Crosslinked tricyclic carbamoylpyridone compounds and their use

Abstract

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

Description

Technical Field

[0001] (Cross - Reference to Related Applications) This application claims priority to U.S. Provisional Patent Application No. 63 / 085,704, filed September 30, 2020, the entire disclosure of which is incorporated herein by reference for all purposes.

[0002] (Field of the Invention) The present disclosure generally relates to certain tricyclic compounds, pharmaceutical compositions comprising such compounds, and methods of making and using such compounds and pharmaceutical compositions.

Background Art

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

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

[0005] Furthermore, the HIV virus is known to mutate in infected subjects (Tang, et al. Drugs (2012) 72(9) e1-e25). Because the HIV virus tends to mutate, there is a need for anti-HIV drugs that are effective against various known HIV variants (Hurt, et al. HIV / AIDS CID (2014) 58, 423-431). In certain patients, for example, those with difficult or limited access to healthcare, it can be difficult to adhere to a daily oral treatment or prophylaxis regimen. Drugs that provide favorable pharmaceutical properties (e.g., improved efficacy, long-acting pharmacokinetics, low solubility, low clearance, and / or other properties) are suitable for less frequent dosing and provide better patient compliance. Such improvements in turn result in optimization of drug exposure and limitation of the emergence of drug resistance.

Prior Art Documents

Non-Patent Documents

[0006]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Non-Patent Document 5

Summary of the Invention

Means for Solving the Problems

[0007] In some embodiments, the present disclosure provides a compound of formula I,

Chemical formula

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

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

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

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

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

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

[0014] In some embodiments, the present disclosure provides the use of a compound of Formula I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the manufacture of a medicament for treating HIV infection in a human having or at risk of having the infection.

BRIEF DESCRIPTION OF THE DRAWINGS

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

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

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

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

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

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

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

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

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

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

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

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

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

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

[0029] "Heteroaryl" refers to an aromatic group having a monocyclic, polycyclic, or fused polycyclic ring having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl contains 5 to 20 ring atoms (5- to 20-membered heteroaromatic ring), contains 5 to 12 ring atoms (5- to 12-membered heteroaromatic ring), contains 5 to 10 ring atoms (5- to 10-membered heteroaromatic ring), or contains 5 to 6 ring atoms (5- to 6-membered heteroaromatic ring), and contains 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include pyrimidinyl, purinyl, pyridyl, pyridazinyl, benzothiazolyl, and pyrazolyl. Heteroaryl does not include aryl as defined above and does not overlap with aryl.

[0030] "Heterocyclic ring" refers to a non-aromatic radical or ring having 3 to 15 atoms, wherein 1 to 6 atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, and are bonded to the remainder of the molecule by single bonds. In certain embodiments, "heterocyclyl" has 3 to 10 atoms, or 3 to 7 atoms, wherein 1 to 4 atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur, or 1 to 2 atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen, carbon, or sulfur atoms in heterocyclyl may optionally be oxidized, and the nitrogen atoms may optionally be quaternized. As used herein, heterocyclic ring refers to a saturated or partially saturated ring. Examples of such heterocyclic rings include, but are not limited to, dioxolanyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydrofuran, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. The term includes groups having monocyclic, or polycyclic rings including fused ring systems, bridged ring systems, and spiro ring systems.

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

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

[0033] Substitution with a positron-emitting isotope, for example, 11 C, 18 F, 15 O, and 13 N can be useful in positron emission topography (PET) studies for examining substrate receptor occupancy. The isotopically labeled compounds of Formula I, Ia, Ib, Ic, Id, or II can be prepared by conventional techniques known to those skilled in the art using appropriate isotopically labeled reagents in place of the previously used unlabeled reagents, or by a process similar to that described in the Examples below.

[0034] The methods, compositions, kits, and articles of manufacture provided herein use or comprise a compound (e.g., a compound of Formula I, Ia, Ib, Ic, Id, or II) or a pharmaceutically acceptable salt thereof, wherein 1 to n hydrogen atoms attached to a carbon atom (wherein n is the number of hydrogen atoms in the molecule) may be replaced by deuterium atoms or D. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds are useful for increasing the half-life of a compound or a pharmaceutically acceptable salt thereof when administered to a mammal, as they increase resistance to metabolism. 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 a starting material in which one or more hydrogen atoms have been replaced by deuterium.

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

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

[0037] The terms "optional" or "optionally" mean that the event or situation described thereafter may or may not occur, and that the description includes both the case where the event or situation occurs and the case where the event or situation does not occur. For example, "optionally substituted alkyl" means that the alkyl group may or may not be substituted, and the description means that it includes both substituted alkyl groups and unsubstituted alkyl groups.

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

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

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

[0041] Metal salts are typically prepared by reacting a metal hydroxide with a compound according to the embodiments disclosed herein. Examples of metal salts prepared in this way are Li + 、Na + 、and K+ It is a salt containing. By adding a suitable metal compound, a metal salt with lower solubility can be precipitated from a solution of a salt with higher solubility.

[0042] Furthermore, the salt may be formed by adding a certain specific organic acid and inorganic acid, such as HCl, HBr, H 2 SO 4 、H 3 PO 4 、or an organic sulfonic acid to a base center, typically an amine. Finally, it should be understood that the compositions herein include the compounds disclosed herein in non-ionized and zwitterionic forms.

[0043] "Pharmaceutical composition" refers to a formulation of a compound of an embodiment disclosed herein and a medium generally accepted in the art for delivering a biologically active compound to a mammal, such as a human. Such media include all pharmaceutically acceptable Add agents.

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

[0045] As used herein, the terms "treating" and "treatment" are intended to mean administering a compound or composition according to the embodiments disclosed herein to reduce or eliminate one or more symptoms of HIV infection and / or to reduce the viral load in a patient. In certain embodiments, the terms "treating" and "treatment" also refer to administering a compound or composition according to the embodiments disclosed herein to prevent the appearance of symptoms of the disease and / or to prevent the virus from reaching a detectable level in the blood after an individual has been exposed to the virus but before the symptoms of the disease appear and / or before the virus is detected in the blood, and to prevent perinatal transmission of HIV from mother to infant by administering to a mother before delivery and to an infant within a few days after birth a compound or composition according to the embodiments disclosed herein. The terms "treating" and "treatment" also include administering a compound or composition according to the embodiments disclosed herein before an individual is exposed to the virus to prevent the establishment of an HIV infection and / or to prevent the virus from establishing a permanent infection and / or to prevent the appearance of symptoms of the disease and / or to prevent the virus from reaching a detectable level in the blood (also referred to as pre-exposure prophylaxis or PrEP). The terms "treating" and "treatment" also include administering a compound or composition according to the embodiments disclosed herein both before and after an individual is exposed to the virus.

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

[0047] The compounds of the embodiments disclosed herein or their pharmaceutically acceptable salts may contain one or more asymmetric centers and, thus, can give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined as (R)- or (S)- with respect to absolute stereochemistry or as (D)- or (L)- with respect to amino acids. This disclosure is meant to include all such possible isomers, as well as their racemic, scalemic, and optically pure forms. The optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using a chiral synthon or chiral reagent or resolved using methods such as chromatography and fractional crystallization. Techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of a racemic compound (or a racemic compound of a salt or derivative) using, for example, chiral high pressure liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other geometrically asymmetric centers and are not otherwise specified, these compounds are intended to include both E and Z geometric isomers. Similarly, all tautomeric forms are also intended to be included.

[0048] "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 interchangeable. This disclosure contemplates various stereoisomers and mixtures thereof and includes "enantiomers," which refer to two stereoisomers that are mirror images of each other and whose molecules cannot be superimposed on one another. In any of the embodiments disclosed herein, the compounds disclosed herein may be in the form of their stereoisomers.

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

[0050] In some embodiments, this disclosure provides a compound of formula I, [Chemical formula] or a pharmaceutically acceptable salt thereof, wherein R 1 is C 6~10 aryl or 5- to 10-membered heteroaryl, and C 6~10 aryl or 5- to 10-membered heteroaryl is optionally substituted with 1 to 4 R A1 each R A1 is independently halo, C 1~6 alkyl, C 1~4 haloalkyl, cyano, -O-C 1~4 alkyl, or C 1~4 alkyl-O-C 1~4 alkyl, R 2 is H, C 1~6 alkyl, or C 1~4 haloalkyl, R 3 is halo or -OR 3a wherein R 3a is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 3~6 cycloalkyl, or R 3a and R 2 R 5a and R 6a any one of which, together with the carbon to which they are attached, forms a 4- to 6-membered heterocycle containing one or two heteroatoms independently selected from N, O, and S, R 3b is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 1~4 alkylene-O-C 1~4 alkyl, R 4a is -C 1~6 alkyl or -C 1~4 haloalkyl, R 4b is H, halo, -C 1~6 alkyl, or -C 1~4is a haloalkyl, W 1 is a bond or -CR 5a R 5b -, R 5a and R 5b are independently H, C 1~6 alkyl, C 1~4 haloalkyl, or halo, or R 5a and R 3a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 5b is H, C 1~6 alkyl, C 1~4 haloalkyl, or halo, W 2 is -CR 6a R 6b - or -CR 7a =CR 7b -, R 6a and R 6b are independently H, C 1~6 alkyl, C 1~4 haloalkyl, halo, hydroxyl, cyano, -O-C 1~4 alkyl, or C 1~4 alkylene-O-C 1~4 alkyl, or R 6a and R 3a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 6b is H, C 1~6 alkyl, C 1~4 haloalkyl, halo, hydroxyl, cyano, -O-C 1~4 alkyl, or C 1~4 alkylene-O-C 1~4 alkyl, R 7a and R 7b are independently H, halo, C 1~4 haloalkyl, or C 1~6 alkyl, or R 7a and R 7b together with the carbon to which they are attached form a C A2 optionally substituted with 1 to 4 R 5~10 aryl, and each R A2 is independently halo, cyano, or C 1~4 alkyl.

[0051] It is desirable to discover compounds or pharmaceutically acceptable salts thereof having good stability, i.e., physical stability, chemical stability, and / or metabolic stability. An increase in the overall stability of a compound can provide an increase in the circulation time in the body. The less degradation, the lower the dose of the stable compound can be administered while still maintaining efficacy. Also, the less degradation, the less concern there is regarding by-products from the degradation of the compound. Higher stability of a drug means that more of the drug is available to the target cells without being metabolized.

[0052] It is further desirable to discover compounds or pharmaceutically acceptable salts thereof having improved pharmacokinetic and / or pharmacodynamic profiles, and a long half-life. This can lead to good bioavailability and high systemic exposure, so it is advantageous for a drug to have moderate or low clearance and a long half-life. Reducing clearance and increasing the half-life time of a compound can reduce the daily dose required for efficacy and thus result in a better efficacy and safety profile. Thus, improved pharmacokinetic and / or pharmacodynamic profiles, and a long half-life can provide better patient compliance.

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

Chem.

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

[0055] In some embodiments, the compounds of formula I provided herein are compounds of formula Ia:

Chem.

[0056] In some embodiments, the compounds of formula I provided herein are compounds of formula Ib:

Chem.

[0057] In some embodiments, the compounds of formula I provided herein are compounds of formula Ic:

Chem.

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

Chemical formula

[0059] In some embodiments of the compound of Formula I, Ia, Ib, Ic, or Id, or a pharmaceutically acceptable salt thereof, R 1 is C 6~10 aryl or 5- to 10-membered heteroaryl, and C 6~10 aryl or 5- to 10-membered heteroaryl is optionally substituted with 1 to 4 R A1 , and each R A1 is independently halo, C 1~6 alkyl, C 1~4 haloalkyl, cyano, -O-C 1~4 alkyl, or C 1~4 alkyl-O-C 1~4 alkyl. In some embodiments, R 1 is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, and phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine is optionally substituted with 1, 2, 3, or 4 R A1 , and each R A1 is independently halo, C 1~6 alkyl, C 1~4 haloalkyl, cyano, -O-C 1~4 alkyl, or C 1~4 alkyl-O-C 1~4 alkyl. In some embodiments, R 1 is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, optionally substituted with 1, 2, 3, or 4 R A1 , and 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 1, 2, 3, or 4 RA1 phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine optionally substituted with A1 , and each R A1 is independently halo, C 1~4 alkyl, or -O-C 1~4 alkyl. In some embodiments, R 1 is phenyl, pyridyl, pyridazine, or pyrazine optionally substituted with one, two, three, or four R A1 s, and each R A1 is independently halo or C 1~4 alkyl. In some embodiments, R 1 is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine optionally substituted with one, two, three, or four R A1 s, and each R A1 is independently halo or -O-C 1~4 alkyl. In some embodiments, R 1 is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine substituted with one, two, three, or four R A1 s, and each R A1 is independently halogen. In some embodiments, R 1 is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine substituted with two or three R A1 s, and each R A1 is independently halogen. In some embodiments, R 1 is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine substituted with two or three R A1 s, and each R A1 is independently selected from chloro and fluoro.

[0060] In some embodiments of the compounds of formula I, Ia, Ib, Ic, or Id, or pharmaceutically acceptable salts thereof, R 1 is phenyl or pyridyl, and the phenyl or pyridyl is optionally substituted with one, two, three, or four R A1 s, and each R A1 is independently halo, C 1~6 alkyl, C1~4 Haloalkyl, cyano, -O-C 1~4 alkyl, or -C 1~4 alkyl-O-C 1~4 alkyl. In some embodiments, R 1 is phenyl or pyridyl, and phenyl or pyridyl is optionally substituted with one, two, three, or four R A1 s, and 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 or pyridyl, and phenyl or pyridyl is optionally substituted with one, two, three, or four R A1 s, and each R A1 is independently halo, C 1~4 alkyl, or -O-C 1~4 alkyl. In some embodiments, R 1 is phenyl or pyridyl, and phenyl or pyridyl is optionally substituted with one, two, three, or four R A1 s, and each R A1 is independently halo or C 1~4 alkyl. In some embodiments, R 1 is phenyl or pyridyl, and phenyl or pyridyl is optionally substituted with one, two, three, or four R A1 s, and each R A1 is independently halo or -O-C 1~4 alkyl. In some embodiments, R 1 is phenyl or pyridyl, and phenyl or pyridyl is substituted with one, two, three, or four R A1 s, and each R A1 is independently halogen. In some embodiments, R 1 is phenyl or pyridyl, and phenyl or pyridyl is substituted with two or three R A1 s, and each R A1 is independently halogen. In some embodiments, R 1is phenyl or pyridine, and the phenyl or pyridine is substituted with two or three Rs A1 and each R A1 is independently selected from chloro and fluoro.

[0061] In some embodiments of the compound of formula I, Ia, Ib, Ic, or Id, or a pharmaceutically acceptable salt thereof, R 1 is pyridyl, and the pyridyl is optionally substituted with one, two, three, or four Rs A1 and each R A1 is independently halo, C 1~6 alkyl, C 1~4 haloalkyl, cyano, -O-C 1~4 alkyl, or -C 1~4 alkyl-O-C 1~4 alkyl. In some embodiments, R 1 is pyridyl, and the pyridyl is optionally substituted with one, two, three, or four Rs A1 and 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 pyridyl, and the pyridyl is optionally substituted with one, two, three, or four Rs A1 and each R A1 is independently halo, C 1~4 alkyl, or -O-C 1~4 alkyl. In some embodiments, R 1 is pyridyl, and the pyridyl is optionally substituted with one, two, three, or four Rs A1 and each R A1 is independently halo or C 1~4 alkyl. In some embodiments, R 1 is pyridyl, and the pyridyl is optionally substituted with one, two, three, or four Rs A1 and each R A1 is independently halo or -O-C 1~4 alkyl. In some embodiments, R 1is pyridyl, and the pyridyl is substituted with 1, 2, 3, or 4 R A1 and each R A1 is independently halogen. In some embodiments, R 1 is pyridyl, and the pyridyl is substituted with 2 or 3 R A1 and each R A1 is independently halogen. In some embodiments, R 1 is pyridyl, and the pyridyl is substituted with 2 or 3 R A1 and each R A1 is independently selected from chloro and fluoro.

[0062] In some embodiments of the compound of formula I, Ia, Ib, Ic, or Id, or a pharmaceutically acceptable salt thereof, R 1 is phenyl, and the phenyl is optionally substituted with 1, 2, 3, or 4 R A1 and each R A1 is independently halo, C 1~6 alkyl, C 1~4 haloalkyl, cyano, -O-C 1~4 alkyl, or -C 1~4 alkyl-O-C 1~4 alkyl. In some embodiments, R 1 is phenyl, and the phenyl is optionally substituted with 1, 2, 3, or 4 R A1 and 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, and the phenyl is optionally substituted with 1, 2, 3, or 4 R A1 and each R A1 is independently halo, C 1~4 alkyl, or -O-C 1~4 alkyl. In some embodiments, R 1 is phenyl, and the phenyl is optionally substituted with 1, 2, 3, or 4 R A1 and each R A1is, independently, halo or C 1~4 alkyl. In some embodiments, R 1 is phenyl, and the phenyl is optionally substituted with 1, 2, 3, or 4 R A1 , and each R A1 is, independently, halo or -O-C 1~4 alkyl. In some embodiments, R 1 is phenyl, and the phenyl is substituted with 1, 2, 3, or 4 R A1 , and each R A1 is, independently, halogen. In some embodiments, R 1 is phenyl, and the phenyl is substituted with 2 or 3 R A1 , and each R A1 is, independently, halogen. In some embodiments, R 1 is phenyl, and the phenyl is substituted with 2 or 3 R A1 , and each R A1 is, independently, selected from chloro and fluoro.

[0063] In some embodiments of the compound of formula I, Ia, Ib, Ic, or Id, or a pharmaceutically acceptable salt thereof, R 1 is

Chemical formula

[0064] In some embodiments, the compound of formula I, Ia, Ib, Ic, or Id is a compound of formula II,

Chemical formula

[0065] In some embodiments of the compound of formula II, n is 2, 3, or 4, and each R A1 is independently halo, C 1~4 alkyl, C 1~4 haloalkyl, cyano, or -O-C 1~4 alkyl. In some embodiments, n is 2, 3, or 4, and each R A1 is independently halo, C 1~4 alkyl, C 1~4 haloalkyl, or -O-C 1~4 alkyl. In some embodiments, n is 2, 3, or 4, and each R A1 is independently halo, C 1~4 alkyl, or -O-C 1~4 alkyl. In some embodiments, n is 2, 3, or 4, and each R A1 is independently halo or C 1~4 alkyl. In some embodiments, n is 2, 3, or 4, and each R A1 is independently halo or -O-C 1~4 alkyl. In some embodiments, n is 2, 3, or 4, and each R A1 is independently halogen. In some embodiments, n is 2, 3, or 4, and each R A1 is independently selected from chloro and fluoro.

[0066] In some embodiments of the compound of formula II, n is 2 or 3, and each R A1 is independently halo, C 1~4 alkyl, C 1~4 haloalkyl, cyano, or -O-C 1~4 alkyl. In some embodiments, n is 2 or 3, and each R A1 is independently halo, C 1~4 alkyl, C 1~4 haloalkyl, or -O-C 1~4 alkyl. In some embodiments, n is 2 or 3, and each R A1 is independently halo, C 1~4 alkyl, or -O-C 1~4is alkyl. In some embodiments, n is 2 or 3, and each R A1 is independently halo or C 1~4 alkyl. In some embodiments, is 2 or 3, and each R A1 is independently halo or -O-C 1~4 alkyl. In some embodiments, n is 2 or 3, and each R A1 is independently halogen. In some embodiments, n is 2 or 3, and each R A1 is independently selected from chloro and fluoro.

[0067] In some embodiments of the compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, R 2 is H, C 1~6 alkyl, or C 1~4 haloalkyl. In some embodiments, R 2 is H or C 1~6 alkyl. In some embodiments, R 2 is H or C 1~4 haloalkyl. In some embodiments, R 2 is C 1~6 alkyl or C 1~4 haloalkyl. In some embodiments, R2 is C1-3 alkyl. In some embodiments, R 2 is methyl. In some embodiments, R 2 is H.

[0068] In some embodiments of the compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, R 3 is halo. In some embodiments, R 3 is chloro.

[0069] In some embodiments of the compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, R 3 is OR 3a wherein R 3a is H, -C1~6 alkyl, -C 1~4 haloalkyl, or -C 3~6 is cycloalkyl, and R 3b is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 1~4 alkylene-O-C 1~4 alkyl. In some embodiments, R 3a is -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 3~6 is cycloalkyl, and R 3b is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 1~4 alkylene-O-C 1~4 alkyl. In some embodiments, R 3a is -C 1~6 alkyl or -C 1~4 haloalkyl, and R 3b is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 1~4 alkylene-O-C 1~4 alkyl. In some embodiments, R 3a is -C 1~6 alkyl, and R 3b is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 1~4 alkylene-O-C 1~4 alkyl. In some embodiments, R 3a is methyl or ethyl, and R 3b is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 1~4 alkylene-O-C 1~4 alkyl. In some embodiments, R 3a is methyl, and R 3b is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 1~4 alkylene-O-C 1~4It is alkyl.

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

[0071] In some embodiments of the compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, R 3 is OR 3a and R 3a is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 3~6 cycloalkyl, and R 3b is H or -C 1~6 alkyl. In some embodiments, R 3a is -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 3~6 cycloalkyl, and R 3b is H or -C 1~6 alkyl. In some embodiments, R 3a is -C 1~6 alkyl or -C 1~4 haloalkyl, and R 3b is H or -C 1~6 alkyl. In some embodiments, R 3a is -C 1~6 alkyl, and R 3b is H or -C 1~6 alkyl. In some embodiments, R 3a is methyl or ethyl, and R 3b is H or -C 1~6 alkyl. In some embodiments, R 3a is methyl, and R 3b is H or -C 1~6 alkyl.

[0072] In some embodiments of the compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, R 3 is OR 3a and R 3a is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 3~6 cycloalkyl, and R 3b is H or -C 1~3 alkyl. In some embodiments, R3a is -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 3~6 cycloalkyl, and R 3b is H or -C 1~3 alkyl. In some embodiments, R 3a is -C 1~6 alkyl or -C 1~4 haloalkyl, and R 3b is H or -C 1~3 alkyl. In some embodiments, R 3a is -C 1~6 alkyl, and R 3b is H or -C 1~3 alkyl. In some embodiments, R 3a is methyl or ethyl, and R 3b is H or -C 1~6 alkyl. In some embodiments, R 3a is methyl, and R 3b is H or -C 1~3 alkyl.

[0073] In some embodiments of the compound of formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3 is OR 3a and R 3a is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 3~6 cycloalkyl, and R 3b is H or methyl. In some embodiments, R 3a is -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 3~6 cycloalkyl, and R 3b is H or methyl. In some embodiments, R 3a is -C 1~6 alkyl or -C 1~4 haloalkyl, and R 3b is H or methyl. In some embodiments, R 3a is -C 1~6is alkyl, and R 3b is H or methyl. In some embodiments, R 3a is methyl or ethyl, and R 3b is H or methyl. In some embodiments, R 3a is methyl, and R 3b is H or methyl.

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

[0075] In some embodiments of the compound of formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3a as well as R 2 , R 5a and R 6aOne of them, together with the carbon to which they are attached, forms a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 1~4 alkylene-O-C 1~4 alkyl. In some embodiments, R 3a as well as R 2 , R 5a and R 6a One of them, together with the carbon to which they are attached, forms a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H, -C 1~6 alkyl or -C 1~4 haloalkyl. In some embodiments, R 3a as well as R 2 , R 5a and R 6a One of them, together with the carbon to which they are attached, forms a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H or -C 1~6 alkyl. In some embodiments, R 3a as well as R 2 , R 5a and R 6a One of them, together with the carbon to which they are attached, forms a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H or -C 1~3 alkyl. In some embodiments, R 3a as well as R 2 , R 5a and R 6a One of them, together with the carbon to which they are attached, forms a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H or methyl. In some embodiments, R 3a as well as R2 , R 5a and R 6a Any one of them, together with the carbon to which they are attached, forms a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H.

[0076] In some embodiments of the compound of formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3a as well as R 2 , R 5a and R 6a Any one of them, together with the carbon to which they are attached, forms a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 1~4 alkylene - O - C 1~4 alkyl. In some embodiments, R 3a as well as R 2 , R 5a and R 6a Any one of them, together with the carbon to which they are attached, forms a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H, -C 1~6 alkyl or -C 1~4 haloalkyl. In some embodiments, R 3a as well as R 2 , R 5a and R 6a Any one of them, together with the carbon to which they are attached, forms a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H or -C 1~6 alkyl. In some embodiments, R 3a as well as R 2 , R 5a and R 6a Any one of them, together with the carbon to which they are attached, forms a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H or -C 1~3 alkyl. In some embodiments, R3a and R 2 , R 5a and R 6a Any one of them, together with the carbon to which they are attached, forms a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H or methyl. In some embodiments, R 3a and R 2 , R 5a and R 6a Any one of them, together with the carbon to which they are attached, forms a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H.

[0077] In some embodiments of the compound of formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, R 3a and R 2 together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 1~4 alkylene - O - C 1~4 alkyl. In some embodiments, R 3a and R 2 together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H, -C 1~6 alkyl, or -C 1~4 haloalkyl. In some embodiments, R 3a and R 2 together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H or -C 1~6 alkyl. In some embodiments, R 3a and R 2together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H or -C 1~3 alkyl. In some embodiments, R 3a and R 2 together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H or methyl. In some embodiments, R 3a and R 2 together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H.

[0078] In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, R 3a and R 2 together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 1~4 alkylene -O -C 1~4 alkyl. In some embodiments, R 3a and R 2 together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H, -C 1~6 alkyl, or -C 1~4 haloalkyl. In some embodiments, R 3a and R 2 together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H or -C 1~6 alkyl. In some embodiments, R 3a and R 2together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H or -C 1~3 alkyl. In some embodiments, R 3a and R 2 together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H or methyl. In some embodiments, R 3a and R 2 together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H.

[0079] In some embodiments of the compounds of formula I, Ia, Ib, Ic, Id, or II, R 3a and R 5a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 1~4 alkylene - O - C 1~4 alkyl. In some embodiments, R 3a and R 5a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H, -C 1~6 alkyl, or -C 1~4 haloalkyl. In some embodiments, R 3a and R 5a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H or -C 1~6 alkyl. In some embodiments, R 3a and R 5atogether with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H or -C 1~3 alkyl. In some embodiments, R 3a and R 5a together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H methyl. In some embodiments, R 3a and R 5a together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H.

[0080] In some embodiments of the compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, R 3a and R 5a together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 1~4 alkylene -O -C 1~4 alkyl. In some embodiments, R 3a and R 5a together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H, -C 1~6 alkyl, or -C 1~4 haloalkyl. In some embodiments, R 3a and R 5a together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H or -C 1~6 alkyl. In some embodiments, R 3a and R 5atogether with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H or -C 1~3 alkyl. In some embodiments, R 3a and R 5a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H or methyl. In some embodiments, R 3a and R 5a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H.

[0081] In some embodiments of the compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, R 3a and R 6a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 1~4 alkylene -O -C 1~4 alkyl. In some embodiments, R 3a and R 6a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H, -C 1~6 alkyl, or -C 1~4 haloalkyl. In some embodiments, R 3a and R 6a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H or -C 1~6 alkyl. In some embodiments, R 3a and R 6atogether with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H or -C 1~3 alkyl. In some embodiments, R 3a and R 6a together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H or methyl. In some embodiments, R 3a and R 6a together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms independently selected from N, O, and S, and R 3b is H.

[0082] In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, R 3a and R 6a together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 1~4 alkylene-O-C 1~4 alkyl. In some embodiments, R 3a and R 6a together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H, -C 1~6 alkyl, or -C 1~4 haloalkyl. In some embodiments, R 3a and R 6a together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H or -C 1~6 alkyl. In some embodiments, R 3a and R 6atogether with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H or -C 1~3 alkyl. In some embodiments, R 3a and R 6a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H or methyl. In some embodiments, R 3a and R 6a together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one oxygen atom, and R 3b is H.

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

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

[0085] In some embodiments of the compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, R 4a is -C 1~6 alkyl or -C 1~4 haloalkyl, and R 4b is H, halo, -C 1~6 alkyl, or -C 1~4 haloalkyl. In some embodiments, R 4a is -C 1~6 alkyl or -C 1~4 haloalkyl, and R 4b is H or C 1~3 alkyl. In some embodiments, R 4a is -C 1~6 alkyl or -C 1~4 haloalkyl, and R 4b is -C 1~3 alkyl or -C 1~4 haloalkyl. In some embodiments, R 4a is -C 1~6 alkyl or -C 1~4 haloalkyl, and R 4b is -C 1~3 alkyl. In some embodiments, R 4a is -C 1~6 alkyl or -C 1~4 haloalkyl, and R 4b is -C 1~4 haloalkyl. In some embodiments, R 4a is -C 1~6 alkyl or -C 1~4 haloalkyl, and R 4b is H.

[0086] In some embodiments of the compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, R4a is -C 1~3 alkyl, and R 4b is H, halo, -C 1~6 alkyl, or -C 1~4 haloalkyl. In some embodiments, R 4a is -C 1~3 alkyl, and R 4b is H, -C 1~3 alkyl, or -C 1~4 haloalkyl. In some embodiments, R 4a is -C 1~3 alkyl, and R 4b is H or C 1~3 alkyl. In some embodiments, R 4a is -C 1~3 alkyl, and R 4b is -C 1~3 alkyl or -C 1~4 haloalkyl. In some embodiments, R 4a is -C 1~3 alkyl, and R 4b is -C 1~3 alkyl. In some embodiments, R 4a is -C 1~3 alkyl, and R 4b is -C 1~4 haloalkyl. In some embodiments, R 4a is -C 1~3 alkyl, and R 4b is H.

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

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

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

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

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

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

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

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

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

[0096] In some embodiments of the compounds of Formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, W 2 is -CR 6a R 6b -, where R 6a is H, and R 6b is H, C 1~6 alkyl, C 1~4 haloalkyl, halo, hydroxyl, cyano, -O-C 1~4 alkyl, or C 1~4 alkylene-O-C 1~4 alkyl. In some embodiments, R 6a is H, and R 6b is H, C 1~6 alkyl, C 1~4 haloalkyl, halo, hydroxyl, cyano, or -O-C 1~4 alkyl. In some embodiments, R 6a is H, and R 6b is H, C 1~6 alkyl, C 1~4 haloalkyl, halo, hydroxyl or cyano. In some embodiments, R 6a is H, and R 6b is H, C 1~6 alkyl, C 1~4is haloalkyl, halo, or hydroxyl. In some embodiments, R 6a is H, and R 6b is H, C 1~6 alkyl, C 1~4 haloalkyl, or halo. In some embodiments, R 6a is H, and R 6b is H, C 1~6 alkyl, or C 1~4 haloalkyl. In some embodiments, R 6a is H, and R 6b is H or C 1~6 alkyl. In some embodiments, R 6a is H, and R 6b is H.

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

[0098] In some embodiments of the compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, W 2 is -CR 6a R 6b -, and R 6a and R 3a together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one heteroatom selected from N, O, and S, and R 6b is H, C 1~6 alkyl, C 1~4 haloalkyl, halo, hydroxyl, cyano, -O-C 1~4 alkyl, or C 1~4 alkylene-O-C 1~4 alkyl. In some embodiments, R 6a and R 3a together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one heteroatom selected from N, O, and S, and R 6b is H, C 1~6 alkyl, C 1~4 haloalkyl, halo. In some embodiments, R 6a and R 3a together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one heteroatom selected from N, O, and S, and R 6b is H.

[0099] In some embodiments of the compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, W 2 is -CR 7a =CR 7b -, and R 7a and R 7b are independently H, halo, C 1~4 haloalkyl, or C 1~6 alkyl, and R 7a and R7b together with the carbon to which they are attached form a C aryl optionally substituted with 1 to 4 R A2 where each R is independently halo, cyano, or C alkyl 5~10 In some embodiments, W is -CR =CR - where R and R A2 are independently H, halo, C haloalkyl, or C alkyl 1~4 In some embodiments, W is -CR =CR - where R and R 2 are independently H, halo, or C alkyl 7a In some embodiments, W is -CR =CR - where R and R 7b are independently H or C alkyl 7a In some embodiments, W is -CR =CR - where both R and R 7b are H 1~4 In some embodiments of the compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, W 1~6 is -CR =CR - where R and R 2 together with the carbon atom to which they are attached form a C aryl optionally substituted with 1 to 4 R 7a where each R is independently halo, cyano, or C alkyl 7b In some embodiments, R and R 7a are as defined above 7b In some embodiments, R and R 1~6 are as defined above 2 In some embodiments, R and R 7a are as defined above 7b In some embodiments, R and R 7a are as defined above 7b In some embodiments, R and R 1~6 are as defined above 2 In some embodiments, R and R 7a are as defined above 7b In some embodiments, R and R 7a are both H 7b In some embodiments of the compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, W

[0100] is -CR =CR - where R and R 2 together with the carbon atom to which they are attached form a C aryl optionally substituted with 1 to 4 R 7a where each R is independently halo, cyano, or C alkyl 7b In some embodiments, R and R 7a are as defined above 7b In some embodiments, R and R A2 are as defined above 5~10 In some embodiments, R and R A2 are as defined above 1~4 In some embodiments, R and R 7a are as defined above 7btogether with the carbon atom to which they are attached form a fused phenyl optionally substituted with 1 to 4 R A2 each R A4 independently is halo, cyano, or C 1~4 alkyl. In some embodiments, R 7a and R 7b together with the carbon atom to which they are attached form an unsubstituted fused phenyl.

[0101] In some embodiments of the compounds of formula I, Ia, Ib, Ic, or Id, or pharmaceutically acceptable salts thereof, R 1 is C 6~10 aryl, and C 6~10 aryl is optionally substituted with 1 to 4 R A1 each R A1 independently is halo, C 1~6 alkyl, C 1~4 haloalkyl, cyano, -O-C 1~4 alkyl, or C 1~4 alkyl-O-C 1~4 alkyl, R 2 is H, C 1~6 alkyl, or C 1~4 haloalkyl, R 3 is halo or -OR 3a wherein R 3a is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 3~6 cycloalkyl, R 3b is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 1~4 alkylene-O-C 1~4 alkyl, R 4a is -C 1~6 alkyl or -C 1~4 haloalkyl, R 4b is H, halo, -C 1~6 alkyl, or -C1~4 is a haloalkyl, W 1 is a bond or -CR 5a R 5b -, R 5a and R 5b are independently H, C 1~6 alkyl, C 1~4 haloalkyl, or halo, W 2 is -CR 6a R 6b - or -CR 7a =CR 7b -, R 6a and R 6b are independently H, C 1~6 alkyl, C 1~4 haloalkyl, halo, hydroxyl, cyano, -O-C 1~4 alkyl, or C 1~4 alkylene-O-C 1~4 alkyl, R 7a and R 7b are independently H, halo, C 1~4 haloalkyl, or C 1~6 alkyl.

[0102] In some embodiments of the compounds of formula I, Ia, Ib, Ic, or Id, or pharmaceutically acceptable salts thereof, R 1 is C 6~10 aryl, and C 6~10 aryl is optionally substituted with 1 to 4 R A1 s, and each R A1 is independently halo, C 1~6 alkyl, C 1~4 haloalkyl, cyano, -O-C 1~4 alkyl, or C 1~4 alkyl-O-C 1~4 alkyl, R 2 is H, C 1~6 alkyl, or C 1~4 haloalkyl, R 3 is -OR3a and R 3a is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 3~6 cycloalkyl, R 3b is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 1~4 alkylene - O - C 1~4 alkyl, R 4a is -C 1~6 alkyl or -C 1~4 haloalkyl, R 4b is H, halo, -C 1~6 alkyl, or -C 1~4 haloalkyl, W 1 is a bond or -CR 5a R 5b -, R 5a and R 5b are independently H, C 1~6 alkyl, C 1~4 haloalkyl, or halo, W 2 is -CR 6a R 6b - or -CR 7a =CR 7b -, R 6a and R 6b are independently H, C 1~6 alkyl, C 1~4 haloalkyl, halo, hydroxyl, cyano, -O - C 1~4 alkyl, or C 1~4 alkylene - O - C 1~4 alkyl, R 7a and R 7b are independently H, halo, C 1~4 haloalkyl, or C 1~6 alkyl.

[0103] In some embodiments of the compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, R 1 is phenyl substituted with two, three, or four R A1 each R A1 is independently halo, C 1~6 alkyl, C 1~4 haloalkyl, cyano, -O-C 1~4 alkyl, or C 1~4 alkyl-O-C 1~4 alkyl, R 2 is H, C 1~6 alkyl, or C 1~4 haloalkyl, R 3 is -OR 3a wherein R 3a is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 3~6 cycloalkyl, R 3b is H, -C 1~6 alkyl, -C 1~4 haloalkyl, or -C 1~4 alkylene-O-C 1~4 alkyl, R 4a is -C 1~6 alkyl or -C 1~4 haloalkyl, R 4b is H, halo, -C 1~6 alkyl, or -C 1~4 haloalkyl, W 1 is a bond or -CR 5a R 5b -, R 5a and R 5b are independently H, C 1~6 alkyl, C 1~4 haloalkyl, or halo, W 2 is -CR 6a R 6b - or -CR 7a =CR7b - and R 6a and R 6b are, independently, H, C 1~6 alkyl, C 1~4 haloalkyl, halo, hydroxyl, cyano, -O-C 1~4 alkyl, or C 1~4 alkylene-O-C 1~4 alkyl, and R 7a and R 7b are, independently, H, halo, C 1~4 haloalkyl, or C 1~6 alkyl.

[0104] In some embodiments, the compound of formula I, Ia, Ib, Ic, Id or II is

Chemical formula

[0105] In some embodiments, the compound of formula I, Ia, Ib, Ic, Id or II is

Chemical formula

Chemical formula

Chemical formula

[0106] In some embodiments, the compound of formula I, Ia, or II is

Chemical formula

[0107] In some embodiments, the compound of formula I, Ic, or II is

Chemical formula

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

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

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

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

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

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

[0114] In some embodiments, the compound of formula I is [Chem.] is as follows.

[0115] In some embodiments, the compound of formula I is [Chem.] is as follows.

[0116] In some embodiments, the compound of formula I is [Chem.] is as follows.

[0117] In some embodiments, the compound of formula I is [Chem.] is as follows.

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

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

[0120] In one aspect, provided herein is a pharmaceutical composition comprising a compound provided herein (e.g., a compound of formula I, Ia, Ib, Ic, Id, or II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable Add agent or carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable Add agent or carrier.

[0121] In some embodiments, the pharmaceutical compositions provided herein further comprise one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, or pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition further comprises a therapeutically effective amount of one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, or pharmaceutically acceptable salts thereof.

[0122] The pharmaceutical composition can be administered either as a single dose or multiple doses. The pharmaceutical composition can be administered by various methods including, for example, rectal, oral, intranasal, and transdermal routes. In some embodiments, the pharmaceutical composition can be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0123] One mode of administration is parenteral, for example, by injection. Forms in which the pharmaceutical composition described in the present disclosure can be incorporated for administration by injection include, for example, aqueous suspensions or oily suspensions, or emulsions having sesame oil, corn oil, cottonseed oil, or peanut oil, or elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0124] Oral administration can be another route for administration of the compounds provided herein. The administration can be, for example, by capsules or enteric-coated tablets. When manufacturing a pharmaceutical composition comprising at least one compound provided herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, the active ingredient (such as the compounds provided herein) is usually Add diluted by an agent and / or enclosed in a carrier which can be in the form of capsules, sachets, paper, or other containers. Add When the agent functions as a diluent, Add the agent can be in the form of a solid, semi-solid or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the pharmaceutical composition can be in the form of tablets, pills, powders, troches, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solvents, and sterile packaged powders.

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

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

[0127] To prepare solid compositions such as tablets, the principal active ingredient is mixed with a pharmaceutical AddIt can be mixed with an agent to form a solid preformulation composition containing a homogeneous mixture of the compounds described herein or their pharmaceutically acceptable salts, isomers, or mixtures. When these preformulation compositions are referred to as homogeneous, the active ingredient may be uniformly dispersed throughout the composition, such that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

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

[0129] Pharmaceutical compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable Add agents as described above. In some embodiments, the composition is administered by the oral or nasal respiratory route for local or systemic effects. In other embodiments, the composition in a pharmaceutically acceptable solvent may be nebulized by the use of an inert gas. The nebulized solution may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing simulator. The solution, suspension, or powder composition may be preferably administered orally or nasally from a device that delivers the formulation in an appropriate manner.

[0130] In one aspect, provided herein is a kit comprising a compound provided herein (e.g., a compound of formula I, Ia, Ib, Ic, Id, or II), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a suitable package. In some embodiments, the kit further comprises instructions for use. In some embodiments, the kit comprises a compound provided herein (e.g., a compound of formula I, Ia, Ib, Ic, Id, or II), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a label and / or instructions for use of the compound in the treatment of an indication comprising a disease or condition described herein.

[0131] In some embodiments, the kit further comprises one or more (e.g., one, two, three, four, one or two, one to three, or one to four) additional therapeutic agents, or a pharmaceutically acceptable salt thereof.

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

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

[0134] In some embodiments, the method further comprises administering to the human a therapeutically effective amount of one, two, three, or four additional therapeutic agents. In certain embodiments, the additional therapeutic agent is an anti-HIV agent. In specific embodiments, the additional therapeutic agent is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gpl20 inhibitor, a CCR5 inhibitor, a latent infection reactivator, a capsid polymerization inhibitor, an HIV bNAb (broadly neutralizing HIV antibody), a TLR7 agonist, a pharmacokinetic enhancer, another drug for treating HIV, or a combination thereof. In one embodiment, the additional therapeutic agent is abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-1-(3-(4-chloro-3-(methylsulfonamido)-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl)-6-(3-methyl-3-(methylsulfonyl)but-1-yn-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl)acetamide, or a pharmaceutically acceptable salt thereof.

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

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

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

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

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

[0140] In another embodiment, provided is a compound of formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I, Ia, Ib, Ic, Id, or II, or a pharmaceutically acceptable salt thereof, for use in a method of treating HIV infection in a human having or at risk of having the infection, the method further comprising administering to the human one, two, three, or four additional therapeutic agents selected from the group consisting of an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latent infection reactivator, a capsid polymerization inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, 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 latent infection reactivator, an HIV capsid inhibitor, an HIV bNAb, a TLR7 agonist, and combinations thereof.

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

[0142] In another embodiment, provided are compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, for use in a method of treating HIV infection in a human having or at risk of having the infection, the method further comprising administering to the human a therapeutically effective amount of tenofovir alafenamide and emtricitabine.

[0143] In another embodiment, provided are compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, for use in a method of treating HIV infection in a human having or at risk of having the infection, the method further comprising administering to the human a therapeutically effective amount of tenofovir disoproxil.

[0144] In another embodiment, provided are compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, or pharmaceutical compositions of compounds of formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof, for use in a method of treating HIV infection in a human having or at risk of having the infection, the method further comprising administering to the human a therapeutically effective amount of tenofovir alafenamide.

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

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

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

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

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

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

[0151] In another embodiment, an article of manufacture comprising a composition effective for treating HIV infection, and a packaging material including a label indicating that the composition can be used for treating an infection caused by HIV are disclosed. Exemplary compositions include compounds of Formula I, Ia, Ib, Ic, Id, or II, or pharmaceutically acceptable salts thereof.

[0152] 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, Ia, Ib, Ic, Id or II, or a salt thereof, under conditions in which HIV replication is inhibited.

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

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

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

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

[0157] The specific dosage level of the compounds of the present disclosure for any particular subject will depend on a variety of factors including the activity of the specific compound being used, age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combinations, and the severity of the particular disease being treated in the subject. For example, the dosage may be expressed as the number of milligrams of the compound described herein per kilogram of body weight of the subject (mg / kg). Dosages of about 0.1 to 150 mg / kg may be appropriate. In some embodiments, dosages of about 0.1 and 100 mg / kg may be appropriate. In other embodiments, dosages of 0.5 to 60 mg / kg may be appropriate. Normalizing by the body weight of the subject is particularly useful when adjusting dosages between subjects of widely different sizes, such as when using a drug in both pediatric and adult humans or when converting an effective dosage in a non-human subject such as a dog to a dosage suitable for a human subject.

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

[0159] The dosage or dosing frequency of the compounds of the present disclosure can be adjusted over the course of treatment based on the judgment of the prescribing physician.

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

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

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

[0163] In some embodiments, the method includes administering to a subject an initial daily dose of from about 1 to 500 mg of the compound p herein and increasing the dose in increments until clinical efficacy is achieved. Increments of about 5, 10, 25, 50, or 100 mg can be used to increase the dose. The dose can be increased daily, once a day, twice a week, once a week, once every two weeks, once every three weeks, or once a month.

[0164] When administered orally, the total daily dosage for a human subject may be about 1 mg to 1,000 mg, about 10 to 500 mg / day, about 50 to 300 mg / day, about 75 to 200 mg / day, or about 100 to 150 mg / day. In some embodiments, the total daily dosage for a human subject may be about 100, 200, 300, 400, 500, 600, 700, 800, 900, or 1,000 mg / day administered as a single dose. In some embodiments, the total daily dosage for a human subject may be about 200, 300, 400, 500, 600, 700, or 800 mg / day administered as a single dose. In some embodiments, the total daily dosage for a human subject may be about 300, 400, 500, or 600 mg / day administered as a single dose.

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

[0166] The single dose can be administered hourly, daily, weekly, or monthly. For example, the single dose can be administered once every 1, 2, 3, 4, 6, 8, 12, 16 hours, or once every 24 hours. The single dose can also be administered once every 1, 2, 3, 4, 5, 6 days, or once every 7 days. The single dose can also be administered once every 1, 2, 3 weeks, or once every 4 weeks. In some embodiments, the single dose can be administered once a week. The single dose can also be administered once a month. In some embodiments, the compounds disclosed herein are administered once a day by the methods disclosed herein. In some embodiments, the compounds disclosed herein are administered twice a day by the methods disclosed herein.

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

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

[0169] The compounds or pharmaceutical compositions thereof of the present disclosure may be administered once, twice, three times, or four times a day using any of the above suitable modes. Also, the administration or treatment with the compound may be continued for several days. For example, usually, the treatment will continue for at least 7 days, 14 days, or 28 days for one treatment cycle. Treatment cycles are well known in cancer chemotherapy and frequently alternate with a rest period of about 1 to 28 days, generally about 7 days or about 14 days, between cycles. The treatment cycles may also be continuous in other embodiments. VI. Combination Therapy

[0170] In certain embodiments, there is provided a method for treating or preventing HIV infection in a human having or at risk of having the infection, the method comprising administering to the human a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with a therapeutically effective amount of one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. In one embodiment, there is provided a method for treating HIV infection in a human having or at risk of having the 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 or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

[0171] In one embodiment, a compound disclosed herein, or a pharmaceutically acceptable salt thereof, is combined with one or more (e.g., 1, 2, 3, 1 or 2, or 1 to 3) additional therapeutic agents and a pharmaceutically acceptable carrier, diluent, or Add agent to provide a pharmaceutical composition.

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

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

[0174] In certain embodiments, the compound disclosed herein is administered with one or more additional therapeutic agents. Co - administration of the compound disclosed herein and one or more additional therapeutic agents generally refers to simultaneously or sequentially administering the compound disclosed herein and the one or more additional therapeutic agents such that a therapeutically effective amount of both the compound disclosed herein and the one or more additional therapeutic agents are present in the patient's body. When administered sequentially, the combination may be administered in more than one dose.

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

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

[0177] In certain embodiments, a compound of formula I, Ia, Ib, Ic, Id, or II is formulated as a tablet optionally containing one or more other compounds useful for the treatment of HIV. In one embodiment, the tablet can contain other active ingredients for the treatment of HIV, such as an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitor, an HIV nucleoside or nucleotide reverse transcriptase inhibitor, an HIV integrase inhibitor, an HIV non-catalytic site (or allosteric) integrase inhibitor, a pharmacokinetic enhancer, and combinations thereof.

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

[0179] In the above embodiment, the additional therapeutic agent may be an anti-HIV agent. HIV protease inhibitor, non-nucleoside or non-nucleotide inhibitor of reverse transcriptase, nucleoside or nucleotide inhibitor of reverse transcriptase, HIV integrase inhibitor, HIV non-catalytic site (or allosteric) integrase inhibitor, HIV entry inhibitor, HIV maturation inhibitor, immunomodulator, immunotherapy agent, antibody-drug conjugate, gene modifier, gene editing agent (CRISPR / Cas9, zinc finger nuclease, homing nuclease, synthetic nuclease, TALEN, etc.), cell therapy agent (chimeric antigen receptor T cell, CAR-T, and engineered T cell receptor, TCR-T, autologous T cell therapy agent, etc.), latent infection reactivator, compound targeting HIV capsid, immune system therapy agent, phosphatidylinositol 3-kinase (PI3K) inhibitor, HIV antibody, bispecific antibody and "antibody-like" therapeutic protein, HIV p17 matrix protein inhibitor, IL-13 antagonist, peptidyl-prolyl cis-trans isomerase A modulator, protein disulfide isomerase inhibitor, complement C5a receptor antagonist, DNA methyltransferase inhibitor, HIV vif gene modulator, Vif dimerization antagonist, HIV-1 viral infectivity factor inhibitor, TAT protein inhibitor, HIV-1 Nef modulator, Hck tyrosine kinase modulator, mixed lineage kinase-3 (MLK-3) inhibitor, HIV-1 splicing inhibitor, Rev protein inhibitor, integrin antagonist, nucleoprotein inhibitor, splicing factor modulator, COMM domain-containing protein 1 modulator, CD4 modulator, CD4 antagonist, HIV ribonuclease H inhibitor, retrocyclin modulator, CDK-9 inhibitor, CCR5 chemokine antagonist, CCR5 gene modulator, dendritic ICAM-3-grabbing non-integrin 1 inhibitor, HIV GAG protein inhibitor, HIVPOL protein inhibitor, hyaluronidase inhibitor, Nef antagonist, Nef inhibitor, protease-activated receptor-1 antagonist, TNFα ligand inhibitor, PDE4 inhibitor, complement factor H modulator, ubiquitin ligase inhibitor, deoxycytidine kinase inhibitor, cyclin-dependent kinase inhibitor, proprotein convertase PC9 stimulator, ATP-dependent RNA helicase DDX3X inhibitor, reverse transcriptase priming complex inhibitor, G6PD and NADH-oxidase inhibitor, pharmacokinetic enhancer, HIV gene therapy agent, HIV vaccine, and combinations thereof.

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

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

[0182] Examples of other drugs for treating HIV include acemannan, alisporivir, astodrimer, BanLec, CC-11050, deferiprone, Gamimune, griffithsin, metenkephalin, naltrexone, Prolastin, REP9, RPI-MN, Vorapaxar, VSSP, H1viral, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy agent, MK-8527, BlockAide, PSC-RANTES, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-2048, MK-4250, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo, and VIR-576. HIV protease inhibitor

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

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

[0186] Examples of HIV integrase inhibitors include elvitegravir, curcumin, curcumin derivatives, cholic acid, cholic acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurintricarboxylic acid, aurintricarboxylic acid derivatives, caffeic acid phenethyl ester, caffeic acid phenethyl ester derivatives, tilorone, tilorone derivatives, quercetin, quercetin derivatives, raltegravir, dolutegravir, JTK-351, bictegravir, AVX-15567, BMS-986197, cabotegravir (long-acting injection), diketoquinoline 4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbenedisulfonic acid, T-169, VM-3500, and cabotegravir.

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

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

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

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

[0191] Examples of CD4 binding inhibitors include ibalizumab and 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, BMS-986197, GSK-3640254, and GSK-2838232. Latent infection reactivator

[0195] Examples of latent infection reactivators include histone deacetylase (HDAC) inhibitors, proteasome inhibitors such as bortezomib and ixazomib citrate, protein kinase C (PKC) theta, Smyd2 inhibitors, BET-bromodomain 4 (BRD4) inhibitors, ionomycin, PMA, SAHA (suberanilohydroxamic acid, or suberoyl, anilide, and hydroxamic acid), IL-15 modulating antibody, JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors such as larazotide analogs, APH-0812, and GSK-343.

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

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

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

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

[0200] Examples of TLR agonists: besatolimod (GS-9620), GS-986, IR-103, refitrimod, tilsotrimod, lintrimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motrimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, tellurtrimod, RO-7020531. Phosphatidylinositol 3-kinase (PI3K) 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. α-4 / β-7 antagonist

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

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

[0204] Examples of agents that target HIV in such a manner include bavituximab, UB-421, C2F5, 2G12, C4E10, C2F5 + C2G12 + C4E10, 8ANC195, 3BNC117, 3BNC117-LS, 3BNC60, D1D2, 10-1074, 10-1074-LS, GS-9722, DH411-2, BG18, PGT145, PGT121, PGT122, PGT-151, PGT-133, PGT-135, PGT-128, MDX010 (ipilimumab), DH511, DH511-2, N6, N6LS, N49P6, N49P7, N49P7.1, N49P9, N49P11, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH45-46, PG9, PG16, 8ANC195, 2Dm2m, 4Dm2m, 6Dm2m, VRC-01, VRC-01-LS, PGDM1400, A32, 7B2, 10E8, 10E8VLS, 3810109, 10E8v4, 10E8.4 / iMab, VRC-01 / PGDM-1400 / 10E8v4, IMC-HIV, iMabm36, 10E8v4 / PGT121-VRC01, eCD4-Ig, IOMA, CAP256-VRC26.25, DRVIA7, SAR-441236, VRC-07-523, VRC07-523LS, VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, and VRC07. Examples of HIV bispecific antibodies include MGD014, TMB-bispecific.

[0205] Examples of in vivo delivered bnAbs such as AAV8-VRC07; mRNA encoding the anti-HIV antibody VRC01. Pharmacokinetic enhancer

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

[0207] Examples of additional therapeutic agents include compounds disclosed in WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO 2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO 2014 / 100323 (Gilead Sciences), US 2013 / 0165489 (University of Pennsylvania), US 2014 / 0221378 (Japan Tobacco), US 2014 / 0221380 (Japan Tobacco), WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), US 2014 / 0221356 (Gilead Sciences), US 2010 / 0143301 (Gilead Sciences), and WO 2013 / 091096 (Boehringer Ingelheim). HIV vaccine

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

[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; prostratin; fosamprenavir; fosamprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate;Interferon; Zidanosine; Stavudine; Indinavir; Indinavir Sulfate; Tenofovir and Lamivudine; Didobuzine; Nevirapine; Saquinavir; Saquinavir Mesylate; Aldesleukin; Zalcitabine; Tipranavir; Amprenavir; Delavirdine; Delavirdine Mesylate; Radha-108 (Receptol); Lamivudine and Tenofovir Disoproxil Fumarate; Efavirenz, Lamivudine, and Tenofovir Disoproxil Fumarate; Phosphazide; Lamivudine, Nevirapine, and Didobuzine; Abacavir, and Abacavir Sulfate, is combined with one, two, three, four, or more additional therapeutic agents selected from the group consisting of:;

[0210] It will be understood by those skilled in the art that the additional therapeutic agents listed above may be included in two or more of the classes listed above. The particular classes are not intended to limit the functionality of these compounds listed in those classes.;

[0211] 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 non-nucleoside reverse transcriptase inhibitor. In another particular 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 one embodiment, 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.;

[0212] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with abacavir sulfate, tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir disoproxil hemifumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

[0213] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with tenofovir, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir alafenamide, or tenofovir alafenamide hemifumarate.

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

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

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

[0217] In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 5 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 5 to 10, 5 to 15, 5 to 20, 5 to 25, 25 to 30, 20 to 30, 15 to 30, or 10 to 30 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 10 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. In certain embodiments, the compounds disclosed herein, or pharmaceutically acceptable salts thereof, are combined with 25 mg of tenofovir alafenamide fumarate, tenofovir alafenamide hemifumarate, or tenofovir alafenamide, and 200 mg of emtricitabine. The compounds disclosed herein (e.g., compounds of Formula I) may be combined with any dosage of the compound (e.g., 1 mg to 500 mg of the compound) as well, in the same manner as when each combination of dosages of the agents provided herein is specifically and individually recited.

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

[0219] In one embodiment, a kit is provided that comprises the compounds disclosed herein, or pharmaceutically acceptable salts thereof, in combination with one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents. Combined therapy for fertility regulation (contraception)

[0220] Therapeutic agents used for fertility regulation (contraception) include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinyl estradiol, ethinodiol, etonogestrel, levonorgestrel, norethisterone, lynestrenol, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, noregestromin, norethindrone, nortestosterone, norgestimate, ormeloxifene, segesterone acetate, ulipristal acetate, and any combination thereof. Gene therapy and cell therapy

[0221] Gene therapy and cell therapy include gene modification for gene silencing; genetic approaches for directly killing infected cells; replacing most of the patient's own immune system or activating the patient's own immune system to kill infected cells or injecting immune cells designed to find and kill infected cells to enhance the immune response against infected cells; genetic approaches for modifying cell activity to further alter the endogenous immune responsiveness to infection.

[0222] Examples of dendritic cell therapy include AGS-004.

[0223] Examples of CCR5 gene editing agents, for example, SB-728T.

[0224] Examples of CCR5 gene inhibitors, for example, Cal-1.

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

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

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

[0228] The genome editing system is selected from the group consisting of the CRISPR / Cas9 system, the zinc finger nuclease system, the TALEN system, the homing endonuclease system, and the meganuclease system.

[0229] Examples of the HIV-targeted CRISPR / Cas9 system include EBT-101. CAR-T cell therapy

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

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

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

Examples

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

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

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

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

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

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

Chemical Structure

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

Chemical formula

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

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

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

[0243] To a solution of (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (10 mg, 0.018 mmol) in ethanol (1 mL) was added palladium carbon (10 mg). The reaction mixture was stirred under an H 2 balloon for 30 minutes. The reaction mixture was filtered through celite. The filtrate was concentrated and the residue was purified by reverse-phase HPLC chromatography (eluting with 5 - 100% acetonitrile / water containing 0.1% TFA) to afford the title product. MS (m / z) 452.3 [M + H] + . 1 1H NMR (400 MHz, methanol-d4) δ 8.40 (s, 1H), 6.98 - 6.86 (m, 2H), 4.68 (s, 2H), 4.67 - 4.60 (m, 1H), 4.56 (s, 1H), 4.02 - 3.90 (m, 1H), 3.75 (s, 2H), 2.07 (dt, J = 14.5, 7.1 Hz, 1H), 1.81 (ddd, J = 14.8, 7.6, 3.8 Hz, 1H), 1.59 (dt, J = 15.0, 11.3 Hz, 1H), 1.28 (d, J = 6.7 Hz, 3H), 1.19 (dt, J = 14.8, 11.7 Hz, 1H). Example 3: (3S,6S,7R)-N-(2,4-Difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide

Chem.

[0244] (3S,7R)-12-(Benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (Intermediate A) was replaced with (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (Intermediate B), and in the same manner as in Example 1, (3S,6S,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide was produced. MS (m / z) 448.2 [M+H] + 。 1 H NMR (400 MHz, methanol-d4) δ 8.37 (s, 1H), 7.45 (q, J = 7.8 Hz, 1H), 7.09 - 6.88 (m, 2H), 4.65 (s, 4H), 3.75 (s, 2H), 3.56 (d, J = 11.1 Hz, 1H), 3.46 (s, 3H), 2.18 - 1.98 (m, 2H), 1.54 (dd, J = 25.7, 11.4 Hz, 1H), 1.29 (d, J = 6.6 Hz, 3H), 1.01 (q, J = 12.1 Hz, 1H). Example 4: (3S,6R,7R)-12-Hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide [Chemical formula] Preparation of (3S,6R,7R)-12-(benzyloxy)-3-methyl-1,11-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-6-yl benzoate:

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

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

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

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

Chemical formula

[0249] To a solution of (3S,6R,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide (10 mg, 0.018 mmol) in ethanol (1 mL), palladium carbon (10 mg) was added. The reaction was carried out under H 2It was stirred for 30 minutes under a balloon. The reaction mixture was filtered through celite. The filtrate was concentrated, and the residue was purified by reverse-phase HPLC chromatography (eluted with 5-100% acetonitrile / water containing 0.1% TFA) to obtain the title product. MS (m / z) 452.2 [M+H] + 。 1 1H NMR (400 MHz, methanol-d4) δ 8.46 (s, 1H), 6.99 - 6.85 (m, 2H), 4.68 (s, 2H), 4.58 (dt, J = 10.7, 6.5 Hz, 1H), 4.40 (s, 1H), 4.04 (d, J = 3.9 Hz, 1H), 3.81 (d, J = 14.8 Hz, 1H), 3.69 (d, J = 14.7 Hz, 1H), 2.01 (dd, J = 14.5, 11.3 Hz, 1H), 1.95 - 1.79 (m, 2H), 1.38 - 1.30 (m, 1H), 1.29 (d, J = 6.6 Hz, 3H). Example 6: (3S,6R,7R)-12-Hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide

Chemical formula

[0250] To a solution of (3S,6R,7R)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (Example 4) (18 mg, 0.039 mmol) in EtOH (2 mL), Pd(OH) 2 / C (10 mg) was added. H 2 A balloon was attached, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through celite, the filtrate was concentrated, and the residue was purified by reverse-phase chromatography (eluted with 5-100% acetonitrile / water containing 0.1% TFA) to obtain the title product. MS (m / z) 466.2 [M+H] + 。 11H NMR (400 MHz, methanol-d4) δ 8.37 (s, 1H), 7.45 (q, J = 7.8 Hz, 1H), 7.09 - 6.88 (m, 2H), 4.65 (s, 4H), 3.75 (s, 2H), 3.56 (d, J = 11.1 Hz, 1H), 3.46 (s, 3H), 2.18 - 1.98 (m, 2H), 1.54 (dd, J = 25.7, 11.4 Hz, 1H), 1.29 (d, J = 6.6 Hz, 3H), 1.01 (q, J = 12.1 Hz, 1H). 1H NMR (400 MHz, methanol-d4) δ 8.51 (s, 1H), 6.98 - 6.85 (m, 2H), 4.68 (s, 2H), 4.66 - 4.50 (m, 2H), 3.75 (d, J = 14.9 Hz, 1H), 3.72 - 3.60 (m, 2H), 3.48 (s, 3H), 2.09 (dt, J = 15.0, 4.6 Hz, 1H), 1.86 (td, J = 9.6, 2.7 Hz, 2H), 1.28 (d, J = 6.7 Hz, 3H), 1.24 - 1.15 (m, 1H). Example 7: (3S,6R,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide [Chemical formula]

[0251] Instead of (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide, (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (see Example 3) was used, and (3S,6R,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide was prepared in a similar manner to the preparation of (3S,6R,7R)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (Example 4). MS (m / z) 446.2 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.47 (s, 1H), 7.45 (td, J = 8.4, 6.3 Hz, 1H), 7.03 - 6.90 (m, 2H), 5.77 (dt, J = 11.8, 2.8 Hz, 1H), 5.56 (ddd, J = 11.8, 2.7, 1.7 Hz, 1H), 5.34 (dq, J = 7.4, 2.8 Hz, 1H), 4.67 - 4.56 (m, 3H), 4.29 (dq, J = 5.6, 2.9 Hz, 1H), 4.11 (dd, J = 14.4, 3.0 Hz, 1H), 3.65 (d, J = 14.2 Hz, 1H), 3.34 (s, 3H), 1.39 (d, J = 7.3 Hz, 3H). Example 8: (3S,6R,7R)-6,12-Dihydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide [Chemistry]

[0252] To a solution of (3S,6R,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide (Example 7) (20 mg, 0.045 mmol) in EtOH (2 mL) was added Pd(OH) 2 / C (7 mg). H 2 A balloon was attached and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was filtered through celite, the filtrate was concentrated, and the residue was purified by reverse-phase chromatography (eluting with 5 - 100% acetonitrile / water containing 0.1% TFA) to give the title product. MS (m / z) 448.3 [M+H] + . 1 H NMR (400 MHz, methanol-d4) δ 8.53 (s, 1H), 7.50 - 7.40 (m, 1H), 6.97 (dddd, J = 12.6, 11.1, 8.9, 2.6 Hz, 2H), 4.65 (s, 2H), 4.62 - 4.52 (m, 2H), 3.80 - 3.59 (m, 3H), 3.48 (s, 3H), 2.10 (dt, J = 15.1, 4.6 Hz, 1H), 1.85 (tt, J = 9.4, 5.2 Hz, 2H), 1.36 - 1.16 (m, 4H). Example 9: (3S,6S,7R)-N-(3-chloro-2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide [Chemistry] Preparation of ethyl (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxylate:

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

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

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

[0256] A reaction mixture of (3S,7S)-12-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocine-10-carboxamide (0.48 g, 0.89 mmol) and selenium dioxide (0.986 g, 8.9 mmol) in dioxane was stirred at 100 °C overnight. The reaction mixture was cooled and filtered to remove the solid. The filtrate was diluted with EtOAc and washed with saturated NaHCO3. The organic phase was dried over MgSO 4 , filtered, concentrated, and purified by silica gel chromatography eluting with 0 - 100% hexane / EtOAc to afford the title compound. (3S,6S,7R)-N-(3-chloro-2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide Preparation:

[0257] (3S,6S,7R)-N-(3-chloro-2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide was prepared in the same manner as in the production of Example 1, except that (3S,7R)-12-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide was used instead of (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (Intermediate A). MS (m / z) 482.4 [M+H] + 。 1 H NMR (400 MHz, methanol-d4) δ 8.35 (s, 1H), 7.40 (td, J = 8.4, 6.0 Hz, 1H), 7.11 (td, J = 8.7, 1.9 Hz, 1H), 4.74 (s, 1H), 4.71 - 4.57 (m, 3H), 3.83 - 3.67 (m, 2H), 3.61 - 3.50 (m, 1H), 3.46 (s, 3H), 2.18 - 1.98 (m, 3H), 1.54 (dt, J = 14.4, 11.2 Hz, 1H), 1.28 (d, J = 6.7 Hz, 3H), 1.01 (dt, J = 14.9, 11.7 Hz, 1H). Example 10: (3S,6R,7R)-N-(3-chloro-2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide [Chemical formula]

[0258] (3S,6S,7R)-12-(Benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide was replaced with (3S,6S,7R)-12-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-6-hydroxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide, and (3S,6R,7R)-N-(3-chloro-2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide was prepared in the same manner as in the production of Example 4, except for the above replacement. MS (m / z) 480.2 [M+H] + . 1 H NMR (400 MHz, acetonitrile-d3) δ 10.38 (s, 1H), 8.35 (s, 1H), 7.39 (q, J = 8.1 Hz, 1H), 7.18 - 7.04 (m, 1H), 5.72 (dq, J = 8.7, 2.8 Hz, 1H), 5.63 - 5.48 (m, 1H), 5.30 (s, 1H), 4.73 - 4.60 (m, 3H), 4.46 (s, 1H), 4.27 (s, 1H), 4.01 (dd, J = 14.4, 2.9 Hz, 1H), 3.58 (d, J = 14.4 Hz, 1H), 3.29 (d, J = 4.3 Hz, 3H), 1.34 (d, J = 7.3 Hz, 3H). Example 11. (3S,6S,7R)-12-(Benzyloxy)-6-hydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide

Chem.

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

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

[0261] In Project 1, this compound was prepared by following the same procedure as the synthesis of Example 11, except that (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide was used instead of (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide. The stereochemistry was not confirmed. LCMS-ESI+(m / z): Calculated H+ value for C22H23F2N3O5, theoretical value: 447.16, measured value: 448.22. 1 H NMR(400MHz,DMSO-d6)δ 10.98(s,1H),10.46(t,J=6.0Hz,1H),8.34(s,1H),7.40(td,J=8.7,6.7Hz,1H),7.25(ddd,J=10.6,9.3,2.6Hz,1H),7.12-7.03(m,1H),5.03-4.83(m,1H),4.56(d,J=5.9Hz,2H),4.47(dt,J=12.2,6.5Hz,1H),4.28(s,1H),3.67(d,J=3.2Hz,2H),1.87(dt,J=14.3,7.1Hz,1H),1.42(dd,J=14.4,7.7Hz,2H),1.35(s,3H),1.25-1.12(m,4H). Example 13: Preparation of (3S,6R,7R)-6-chloro-N-(2,4-difluorobenzyl)-12-hydroxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide [Chemical formula] (3S,6R,7R)-12-(Benzyloxy)-6-chloro-N-(2,4-difluorobenzyl)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide Preparation:

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

[0263] A solution of (3S,6R,7R)-12-(benzyloxy)-6-chloro-N-(2,4-difluorobenzyl)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (63 mg, 0.116 mmol) in toluene / TFA (1:1) (10 mL) was stirred at room temperature for 2.75 h. The reaction was quenched with saturated aqueous sodium bicarbonate until the pH was above 7. EtOAc was added and the layers were separated. The aqueous layer was washed with EtOAc. The combined organic layers were then washed with brine, dried over Na 2 SO 4 4, filtered, concentrated, and purified by reverse-phase HPLC chromatography (eluting with 5 - 100% acetonitrile in water containing 0.1% TFA) to afford the title product (34 mg, 65%). MS (m / z) 450.100 [M + H] + . 1H NMR (400 MHz, MeOD) δ 8.50 (s, 1H), 7.46 - 7.40 (m, 1H), 6.99 - 6.91 (m, 2H), 5.76 (dt, J = 11.9, 3.1 Hz, 1H), 5.55 (dt, J = 11.9, 2.3 Hz, 1H), 5.35 - 5.33 (m, 1H), 5.13 (s, 1H), 4.98 (s, 1H), 4.63 (s, 2H), 4.20 (d, J = 14.5 Hz, 1H), 3.73 (d, J = 14.5 Hz, 1H), 1.39 (d, J = 7.3 Hz, 3H). Example 14: (3S,6S,7R)-6,12-Dihydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide [Chemical formula]

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

Chemical Structure

[0265] (1R,10S)-6-Hydroxy-10-methyl-5,8,13-trioxo-N-[(2,4,6-trifluorophenyl)methyl]-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide (15 mg, 0.0335 mmol) was dissolved in THF (0.5 mL) and cooled to -78 °C. To this stirred cold mixture was added dropwise 3.0 M MeMgBr in diethyl ether (0.056 mL, 0.168 mmol). The resulting mixture was stirred at -78 °C for 5 minutes and then warmed to 0 °C for 5 minutes. The reaction was quenched with acetic acid, filtered, and purified by reverse-phase preparative HPLC. LCMS-ESI+(m / z): calculated for H+ of C22H20F3N3O5, theoretical value: 463.14, measured value: 464.02. 1H NMR (400 MHz, DMSO-d6) δ 10.46 (t, J = 5.8 Hz, 1H), 8.36 (s, 1H), 7.25 - 7.23 (m, 1H), 7.22 - 7.19 (m, 2H), 5.54 (dd, J = 11.9, 2.3 Hz, 1H), 5.39 (dd, J = 11.8, 2.6 Hz, 1H), 5.18 - 5.08 (m, 1H), 4.68 (s, 1H), 4.59 - 4.55 (m, 3H), 3.86 (dd, J = 14.7, 2.6 Hz, 1H), 3.63 (d, J = 14.2 Hz, 1H), 1.38 (s, 3H), 1.27 (d, J = 7.3 Hz, 3H). Example 16: (3S,6S,7R)-N-(2,4-Difluorobenzyl)-6,12-dihydroxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide [Chemical Structure] Synthesis of (3S,6S,7R)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide:

[0266] (3S,6S,7R)-12-(Benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (10 mg, 0.019 mmol) was dissolved in 3 mL of ethanol and 3 mL of ethyl acetate and sparged under an argon atmosphere. Palladium on carbon (10 wt%, wet) E101 NE / W (4.08 mg, 0.0038 mmol) was added. The mixture was sparged under a hydrogen atmosphere (1 atm, balloon), stirred vigorously for 2 h, and then sparged under an argon atmosphere. It was filtered through a pad of Celite®. The Celite® was washed with absolute ethanol and the filtrate was concentrated to dryness. The residue was purified by RP-HPLC to give the title compound. MS (m / z): 434.113 [M+H]+. 1 H NMR (400 MHz, methanol-d4) δ 8.43 (s, 1H), 7.56 - 7.31 (m, 1H), 7.03 - 6.91 (m, 2H), 4.70 - 4.55 (m, 4H), 3.95 (dt, J = 11.8, 4.4 Hz, 1H), 3.76 (d, J = 1.8 Hz, 2H), 2.14 - 2.01 (m, 1H), 1.82 (ddd, J = 14.7, 7.6, 3.8 Hz, 1H), 1.59 (dt, J = 15.0, 11.3 Hz, 1H), 1.28 (d, J = 6.7 Hz, 3H), 1.27 - 1.13 (m, 1H). Example 17: Preparation of (1R,10S,13S)-N-[(2,4-difluorophenyl)methyl]-6,13-dihydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide:

Chemical Structure

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

[0268] (1R,10S,13S)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-13-hydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide (13.0 mg, 0.0243 mmol) of Project 1 was treated with a mixture of DCM (0.2 mL) and TFA (0.2 mL) at room temperature for 4 hours. The reaction mixture was concentrated, redissolved in DMF, filtered, and purified by reverse-phase preparative HPLC. LCMS-ESI+(m / z): Calculated value of H+ for C22H21F2N3O5, theoretical value: 445.14, measured value: 446.04. 1H NMR (400 MHz, acetone-d6) δ 10.51 (s, 1H), 8.38 (s, 1H), 7.49 (q, J = 8.3 Hz, 1H), 7.08 - 6.95 (m, 2H), 6.25 (s, 1H), 5.74 (dd, J = 11.9, 2.5 Hz, 1H), 5.53 (dd, J = 11.8, 2.5 Hz, 1H), 5.35 - 5.23 (m, 1H), 4.79 - 4.69 (m, 2H), 4.63 (d, J = 6.0 Hz, 2H), 4.12 (dd, J = 14.7, 2.7 Hz, 1H), 3.85 (dd, J = 14.6, 1.8 Hz, 1H), 1.60 (s, 3H), 1.39 (d, J = 7.3 Hz, 3H). Example 18: (3S,6S,7R)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide [Chemical formula] (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide Preparation:

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

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

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

Chemical formula

[0272] Instead of (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide, (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide was used. Except for using -10-carboxamide, in the same manner as in Example 18, (3S,6S,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide was prepared. MS (m / z) 446.22 [M+H] + 。 1 H NMR (400 MHz, methanol-d4) δ 8.50 (s, 1H), 7.45 (td, J = 8.4, 6.3 Hz, 1H), 7.04 - 6.90 (m, 2H), 6.00 (ddd, J = 11.6, 6.6, 2.6 Hz, 1H), 5.76 (dd, J = 11.7, 2.0 Hz, 1H), 5.28 (tdt, J = 7.4, 4.7, 2.4 Hz, 1H), 5.00 (d, J = 6.9 Hz, 1H), 4.65 (s, 2H), 4.29 (t, J = 7.0 Hz, 1H), 3.97 (dd, J = 14.6, 2.4 Hz, 1H), 3.66 (d, J = 14.5 Hz, 1H), 3.13 (s, 3H), 1.39 (d, J = 7.3 Hz, 3H). Example 20: (3S,6S,7R)-N-(2,4-Difluorobenzyl)-6,12-dihydroxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide

Chemical Structure

[0273] (3S,6S,7R)-12-(Benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide (10 mg, 0.19 mmol) prepared according to Example 3 was dissolved in 1 mL of toluene and 1 mL of TFA. This was stirred at room temperature for 1 hour and concentrated to dryness. The residue was purified by RP-HPLC to obtain the title compound. MS (m / z): 432.124 [M+H]+. 1 1H NMR (400 MHz, DMSO-d6) δ 10.49 - 10.39 (m, 2H), 8.42 (s, 1H), 7.41 (td, J = 8.7, 6.6 Hz, 1H), 7.25 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.07 (td, J = 8.5, 2.6 Hz, 1H), 5.67 (ddd, J = 11.9, 5.6, 2.1 Hz, 1H), 5.57 - 5.48 (m, 2H), 5.20 - 5.12 (m, 1H), 4.93 (d, J = 7.3 Hz, 1H), 4.58 (dd, J = 13.2, 6.2 Hz, 3H), 3.83 (dd, J = 14.8, 2.4 Hz, 1H), 3.68 (dd, J = 14.7, 2.0 Hz, 1H), 1.28 (d, J = 7.3 Hz, 3H). Example 21: (3S,6S,7R)-N-(2,4-Difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-6-d-10-carboxamide

Chemical formula

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

Chemical Structure

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

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

Chem.

[0277] (3S,6S,7R)-6,12-Dihydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (product of Step 1 of Example 11, 25 mg, 0.045 mmol) was dissolved in anhydrous DMF (0.90 mL), and the resulting mixture was cooled to 0 °C. To this stirred cold mixture was added 60% sodium hydride in mineral oil (2.6 mg, 0.068 mmol), followed by iodomethane (10 mg, 0.068 mmol). After stirring for 5 minutes, the reaction was quenched with 10% aqueous citric acid. The mixture was extracted with EtOAc, and the organic layer was washed with water, then saturated aqueous sodium bicarbonate, then brine, dried over magnesium sulfate, filtered, and concentrated. The product was obtained by flash column chromatography (silica gel, EtOAc / hexane) (the stereochemical assignment is tentative). 1H NMR (400 MHz, chloroform-d) δ 10.47 (s, 1H), 8.35 (s, 1H), 7.59 - 7.53 (m, 2H), 7.37 - 7.27 (m, 3H), 6.66 (dd, J = 8.8, 7.5 Hz, 2H), 5.63 (dd, J = 11.6, 1.8 Hz, 1H), 5.52 - 5.41 (m, 2H), 5.39 - 5.29 (m, 1H), 5.21 (d, J = 10.3 Hz, 1H), 4.66 (d, J = 5.4 Hz, 2H), 4.11 (s, 1H), 3.78 (dd, J = 14.5, 2.9 Hz, 1H), 3.27 (dd, J = 14.5, 1.3 Hz, 1H), 3.00 (s, 3H), 1.45 (s, 3H), 1.29 (d, J = 7.4 Hz, 3H). LCMS-ESI+(m / z): C 30 H 28 F 3 N 3 O 5 Calculated H+ value, theoretical value: 568.21, measured value: 568.19. Synthesis of (3S,6S,7R)-12-Hydroxy-6-methoxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide:

[0278] (3S,6S,7R)-12-(Benzyloxy)-6-methoxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (20.0 mg, 0.035 mmol) was dissolved in EtOH (1.0 mL) at room temperature and treated with 1.2 mg of 20% Pd(OH) 2 / C (50 wt% water). The mixture was degassed, flushed three times with hydrogen, and then stirred under a hydrogen atmosphere for 45 minutes. The reaction was then degassed, flushed with nitrogen, filtered through a pad of celite, concentrated, and the resulting residue was purified by flash column chromatography (silica gel, dichloromethane / methanol) to give the product (stereochemical assignment is tentative). 1H NMR (400 MHz, chloroform-d) δ 10.48 (s, 1H), 6.65 (dd, J = 8.8, 7.5 Hz, 2H), 4.75 - 4.58 (m, 3H), 3.67 (dd, J = 15.3, 3.0 Hz, 1H), 3.44 (d, J = 15.2 Hz, 1H), 3.12 (s, 3H), 2.13 - 2.01 (m, 1H), 1.91 (dd, J = 14.8, 7.7 Hz, 1H), 1.41 (s, 3H), 1.36 - 1.28 (m, 1H), 1.26 (d, J = 6.7 Hz, 3H), 1.24 - 1.06 (m, 2H). LCMS-ESI+(m / z): C 23 H 24 F 3 N 3 O 5 Calculated H+ for C Example 24: Synthesis of (3S,6S,7R)-12-hydroxy-6-methoxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide: [Chemical formula]

[0279] (3S,6S,7R)-12-(Benzyloxy)-6-methoxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (16 mg, 0.028 mmol from step 1 of Example 23) was dissolved in 1:1 toluene:trifluoroacetic acid (1.16 mL). The resulting solution was stirred at 20 °C for 8 h and then left at 0 °C for 12 h. The solution was diluted with acetonitrile and concentrated in vacuo, and the resulting crude product was purified by flash column chromatography (silica gel, dichloromethane / methanol) to give the product (the stereochemical assignment is provisional). 1H NMR (400 MHz, chloroform-d) δ 10.36 (s, 1H), 8.32 (s, 1H), 6.65 (dd, J = 8.7, 7.5 Hz, 2H), 5.64 (dd, J = 11.6, 1.8 Hz, 1H), 5.53 (dd, J = 11.6, 2.7 Hz, 1H), 5.29 - 5.20 (m, 1H), 4.77 - 4.55 (m, 2H), 4.23 (s, 1H), 3.93 (dd, J = 14.3, 3.0 Hz, 1H), 3.54 (dd, J = 14.3, 1.3 Hz, 1H), 2.97 (s, 3H), 1.45 (s, 3H), 1.36 (d, J = 7.4 Hz, 3H). LCMS-ESI+ (m / z): C 23 H 22 F 3 N 3 O 5 Calculated H+ value for C Example 25: Preparation of (3S,6S,7R)-6-ethoxy-12-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide

Chemical Structure

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

[0281] At room temperature, (3S,6S,7R)-12-(benzyloxy)-6-ethoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (5 mg) was dissolved in toluene (0.5 mL), and TFA (0.5 mL) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified by preparative HPLC eluting with 10 - 60% acetonitrile (0.1% TFA) in water (0.1% TFA). The combined fractions were lyophilized to give the title compound. MS (m / z) 478.32 [M+H] + 1H NMR (400 MHz, acetonitrile-d3) δ 8.44 (d, J = 22.1 Hz, 1H), 7.00 - 6.81 (m, 1H), 6.73 (t, J = 8.5 Hz, 1H), 6.02 - 5.84 (m, 1H), 5.79 - 5.60 (m, 1H), 5.24 (d, J = 7.9 Hz, 1H), 5.03 (dd, J = 42.6, 7.4 Hz, 1H), 4.82 (dd, J = 15.0, 6.8 Hz, 1H), 4.70 - 4.58 (m, 1H), 4.52 (d, J = 12.9 Hz, 1H), 4.44 - 4.29 (m, 1H), 3.81 (t, J = 12.5 Hz, 1H), 3.70 - 3.54 (m, 1H), 3.41 (p, J = 6.9 Hz, 1H), 1.43 - 1.24 (m, 3H), 0.92 - 0.68 (m, 3H). Example 26: Preparation of (3S,6S,7R)-6-ethoxy-12-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide

Chemical Structure

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

Chem.

[0283] Instead of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide, (3S,6S,7R)-12-(benzyloxy)-6-(difluoromethoxy)-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (prepared according to Example 22) was used and it was prepared in a similar manner to (3S,6S,7R)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (Example 16). MS (m / z): 502.137 [M+H]+. 1H NMR (400 MHz, methanol-d4) δ 10.56 (s, 1H), 8.35 (s, 1H), 6.92 (t, J = 8.4 Hz, 2H), 6.58 (t, J = 73.8 Hz, 1H), 4.79 - 4.44 (m, 5H), 3.81 (s, 2H), 2.14 (dt, J = 14.7, 7.2 Hz, 1H), 2.02 - 1.81 (m, 1H), 1.74 - 1.60 (m, 1H), 1.45 - 1.30 (m, 1H), 1.29 (d, J = 6.7 Hz, 3H). Example 28: Preparation of (3S,6S,7R)-6-ethyl-6,12-dihydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide [Chemical formula] (3S,6S,7R)-12-(Benzyloxy)-6-ethyl-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide Synthesis:

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

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

Chemical Structure

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

Chemical formula

[0287] Instead of (1R,10S)-6-benzyloxy-10-methyl-5,8,13-trioxo-N-[(2,4,6-trifluorophenyl)methyl]-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide, the title compound was prepared in the same manner as in the synthesis of Example 29, except that (1R,10S)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-methyl-5,8,13-trioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide was used. LCMS-ESI+(m / z): Calculated for H+ of C22H18D3F2N3O5, theoretical value: 448.16, measured value: 449.23. 1H NMR (400 MHz, DMSO-d6) δ 10.44 (t, J = 5.9 Hz, 1H), 8.38 (s, 1H), 7.42 (td, J = 8.7, 6.6 Hz, 1H), 7.25 (ddd, J = 11.9, 9.3, 2.6 Hz, 1H), 7.08 (td, J = 8.5, 2.7 Hz, 1H), 5.54 (dd, J = 11.9, 2.3 Hz, 1H), 5.40 (dd, J = 11.9, 2.6 Hz, 2H), 5.13 (dt, J = 7.1, 2.3 Hz, 1H), 4.70 (d, J = 2.2 Hz, 1H), 4.56 (d, J = 5.9 Hz, 2H), 3.87 (dd, J = 14.7, 2.7 Hz, 1H), 3.65 (dd, J = 14.7, 1.9 Hz, 1H), 1.28 (d, J = 7.3 Hz, 3H). Example 31: Synthesis of (1R,10S,13S)-N-[(2,4-difluorophenyl)methyl]-6,13-dihydroxy-10-methyl-5,8-dioxo-13-(trideuterio-methyl)-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide: [Chemical formula] Step 1: Synthesis of (1R,10S)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-methyl-5,8,13-trioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide:

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

[0289] Instead of (1R,10S)-6-benzyloxy-10-methyl-5,8,13-trioxo-N-[(2,4,6-trifluorophenyl)methyl]-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide, the compound was prepared according to the synthesis of Example 29, except that (1R,10S)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-methyl-5,8,13-trioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide was used. LCMS-ESI+(m / z): calculated value of H+ for C22H20D3F2N3O5, theoretical value: 450.18, measured value: 451.28. 1H NMR (400 MHz, DMSO-d6) δ 10.98 (s, 1H), 10.46 (t, J = 6.0 Hz, 1H), 8.34 (s, 1H), 7.40 (td, J = 8.7, 6.6 Hz, 1H), 7.25 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.07 (td, J = 8.5, 2.6 Hz, 1H), 4.93 (s, 1H), 4.56 (d, J = 5.9 Hz, 2H), 4.47 (dt, J = 10.4, 6.5 Hz, 1H), 4.28 (s, 1H), 3.67 (t, J = 2.5 Hz, 2H), 1.87 (dt, J = 14.4, 7.0 Hz, 1H), 1.52 - 1.34 (m, 2H), 1.17 (t, J = 7.6 Hz, 4H). Example 32: Synthesis of (3S,6R,7R)-6,12-dihydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide: [Chemical formula] Synthesis of (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide:

[0290] ((1R,10S,13S)-6,13-Dihydroxy-10,13-dimethyl-5,8-dioxo-N-[(2,4,6-trifluorophenyl)methyl]-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide (Example 11, 165 mg, 0.355 mmol) was treated with DMF (7.0 mL), followed by potassium carbonate, and then benzyl bromide. The mixture was stirred at 20 °C for 4 h. The reaction was extracted with EtOAc, and the organic layer was washed with water and then brine, dried over magnesium sulfate, filtered, and concentrated. The product was obtained by flash column chromatography (silica gel, EtOAc / hexane) (stereochemical assignment is tentative). 1H NMR (400 MHz, chloroform-d) δ 10.40 (t, J = 5.6 Hz, 1H), 8.46 (s, 1H), 7.59 - 7.49 (m, 2H), 7.39 - 7.27 (m, 3H), 6.62 (dd, J = 8.8, 7.4 Hz, 2H), 5.28 (d, J = 10.3 Hz, 1H), 5.15 (d, J = 10.3 Hz, 1H), 4.78 (dt, J = 10.5, 6.7 Hz, 1H), 4.57 (dd, J = 14.5, 5.7 Hz, 1H), 4.49 (dd, J = 14.5, 5.4 Hz, 1H), 4.38 (s, 1H), 4.03 (s, 1H), 3.26 (dd, J = 15.3, 3.0 Hz, 1H), 3.06 (dd, J = 15.0, 1.5 Hz, 1H), 1.98 (dt, J = 13.4, 6.8 Hz, 1H), 1.62 - 1.47 (m, 2H), 1.39 (s, 3H), 1.15 (d, J = 6.7 Hz, 3H). LCMS-ESI+(m / z): C 23 H 22 F 3 N 3 O 5 Calculated H+ value, theoretical value 556.21, measured value: 556.20. Synthesis of (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide:

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

[0292] (3S,7S)-12-(Benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (30 mg, 0.0558 mmol) was dissolved in dichloromethane (3.0 mL), and then 3-chloroperoxybenzoic acid (88 mg, 0.391 mmol) was added. The mixture was stirred at 45 °C for 48 h in a metal heating block. The reaction mixture was diluted with additional dichloromethane, and then the organic phase was washed with 2N aqueous sodium hydroxide solution and then with brine. The combined aqueous phases were extracted with additional dichloromethane. The combined organic phases were dried over magnesium sulfate, filtered, and concentrated. The product was obtained by flash column chromatography (silica gel, EtOAc / hexane) (the stereochemical assignment is tentative). 1H NMR (400 MHz, chloroform-d) δ 10.33 (s, 1H), 8.33 (s, 1H), 7.61 - 7.51 (m, 2H), 7.32 (dd, J = 12.1, 7.2 Hz, 3H), 6.67 (t, J = 8.1 Hz, 2H), 5.54 (d, J = 10.2 Hz, 1H), 5.17 (d, J = 10.2 Hz, 1H), 4.90 (dt, J = 10.7, 6.6 Hz, 1H), 4.66 (dd, J = 5.6, 3.1 Hz, 2H), 3.64 (dd, J = 14.9, 1.8 Hz, 1H), 3.52 (s, 1H), 3.44 (dd, J = 15.1, 2.5 Hz, 1H), 3.21 (d, J = 3.7 Hz, 1H), 2.79 (d, J = 3.7 Hz, 1H), 2.07 - 1.98 (m, 1H), 1.79 (ddd, J = 39.5, 15.0, 11.6 Hz, 2H), 1.24 (d, J = 6.8 Hz, 3H). LCMS-ESI+ (m / z): C 29 H 26 F 3 N 3 O 5 Calculated H+ value, theoretical value 554.19, measured value: 554.21. Synthesis of (3S,6R,7R)-6,12-dihydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide:

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

Chemical formula

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

[0295] (1R,10S)-6-Benzyloxy-N-[(2,4-difluorophenyl)methyl]-13-hydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-4-carboxamide (81 mg, 0.151 mmol) was dissolved in toluene (3.0 mL) at room temperature and treated with Martin sulfurane dehydrating reagent (507 mg, 0.753 mmol) for 20 minutes. The reaction was concentrated and purified by normal phase chromatography. LCMS-ESI+(m / z): Calculated for H+ of C29H27F2N3O4, Theoretical: 519.20, Observed: 520.22. Step 3: Synthesis of (1R,10S,13R)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-methyl-5,8-dioxo-spiro[2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-13,2'-oxirane]-4-carboxamide:

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

[0297] (1R,10S,13R)-6-Benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-methyl-5,8-dioxo-spiro[2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6-diene-13,2'-oxirane]-4-carboxamide (10 mg, 0.0187 mmol) was dissolved in EtOH (0.5 mL) and treated with ammonium formate (59 mg, 0.934 mmol) and 10% Pd / C (3.97 mg). The resulting mixture was degassed and flushed with nitrogen three times and then heated at 70 °C for 3 h under nitrogen. The reaction was then cooled to room temperature, filtered, concentrated, redissolved in DMF, filtered, and purified by reverse-phase preparative HPLC. LCMS-ESI+(m / z): Calculated for H+ of C22H23F2N3O5, theoretical: 447.16, found: 448.256. 1H NMR (400 MHz, DMSO-d6) δ 11.04 (s, 1H), 10.37 (t, J = 6.0 Hz, 1H), 8.38 (s, 1H), 7.41 (td, J = 8.6, 6.5 Hz, 1H), 7.34 - 7.18 (m, 1H), 7.08 (td, J = 8.6, 2.7 Hz, 1H), 5.16 (s, 1H), 4.52 (dt, J = 22.6, 6.3 Hz, 3H), 4.30 (s, 1H), 3.75 - 3.61 (m, 2H), 1.92 - 1.64 (m, 2H), 1.53 (dd, J = 15.3, 6.7 Hz, 1H), 1.17 (d, J = 6.7 Hz, 4H), 1.03 (s, 3H). Example 34: (3S,6S,7R)-N-(2,4-Difluorobenzyl)-12-hydroxy-6-(methoxy-d3)-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide

Chemical formula

[0298] Except for using iodomethane-d3 instead of iodomethane and using (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide instead of (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide, (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-(methoxy-d3)-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide was prepared in the same manner as (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-methoxy-3-methyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide of Example 18. Preparation of (3S,6S,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-6-(methoxy-d3)-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide:

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

Chem.

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

[0301] The residue from the previous step (2.36 g, 5.72 mmol) and methyl 3-benzyloxy-4-oxo-5-[(2,4,6-trifluorophenyl)methylcarbamoyl]pyran-2-carboxylate (1.08 g, 2.52 mmol) were suspended in a mixture of THF (6.0 mL), ethanol (1.0 mL), and triethylamine (5.36 g, 53 mmol). The resulting mixture was heated at 40 °C overnight. The reaction was cooled to room temperature. The residue was partitioned between EtOAc and water, and the organic layer was washed with 10% citric acid, water, brine, dried over sodium sulfate, filtered, concentrated, and purified by normal-phase chromatography. LCMS-ESI+ (m / z): Calculated for H+ of C29H25F2N3O6, theoretical value: 549.17, measured value: 550.10. Step 3: Synthesis of (1R,10R)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-10-methyl-5,8,13-trioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide:

[0302] (1S,10R)-6-Benzyloxy-4-[(2,4-difluorophenyl)methylcarbamoyl]-10-methyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-1-carboxylic acid (470 mg, 0.855 mmol) was dissolved in 1,4-dioxane (8.0 mL) and treated with selenium dioxide (753 mg, 6.84 mmol) at 100 °C for 8 h. The reaction mixture was cooled to room temperature, filtered, concentrated, and purified by normal phase chromatography. LCMS-ESI+(m / z): calculated for H+ of C29H23F2N3O6, theoretical: 519.16, found: 520.04. Step 4: Synthesis of (1R,10R,13S)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-13-hydroxy-10,13-dimethyl-5,8-dioxo-2,9-diazatricyclo[7.4.1.02,7]tetradeca-3,6,11-triene-4-carboxamide:

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

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

[0305] (3S,7S)-12-(Benzyloxy)-3-methyl-1,4,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,4,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (Intermediate C) was synthesized in the same manner as Intermediate A and isolated as a further product from the same reaction conditions. 1H NMR (400 MHz, chloroform-d) δ 10.41 (t, J = 5.8 Hz, 1H), 8.66 (s, 1H), 7.58 - 7.46 (m, 2H), 7.41 - 7.27 (m, 3H), 6.76 - 6.56 (m, 2H), 6.31 (d, J = 12.4 Hz, 1H), 6.11 (d, J = 12.2 Hz, 1H), 5.50 (d, J = 10.2 Hz, 1H), 5.28 (q, J = 7.0 Hz, 1H), 5.15 (d, J = 10.2 Hz, 1H), 4.98 (s, 1H), 4.66 (d, J = 5.7 Hz, 2H), 3.75 (d, J = 15.0 Hz, 1H), 3.50 (d, J = 14.9 Hz, 1H), 1.46 (d, J = 7.0 Hz, 3H). LCMS-ESI+ (m / z): C 28 H 22 F 3 N 3 O 5 Calculated value of H+ for, theoretical value 538.16, measured value: 538.10. Example 36: Preparation of (3S,6R,7R)-4,4-difluoro-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide:

Chemical Structure

[0306] (3S,7S)-12-(Benzyloxy)-3-methyl-1,4,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,4,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (Intermediate C, 50 mg, 0.093 mmol) was treated with triethylammonium hydrochloride (12.8 mg, 0.093 mmol), then methanol (2.0 mL), then water (0.5 mL), then triethylamine (30 μL, 0.214 mmol), and then potassium cyanide (6.0 mg, 0.093 mmol). The reaction mixture was stirred at 60 °C for 1 h in a metal heating block. The reaction mixture was partitioned between EtOAc and 10% aqueous sodium carbonate. The organic phase was washed with saturated aqueous ammonium chloride and then brine. Na 2 CO 3 The aqueous phase was extracted with additional ethyl acetate. The combined organic phases were dried over MgSO 4 , filtered, and concentrated in vacuo. The product was obtained by flash column chromatography (silica gel, EtOAc / hexanes) (stereochemical assignment is tentative). 1H NMR (400 MHz, chloroform-d) δ 10.27 (t, J = 6.0 Hz, 1H), 8.52 (s, 1H), 7.61 - 7.48 (m, 2H), 7.46 - 7.29 (m, 3H), 6.67 (dd, J = 8.7, 7.5 Hz, 2H), 5.57 (d, J = 10.3 Hz, 1H), 5.16 (d, J = 10.3 Hz, 1H), 5.10 (d, J = 7.0 Hz, 1H), 4.67 (dd, J = 5.7, 3.6 Hz, 2H), 4.24 (s, 1H), 3.80 (t, J = 4.1 Hz, 1H), 3.55 (dt, J = 15.3, 1.8 Hz, 1H), 3.48 (s, 3H), 3.45 (dd, J = 15.2, 1.8 Hz, 1H), 2.91 (dd, J = 13.6, 5.7 Hz, 1H), 2.70 (dd, J = 13.5, 1.6 Hz, 1H), 1.36 (d, J = 7.0 Hz, 3H). LCMS-ESI+ (m / z): C 29 H 26 F 3 N 3 O 6 H+ calculated for C Step 2: Synthesis of (3S,6R,7R)-12-(benzyloxy)-4,4-difluoro-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide:

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

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

Chemical Structure

[0309] A mixture of (3S,6R,7R)-12-(benzyloxy)-6-methoxy-3-methyl-1,4,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (770.8 mg, 1.35 mmol) in methanol (30 mL) prepared according to Example 36 was stirred at 0 °C and NaBH4 (57.7 mg, 1.53 mmol) was added. After 3 minutes, the insoluble material was dissolved with THF (about 10 mL). The reaction mixture was concentrated and the residue was dissolved in ethyl acetate (about 50 mL), saturated NaHCO3 (about 25 mL) and water (about 25 mL). After separating the two layers, the aqueous fraction was extracted with ethyl acetate (about 50 mL). The two organic fractions were washed with brine, combined, dried (MgSO4) and concentrated. The residue was purified by column chromatography (80 g column) on silica gel eluting with 0 - 10% methanol in CH2Cl2 to give (3S,4R,6R,7R)-12-(benzyloxy)-4-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide. ES / MS m / z: Calculated for C29H29F3N3O6 (M + H), theoretical value 572.20, measured value: 572.20. Step 2: Synthesis of (3S,4S,6R,7R)-12-(benzyloxy)-4-fluoro-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide:

[0310] A solution of (3S,4R,6R,7R)-12-(benzyloxy)-4-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide (811.2 mg, 1.42 mmol) in CH2Cl2 (14 mL) was stirred at 0 °C while adding a solution of 2.7 M Deoxo-Fluor (bis(2-methoxyethyl)aminosulfur trifluoride) in toluene (1.39 mL, 3.75 mmol). After 30 minutes, the reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled and stirred at 0 °C while adding saturated NaHCO3 (about 40 mL). After adding water (about 40 mL), the product was extracted with ethyl acetate (about 70 mL × 2). The extracts were washed with brine (about 70 mL × 1), and the combined organic fractions were dried (MgSO4). The residue was purified by column chromatography on silica gel (80 g column) eluting with 50 - 100% ethyl acetate in hexane to give (3S,4S,6R,7R)-12-(benzyloxy)-4-fluoro-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide: ES / MS m / z: calculated for C29H28F4N3O5 (M + H): 574.20, found: 574.30.

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

[0312] (3S,4S,6R,7R)-12-(Benzyloxy)-4-fluoro-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (556.5 mg, 0.970 mmol) was dissolved in toluene (0.25 mL) and trifluoroacetic acid (10 mL). The resulting mixture was stirred at room temperature for 1 hour and at 60 °C for 1 hour. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate (ca. 25 mL) and then washed with saturated NaHCO3 (ca. 25 mL). After separating the two layers, the aqueous fraction was extracted with ethyl acetate (ca. 25 mL). The organic fractions were washed with brine, combined, dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel (50 g column) eluting with 0–10% methanol / CH2Cl2 to give the product.The crude product was purified again using column chromatography on silica gel (40 g column) eluting with 0 - 10% methanol in ethyl acetate to give (3S,4S,6R,7R)-4-fluoro-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide: 1H NMR (400 MHz, acetonitrile-d3) δ 10.62 (s, 1H), 10.31 (t, J = 6.0 Hz, 1H), 8.37 (s, 1H), 6.84 (t, J = 8.5 Hz, 2H), 5.01 - 4.70 (m, 2H), 4.60 (d, J = 5.9 Hz, 2H), 4.48 (q, J = 2.4 Hz, 1H), 3.91 (dd, J = 15.1, 2.3 Hz, 1H), 3.73 - 3.57 (m, 2H), 3.37 (s, 3H), 2.53 (ddd, J = 15.3, 8.4, 6.5 Hz, 1H), 1.85 - 1.65 (m, 1H), 1.33 (dd, J = 7.1, 2.7 Hz, 3H); 19F NMR (376 MHz, acetonitrile-d3) δ -111.21 (ddd, J = 15.3, 9.1, 6.1 Hz), -113.91 (t, J = 7.0 Hz), -193.86 (ddd, J = 46.9, 31.9, 16.7 Hz); ES / MS m / z: calculated for C22H22F4N3O5 (M + H): 484.15, found: 484.20. Example 38: (3S,4R,6R,7R)-4-Fluoro-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide [Chemical formula] Step 1: Synthesis of (3S,4S,6R,7R)-12-(benzyloxy)-6-methoxy-3-methyl-1,11-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-4-yl benzoate:

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

[0314] (3S,4S,6R,7R)-12-(Benzyloxy)-6-methoxy-3-methyl-1,11-dioxo-10-((2,4,6-trifluorobenzyl)carbamoyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-4-yl benzoate (65 mg, 0.0962 mmol) was treated with methanol (2 mL), then THF (2 mL), then water (0.5 mL), then lithium hydroxide monohydrate (40 mg, 0.962 mmol). The reaction mixture was stirred at 20 °C for 1.5 h. The reaction mixture was then partitioned between ethyl acetate and saturated aqueous sodium bicarbonate. The organic layer was further washed with brine, dried over MgSO4, and concentrated in vacuo. The product was obtained by flash column chromatography (silica gel, EtOAc / hexanes) (stereochemical assignment is tentative). 1H NMR (400 MHz, chloroform-d) δ 10.35 (t, J = 5.8 Hz, 1H), 8.46 (s, 1H), 7.57 - 7.48 (m, 2H), 7.34 (d, J = 6.6 Hz, 3H), 6.72 - 6.61 (m, 2H), 5.50 (d, J = 10.3 Hz, 1H), 5.13 (d, J = 10.3 Hz, 1H), 4.74 - 4.59 (m, 2H), 4.53 - 4.43 (m, 1H), 4.12 (d, J = 7.0 Hz, 1H), 3.86 (t, J = 9.3 Hz, 1H), 3.64 - 3.57 (m, 1H), 3.45 (s, 3H), 3.45 - 3.38 (m, 1H), 3.36 - 3.27 (m, 1H), 2.18 - 2.10 (m, 1H), 1.76 (ddd, J = 15.4, 10.6, 1.5 Hz, 1H), 1.34 (d, J = 6.8 Hz, 3H). LCMS-ESI+(m / z): C 29 H 28 F 3 N 3 O 6 Calculated for H+ of C572.20, found: 572.16. Step 3: Synthesis of (3S,4R,6R,7R)-12-(Benzyloxy)-4-fluoro-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide:

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

[0316] (3S,4R,6R,7R)-12-(Benzyloxy)-4-fluoro-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (7 mg) was dissolved in 1:1 toluene:trifluoroacetic acid (0.48 mL). The resulting solution was stirred at 60 °C for 30 minutes. The solution was diluted with acetonitrile and concentrated in vacuo, and the resulting crude product was purified by reverse-phase preparative HPLC (acetonitrile / water, 0.1% trifluoroacetic acid) to give the product (the stereochemical assignment is provisional). 1H NMR (400 MHz, acetonitrile-d3) δ 10.31 (s, 1H), 8.37 (s, 1H), 6.85 (dd, J = 9.1, 8.0 Hz, 2H), 5.00 - 4.73 (m, 2H), 4.60 (d, J = 5.7 Hz, 2H), 4.48 (d, J = 2.5 Hz, 1H), 3.91 (dd, J = 15.1, 2.3 Hz, 1H), 3.65 (d, J = 8.1 Hz, 1H), 3.63 (s, 1H), 3.37 (s, 3H), 2.53 (ddd, J = 15.3, 8.2, 6.4 Hz, 1H), 1.86 - 1.66 (m, 1H), 1.33 (dd, J = 7.1, 2.7 Hz, 3H). LCMS-ESI+(m / z): C 22 H 21 F 4 N 3 O 5 Calculated H+ value for C, H, F, N, O: 484.15, found: 484.23. Example 39: (3S,4R,6S,7R)-4-Fluoro-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide

Chem.

[0317] (3S,6S,7R)-12-(Benzyloxy)-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (50 mg, 0.0903 mmol, from Step 2 of Example 1) was charged with isopropanol (2.5 mL), then phenylsilane (20 mg, 0.181 mmol), then benzoic acid (25 mg, 0.205 mmol), then tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (1.6 mg, 0.0027 mmol). The reaction was cycled three times between vacuum and oxygen, then stirred vigorously at 20 °C for 45 min under oxygen, then additional tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (0.5 mg, 0.0009 mmol) was added. The reaction was stirred vigorously at 20 °C for 45 min under oxygen. Then, 1 N aqueous sodium thiosulfate solution was added and the phases were mixed for 60 min. Then, the reaction was extracted with ethyl acetate. The organic phase was washed with brine, dried over MgSO4, filtered, and concentrated in vacuo. Flash column chromatography (silica gel, EtOAc / hexane) gave the product as the major diastereomer (stereochemical assignment is tentative). 1H NMR (400 MHz, chloroform-d) δ 10.43 (s, 1H), 8.48 (s, 1H), 7.66 - 7.50 (m, 2H), 7.46 - 7.27 (m, 3H), 6.66 (t, J = 8.1 Hz, 2H), 5.42 (d, J = 10.3 Hz, 1H), 5.14 (d, J = 10.3 Hz, 1H), 4.72 - 4.59 (m, 2H), 4.54 (q, J = 7.2 Hz, 1H), 4.40 (s, 1H), 3.52 - 3.28 (m, 3H), 3.41 (s, 3H), 3.12 (d, J = 15.3 Hz, 1H), 2.06 (d, J = 13.2 Hz, 1H), 1.72 - 1.57 (m, 1H), 1.33 (d, J = 6.7 Hz, 3H). LCMS-ESI+(m / z): C 29 H 28 F 3 N 3 O 6 Calculated H+ value, theoretical value 572.20, measured value: 572.02. Steps 2 - 3: Synthesis of (3S,4R,6S,7R)-4-fluoro-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide:

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

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

[0320] While adding NaBH4 (157 mg, 4.15 mmol), the above solution was stirred at 0 °C. After 30 minutes at 0 °C, the reaction mixture was concentrated, and the residue was dissolved in saturated NaHCO3, and then the product was extracted with ethyl acetate (×2). The organic extract was washed with brine (×1), and then the organic fractions were combined, dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel (80 g column) eluting with 0 - 5% methanol in CH2Cl2, and preparative HPLC (column, Gemini 5um C18 110A, LC column 100×30 mm) eluting with 23 - 90% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 minutes. The combined fractions were neutralized by adding saturated NaHCO3 (about 1 mL), and then the solution was concentrated to remove most of the acetonitrile. The resulting aqueous mixture was extracted with EA (about 25 mL×2), the extracts were washed with brine (×1), combined, dried (MgSO4), and concentrated to give (3S,4R,6S,7R)-12-(benzyloxy)-4-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide. ES / MS m / z: Calculated for C29H29F3N3O6(M + H): 572.20, Found: 572.27. Step 2: Synthesis of (3S,4S,6S,7R)-12-(benzyloxy)-4-fluoro-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide:

[0321] A solution of (3S,4R,6S,7R)-12-(benzyloxy)-4-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide (81.8 mg, 0.143 mmol) in CH2Cl2 (2 mL) was stirred at 0 °C while adding 2.7 M bis(2-methoxyethyl)aminosulfur trifluoride solution in toluene (0.14 mL, 0.378 mmol). After 30 minutes, the reaction mixture was stirred at room temperature for 2.5 hours while adding saturated NaHCO3 (10 mL), and then cooled to 0 °C. After adding water (20 mL), the product was extracted with ethyl acetate (25 mL × 2). The combined extracts were dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel eluting with 20 - 100% EA in hexane (using a 12 g column) to give (3S,4S,6S,7R)-12-(benzyloxy)-4-fluoro-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide: ES / MS m / z: calculated for C29H28F4N3O5(M + H): 574.20, found: 574.30. Step 3: Synthesis of (3S,4S,6S,7R)-4-fluoro-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide:

[0322] (3S,4S,6S,7R)-12-(Benzyloxy)-4-fluoro-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (50.3 mg, 0.0877 mmol) was dissolved in toluene (0.02 mL) and trifluoroacetic acid (2 mL). After stirring at room temperature for 1 hour, the reaction mixture was concentrated completely, and the residue was purified by preparative HPLC (2 injections) eluting with 20 - 65% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 minutes (column, Gemini 5um C18 110A, LC column 100×30 mm). The combined fractions were neutralized by the addition of saturated NaHCO3 (ca. 1 mL), then concentrated to remove most of the acetonitrile. The concentrated solution was extracted with ethyl acetate (ca. 20 mL × 2). The extracted fractions were washed with brine (×1), combined, dried (MgSO4), concentrated, and dried in vacuo to give (3S,4S,6S,7R)-4-fluoro-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide.1H NMR (400 MHz, chloroform-d) δ 10.39 (s, 1H), 10.19 (s, 1H), 8.44 (s, 1H), 6.74 - 6.59 (m, 2H), 4.97 (dt, J = 46.8, 6.4 Hz, 1H), 4.82 (dp, J = 19.9, 6.8 Hz, 1H), 4.74 - 4.59 (m, 2H), 4.39 (d, J = 2.4 Hz, 1H), 4.02 (dd, J = 14.7, 2.1 Hz, 1H), 3.73 - 3.58 (m, 2H), 3.45 (s, 3H), 2.68 (ddd, J = 16.0, 7.5, 5.1 Hz, 1H), 1.73 - 1.55 (m, 1H), 1.41 (dd, J = 7.1, 2.6 Hz, 3H); 19F NMR (376 MHz, acetonitrile-d3) δ -111.29 (q, J = 7.8, 7.3 Hz), -113.92 (t, J = 7.1 Hz), -200.03 - -200.69 (m); ES / MS m / z: Calculated for C22H22F4N3O5 (M + H): 484.15, Found: 484.20. Example 41: (3R,6S,7R)-N-(2,4-Difluorobenzyl)-3-(fluoromethyl)-12-hydroxy-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide

Chemical formula

[0323] (3R,7S)-12-(Benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide was prepared according to the procedure for preparing Intermediate B, except that Benzyl(3S,7R)-3-(((benzyloxy)carbonyl)amino)-7-(((tert-butyldimethylsilyl)oxy)methyl)-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate was used in the first step. ES / MS m / z: Calculated for C28H26F2N3O5(M+H): 522.18, Found: 522.20. Steps 3-4: Synthesis of (3R,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide:

[0324] A solution of (3R,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (2971.9 mg, 5.70 mmol) and imidazole (601.0 mg, 8.83 mmol) in CH2Cl2 (45 mL) was added with tert-butyldimethylsilyl chloride (1039.7 mg, 6.90 mmol) at room temperature, and the resulting solution was stirred at room temperature. After 16 h, the reaction mixture was diluted with CH2Cl2, washed with water (×1), and the two layers were separated. The aqueous fraction was extracted with ethyl acetate (×1), and then the organic fractions were combined, dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel eluting with 0 - 100% ethyl acetate in hexane (120 g column) to give (3R,7S)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide. ES / MS m / z: calculated for C34H40F2N3O5Si(M+H): 636.27, found: 636.30.

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

[0326] A mixture of (3R,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (1420.6 mg, 2.19 mmol) and 10% palladium on carbon (151.3 mg) in ethanol (30 mL) was stirred at room temperature under a H2 atmosphere. After 2 hours, the reaction mixture was filtered, the filtrate was concentrated, and dried in vacuo for 30 minutes. ES / MS m / z: Calculated for C29H40F2N3O7Si (M+EtOH+H): 608.26, Found: 608.30.

[0327] The above residue and potassium carbonate (614.5 mg, 4.45 mmol) in DMF (13 mL) were stirred at room temperature, and benzyl bromide (0.35 mL, 2.94 mmol) was added. After stirring overnight at room temperature, the reaction mixture was diluted with water (about 30 mL), and the product was extracted with ethyl acetate (×2). The extracts were washed with water (×1), combined, dried (MgSO4), and concentrated. The residue was purified by column chromatography (40 g column) on silica gel eluting with 0 - 10% methanol in CH2Cl2 to give (3R,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide: ES / MS m / z: calculated for C34H42F2N3O7Si(M + H2O + H): 670.28, found: 670.30; calculated for C35H44F2N3O7Si(M + MeOH + H): 684.29, found: 684.40. Steps 7 - 8: Synthesis of (3R,6S,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide:

[0328] A solution of (3R,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (1234.0 mg, 1.89 mmol) in methanol (18 mL) was stirred at 0 °C while adding NaBH4 (156.2 mg, 4.13 mmol). After 1 hour at 0 °C, the reaction mixture was concentrated, the residue was dissolved in water, and then extracted with EtOAc (×2). The combined extracts were dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (80 g column) eluting with 0 - 10% methanol in CH2Cl2 to give (3R,6S,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-6-hydroxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide. ES / MS m / z: Calculated for C34H42F2N3O6Si (M + H): 654.28, Found: 654.30.

[0329] A solution of the above product (221.3 mg, 0.338 mmol) in DMF (2.25 mL) was stirred at 0 °C while adding 60% sodium hydride dispersion (19.1 mg, 0.498 mmol). After 20 minutes at 0 °C, a solution of iodomethane (0.021 mL, 0.337 mmol) was added. After 1 hour at 0 °C, additional iodomethane (0.021 mL, 0.337 mmol) was added to the reaction mixture. After about 1 hour at 0 °C, the reaction mixture was diluted with saturated NH4Cl and the product was extracted with ethyl acetate (×2). The extract was washed with water (×1), then the organic fractions were combined, dried (MgSO4), and concentrated. The residue was purified by column chromatography (120 g column) on silica gel eluting with 0 - 10% methanol in CH2Cl2. The fractions containing the product were combined, concentrated, and the residue was purified again by column chromatography on silica gel (24 g column) eluting with 20 - 100% ethyl acetate in hexane to give a mixture of the reactant and (3R,6S,7R)-12-(benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide. ES / MS m / z: Calculated for C35H44F2N3O6Si(M+H): 668.30, Found: 668.30. Step 9: Synthesis of (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide:

[0330] (3R,6S,7R)-12-(Benzyloxy)-3-(((tert-butyldimethylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (333 mg, 0.494 mmol) was dissolved in 4N HCl (3 mL) in dioxane in a 0 °C bath and stirred at 0 °C for 30 minutes. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel eluting with 0-15% methanol in CH2Cl2 (24 g column) to give (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide. ES / MS m / z: Calculated for C28H28F2N3O6 (M+H): 554.21, Found: 554.30. Steps 10-11 Synthesis of (3R,6S,7R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12-hydroxy-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide:

[0331] A solution of (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide (50.3 mg, 0.0909 mmol) in CH2Cl2 (2.5 mL) was stirred at 0 °C while adding (diethylamino)sulfur trifluoride (0.05 mL, 0.378 mmol). After 30 minutes, the reaction mixture was stirred at room temperature overnight. The reaction mixture was stirred at 0 °C and saturated NaHCO3 (5 mL) was added. The mixture was diluted with water (20 mL) and the product was extracted with CH2Cl2 (2 × 20 mL). The combined extracts were dried (MgSO4) and concentrated to give the crude product (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazepine-10-carboxamide. ES / MS m / z: calculated for C29H29F3N3O5(M+H): 556.21, found: 556.30.

[0332] The fluorinated crude product was dissolved in trifluoroacetic acid (3 mL) and stirred at room temperature for 1.5 h. The reaction mixture was concentrated, and the residue was purified by preparative HPLC eluting with 15 - 70% acetonitrile (0.1% TFA) in water (0.1% TFA) over 20 min (column, Gemini 5um C18 110A, LC column 100×30 mm) to give (3R,6S,7R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12-hydroxy-6-methoxy-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide. 1H NMR (400 MHz, chloroform-d) δ 10.49 (t, J = 5.9 Hz, 1H), 9.63 (s, 2H), 8.44 (s, 1H), 7.36 (td, J = 8.6, 6.6 Hz, 1H), 6.87 - 6.74 (m, 2H), 4.84 - 4.67 (m, 1H), 4.67 - 4.62 (m, 3H), 4.62 - 4.50 (m, 1H), 4.48 (dd, J = 5.7, 2.8 Hz, 1H), 3.86 (dd, J = 15.5, 3.1 Hz, 1H), 3.74 (dt, J = 15.5, 1.3 Hz, 1H), 3.50 - 3.42 (m, 1H), 3.41 (s, 3H), 2.20 - 2.01 (m, 2H), 1.98 - 1.79 (m, 1H), 1.14 (dt, J = 13.9, 11.6 Hz, 1H); 19F NMR (376 MHz, chloroform-d) δ -76.43, -111.94 (p, J = 7.8 Hz), -114.64--114.87 (m); ES / MS m / z: calculated for C22H23F3N3O5 (M + H): 466.16, found: 466.20. Example 42: (3R,6S,7R)-N-(2,4-Difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide [Chemical Structure] Project 1-2: Synthesis of (3R,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide:

[0333] (3R,7R)-12-(Benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide was prepared according to the procedure for preparing Intermediate B, except that benzyl (3S,7R)-3-(((benzyloxy)carbonyl)amino)-7-methyl-2,3,4,7-tetrahydro-1H-azepine-1-carboxylate was used in the first step. ES / MS m / z: Calculated value for C28H24F2N3O5(M+H): 520.17, Measured value: 520.20.

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

[0335] A mixture of (3R,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (0.637 mmol) and 10% palladium on carbon (70 mg) in ethanol (10 mL) was stirred at room temperature for 4 hours under a H2 atmosphere. The reaction mixture was filtered, the filtrate was concentrated, and dried in vacuo for 30 minutes.

[0336] When adding benzyl bromide (0.1 mg, 0.841 mmol), the residue in DMF (3.8 mL) and potassium carbonate (179.0 mg, 1.3 mmol) were stirred at room temperature. After one night, the reaction mixture was diluted with water (30 mL), and the product was extracted with ethyl acetate (×2). The extracts were washed with water (×1), combined, dried (MgSO4), and concentrated. The residue was purified by column chromatography on silica gel (40 g column) eluting with 20 - 100% ethyl acetate in hexane to obtain (3R,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide. ES / MS m / z: Calculated for C28H26F2N3O5(M + H): 522.18, Found: 522.20. Step 4: Synthesis of (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-methoxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide:

[0337] A solution of (3R,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (125.1 mg, 0.24 mmol) in methanol (3 mL) was stirred at 0 °C while adding NaBH4 (28.9 mg, 0.764 mmol). After 1 hour at 0 °C, the reaction mixture was concentrated, and the residue was dissolved in water (ca. 30 mL) and then extracted with ethyl acetate (20 mL × 2). The combined extracts were dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (24 g column) eluting with 0–20% methanol in CH2Cl2 to give (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide: ES / MS m / z: calculated for C28H28F2N3O5(M+H): 524.20, found: 524.30.

[0338] A solution of the above alcohol (73.2 mg, 0.140 mmol) in DMF (1.5 mL) was stirred at 0 °C while adding 60% sodium hydride dispersion (10.5 mg, 0.274 mmol). After 20 minutes at 0 °C, a solution of iodomethane (0.0104 mL, 0.168 mmol), 0.21 mL, 0.337 mmol) was added. After 1 hour at 0 °C, the reaction mixture was diluted with saturated NaHCO3 solution, and the product was extracted with ethyl acetate (×2). The combined extracts were dried (MgSO4) and concentrated. The residue was purified by preparative HPLC eluting with 20 - 100% acetonitrile (0.1% TFA) in water (0.1% TFA) over 30 minutes (column, Gemini 5um C18 110A, LC column 100×30 mm) to obtain (3R,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-methoxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide. ES / MS m / z: Calculated for C29H30F2N3O5(M+H): 538.22, Found: 538.30. Step 5: Synthesis of (3R,6S,7R)-N-(2,4-difluorobenzyl)-12-hydroxy-6-methoxy-3-methyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide:

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

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

[0341] To a stirred solution of (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (220 mg, 0.409 mmol) in a dry mixture of THF:Et 2 O (12 mL, 1:1, v / v) cooled to -78 °C was added fluoromethyliodide (164 mg, 2.5 equiv). Then a solution of the MeLi-LiBr complex (1.5 M in Et2O, 2 equiv) was added dropwise. After stirring at -78 °C for 5 minutes, the reaction mixture was quenched with saturated NH 4 Cl aqueous solution (1 mL). The mixture was poured into water (50 mL) and extracted with EtOAc. The organic layer was dried over MgSO 4 and filtered, and concentrated under vacuum. The crude product was subjected to flash chromatography to give (3S,6S,7R)-12-(benzyloxy)-6-(fluoromethyl)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide. MS (m / z) 572.157 [M+H] + . Step 2: Synthesis of (3S,6S,7R)-6-(fluoromethyl)-6,12-dihydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide:

[0342] (3S,6S,7R)-12-(Benzyloxy)-6-(fluoromethyl)-6-hydroxy-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazocin-10-carboxamide (5.8 mg, 0.0102 mmol) was dissolved in MeOH (5.0 mL) at room temperature and treated with 2 mg of 20% Pd(OH) 2 / C (50 wt% water). The mixture was degassed and flushed three times with hydrogen, then hydrogenated overnight under a hydrogen balloon. The reaction was then degassed, flushed with nitrogen, filtered through a pad of celite, concentrated, and the resulting residue was redissolved in DMF, filtered, and purified by reverse-phase HPLC. MS (m / z) 484.227 [M+H] + . 1H NMR (400 MHz, chloroform-d) δ 11.12 (s, 1H), 10.22 (t, J = 5.7 Hz, 1H), 8.35 (s, 1H), 6.65 (dd, J = 8.7, 7.5 Hz, 2H), 4.81 - 4.60 (m, 4H), 4.60 - 4.49 (m, 1H), 4.45 (dd, J = 14.5, 5.1 Hz, 1H), 4.26 (s, 1H), 3.79 - 3.62 (m, 2H), 2.15 - 2.05 (m, 1H), 2.00 - 1.92 (m, 1H), 1.80 (s, 1H), 1.65 (s, 1H), 1.29 (d, J = 6.8 Hz, 3H). Example 45: Preparation of (3S,4S,7R,8R)-N-(2,4-difluorobenzyl)-13-hydroxy-3-methyl-1,12-dioxo-1,4,5,7,8,12-hexahydro-3H-2,8:4,7-dimethanopyrido[1,2-d][1,4,7]oxadiazocin-11-carboxamide

Chemical formula

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

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

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

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

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

Chemical Structure

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

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

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

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

[0352] The ability to inhibit the replication of HIV-1 (IIIB) in MT-4 cells was tested for compounds in a high-throughput 384-well assay format. Compounds were serially diluted (1:3) in DMSO on 384-well polypropylene plates and further diluted 200-fold in complete RPMI medium (10% FBS, 1% P / S) using a Biotek Micro Flow and a Labcyte ECHO acoustic dispenser. Each plate contained up to 8 test compounds, with negative (no drug control) and 5 μM AZT positive controls. MT-4 cells were pre-infected with either 10 μL of RPMI (mock infection) or fresh 1:250 dilution of the HIV-1 IIIB concentrated virus stock. Infected and uninfected MT-4 cells were further diluted in complete RPMI medium and added to each plate using the Micro Flow dispenser. After incubation for 5 days in a humidified and temperature-controlled incubator (37 °C), Cell Titer Glo (Promega) was added to the assay plates and chemiluminescence was read using an Envision plate reader. EC 50 50 values were defined as the compound concentration that reduced the luminescence signal by 50% and were calculated using a sigmoid dose-response model to generate curve fitting. Cytotoxicity assay in MT-4 cells

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

[0354] To quantify the protein binding amount to human serum, the compound was serially diluted (1:3) in DMSO and acoustically transferred onto 384-well assay plates by a Labcyte ECHO robot. Each plate contained up to 8 test compounds, including negative and positive controls (DMSO and 5 μM AZT, respectively). Two sets of assay plates were prepared and tested either in CCM (cell culture medium) or HS / CCM (human serum / cell culture medium). MT-4 cells were first pre-infected with pLai RLuc reporter virus at 37 °C for 2 hours and then further diluted in CCM (RPMI medium, 10% FBS, 1% P / S) or HS / CCM (RPMI medium, 10% FBS, 50% HS, 1% P / S), and then added to each plate using a Biotek Micro Flow dispenser. After incubation for 72 hours in a humidified and temperature-controlled incubator (37 °C), Renilla Glo (Promega) was added to all assay plates and chemiluminescence readings were taken using an Envision plate reader. EC 50 values were defined as the compound concentration that reduced the luminescence signal by 50% and were calculated using a sigmoid dose-response model to generate curve fitting. To determine the protein binding amount, the fold shift of EC 50 (or EC 50 shift) was calculated by dividing EC 50 (HS / CCM) by EC 50 (CCM).

[0355] The compounds of the present disclosure exhibit antiviral activity in this assay, as shown in Table 1 below. Accordingly, the compounds of the embodiments disclosed herein may be useful for the growth of HIV virus, the treatment of AIDS, or the delay in the onset of AIDS or ARC symptoms. Example 49: High-Throughput Microsome Stability Assay

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

[0357] A 2 mg / ml solution of alamethicin (Sigma-Aldrich) from Trichoderma viride in 100 mM K 2 HPO 4 / KH 2 PO 4 (pH 7.4) of human (Corning® Gentest™ human pooled microsomes) or rat (Corning® Gentest™ rat [Sprague-Dawley] pooled liver microsomes) liver microsomes was incubated on ice for 15 minutes. After incubation at room temperature for 15 minutes, 5 μL of this solution was added to each well, and 5 μL of an NADPH regeneration solution (Corning® Gentest™ UGT reaction mix) containing cofactors including 100 mM K 2 HPO 4 / KH 2 PO 4 (pH 7.4), 2.6 mM NADP+, 6.6 mM glucose-6-phosphate, 6.6 mM MgCl 2 , 0.8 U / mL glucose-6-phosphate dehydrogenase, 0.1 mM sodium citrate, and 6.8 mM uridine diphosphate-glucuronic acid was added to replenish. The final concentration of the compound to be analyzed at the start of the reaction was 1 μM. The reaction was incubated at 37 °C, and time points at 0, 5, 15, 30, 40, 50, 60, and 70 minutes were collected for further analysis. Background data was collected using a reaction without the analyte compound.

[0358] At the time of collecting the reaction point, the sample was quenched with a solution of 72% acetonitrile, 8% methanol, 0.1% formic acid, 19.9% water, and 30 uL of internal standard (IS). After diluting 10 uL of the quenched reactant with 40 uL of deionized water, the reaction plate was centrifuged at 4,000 rcf for 30 minutes at 4 °C to obtain an assay plate.

[0359] The assay plate was analyzed using a C4 type A solid cartridge with solid-phase extraction coupled to a quadrupole time-of-flight mass spectrometer using an Agilent QToF 6530 RapidFire 360 system. The analysis was performed in either positive or negative ionization mode. The mobile phase contained 0.1% formic acid in water for loading the analyte onto the solid-phase extraction cartridge and 0.1% formic acid in acetonitrile for eluting into the mass spectrometer in positive ionization mode, or 0.1% acetic acid in water for loading and 0.1% acetic acid in acetonitrile for extraction in negative ionization mode. The peak area ratio of the integrated count of the individual compound to the IS was plotted as a semi-log chart of logarithm vs. time. The initial linear portion of the decay was fitted to a linear regression equation to derive the half-life of the compound decay.

[0360] Pharmacological parameters for analyte compound metabolism were calculated using the following equations.

Table 1

Equation

[0361] Concentration refers to the protein concentration (mg / mL) in the reactant.

Table 2

[0362] Thus, in vitro intrinsic clearance is determined with the predicted value for the total mass of liver tissue as the upper limit (however, there is no restriction by blood flow). The value depends on the size of the liver (species-dependent) and, if necessary, the yield of microsomal protein (assumed to be species-independent).

Number

Table 3

Table 4

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

Number

Table 5

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

[0365] The intrinsic clearances of the compounds of the present invention and reference compounds A - F were calculated according to the above procedure. The results of these compounds are shown in Table 2 below. As can be seen, the compounds of the present invention are 1.5 - 3.6 times more stable than reference compounds A - F.

Table 6

Table 7-1

Table 7-2

Table 7-3

[0366] All references, including publications, patents, and patent documents, are hereby incorporated by reference as if individually incorporated by reference. The present disclosure refers to various embodiments and techniques. However, it should be understood that many variations and modifications can be made while staying within the spirit and scope of the present disclosure. The description should be regarded as illustrative of the claimed subject matter and is not intended to limit the appended claims to the specific embodiments illustrated. In one embodiment, for example, the following items are provided. (Item 1) A compound of formula I,

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Chem.

Claims

1. A compound of formula I, 【Chemical 1】 wherein, R １ is C ６～１０ aryl or 5- to 10-membered heteroaryl, and said C ６～１０ aryl or 5- to 10-membered heteroaryl is optionally substituted with 1 to 4 R Ａ１ s, each R Ａ１ independently being halo, C １～６ alkyl, C １～４ haloalkyl, cyano, -O-C １～４ alkyl, or C １～４ alkyl-O-C １～４ alkyl; R ２ is H, C １～６ alkyl, or C １～４ haloalkyl, and R ３ is a halo or -OR ３ａ wherein R ３ａ is H, -C １～６ alkyl, -C １～４ haloalkyl, or -C ３～６ cycloalkyl, or R ３ａ and R ６ａ together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms of O, R ３ｂ is H, -C １～６ alkyl, -C １～４ haloalkyl, or -C １～４ alkylene - O - C １～４ alkyl, and R ４ａ is -C １～６ alkyl or -C １～４ haloalkyl, and R ４ｂ is H, halo, -C １～６ alkyl, or -C １～４ haloalkyl, and W １ is bonded or -CR ５ａ R ５ｂ - and R ５ａ and R ５ｂ are each, independently, H, C １～６ alkyl, C １～４ haloalkyl, or halo, and W ２ is -CR ６ａ R ６ｂ - or -CR ７ａ =CR ７ｂ - and R ６ａ and R ６ｂ are each 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 R ６ａ and R ３ａ together with the carbon to which they are attached form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms of O, and R ６ｂ is H, C １～６ alkyl, C １～４ haloalkyl, halo, hydroxyl, cyano, -O-C １～４ alkyl, or C １～４ alkylene-O-C １～４ alkyl, and R ７ａ and R ７ｂ are each, independently, H, halo, C １～４ haloalkyl, or C １～６ alkyl, a compound or a pharmaceutically acceptable salt thereof.

2. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula Ia: 【Chemical 2】

3. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula Ib: [Chemical Formula 3]

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula Ic: [Chemical Formula 4]

5. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is a compound of formula Id: [Chemical Formula 5]

6. R １ is phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine, and the phenyl, pyridyl, pyridazine, pyrazine, or pyrimidine is optionally substituted with one, two, three, or four R Ａ１ groups, and each R Ａ１ is independently halo, C １～６ alkyl, C １～４ haloalkyl, cyano, -O-C １～４ alkyl, or -C １～４ alkyl-O-C １～４ alkyl, a compound according to any one of claims 1 to 5 or a pharmaceutically acceptable salt thereof.

7. R １ is phenyl or pyridyl, and said phenyl or pyridyl is optionally substituted with one, two, three, or four R Ａ１ groups, each R Ａ１ independently being halo, C １～６ alkyl, C １～４ haloalkyl, cyano, -O-C １～４ alkyl, or -C １～４ alkyl-O-C １～４ alkyl, a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

8. R １ is phenyl or pyridyl, and the phenyl or pyridyl is substituted with one, two, three, or four R Ａ１ groups, and each R Ａ１ is independently halogen, the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof.

9. R １ is phenyl or pyridyl, and the phenyl or pyridyl is substituted with two or three R Ａ１ groups, and each R Ａ１ is independently selected from chloro and fluoro, a compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

10. R １ is pyridyl, and said pyridyl is optionally substituted with one, two, three, or four R Ａ１ , and each R Ａ１ is independently halo, C １～６ alkyl, C １～４ haloalkyl, cyano, -O-C １～４ alkyl, or -C １～４ alkyl-O-C １～４ alkyl, a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

11. R １ is pyridyl, and the pyridyl is substituted with one, two, three, or four R Ａ１ groups, and each R Ａ１ is independently halogen, the compound according to any one of claims 1 to 8 and 10, or a pharmaceutically acceptable salt thereof.

12. R １ is pyridyl, and the pyridyl is substituted with two or three R Ａ１ s, and each R Ａ１ is independently selected from chloro and fluoro, the compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof.

13. R １ is phenyl optionally substituted with one, two, three, or four R Ａ１ each R Ａ１ being independently halo, C １～４ alkyl, C １～４ haloalkyl, or -O-C １～４ alkyl, a compound according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

14. R １ is phenyl substituted with one, two, three or four R Ａ１ and each R Ａ１ is independently halogen, a compound according to any one of claims 1 to 7 and 13 or a pharmaceutically acceptable salt thereof.

15. R １ is phenyl substituted with two or three R Ａ１ where each R Ａ１ is independently selected from chloro and fluoro, a compound according to any one of claims 1 to 7, 13, and 14, or a pharmaceutically acceptable salt thereof.

16. R １ is 【Chemical Formula 6】 The compound according to any one of claims 1 to 15, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

17. The compound has formula II, [Chemical Formula 7] wherein n is 2, 3, or 4, and each R Ａ１ is independently halo, C １～６ alkyl, C １～４ haloalkyl, cyano, -O-C １～４ alkyl, or C １～４ alkyl-O-C １～４ alkyl, a compound according to any one of claims 1 to 8 and 13 to 15, or a pharmaceutically acceptable salt thereof.

18. Each R Ａ１ is independently halo, C １～６ alkyl, C １～４ haloalkyl, cyano, or -O-C １～４ alkyl, a compound according to any one of claims 1 to 17 or a pharmaceutically acceptable salt thereof.

19. Each R Ａ１ is independently a halo, a compound according to any one of claims 1 to 18 or a pharmaceutically acceptable salt thereof.

20. Each R Ａ１ is independently chloro or fluoro, a compound according to any one of claims 1 to 19 or a pharmaceutically acceptable salt thereof.

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

22. R ２ is H or C １～４ The compound according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, wherein R is haloalkyl.

23. R ２ is C １～６ alkyl or C １～４ haloalkyl, the compound according to any one of claims 1 to 20 or a pharmaceutically acceptable salt thereof.

24. R ２ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 22, wherein R is H.

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

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

27. R ３ is OR ３ａ The compound according to any one of claims 1 to 24 or a pharmaceutically acceptable salt thereof, wherein

28. R ４ａ is -C １～４ is haloalkyl, the compound according to any one of claims 1 to 27 or a pharmaceutically acceptable salt thereof.

29. R ４ａ is -C １～３ alkyl, the compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof.

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

31. R ４ｂ is H, -C １～４ haloalkyl, or -C １～３ alkyl, a compound according to any one of claims 1 to 30 or a pharmaceutically acceptable salt thereof.

32. R ４ｂ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 31, wherein R is H.

33. R ３ａ is -C １～６ alkyl, -C １～４ haloalkyl, or -C ３～６ cycloalkyl, and R ３ｂ is H, -C １～６ alkyl, -C １～４ haloalkyl, or -C １～４ alkylene-O-C １～４ alkyl, a compound according to any one of claims 27 to 32 when not dependent on claims 1 to 24 and claim 25 or 26, or a pharmaceutically acceptable salt thereof.

34. R ３ａ is -C １～６ alkyl or -C １～４ haloalkyl, a compound according to any one of claims 27 to 33 when not dependent on claims 1 to 24 and claim 25 or 26, or a pharmaceutically acceptable salt thereof.

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

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

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

38. R ３ａ and R ６ａ which, together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one or two heteroatoms of O, a compound according to any one of claims 27 to 32 or a pharmaceutically acceptable salt thereof when not dependent on claims 1 to 24 and claim 25 or 26.

39. R ３ａ and R ６ａ which, together with the carbon to which they are attached, form a 4- to 6-membered heterocyclic ring containing one oxygen atom, a compound according to any one of claims 27 to 32 and 38 or a pharmaceutically acceptable salt thereof when not dependent on claims 1 to 24 and claim 25 or 26.

40. R ３ｂ is H, -C １～６ alkyl, -C １～４ haloalkyl, the compound according to any one of claims 1 to 39 or a pharmaceutically acceptable salt thereof.

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

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

43. R ３ｂ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 42, wherein R is H or methyl.

44. R ３ｂ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 43, wherein R is H.

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

46. W １ is -CR ５ａ R ５ｂ - and is the compound according to any one of claims 1 to 44 or a pharmaceutically acceptable salt thereof.

47. R ５ａ is H, C １～６ alkyl, C １～４ haloalkyl, or halo, and R ５ｂ is H or halo, the compound according to any one of claims 1 to 46 or a pharmaceutically acceptable salt thereof.

48. R ５ａ is H or halo, and R ５ｂ is H or halo, a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof.

49. R ５ａ is H, C １～６ alkyl, C １～４ haloalkyl, or halo, and R ５ｂ is H, a compound according to any one of claims 1 to 47 or a pharmaceutically acceptable salt thereof.

50. R ５ａ is H, and R ５ｂ is H, the compound according to any one of claims 1 to 49 or a pharmaceutically acceptable salt thereof.

51. W ２ is -CR ６ａ R ６ｂ -, the compound according to any one of claims 1 to 50 or a pharmaceutically acceptable salt thereof.

52. R ６ａ is H, and R ６ｂ is H, C １～６ alkyl, C １～４ haloalkyl, halo, hydroxyl, cyano, -O-C １～４ alkyl, or C １～４ alkylene-O-C １～４ alkyl, the compound according to any one of claims 1 to 51 or a pharmaceutically acceptable salt thereof.

53. R ６ａ is H, and R ６ｂ is H, the compound according to any one of claims 1 to 52, or a pharmaceutically acceptable salt thereof.

54. W ２ is -CR ７ａ =CR ７ｂ —, a compound according to any one of claims 1 to 53 or a pharmaceutically acceptable salt thereof.

55. R ７ａ and R ７ｂ are each, independently, H, halo, C １～４ haloalkyl, or C １～６ alkyl, a compound according to any one of claims 1 to 50 and 54 or a pharmaceutically acceptable salt thereof.

56. R ７ａ is H, and R ７ｂ is H, the compound according to any one of claims 1 to 50 and 54 to 55, or a pharmaceutically acceptable salt thereof.

57. A compound of formula Ic, 【Chemical 1】 wherein, R １ is phenyl or pyridyl, and the phenyl or pyridyl is substituted with one, two, three, or four R Ａ１ groups, where each R Ａ１ is independently halogen, R ２ is H or C １～６ and is alkyl, R ３ａ is H, -C １～６ alkyl, -C １～４ haloalkyl, or -C ３～６ cycloalkyl, and R ３ｂ is H, -C １～６ alkyl, -C １～４ haloalkyl, or -C １～４ alkylene-O-C １～４ alkyl, and R ４ａ is -C １～３ alkyl, and R ４ｂ is H, and W １ is -CR ５ａ R ５ｂ -. R ５ａ and R ５ｂ are each independently H, C １～６ alkyl, C １～４ haloalkyl, or halo, W ２ is -CR ６ａ R ６ｂ -, and R ６ａ and R ６ｂ are each 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, the compound or a pharmaceutically acceptable salt thereof.

58. R １ is phenyl or pyridyl, wherein said phenyl or pyridyl is substituted with two or three Rs Ａ１ and each R Ａ１ is independently selected from chloro and fluoro, the compound according to claim 57 or a pharmaceutically acceptable salt thereof.

59. R １ is phenyl substituted with one, two, three, or four Rs Ａ１ wherein each R Ａ１ is independently halogen, the compound according to claim 57, or a pharmaceutically acceptable salt thereof.

60. R １ is phenyl substituted with two or three Rs Ａ１ and each R Ａ１ is independently selected from chloro and fluoro, a compound according to any one of claims 57 to 59 or a pharmaceutically acceptable salt thereof.

61. R １ is 【Chemical Formula 6】 The compound according to any one of claims 57 to 60, or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

62. Each R Ａ１ is independently chloro or fluoro, a compound according to any one of claims 57 to 61 or a pharmaceutically acceptable salt thereof.

63. R ２ The compound according to any one of claims 57 to 62, or a pharmaceutically acceptable salt thereof, wherein R is H.

64. R ３ａ is -C １～６ alkyl or -C １～４ haloalkyl, a compound according to any one of claims 57 to 63 or a pharmaceutically acceptable salt thereof.

65. R ３ａ is -C １～６ alkyl, a compound according to any one of claims 57 to 64 or a pharmaceutically acceptable salt thereof.

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

67. R ３ｂ is H, -C １～６ alkyl, -C １～４ haloalkyl, a compound according to any one of claims 57 to 66 or a pharmaceutically acceptable salt thereof.

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

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

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

71. R ３ｂ The compound or a pharmaceutically acceptable salt thereof according to any one of claims 57 to 70, wherein R is H.

72. R ５ａ is H, C １～６ alkyl, C １～４ haloalkyl, or halo, and R ５ｂ is H or halo, the compound according to any one of claims 57 to 71, or a pharmaceutically acceptable salt thereof.

73. R ５ａ is H or halo, and R ５ｂ is H or halo, the compound according to any one of claims 57 to 72 or a pharmaceutically acceptable salt thereof.

74. R ６ａ is H, and R ６ｂ is H, C １～６ alkyl, C １～４ haloalkyl, halo, hydroxyl, cyano, -O-C １～４ alkyl, or C １～４ alkylene-O-C １～４ alkyl, the compound according to any one of claims 57 to 73 or a pharmaceutically acceptable salt thereof.

75. R ６ａ is H and R ６ｂ is H, a compound according to any one of claims 57 to 74 or a pharmaceutically acceptable salt thereof.

76. 【Fig. 8】 The compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

77. 【Fig. 9】 【Chemical 10】 【Chemical 11】 The compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

78. 【Fig. 12】 The compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

79. 【Fig. 13】 【Chemical Formula 14】 【Chemical Formula 15】 The compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

80. 【Fig. 16】 A compound selected from the group consisting of or a pharmaceutically acceptable salt thereof.

81. Formula: 【Chemical 17】 The compound of or a pharmaceutically acceptable salt thereof.

82. Formula: 【Chemical Formula 18】 The compound of or a pharmaceutically acceptable salt thereof.

83. Formula: 【Chemical Formula 19】 The compound of or a pharmaceutically acceptable salt thereof.

84. Formula: 【Chemical 20】 The compound of or a pharmaceutically acceptable salt thereof.

85. Formula: 【Chemical 21】 The compound of or a pharmaceutically acceptable salt thereof.

86. Formula: 【Chemical 22】 The compound of or a pharmaceutically acceptable salt thereof.

87. Formula: 【Chemical 23】 The compound of or a pharmaceutically acceptable salt thereof.

88. Formula: 【Chemical 24】 The compound of or a pharmaceutically acceptable salt thereof.

89. Formula: 【Chemical 25】 The compound of or a pharmaceutically acceptable salt thereof.

90. Formula: 【Chemical 26】 The compound of or a pharmaceutically acceptable salt thereof.

91. A pharmaceutical composition comprising a therapeutically effective amount of the compound according to any one of claims 1 to 90 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable additive.

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

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

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

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

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

97. A kit comprising the compound according to any one of claims 1 to 90 or a pharmaceutically acceptable salt thereof and an instruction manual.

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

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

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

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

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

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

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

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

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

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

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

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

110. The composition according to claim 109, characterized in that the composition is used in combination with one, two, three or four additional therapeutic agents.

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

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

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

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

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

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