mmol, 2 Eq) and the resulting mixture was stirred for 10 minutes at room temperature then concentrated in vacuo. Water was added and the pH was adjusted to ˜5 by addition of dilute acetic acid. The mixture was extracted twice with DCM and the combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The resulting residue was purified by reverse phase preparative high performance liquid chromatography using a gradient of MeCN in H2O (40% to 80% with 0.1% TFA) to afford the desired product.

Step 4: Preparation of (3S,4S,6S,7R)-12-(benzyloxy)-4-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonine-10-carboxamide

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

Step 5: Preparation of (3S,4S,7R,8R)—N-(2,4-difluorobenzyl)-13-hydroxy-3-methyl-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8:4,7-dimethanopyrido[1,2-d][1,4,7]oxadiazecine-11-carboxamide

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

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

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

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]diazonine-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 adding sat. NaHCO3, extracted with EtOAc, the organic phase was separated, dried over MgSO4, filtered, concentrated down and the resulting product was used in next step without further purification.

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

Example 47: HIV MT-4 Antiviral and Cytotoxicity Assay

Antiviral Assay in MT-4 Cells

Compounds were tested in a high-throughput 384-well assay format for their ability to inhibit the replication of HIV-1 (IIIB) in MT-4 cells. 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 the Biotek Micro Flow and Labcyte ECHO acoustic dispenser. Each plate contained up to 8 test compounds, with negative (No Drug Control) and 5 μM AZT positive controls. MT-4 cells were pre-infected with 10 μL of either RPMI (mock-infected) or a fresh 1:250 dilution of HIV-1 IIIB concentrated virus stock. Infected and uninfected MT-4 cells were further diluted in complete RPMI media and added to each plate using a Micro Flow dispenser. After 5 days incubation in a humidified and temperature controlled incubator (37° C.), Cell Titer Glo (Promega) was added to the assay plates and chemiluminescence read using an Envision plate-reader. EC50values were defined as the compound concentration that causes a 50% decrease in luminescence signal, and were calculated using a sigmoidal dose-response model to generate curve fits.

Cytotoxicity Assay in MT-4 Cells

Assays were performed as above except uninfected MT-4 cells were added to each well containing test compound. In addition, 10 μM puromycin was added to the last column of each assay plate to assess a base level of cytotoxicity.

Example 48: HIV MT-4 Serum Shift Antiviral Reporter Assay

To quantify the amount of protein binding to human serum, compounds were serially diluted (1:3) in DMSO and acoustically transferred onto 384-well assay plates via a Labcyte ECHO robot. Each plate contained up to 8 test compounds, including negative and positive controls, (DMSO, 5 μM AZT respectively). Assay plates were prepared in duplicate, and tested in either CCM (cell culture media) or HS/CCM (human serum/cell culture media). MT-4 cells were first pre-infected with pLai RLuc reporter virus for 2 h at 37° C., then further diluted in either CCM (RPMI media, 10% FBS, 1% P/S) or HS/CCM (RPMI media, 10% FBS, 50% HS, 1% P/S), and subsequently added to each plate using a Biotek Micro Flow dispenser. After a 72-h incubation in a humidified and temperature controlled incubator (37° C.),RenillaGlo (Promega) was added to all assay plates and chemiluminescence read using an Envision plate-reader. EC50values were defined as the compound concentration that causes a 50% decrease in luminescence signal, and were calculated using a sigmoidal dose-response model to generate curve fits. To determine the amount of protein binding, EC50fold shifts (or EC50shifts) were calculated by dividing EC50(HS/CCM)/EC50(CCM).

Compounds of the present disclosure demonstrate antiviral activity in this assay as depicted in Table 1 below. Accordingly, the compounds of the embodiments disclosed herein may be useful for treating the proliferation of the HIV virus, treating AIDS, or delaying the onset of AIDS or ARC symptoms.

Example 49: High Throughput Microsomal Stability Assay

Metabolic stability of compounds was assessed using Human, or Rat Liver Microsomal assays (Corning). In this assay, 10 nL compounds at concentration of 1 mM in 100% DMSO were dispensed into 384-well polypropylene plates using the Echo 550 acoustic liquid dispenser (Labcyte®). Each plate contained 384 wells with a single test compound in each well.

A solution of human (Corning® Gentest™ Human Mixed Pooled Microsomes), or rat (Corning® Gentest™ Rat [Sprague-Dawley] Pooled Liver Microsomes) liver microsomes at 2 mg/ml in 100 mM K2HPO4/KH2PO4pH 7.4 with Alamethicin fromTrichoderma viride(Sigma-Aldrich) 0.0225 mg/ml were incubated on ice for 15 minutes. 5 uL of this solution was added to individual wells following 15 minute incubation at room temperature; and supplemented with 5 uL NADPH Regenerating Solution of cofactors (Corning® Gentest™ UGT Reaction Mix) containing 100 mM K2HPO4/KH2PO4pH 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-glucuronic acid. Final concentration of analyte compounds at the beginning of the reaction was 1 uM. The reactions were incubated at 37° C. and time points of 0, 5, 15, 30, 40, 50, 60, and 70 minutes were collected for further analysis. Background data were collected using reactions without analyte compounds.

Upon collection of the reaction time points, samples were quenched with 30 uL of a solution of 72% acetonitrile, 8% methanol, 0.1% formic acid, 19.9% water, and internal standard (IS). Reaction plates were span in a centrifuge at speed of 4,000 rcf for 30 minutes and 4° C., following a dilution of the 10 uL quenched reaction into 40 uL de-ionized water, yielding assay plates.

Assay plates were analyzed using solid-state extraction coupled with quadrupole time-of-flight mass spectrometer, using Agilent QToF 6530 RapidFire 360 system, with C4 type A solid state cartridges. Analysis was performed in either positive or negative ionization modes. Mobile phases contained 0.1% formic acid in water for loading analytes onto solid state extraction cartridges, and 0.1% formic acid in acetonitrile for elution into mass spectrometer in positive ionization mode, or 0.1% acetic acid in water for loading and 0.1% acetic acid in acetonitrile for extraction in negative ionization mode. Peak-area ratios of integrated counts for individual compounds to IS were plotted as semi-logarithmic chart of log vs time. Initial, linear portion of decay was fitted to a linear regression equation to derive half time of a compound decay.

Pharmacological parameters for an analyte compound metabolism were calculated using the following equations:

Calculation of In Vitro Intrinsic Clearance

Concentration refers to the protein concentration (mg/mL) in the reaction.

Calculation of In Vivo Intrinsic Clearance

This scales the in vitro intrinsic clearance up to the value that would be predicted for the entire mass of liver tissue (but with no restriction by blood flow). The value depends upon the size of the liver (species-dependent) and the yield of microsomal protein as appropriate (assumed to be species-independent).

Calculation of Predicted Clearance

Hepatic clearance will depend upon the inter-relationship of intrinsic clearance and hepatic blood flow and can be predicted from in vitro data using a variety of approaches.

Calculation of Hepatic Extraction

This is simply the predicted clearance expressed as a proportion of hepatic blood flow.

Intrinsic clearance of the instant compounds, as well as for reference compounds A-F, were calculated following the procedure above. The results of these compounds are shown in Table 2 below. As seen, the instant compounds are 1.5 to 3.6 times more stable than the Reference compounds A-F.

TABLE 2MSCompoundGS No.StructureClMS Cl improvementA (186)GS-10749610.68Example 1GS-11522210.213.2 times relative to compound AB (187)GS-10752330.48Example 3GS-1153195.153.2 times relative to compound BC (176)GS-10737950.51Example 4GS-11531960.143.6 times relative to compound CD (174)GS-10736990.68Example 6GS-11553720.292.3 times relative to compound DExample 11GS-11520960.252.7 times relative to compound DE (177)GS-1073796 (lead)0.39Example 7GS-11560050.22.0 times relative to compound EExample 13GS-11513830.261.5 times relative to compound EF (175)GS-10737010.49Example 8GS-1156006.222.2 times relative to compound FExample 12GS-11521070.153.3 times relative to compound FExample 33GS-11597760.35Example 35GS-11612340.62

All references, including publications, patents, and patent documents are incorporated are incorporated by reference herein, as though individually incorporated by reference. The present disclosure provides reference to various embodiments and techniques. However, it should be understood that many variations and modifications may be made while remaining within the spirit and scope of the present disclosure. The description is made with the understanding that it is to be considered an exemplification of the claimed subject matter, and is not intended to limit the appended claims to the specific embodiments illustrated.