Crosslinked tricyclic carbamoylpyridone compounds and their use

Abstract

Providing a crosslinked tricyclic carbamoylpyridone compound and its use. [Solution] This disclosure generally relates to compounds of formula I. Pharmaceutical compositions containing such compounds and methods for preparing such compounds are also disclosed. The compounds of this disclosure are useful for treating or preventing human immunodeficiency virus (HIV) infection. This disclosure relates to novel compounds having antiviral activity and pharmaceutically acceptable salts thereof. In some embodiments, the compounds may be used to treat HIV infection, to inhibit the activity of HIV integrase, and / or to reduce HIV replication. TIFF2026099939000408.tif31128

Description

[Technical Field]

[0001] Cross-reference of related applications This application claims priority to U.S. Provisional Patent Application No. 63 / 328,061, filed on April 6, 2022, and to U.S. Provisional Patent Application No. 63 / 476,873, filed on December 22, 2022. The entire contents of these applications are incorporated herein by reference for all purposes.

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

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

[0004] The goal of antiretroviral therapy is to achieve viral suppression in HIV-infected patients. Current treatment guidelines published by the United States Department of Health and Human Services indicate that achieving viral suppression requires the use of combination therapy, i.e., the use of several drugs from at least two or more drug classes (Panel on Antiretroviral Guidelines for Adults and Adolescents.Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV.Department of Health and Human Services.Available at http: / / www.aidsinfo.nih.gov / ContentFiles / AdultandAdolescentGL.pdf.Accessed February 12, 2019). In addition, decisions regarding the treatment of HIV-infected patients are complicated when patients require treatment for other medical conditions (ibid. F-8). Standard treatment requires the use of multiple different drugs to suppress HIV and to treat other conditions the patient may experience, so the possibility of drug interactions is a criterion for selecting drug regimens. Therefore, antiretroviral therapies with a reduced likelihood of drug interactions are needed.

[0005] In addition, the HIV virus is known to mutate in infected individuals (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). For certain patients, for example, those with limited or difficult access to healthcare, adhering to daily oral therapy or prophylactic regimens can be challenging. Drugs offering desirable pharmaceutical properties (e.g., improved potency, long-acting pharmacokinetics, low solubility, low clearance, and / or other properties) are suitable for less frequent administration and provide better patient compliance. Such improvements, in turn, lead to optimized drug exposure and limited development of drug tolerance. [Prior art documents] [Non-patent literature]

[0006] [Non-Patent Document 1] Palella, et al. N. Engl. J Med. (1998) 338:853-860 [Non-Patent Document 2] Richman, DDNature (2001) 410:995-1001 [Non-Patent Document 3] Panel on Antiretroviral Guidelines for Adults and Adolescents.Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV.Department of Health and Human Services.http: / / www.aidsinfo.nih.gov / ContentFiles / AdultandAdolescentGL.pdf. [Non-Patent Document 4] Tang,et al.Drugs(2012)72(9)e1-e25 [Non-Patent Document 5] Hurt, et al.HIV / AIDS CID(2014)58,423-431 [Overview of the Initiative]

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

[0008] In one embodiment, the present disclosure provides a compound of formula (I),

Chemical formula

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

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

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

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

[0013] In another embodiment, the use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, is provided in the manufacture of a medicament for treating HIV infection in a person who has or is at risk of having the infection.

[0014] In another embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, is provided for use in medical therapy.

[0015] In another embodiment, a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of HIV infection.

[0016] Other embodiments, purposes, features, and advantages may be described in the following detailed descriptions of embodiments, some of which may be apparent from the description of the claimed embodiments or may be acquired through practice. These purposes and advantages may be realized and achieved by processes and compositions specifically indicated in the detailed descriptions and claims. The above summary should be considered as a brief and general overview of some of the embodiments disclosed herein, provided for the benefit and convenience of the reader, and made with the understanding that the appended claims are not intended to limit in any way the scope of legal rights or equivalents. [Modes for carrying out the invention]

[0017] The following description includes certain specific details in order to provide a complete understanding of the various embodiments disclosed herein. However, those skilled in the art will understand that the embodiments disclosed herein can be carried out without these details. The following descriptions of some embodiments are made with the understanding that this disclosure should be considered as illustrative of the subject matter described in the claims and is not intended to limit the appended claims to the specific embodiments described herein. The headings used throughout this disclosure are provided for convenience only and should not be construed as limiting the claims. Embodiments illustrated under any heading may be combined with embodiments illustrated under any other heading.

[0018] I. Definition Unless otherwise required by context, the word “comprise” and its variations, such as “comprises,” throughout this specification and the claims, shall not be used. The term "comprising" should be interpreted in an open and inclusive sense, meaning "includes, but is not limited to."

[0019] Throughout this specification, any reference to “one embodiment” or “embodiment” means that a particular feature, structure, or characteristic described in relation to an embodiment is included in at least one embodiment disclosed herein. Therefore, occurrences of the phrase “in one embodiment” or “in an embodiment” in various places throughout this specification do not necessarily all refer to the same embodiment. Furthermore, a particular feature, structure, or characteristic may be combined in any preferred manner in one or more embodiments.

[0020] "Amino" refers to the -NH2 radical.

[0021] "Hydroxy" or "hydroxyl" refers to the -OH radical.

[0022] As used herein, the term "C 1~n"Alkyl" is intended to mean an acyclic, linear, or branched alkyl radical containing 1 to n carbon atoms, either alone or in combination with another radical. 1~6 "Alkyl" includes, but is not limited to, methyl, ethyl, propyl (n-propyl), butyl (n-butyl), 1-methylethyl (isopropyl), 1-methylpropyl (sec-butyl), 2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), pentyl, and hexyl. The abbreviations Me represents a methyl group, Et represents an ethyl group, Pr represents a propyl group, iPr represents a 1-methylethyl group, Bu represents a butyl group, and tBu represents a 1,1-dimethylethyl group.

[0023] "Alkyl" refers to hydrocarbons containing normal, secondary, or tertiary atoms. For example, alkyl groups contain 1 to 20 carbon atoms (i.e., C1-). 20 Alkyl), 1 to 10 carbon atoms (i.e., C1- 10The alkyl group may have 1 to 8 carbon atoms (i.e., C1-8 alkyl) or 1 to 6 carbon atoms (i.e., C1-6 alkyl). Suitable examples of alkyl groups include methyl (Me, -CH3), ethyl (Et, CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, CH(CH3)CH2CH3), and 2-methyl-2-propyl (t-Bu, t Butyl, -C(CH3)3), 1-Pentyl (n-Pentyl, CH2CH2CH2CH2CH3), 2-Pentyl (CH(CH3)CH2CH2CH3), 3-Pentyl (CH(CH2CH3)2), 2-Methyl-2-butyl (C(CH3)2CH2CH3), 3-Methyl-2-butyl (CH(CH3)CH(CH3)2), 3-Methyl-1-butyl (CH2CH2CH(CH3)2), 2-Methyl-1-butyl (CH2CH(CH3)CH2CH3), 1-Hexyl (CH2CH2CH2CH2CH2 CH3), 2-hexyl(CH(CH3)CH2CH2CH2CH3), 3-hexyl(CH(CH2CH3)(CH2CH2CH3)), 2methyl-2-pentyl(C(CH3)2CH2CH2CH3), 3methyl-2-pentyl(CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl(CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl(-C(CH3)(CH2CH3)2), 2methyl-3-pentyl(-CH(CH2CH3)CH(CH3)2) Examples include, but are not limited to, 2,3-dimethyl-2-butyl (C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), and octyl ((CH2)7CH3). "Alkyl" also refers to a saturated branched or linear 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, alkyl groups have 1 to 10 carbon atoms (i.e., C1- 10Alkyl radicals may have 1 to 6 carbon atoms (i.e., C1-6 alkyl) or 1 to 3 carbon atoms (i.e., C1-3 alkyl). Typical alkyl radicals include, but are not limited to, methylene (CH2), 1,1-ethyl (CH(CH3)), 1,2-ethyl (CH2CH2), 1,1-propyl (CH(CH2CH3)), 1,2-propyl (CH2CH(CH3)), 1,3-propyl (CH2CH2CH2), and 1,4-butyl (CH2CH2CH2CH2).

[0024] As used herein, the term “alkenyl” means a carbon atom comprising normal, secondary, or tertiary carbon atoms, with at least one unsaturated site, i.e., carbon-carbon, sp 2 This refers to a straight-chain or branched hydrocarbon having a double bond. For example, an alkenyl group has 2 to 20 carbon atoms (i.e., C2 to C2). 20 Alkenyl, or C2~ 20 The alkenyl group may have 2 to 8 carbon atoms (i.e., C2-C8 alkenyl or C2-8), or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl or C2-6 alkenyl). Suitable examples of alkenyl groups include, but are not limited to, ethylene or vinyl (CH=CH2), allyl (CH2CH=CH2), cyclopentenyl (C5H7), and 5-hexenyl (CH2CH2CH2CH2CH=CH2).

[0025] When used herein, "C 2~n The term "alkenyl" (wherein n is an integer) is intended to mean an unsaturated acyclic straight-chain or branched-chain radical containing 2 to n carbon atoms (at least two of which are bonded to each other by double bonds), either alone or in combination with another radical. Examples of such radicals include, but are not limited to, ethenyl (vinyl), 1-propenyl, 2-propenyl, and 1-butenyl. Unless otherwise specified, "C 2~n The term “alkenyl” is understood to encompass individual stereoisomers, including, but not limited to, the (E) and (Z) isomers, as well as mixtures thereof, where possible.2~n When an alkenyl group is substituted, unless otherwise specified, it is understood that the substitution occurs on any carbon atom that would otherwise support a hydrogen atom, and that the substitution results in a chemically stable compound as recognized by those skilled in the art.

[0026] "Alkynyl" is a straight-chain or branched-chain hydrocarbon containing normal, secondary, or tertiary carbon atoms and having at least one unsaturated site, i.e., a carbon-carbon, sp triple bond. For example, an alkynyl group has 2 to 20 carbon atoms (i.e., C2- 20 The alkynyl group may have 2 to 8 carbon atoms (i.e., C2-8 alkynes), or 2 to 6 carbon atoms (i.e., C2-6 alkynyl). Suitable examples of alkynyl groups include, but are not limited to, acetylenyl (C=CH) and propargyl (CH2C=CH).

[0027] When used herein, "C 2~n The term "alkynyl" (wherein n is an integer) is intended to mean an unsaturated acyclic linear or branched radical containing 2 to n carbon atoms (at least two of which are bonded to each other by triple bonds), either alone or in combination with another radical. Examples of such radicals include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, and 1-butynyl. 2~n When an alkynyl group is substituted, unless otherwise specified, it is understood that the substitution occurs on any carbon atom that would otherwise support a hydrogen atom, and as a result, the substitution produces a chemically stable compound as recognized by those skilled in the art.

[0028] "Cyano" or "carbonitrile" refers to the -CN group.

[0029] The terms "halo" or "halogen" as used herein refer to fluoro, chloro, bromo, or iodine.

[0030] The term "haloalkyl," as used herein, refers to an alkyl group as defined herein, in which one or more hydrogen atoms are replaced by halo substituents. For example, a C1-6 haloalkyl group is a C1-6 alkyl group in which one or more of the hydrogen atoms are replaced by halo substituents. Such a range includes one halo substituent on the alkyl group to complete the halogenation of the alkyl group.

[0031] When used herein, "C 1~n The term "haloalkyl" (wherein n is an integer) is intended to mean an alkyl radical having 1 to n carbon atoms as defined above, either alone or in combination with another radical, where one or more hydrogen atoms are each replaced by a halo substituent. 1~n Examples of haloalkyls include, but are not limited to, chloromethyl, chloroethyl, dichloroethyl, bromomethyl, bromoethyl, dibromoethyl, fluoromethyl, difluoromethyl, trifluoromethyl, fluoroethyl, and difluoroethyl.

[0032] As used herein, the term “aryl” refers to a single aromatic ring, or a bicyclic or polycyclic ring. For example, an aryl group may have 6 to 20 carbon atoms, 6 to 14 carbon atoms, or 6 to 12 carbon atoms. Aryls include phenyl radicals or ortho-condensed bicyclic or polycyclic radicals having about 9 to 14 atoms, where at least one ring is an aromatic ring (e.g., one or more aryl rings or aryl rings fused to a carbocyclic ring). Such bicyclic or polycyclic rings may be optionally substituted on any carbocyclic portion of the bicyclic or polycyclic ring with one or more (e.g., 1, 2, or 3) oxo groups. It should be understood that the bonding sites of the bicyclic or polycyclic radicals defined above can be at any position on the ring, including the aryl or carbocyclic portion of the ring. Typical aryl groups include, but are not limited to, phenyl, indenyl, naphthyl, 1,2,3,4-tetrahydronaphthyl, and anthracenyl.

[0033] The terms “heteroaryl,” “heteroaryl ring,” or “heteroaromatic ring,” as used herein, refer to a single aromatic ring or a multiple condensed ring. The term includes an aromatic monoring of about 1 to 6 carbon atoms and about 1 to 4 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The sulfur and nitrogen atoms may be present in oxidized forms, however the ring is aromatic. Such rings include, but are not limited to, pyridyl, pyrimidinyl, oxazolyl, or furyl. The term also includes multiple condensed rings (e.g., ring systems containing two or three rings), where a heteroaryl group as defined above may condense with one or more heteroaryls (e.g., naphthilidinyl), carbocyclics (e.g., 5,6,7,8-tetrahydroquinolyl), or aryls (e.g., indazolyl) to form a multiple condensed ring. This multiple condensed ring may optionally have the carbocyclic portion of the condensed ring substituted with one or more (e.g., 1, 2, or 3) oxo groups. It should be understood that the bond sites of the heteroaryl multiple condensed ring defined above can be at any position on the ring, including the heteroaryl, aryl, or carbocyclic portion of the ring. Examples of heteroaryls include, but are not limited to, pyridyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyridadinyl, pyrazolyl, thienyl, indolyl, imidazolyl, oxazolyl, thiazolyl, furyl, oxadiazolyl, thiadiazolyl, quinolyl, isoquinolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinoxalyl, quinazolyl, 5,6,7,8-tetrahydroisoquinolinyl, benzofuranil, benzimidazolyl, and thianaphthenyl.

[0034] As used herein, “heterocyclyl,” “heterocyclic,” or “halocycloalkyl” refers to a single saturated or partially unsaturated ring or a multiple fused ring. This term includes saturated or partially unsaturated monocyclic rings (e.g., 3, 4, 5, 6, or 7-membered rings) having about 1 to 6 carbon atoms and about 1 to 3 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur. The ring may be substituted with one or more (e.g., 1, 2, or 3) oxo groups, and the sulfur and nitrogen atoms may also be present in their oxidized forms. Examples of such rings include, but are not limited to, azetidinyl, tetrahydrofuranyl, or piperidinyl. This term also includes multiple fused ring systems (e.g., ring systems containing two or three rings), where a heterocyclic group (as defined above) can be bonded to one or more heterocyclic groups (e.g., decahydronaphthilidinyl), heteroaryl groups (e.g., 1,2,3,4-tetrahydronaphthilidinyl), carbocyclic groups (e.g., decahydroquinolyl), or two adjacent atoms (fused heterocyclic rings) having an aryl group. It should be understood that the bond points of the multiple fused rings of heterocyclic rings as defined above can be at any position on the ring, including the heterocyclyl, heteroaryl, aryl, or carbocyclic parts of the ring. Examples of heterocycles include, but are not limited to, azilidinyl, azetidinyl, pyrrolidinyl, piperidinyl, homopiperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, tetrahydrofuranil, dihydroxazolyl, tetrahydropyranil, tetrahydrothiopyranil, 1,2,3,4-tetrahydroquinolyl, benzoxazinyl, dihydroxazolyl, chromanil, 1,2-dihydropyridinyl, 2,3-dihydrobenzofuranil, 1,3-benzodioxolyl, and 1,4-benzodioxanil.

[0035] As used herein, the term “ring” refers to a cycloalkyl or heterocyclyl group. As used herein, the term “ring” includes, but is not limited to, a spiroring, a bridging ring, and a fused ring. The ring may be fully saturated or partially unsaturated.

[0036] As used herein, the term “condensed ring” refers to a carbocyclic, heterocyclic, aromatic, or heteroaromatic ring structure described herein that is linked to an existing ring structure in a compound disclosed herein via two adjacent atoms shared by the condensed ring structure and the existing ring structure. For example, the bicyclic compounds shown below incorporate condensed cyclopropane (i.e., a cyclopropane ring condensed to a cyclohexane ring), condensed pyrrolidine (i.e., a pyrrolidine ring condensed to a benzene ring), and condensed thiophene (i.e., a tiene ring condensed to a furan ring), respectively. [ka]

[0037] When used herein, "C 3~m The term "cycloalkyl" (wherein m is an integer) refers to a cycloalkyl substituent containing 3 to m carbon atoms, either alone or in combination with another radical. Examples include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. This term includes both fully saturated and partially unsaturated rings.

[0038] When a variable is substituted, for example, when it is expressed by the phrase "C1-6 alkyl is optionally substituted, either alone or as part of a group," this phrase should be understood to mean that the variable C1-6 alkyl can be substituted on its own, and also when the variable "C1-6 alkyl" is part of a larger group. Similarly, when described in this way, other variable parts (e.g., C2-C6 alkynyl, aryl, heteroaryl, heterocycle, etc.) can also be substituted "alone or as part of a group."

[0039] It should be understood that a particular variable in formula I that links two chemical groups can be oriented in either direction. Therefore, for the X group of formula I (e.g., O, C(O), C(O)O, S, S(O), SO2, (C1~C6)alkylO-, (C1~C6)alkylC(O), (C1~C6)alkylC(O)O, (C1~C6)alkylS, (C1~C6)alkylS(O), and (C1~C6)alkylSO2), a particular asymmetric value of X can be oriented in either direction. For example, C(O)O can be oriented as either C(O)O or OC(O) with respect to the group it connects to.

[0040] The term "chiral" refers to molecules that possess the property of non-superimposability of their mirror image partners, while the term "achiral" refers to molecules that possess the property of non-superimposability of their mirror image partners. This refers to molecules that can be superimposed on a partner molecule.

[0041] The term "stereoisomer" refers to compounds that have the same chemical structure but differ in the arrangement of atoms or groups in space.

[0042] A "diastereomer" refers to a stereoisomer having two or more chirality centers or axes, whose molecules are not mirror images of each other. Diastereomers typically have different physical properties, such as melting point, boiling point, spectral properties, and reactivity. Mixtures of diastereomers can be separated under high-resolution analytical procedures, such as electrophoresis and chromatography.

[0043] An "enantiomer" refers to two stereoisomers of a compound that are mirror images of each other and cannot be superimposed.

[0044] With respect to a disease or condition, the terms “treatment” or “treating” include preventing the onset of a disease or condition, inhibiting a disease or condition, eliminating a disease or condition, and / or alleviating one or more symptoms of a disease or condition.

[0045] With respect to the treatment of a disease state in a patient, the term “to treat” includes (i) inhibiting or improving the patient’s disease state, for example, preventing or delaying its onset, or (ii) alleviating the patient’s disease state, i.e., causing a regression or cure of the disease state. In the case of HIV, treatment includes reducing the level of HIV viral load in the patient.

[0046] As used herein, the term “treatment” is intended to mean administering a compound or composition according to the present invention to alleviate or eliminate symptoms of HIV infection and / or to reduce the viral load in a patient. The term “treatment” also includes administering a compound or composition according to the present invention to prevent the onset 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 symptoms of the disease appear and / or before the virus is detected in the blood, and administering a compound or composition according to the present invention to prevent perinatal transmission of HIV from mother to infant by administering it to a mother before childbirth and to a child within a few days of birth.

[0047] A "protecting group" refers to a part of a compound that shields or alters the properties of a functional group or the compound as a whole. Chemical protecting groups and strategies for protection / deprotection are well known in the art. See, for example, Protective Groups in Organic Chemistry, Theodora W. Greene, John Wiley & Sons, Inc., New York, 1991. Protecting groups are often used to shield the reactivity of a particular functional group, thereby assisting the effectiveness of a desired chemical reaction, for example, to create and break chemical bonds regularly and systematically. Protecting a functional group of a compound alters other physical properties besides the reactivity of the protected functional group, such as polarity, lipophilicity (hydrophobicity), and other properties that can be measured by common analytical tools. Chemically protected intermediates may themselves be biologically active or inactive.

[0048] Protected compounds may also exhibit modified, and potentially optimized, in vitro and in vivo properties, such as resistance to cell membrane passage and enzymatic degradation or sequestration. In this role, protected compounds with intended therapeutic effects may be called prodrugs. Another function of protecting groups is to convert parent drugs into prodrugs, thereby releasing the parent drug upon in vivo conversion to the prodrug. Because active prodrugs can be absorbed more effectively than parent drugs, prodrugs may have greater in vivo potency than their parent drugs. Protecting groups are removed in vitro in the case of chemical intermediates, or in vivo in the case of prodrugs. In the case of chemical intermediates, it is not particularly important that the product obtained after deprotection, e.g., an alcohol, is physiologically acceptable, but generally, it is more desirable if the product is pharmacologically harmless.

[0049] Protecting groups are available, commonly known, and used, and are optionally used to prevent side reactions with the protected group during the synthetic procedure, i.e., the route or method, for preparing the compounds of the present invention. In most cases, the decision of which group to protect, when to protect it, and the nature of the chemical protecting group "PG" depends on the chemical nature of the reaction to be protected (e.g., acidic, basic, oxidative, reductive, or other conditions) and the intended direction of the synthesis. If a compound is substituted with multiple PGs, the PGs do not have to be the same, and are generally not the same. Generally, PGs are used to protect functional groups such as carboxyl groups, hydroxyl groups, thio groups, or amino groups, and thus prevent side reactions or otherwise facilitate the efficiency of the synthesis. The order of deprotection to obtain a free deprotected group depends on the intended direction of the synthesis and the reaction conditions encountered, and can occur in any order determined by those skilled in the art.

[0050] The compounds of the present invention can protect various functional groups. For example, protecting groups for -OH groups (whether hydroxyl, carboxylic acid, phosphonic acid, or any other functional group) include "ether or ester-forming groups." Ether or ester-forming groups can function as chemical protecting groups in the synthetic schemes described herein. However, some hydroxyl protecting groups and thio protecting groups are not ether-forming or ester-forming groups, as will be understood by those skilled in the art, and are included together with the amides discussed below.

[0051] A very large number of hydroxyl protecting groups and amide-forming groups, as well as their corresponding chemical cleavage reactions, are described in Protective Groups in Organic Synthesis, Theodora W. Greene (John Wiley & Sons, Inc., New York, 1991, ISBN 0-471~62301~6) ("Greene"). See also Kocienski, Philip J.; Protecting Groups (Georg Thieme Verlag Stuttgart, New York, 1994) (which is incorporated herein by reference in its entirety). In particular, see Chapter 1, Protecting Groups: An Overview, pages 1-20; Chapter 2, Hydroxyl Protecting Groups, pages 21-94; Chapter 3, Diol Protecting Groups, pages 95-117; Chapter 4, Carboxyl Protecting Groups, pages 118-154; Chapter 5, Carbonyl Protecting Groups, pages 155-184. For protecting groups of carboxylic acids, phosphonic acids, phosphonates, sulfonic acids, and other acid protecting groups, see Greene below.

[0052] As used herein, the term “protecting group” is intended to mean a protecting group that may be used in a synthetic transformation, including, but not limited to, the examples listed in Greene, “Protective Groups in Organic Chemistry,” John Wiley & Sons, New York (1981) and its more recent editions.

[0053] The term "solvate" refers to a crystalline solid containing an amount of solvent incorporated into its crystalline structure. As used herein, the term "solvate" includes hydrates.

[0054] The term "non-solvate" refers to a crystalline solid in which solvent molecules do not occupy specific crystallographic positions.

[0055] As used herein, the term “pharmaceutically acceptable” with respect to a substance means, within the bounds of sound medical judgment, that it is free from excessive toxicity, irritation, or allergic reactions, suitable for use in contact with human and lower animal tissues, has a reasonable benefit-to-risk ratio, and is effective for the intended purpose when used in a pharmaceutical composition.

[0056] As used herein, the term “pharmaceutically acceptable salt” is intended to mean a salt of a compound according to the present invention that, within the bounds of sound medical judgment, is free from excessive toxicity, irritation, allergic reactions, etc., is suitable for use in contact with human and lower animal tissues, is commensurate with a reasonable benefit / risk ratio, is generally water-soluble, oil-soluble, or dispersible, and is effective for its intended use. The term includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts. A list of suitable salts can be found, for example, in SMBirge et al., J. Pharm. Sci., 1977, 66, pp. 1-19.

[0057] As used herein, the term “pharmaceutically acceptable acid addition salt” means an inorganic acid that retains the biological efficacy and properties of the free base and is not biologically or otherwise undesirable, including but not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, sulfamic acid, nitric acid, phosphoric acid, as well as acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, butyric acid, camphoric acid, camphorsulfonic acid, cinnamic acid, citric acid, digluconic acid, ethanesulfonic acid, glutamic acid, glycolic acid, glycerophosphate, hemisulfonic acid, hexa Examples include, but are not limited to, organic acids such as nic acid, formic acid, fumaric acid, 2-hydroxyethanesulfonic acid (isethionic acid), lactic acid, hydroxymaleic acid, malic acid, malonic acid, mandelic acid, mesitylenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, nicotinic acid, 2-naphthalenesulfonic acid, oxalic acid, pamoic acid, pectinic acid, phenylacetic acid, 3-phenylpropionic acid, pivalic acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, succinic acid, sulfanilic acid, tartaric acid, p-toluenesulfonic acid, and undecanoic acid, and the term is intended to refer to salts formed with organic acids.

[0058] As used herein, the term “pharmaceutically acceptable base addition salt” is intended to mean a salt formed with ammonia, or ammonium hydroxide, carbonate, or bicarbonate, or a metal cation, such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, or aluminum, with an inorganic base, such as sodium, potassium, lithium, calcium, magnesium, iron, zinc, copper, manganese, or aluminum, which retains the biological efficacy and properties of the free acid and is not biologically or otherwise undesirable. Particularly preferred are ammonium salts, potassium salts, sodium salts, calcium salts, and magnesium salts. Examples of pharmaceutically acceptable salts derived from organic non-toxic bases include primary, secondary, and tertiary amines, quaternary amine compounds, substituted amines such as naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine, tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, Examples of non-toxic organic bases include, but are not limited to, salts of caffeine, hydravamin, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine, N-ethylpiperidine, tetramethylammonium compounds, tetraethylammonium compounds, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, N,N'-dibenzylethylenediamine, and polyamine resins. Particularly preferred non-toxic organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.

[0059] As used herein, the term “antiviral agent” is intended to mean an agent effective in inhibiting the formation and / or replication of a virus in humans, including but not limited to agents that interfere with the host or viral mechanism of action necessary for the formation and / or replication of a virus in humans.The term "antiviral agent" can refer to, for example, HIV integrase catalytic site inhibitors selected from the group consisting of raltegravir (ISENTRESS®, Merck), elvitegravir (Gilead), soltegravir (GSK, ViiV), GSK1265744 (GSK, ViiV), and dolutegravir, as well as abacavir (ZIAGEN®, GSK), didanosine (VIDEX®, BMS), tenofovir (VIREAD®, Gilead), and emtricitabine (EMTRIVA®). HIV nucleoside reverse transcriptase inhibitors selected from the group consisting of ), Gilead), lamivudine (EPIVIR®, GSK / Shire), stabudine (ZERIT®, BMS), zidovudine (RETROVIR®, GSK), erbucitabine (Achillion), and festinavir (Oncolys), nevirapine (VIRAMUNE®, BI), efavirenz (SUSTIVA®, BMS), etravirine (INTELENCE®, J&J), rilpivirine (TMC) HIV non-nucleoside reverse transcriptase inhibitors selected from the group consisting of 278, R278474, J&J), fosdevine (GSK / ViiV), and relcivirine (Pfizer / ViiV), atazanavir (REYATAZ®, BMS), darunavir (PREZISTA®, J&J), indinavir (CRIXIVAN®, Merck), lopinavir (KELETRA®, Abbott), nelfinavir (VIRACEPT®, Pfizer), saquinavir (INVIRASE®, registered trademark). ), Hoffmann-LaRoche), tipranavir (APTIVUS®, BI), ritonavir (NORVIR®, Abbott), and fosamprenavir (LEXIVA®, GSK / Vertex), HIV entry inhibitors selected from maraviroc (SELZENTRY®, Pfizer), enfuvirtide (FUZEON®, Trimeris), and BMS-663068 (BMS), and bevirimat (Myriad). Examples include HIV maturation inhibitors selected from the Genetics (genetics) field.

[0060] As used herein, the term “antiviral agent” is intended to mean an agent effective in inhibiting the formation and / or replication of a virus in a mammal, including but not limited to agents that interfere with the mechanism of action of either the host or the virus necessary for the formation and / or replication of the virus in the mammal.

[0061] As used herein, the term “HIV replication inhibitor” is intended to mean any agent capable of reducing or eliminating the replication capacity of HIV in host cells, whether in vitro, ex vivo, or in vivo.

[0062] As used herein, the term “substituent” is intended to mean an atom, radical, or group that can bond to a carbon atom, a heteroatom, or any other atom that may form part of a molecule or fragment thereof, or otherwise bond to at least one hydrogen atom, unless otherwise specified. A substituent contemplated in the context of a particular molecule or fragment thereof is a substituent that results in a chemically stable compound, as recognized by those skilled in the art.

[0063] As used herein, the term "heteroatom" is intended to mean O, S, or N.

[0064] The term "OC" is used interchangeably in this specification. 1~n "Alkyl" or "C 1~n "Alkoxy" is intended to mean an oxygen atom further bonded to an alkyl group having 1 to n carbon atoms as defined above, where n is an integer, either alone or in combination with another radical. 1~n Examples of alkoxys include, but are not limited to, methoxy(CH3O-), ethoxy(CH3CH2O-), propoxy(CH3CH2CH2O-), 1-methylethoxy(iso-propoxy, (CH3)2CHO), and 1,1-dimethylethoxy(tert-butoxy, (CH3)3CO).1~n When an alkoxy is substituted, the substitution occurs on the alkyl portion, and as a result, the substitution is understood to produce a chemically stable compound as recognized by those skilled in the art.

[0065] As used herein, the term "oxo" is intended to mean an oxygen atom bonded to a carbon atom as a substituent by a double bond (=O).

[0066] As used herein, the term “mammal” is intended to include humans and non-human mammals susceptible to HIV infection. Non-human mammals include, but are not limited to, domesticated animals such as cattle, pigs, horses, dogs, cats, rabbits, rats, and mice, as well as non-domesticated animals.

[0067] The embodiments disclosed herein also encompass all pharmaceutically acceptable compounds of formula I that are isotope-labeled by replacing one or more atoms with atoms having different atomic masses or mass numbers. 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, respectively. 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 125I is one example. In some embodiments, these radiolabeled compounds are useful in determining or measuring the efficacy of a compound by characterizing, for example, the site or mode of action, or the binding affinity to a pharmacologically important site of action. Specific isotope-labeled compounds of formula I, for example, those incorporating radioisotopes, are useful in drug research and / or substrate tissue distribution studies. Radioisotope tritium, i.e., 3 H, and carbon-14, that is, 14 C is particularly useful for this purpose due to its ease of implementation and readily available detection means.

[0068] In a particular embodiment, deuterium, i.e., 2 Substitution with heavier isotopes, such as 1H, can offer certain therapeutic advantages due to greater metabolic stability. For example, the in vivo half-life may increase, or the required dose may decrease. Therefore, in some situations, heavier isotopes may be preferable.

[0069] Substitution with positron-emitting isotopes, for example, 11 C, 18 F, 15 O, and 13 N may be useful in positron emission tomography (PET) studies to investigate substrate receptor occupancy. The isotopically labeled compounds of the compounds disclosed herein may be prepared by conventional techniques known to those skilled in the art, using appropriate isotopic labeling reagents instead of previously used unlabeled reagents, or by processes similar to those described in the examples below.

[0070] The methods, compositions, kits, and products provided herein use or contain compounds (e.g., compounds of formula I) or pharmaceutically acceptable salts thereof, wherein 1 to n hydrogen atoms bonded to carbon atoms may be replaced by deuterium atoms or D, where n is the number of hydrogen atoms in the molecule. As is known in the art, deuterium atoms are non-radioactive isotopes of hydrogen atoms. Such compounds enhance resistance to metabolism and are therefore useful for increasing the half-life of compounds or pharmaceutically acceptable salts thereof when administered to mammals. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism," Trends. See Pharmacol. Sci., 5(12):524-527 (1984). Such compounds can be synthesized by means known in the art, for example, by using starting materials in which one or more hydrogen atoms are replaced with deuterium.

[0071] The embodiments disclosed herein also encompass in vivo metabolites of the compounds disclosed herein. Such products may arise, for example, from oxidation, reduction, hydrolysis, amidation, esterification, etc., of the administered compound, primarily by enzymatic processes. Accordingly, the embodiments disclosed herein include compounds produced by processes, which involve administering the compounds according to the embodiments disclosed herein to mammals for a period of time sufficient to obtain their metabolites. Such products are typically identified by administering the radiolabeled compounds according to the embodiments disclosed herein to animals such as rats, mice, guinea pigs, monkeys, or humans in a detectable dose, allowing sufficient time for metabolism to occur, and then isolating the conversion products from urine, blood, or other biological samples.

[0072] The compounds disclosed herein, or their pharmaceutically acceptable salts, may contain one or more chiral centers and thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that can be defined with respect to absolute stereochemistry as (R)- or (S)-, or with respect to amino acids as (D)- or (L)-. This disclosure includes all such possible isomers, as well as their racemic, scalemic, and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or may be resolved using methods such as chromatography and fractional crystallization. Techniques for the preparation / isolation of individual enantiomers include chiral synthesis from suitable optically pure precursors, or resolution of racemic compounds (or racemic compounds of salts or derivatives) using, for example, chiral high-pressure liquid chromatography (HPLC). When the compounds described herein contain an olefinic double bond or other geometrically asymmetric center, and unless otherwise specified, these compounds are intended to include both E and Z geometric isomers. Similarly, all tautomer forms are also intended to be included.

[0073] 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 cases in which the event or situation occurs and the cases in which it does not occur. For example, "optionally substituted heterocyclyl" means that the heterocyclyl radical may or may not be substituted, and that the description includes both substituted and unsubstituted heterocyclyl radicals.

[0074] II. Compounds In some embodiments, the present disclosure relates to a compound of formula I, [ka] Or provide a pharmaceutically acceptable salt thereof, in the formula, R 1 H, C 6~10 An aryl or 5-10 membered heteroaryl containing 1, 2, 3, or 4 heteroatoms independently selected from N, O, and S, C 6~10 Aryl or 5-10 member heteroaryls have 1, 2, 3, or 4 R A1 It is replaced by an optional choice, and each R A1 It is independently, Halo, C 1~6 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkyl-OC 1~4 It is alkyl, R 2 H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, L is -CR 3a R 3b -, -C(O)-, -SO2-, -CH2-CH2-, or -N(R a )- and, W 1 However, combined or -CR 4a R 4b -and, W 2 -CR 5a R 5b -, -CR 5a R 5b CR 5c R 5d -, -CR 6a =CR 6b -, -N(R 7 )-, -O-, -S(O) n -, -C(O)-, -C(O)O-, -C(O)NH-, -CR 5a R 5b -N(R 7 )-,-CR 5a R 5b -O-, -CR 5a R 5b -S(O) n -, -CR 5a R 5b -C(O)-, -CR5a R 5b -C(O)O-, -CR 5a R 5b -OC(O)-, -CR 5a R 5b -C(O)NH-, or -CR 5a R 5b -NHC(O)-, Y is -C(O)NH-, [ka] And, [ka] This is a 3- to 7-membered spiro ring containing 1, 2, or 3 heteroatoms selected from N, O, and S, and the spiro ring has 1, 2, 3, or 4 R 8 It is replaced by an optional choice in the base, Z is -CR 9a R 9b -, -CR 9a R 9b CR 9c R 9d -, or -CR 10a =CR 10b -and, R 3a and R 3b H and C are independent of each other. 1~6 Alkyl, C 1~4 Haloalkyl, or -OC 1~4 It is alkyl, or, R 3a and R 3b Together with the carbon atoms to which they are bonded, they form a 3- to 7-membered spiro ring containing 0, 1, or 2 heteroatoms selected from N, O, and S, and the spiro ring contains 1, 2, or 3 R A2 It is replaced by an optional choice, and each R A2 It is independently, Halo, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 4a and R 4b H and C are independent of each other. 1~6Alkyl, C 1~4 It is a haloalkyl or halo, R 5a , R 5b , R 5c , and R 5d H and C are independent of each other. 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkylene-OC 1~4 It is alkyl, or, R 5a and R 5b or R 5c and R 5d Together with the carbon atoms to which they are bonded, they form a 3- to 7-membered spiro ring containing 0, 1, or 2 heteroatoms selected from N, O, and S, and the spiro ring contains 1, 2, or 3 R A3 It is replaced by an optional choice, and each R A3 It is independently, Halo, C 1~4 Alkyl or C 1~4 It is either a haloalkyl or R 5a and R 5c or R 5b and R 5d Each of these atoms, together with the carbon atom to which it is bonded, forms a 3- to 7-membered fused ring containing 0 or 1 heteroatom selected from N, O, and S, and the fused ring has 1 to 3 R A3 It is replaced by an optional choice, and each R A3 It is independently, Halo, C 1~4 Alkyl or C 1~4 It is a haloalkyl, Each R 6a and R 6b These are H, Halo, and C, independently. 1~4 Haloalkyl, or C 1~6 It is alkyl, or, R 6a and R 6bEach of these atoms, together with the carbon atoms to which it is bonded, forms a 5-10 member partially unsaturated condensed ring or a 5-10 member condensed aromatic ring containing 0 or 1 heteroatom selected from N, O, and S, or a 5-10 member condensed heteroaromatic ring containing 1 or 2 heteroatoms selected from N, O, and S, and the partially unsaturated condensed ring, condensed aromatic ring, or condensed heteroaromatic ring has 1, 2, 3, or 4 R A4 It is replaced by an optional choice, and each R A4 These are independently, halo or C 1~4 It is alkyl, R 7 H, C 1~6 Alkyl, C 1~4 Haloalkyl, C(O)R c , or SO2R c And, Each R 8 Independently, (i) Hello, (ii) C which is optionally replaced with OH 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 A 5-10 membered heteroaryl containing an aryl or one, two, or three heteroatoms independently selected from N, O, and S, C 6~10 The aryl or 5-10 membered heteroaryl is optionally substituted with 1-4 substituents independently selected from 3-7 membered halocycloalkyls containing 1, 2, or 3 heteroatoms selected from C1-C3 alkyl, C1-C3 alkoxy, halo, CN, C1-C3 haloalkyl, C3-C7 cycloalkyl, and N, O, and S. (iii) C which is optionally replaced with OH 1~6 Haloalkyl, C 1~6 Alkoxy, C 6~10 A 5-10 membered heteroaryl containing an aryl or one, two, or three heteroatoms independently selected from N, O, and S, C 6~10The aryl or 5-10 membered heteroaryl is optionally substituted with 1-4 substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halo, CN, C1-C3 haloalkyl, C3-C7 cycloalkyl, and 3-7 membered halocycloalkyls containing 1, 2, or 3 heteroatoms selected from N, O, and S. (iv)CN, (v) oxo, (vi)-XR A5 And, In the formula, X is either O or S, and R A5 H, C 1~6 A 3- to 7-membered ring containing alkyl or 0, 1, or 2 heteroatoms selected from N, O, and S, C1-C6 alkyl or 3-7 membered rings are CN, halo, C1-C6 alkoxy, C 6~10 aryls, and 5- to 10-membered heteroaryls containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, are optionally substituted with 1, 2, or 3 groups. (vii) NHR A6 And, In the formula, R A6 These are C1-C6 alkyl groups. (viii)NR A7 R A8 And, In the formula, R A7 These are C1-C6 alkyl groups, R A8 These are C1-C6 alkyl groups. (ix)C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, CN, C 3~7 Cycloalkyl, and C 1~6 C is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the alkoxy. 6~10 It is Ariel, C 3~7 Cycloalkyl groups are those optionally substituted with 1, 2, 3, or 4 independent halo groups. (x) A 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S, 3-7 member rings are halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 Substituting with one, two, or three substituents independently selected from the cycloalkyl group, (xi) A 5-10 membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, A 5-10 member heteroaryl ring is a halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 Substituting with one, two, or three substituents independently selected from the cycloalkyl group, (xii)-SO2R A13 And, R A13 This is a 3-7 membered ring containing 0, 1, or 2 heteroatoms selected from C1-C6 alkyl or N, O, and S. C 1~6 The alkyl or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halo, and C1-C6 alkoxy groups. (xiii)-SO(NR A14 )2, Each R A14 H and C are independent of each other. 1~6 A 3- to 7-membered ring containing an alkyl group or 0, 1, or 2 heteroatoms independently selected from N, O, and S, C 1~6 The alkyl or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halo, and C1-C6 alkoxy groups. (xiv)C 1~6 Alkoxy, OH, -SO2-(C 1~3 C is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl. 2~6Selected from the group consisting of alkynyl, or Two R's 8 The groups are linked together to form condensed, spiro, or bridging 3- to 7-membered rings containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S. 3-7 member rings are halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 It is optionally substituted with one, two, or three substituents independently selected from the cycloalkyl group, or Two R atoms on adjacent carbon atoms 8 The groups are linked together to form a condensed 6-10 membered aromatic ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S. The condensed 6-10 member aromatic ring is a halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 It is optionally substituted with one, two, or three substituents independently selected from the cycloalkyl group. R 9a , R 9b , R 9c , and R 9d These are H and C, respectively, independently. 1~6 Alkyl, C 1~4 It is either a haloalkyl or a halo, or R 9a and R 9b or R 9c and R 9d Together with the carbon atoms to which they are bonded, they form a 3- to 7-membered spiro ring containing 0, 1, or 2 heteroatoms selected from N, O, and S, and the spiro ring contains 1, 2, or 3 R A9 It is replaced by an optional choice, and each R A9 It is independently, Halo, C 1~4 Alkyl or C 1~4 It is either a haloalkyl or R 9a and R 9c or R 9b and R 9dEach of these atoms, together with the carbon atom to which it is bonded, forms a 3- to 7-membered fused ring containing 0 or 1 heteroatom selected from N, O, and S, and the fused ring has 1, 2, or 3 R atoms. A10 It is replaced by an optional choice, and each R A10 It is independently, Halo, C 1~4 Alkyl or C 1~4 It is either a haloalkyl or R 9a , R 9b , R 9c , and R 9d One of the following, and R 4a , R 4b , R 5a , R 5b , and R 7 One of these, together with the atom to which it is bonded, forms a 3- to 7-membered condensed ring containing 0, 1, or 2 heteroatoms selected from N, O, and S, and the condensed ring has 1, 2, 3, or 4 R A11 It is replaced by an optional choice, and each R A11 These are independently, halo or C 1~4 It is alkyl, R 10a and R 10b These are H, Halo, and C, independently. 1~4 Haloalkyl, or C 1~6 It is alkyl, or, R 10a and R 10b Each of these atoms, together with the carbon atoms to which it is bonded, forms a 5-10 member partially unsaturated condensed ring or a 5-10 member condensed aromatic ring containing 0 or 1 heteroatom selected from N, O, and S, or a 5-10 member condensed heteroaromatic ring containing 1 or 2 heteroatoms selected from N, O, and S, and the partially unsaturated condensed ring, condensed aromatic ring, or condensed heteroaromatic ring contains 1-4 R A12 It is replaced by an optional choice, and each R A12 These are independently, halo or C 1~4 It is alkyl, R a H and C are independent of each other. 1~6 Alkyl, C 1~6 Haloalkyl, C(O)R c, or SO2R c And, R b is H or C 1~4 It is alkyl, R c C 1~4 Alkyl or C 1~4 It is an alkyloxy, Each n is independently 0, 1, or 2.

[0075] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] is 1, 2, 3, or 4 R 8 Substituted with at least one R 8 The basis is, (i) C substituted with OH 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 A 5-10 membered heteroaryl containing an aryl or one, two, or three heteroatoms independently selected from N, O, and S, C 6~10 The aryl or 5-10 membered heteroaryl is optionally substituted with 1-4 substituents independently selected from 3-7 membered halocycloalkyls containing 1, 2, or 3 heteroatoms selected from C1-C3 alkyl, C1-C3 alkoxy, halo, CN, C1-C3 haloalkyl, C3-C7 cycloalkyl, and N, O, and S. (ii) C substituted with OH 1~6 Haloalkyl, C 1~6 Alkoxy, C 6~10 A 5-10 membered heteroaryl containing an aryl or one, two, or three heteroatoms independently selected from N, O, and S, C 6~10The aryl or 5-10 membered heteroaryl is optionally substituted with 1-4 substituents selected from C1-C3 alkyl, C1-C3 alkoxy, halo, CN, C1-C3 haloalkyl, C3-C7 cycloalkyl, and 3-7 membered halocycloalkyls containing 1, 2, or 3 heteroatoms selected from N, O, and S. (iii) CN, (iv) Oxo, (v)-XR A5 And, In the formula, X is either O or S, and R A5 H, C 1~6 A 3- to 7-membered ring containing alkyl or 0, 1, or 2 heteroatoms selected from N, O, and S, C1-C6 alkyl or 3-7 membered rings are CN, halo, C1-C6 alkoxy, C 6~10 aryls, and 5- to 10-membered heteroaryls containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, are optionally substituted with 1, 2, or 3 groups. (vi) NHR A6 And, In the formula, R A6 These are C1-C6 alkyl groups. (vii)NR A7 R A8 And, In the formula, R A7 It is a C1-C6 alkyl group, and R A8 These are C1-C6 alkyl groups. (viii)C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, CN, C 3~7 Cycloalkyl, and C 1~6 C is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the alkoxy. 6~10 It is an arrow, C 3~7 Cycloalkyl groups are those optionally substituted with 1, 2, 3, or 4 independent halo groups. (ix) A 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S, 3-7 member rings are halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 Substituting with one, two, or three substituents independently selected from the cycloalkyl group, (x) A 5-10 membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, A 5-10 member heteroaryl ring is a halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 Substituting with one, two, or three substituents independently selected from the cycloalkyl group, (xi)-SO2R A13 And, R A13 This is a 3-7 membered ring containing 0, 1, or 2 heteroatoms selected from C1-C6 alkyl or N, O, and S. C 1~6 The alkyl or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halo, and C1-C6 alkoxy groups. (xii)-SO(NR A14 )2, Each R A14 H and C are independent of each other. 1~6 A 3- to 7-membered ring containing an alkyl group or 0, 1, or 2 heteroatoms independently selected from N, O, and S, C 1~6 The alkyl or 3- to 7-membered ring is optionally substituted with 1, 2, or 3 groups selected from CN, halo, and C1-C6 alkoxy groups. (xiii)C 1~6 Alkoxy, OH, -SO2-(C 1~3 C is optionally substituted with 1, 2, 3, or 4 substituents independently selected from alkyl. 2~6Selected from the group consisting of alkynyl, or Two R's 8 The groups are linked together to form condensed, spiro, or bridging 3- to 7-membered rings containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S. 3-7 member rings are halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 It is optionally substituted with one, two, or three substituents independently selected from the cycloalkyl group, or Two R atoms on adjacent carbon atoms 8 The groups are linked together to form a condensed 6-10 membered aromatic ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S. The condensed 6-10 member aromatic ring is a halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 It is optionally substituted with one, two, or three substituents independently selected from the cycloalkyl group.

[0076] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] It is a 6-membered spiro ring containing one or two heteroatoms selected from N, O, and S, and the spiro ring has 1, 2, 3, or 4 R 8 The group is optionally substituted. In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] It is a 6-membered spiro ring containing one or two heteroatoms selected from N, O, and S, and the spiro ring has 1, 2, or 3 R 8 The group is optionally substituted. In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] It is a 6-membered spiro ring containing one or two heteroatoms selected from N, O, and S, and the spiro ring has one or two R 8 It is being replaced by an optional choice in the base.

[0077] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] It is a 6-membered spiro ring containing one or two heteroatoms selected from N and O, and the spiro ring has 1, 2, 3, or 4 R 8 The group is optionally substituted. In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] It is a 6-membered spiro ring containing one or two heteroatoms selected from N and O, and the spiro ring has 1, 2, or 3 R 8 The group is optionally substituted. In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] It is a 6-membered spiro ring containing one or two heteroatoms selected from N and O, and the spiro ring has one or two R 8 It is being replaced by an optional choice in the base.

[0078] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] It is a five-membered spiro ring containing one or two heteroatoms selected from N, O, and S, and the spiro ring has 1, 2, 3, or 4 R8 The group is optionally substituted. In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] It is a five-membered spiro ring containing one or two heteroatoms selected from N, O, and S, and the spiro ring has 1, 2, or 3 R 8 The group is optionally substituted. In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] It is a five-membered spiro ring containing one or two heteroatoms selected from N, O, and S, and the spiro ring has one or two R 8 It is being replaced by an optional choice in the base.

[0079] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] It is a five-membered spiro ring containing one or two heteroatoms selected from N and O, and the spiro ring has 1, 2, 3, or 4 R 8 The group is optionally substituted. In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] It is a five-membered spiro ring containing one or two heteroatoms selected from N and O, and the spiro ring has 1, 2, or 3 R 8 The group is optionally substituted. In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] It is a five-membered spiro ring containing one or two heteroatoms selected from N and O, and the spiro ring has one or two R 8 It is being replaced by an optional choice in the base.

[0080] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] This is a four-membered spiro ring containing one or two heteroatoms selected from N, O, and S, and the spiro ring has 1, 2, 3, or 4 R 8 The group is optionally substituted. In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] It is a four-membered spiro ring containing one or two heteroatoms selected from N, O, and S, and the spiro ring has 1, 2, or 3 R 8 The group is optionally substituted. In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] It is a four-membered spiro ring containing one or two heteroatoms selected from N, O, and S, and the spiro ring has one or two R 8 It is being replaced by an optional choice in the base.

[0081] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] This is a four-membered spiro ring containing one or two heteroatoms selected from N and S, and the spiro ring has 1, 2, 3, or 4 R 8 The group is optionally substituted. In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] It is a four-membered spiro ring containing one or two heteroatoms selected from N and S, and the spiro ring has one, two or three R 8 The group is optionally substituted. In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] It is a four-membered spiro ring containing one or two heteroatoms selected from N and S, and the spiro ring has one or two R 8 It is being replaced by an optional choice in the base.

[0082] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] teeth, [ka] Selected from the group consisting of, in the formula, * teeth, [ka] Show the connection point of the remaining equation I, R d H, C 1~4 Alkyl or C 1~4 It is a haloalkyl, and m is 0, 1, 2, 3, or 4.

[0083] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] teeth, [ka] Selected from the group consisting of, in the formula, * teeth, [ka] Show the connection point of the remaining equation I, R d H, C 1~4 Alkyl or C 1~4 It is a haloalkyl, and m is 0, 1, 2, 3, or 4.

[0084] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] teeth, [ka] Selected from the group consisting of: In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] teeth, [ka] In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] That is the case.

[0085] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] teeth, [ka] It is selected from the group consisting of the following.

[0086] In some embodiments of the compound of formula I, or its pharmaceutically acceptable salt, [ka] teeth, [ka] In the formula, m is 0, 1, 2, or 3. In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] In the formula, m is 0, 1, 2, or 3. In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] In the formula, m is 0, 1, 2, 3, or 4. In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] In the formula, m is 0, 1, 2, or 3. In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] In the formula, m is 0, 1, 2, or 3. In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, [ka] teeth, [ka] The formula is such that m is 0, 1, 2, or 3.

[0087] In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, the compound has formula IA, [ka] In the formula, m is 0, 1, 2, or 3.

[0088] In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, the compound has formula IB, [ka] In the formula, m is 0, 1, 2, or 3.

[0089] In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, the compound has formula IC, [ka] In the formula, R d H, C 1~4 Alkyl or C 1~4 It is a haloalkyl, and m is 0, 1, 2, or 3.

[0090] In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, the compound has formula ID, [ka] In the formula, R d H, C 1~4 Alkyl or C 1~4 It is a haloalkyl, and m is 0, 1, 2, or 3.

[0091] In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, the compound has formula IE, [ka] In the formula, R d H, C 1~4 Alkyl or C 1~4It is a haloalkyl, and m is 0, 1, 2, or 3.

[0092] In some embodiments of the compound of formula I, or a pharmaceutically acceptable salt thereof, the compound has formula IF, [ka] In the formula, m is 0, 1, 2, 3, or 4.

[0093] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, or IF, or pharmaceutically acceptable salts thereof, R 2 is H or C 1~6 It is alkyl. In some embodiments, R 2 H is H. In some embodiments, R 2 C 1~6 It is alkyl. In some embodiments, R 2 C 1~3 It is alkyl. In some embodiments, R 2 C 1~4 It is a haloalkyl group.

[0094] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, or IF, or pharmaceutically acceptable salts thereof, Y is -C(O)NH-, [ka] Selected from the group consisting of . In some embodiments, Y is -C(O)NH-. In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] In some embodiments, Y is [ka] That is the case.

[0095] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, or IF, or pharmaceutically acceptable salts thereof, Y is -C(O)NH-, and R 2 is H or C 1~6 It is alkyl.

[0096] In some embodiments of formula I or IA, or its pharmaceutically acceptable salts, the compound has formula II-A, [ka] In the formula, m is 0, 1, 2, or 3.

[0097] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, or II-A, or pharmaceutically acceptable salts thereof, R 1 is 1, 2, 3, or 4 R A1 The phenyl is optionally substituted, and each R A1 It is independently, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkyl-OC1~4 It is alkyl. In some embodiments, R 1 is 1, 2, 3, or 4 R A1 The phenyl is optionally substituted, and each R A1 It is independently, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, or -OC 1~4 It is alkyl. In some embodiments, R 1 is 1, 2, 3, or 4 R A1 It is a phenyl compound that is substituted with each R A1 These are independently, halo or -OC 1~4 It is alkyl. In some embodiments, R 1 is a phenyl compound substituted with 1, 2, 3, or 4 halogens. In some embodiments, R 1 R is a phenyl compound substituted with two or three halogens selected from chloro and fluoro. In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] That is the case.

[0098] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] That is the case.

[0099] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] In some embodiments, R 1 teeth, [ka] That is the case.

[0100] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, or II-A, or pharmaceutically acceptable salts thereof, R 1 is 1, 2, 3, or 4 R A1 It is a pyridyl that is optionally substituted, and each R A1 It is independently, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkyl-OC 1~4 It is alkyl. In some embodiments, R 1 is 1, 2, 3, or 4 R A1 It is a pyridyl that is optionally substituted, and each R A1 It is independently, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, or -OC 1~4 It is alkyl. In some embodiments, R 1 is 1, 2, 3, or 4 R A1 It is a pyridyl that is substituted with each R A1 These are independently, halo or -OC 1~4 It is alkyl. In some embodiments, R 1 is a pyridyl substituted with 1, 2, 3, or 4 halogens. In some embodiments, R 1 is a pyridyl substituted with two or three halogens selected from chloro and fluoro. In some embodiments, R 1 teeth, [ka] That is the case.

[0101] In some embodiments of compounds of formula I, IA, or II-A, or pharmaceutically acceptable salts thereof, the compound has formula II-Aa or II-Ab, [ka] In the formula, m is 0, 1, 2, or 3.

[0102] In some embodiments of compounds of formula I, IA, or II-A, or pharmaceutically acceptable salts thereof, the compound has formula II-Aa. In some embodiments of compounds of formula I, IA, or II-A, or pharmaceutically acceptable salts thereof, the compound has formula II-Ab.

[0103] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, or II-Ab, or pharmaceutically acceptable salts thereof, L is -CR 3a R 3b - and in the formula, R 3a and R 3b H and C are independent of each other. 1~6 Alkyl, C 1~4 Haloalkyl, or -OC 1~4 It is alkyl. In some embodiments, L is -CR 3a R 3b - and in the formula, R 3a and R 3b H and C are independent of each other. 1~6 Alkyl or C 1~4 It is a haloalkyl. In some embodiments, L is -CR. 3a R 3b - and in the formula, R 3a and R 3b H or C 1~6 It is alkyl. In some embodiments, L is -CR 3a R 3b - and in the formula, R 3a and R 3bBoth are H. In some embodiments, L is -C(O)-. In some embodiments, R3 is -SO2-. In some embodiments, L is -CH2-CH2-. In some embodiments, L is or -N(R a )-. In some embodiments, L is NH.

[0104] In some embodiments of compounds of formula I, IA, II-A, II-Aa, or II-Ab, the compound has formula III, [ka] In the formula, m is 0, 1, 2, or 3.

[0105] In some embodiments of formulas I, IA, II-A, II-Aa, II-Ab, or III, the compound has formula IIIa or IIIb, [ka] In the formula, m is 0, 1, 2, or 3.

[0106] In some embodiments of formulas I, IA, II-A, II-Aa, or III, the compound has formula IIIa. In some embodiments of formulas I, IA, II-A, II-Ab, or III, the compound has formula IIIb.

[0107] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, II-Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, W 1 is a combination or -CR 4a R 4b - and in the formula, R 4a and R 4b H and C are independent of each other. 1~6 Alkyl, C 1~4 It is a haloalkyl or halo. In some embodiments, W 1 is a combination or -CR4a R 4b - and in the formula, R 4a and R 4b H and C are independent of each other. 1~6 It is alkyl or halo. In some embodiments, W 1 is a combination or -CR 4a R 4b - and in the formula, R 4a and R 4b These are independently H, -CH3, or halo. In some embodiments, W 1 is a combination or -CR 4a H-, and in the formula, R 4a H, C 1~6 It is alkyl or halo. In some embodiments, W 1 These are bonds, -CH2, or -CH(F)-.

[0108] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-A, IIAa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, Y is -C(O)NH-, and R 2 is H or C 1~6 It is alkyl, W 1 is a combination or -CR 4a R 4b - and in the formula, R 4a and R 4b H and C are independent of each other. 1~6 Alkyl, C 1~4 It is a haloalkyl or halo. In some embodiments, Y is -C(O)NH- and R 2 is H or C 1~6 It is alkyl, W 1 is a combination or -CR 4a R 4b - and in the formula, R 4a and R 4b H and C are independent of each other. 1~6 It is alkyl or halo. In some embodiments, Y is -C(O)NH- and R 2 is H or C 1~6 It is alkyl, W 1 is a combination or -CR 4a R4b - and in the formula, R 4a and R 4b These are independently H, -CH3, or halo. In some embodiments, Y is -C(O)NH- and R 2 is H or C 1~6 It is alkyl, W 1 is a combination or -CR 4a H-, and in the formula, R 4a H, C 1~6 It is alkyl or halo. In some embodiments, Y is -C(O)NH- and R 2 is H or C 1~6 It is alkyl, W 1 These are bonds, -CH2- or -CH(F)-.

[0109] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, II-Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, Z is -CR 9a R 9b - and in the formula, R 9a and R 9b These are H and C, respectively, independently. 1~6 Alkyl, C 1~4 It is a haloalkyl or halo. In some embodiments, Z is -CR 9a R 9b - and in the formula, R 9a and R 9b These are H and C, respectively, independently. 1~6 Alkyl, or C 1~4 It is a haloalkyl. In some embodiments, Z is -CH(CH3)- or -CH(CH2F)-.

[0110] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, Y is -C(O)NH-, and R 2 is H or C 1~6 It is alkyl, W 1 is a combination or -CR4a R 4b - and in the formula, R 4a and R 4b H and C are independent of each other. 1~6 Alkyl, C 1~4 It is a haloalkyl or halo, and Z is -CR 9a R 9b - and in the formula, R 9a and R 9b These are H and C, respectively, independently. 1~6 Alkyl, C 1~4 It is a haloalkyl or halo. In some embodiments, Y is -C(O)NH- and R 2 is H or C 1~6 It is alkyl, W 1 is a combination or -CR 4a R 4b - and in the formula, R 4a and R 4b H and C are independent of each other. 1~6 Alkyl or halo, where Z is -CR 9a R 9b - and in the formula, R 9a and R 9b These are H and C, respectively, independently. 1~6 Alkyl, or C 1~4 It is a haloalkyl. In some embodiments, Y is -C(O)NH- and R 2 is H or C 1~6 It is alkyl, W 1 is a combination or -CR 4a R 4b - and in the formula, R 4a and R 4b These are independently H, -CH3, or halo, and Z is -CR 9a R 9b - and in the formula, R 9a and R 9b These are H and C, respectively, independently. 1~6 Alkyl, or C 1~4 It is a haloalkyl. In some embodiments, Y is -C(O)NH- and R 2 is H or C 1~6 It is alkyl, W 1 is a combination or -CR 4a H-, and in the formula, R4a H, C 1~6 Alkyl or halo, where Z is -CR 9a R 9b - and in the formula, R 9a and R 9b These are H and C, respectively, independently. 1~6 Alkyl, or C 1~4 It is a haloalkyl. In some embodiments, Y is -C(O)NH- and R 2 is H or C 1~6 It is alkyl, W 1 Z is a bond, -CH2- or -CH(F)-, and Z is -CH(CH3- or -CH(CH2F)-.

[0111] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, W 2 -CR 5a R 5b - or -CR 6a =CR 6b - and in the formula, R 5a and R 5b H and C are independent of each other. 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkylene-OC 1~4 It is alkyl, R 6a and R 6b These are H, Halo, and C, independently. 1~4 Haloalkyl, or C 1~6 It is alkyl. In some embodiments, W 2 -CR 5a R 5b - or -CR 6a =CR 6b - and in the formula, R 5a and R 5b H and C are independent of each other. 1~6 Alkyl, C 1~4 Haloalkyl, halo, or -OC 1~4 It is alkyl, R 6a and R6b These are H, Halo, and C, independently. 1~4 Haloalkyl, or C 1~6 It is alkyl. In some embodiments, W 2 -CR 5a R 5b - or -CR 6a =CR 6b - and in the formula, R 5a and R 5b H and C are independent of each other. 1~6 Alkyl or halo, R 6a and R 6b These are independently H, halo, or C 1~6 It is alkyl. In some embodiments, W 2 is -CH2- or -CH=CH-. In some embodiments, W 2 is -CH2-. In some embodiments, W 2 Therefore, -CH=CH-.

[0112] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, Y is -C(O)NH-, and R 2 is H or C 1~6 It is alkyl, W 1 However, combined or -CR 4a R 4b - and in the formula, R 4a and R 4b H and C are independent of each other. 1~6 Alkyl, C 1~4 It is a haloalkyl or halo, where Z is -CR 9a R 9b - and in the formula, R 9a and R 9b These are H and C, respectively, independently. 1~6 Alkyl, C 1~4 It is a haloalkyl or halo, and W 2 -CR 5a R 5b - or -CR 6a =CR 6b - and in the formula, R 5a and R5b H and C are independent of each other. 1~6 Alkyl, C 1~4 Haloalkyl, halo, hydroxyl, cyano, -OC 1~4 Alkyl, or C 1~4 Alkylene-OC 1~4 It is alkyl, R 6a and R 6b These are H, Halo, and C, independently. 1~4 Haloalkyl, or C 1~6 It is alkyl.

[0113] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, Y is -C(O)NH-, and R 2 is H or C 1~6 It is alkyl, W 1 However, combined or -CR 4a R 4b - and in the formula, R 4a and R 4b H and C are independent of each other. 1~6 Alkyl or halo, where Z is -CR 9a R 9b - and in the formula, R 9a and R 9b These are H and C, respectively, independently. 1~6 Alkyl, or C 1~4 It is a haloalkyl, W 2 -CR 5a R 5b - or -CR 6a =CR 6b - and in the formula, R 5a and R 5b H and C are independent of each other. 1~6 Alkyl, C 1~4 Haloalkyl, halo, or -OC 1~4 It is alkyl, R 6a and R 6b These are H, Halo, and C, independently. 1~4 Haloalkyl, or C 1~6 It is alkyl.

[0114] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-II-A, III, IIIa, or IIIb, or a pharmaceutically acceptable salt thereof, Y is -C(O)NH-, and R 2 is H or C 1~6 alkyl, and W 1 is a bond or -CR 4a R 4b -, wherein R 4a and R 4b are independently H, -CH3, or halo, and Z is -CR 9a R 9b -, wherein R 9a and R 9b are each independently H, C 1~6 alkyl, or C 1~4 haloalkyl, and W 2 is -CR 5a R 5b - or -CR 6a =CR 6b -, wherein R 5a and R 5b are independently H, C 1~6 alkyl, or halo, and R 6a and R 6b are independently H, halo, or C 1~6 alkyl.

[0115] In some embodiments of the compounds of formula I, I-A, I-B, I-C, I-D, I-E, I-F, II-II-A, III, IIIa, or IIIb, or a pharmaceutically acceptable salt thereof, Y is -C(O)NH-, and R 2 is H or C 1~6 alkyl, and W 1 is a bond or -CR 4a H-, wherein R 4a is H, C 1~6 alkyl, or halo, and Z is -CR 9a R 9b -, wherein R 9a and R 9b are each independently H, C 1~6 alkyl, or C1~4 It is a haloalkyl, W 2 This is -CH2- or -CH=CH-.

[0116] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, Y is -C(O)NH-, and R 2 is H or C 1~6 It is alkyl, W 1 is a combination or -CR 4a H-, and in the formula, R 4a H, C 1~6 Alkyl or halo, where Z is -CR 9a R 9b - and in the formula, R 9a and R 9b These are H and C, respectively, independently. 1~6 Alkyl, or C 1~4 It is a haloalkyl, W 2 It is -CH2-.

[0117] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, Y is -C(O)NH-, and R 2 is H or C 1~6 It is alkyl, W 1 is a combination or -CR 4a H-, and in the formula, R 4a H, C 1~6 Alkyl or halo, where Z is -CR 9a R 9b - and in the formula, R 9a and R 9b These are H and C, respectively, independently. 1~6 Alkyl, or C 1~4 It is a haloalkyl, W 2 Therefore, -CH=CH-.

[0118] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, Y is -C(O)NH-, and R 2 is H or C 1~6 It is alkyl, W 1 is a bond, -CH2- or -CH(F)-, Z is -CH(CH3)- or -CH(CH2F)-, and W 2 This is -CH2- or -CH=CH-.

[0119] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, or IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, Y is -C(O)NH-, and R 2 is H or C 1~6 It is alkyl, W 1 is a bond, -CH2- or -CH(F)-, Z is -CH(CH3)- or -CH(CH2F)-, and W 2 It is -CH2-.

[0120] In some embodiments of compounds of formula I, IA, IB, IC, ID, IE, or IF, II-II-A, Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, Y is -C(O)NH-, and R 2 is H or C 1~6 It is alkyl, W 1 is a bond, -CH2- or -CH(F)-, Z is -CH(CH3)- or -CH(CH2F)-, and W 2 Therefore, -CH=CH-.

[0121] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, or IIIb, or pharmaceutically acceptable salts thereof, the compound has formula IV, [ka] In the formula, m is 0, 1, 2, or 3.

[0122] In some embodiments of compounds of formula I, IA, II-A, II-Aa, III, IIIa, or IV, or pharmaceutically acceptable salts thereof, the compound has formula IVa, [ka] In the formula, m is 0, 1, 2, or 3.

[0123] In some embodiments of compounds of formula I, IA, II-A, II-Ab, III, IIIb, or IV, or pharmaceutically acceptable salts thereof, the compound has formula IVb, [ka] In the formula, m is 0, 1, 2, or 3.

[0124] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl group.

[0125] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl.

[0126] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, R 4a H, C1~6 is alkyl, or C 1~4 is haloalkyl, and R 5a is H, halo, C 1~4 is haloalkyl, or C 1~6 is alkyl.

[0127] In some embodiments of the compounds of Formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, R 9a is H, C 1~6 is alkyl, C 1~4 is haloalkyl, or halo. In some embodiments, R 9a is C 1~6 is alkyl, C 1~4 is haloalkyl, or halo. In some embodiments, R 9a is C 1~6 is alkyl or C 1~4 is haloalkyl. In some embodiments, R 9a is -CH3 or -CH2F.

[0128] In some embodiments of the compounds of Formula I, I-A, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, R 4a is H, C 1~6 is alkyl, or C 1~4 is haloalkyl, and R 5a is H, halo, C 1~4 is haloalkyl, or C 1~6 is alkyl, and R 9a is H, C[[ID=…]] 1~6 is alkyl, C 1~4 is haloalkyl, or halo. In some embodiments, R 4a is H, C 1~6 is alkyl, or C 1~4 is haloalkyl, and R 5a is H, halo, C 1~4 is haloalkyl, or C 1~6 is alkyl, and R 9a is C 1~6 is alkyl, C 1~4It is a haloalkyl or halo. In some embodiments, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a C 1~6 Alkyl or C 1~4 In some embodiments, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a This is either -CH3 or -CH2F.

[0129] In some embodiments of compounds of formulas I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, each R 8 Independently, (i) Hello, (ii) C which is optionally replaced with OH 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 A 5-10 membered heteroaryl containing aryl or 1, 2, or 3 heteroatoms independently selected from N, O, and S. (iii) C 1~6 Haloalkyl, (iv)CN, (v) oxo, (vi)-XR A5 And, In the formula, X is either O or S, and R A5 H, C 1~6 A 3- to 7-membered ring containing alkyl or 0, 1, or 2 heteroatoms selected from N, O, and S, C1-C6 alkyl or 3-7 membered rings are CN, halo, C1-C6 alkoxy, C6~10 aryls, and 5- to 10-membered heteroaryls containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, are optionally substituted with 1, 2, or 3 groups. (vii) NHR A6 And, In the formula, R A6 These are C1-C6 alkyl groups. (viii)NR A7 R A8 And, In the formula, R A7 These are C1-C6 alkyl groups, R A8 These are C1-C6 alkyl groups. (ix)C 1~6 Alkyl, C 1~6 Haloalkyl, Halo, CN, C 3~7 Cycloalkyl, and C 1~6 C is optionally substituted with 1, 2, 3, or 4 substituents independently selected from the alkoxy. 6~10 It is Ariel, C 3~7 Cycloalkyl groups are those optionally substituted with 1, 2, 3, or 4 independent halo groups. (x) A 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S, 3-7 member rings are halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 Optionally substituted with one, two, or three substituents independently selected from the cycloalkyl group, or (xi) A 5-10 membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or A 5-10 member heteroaryl ring is a halo, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7It is optionally substituted with one, two, or three substituents independently selected from the cycloalkyl group, or Two R's 8 The groups are linked together to form condensed, spiro, or bridging 3- to 7-membered rings containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S. 3-7 member rings are halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 It is optionally substituted with one, two, or three substituents independently selected from the cycloalkyl group, or Two R atoms on adjacent carbon atoms 8 The groups are linked together to form a condensed 6-10 membered aromatic ring containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S. The condensed 6-10 member aromatic ring is a halo, OH, C 1~6 Alkyl, C 1~6 Haloalkyl, C 1~6 Alkoxy, and C 3~7 It is optionally substituted with one, two, or three substituents independently selected from the cycloalkyl group.

[0130] In some embodiments of compounds of formulas I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, each R 8 Independently, (i) Hello, (ii) C which is optionally replaced with OH 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 A 5-10 membered heteroaryl containing aryl or 1, 2, or 3 heteroatoms independently selected from N, O, and S. (iii) C 1~6 Haloalkyl, (iv)CN, (v) oxo, (vi)-XR A5 And, In the formula, X is either O or S, and R A5 H, C 1~6 A 3- to 7-membered ring containing alkyl or 0, 1, or 2 heteroatoms selected from N, O, and S, C1-C6 alkyl or 3-7 membered rings are CN, halo, C1-C6 alkoxy, C 6~10 aryls, and 5- to 10-membered heteroaryls containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, are optionally substituted with 1, 2, or 3 groups. (vii) NHR A6 And, In the formula, R A6 These are C1-C6 alkyl groups. (viii)NR A7 R A8 And, In the formula, R A7 These are C1-C6 alkyl groups, R A8 These are C1-C6 alkyl groups. (ix)C 6~10 Ariel, (x) A 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S, or (xi) A 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or Two R's 8 The groups link together to form condensed, spiro, or bridging 3- to 7-membered rings containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S.

[0131] In some embodiments of compounds of formulas I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, each R 8These are independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CH2OMe, NHMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CHF2, CH2CF3, (CH2)4Cl, CH2F, CH2CH2F, CH(CH3)F, CF2CH3, CF3, [ka] That is the case.

[0132] In some embodiments of compounds of formulas I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, each R 8 These are independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CH2OMe, NHMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl, [ka] That is the case.

[0133] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a H, C 1~6 Alkyl, C 1~4 It is a haloalkyl or halo, Each R 8Independently, (i) Hello, (ii) C which is optionally replaced with OH 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 A 5-10 membered heteroaryl containing aryl or 1, 2, or 3 heteroatoms independently selected from N, O, and S. (iii) C 1~6 Haloalkyl, (iv)CN, (v) oxo, (vi)-XR A5 And, In the formula, X is either O or S, and R A5 H, C 1~6 A 3- to 7-membered ring containing alkyl or 0, 1, or 2 heteroatoms selected from N, O, and S, C1-C6 alkyl or 3-7 membered rings are CN, halo, C1-C6 alkoxy, C 6~10 aryls, and 5- to 10-membered heteroaryls containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, are optionally substituted with 1, 2, or 3 groups. (vii) NHR A6 And, In the formula, R A6 These are C1-C6 alkyl groups. (viii)NR A7 R A8 And, In the formula, R A7 These are C1-C6 alkyl groups, R A8 These are C1-C6 alkyl groups. (ix)C 6~10 Ariel, (x) A 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S, or (xi) A 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or Two R's 8The groups link together to form condensed, spiro, or bridging 3- to 7-membered rings containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S.

[0134] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a C 1~6 Alkyl, C 1~4 It is a haloalkyl or halo, Each R 8 Independently, (i) Hello, (ii) C which is optionally replaced with OH 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 A 5-10 membered heteroaryl containing aryl or 1, 2, or 3 heteroatoms independently selected from N, O, and S. (iii) C 1~6 Haloalkyl, (iv)CN, (v) oxo, (vi)-XR A5 And, In the formula, X is either O or S, and R A5 H, C 1~6 A 3- to 7-membered ring containing alkyl or 0, 1, or 2 heteroatoms selected from N, O, and S, C1-C6 alkyl or 3-7 membered rings are CN, halo, C1-C6 alkoxy, C 6~10aryls, and 5- to 10-membered heteroaryls containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, are optionally substituted with 1, 2, or 3 groups. (vii) NHR A6 And, In the formula, R A6 These are C1-C6 alkyl groups. (viii)NR A7 R A8 And, In the formula, R A7 These are C1-C6 alkyl groups, R A8 These are C1-C6 alkyl groups. (ix)C 6~10 Ariel, (x) A 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S, or (xi) A 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or Two R's 8 The groups link together to form condensed, spiro, or bridging 3- to 7-membered rings containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S.

[0135] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a C 1~6 Alkyl or C 1~4 It is a haloalkyl, Each R 8 Independently, (i) Hello, (ii) C which is optionally replaced with OH 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 A 5-10 membered heteroaryl containing aryl or 1, 2, or 3 heteroatoms independently selected from N, O, and S. (iii) C 1~6 Haloalkyl, (iv)CN, (v) oxo, (vi)-XR A5 And, In the formula, X is either O or S, and R A5 H, C 1~6 A 3- to 7-membered ring containing alkyl or 0, 1, or 2 heteroatoms selected from N, O, and S, C1-C6 alkyl or 3-7 membered rings are CN, halo, C1-C6 alkoxy, C 6~10 aryls, and 5- to 10-membered heteroaryls containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, are optionally substituted with 1, 2, or 3 groups. (vii) NHR A6 And, In the formula, R A6 These are C1-C6 alkyl groups. (viii)NR A7 R A8 And, In the formula, R A7 These are C1-C6 alkyl groups, R A8 These are C1-C6 alkyl groups. (ix)C 6~10 Ariel, (x) A 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S, or (xi) A 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or Two R's 8The groups link together to form condensed, spiro, or bridging 3- to 7-membered rings containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S.

[0136] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a This is either -CH3 or -CH2F. Each R 8 Independently, (i) Hello, (ii) C which is optionally replaced with OH 1~6 Alkyl, C 1~6 Alkoxy, C 6~10 A 5-10 membered heteroaryl containing aryl or 1, 2, or 3 heteroatoms independently selected from N, O, and S. (iii) C 1~6 Haloalkyl, (iv)CN, (v) oxo, (vi)-XR A5 And, In the formula, X is either O or S, and R A5 H, C 1~6 A 3- to 7-membered ring containing alkyl or 0, 1, or 2 heteroatoms selected from N, O, and S, C1-C6 alkyl or 3-7 membered rings are CN, halo, C1-C6 alkoxy, C 6~10 aryls, and 5- to 10-membered heteroaryls containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, are optionally substituted with 1, 2, or 3 groups. (vii) NHRA6 And, In the formula, R A6 These are C1-C6 alkyl groups. (viii)NR A7 R A8 And, In the formula, R A7 These are C1-C6 alkyl groups, R A8 These are C1-C6 alkyl groups. (ix)C 6~10 Ariel, (x) A 3- to 7-membered ring containing 0, 1, or 2 heteroatoms independently selected from N, O, and S, or (xi) A 5- to 10-membered heteroaryl ring containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, or Two R's 8 The groups link together to form condensed, spiro, or bridging 3- to 7-membered rings containing 0, 1, 2, or 3 heteroatoms selected from N, O, and S.

[0137] In some embodiments of compounds of formulas I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, each R 8 These are independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CH2OMe, NHMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl, [ka] That is the case.

[0138] In some embodiments of compounds of formulas I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, each R 8These are independently -Cl, -F, -Br, oxo, -CN, methyl, ethyl, propyl, -CH2Ph, -CH2CH2Ph, -CH(CH3)Ph, -CH2C(CH3)2, -CH2OH, -CH2OMe, -NHMe, -NMe2, -OH, -OMe, -OCD3, -OCD3OCH2CF3, -OCH2CHF2, -OCH2C(CH3)2, -OCH2CH2OMe, -SMe, -CH2F, -CHF2, -CF3, -CH2CF3, -(CH2)4Cl, -SMe, -SO2Me, -CH2CH2F, -CH(CH3)F, -C(F)2CH3, -CF3, -OCH2CF3, -C=CC(CH3)2SO2CH3, -C=CC(CH3)2OH [ka] That is the case.

[0139] In some embodiments of compounds of formulas I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, two R 8 These connect to form a condensed six-membered ring containing one oxygen atom.

[0140] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a H, C 1~6 Alkyl, C 1~4 It is a haloalkyl or halo, Each R 8These are independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CH2OMe, NMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl, [ka] That is the case.

[0141] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a C 1~6 Alkyl, C 1~4 It is a haloalkyl or halo, Each R 8 These are independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CH2OMe, NMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl, [ka] That is the case.

[0142] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a C 1~6 Alkyl or C 1~4 It is a haloalkyl, Each R 8 These are independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CH2OMe, NMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl, [ka] That is the case.

[0143] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a C 1~6 Alkyl or C 1~4 It is a haloalkyl, Each R 8 These are independently Cl, F, Br, oxo, CN, methyl, ethyl, propyl, CH2Ph, CH2OH, CH2OMe, NMe, NMe2, OH, OMe, OCH2CF3, OCH2CHF2, OCH2CH2OMe, SMe, CH2F, CHF2, CH2CF3, (CH2)4Cl, [ka] That is the case.

[0144] In some embodiments of compounds of formulas I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, m is 0, 1, or 2. In some embodiments, m is 0. In some embodiments, m is 1. In some embodiments, m is 2.

[0145] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, or IVb, or pharmaceutically acceptable salts thereof, the compound has formula V, [ka] In the formula, R 8A and R 8B These are H, Halo, and C, respectively, and are independent of each other. 1~4 Alkyl, or C 1~4 It is a haloalkyl group.

[0146] In some embodiments of compounds of formula I, IA, II-A, II-Aa, III, IIIa, IV, IVa, or V, or pharmaceutically acceptable salts thereof, the compound has formula Va, [ka] In the formula, R 8A and R 8B These are H, Halo, and C, respectively, and are independent of each other. 1~4 Alkyl, or C 1~4 It is a haloalkyl group.

[0147] In some embodiments of compounds of formula I, IA, II-A, II-Ab, III, IIIb, IV, IVb, or V, or pharmaceutically acceptable salts thereof, the compound has formula Vb, [ka] In the formula, R 8A and R 8B These are H, Halo, and C, respectively, and are independent of each other. 1~4 Alkyl, or C 1~4 It is a haloalkyl group.

[0148] In some embodiments of compounds of formula V, Va, or Vb, or pharmaceutically acceptable salts thereof, R 8A Hello, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 8B H, Halo, C 1~4 Alkyl or C 1~4 In some embodiments, R 8A Hello, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 8B H is H. In some embodiments, R 8A H, Halo, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 8B Hello, C 1~4 Alkyl or C 1~4 In some embodiments, R 8A H is R 8B Hello, C 1~4 Alkyl or C 1~4 It is a haloalkyl group.

[0149] In some embodiments of compounds of formula V, Va, or Vb, or pharmaceutically acceptable salts thereof, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl group.

[0150] In some embodiments of compounds of formula V, Va, or Vb, or pharmaceutically acceptable salts thereof, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl.

[0151] In some embodiments of formulas V, Va, or Vb, or their pharmaceutically acceptable salts, R 9a H, C 1~6 Alkyl, C 1~4 It is a haloalkyl or halo. In some embodiments, R 9a C 1~6 Alkyl, C 1~4 It is a haloalkyl or halo. In some embodiments, R 9a C 1~6 It is alkyl.

[0152] In some embodiments of compounds of formula V, Va, or Vb, or pharmaceutically acceptable salts thereof, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl group.

[0153] In some embodiments of compounds of formula V, Va, or Vb, or pharmaceutically acceptable salts thereof, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl.

[0154] In some embodiments of formulas V, Va, or Vb, or their pharmaceutically acceptable salts, R 9a H, C 1~6 Alkyl, C 1~4 It is a haloalkyl or halo. In some embodiments, R 9a C 1~6 Alkyl, C 1~4 It is a haloalkyl or halo. In some embodiments, R 9a C 1~6 It is alkyl.

[0155] In some embodiments of formulas V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A Hello, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 8B H, Halo, C 1~4 Alkyl or C 1~4It is a haloalkyl, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a H, C 1~6 Alkyl, C 1~4 It is a haloalkyl or halo.

[0156] In some embodiments of formulas V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A Hello, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 8B H is R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a H, C 1~6 Alkyl, C 1~4 It is a haloalkyl or halo.

[0157] In some embodiments of formulas V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A H, Halo, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 8B Hello, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a H, C 1~6 Alkyl, C 1~4 It is a haloalkyl or halo.

[0158] In some embodiments of formulas V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A H is R 8B Hello, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a H, C 1~6 Alkyl, C 1~4 It is a haloalkyl or halo.

[0159] In some embodiments of formulas V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A Hello, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 8B H, Halo, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a C 1~6 Alkyl, C 1~4 It is a haloalkyl or halo.

[0160] In some embodiments of formulas V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A Hello, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 8B H is R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C1~6 It is alkyl, R 9a C 1~6 Alkyl, C 1~4 It is a haloalkyl or halo.

[0161] In some embodiments of formulas V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A H, Halo, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 8B Hello, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a C 1~6 Alkyl, C 1~4 It is a haloalkyl or halo.

[0162] In some embodiments of formulas V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A H is R 8B Hello, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a C 1~6 Alkyl, C 1~4 It is a haloalkyl or halo.

[0163] In some embodiments of formulas V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A Hello, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 8BH, Halo, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a C 1~6 It is alkyl.

[0164] In some embodiments of formulas V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A Hello, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 8B H is R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a C 1~6 It is alkyl.

[0165] In some embodiments of formulas V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A H, Halo, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 8B Hello, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a C 1~6 It is alkyl.

[0166] In some embodiments of formulas V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A H is R 8B Hello, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a C 1~6 It is alkyl.

[0167] In some embodiments of formulas V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A H is R 8B Hello, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a C 1~6 It is alkyl, R 1 is 1, 2, 3, or 4 R A1 The phenyl is optionally substituted, and each R A1 It is independently, Halo, C 1~4 Alkyl, C 1~4 Haloalkyl, or -OC 1~4 It is alkyl.

[0168] In some embodiments of formulas V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A H is R 8B Hello, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 4a H, C 1~6 Alkyl, or C 1~4It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a C 1~6 It is alkyl, R 1 is 1, 2, 3, or 4 R A1 The phenyl is optionally substituted, and each R A1 These are independently, halo or -OC 1~4 It is alkyl.

[0169] In some embodiments of formulas V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A H is R 8B Hello, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a C 1~6 It is alkyl, R 1 This is a phenyl compound that is optionally substituted with one, two, three, or four halogens.

[0170] In some embodiments of formulas V, Va, or Vb, or their pharmaceutically acceptable salts, R 8A H is R 8B Hello, C 1~4 Alkyl or C 1~4 It is a haloalkyl, R 4a H, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a C 1~6 It is alkyl, R 1This is a phenyl compound optionally substituted with two or three halogens selected from chloro and fluoro compounds.

[0171] In some embodiments of compounds of formula V, Va, or Vb, or pharmaceutically acceptable salts thereof, R 8A and R 8B These are H, Halo, and C, respectively, and are independent of each other. 1~4 Alkyl, C 1~4 Haloalkyl or -XR A5 In the equation, X is O and R A5 H, C 1~6 Alkyl, C 1~6 It is a haloalkyl group or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S.

[0172] In some embodiments of compounds of formula V, Va, or Vb, or pharmaceutically acceptable salts thereof, R 8A and R 8B These are H, Halo, and C, respectively, and are independent of each other. 1~4 Alkyl, C 1~4 Haloalkyl or -XR A5 In the equation, X is O and R A5 H, C 1~6 Alkyl, C 1~6 A haloalkyl group, or a 3- to 7-membered ring containing 0, 1, or 2 heteroatoms selected from N, O, and S, R 1 This is a phenyl compound substituted with two or three halogens selected from chloro and fluoro compounds. R 4a R 4a H, Halo, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a C 1~6 Alkyl or C 1~4 It is a haloalkyl group.

[0173] In some embodiments of compounds of formula V, Va, or Vb, or pharmaceutically acceptable salts thereof, R 8A and R 8B These are H, Halo, and C, respectively, and are independent of each other. 1~4 Alkyl, C 1~4 Haloalkyl or -XR A5 In the equation, X is O and R A5 C 1~6 Alkyl or C 1~6 It is a haloalkyl group.

[0174] In some embodiments of compounds of formula V, Va, or Vb, or pharmaceutically acceptable salts thereof, R 8A and R 8B These are H, Halo, and C, respectively, and are independent of each other. 1~4 Alkyl, C 1~4 Haloalkyl or -XR A5 In the equation, X is O and R A5 C 1~6 Alkyl or C 1~6 It is a haloalkyl, R 1 This is a phenyl compound substituted with two or three halogens selected from chloro and fluoro compounds. R 4a R 4a H, Halo, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a C 1~6 Alkyl or C 1~4 It is a haloalkyl group.

[0175] In some embodiments of compounds of formula V, Va, or Vb, or pharmaceutically acceptable salts thereof, R 8A and R 8B These are H, Halo, and C, respectively, and are independent of each other. 1~4Alkyl, C 1~4 Haloalkyl or -XR A5 In the equation, X is O and R A5 C 1~6 It is alkyl.

[0176] In some embodiments of compounds of formula V, Va, or Vb, or pharmaceutically acceptable salts thereof, R 8A and R 8B These are H, Halo, and C, respectively, and are independent of each other. 1~4 Alkyl, C 1~4 Haloalkyl or -XR A5 In the equation, X is O and R A5 C 1~6 It is alkyl, R 1 This is a phenyl compound substituted with two or three halogens selected from chloro and fluoro compounds. R 4a R 4a H, Halo, C 1~6 Alkyl, or C 1~4 It is a haloalkyl, R 5a H, Halo, C 1~4 Haloalkyl, or C 1~6 It is alkyl, R 9a C 1~6 Alkyl or C 1~4 It is a haloalkyl group.

[0177] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is [ka] That is the case.

[0178] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is [ka] That is the case.

[0179] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is [ka] That is the case.

[0180] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is [ka] That is the case.

[0181] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is [ka] That is the case.

[0182] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is [ka] That is the case.

[0183] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is [ka] That is the case.

[0184] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is [ka] That is the case.

[0185] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is [ka] That is the case.

[0186] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is [ka] [ka] [ka] [ka] [ka] [ka] It is selected from the group consisting of the following.

[0187] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] [ka] It is selected from the group consisting of the following.

[0188] In some embodiments of compounds of formula I, IA, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb, or pharmaceutically acceptable salts thereof, the compound is [ka] [ka] [ka] [ka] That is the case.

[0189] III. Pharmaceutical Compositions The compounds provided herein are typically administered in the form of pharmaceutical compositions. Accordingly, pharmaceutical compositions comprising one or more of the compounds provided herein, or their pharmaceutically acceptable salts, isomers, or mixtures, and one or more pharmaceutically acceptable vehicles selected from carriers, auxiliaries, and excipients are also provided herein. The compounds provided herein may be the sole active ingredient or one of the active ingredients of a pharmaceutical composition. Suitable pharmaceutically acceptable vehicles include, for example, inert solid diluents and fillers, diluents containing sterile aqueous solutions and various organic solvents, penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared in manner well known in the pharmaceutical field. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa. 17th Ed. (1985), and Modern Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (see GSBanker & CTRhodes, Eds.).

[0190] In one embodiment, a pharmaceutical composition is provided herein comprising a compound provided herein (e.g., a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, V, Va, or Vb), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier. In some embodiments, the pharmaceutical composition comprises a therapeutically effective amount of a compound provided herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient or carrier.

[0191] In some embodiments, the pharmaceutical composition provided herein 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 pharmaceutically acceptable salts thereof. In some embodiments, the pharmaceutical composition 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 pharmaceutically acceptable salts thereof in a therapeutically effective amount.

[0192] The pharmaceutical composition may be administered in single or multiple doses. The pharmaceutical composition may be administered by various methods, including, for example, rectally, orally, intranasally, and transdermally. In some embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0193] One mode of administration is parenteral, for example, by injection. Forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oily suspensions, or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, or elixirs, mannitol, dextrose, or sterile aqueous solutions, and similar pharmaceutical vehicles.

[0194] Oral administration may be another route for administering the compounds provided herein. Administration may be, for example, by capsule or enteric-coated tablet. When preparing a pharmaceutical composition comprising at least one of the compounds provided herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, the active ingredient (such as the compounds provided herein) is usually diluted with an excipient and / or encapsulated in a carrier, which may be in the form of a capsule, sachet, paper, or other container. When the excipient functions as a diluent, the excipient may be in the form of a solid, semi-solid, or liquid material acting as a vehicle, carrier, or medium for the active ingredient. Thus, the pharmaceutical composition may be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solid or in a liquid medium), ointments, soft and hard gelatin capsules, sterile injectable solvents, and sterile packaged powders, for example, containing up to 10% by weight of the active compound.

[0195] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose, or any combination thereof. The pharmaceutical composition may further include lubricants, wetting agents, emulsifiers and suspending agents such as talc, magnesium stearate, and mineral oil, preservatives, sweeteners and flavoring agents such as methyl hydroxybenzoate and propyl hydroxybenzoate, or any combination thereof.

[0196] Pharmaceutical compositions comprising at least one compound described herein, or a pharmaceutically acceptable salt, isomer, or mixture thereof, can be formulated to provide rapid, sustained, or delayed release of the active ingredient (such as the compounds provided herein) after administration to a subject 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. Patents 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 may be used to provide continuous or discontinuous infusions of the compounds provided herein in controlled amounts. The construction and use of transdermal patches for drug delivery are well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445, and 5,001,139. ​​Such patches may be constructed for continuous, pulsed, or on-demand delivery of pharmaceuticals.

[0197] To prepare solid compositions such as tablets, the main active ingredient may be mixed with pharmaceutical excipients to form a solid preformulation composition containing a homogeneous mixture of the compounds described herein, or pharmaceutically acceptable salts, isomers, or mixtures thereof. When these preformulation compositions are referred to as homogeneous, the active ingredient may be uniformly dispersed throughout the composition, and as a result, the composition can be easily subdivided into uniformly effective unit dosage forms such as tablets, pills, and capsules.

[0198] Tablets or pills of the compounds described herein may be coated or otherwise formulated to provide a dosage form that offers the benefit of long-term action or to protect from the acidic conditions of the stomach. For example, a tablet or pill may contain an inner dose and an outer dose component, the latter in the form of an envelope covering the former. The two components may be separated by an enteric coating that resists disintegration in the stomach, allows the inner component to pass through the duodenum intact, or allows for delayed release. A variety of materials may be used for such enteric coatings or layers, including many high molecular weight acids, as well as mixtures of high molecular weight acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0199] Pharmaceutical compositions for inhalation or inhalation may include solutions and suspensions in pharmaceutically acceptable aqueous solvents or organic solvents or mixtures thereof, as well as powders. Liquid or solid compositions may include suitable pharmaceutically acceptable excipients as described above. In some embodiments, compositions are administered orally or via nasal respiration for topical or systemic effects. In other embodiments, compositions in pharmaceutically acceptable solvents may be atomized using an inert gas. The atomized solution may be inhaled directly from a spraying device, or the spraying device may be attached to a face mask tent or an intermittent positive pressure respirator. The solution, suspension, or powder composition may be administered preferably orally or nasally from a device for delivering the formulation in an appropriate manner.

[0200] IV. Treatment method In one embodiment, a method is provided for treating HIV (e.g., HIV-1 and / or HIV-2) infection in a person who has or is at risk of having the infection, comprising administering to the person a therapeutically effective amount of a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof.

[0201] In some embodiments, the method further comprises administering to the person a therapeutically effective dose of one, two, three, or four additional therapeutic agents. In certain embodiments, the additional therapeutic agents are anti-HIV agents. In certain embodiments, the additional therapeutic agents are HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gpl20 inhibitors, CCR5 inhibitors, latent infection reactivators, capsid polymerization inhibitors, HIV bNAb (broadly neutralizing HIV antibody), TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. In one embodiment, the additional therapeutic agent is abacavir, tenofovir alafenamide, tenofovir disoproxil, lenacapapvir, or pharmaceutically acceptable salts thereof. In one embodiment, the additional therapeutic agent is abacavir, tenofovir alafenamide, tenofovir disoproxil, lenacapavir, GS-5894, islatravir, or a pharmaceutically acceptable salt thereof. In some embodiments, the additional therapeutic agent is lenacapavir or islatravir. In some embodiments, the additional therapeutic agent is lenacapavir. In some embodiments, the additional therapeutic agent is islatravir.

[0202] In another embodiment, the use of a pharmaceutical composition of a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for the treatment of HIV (e.g., HIV-1 and / or HIV-2) infection in a person who has or is at risk of having the infection is provided.

[0203] In another embodiment, a pharmaceutical composition is provided of a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in medical therapy.

[0204] In another embodiment, a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, is provided for use in the treatment of HIV infection.

[0205] In another embodiment, a pharmaceutical composition of a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, is provided for use in a method of treating HIV infection in a person who has or is at risk of having HIV infection.

[0206] In another embodiment, a pharmaceutical composition of a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, is provided for use in a method of treating HIV infection in a person who has or is at risk of having HIV infection, the method further comprising administering 1, 2, 3, or 4 additional therapeutic agents to a person.

[0207] In another embodiment, a pharmaceutical composition of a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, is provided for use in a method of treating HIV infection in a person who has or is at risk of having HIV infection, the method being used 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, or an HIV The present invention further comprises administering to a human being one, two, three, or four additional therapeutic agents selected from the group consisting of bNAbs, TLR7 agonists, pharmacokinetic enhancers, other drugs for treating HIV, or combinations thereof. In one embodiment, one, two, three, or four additional therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, latent infection reactivators, HIV capsid inhibitors, HIV bNAbs, TLR7 agonists, and combinations thereof.

[0208] In another embodiment, a pharmaceutical composition of a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, is provided for use in a method of treating HIV infection in a person who has or is at risk of having HIV infection, the method further comprising administering a therapeutically effective amount of tenofovir disoproxil and emtricitabine to a person.

[0209] In another embodiment, a pharmaceutical composition of a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, is provided for use in a method of treating HIV infection in a person who has, has, or is at risk of having HIV infection, the method further comprising administering a therapeutically effective amount of tenofovir alafenamide and emtricitabine to a person.

[0210] In another embodiment, a pharmaceutical composition of a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, is provided for use in a method of treating HIV infection in a person who has or is at risk of having HIV infection, the method further comprising administering a therapeutically effective amount of tenofovir disoproxil to a person.

[0211] In another embodiment, a pharmaceutical composition of a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, is provided for use in a method of treating HIV infection in a person who has or is at risk of having HIV infection, the method further comprising administering a therapeutically effective amount of tenofovir alafenamide to a person.

[0212] In another embodiment, methods are provided for therapeutic use of compounds of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb. In particular, methods are provided for treating the replication of the HIV virus, treating AIDS, or delaying the onset of AIDS or ARC symptoms in a mammal (e.g., a human), comprising administering a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient to a mammal.

[0213] In another embodiment, a composition is provided comprising a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient, for use in a mammal (e.g., human) in a manner that treats the replication of the HIV virus, treats AIDS, or delays the onset of AIDS or ARC symptoms.

[0214] In one embodiment, a pharmaceutical composition is provided of a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, for use in the prevention of HIV infection.

[0215] For example, in one embodiment, a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, is provided for use as pre-exposure prophylaxis (PrEP), i.e., before an individual is exposed to the HIV virus, to prevent the establishment of HIV infection in an individual who has been exposed to the virus, and / or to prevent the virus from establishing a permanent infection, and / or to prevent the onset of symptoms of the disease, and / or to prevent the virus from reaching a detectable level in the blood.

[0216] In another embodiment, the use of compounds of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or pharmaceutically acceptable salts thereof, for the manufacture of a medicament for the treatment of HIV infection in a person who has or is at risk of having HIV infection is disclosed.

[0217] In another embodiment, the use of compounds of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or pharmaceutically acceptable salts thereof, as research tools is disclosed.

[0218] In another embodiment, a manufactured article comprising a composition effective for treating HIV infection is disclosed, as well as packaging material comprising a label indicating that the composition can be used to treat HIV infection. Exemplary compositions include compounds of formulas I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or pharmaceutically acceptable salts thereof.

[0219] In yet another embodiment, a method for inhibiting HIV replication is disclosed. The method comprises exposing the virus to an effective amount of a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or a pharmaceutically acceptable salt thereof, under conditions that inhibit HIV replication.

[0220] In another embodiment, the use of compounds of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIaIIIb, IV, IVa, IVb, V, Va, or Vb, or pharmaceutically acceptable salts thereof, for inhibiting the activity of HIV integrase enzymes is disclosed. In another embodiment, the use of compounds of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or pharmaceutically acceptable salts thereof, for inhibiting HIV replication is disclosed.

[0221] v. Administration The compounds of this disclosure (e.g., compounds of formulas I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb) may be administered by any route appropriate to the condition being treated. Preferred routes include oral, rectal, nasal, topical (including buccal and sublingual), percutaneous, vaginal, and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural). It will be understood that the preferred route may vary, for example, depending on the recipient's condition. An advantage of certain compounds disclosed herein is that they are orally bioavailable and can be administered orally.

[0222] The compounds of this disclosure may be administered to an individual according to an effective administration plan for a desired period or duration, such as at least about one month, at least about two months, at least about three months, at least about six months, or at least about twelve months or more. In some embodiments, the compounds are administered daily or on an intermittent schedule over the lifespan of the individual.

[0223] The specific dose levels of the compounds of this disclosure for any particular subject will depend on a variety of factors, including the activity of the specific compound used, age, body weight, overall health, sex, diet, administration time, route of administration, and excretion rate, drug combinations, and the severity of the particular disease in the subject receiving treatment. For example, the dose may be expressed as milligrams (mg / kg) of the compound described herein per kilogram of body weight of the subject. Doses of about 0.1 to 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments, doses of 0.5 to 60 mg / kg may be appropriate. Normalization by body weight of the subject is particularly useful when adjusting doses between subjects of widely different sizes, such as when using drugs in both children and adults, or when converting effective doses in non-human subjects such as dogs to doses suitable for human subjects.

[0224] Dosage may also be expressed as the total amount of the compound described herein administered per single dose. Doses of compounds of formulas I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb, or their pharmaceutically acceptable salts or pharmaceutically acceptable tautomers, may be about 1 mg to 4,000 mg, about 2,000 to 4,000 mg, about 1 to 2,000 mg, about 1 to 1,000 mg, about 10 to 500 mg, about 20 to 500 mg, about 50 to 300 mg, about 75 to 200 mg, or about 15 to 150 mg.

[0225] The dosage or frequency of administration of the compounds disclosed herein may be adjusted throughout the course of treatment at the discretion of the administering physician.

[0226] The compounds of this disclosure may be administered to an individual (e.g., a human) in a therapeutically effective dose. In some embodiments, the compound is administered once daily. In some embodiments, the compound is administered once weekly. In some embodiments, the compound is administered once monthly. In some embodiments, the compound is administered every two months. In some embodiments, the compound is administered every three months. In some embodiments, the compound is administered every four months. In some embodiments, the compound is administered every five months. In some embodiments, the compound is administered every six months. In some embodiments, the compound is administered every seven months. In some embodiments, the compound is administered every eight months. In some embodiments, the compound is administered every nine months. In some embodiments, the compound is administered every ten months. In some embodiments, the compound is administered every eleven months. In some embodiments, the compound is administered annually.

[0227] The compounds provided herein may be administered by any convenient route and means, such as oral or parenteral (e.g., intravenous) administration. The therapeutically effective dose of the compounds may include about 0.00001 mg / kg body weight to about 10 mg / kg body weight per day, for example, about 0.0001 mg / kg body weight to about 10 mg / kg body weight per day, or for example, about 0.001 mg / kg body weight to about 1 mg / kg body weight per day, or for example, about 0.01 mg / kg body weight to about 1 mg / kg body weight per day, or about 0.05 mg / kg body weight to about 0.5 mg / kg body weight per day. In some embodiments, the therapeutically effective dose of the compounds provided herein may include about 0.3 mg to about 30 mg per dose, or about 30 mg to about 300 mg per dose, or about 0.3 μg to about 30 mg per dose, or about 30 μg to about 300 μg per dose.

[0228] The compounds of this disclosure can be combined with one or more additional therapeutic agents at any dose of the compounds of this disclosure (e.g., 1 mg to 1000 mg of the compounds). The therapeutically effective dose may include approximately 0.1 mg to approximately 1000 mg per dose, for example, approximately 50 mg to approximately 500 mg per dose, or for example, approximately 100 mg to approximately 400 mg per dose, or for example, approximately 150 mg to approximately 350 mg per dose, or for example, approximately 200 mg to approximately 300 mg per dose, or for example, approximately 0.01 mg to approximately 1000 mg per dose, or for example, approximately 0.01 mg to approximately 100 mg per dose, or for example, approximately 0.1 mg to approximately 100 mg per dose, or for example, approximately 1 mg to approximately 100 mg per dose, or for example, approximately 1 mg to approximately 100 mg per dose. Other therapeutically effective doses of the compound of formula I are approximately 1 mg per dose, or approximately 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 approximately 100 mg per dose. Other therapeutically effective doses of the compounds disclosed herein are approximately 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 approximately 1000 mg per dose.

[0229] In some embodiments, the methods described herein include administering a target compound p of this specification to an initial daily dose of about 1 to 500 mg, and increasing the dose incrementally until clinical efficacy is achieved. The dose can be increased using increments of about 5, 10, 25, 50, or 100 mg. The dose can be increased daily, every other day, twice a week, once a week, every two weeks, every three weeks, or once a month.

[0230] When administered orally, the total daily dose for human subjects may be approximately 1 mg to 1,000 mg, approximately 10 to 500 mg / day, approximately 50 to 300 mg / day, approximately 75 to 200 mg / day, or approximately 100 to 150 mg / day. In some embodiments, the total daily dose for human subjects may be approximately 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 dose for human subjects may be approximately 200, 300, 400, 500, 600, 700, or 800 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 300, 400, 500, or 600 mg / day administered as a single dose.

[0231] In some embodiments, the total daily dose for human subjects may be about 100 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 150 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 200 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 250 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 300 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 350 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 400 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 450 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be about 500 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 550 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 600 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 650 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 700 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 750 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 800 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 850 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 900 mg / day administered as a single dose. In some embodiments, the total daily dose for human subjects may be approximately 950 mg / day administered as a single dose.In some embodiments, the total daily dose for human subjects may be approximately 1000 mg / day administered as a single dose.

[0232] A single dose may be administered hourly, daily, weekly, or monthly. For example, a single dose may be administered once every 1, 2, 3, 4, 6, 8, 12, or 16 hours, or once every 24 hours. A single dose may also be administered once every 1, 2, 3, 4, 5, or 6 days, or once every 7 days. A single dose may also be administered once every 1, 2, or 3 weeks, or once every 4 weeks. In certain embodiments, a single dose may be administered once every week. A single dose may also be administered once every month. In some embodiments, the compounds disclosed herein are administered once daily in the manner disclosed herein. In some embodiments, the compounds disclosed herein are administered twice daily in the manner disclosed herein.

[0233] In some embodiments, the compounds disclosed herein are administered once every 10 days. In some embodiments, the compounds disclosed herein are administered once every 15 days. In some embodiments, the compounds disclosed herein are administered once every 20 days. In some embodiments, the compounds disclosed herein are administered once every 10 to 15 days. In some embodiments, the compounds disclosed herein are administered once every 15 to 20 days. In some embodiments, the compounds disclosed herein are administered once every 10 to 20 days. In some embodiments, the compounds disclosed herein are administered once a month. In some embodiments, the compounds disclosed herein are administered once every two months. In some embodiments, the compounds disclosed herein are administered once every three months. In some embodiments, the compounds disclosed herein are administered once every four months. In some embodiments, the compounds disclosed herein are administered once every five months. In some embodiments, the compounds disclosed herein are administered once every six months. In some embodiments, the compounds disclosed herein are administered once every eight months. In some embodiments, the compounds disclosed herein are administered once every 10 months. In some embodiments, the compounds disclosed herein are administered once a year.

[0234] The frequency of administration of the compounds disclosed herein is determined by the individual patient's needs and may be, for example, once daily, once weekly, once every two weeks, once monthly, once every two months, once every three months, once every four months, once every six months, or less. Administration of the compounds will continue as long as necessary to treat HIV infection.

[0235] VI. Kits and manufactured products In one embodiment, a kit is provided herein comprising a compound provided herein (e.g., a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and suitable packaging. In some embodiments, the kit further comprises instructions for use. In some embodiments, the kit comprises a compound provided herein (e.g., a compound of formula I, IA, IB, IC, ID, IE, IF, II-A, II-Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb), or a pharmaceutically acceptable salt, stereoisomer, prodrug, or solvate thereof, and a label and / or instructions for the use of the compound in the treatment of indications including diseases or conditions described herein.

[0236] 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 pharmaceutically acceptable salts thereof.

[0237] In one embodiment, a manufactured article comprising a compound described herein or a pharmaceutically acceptable salt, isomer, or mixture thereof in a suitable container is provided herein. In some embodiments, the container may be a vial, a wide-mouthed bottle, an ampoule, a filled syringe, or an infusion bag.

[0238] VII. Combination Therapy In one particular embodiment, a method is provided for treating HIV infection, comprising administering to a human being a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with one, two, three, or four additional therapeutic agents.

[0239] In one embodiment, a pharmaceutical composition is provided comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with one, two, three, or four additional therapeutic agents, and a pharmaceutically acceptable carrier, diluent, or excipient.

[0240] In certain embodiments, the Disclosure provides a method for treating HIV infection, comprising administering to a subject in need of such treatment a therapeutically effective amount of a compound disclosed herein or a pharmaceutically acceptable salt thereof, in combination with a therapeutically effective amount of one, two, three, or four additional therapeutic agents suitable for treating HIV infection.

[0241] In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with one, two, three, four, or more additional therapeutic agents. In certain embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with one, two, three, or four additional therapeutic agents. In some embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with two additional therapeutic agents. In other embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with three additional therapeutic agents. In further embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with four additional therapeutic agents. The one, two, three, four, or more additional therapeutic agents may be different therapeutic agents selected from the same class and / or may be selected from different classes of therapeutic agents.

[0242] Administration of HIV combination therapy In certain embodiments, the compounds disclosed herein are administered together with one, two, three, or four additional therapeutic agents. Co-administration of the compounds disclosed herein with one, two, three, or four additional therapeutic agents generally refers to the simultaneous or sequential administration of the compounds disclosed herein and one, two, three, or four additional therapeutic agents so that both therapeutically effective amounts of the compounds disclosed herein and one, two, three, or four additional therapeutic agents are present in the patient's body. When administered sequentially, the combination may be administered in two or more doses.

[0243] Co-administration involves administering a unit dose of the compound disclosed herein, either before or after the administration of a unit dose of one, two, three, or four additional therapeutic agents. For example, the compound disclosed herein may be administered within seconds, minutes, or hours of the administration of one, two, three, or four additional therapeutic agents. In some embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one, two, three, or four additional therapeutic agents within seconds or minutes. Alternatively, a unit dose of one, two, three, or four additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein within seconds or minutes. In other embodiments, a unit dose of the compound disclosed herein is administered first, followed by a unit dose of one, two, three, or four additional therapeutic agents several hours later (e.g., 1 to 12 hours). In yet another embodiment, a unit dose of one, two, three, or four additional therapeutic agents is administered first, followed by a unit dose of the compound disclosed herein several hours later (e.g., 1 to 12 hours).

[0244] In certain embodiments, a kit is provided comprising one or more (e.g., 1, 2, 3, or 4) additional therapeutic agents, each containing one of the compounds disclosed herein (e.g., formulas I, IA, IB, IC, ID, IE, IF, II-II-A, Aa, II-Ab, III, IIIa, IIIb, IV, IVa, IVb, V, Va, or Vb), or a pharmaceutically acceptable salt thereof.

[0245] In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV capsid inhibitor or HIV capsid polymerization inhibitor.

[0246] HIV combination therapy In the embodiments described above, additional or multiple therapeutic agents may be anti-HIV agents. In some examples, additional therapeutic agents are HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, HIV capsid inhibitors, nucleocapsid protein 7 (NCp7) inhibitors, and HIV Tat or Rev inhibitors, Tat-TAR-P-TEFb inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), cell therapies (chimeric antigen receptor T cells, T cells, CAR-T, and engineered T cell receptors, TCR-T, autologous T cell therapy, engineered B cells, NK cells, etc.), latent infection reactivators, immune system therapeutics, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, fatty acid synthase inhibitors, HIV vif gene modulator, Vif dimerizing antagonist, HIV-1 virus infectivity factor inhibitor, HIV-1 Nef modulator, TNF α ligand inhibitor, HIV Nef inhibitor, Hck tyrosine kinase modulator, mixed lineage kinase-3 (MLK-3) inhibitor, HIV-1 splicing inhibitor, integrin antagonist, nucleoprotein inhibitor, splicing factor modulator, COMM domain-containing protein 1 modulator, HIV ribonuclease H inhibitor, IFN antagonist, retrocycline modulator, CD3 antagonist, CDK-4 inhibitor, CDK-6 inhibitor, CDK-9 inhibitor, cytochrome P450 3 inhibitor, CXCR4 modulator, dendritic ICAM-3 grabbing nonintegrin 1 inhibitor, HIV GAG protein inhibitor, HIV These may include POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, HPK1 (MAP4K1) inhibitors, proprotein convertase PC9 stimulants, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, mTOR complex 1 inhibitors, mTOR complex 2 inhibitors, P-glycoprotein modulators, RNA polymerase modulators, TAT protein inhibitors, prolyl endopeptidase inhibitors, phospholipase A2 inhibitors, pharmacokinetic enhancers, HIV gene therapies, HIV vaccines, and anti-HIV peptides, as well as combinations thereof.

[0247] In some embodiments, additional therapeutic agents or additional multiple therapeutic agents are selected from HIV combination drugs, other HIV therapeutic agents, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latent infection reactivators, capsid inhibitors, immune system therapeutic agents, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and “antibody-like” therapeutic proteins, as well as combinations thereof.

[0248] In some embodiments, additional therapeutic agents are selected from the group consisting of HIV combination drugs, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latent infection reactivators, capsid inhibitors, immune system therapeutic agents, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and “antibody-like” therapeutic proteins, as well as combinations thereof.

[0249] In some embodiments, additional therapeutic agents or additional multiple therapeutic agents are selected from HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, Nef inhibitors, latent infection reactivators, HIV bNAbs, TLR7, TLR8, and TLR9 agonists, HIV vaccines, cytokines, immune checkpoint inhibitors, FLT3 ligands, bispecific antibodies to replenish T cells and NK cells, HIV antigen-targeted chimeric T cell receptors, pharmacokinetic enhancers, and other drugs for treating HIV, as well as combinations thereof.

[0250] In some embodiments, additional therapeutic agents or additional multiple therapeutic agents are selected from dolutegravir, cabotegravir, islatravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir, and combinations thereof.

[0251] HIV combination drugs Examples of concomitant medications include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and emtricitabine); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and emtricitabine); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine); TRUVADA® (tenofovir disoproxil fumarate and emtricitabine; TDF+FTC); DESCO VY (registered trademark) (tenofovir alafenamide and emtricitabine); ODEFSEY (registered trademark) (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA (registered trademark) (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); darunavir, tenofovir alafenamide hemifumarate, emtricitabine, and cobicistat; efavirenz, lamivudine, and tenofovir disoproxil fumarate; lamivudine and tenofovir disoproxil fumarate; tenofovir and lar Mivudine; Tenofovir alafenamide and emtricitabine; Tenofovir alafenamide hemifumarate and emtricitabine; Tenofovir alafenamide hemifumarate, emtricitabine, and rilpivirine; Tenofovir alafenamide hemifumarate, emtricitabine, cobicistat, and elvitegravir; Tenofovir analogues; COMBIVIR® (Zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; Abacavir sulfate and lamivudine; ABC+3TC); KALETR A(registered trademark) (ALUVIA(registered trademark), lopinavir and ritonavir), TRIUMEQ(registered trademark) (dolutegravir, abacavir and lamivudine); BIKTARVY(registered trademark) (bictegravir + emtricitabine + tenofovir alafenamide), DOVATO(registered trademark) (dolutegravir + lamivudine), TRIZIVIR(registered trademark) (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; dolutegravir + lamivudine, lamivudine + abacavir + zidovudine, lamivudine + abacavir, lamivudine + tenofovir disoproxil fumarate, lamivudine + zidovudine + nevirapine, lopinavir + ritonavir, lopinavir + ritonavir + Examples include, but are not limited to, abacavir + lamivudine, lopinavir + ritonavir + zidovudine + lamivudine, tenofovir + lamivudine, and tenofovir disoproxil fumarate + emtricitabine + rilpivirine hydrochloride, lopinavir, ritonavir, zidovudine, lopinavir + ritonavir + abacavir + lamivudine, lamivudine, cabotegravir + rilpivirine, 3-BNC117 + albuvirtide, elpida (el-sulfavirine, VM-1500), and VM-1500A, renacapavir + islatravir (oral, injectable), and dual-target HIV-1 reverse transcriptase / nucleocapsid protein 7 inhibitors.

[0252] Other HIV drugs Other drugs used to treat HIV include, but are not limited to, aspergrin C, acemannan, arispolivir, BanLec, deferipron, gamimune, methenkephalin, naltrexone, prolastine, REP 9, RPI-MN, VSSP, H1viral, SB-728-T, 1,5-Dicameoylquinic acid, rHIV7-shl-TAR-CCR5RZ, AAV-eCD4-Ig gene therapy, MazF gene therapy, BlockAide, Bevirimat derivative, ABBV-382, ABX-464, AG-1105, APH-0812, APH0202, Briostatin-1, Briostatin analog, BIT-225, BRII-732, BRII-778, CYT-107, CS-TATI-1, Fluoro-beta-D-arabinose nucleic acid (FANA) modified antisense Ligonucleotide, FX-101, Grifficin, GSK-3739937, GSK-3739937 (long-acting), HGTV-43, HPH-116, HS-10234, Hydroxychloroquine, IMB-10035, IMO-3100, IND-02, JL-18008, LADAVRU, MK-1376, MK-2048, MK-4250, MK-8507, MK-8558, MK-8591 (Islatravir), NOV-205, OB-002H, ODE-Bn-TFV, PA- 1050040(PA-040), PC-707, PGN-007, QF-036, S-648414, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, DIACC-1010, Fasnall, Immuglo, 2-CLIPS peptide, HRF-4467, Thrombospongin analog, TBL-1004HI, VG-1177, xl-081, AVI-CO-004 Examples include rfhSP-D, [18F]-MC-225, URMC-099-C, RES-529, Verdinexor, IMC-M113V, IML-106, antiviral fc conjugate (AVC), WP-1096, WP-1097, Gammora, ISR-CO48, ISR-48, ISR-49, MK-8527, cannabinoids, ENOB-HV-32, HiviCide-I, T-1144, VIR-576, Nipapovir, Covimro, and ABBV-1882.

[0253] HIV protease inhibitors Examples of HIV protease inhibitors include, but are not limited to, amprenavir, atazanavir, brekanavir, darunavir, fosamprenavir, fosamprenavir calcium, indinavir, indinavir sulfate, lopinavir, nelfinavir, nelfinavir mesylate, ritonavir, saquinavir, saquinavir mesylate, tipranavir, ASC-09+ritonavir, AEBL-2, DG-17, GS-1156, TMB-657 (PPL-100), T-169, BL-008, MK-8122, TMB-607, GRL-02031, and TMC-310911.

[0254] Examples of additional HIV protease inhibitors are described, for example, in U.S. Patent No. 10,294,234, and U.S. Patent Application Publication No. 2020 / 030327, and U.S. Patent Application Publication No. 2019 / 210978.

[0255] HIV Gag protein inhibitors Examples of HIV Gag protein inhibitors include, but are not limited to, HRF-10071.

[0256] HIV ribonuclease H inhibitors Examples of HIV ribonuclease H inhibitors include, but are not limited to, NSC-727447.

[0257] HIV Nef inhibitors Examples of HIV Nef inhibitors include, but are not limited to, FP-1.

[0258] HIV reverse transcriptase inhibitors Examples of reverse transcriptase HIV non-nucleoside or non-nucleotide inhibitors include, but are not limited to, dapivine, delaviridine, delaviridine mesylate, doravirine, efavirenz, etravirine, lentinan, nevirapine, rilpivirine, ACC-007, ACC-008, AIC-292, F-18, KM-023, PC-1005, M1-TFV, M2-TFV, VM-1500A-LAI, PF-3450074, elsulfavirine (sustained-release oral formulation, for HIV infection), doravirine + islatravir (fixed-dose combination / oral tablet formulation, for HIV-1 infection), elsulfavirine (long-acting injectable nanosuspension, for HIV infection), and elsulfarabine (VM-1500).

[0259] Examples of reverse transcriptase HIV nucleoside or nucleotide inhibitors include adefovir, adefovir dipivoxil, azuvudine, emtricitabine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemi-fumarate, tenofovir disoproxil, tenofovir disoproxil fumarate, tenofovir octadecyloxyethyl ester (AGX-1009), tenofovir disoproxil hemi-fumarate, VIDEX® and VIDEXEC® (didanosine, ddl), and abacavir. Examples include, but are not limited to, abacavir sulfate, alovudine, applicitabine, sensabudine, didanosine, erbucitabine, festinavir, fosalvudine tidoxil, CMX-157, dapivine, doravirine, etozidovudine lavirine, etravirine, OCR-5753, tenofovir disoproxil orotate, fozivudine tidoxil, lamivudine, phosphazide, stabudine, zalcitabine, lovahovir etalafenamide (GS-9131), GS-9148, MK-8504, islatravir, MK-8583, VM-2500, and KP-1461.

[0260] Additional examples of reverse transcriptase HIV nucleoside or nucleotide inhibitors are described in U.S. Patent Publication Nos. 2007 / 049754, 2016 / 250215, 2016 / 237062, 2016 / 251347, 2002 / 119443, 2013 / 065856, 2013 / 090473, 2014 / 221356, and International Publication No. 04096286, but are not limited to those described therein.

[0261] HIV integrase inhibitors Examples of HIV integrase inhibitors include elvitegravir, elvitegravir (sustained-release microcapsules), curcumin, curcumin derivatives, chicoriate derivatives, 3,5-dicaffeoylquinic acid, derivatives of 3,5-dicaffeoylquinic acid, aurintricarboxylic acid, aurintricarboxylic acid derivatives, phenethyl caffeate, phenethyl caffeate derivatives, tyrofostine, tyrofostine derivatives, quercetin, quercetin derivatives, raltegravir, pegylated raltegravir, dolutegravir, JTK-351, bictegravir. Examples include, but are not limited to, AVX-15567, cabotegravir (long-acting injection), diketoquinoline 4-1 derivatives, integrase-LEDGF inhibitors, ledgins, M-522, M-532, MK-0536, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbendesulfonic acid, T169, STP-0404, VM-3500, XVIR-110, and ACC-017.

[0262] HIV non-catalytic site or allosteric integrase inhibitors An example of an allosteric, integrase inhibitor (NCINI) is CX-050. Examples include, but are not limited to, 45, CX-05168, and CX-14442.

[0263] Examples of additional HIV capsid inhibitors include, but are not limited to, those described in U.S. Patent Application Publications 2020 / 0317689, 2021 / 0284642, 2014 / 221356, and 2016 / 016973.

[0264] HIV virus infectious factor inhibitors Examples of HIV virus infectivity factor inhibitors include, but are not limited to, 2-amino-N-(2-methoxyphenyl)-6-((4-nitrophenyl)thio)benzamide derivatives and Irino-L.

[0265] HIV entry inhibitors Examples of HIV entry (fusion) inhibitors include, but are not limited to, AAR-501, LBT-5001, cenicliviroc, CCR5 inhibitors, gp41 inhibitors, CD4 adhesion inhibitors, gp120 inhibitors, gp160 inhibitors, and CXCR4 inhibitors.

[0266] Examples of CCR5 inhibitors include aplaviroc, bicriviroc, maraviroc, maraviroc (long-acting injectable nanoemulsion), senicliviroc, leronlimab (PRO-140), adaptervir (RAP-101), nifeviroc (TD-0232), anti-GP120 / CD4 or CCR5 bispecific antibodies, B-07, MB-66, polypeptide C25P, TD-0680, thioraviroc, and vMIP (Hai Examples include, but are not limited to, mipu.

[0267] Examples of gp41 inhibitors include albuvirtide, enfuvirtide, and g Examples include rififiscin (gp41 / gp120 / gp160 inhibitor), BMS-986197, enfuvirtide Biobetter, HIV-1 fusion inhibitor (P26-Bapc), ITV-1, ITV-2, ITV-3, ITV-4, CPT-31, Cl3hmAb, lipuvirtide, PIE-12 trimer, and shifvirtide, but these include Not limited.

[0268] Examples of CD4 binding inhibitors include, but are not limited to, ivalizumab and CADA analogs.

[0269] Examples of gp120 inhibitors include, but are not limited to, anti-HIV bactericides, Radha-108 (Receptol) 3B3-PE38, BMS818251, BanLec, bentonite-based nanomedicines, Fostema savir tromethamine, IQP-0831, VVX-004, and BMS-663068.

[0270] Examples of gp160 inhibitors include, but are not limited to, fungus quinoline.

[0271] Examples of CXCR4 inhibitors, though not limited to them, include plerixafor, ALT-1188, N15 peptide, and vMIP (Haimipu).

[0272] HIV maturation inhibitors Examples of HIV maturation inhibitors include, but are not limited to, BMS-955176, GSK-3640254, and GSK-2838232.

[0273] Latent infection reactivator Examples of latent infection reactivators include Toll-like receptors (TLRs). ) Agonists (including TLR7 agonists, e.g., GS-9620, TLR8 agonists, and TLR9 agonists), histone deacetylase (HDAC) inhibitors, proteasome inhibitors, e.g., Velcade, protein kinase C (PKC) activators, Smyd2 inhibitors, BET-bromodomain 4 Examples of 4, BRD4 inhibitors (e.g., ZL-0580, apavetalon), ionomycin, IAP antagonists (inhibitors of apoptotic proteins such as APG-1387, LBW-242), SMAC mimetics (including TL32711, LCL161, GDC-0917, HGS1029, AT-406, Debio-1143), PMA, SAHA (suberoyl anilide hydroxamic acid or suberoyl, anilide, and hydroxamic acid), NIZ-985, IL-15 regulatory antibodies (IL-15, IL-15 fusion protein, and IL-15 receptor agonists), JQ1, disulfiram, amphotericin B, and ubiquitin inhibitors, such as largazole analogs, APH-0812, and GSK-343, but not limited to these. Examples of PKC activators include, but are not limited to, indolactam, prostratin, ingenol B, and DAG-lactone.

[0274] Additional examples of TLR7 agonists include, but are not limited to, those described in U.S. Patent Application Publication 2010 / 143301.

[0275] Additional examples of TLR8 agonists include, but are not limited to, those described in U.S. Patent Application Publication No. 2017 / 071944.

[0276] Histone deacetylase (HDAC) inhibitors In some embodiments, the agents described herein are further combined with inhibitors of histone deacetylases, such as histone deacetylase 1 and histone deacetylase 9 (HDAC9, HD7, HD7b, HD9, HDAC, HDAC7, HDAC7B, HDAC9B, HDAC9FL, HDRP, MITR; gene ID: 9734). Examples of HDAC inhibitors include, but are not limited to, abexinostat, ACY-241, AR-42, BEBT-908, bellinostat, CKD-581, CS-055 (HBI-8000), CT-101, CUDC-907 (fimepinostat), entinostat, gibinostat, mosetinostat, panobinostat, prasinostat, xinostat (JNJ-26481585), resminostat, licorinostat, SHP-141, TMB-ADC, valproic acid (VAL-001), vorinostat, tinostamstine, remetinostat, and entinostat.

[0277] Capsid inhibitors Examples of capsid inhibitors include, but are not limited to, capsid polymerization inhibitors or capsid disruption compounds, HIV nucleocapsid p7 (NCp7) inhibitors such as azodicarbonamides, HIV p24 capsid protein inhibitors, lenacavir (GS-6207), GS-CA1, AVI-621, AVI-101, AVI-201, AVI-301, and the AVI-CAN1-15 series, PF-3450074, HIV-1 capsid inhibitors (HIV-1 infection, Shandong University), and compounds described in (GSK International Publication No. 2019 / 087016).

[0278] Additional examples of capsid inhibitors include, but are not limited to, those described in U.S. Patent Publication No. 2018 / 051005 and U.S. Patent Publication No. 2016 / 108030.

[0279] Cytochrome P450 3 inhibitors Examples of cytochrome P450 3 inhibitors include, but are not limited to, those described in U.S. Patent No. 7,939,553.

[0280] RNA polymerase modulator Examples of RNA polymerase modulators include, but are not limited to, those described in U.S. Patent No. 10,065,958 and U.S. Patent No. 8,008,264.

[0281] Immune checkpoint modulator In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of inhibitory immune checkpoint proteins or receptors, and / or one or more stimulants, activators, or agonists of one or more stimulating immune checkpoint proteins or receptors. Blocking or inhibiting inhibitory immune checkpoints can reliably regulate T cell or NK cell activation and prevent immune leaks in infected cells. Activation or stimulation of stimulating immune checkpoints can enhance the effects of immune checkpoint inhibitors in infection treatment agents. In various embodiments, immune checkpoint proteins or receptors regulate the T cell response (for example, as outlined in Xu, et al., J Exp Clin Cancer Res. (2018) 37:110). In various embodiments, immune checkpoint proteins or receptors regulate the NK cell response (see, for example, Davis et al., Semin Immunol. (2017) 31:64-75 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688).

[0282] Examples of immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; CD47, CD48 (SLAMF2), transmembrane and immunoglobulin domain-containing proteins (TMIGD2, CD28H), CD84 (LY9B, SLAMF5), CD96, CD160, MS4A1 (CD20), CD244 (SLAMF4); CD276 (B7H3); V-set domain-containing T cell activation inhibitors (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily members (IGSF11, VSIG3); natural killer cytotoxic receptor ligands (NCR3LG1, B7H6); HERV-H LTR-related 2 (HHLA2, B7H7); Inducible T cell costimulatory molecules (ICOS, CD278); Inducible T cell costimulatory molecule ligands (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF8 (CD30), TNFSF8 (CD30L); TNFRSF10A (CD261, DR4, TRAILR1), TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF10B (CD262, DR5, TRAILR2), TNFRSF10 (TRAIL); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-related (BT) LA));TNFRSF17(BCMA, CD269), TNFSF13B(BAFF);TNFRSF18(GITR), TNFSF18(GITRL);MHC class I polypeptide-related sequence A(MICA);MHC class I polypeptide-related sequence B(MICB);CD274(CD274, PDL1, PD-L1);Programmed cell death 1(PDCD1, PD1, PD-1);Cytotoxic T lymphocyte-related protein 4(CTLA4, CD152);CD80(B7-1), CD28;Nectin cell adhesion molecule 2(NECTIN2, CD112);CD226(DNAM-1);Poliovirus receptor (PVR) cell adhesion molecule(PVR, CD155);PVR-related immunoglobulin domain-containing(PVRIG, CD112R);T cell immune receptors containing Ig and ITIM domains (TIGIT); T cell immunoglobulins and mucin domains (TIMD4; TIM4); Hepatitis A virus cell receptors (HAVCR2, TIMD3, TIM3); Galectin 9 (LGALS9); Lymphocyte activators (LAG3, CD223); Signal transduction lymphocyte activating molecule family members (SLAMF1, SLAM, CD150); Lymphocyte antigens (LY9, CD229, SLAMF3); SLAM family member 6 (SLA MF6, CD352); SLAM family member 7 (SLAMF7, CD319); UL16-binding protein 1 (ULBP1); UL16-binding protein 2 (ULBP2); UL16-binding protein 3 (ULBP3); retinoic acid initial transcript 1E (RAET1E; ULBP4); retinoic acid initial transcript 1G (RAET1G; ULBP5); retinoic acid initial transcript 1L (RAET1L; ULBP6); lymphocyte activation 3 (CD223); killer cell immunoglobulin-like receptor, 3 Ig domains , and long cytoplasmic terminal 1 (KIR, CD158E1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); killer cell lectin-like receptor C2 (KLRC2, CD159c, NKG2C); killer cell lectin-like receptor C3 (KLRC3, NKG2E); killer cell lectin-like receptor C4 (KLRC4, NKG2F); killer cell immunoglobulin-like receptor, one Ig domain, and long cytoplasmic tail Part 2 (KIR2DL1); killer cell immunoglobulin-like receptor, two Ig domains, and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 2 (KIR2DL3); killer cell immunoglobulin-like receptor, three Ig domains, and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor D1 (KLRD1); SLAM family member 7 (SLAMF7); and hematopoietic progenitor cell kinases 1 (HPK1, MAP4K1).

[0283] In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of one or more T cell inhibitory immune checkpoint proteins or receptors. Exemplary T cell suppressive immune checkpoint proteins or receptors include, but are not limited to, CD274 (CD274, PDL1, PD-L1); programmed cell death ligand 1 (PDCD1LG2, PD-L2, CD273); programmed cell death 1 (PDCD1, PD1, PD-1); cytotoxic T lymphocyte-associated protein 4 (CTLA4, CD152); CD276 (B7H3); V-set domain-containing T cell activation inhibitor 1 (VTCN1, B7H4); V-set immunomodulatory receptors (VSIR, B7H5, VISTA); immunoglobulin superfamily member 11 (IGSF11, VSIG3); TNFRSF14 (HVEM, CD270), TNFSF14 (HVEML); CD272 (B and T lymphocyte-associated (BTLA)); PVR-associated immunoglobulin-containing (PVRIG, CD112R); T cell immune receptor having Ig and ITIM domains (TIGIT); Lymphocyte activation 3 (LAG3, CD223); Hepatitis A virus cell receptor 2 (HAVCR2, TIMD3, TIM3); Galectin 9 (LGALS9); Killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic terminal 1 (KIR, CD158E1); Killer cell immunoglobulin-like receptor, 1 Ig domain and long cytoplasmic tail 2 (KIR2DL1); Killer cell immunoglobulin-like receptor, 2 Ig domains and long cytoplasmic tail 2 (KIR2DL2); Killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 2 (KIR2DL3); and Killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 1 (KIR3DL1). In various embodiments, the agents described herein are combined with one or more agonists or activators of one or more T cell-stimulating immune checkpoint proteins or receptors.Examples of T cell-stimulating immune checkpoint proteins or receptors include, but are not limited to, CD27, CD70; CD40, CD40LG; inducible T cell costimulatory molecules (ICOS, CD278); inducible T cell costimulatory molecule ligands (ICOSLG, B7H2); TNF receptor superfamily member 4 (TNFRSF4, OX40); TNF superfamily member 4 (TNFSF4, OX40L); TNFRSF9 (CD137), TNFSF9 (CD137L); TNFRSF18 (GITR), TNFSF18 (GITRL); CD80 (B7-1), CD28; nectin cell adhesion molecule 2 (NECTIN2, CD112); CD226 (DNAM-1); CD244 (2B4, SLAMF4); poliovirus receptor (PVR) cell adhesion molecule (PVR, CD155). For example, see Xu, et al., J Exp Clin Cancer Res. (2018) 37:110.

[0284] In various embodiments, the agents described herein are combined with one or more blockers or inhibitors of one or more NK cell-inhibitory immune checkpoint proteins or receptors. Examples of NK cell suppressive immune checkpoint proteins or receptors include, but are not limited to, the following: killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 1 (KIR, CD158E1); killer cell immunoglobulin-like receptor, 1 Ig domain and long cytoplasmic tail 2 (KIR2DL1); killer cell immunoglobulin-like receptor, 2 Ig domains and long cytoplasmic tail 2 (KIR2DL2); killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 2 (KIR2DL3); killer cell immunoglobulin-like receptor, 3 Ig domains and long cytoplasmic tail 1 (KIR3DL1); killer cell lectin-like receptor C1 (KLRC1, NKG2A, CD159A); and killer cell lectin-like receptor D1 (KLRD1, CD94). In various embodiments, the agents described herein are combined with one or more agonists or activators of one or more NK cell-stimulating immune checkpoint proteins or receptors. Examples of NK cell-stimulating immune checkpoint proteins or receptors include, but are not limited to, CD16, CD226 (DNAM-1); CD244 (2B4, SLAMF4); killer cell lectin-like receptor K1 (KLRK1, NKG2D, CD314); and SLAM family member 7 (SLAMF7). See, for example, Davis, et al., Semin Immunol. (2017) 31:64-75; Fang, et al., Semin Immunol. (2017) 31:37-54 and Chiossone, et al., Nat Rev Immunol. (2018) 18(11):671-688.

[0285] In some embodiments, one or more immune checkpoint inhibitors include protein-based (e.g., antibody or fragment thereof, or antibody mimetic) inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, one or more immune checkpoint inhibitors include organic small molecule inhibitors of PD-L1 (CD274), PD-1 (PDCD1), or CTLA4. In some embodiments, the small molecule inhibitor of CD274 or PDCD1 is selected from the group consisting of GS-4224, GS-4416, INCB086550, and MAX10181. In some embodiments, the small molecule inhibitor of CTLA4 includes BPI-002.

[0286] Examples of CTLA4 inhibitors that can be co-administered include ipilimumab, tremelimumab, BMS-986218, AGEN1181, AGEN1884, BMS-986249, MK-1308, REGN-4659, ADU-1604, CS-1002, BCD-145, APL-509, JS-007, BA-3071, ONC-392, AGEN-2041, JHL-1155, KN-044, CG-0161, ATOR-1144, and PBI. Examples include, but are not limited to, -5D3H5, BPI-002, and the multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-019 (PD-1 / CTLA4), KN-046 (PD-1 / CTLA4), MEDI-5752 (CTLA4 / PD-1), XmAb-20717 (PD-1 / CTLA4), and AK-104 (CTLA4 / PD-1).

[0287] Examples of PD-L1 (CD274) or PD-1 (PDCD1) inhibitors that can be co-administered include pembrolizumab, nivolumab, semiprimab, pidilizumab, AMP-224, MEDI0680 (AMP-514), spartalizumab, atezolizumab, avelumab, durvalumab, BMS-936559, CK-301, PF-06801591, BGB-A317 (tislerizumab), GLS-010 (WBP-3055), AK-103 (HX-008), AK-105, CS-1003, HLX-10, MGA-012, and BI-75409. 1. AGEN-2034, JS-001 (tripalimab), JNJ-63723283, genolimuzumab (CBT-501), LZM-009, BCD-100, LY-3300054, SHR-1201, SHR-1210 (camrelizumab), Sym-021, ABBV-181 (budigalimab), PD1-PIK, BAT-1306, (MSB0010718C), CX-072, CBT-502, TSR-042 (dostallumab), MSB-2311, JTX-4014, BGB-A333, SHR-1316, CS-1001 (WBP-3155, KN-035, IBI-308 (Scintilimab), HLX-20, KL-A167, STI-A1014, STI-A1015 (IMC-001), BCD-135, FAZ-053, TQB-2450, MDX1105-01, GS-4224, GS-4416, INCB086550, MAX10181, and multispecific inhibitors FPT-155 (CTLA4 / PD-L1 / CD28), PF-06936308 (PD-1 / CTLA4), MGD-013 (PD-1 / LAG-3), FS-118 (LAG-3 / Examples include PD-L1)MGD-019(PD-1 / CTLA4), KN-046(PD-1 / CTLA4), MEDI-5752(CTLA4 / PD-1), RO-7121661(PD-1 / TIM-3), XmAb-20717(PD-1 / CTLA4), AK-104(CTLA4 / PD-1), M7824(PD-L1 / TGFβ-EC domain), CA-170(PD-L1 / VISTA), CDX-527(CD27 / PD-L1), LY-3415244(TIM3 / PDL1), and INBRX-105(4-1BB / PDL1),This is not limited to these.

[0288] In various embodiments, the agents described herein are combined with anti-TIGIT antibodies such as BMS-986207, RG-6058, and AGEN-1307.

[0289] Agonists or activators of members of the TNF receptor superfamily (TNFRSF). In various embodiments, the agents described herein are agonists of one or more members of the TNF receptor superfamily (TNFRSF), such as TNFRSF1A (NCBI gene number 7132), TNFRSF1B (NCBI gene number 7133), TNFRSF4 (OX40, CD134; NCBI gene ID; 7293), TNFRSF5 (CD40; NCBI gene ID; 958), TNFRSF6 (FAS, NCBI gene ID; 355), TNFRSF7 (C D27, NCBI gene ID; 939), TNFRSF8 (CD30, NCBI gene ID; 943), TNFRSF9 (4-1BB, CD137, NCBI gene ID; 3604), TNFRSF10A (CD261, DR4, TRAILR1, NCBI gene ID; 8797), TNFRSF10B (CD262, DR5, TRAILR2, NCBI gene ID; 8795), TNFRSF10C (CD263, TRAILR3, NCBI gene ID; 8794), T NFRSF10D (CD264, TRAILR4, NCBI gene ID; 8793), TNFRSF11A (CD265, RANK, NCBI gene ID; 8792), TNFRSF11B (NCBI gene ID; 4982), TNFRSF12A (CD266, NCBI gene ID; 51330), TNFRSF13B (CD267, NCBI gene ID; 23495), TNFRSF13C (CD268, NCBI gene ID; 115650), TNFRSF16 (N It is combined with one or more agonists from the following: GFR (CD271, NCBI gene ID; 4804), TNFRSF17 (BCMA, CD269, NCBI gene ID; 608), TNFRSF18 (GITR, CD357, NCBI gene ID; 8784), TNFRSF19 (NCBI gene ID; 55504), TNFRSF21 (CD358, DR6, NCBI gene ID; 27242), and TNFRSF25 (DR3, NCBI gene ID; 8718).

[0290] Examples of anti-TNFRSF4 (OX40) antibodies that can be co-administered include, but are not limited to, MEDI6469, MEDI6383, MEDI0562 (tavorixizumab), MOXR0916, PF-04518600, RG-7888, GSK-3174998, INCAGN1949, BMS-986178, GBR-8383, ABBV-368, and antibodies described in International Publication Nos. 2016179517, 2017096179, 2017096182, 2017096281, and 2018089628.

[0291] Examples of anti-TNFRSF5 (CD40) antibodies that may be co-administered include, but are not limited to, RG7876, SEA-CD40, APX-005M, and ABBV-428.

[0292] In some embodiments, the anti-TNFRSF7 (CD27) antibody varylumab (CDX-1127) is co-administered.

[0293] Examples of anti-TNFRSF9 (4-1BB, CD137) antibodies that may be co-administered include, but are not limited to, urelumab, utomirumab (PF-05082566), AGEN2373, and ADG-106.

[0294] Examples of anti-TNFRSF18(GITR) antibodies that may be co-administered include, but are not limited to, MEDI1873, FPA-154, INCAGN-1876, TRX-518, BMS-986156, MK-1248, GWN-323, and those described in International Publications 2017 / 096179, 2017 / 096276, 2017 / 096189, and 2018 / 089628. In some embodiments, antibodies or fragments thereof that simultaneously target TNFRSF4(OX40) and TNFRSF18(GITR) are co-administered. Such antibodies are described, for example, in International Publications 2017 / 096179 and 2018 / 089628.

[0295] Bispecific and tripspecific natural killer (NK) cell engineering Ja In various embodiments, the agents described herein include NK cell activating receptors, e.g., CD16A, type C lectin receptors (CD94 / NKG2C, NKG2D, NKG2E / H, and NKG2F), innate cytotoxic receptors (NKp30, NKp44, and NKp46), killer cell type C lectin-like receptors (NKp65, NKp80), Fc receptor FcγR (mediating antibody-dependent cell-mediated cytotoxicity), SLAM family receptors (e.g., 2B4, SLAM6, and SLAM7), killer cell immunoglobulin-like receptors (KIR) (KIR-2DS and KIR-3DS), and DNAM-1. , and bispecific NK cell handlers for CD137 (41BB) It is combined with an NK-cell engager (BiKE) or a tri-specific NK-cell engager (TriKE) (e.g., without Fc) or a bispecific antibody (e.g., with Fc). The anti-CD16 binding bispecific molecule may or may not have Fc, as needed. Exemplary bispecific NK-cell engagers that may be co-administered target CD16 and one or more HIV-related antigens, as described herein. BiKE and TriKE are described, for example, in Felices, et al., Methods Mol Biol. (2016) 1441:333-346 and Fang, et al., Semin Immunol. (2017) 31:37-54. Examples of tri-specific NK-cell engagers (TRiKE) include, but are not limited to, OXS-3550, HIV-TriKE, and CD16-IL-15-B7H3TriKe.

[0296] Indoleamine-pyrrole-2,3-dioxygenase (IDO1) inhibitors In various embodiments, the agents described herein are combined with inhibitors of indoleamine 2,3-dioxygenase 1 (IDO1; NCBI gene ID: 3620). Examples of IDO1 inhibitors include, but are not limited to, BLV-0801, epacadostat, F-001287, GBV-1012, GBV-1028, GDC-0919, indoximod, NKTR-218, NLG-919 vaccine, PF-06840003, pyranonaphthoquinone derivative (SN-35837), resminostat, SBLK-200802, BMS-986205, shIDO-ST, EOS-200271, KHK-2455, and LY-3381916.

[0297] Toll-like receptor (TLR) agonist In some embodiments, the agents described herein are combined with agonists of Toll-like receptors (TLRs), such as TLR1 (NCBI gene ID: 7096), TLR2 (NCBI gene ID: 7097), TLR3 (NCBI gene ID: 7098), TLR4 (NCBI gene ID: 7099), TLR5 (NCBI gene ID: 7100), TLR6 (NCBI gene ID: 10333), TLR7 (NCBI gene ID: 51284), TLR8 (NCBI gene ID: 51311), TLR9 (NCBI gene ID: 54106), and / or TLR10 (NCBI gene ID: 81793). Exemplary TLR7 agonists that can be co-administered include AL-034, DSP-0509, GS-9620 (Besatrimod), Besatrimod analogues, LHC-165, TMX-101 (Imiquimod), GSK-2245035, Reciquimod, DSR-6434, DSP-3025, IMO-4200, MCT-465, MEDI-9197, 3M-051, SB-9922, 3M-052, Limtop, TMX-30X, TMX-202, RG-7863, RG-7854, RG-7795, and U.S. Patent Application Publication No. 20100143301 (Gilead Sciences), and U.S. Patent Application Publication No. 20110098248 (Gilead Sciences). Sciences), and the same, No. 20090047249 (Gilead Sciences), Patent No. 20140045849 (Janssen), Patent No. 20140073642 (Janssen), International Publication No. 2014 / 056953 (Janssen), International Publication No. 2014 / 076221 (Janssen), International Publication No. 2014 / 128189 (Janssen), US Patent Application Publication No. 20140350031 (Janssen), International Publication No. 2014 / 023813 (Janssen), US Patent Application Publication No. 20080234251 (Array Biopharma), International Publication No. 20080306050 (Array Biopharma), International Publication No. 20100029585 (Ventirx Pharma), International Publication No. 20110092485 (Ventirx Pharma), No. 20110118235 (Ventirx Pharma), No. 20120082658 (Ventirx Pharma), No. 20120219615 (Ventirx Pharma), No. 20140066432 (Ventirx Examples of compounds disclosed include, but are not limited to, those disclosed in (Pharma), (Ventirx Pharma) No. 20140088085, (Novira Therapeutics) No. 20140275167, and (Novira Therapeutics) No. 20130251673. Examples of TLR7 / TLR8 agonists include, but are not limited to, NKTR-262, tellatrimod, and BDB-001. TLR8 agonists include E-6887, IMO-4200, IMO-8400, IMO-9200, MCT-465, MEDI-9197, Motorimodo, Reshikimod, GS-9688, VTX-1463, VTX-763, 3M-051, 3M-052, and U.S. Patent Publication No. 20140045849 (Janssen), U.S. Patent Publication No. 20140073642 (J Janssen), International Publication No. 2014 / 056953 (Janssen), International Publication No. 2014 / 076221 (Janssen), International Publication No. 2014 / 128189 (Janssen), US Patent Application Publication No. 20140350031 (Janssen), International Publication No. 2014 / 023813 (Janssen), US Patent Application Publication No. 20080234251 (Array Array Biopharma, U.S. Patent Application Publication No. 20080306050 (Array Biopharma), U.S. Patent Application Publication No. 20100029585 (Ventirx Pharma), U.S. Patent Application Publication No. 20110092485 (Ventirx Pharma), U.S. Patent Application Publication No. 20110118235 (Ventirx Pharma), U.S. Patent Application Publication No. 20120082658 (Ventirx Pharma), U.S. Patent Application Publication No. 20120219615 (Ventirx Pharma), U.S. Patent Application Publication No. 20140066432 (Ventirx Pharma), U.S. Patent Application Publication No. 20140088085 (Ventirx Pharma), U.S. Patent Application Publication No. 20140275167 (Novira Examples include, but are not limited to, the compounds disclosed in Therapeutics and U.S. Patent Application Publication No. 20130251673 (Novira Therapeutics).Examples of TLR9 agonists include, but are not limited to, AST-008, kovitrimod, CMP-001, IMO-2055, IMO-2125, S-540956, ritenimod, MGN-1601, BB-001, BB-006, IMO-3100, IMO-8400, IR-103, IMO-9200, agatrimod, DIMS-9054, DV-1079, DV-1179, AZD-1419, refitrimod (MGN-1703), CYT-003, CYT-003-QbG10, tilsotrimod, and PUL-042. Examples of TLR3 agonists include lintatrimod, poly-ICLC, RIBOXXON®, Apoxxim, RIBOXXIM®, IPH-33, MCT-465, MCT-475, and ND-1.1. Examples of TLR4 agonists include, but are not limited to, G-100 and GSK-1795091.

[0298] CDK inhibitors or antagonists In some embodiments, the agents described herein are combined with a CDK inhibitor or antagonist. In some embodiments, the CDK inhibitor or antagonist is selected from the group consisting of VS2-370.

[0299] STING agonist, RIG-I and NOD2 modulator In some embodiments, the agents described herein are combined with an interferon gene stimulator (STING). In some embodiments, the STING receptor agonist or activator is selected from the group consisting of ADU-S100 (MIW-815), SB-11285, MK-1454, SR-8291, AdVCA0848, GSK-532, SYN-STING, MSA-1, SR-8291, STING agonist (latent HIV), 5,6-dimethylxanthenone-4-acetic acid (DMXAA), cyclic GAMP (cGAMP), and cyclic diAMP. In some embodiments, the agents described herein are combined with a RIG-I modulator such as RGT-100, or a NOD2 modulator such as SB-9200 and IR-103.

[0300] LAG-3 and TIM-3 inhibitors In certain embodiments, the agents described herein are combined with anti-TIM-3 antibodies such as TSR-022, LY-3321367, MBG-453, and INCAGN-2390.

[0301] In certain embodiments, the antibodies or antigen-binding fragments described herein are combined with anti-LAG-3 (lymphocyte-activating) antibodies such as relatrimab (ONO-4482), LAG-525, MK-4280, REGN-3767, and INCAGN2385.

[0302] Interleukin agonists In certain embodiments, the agents described herein include interleukin agonists such as IL-2, IL-7, IL-15, IL-10, and IL-12 agonists; examples of IL-2 agonists such as proleukin (aldesleukin, IL-2); BC-IL (Cel-Sci), pegylated IL-2 (e.g., NKTR-214), modified variants of IL-2 (e.g., THOR-707), benpegaldesleukin, AIC-284, and ALKS-4230. Examples of IL-15 agonists include CUI-101, Neo-2 / 15; ALT-803, NKTR-255, and hetIL-15, interleukin-15 / Fc fusion protein, AM-0015, NIZ-985, SO-C101, IL-15 symbolin (PEGylated IL-15), P-22339, and IL-15-PD-1 fusion protein N-809, and IL-7 is combined with, but is not limited to, CYT-107.

[0303] Examples of additional immunotherapeutic agents that can be combined with the agents of this disclosure include, but are not limited to, interferon α, interferon α-2b, interferon α-n3, pegylated interferon α, interferon γ; CDX-301, GS-3583, gapoon, nucleoferon, pegylated interferon α-2a, pegylated interferon α-2b, and FLT3 agonists such as RPI-MN.

[0304] Phosphatidylinositol 3-kinase (PI3K) inhibitors Examples of PI3K inhibitors include idelalisib, alpelisib, buparisib, CAI orotinate, copanlisib, duvelisib, gedatricib, neratinib, panulisib, perifosin, pictilisib, piraralisib, pukitinib mesylate, rigosertib, rigosertib sodium, sonolicid, taselicib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, and DS-742. Examples include, but are not limited to, 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.

[0305] α-4 / β-7 antagonist Examples of integrin α-4 / β-7 antagonists include, but are not limited to, PTG-100, TRK-170, abrilumab, etrolizumab, carotegrastomethyl, and vedolizumab.

[0306] HPK1 inhibitors Examples of HPK1 inhibitors include, but are not limited to, ZYF-0272 and ZYF-0057.

[0307] HIV targeting antibody Examples of HIV antibodies, bispecific antibodies, and "antibody-like" therapeutic proteins include DART®, DUOBODIES®, BITES®, XmAbs®, TandAbs®, Fab derivatives, bNAb (broadly neutralizing HIV-1 antibody), TMB-360, TMB-370, and HIV Examples include, but are not limited to, those targeting gp120 or gp41, HIV-targeting antibody mobilization molecules, anti-CD63 monoclonal antibodies, anti-GB virus C antibodies, anti-GP120 / CD4, gp120 bispecific monoclonal antibodies, CCR5 bispecific antibodies, anti-Nef monodomain antibodies, anti-Rev antibodies, camelid-derived anti-CD18 antibodies, camelid-derived anti-ICAM-1 antibodies, DCVax-001, gp140-targeted antibodies, gp41-based HIV therapeutic antibodies, human recombinant mAbs (PGT-121), PGT121.414.LS, ivalizumab, ivalizumab (second generation), Immuglo, MB-66, KLIC-targeted clone 3 human monoclonal antibody (HIV infection), GS-9721, BG-HIV, and VRC-HIVMAB091-00-AB.

[0308] Various bNAb can be used. Examples include those described in U.S. Patent Nos. 8,673,307, 9,493,549, 9,783,594, and 10,239,935, U.S. Patent Application Publications 2018 / 371086 and 2020 / 223907, International Publications 2014 / 063059, 2012 / 158948 and 2015 / 117008, and International Application PCT / US2015 / 41272 and International Publication 2017 / 096221. The following are some of the antibodies listed, but are not limited to them: 12A12, 12A21, NIH45-46, BANC131, 8ANC134, IB2530, INC9, 8ANC195, 8ANC196, 10-259, 10-303, 10-410, 10-847, 10-996, 10-1074, 10-1121, 10-1130, 10-1146, 10-1341, 10-1369, and 10-1074GM. Additional examples include Klein et al., Nature, 492(7427):118-22 (2012), Horwitz et al., Proc Natl Acad Sci USA, 110(41):16538-43 (2013), Scheid, et al., Science, 333:1633-1637 (2011), Scheid, et al., Nature, 458:636-640 (2009), Eroshkin et al, Nucleic Acids Res., 42 (database publication): Dl 133-9 (2014), and Mascola et al., Immunol Examples of those described in Rev., 254(l):225-44(2013) include 2F5, 4E10, M66.6, CAP206-CH12, 10E81, etc. (all of which bind to the MPER of gp41); PG9, PG16, CH01-04 (all of which bind to V1V2-glycans), 2G12 (which binds to the outer domain glycan); b12, HJ16, CH103-106, VRC01-03, VRC-PG04, 04b, VRC-CH30-34, 3BNC62, 3BNC89, 3BNC91, 3BNC95, 3BNC104, 3BNC176, and 8ANC131 (all of which bind to the CD4 binding site).

[0309] A broader range of neutralizing antibodies that can be used as a second therapeutic agent in combination therapy include, for example, U.S. Patent Nos. 8,673,307, 9,493,549, and 9,783,594, and International Publication Nos. 2012 / 154312, 2012 / 158948, 2013 / 086533, 2013 / 142324, 2014 / 063059, 2014 / 089152, and 2015 / 048. These documents are listed in issues 462, 2015 / 103549, 2015 / 117008, 2016 / 014484, 2016 / 154003, 2016 / 196975, 2016 / 149710, 2017 / 096221, 2017 / 133639, and 2017 / 133640, and for all purposes, these documents are incorporated herein by reference in their entirety. Further examples, though not limited to them, include Sajadi et al., Cell. (2018) 173(7): 1783-1795, Sajadi, et al., J Infect Dis. (2016) 213(1): 156-64, Klein et al., Nature, 492(7427): 118-22 (2012), and Horwitz et al., Proc Natl Academia. Sci USA,110(41):16538-43(2013),Scheid Examples include those listed in et al., Science, 333:1633-1637 (2011), Scheid et al., Nature, 458:636-640 (2009), Eroshkin et al., Nucleic Acids Res., 42 (Database issue): Dl 133-9 (2014), and Mascola et al., Immunol Rev., 254 (l):225-44 (2013), such as 2F5, 4E10, M66.6, CAP206-CH12, 10E8, 10E8v4, 10E8-5R-100cF, DH511.11P, 7b2, 10-1074, and LN01 (all of which bind to the MPER of gp41).

[0310] Examples of additional antibodies include bavituximab, UB-421, BF520.1, BiIA-SG, CH01, CH59, C2F5, C4E10, C2F5+C2G12+C4E10, CAP256V2LS, 3BNC117, 3BNC117-LS, 3BNC60, DH270.1, DH270.6, D1D2, 10-1074-LS, Cl3hmAb, GS-9722 (eripovimab), DH411-2, BG18, GS-9721, GS-9723, PGT145, PGT121, PGT-121.60, and PGT-121. 66, PGT122, PGT-123, PGT-124, PGT-125, PGT-126, PGT-151, PGT-130, PGT-133, PGT-134, PGT-135, PGT-128, PGT-136, PGT-137, PGT-138, PGT- 139, MDX010 (ipilimumab), DH511, DH511-2, N6, N6LS, N49P6, N49P7, N49P7.1, N49P9, N49P11, N60P1.1, N60P25.1, N60P2.1, N60P31.1, N60P22, NIH 45-46, PGC14, PGG14, PGT-142, PGT-143, PGT-144, PGDM1400, PGDM12, PGDM21, PCDN-33A, 2Dm2m, 4Dm2m, 6Dm2m, PGDM1400, MDX010 (ipilimumab), VRC01, VRC-01-LS, A32, 7B2, 10E8, VRC-07-523, VRC07-523LS, VRC24, VRC41.01, 10E8VLS, 3810109, 10E8v4, IMC-HIV, iMabm36, eCD4-Ig, IOMA, CAP256-VRC26.25, DR VIA7,VRC-HIVMAB080-00-AB, VRC-HIVMAB060-00-AB, P2G12, VRC07, 354BG8, 354BG18, 354BG42, 354BG33, 354BG129, 354BG188, 354BG411, 354BG426, VRC 29.03, CAP256, CAP256-VRC26.08, CAP256-VRC26.09, CAP256-VRC26.25, PCT64-24E, and VRC38.01, PGT-151, CAP248-2B, 35O22, ACS202, VRC34, and VRC34.Examples include, but are not limited to, 01, 10E8, 10E8v4, 10E8-5R-100cF, 4E10, DH511.11P, 2F5, 7b2, and LN01.

[0311] Examples of HIV bispecific and trispecific antibodies include, but are not limited to, MGD014, B12BiTe, BiIA-SG, TMB bispecificity, SAR-441236, VRC-01 / PGDM-1400 / 10E8v4, 10E8.4 / iMab, and 10E8v4 / PGT121-VRC01.

[0312] Examples of in vivo delivered bNAbs include, but are not limited to, AAV8-VRC07; mRNA encoding the anti-HIV antibody VRC01; and genetically modified B cells encoding 3BNC117 (Hartweger et al., J.Exp.Med.2019, 1301).

[0313] Pharmacokinetic enhancers Examples of pharmacokinetic enhancers, though not limited to them, include cobicistat and ritonavir.

[0314] Additional treatments Examples of additional therapeutic agents include International Publication No. 2004 / 096286 (Gilead Sciences), 2006 / 015261 (Gilead Sciences), 2006 / 110157 (Gilead Sciences), 2012 / 003497 (Gilead Sciences), 2012 / 003498 (Gilead Sciences), 2012 / 145728 (Gilead Sciences), 2013 / 006738 (Gilead Sciences), 2013 / 159064 (Gilead Sciences), 2014 / 100323 (Gilead Sciences), and U.S. Patent Application Publication No. 2013 / 0165489 (University of Examples of compounds disclosed include, but are not limited to, those disclosed in U.S. Patent Publication No. 2014 / 0221378 (Japan Tobacco), No. 2014 / 0221380 (Japan Tobacco), International Publication No. 2009 / 062285 (Boehringer Ingelheim), No. 2010 / 130034 (Boehringer Ingelheim), No. 2013 / 006792 (Pharma Resources), U.S. Patent Application Publication No. 20140221356 (Gilead Sciences), No. 20100143301 (Gilead Sciences), and International Publication No. 2013 / 091096 (Boehringer Ingelheim).

[0315] HIV vaccine Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, HIV MAG DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, adenovirus vector vaccines (adenovirus vectors such as Ad5, Ad26, or Ad35), monkey adenovirus vaccines (chimpanzee, gorilla, rhesus monkey, i.e., rhAd), adeno-associated virus vector vaccines, chimpanzee adenovirus vaccines (e.g., ChAdOX1, ChAd68, ChAd3, ChAd63, ChAd83, ChAd155, ChAd157, Pan5, Pan6, Pan7, Pan9), and coxsackievirus vaccines. Enterovirus vaccines, gorilla adenovirus vaccines, lentiviral vector vaccines, arenavirus vaccines (e.g., LCMV, Pichinde), two-segment or three-segment arenavirus vaccines, triper-type HIV-1 vaccines, measles virus vaccines, flavivirus vector vaccines, tobacco mosaic virus vector vaccines, varicella-zoster virus vaccines, human parainfluenza virus 3 (PIV3) vaccines, poxvirus vaccines (modified vaccinia virus Ankara (MVA), orthopoxvirus-derived NYVAC, avipox virus) ALVAC (canarypox virus) strains derived from sviruses; fowlpox virus vaccines, rhabdovirus vaccines, e.g., VSV and maraba virus; recombinant human CMV (rhCMV) vaccines, alphavirus vaccines, e.g., Examples include, but are not limited to, the Semliki forest virus, Venezuelan encephalitis virus, and Sindbisvirus; (see Lauer, Clinical and Vaccine Immunology, 2017, DOI:10.1128 / CVI.00298-16); LNP-formulated mRNA-based therapeutic vaccines; and LNP-formulated self-replicating RNA / self-amplifying RNA vaccines.

[0316] Examples of vaccines include AAVLP-HIV vaccine, AE-298p, anti-CD40.Env-gp140 vaccine, Ad4-EnvC150, BG505 SOSIP.664 gp140 adjuvant vaccine, BG505 SOSIP.GT1.1 gp140 adjuvant vaccine, ChAdOx1.tHIVconsv1 vaccine, CMV-MVA triple vaccine, ChAdOx1.HTI, Chimigen HIV vaccine, ConM SOSIP.v7 gp140, ALVAC HIV (vCP1521), AIDSVAX B / E (gp120), monomer gp120 HIV-1 subtype C vaccine, MPER-656 liposome subunit vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, Multiclade DNA Recombinant Adenovirus-5 (rAd5), rAd5 gag-pol env A / B / C vaccine, Pennvax-G, Pennvax-GP, Pennvax-G / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, NAcGM3 / VSSP ISA-51, Poly-ICLC Adjuvant Vaccine, TatImmune, GTU-multiHIV (FIT-06), ChAdV63.HIVconsv, gp140[Delta]V2.TV1+MF-59, rVSVIN HIV-1 gag vaccine, SeV-EnvF, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, N123-VRC-34.01 (including epitope-based HIV vaccines), NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, GOVX-C55, TVI-HIV-1, Ad-4 (Ad4-env clade C + Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, ENOB-HV-11, ENOB-HV-12, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, MagaVax, DNA-Ad5 Virus-like particle vaccines such as gag / pol / nef / nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, DNA and Sev vector vaccines expressing SCaVII, 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, VIR-1111, IHV-001, and pseudovirion vaccines, CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccines, conjugate polypeptide vaccines, dendritic cell vaccines (such as DermaVir), gag-based DNA vaccines, GI-2010, gp41 HIV-1 vaccine, HIV vaccine (PIKA adjuvant), i-key / MHC class II epitope hybrid peptide vaccine, ITV-2, ITV-3, ITV-4, LIPO-5, multiclade Env vaccine, MVA vaccine, Pennvax-GP, pp71-deficient HCMV vector HIV gag vaccine, -rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, UBI HIV gp120, Vacc-4x + romidepsin, mutant gp120 polypeptide vaccine, rAd5 gag-pol env A / B / C vaccine, DNA.HTI and MVA.HTI, VRC-HIVDNA016-00-VP+VRC-HIVADV014-00-VP, INO-6145, JNJ-9220, gp145 C.6980, eOD-GT8 60-dose 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 immunostimulatory), HIV p24gag basal-enhancing plasmid DNA vaccine, HIV-1 iglb12 neutralizing VRC-01 antibody-stimulating anti-CD4 vaccine, arenavirus vector vaccines (Vaxwave, TheraT), MVA-BN Examples include HIV-1 vaccine regimens, mRNA-based prophylactic vaccines, VPI-211, multimer HIV gp120 vaccine (Fred Hutchinson Cancer Center), TBL-1203HI, CH505 TF chTrimer, CD40.HIVRI.Env vaccine, Drep-HIV-PT-1, mRNA-1644, and mRNA-1574.

[0317] Combination therapy for contraception In certain embodiments, the agents described herein are combined with a fertility control or contraceptive regimen. Therapeutic agents used for fertility control (contraception) that can be combined with the agents of this disclosure include, but are not limited to, cyproterone acetate, desostryl, ethinylestradiol, ethinodiol, etonogestril, levomate acid, levonorgestril, linepolistrin, misoprostrol, nomedistrol acetate, norelgestromine, norethindrone, noregestrol, norelgestromine, norethoxyphene, cedisterone acetate, and any combination thereof.

[0318] In certain embodiments, the compounds disclosed herein or their pharmaceutically acceptable salts 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); Malate and emtricitabine; TDF+FTC); DESCOVY(registered trademark) (tenofovir alafenamide and emtricitabine); ODEFSEY(registered trademark) (tenofovir alafenamide, emtricitabine, and rilpivirine); GENVOYA(registered trademark) (tenofovir alafenamide, emtricitabine, cobicistat, and elvitegravir); BIKTARVY(registered trademark) (bictegravir + emtricitabine + tenofovir alafenamide), adefovir; adefovir dipivoxil; cobicistat; emtricitabine; tenofo Fovir; Tenofovir alafenamide and elvitegravir; Tenofovir alafenamide + elvitegravir (rectal preparation, HIV infection), Tenofovir disoproxil; Tenofovir disoproxil fumarate; Tenofovir alafenamide; Tenofovir alafenamide hemi fumarate; TRIUMEQ (registered trademark) (dolutegravir, abacavir, and lamivudine); Dolutegravir, abacavir sulfate, and lamivudine; Raltegravir; Pegylated raltegravir; Raltegravir and lamivudine; Lamivudine + lopinavir + ritonavir + abacavir; Mala Viroc; Tenofovir + Emtricitabine + Maraviroc, Enfuvirtide; ALUVIA(registered trademark) (KALETRA(registered trademark); Lopinavir and Ritonavir); COMBIVIR(registered trademark) (Zidovudine and Lamivudine; AZT+3TC); EPZICOM(registered trademark) (LIVEXA(registered trademark); Abacavir Sulfate and Lamivudine; ABC+3TC); TRIZIVIR(registered trademark) (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; prolastine; fosanprenavir; fosanprenavir calcium efavirenz; etravirine; nelfinavir; nelfinavir mesylate; interferon; didanosine; stabudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevira Pine; saquinavir; saquinavir mesylate; aldezleukin; zalcitabine; tipranavir; amprenavir; delavirdin; delavirdin mesylate; Radha-108 (receptol); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine, and tenofovir disoproxil fumarate; phosphazide; lamivudine, nevirapine, and zidovudine; abacavir; and abacavir sulfate are combined with one, two, three, or four additional therapeutic agents selected from these.

[0319] In some embodiments, the agents or pharmaceutical compositions disclosed herein are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase and HIV non-nucleoside inhibitors of reverse transcriptase. In another specific embodiment, the agents or pharmaceutical compositions disclosed herein are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase and HIV protease inhibitor compounds. In an additional embodiment, the agents or pharmaceutical compositions disclosed herein are combined with HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV non-nucleoside inhibitors of reverse transcriptase and pharmacokinetic enhancers. In one specific embodiment, the agents or pharmaceutical compositions disclosed herein are combined with at least one HIV nucleoside inhibitor, an integrase inhibitor, and a pharmacokinetic enhancer of reverse transcriptase. In another embodiment, the agents or pharmaceutical compositions disclosed herein are combined with two HIV nucleoside or nucleotide inhibitors of reverse transcriptase.

[0320] In another embodiment, the agents or pharmaceutically active compositions disclosed herein are combined with a first additional therapeutic agent selected from dolutegravir, cabotegravir, islatravir, darunavir, bictegravir, elsulfavirine, rilpivirine, and lenacapavir, and a second additional therapeutic agent selected from emtricitabine and lamivudine.

[0321] In some embodiments, the agents or pharmaceutical compositions disclosed herein are combined with a first additional therapeutic agent (contraceptive) selected from the group consisting of cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinylestradiol, etinodiol, etonogestrel, levomefolate, levonorgestrel, linestreno, medroxyprogesterone acetate, mestranol, mifepristone, misoprostol, nomegestrol acetate, norelgestromine, norethindrone, norethinodrel, norgestimate, olmeloxifen, segesterone acetate, ulipristal acetate, and any combination thereof.

[0322] Gene therapy and cell therapy In certain embodiments, the agents described herein are combined with gene or cell therapy regimens. Gene and cell therapies include, but are not limited to, gene modifications for silencing genes; genetic approaches for directly killing infected cells; injections of immune cells designed to replace a large portion of the patient's own immune system to enhance the immune response to infected cells, or to activate the patient's own immune system to kill infected cells, or to locate and kill infected cells; and genetic approaches for modifying cell activity to further alter the endogenous immune response to infection. Examples of cell therapies include, but are not limited to, LB-1903, ENOB-HV-01, ENOB-HV-21, ENOB-HV-31, GOVX-B01, HSPC-overexpressing ALDH1 (LV-800, HIV infection), AGT103-T, and SupT1 cell-based therapies. Examples of dendritic cell therapies include, but are not limited to, AGS-004. CCR5 gene editing agents include, but are not limited to, SB-728T and SB-728-HSPC. CCR5 gene inhibitors include, but are not limited to, Cal-1 and lentiviral vector CCR5 shRNA / TRIM5α / TAR decoy transduced autologous CD34-positive hematopoietic progenitor cells (HIV infection / HIV-associated lymphoma). In some embodiments, C34-CCR5 / C34-CXCR4 expressing CD4-positive T cells are co-administered with one or more multispecific antigen-binding molecules. In some embodiments, the agents described herein are co-administered with AGT-103 transduced autologous T cell therapy or AAV-eCD4-Ig gene therapy.

[0323] Gene editor In certain embodiments, the agents described herein are combined with gene editors, such as HIV-targeting gene editors. In various embodiments, the genome editing system can be selected from the group consisting of CRISPR / Cas9 complexes, zinc finger nuclease complexes, TALEN complexes, homing endonuclease complexes, and meganuclease complexes. Exemplary HIVs that target the CRISPR / Cas9 system include, but are not limited to, EBT-101.

[0324] CAR-T cell therapy In some embodiments, the active agents described herein are used in immunoeffector cells engineered to express chimeric antigen receptors (CARs). It can be co-administered with the population, and the CAR contains an HIV antigen-binding domain. The HIV antigen includes the HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, a CD4 induction binding site on gp120, an N-glycan on gp120, V2 of gp120, and a membrane proximal region on gp41. The immune effector cells are T cells or NK cells. In some embodiments, the T cells are CD4+ T cells, CD8+ T cells, or a combination thereof. The cells can be autologous or allogeneic. Examples of HIV CAR-T include A-1801, A-1902, convertible CAR-T, VC-CAR-T, CMV-N6-CART, anti-HIV duoCAR-T, anti-CD4 CART cell therapy, and CD4 CAR+C34-CXCR4+CCR5 ZFN. Examples include T cells, dual anti-CD4 CAR T-cell therapy (CD4 CAR + C34-CXCR4 T cells), anti-CD4 MicAbody antibody + anti-MicAbody CAR T-cell therapy (iNKG2D CAR, HIV infection), GP-120 CAR-T therapy, autologous hematopoietic stem cells genetically engineered to express CD4 CAR, and C46 peptide.

[0325] TCR-T cell therapy In certain embodiments, the agents described herein are combined with a population of TCR-T cells. The TCR-T cells are genetically engineered to target HIV-derived peptides, such as ImmTAV, present on the surface of virus-infected cells.

[0326] B cell therapy In certain embodiments, the antibody or antigen-binding fragment described herein is combined with a population of B cells genetically engineered to express a broad-spectrum neutralizing antibody such as 3BNC117 (Hartweger et al, J.Exp.Med.2019, 1301, Moffett et al., Sci.Immunol.4, eaax0644(2019) 17 May 2019).

[0327] The compounds disclosed herein (e.g., any compound of formula I) may be combined with one, two, three, or four additional therapeutic agents in any dose (e.g., 1 mg to 500 mg of the compound) relative to the compound of formula I.

[0328] In one embodiment, a kit is provided comprising a compound disclosed herein or a pharmaceutically acceptable salt thereof in combination with one or more (e.g., one; two; three; one or two; or one to three) additional therapeutic agents.

[0329] In one embodiment, additional therapeutic agents or additional multiple therapeutic agents of the kit include HIV protease inhibitors, HIV non-nucleoside or non-nucleotide inhibitors of reverse transcriptase, HIV nucleoside or nucleotide inhibitors of reverse transcriptase, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editors (CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALENs, etc.), cell therapies (chimeric antigen receptor T cells, T cells, CAR-T, and genetically modified T cell receptors, TCR-T, autologous T cell therapy, etc.), compounds targeting HIV capsids, latent infection reactivators, capsid polymerization inhibitors, HIV bNAbs, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, broad-spectrum neutralizing HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, and HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV virus infectivity factor inhibitors, TAT protein inhibitors, HIV Nef modulators, Hck tyrosine kinase modulators, mixed lineage kinase-3 (MLK-3) inhibitors, HIV splicing inhibitors, Rev protein inhibitors, integrin antagonists, nucleoprotein inhibitors, splicing factor modulators, COMM domain-containing protein 1 modulators, HIV ribonuclease H inhibitors, retrocycline modulators, CDK-9 inhibitors, dendritic ICAM-3 grabbing non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIVThese include anti-HIV agents selected from POL protein inhibitors, complement factor H modulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulants, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase priming complex inhibitors, G6PD and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines, and combinations thereof.

[0330] In some embodiments, additional therapeutic agents or additional therapeutic agents of the kit are selected from HIV combination drugs, other HIV therapeutic agents, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic (or allosteric) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latent infection reactivators, capsid inhibitors, immune system therapeutic agents, PI3K inhibitors, HIV antibodies, and bispecific antibodies, and “antibody-like” therapeutic proteins, as well as combinations thereof.

[0331] In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV non-nucleoside inhibitor of reverse transcriptase. In another particular embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, and an HIV protease inhibitor compound. In an additional embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide inhibitor of reverse transcriptase, an HIV non-nucleoside inhibitor of reverse transcriptase, and a pharmacokinetic enhancer. In a particular embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, at least one HIV nucleoside inhibitor of reverse transcriptase, an integrase inhibitor, and a pharmacokinetic enhancer. In another embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and two HIV nucleoside or nucleotide inhibitors of reverse transcriptase. In a particular embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and HIV nucleoside or nucleotide inhibitors and HIV capsid inhibitors of reverse transcriptase. In a particular embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and HIV nucleoside inhibitors and HIV capsid inhibitors of reverse transcriptase. In a particular embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and HIV capsid inhibitors. In a particular embodiment, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof and one, two, three, or four HIV bNAbs. In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAbs, and an HIV capsid inhibitor.In certain embodiments, the kit comprises a compound disclosed herein or a pharmaceutically acceptable salt thereof, one, two, three, or four HIV bNAbs, an HIV capsid inhibitor, and an HIV nucleoside inhibitor of reverse transcriptase.

[0332] HIV long-acting therapy Examples of drugs being developed as long-acting regimens include, but are not limited to, cabotegravir, rilpivirine, any integrase LA, VM-1500 LAI, maraviroc (LAI), tenofovir implant, islatravir implant, doravirine, raltegravir, and long-acting dolutegravir. VII. Examples Intermediate A: (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide [ka]

[0333] Step 1: Synthesis of (3S,7S)-7-methyl-2,3,4,7-tetrahydro-1H-azepine-3-amine: 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 hours. The reaction mixture was concentrated, and the crude product was used directly in the next step.

[0334] Step 2: Synthesis of (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: 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-azepine-3-amine (crude product from the previous step). At room temperature, NaHCO3 (13.2 g, 157 mmol) was added to the reaction mixture. The reaction mixture was stirred overnight at room temperature, and then heated to 60°C for 5 hours. The reaction mixture was concentrated, then ethyl acetate was added, and it was washed with saturated ammonium chloride solution. The organic layer was concentrated and purified by silica chromatography (eluted with 0-10% MeOH / DCM) to obtain (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. MS(m / z) 524.11[M+H]+.

[0335] Step 3: Synthesis of (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: Selenium dioxide (17.4 g, 157 mmol) was added to (3S,7S)-12-(benzyloxy)-3-methyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (product from the previous step, 15.7 mmol) in dioxane (160 mL). The reaction mixture was then heated at 105°C overnight. The reaction mixture was cooled, and the solid was filtered off. The filtrate was extracted using ethyl acetate and saturated ammonium chloride solution. The organic layer was concentrated and purified by silica chromatography (eluted with 40-100% ethyl acetate / hexane) to obtain (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. MS(m / z) 538.095[M+H]+. Intermediate B: (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: [ka]

[0336] (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (132 mg, 0.246 mmol) was dissolved in anhydrous THF (3.0 mL), and the resulting mixture was cooled to -20°C. To this stirred cold mixture, a 3.0 M ether solution of methylmagnesium bromide (0.41 mL, 1.23 mmol) was added. After stirring for 20 minutes, the reaction product was quenched with saturated NH4Cl. The reaction product was extracted with ELISA, the organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The resulting product was purified by silica gel chromatography (0-100% ELISA / hexane). MS(m / z)553.95[M+H]+. Synthesis of intermediate C:(3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: [ka]

[0337] Step 1: Synthesis of (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: In a round-bottom flask, (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (3.15 g, 5.69 mmol), followed by Fe(acac)3 (1.01 g, 2.85 mmol), EtOH (60 mL), PhSiH3 (2.90 mL, 22.8 mmol), and PhSH (5.69 mL, 2.85 mmol, 0.5 M in iPrOH). The resulting slurry was stirred at room temperature for 48 hours. Next, the reaction mixture was concentrated under vacuum, and the residue was purified by silica gel chromatography (20-100% ethyl acetate in hexane), and then by reverse-phase chromatography (5-100% acetonitrile in water buffered with 10 mM ammonium formate, pH=3.8). The corresponding fractions were combined, extracted with dichloromethane, and concentrated under vacuum to obtain (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. MS(m / z) 556.4[M+H]+.

[0338] Step 2: Synthesis of (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: In a round-bottom flask, (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (3.20 g, 5.76 mmol), followed by dichloromethane (90 mL). Martinsulfuran was added to this suspension in two portions (8.91 g, 13.2 mmol), and the mixture was stirred at room temperature for 1 hour. The resulting solution was then concentrated under vacuum, and the residue was purified by reverse-phase chromatography (5-100% acetonitrile in water buffered with 10 mM ammonium formate, pH=3.8). The corresponding fractions were combined and freeze-dried to obtain (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. MS(m / z) 538.4[M+H]+. Intermediate D: (3S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-1,6,11-trioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: [ka]

[0339] This intermediate was prepared in the same manner as (3S,7R)-12-(benzyloxy)-3-methyl-1,6,11-trioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (intermediate A), except that methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)carbamoyl)-4-oxo-4H-pyran-2-carboxylate was used in the second step. MS(m / z) 520.200[M+H]+. Intermediate E: (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: [ka]

[0340] This intermediate was prepared in the same manner as (3S,6S,7R)-12-(benzyloxy)-6-hydroxy-3,6-dimethyl-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (intermediate B), except that). MS(m / z) 536.4[M+H]+. Intermediate F: (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: [ka]

[0341] Step 1: (3S,6S,7R)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-3,6-dimethyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (5.90 g, 11.0 mmol, 1 equivalent) was dissolved in methanol (500 mL) and CH2Cl2 (170 mL), to which platinum(IV) oxide (0.72 g, 3.17 mmol, 0.29 equivalents) was added. The flask was degassed, refilled with nitrogen (3 times), then degassed again, and refilled with hydrogen gas (3 times). The reaction mixture was stirred at room temperature for 16 hours and diluted with CH2Cl2. The reaction mixture was filtered through Celite and concentrated. The residue was purified by column chromatography (0-10% MeOH / CH2Cl2), and the fraction containing the product was pooled and concentrated. The residue was triturated with MeOH and dried in a vacuum oven to obtain (3S,6S,7R)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-3,6-dimethyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. MS(m / z) 448.26[M+H]+.

[0342] Step 2: Synthesis of (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: (3S,6S,7R)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-3,6-dimethyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (1.202 g, 2.69 mmol, 1 equivalent) and potassium carbonate (2.225 g, 16.1 mmol, 6 equivalents) were suspended in DMF (27 mL) and benzyl bromide (0.957 mL, 8.06 mmol, 3 equivalents) was added. The reaction mixture was stirred at rt for 16 hours. The reaction mixture was diluted with SiO2 and washed with water and brine. The organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography (0-100% ethyl acetate / hexane) to obtain (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. MS(m / z) 538.11[M+H]+.

[0343] Step 3: Synthesis of (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (1.258 g, 2.34 mmol, 1 equivalent) was dissolved in toluene (15 mL) and martinsulfuran (3.933 g, 5.85 mmol, 2.5 equivalents) was added. The reaction mixture was heated at 40°C for 1 hour and concentrated. The residue was purified by column chromatography (0-100% ethyl acetate / hexane) to obtain (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. MS(m / z) 520.12[M+H]+. Intermediate G: (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: [ka]

[0344] (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (0.525 g, 0.98 mmol) (intermediate E) was suspended in toluene (10 mL) and martinsulfuran (1.98 g, 2.94 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was diluted with SiO2 and washed with H2O and brine. The organic phase was dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide. MS(m / z) 518.23[M+H]+. Example 1: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0345] Step 1: (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide and Preparation of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of acetaldehyde oxime (666 mg, 11.3 mmol) in DMF (50 mL), N-chlorosuccinimide (1.51 g, 11.3 mmol) was added at room temperature, and the mixture was then heated to 60 °C for 1 hour. After cooling to room temperature, (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 (intermediate F) (1.58 g, 3.04 mmol) and triethylamine (1.539 g, 15.2 mmol) were added at room temperature. The reaction mixture was stirred overnight at room temperature, and then the reaction was quenched by adding saturated NaHCO3 solution. The mixture was extracted with toluene, the organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography column (eluted with 0-100% toluene / hexane) to obtain two distinct isomers: MS(m / z) 577.135[M+H]+ (major) and 577.115[M+H]+ (minor).

[0346] Step 2: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyride[1,2-a][1,4]diazonin]-10'-carboxamide (64.7 mg, 0.112 mmol) was dissolved in toluene (2 mL), to which TFA (0.5 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC eluting with 10-90% acetonitrile in water to obtain the title compound. MS (m / z) 487.12 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ10.53(s,1H),8.43(s,1H),7.37(td,J=8.6,6.3Hz,1H),6.92-6. 78(m,2H),4.82-4.70(m,1H),4.67(t,J=4.8Hz,2H),4.18(d,J=2.2Hz,1H),3.86(dd,J=14 .9,1.9Hz,1H),3.72(dd,J=14.9,2.7Hz,1H),2.94(d,J=17.8Hz,1H),2.53(d,J=17.7Hz,1 H),2.06(s,3H),2.04-1.88(m,3H),1.56(dd,J=14.3,11.2Hz,1H),1.32(d,J=6.6Hz,3H). Example 2: Preparation of (3'S,5R,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0347] To a solution of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (396 mg, 0.687 mmol) prepared according to Example 1 in toluene (5 mL), TFA (1 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC eluting with 10-90% acetonitrile in water to obtain the title compound. MS (m / z) 487.103 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ10.53(d,J=5.8Hz,1H),8.41(s,1H),7.38(q,J=7.8Hz,1H),6.95-6.74 (m,2H),4.83-4.69(m,1H),4.65(d,J=5.6Hz,2H),4.25(s,1H),3.77(dd,J=15.2,3.0Hz,1H),3. 44(d,J=15.2Hz,1H),3.00(d,J=16.9Hz,1H),2.83(d,J=16.9Hz,1H),2.32-2.12(m,1H),2.04(s ,3H),1.83(dd,J=15.3,7.4Hz,1H),1.75-1.58(m,1H),1.42-1.33(m,1H),1.30(d,J=6.6Hz,3H). Example 3: Preparation of (3'S,5S,7'R)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0348] Step 1: (3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide and Preparation of (3'S,5R,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of acetaldehyde oxime (160 mg, 2.71 mmol) in DMF (5 mL), N-chlorosuccinimide (90.5 mg, 0.68 mmol) was added at room temperature, and the mixture was then heated to 60 °C for 1 hour. After cooling to room temperature, (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (intermediate C) (119 mg, 0.221 mmol) and triethylamine (112 mg, 1.1 mmol) were added at room temperature. The reaction mixture was stirred overnight at room temperature, and then the reaction was quenched by adding saturated NaHCO3 solution. The mixture was extracted with toluene, the organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography column (eluted with 0-100% toluene / hexane) to obtain two distinct isomers: MS(m / z) 595.06[M+H]+ (major) and 595.09[M+H]+ (minor).

[0349] Step 2: Preparation of (3'S,5S,7'R)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: (3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyride[1,2-a][1,4]diazonin]-10'-carboxamide (72.3 mg, 0.122 mmol) was dissolved in toluene (2 mL), to which TFA (0.5 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC eluting with 10-90% acetonitrile in water to obtain the title compound. MS (m / z) 505.129 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ10.51-10.41(m,1H),8.40(s,1H),6.70(dd,J=8.7,7.5 Hz,2H),4.71(ddd,J=17.6,11.2,5.9Hz,3H),4.13(d,J=2.6Hz,1H),3.86(dd,J= 14.9,1.8Hz,1H),3.70(dd,J=14.9,2.7Hz,1H),2.93(d,J=17.8Hz,1H),2.52(d, J=17.8Hz,1H),2.13-1.89(m,6H),1.57(d,J=10.9Hz,1H),1.31(d,J=6.6Hz,3H). Example 4: Preparation of (3'S,5R,7'R)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0350] To a solution of (3'S,5R,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyride[1,2-a][1,4]diazonin]-10'-carboxamide (10.8 mg, 0.018 mmol) prepared according to Example 3 in toluene (1 mL), TFA (0.5 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC eluting with 10-90% acetonitrile in water to obtain the title compound. MS (m / z) 505.142 [M+H] + . 1 ¹H NMR (400MHz, chloroform-d) δ 10.41 (s, 1H), 8.37 (s, 1H), 6.78-6.59 (m, 2H), 4.86-4.56 (m, 3H), 4.13 (s, 1H), 3.76 (dd, J=15.2, 3.0Hz, 1H), 3.43 (d, J=15.5Hz, 1H), 3.02 ( d,J=16.9Hz,1H),2.81(d,J=16.9Hz,1H),2.27-2.17(m,1H),2.06(s,3H),1.82(dd ,J=15.3,7.4Hz,1H),1.74-1.63(m,1H),1.40-1.32(m,1H),1.30(d,J=6.6Hz,3H). Example 5: Preparation of (3'S,4'S,5R,7'R)-N-(2,4-difluorobenzyl)-4'-fluoro-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0351] Step 1: Preparation of (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide: (3S,6S,7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-3,6-dimethyl-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (intermediate E) (0.525 g, 0.98 mmol) was added to a suspension in toluene (10 mL) with martinsulfuran (1.98 g, 2.94 mmol). The reaction mixture was then stirred at room temperature for 20 minutes. The reaction mixture was diluted with SiO2 and washed with H2O and brine. The organic phase was dried over MgSO4. After removing the solvent under vacuum, the residue was purified by silica gel chromatography to obtain the title compound. MS (m / z) 518.23 [M+H]+.

[0352] Step 2: Preparation of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (0.335 g, 0.647 mmol) was dissolved in DMF (2 mL), to which (1Z)-N-hydroxyacetimidoyl chloride (0.303 g, 3.24 mmol) was added, followed by triethylamine (0.655 g, 6.47 mmol). The reaction mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ELISA and washed with H2O, 5% LiCl (aqueous solution), and brine. The organic phase was dried over MgSO4. After removing the solvent under vacuum, the residue was purified by silica gel chromatography to obtain the title compound. MS(m / z)575.58[M+H]+.

[0353] Step 3: Preparation of (3'S,4'R,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (0.2 g, 0.353 mmol) was dissolved in i-PrOH (3 mL) and DCM (2 mL), to which phenylsilane (0.11 g, 1.06 mmol) was added, followed by tris(2,2,6,6-tetramethyl-3,5-heptanedionato)manganese(III) (0.011 g, 0.0018 mmol). The reaction mixture was then stirred under an O2 (g) atmosphere for 24 hours. The reaction was quenched by adding 10% sodium thiosulfate, and then extracted with RINKAN. The organic phase was washed with H2O and brine and dried over MgSO4. After removing the solvent under vacuum, the residue was purified by silica gel chromatography to obtain the title compound. MS (m / z) 593.05 [M+H]+.

[0354] Step 4: Preparation of (3'S,4'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-fluoro-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: (3'S,4'R,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide (60 mg, 0.101 mmol) was added to a solution of deoxofluoride in toluene (50%, 0.375 mL, 1.01 mmol) in DCM (2 mL) at 0°C. The reaction mixture was stirred at 0°C for 15 minutes, and the reaction was quenched by adding saturated NaHCO3 solution. The mixture was extracted by DCM, the organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography (eluting with 0-100% hexane / toluene) to obtain the title compound. MS (m / z) 595.04 [M+H]+.

[0355] Step 5: Preparation of (3'S,4'S,5R,7'R)-N-(2,4-difluorobenzyl)-4'-fluoro-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: (3'S,4'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-fluoro-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyride[1,2-a][1,4]diazonin]-10'-carboxamide (11 mg, 0.0185 mmol) was dissolved in toluene (1 mL), to which TFA (1 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC eluting with 5-100% acetonitrile in water to obtain the title compound. MS (m / z) 505.40 [M+H] +. 1H NMR(400MHz,chloroform-d)δ10.24(t,J=5.9Hz,1H),8.23(s,1H),7.39(td,J=8.6, 8.2,6.2Hz,1H),6.91-6.57(m,2H),5.03(dt,J=46.9,5.7Hz,1H),4.93-4.78(m ,1H),4.76-4.52(m,2H),4.26(dd,J=17.1,2.7Hz,2H),3.81(d,J=14.4Hz,1H), 2.84-2.65(m,3H),2.14(s,3H),2.03-1.82(m,1H),1.48(dd,J=7.1,2.3Hz,3H). Example 6: Preparation of (3'S,5S,7'R)-N-(3-chloro-2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0356] Step 1: Preparation of tert-butyl((3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carbonyl)(2,4-difluorobenzyl)carbamate: (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide (631 mg, 1.11 mmol) prepared according to Example 1 was dissolved in toluene (20 mL) and di-tert-butyl dicarbonate (1.45 g, 6.64 mmol) and DMAP (608 mg, 4.98 mmol) were added. Subsequently, the reaction mixture was heated to 110 °C for 4 hours. After the reaction mixture was cooled to room temperature, the reaction was quenched by adding saturated NaHCO3 solution. The mixture was extracted with toluene, the organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (eluted with 30-100% toluene / hexane) to obtain the title compound. MS (m / z) 676.924 [M+H]+.

[0357] Step 2: Preparation of (3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxylic acid: 590 mg, 0.872 mmol of tert-butyl((3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carbonyl)(2,4-difluorobenzyl)carbamate (590 mg, 0.872 mmol) was added to a solution of 10 mL of MeOH with 3 mL of 1 N NaOH solution at room temperature. After 1 hour at room temperature, the reaction was quenched by adding 1 N HCl solution. The mixture was extracted with ELISA, the organic phase was separated, dried over MgSO4, filtered, and concentrated to obtain the crude title compound, which was used without purification. MS (m / z) 452.127 [M+H] +.

[0358] Step 3: Preparation of (3'S,5S,7'R)-12'-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: (3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxylic acid (65 mg, 0.144 mmol) was dissolved in DMF (5 mL) with (3-chloro-2,4-difluorophenyl)methaneamine (30.7 mg, 0.173 mmol), HATU (98.5 mg, 0.259 mmol), and DEA (149 mg, 1.15 mmol) added at room temperature. After 1 hour at room temperature, the reaction was quenched by adding saturated NaHCO3 solution. The mixture was extracted with toluene, the organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography column (eluted with 50-100% toluene / hexane) to obtain the title compound. MS (m / z) 611.075 [M+H]+.

[0359] Step 4: Preparation of (3'S,5S,7'R)-N-(3-chloro-2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: (3'S,5S,7'R)-12'-(benzyloxy)-N-(3-chloro-2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyride[1,2-a][1,4]diazonin]-10'-carboxamide (88 mg, 0.144 mmol) was dissolved in toluene (2 mL), to which TFA (0.5 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC eluting with 10-90% acetonitrile in water to obtain the title compound. MS (m / z) 521.181 [M+H] + . 1 ¹H NMR (400MHz, chloroform-d) δ 10.59-10.49 (m, 1H), 8.39 (s, 1H), 7.32-7.27 (m, 1H), 6.96 (td, J=8.5, 1.8Hz, 1H), 4.72 (ddd, J=19.4, 7.9, 4.5Hz, 3H), 4.15 (s, 1H), 3.87 (dd, J=14.9,1.9Hz,1H),3.71(dd,J=14.9,2.7Hz,1H),2.93(d,J=17.7Hz,1H),2.59-2. 49(m,1H),2.15-1.92(m,6H),1.56(dd,J=14.2,11.2Hz,1H),1.32(d,J=6.6Hz,3H). Example 7: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3-isopropyl-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0360] (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3-isopropyl-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide was prepared in the same manner as in Example 1, except that isobutyraldehyde oxime was used in step 1. MS(m / z) 515.152[M+H] + . 1 ¹H NMR (400MHz, chloroform-d) δ 10.40 (s, 1H), 8.32 (s, 1H), 7.40 (d, J=7.2Hz, 1H), 6.83 (q, J=9.7, 9.1Hz, 2H), 4.84-4.75 (m, 1H), 4.67 (t, J=5.4Hz, 2H), 4.02 (s, 1H), 3.77 (dd, J=15.2 ,3.0Hz,1H),3.49-3.42(m,1H),3.01(d,J=16.8Hz,1H),2.83-2.71(m,2H),2.24(d,J=7 .7Hz,1H),1.86-1.81(m,2H),1.70(s,1H),1.31(d,J=6.5Hz,3H),1.23(d,J=6.9Hz,6H). Example 8: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-ethyl-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0361] The title compound was prepared in the same manner as in Example 1, except that propanal oxime was used instead of acetaldehyde oxime in step 1. MS(m / z)501.2[M+H]+. 1H NMR(400MHz,chloroform-d)δ10.76(s,1H),8.61(s,1H),7.38(t,J=8.0Hz,1H),6.88(m,2H),4.74-4.53(m,5H),3.76(d,J=14.7Hz,1H),3. 56(d,J=14.8Hz,1H),2.75(d,J=16.7Hz,1H),2.47(d,J=16.8Hz,1H),1.97-1.50(m,7H),1.45(t,J=12.7Hz,1H),1.31(d,J=6.6Hz,3H). Example 9: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-3-(2,2,2-trifluoroethyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0362] The title compound was prepared in the same manner as in Example 3, except that 3,3,3-trifluoropropanal oxime was used instead of acetaldehyde oxime in step 1. MS (m / z) 573.09 [M+H]+. ¹H NMR (400 MHz, chloroform-d) δ 10.55 (t, J=5.8 Hz, ¹H), 8.55 (s, ¹H), 6.76-6.64 (m, ²H), 4.83-4.68 (m, ²H), 4.66 (dd, J=14.6, 5.6 Hz, ¹H), 4.26 (d, J=2.2 Hz, ¹H), 3.86 (dd, J=15.0 ,1.8Hz,1H),3.74(dd,J=15.0,2.6Hz,1H),3.47-3.17(m,2H),3.11(d,J=18.0Hz,1H) ,2.65(d,J=18.0Hz,1H),2.15-1.90(m,3H),1.63-1.50(m,1H),1.33(d,J=6.6Hz,3H). Example 10: Preparation of (3'S,5S,7'R)-3-(4-chlorobutyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0363] The title compound was prepared in the same manner as in Example 3, except that 5-bromopentanal oxime was used instead of acetaldehyde oxime in step 1. MS(m / z) 581.223[M+H] + . 1H NMR (400MHz, chloroform-d) δ10.35(t,J=5.7Hz,1H),8.33(s,1H),6.77-6.62(m,2H),4.70(td,J=12. 4,10.4,5.9Hz,3H),4.08(s,1H),3.85(dd,J=14.9,1.8Hz,1H),3.76-3.66(m,1H),3.61(td,J=6. 3,2.4Hz,2H),2.91(d,J=17.7Hz,1H),2.57(s,1H),2.53(s,1H),2.49-2.41(m,2H),1.99(dd,J=1 5.9,9.1Hz,2H),1.95-1.83(m,2H),1.83-1.73(m,2H),1.62-1.52(m,1H),1.31(d,J=6.6Hz,3H). Example 11: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-3-phenyl-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0364] The title compound was prepared in the same manner as in Example 1, except that benzaldehyde oxime was used instead of acetaldehyde oxime in step 1. MS(m / z) 549.127[M+H] + . 1H NMR (400MHz, chloroform-d) δ10.44(t,J=5.9Hz,1H),8.48(s,1H),7.68-7.56(m,2H),7.52-7.39(m,3H) ,7.37(d,J=6.4Hz,1H),6.91-6.76(m,2H),4.80(d,J=6.7Hz,1H),4.65(dd,J=12.1,5.9Hz,2H),4.3 2(d,J=2.3Hz,1H),3.93(dd,J=14.9,1.9Hz,1H),3.76(dd,J=14.9,2.7Hz,1H),3.38(d,J=17.2Hz,1 H),2.94(d,J=17.2Hz,1H),2.20-1.96(m,3H),1.64(dd,J=14.7,11.5Hz,1H),1.35(d,J=6.6Hz,3H). Example 12: Preparation of (3'S,5S,7'R)-3-benzyl-N-(2,4-difluorobenzyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0365] The title compound was prepared in the same manner as in Example 1, except that 2-phenylacetaldehyde oxime was used instead of acetaldehyde oxime in step 1. MS(m / z) 563.165[M+H] + . 1H NMR (400MHz, chloroform-d) δ10.45(t,J=5.9Hz,1H),8.36(s,1H),7.39(d,J=6.4Hz,1H),7.36-7.30(m,2H),7.27(s ,1H),7.20(dd,J=6.9,1.7Hz,2H),6.95-6.75(m,2H),4.68(d,J=6.0Hz,3H),4.18(s,1H),3.93(d,J=15.1Hz,1H) ,3.84(dd,J=14.9,1.9Hz,1H),3.70(dd,J=14.9,2.7Hz,1H),3.56(d,J=15.1Hz,1H),2.85(d,J=17.6Hz,1H),2. 35(d,J=17.6Hz,1H),2.11-1.89(m,2H),1.80(dd,J=15.6,6.4Hz,1H),1.48-1.35(m,1H),1.31(d,J=6.7Hz,3H). Example 13: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-3-(pyridine-2-yl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0366] The title compound was prepared in the same manner as in Example 1, except that -hydroxypicolinimidoyl chloride was used instead of N-hydroxyacetimidoyl chloride in step 1. MS(m / z) 550.177[M+H] + . 1¹H NMR (400MHz, chloroform-d) δ 10.50 (t, J=5.9Hz, 1H), 8.66 (dd, J=4.9, 1.5Hz, 1H), 8.43 (s, 1H), 8.16 (d, J=8.0Hz, 1H), 7.96-7.83 (m, 1H), 7.55-7.43 (m, 1H), 7.39 (d, J=7.0Hz, 1H), 6.93-6.74 (m, 2H), 4.89-4.75 (m, 1H),4.67(t,J=5.1Hz,1H),4.26(s,1H),3.80(dd,J=15.3,3.1Hz,1H),3.56(d,J=3.5Hz,2H),2.36-2.26 (m,3H),1.95(dd,J=15.2,7.3Hz,1H),1.81(dd,J=15.1,11.8Hz,1H),1.52(s,1H),1.34(d,J=6.6Hz,3H). Example 14: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-3-(pyridine-3-yl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0367] The title compound was prepared in the same manner as in Example 1, except that N-hydroxynicotinimidoyl chloride was used instead of N-hydroxyacetimidoyl chloride in step 1. MS(m / z) 550.191[M+H] + . 1H NMR (400MHz, chloroform-d) δ10.41(t,J=5.9Hz,1H),8.95-8.90(m,1H),8.77(dd,J=5.1,1.6Hz,1H),8.46(s, 1H),8.25(dd,J=8.1,1.8Hz,1H),7.63(dd,J=8.1,5.1Hz,1H),7.41-7.32(m,1H),6.91-6.80(m,2H),4.85- 4.77(m,1H),4.70-4.60(m,2H),4.30(s,1H),3.93(dd,J=14.9,1.9Hz,1H),3.78(dd,J=15.0,2.7Hz,1H),3 .43(d,J=17.3Hz,1H),2.99(d,J=17.3Hz,1H),2.05(s,2H),1.70(d,J=14.8Hz,2H),1.36(d,J=6.7Hz,3H). Example 15: Preparation of (3'S,5S,7'R)-3-cyclopropyl-N-(2,4-difluorobenzyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0368] The title compound was prepared in the same manner as in Example 1, except that cyclopropanecarbaldehyde oxime was used instead of acetaldehyde oxime in step 1. MS(m / z) 513.16[M+H] + . 1¹H NMR (400MHz, chloroform-d) δ 10.43 (s, 1H), 8.35 (s, 1H), 7.39 (d, J=7.4Hz, 1H), 6.83 (q, J=10.0, 9.6Hz, 2H), 4.83-4.71 (m, 1H), 4.67 (d, J=5.5Hz, 2H), 4.07 (s, 1H), 3.77 (d, J=15.8Hz, 1H), 3.42 (d, J=15. 1Hz,1H),2.89(d,J=16.6Hz,1H),2.63(d,J=16.6Hz,1H),2.22(dd,J=15.0,7.2Hz,2H),1.81(d,J=7 .7Hz,2H),1.70(d,J=11.8Hz,1H),1.30(d,J=6.4Hz,3H),1.00(d,J=8.3Hz,2H),0.88-0.77(m,2H). Example 16: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0369] The title compound was prepared in the same manner as in Example 1, except that 2-((tert-butyldimethylsilyl)oxy)acetaldehyde oxime was used instead of acetaldehyde oxime in step 1. MS(m / z)503.154[M+H] + . 1H NMR (400MHz, chloroform-d) δ10.63(d,J=6.0Hz,1H),8.62(s,1H),7.44-7.32(m,1H),6. 91-6.71(m,2H),4.73(dd,J=14.8,6.5Hz,2H),4.65-4.49(m,2H),4.37(d,J=13.9Hz, 1H),4.28(s,1H),3.87-3.78(m,1H),3.66(d,J=2.7Hz,1H),3.14(d,J=17.9Hz,1H), 2.67(d,J=17.9Hz,1H),2.12-1.96(m,3H),1.78-1.65(m,1H),1.32(d,J=6.7Hz,3H). Example 17: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0370] Step 1: Preparation of (E)-2-((tert-butyldiphenylsilyl)oxy)acetaldehyde oxime: To a solution of 2-[tert-butyl(diphenyl)silyl]oxyacetaldehyde (1 g, 3.35 mmol) in MeOH (15 mL) and H2O (5 mL), hydroxylamine hydrochloride (0.28 g, 4.02 mmol) was added, followed by sodium bicarbonate (0.245 g, 4.02 mmol). The reaction mixture was stirred at room temperature for 2 hours. This was diluted with ELISA and washed with H2O and brine. The organic phase was dried over MgSO4, and the solvent was removed under vacuum. The resulting residue was purified by silica gel chromatography to obtain the title compound. MS (m / z) 314.05 [M+H]+.

[0371] Step 2: (3'S,5S,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide and Preparation of (3'S,5R,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: The title compound was prepared in the same manner as in Example 1, except that (E)-2-((tert-butyldiphenylsilyl)oxy)acetaldehyde oxime was used instead of acetaldehyde oxime. (3'S,5S,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide was obtained as the major stereoisomer. (3'S,5R,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide was obtained as a minor stereoisomer. MS(m / z) 831.12[M+H]+ (major), 831.13[M+H]+ (minor).

[0372] Step 3: Preparation of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: (3'S,5S,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (160 mg, 0.193 mmol) was dissolved in THF (2 mL) and TBAF (1 N) (0.578 mL, 0.578 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. This was diluted with ELISA and washed with saturated NaHCO3 and brine. The organic phase was dried over MgSO4 and the solvent was removed under vacuum. The resulting residue was purified by silica gel chromatography to obtain the title compound. MS(m / z) 593.07[M+H]+.

[0373] Step 4: Preparation of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: The title compound should be (3'S,4'R,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide instead of (3'S,5S, It was prepared in the same manner as in step 4 of Example 5, except that 7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide was used. MS(m / z) 595.09[M+H]+.

[0374] Step 5: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: The title compound should be (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide instead of (3'S,5S,7'R)-1 It was prepared in the same manner as in step 2 of Example 1, except that 2'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide was used. MS(m / z) 505.18[M+H]+. 1 ¹H NMR (400MHz, chloroform-d): δ 10.49 (t, J=6.0Hz, 1H), 8.50 (s, 1H), 7.38 (td, J=8.6, 6.4Hz, 1H), 6.91-6.78 (m, 2H), 5.32 (s, 1H), 5.23 (s, 1H), 5.11 (s, 1H), 4.83-4.58 (m, 2H), 4.22 (s, 1H) ,3.87(dd,J=15.0,1.8Hz,1H),3.74(dd,J=15.0,2.6Hz,1H),3.13(dd,J=18.0,2.1Hz,1H), 2.71(dd,J=17.9,2.4Hz,1H),2.14-1.97(m,3H),1.68-1.57(m,1H),1.33(d,J=6.7Hz,3H). Example 18: Preparation of (3'S,5R,7'R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0375] In step 3, replace (3'S,5S,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide with (3'S,5R,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1 It was prepared in the same manner as (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide in Example 17, except that ',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide. MS (m / z) 505.18 [M+H]+. 1H NMR (400MHz, chloroform-d) δ 10.50 (t, J=6.0Hz, 1H), 8.40 (s, 1H), 7.38 (q, J=8.1Hz, 1H), 6.84 (q, J=9.0Hz, 2H), 5.25 (s, 1H), 5.13 (s, 1H), 4.79 (dt, J=10.6, 6.7Hz, 1H), 4.66 (d, J=5.8Hz, 2H), 4.23 (s, 1H ),3.79(dd,J=15.3,3.1Hz,1H),3.51-3.42(m,1H),3.17(d,J=16.8Hz,1H),3.02(d,J=17.2Hz,1H) ,2.26(dt,J=14.7,7.0Hz,1H),1.88(dd,J=15.2,7.4Hz,1H),1.80-1.69(m,1H),1.46-1.25(m,4H). Example 19: Preparation of (3'S,5S,7'R)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0376] In step 2, the title compound is replaced with (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (intermediate F) by (3S,7S)-12-(benzyloxy)-3-methyl-6-methylene-1,11-dioxo-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3 This preparation was carried out in the same manner as in Example 17, (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-(fluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide, except that H-2,7-methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide was used. MS(m / z) 523.21[M+H]+. 1H NMR (400MHz, chloroform-d)δ 10.41 (t, J=5.7Hz, 1H), 8.52 (s, 1H), 6.81-6.57 (m, 2H), 5.16 (d, J=46.5Hz, 2H), 4.76 (dt, J=12.0, 7.4Hz, 2H), 4.63 (dd, J=14.5, 5.5Hz, 1H), 4.26 (s, 1H),3.86(dd,J=15.0,1.9Hz,1H),3.73(dd,J=15.0,2.7Hz,1H),3.23-3.05(m,1H),2.7 0(dd,J=17.8,2.3Hz,1H),2.09-1.89(m,3H),1.72-1.51(m,1H),1.33(d,J=6.7Hz,3H). Example 20: Preparation of (3'S,5S,7'R)-3-(difluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0377] Step 1: Preparation of (3'S,5S,7'R)-12'-(benzyloxy)-3-formyl-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: To a mixture of DMSO (0.215 mL, 3.03 mmol) in DCM (2 mL) at -78°C, oxalyl chloride (0.118 mL, 1.39 mmol) was added dropwise. After stirring the mixture at -78°C for 10 minutes, (3'S,5S,7'R)-12'-(benzyloxy)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (370 mg, 0.606 mmol) prepared according to Example 19 in DCM (2 mL) was added dropwise. The resulting mixture was stirred at -78°C for 15 minutes. Triethylamine (0.426 mL, 3.03 mmol) was added to the reaction mixture, and the cold bath was removed. The reaction mixture was stirred at room temperature for 30 minutes. After diluting the reaction mixture with RINKAN, H2O and brine were added. The organic phase was dried over MgSO4, and the solvent was removed under vacuum. The resulting residue was purified by silica gel chromatography to obtain the title compound. MS (m / z) 609.09 [M+H]+.

[0378] Step 2: Preparation of (3'S,5S,7'R)-12'-(benzyloxy)-3-(difluoromethyl)-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: The title compound should be (3'S,4'R,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide instead of (3'S, The preparation was carried out in the same manner as in step 4 of Example 5, except that 5S,7'R)-12'-(benzyloxy)-3-formyl-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide was used. MS(m / z)631.13[M+H]+.

[0379] Step 3: Preparation of (3'S,5S,7'R)-3-(difluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: The title compound should be (3'S,4'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4'-fluoro-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide instead of (3'S,5S,7' Prepared in the same manner as in step 5 of Example 5, except that R)-12'-(benzyloxy)-3-(difluoromethyl)-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide was used. MS(m / z) 541.21[M+H]+. 1H NMR (400MHz, chloroform-d) δ 10.55 (t, J=5.9Hz, 1H), 8.95 (s, 1H), 6.68 (t, J=8.1Hz, 2H), 6.57-6.30 (m, 1H), 4.89-4.73 (m, 3H), 4.50 (dd, J=14.7, 4.9Hz, 1H), 3.87 (dd, J=15.1, 1.8 Hz,1H),3.78(dd,J=15.0,2.5Hz,1H),3.22(d,J=17.9Hz,1H),2.66(d,J=17.8Hz,1H),2 .02(dq,J=20.9,8.3,6.4Hz,3H),1.62(dd,J=13.9,11.0Hz,1H),1.34(d,J=6.6Hz,3H). Example 21: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-3-(difluoromethyl)-12'-hydroxy-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0380] In step 1, replace (3'S,5S,7'R)-12'-(benzyloxy)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide with (3' Prepared in the same manner as in Example 20, except that S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide was used. MS(m / z) 523.10[M+H]+. 1H NMR (400MHz, chloroform-d) δ10.59(t,J=5.8Hz,1H),8.85(s,1H),7.36(q,J=8.1Hz, 1H),6.92-6.79(m,2H),6.61-6.34(m,1H),4.83-4.60(m,3H),4.50(s,1H),3.87( dd,J=15.0,1.7Hz,1H),3.77(dd,J=15.0,2.5Hz,1H),3.19(d,J=17.9Hz,1H),2.7 1(d,J=17.9Hz,1H),2.16-1.96(m,3H),1.70-1.58(m,1H),1.34(d,J=6.6Hz,3H). Example 22: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3-(methoxymethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0381] Step 1: Preparation of (3'S,5R,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: The title compound was prepared in the same manner as in steps 1-2 of Example 17, except that (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,4,5,6,7,11-hexahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (intermediate G) was used instead of (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (intermediate G) instead of (3S,7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-3-methyl-6-methylene-1,11-dioxo-1,6,7,11-tetrahydro-3H-2,7-methanopyrido[1,2-a][1,4]diazonin-10-carboxamide (intermediate G). MS(m / z)829.12[M+H]+.

[0382] Step 2: Preparation of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: The title compound should be (3'S,5S,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide instead of (3'S,5 It was prepared in the same manner as in step 3 of Example 17, except that R,7'R)-12'-(benzyloxy)-3-(((tert-butyldiphenylsilyl)oxy)methyl)-N-(2,4-difluorobenzyl)-3'-methyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide was used. MS(m / z)591.13[M+H]+.

[0383] Step 3: Preparation of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(methoxymethyl)-3'-methyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(hydroxymethyl)-3'-methyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (41 mg, 0.0694 mmol) was dissolved in DMF (2 mL), to which NaH (60% in mineral oil) (5.4 mg, 0.14 mmol), followed by MeI (0.004 mL, 0.0694 mmol) was added at 0°C. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with ELISA and washed with H2O and brine. The organic phase was dried over MgSO4 and the solvent was removed under vacuum. The resulting residue was purified by silica gel column chromatography to obtain the title compound. MS(m / z)605.09[M+H]+.

[0384] Step 4: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3-(methoxymethyl)-3'-methyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: A mixture of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3-(methoxymethyl)-3'-methyl-1',11'-dioxo-1',11'-dihydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (27 mg, 0.045 mmol) and 10% Pd / C (3.8 mg) in EtOH (2 mL) was stirred at room temperature under 1 atm of H2 (g). After 2 hours, the reaction mixture was filtered, concentrated, and purified by reverse-phase preparative HPLC (containing 5-100% MeCN / water and 0.1% TFA) to obtain the title compound. MS (m / z) 517.19 [M+H]+. ¹H NMR (400MHz, chloroform-d) δ 10.37 (s, 1H), 8.39 (s, 1H), 7.39 (q, J=8.2, 7.6Hz, 1H), 6.84 (q, J=8.1, 7.6Hz, 2H), 4.80-4.59 (m, 2H), 4.25 (d, J=12.3Hz, 1H), 4.19 (d, J=12.3Hz, 1H), 4.10 (s,1H),3.91-3.82(m,1H),3.70(dd,J=14.8,2.7Hz,1H),3.45(s,3H),3.03(d,J=17.9Hz, 1H), 2.65(d,J=17.9Hz,1H),2.12-1.95(m,3H),1.69-1.58(m,2H),1.32(d,J=6.7Hz,3H). Example 23: Preparation of (3'S,5R,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0385] Step 1: (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide and ( Preparation of 3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide:

[0386] A 1M solution of LiHMDS in THF (0.373 mL) was added at -78°C to a solution of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyride[1,2-a][1,4]diazonin]-10'-carboxamide (43 mg, 0.075 mmol) in THF (10 mL) prepared according to Example 1. After 30 minutes, a solution of MeI in THF (12.7 mg in 2 mL) was added at -78°C, and the mixture was then heated to -20°C. After 2 hours, the reaction was quenched by adding a saturated NH4Cl solution. The mixture was extracted with toluene to separate the organic phase, dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography column (eluted with 0-5% MeOH / toluene) to obtain the title compound. MS(m / z) 591.138[M+H]+ and MS(m / z) 593.189[M+H]+.

[0387] Step 2: Preparation of (3'S,5R,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: To the solution, (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyride[1,2-a][1,4]diazonin]-10'-carboxamide (14 mg, 0.024 mmol) in toluene (1 mL) was added, to which TFA (0.3 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC eluting with 10-90% acetonitrile in water to obtain the title compound. MS (m / z) 501.282 [M+H] + . 1 ¹H NMR (400MHz, chloroform-d) δ 10.53 (s, 1H), 8.29 (s, 1H), 7.45-7.33 (m, 1H), 6.84 (q, J=9.6, 9.0Hz, 2H), 4.65 (t, J=5.5Hz, 3H), 4.10 (s, 1H), 3.76 (dd, J=15.3, 3.1Hz, 1H), 3.59-3.49 (m, 1H) ),2.76(d,J=7.1Hz,1H),2.31-2.20(m,1H),2.08(s,3H),1.99(dd,J=15.6,7.9Hz,1H),1.5 8(dd,J=15.6,11.6Hz,1H),1.47-1.35(m,1H),1.31(d,J=6.6Hz,3H),1.21(d,J=7.1Hz,3H). Example 24: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-4,12'-dihydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0388] To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyride[1,2-a][1,4]diazonin]-10'-carboxamide (14 mg, 0.024 mmol) prepared according to Example 23 in toluene (1 mL), TFA (0.3 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC eluting with 10-90% acetonitrile in water to obtain the title compound. MS (m / z) 503.265 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ10.91(s,1H),8.33(s,1H),7.32(d,J=6.8Hz,1H),6.92-6.77(m,2H),4.89(s,1H),4.80(s,1H),4.72(d ,J=7.1Hz,1H),4.62(td,J=13.3,11.4,5.8Hz,2H),3.70-3.51(m,2H),2.10(d,J=7.1Hz,4H),1.66(s,3H),1.30(d,J=6.6Hz,3H). Example 25: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',4,11'-trioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0389] Step 1: Preparation of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',4,11'-trioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (9 mg, 0.0152 mmol) prepared according to Example 23 in DCM (3 mL), 1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3-(1H)-one (desmartin periodinane) (10 mg, 0.023 mmol) was added at room temperature. The reaction was quenched by adding saturated NaHCO3 and Na2SO3 solutions. The mixture was extracted with toluene, the organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (eluted with 50-100% toluene / hexane) to obtain the title compound. MS (m / z) 590.906 [M+H]+.

[0390] Step 2: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',4,11'-trioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',4,11'-trioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyride[1,2-a][1,4]diazonin]-10'-carboxamide (8.97 mg, 0.0152 mmol) was dissolved in toluene (1 mL), to which TFA (0.3 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by reverse-phase HPLC eluting with 10-90% acetonitrile in water to obtain the title compound. MS (m / z) 500.995 [M+H] + . 1 H NMR(400MHz,chloroform-d)δ10.42(s,1H),8.37(s,1H),7.38(q,J=8.1Hz,1H),6.84(q,J=9.1,8.6Hz,2H),4.81(s,1H),4.65(d,J=5.8Hz,1H),4.1 3-3.99(m,2H),3.74(dd,J=15.3,2.8Hz,1H),2.19(s,3H),2.12(d,J=15 .4Hz,1H),1.94-1.85(m,3H),1.66-1.59(m,1H),1.38(d,J=6.7Hz,3H). Example 26: Preparation of (3'S,4S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0391] (3'S,4S,5S,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide is converted in step 2 to (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H, Prepared in the same manner as in Example 23, except that (3'S,4S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3',4-trimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyride[1,2-a][1,4]diazonin]-10'-carboxamide was used instead of 4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyride[1,2-a][1,4]diazonin]-10'-carboxamide. MS(m / z) 501.193[M+H] + . 1 H NMR (400MHz, chloroform-d) δ10.47(s,1H),8.40(s,1H),7.47-7.34(m,1H),6.9 3-6.75(m,2H),4.69(dt,J=14.6,6.8Hz,3H),4.18(s,1H),3.85(dd,J=14.9 ,1.9Hz,1H),3.76-3.61(m,1H),3.18(d,J=7.3Hz,1H),2.12-1.87(m,6H),1 .32(d,J=6.7Hz,3H),1.23(dd,J=14.5,11.1Hz,1H),0.82(d,J=7.3Hz,3H). Example 27: (3'S,4S,5R,7'R)-N-(2,4-difluorobenzyl)-4-fluoro-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide (peak 1) Preparation of (3'S,4R,5R,7'R)-N-(2,4-difluorobenzyl)-4-fluoro-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (peak 2): [ka]

[0392] Step 1: Preparation of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-fluoro-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyride[1,2-a][1,4]diazonin]-10'-carboxamide (82 mg, 0.138 mmol) prepared according to Example 26 in DCM (4 mL), bis(2-methoxyethyl)aminosulfur trifluoride (153 mg, 0.692 mmol) was added at 0°C. After 30 minutes, the reaction was quenched by adding saturated NaHCO3 solution. The mixture was extracted with toluene, the organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by silica gel chromatography column (eluted with 0-100% toluene / hexane) to obtain the title compound as a mixture of stereoisomers. MS (m / z) 595.046

[0393] Step 2: Preparation of (3'S,5S,7'R)-N-(2,4-difluorobenzyl)-4-fluoro-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: To a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-fluoro-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (25.1 mg, 0.0422 mmol) in toluene (2 mL), TFA (1 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, the residue was separated, and the compound was purified by reverse-phase preparative HPLC eluting with 10-90% acetonitrile in water to obtain the title compound. Peak 1: MS (m / z) 505.173 [M+H] + . 1H NMR (400MHz, chloroform-d) δ10.33(d,J=5.9Hz,1H),8.61(d,J=6.2Hz,1H),7.44-7.33(m,1H),6.83(q,J=7.9Hz,2H),5.03(d,J=53.7Hz,1H),4.84(d,J=10). 5Hz,1H),4.75-4.54(m,3H),3.81(dd,J=4.2,2.3Hz,2H),2.18(d,J=3.3Hz, 3H),2.09-1.98(m,3H),1.54(dd,J=15.8,6.2Hz,1H),1.33(d,J=6.7Hz,3H).

[0394] Peak 2: MS (m / z) 505.154 [M+H] + . 1 H NMR (400MHz, chloroform-d) δ10.50(d,J=5.9Hz,1H),8.33(s,1H),7.38(q,J=8.4,8.0Hz,1 H),6.92-6.78(m,2H),5.34(d,J=53.8Hz,1H),4.85-4.59(m,3H),3.93(dd,J=14.9,1. 8Hz,1H),3.87(s,1H),3.75(d,J=14.7Hz,1H),2.21(d,J=2.5Hz,3H),2.19-2.15(m,1H ),2.12(d,J=7.0Hz,1H),2.06-1.99(m,1H),1.53-1.44(m,1H),1.35(d,J=6.6Hz,3H). Example 28: Preparation of (3'S,4S,5R,7'R)-N-(2,4-difluorobenzyl)-4,12'-dihydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0395] The title compound was prepared according to Example 26 instead of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (3' Prepared in the same manner as in Example 24, except that S,4S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide was used. MS(m / z)503.299[M+H] + . 1 H NMR (400MHz, chloroform-d) δ11.60(s,1H),9.95-9.84(m,1H),8.33(s,1H),7.40(q,J=8.3,7. 8Hz,1H),6.86(dt,J=10.2,6.9Hz,2H),5.16(s,1H),4.86(td,J=14.8,7.2Hz,2H),4.40(d d,J=14.9,3.9Hz,1H),3.98-3.84(m,2H),3.66(dd,J=14.6,2.7Hz,1H),2.29(dd,J=16.4, 6.3Hz,1H),2.10(s,3H),2.08-1.94(m,2H),1.31(d,J=6.6Hz,3H),0.93(q,J=7.5Hz,1H). Example 29: Preparation of (3'S,5R,7'R)-N-(2,4-difluorobenzyl)-12'-hydroxy-3,3'-dimethyl-1',4,11'-trioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0396] The title compound was prepared according to Example 26 instead of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide (3' Prepared in the same manner as in Example 25, except that S,4S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide was used. MS(m / z)500.97[M+H] + . 1 H NMR(400MHz,chloroform-d)δ10.46(s,1H),8.13(s,1H),7.42-7.33(m,1H),6.84(q,J=9.4,8.7Hz,2H),4.81(dd,J=11.3,6.1Hz,1H),4.73(dd,J=15.4,6. 2Hz,1H),4.55(dd,J=15.4,5.4Hz,1H),4.22(s,1H),3.95-3.78(m,2H),2. 18(s,3H),2.14-2.05(m,2H),1.63(t,J=5.1Hz,2H),1.37(d,J=6.6Hz,3H). Example 30: Preparation of (3'S,4R,5R,7'R)-N-(2,4-difluorobenzyl)-4,12'-dihydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0397] Step 1: (3'S,4S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide (peak 1) and Preparation of (3'S,4R,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide (peak 2): Sodium borohydride (2.4 mg, 0.064 mmol) was added at room temperature to a solution of (3'S,5R,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-3,3'-dimethyl-1',4,11'-trioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyride[1,2-a][1,4]diazonin]-10'-carboxamide (25 mg, 0.0423 mmol) in DCM (3 mL). After completion, the reaction was quenched by adding saturated NaHCO3 solution. The mixture was extracted with dimethylammonium

[0398] Step 2: Preparation of (3'S,4R,5R,7'R)-N-(2,4-difluorobenzyl)-4,12'-dihydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: The title compound is (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide instead of (3'S,4R,5R,7'R) Prepared in the same manner as in Example 24, except that -12'-(benzyloxy)-N-(2,4-difluorobenzyl)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide (peak 2 in step 1) was used. MS(m / z) 503.231[M+H] + . 1 ¹H NMR (400MHz, chloroform-d) δ 10.16 (s, 1H), 8.89 (s, 1H), 7.47-7.32 (m, 1H), 6.90-6.76 (m, 2H), 4.91-4.82 (m, 1H), 4.81 (s, 1H), 4.71 (d, J=10.4Hz, 1H), 4.40 (d, J=17.4Hz, 1H), 3.95- 3.87(m,1H),3.79(d,J=14.6Hz,1H),3.70-3.61(m,1H),2.11(d,J=5.1Hz,3H),2.01(s,1 H),1.70(s,1H),1.64-1.56(m,1H),1.45(d,J=11.8Hz,1H),1.31(dd,J=6.7,2.3Hz,3H). Example 31: Preparation of (3'S,4S,5R,7'R)-4,12'-dihydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0399] Step 1: Preparation of (3'S,4S,5R,7'R)-12'-(benzyloxy)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: A 1N solution of LiHMDS in THF (1.2 mL, 1.2 mmol) was added to a solution of (3'S,5S,7'R)-12'-(benzyloxy)-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyride[1,2-a][1,4]diazonin]-10'-carboxamide (204 mg, 0.343 mmol) in THF (10 mL) under air conditions at -40°C. After 30 minutes, a solution of MeI in THF (73 mg, 0.515 mmol) was added at -40°C, and the mixture was then heated to -20°C for more than 2 hours. The reaction was quenched by adding a saturated NH4Cl solution. The mixture was extracted with toluene, the organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (eluted with 10-80% toluene / hexane) to obtain the title compound. MS (m / z) 611.058 [M+H]+.

[0400] Step 2: Preparation of (3'S,4S,5R,7'R)-4,12'-dihydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: (3'S,4S,5R,7'R)-12'-(benzyloxy)-4-hydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyride[1,2-a][1,4]diazonin]-10'-carboxamide (75 mg, 0.123 mmol) was dissolved in toluene (2 mL), to which TFA (0.5 mL) was added. The reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated, the residue was separated, and the compound was purified by reverse-phase HPLC eluting with 10-90% acetonitrile in water to obtain the title compound. MS (m / z) 521.234 [M+H]+. 1 ¹H NMR (400MHz, chloroform-d) δ 11.60 (s, 1H), 10.11-9.97 (m, 1H), 8.40 (s, 1H), 6.69 (t, J=8.1Hz, 2H), 5.32 (s, 1H), 5.23 (s, 1H), 5.01 (dd, J=14.5, 8.1Hz, 1H), 4.89-4.77 (m, 1H), 4.37 (dd, J=14.6, 3. 8Hz,1H),3.94(s,1H),3.93-3.84(m,1H),3.65(dd,J=14.8,2.7Hz,1H),2.30(dd,J=16.4,6.3Hz ,1H),2.19(s,3H),2.06(d,J=8.2Hz,1H),1.64(dd,J=16.5,11.2Hz,1H),1.31(d,J=6.6Hz,3H). Example 32: Preparation of (3'S,4S,5R,7'R)-4-fluoro-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrido[1,2-a][1,4]diazonin]-10'-carboxamide: [ka]

[0401] Step 1: Preparation of (3'S,4S,5R,7'R)-12'-(benzyloxy)-4-fluoro-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: A 1M solution of LiHMDS in THF (0.15 mL) was added at -78°C to a solution of (3'S,5S,7'R)-12'-(benzyloxy)-N-(2,4-difluoro-6-methylbenzyl)-3,3'-dimethyl-1',11'-dioxo-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide (35 mg, 0.059 mmol) and N-(benzenesulfonyl)-N-fluorobenzenesulfonamide (22.5 mg, 0.072 mmol) in THF (10 mL). After 30 minutes, the reaction mixture was heated to room temperature. Next, the reaction was quenched by adding a saturated NH4Cl solution. The mixture was extracted with toluene, the organic phase was separated, dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography (eluted with 0-80% toluene / hexane) to obtain the title compound. MS (m / z) 613.029 [M+H]+.

[0402] Step 2: Preparation of (3'S,4S,5R,7'R)-4-fluoro-12'-hydroxy-3,3'-dimethyl-1',11'-dioxo-N-(2,4,6-trifluorobenzyl)-1',4',5',11'-tetrahydro-3'H,4H,7'H-spiro[isoxazole-5,6'-[2,7]methanopyrid[1,2-a][1,4]diazonin]-10'-carboxamide: (3'S,4S,5R,7...

Claims

[Claim 1] The invention described in the specification.

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