Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical uses

Abstract

To provide a method for treating a disease Compounds for use in the treatment or prevention of human immunodeficiency virus (HIV) infection are disclosed. These compounds have the following formula (I): TIFF2023033640000385.tif3341, including stereoisomers and pharmaceutically acceptable salts thereof, wherein R 1 , R 2 , L, W 1 , W 2 , X, Y, and Z are as defined herein. Methods related to the preparation and use of such compounds, as well as pharmaceutical compositions containing such compounds, are also disclosed.

Description

Technical Field

[0001] Incorporation by reference This application claims priority to U.S. Provisional Application No. 62 / 822,703, filed Mar. 22, 2019, and U.S. Provisional Application No. 62 / 948,697, filed Dec. 16, 2019. Both of these U.S. provisional applications are hereby incorporated by reference in their entirety for all purposes.

[0002] Background Field Compounds, compositions, and methods that can be used to treat or prevent human immunodeficiency virus (HIV) infection are disclosed. In particular, novel bridged tricyclic carbamoylpyridone compounds and methods for their preparation, as well as their use as therapeutic or prophylactic agents, are disclosed.

Background Art

[0003] Description of Related Art Human immunodeficiency virus infection and related diseases are major public health problems worldwide. The human immunodeficiency virus encodes three enzymes required for viral replication, namely, reverse transcriptase, protease, and integrase. Drugs targeting reverse transcriptase and protease are widely used and have shown effectiveness, particularly when used in combination, but toxicity and the emergence of resistant strains can limit their usefulness (Palella, et al. N. Engl. J Med. (1998) 338:853 - 860; Richman, D.D. Nature (2001) 410:995 - 1001). Thus, there is a need for new agents that inhibit HIV replication.

[0004] The goal of antiretroviral therapy is to achieve viral suppression in patients infected with HIV. Current treatment guidelines published by the United States Department of Health and Human Services provide that achieving viral suppression requires the use of combination therapy, i.e., several drugs from at least two or more drug classes (Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. Available at http: / / www.aidsinfo.nih.gov / ContentFiles / AdultandAdolescentGL.pdf. Accessed February 12, 2019). Further, decisions regarding the treatment of patients infected with HIV are complicated when this patient requires treatment for other medical conditions (ibid., F-8). Since the standards of care require the use of multiple different drugs to suppress HIV and to treat other conditions the patient may be experiencing, the potential for drug interactions is a criterion for the selection of a drug regimen. Accordingly, there is a need for antiretroviral therapy with a reduced potential for drug interactions.

[0005] Furthermore, the HIV virus is known to mutate within an infected subject (Tang, et al. Drugs (2012) 72(9) e1-e25). Due to the tendency of the HIV virus to mutate, antiretroviral drugs are required to be effective against certain known HIV variants (Hurt, et al. HIV / AIDS CID (2014) 58, 423-431). For certain patients, for example those for whom healthcare is difficult or access is restricted, it may be difficult to adhere to a daily oral treatment or prevention regimen. Drugs that confer favorable pharmaceutical properties (e.g., improved efficacy, long-acting pharmacokinetics, low solubility, low clearance, and / or other properties) allow for less frequent dosing and provide better patient compliance. Such improvements can then optimize drug exposure and limit the emergence of drug resistance.

PRIOR ART DOCUMENTS

NON-PATENT DOCUMENTS

[0006]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

SUMMARY OF THE INVENTION

MEANS FOR SOLVING THE PROBLEM

[0007] Abstract The present disclosure relates to novel compounds having antiviral activity and pharmaceutically acceptable salts thereof. In some embodiments, these compounds can be used for treating HIV infections, inhibiting the activity of HIV integrase, and / or reducing HIV replication. In some embodiments, the compounds disclosed herein can be effective against certain known drug-resistant HIV variants. In some embodiments, the compounds disclosed herein may have a tendency to cause drug-drug interactions when co-administered with other drugs. In some embodiments, the compounds disclosed herein can be administered at a frequency lower than once a day, for example, once a week, once a month, or at longer intervals.

[0008] In one embodiment, there is provided a compound having the following formula (I) or a pharmaceutically acceptable salt thereof:

Chemical formula

Chemical formula

[0009] In one aspect, there is provided a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0010] In another embodiment, there is provided a kit or article of manufacture comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and instructions for use.

[0011] In another embodiment, there is provided a method for treating HIV infection in a human having or at risk of having HIV infection by administering to the human a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0012] In another embodiment, there is provided the use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, for treating HIV infection in a human having or at risk of having HIV infection.

[0013] In another embodiment, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, for use in medical treatment.

[0014] In another embodiment, there is provided a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, for use in the treatment of HIV infection.

[0015] In another embodiment, there is provided the use of a compound of formula I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating HIV infection in a human having or at risk of having HIV infection.

[0016] In another embodiment, there is provided a method of using a compound of formula I in treatment. Specifically, there is provided a method for treating the growth of HIV virus, treating AIDS, or delaying the onset of symptoms of AIDS or ARC in a mammal (e.g., a human), the method comprising administering to the mammal a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0017] In another embodiment, provided is a composition for use in a method of treating the growth of the HIV virus, treating AIDS, or delaying the onset of symptoms of AIDS or ARC in a mammal (e.g., a human), which composition comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0018] In another embodiment, a composition effective for treating or preventing HIV infection; and indicating that this composition can be used for treating or preventing an infection caused by HIV Provided is a kit or a manufactured article comprising a packaging material containing a bell. Exemplary compositions contain a compound of formula I or a pharmaceutically acceptable salt thereof disclosed herein.

[0019] In yet another embodiment, provided is a method of inhibiting HIV replication. This method includes the step of exposing the virus to an effective amount of a compound of formula I or a salt thereof under conditions such that HIV replication is inhibited.

[0020] In another embodiment, provided is the use of a compound of formula I for inhibiting the activity of the HIV integrase enzyme.

[0021] In another embodiment, provided is the use of a compound of formula I or a pharmaceutically acceptable salt thereof for inhibiting the activity of the HIV integrase enzyme.

[0022] In another embodiment, provided is the use of a compound of formula I or a salt thereof for inhibiting HIV replication.

[0023] In another embodiment, provided is the use of a compound of formula I or a pharmaceutically acceptable salt thereof as a research tool.

[0024] Other embodiments, objects, features, and advantages may be described in the detailed description of the following embodiments, and may in part be apparent from the description of the embodiments of the present application, or may be learned by the implementation thereof. These objects and advantages may be realized and achieved by the processes and compositions specifically pointed out in this specification and its claims. The above summary should be regarded as a brief general overview of some of the embodiments disclosed in this specification, provided for the benefit and convenience of the reader, and it is intended that the appended claims not limit the scope of legal rights or the area of equivalents in any way.

Mode for Carrying Out the Invention

[0025] Detailed Description It is to be understood that the following description of several embodiments is made with the understanding that the present disclosure is considered as an illustration of the claimed invention and is not intended to limit the appended claims to the specific embodiments illustrated. The headings used throughout the present disclosure are provided for convenience only and should not be construed as limiting the claims in any way. The embodiments illustrated under any heading may be combined with the embodiments illustrated under any other heading.

[0026] Definitions Unless the context requires otherwise, throughout the present disclosure and the claims, the term "comprise" and its variations, for example, "comprises" and "comprising", should be interpreted in an open, inclusive sense, that is, "including but not limited to".

[0027] References to "one embodiment" or "an embodiment" throughout this specification mean that a particular feature, structure, or characteristic described in connection with that embodiment is included in at least one embodiment disclosed herein. Thus, appearances of the phrases "one embodiment" or "an embodiment" in various places throughout this specification are not necessarily all referring to the same embodiment. Further, the particular features, structures, or characteristics may be combined in any suitable manner in one or more embodiments.

[0028] "Amino" refers to the -NH2 radical.

[0029] "Hydroxy" or "hydroxyl" refers to the -OH radical.

[0030] "Oxo" refers to the =O substituent.

[0031] "C u~v " or a prefix such as (C u~ C v ) indicates that the subsequent group has from u to v carbon atoms. For example, "C 1~6 alkyl" indicates that this alkyl group has from 1 to 6 carbon atoms.

[0032] "Alkyl" consists of carbon and hydrogen atoms, is saturated, and has from 1 to 12 carbon atoms (C 1~12 alkyl), in certain embodiments from 1 to 8 carbon atoms (C 1~8 alkyl) or from 1 to 6 carbon atoms (C 1~6 alkyl), or from 1 to 4 carbon atoms (C 1~4 alkyl), and is a straight-chain or branched hydrocarbon radical bonded by a single bond to the remainder of the molecule, for example, 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, and 2-methylhexyl, etc.

[0033] "Alkylene" refers to a saturated, branched or straight-chain, or cyclic hydrocarbon radical having two monovalent radical centers derived by removing two hydrogen atoms from the same carbon atom or two different atoms of the parent alkane. For example, an alkylene group may have 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 atoms. Representative 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-), and 1,4-butyl (-CH2CH2CH2CH2-).

[0034] "Aryl" or "aromatic ring" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings including a fused system (e.g., bicyclic or tricyclic). As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C 6~20 aryl), 6 to 12 carbon ring atoms (i.e., C 6~12 aryl), 6 to 10 carbon ring atoms (i.e., C 6~10 aryl), or 5 to 10 carbon ring atoms (i.e., C 5~10 aryl). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthryl.

[0035] "Cyano" or "carbonitrile" refers to the group -CN.

[0036] The "carbocyclic ring" consists of carbon atoms and hydrogen atoms, has 3 to 15 carbon atoms, in certain embodiments has 3 to 10 carbon atoms, or 3 to 7 carbon atoms, and is saturated or partially unsaturated, and is a non-aromatic carbocyclic ring that is bonded to the rest of the molecule by a single bond. Examples of carbocyclic rings include, for example, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane.

[0037] "Fused" refers to a carbocyclic, heterocyclic, aromatic, or heteroaromatic ring structure described herein that is bonded to an existing ring structure in a compound disclosed herein through two adjacent atoms taught by the fused ring structure and the existing ring structure. For example , the bicyclic compounds illustrated below each contain a fused cyclopropane (i.e., a cyclopropane ring fused to a cyclohexane ring), a fused pyrrolidine (i.e., a pyrrolidine ring fused to a benzene ring), and a fused thiophene (i.e., a thiophene ring fused to a furan ring):

Chem.

[0038] "Spiro" or "spirocyclic" refers to a carbocyclic or heterocyclic ring structure described herein that is bonded to an existing ring structure in a compound disclosed herein through one atom taught by the spiro ring structure and the existing ring structure. For example, the following bicyclic compounds each contain a spirocyclopropane (i.e., a cyclopropane ring that is spirocyclic with a cyclohexane ring), a spiro 1,3-dithiolane (i.e., a 1,3-dithiolane ring that is spirocyclic with a cycloheptane ring), and a spirocyclopentene (i.e., a cyclopentene ring that is spirocyclic with a cyclohexene ring):

Chem.

[0039] "Halo" or "halogen" means bromo, chloro, fluoro or iodo.

[0040] "Haloalkyl" means an alkyl group as defined above substituted by one or more of the haloradicals as defined above, for example, trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, and 1,2-dibromoethyl, etc.

[0041] "Heteroaromatic ring" means an aromatic ring having a single ring, multiple rings, or multiple fused rings and having one or more ring heteroatoms (for example, 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom) independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl contains 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). Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl.

[0042] "Heterocyclyl" or "heterocyclic ring" refers to a non-aromatic radical or ring having from 3 to 15 atoms, one to six of which are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and which is bonded to the remainder of the molecule by a single bond. In certain embodiments, "heterocyclyl" has from 3 to 10 atoms, one to four of which are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or has from 3 to 7 atoms, one or two of which are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. Nitrogen atoms, carbon atoms, or sulfur atoms within the heterocyclyl may be oxidized as necessary; nitrogen atoms may be quaternized as necessary. As used herein, "Heterocyclyl" or "heterocyclic ring" refers to a ring that is saturated unless otherwise indicated, for example, in some embodiments, "heterocyclyl" or "heterocyclic ring" refers to a ring that is saturated or partially saturated when specified. Examples of such heterocyclyls include, but are not limited to, dioxolanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuranyl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl.

[0043] The embodiments disclosed herein are also intended to encompass all pharmaceutically acceptable compounds of Formula I that are isotopically labeled by replacement of one or more atoms with atoms having different atomic masses or mass numbers. Examples of isotopes that can be incorporated into the compounds of the present disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and sulfur, for example, 2 H, 3 H, 11 C,13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. In certain embodiments, radiolabeled compounds are useful for helping to determine or measure the effectiveness of those compounds, for example, by characterizing the site or mode of action or the binding affinity to a pharmacologically acceptable site of action. Isotope-labeled compounds of certain Formulas I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, for example, compounds incorporating a radioisotope, are useful in tissue distribution studies of drugs and / or substrates. Tritium, i.e., 3 H, and carbon-14, i.e., 14 C are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[0044] In certain embodiments, substitution with a heavier isotope, such as deuterium, i.e., 2 H, can provide certain therapeutic advantages obtained from greater metabolic stability. For example, the in vivo half-life can be increased or the dosage requirement can be decreased. Thus, heavier isotopes can be preferred in some situations.

[0045] 11 C, 18 F, 15 O and 13Substitution with a positron-emitting isotope such as N can be useful in positron emission tomography (PET) studies to test receptor occupancy of a substrate. The isotopically labeled compound of formula I can be prepared by using appropriate isotopically labeled reagents, by techniques known to those of skill in the art, or by methods similar to those described in the examples set forth below, in place of the unlabeled reagents used previously.

[0046] The methods, compositions, kits, and articles of manufacture provided herein include a compound (e.g., a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb) or a pharmaceutically acceptable salt thereof, wherein one to n hydrogens attached to a carbon atom are replaced with deuterium, where n is the number of hydrogens in the molecule. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of the compound or its pharmaceutically acceptable salt when administered to a mammal. See, e.g., Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds can be synthesized by means known in the art, e.g., by using starting materials in which one or more hydrogens are replaced with deuterium. can be

[0047] The embodiments disclosed herein are also intended to encompass the in vivo metabolites of the compounds of the present disclosure. Such products can result from the administered compound, primarily due to enzymatic processes, such as oxidation, reduction, hydrolysis, amidation, and esterification. Accordingly, the embodiments disclosed herein include compounds produced by a process that includes administering a compound according to the embodiments disclosed herein to a mammal for a period of time sufficient to obtain its metabolites. Such products are typically identified by administering a radiolabeled compound according to the embodiments disclosed herein in a detectable dose to a mammal such as a rat, mouse, guinea pig, monkey, or human, allowing sufficient time for metabolism to occur, and isolating the conversion products from urine, blood, or other biological samples.

[0048] "Mammal" includes both humans and domesticated animals (e.g., laboratory animals and household animals such as cats, dogs, pigs, cows, sheep, goats, horses, rabbits) and non-domesticated animals (e.g., wildlife, etc.).

[0049] "Optional" or "optionally" means that the subsequent recited event or circumstance may or may not occur, and that the description includes both examples in which the event or circumstance occurs and examples in which it does not. For example, "optionally substituted heterocyclyl" means that the heterocyclyl radical may or may not be substituted, and that the description includes both substituted heterocyclyl radicals and heterocyclyl radicals having no substitution.

[0050] Examples of "pharmaceutically acceptable excipients" include any adjuvant, carrier, excipient, glidant, sweetening agent, diluent, preservative, dye / colorant, flavor enhancer, surfactant, wetting agent, dispersing agent, suspending agent, stabilizer, isotonic agent, solvent, emulsifying agent, or other pharmacologically inactive substance that is formulated in combination with the pharmaceutically active ingredient of the pharmaceutical composition, is compatible with the other ingredients of the formulation, and is suitable for use in humans or domestic animals without undue toxicity, irritation, and allergic response, but are not limited thereto.

[0051] Examples of "pharmaceutically acceptable salts" of the compounds disclosed herein include salts derived from suitable bases such as alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and NX4 + (where X is C 1~4 alkyl). Pharmaceutically acceptable salts of the nitrogen atom of the amino group include, for example, organic carboxylic acids such as acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, butyric acid, camphoric acid, cinnamic acid, citric acid, digluconic acid, glutamic acid, glycolic acid, glycerophosphoric acid, formic acid, hexanoic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, hydroxymaleic acid, malonic acid, malic acid, mandelic acid, isethionic acid, lactobionic acid, nicotinic acid, oxalic acid, pamoic acid, pectinic acid, phenylacetic acid, 3-phenylpropionic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, sulfanilic acid, tartaric acid, undecanoic acid, and succinic acid; organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, mesitylenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and 2-naphthalenesulfonic acid; and salts of inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and sulfamic acid. Pharmaceutically acceptable salts of the hydroxy group of the compound include Na + and NX4 + (where X is independently H or C 1~4Examples of anions of this compound combined with suitable cations (such as those selected from alkyl groups) are included.

[0052] For therapeutic use, salts of the active ingredients of the compounds disclosed herein are typically pharmaceutically acceptable. That is, these salts are salts derived from physiologically acceptable acids or bases. However, salts of acids or bases that are not pharmaceutically acceptable may also find use, for example, in the preparation or purification of compounds of formula I or another compound of the embodiments disclosed herein. Whether or not they are derived from physiologically acceptable acids or bases, all salts are within the scope of the embodiments disclosed herein. Metal salts are typically prepared by reacting metal hydroxides with compounds according to the embodiments disclosed herein. Examples of metal salts prepared in this way are salts containing Li, Na, and K. Metal salts with low solubility can precipitate from solutions of more soluble salts by the addition of appropriate metal compounds.

[0053] Furthermore, salts can be formed from the addition of acids, such as specific organic and inorganic acids (e.g., HCl, HBr, H2SO4, H3PO4, or organic sulfonic acids), to basic centers, typically amines. Finally, it should be understood that the compositions herein contain the compounds disclosed herein in their unionized and zwitterionic forms. + Na + K + "Pharmaceutical composition" refers to a formulation of a compound of the embodiments disclosed herein with a medium generally approved in the art for the delivery of biologically active compounds to mammals (e.g., humans). Such media include all pharmaceutically acceptable excipients.

[0054]

[0055]

[0056] "Effective amount" or "therapeutically effective amount" refers to the amount of a compound according to the embodiments disclosed herein that is sufficient to effect treatment of a disease state, condition or disorder disclosed herein when administered to a patient in need thereof. Such amount is sufficient to elicit a biological or medical response in a tissue system or patient as determined by a researcher or clinician. The amount of a compound according to the embodiments disclosed herein that constitutes a therapeutically effective amount will vary depending upon factors such as the compound and its biological activity, the composition used for administration, the time of administration, the route of administration, the rate of excretion of the compound, the duration of the treatment, the type and severity of the disease state or disorder being treated, drugs used in combination with or simultaneously with the compound of the embodiments disclosed herein, and factors such as the age, weight, general health, sex and diet of the patient. Such therapeutically effective amount can be determined by one of ordinary skill in the art in view of their knowledge, level of skill, and the present disclosure.

[0057] As used herein, the terms "treating" and "treatment" are intended to mean the administration of a compound or composition according to the embodiments disclosed herein for reducing or eliminating one or more symptoms of HIV infection and / or for reducing the viral load in a patient. In certain embodiments, the terms "treating" and "treatment" also refer to preventing the onset of symptoms of a disease and / or preventing the virus from reaching a detectable level in the blood after an individual's exposure to the virus but before the appearance of symptoms of the disease and / or before detection of the virus in the blood, and the administration of a compound or composition according to the embodiments disclosed herein for preventing perinatal transmission of HIV from mother to newborn, including administration to the mother before delivery and to the child during the day of birth. The terms "treating" and "treatment" also include the administration of a compound or composition according to the embodiments disclosed herein to prevent the establishment of HIV infection and / or to prevent the virus from establishing a persistent infection and / or to prevent the onset of symptoms of the disease and / or to prevent the virus from reaching a detectable level in the blood when an individual is exposed to the virus (also referred to as pre-exposure prophylaxis or PrEP). The terms "treating" and "treatment" also include the administration of a compound or composition according to the embodiments disclosed herein both before and after an individual's exposure to the virus. including the administration of a compound or composition according to the embodiments disclosed herein.

[0058] As used herein, the terms "prevent" and "prevention" refer to the administration of a compound, composition, or pharmaceutical salt according to the present disclosure, either before or after human exposure to a virus, but before the appearance of symptoms of the disease and / or before detection of the virus in the blood. These terms also refer to preventing the appearance of symptoms of the disease and / or preventing the virus from reaching a detectable level in the blood. These terms encompass both pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP), as well as event-driven or "on-demand" prophylaxis. These terms also refer to the prevention of perinatal transmission of HIV from mother to newborn by administration to the mother before childbirth and to the child during the day of birth. These terms also refer to the prevention of transmission of HIV by blood transfusion.

[0059] The term "antiviral agent", as used herein, is intended to mean an agent (compound or biological substance) that is effective for inhibiting the formation and / or replication of a virus in humans, and antiviral agents include, but are not limited to, agents that interfere with any mechanism, either of the host or of the virus, that is necessary for the formation and / or replication of the virus in humans.

[0060] The term "inhibitor of HIV replication", as used herein, is intended to mean an agent that is capable of reducing or eliminating the ability of HIV to replicate within a host cell, whether in vitro, ex vivo, or in vivo.

[0061] The compounds of the embodiments disclosed herein or pharmaceutically acceptable salts thereof may contain one or more chiral centers and thus, with respect to absolute stereochemistry, may result in enantiomers, diastereomers, scalemic, and other stereoisomeric forms that can be defined as (R)- or (S)-, or for amino acids, (D)- or (L)-. This disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)-isomers can be prepared using a chiral synthon or chiral reagent or can be resolved using methods such as chromatography and fractional crystallization. Techniques for the preparation / isolation of individual enantiomers include chiral synthesis from an appropriate optically pure precursor or resolution of a racemate (or racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometrically chiral centers, unless otherwise specified, these compounds are intended to include both E and Z geometric isomers. Similarly, all tautomeric forms are intended to be included.

[0062] "Stereoisomers" refer to compounds that are composed of the same atoms bonded by the same bonds but have different three-dimensional structures that are not interconvertible. This disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers," which refer to two stereoisomers that are mirror images of each other and whose molecules cannot be superimposed on one another. In any of the embodiments disclosed herein, the compounds disclosed herein can be in the form of their stereoisomers.

[0063] "Partially unsaturated" refers to a cyclic group that contains at least one double bond but is not aromatic. Compound

[0064] In this specification, compounds that function as anti-HIV agents, such compounds in combination with one or more (e.g., two, three, or four) additional therapeutic agents as needed and pharmaceutical compositions containing them, as well as methods of using such compounds and compositions are provided. Embodiments of all compounds described herein include any pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers thereof.

[0065] In one embodiment, the following formula (I):

Chemical formula

Chemical formula

[0066] In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, R 2 is H, C 1~4 alkyl, or C 1~4 haloalkyl. In some embodiments, R 2 is H or C 1~4 alkyl. In some embodiments, R 2 is H. In some embodiments, R 2 is C 1~4 alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is H or methyl. In some embodiments, R 2 is C 1~4 haloalkyl.

[0067] In some embodiments, R 2 is selected from the group consisting of H, -CH3, -CH2CH3, and -CH2F, or R 2 and R 8b together with the carbon to which they are attached form a 3-membered fused carbocyclic ring. In some embodiments, R 2 is selected from the group consisting of H, -CH3, -CH2CH3, and -CH2F. In some embodiments, R 2 and R 8b together with the carbon to which they are attached form a 3-membered fused carbocyclic ring.

[0068] In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, Y is -C(O)NH-. In some embodiments, Y is Q. In some embodiments, Y is [Chemical formula] is.

[0069] In some embodiments, the compound of formula I is a compound of formula (II): [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R 1 , L, W 1 , W 2 , X, and Z are as defined in formula I.

[0070] In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, R 1 is H. In some embodiments, R 1 is C 6~10 aryl. In some embodiments, R 1 is phenyl optionally substituted with 1 to 4 R A1 , where each R A1 is independently halo, C 1~4 alkyl, C 1~4Haloalkyl, cyano, -O-C 1~4 alkyl, or C 1~4 alkyl-O-C 1~4 is alkyl. In some embodiments, R 1 is phenyl substituted with one, two, three, or four R A1 s. In some embodiments, R 1 is phenyl substituted with one, two, three, or four R A1 s. In some embodiments, R 1 is phenyl substituted with one, two, three, or four R A1 s, where each R A1 is independently halo, C 1~4 alkyl, C 1~4 haloalkyl, or -O-C 1~4 alkyl. In some embodiments, R 1 is phenyl substituted with one, two, three, or four R A1 s, where each R A1 is independently halo, C 1~4 alkyl, or C 1~4 haloalkyl. In some embodiments, R 1 is phenyl substituted with one, two, three, or four R A1 s, where each R A1 is independently halo or -O-C 1~4 alkyl. In some embodiments, R 1 is phenyl substituted with one, two, three, or four halogens. In some embodiments, R 1 is phenyl substituted with one, two, or three halogens. In some embodiments, R 1 is phenyl substituted with two or three halogens. In some embodiments, R 1 is phenyl substituted with two or three halogens selected from chloro and fluoro. In some embodiments, R 1 is

Chemical formula

[0071] In some embodiments of the compound of I or II, R 1 is [Chemical formula] selected from the group consisting of. In some embodiments of the compound of formula I or II, R 1 is [Chemical formula] selected from the group consisting of. In some embodiments, R 1 is [Chemical formula] selected from the group consisting of.

[0072] In some embodiments of the compound of formula I or II, or a pharmaceutically acceptable salt thereof, L is -CR 3a R 3b -, where R 3a and R 3b are independently H, C 1~4 alkyl, C 1~6 haloalkyl, C(O)R c , or SO2R c . In some embodiments, L is -CR 3a R 3b -, where R 3a and R 3b are independently H or C 1~4 alkyl. In some embodiments, L is -CH2-. In some embodiments, L is -CH(CH3)-. In some embodiments, L is -C(O)-. In some embodiments, L is also or -CH2-CH2-. In some embodiments, L is, -CH2-, -CH(CH3)-, -C(O)-, or -CH2-CH2-. In some embodiments, L is and -N(R a )-.

[0073] In some embodiments, a compound of Formula I or II is of the formula:

Chemical formula

[0074] In some embodiments, a compound of Formula I or II is of the formula (IV):

Chemical formula

[0075] In some embodiments, a compound of Formula I, II, or IV is of the formula:

Chemical formula

[0076] In some embodiments, a compound of Formula I or II is of the formula (VI):

Chemical formula

[0077] In some embodiments, a compound of Formula I, II, or VI is of the formula:

Chemical formula

[0078] In some embodiments of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, or VIIb, or a pharmaceutically acceptable salt thereof, W 1 is a bond. In some embodiments, W 1 is -CR 4a R 4b -. In some embodiments, W 1 is -CR 4a R 4b -, where R 4a and R 4b are independently H or halo. In some embodiments, W 1 is -CH2-. In some embodiments, W 1 is -CF2-. In some embodiments, W 1 is -CH(F)-. In some embodiments, W 1 is a bond, -CH2-, -CF2- or -CH(F)-. In some embodiments, W 1 is a bond or -CH2-.

[0079] In some embodiments of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, or VIIb, or a pharmaceutically acceptable salt thereof, W 1 is a bond or -CR 4a R 4b -, where each of R 4a and R 4b is independently H, halo, or C 1~6 alkyl. In any embodiment, W 1 is a bond or -CR 4a R 4b --, where each R 4a and R 4bis independently H, halo, or -CH3. In some embodiments, W 1 is a bond, -CH2-, -CH(F)-, CF2, -CH(CH3)-, or -CF(CH3)-.

[0080] In some embodiments of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, or VIIb, or a pharmaceutically acceptable salt thereof, W 2 is -CR 5a R 5b -, -CR 5a R 5b -CR 5c R 5d -,-CR 6a =CR 6b -,-N(R 7 )-,-O-,-CR 5a R 5b -N(R 7 )-or -CR 5a R 5b -O-, where R 5a , R 5b , R 5c , R 5d , R 6a , R 6b , and R 7 are as defined for formula I. In some embodiments, W 2 is -CR 5 a R 5b -. In some embodiments, W 2 is -CR 5a R 5b -, where R 5a and R 5b are independently H, C 1~4 alkyl, C 1~4 haloalkyl, halo, hydroxyl, cyano, -O-C 1~4 alkyl, or C 1~4 alkylene - O - C 1~4 alkyl. In some embodiments, W 2 is -CR 5a R 5b -, where R 5aand R 5b is independently H, C 1~4 alkyl, C 1~4 haloalkyl, halo, or hydroxyl. In some embodiments, W 2 is -CR 5a R 5b -, where R 5a and R 5b are independently H or halo. In some embodiments, W 2 is -CH2-. In some embodiments, W 2 is -CF2-. In some embodiments, W 2 is -CH(F)-. In some embodiments, W 2 is -CR 5a R 5b -CR 5c R 5d -. In some embodiments, W 2 is -CR 5a R 5b -CR 5c R 5d -, where R 5a , R 5b , R 5c , and R 5d are independently H, C 1~4 alkyl, C 1~4 haloalkyl, halo, hydroxyl, cyano, -O-C 1~4 alkyl, or C 1~4 alkylene-O-C 1~4 alkyl. In some embodiments, W 2 is -CR 5a R 5b -CR 5c R 5d -, where R 5a , R 5b , R 5c , and R 5d are independently H, C 1~4 alkyl, C 1~4 haloalkyl, halo, hydroxyl. In some embodiments, W 2 is -CR 5a R 5b -CR 5c R5d - and wherein R 5a , R 5b , R 5c , and R 5d are each independently H or halo. In some embodiments, W 2 is -CH2CH2-. In some embodiments, W 2 is -CR 5a R 5b -CR 5c R 5d -, wherein R 5a and R 5c are each independently H or halo, and R 5b and R 5d together with the carbon atom to which each is attached form a 3- to 7-membered saturated or partially unsaturated fused carbocyclic ring optionally substituted with one to three R A3 s, where each R A3 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl. In some embodiments, W 2 is -CR 5a R 5b -CR 5c R 5d -, wherein R 5a and R 5c are each independently H or halo, and R 5b and R 5d together with the carbon atom to which each is attached form a 3- to 5-membered saturated fused carbocyclic ring. In some embodiments, W 2 is -CHR 5b -CHR 5d -, wherein R 5b and R 5d together with the carbon atom to which each is attached form a 3-, 4-, or 5-membered saturated fused carbocyclic ring. In some embodiments, W 2 is

Chemical formula

Chemical formula

[0081] In some embodiments of the compounds of formula I, II, IIIa, IIIb, IV, Va, or Vb, the compound has the formula (X):

Chemical formula

[0082] In some embodiments of the compounds of formula I, II, IIIa, IIIb, IV, Va, or Vb, the compound has the formula (Xa):

Chemical formula

[0083] In some embodiments of the compounds of Formula I, II, IIIa, IIIb, IV, Va, or Vb, the compound is of Formula (Xb): [Chemical formula] and has

[0084] In some embodiments of the compounds of Formula I, II, IIIa, IIIb, IV, Va, or Vb, the compound is of Formula (XI): [Chemical formula] and has

[0085] In some embodiments of the compounds of Formula I, II, IIIa, IIIb, IV, Va, Vb or X, the compound is of Formula (XIa): [Chemical formula] and has

[0086] In some embodiments, the compounds of Formula I, II, IIIa, IIIb, IV, Va, Vb or X are of Formula (XIb): [Chemical formula] and has

[0087] In some embodiments of the compounds of Formula X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, X is a bond or -CR 8a R 8b -; wherein R 8a and R 8b are each independently H, hydroxyl, -O-C 1~4 alkyl, C 1~4 alkylene-O-C 1~4 alkyl, C 1~6 alkyl, C 1~4 haloalkyl, cyano, or halo. In some embodiments, X is a bond. In some embodiments, X is -CR 8a R8b - and where R 8a and R 8b are each independently H, hydroxyl, -O-C 1~4 alkyl, C 1~4 alkylene-O-C 1~4 alkyl, C 1~6 alkyl, C 1~4 haloalkyl, cyano, or halo. In some embodiments, X is -CR 8a R 8b - and where R 8a and R 8b are each independently H, C 1~6 alkyl, C 1~4 haloalkyl, or halo. In some embodiments, R 8a and R 8b are each independently H, -CH3, -CHF2, -CH2F, or halo.

[0088] In some embodiments for a compound of formula X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, Z is -CR 9a R 9b - or -CR 9a R 9b CR 9c R 9d - and where R 9a , R 9b , R 9c , and R 9d are each independently H, C 1~6 alkyl, or C 1~4 haloalkyl. In some embodiments, Z is -CR 9a R 9b -. In any embodiment, Z is -CR 9a R 9b CR 9c R 9d -. In some embodiments, R 9a , R 9b , R 9c , and R 9d are each independently H, -CH3, -CHF2, or -CH2F.

[0089] In some embodiments of the compounds of formula XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, R 6a and R 6b each independently is H, halo, C 1~4 haloalkyl, or C 1~6 alkyl.

[0090] In some embodiments of the compounds of formula X, Xa, or Xb, or pharmaceutically acceptable salts thereof, R 5a , R 5b , R 5c , and R 5d each independently is H, halo, C 1~4 haloalkyl, or C 1~6 alkyl.

[0091] In some embodiments of the compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, X is a bond. In some embodiments, X is -CR 8a R 8b -. In some embodiments, X is -CR 8a R 8b -, where R 8a and R 8b are independently H, hydroxyl, C 1~4 alkyl, or halo. In some embodiments, X is -CR 8a R 8b -, where R 8a is H, fluoro, or hydroxyl, and R 8b is H or fluoro. In some embodiments, X is -CH2-. In some embodiments wherein X is -CF2-. In some embodiments, X is -CH(F)-. In some embodiments, X is -CH(OH)-. In some embodiments, X is -CH(CH3)-. In some embodiments, X is -CF(CH3)-. In some embodiments, X is -CH2-, -CF2-, -CH(F)-, -CH(OH)-, -CH(CH3) or -CF(CH3)-. In some embodiments, X is -CR 8a R 8b -, where R 8a and R 8b together with the carbon to which they are attached form a 3-, 4- or 5-membered saturated spiro ring containing from 0 to 2 heteroatoms selected from N, O, and S, where the spiro ring is optionally substituted with from 1 to 4 R A5 s, where each R A5 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl. In some embodiments, X is -CR 8a R 8b -, where R 8a and R 8b together with the carbon to which they are attached form a 3- to 5-membered saturated spiro ring containing 0 heteroatoms, where the spiro ring is optionally substituted with from 1 to 4 R A5 s, where each R A5 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl. In some embodiments, X is -CR 8a R 8b -, where R 8a and R 8b together with the carbon to which they are attached form a spirocyclopropane ring.

[0092] In some embodiments of the compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, X is a bond or -CR8a R 8b - and where R 8a and R 8b are independently H, hydroxyl, -O-C 1~4 alkyl, C 1~4 alkyl, C 1~4 haloalkyl, or halo, or R 8a and R 8b together with the carbon to which they are attached form a 3- to 5-membered saturated spiro ring containing from 0 to 2 heteroatoms selected from N, O, and S, where this spiro ring is optionally substituted with from 1 to 4 R A5 and where each R A5 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl.

[0093] In some embodiments of the compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, X is a bond or -CR 8a R 8b - and where R 8a and R 8b are independently H, hydroxyl, -O-C 1~4 alkyl, C 1~4 alkyl, C 1~4 haloalkyl, or halo, or R 8a and R 8b together with the carbon to which they are attached form a 3- to 5-membered saturated spiro heterocyclic ring containing 1 or 2 heteroatoms selected from N, O, and S, where this spiro ring is optionally substituted with from 1 to 4 R A5 and where each R A5 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl. In some embodiments, X is a bond or -CR 8a R 8b - and where R 8a and R 8bis independently H, hydroxyl, -O-C 1~4 alkyl, C 1~4 alkyl, C 1~4 haloalkyl, or halo, or R 8a and R 8b together with the carbon to which they are attached form a 3- to 5-membered saturated spiro heterocyclic ring containing one or two heteroatoms selected from N, O, and S.

[0094] In some embodiments of the compounds of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, X is a bond or -CR 8a R 8b -, where R 8a and R 8b are independently H, hydroxyl, -O-C 1~4 alkyl, C 1~4 alkyl, C 1~4 haloalkyl, or halo, or R 8a and R 8b together with the carbon to which they are attached form a 3- to 5-membered saturated spiro carbocyclic ring, where the 3- to 5-membered saturated spiro carbocyclic ring is optionally substituted with one to four R A5 s, where each R A5 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl. In some embodiments, X is a bond or -CR 8a R 8b -, where R 8a and R 8b are independently H, hydroxyl, -O-C 1~4 alkyl, C 1~4 alkyl, C 1~4 haloalkyl, or halo, or R 8a and R 8b together with the carbon to which they are attached form a 3- to 5-membered saturated spiro carbocyclic ring.

[0095] In some embodiments of the compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, X is a bond or -CR 8a R 8b -, where R 8a and R 8b are independently H, hydroxyl, -O-C 1~4 alkyl, C 1~4 alkyl, C 1~4 haloalkyl, or halo, or R 8a and R 8b together with the carbon to which they are attached form a 3-membered saturated spirocarbocyclic ring, where this 3-membered saturated spirocarbocyclic ring is optionally substituted with 1 to 4 R A5 's, where each R A5 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl. In some embodiments, X is a bond or -CR 8a R 8b -, where R 8a and R 8b are independently H, hydroxyl, -O-C 1~4 alkyl, C 1~4 alkyl, C 1~4 haloalkyl, or halo, or R 8a and R 8b together with the carbon to which they are attached form a 3-membered saturated spirocarbocyclic ring.

[0096] In some embodiments of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, X is a bond, -CH2-, -CF2-, -CH(F)-, -CH(Cl)-, -CH(OH)-, -C(CH2F)(OH)-, -C(CH3)(OH)-, -CH(OCH3)-, -C(CH2CH3)(OCH3)-, -C(CH2CH3)(OH)-, -CH(CH3)-, -CH(CH2CH3)-, -CF(CH3)-, -CF(CH2CH3)-, or -CR 8a R 8b -, where R 8a and R 8b together with the carbon to which they are attached form a 3-membered saturated spiro carbocyclic ring. In some embodiments, X is a bond, -CH2-, -CF2-, -CH(F)-, -CH(Cl)-, -CH(OH)-, -C(CH2F)(OH)-, -C(CH3)(OH)-, -CH(OCH3)-, -C(CH2CH3)(OCH3)-, -C(CH2CH3)(OH)-, -CH(CH3)-, -CH(CH2CH3)-, -CF(CH3)-, or -CF(CH2CH3)-.

[0097] In some embodiments, X is a bond, -CH2-, -CF2-, -CH(F)-, -CH(Cl)-, -CH(OH)-, -C(CH2F)(OH)-, -C(CH3)(OH)-, -CH(OCH3)-, -C(CH2CH3)(OCH3)-, -C(CH2CH3)(OH)-, -CH(CH3)-, -CH(CH2CH3)-, -CF(CH3)-, -CF(CH2CH3)-, -C(CH2F)(H)-, or -CR 8a R 8b -, where R 8a and R 8btogether with the carbon to which they are attached, form a 3-membered saturated spirocarbocyclic ring. In some embodiments, X is a bond, -CH2-, -CF2-, -CH(F)-, -CH(Cl)-, -CH(OH)-, -C(CH2F)(OH)-, -C(CH3)(OH)-, -CH(OCH3)-, -C(CH2CH3)(OCH3)-, -C(CH2CH3)(OH)-, -CH(CH3)-, -CH(CH2CH3)-, -CF(CH3)-, -C(CH2F)(H)-, or -CF(CH2CH3)-.

[0098] In some embodiments of the compounds of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, X is -CR 8a R 8b -, where R 8a and R 8b together with the carbon to which they are attached, form a 3- to 5-membered saturated spiro ring containing from 0 to 2 heteroatoms selected from N, O, and S, where the spiro ring is optionally substituted with from 1 to 4 R A5 s, where each R A5 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl (C 1-4 haloalky). In some embodiments, X is -CR 8a R 8b -, where R 8a and R 8b together with the carbon to which they are attached, form a 3- to 5-membered saturated spirocarbocyclic ring, where the 3- to 5-membered saturated spirocarbocyclic ring is optionally substituted with from 1 to 4 R A5 s, where each R A5 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl. In some embodiments, X is -CR 8a R 8b -, where R 8a and R8b Together with the carbon to which they are attached, they form a 3-membered spiro carbon cyclic ring. In some embodiments, X is -CR 8a R 8b -, where R 8a and R 8b Together with the carbon to which they are attached, form a 3- to 5-membered saturated spiro heterocyclic ring containing one or two heteroatoms selected from N, O, and S, where the 3- to 5-membered saturated spiro heterocyclic ring is optionally substituted with one to four R A5 s, where each R A5 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl. In some embodiments, X is -CR 8a R 8b -, where R 8a and R 8b Together with the carbon to which they are attached, form a 3- to 5-membered saturated spiro heterocyclic ring containing one or two heteroatoms selected from N, O, and S.

[0099] In some embodiments, the compound of formula I or II is a compound of formula (VIII):

Chemical formula

[0100] In some embodiments of the compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, Z is -CR 9a R 9b -. In some embodiments, Z is -CR 9a R 9b -, where R 9a and R 9bis independently H, C 1~4 alkyl, C 1~4 haloalkyl, or halo. In some embodiments, Z is -CR 9a R 9b -, where R 9a and R 9b are independently H or C 1~4 alkyl. In some embodiments, Z is -CH2-. In some embodiments, Z is -CH(CH3)-. In some embodiments, Z is -CR 9a R 9b -CR 9c R 9d -. In some embodiments, Z is, -CR 9a R 9b -CR 9c R 9d -, where R 9a , R 9b , R 9c , and R 9d are independently H, C 1~4 alkyl, C 1~4 haloalkyl, or halo. In some embodiments, Z is -CH2-CH2-. In some embodiments, Z is -CR 10a =CR 10b -. In some embodiments, Z is -CR 10a =CR 10b -, where R 10a and R 10b . In some embodiments, Z is -CR 10a =CR 10b -, where R 10a and R 10 b together with the carbon atom to which each is attached form a 5- to 10-membered partially unsaturated fused ring, or 5- to 10-membered fused aromatic ring, or 5- to 10-membered fused heteroaromatic ring containing one to two heteroatoms selected from N, O, and S, containing zero heteroatoms or one heteroatom selected from N, O, and S, where this partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring has one to four R A7is optionally replaced herein, where each R A7 is independently halo or C 1~4 alkyl. In some embodiments, Z is -CR 10a =CR 10b -, where R 10a and R 10b together with the carbon atom to which each is attached form a 5- to 10-membered partially unsaturated fused ring optionally substituted with 0 to 4 R A7 and containing 0 heteroatoms or 1 heteroatom selected from N, O, and S, where each R A7 is independently halo or C 1~4 alkyl. In some embodiments, Z is -CR 10a =CR 10b -, where R 10a and R 10b together with the carbon atom to which each is attached form a 5- to 10-membered fused aromatic ring optionally substituted with 1 to 4 R A7 where each R A7 is independently halo or C 1~4 alkyl. In some embodiments, Z is -CR 10a =CR 10b -, where R 10a and R 10b together with the carbon atom to which each is attached form a 5- to 10-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O, and S and optionally substituted with 1 to 4 R A7 where each R A7 is independently halo or C 1~4 alkyl. In some embodiments, Z is -CR 10a =CR 10b -, where R 10a and R 10b together with the atom to which each is attached form a fused 1,2-phenylene ring optionally substituted with 1 to 4 R A7 where each R A7 is independently halo or C 1~4 alkyl. In some embodiments, Z is, [ka] where q is 0, 1, 2, 3, or 4. In some embodiments, Z is [ka] where each R A4 is independently halo. In some embodiments, Z is [ka] where each R A4 is independently halo, and q is 0, 1, 2, or 3. In some embodiments, Z is [ka] where each R A4 is independently halo, and q is 0, 1, or 2. In some embodiments, Z is [ka] In some embodiments, Z is [ka] In some embodiments, Z is [ka] In some embodiments, Z is -CH2-, -CH(CH3)-, -CH2-CH2-, [ka] It is.

[0101] In some embodiments of the compound of Formula I, II, IIIa, IIIb, or VIII, or a pharma- ceutically acceptable salt thereof, L is -CR 3a R 3b- and R 3a and R 3b are independently H, C 1~4 alkyl, C 1~4 haloalkyl, or -O-C 1~4 alkyl. In some embodiments, R 3a and R 3b are independently H or C 1~4 alkyl. In some embodiments, R 3a and R 3b are H. In some embodiments, R 3a and R 3b are C 1~4 alkyl. In some embodiments, R 3a is H and R 3b is C 1~4 alkyl. In some embodiments, R 3a is H and R 3b is methyl. In some embodiments, R 3a and R 3b together with the carbon atom to which they are attached form a 3- to 7-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, where the spiro ring is optionally substituted with 1 to 3 R A2 where each R A2 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl. In some embodiments, R 3a and R 3b together with the carbon atom to which they are attached form a 3-, 4-, or 5-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, where the spiro ring is optionally substituted with 1 to 3 R A2 where each R A2 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl. In some embodiments, R 3a and R 3b are the carbon to which they are attached... forms a 3- or 4-membered saturated spiro ring together with the elemental atom and containing 0 heteroatoms or 1 heteroatom selected from N, O, and S, wherein this spiro ring is substituted with 1 to 3 Rs A2 optionally, where each R A2 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl. In some embodiments, R 3a and R 3b form a 3-membered saturated spiro ring together with the carbon atom to which they are attached and containing 0 heteroatoms or 1 heteroatom selected from N, O, and S, wherein this spiro ring is substituted with 1 to 3 Rs A2 optionally, where each R A2 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl. In some embodiments, R 3a and R 3b form a spirocyclopropane ring together with the carbon atom to which they are attached.

[0102] In some embodiments of the compounds of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, or VIII, or pharmaceutically acceptable salts thereof, W 1 is -CR 4a R 4b -, and R 4a and R 4b are independently H, C 1~4 alkyl, C 1~4 haloalkyl, or halo. In some embodiments, R 4a and R 4b are independently H or halo. In some embodiments, R 4a and R 4b are H. In some embodiments, R 4a and R 4b are halo. In some embodiments, R 4a and R 4bis fluoro. In some embodiments, R 4a is H, and R 4b is halo. In some embodiments, R 4a is H, and R 4b is fluoro.

[0103] In some embodiments of the compounds of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, W 2 is -CR 5a R 5b -, and R 5a and R 5b are independently H, C 1~4 alkyl, C 1~4 haloalkyl, halo, hydroxyl, cyano, -O-C 1~4 alkyl, or C 1~4 alkylene-O-C 1~4 alkyl. In some embodiments, R 5a and R 5b are independently H, C 1~4 alkyl, C 1~4 haloalkyl, halo, or hydroxyl. In some embodiments, R 5a and R 5b are independently H or halo. In some embodiments, R 5a and R 5b are H. In any embodiment, R 5a and R 5b are halo. In some embodiments, R 5a and R 5b are fluoro. In some embodiments, R 5a is H, and R 5b is halo. In some embodiments, R 5a is H, and R 5b is fluoro. In some embodiments, R 5a and R 5btogether with the carbon atoms to which they are attached form a 3- to 7-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is optionally substituted with 1 to 3 R A3 and wherein each R A3 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl. In some embodiments, R 5a and R 5b together with the carbon atoms to which they are attached form a 3-, 4-, or 5-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is optionally substituted with 1 to 3 R A3 and wherein each R A3 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl. In some embodiments, R 5a and R 5b together with the carbon atoms to which they are attached form a 3- or 4-membered saturated spiro ring containing 0 heteroatoms or 1 heteroatom selected from N, O, and S, wherein the spiro ring is optionally substituted with 1 to 3 R A3 and wherein each R A3 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl. In some embodiments, R 5a and R 5b together with the carbon atoms to which they are attached form a 3-membered saturated spiro ring containing 0 heteroatoms or 1 heteroatom selected from N, O, and S, wherein the spiro ring is optionally substituted with 1 to 3 R A3 and wherein each R is independently halo, C A3 alkyl or C 1~4 haloalkyl. In some embodiments, R 1~4 and R 5a and R 5bTogether with the carbon atoms to which they are attached, they form a spirocyclopropane ring.

[0104] In some embodiments of the compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, W 2 is -CR 5a R 5b CR 5c R 5d -, and R 5a , R 5b , R 5c , and R 5d are independently H, C 1~4 alkyl, C 1~4 haloalkyl, halo, hydroxyl, cyano, -O-C 1~4 alkyl, or C 1~4 alkylene-O-C 1~4 alkyl. In some embodiments, R 5a , R 5b , R 5c , and R 5d are independently H, C 1~4 alkyl, C 1~4 haloalkyl, halo, or hydroxyl. In some embodiments, R 5a , R 5b , R 5c , and R 5d are independently H or halo. In some embodiments, R 5a , R 5b , R 5c , and R 5d are H. In some embodiments, R 5a and R 5c are independently H or halo, and R 5b and R 5d , together with the carbon atoms to which each is attached, form a 3- to 7-membered saturated or partially unsaturated fused carbocyclic ring optionally substituted with one to three R A3 , where each R A3 is independently halo, C 1~4 alkyl or C1~4 is a haloalkyl. In some embodiments, R 5a and R 5c are independently H or halo, and R 5b and R 5d together with the carbon atom to which each is attached form a 3-, 4-, or 5-membered saturated fused carbocyclic ring. In some embodiments, R 5a and R 5c are H, and R 5b and R 5d together with the carbon atom to which each is attached form a 3-, 4-, or 5-membered saturated fused carbocyclic ring. In some embodiments, R 5a and R 5c are H, and R 5b and R 5d together with the carbon atom to which each is attached form a fused cyclopropane ring.

[0105] In some embodiments of the compounds of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, W 2 is -CR 6a =CR 6b -, and R 6a and R 6b are independently H, halo, C 1~4 haloalkyl, or C 1~4 alkyl. In some embodiments, R 6a and R 6b are independently H or halo. In some embodiments, R 6a and R 6b are H. In some embodiments, R 6a and R 6b together with the atoms to which each is attached form a 5- to 10-membered fused aromatic ring optionally substituted with from 1 to 4 R A4 , where each R A4 is independently halo or C 1~4 alkyl. In some embodiments, R6a and R 6b together with the atoms to which each is attached form a fused 1,2-phenylene ring optionally substituted with from 1 to 4 Rs A4 where each R A4 is independently halo or C 1~4 alkyl. In some embodiments, R 6a and R 6b together with the atoms to which each is attached form

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0106] In some embodiments of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, W 2 is -N(R 7 )-, and R 7 is H, C 1~4 alkyl, C 1~4 haloalkyl, C(O)R c , or SO2R c . In some embodiments, R 7 is H, C 1~4 alkyl, C(O)R c , or SO2R c . In some embodiments, R 7 is H. In some embodiments, R 7 is C 1~4 alkyl. In some embodiments, R 7 is methyl or 1-methylethyl. In some embodiments, R 7 is C(O)R c . In some embodiments, R 7 is -C(O)-C 1~4 alkyl. In some embodiments, R 7 is -C(O)CH3. In some embodiments, R 7 is SO2R c . In some embodiments, R 7 is -SO2-C 1~4 alkyl. In some embodiments, R 7 is -SO2CH3.

[0107] In some embodiments of the compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, W 2 is selected from the group consisting of -CR 5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =CR 6b -, -N(R 7 ), -, -O-, -S(O) n -, -C(O)-, -CR 5a R 5b -C(O)-, and -CR 5a R 5b -O-; wherein each of R 5a , R 5b , R 5c , and R 5d is independently H, C 1~4 alkyl, C 1~4 haloalkyl, halo, hydroxyl, cyano, -O-C 1~4 alkyl, or C 1~4 alkylene-O-C 1~4 alkyl; or R 5a and R 5b , R 5c and R 5d , R 5a and R 5c , or R 5b and R 5d together with the carbon atom to which each is attached form a 3- to 7-membered saturated or partially unsaturated carbocyclic ring optionally substituted with one to three R A3 wherein each R A3 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl; each of R 6a and R 6b is independently H, halo, C 1~4 haloalkyl, or C 1~4 alkyl; or R 6a and R 6bTogether with the atoms to which each is attached, form (i) a 5- to 10-membered fused aromatic ring, or (ii) a 5- to 10-membered fused heteroaromatic ring containing one or two heteroatoms selected from N, O, and S, where this 5- to 10-membered fused aromatic ring or this 5- to 10-membered fused heteroaromatic ring is optionally substituted with one to four R A4 and where each R A4 is independently halo or C 1~4 alkyl; R 7 is H, C 1~4 alkyl, C 1~4 haloalkyl, C(O)R c , or SO2R c ; and R c is C 1~4 alkyl; and n is 0, 1, or 2.

[0108] In some embodiments of the compounds of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, W 2 is selected from the group consisting of -CR 5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =CR 6b -, -N(R 7 )-, -O-, -S(O) n -, -C(O)-, -CR 5a R 5b -C(O)-, and -CR 5a R 5b -O-; where each of R 5a , R 5b , R 5c , and R 5d is independently H, C 1~4 alkyl, C 1~4 haloalkyl, halo, hydroxyl, cyano, -O-C 1~4 alkyl, or C 1~4 alkylene-O-C 1~4 alkyl; or alternatively R5a and R 5b 、R 5c and R 5d 、R 5a and R 5c 、or R 5b and R 5d each, together with the carbon atom to which it is attached, forms a 3-membered carbocyclic ring optionally substituted with 1 to 3 R A3 where each R A3 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl; R 6a and R 6b each is independently H, halo, C 1~4 haloalkyl, or C 1~4 alkyl; or R 6a and R 6b together with the atom to which each is attached, form (i) a fused phenyl ring, or (ii) a 5- to 6-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O, and S, where this fused phenyl ring or this 5- to 6-membered fused heteroaromatic ring is optionally substituted with 1 to 4 R A4 where each R A4 is independently halo or C 1~4 alkyl; R 7 is H, C 1~4 alkyl, C 1~4 haloalkyl, C(O)R c 、or SO2R c ; Rc is C 1~4 alkyl; and n is 0, 1, or 2.

[0109] In some embodiments of the compounds of Formulas I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, W 2 is -CR 5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a=CR 6b -, -N(R 7 )-, -O-, -S(O) n -, -C(O)-, -CR 5a R 5b -C(O)-, and -CR 5a R 5b -O- selected from the group consisting of; where R 5a , R 5b , R 5c , and R 5d each is independently H, C 1~4 alkyl, halo, hydroxyl, or -O-C 1~4 alkyl; or R 5a and R 5b , R 5c and R 5d , R 5a and R 5c , or R 5b and R 5d are each joined to the carbon atom to which they are attached to form a 3-membered carbocyclic ring; R 6a and R 6b each is independently H, halo, or C 1~4 alkyl; or R 6a and R 6b are each joined to the atom to which they are attached to form (i) a fused phenyl ring, or (ii) a 5- to 6-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N and O, where this fused phenyl ring or this 5- to 6-membered fused heteroaromatic ring is optionally substituted with one or two R A4 where each R A4 is independently halo or C 1~4 alkyl; R 7 is H, C 1~4 alkyl, C 1~4 haloalkyl, C(O)R c , or SO2R c ; R c is C 1~4 alkyl; and n is 0 or 1.

[0110] In some embodiments, W 2 is -CR5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =CR 6b -, -N(R 7 )-, -O-, -S(O) n -, -C(O)-, -CR 5a R 5b -C(O)-, and -CR 5a R 5b -O- selected from the group consisting of; where R 5a , R 5b , R 5c , and R 5d each is independently H, -CH3, halo, hydroxyl, or -OCH3; or R 5a and R 5b , R 5c and R 5d , R 5a and R 5c , or R 5b and R 5d together with the carbon atom to which each is attached form a 3-membered carbocyclic ring; R 6a and R 6b each is independently H, halo, or CH3; or R 6a and R 6b together with the atom to which each is attached form (i) a fused phenyl ring, or (ii) a 5-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N and O, where this fused phenyl ring or 5- to 6-membered fused heteroaromatic ring is optionally substituted with one or two R A4 where each R A4 is independently halo or CH3; R 7 is H, -CH3, -CH(CH3)2, -CF3, -C(O)R c , or -SO2R c ; R c is -CH3; and n is 0 or 1.

[0111] In some embodiments, W 2 is, -CR5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =CR 6b -, -N(R 7 )-, -O-, -S(O) n -, -C(O)-, -CR 5a R 5b -C(O)-, and -CR 5a R 5b -O- selected from the group consisting of; where R 5a , R 5b , R 5c , and R 5d each of is independently H, -CH3, halo, hydroxyl, or -OCH3; R 6a and R 6b each of is independently H, halo, or -CH3; R 7 is H, -CH3, -CH(CH3)2, -CF3, -C(O)R c , or -SO2R c ; R c is -CH3; and n is 0 or 1.

[0112] In some embodiments of the compounds of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, X is -CR 8a R 8b -; and R 8a and R 8b are independently H, hydroxyl, -O-C 1~4 alkyl, C 1~4 alkylene -O-C 1~4 alkyl, C 1~4 alkyl, C 1~4 haloalkyl, cyano, or halo. In some embodiments, R 8a and R 8b are independently H, hydroxyl, C 1~4 alkyl, or halo. In some embodiments, R 8ais H, fluoro, or hydroxyl, and R 8b is H or fluoro. In some embodiments, R 8a and R 8b are H. In some embodiments, R 8a and R 8b are fluoro. In some embodiments, R 8a is H and R 8b is halo. In some embodiments, R 8a is H and R 8b is fluoro. In some embodiments, R 8a is H and R 8b is hydroxyl. In some embodiments, R 8a is H and R 8b is C 1~4 alkyl. In some embodiments, R 8a is H and R 8b is methyl. In some embodiments, R 8a is halo and R 8b is C 1~4 alkyl. In some embodiments, R 8a is flu oro and R 8b is methyl. In some embodiments, R 8a and R 8b together with the carbon to which they are attached form a 3-, 4-, or 5-membered saturated spiro ring containing from 0 to 2 heteroatoms selected from N, O, and S, where the spiro ring is optionally substituted with from 1 to 4 R A5 s, where each R A5 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl. In some embodiments, R 8a and R 8b together with the carbon to which they are attached form a 3-, 4-, or 5-membered saturated spiro ring containing 0 heteroatoms, where the spiro ring is optionally substituted with from 1 to 4 R A5is optionally replaced herein, where each R A5 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl. In some embodiments, R 8a and R 8b together with the carbon to which they are attached form a spirocyclopropane ring.

[0113] In some embodiments of the compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, Z is -CR 9a R 9b -, and R 9a and R 9b are independently H, C 1~4 alkyl, C 1~4 haloalkyl, or halo. In some embodiments, R 9a and R 9b are independently H or C 1~4 alkyl. In some embodiments, R 9a and R 9b are H. In some embodiments, R 9a and R 9b are C 1~4 alkyl. In some embodiments, R 9a is H and R 9b is C 1~4 alkyl. In some embodiments, R 9a is H and R 9b is methyl.

[0114] In some embodiments of the compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, Z is -CR 9a R 9b -CR 9c R 9d -, and R 9a , R9b , R 9c , and R 9d are independently H, C 1~4 alkyl, C 1~4 haloalkyl, or halo. In some embodiments, R 9a , R 9b , R 9c , and R 9d are independently H or C 1~4 alkyl. In some embodiments, R 9a , R 9b , R 9c , and R 9d is H.

[0115] In some embodiments of the compounds of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, Z is -CR 10a =CR 10b -, and R 10a and R 10b are independently H, halo, C 1~4 haloalkyl, or C 1~4 alkyl. In some embodiments, R 10a and R 10b together with the atoms to which each is attached form a 5- to 10-membered fused aromatic or heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O, and S, where this aromatic or heteroaromatic ring is optionally substituted with 1 to 4 R A7 s, where each R A7 is independently halo or C 1~4 alkyl. In some embodiments, R 10a and R 10b together with the atoms to which each is attached form a 5- to 10-membered fused aromatic ring optionally substituted with 1 to 4 R A7 s, where each R A7 is independently halo or C 1~4 alkyl. In some embodiments, R 10a and R 10bcombines with the atoms to which each is attached to form a fused 1,2-phenylene ring optionally substituted with 1 to 4 Rs, where each R A7 is independently halo or C A7 alkyl. In some embodiments, R 1~4 and R 10a combine with the atoms to which each is attached to form 10b where q is 0, 1, 2, 3, or 4. In some embodiments, R

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0116] In some embodiments of the compounds of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, Z is -CR 9a R 9b -, -CR 9a R 9b CR 9c R 9d -, or -CR 10a =CR 10b -; wherein R 9a , R 9b , R 9c , and R 9d are each independently H, C 1~6 alkyl, C 1~4 haloalkyl, or halo; or alternatively R 9a and R 9b , or R 9c and R 9d together with the carbon atoms to which they are attached form a 3- to 7-membered saturated or partially unsaturated ring containing from 0 to 2 heteroatoms selected from N, O, and S, where the spiro ring is optionally substituted with from 1 to 3 R A6 s, where each R A6 is independently halo, C 1~4 alkyl or C 1~4 haloalkyl; R 10a and R 10b are each independently H, halo, C 1~4 haloalkyl, or C 1~6 alkyl; or alternatively R10a and R 10b each, together with the carbon atom to which it is attached, forms a 5- to 10-membered partially unsaturated fused ring containing (i) 0 heteroatoms or 1 heteroatom selected from N, O, and S, (ii) a 5- to 10-membered fused aromatic ring, or (iii) a 5- to 10-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O, and S, wherein the 5- to 10-membered partially unsaturated fused ring, 5- to 10-membered fused aromatic ring, or 5- to 10-membered fused heteroaromatic ring is optionally substituted with 1 to 4 R A7 wherein each R A7 is independently halo or C 1~4 alkyl.

[0117] In some embodiments of the compounds of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, or VIII, or pharmaceutically acceptable salts thereof, Z is -CR 9a R 9b -, -CR 9a R 9b CR 9c R 9d -, or -CR 10a =CR 10b -; wherein R 9a , R 9b , R 9c , and R 9d are each independently H, CH3, CH2CH3, CHF2, or halo; or R 9a and R 9b , or R 9c and R 9d together with the carbon atom to which they are attached form a 3-membered carbocyclic ring; R 10a and R 10b are each independently H, halo, or CH3; or R 10a and R 10b each, together with the carbon atom to which it is attached, forms (i) a fused phenyl ring, or (ii) a 5- to 6-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O, and S, wherein the fused phenyl ring or the fused heteroaromatic ring is optionally substituted with 1 to 2 RA7 is optionally replaced as necessary, where each R A7 is independently halo or CH3.

[0118] In some embodiments of the compounds of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, or VIII, or pharmaceutically acceptable salts thereof, R 1 is phenyl substituted with one, two, three, or four R A1 where each R A1 is independently halo or -O-C 1~4 alkyl; X is a bond or CR 8a R 8b - where R 8a and R 8b are independently H, hydroxyl, -O-C 1~4 alkyl, C 1~4 alkyl, C 1~4 haloalkyl, or halo, or R 8a and R 8b together with the carbon to which they are attached form a 3-membered saturated spiro carbocyclic ring; W 1 is a bond or -CR 4a R 4b -; where R 4a and R 4b are independently , H, C 1~6 alkyl, or halo; W 2 is -CR 5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =CR 6b -, -N(R 7 )-, -O-, -S(O) n -, -C(O)-, -CR 5a R 5b -C(O)-, and -CR 5a R 5bselected from the group consisting of -O-; wherein R 5a 、R 5b 、R 5c 、and R 5d each independently is H, C 1~4 alkyl, halo, hydroxyl, or -O-C 1~4 alkyl; R 6a and R 6b each independently is H, halo, or C 1~4 alkyl; R 7 is H, C 1~4 alkyl, C 1~4 haloalkyl, C(O)R c 、or SO2R c ; R c is C 1~4 alkyl; and n is 0 or 1; and Z is -CR 9a R 9b -, -CR 9a R 9b CR 9c R 9d -, or -CR 10a =CR 10b -; wherein R 9a 、R 9b 、R 9c 、and R 9d each independently is H, C 1~6 alkyl, C 1~4 haloalkyl, or halo; or R 9a and R 9b 、or R 9c and R 9d together with the carbon atom to which they are attached form a 3-membered carbocyclic ring; and R 10a and R 10b each independently is H, halo, C 1~4 haloalkyl, or C 1~6 alkyl.

[0119] In some embodiments of the compounds of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, or VIII, or pharmaceutically acceptable salts thereof, R 1is phenyl substituted with 1, 2, 3, or 4 R A1 where each R A1 is independently halo or -O-C 1~4 alkyl; X is a bond or CR 8a R 8b - where R 8a and R 8b are independently H, hydroxyl, -O-C 1~4 alkyl, C 1~4 alkyl, C 1~4 haloalkyl, or halo; W 1 is a bond or -CR 4a R 4b - where R 4a and R 4b are independently H, C 1~6 alkyl, or halo; W 2 is -CR 5a R 5b - where R 5a and R 5b each are independently H, C 1~4 alkyl, halo, hydroxyl, or -O-C 1~4 alkyl; and Z is -CR 9a R 9b - where R 9a and R 9b are each independently H, C 1~6 alkyl, C 1~4 haloalkyl, or halo.

[0120] In some embodiments of the compounds of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, R a are independently H, C 1~4 alkyl, C 1~6 haloalkyl, C(O)R c , or SO2R c .

[0121] In some embodiments of the compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, R b is H. In some embodiments, R b is C 1~4 alkyl. In some embodiments, R b is methyl.

[0122] In some embodiments of the compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, R c is C 1~4 alkyl. In some embodiments, R c is methyl. In some embodiments, R c is -O-C 1~4 alkyl.

[0123] In some embodiments of the compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, or VIII, X, Xa, Xb, XI, XIa, or XIb, or pharmaceutically acceptable salts thereof, n is 0. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, the compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, or VIII are compounds of formula (IX):

[0124] wherein R

Chemical formula

[0125] In some embodiments, a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, or IX is a compound of formula (IXa):

Chemical formula

[0126] In some embodiments, a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, or IX is a compound of formula (IXb):

Chemical formula

[0127] In some embodiments of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, or Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, R 1 is H. In some embodiments, R 1 is C 6~10It is aryl. In some embodiments, R 1 is phenyl optionally substituted with from 1 to 4 R A1 , where each R A1 is independently halo, C 1~4 alkyl, C 1~4 haloalkyl, cyano, -O-C 1~4 alkyl, or C 1~4 alkyl-O-C 1~4 alkyl. In some embodiments, R 1 is phenyl substituted with 1, 2, 3, or 4 R A1 . In some embodiments, R 1 is phenyl substituted with 1, 2, 3, or 4 R A1 . In some embodiments, R 1 is phenyl substituted with 1, 2, 3, or 4 R A1 , where each R A1 is independently halo, C 1~4 alkyl, C 1~4 haloalkyl, or -O-C 1~4 alkyl. In some embodiments, R 1 is phenyl substituted with 1, 2, 3, or 4 R A1 , where each R A1 is independently halo, C 1~4 alkyl, or C 1~4 haloalkyl. In some embodiments, R 1 is phenyl substituted with 1, 2, 3, or 4 R A1 , where each R A1 is independently halo or -O-C 1~4 alkyl. In some embodiments, R 1 is phenyl substituted with 1, 2, 3, or 4 halogens. In some embodiments, R 1 is phenyl substituted with 1, 2, or 3 halogens. In some embodiments, R 1 is phenyl substituted with 2 or 3 halogens. In some embodiments, R1 is phenyl substituted with two or three halogens selected from chloro and fluoro. In some embodiments, R 1 is

Chemical formula

[0128] In some embodiments of the compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, R 1 is

Chemical formula

Chemical formula

[0129] In some embodiments, the compound has the formula:

Chemical formula

Chemical formula

[0130] In some embodiments, the compound has the formula:

Chemical formula

Chemical formula

[0131] In some embodiments, the compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0132] In some embodiments, the compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, or IXb, X, Xa, Xb, XI, XIa, or XIb is

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0133] Compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb are the rings A, B, and C illustrated below for formula I: [Chemistry] Can be described with reference to, where A represents a ring bridged to ring B, B represents a ring bridged to a fused ring with respect to ring A and ring C, and C represents a fused ring with respect to ring B. As described above, these compounds may have one or more additional fused rings or spirocyclic rings.

[0134] When any variable is an asymmetric group, unless otherwise specified, both orientations of this group are intended to be covered. For example, W 2 is -CR 5a R 5b -N(R 7 ), when it is -CR 5a R 5b -N(R 7 ), both orientations of -CR 1 -CR 5a R 5b -N(R 7 )-X and Z-W 1 -N(R 7 )-CR 5a R 5b -X are included (i.e., both Z-W

Chemical formula

Chemical formula

Chemical formula

[0135] Any embodiment of a compound of any one of Formulas I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, and any specific group or substituent described herein (e.g., R 1 , R 2 , L, W 1 , W 2, X, Y, Z, and their substituents) may independently be combined with other embodiments and / or substituents of any one compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb to form embodiments not specifically described above, which is understood. Further, in certain embodiments and / or claims, if the listing of substituents does not list any of the specific R 1 , R 2 , L, W 1 , W 2 , X, Y, and Z groups, it is understood that each individual substituent may be deleted from that particular embodiment and / or claim, and the remaining listing of substituents is considered to be within the scope of the embodiments disclosed herein. Pharmaceutical composition

[0136] In another embodiment, there is provided a pharmaceutical composition comprising a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0137] In some embodiments, these pharmaceutical compositions further contain one, two, three, or four additional therapeutic agents. In certain embodiments, this additional therapeutic agent(s) is an anti-HIV agent. In specific embodiments, this additional therapeutic agent(s) is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latency reversing agent, a capsid polymerization inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof. In one embodiment, this additional therapeutic agent(s) is abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, or a pharmaceutically acceptable salt thereof. Kits and Manufactured Articles

[0138] In some embodiments, the present disclosure relates to a kit comprising a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof. In one embodiment, the kit may comprise one, two, three, or four additional therapeutic agents as previously described herein. The kit may further comprise instructions for use, for example, for use in inhibiting HIV integrase, for example, for use in treating HIV infection or AIDS, or for use as a research tool. These instructions for use are generally the described instructions, although an electronic storage medium (e.g., magnetic disk or optical disk) containing the instructions is also acceptable.

[0139] In some embodiments, the present disclosure also relates to a pharmaceutical kit comprising one or more containers containing a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof. Such container(s) may be associated, as appropriate, with a notice in a form prescribed by a governmental agency that regulates the manufacture, use, or sale of pharmaceuticals, which notice reflects approval by that agency of manufacture, use, or sale for human administration. Each component, if more than one component is present, may be packaged in a separate container or, where cross-reactivity and shelf-life permit, several components may be combined in one container. These kits may be in unit dosage form, bulk packaging (e.g., multi-dose packaging), or partial unit dosage. The kit may also comprise a plurality of unit doses of the compound, and instructions for use, and may be packaged in an amount sufficient for storage and use in pharmacies (e.g., hospital pharmacies and compounding pharmacies).

[0140] In some embodiments, the unit dosage of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, A manufactured article is disclosed herein that comprises a compound of Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, in a suitable package for use by the methods described herein. Suitable packages are known in the art and include, for example, vials, containers, ampoules, bottles, jars, and flexible packaging materials. The manufactured article can further be sterilized and / or sealed. Method of treatment

[0141] In one embodiment, there is provided a method of treating HIV (e.g., HIV-1 and / or HIV-2) infection in a human having or at risk of having the infection, the method comprising administering to the human a therapeutically effective amount of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof.

[0142] In some embodiments, these 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(s) is an anti-HIV agent. In specific embodiments, the additional therapeutic agent(s) is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latency reversing agent, a capsid polymerization inhibitor, an HIV bNAb (broadly neutralizing HIV antibody), a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof. In one embodiment, the additional therapeutic agent(s) is abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, or a pharmaceutically acceptable salt thereof.

[0143] In another embodiment, there is provided the use of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, for treating HIV (e.g., HIV-1 and / or HIV-2) infection in a human having or at risk of having the infection.

[0144] In another embodiment, a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb or a pharmaceutically acceptable salt thereof is provided for use in medical treatment.

[0145] In another embodiment, a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb or a pharmaceutically acceptable salt thereof is provided for use in the treatment of HIV infection.

[0146] In another embodiment, a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb or a pharmaceutically acceptable salt thereof is provided for use in a method of treating HIV infection in a human having or at risk of having HIV infection.

[0147] In another embodiment, provided is a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb or a pharmaceutically acceptable salt thereof for use in a method of treating HIV infection in a human having or at risk of having HIV infection, wherein the method further comprises administering to the human one, two, three or four additional therapeutic agents.

[0148] In another embodiment, provided is a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb or a pharmaceutically acceptable salt thereof for use in a method of treating HIV infection in a human having or at risk of having HIV infection, wherein the method further comprises administering to the human one, two, three, or four additional therapeutic agents selected from the group consisting of an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gpl20 inhibitor, a CCR5 inhibitor, a latency reversing agent, a capsid polymerization inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or combinations thereof. In one embodiment, the one, two, three, or four additional therapeutic agents are selected from an HIV protease inhibitor, an HIV non-nucleoside inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, a latency reversing agent, an HIV capsid inhibitor, an HIV bNAb, a TLR7 agonist, and combinations thereof.

[0149] In another embodiment, provided is a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VI There is provided a pharmaceutical composition of a compound of Ia, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb or a pharmaceutically acceptable salt thereof, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir disoproxil and emtricitabine.

[0150] In another embodiment, there is provided a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb or a pharmaceutically acceptable salt thereof for use in a method of treating HIV infection in a human having or at risk of having HIV infection, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir alafenamide and emtricitabine.

[0151] In another embodiment, there is provided a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb or a pharmaceutically acceptable salt thereof for use in a method of treating HIV infection in a human having or at risk of having HIV infection, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir disoproxil.

[0152] In another embodiment, provided is a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb or a pharmaceutically acceptable salt thereof for use in a method of treating HIV infection in a human having or at risk of having HIV infection, wherein the method further comprises administering to the human a therapeutically effective amount of tenofovir alafenamide.

[0153] In another embodiment, provided is a method of using a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb in therapy. Specifically, provided is a method of treating the growth of HIV virus, treating AIDS, or delaying the onset of symptoms of AIDS or ARC in a mammal (e.g., a human), the method comprising administering to the mammal a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0154] In another embodiment, provided is a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient for use in a method of treating the growth of HIV virus, treating AIDS, or delaying the onset of symptoms of AIDS or ARC in a mammal (e.g., a human).

[0155] In one embodiment, a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is provided for use in the prevention of HIV infection.

[0156] For example, in one embodiment, for pre-exposure prophylaxis (PrEP), i.e., used prior to an individual's exposure to the HIV virus to prevent the establishment of HIV infection if the individual is exposed to the virus, and / or to prevent the virus from establishing a persistent infection, and / or to prevent the onset of disease symptoms, and / or to prevent the virus from reaching a detectable level in the blood, a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is provided.

[0157] In another embodiment, the use of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating HIV infection in a human having or at risk of having the infection is disclosed.

[0158] In another embodiment, the use of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, as a research tool is disclosed.

[0159] In another embodiment, a manufactured article is disclosed that includes a composition effective to treat an HIV infection; and a packaging material bearing a label indicating that the composition can be used to treat an infection by HIV. Exemplary compositions contain a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof.

[0160] In yet another embodiment, a method of inhibiting HIV replication is disclosed. The method includes exposing the virus to an effective amount of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a salt thereof, under conditions such that HIV replication is inhibited.

[0161] In another embodiment, the use of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb to inhibit the activity of the HIV integrase enzyme is disclosed.

[0162] In another embodiment, the use of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a salt thereof, to inhibit HIV replication is disclosed. Administration

[0163] For the purposes of administration, in certain embodiments, the compounds described herein are administered as raw chemical substances or formulated as pharmaceutical compositions. Pharmaceutical compositions within the scope of the embodiments disclosed herein contain a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb and a pharmaceutically acceptable excipient. The compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb is present in the composition in an amount effective to treat a particular disease or condition of interest. The activity of the compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb can be determined as described in the examples below.

[0164] Administration of the compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts, in pure form or in suitable pharmaceutical compositions, can be effected by any of the accepted methods of administering agents for similar utilities. The pharmaceutical compositions of the embodiments disclosed herein can be prepared by combining a compound of the embodiments disclosed herein with suitable pharmaceutically acceptable excipients, and formulated into preparations in solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres, and aerosols. Representative routes of administration of such pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, parenteral, injectable, sublingual, buccal, rectal, vaginal, and intranasal. The pharmaceutical compositions of the embodiments disclosed herein are formulated so as to make the active ingredient contained therein bioavailable when the composition is administered to a patient. The composition administered to a subject or patient is in the form of one or more dosage units, where, for example, a tablet can be a single dosage unit, and a container of an aerosol form of a compound of the embodiments disclosed herein can hold multiple dosage units. The actual methods of preparing such dosage forms are known or will be apparent to those skilled in the art. See, for example, Remington: The Science and Practice of Pharmacy, 20th Edition (Philadelphia College of Pharmacy and Science, 2000). In any event, the composition to be administered contains a therapeutically effective amount of a compound of the embodiments disclosed herein, or a pharmaceutically acceptable salt thereof, for treating the targeted disease or condition in accordance with the teachings of this disclosure.

[0165] In one embodiment, the pharmaceutical composition is an oral dosage unit. In one embodiment, the pharmaceutical composition is a solid oral dosage unit. In one embodiment, the pharmaceutical composition is a tablet.

[0166] In one embodiment, the pharmaceutical composition is a parenteral dosage unit. In one embodiment, the pharmaceutical composition is a subcutaneous, intramuscular, intravenous, intradermal, intrathecal, or epidural dosage unit. In one embodiment, the pharmaceutical composition is a subcutaneous, intramuscular, or intravenous dosage unit. In one embodiment, the pharmaceutical composition is injectable.

[0167] The pharmaceutical compositions disclosed herein can be prepared by methods well known in the pharmaceutical arts. For example, a pharmaceutical composition intended for administration by injection can be prepared by combining a compound of an embodiment disclosed herein with sterile distilled water to form a solution. A surfactant can be added to facilitate the formation of a homogeneous solution or suspension. A surfactant is a compound that non-covalently interacts with a compound of an embodiment disclosed herein to facilitate the dissolution or homogeneous suspension of the compound in an aqueous delivery system.

[0168] The compounds of the embodiments disclosed herein, or pharmaceutically acceptable salts thereof, are administered in a therapeutically effective amount, which will vary depending on various factors including the activity of the specific compound used; the metabolic stability and length of action of that compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; drug combinations; the severity of the particular disorder or condition; and the treatment the subject is undergoing. Combination therapy

[0169] In certain embodiments, provided is a method for treating HIV infection in a human having or at risk of having HIV infection, the method 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, two, three or four additional therapeutic agents. In one embodiment, provided is a method for treating HIV infection in a human having or at risk of having HIV infection, the method 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, two, three or four additional therapeutic agents.

[0170] In one embodiment, provided is a pharmaceutical composition comprising a compound disclosed herein, or a pharmaceutically acceptable salt thereof, in combination with one, two, three or four additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0171] In certain embodiments, the disclosure provides a method of treating HIV infection, the method comprising administering to a patient in need thereof a therapeutically effective amount of a compound or a pharmaceutically acceptable salt thereof disclosed herein in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents suitable for treating HIV infection.

[0172] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with two additional therapeutic agents. In other embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with three additional therapeutic agents. In further embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class of therapeutic agents, and / or they may be selected from different classes of therapeutic agents. Administration of combination HIV therapy

[0173] In certain embodiments, the compounds disclosed herein are administered with one, two, three, or four additional therapeutic agents. Co-administration of the compounds disclosed herein with one, two, three, or four additional therapeutic agents generally refers to simultaneously or sequentially administering the compounds disclosed herein and the one, two, three, or four additional therapeutic agents such that a therapeutically effective amount of both are present in the patient's body. In the case of sequential administration, the combination may be administered in two or more administrations. For sequential administration, the combination may be administered in two or more administrations.

[0174] Co-administration involves administering a unit dose of the compounds disclosed herein before or after administering one, two, three, or four additional therapeutic agents per unit dose. For example, the compounds disclosed herein may be administered within seconds, minutes, or hours of administering one, two, three, or four additional therapeutic agents. In some embodiments, the compound disclosed herein is administered first as a unit dose, followed by administering one, two, three, or four additional therapeutic agents as a unit dose within seconds or minutes. Alternatively, one, two, three, or four additional therapeutic agents as a unit dose are administered first, followed by administering the compound disclosed herein as a unit dose within seconds or minutes. In other embodiments, the compound disclosed herein is administered first as a unit dose, followed by administering one, two, three, or four additional therapeutic agents as a unit dose after a period of time (e.g., 1 to 12 hours). In still other embodiments, one, two, three, or four additional therapeutic agents as a unit dose are administered first, followed by administering the compound disclosed herein as a unit dose after a period of time (e.g., 1 to 12 hours).

[0175] In certain embodiments, the compounds disclosed herein are combined with one, two, three, or four additional therapeutic agents in a unit dosage form for co-administration to a patient, e.g., as a solid dosage form for oral administration.

[0176] In certain embodiments, a kit is provided that contains a compound disclosed herein (e.g., a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb), or a pharmaceutically acceptable salt thereof, in combination with one or more (e.g., one, two, three, or four) additional therapeutic agents.

[0177] In certain embodiments, a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb 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 an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, a pharmacokinetic enhancer, and combinations thereof.

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

[0179] In the above embodiments, the additional therapeutic agent(s) can be other drugs for treating HIV, an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, an HIV entry inhibitor, an immunomodulator, an immunotherapy agent, an antibody-drug conjugate, a gene modifier, a gene editing agent (such as CRISPR / Cas9, zinc finger nuclease, homing nuclease, synthetic nuclease, TALEN, etc.), cell therapy (chimeric antigen receptor T cells, CAR-T and modified T cell receptors, TCR-T, autologous T cell therapy), a latency reversing agent, a compound targeting the HIV capsid, a capsid polymerization inhibitor, HIV They can be anti-HIV agents selected from bNAbs, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, broad neutralizing HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV viral infectivity factor inhibitors, TAT protein inhibitors, HIV Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-binding non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxythymidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulants, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapies and HIV vaccines, and any combination thereof.

[0180] In some embodiments, the additional therapeutic agent(s) 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

[0181] Examples of combination drugs include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); SYMTUZA® (darunavir, tenofovir alafenamide, emtricitabine, and cobicistat); BIKTARVY® (bictegravir, tenofovir alafenamide, and emtricitabine); bictegravir, tenofovir disoproxil, and emtricitabine; bictegravir, tenofovir alafenamide, and lamivudine; bictegravir, tenofovir disoproxil, and lamivudine; bictegravir, abacavir, and lamivudine; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lamivudine; tenofovir alafenamide and emtricitabine; tenofovir alafenamide hemifumarate and emtricitabine; tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (AL UVIA (Registered Trademark); lopinavir and ritonavir); TRIUMEQ (Registered Trademark) (dolutegravir, abacavir and lamivudine); JULUCA (Registered Trademark) (dolutegravir, rilpivirine); TRIZIVIR (Registered Trademark) (abacavir sulfate, zidovudine and lamivudine; ABC+AZT+3TC); dolutegravir and lamivudine; dolutegravir and abacavir; cabotegravir and lamivudine; cabotegravir and abacavir; cabotegravir and rilpivirine; atazanavir and cobicistat; atazanavir sulfate and cobicistat; atazanavir sulfate and ritonavir; darunavir and cobicistat; dolutegravir and rilpivirine; dolutegravir and rilpivirine hydrochloride; dolutegravir, abacavir sulfate and lamivudine; lamivudine, nevirapine and zidovudine; raltegravir and lamivudine; doravirine, lamivudine and tenofovir disoproxil fumarate; doravirine, lamivudine and tenofovir disoproxil; dolutegravir + lamivudine; lamivudine + abacavir + zidovudine; lamivudine + abacavir; lamivudine + tenofovir disoproxil fumarate; lamivudine + zidovudine + nevirapine; lopinavir + ritonavir; lopinavir + ritonavir + abacavir + lamivudine; lopinavir + ritonavir + zidovudine + lamivudine; tenofovir + lamivudine and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride are included. Other HIV drugs

[0182] Examples of other drugs for treating HIV include acemannan, alisporivir, BanLec, deferiprone, Gamimune, metenkephalin, naltrexone, prolastin, REP9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy, BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-2048, MK-4250, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576. HIV protease inhibitor

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

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

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

[0186] Examples of HIV integrase inhibitors include elvitegravir, curcumin, derivatives of curcumin, chicoric acid, derivatives of chicoric acid, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, derivatives of aurintricarboxylic acid, caffeic acid phenethyl ester, derivatives of caffeic acid phenethyl ester, tiloridine, derivatives of tiloridine, quercetin, derivatives of quercetin, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, VM-3500, and cabotegravir.

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

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

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

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

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

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

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

[0194] Examples of HIV maturation inhibitors include BMS-955176, GSK-3640254, and GSK-2838232. Latency reversal agents

[0195] Examples of latency reversal agents include histone deacetylase (HDAC) inhibitors, proteasome inhibitors (such as bortezomib), protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (suberoylanilide hydroxamic acid, or suberoyl, anilide, and hydroxamic acid), IL-15 modulating antibodies, JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors (such as largazole analogs), APH-0812, GSK-343, and toll-like receptor modulators.

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

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

[0198] Examples of capsid inhibitors include capsid polymerization inhibitors or capsid disrupting compounds, HIV nucleocapsid p7 (NCp7) inhibitors (such as azodicarbonamide), HIV p24 capsid protein inhibitors, GS-6207, AVI-621, AVI-101, AVI-201, AVI-301, and the AVI-CAN1-15 series. Immune-based therapies

[0199] Examples of immune-based therapies include toll-like receptor modulators such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13; programmed cell death protein 1 (Pd-1) modulators; programmed death ligand 1 (PDL-1) modulators; IL-15 modulators; DermaVir; interleukin-7; plaquenil (hydroxychloroquine); proleukin (aldesleukin, IL-2); interferon alpha; interferon alpha-2b; interferon alpha-n3; pegylated interferon alpha; interferon gamma; hydroxyurea; mycophenolate mofetil (MPA) and its ester derivative mycophenolate mofetil (MMF); ribavirin; polymeric polyethyleneimine (PEI); gepon; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, interleukin-15 / Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255, normiferon, peginterferon alpha-2a, peginterferon alpha-2b, recombinant interleukin-15, RPI-MN, STING modulators, RIG-I modulators, NOD2 modulators, SB-9200, and IR-103.

[0200] Examples of TLR agonists include vesatolimod (GS-9620), lefitolimod, tilsotolimod, rintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-78 54, and telratolimod. Phosphatidylinositol 3-kinase (PI3K) inhibitors

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

[0202] Examples of integrin alpha-4 / beta-7 antagonists include PTG-100, TRK-170, abrilumab, etrolizumab, carotegrast methyl, and vedolizumab. HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins

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

[0204] Examples of those targeting HIV in this manner include bavituximab, UB-421, C2F5, 2G12, C4E10, C2F5 + C2G12 + C4E10, 8ANC195, 3BNC117, 3BNC117-LS, 3BNC60, 10-1074, 10-1074-LS, GS-9722, DH411-2, PGT145, PGT121, PGT-151, PGT-133, MDX010 (ipilimumab), DH511, N6, N6LS, N49P6, N49P7, N49P9, N49P11, VRC01 VRC-01-LS, PGDM1400, A32, 7B2, 10E8, 10E8VLS, 3810109, 10E8v4, CAP256-VRC26.25, DRVIA7, SAR-441236, VRC-07-523, VRC07-523LS, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, and VRC07. Examples of HIV bispecific antibodies include MGD014, and TMB-bispecific.

[0205] Examples of bNAbs delivered in vivo, e.g., AAV8-VRC07; mRNA-encoded anti-HIV antibody VRC01. Pharmacokinetic enhancer

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

[0207] Examples of additional therapeutic agents include the compounds disclosed in WO2004 / 096286 (Gilead Sciences), WO2006 / 015261 (Gilead Sciences), WO2006 / 110157 (Gilead Sciences), WO2012 / 003497 (Gilead Sciences), WO2012 / 003498 (Gilead Sciences), WO2012 / 145728 (Gilead Sciences), WO2013 / 006738 (Gilead Sciences), WO2013 / 159064 (Gilead Sciences), WO2014 / 100323 (Gilead Sciences), US2013 / 0165489 (University of Pennsylvania), US2014 / 0221378 (Japan Tobacco), US2014 / 0221380 (Japan Tobacco), WO2009 / 062285 (Boehringer Ingelheim), WO2010 / 130034 (Boehringer Ingelheim), WO2013 / 006792 (Pharma Resources), US20140221356 (Gilead Sciences), US20100143301 (Gilead Sciences), WO2013 / 091096 (Boehringer Ingelheim), WO2018 / 145021 (Gilead Sciences), and WO2017 / 106346 (Gilead Sciences), each of which is hereby incorporated by reference in its entirety. HIV vaccine

[0208] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521) / AIDSVAX B / E (gp120) (RV144), monomeric gp120 HIV-1 subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multiclade DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol env A / B / C vaccine, Pennvax-G, Pennvax-G / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSP ISA-51, poly-ICLC adjuvant vaccine, TatImmune, GTU-multiHIV (FIT-06), gp140[delta]V2.TV1+MF-59, rVSVIN HIV gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV-1, Ad-4 (Ad4-env Clade C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag / pol / nef / nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.HIV+MVA mosaic vaccine+gp140, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001, and virus-like particle vaccines (such as pseudovirus vaccines), CombiVICHvac, LFn-p24B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccine, conjugate polypeptide vaccine, dendritic cell vaccine, gag-based DNA vaccine, GI-20. 10, gp41 HIV vaccine, HIV vaccine (PIKA adjuvant), I i-key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x + romidepsin, mutant gp120 polypeptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP + VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980; eOD-GT8 60-mer-based vaccine, PD-201401, env(A, B, C, A / E) / gag(C) DNA vaccine, gp120(A, B, C, A / E) protein vaccine, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV vaccine (GLA-SE adjuvant), HIV p24gag pri, me-boost plasmid DNA vaccine, arenavirus vector-based immunotherapeutic agent (Vaxwave, TheraT), MVA-BN HIV vaccine regimen, UBI HIV gp120, mRNA-based prophylactic vaccine, and TBL-1203HI are included. HIV combination therapy

[0209] In certain embodiments, the compounds or pharmaceutically acceptable salts thereof disclosed herein are ATRIPLA® (efavirenz, tenofovir disoproxil fumarate and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCCOVY® (tenofovir alafenamide and emtricitabine); ODEFSEY® (tenofovir alafenamide, emtricitabine and rilpivirine); GENVOYA® (tenofovir alafenamide, emtricitabine, cobicistat and elvitegravir); adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofovir; tenofovir disoproxil; tenofovir disoproxil fumarate; tenofovir alafenamide; tenofovir alafenamide hemifumarate; TRIUMEQ® (dolutegravir, abacavir and lamivudine); dolutegravir, abacavir sulfate and lamivudine; raltegravir; raltegravir and lamivudine; maraviroc; enfuvirtide; ALUVIA® (KALETRA®; lopinavir and ritonavir); COMBIVIR® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); TRIZIVIR® (abacavir sulfate, zidovudine and lamivudine; ABC+AZT+3TC); rilpivirine; rilpivirine hydrochloride; atazanavir sulfate and cobicistat; atazanavir and cobicistat; darunavir and cobicistat; atazanavir; atazanavir sulfate; dolutegravir; elvitegravir; ritonavir; atazanavir sulfate and ritonavir; darunavir; lamivudine; prolasin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine;Nelfinavir; Nelfinavir mesylate; Interferon; Didanosine; Stavudine; Indinavir; Indinavir sulfate; Tenofovir and Lamivudine; Zidovudine; Nevirapine; Saquinavir; Saquinavir mesylate; Aldesleukin; Zalcitabine; Tipranavir; Amprenavir; Delavirdine; Delavirdine mesylate; Radha-108 (Receptol); Lamivudine and Tenofovir disoproxil fumarate; Efavirenz, la; Selected from Lamivudine and Tenofovir disoproxil fumarate; Phosphazide; Lamivudine, Nevirapine and Zidovudine; Abacavir; and Abacavir sulfate, and is combined with one, two, three, four or more additional therapeutic agents.

[0210] Those skilled in the art will recognize that the additional therapeutic agents listed above may be included in more than one of the classes listed above. It is not intended that a particular class limit the functional groups of the compounds listed in such class.

[0211] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor. In specific embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor and an HIV non-nucleoside reverse transcriptase inhibitor. In another specific embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor and an HIV protease inhibitor compound. In additional embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor, an HIV non-nucleoside reverse transcriptase inhibitor, and a pharmacokinetic enhancer. In certain embodiments, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with at least one HIV nucleoside reverse transcriptase inhibitor, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the compounds disclosed herein or pharmaceutically acceptable salts thereof are combined with two HIV nucleoside or nucleotide reverse transcriptase inhibitors. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with an HIV nucleoside or nucleotide reverse transcriptase inhibitor, and an HIV capsid inhibitor or an HIV capsid polymerization inhibitor. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with an HIV capsid inhibitor, or an HIV capsid polymerization inhibitor. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with one, two, three, or four HIV bNAbs. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with one, two, three, or four HIV bNAbs and an HIV capsid inhibitor or an HIV capsid polymerization inhibitor.In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with one, two, three, or four HIV bNAbs, HIV capsid inhibitors, or HIV capsid polymerization inhibitors, and HIV nucleoside or nucleotide reverse transcriptase inhibitors.

[0212] The compounds disclosed herein (e.g., any compound of Formula I) may be combined with one, two, three, or four additional therapeutic agents at any dosage of the compound of Formula I (e.g., 1 mg to 500 mg of the compound).

[0213] In one embodiment, a kit is provided that comprises the compounds disclosed herein, or pharmaceutically acceptable salts thereof, in combination with one or more (e.g., one, two, three, one or two, or 1 to 3) additional therapeutic agents.

[0214] In one embodiment, the additional therapeutic agent(s) of the kit is / are other drugs for treating HIV, HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or allosteric) integrase inhibitors, HIV entry inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editing agents (CRISPR / Cas9, zinc finger Anti-HIV agents selected from the group consisting of nuclease (e.g., gRNA nuclease, homing nuclease, synthetic nuclease, TALEN, etc.), cell therapy (e.g., chimeric antigen receptor T cells, CAR-T and modified T cell receptors, TCR-T, autologous T cell therapy), compounds targeting the HIV capsid, latency reversing agents, capsid polymerization inhibitors, HIV bNAbs, immune-based therapies, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, broadly neutralizing HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV viral infectivity factor inhibitors, TAT protein inhibitors, HIV Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocyclin modulators, CDK-9 inhibitors, dendritic ICAM-3-binding non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxythymidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulants, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy and HIV vaccines, and any combination thereof.

[0215] In some embodiments, the additional therapeutic agent(s) of the kit are 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.

[0216] In certain embodiments, these kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an HIV nucleoside or nucleotide inhibitor of reverse transcriptase. In certain embodiments, these kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV non-nucleoside inhibitor of reverse transcriptase. In another specific embodiment, these kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibitor compound. In a further embodiment, these kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In certain embodiments, these kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, these kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and two HIV nucleoside or nucleotide inhibitors of reverse transcriptase. In certain embodiments, these kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase and an HIV capsid inhibitor or an HIV capsid polymerization inhibitor. In certain embodiments, these kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and an HIV capsid inhibitor or an HIV capsid polymerization inhibitor. In certain embodiments, these kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, and one, two, three, or four HIV bNAbs. In certain embodiments, these kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAbs, and an HIV capsid inhibitor or an HIV capsid polymerization inhibitor. In certain embodiments, these kits contain a compound disclosed herein, or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAbs, an HIV capsid inhibitor or an HIV capsid polymerization inhibitor, and an HIV nucleoside or nucleotide inhibitor of reverse transcriptase. Combined therapy with contraceptives

[0217] Therapeutic agents (contraceptives) used for contraception include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, ethinodiol, etonogestrel, levomefolate, levonorgestrel, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norelgestromin, norethindrone, noretynodrel, norgestimate, ormeloxifene, segestersone acetate, ulipristal acetate, and any combination thereof. Gene therapy and cell therapy

[0218] Gene therapy and cell therapy including gene modification for gene silencing; genetic techniques for directly killing infected cells, replacing most of the patient's own immune system to enhance the immune response against infected cells, or activating the patient's own immune system to kill infected cells, or injecting immune cells designed to detect and kill infected cells; genetic techniques for modifying cell activity to further modify the endogenous immune response to infection.

[0219] Examples of dendritic cell therapies include AGS-004.

[0220] Examples of CCR5 gene editing drugs such as SB-728T

[0221] Examples of CCR5 gene editing drugs such as Cal-1

[0222] C34-CCR5 / C34-CXCR4-expressing CD4-positive T cells

[0223] AGT-103 converted autologous T cell therapy

[0224] AAV-eCD4-Ig gene therapy Gene editing agents

[0225] The genome editing system is selected from the group consisting of the CRISPR / Cas9 system, the zinc finger nuclease system, the TALEN system, the homing endonuclease system and the meganuclease system.

[0226] Examples of the HIV-targeted CRISPR / Cas9 system include EBT-101. CAR-T cell therapy

[0227] A population of immune effector cells engineered to express a chimeric antigen receptor (CAR) containing an HIV antigen-binding domain. HIV antigens include the HIV envelope protein Or a part thereof, gp120 or a part thereof, the CD4 binding site of gp120, the CD4-induced binding site of gp120, the N-glycan of gp120, V2 of gp120, and the membrane-proximal region of gp41 are included. The immune effector cells are T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, or a combination thereof. The cells can be autologous or allogeneic.

[0228] Examples of HIV CAR-T include VC-CAR-T, anti-CD4 CART cell therapy, autologous hematopoietic stem cells genetically engineered to express CD4 CAR, and C46 peptide. TCR-T cell therapy

[0229] TCR-T cells are engineered to target HIV-derived peptides present on the surface of virus-infected cells. Long-acting HIV therapy

[0230] Examples of drugs developed as long-acting regimens include cabotegravir, rilpivirine, any integrase LA, VM-1500 LAI, maraviroc (LAI), tenofovir implant, MK-8591 implant, doravirine, raltegravir, and long-acting dolutegravir.

[0231] In certain embodiments, when the compounds disclosed herein are combined with one, two, three, or four additional therapeutic agents as described above, the components of this composition are administered as a concurrent regimen or a sequential regimen. When administered sequentially, this combination can be administered in two or more administrations. Route of administration

[0232] Compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof (also referred to herein as the active ingredient), 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). The appropriate route can vary, for example, depending on the condition of the recipient. In certain embodiments, the disclosed compounds can be administered parenterally. In certain embodiments, the disclosed compounds can be administered intravenously, subcutaneously, or intramuscularly. In certain embodiments, the disclosed compounds are orally bioavailable and can be administered orally.

[0233] In some embodiments, compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, are administered using a syringe suitable for administration of the compound. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-filled with a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof.

[0234] In some embodiments, compounds of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, are provided with a syringe It is administered using an autoinjector. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is prefilled with a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof. Dosing regimen

[0235] In some embodiments, a compound, such as a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered to a subject according to an effective dosing regimen over a desired duration, e.g., at least once a day, at least once a week, at least once a month, at least once every two months, at least once every three months, at least once every four months, at least once every six months, or at least once every twelve months or longer. In some embodiments, the compound is administered daily or on an intermittent schedule. In some embodiments, the compound is administered on a weekly schedule. In some embodiments, the compound is administered on a monthly schedule. In some embodiments, the compound is administered every two months. In some embodiments, the compound is administered every three months. In some embodiments, the compound is administered every four months. In some embodiments, the compound is administered every five months. In some embodiments, the compound is administered every six months.

[0236] In some embodiments, a compound, e.g., a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered subcutaneously or intramuscularly to a subject at least once a month. In some embodiments, the compound (e.g., a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof) is administered subcutaneously or intramuscularly to a subject at least once every two months, or at least once every three months, or at least once every four months, or at least once every six months. In some embodiments, the compound (e.g., a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof) is administered subcutaneously to a subject at least once a month. In some embodiments, the compound (e.g., a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof) is administered subcutaneously to a subject at least once every two months. In some embodiments, the compound (e.g., a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof) is administered subcutaneously to a subject at least once every three months.

[0237] In some embodiments, the dosage or dosing frequency of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is adjusted based on the judgment of the physician administering it over the course of the treatment.

[0238] In some embodiments, the compounds disclosed herein (e.g., compounds of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb XI, XIa, or XIb) or pharmaceutically acceptable salts thereof can be administered in an effective dosage amount. For example, this dosage amount can be from 1 mg to 1000 mg of the compound.

[0239] In some embodiments, the methods disclosed herein include the forced administration to a subject of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof.

[0240] As used herein, the terms "forced by an event" and "forced administration by an event" refer to the administration of a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, (1) before an event that exposes an individual to HIV (or otherwise increases the risk of an individual acquiring HIV) (e.g., 2 hours, 1 day, 2 days, 5 days, or 7 days or more days before the event); and / or (2) during an event that exposes an individual to HIV (or otherwise increases the risk of an individual acquiring HIV) (or an event that recurs more than once); and / or (3) after an event that exposes an individual to HIV (or otherwise increases the risk of an individual acquiring HIV) (or after the final event of a series of recurring events). In some embodiments, the forced administration by an event is performed before the subject's exposure to HIV. In some embodiments, the forced administration by an event is performed after the subject's exposure to HIV. In some embodiments, the forced administration by an event is performed before and after the subject's exposure to HIV.

[0241] In some embodiments, a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered prior to exposure of the subject to HIV.

[0242] An example of a dosing regimen dictated by the event is administration of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, within 24 to 2 hours prior to HIV exposure (e.g., first sexual activity with a sexual partner known to be HIV positive, including sexual intercourse), followed by administration every 24 hours during the period of exposure (e.g., sexual activity with a sexual partner known to be HIV positive), followed by further administration after the last exposure (e.g., sexual activity with a sexual partner known to be HIV positive), and a final single administration 24 hours after the last administration of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof.

[0243] Further examples of dosing regimens forced by events include administration within 24 hours prior to HIV exposure (e.g., sexual activity with a sexual partner known to be HIV positive) of a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, followed by daily administration during the period of exposure (e.g., sexual activity with a sexual partner known to be HIV positive, including the last sexual intercourse), and then a final dose approximately 24 hours after the last exposure (which may be an increased dose such as a double dose). This includes sexual activity with a sexual partner known to be HIV positive, including the last sexual intercourse, followed by daily administration during the period of exposure, and then a final dose approximately 24 hours after the last exposure (which may be an increased dose such as a double dose).

[0244] In certain embodiments, for example, when administered as PrEP, a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered daily. In certain embodiments, for example, when administered as event-driven PrEP, a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered 1 hour to 10 days, 1 hour to 7 days, 1 hour to 5 days, 1 to 72 hours, 1 to 48 hours, 1 to 24 hours, or 12 to 12 hours before an event that increases an individual's risk of acquiring HIV (e.g., before sexual intercourse or other exposure to the HIV virus). In some embodiments, a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered within 10 days, 7 days, 5 days, 72 hours, 60 hours, 48 hours, 24 hours, 12 hours, 9 hours, 6 hours, 4 hours, 3 hours, 2 hours, or 1 hour before an event that increases an individual's risk of acquiring HIV (e.g., before sexual intercourse or other exposure to the HIV virus). In certain embodiments, when a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered before an event that increases an individual's risk of acquiring HIV (e.g., before the event), this is administered daily before the event (e.g., sexual activity). In certain embodiments, when a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered during an event that increases an individual's risk of acquiring HIV, this is administered 1 to 3 times before this event.

[0245] In some embodiments, for example, when administered as part of a PrEP regimen mandated by an event, a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered during the time of HIV exposure. In certain embodiments where a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb is administered to an at-risk individual, the compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered daily (e.g., as a single dose) during the time of HIV exposure (e.g., during the period of sexual activity with a sexual partner known to be HIV positive). In some embodiments, a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, is administered daily (e.g., for 1 - 7 days) after the last exposure to HIV (e.g., after the period of sexual activity with a sexual partner known to be HIV positive). In some embodiments, this administration is continued for 1 or 2 days after the final exposure to HIV.

[0246] Further examples of PrEP and / or PEP are, for example, in the article entitled “On Demand Antiretroviral Pre-exposure Prophylaxis” Summary of clinical trial “for HIV Infection in Men Who Have Sex With Men” (Clinical Trial # NCT01473472); summary of clinical trial “Prevention of HIV in Ile-de-France” (Clinical Trials # NCT03113123), and Molina, et al. N. Engl. J. Med. 2015, 353:2237 - 2246, the disclosures of each of which are hereby incorporated by reference in their entirety.

[0247] In some embodiments, a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2) comprises administering a compound of formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb, XI, XIa, or XIb, or a pharmaceutically acceptable salt thereof, in combination with safer sex practices. In certain embodiments, a method for reducing the risk of acquiring HIV (e.g., HIV-1 and / or HIV-2) comprises administering to a subject at risk of acquiring HIV. Examples of individuals at high risk of acquiring HIV include, but are not limited to, individuals at risk of sexual transmission of HIV.

[0248] In some embodiments, the reduction in the risk of acquiring HIV is at least about 40%, 50%, 60%, 70%, 80%, 90%, or 95%. In some embodiments, the reduction in the risk of acquiring HIV is at least about 75%. In some embodiments, the reduction in the risk of acquiring HIV is about 80%, 85%, 90%. Formulation

[0249] Formulations suitable for parenteral administration may include aqueous and non-aqueous sterile injection solutions which may contain antioxidants, buffers, bacteriostats, and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may contain suspending and thickening agents. In certain embodiments, the suspension is a micro-suspension. In certain embodiments, the suspension is a nano-suspension.

[0250] In some embodiments, formulations suitable for parenteral administration (e.g., intramuscular (IM) and subcutaneous (SC) administration) may contain one or more excipients. The excipients should be compatible with the other components of the formulation and should be physiologically innocuous to its recipient. Examples of suitable excipients are well known to those skilled in the art of parenteral formulations and may be found, for example, in Handbook of Pharmaceutical Excipients (editors Rowe, Sheskey & Quinn), 6th edition 2009.

[0251] In certain embodiments, the active ingredient (e.g., a compound of Formula I, II, IIIa, IIIb, IV, Va, Vb, VI, VIIa, VIIb, VIII, IX, IXa, IXb, X, Xa, Xb XI, XIa, or XIb) is present as the free acid.

[0252] In certain embodiments, the pharmaceutical compositions disclosed herein are parenteral formulations. In certain embodiments, the formulation is administered subcutaneously to a subject in need thereof. In certain embodiments, the formulation is administered intramuscularly to a subject in need thereof.

[0253] The amount of active ingredient that may be combined with the inert ingredients to produce a dosage form may vary depending upon the intended subject and the specific mode of administration. For example, in some embodiments, a dosage form for oral administration to humans may contain approximately 1 to 1000 mg of the active ingredient formulated with a suitable and convenient amount of a carrier substance (e.g., an inert ingredient or excipient substance). It varies from about 5% to about 95% (weight: weight) of the total composition.

[0254] In addition to the components specifically described above, the compositions of these embodiments may contain other agents that are conventional in the art relevant to the type of composition in question. For example, for those suitable for oral administration, flavoring and masking agents may be included. It should be understood that this is the case. Abbreviations

[0255] The abbreviations used in this specification have the following representative meanings:

Table A-1

Table A-2

Table A-3

Table A-4

Table A-5

Table A-6

Table A-7

Examples

[0256] Example 1: Preparation of (S)- and (R)-N-(2,4-difluorobenzyl)-13-hydroxy-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazepine-11-carboxamide (1-1, 1-2):

Chemical formula

[0257] tert-Butyl 3-methylene-1,5-oxazocane-5-carboxylate (1a, 339 mg, 1.49 mmol) in methanol (10 mL) was stirred in a -78 °C bath while ozone was bubbled into the mixture until a blue color appeared. When the blue ozone color appeared, dimethyl sulfide (5 mL) was added and the resulting solution was stirred at room temperature for 2 hours. The solution was concentrated and the residue was purified by column chromatography on silica gel eluting with 0 - 100% ethyl acetate in hexane to give the title compound. MS (m / z) 251.96 [M + Na] + 。 Synthesis of tert-butyl 3-((tert-butylsulfinyl)amino)-1,5-oxazocane-5-carboxylate (1c):

[0258] A solution of 1b (315 mg, 1.38 mmol), rac-2-methylpropane-2-sulfinamide (170.3 mg, 1.41 mmol), and titanium(IV) ethoxide (0.59 mL, 2.81 mmol) in THF (5.5 mL) was refluxed in a 70 °C bath for 1 h. The reaction mixture was cooled to room temperature and then further cooled to approximately -50 °C, after which 1 M L-Selectride in THF (5.5 mL) was added. After 30 min, the reaction mixture was slowly warmed to room temperature over 2 h. The reaction mixture was cooled to 0 °C again and methanol was added until gas evolution ceased. Brine was added to this solution with vigorous stirring, the resulting mixture was filtered through Celite®, and the solid was washed with ethyl acetate. The filtrate was extracted with ethyl acetate (3 times), the combined organic fractions were washed with brine (1 time), combined, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 50 - 100% ethyl acetate in hexanes followed by 0 - 20% methanol in ethyl acetate to afford the title compound. MS (m / z) 334.94 [M+H] + 。 Synthesis of methyl 13-methoxy-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazecine-11-carboxylate (1d):

[0259] A solution of 1c (274 mg, 0.82 mmol) in dichloromethane (2 mL) was stirred at room temperature while adding 4 N HCl in dioxane (4 mL). After 1 h, the resulting suspension was concentrated and dried overnight. To the flask containing this residue was added water (1 mL) and dimethyl 3-methoxy-4-oxo-4H-pyran-2,5-dicarboxylate (242.5 mg, 1.00 mmol) and sodium bicarbonate (278.4 mg, 3.31 mmol) in methanol (3 mL), and the resulting mixture was stirred at room temperature for 24 h and in a 40 °C bath.

[0260] The reaction mixture was cooled to room temperature, concentrated, and the residue was dissolved in aqueous DMF, filtered, and purified by preparative HPLC (column, Gemini 10μ C18 110A, AXI / ; 250×21.2 mm) for 20 minutes with elution using 10 - 60% acetonitrile (0.1% TFA) in water (0.1% TFA). The combined fractions were freeze - dried to give the title compound. MS (m / z) 323.16 [M+H] + 。 Synthesis of N-(2,4 - difluorobenzyl)-13 - methoxy - 1,12 - dioxo - 1,4,5,7,8,12 - hexahydro - 3H - 2,8 - methanopyrido[1,2 - d][1,4,7]oxadiazocin - 11 - carboxamide (1e):

[0261] A solution of methyl 13-methoxy-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazepine-11-carboxylate (1d, 30.8 mg, 95.6 μmol) in methanol (0.5 mL) was added 1N lithium hydroxide (0.2 mL) at room temperature and stirred at room temperature for 1 h. After the reaction mixture was acidified with 1N HCl (ca. 0.2 mL), the resulting solution was concentrated to dryness and co-evaporated with toluene (3 times). To the previous residue were added (2,4-difluorophenyl)methanamine (26.1 mg, 182 μmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 62.2 mg, 163.5 μmol), and DMF (1 mL), and stirred at room temperature together with N,N-diisopropylethylamine (0.1 mL, 574.1 μmol). After 1 h, the reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution (2 times), saturated sodium bicarbonate solution (2 times) and brine (1 time). The aqueous fraction was extracted with ethyl acetate (1 time), then the two organic fractions were combined, dried over MgSO4, filtered and concentrated. The residue was dissolved in DMF, filtered and purified by preparative HPLC eluting with 10 - 60% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 min (column, Gemini 10μ C18 110A, AXI / ; 250×21.2 mm). The combined fractions were freeze-dried to give the title compound. MS (m / z) 434.22 [M+H] + 。 (rac), (S)- and (R)-N-(2,4-Difluorobenzyl)-13-hydroxy-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazepine-11-carboxamide (1, 1-1, 1-2) Synthesis:

[0262] A solution of N-(2,4-difluorobenzyl)-13-methoxy-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazepine-11-carboxamide (1e, 13.7 mg, 31.6 μmol) in acetonitrile (1 mL) was added with magnesium bromide (16.2 mg, 88.5 μmol) at room temperature, and the resulting mixture was stirred in a 50 °C bath. After 1 hour, the reaction mixture was concentrated, and the residue was triturated with 2N HCl (about 0.5 mL) and water (about 1.5 mL) at 0 °C. After sonication, the suspension was diluted with DMF (3 mL) to make it a solution, and then filtered. The filtered solid was purified by preparative HPLC eluting with 10 - 60% acetonitrile (0.1% TFA) in water (0.1% TFA) (column, Gemini 10μ C18 110A, AXI / ; 250×21.2 mm) over 20 minutes. The combined fractions were freeze-dried to obtain the title compound. MS (m / z) 420.23 [M+H] + 。 1 H NMR (400 MHz, acetonitrile-d3) δ10.31 (s, 1H), 8.40 (s, 1H), 7.40 (td, J = 8.8, 6.4 Hz, 1H), 6.93 (ddq, J =10.8, 5.8, 2.8 Hz, 2H), 4.57 (d, J = 5.2 Hz, 2H), 4.43 - 4.26 (m, 2H), 4.07 (d,J = 33.0 Hz, 4H), 3.95 (dd, J = 14.9, 1.7 Hz, 1H), 3.75 (s, 1H), 3.13 (ddd, J = 13.9, 7.5, 4.6 Hz, 1H), 2.06- 1.96 (m, 1H), 1.86 (s, 1H). 19 F NMR (376 MHz, acetonitrile-d3)δ -114.07 (p, J = 7.6 Hz), -116.55 (q, J = 8.7 Hz).

[0263] N-(2,4-Difluorobenzyl)-13-hydroxy-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazepine-11-carboxamide (1, 15 mg) was separated into its individual enantiomers by preparative SFC chromatography on an AZ-H column using an ethanol-TFA co-solvent to obtain 1-1 and 1-2. Example 2: Preparation of 13-hydroxy-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazepine-11-carboxamide (2):

Chemical formula

[0264] A solution of methyl 13-methoxy-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazepine-11-carboxylate (1d, 32.7 mg, 101.5 μmol) in methanol (0.5 mL) was added with 1N lithium hydroxide (0.2 mL) at room temperature and stirred at room temperature for 1 hour. After the reaction mixture was acidified with 1N HCl (ca. 0.2 mL), the resulting solution was concentrated to dryness and co-evaporated with toluene (3 times). To the previous residue were added (2,4,6-trifluorophenyl)methanamine (30.8 mg, 191.15 μmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazol[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 57.9 mg, 152.2 μmol), and DMF (1 mL), and stirred at room temperature together with N,N-diisopropylethylamine (0.1 mL, 574.1 μmol). After 1 hour, the reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution (2 times), saturated sodium bicarbonate solution (2 times) and brine (1 time). The aqueous fraction was extracted with ethyl acetate (1 time), then the two organic fractions were combined, dried over MgSO4, filtered and concentrated. The residue was dissolved in DMF, filtered, and purified twice over 20 minutes by preparative HPLC eluting with 10 - 60% acetonitrile (0.1% TFA) in water (0.1% TFA) (column, Gemini 10μ C18 110A, AXI / ; 250×21.2 mm). The combined fractions were freeze-dried to give the title compound. MS (m / z) 452.23 [M+H] + 。 Synthesis of 13-hydroxy-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazepine-11-carboxamide (2):

[0265] A solution of 13-methoxy-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,7,8,12-hexahydro-3H-2,8-methanopyrido[1,2-d][1,4,7]oxadiazepine-11-carboxamide (2a, 9.3 mg, 20.6 μmol) in acetonitrile (1 mL) was added magnesium bromide (16.2 mg, 88.0 μmol) at room temperature, and the resulting mixture was stirred in a 50 °C bath. After 30 minutes, the reaction mixture was cooled and filtered, and the residue was dissolved in DMF (0.5 mL) and 2 N HCl (0.1 mL). After filtering this solution, the filtrate was purified by preparative HPLC eluting with 10 - 60% acetonitrile (0.1% TFA) in water (0.1% TFA) (column, Gemini 10 μ C18 110A, AXI / ; 250×21.2 mm) over 20 minutes. The combined fractions were freeze-dried to give the title compound. MS (m / z) 420.23 [M+H] + 。 1 H NMR (400 MHz, acetonitrile-d3) δ 10.31 (s, 1H), 8.40 (s, 1H), 7.40 (td, J = 8.8, 6.4 Hz, 1H), 6.93 (ddq, J =10.8, 5.8, 2.8 Hz, 2H), 4.57 (d, J = 5.2 Hz, 2H), 4.43 - 4.26 (m, 2H), 4.07 (d, J =33.0 Hz, 4H), 3.95 (dd, J = 14.9, 1.7 Hz, 1H), 3.75 (s, 1H), 3.13 (ddd, J =13.9, 7.5, 4.6 Hz, 1H), 2.06 - 1.96 (m, 1H), 1.86 (s, 1H). 19 F NMR (376MHz, acetonitrile-d3) δ -114.07 (p, J = 7.6 Hz), -116.55 (q, J = 8.7 Hz). Example 3: Preparation of (R)- and (S)-(7R)-4,4-difluoro-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (3-1, 3-2):

Chemical formula

[0266] A solution of 1-tert-butoxycarbonyl-5,5-difluoro-piperidine-2-carboxylic acid (3a, 1.999 g, 7.54 mmol) in methanol was dissolved at 0 °C, and 2 M (trimethylsilyl)diazomethane in diethyl ether (about 10 mL) was added until the yellow color persisted. After 15 minutes, dilute acetic acid was added to this reaction mixture until the yellow color disappeared, and the mixture was concentrated. The resulting residue was purified by column chromatography on silica gel eluting with 0 - 30% ethyl acetate in hexane to obtain 5,5-difluoropiperidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester. ester was obtained.

[0267] A solution of 5,5-difluoropiperidine-1,2-dicarboxylic acid 1-(tert-butyl) 2-methyl ester (1.94 g, 6.93 mmol) in dichloromethane (15 mL) and 4 N HCl in dioxane (15 mL) was dissolved and stirred at room temperature. After 3 hours, the solution was concentrated, and the residue was dissolved in saturated sodium bicarbonate solution, and the product was extracted with ethyl acetate (twice). The organic extract was washed with brine (once), dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 0 - 100% ethyl acetate in hexane to obtain methyl 5,5-difluoropiperidine-2-carboxylate.

[0268] A solution of methyl 5,5-difluoropiperidine-2-carboxylate (962 mg, 5.37 mmol) in DMF (15 mL) was stirred at 0 °C while adding sodium hydride (305 mg, 7.63 mmol, 60% in mineral oil) portionwise. After 30 minutes at 0 °C, benzyl bromide (0.96 mL, 8.1 mmol) was added. The reaction mixture was stirred at 0 °C for 1 hour and at room temperature for 1 hour, then additional sodium hydride (150 mg, 3.75 mmol, 60% in mineral oil) and benzyl bromide (0.5 mL, 4.20 mmol) were added at room temperature and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was quenched with 2 N HCl (ca. 4 mL) at 0 °C and diluted with saturated sodium bicarbonate solution (ca. 100 mL), then the product was extracted with ethyl acetate (ca. 100 mL × 2). The organic extract was washed with water (150 mL × 1), combined, dried over MgSO4, filtered, concentrated, and purified by column chromatography on silica gel eluting with 0 - 100% ethyl acetate in hexane to afford the title compound. MS (m / z) 270.10 [M+H] + 。 Synthesis of 6-azido-1-benzyl-3,3-difluoroazepane (3c):

[0269] A solution of methyl 1-benzyl-5,5-difluoropiperidine-2-carboxylate (1011 mg, 3.76 mmol) in THF (10 mL) was stirred at 0 °C while adding 1 M LiAlH4 (5 mL, 5 mmol). After 30 minutes at 0 °C, the reaction mixture was quenched by adding water (0.19 mL), 15% NaOH (0.19 mL), and water (0.57 mL) dropwise with vigorous stirring at 0 °C and diluted with ethyl ether (ca. 15 mL). The resulting suspension was stirred vigorously at 0 °C for 30 minutes, then the mixture was filtered through Celite® and the filtrate was treated with MgSO4 and filtered again. The filtrate was concentrated to afford (1-benzyl-5,5-difluoropiperidin-2-yl)methanol. MS (m / z) 242.10 [M+H] + 。

[0270] (1-Benzyl-5,5-difluoro-2-piperidyl)methanol (606.6 mg, 2.51 mmol) was dissolved in toluene (10 mL), and thionyl chloride (3 mL, 41.1 mmol) was added. The resulting mixture was stirred at 60 °C. After 1.25 h, the reaction mixture was concentrated, and the residue was dissolved in saturated sodium bicarbonate solution (ca. 20 mL) and ethyl acetate (ca. 25 mL). After separating the two fractions, the aqueous fraction was extracted with ethyl acetate (ca. 25 mL×1). The organic fractions were washed with brine (ca. 20 mL×1), combined, dried over MgSO4, filtered, and concentrated to give crude 1-benzyl-2-(chloromethyl)-5,5-difluoropiperidine. MS (m / z) 260.10 [M+H] + 。

[0271] The above crude chloride and sodium azide (187 mg, 2.88 mmol) in DMSO (4 mL) were stirred in a 90 °C bath for 4 h and cooled to room temperature. The reaction mixture was diluted with water (ca. 50 mL) and saturated sodium bicarbonate solution (ca. 5 mL), and the product was extracted with ethyl acetate (ca. 30 mL×3). The extracts were washed with water (ca. 50 mL×1), combined, dried (Na2SO4), and concentrated. The residue was purified using silica gel column chromatography eluting with 0–10% ethyl acetate in hexane to give the title compound. MS (m / z) 267.06 [M+H] 。 + 。 Synthesis of 12-(benzyloxy)-4,4-difluoro-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (3d):

[0272] A suspension of 6-azido-1-benzyl-3,3-difluoro-azepane (323 mg, 1.21 mmol) and 20% palladium hydroxide on carbon (49 mg) in methanol (10 mL) and concentrated HCl (0.5 mL) was stirred under a H2 atmosphere for 3 h. The reaction mixture was filtered through Celite® and washed with methanol. The filtrate and washings were combined and concentrated completely to give crude 6,6-difluoroazepan-3-amine dihydrochloride.

[0273] Crude 6,6-difluoroazepan-3-amine dihydrochloride (119.9 mg, 0.54 mmol), methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate (280.8 mg, 0.63 mmol), and sodium bicarbonate (238.7 mg, 2.84 mmol) were dissolved in methanol (5 mL) and water (1 mL), and the resulting solution was stirred in a 55 °C bath for 20 h. The reaction mixture was concentrated and the residue was dissolved in ethyl acetate and water. After separating the two fractions, the aqueous fraction was extracted with ethyl acetate (1 time), and the two organic fractions were washed with water (1 time), combined, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 0 - 5% methanol in dichloromethane to give a partially purified product.

[0274] The above partially purified product was dissolved in DMF, filtered, and purified by preparative HPLC eluting with 30 - 90% acetonitrile (0.1% TFA) in water (0.1% TFA) (column, Gemini 10μ C18 110A, AXI / ; 250×21.2 mm) over 20 min, and the collected fractions were freeze-dried to give the title compound. MS (m / z) 548.14 [M+H] + 。 (R)- and (S)-(7R)-4,4-Difluoro-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (3-1.3-2) Synthesis

[0275] 12-(Benzyloxy)-4,4-difluoro-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (3d, 140.7 mg) was separated into enantiomers by preparative SFC chromatography on an IA column using methanol as a co-solvent to give 47.4 mg of 3d-1 and 46.9 mg of 3d-2. The separated enantiomers were dissolved in toluene (0.5 mL) and trifluoroacetic acid (3 mL) and stirred at room temperature for 30 minutes. The individual reactions were concentrated and the residue was purified using column chromatography on silica gel eluting with 0 - 14% methanol in dichloromethane to give the respective title compounds. MS (m / z) 458.16 [M+H] + 。 1 H NMR (400 MHz, acetonitrile-d3) δ 12.34 (s, 1H), 10.38 (s, 1H), 8.27 (s, 1H), 7.02 - 6.66 (m, 2H), 5.45 (s,2H), 4.70 (ddt, J = 14.4, 11.6, 2.8 Hz, 1H), 4.59 (d, J = 5.8 Hz, 1H), 4.37(dd, J = 13.5, 4.2 Hz, 1H), 4.04 (dd, J = 13.6, 8.2 Hz, 1H), 3.89 (ddt, J =11.8, 7.8, 3.7 Hz, 1H), 3.19 (ddd, J = 31.8, 14.2, 1.9 Hz, 1H), 2.42 - 2.22 (m,1H), 2.22 - 2.06 (m, 1H), 2.06 - 1.98 (m, 1H), 1.80 - 1.62 (m, 1H). Example 4: Preparation of (R)- and (S)-(7R)-N-(2,4-difluorobenzyl)-4,4-difluoro-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (4-1, 4-2):

Chemical formula

[0276] Unpurified 6,6-difluoroazepan-3-amine dihydrochloride (116.7 mg, 0.52 mmol), methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate (273.2 mg, 0.64 mmol), and sodium bicarbonate (225.7 mg, 2.69 mmol) were dissolved in methanol (5 mL) and water (1 mL), and the resulting solution was stirred in a 55 °C bath for 20 hours. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate and water. After separating the two fractions, the aqueous fraction was extracted with ethyl acetate (once), and the two organic fractions were washed with water (once), combined, dried over MgSO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel eluting with 0 - 5% methanol in dichloromethane to obtain a partially purified product.

[0277] The above partially purified product was dissolved in DMF, filtered, and purified by preparative HPLC (column, Gemini 10μ C18 110A, AXI / ; 250×21.2 mm) eluting with 30 - 90% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 minutes, and the collected fractions were freeze-dried to obtain the title compound. MS (m / z) 530.12 [M+H]+ . (R)- and (S)-(7R)-N-(2,4-Difluorobenzyl)-4,4-difluoro-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (4-1, 4-2) Synthesis:

[0278] 12-(Benzyloxy)-N-(2,4-difluorobenzyl)-4,4-difluoro-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (4a, 133 mg) was separated into its individual enantiomers by preparative SFC chromatography on an IA column using methanol co-solvent to obtain 4a-1 and 4a-2. The separated enantiomers were dissolved in toluene (0.5 mL) and trifluoroacetic acid (3 mL) and stirred at room temperature for 30 minutes. The individual reactions were concentrated and the residue was purified using column chromatography on silica gel eluting with 0 - 14% methanol in dichloromethane to obtain the title compound. MS (m / z) 440.19 [M+H] + . 1 H NMR (400 MHz, ace tonitrile-d3) δ 12.36 (s, 1H), 10.40 (s, 1H), 8.28 (s, 1H), 7.47 - 7.31(m, 1H), 6.94 (ddq, J = 11.0, 5.2, 2.8 Hz, 2H), 4.71 (tt, J = 11.7, 2.8 Hz,1H), 4.57 (d, J = 6.0 Hz, 2H), 4.38 (dd, J = 13.5, 4.2 Hz, 1H), 4.06 (dd, J =13.6, 8.1 Hz, 1H), 3.90 (td, J = 8.2, 4.2 Hz, 1H), 3.20 (ddd, J = 31.8, 14.2,1.9 Hz, 1H), 2.38 - 2.22 (m, 1H), 2.19 - 2.08 (m, 1H), 2.07 - 1.98 (m, 1H), 1.80 - 1.63 (m, 1H). Example 5: Preparation of (R)- and (S)-N-(2,4-difluorobenzyl)-13-hydroxy-1,12-dioxo-1,3,4,5,6,7,8,12-octahydro-2,8-methanopyrido[1,2-a][1,4]diazepine-11-carboxamide (5-1, 5-2): [Chemical formula] Synthesis of methyl 13-methoxy-1,12-dioxo-1,3,4,5,6,7,8,12-octahydro-2,8-methanopyrido[1,2-a][1,4]diazepine-11-carboxylate (5a):

[0279] To a vial were added azocan-3-amine (0.13 g, 1.0 mmol), sodium bicarbonate (66 mg, 0.79 mmol), methanol (3 mL), and water (0.3 mL). Dimethyl 3-methoxy-4-oxo-4H-pyran-2,5-dicarboxylate (100 mg, 0.41 mmol) was added, and the mixture was stirred at 30 °C. After 2 hours, the mixture was concentrated to dryness and purified by flash column chromatography (hexane / EtOAc / MeOH) to afford the title compound. MS (m / z) 321.1 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d3) δ 8.07 (s, 1H), 4.43 (ddd, J = 13.6, 8.8, 4.4 Hz, 1H), 4.18 (ddt, J = 7.9, 5.3, 2.2 Hz, 1H), 4.05 (s, 3H), 3.94 (dd, J = 14.4, 2.7 Hz, 1H), 3.85 (s, 3H), 3.65 (dd, J = 14.5, 2.1 Hz, 1H), 2.86 (ddd, J= 14.0, 6.2, 4.2 Hz, 1H), 2.16 (ddd, J = 15.1, 8.7, 5.4 Hz, 1H), 2.00 - 1.56 (m,6H), 1.57 - 1.45 (m, 1H). Synthesis of N-(2,4-difluorobenzyl)-13-methoxy-1,12-dioxo-1,3,4,5,6,7,8,12-octahydro-2,8-methanopyrido[1,2-a][1,4]diazepine-11-carboxamide (5b):

[0280] 13-methoxy-1,12-dioxo-1,3,4,5,6,7,8,12-octah Methyl 13-methoxy-1,12-dioxo-1,3,4,5,6,7,8,12-octahydro-2,8-methanopyrido[1,2-a][1,4]diazepine-11-carboxylate (80 mg, 0.25 mmol) was dissolved in methanol (3 mL), and 1 M NaOH (0.75 mL, 0.75 mmol) was added. After 25 minutes, the reaction was quenched by the addition of 2 M HCl and concentrated to dryness. The residue was dissolved in DCM (2 mL) containing (2,4-difluorophenyl)methanamine (54 mg, 0.37 mmol) and triethylamine (0.10 mL, 0.75 mmol). HATU (114 mg, 0.30 mmol) was added and the mixture was stirred at room temperature. After 15 minutes, the reaction was concentrated to dryness, purified by preparative HPLC (MeCN / water (containing 0.1% TFA)), and lyophilized to give the title compound. MS (m / z) 432.2 [M+H] + . (8R)- and (8S)-N-(2,4-difluorobenzyl)-13-hydroxy-1,12-dioxo-1,3,4,5,6,7,8,12-octahydro-2,8-methanopyrido[1,2-a][1,4]diazepine-11-carboxamide (5-1, 5-2) synthesis:

[0281] N-(2,4-Difluorobenzyl)-13-methoxy-1,12-dioxo-1,3,4,5,6,7,8,12-octahydro-2,8-methanopyrido[1,2-a][1,4]diazepine-11-carboxamide (43 mg) was separated into its individual enantiomers by preparative SFC chromatography on an IB column using MeOH as a co-solvent to give 5c-1 and 5c-2. The separated enantiomers were dissolved in DMF (0.5 mL) containing lithium chloride (84 mg, 2.0 mmol) and stirred at 100 °C for 1 h. The individual reactions were cooled to room temperature, diluted with aqueous TFA, purified by preparative HPLC (MeCN / H2O (containing 0.1% TFA)), and lyophilized to give the title compound. MS (m / z) 418.2 [M+H] + 。 1 H NMR (400 MHz, acetonitrile-d3) δ 10.47 (s, 1H), 8.37 (s, 1H), 7.43 (td, J = 9.3, 8.8, 6.5 Hz, 1H), 7.10 - 6.83 (m,2H), 4.60 (d, J = 5.8 Hz, 2H), 4.48 (tt, J = 6.1, 2.5 Hz, 1H), 4.25 (ddd, J =13.6, 8.3, 5.2 Hz, 1H), 3.91 (dd, J = 14.5, 2.8 Hz, 1H), 3.80 (dd, J = 14.5, 2.1 Hz, 1H),3.03 (ddd, J = 13.8, 6.0, 4.8 Hz, 1H), 2.30 - 2.17 (m, 1H), 1.94 - 1.70 (m,3H), 1.62 - 1.47 (m, 4H). Example 6: Preparation of (7R,13R)-N-(2,4-Difluorobenzyl)-12-hydroxy-13-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide (7):

Chemical Structure

[0282] (3R)-3-Aminoazepan-2-one (1.51 g, 11.8 mmol) was combined with benzaldehyde (3.61 mL, 35 mmol) and molecular sieves (4 g) in 1,2-DCE at 15 °C. Sodium triacetoxyborohydride (7.49 g, 35.3 mmol) was added. After stirring for 90 minutes, the mixture was quenched with aqueous sodium bicarbonate and filtered. The organic layer was separated, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography (hexane / EtOAc) to give the title compound. MS (m / z) 309.4 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 7.41 (d, J = 7.2 Hz, 4H), 7.37 - 7.30 (m, 4H), 7.27 - 7.19 (m, 2H), 5.64 (s, 1H), 4.09 (d, J = 14.4 Hz, 2H), 3.91 (d, J = 14.4 Hz, 2H), 3.44 (d, J = 10.1 Hz, 1H), 3.12 (dt, J = 14.0, 6.7 Hz, 1H), 2.92 (ddd, J = 15.3, 10.8, 5.4 Hz, 1H), 2.01 (d, J = 11.4 Hz, 2H), 1.96 - 1.65 (m, 2H), 1.53 - 1.32 (m, 2H). (2R,3R)-N,N-Dibenzyl-2-methylazepan-3-amine (7b) Synthesis:

[0283] (3R)-3-(Dibenzylamino)azepan-2-one (7a, 637 mg, 2.07 mmol) was suspended in toluene (20 mL) containing triethylamine (0.57 mL, 4.1 mmol) at 0 °C. Chlorotrimethylsilane (0.29 mL, 2.3 mmol) in toluene (3 mL) was added dropwise. After 5 minutes, the mixture was warmed to 50 °C and stirred for 3 hours. The slurry was cooled to 5 °C and the precipitate was removed by filtration, washing it through with 1:1 hexane:ether. The supernatant was concentrated to dryness and left under high vacuum overnight. The residue was dissolved in ether (30 mL), cooled to -78 °C, and 1.6 M MeLi (2.84 mL) was added slowly. The reaction was warmed to room temperature and an additional 1.6 M MeLi (1 mL) was added. After 3 hours, the reaction was cooled to 5 °C, quenched with aqueous ammonium chloride, and diluted with aqueous sodium bicarbonate and ethyl acetate. The organic layer was removed, dried over Na2SO4, filtered, and concentrated. The crude mixture was dissolved in DCM (50 mL) containing 5 g of 3 Å molecular sieves at 5 °C. After stirring for 5 minutes, sodium triacetoxyborohydride (0.88 g, 4.1 mmol) was added and the reaction was stirred overnight while warming slowly to room temperature. The reaction was quenched with aqueous sodium bicarbonate and filtered. The organic layer was separated, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography (hexane / EtOAc) to give the title compound. MS (m / z) 309.2 [M+H] + 。 11H NMR (400 MHz, chloroform-d) δ 7.48 (d, J = 7.2 Hz, 4H), 7.33 (dd, J = 8.3, 6.8 Hz, 4H), 7.24 (t, J = 7.2 Hz, 2H), 4.15 (d, J = 14.3 Hz, 2H), 3.53 (d, J = 14.3 Hz, 2H), 3.19 - 3.01 (m, 1H), 2.96 - 2.79 (m, 1H), 2.69 (dt, J = 10.4, 6.1 Hz, 1H), 2.45 (td, J = 12.3, 3.1 Hz, 1H), 2.13 - 2.00 (m, 1H), 1.94 - 1.68 (m, 3H), 1.58 - 1.38 (m, 1H), 1.28 (d, J = 6.9 Hz, 3H), 1.26 - 1.11 (m, 1H). (7R,13R)-12-(Benzyloxy)-N-(2,4-difluorobenzyl)-13-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (7c) synthesis:

[0284] (2R,3R)-N,N-Dibenzyl-2-methyl-azepan-3-amine (7b, 90 mg, 290 μmol) was combined with Pd / C (10 wt%, wet, E101 NE / W, 155 mg) in ethanol (20 mL) and stirred for 120 h under an atmosphere of hydrogen gas. The mixture was degassed with argon, filtered through Celite®, and 2 M HCl (2 mL) was added. The solution was concentrated to dryness to afford (2R,3R)-2-methylazepan-3-amine as its hydrochloride salt. MS (m / z) 129.2 [M+H] + .

[0285] (2R,3R)-2-Methylazepan-3-amine dihydrochloride (58 mg, 0.29 mmol) was dissolved in methanol (3 mL) and water (0.5 mL) containing sodium bicarbonate (151 mg, 1.79 mmol). Methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate (110 mg, 0.26 mmol) was added and the mixture was stirred at 65 °C for 4 h. The mixture was cooled to room temperature, concentrated, dissolved in DCM, filtered, concentrated, purified by preparative HPLC (MeCN / water (containing 0.1% TFA)), and lyophilized to give the title compound. MS (m / z) 508.6 [M+H] + 。 Synthesis of (1R,14R)-N-[(2,4-difluorophenyl)methyl]-6-hydroxy-14-methyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide (7):

[0286] (7R,13R)-12-(Benzyloxy)-N-(2,4-difluorobenzyl)-13-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (66 mg, 0.13 mmol) was dissolved in toluene (1 mL) containing TFA (2 mL). After 135 min, the reaction was concentrated to dryness, purified by preparative HPLC (MeCN / water (containing 0.1% TFA)), and lyophilized to give the title compound. Chiral HPLC analysis revealed that this was a mixture of enantiomers. MS (m / z) 418.4 [M+H] + 。 1 H NMR (400 MHz, acetonitrile-d3) δ 10.43 (s, 1H), 8.43 (s, 1H), 7.44 (td, J = 9.3, 8.8, 6.5 Hz, 1H), 7.21 - 6.78 (m, 2H), 4.60 (d, J = 5.9 Hz,2H), 4.44 (dt, J = 5.2, 2.2 Hz, 1H), 4.26 (ddd, J = 13.3, 8.9, 7.5 Hz, 1H),3.86 (qd, J = 6.9, 1.7 Hz, 1H), 3.21 (ddd, J = 13.3, 7.4, 2.9 Hz, 1H), 2.13 - 1.99(m, 1H), 1.89 - 1.60 (m, 1H), 1.28 (d, J = 15.2 Hz, 1H), 1.22 (d, J = 6.9 Hz,3H). Example 7: Preparation of (7S,13S)-12-hydroxy-13-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (8): [Chemical formula]

[0287] (7S,13S)-12-Hydroxy-13-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (8) was prepared starting from (S)-3-aminoazepan-2-one and using methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate instead of methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate in the same manner as (7R,13R)-N-(2,4-difluorobenzyl)-12-hydroxy-13-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (7). HPLC analysis showed a mixture of enantiomers. MS (m / z) 436.2 [M+H] + 。 1 H NMR (400 MHz, acetonitrile-d3) δ 10.40(s, 1H), 8.43 (s, 1H), 6.98 - 6.79 (m, 2H), 4.62 (d, J = 5.5 Hz, 2H), 4.52 - 4.37 (m, 1H), 4.24 (ddd,J = 13.3, 8.9, 7.5 Hz, 1H), 3.86 (qd, J = 6.9, 1.7 Hz, 1H), 3.20 (ddd, J =13.4, 7.4, 2.9 Hz, 1H), 2.06 - 2.00 (m, 1H), 1.88 - 1.66 (m, 2H), 1.34 - 1.13 (m, 4H). Example 8: Preparation of (7R,13S)-N-(2,4-difluorobenzyl)-12-hydroxy-13-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (9):

Chemical Structure

[0288] (3R)-3-(Dibenzylamino)azepan-2-one (7a, 735 mg, 2.38 mmol) was combined with triethylamine (0.66 mL, 4.77 mmol), 4-(dimethylamino)pyridine (87 mg, 0.71 mmol), and Boc2O (780 mg, 3.6 mmol) in 1,2-DCE. The mixture was stirred at 35 °C for 3 days. Additional 4-(dimethylamino)pyridine (291 mg, 2.38 mmol) and Boc2O (630 mg, 2.9 mmol) were added, and the mixture was stirred at 60 °C for 4.5 h. The mixture was cooled to 45 °C, and additional Boc2O (1040 mg, 4.77 mmol) was added. The reaction was stirred overnight, cooled to room temperature, and quenched with aqueous ammonium chloride. The organic layer was separated, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography (hexane / EtOAc) to give (R)-3-(dibenzylamino)-2-oxoazepane-1-carboxylic acid tert-butyl. MS (m / z) 409.5 [M+H] + 。 1 H NMR (400 MHz, chloroform-d) δ 7.37 (d,J = 7.2 Hz, 4H), 7.30 (t, J = 7.4 Hz, 4H), 7.22 (t, J = 7.2 Hz, 2H), 4.12 - 4.07(m, 1H), 4.05 (d, J = 14.5 Hz, 2H), 3.87 (d, J = 14.3 Hz, 2H), 3.63 - 3.47 (m,1H), 2.83 (dd, J = 15.4, 10.4 Hz, 1H), 2.03 - 1.68 (m, 3H), 1.55 (d, J = 0.8Hz, 9H), 1.53 - 1.38 (m, 2H).

[0289] (3R)-3-(Dibenzylamino)-2-oxo-azepane-1-carboxylic acid tert-butyl (463 mg, 1.13 mmol) was placed in a round-bottom flask under argon, and a solution of dimethyltitanocene (5% in toluene / THF, 16 mL) was added. The mixture was stirred at 80 °C for 75 minutes, cooled to 15 °C, and quenched with aqueous sodium bicarbonate. The organic layer was separated, dried over Na2SO4, filtered, concentrated, and purified by flash column chromatography (hexane / EtOAc) to afford the title compound. MS (m / z) 407.5 [M+H] 。 + 。 1 1H NMR (400 MHz, chloroform-d) δ 7.41 (d, J = 7.2 Hz, 4H), 7.37 - 7.29 (m, 4H), 7.27 - 7.19 (m, 2H), 5.82 (d, J = 2.0 Hz, 1H), 5.17 (s, 1H), 3.97 (d, J = 14.0 Hz, 2H), 3.79 (dt, J = 14.1, 4.4 Hz, 1H), 3.47 (d, J = 14.0 Hz, 2H), 3.35 (dt, J = 9.9, 2.4 Hz, 1H), 2.85 (s, 1H), 1.95 (q, J = 16.1, 12.0 Hz, 2H), 1.69 - 1.58 (m, 1H), 1.55 - 1.47 (m, 1H), 1.38 (s, 9H), 1.25 - 1.16 (m, 1H). Synthesis of (3R)-3-(benzylamino)-2-methyl-azepane-1-carboxylic acid tert-butyl (9b):

[0290] (3R)-3-(Dibenzylamino)-2-methylene-azepane-1-carboxylic acid tert-butyl (9a, 256 mg, 0.63 mmol) was combined with tert-butyl hydroperoxide (5 - 6 M in decane, 214 μl) and phenylsilane (78 μl, 0.63 mmol) in isopropanol (3 mL) under argon. Tris(dipivaloylmethanato)manganese(III) (34 mg, 0.056 mmol) was added and the reaction was stirred at room temperature. After 1 hour, additional tris(dipivaloylmethanato)manganese(III) (11 mg, 0.019 mmol) was added and stirring was continued. After an additional 30 minutes, the reaction was concentrated and purified by flash column chromatography (hexane / EtOAc) to afford the title compound as a mixture of diastereomers. MS (m / z) 319.3 [M+H] + . Synthesis of (7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-13-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (9c):

[0291] (3R)-3-(Benzylamino)-2-methyl-azepane-1-carboxylic acid tert-butyl (138 mg, 433 μmol) was combined with Pd / C (10 wt%, wet, E101 NE / W, 138 mg) in ethanol (10 mL) under an atmosphere of hydrogen gas and stirred vigorously overnight. The reaction was filtered through Celite® and concentrated to dryness to afford crude (3R)-3-amino-2-methyl-azepane-1-carboxylic acid tert-butyl. MS (m / z) 229.0 [M+H] +This substance was dissolved in methanol (5 mL) and water (0.5 mL), and sodium bicarbonate (146 mg, 1.73 mmol) was added. Then, methyl 3-benzyloxy-5-[(2,4-difluorophenyl)methylcarbamoyl]-4-oxo-pyran-2-carboxylate (186 mg, 0.43 mmol) was added. The mixture was stirred at 45 °C for 5 minutes, warmed to 65 °C, and stirred for 40 minutes. The reaction was cooled to room temperature, concentrated to dryness, dissolved in DCM, dried over Na2SO4, filtered, and concentrated. The residue was dissolved in toluene (4 mL), and TFA (2 mL) was added. The reaction was concentrated to dryness, dissolved in methanol (5 mL), and triethylamine (2 mL) was added. The mixture was warmed to 60 °C and stirred overnight. The reaction was concentrated to dryness, purified by preparative HPLC (MeCN / water (containing 0.1% TFA)), and lyophilized to obtain the title compound as a mixture of diastereomers. The major isomer was (7R,13S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-13-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide. MS (m / z) 508.4 [M+H] + 。 Synthesis of (7R,13S)-N-(2,4-difluorobenzyl)-12-hydroxy-13-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (9):

[0292] (1R)-6-Benzyloxy-N-[(2,4-difluorophenyl)methyl]-14-methyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide (99 mg, 0.20 mmol) was dissolved in 4 mL of toluene and 2 mL of TFA and stirred at 30 °C. After 1 hour, the reaction was concentrated, purified by preparative HPLC (MeCN / H2O (containing 0.1% TFA)), and lyophilized to give the title compound. MS (m / z) 418.3 [M+H] + 。 1 H NMR (400 MHz, acetonitrile-d3) δ 10.42 (s, 1H), 8.38 (s, 1H), 7.51 - 7.35 (m, 1H), 7.09 - 6.91 (m, 2H), 4.60 (d, J = 5.8 Hz, 2H), 4.44 (d, J = 4.4 Hz, 1H), 4.37 (dt, J = 14.3, 9.4 Hz, 1H), 4.24 - 4.14 (m, 1H), 2.23 - 2.05 (m, 2H), 2.04 - 1.98 (m, 1H), 1.78 - 1.62 (m, 2H), 1.50 (d, J = 7.4 Hz, 3H), 1.19 - 1.02 (m, 1H). Example 9: Preparation of (7S- and 7R)-6,6-difluoro-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (10-1, 10-2):

Chemical Structure

[0293] To a vial were added methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate (350 mg, 0.78 mmol), tert-butyl 3-amino-4-hydroxyazepane-1-carboxylate (180 mg, 0.78 mmol), and sodium bicarbonate (131 mg, 1.56 mmol). Methanol (3.5 mL), water (3.5 mL), and 2-methyltetrahydrofuran (2 mL) were added. The reaction mixture was stirred at room temperature overnight and then partitioned between 1N HCl and ethyl acetate. The organic layer was separated and concentrated to dryness. The residue was dissolved in 1 mL of DCM and 3 mL of 4N HCl in dioxane, and the solution was stirred at room temperature for 2 hours to remove the Boc protecting group and then concentrated to dryness. To the residue were added 10 mL of ethanol and DBU (0.47 mL, 3.12 mmol) The reaction mixture was heated in a microwave to 120 °C for 30 minutes. After cooling to room temperature, the reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was separated and concentrated to dryness to afford the title compound. MS (m / z) 528.17 [M+H] + . Synthesis of 12-(benzyloxy)-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (10b):

[0294] A solution of 12-(benzyloxy)-6-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (10a) (320 mg, 0.61 mmol) in dry DCM (15 mL) was added Dess Martin periodinane and the mixture was stirred at room temperature for 20 minutes. DCM was added and the organic phase was washed twice with 10% sodium thiosulfate solution, twice with 0.5 N NaOH, and with brine. The organic phase was dried and evaporated. The residue was purified by silica gel chromatography eluting with methanol in DCM to afford the title compound. MS (m / z) 526.28 [M+H] + 。 Synthesis of 12-(benzyloxy)-6,6-difluoro-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (10c):

[0295] A solution of 12-(benzyloxy)-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide (10b) (200 mg, 0.38 mmol) in DCM (5 mL) cooled to -78 °C under argon was added with Deoxo-Fluor® (1.1 mmol, 0.42 mL, 50% in toluene) under argon. The resulting mixture was stirred at -78 °C and gradually warmed to room temperature overnight. The mixture was cooled to -78 °C and Deoxo-Fluor® (0.76 mmol, 0.28 mL, 50% in toluene) was added under argon. The reaction mixture was stirred at room temperature for 1 day and diluted with DCM. The mixture was cooled in an ice / water bath and quenched by adding saturated aqueous sodium bicarbonate dropwise. The resulting mixture was stirred for 1 h, additional saturated aqueous sodium bicarbonate was added, and stirring was continued for 10 min until foaming ceased. The organic layer was separated, dried over Na2SO4, and filtered. The filtrate was concentrated to dryness. The residue was purified by silica gel chromatography eluting with EtOAc / hexane and by preparative HPLC (MeCN / water (containing 0.1% TFA)) and lyophilized to give the title compound. MS (m / z) 548.25 [M+H] + 。 (7S- and 7R)-6,6-Difluoro-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide (10-1, 10-2) Synthesis:

[0296] 12-(Benzyloxy)-6,6-difluoro-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (10c, 40 mg) was separated into its individual enantiomers by preparative SFC chromatography on an IA column using MeOH as a co-solvent to give 10c-1 and 10c-2. The separated enantiomers were dissolved in 0.5 mL of toluene and 1 mL of TFA and stirred at room temperature for 1 h. The reaction mixture was concentrated and purified by RP-HPLC eluting with ACN / H2O (0.1% TF A) to give the title compound. Peak 1: MS (m / z) 458.12 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 10.26 (t, J = 5.8 Hz, 1H), 8.48 (s, 1H), 7.22 (t, J = 8.7 Hz, 2H), 5.26 - 5.17 (m, 1H), 4.58 (d, J = 5.8 Hz, 2H), 4.20 (dt, J = 13.3, 8.7 Hz, 1H), 4.07 - 3.97 (m, 1H), 3.87 (dd, J = 15.5, 1.9 Hz, 1H), 3.18 (dd, J = 13.3, 6.7 Hz, 1H), 2.21 (s, 1H), 2.05 - 1.83 (m, 2H), 1.60 (dt, J = 34.9, 14.0 Hz, 1H). Peak 2: MS (m / z) 458.13 [M+H]+. 11H NMR (400 MHz, DMSO-d6) δ 10.63 (s, 1H), 10.27 (t, J = 5.8 Hz, 1H), 8.48 (s,1H), 7.22 (t, J = 8.7 Hz, 2H), 5.21 (d, J = 8.0 Hz, 1H), 4.58 (d, J = 5.8 Hz,2H), 4.32 - 4.15 (m, 1H), 4.10 - 3.94 (m, 1H), 3.87 (dd, J = 15.5, 2.0 Hz, 1H),3.18 (dd, J = 13.4, 6.6 Hz, 1H), 2.22 (s, 1H), 1.92 (d, J = 8.1 Hz, 2H), 1.71 -1.43 (m, 1H). Example 10: Preparation of 6,12-dihydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (11): [Chemical formula]

[0297] 12-(Benzyloxy)-6-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (10a) (20 mg) was dissolved in 0.3 mL of toluene and 0.6 mL of TFA and stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness and the residue was purified by RP-HPLC eluting with ACN / H2O (0.1% TFA) to give the title compound. MS (m / z) 438.18 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 10.44 (t, J = 5.8 Hz, 1H), 8.28 (s, 1H), 7.28 - 7.15 (m, 2H), 4.57 (d, J = 5.6 Hz, 3H), 4.13 (dt, J = 13.2, 9.2 Hz, 1H), 3.91 - 3.78 (m, 2H), 3.62 (dd, J = 15.0, 1.6 Hz, 1H), 3.12 (dt, J = 13.1, 4.5 Hz, 1H), 1.84 (d, J = 6.8 Hz, 2H), 1.66 (d, J = 14.5 Hz, 1H), 1.02 (td, J = 14.4, 13.5, 5.8 Hz, 1H). Example 11: Preparation of N-(2,4-difluorobenzyl)-6,12-dihydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (12): [Chemical formula] Synthesis of 12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (12a):

[0298] 12-(Benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (12a) was prepared in the same manner as compound 10a using methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate. MS (m / z) 510.23 [M+H] + . Synthesis of N-(2,4-difluorobenzyl)-6,12-dihydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (12):

[0299] The title compound was prepared using compound 12a in the same manner as compound 11. MS (m / z) 420.15 [M+H] + 。 1 HNMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 10.43 (t, J = 5.9 Hz, 1H), 8.31 (s,1H), 7.41 (td, J = 8.7, 6.6 Hz, 1H), 7.25 (ddd, J = 10.6, 9.3, 2.6 Hz, 1H),7.12 - 7.02 (m, 1H), 5.37 (s, 1H), 4.61 - 4.52 (m, 3H), 4.20 - 4.08 (m, 1H),3.86 (td, J = 14.0, 13.0, 4.4 Hz, 2H), 3.68 - 3.59 (m, 1H), 3.17 - 3.09 (m, 1H), 1.85 (d, J = 7.4 Hz, 2H), 1.68 (d, J = 14.9 Hz, 1H), 1.04 (s, 1H). Example 12: Preparation of N-(2,4-difluorobenzyl)-6-fluoro-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (13):

Chemical formula

[0300] 12-(Benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-1,11-dioxo-1,4,5,6,7,11-he To a solution of 12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (12a, 47 mg, 0.092 mmol) in DCM (3 mL) was added Deoxo-Fluor® (0.14 mmol, 0.05 mL, 50% in toluene) under argon. The resulting mixture was stirred at -78 °C and then gradually warmed to room temperature overnight. The mixture was cooled to -78 °C and Deoxo-Fluor® (0.14 mmol, 0.05 mL, 50% in toluene) was added under argon. The reaction mixture was stirred at room temperature for 2 h and diluted with DCM. The mixture was cooled in an ice / water bath and the reaction was quenched by dropwise addition of saturated aqueous sodium bicarbonate. The resulting mixture was stirred for 1 h and additional saturated aqueous sodium bicarbonate was added and stirring was continued for 10 min until foaming ceased. The organic layer was separated, dried over Na2SO4 and filtered. The filtrate was concentrated to dryness to afford the title compound. MS (m / z) 512.22 [M+H] + 。 Synthesis of N-(2,4-difluorobenzyl)-6-fluoro-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (13):

[0301] The title compound was prepared using 13a in the same manner as compound 11. MS (m / z) 422.18 [M+H] + 。 1HNMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 10.33 (t, J = 5.9 Hz, 1H), 8.60 (s,1H), 7.41 (td, J = 8.7, 6.6 Hz, 1H), 7.25 (td, J = 9.6, 2.6 Hz, 1H), 7.07 (td,J = 8.7, 2.5 Hz, 1H), 5.10 - 5.03 (m, 1H), 4.98 - 4.89 (m, 1H), 4.56 (d, J =6.0 Hz, 2H), 4.13 (dt, J = 13.2, 7.9 Hz, 1H), 3.90 (d, J = 15.0 Hz, 1H), 3.83(dd, J = 15.1, 2.0 Hz, 1H), 3.13 (ddd, J = 13.2, 7.1, 2.9 Hz, 1H), 2.18 - 2.05(m, 1H), 2.04 (s, 1H), 1.82 - 1.64 (m, 1H), 1.53 - 1.20 (m, 1H). Example 13: Preparation of (6S,7R)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-6-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide and (6R,7S)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-6-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (14-1, 14-2):

Chemical formula

[0302] A solution of benzyl 3-amino-4-hydroxyazepane-1-carboxylate (1.1 g, 4.16 mmol) and Na2CO3 (310 mg, 4.99 mmol) in dioxane (7 mL) and water (7 mL) was added Cbz-Cl (0.7 mL, 4.99 mmol) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 3 h. Ethyl acetate was added. The organic layer was separated, washed with brine, dried (sodium sulfate), filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with hexane / ethyl acetate to give the title compound. MS (m / z) 399.26 [M+H] + 。 (S)- and (R)-Benzyl 3-(((benzyloxy)carbonyl)amino)-4-oxoazepane-1-carboxylate (14c-1 and 14c-2) synthesis:

[0303] To a solution of benzyl 3-(((benzyloxy)carbonyl)amino)-4-hydroxyazepane-1-carboxylate (14b) (760 mg, 1.9 mmol) in 5 mL of DCM was added Dess Martin periodinane (1.2 g, 2.8 mmol). The reaction mixture was stirred at room temperature for 30 min. DCM was added and the organic phase was washed twice with 10% sodium thiosulfate solution, twice with 0.5 M NaOH, and with brine. The organic phase was dried and evaporated. The residue was purified by SGC eluting with EtOAc / hexane to give benzyl 3-(((benzyloxy)carbonyl)amino)-4-oxoazepane-1-carboxylate (14c). MS (m / z) 397.53 [M+H]+. Compound 14c was separated into the individual enantiomers by preparative SFC chromatography on an IA column using MeOH as co-solvent to give 14c-1 and 14c-2. ((3S,4R)- and (3R,4S)-4-Hydroxy-4-methylazepan-3 -yl)carbamic acid benzyl ester (14d-1, 14d-2) synthesis:

[0304] To the flask, methylmagnesium chloride (1.02 mL, 3.05 mmol, 3 M in Et2O) was added at 0 °C. A solution of 14c-1 or 14c-2 (302 mg, 0.76 mmol) in 1 mL of THF was slowly added with stirring. The reaction mixture was warmed to room temperature and stirred overnight. The reaction was quenched with NH4Cl and extracted into ethyl acetate, washed with brine, dried over MgSO4, filtered, and the solvent was removed under reduced pressure to obtain benzyl ((3S,4R)-4-hydroxy-4-methylazepan-3-yl)carbamate or benzyl ((3R,4S)-4-hydroxy-4-methylazepan-3-yl)carbamate. MS (m / z) 413.50 [M+H] + .

[0305] The residue was dissolved in absolute ethanol and sparged under an argon atmosphere. Palladium hydroxide (101 mg, 20% Pd by weight) was added and the mixture was sparged under a hydrogen atmosphere (1 atm, balloon). The mixture was stirred vigorously over the weekend and sparged under an argon atmosphere. It was filtered through a pad of Celite®. The Celite® was washed with absolute ethanol and the filtrate was concentrated under reduced pressure to obtain the title compound. MS (m / z) 145.16 [M+H] + . (6S,7R)- and (6R,7S)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-6-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (14-1, 14-2) synthesis:

[0306] The title compound was prepared in the same manner as Compound 12 using Compounds 14d-1 and 14d-2. MS (m / z) 434.15 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.46 (t, J = 6.0 Hz, 1H), 8.34 (s,1H), 7.41 (td, J = 8.7, 6.6 Hz, 1H), 7.25 (ddd, J = 11.7, 9.4, 2.6 Hz, 1H),7.08 (td, J = 8.6, 2.7 Hz, 1H), 4.99 (s, 1H), 4.56 (d, J = 5.9 Hz, 2H), 4.30(s, 1H), 4.15 (dt, J = 13.0, 8.8 Hz, 1H), 3.85 (dd, J = 15.2, 3.0 Hz, 1H), 3.68 (dd, J = 15.2, 1.7 Hz, 1H), 3.10 (dt, J = 13.0, 4.8 Hz, 1H), 1.81 (d, J = 7.2 Hz, 2H), 1.47 (d, J = 15.4 Hz, 1H), 1.35 (s, 3H), 1.23(dt, J = 14.4, 6.5 Hz, 1H). Example 14: Preparation of (6R,7S)- and (6S,7R)-6-fluoro-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (15-1, 15-2): [Chemical formula] Synthesis of (7S)- and (7R)-12-(benzyloxy)-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (15a-1, 15a-2):

[0307] 12-(Benzyloxy)-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (10b) (350 mg) was separated into its individual enantiomers by preparative SFC chromatography on an IA column using MeOH as a co-solvent to give 15a-1 and 15a-2. MS (m / z) 526.00 [M+H]+. (6S,7S)-, and (6R,7R)-12-(Benzyloxy)-6-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (15b-1, 15b-2) Synthesis:

[0308] To a solution of 15a-1 or 15a-2 (150 mg, 0.285 mmol) in 7 mL of methanol was added NaBH4 (21.6 mg, 0.57 mmol) at 0 °C. The reaction was stirred at room temperature for 30 minutes. The reaction was quenched with 1 N HCl and extracted with DCM. The organic phase was dried over MgSO4 and concentrated in vacuo to give the title compound. MS (m / z) 528.26 [M+H]+. (6R,7S)-, and (6S,7R)-6-Fluoro-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (15-1, 15-2) Synthesis:

[0309] The title compound was prepared using compounds 15b-1 and 15b-2 in the same manner as compound 13. 15-1: MS (m / z) 440.22 [M+H]+. 1 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 10.35 (t, J = 5.8 Hz, 1H), 8.58 (s, 1H), 7.28 - 7.15 (m, 2H), 5.12 - 4.78(m, 2H), 4.65 - 4.50 (m, 2H), 4.18 - 4.06 (m, 1H), 3.89 - 3.80 (m, 2H), 3.12(ddd, J = 13.2, 7.2, 2.9 Hz, 1H), 2.19 - 1.95 (m, 2H), 1.79 - 1.70 (m, 1H),1.56 - 1.21 (m, 1H). 15-2: MS (m / z) 440.20 [M+H] + 。 1 1H NMR(400 MHz, DMSO-d6) δ 10.57 (s, 1H), 10.35 (t, J = 5.8 Hz, 1H), 8.58 (s, 1H),7.28 - 7.15 (m, 2H), 5.12 - 4.81 (m, 2H), 4.65 - 4.50 (m, 2H), 4.12 (dt, J = 13.3, 8.1 Hz, 1H), 3.89 (d, J= 15.0 Hz, 1H), 3.86 - 3.77 (m, 1H), 3.12 (ddd, J = 13.1, 7.0, 2.9 Hz, 1H),2.22 - 1.95 (m, 2H), 1.79 - 1.70 (m, 1H), 1.50 - 1.28 (m, 1H). Example 15: Preparation of (7S)- and (7R)-N-(2,4-difluorobenzyl)-6,6-difluoro-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (16-1, 16-2):

Chemical formula

[0310] 12-(Benzyloxy)-N-(2,4-difluorobenzyl)-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (16a) was prepared in the same manner as compound 10b using methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate (16a). MS (m / z) 508.15 [M+H]+. Compound 16a was separated into its individual enantiomers by preparative SFC chromatography on an OD-H column using an IPA-NH3 co-solvent to obtain 16a-1 and 16a-2. (7S)-, and (7R)-N-(2,4-difluorobenzyl)-6,6-difluoro-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (16-1, 16-2) synthesis:

[0311] The title compound was prepared using 16a-1 and 16a-2 in the same manner as compounds 10-1 and 10-2. 16-1: MS (m / z) 440.20 [M+H] + 。 1 HNMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 10.24 (t, J = 6.0 Hz, 1H), 8.50 (s,1H), 7.42 (td, J = 8.6, 6.6 Hz, 1H), 7.26 (ddd, J = 10.5, 9.4, 2.6 Hz, 1H),7.07 (td, J = 8.5, 7.6, 4.2 Hz, 1H), 5.24 (s, 1H), 4.56 (d, J = 5.8 Hz, 2H),4.27 - 4.15 (m, 1H), 4.04 (d, J = 16.5 Hz, 1H), 3.92 - 3.83 (m, 1H), 3.19 (dd, J = 13.2, 6.8 Hz, 1H), 2.22 (s,1H), 1.96 (d, J = 21.8 Hz, 2H), 1.71 - 1.54 (m, 1H). 16 - 2: MS (m / z) 440.27 [M+H]+。 1 1H NMR (400 MHz, DMSO - d6) δ 10.64 (s, 1H), 10.24 (t, J = 5.9 Hz, 1H), 8.50 (s, 1H), 7.42 (td, J = 8.7, 6.6 Hz, 1H), 7.31 - 7.20 (m, 1H), 7.07 (td, J =8.4, 2.7 Hz, 1H), 5.24 (s, 1H), 4.56 (d, J = 5.9 Hz, 2H), 4.21 (q, J = 10.2,9.7 Hz, 1H), 4.04 (d, J = 15.8 Hz, 1H), 3.88 (dd, J = 15.4, 2.0 Hz, 1H), 3.18(dd, J = 13.1, 6.7 Hz, 1H), 2.22 (s, 1H), 1.97 (d, J = 22.4 Hz, 2H), 1.62 (dd, J = 35.1, 14.3 Hz, 1H). Example 16: Preparation of N-(2,4-difluorobenzyl)-6-fluoro-12-hydroxy-6-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (17-1a) and N-(2,4-difluorobenzyl)-12-hydroxy-6-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (17-1b, 17-2b):

Chemical formula

[0312] The title compound was prepared in the same manner as compound 13a using compounds 14e-1 and 14e-2. MS (m / z) 526.16 [M+H]+. By-products (17a-1b, 17a-2b) were formed. MS (m / z) 506.13 [M+H]+. Synthesis of N-(2,4-difluorobenzyl)-6-fluoro-12-hydroxy-6-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (17-1a) and N-(2,4-difluorobenzyl)-12-hydroxy-6-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (17-1b, 17-2b):

[0313] The mixture of products obtained from the previous step (17a-1a and 17a-1b, 40 mg, about 0.07 mmol) or (17a-2a and 17a-2b) was dissolved in absolute ethanol (10 mL), and the solution was sparged under an argon atmosphere. Palladium hydroxide (20%, 11 mg) was added, and the mixture was sparged under a hydrogen atmosphere (1 atm, balloon). The mixture was stirred vigorously for 2 hours, sparged under an argon atmosphere, and filtered through a pad of Celite®. The Celite® was washed with absolute ethanol, and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (MeCN / water (containing 0.1% TFA)) and lyophilized to obtain the title compound. For 17-1a: MS (m / z) 436.25 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.82 (s,1H), 10.33 (t, J = 6.0 Hz, 1H), 8.65 (s, 1H), 7.42 (td, J = 8.7, 6.6 Hz, 1H),7.26 (ddd, J = 10.6, 9.3, 2.6 Hz, 1H), 7.08 (td, J = 8.6, 2.7 Hz, 1H), 4.81 (d,J = 11.5 Hz, 1H), 4.63 - 4.48 (m, 2H), 4.16 (q, J = 11.1 Hz, 1H), 3.92 (dd, J =15.0, 2.5 Hz, 1H), 3.80 (d, J = 16.1 Hz, 1H), 3.16 (dd, J = 13.0, 7 .8 Hz, 1H), 2.17 - 2.06 (m, 1H), 1.92 (dt, J = 13.7, 6.4 Hz, 1H), 1.73 (dt, J =19.6, 9.6 Hz, 1H), 1.49 - 1.16 (m, 4H). For 17-1b: MS (m / z) 418.28 [M+H]+. 1HNMR (400 MHz, DMSO-d6) δ 10.90 (s, 1H), 10.42 (t, J = 5.9 Hz, 1H), 8.63 (d, J =18.6 Hz, 0H), 8.43 (s, 1H), 7.42 (td, J = 8.7, 6.6 Hz, 1H), 7.26 (ddd, J = 10.6, 9.3, 2.6 Hz, 1H), 7.13 - 7.03 (m, 1H), 4.69 (s, 1H), 4.63 - 4.48 (m,2H), 4.22 - 4.09 (m, 1H), 3.94 (dd, J = 14.6, 2.8 Hz, 1H), 3.71 (dd, J = 14.4,1.7 Hz, 1H), 3.14 (dd, J = 12.9, 6.7 Hz, 1H), 2.11 - 1.99 (m, 1H), 1.91 (t, J = 7.8 Hz, 2H), 1.55 (m, 1H), 1.50 (m, 1H), 0.85 (d, J = 6.9 Hz, 3H). For 17-2b: MS (m / z) 418.24 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.90 (s,1H), 10.42 (t, J = 6.0 Hz, 1H), 8.43 (s, 1H), 7.48 - 7.37 (m, 1H), 7.31 - 7.21(m, 1H), 7.08 (t, J = 9.7 Hz, 1H), 4.69 (s, 1H), 4.56 (d, J = 5.1 Hz, 2H), 4.22- 4.11 (m, 1H), 3.98 - 3.89 (m, 1H), 3.70 (d, J = 14.6 Hz, 1H), 3.14 (dd, J =12.9, 6.3 Hz, 1H), 2.01 (m, 1H), 1.92 (m, 2H), 1.55 (m, 1H), 1.50 (m, 1H), 0.85(d, J = 6.9 Hz, 3H). Example 17: Preparation of 12-Hydroxy-7-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (18):

Chem.

[0314] To a solution of tert-butyl 3-oxoazepane-1-carboxylate (0.52 g, 2.44 mmol) and 2-methylpropan-2-sulfinamide (0.35 g, 2.93 mmol) in THF (10 mL) was added titanium(IV) ethoxide (1.03 mL, 4.91 mmol) at room temperature. The resulting solution was stirred at room temperature overnight.

[0315] The reaction mixture was diluted with ethyl acetate (10 mL) and quenched with aq. NaHCO3 (ca. 5 mL). Celite® was added to this mixture and the solid was filtered off and the filter cake was washed with ethyl acetate (10 mL × 2). The combined washings were concentrated under reduced pressure. The residue was purified by CombiFla sh® using EtOAc / hexane to give the title compound. MS (m / z) 317.2 [M+H] + . Synthesis of tert-butyl 3-((tert-butylsulfinyl)amino)-3-methylazepane-1-carboxylate (18b):

[0316] To (E)-3-((tert-butylsulfinyl)imino)azepane-1-carboxylic acid tert-butyl (0.15 g, 0.47 mmol) in DCM at 0 °C was added 3 M MeMgBr (0.95 mL) dropwise. The reaction mixture was warmed to room temperature and stirred at room temperature overnight.

[0317] The reaction mixture was diluted with ethyl acetate and washed with saturated NH4Cl and brine. The mixture was dried over MgSO4 and the solvent was removed under reduced pressure. The residue was purified by silica gel column using ethyl acetate / hexane to afford the title compound. MS (m / z) 333.2 [M+H] + 。 Synthesis of 3-methylazepan-3-amine (18c):

[0318] At room temperature, 4 M HCl in dioxane (0.07 mL) was added to a solution of tert-butyl 3-(tert-butylsulfinylamino)-3-methyl-azepane-1-carboxylate (18b, 0.03 g, 0.1 mmol) in DCM (2 mL). After 2 h, the solvent was removed under reduced pressure and the crude material was used directly in the next step. MS (m / z) 129.2 [M+H] + 。 Synthesis of methyl 12-(benzyloxy)-7-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]diazepine-10-carboxamide (18d):

[0319] To a mixture of 3-methylazepan-3-amine (18c, 0.013 g, 0.1 mmol) and sodium bicarbonate (45.07 mg, 0.54 mmol) in MeOH (2 mL) and water (2 mL) was added methyl 3-benzyloxy-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyran-2-carboxylate (30 mg, 0.07 mmol) at room temperature. The mixture was stirred at 60 °C for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine and dried over MgSO4. The solvent was removed under reduced pressure and the residue was purified to afford the title compound. MS (m / z) 526.2 [M+H] + 。 Synthesis of 12-Hydroxy-7-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (18):

[0320] 12-(Benzyloxy)-7-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (0.03 g, 0.06 mmol) was dissolved in toluene (2 mL), and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The solvent was removed under reduced pressure, and the residue was purified by HPLC to give the title compound. MS (m / z) 436.1 [M+H] + 1H NMR (400 MHz, chloroform-d) δ 10.46 (s, 1H), 8.57(s, 1H), 6.74 - 6.62 (m, 2H), 4.69 (m, 1H), 4.47 (m, 1H), 4.30 - 4.14 (m, 1H),3.65-3.77 (m, 3H), 3.40 (m, 1H), 3.09 (m, 1H), 2.15 - 1.7 (m, 7H). Example 18: Preparation of (7S)-12-Hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,6,7,11-hexahydro-2,7-methanopyrido[1,2-d][1,4,7]oxadiazocin-10-carboxamide (19) Preparation:

Chemical Structure

[0321] (7S)-12-Hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,6,7,11-hexahydro-2,7-methanopyrido[1,2-d][1,4,7]oxadiazonin-10-carboxamide (19) was prepared in the same manner as 12-hydroxy-7-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (18), replacing (S)-1,4-oxazepan-6-amine with 3-methylazepan-3-amine. 1H NMR (400 MHz, DMSO-d6) δ 10.41 (t, J = 5.8 Hz, 1H), 8.51 (s, 1H), 7.35 - 6.97 (m, 2H), 4.71 (s, 1H), 4.57 (d, J = 5.7 Hz, 2H), 4.28 (ddd, J = 13.1, 9.4, 7.3 Hz, 1H), 4.11 (d, J = 13.9 Hz, 1H), 4.07 - 3.78 (m, 6H). MS (m / z) 514.2 [M+H] + 。 Example 19: Preparation of (7R)-12-Hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (20):

Chemical formula

[0322] (7R)-12-Hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,6,7,11-hexahydro-2,7-methanopyrido[1,2-d][1,4,7]oxadiazocin-10-carboxamide (20) was prepared in the same manner as 12-hydroxy-7-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (18), replacing (R)-1,4-oxazepan-6-amine with 3-methylazepan-3-amine. 1 HNMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.51 (s, 1H), 7.22 (dd, J = 9.2, 8.0 Hz, 2H), 4.71 (d, J = 3.1 Hz, 1H), 4.57 (d, J = 5.7 Hz, 2H), 4.27 (ddd, J = 12.9, 9.1, 7.1 Hz, 1H), 4.16 - 3.62 (m, 6H). MS (m / z) 514.2 [M+H] + 。 Example 20: Preparation of N-(2,4-difluorobenzyl)-11-hydroxy-1,10-dioxo-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide (23):

Chemical Structure

[0323] 3-tert-Butyl 3-azepane-1-carboxylate (588 mg, 3 mmol) was placed in a reactor, and NaHCO3 (576 mg, 7 mmol) and diethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate (950 mg, 3 mmol) in EtOH / H2O (9 mL / 6 mL) were added. The reaction mixture was heated to 50 °C overnight. The reaction was cooled to room temperature and extracted with ethyl acetate (100 mL). The organic layer was concentrated under reduced pressure. The residue was used in the next step without purification.

[0324] To the above residue in DCM (10 mL), 4N HCl solution in dioxane (3 mL) was added. After 2 h at room temperature, the solvent was removed under reduced pressure to give the title compound, which was used in the next step without purification. MS (m / z) 442.945 [M+H] + 。 Synthesis of ethyl 11-(benzyloxy)-1,10-dioxo-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxylate (23b):

[0325] EtOH (20 mL) and DBU (2.2 g, 15 mmol) were added to the above residue. After heating to 110 °C for 1 h under a microwave reactor, the reaction mixture was cooled to room temperature and extracted with ethyl acetate (100 mL). The organic layer was concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography to give the title compound. MS (m / z) 397.113 [M+H] + 。 Synthesis of 11-(benzyloxy)-1,10-dioxo-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxylic acid (23c):

[0326] To the above residue (114 mg, 0.288 mmol) in MeOH (6 mL) was added 2N LiOH (1 mL) at room temperature. After 2 hours, the reaction mixture was diluted with ethyl acetate (100 mL) and 1N HCl (20 mL). The organic layer was dried and concentrated under reduced pressure. The resulting residue was used in the next reaction without purification. MS (m / z) 369.131 [M+H] + 。 Synthesis of 11-(benzyloxy)-N-(2,4-difluorobenzyl)-1,10-dioxo-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide (23d):

[0327] To the above residue (57 mg, 0.155 mmol) in DCM (5 mL) were added (2,4-difluorophenyl)methanamine (27.4 mg, 0.17 mmol), DIPEA (60 mg, 0.46 mmol) and HATU (60.2 mg, 0.186 mmol) at room temperature. After 1 hour, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with brine. The organic layer was dried and concentrated under reduced pressure. The resulting residue was used in the next step. MS (m / z) 512.147 [M+H] + 。 Synthesis of 11-hydroxy-1,10-dioxo-N-(2,4-difluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide (23):

[0328] To a solution of 11-(benzyloxy)-1,10-dioxo-N-(2,4-difluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide (163 mg) in DCM (2 mL) was added TFA (1 mL). After 4 hours, the solvent was removed. The resulting residue was purified by RP-HPLC eluting with ACN / H2O (0.1% TFA) to give the title compound as the TFA salt. MS(m / z) 404.154 [M+H] + 。1 1H NMR (400 MHz, DMSO-d6) δ 10.41 (t, J = 5.9 Hz, 1H), 8.33 (s, 1H), 7.39 (dd, J = 8.6, 6.6 Hz, 2H), 7.22 (ddd, J = 10.7, 9.3, 2.6 Hz, 1H), 7.07 - 7.01 (m, 1H), 4.99 (d, J = 11.6 Hz, 1H), 4.59 - 4.46 (m, 2H), 4.30 - 4.19 (m, 1H), 3.15 - 3.07 (m, 1H), 2.42 - 2.15 (m, 3H), 2.07 - 1.91 (m, 2H), 1.73 (d, J = 46.6 Hz, 3H). Example 21: Preparation of racemic- and (R)- or (S)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide (24 and 24-1): [Chemical formula] Synthesis of racemic-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide (24):

[0329] Racemic 11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide (24) was synthesized from 11-(benzyloxy)-1,10-dioxo-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxylic acid and (2,4,6-trifluorophenyl)methanamine in the same manner as the synthesis of Compound 5. MS (m / z) 422.089 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 10.41 (t, J = 5.9 Hz, 1H), 8.33 (s, 1H), 7 .39 (dd, J = 8.6, 6.6 Hz, 2H), 7.22 (ddd, J = 10.7, 9.3, 2.6 Hz, 1H), 7.07 - 7.01 (m, 1H), 4.99 (d, J = 11.6 Hz, 1H), 4.59 - 4.46 (m, 2H), 4.30 - 4.19 (m, 1H), 3.15 - 3.07 (m, 1H), 2.42 - 2.15 (m, 2H), 2.07 - 1.91 (m, 2H), 1.73 (d, J = 46.6 Hz, 2H). Synthesis of (R)- or (S)-11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide (24-1):

[0330] (R)- or (S)-11-(Benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide peak 1 (24a-1) was separated from racemic-11-(benzyloxy)-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide (24a) by chiral HPLC separation (SFC chromatography on an IB 4.6×100mm 5mic column using MeOH(20) as co-solvent). Using the separated peak 1, 11-hydroxy-1,10-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethanopyrido[1,2-a][1,4]diazocine-9-carboxamide (24-1) was prepared. MS (m / z) 422.124 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 10.45 (t, J = 5.8 Hz, 1H), 8.31 (s, 1H), 7.28 - 7.10 (m, 2H), 4.97 (d, J = 11.3 Hz, 2H), 4.61 (dd, J = 14.5, 6.1 Hz, 1H), 4.48 (dd, J = 14.6, 5.5 Hz, 1H), 4.24 (d, J = 13.0 Hz, 2H), 3.11 (dd, J = 13.5, 8.3 Hz, 1H), 2.37 - 2.21 (m, 2H), 2.00 (d, J = 40.1 Hz, 2H), 1.70 (d, J = 31.2 Hz, 2H). Example 22: Preparation of racemate and (7R)- and (7S)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (25, 25-1, 25-2):

Chemical formula

[0331] 12-(Benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (25d) was synthesized from diethyl 3-(benzyloxy)-4-oxo-4H-pyran-2,5-dicarboxylate and tert-butyl 3-aminoazepane-1-carboxylate as starting materials according to a procedure similar to that of compound 24a. MS (m / z) 494.181 [M+H] + . Synthesis of racemic N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (25):

[0332] To a solution of 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (25d) (5.5 mg) in toluene (0.2 mL) was added TFA (0.2 mL) at room temperature. After 4 h, the solvent was removed. The resulting residue was purified by RP-HPLC eluting with ACN / H2O (0.1% TFA) to give the title compound as the TFA salt. MS (m / z) 404.134 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 10.38 (t, J = 6.0 Hz, 1H), 8.47 (s,1H), 7.38 (td, J = 8.7, 6.6 Hz, 1H), 7.22 (ddd, J = 10.6, 9.3, 2.6 Hz, 1H),7.04 (td, J = 8.6, 2.6 Hz, 1H), 4.75 (dd, J = 5.9, 2.8 Hz, 1H), 4.53 (d, J =5.9 Hz, 2H), 4.12 (d, J = 13.3 Hz, 1H), 3.90 - 3.84 (m, 1H), 3.65 (dd, J =14.7, 1.9 Hz, 1H), 3.07 (td, J = 6.6, 3.6 Hz, 1H), 2.02 - 1.94 (m, 1H), 1.89 -1.74 (m, 3H), 1.62 (d, J = 7.6 Hz, 1H), 1.12 (d, J = 12.1 Hz, 1H). (7R)-12-(Benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide and (7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (25d-1, 25d-2) Synthesis:

[0333] (7R)-12-(Benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (25d-1) as peak 1, and (7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (25d-2) as peak 2 were separated from the racemate of 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (25d) by chiral HPLC separation (SFC chromatography on an IB 4.6×100mm 5mic column using MeOH(20) as a co-solvent). The structure of peak 1 was confirmed by synthesis starting from (R)-azepan-3-amine. (7R)-N-(2,4-Difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (25-1) and (7S)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (25-2) Synthesis:

[0334] (7R)-N-(2,4-Difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (25-1) and (7S)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (25-2) were synthesized from peak 1 and peak 2 respectively according to the reaction conditions similar to those used for preparing compound 25. Compound 25-1: MS (m / z) 404.186 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 10.59(s, 1H), 10.38 (t, J = 5.9 Hz, 1H), 8.47 (s, 1H), 7.38 (td, J = 8.7, 6.6 Hz,1H), 7.22 (ddd, J = 10.6, 9.3, 2.6 Hz, 1H), 7.04 (tdd, J = 8.6, 2.6, 1.1 Hz,1H), 4.75 (d, J = 5.4 Hz, 1H), 4.53 (d, J = 5.9 Hz, 2H), 4.17 - 4.05 (m, 1H),3.86 (d, J = 14.6 Hz, 1H), 3.65 (dd, J = 14.7, 1.9 Hz, 1H), 3.06 (ddd, J = 13.1, 6.9, 3.6Hz, 1H), 1.99 (s, 1H), 1.89 - 1.74 (m, 3H), 1.62 (d, J = 8.0 Hz, 1H). Compound 25-2: MS (m / z) 404.165 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 10.61(s, 1H), 10.38 (t, J = 5.9 Hz, 1H), 8.47 (s, 1H), 7.38 (td, J = 8.7, 6.6 Hz, 1H), 7.22 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.09 - 6.99 (m, 1H), 4.75 (s, 1H), 4.53 (d, J = 5.9Hz, 2H), 4.12 (d, J = 13.3 Hz, 1H), 3.86 (d, J = 14.6 Hz, 1H), 3.69 - 3.60 (m,1H), 3.06 (ddd, J = 13.1, 6.8, 3.6 Hz, 1H), 1.99 (s, 1H), 1.83 (d, J = 13.3 Hz,3H ), 1.67 - 1.60 (m, 1H). Example 23: Preparation of racemic-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide (26), (7R)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide (26-1) and (7S)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide (26-2): [Chemical formula] Synthesis of 12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide (26):

[0335] 12-(Benzyloxy)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxylic acid (57 mg, 0.155 mmol) was dissolved in DCM (2 mL) containing (2,4,6-trifluorophenyl)methanamine (27 mg, 0.17 mmol) and triethylamine (60 mg, 0.464 mmol). HATU (60 mg, 0.186 mmol) was added and the mixture was stirred at room temperature. After overnight reaction, the reaction was concentrated to dryness and purified by silica gel chromatography to afford compound 12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (26a). MS (m / z) 512.06 [M+H] + .

[0336] Compound 12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (26a) (7 mg, 0.014 mmol) was dissolved in toluene (1 mL), and then TFA (1 mL) was added. The resulting mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was purified by HPLC to afford the title compound (26). MS (m / z) 422.091 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 10.39 (t, J = 5.8 Hz, 1H), 8.45 (s, 1H), 7.24 - 7.11 (m, 2H), 4.72 (dd, J = 5.9, 2.9 Hz, 1H), 4.54 (dd, J = 6.0, 2.4 Hz, 2H), 4.11 (d, J = 13.3 Hz, 1H), 3.88 - 3.79 (m, 1H), 3.64 (dd, J = 14.7, 1.9 Hz, 1H), 3.05 (dq, J = 9.5, 3.4 Hz, 1H), 2.06 - 1.91 (m, 1H), 1.89 - 1.74 (m, 3H), 1.61 (d, J = 7.7 Hz, 1H), 1.11 (d, J = 12.7 Hz, 1H). Synthesis of (7S)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (26-2) and (7R)-12-hydroxy-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (26-1):

[0337] The racemate 12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide (26a) was separated by chiral HPLC separation (SFC chromatography on an IB 4.6×100 mm 5 mic column using MeOH(20) as a co-solvent) to obtain the compounds (7R)-12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide (26a-1) and (7S)-12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide (26a-2).

[0338] Compound (7S)-12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide (26a-2) (20 mg, 0.039 mmol) was dissolved in toluene (1 mL), and then TFA (1 mL) was added. The resulting mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by HPLC to obtain the title compound (26-2). (MS (m / z) 422.123 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 10.59(s, 1H), 10.39 (d, J = 5.9 Hz, 1H), 8.45 (s, 1H), 7.18 (t, J = 8.6 Hz, 2H), 4.72(s, 1H), 4.59 - 4.48 (m, 2H), 4.11 (d, J = 13.2 Hz, 1H), 3.85 (d, J = 14.6 Hz,1H), 3.69 - 3.59 (m, 1H), 3.05 (ddd, J = 11.3, 6.7, 3.6 Hz, 1H), 1.97 (m, 1H),1.87 - 1.71 (m, 3H), 1.67 - 1.55 (m, 1H), 1.10 (m, 1H).

[0339] Compound (7R)-12-(benzyloxy)-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (26a-1) (20 mg, 0.039 mmol) was dissolved in toluene (1 mL), and then TFA (1 mL) was added. The resulting mixture was stirred overnight at room temperature. The solvent was removed under reduced pressure, and the residue was purified by HPLC to give the title compound (26-1). MS (m / z) 422.116 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.58 (s , 1H), 10.39 (t, J = 5.8 Hz, 1H), 8.45 (s, 1H), 7.18 (dd, J = 9.2, 8.0 Hz, 2H),4.73 (s, 1H), 4.58 - 4.49 (m, 2H), 4.11 (d, J = 13.3 Hz, 1H), 3.85 (d, J = 14.6Hz, 1H), 3.65 (d, J = 14.2 Hz, 1H), 3.10 - 3.00 (m, 1H), 1.96 (m, 1H), 1.82 (d,J = 12.2 Hz, 3H), 1.61 (d, J = 7.4 Hz, 1H), 1.18 - 1.05 (m, 1H). Example 24: Preparation of N-(2,4-difluorobenzyl)-7-hydroxy-6,8,15-trioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide (27):

Chem.

[0340] To a solution of tert-butyl (2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (55 mg, 0.02 mmol) in DCM (3 mL) was added TFA (1 mL) at room temperature. After 4 hours, the solvent and excess TFA were removed to give 3-amino-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one. MS (m / z) 276.676 [M+H] + . Synthesis of 7-(benzyloxy)-N-(2,4-difluorobenzyl)-6,8,15-trioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide (27b):

[0341] 7-(Benzyloxy)-N-(2,4-difluorobenzyl)-6,8,15-trioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide was prepared from 3-amino-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one TFA salt (45 mg, 0.163 mmol) and methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate (70 mg, 0.163 mmol) according to a procedure similar to that for compound 25. MS (m / z) 555.034 [M+H] + . Synthesis of N-(2,4-difluorobenzyl)-7-hydroxy-6,8,15-trioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide (27):

[0342] N-(2,4-Difluorobenzyl)-7-hydroxy-6,8,15-trioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide (27) was prepared following the same procedure as for compound 26, starting from 7-(benzyloxy)-N-(2,4-difluorobenzyl)-6,8,15-trioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide (11 mg). MS (m / z) 465.05 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 10.25 (t, J = 5.9 Hz, 1H), 8.61 (s, 1H), 7.42 (d, J = 7.1 Hz, 1H), 7.29 (ddd, J = 12.1, 9.4, 2.8 Hz, 1H), 7.25 - 7.18 (m, 2H), 7.14 - 7.01 (m, 3H), 5.74 (s, 2H), 5.45 (s, 1H), 4.54 (d, J = 5.8 Hz, 1H), 3.68 (s, 2H), 3.64 (d, J = 2.8 Hz, 1H) 。 Example 25: Preparation of (7S)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,3,4,6,7,11-hexahydro-2,7-methanopyrido[1,2-d][1,4,7]oxadiazocin-10-carboxamide (28):

Chemical Structure

[0343] To a solution of 1,4-oxazepan-6-amine (18.9 mg, 0.16 mmol) in MeOH (6 mL) and water (1 mL) were added sodium bicarbonate (109.6 mg, 1.3 mmol) and methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate (70 mg, 0.163 mmol). The reaction mixture was heated to 50 °C overnight. The reaction was cooled to room temperature and extracted with ethyl acetate (100 mL). The organic layer was concentrated under reduced pressure. The residue was used in the next step without purification. MS (m / z) 496.016 [M+H] + 。 (7S)-N-(2,4-Difluorobenzyl)-12-hydroxy-1,11-dioxo-1,3,4,6,7,11-hexahydro-2,7-methanopyrido[1,2-d][1,4,7]oxadiazocin-10-carboxamide (28) Synthesis:

[0344] To the solution of (7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,3,4,6,7,11-hexahydro-2,7-methanopyrido[1,2-d][1,4,7]oxadiazocin-10-carboxamide (28a) obtained from the above reaction were added toluene (1 mL) and TFA (1 mL). After 4 hours at room temperature, the solvent and excess TFA were removed under reduced pressure. The residue was dissolved in DMF and subjected to prep.HPLC purification to give the title compound. MS(m / z) 406.83 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (t, J = 5.9 Hz, 1H), 8.50 (s, 1H), 7.39 (td, J =8.7, 6.6 Hz, 1H), 7.27 - 7.20 (m, 1H), 7.05 (td, J = 7.6, 6.7, 4.0 Hz, 1H),5.73 (s, 2H), 4.54 (d, J = 5.9 Hz, 2H), 4.34 - 4.23 (m, 1H), 4.10 (d, J = 14.3Hz, 2H), 4.00 - 3.82 (m, 4H). Example 26: Preparation of (7R)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,3,4,6,7,11-hexahydro-2,7-methanopyrido[1,2-d][1,4,7]oxadiazocin-10-carboxamide (29):

Chem.

[0345] (7R)-N-(2,4-Difluorobenzyl)-12-hydroxy-1,11-dioxo-1,3,4,6,7,11-hexahydro-2,7-methanopyrido[1,2-d][1,4,7]oxadiazocin-10-carboxamide (29) was synthesized from (R)-1,4-oxazepan-6-amine (18.9 mg, 0.163 mmol) and methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate (70 mg, 0.163 mmol) according to a procedure similar to that for compound (28). MS (m / z) 406.136 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 10.36 (t, J = 5.9 Hz, 1H), 8.51 (s, 1H), 7.42 - 7.37 (m, 1H), 7.21 (dd, J =9.9, 2.5 Hz, 1H), 7.07 - 7.02 (m, 1H), 4.70 (s, 1H), 4.54 (d, J = 5.9 Hz, 2H),4.30 - 4.23 (m, 1H), 4.09 (d, J = 5.8 Hz, 1H), 4.00 (d, J = 12.0 Hz, 1H), 3.89(t, J = 8.9 Hz, 3H), 3.66 (d, J = 10.0 Hz, 2H). Example 27: Preparation of N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazocin-10-carboxamide (30): [Chemical formula]

[0346] N-(2,4-Difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazocin-10-carboxamide (30) was synthesized from 1,4-diazepan-6-amine (75.1 mg, 0.652 mmol) and methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate (140 mg, 0.326 mmol) according to a procedure similar to that for compound 28. MS (m / z) 405.183 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 10.37 (s, 1H), 8.52 (s, 1H), 7.42 - 7.34 (m, 1H), 7.22 (s, 1H), 7.05 (d, J = 2.6 Hz, 1H), 4.72 (s, 1H), 4.54 (d, J = 5.7 Hz, 2H), 4.16 (d, J = 12.8 Hz, 2H), 3.92 (d, J = 14.8 Hz, 2H), 3.72 (d, J = 15.0 Hz, 2H), 3.15 (s, 2H). Example 28: Preparation of 5-acetyl-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazocin-10-carboxamide (31): [Chemical formula] Synthesis of 5-acetyl-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazocin-10-carboxamide (31):

[0347] To a solution of 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazocin-10-carboxamide (30a, 26 mg, 0.053 mmol) in DCM (5 mL), DIPEA (27.2 mg, 0.21 mmol) and acetyl chloride (6.2 mg, 0.079 mmol) were added under cooling in an ice-water bath. After stirring for 4 hours, the reaction mixture was extracted with ethyl acetate (100 mL). The organic layer was concentrated under reduced pressure. The residue was used in the next step without purification. MS (m / z) 537.013 [M+H] + .

[0348] 5-Acetyl-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazocine-10-carboxamide (31) was synthesized from 5-acetyl-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazocine-10-carboxamide (31a) according to debenzylation conditions similar to those used to prepare Compound 30. MS (m / z) 447.159 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (t, J = 5.9 Hz, 1H), 8.59 (d, J = 19.5 Hz, 1H), 7.39 (td, J = 8.7, 6.6 Hz, 1H), 7.22 (ddd, J = 10.6, 9.4, 2.7 Hz, 1H), 7.05 (ddt, J = 10.0, 7.4, 1.3 Hz, 1H), 5.73 (s, 2H), 4.54 (d, J = 6.0 Hz, 2H), 4.42 - 4.32 (m, 1H), 3.97 - 3.88 (m, 2H), 3.78 (d, J = 15.1 Hz, 2H), 3.20 - 3.15 (m, 1H), 1.86 (s, 3H). Example 29: Preparation of N-(2,4-Difluorobenzyl)-12-hydroxy-5-(methylsulfonyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazocine-10-carboxamide (32):

Chem.

[0349] N-(2,4-Difluorobenzyl)-12-hydroxy-5-(methylsulfonyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazocin-10-carboxamide (32) was synthesized from 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2- a][1,4,7]triazocin-10-carboxamide (26 mg, 0.053 mmol) following the same procedure used to prepare Compound 31 and using methanesulfonyl chloride (9 mg, 0.079 mmol). MS (m / z) 483.083 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 10.36 (t, J = 6.0 Hz, 1H), 8.56 (s, 1H), 7.38 (dd, J = 8.7, 6.7 Hz, 1H), 7.22 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.14 - 6.96 (m, 1H), 4.54 (d, J = 5.9 Hz, 2H), 4.21 (dd, J = 6.6, 3.3 Hz, 1H), 3.98 (s, 2H), 3.90 - 3.75 (m, 4H), 3.45 (d, J = 15.0 Hz, 1H), 3.29 (d, J = 9.2 Hz, 1H), 3.23 - 3.10 (m, 1H), 2.88 (s, 3H). Example 30: Preparation of N-(2,4-Difluorobenzyl)-12-hydroxy-5-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazocin-10-carboxamide (33):

Chemical Structure

[0350] To a solution of 12-(Benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazocin-10-carboxamide (24 mg, 0.049 mmol) in DMF (1.5 mL) were added DIPEA (25.1 mg, 0.194 mmol) and MeI (10.3 mg, 0.073 mmol) at room temperature. After stirring for 4 h, the reaction mixture was extracted with ethyl acetate (100 mL). The organic layer was concentrated under reduced pressure. The residue was used in the next step without purification. MS (m / z) 509.11 [M+H] + 。

[0351] N-(2,4-Difluorobenzyl)-12-hydroxy-5-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazocin-10-carboxamide (33) was synthesized from 12-(Benzyloxy)-N-(2,4-difluorobenzyl)-5-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazocin-10-carboxamide (33a) according to the same debenzylation conditions used to prepare Compound 30. MS (m / z) 419.2 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 8.60 - 8.18 (m, 2H), 7.40 (td, J = 8.6, 6.6 Hz, 1H), 7.23 (td, J = 9.9, 2.6 Hz, 1H), 7.05 (td, J = 8.5, 2.5 Hz, 1H), 4.54 (d, J = 5.9 Hz, 2H), 4.17 (dt, J = 13.1, 8.1 Hz, 1H), 3.89 - 3.77 (m, 3H), 3.71 - 3.60 (m, 1H), 3.28 (d, J = 7.3 Hz, 3H), 2.78 (s, 3H), 2.27 (s, 1H). Example 31: Preparation of N-(2,4-difluorobenzyl)-12-hydroxy-5-isopropyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazocin-10-carboxamide (34): [Chemical formula]

[0352] N-(2,4-Difluorobenzyl)-12-hydroxy-5-isopropyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazocin-10-carboxamide (34) was synthesized using 2-iodopropane (12.38 mg, 0.073 mmol) according to a procedure similar to that used to prepare Compound 33 from 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4,7]triazocin-10-carboxamide (24 mg, 0.049 mmol). MS (m / z) 447.2 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 10.40 - 10.30 (m, 1H), 8.58 (d, J = 17.2 Hz, 1H), 8.50 (s, 1H), 7.81 (d, J = 12.3 Hz, 1H), 7.38 (dd, J = 9.0, 6.8 Hz, 2H), 7.22 (ddd, J = 10.7, 9.3, 2.6 Hz, 2H), 7.05 (td, J = 8.5, 2.5 Hz, 2H), 4.53 (d, J = 5.7 Hz, 5H), 4.26 (s, 2H), 4.08 (s, 3H), 3.97 - 3.80 (m, 3H), 3.04 (s, 4H), 2.71 (s, 2H), 0.83 (s, 3H), 0.66 (s, 3H). Example 32: Preparation of (7R)-N-(3-chloro-2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (35): [Chemical formula]

[0353] (7R)-N-(3-chloro-2,4-difluorobenzyl)-12-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (35) was synthesized from ethyl 3-(benzyloxy)-5-((3-chloro-2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate (170 mg, 0.356 mmol) and (R)-azepan-3-amine (48.7 mg, 0.427 mmol) according to the same procedure used to prepare compound 28. MS (m / z) 438.1 [M+H] + . 11H NMR (400 MHz, DMSO-d6) δ 10.42 (t, J = 6.0 Hz, 1H), 8.47 (s, 1H), 7.37 (td, J = 8.4, 6.2 Hz, 1H), 7.27 (td, J = 8.8, 1.6 Hz, 1H), 4.78 - 4.70 (m, 1H), 4.57 (d, J = 5.9 Hz, 2H), 4.16 - 4.08 (m, 2H), 3.86 (d, J = 14.9 Hz, 1H), 3.65 (dd, J = 14.7, 1.8 Hz, 1H), 3.06 (ddd, J = 13.2, 6.9, 3.5 Hz, 1H), 1.98 (dd, J = 7.5, 4.4 Hz, 1H), 1.90 - 1.70 (m, 3H), 1.62 (d, J = 7.5 Hz, 1H), 1.12 (d, J = 12.7 Hz, 1H). Example 33: Preparation of N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide (36):

Chemical Structure

[0354] A solution of tert-butyl (2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (36a) (300 mg, 1.086 mmol) in THF (5 mL) was added with a BH3-THF solution (6 mL, 1 N, 6 mmol) at room temperature. After stirring overnight, the reaction was quenched by the addition of MeOH and an aqueous sodium bicarbonate solution. The resulting mixture was extracted with ethyl acetate (100 mL). The organic layer was concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain tert-butyl (2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate. MS (m / z) 262.897 [M+H] + 。 Synthesis of 2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-amine (36c):

[0355] TFA (1 mL) was added to a solution of tert-butyl (2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (36b) (13 mg, 0.05 mmol) in DCM (1 mL) at room temperature. After 2 hours, the solvent and excess TFA were removed. The residue was used in the next step without purification. MS (m / z) 162.952 [M+H] + 。 Synthesis of N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide (36):

[0356] N-(2,4-Difluorobenzyl)-7-hydroxy-6,8-dioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide (36) was synthesized according to the same procedure used to prepare Compound 28 from methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate (30 mg, 0.07 mmol) and 2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-amine. MS (m / z) 452.152 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 10.34 (t, J = 5.9 Hz, 1H), 8.59 (s, 1H), 7.41 (s, 1H), 7.36 - 7.16 (m, 5H), 7.05 (tdd, J = 8.5, 2.7, 1.1 Hz, 1H), 4.89 (s, 1H), 4.55 (d, J = 6.0 Hz, 2H), 4.18 (s, 1H), 3.74 (d, J = 2.1 Hz, 1H), 2.83 - 2.67 (m, 2H), 2.24 (s, 1H), 2.10 (s, 1H). Example 34: Preparation of (12R)- and (12S)-N-(2,4-Difluorobenzyl)-7-hydroxy-6,8-dioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide (37-1, 37-2):

Chem.

[0357] (12R)- and (12S)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxo-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide (37-1, 37-2) were synthesized from (R)- and (S)-(2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamic acid tert-butyl (37a-1, 37a-2, 164 mg, 0.625 mmol for each enantiomer), and this was separated from racemic (2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamic acid tert-butyl (36b) according to the same procedure used to prepare Compound 28 by chiral HPLC separation (SFC chromatography on an IB 4.6×100 mm 5 mic column using EtOH(15%) as a co-solvent). Peak 1 (37a-1) gave 37-1. MS (m / z) 452.16 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (t, J = 5.9 Hz, 1H), 8.62 (s, 1H), 7.48 - 7.21 (m, 7H), 7.13 - 7.03 (m, 1H), 4.91 (dq, J = 4.9, 2.5 Hz, 1H), 4.58 (d, J = 5.9 Hz, 2H), 4.23 - 4.14 (m, 1H), 3.75 (dd, J = 14.8, 2.1 Hz, 1H), 2.79 (dtd, J = 17.3, 14.5, 9.6 Hz, 2H), 2.27 (td, J = 12.1, 11.6, 4.8 Hz, 1H), 2.15 - 2.05 (m, 1H). Peak 2 (37a-2) gave 37-2. MS (m / z) 452.2 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 10.33 (t, J = 5.9 Hz, 1H), 8.59 (s, 1H), 7.40 (d, J = 6.9 Hz, 1H), 7.36 - 7.18 (m, 5H), 7.05 (td, J = 8.4, 2.5 Hz, 1H), 4.89 (s, 1H), 4.55 (d, J = 5.9 Hz, 2H), 4.16 (d, J = 14.5 Hz, 1H), 3.86 (s, 1H), 2.81 - 2.70 (m, 2H), 2.24 (d, J = 3.5 Hz, 1H), 2.09 (d, J = 8.4 Hz, 1H). Example 35: Preparation of (12R)- and (12S)-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide (38-1, 38-2): [Chemical formula]

[0358] (12R)- and (12S)-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide (38-1 and 38-2) were synthesized in the same manner as 37-1 and 37-2, using methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate instead of methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate. MS (m / z) 470.1 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 10.36 (t, J = 5.8 Hz, 1H), 10.25 (s, 1H), 8.57 (s, 1H), 7.36 - 7.24 (m, 4H), 7.19 (t, J = 8.6 Hz, 2H), 4.86 (s, 1H), 4.56 (d, J = 5.8 Hz, 2H), 4.14 (d, J = 14.5 Hz, 1H), 3.71 (dd, J = 14.8, 2.0 Hz, 1H), 2.81 - 2.69 (m, 2H), 2.27 - 2.17 (m, 1H), 2.08 (d, J = 9.7 Hz, 1H). Example 37: Preparation of (4R,7S,8S)- and (4S,7R,8R)-13-hydroxy-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,12-octahydro-2,8:4,7-dimethanopyrido[1,2-a][1,4]diazepine-11-carboxamide (40-1, 40-2):

Chemical Structure

Chemical Structure

[0359] To a solution of 2-azabicyclo[4.2.1]nonan-3-one (1 g, 7.18 mmol) in DCM (30 mL) was added PCl5 (1.496 g, 7 mmol) while cooling in an ice-water bath. After stirring at 0 - 5 °C for 1 h, iodine (18.2 mg, 0.7 mmol) was added and the mixture was stirred for 5 min. A solution of bromine (1.148 g, 7 mmol) in DCM (5 mL) was added at -5 °C and the mixture was stirred at room temperature for 1.5 h. Ice water was added and stirring was continued for 30 min. The mixture was extracted with ethyl acetate (100 mL) and washed with aqueous Na2S2O3 and brine. After drying and removal of the solvent, the residue was crystallized from DCM and hexane to give the title compound. MS (m / z) 218.1 [M+H] added and stirring was continued for 30 min. The mixture was extracted with ethyl acetate (100 mL) and washed with water and brine. After drying and removal of the solvent, the residue was crystallized from DCM and hexane to give the title compound. MS (m / z) 218.1 [M+H] + . Synthesis of 4-azido-2-azabicyclo[4.2.1]nonan-3-one (40b):

[0360] A mixture of 4-bromo-2-azabicyclo[4.2.1]nonan-3-one (40a) (330 mg, 1.513 mmol) and NaN3 (394 mg, 6 mmol) in DMF (10 mL) was heated overnight at 120 °C under a microwave reactor. This reaction mixture was extracted with ethyl acetate (100 mL), and the extract was washed with brine, then dried, and the solvent was removed. The residue was purified by silica gel chromatography to give 4-azido-2-azabicyclo[4.2.1]nonan-3-one (40b). MS (m / z) 181.12 [M+H] + . rel-((1R,4S,6S)-3-oxo-2-azabicyclo[4.2.1]nonan-4-yl)carbamic acid tert- butyl (40c) and rel-((1R,4R,6S)-3-oxo-2-azabicyclo[4.2.1]nonan-4-yl)carbamic acid tert-butyl (40d) synthesis:

[0361] To a reactor were added 4-azido-2-azabicyclo[4.2.1]nonan-3-one (40b) (500 mg, 2.775 mmol), di-tert-butyl dicarbonate (1.21 g, 6 mmol), and palladium on carbon (10 wt%, wet, 296 mg) in EtOH (30 mL) under argon. The reaction mixture was placed under reduced pressure and backfilled with hydrogen gas. After stirring vigorously for 2 hours, the reaction mixture was diluted with EtOH (50 mL), filtered through Celite® and washed with ethyl acetate. The solvent was removed, and the residue was purified by silica gel chromatography to give two diastereomeric peaks 1 and 2 of the product. Peak 1, rel-((1R,4S,6S)-3-oxo-2-azabicyclo[4.2.1]nonan-4-yl)carbamic acid tert-butyl (40c). MS (m / z) 255.02 [M+H] +。 1 H NMR (400 MHz, chloroform-d) δ 6.10 - 5.84 (m, 2H), 4.12 (d, J = 4.9 Hz, 1H), 3.25 (dd, J =14.6, 3.1 Hz, 1H), 3.10 (dddd, J = 14.8, 8.4, 6.9, 1.4 Hz, 1H), 2.53 (s, 1H),2.36 (d, J = 6.2 Hz, 1H), 1.99 - 1.82 (m, 2H), 1.73 - 1.58 (m, 3H), 1.50 (d, J = 1.9 Hz, 1H), 1.45 (s, 9H). Peak 2, rel-((1R,4R,6S)-3-oxo-2-azabicyclo[4.2.1]nonan-4-yl)carbamic acid tert-butyl (40d). MS (m / z) 277.2 [M+Na] + 。 1 H NMR (400 MHz, chloroform-d) δ 5.89 (s,1H), 5.56 (s, 1H), 4.02 (dd, J = 6.9, 4.5 Hz, 1H), 3.36 (ddd, J = 15.3, 7.6,6.0 Hz, 1H), 2.76 (dt, J = 15.4, 6.5 Hz, 1H), 2.42 - 2.31 (m, 1H), 2.17 (s,1H), 1.97 (s, 2H), 1.75 (d, J = 12.7 Hz, 2H), 1.67 - 1.55 (m, 1H), 1.45 (s, 9H),1.41 (d, J = 5.7 Hz, 1H). Synthesis of rel-(1R,4S,6R)-2-azabicyclo[4.2.1]nonan-4-amine (40f):

[0362] rel-(1R,4S,6R)-2-azabicyclo[4.2.1]nonan-4-amine (40f) was synthesized from rel-((1R,4S,6S)-3-oxo-2-azabicyclo[4.2.1]nonan-4-yl)carbamic acid tert-butyl (40c) in the same manner as the synthesis of (2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamic acid tert-butyl (36a) from 2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-amine (36c). Synthesis of (4S,7R,8R)- and (4R,7S,8S)-13-(benzyloxy)-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,12-octahydro-2,8:4,7-dimethanopyrido[1,2-a][1,4]diazepine-11-carboxamide (40g-1, 40g-2):

[0363] rel-(4R,7S,8S)-13-(benzyloxy)-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,12-octahydro-2,8:4,7-dimethanopyrido[1,2-a][1,4]diazepine-11-carboxamide (40g) was synthesized from rel-(1R,4S,6R)-2-azabicyclo[4.2.1]nonan-4-amine (40f) and methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate by the same procedure used to prepare Compound 28, and then chiral HPLC separation was performed to obtain Peak 1 (40g-1) and Peak 2 (40g-2). MS (m / z) 538.2 [M+H] + 。 Synthesis of (4R,7S,8S)- and (4S,7R,8R)-13-hydroxy-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,12-octahydro-2,8:4,7-dimethanopyrido[1,2-a][1,4]diazepine-11-carboxamide (40-1 and 40-2):

[0364] (4R,7S,8S)- and (4S,7R,8R)-13-hydroxy-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,12-octahydro-2,8:4,7-dimethanopyrido[1,2-a][1,4]diazepine-11-carboxamide (40-1, 40-2) were synthesized from compounds 40h-1 and 40h-2 respectively, according to the same procedure used to prepare compound 28. MS (m / z) 448.2 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 10.37 (t, J = 5.8 Hz, 1H), 8.50 (s, 1H), 7.19 (t, J = 8.6 Hz, 2H), 4.55 (dd, J = 5.9, 2.8Hz, 2H), 4.51 - 4.38 (m, 1H), 4.21 (dd, J = 13.4, 7.0 Hz, 1H), 3.80 (d, J =15.1 Hz, 1H), 2.90 - 2.68 (m, 2H), 2.68 - 2.59 (m, 1H), 2.57 - 2.50 (m, 1H),2.15 - 1.99 (m, 1H) , 1.74 (d, J = 7.0 Hz, 2H), 1.49 (dd, J = 14.1, 6.9 Hz, 2H), 1.16 (d, J = 14.4Hz, 1H). Example 38: Preparation of (4S,7R,8S)- and (4R,7S,8R)-13-hydroxy-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,12-octahydro-2,8:4,7-dimethanopyrido[1,2-a][1,4]diazepine-11-carboxamide (41-1 and 41-2):

Chemical formula

[0365] (4S,7R,8S)- and (4R,7S,8R)-13-hydroxy-1,12-dioxo-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,12-octahydro-2,8:4,7-dimethanopyrido[1,2-a][1,4]diazecine-11-carboxamide (41-1 and 41-2) were synthesized from rel-((1R,4R,6S)-3-oxo-2-azabicyclo[4.2.1]nonan-4-yl)carbamic acid tert-butyl (40d) in the same manner as the preparation of compounds 40-1 and 40-2. MS (m / z) 448.2 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 10.38 (t, J = 5.8 Hz, 1H), 8.48 (s, 1H), 7.19 (t, J = 8.6 Hz, 2H), 4.78 (d, J = 9.2 Hz, 1H), 4.55 (t, J = 5.7 Hz, 2H), 4.08 (d, J = 13.3 Hz, 1H), 3.82 (d, J = 2.5 Hz, 1H), 3.05 - 2.88 (m, 2H), 2.42 (s, 1H), 2.19 (d, J = 14.0 Hz, 1H), 1.63 (dd, J = 13.2, 7.2 Hz, 3H), 1.40 (d, J = 11.9 Hz, 1H), 0.92 (d, J = 3.7 Hz, 1H). Example 39a: Preparation of N-(2,4-difluorobenzyl)-5-hydroxy-4,6-dioxo-1,1a,2,4,6,10,11,11a-octahydro-3,10-methanocyclopropa[f]pyrido[1,2-a][1,4]diazocin-7-carboxamide (42-1):

Chemical formula

[0366] To a single round-bottom flask was added 2-aminopenta-4-en-1-ol (2000 mg, 19.8 mmol), 100 mL of water, and potassium carbonate anhydrous (2.5 g, 40 mmol). To a second round-bottom flask was added 100 mL of dioxane and benzyl chloroformate (3.1 mL, 22 mmol). Each mixture was stirred to dissolve. The amine mixture was cooled in an ice bath and the dioxane mixture was added. The reaction mixture was slowly warmed to room temperature while stirring overnight. The reaction mixture was diluted with DCM and extracted twice with DCM. The organic extract was washed with NH4Cl, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography to afford the title compound. MS (m / z) 235.9 [M+H] + . Synthesis of benzyl (1-oxopenta-4-en-2-yl)carbamate (42b):

[0367] To a round-bottom flask was added benzyl (1-hydroxypenta-4-en-2-yl)carbamate (42a, 3 g, 13 mmol) and 200 mL of DCM, followed by addition of Dess Martin periodinane (6 g, 14.2 mmol). After stirring for 1 hour, additional Dess-Martin periodinane (2 g, 4.7 mmol) was added to the reaction mixture and stirring was continued for an additional 30 minutes. The mixture was diluted with DCM, saturated NaHCO3 solution and 11 g of sodium thiosulfate were added. The resulting mixture was stirred for about 10 minutes and extracted twice with DCM. The organic extract was washed with a mixture of brine, water , and NaHCO3, dried over sodium sulfate, and concentrated to afford the title compound. MS (m / z) 234.0 [M+H] + . Synthesis of benzyl (1-(allylamino)penta-4-en-2-yl)carbamate (42c):

[0368] To a round-bottom flask were added benzyl (1-oxopent-4-en-2-yl)carbamate (6 g, 26 mmol) and THF (100 mL). Allylamine (2.1 mL, 28.3 mmol) and sodium triacetoxyborohydride (8.2 g, 39 mmol) were added, and the reaction mixture was stirred overnight. The reaction was quenched with saturated aqueous NaHCO3 (20 mL), and the mixture was extracted with EtOAc (100 mL × 3). The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the title compound. MS (m / z) 275.2 [M+H] + . Synthesis of benzyl allyl(2-(((benzyloxy)carbonyl)amino)penta-4-en-1-yl)carbamate (42d):

[0369] To a single round-bottom flask were added benzyl (1-(allylamino)penta-4-en-2-yl)carbamate (42c, 6.3 g, 23.1 mmol), 120 mL of water, and potassium carbonate anhydrous (2.9 g, 46.2 mmol). To a second round-bottom flask were added 120 mL of dioxane and benzyl chloroformate (3.6 mL, 25.4 mmol). Each mixture was stirred to dissolve. The amine mixture was cooled in an ice bath and the dioxane mixture was added. The reaction mixture was slowly warmed to room temperature with stirring overnight. The reaction mixture was diluted with DCM and extracted twice with DCM. The organic extract was washed with NH4Cl, dried over sodium sulfate, and concentrated. The residue was purified by silica gel chromatography to give the title compound. MS (m / z) 409.7 [M+H] + . Synthesis of benzyl 3-(((benzyloxy)carbonyl)amino)azepane-1-carboxylate (42e-1 and 42e-2):

[0370] To a round-bottom flask, benzyl allyl(2-(((benzyloxy)carbonyl)amino)penta-4-en-1-yl)carbamate (42d, 6.3 mg, 16 mmol), DCM (400 mL), and bis(tricyclohexylphosphine)benzylidenetitanium(IV) dichloride (Grubbs catalyst TM 1st generation) (500 mg, 0.6 mmol) were added. The mixture was heated to reflux overnight and then concentrated. The residue was dissolved in DCM and purified by silica gel chromatography. The mixture of enantiomers was separated into the individual enantiomers by preparative SFC chromatography on a Chiralcel® OJ-H column using MeOH as a co-solvent to obtain 42e-1 (peak 1) and 42e-2 (peak 2). MS (m / z) 381.5 [M+H] + . Synthesis of benzyl 5-(((benzyloxy)carbonyl)amino)-3-azabicyclo[5.1.0]octane-3-carboxylate (42f-1):

[0371] To a three-necked flask, 42e-1 (626 mg, 1.6 mmol) and DCM (3 mL) were added. The resulting mixture was cooled to 0 °C and 1 M diethylzinc in hexane (3.46 mL) was slowly added, followed by slow addition of diiodomethane (0.5 mL, 6.6 mmol). The reaction mixture was stirred at 0 °C for 10 minutes and a second portion of diethylzinc and diiodomethane was added. The mixture was stirred at 0 °C for 2 hours, removed from the ice bath and stirred for an additional 2 hours. A third portion of diethylzinc and diiodomethane was added and the mixture was stirred overnight. The reaction was quenched with water and extracted twice with DCM. The combined organic extracts were dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography to obtain the title compound. MS (m / z) 395.3 [M+H] + . Synthesis of 5-(benzyloxy)-N-(2,4-difluorobenzyl)-4,6-dioxo-1,1a,2,4,6,10,11,11a-octahydro-3,10-methanocyclopropa[f]pyrido[1,2-a][1,4]diazocin-7-carboxamide (42h-1):

[0372] To a round-bottom flask were added 42f-1 (200 mg, 0.5 mmol), ethanol (20 mL), and palladium on carbon 10 wt.% loading (dry basis), matrix carbon powder, wet support (216 mg, 0.2 mmol). The mixture was sparged with N2 and a balloon of H2 was attached. The reaction mixture was stirred overnight, filtered through Celite® and concentrated. The residue was combined with methyl 3-benzyloxy-5-[(2,4-difluorophenyl)methylcarbamoyl]-4-oxo-pyran-2-carboxylate (108.9 mg, 0.5 mmol), NaHCO3 (85 mg, 1 mmol), and MeOH (3 mL). The mixture was stirred at 70 °C for approximately 4 h until crystallization was complete. The solid was filtered off and the solution was concentrated. The residue was dissolved in DMF / water / TFA and purified by HPLC to afford the major diastereomer of the title compound. MS (m / z) 506.2 [M+H] + 。 Synthesis of N-(2,4-difluorobenzyl)-5-hydroxy-4,6-dioxo-1,1a,2,4,6,10,11,11a-octahydro-3,10-methanocyclopropa[f]pyrido[1,2-a][1,4]diazocin-7-carboxamide (42-1):

[0373] To a vial were added 5-(benzyloxy)-N-(2,4-difluorobenzyl)-4,6-dioxo-1,1a,2,4,6,10,11,11a-octahydro-3,10-methanocyclopropa[f]pyrido[1,2-a][1,4]diazocin-7-carboxamide (42h-1, 63 mg, 0.12 mmol), toluene (2 mL), and TFA (1 mL). The reaction mixture was stirred until LCMS indicated complete deprotection, concentrated, diluted with DMF, and purified by HPLC to afford the title compound. MS (m / z) 416.2 [M+H] + . 1 H NMR (400 MHz, chloroform-d) δ 10.59 (s,1H), 8.55 (s, 1H), 7.41 - 7.32 (m, 1H), 6.89 - 6.78 (m, 2H), 4.67 (d, 2H), 4.64- 4.55 (m, 1H), 4.48 (dd, 1H), 4.22 (dd, 1H), 3.94 - 3.83 (m, 1H), 3.75 - 3.66(m, 1H), 2.96 - 2.84 (m, 1H), 1.38 - 1.07 (m, 3H), 0.49 - 0.41 (m, 1H). Example 39b: Preparation of (1aS,10R,11aS)-N-(2,4-difluorobenzyl)-5-hydroxy-4,6-dioxo-1,1a,2,4,6,10,11,11a-octahydro-3,10-methanocyclopropa[f]pyrido[1,2-a][1,4]diazocin-7-carboxamide (42-2): [Chemical formula]

[0374] (1aS,10R,11aS)-N-(2,4-difluorobenzyl)-5-hydroxy-4,6-dioxo-1,1a,2,4,6,10,11,11a-octahydro-3,10-methanocyclopropa[f]pyrido[1,2-a][1,4]diazocin-7-carboxamide (42-2) was prepared in the same manner as 42-1, starting with 42e-2 (peak 2) instead of 42e-1 (peak 1). MS (m / z) 416.2 [M+H] + 。 1 H NMR (400 MHz , chloroform-d) δ 10.46 (s, 1H), 8.43 (s, 1H), 7.40 - 7.30 (m, 1H), 6.87 - 6.75 (m,2H), 4.64 (d, 2H), 4.56 - 4.50 (m, 1H), 4.50 - 4.40 (m, 1H), 4.18 (dd, 1H),3.86 (dd, 1H), 3.67 (d, 1H), 2.93 - 2.80 (m, 1H), 1.37 - 1.04 (m, 3H), 0.91 - 0.76 (m, 1H), 0.47 - 0.34 (m, 1H). Example 40: Preparation of (7S)-12-methoxy-1,11-dioxo-1,3,4,5,6,11-hexahydro-7H-2,7-methanopyrido[2,1-c][1,4]diazocin-10-carboxylic acid 2,4,6-trifluorobenzyl and (7R)-12-methoxy-1,11-dioxo-1,3,4,5,6,11-hexahydro-7H-2,7-methanopyrido[2,1-c][1,4]diazocin-10-carboxylic acid 2,4,6-trifluorobenzyl (43-1, 43-2):

Chemical formula

[0375] To a solution of 6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (1 g, 5.58 mmol) in DCM (25 mL) was added phosphorus pentachloride (1.16 g, 5.58 mmol) under an ice-cooled bath. After stirring the reaction mixture for 5 h, iodine (14.2 mg, 0.558 mmol) was added, followed by bromine (0.892 g, 5.58 mmol). The reaction mixture was warmed to room temperature and stirred for 1.5 h. The reaction mixture was extracted with ethyl acetate and washed with an aqueous solution of Na2S2SO3 and brine. The organic layer was dried over MgSO4 and the solvent was removed by a rotary evaporator. The title compound was crystallized from a mixture of DCM / ethyl acetate MS (m / z) 260 [M+H] + 。 1 H NMR (400 MHz, DMSO-d6) δ 10.18 (s, 1H), 7.25 (td, J = 8.1, 6.3 Hz, 1H), 6.99 (ddd, J = 9.4, 8.4, 1.1Hz, 1H), 6.84 (d, J = 7.9 Hz, 1H), 4.65 (dd, J = 9.2, 7.3 Hz, 1H), 2.96 - 2.83(m, 1H), 2.76 - 2.59 (m, 2H), 2.47 - 2.41 (m, 1H). Synthesis of 3-azido-6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (43b):

[0376] To a solution of 3-bromo-6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (43a, 109 mg, 0.422 mmol) in DMF (5 mL) was added sodium azide (110 mg, 1.69 mmol). After stirring at 60 °C for 4 h, the reaction mixture was extracted with ethyl acetate and washed with brine. The organic layer was dried over MgSO4 and the solvent was removed by a rotary evaporator. The residue was purified by silica gel column to give the title compound. MS (m / z) 221 [M+H] + 。 Synthesis of tert-Butyl (6-Fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (43c):

[0377] To a solution of 3-Azido-6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one (43b, 880 mg, 4 mmol) in THF (30 mL) were added di-tert-butyl dicarbonate (1.308 g, 5.99 mmol) and 10% Pd / C (425 mg), and then the mixture was sparged with hydrogen atmosphere (balloon pressure). After the reaction was stirred for 2 hours, it was filtered through a pad of Celite® and washed with ethyl acetate, and the filtrate was concentrated on a rotary evaporator. The residue was purified by silica gel column to give the title compound. MS (m / z) 317.1 [M+Na] + . 1 H NMR (400 MHz, DMSO-d6) δ9.87 (s, 1H), 7.32 - 7.21 (m, 1H), 7.00 (q, J = 8.5 Hz, 2H), 6.85 (d, J = 7.9 Hz, 1H), 3.91 - 3.78 (m, 1H), 2.96 (dd, J = 14.0, 6.3 Hz, 1H), 2.45 - 2.28 (m, 1H), 2.23 - 1.98 (m, 2H), 1.32 (s, 9H). Synthesis of (S)-(6-Fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamic acid tert-butyl and (R)-(6-Fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (43d-1 and 43d-2):

[0378] A solution of tert-butyl (6-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (43c, 800 mg, 2.72 mmol) in THF (30 mL) was added with BH3-THF solution (1 N, 13 mL) at room temperature. After stirring the reaction overnight, the reaction was quenched with MeOH (1 mL) and an aqueous solution of sodium bicarbonate. The resulting mixture was extracted with ethyl acetate (100 mL) and washed with brine. The organic layer was dried over MgSO4 and concentrated under reduced pressure. The residue was purified by silica gel column to obtain tert-butyl (6-fluoro-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (43d). MS (m / z) 281.2 [M+H] + .

[0379] 43d was separated into individual enantiomers by chiral HPLC (SFC chromatography on an IB 4.6×100 mm 5 mic column using EtOH (15%) as a co-solvent) to obtain the title compound. Synthesis of (S)-6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-amine and (R)-6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-amine (43e-1 and 43e-2)

[0380] (S)-(6-Fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepi n-3-yl)carbamate or (R)-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)carbamate (65 mg, 0.232 mmol) in DCM (5 mL) was added with TFA (1 mL) at room temperature. After 2 hours, the solvent and excess TFA were removed by rotary evaporator to obtain the title compound (43e-1 or 43e-2), which was carried over to the next step without further purification. MS (m / z) 181.2 [M+H] + . (S)-3-(Benzyloxy)-1-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylic acid methyl ester and (R)-3-(benzyloxy)-1-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (43f-1 and 43f-2) Synthesis:

[0381] (S)-6-Fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-amine or (R)-6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-amine (43e-1 or 43e-2, 40 mg, 0.143 mmol) in MeOH / water (v / v = 6 / 1, 3.5 mL) solution, sodium bicarbonate (59.9 mg, 0.713 mmol) and methyl 3-(benzyloxy)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-4H-pyran-2-carboxylate (60 mg, 0.134 mmol) were added. The reaction mixture was stirred at 60 °C overnight, extracted with ethyl acetate (100 mL), and washed with brine. The organic layer was dried over MgSO4, and the solvent was removed by rotary evaporator to obtain the title compound (43f-1 or 43f-2), which was carried over without further purification. MS (m / z) 610.2 [M+H] + 。 (12S)-7-(Benzyloxy)-1-fluoro-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide and (12S)-1-fluoro-7-methoxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide, and (12R)-7-(benzyloxy)-1-fluoro-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide and (12R)-1-fluoro-7-methoxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide mixture (mixture of 43g-1 and 43h-1), and (mixture of 43g-2 and 43h-2) synthesis:

[0382] To a solution of crude (S)- or (R)-2-methyl 5-(2,4,6-trifluorobenzyl) 3-(benzyloxy)-1-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-oxo-1,4-dihydropyridine-2,5-dicarboxylate (43f-1 or 43f-2, 80 mg, 0.131 mmol) in MeOH (6 mL) was added an aqueous solution of LiOH (2N, 2 mL). After stirring the reaction for 2 hours, the solvent was removed and extracted with ethyl acetate (100 mL). The organic layer was dried over MgSO4 and then the solvent was removed by rotary evaporator to give the title compound (mixture of 43g-1 and 43h-1, or mixture of 43g-2 and 43h-2), which was used crude without further purification. 43g-1, 43g-2: MS (m / z) 578.2 [M+H] + 。43h-1, 43h-2: MS (m / z) 501.2 [M+H] + 。 (12S)-1-Fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenz[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide and (12R)-1-fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenz[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide (43-1 and 43-2) synthesis:

[0383] (12S)-7-(Benzyloxy)-1-fluoro-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide and 1-fluoro-7-methoxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide (43g-1 / 43h-1, 198 mg, 0.343 mmol), or (12R)-7-(benzyloxy)-1-fluoro-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide and 1-fluoro-7-methoxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide (43g-2 / 43h-2, 98 mg, 0.17 mmol) in a mixture of DMF (6 mL), LiCl (10 equivalents) was added. After stirring at 105 °C for 1.5 h, the reaction mixture was filtered and purified by preparative HPLC (Gemini 10u C18 110A) eluting with 15 - 80% acetonitrile in water (0.1% TFA) over 15 min to give the title compound (43-1 or 43-2).

[0384] 43-1: MS (m / z) 488.2 [M+H] + 。 11H NMR (400 MHz, DMSO-d6) δ 10.34 (t, J = 5.8 Hz, 1H), 8.58 (s, 1H), 7.32 (dd, J = 8.1, 6.1 Hz, 1H), 7.19 (td, J = 8.3, 3.5 Hz, 4H), 4.95 - 4.85 (m, 1H), 4.56 (d, J = 5.7 Hz, 2H), 4.13 (d, J = 14.7 Hz, 1H), 3.85 (dd, J = 14.9, 2.1 Hz, 1H), 2.88 (dd, J = 17.0, 9.7 Hz, 1H), 2.71 (dd, J = 16.9, 9.2 Hz, 1H), 2.42 - 2.28 (m, 1H), 2.03 - 1.92 (m, 1H).

[0385] 43-2: MS (m / z) 488.1 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 10.34 (t, J = 5.8 Hz, 1H), 8.58 (s, 1H), 7.33 (td, J = 8.1, 6.1 Hz, 1H), 7.19 (td, J = 8.4, 4.0 Hz, 3H), 4.90 (t, J = 5.8 Hz, 1H), 4.56 (d, J = 5.7 Hz, 2H), 4.13 (d, J = 14.6 Hz, 1H), 3.87 (d, J = 2.2 Hz, 1H), 2.88 (dd, J = 16.5, 10.1 Hz, 1H), 2.71 (dd, J = 16.9, 9.2 Hz, 1H), 2.35 (q, J = 7.7, 7.0 Hz, 1H), 1.98 (d, J = 8.6 Hz, 1H). Example 41: Preparation of (8R,Z)-N-(2,4-difluorobenzyl)-13-hydroxy-1,12-dioxo-1,3,4,7,8,12-hexahydro-2,8-methanopyrido[1,2-a][1,4]diazepine-11-carboxamide and (8S,Z)-N-(2,4-difluorobenzyl)-13-hydroxy-1,12-dioxo-1,3,4,7,8,12-hexahydro-2,8-methanopyrido[1,2-a][1,4]diazepine-11-carboxamide (44-1 and 44-2):

Chemical formula

[0386] The title compound was synthesized in a similar manner to 42e-1 and 42e-2, except that 42-b was reacted with but-3-en-1-amine instead of allylamine starting from 2-aminopent-4-en-1-ol. 44a-1: MS (m / z) 395.2 [M+H] + 。44b-1: MS (m / z) 395.2 [M+H] + 。 (R,Z)- and (S,Z)-1,2,3,4,7,8-hexahydroazocin-3-amine (44b-1 and 44b-2) synthesis

[0387] To a vial, (R,Z)-3-(((benzyloxy)carbonyl)amino)-3,4,7,8-tetrahydroazocin-1(2H)-carboxylic acid benzyl or (S,Z)-3-(((benzyloxy)carbonyl)amino)-3,4,7,8-tetrahydroazocin-1(2H)-carboxylate (44a-1 or 44a-2, 500 mg, 1.3 mmol) and 4N HCl in dioxane (6.3 mL, 25 mmol) were added. The reaction mixture was stirred at 95 °C overnight, cooled to room temperature, and concentrated to afford the title compound (44b-1 or 44b-2), which was used without further purification. MS (m / z) 127.2 [M+H] + 。 Synthesis of (8R,Z)-N-(2,4-difluorobenzyl)-13-hydroxy-1,12-dioxo-1,3,4,7,8,12-hexahydro-2,8-methanopyrido[1,2-a][1,4]diazepine-11-carboxamide and (8S,Z)-N-(2,4-difluorobenzyl)-13-hydroxy-1,12-dioxo-1,3,4,7,8,12-hexahydro-2,8-methanopyrido[1,2-a][1,4]diazepine-11-carboxamide (44-1 and 44-2)

[0388] The title compound was synthesized from (R,Z)-1,2,3,4,7,8-hexahydroazocin-3-amine or (S,Z)-1,2,3,4,7,8-hexahydroazocin-3-amine (44b-1 or 44b-2, 18.9 mg, 0.163 mmol) and ethyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate (70 mg, 0.163 mmol) according to a procedure similar to that for the preparation of compound 28.

[0389] 44-1: MS (m / z) 416.3 [M+H] + 。 11H NMR (400 MHz, chloroform-d) δ 10.71 - 10.56 (m, 1H), 8.56 (s, 1H), 7.38 (q, 1H), 6.91 - 6.78 (m, 2H), 6.05 (q, 1H), 5.71 (q, 1H), 4.76 - 4.61 (m, 2H), 4.55 (ddd, 1H), 4.48 - 4.34 (m, 1H), 4.02 - 3.90 (m, 1H), 3.75 (d, 1H), 3.09 - 2.97 (m, 1H), 2.73 - 2.64 (m, 1H), 2.63 - 2.52 (m, 1H), 2.52 - 2.45 (m, 1H), 2.45 - 2.32 (m, 1H).

[0390] 44-2: MS (m / z) 416.2 [M+H] + . 1 1H NMR (400 MHz, chloroform-d) δ 10.66 - 10.51 (m, 1H), 8.52 (s, 1H), 7.38 (q, 1H), 6.84 (q, 2H), 6.05 (q, 1H), 5.71 (q, 1H), 4.74 - 4.62 (m, 2H), 4.56 (ddd, 1H), 4.46 - 4.35 (m, 1H), 3.97 (dd, 1H), 3.75 (d, 1H), 3.08 - 2.99 (m, 1H), 2.71 - 2.63 (m, 1H), 2.63 - 2.54 (m, 1H), 2.53 - 2.45 (m, 1H), 2.44 - 2.32 (m, 1H). Example 42: Preparation of (12S)-1-chloro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide and (12R)-1-chloro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide (45-1 and 45-2): [Chemical formula]

[0391] The title compounds were prepared in the same manner as 43-1 and 43-2, using 6-chloro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one instead of 6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one.

[0392] 45-1: MS (m / z) 504.1 [M+H] + . 1 1H NMR (400 MHz, DMSO-d6) δ 10.38 (t, J = 5.8 Hz, 1H), 8.60 (s, 1H), 7.47 (dd, J = 6.7, 2.8 Hz, 1H), 7.40 - 7.30 (m, 2H), 7.29 - 7.16 (m, 2H), 4.96 - 4.88 (m, 1H), 4.59 (d, J = 5.7 Hz, 2H), 4.15 (dd, J = 15.0, 1.9 Hz, 1H), 3.86 (dd, J = 14.7, 2.2 Hz, 1H), 3.04 (ddd, J = 17.1, 9.7, 2.3 Hz, 1H), 2.86 (ddd, J = 15.8, 10.3, 5.6 Hz, 1H), 2.41 - 2.32 (m, 1H), 2.06 (dd, J = 13.4, 6.9 Hz, 1H).

[0393] 45-2: MS (m / z) 504.1 [M+H] + 。 1 1H NMR (400 MHz, DMSO-d6) δ 10.38 (t, J = 5.8 Hz, 1H), 10.27 (s, 1H), 8.60 (s, 1H), 7.47 (dd, J = 6.7, 2.7 Hz, 1H), 7.41 - 7.30 (m, 2H), 7.29 - 7.16 (m, 2H), 4.96 - 4.88 (m, 1H), 4.59 (d, J = 5.7 Hz, 2H), 4.20 - 4.11 (m, 1H), 3.86 (dd, J = 14.7, 2.2 Hz, 1H), 3.04 (ddd, J = 17.2, 9.8, 2.3 Hz, 1H), 2.86 (dd, J = 16.8, 9.2 Hz, 1H), 2.42 - 2.33 (m, 1H), 2.04 (q, J = 13.0, 9.4 Hz, 1H). Example 43: Preparation of (12S)-4-Fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide and (12R)-4-Fluoro-7-hydroxy-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide (46-1 and 46-2):

Chemical formula

[0394] The title compound was prepared in a similar manner to methyl (S)-3-(benzyloxy)-1-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate and (R)-3-(benzyloxy)-1-(6-fluoro-2,3,4,5-tetrahydro-1H-benzo[b]azepin-3-yl)-4-oxo-5-((2,4,6-trifluorobenzyl)carbamoyl)-1,4-dihydropyridine-2-carboxylate (43f-1 and 43f-2), using 9-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one in place of 6-fluoro-1,3,4,5-tetrahydro-2H-benzo[b]azepin-2-one. Synthesis of (12S)-7-(benzyloxy)-4-fluoro-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide and (12R)-7-(benzyloxy)-4-fluoro-6,8-dioxo-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methanobenzo[e]pyrido[1,2-a][1,4]diazocin-9-carboxamide (46b-1 and 46b-2):

[0395] A solution of methyl (S)-3-(benzyloxy)-1-(9-fluoro-2,3,4,5-tetrahy...

Claims

1. Compound of formula (I): 【Chemical 297】 or a pharmaceutically acceptable salt thereof, wherein in formula (I), R １ is aryl, where C ６～１０ aryl is optionally substituted with 1 to 4 R ６～１０ groups, where each R Ａ１ is independently halo, C Ａ１ alkyl, C １～６ haloalkyl, cyano, -O-C １～４ alkyl, or C １～４ alkyl-O-C １～４ alkyl; １～４ ​ R ２ is H, C １～６ alkyl, or C １～４ haloalkyl; L is -CH ２ -, -CH(CH ３ ), -C(O)-, or -CH ２ -CH ２ -; W １ is a bond or -CR ４ａ R ４ｂ -; W ２ is -CR ５ａ R ５ｂ -, -CR ５ａ R ５ｂ CR ５ｃ R ５ｄ -, -CR ６ａ =CR ６ｂ -, -N(R ７ ), -, -O-, -S(O) ｎ -, -C(O)-, -CR ５ａ R ５ｂ -O-, -CR ５ａ R ５ｂ -C(O)-; X is a bond or -CR ８ａ R ８ｂ -; Y is -C(O)NH- or Q, where Q is 【Chemical Formula 298】 ; Z is -CR ９ａ R ９ｂ -, -CR ９ａ R ９ｂ CR ９ｃ R ９ｄ -, or -CR １０ａ =CR １０ｂ -; R ４ａ and R ４ｂ each independently is H, C １～６ alkyl, C １～４ haloalkyl, or halo; R ５ａ 、 R ５ｂ 、 R ５ｃ 、 and R ５ｄ are independently H, C １～６ alkyl, C １～４ haloalkyl, halo, hydroxyl, cyano, -O-C １～４ alkyl, or C １～４ alkylene-O-C １～４ alkyl; or optionally: R ５ａ and R ５ｂ or R ５ｃ and R ５ｄ together with the carbon atom to which they are attached form a 3- to 7-membered saturated or partially unsaturated spirocarbocyclic ring optionally substituted with one to three R Ａ３ where each R Ａ３ is independently halo, C １～４ alkyl or C １～４ haloalkyl; or R ５ａ and R ５ｃ or R ５ｂ and R ５ｄ together with the carbon atom to which each is attached form a 3- to 7-membered saturated or partially unsaturated fused carbocyclic ring optionally substituted with one to three R Ａ３ where each R Ａ３ is independently halo, C １～４ alkyl or C １～４ haloalkyl; R ６ａ and R ６ｂ each of which is independently H, halo, C １～４ haloalkyl, or C １～６ alkyl; R ６ａ and R ６ｂ together with the carbon atom to which each is attached form (i) a 5- to 10-membered fused aromatic ring or (ii) a 5- to 10-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O, and S, wherein the fused aromatic ring or fused heteroaromatic ring is optionally substituted with 1 to 4 R Ａ４ wherein each R Ａ４ is independently halo or C １～４ alkyl; R ７ is H, C １～６ alkyl, C １～４ haloalkyl, C(O)R ｃ or SO ２ R ｃ ; and R ８ａ and R ８ｂ are each independently H, hydroxyl, -O-C １～４ alkyl, C １～４ alkyl, C １～４ haloalkyl, or halo; or optionally: R ８ａ is H, hydroxyl, -O-C １～４ alkyl, C １～４ alkyl, C １～４ haloalkyl, or halo; and R ８ｂ and R ２ together with the carbon atom to which each is attached form a 3- to 7-membered saturated or partially unsaturated fused ring containing from 0 to 2 heteroatoms selected from N, O and S, where the fused ring is optionally substituted with from 1 to 4 R Ａ５ and each R Ａ５ is independently halo or C １～４ alkyl; R ９ａ 、R ９ｂ 、R ９ｃ 、and R ９ｄ each independently is H, C １～６ alkyl, C １～４ haloalkyl, or halo; or optionally: R ９ａ and R ９ｂ or R ９ｃ and R ９ｄ together with the carbon atom to which they are attached form a 3- to 7-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, where the spiro ring is optionally substituted with 1 to 3 R Ａ６ and each R Ａ６ is independently halo, C １～４ alkyl or C １～４ haloalkyl; or R ９ａ and R ９ｃ or R ９ｂ and R ９ｄ together with the carbon atom to which each is attached form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 heteroatoms or 1 heteroatom selected from N, O, and S, where the fused ring is optionally substituted with 1 to 3 R Ａ６ and each R Ａ６ is independently halo, C １～４ alkyl, or C １～４ haloalkyl; or R ９ａ 、R ９ｂ 、R ９ｃ 、and R ９ｄ of one of them, and R ４ａ 、R ４ｂ 、R ５ａ 、R ５ｂ 、and R ７ of one of them, together with the atoms to which each is attached, form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 to 2 heteroatoms selected from N, O, and S, where the fused ring is optionally substituted with 1 to 4 R Ａ６ s, where each R Ａ６ is independently halo or C １～４ alkyl; R １０ａ and R １０ｂ are each independently H, halo, C １～４ haloalkyl, or C １～６ alkyl; or optionally: R １０ａ and R １０ｂ together with the carbon atom to which each is attached form a 5- to 10-membered partially unsaturated fused ring containing 0 heteroatoms or 1 heteroatom selected from N, O, and S, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O, and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is optionally substituted with 1 to 4 R Ａ７ wherein each R Ａ７ is independently halo or C １～４ alkyl; R ｂ is H or C １～４ alkyl; R ｃ is C １～４ alkyl; and each n is 0, 1, or 2, provided that the compound is not a compound having the formula: 【Chemical 1】 or a pharmaceutically acceptable salt thereof, Compound or a pharmaceutically acceptable salt thereof.

2. R ２ is selected from the group consisting of H, -CH ３ , -CH ２ CH ３ , and -CH ２ F, or R ２ and R ８ｂ together with the carbon to which they are attached form a 3-membered fused carbocyclic ring, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

3. R ２ is H, -CH ３ , -CH ２ CH ３ , and -CH ２ F, the compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, selected from the group consisting of.

4. The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Y is -C(O)NH-.

5. Compound of formula (II): 【Chemical 299】 The compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof, having the formula.

6. R １ is phenyl optionally substituted with from 1 to 4 R Ａ１ where each R Ａ１ is independently halo, C １～４ alkyl, C １～４ haloalkyl, cyano, -O-C １～４ alkyl, or C １～４ alkyl-O-C １～４ alkyl, a compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

7. R １ The compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R is phenyl substituted with one, two, three or four halogens.

8. Compound of formula (IV): 【Chemical 306】 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, having the formula.

9. Compound of the formula: 【Chemical 307】 The compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, having the formula.

10. W １ is a bond or -CR ４ａ R ４ｂ -; wherein R ４ａ and R ４ｂ are independently H, C １～６ alkyl, or halo, a compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof.

11. W １ is a bond, -CH ２ -, -CF ２ -, -CH(F)-, -CH(CH ３ ), or -CF(CH ３ ), or a pharmaceutically acceptable salt thereof, of the compound according to any one of claims 1 to 10.

12. W ２ is selected from the group consisting of -CR ５ａ R ５ｂ -, -CR ５ａ R ５ｂ CR ５ｃ R ５ｄ -, -CR ６ａ =CR ６ｂ -, -N(R ７ ), -, -O-, -S(O) ｎ -, -C(O)-, -CR ５ａ R ５ｂ -C(O)-, and -CR ５ａ R ５ｂ -O-; where R ５ａ 、R ５ｂ 、R ５ｃ 、and R ５ｄ each is independently H, C １～４ alkyl, halo, hydroxyl, or -O-C １～４ alkyl; or R ５ａ and R ５ｂ 、R ５ｃ and R ５ｄ 、R ５ａ and R ５ｃ 、or R ５ｂ and R ５ｄ together with the carbon atoms to which each is attached form a three-membered carbocyclic ring; R ６ａ and R ６ｂ each independently is H, halo, or C １～４ alkyl; or R ６ａ and R ６ｂ together with the atoms to which each is attached form (i) a fused phenyl ring or (ii) a 5- to 6-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N and O, where the fused phenyl ring or the 5- to 6-membered fused heteroaromatic ring is optionally substituted with one or two R Ａ４ and each R Ａ４ is independently halo or C １～４ alkyl; R ７ is H, C １～４ alkyl, C １～４ haloalkyl, C(O)R ｃ or SO ２ R ｃ and; R ｃ is C １～４ alkyl; and The compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

13. The compound according to any one of claims 1 to 12, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1. W ２ is selected from the group consisting of -CR ５ａ R ５ｂ -, -CR ５ａ R ５ｂ CR ５ｃ R ５ｄ -, -CR ６ａ =CR ６ｂ -, -N(R ７ ), -, -O-, -S(O) ｎ -, -C(O)-, -CR ５ａ R ５ｂ -C(O)-, and -CR ５ａ R ５ｂ -O-; where R ５ａ 、R ５ｂ 、R ５ｃ 、and R ５ｄ each of which is independently H, -CH ３ , halo, hydroxyl, or -OCH ３ ; or R ５ａ and R ５ｂ 、R ５ｃ and R ５ｄ 、R ５ａ and R ５ｃ 、or R ５ｂ and R ５ｄ together with the carbon atoms to which each is attached form a 3-membered carbocyclic ring; R ６ａ and R ６ｂ each independently is H, halo, or CH ３ or; alternatively R ６ａ and R ６ｂ together with the atoms to which each is attached form (i) a fused phenyl ring or (ii) a 5-membered fused heteroaromatic ring containing one or two heteroatoms selected from N and O, wherein the fused phenyl ring or the 5-membered fused heteroaromatic ring is optionally substituted with one or two R Ａ４ groups, where each R Ａ４ is independently halo or CH ３ ; R ７ is H, -CH ３ , -CH(CH ３ ), ２ , -CF ３ , -C(O)R ｃ , or -SO ２ R ｃ ; R ｃ is -CH ３ and

14. The compound according to any one of claims 1 to 13, or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

15. W ２ is selected from the group consisting of -CR ５ａ R ５ｂ -, -CR ５ａ R ５ｂ CR ５ｃ R ５ｄ -, -CR ６ａ =CR ６ｂ -, -N(R ７ ), -, -O-, -S(O) ｎ -, -C(O)-, -CR ５ａ R ５ｂ -C(O)-, and -CR ５ａ R ５ｂ -O-; where R ５ａ 、 R ５ｂ 、 R ５ｃ 、 and R ５ｄ each is independently H, -CH ３ 、 halo, hydroxyl, or -OCH ３ ; R ６ａ and R ６ｂ each independently is H, halo, or -CH ３ ; R ７ is H, -CH ３ , -CH(CH ３ ), ２ , -CF ３ , -C(O)R ｃ , or -SO ２ R ｃ ; R ｃ is -CH ３ and

16.

17.

18. W ２ is -CH ２ -, -CH ２ CH ２ -, -CH=CH-, 【Chemical 310】 , -NH-, -N(CH ３ )-,-N(CH(CH ３ ) ２ )-,-N(C(O)CH ３ ) -, -N(SO ２ CH ３ )-, -O-, or -CH ２ 15. The compound of any one of claims 1 to 14, which is -O-, or a pharma- ceutically acceptable salt thereof.

19. X is a bond, -CH ２ -, -CF ２ -, -CH(F)-, -CH(Cl)-, -CH(OH)-, -C(CH ２ F)(H)-, -C(CH ２ F)(OH)-, -C(CH ３ )(OH)-, -CH(OCH ３ )-, -C(CH ２ CH ３ )(OCH ３ )-, -C(CH ２ CH ３ )(OH)-, -CH(CH ３ )-, -CH(CH ２ CH ３ )-, -CF(CH ３ )-, or -CF(CH ２ CH ３ ), or a pharmaceutically acceptable salt thereof, of the compound according to any one of claims 1 to 15.

20. X is a bond, -CH ２ -, -CF ２ -, -CH(F)-, -CH(Cl)-, -CH(OH)-, -C(CH ２ F)(OH)-, -C(CH ３ )(OH)-, -CH(OCH ３ ), -C(CH ２ CH ３ )(OCH ３ ), -C(CH ２ CH ３ )(OH)-, -CH(CH ３ ), -CH(CH ２ CH ３ ), -CF(CH ３ ), or -CF(CH ２ CH ３ ), or a pharmaceutically acceptable salt thereof, of the compound according to any one of claims 1 to 15.

21. Compound of formula (VIII): 【Chemical 311】 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, having the formula.

22. Z is -CR ９ａ R ９ｂ -, -CR ９ａ R ９ｂ CR ９ｃ R ９ｄ -, or -CR １０ａ =CR １０ｂ -; where R ９ａ 、R ９ｂ 、R ９ｃ 、and R ９ｄ are each independently H, C １～６ alkyl, C １～４ haloalkyl, or halo; or R ９ａ and R ９ｂ or R ９ｃ and R ９ｄ together with the carbon atom to which they are attached form a 3- to 7-membered saturated or partially unsaturated spiro ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spiro ring is optionally substituted with 1 to 3 R Ａ６ wherein each R Ａ６ is independently halo, C １～４ alkyl or C １～４ haloalkyl; R １０ａ and R １０ｂ are independently H, halo, C １～４ haloalkyl, or C １～６ alkyl; or R １０ａ and R １０ｂ together with the carbon atom to which each is attached form a 5- to 10-membered partially unsaturated fused ring containing (i) 0 heteroatoms or 1 heteroatom selected from N, O, and S, (ii) a 5- to 10-membered fused aromatic ring, or (iii) a 5- to 10-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O, and S, wherein the 5- to 10-membered partially unsaturated fused ring, 5- to 10-membered fused aromatic ring, or 5- to 10-membered fused heteroaromatic ring is optionally substituted with 1 to 4 R Ａ７ groups, where each R Ａ７ is independently halo or C １～４ alkyl. The compound according to any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof.

23. Z is -CR ９ａ R ９ｂ -, -CR ９ａ R ９ｂ CR ９ｃ R ９ｄ -, or -CR １０ａ =CR １０ｂ -; where R ９ａ 、 R ９ｂ 、 R ９ｃ 、 and R ９ｄ are each independently H, CH ３ 、 CH ２ CH ３ 、 CHF ２ 、 or halo; or R ９ａ and R ９ｂ or R ９ｃ and R ９ｄ together with the carbon atom to which they are attached form a three-membered carbocyclic ring; R １０ａ and R １０ｂ are independently H, halo, or CH ３ or; alternatively R １０ａ and R １０ｂ together with the carbon atom to which each is attached form (i) a fused phenyl ring or (ii) a 5- to 6-membered fused heteroaromatic ring containing one or two heteroatoms selected from N, O and S, where the fused phenyl ring or the fused heteroaromatic ring is optionally substituted with one or two R Ａ７ and each R Ａ７ is independently halo or CH ３ as defined below The compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof.

24. Z is -CH ２ -, -CH(CH ３ ), -CH ２ -CH ２ -, 【Chemical 312】 The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein is.

25. The compound according to any one of claims 1 to 21, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (IX): 【Chemical 313】 having the formula.

26. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (IXa): 【Chemical 314】 having the formula.

27. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (IXb): 【Chemical 315】 having the formula.

28. The compound according to any one of claims 1 to 22, or a pharmaceutically acceptable salt thereof, wherein the compound has the formula (X): 【Chemical 316】 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, having

26. The compound is of formula (Xa): 【Chemical 317】 The compound according to any one of claims 1 to 7 and 25, or a pharmaceutically acceptable salt thereof, having

27. The compound is of formula (Xb): 【Chemical Formula 318】 The compound according to any one of claims 1 to 7 and 25, or a pharmaceutically acceptable salt thereof, having

28. X is a bond or -CR ８ａ R ８ｂ -; where R ８ａ and R ８ｂ are each independently H, hydroxyl, -O-C １～４ alkyl, C １～４ alkyl, C １～４ haloalkyl, or halo, a compound according to any one of claims 25 to 27, or a pharmaceutically acceptable salt thereof.

29. X is -CR ８ａ R ８ｂ -; where R ８ａ and R ８ｂ are each independently H, C １～６ alkyl, C １～４ haloalkyl, or halo, a compound according to any one of claims 25 to 27, or a pharmaceutically acceptable salt thereof.

30. Z is -CR ９ａ R ９ｂ - or -CR ９ａ R ９ｂ CR ９ｃ R ９ｄ wherein; wherein R ９ａ , R ９ｂ , R ９ｃ , and R ９ｄ are each independently H, C １～６ alkyl, or C １～４ haloalkyl, a compound according to any one of claims 25 to 29, or a pharmaceutically acceptable salt thereof.

31. Z is -CR ９ａ R ９ｂ - and is the compound according to any one of claims 25 to 30, or a pharmaceutically acceptable salt thereof.

32. R ９ａ 、 R ９ｂ 、 R ９ｃ 、 and R ９ｄ each independently is H, -CH ３ , -CHF ２ , or -CH ２ F, a compound according to any one of claims 25 to 31, or a pharmaceutically acceptable salt thereof.

33. Each R ５ａ 、R ５ｂ 、R ５ｃ 、and R ５ｄ is independently H, halo, C １～４ haloalkyl, or C １～６ alkyl, a compound according to any one of claims 25 to 32, or a pharmaceutically acceptable salt thereof.

34. The compound is of formula (XI): 【Chemical 319】 The compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, having

35. The compound is of formula (XIa): 【Chemical 320】 The compound according to any one of claims 1 to 7 and 34, or a pharmaceutically acceptable salt thereof, having

36. The compound is of formula (XIb): 【Chemical 321】 The compound according to any one of claims 1 to 7 and 34, or a pharmaceutically acceptable salt thereof, having

37. X is a bond or -CR ８ａ R ８ｂ -; where R ８ａ and R ８ｂ are each independently H, hydroxyl, -O-C １～４ alkyl, C １～４ alkyl, C １～４ haloalkyl, or halo, a compound according to any one of claims 34 to 36, or a pharmaceutically acceptable salt thereof.

38. R ８ａ and R ８ｂ each independently is H, -CH ３ , -CHF ２ , -CH ２ F, or halo, the compound according to any one of claims 34 to 37, or a pharmaceutically acceptable salt thereof.

39. Z is -CR ９ａ R ９ｂ - or -CR ９ａ R ９ｂ CR ９ｃ R ９ｄ wherein R ９ａ , R ９ｂ , R ９ｃ , and R ９ｄ are each independently H, C １～６ alkyl, or C １～４ haloalkyl; a compound according to any one of claims 34 to 38, or a pharmaceutically acceptable salt thereof.

40. R ９ａ 、R ９ｂ 、R ９ｃ 、and R ９ｄ each independently is H, -CH ３ , -CHF ２ , or -CH ２ F, a compound according to any one of claims 34 to 39, or a pharmaceutically acceptable salt thereof.

41. Each R ６ａ and R ６ｂ are independently H, halo, C １～４ haloalkyl, or C １～６ alkyl, the compound according to any one of claims 34 to 40, or a pharmaceutically acceptable salt thereof.

42. Formula 【Chemical 322】 【Chemical 323】 【Chemical 324】 The compound having, or a pharmaceutically acceptable salt thereof.

43. Formula 【Chemical 325】 【Chemical 326】 【Chemical 327】 The compound having, or a pharmaceutically acceptable salt thereof.

44. 【Fig. 328】 【Chemical 329】 【Chemical 330】 【Chemical 331】 【Chemical 332】 【Chemical 333】 【Chemical 334】 【Chemical 335】 【Chemical 336】 【Chemical 337】 【Chemical 338】 A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

45. 【Fig. 339】 【Chemical 340】 【Chemical 341】 【Chemical 342】 【Chemical 343】 【Chemical 344】 【Chemical 345】 【Chemical 346】 【Chemical 347】 【Chemical 348】 【Chemical 349】 【Chemical 350】 【Chemical 351】 【Chemical 352】 【Chemical 353】 A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

46. 【Chemical Formula 354】 【Chemical 355】 【Chemical 356】 A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

47. 【Fig. 357】 【Chemical 358】 【Chemical 359】 A compound selected from the group consisting of, or a pharmaceutically acceptable salt thereof.

48. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

49. The pharmaceutical composition according to claim 48, further comprising one, two, three or four additional therapeutic agents.

50. The pharmaceutical composition according to claim 49, wherein the additional therapeutic agent(s) is / are an anti-HIV agent.

51. The pharmaceutical composition according to claim 49, wherein the additional therapeutic agent(s) is / are an HIV protease inhibitor, a non-nucleoside or non-nucleotide inhibitor of reverse transcriptase of HIV, a nucleoside or nucleotide inhibitor of reverse transcriptase of HIV, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latency reversing agent, a capsid polymerization inhibitor, HIV bNAbs, a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof.

52. The pharmaceutical composition according to any one of claims 49 to 51, wherein the additional therapeutic agent(s) is / are abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-l-(3-(4-chloro-3-(methylsulfonamido)-l-(2,2,2-trifluoroethyl)-lH-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-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.

53. The pharmaceutical composition according to any one of claims 48 to 52, wherein the pharmaceutical composition is for oral administration or parenteral administration.

54. A kit comprising the compound according to any one of claims 1 to 47, or a pharmaceutically acceptable salt thereof, and instructions for use.

55. The kit according to claim 54, further comprising one, two, three or four additional therapeutic agents.

56. The kit according to claim 55, wherein the additional therapeutic agent(s) is / are an anti-HIV agent.

57. The kit according to any one of claims 55 to 56, wherein the additional therapeutic agent(s) is / are an HIV protease inhibitor, a non-nucleoside or non-nucleotide inhibitor of reverse transcriptase of HIV, a nucleoside or nucleotide inhibitor of reverse transcriptase of HIV, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latency reversing agent, a capsid polymerization inhibitor, HIV bNAbs, a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof.

58. The kit according to any one of claims 55 to 57, wherein the additional therapeutic agent(s) is / 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.

59. A composition for treating HIV infection or a pharmaceutical composition according to any one of claims 48 to 53 in a human having or at risk of having HIV infection, wherein the composition comprises a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof.

60. The composition or pharmaceutical composition according to claim 59, wherein the composition or pharmaceutical composition is administered in combination with a therapeutically effective amount of one, two, three or four additional therapeutic agents.

61. The composition or pharmaceutical composition according to claim 60, wherein the additional therapeutic agent(s) is / are an anti-HIV agent.

62. The composition or pharmaceutical composition according to claim 60 or 61, wherein the additional therapeutic agent(s) is / are an HIV protease inhibitor, a non-nucleoside or non-nucleotide inhibitor of reverse transcriptase of HIV, a nucleoside or nucleotide inhibitor of reverse transcriptase of HIV, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latency reversing agent, a capsid polymerization inhibitor, HIV bNAbs, a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof.

63. The composition or pharmaceutical composition according to any one of claims 60 to 62, wherein the additional therapeutic agent(s) is / 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-in-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.

64. The composition or pharmaceutical composition according to any one of claims 59 to 63, wherein the composition or pharmaceutical composition is administered orally, intravenously, subcutaneously, or intramuscularly.

65. A composition comprising the compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 48 to 53, for use in medical treatment.

66. A composition comprising the compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition according to any one of claims 48 to 53, for use in the treatment of HIV infection.

67. Use of a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to any one of claims 48 to 53, in the manufacture of a medicament for treating HIV infection in a human having or at risk of having HIV infection.

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