Bridged tricyclic carbamoylpyridone compounds and their pharmaceutical use

Abstract

This invention discloses compounds for treating or preventing human immunodeficiency virus (HIV) infection. These compounds have the following formula (I): The compounds include their stereoisomers and pharmaceutically acceptable salts, wherein R1, R2, L, W1, W2, X, Y, and Z are as defined herein. Methods associated with the preparation and use of these compounds, as well as pharmaceutical compositions comprising these compounds, are also disclosed.

Description

Technical Field

[0001] This invention discloses compounds, compositions, and methods for treating or preventing human immunodeficiency virus (HIV) infection. Specifically, it discloses novel bridged tricyclic aminopyridone compounds, their preparation methods, and their uses as therapeutic or preventative agents. Prior Technology

[0002] HIV infection and related diseases are a major public health problem worldwide. HIV encodes three enzymes required for viral replication: reverse transcriptase, protease, and integrase. Although drugs targeting reverse transcriptase and protease are widely used and have shown effectiveness, especially when used in combination, the toxicity and development of drug-resistant viral strains may limit their usefulness (Palella et al. N. Engl. J Med. (1998) 338:853-860; Richman, DD Nature (2001) 410:995-1001). Therefore, there is a need for novel agents to inhibit HIV replication.

[0003] The goal of antiretroviral therapy is to achieve viral suppression in patients infected with HIV. Current treatment guidelines published by the United States Department of Health and Human Services state that achieving viral suppression requires the use of combination therapy, i.e., several drugs from at least two or more drug classes (Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. Department of Health and Human Services. Available at http: / / www.aidsinfo.nih.gov / ContentFiles / AdultandAdolescentGL.pdf, accessed February 12, 2019). Furthermore, the decision-making regarding the treatment of patients infected with HIV is complex when patients require treatment for other medical conditions (ibid., at F-8). Because standard care requires the use of multiple different drugs to suppress HIV and treat other conditions that patients may experience, the potential for drug interactions is one of the rules governing drug therapy selection. Therefore, there is a need for antiretroviral therapies with reduced potential for drug interactions.

[0004] In addition, HIV is known to mutate in infected individuals (Tang et al. Drugs (2012) 72 (9) e1-e25). Due to the mutability of HIV, there is a need for anti-HIV drugs that can effectively combat a range of known HIV variants (Hurt et al. HIV / AIDS CID (2014) 58, 423-431).

[0005] For some patients, such as those with limited or no access to healthcare, adhering to daily oral or preventative therapy can be challenging. Medications offering advantageous 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. These improvements can then optimize drug exposure and limit the development of resistance. Summary of the Invention

[0006] This invention relates to novel compounds with antiviral activity and their pharmaceutically acceptable salts. In some embodiments, the compounds can be used to treat HIV infection, to inhibit HIV integrase activity, and / or to reduce HIV replication. In some embodiments, the compounds disclosed herein are effective against a range of known drug-resistant HIV mutants. In some embodiments, the compounds disclosed herein may have a reduced tendency to cause drug-drug interactions when co-administered with other drugs. In some embodiments, the compounds disclosed herein may be administered at less than daily frequencies, such as weekly, monthly, or longer intervals.

[0007] In one embodiment, a method having the following formula is provided ( [I]) compounds or their medically acceptable salts: [] in R1 is H or C6-10 aryl, wherein the C6-10 aryl is substituted by one to four RA1s, wherein each RA1 is independently a halogroup, C1-6 alkyl, C1-4 haloalkyl, cyano, -OC1-4 alkyl, or C1-4 alkyl-OC1-4 alkyl; R2 is H, C1-6 alkyl, or C1-4 haloalkyl; L can be -CR 3aR 3b-, -C(O)-, -SO 2-, -CH 2-CH 2-, or -N(Ra)-; W 1 is a key or -CR 4aR 4b-; W 2 is -CR 5aR 5b-, -CR 5aR 5bCR 5cR 5d-, -CR 6a=CR 6b-, -N(R 7)-, -O-, -S(O) n-, -C(O)-, -C(O)O-, -C(O)NH-, -CR 5aR 5b-N(R 7)-, -CR 5aR 5b-O-, -CR 5aR 5b-S(O) n-, -CR 5aR 5b-C(O)-, -CR 5aR 5b-C(O)O-, -CR 5aR 5b-OC(O)-, -CR 5aR 5b-C(O)NH- or -CR 5aR 5b-NHC(O)-; X is a key or -CR 8aR 8b-; Y is either -C(O)NH- or Q, where Q is ; Z represents -CR 9aR 9b-, -CR 9aR 9bCR 9cR 9d-, or -CR 10a=CR 10b-; R3a and R3b are independently H, C1-6 alkyl, C1-4 haloalkyl, or -OC1-4 alkyl; or as appropriate: R3a and R3b, together with the carbon atoms they are attached to, form a 3- to 7-membered saturated or partially unsaturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spirocyclic ring is, as appropriate, substituted by one to three RA2 groups, each RA2 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group; R4a and R4b are independently H, C1-6 alkyl, C1-4 haloalkyl, or halogroup; R5a, R5b, R5c, and R5d are independently H, C1-6 alkyl, C1-4 haloalkyl, halogen, hydroxyl, cyano, -OC1-4 alkyl, or C1-4 enylalkyl-OC1-4 alkyl; or as appropriate: R5a and R5b or R5c and R5d, together with the carbon atoms they are attached to, form a 3- to 7-membered saturated or partially unsaturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spirocyclic ring is, as appropriate, substituted with one to three RA3 groups, each RA3 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group; or R5a and R5c or R5b and R5d, together with their respective attached carbon atoms, form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 heteroatoms selected from N, O, and S or 1 heteroatom selected from N, O, and S, wherein the fused ring is, as appropriate, substituted by one to three RA3 groups, each RA3 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group; Each R 6a and R 6b is independently H, a halogroup, a C1-4 haloalkyl group, or a C1-6 alkyl group; as appropriate: R6a and R6b, together with their respective attached carbon atoms, form a 5- to 10-membered partially unsaturated fused ring, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing 0 heteroatoms selected from N, O, and S, or 1 heteroatomium selected from N, O, and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is, as appropriate, substituted by one to four RA4 groups, each RA4 group being independently a halogroup or a C1-4 alkyl group; R7 is H, C1-6 alkyl, C1-4 haloalkyl, C(O)Rc, or SO2Rc; R8a and R8b are each independently H, hydroxyl, -OC1-4 alkyl, C1-4 alkyl-OC1-4 alkyl, C1-6 alkyl, C1-4 haloalkyl, cyano, or halo; or as appropriate: R8a and R8b, together with the carbon atom to which they are attached, form a 3- to 7-membered saturated or partially unsaturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spirocyclic ring is, as appropriate, substituted with one to four RA5 groups, each RA5 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group; or, as appropriate: R 8a is H, hydroxyl, -OC 1-4 alkyl, C 1-4 enylalkyl, -OC 1-4 alkyl, C 1-6 alkyl, C 1-4 haloalkyl, cyano, or halo; and R8b and one of R5a, R5b, R5c, R5d and R7, together with the atoms to which they are attached, form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the fused ring is, as appropriate, substituted by one to four RA5 groups, each RA5 group being independently a halogroup or a C1-4 alkyl group; or [] R8b and R2, together with their respective attached carbon atoms, form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the fused ring is, as appropriate, substituted by one to four RA5 groups, each RA5 group being independently a halogroup or a C1-4 alkyl group; R9a, R9b, R9c, and R9d are each independently H, C1-6 alkyl, C1-4 haloalkyl, or halogroup; or as appropriate: R9a and R9b or R9c and R9d, together with the carbon atoms they are attached to, form a 3- to 7-membered saturated or partially unsaturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spirocyclic ring is, as appropriate, substituted by one to three RA6 groups, each RA6 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group; or R9a and R9c or R9b and R9d, together with their respective attached carbon atoms, form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 heteroatoms selected from N, O, and S or 1 heteroatomum selected from N, O, and S, wherein the fused ring is, as appropriate, substituted by one to three RA6 groups, each RA6 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group; or One of R9a, R9b, R9c, and R9d, and one of R4a, R4b, R5a, R5b, and R7, together with the atoms to which they are attached, form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the fused ring is, as appropriate, substituted by one to four RA6 groups, each RA6 group being independently a halogroup or a C1-4 alkyl group; R10a and R10b are independently H, a halogroup, a C1-4 haloalkyl group, or a C1-6 alkyl group; or, as appropriate: R10a and R10b, together with their respective attached carbon atoms, form a 5- to 10-membered partially unsaturated fused ring, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing 0 heteroatoms selected from N, O, and S, or 1 heteroatomium selected from N, O, and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is, as appropriate, substituted by one to four RA7 groups, each RA7 group being independently a halogroup or a C1-4 alkyl group; Ra can be independently H, C1-6 alkyl, C1-6 haloalkyl, C(O)Rc, or SO2Rc; Rb is H or C1-4 alkyl; Rc is a C1-4 alkyl or -OC1-4 alkyl; and Each n can be 0, 1, or 2.

[0008] In one state, a formula containing the effective therapeutic amount is provided. [I] A pharmaceutical composition of a compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient thereof.

[0009] In another embodiment, it comprises a compound of formula I or a pharmaceutically acceptable salt thereof, and a kit or article of instructions for use.

[0010] In another embodiment, a method is provided for treating HIV infection in humans who are infected with HIV or at risk of HIV infection, by administering a therapeutically effective dose to the human. [I] A compound or a pharmaceutically acceptable salt thereof or having the formula [I] A pharmaceutical composition of a compound or a pharmaceutically acceptable salt thereof.

[0011] In another embodiment, the provision is... [I] A compound or a pharmaceutically acceptable salt thereof or having the formula [I] Use of a pharmaceutical composition of a compound or a pharmaceutically acceptable salt thereof for the treatment of infection in humans who are infected with HIV or at risk of being infected with HIV.

[0012] In another embodiment, a formula for use in medical therapy is provided. [I] A compound or a pharmaceutically acceptable salt thereof or having the formula [I] A pharmaceutical composition of a compound or a pharmaceutically acceptable salt thereof.

[0013] In another embodiment, a method for treating HIV infection is provided. [I] A compound or a pharmaceutically acceptable salt thereof or having the formula [I] A pharmaceutical composition of a compound or a pharmaceutically acceptable salt thereof.

[0014] In another embodiment, the provision is... [I] The use of a compound or a pharmaceutically acceptable salt thereof in the manufacture of an agent for treating infection in humans who are infected with HIV or at risk of being infected with HIV.

[0015] In another embodiment, a formula for use in therapy is provided. [I] Methods for administering compounds. Specifically, methods are provided for treating HIV viral replication, treating AIDS, or delaying the onset of AIDS or ARC symptoms in mammals (e.g., humans), comprising administering a compound to the mammal. [I] The compound or its pharmaceutically acceptable salt and pharmaceutically acceptable excipient.

[0016] In another embodiment, a containing [I] A combination of a compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, used in a method of treating HIV viral replication, treating AIDS, or delaying the onset of AIDS or ARC symptoms in mammals (e.g., humans).

[0017] In another embodiment, a kit or article is provided comprising: a composition that can effectively treat or prevent HIV infection; and an encapsulating substance comprising a label indicating that the composition can be used to treat or prevent HIV infection. Exemplary compositions comprise the formula disclosed herein. [I] A compound or a pharmaceutically acceptable salt thereof.

[0018] In yet another embodiment, a method for inhibiting HIV replication is provided. This method includes exposing the virus to an effective amount under conditions where HIV replication is inhibited. [I] A compound or a salt thereof.

[0019] In another embodiment, the provision is... [I] The use of the compound for inhibiting HIV integrase activity.

[0020] In another embodiment, the provision is... [I] Use of a compound or a pharmaceutically acceptable salt thereof for the inhibition of HIV integrase activity.

[0021] In another embodiment, the provision is... [I] The use of the compound or its salt for inhibiting HIV replication.

[0022] In another embodiment, the provision is... [I] The use of a compound or a pharmaceutically acceptable salt thereof as a research tool.

[0023] Other embodiments, objectives, features, and advantages are set forth in the detailed description of the accompanying embodiments, and some may be apparent from the description of the claimed embodiments or learned by practice of the claimed embodiments. These objectives and advantages may be achieved and obtained by the methods and compositions specifically pointed out in their description and claims. The foregoing summary has been made as a concise and outlined representation of some of the embodiments disclosed herein, provided for the benefit and convenience of the reader, and is not intended to limit in any way the scope or extent of the equivalents legally enjoyed by the appended claims. Implementation

[0024] This application cross-references U.S. Provisional Application No. 62 / 822,703, filed March 22, 2019, and U.S. Provisional Application No. 62 / 948,697, filed December 16, 2019, both of which are incorporated herein by reference in their entirety for all purposes.

[0025] In the following description, certain specific details are set forth in order to provide a thorough understanding of the various embodiments disclosed herein. However, those skilled in the art will understand that the embodiments disclosed herein can be practiced without such details. The following description of several embodiments is made in the context of understanding that the invention is regarded as illustrative of the claimed subject matter and is not intended to limit the scope of the appended claims to the specific embodiments described. The headings used throughout this invention are provided for convenience only and are not construed as limiting the scope of the claims in any way. Embodiments described under any heading may be combined with embodiments described under any other heading. definition []

[0026] Unless the context otherwise requires, throughout this invention and the claims, the terms "comprise" and variations thereof, such as "comprises / comprising," are interpreted in an open-ended sense, that is, as "including but not limited to."

[0027] Throughout this specification, references to "one embodiment" or "an embodiment" mean that a particular feature, structure, or characteristic described in connection with an embodiment is included in at least one embodiment disclosed herein. Therefore, the phrases "in one embodiment" or "in one embodiment" appearing throughout this specification do not necessarily refer to the same embodiment. Furthermore, in one or more embodiments, a particular feature, structure, or characteristic may be combined in any suitable manner.

[0028] "Amine group" refers to the -NH 2 group.

[0029] "Hydroxy (hydroxy / hydroxyl)" refers to the -OH group.

[0030] "Side oxygen group" refers to the =O substituent.

[0031] Prefixes such as "C u-v" or (C uC v) indicate that the following groups have u to v carbon atoms. For example, "C 1-6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0032] "alkyl" refers to a straight-chain or branched hydrocarbon group composed of carbon and hydrogen atoms, which is saturated and has one to twelve carbon atoms (C1-12 alkyl), in some embodiments one to eight carbon atoms (C1-8 alkyl), one to six carbon atoms (C1-6 alkyl), or one to four carbon atoms (C1-4 alkyl), and is connected by a single bond to the remainder of a molecule such as: methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, 1-methylpropyl (dibutyl), 2-methylpropyl (isobutyl), 1,1-dimethylethyl (tert-butyl), n-pentyl, hexyl, 3-methylhexyl, 2-methylhexyl, and similar groups.

[0033] "Alkyl group" refers to a saturated, branched, straight, or cyclic hydrocarbon group having two monovalent groups at its center derived by removing two hydrogen atoms from one or two different carbon atoms of a parent alkane. For example, an alkyl group may have 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 6 carbon atoms, or 1 to 4 carbon atoms. Typical alkyl groups include, but are not limited to, methylene (-CH 2-), 1,1-ethyl (-CH(CH 3)-), 1,2-ethyl (-CH 2CH 2-), 1,1-propyl (-CH(CH 2CH 3)-), 1,2-propyl (-CH 2CH(CH 3)-), 1,3-propyl (-CH 2CH 2CH 2-), 1,4-butyl (-CH 2CH 2CH 2CH 2-), and similar groups.

[0034] "Aryl" or "aromatic ring" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic), including fused systems. As used herein, aryl groups have 6 to 20 ring carbon atoms (i.e., C6-20 aryl), 6 to 12 carbocyclic atoms (i.e., C6-12 aryl), 6 to 10 carbocyclic atoms (i.e., C6-10 aryl), or 5 to 10 carbocyclic atoms (i.e., C5-10 aryl). Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, and anthracene.

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

[0036] "Carbocyclic ring" refers to a non-aromatic hydrocarbon ring composed of carbon and hydrogen atoms, having three to fifteen carbon atoms, and in some embodiments three to ten or three to seven carbon atoms, and is saturated or partially unsaturated and connected to the rest of the molecule by single bonds. Carbocyclic rings include, for example, cyclopropane, cyclobutane, cyclopentane, cyclopentene, cyclohexane, cyclohexene, 1,3-cyclohexadiene, 1,4-cyclohexadiene, cycloheptane, cycloheptene, and cyclooctane.

[0037] "Fused" refers to a carbocyclic, heterocyclic, aromatic, or heteroaromatic ring structure described herein, which is connected to an existing ring structure in the compounds disclosed herein via two adjacent atoms, the two adjacent atoms being shared by the fused ring structure and the existing ring structure. For example, the bicyclic compounds described below respectively include fused cyclopropane (i.e., a cyclopropane ring fused to a cyclohexane ring), fused pyrrolidine (i.e., a pyrrolidine ring fused to a benzene ring), and fused thiophene (i.e., a thiophene ring fused to a furan ring): .

[0038] "Spiral" or "spirocyclic" refers to the carbocyclic or heterocyclic structure described herein, which is connected by a single atom to an existing ring structure in the compounds disclosed herein, and that single atom is shared by the spirocyclic structure and the existing ring structure. For example, the following bicyclic compounds each contain spirocyclopropane (i.e., a cyclopropane ring that is spirocyclic relative to a cyclohexane ring), spiro-1,3-dithiocyclopentane (i.e., a 1,3-dithiocyclopentane ring that is spirocyclic relative to a cycloheptane ring), and spirocyclopentene (i.e., a cyclopentene ring that is spirocyclic relative to a cyclohexene ring): .

[0039] "Halogen" or "halogen" refers to bromine, chlorine, fluorine or iodine.

[0040] "Haloalkyl" refers to an alkyl group as defined above that has been substituted with one or more halogen groups as defined above, such as trifluoromethyl, difluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and similar groups.

[0041] "Heteroaromatic ring" refers to an aromatic group having a single ring, multiple rings, or multiple fused rings, wherein the ring or fused ring has one or more cyclic heteroatoms independently selected from nitrogen, oxygen, and sulfur (e.g., 1 to 3 cyclic heteroatoms, 1 to 2 cyclic heteroatoms, or 1 cyclic heteroatomium). As used herein, heteroaryl groups include 5 to 20 ring atoms (5 to 20-membered heteroaryl rings), 5 to 12 ring atoms (5 to 12-membered heteroaryl rings), 5 to 10 ring atoms (5 to 10-membered heteroaryl rings), or 5 to 6 ring atoms (5 to 6-membered heteroaryl rings). Examples of heteroaryl groups include pyrimidinyl, purine, pyridinyl, pyridazinyl, benzothiazolyl, and pyrazolyl.

[0042] "Heterocyclic group" or "heterocycle" refers to a non-aromatic group or ring having three to fifteen atoms (of which one to six atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur) and connected to the remainder of the molecule by single bonds. In some embodiments, the "heterocyclic group" has three to ten atoms, of which one to four atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; or three to seven atoms, of which one to two atoms are heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. The nitrogen, carbon, or sulfur atoms in the heterocyclic group may be oxidized as appropriate; the nitrogen atom may be quaternized as appropriate. As used herein, unless otherwise indicated, "heterocyclic group" or "heterocycle" refers to a saturated ring, for example, in some embodiments, "heterocyclic group" or "heterocycle" refers to a ring that is saturated or partially saturated under specified conditions. Examples of such heterocyclic groups include, but are not limited to, dioxolane, imidazolidine, isothiazolidine, isoxazolidine, morpholino, 2-sideoxypiperazinyl, 2-sideoxypiperidinyl, 2-sideoxypyrrolidine, oxazolidine, piperidinyl, piperazinyl, 4-piperidinoneyl, pyrrolidine, pyrazolidine, thiazolidinyl, tetrahydrofuranyl, trithiaalkyl, tetrahydropiperazinyl, thiomorpholino, thiomorpholino, 1-sideoxy-thiomorpholino, and 1,1-disideoxy-thiomorpholino.

[0043] The embodiments disclosed herein are also intended to cover all medically acceptable methods of isotopic labeling by substituting one or more atoms with different atomic masses or mass numbers. [I] Compounds. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such individually as 2H, 3H, 11C, 13C, 14C, 13N, 15N, 15O, 17O, 18O, 31P, 32P, 35S, 18F, 36Cl, 123I, and 125I. In some embodiments, such radiolabeled compounds can be used to aid in the determination or measurement of compound efficacy by characterizing, for example, the site or mode of action or binding affinity to pharmacologically important sites of action. Certain isotopically labeled formulas [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds, such as those containing radioactive isotopes, can be used for drug and / or tissue distribution studies. Radioactive isotopes tritium (i.e., 3H) and carbon-14 (i.e., 14C) are particularly suitable for this purpose due to their ease of combination and readily available detection methods.

[0044] In some embodiments, substitution with a heavier isotope, such as deuterium (i.e., 2H), can provide certain therapeutic advantages resulting from greater metabolic stability. For example, the in vivo half-life can be prolonged or the dosage requirement can be reduced. Therefore, in some cases, a heavier isotope may be preferred.

[0045] Substitution using positron emission isotopes such as 11C, 18F, 15O, and 13N can be used in positron emission tomography (PET) studies to examine acceptor occupancy. The isotope-labeled formula... [I] The compound can be prepared by means of techniques known to those skilled in the art or by means of methods similar to those described in the examples set forth below, using appropriate isotopically labeled reagents instead of previously used unlabeled reagents.

[0046] The methods, compositions, kits, and articles provided herein use or include compounds (e.g., formula...). [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds) or their pharmaceutically acceptable salts, wherein one to n hydrogen atoms attached to a carbon atom may be replaced by a deuterium atom or a D atom, where n is the number of hydrogen atoms in the molecule. As is known in this art, a deuterium atom is a non-radioactive isotope of a hydrogen atom. These compounds enhance antimetabolism and are therefore used to prolong the half-life of the compounds or their pharmaceutically acceptable salts when administered to mammals. See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol . Sci., 5(12):524-527 (1984). These compounds may be synthesized by means known in this art, for example by using starting materials in which one or more hydrogen atoms have been replaced by deuterium.

[0047] The embodiments disclosed herein are also intended to cover in vivo metabolites of the disclosed compounds. These products can be produced by, for example, oxidation, reduction, hydrolysis, amination, esterification, and the like of the compound administered, primarily due to enzymatic processes. Therefore, the embodiments disclosed herein include compounds produced by methods comprising administering a compound of the embodiments disclosed herein to a mammal for a time sufficient to produce its metabolites. These products are typically identified by administering a detectable dose of the radiolabeled compound of the embodiments disclosed herein to animals such as rats, mice, guinea pigs, monkeys, or to humans, allowing sufficient time for metabolism, and isolating the metabolites from urine, blood, or other biological samples.

[0048] "Mammals" include both humans and domestic animals such as laboratory animals and pets (e.g., cats, dogs, pigs, cattle, sheep, goats, horses, rabbits) and non-domestic animals such as wild animals and similar animals.

[0049] "As appropriate" or "as appropriate" means that the event or situation described below may or may not occur, and the description includes both the possibility that the event or situation occurs and the possibility that it does not occur. For example, "substituted heterocyclic groups as appropriate" means that the heterocyclic group may or may not be substituted, and the description includes both substituted heterocyclic groups and unsubstituted heterocyclic groups.

[0050] "Pharmaceutical acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, lubricants, sweeteners, diluents, preservatives, dyes / colorants, flavor enhancers, surfactants, wetting agents, dispersants, suspending agents, stabilizers, isotonic agents, solvents, emulsifiers, or other pharmacologically inactive substances formulated in combination with the pharmacologically active ingredient of a pharmaceutical composition and compatible with another component of the formulation, and suitable for human or animal use without adverse toxicity, irritation, allergic reactions, or similar effects.

[0051] Examples of pharmaceutically acceptable salts of the compounds disclosed herein include salts derived from suitable bases such as alkali metals (e.g., sodium), alkaline earth metals (e.g., magnesium), ammonium, and NX 4+ (where X is a C 1-4 alkyl group). Pharmaceutically acceptable salts having a nitrogen atom or an amino group include, for example, salts of the following: organic carboxylic acids, such as acetic acid, trifluoroacetic acid, adipic acid, ascorbic acid, aspartic acid, butyric acid, camphoric acid, cinnamic acid, citric acid, digluconic acid, glutamic acid, glycolic acid, glycerophosphate, formic acid, hexanoic acid, benzoic acid, lactic acid, fumaric acid, tartaric acid, maleic acid, hydroxymaleic acid, malonic acid, malic acid, mandelic acid, and hydroxyethanesulfonic acid. Lactobionic acid, nicotinic acid, oxalic acid, pyruvic acid, pectinic acid, phenylacetic acid, 3-phenylpropionic acid, pentyl acid, propionic acid, pyruvic acid, salicylic acid, stearic acid, p-aminobenzenesulfonic acid, tartaric acid, undecanoic acid, and succinic acid; organic sulfonic acids, such as methanesulfonic acid, ethanesulfonic acid, camphorsulfonic acid, mesitylenesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, naphthalenesulfonic acid, and 2-naphthalenesulfonic acid; and inorganic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and aminosulfonic acids. Pharmaceutically acceptable salts of compounds having a hydroxyl group include combinations of the compound's anion with suitable cations such as Na+ and N×4+ (where X is independently selected from H or C1-4 alkyl groups).

[0052] For therapeutic use, the salts of the active ingredients of the compounds disclosed herein are generally pharmaceutically acceptable, i.e., derived from physiologically acceptable salts of acids or bases. However, salts of pharmaceutically unacceptable acids or bases may also be used, for example, in the preparation or purification of... [I] Compounds or other compounds of the embodiments disclosed herein. All salts, whether or not derived from physiologically acceptable acids or bases, are within the scope of the embodiments disclosed herein.

[0053] Metal salts are typically prepared by reacting a metal hydroxide with the compounds of the examples disclosed herein. Examples of metal salts prepared in this manner include salts containing Li+, Na+, and K+. Metal salts with lower solubility can be precipitated from solutions of salts with higher solubility by adding a suitable metal compound.

[0054] Additionally, salts can be formed by adding certain organic and inorganic acids, such as HCl, HBr, H₂SO₄, H₃PO₄, or organic sulfonic acids, to a basic center, typically an amine. Finally, it should be understood that the compositions described herein comprise the compounds disclosed herein in both their unionized and zwitterionic forms.

[0055] "Pharmaceutical composition" means a formulation having the compounds of the embodiments disclosed herein and a medium generally accepted in this art for delivering bioactive compounds to mammals such as humans. Such media include all pharmaceutically acceptable excipients.

[0056] "Effective amount" or "therapeutic effective amount" means the amount of a compound of the embodiments disclosed herein that, when administered to a patient in need, is sufficient to treat the disease state, condition, or symptom disclosed herein. Such an amount is sufficient to elicit a biological or medical response in the tissue system or in the patient sought by the researcher or clinician. The amount of a compound of the embodiments disclosed herein constituting a therapeutic effective amount varies depending on factors such as: the compound and its biological activity, the composition in which it is administered, the time of administration, the route of administration, the rate of compound excretion, the duration of treatment, the type and severity of the disease state or symptom being treated, any drugs used in combination with or concurrently with the compounds of the embodiments disclosed herein, and the patient's age, weight, general health, sex, and diet. Such a therapeutic effective amount can be determined by one of ordinary skill in the art, taking into account their own knowledge, the level of the art, and the present invention.

[0057] As used herein, the term "treatment" is intended to mean administering the compounds or compositions of the embodiments of the invention disclosed herein to alleviate or eliminate one or more symptoms of HIV infection and / or reduce viral load in a patient. In some embodiments, the term "treatment" also encompasses administering the compounds or compositions of the embodiments of the invention disclosed herein after an individual's exposure to the virus, but before the onset of disease symptoms and / or before the virus is detected in the blood, to prevent the onset of disease symptoms and / or to prevent the virus in the blood from reaching a detectable level; and administering the compounds or compositions of the embodiments of the invention disclosed herein to prevent perinatal HIV transmission from mother to infant, which is done by administering them to the mother before childbirth and to the infant on the first day of life. The term "treatment" also encompasses administering the compounds or compositions of the embodiments of the invention disclosed herein (also referred to as pre-exposure prophylaxis or PrEP) before an individual's exposure to the virus to prevent the spread of HIV infection and / or prevent the establishment of permanent infection and / or prevent the onset of disease symptoms and / or prevent the virus in the blood from reaching a detectable level. The term "treatment" also covers the administration of compounds or compositions of the embodiments of the invention disclosed herein to an individual before and after exposure to the virus.

[0058] As used herein, the term "preventing / prevention" refers to the administration of the compounds, compositions, or pharmaceutically acceptable salts of the present invention to a human before or after exposure to a virus, but before the onset of disease symptoms and / or before the virus is detected in the blood. These terms also refer to the prevention of the onset of disease symptoms and / or the prevention of the virus in the blood to reach detectable levels. These terms include both pre-exposure prophylaxis (PrEP) and post-exposure prophylaxis (PEP), as well as event-driven or "on-demand" prophylaxis. These terms also refer to the prevention of perinatal HIV transmission from mother to infant by administration to the mother before conception and to the infant on the first day of life. These terms also refer to the prevention of HIV transmission via blood transfusion.

[0059] As used herein, the term "antiviral agent" is intended to mean an agent (compound or biological agent) that can effectively inhibit the formation and / or replication of viruses in humans, including but not limited to agents that interfere with the host or viral mechanisms necessary for the formation and / or replication of viruses in humans.

[0060] As used in this article, the term "HIV replication inhibitor" is intended to mean an agent that can reduce or eliminate the ability of HIV to replicate in host cells, whether in vitro, in vivo, or in vivo.

[0061] The compounds of the embodiments disclosed herein, or their pharmaceutically acceptable salts, may contain one or more asymmetric centers, and may thus produce enantiomers, diastereomers, and other stereoisomers, which may be defined, in absolute stereochemistry, as (R)- or (S)- or (D)- or (L)- for amino acids. The present invention is intended to include all such possible isomers and their racemic, non-racemic, and optically pure forms. Optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers may be prepared using palmitic synthons or palmitic reagents, or decomposed using methods such as chromatography and stepwise crystallization. Techniques for preparing / separating individual enantiomers include palmitic synthesis from suitable optically pure precursors or decomposition of racemates (or racemates of salts or derivatives) using, for example, palmitic high-performance liquid chromatography (HPLC). When the compounds described herein contain diene bonds or other geometrically asymmetric centers, it is intended that the compounds include both E-type and Z-type geometric isomers, unless otherwise specified. Similarly, it is intended that all tautomers be included.

[0062] "Stereoisomers" refer to compounds composed of identical atoms bonded by the same bonds but having different three-dimensional structures that are not interchangeable. This invention covers various stereoisomers and mixtures thereof, including "enantiomers," which are two stereoisomers whose molecules are non-overlapping mirror images of each other. In any of the embodiments disclosed herein, the compound disclosed herein may be in its stereoisomer form.

[0063] "Partially unsaturated" refers to a compound containing at least one double bond but not an aromatic cyclic group. compound []

[0064] This document provides compounds that act as anti-HIV agents, pharmaceutical compositions comprising such compounds in combination with one or more (e.g., two, three, or four) additional therapeutic agents, and methods of using such compounds and compositions. All compound examples described herein include any pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers.

[0065] In one embodiment, the following formula is provided ( [I]) Compound: [] Or a medically acceptable salt, in which R1 is H or C6-10 aryl, wherein the C6-10 aryl is substituted by one to four RA1s, wherein each RA1 is independently a halogroup, C1-6 alkyl, C1-4 haloalkyl, cyano, -OC1-4 alkyl, or C1-4 alkyl-OC1-4 alkyl; R2 is H, C1-6 alkyl, or C1-4 haloalkyl; L can be -CR 3aR 3b-, -C(O)-, -SO 2-, -CH 2-CH 2-, or -N(Ra)-; W 1 is a key or -CR 4aR 4b-; W 2 is -CR 5aR 5b-, -CR 5aR 5bCR 5cR 5d-, -CR 6a=CR 6b-, -N(R 7)-, -O-, -S(O) n-, -C(O)-, -C(O)O-, -C(O)NH-, -CR 5aR 5b-N(R 7)-, -CR 5aR 5b-O-, -CR 5aR 5b-S(O) n-, -CR 5aR 5b-C(O)-, -CR 5aR 5b-C(O)O-, -CR 5aR 5b-OC(O)-, -CR 5aR 5b-C(O)NH- or -CR 5aR 5b-NHC(O)-; X is a key or -CR 8aR 8b-; Y is either -C(O)NH- or Q, where Q is ; Z is -CR 9aR 9b-, -CR 9aR 9b-CR 9cR 9d- or -CR 10a=CR 10b-; R3a and R3b are independently H, C1-6 alkyl, C1-4 haloalkyl, or -OC1-4 alkyl; or as appropriate: R3a and R3b, together with the carbon atoms they are attached to, form a 3- to 7-membered saturated or partially unsaturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spirocyclic ring is, as appropriate, substituted by one to three RA2 groups, each RA2 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group; R4a and R4b are independently H, C1-6 alkyl, C1-4 haloalkyl, or halogroup; R5a, R5b, R5c, and R5d are independently H, C1-6 alkyl, C1-4 haloalkyl, halogen, hydroxyl, cyano, -OC1-4 alkyl, or C1-4 enylalkyl-OC1-4 alkyl; or as appropriate: R5a and R5b or R5c and R5d, together with the carbon atoms they are attached to, form a 3- to 7-membered saturated or partially unsaturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spirocyclic ring is, as appropriate, substituted with one to three RA3 groups, each RA3 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group; or R5a and R5c or R5b and R5d, together with their respective attached carbon atoms, form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 heteroatoms selected from N, O, and S or 1 heteroatom selected from N, O, and S, wherein the fused ring is, as appropriate, substituted by one to three RA3 groups, each RA3 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group; Each R 6a and R 6b is independently H, a halogroup, a C1-4 haloalkyl group, or a C1-6 alkyl group; as appropriate: R6a and R6b, together with their respective attached carbon atoms, form a 5- to 10-membered partially unsaturated fused ring, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing 0 heteroatoms selected from N, O, and S, or 1 heteroatomium selected from N, O, and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is, as appropriate, substituted by one to four RA4 groups, each RA4 group being independently a halogroup or a C1-4 alkyl group; R7 is H, C1-6 alkyl, C1-4 haloalkyl, C(O)Rc, or SO2Rc; R8a and R8b are each independently H, hydroxyl, -OC1-4 alkyl, C1-4 alkyl-OC1-4 alkyl, C1-6 alkyl, C1-4 haloalkyl, cyano, or halo; or as appropriate: R8a and R8b, together with the carbon atom to which they are attached, form a 3- to 7-membered saturated or partially unsaturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spirocyclic ring is, as appropriate, substituted with one to four RA5 groups, each RA5 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group; or, as appropriate: R 8a is H, hydroxyl, -OC 1-4 alkyl, C 1-4 enylalkyl, -OC 1-4 alkyl, C 1-6 alkyl, C 1-4 haloalkyl, cyano, or halo; and R8b and one of R5a, R5b, R5c, R5d and R7, together with the atoms to which they are attached, form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the fused ring is, as appropriate, substituted by one to four RA5 groups, each RA5 group being independently a halogroup or a C1-4 alkyl group; or [] R8b and R2, together with their respective attached carbon atoms, form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the fused ring is, as appropriate, substituted by one to four RA5 groups, each RA5 group being independently a halogroup or a C1-4 alkyl group; R9a, R9b, R9c, and R9d are each independently H, C1-6 alkyl, C1-4 haloalkyl, or halogroup; or as appropriate: R9a and R9b or R9c and R9d, together with the carbon atoms they are attached to, form a 3- to 7-membered saturated or partially unsaturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spirocyclic ring is, as appropriate, substituted by one to three RA6 groups, each RA6 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group; or R9a and R9c or R9b and R9d, together with their respective attached carbon atoms, form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 heteroatoms selected from N, O, and S or 1 heteroatomum selected from N, O, and S, wherein the fused ring is, as appropriate, substituted by one to three RA6 groups, each RA6 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group; or One of R9a, R9b, R9c, and R9d, and one of R4a, R4b, R5a, R5b, and R7, together with the atoms to which they are attached, form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the fused ring is, as appropriate, substituted by one to four RA6 groups, each RA6 group being independently a halogroup or a C1-4 alkyl group; R10a and R10b are independently H, a halogroup, a C1-4 haloalkyl group, or a C1-6 alkyl group; or, as appropriate: R10a and R10b, together with their respective attached carbon atoms, form a 5- to 10-membered partially unsaturated fused ring, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing 0 heteroatoms selected from N, O, and S, or 1 heteroatomium selected from N, O, and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is, as appropriate, substituted by one to four RA7 groups, each RA7 group being independently a halogroup or a C1-4 alkyl group; Ra can be independently H, C1-6 alkyl, C1-6 haloalkyl, C(O)Rc, or SO2Rc; Rb is H or C1-4 alkyl; Rc is a C1-4 alkyl or -OC1-4 alkyl; and Each n can be 0, 1, or 2.

[0066] In the formula [I] In some embodiments of the compound or its pharmaceutically acceptable salt, R2 is H, a C1-4 alkyl, or a C1-4 haloalkyl. In some embodiments, R2 is H or a C1-4 alkyl. In some embodiments, R2 is H. In some embodiments, R2 is a C1-4 alkyl. In some embodiments, R2 is methyl. In some embodiments, R2 is H or methyl. In some embodiments, R2 is a C1-4 haloalkyl.

[0067] In some embodiments, R2 is selected from the group consisting of H, -CH3, -CH2CH3, and -CH2F, or R2 and R8b together with the carbon atoms they are attached to form a 3-membered fused carbide ring. In some embodiments, R2 is selected from the group consisting of H, -CH3, -CH2CH3, and -CH2F. In some embodiments, R2 and R8b together with the carbon atoms they are attached to form a 3-membered fused carbide ring.

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

[0069] In some embodiments, the formula [I] The compound is of formula ( [II]) Compound: [] Or a medically acceptable salt thereof, wherein R1, L, W1, W2, X and Z are as follows: Defined in [I].

[0070] In the formula [I] or [II] In some embodiments of the compound or a pharmaceutically acceptable salt thereof, R1 is H. In some embodiments, R1 is a C6-10 aryl group. In some embodiments, R1 is a phenyl group substituted with one to four RA1 groups, wherein each RA1 group is independently a halogroup, a C1-4 alkyl group, a C1-4 haloalkyl group, a cyano group, an -OC1-4 alkyl group, or a C1-4 alkyl-OC1-4 alkyl group. In some embodiments, R1 is a phenyl group substituted with one, two, three, or four RA1 groups. In some embodiments, R1 is a phenyl group substituted with one, two, three, or four RA1 groups, wherein each RA1 group is independently a halogroup, a C1-4 alkyl group, a C1-4 haloalkyl group, or an -OC1-4 alkyl group. In some embodiments, R1 is a phenyl group substituted with one, two, three, or four R1 groups, wherein each R1 group is independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group. In some embodiments, R1 is a phenyl group substituted with one, two, three, or four R1 groups, wherein each R1 group is independently a halogroup or a C1-4 alkyl group. In some embodiments, R1 is a phenyl group substituted with one, two, three, or more halogens. In some embodiments, R1 is a phenyl group substituted with two or three halogens selected from chlorine and fluorine. In some embodiments, R1 is... .

[0071] exist [I] or [II] In some embodiments of the compound, R1 is selected from the group consisting of: In the formula [I] or [II] In some embodiments of the compound, R1 is selected from the group consisting of: In some embodiments, R1 is selected from the group consisting of: .

[0072] In the formula [I] or [II] In some embodiments of the compound or a pharmaceutically acceptable salt thereof, L is -CR 3aR 3b-, wherein R 3a and R 3b are independently H, C1-4 alkyl, C1-6 haloalkyl, C(O)Rc, or SO2Rc. In some embodiments, L is -CR 3aR 3b-, wherein R 3a and R 3b are independently H or C1-4 alkyl. In some embodiments, L is -CH 2-. In some embodiments, L is -CH(CH 3)-. In some embodiments, L is -C(O)-. In some embodiments, L is -CH 2-CH 2-. In some embodiments, L is -CH 2-, -CH(CH 3)-, -C(O)-, or -CH 2-CH 2-. In some embodiments, L is -N(Ra)-.

[0073] In some embodiments, the formula [I] or [II] The compound is of the following formula: [] Or a medically acceptable salt thereof, wherein R1, L, W1, W2, X and Z are as follows: Defined in [I].

[0074] In some embodiments, the formula [I] or [II] The compound is of formula ( [IV]) Compounds: [] Or a medically acceptable salt thereof, wherein R1, W1, W2, X and Z are as follows: Defined in [I].

[0075] In some embodiments, the formula [I]、 [II] or [IV] The compound is of the following formula: [] Or a medically acceptable salt thereof, wherein R1, W1, W2, X and Z are as follows: Defined in [I].

[0076] In some embodiments, the formula [I] [or] [II] The compound is of formula ( [VI]) Compounds: . []

[0077] In some embodiments, the formula [I]、 [II] or [VI] The compound is of the following formula: [] Or a medically acceptable salt thereof, wherein R1, W1, W2, X and Z are as follows: Defined in [I].

[0078] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa] or [VIIb] In some embodiments of the compound or its pharmaceutically acceptable salt, W1 is a bond. In some embodiments, W1 is -CR 4aR 4b-. In some embodiments, W1 is -CR 4aR 4b-, wherein R 4a and R 4b are independently H or a halide group. In some embodiments, W1 is -CH 2-. In some embodiments, W1 is -CF 2-. In some embodiments, W1 is -CH(F)-. In some embodiments, W1 is a bond, -CH 2-, -CF 2-, or -CH(F)-. In some embodiments, W1 is a bond or -CH 2-.

[0079] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa] or [VIIb] In some embodiments of the compound or a pharmaceutically acceptable salt thereof, W1 is a bond or -CR 4aR 4b-, wherein each R 4a and R 4b is independently H, a halogroup, or a C1-6 alkyl group. In some embodiments, W1 is a bond or -CR 4aR 4b-, wherein each R 4a and R 4b is independently H, a halogroup, or -CH 3. In some embodiments, W1 is a bond, -CH 2-, -CH(F)-, CF 2, -CH(CH 3)-, or -CF(CH 3)-.

[0080] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa] or [VIIb] In some embodiments of the compound or a pharmaceutically acceptable salt thereof, W2 is -CR5aR5b-, -CR5aR5b-CR5cR5d-, -CR6a=CR6b-, -N(R7)-, -O-, -CR5aR5b-N(R7)- or -CR5aR5b-O-, wherein R5a, R5b, R5c, R5d, R6a, R6b and R7 are as per the formula [I] as defined. In some embodiments, W2 is -CR 5aR 5b-. In some embodiments, W2 is -CR 5aR 5b-, wherein R 5a and R 5b are independently H, C1-4 alkyl, C1-4 haloalkyl, halo, hydroxyl, cyano, -OC 1-4 alkyl, or C1-4 alkyl-OC 1-4 alkyl. In some embodiments, W2 is -CR 5aR 5b-, wherein R 5a and R 5b are independently H, C1-4 alkyl, C1-4 haloalkyl, halo, or hydroxyl. In some embodiments, W2 is -CR 5aR 5b-, wherein R 5a and R 5b are independently H or halo. In some embodiments, W2 is -CH 2-. In some embodiments, W2 is -CF 2-. In some embodiments, W2 is -CH(F)-. In some embodiments, W2 is -CR 5aR 5b-CR 5cR 5d-. In some embodiments, W2 is -CR 5aR 5b-CR 5cR 5d-, wherein R 5a, R 5b, R 5c and R 5d are independently H, C1-4 alkyl, C1-4 haloalkyl, halogen, hydroxyl, cyano, -OC1-4 alkyl or C1-4 alkyl-OC1-4 alkyl. In some embodiments, W2 is -CR 5aR 5b-CR 5cR 5d-, wherein R 5a, R 5b, R 5c and R 5d are independently H, C1-4 alkyl, C1-4 haloalkyl, halogen, hydroxyl. In some embodiments, W2 is -CR5aR5b-CR5cR5d-, wherein R5a, R5b, R5c, and R5d are independently H or halogens. In some embodiments, W2 is -CH2CH2-. In some embodiments, W2 is -CR5aR5b-CR5cR5d-, wherein R5a and R5c are independently H or halogens and R5b and R5d, together with their respective attached carbon atoms, form a 3- to 7-member saturated or partially unsaturated fused carbon ring, which may be substituted with one to three RA3s, wherein each RA3 is independently a halogen, a C1-4 alkyl, or a C1-4 haloalkyl. In some embodiments, W2 is -CR5aR5b-CR5cR5d-, wherein R5a and R5c are independently H or halogen groups and R5b and R5d, together with their respective attached carbon atoms, form a 3- to 5-membered saturated fused carbon ring. In some embodiments, W2 is -CHR5b-CHR5d-, wherein R5b and R5d, together with their respective attached carbon atoms, form a 3-, 4-, or 5-membered saturated fused carbon ring. In some embodiments, W2 is In some embodiments, W2 is -CR 6a=CR 6b-. In some embodiments, W2 is -CR 6a=CR 6b-, wherein R 6a and R 6b are independently H, a halogroup, a C1-4 haloalkyl group, or a C1-4 alkyl group. In some embodiments, W2 is -CR 6a=CR 6b-, wherein R 6a and R 6b are independently H or a halogroup. In some embodiments, W2 is -CH=CH-. In some embodiments, W2 is -CR6a=CR6b-, wherein R6a and R6b, together with their respective attached carbon atoms, form a 5- to 10-member partially unsaturated fused ring containing 0 heteroatoms selected from N, O, and S or 1 heteroatom selected from N, O, and S, or a 5- to 10-member fused aromatic ring containing 1 to 2 heteroatoms selected from N, O, and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused hetero aromatic ring is, as appropriate, substituted by one to four RA4s, wherein each RA4 is independently a halogroup or a C1-4 alkyl group. In some embodiments, W2 is -CR6a=CR6b-, wherein R6a and R6b, together with their respective attached carbon atoms, form a 5- to 10-membered partially unsaturated fused ring containing 0 heteroatoms selected from N, O, and S or 1 heteroatom selected from N, O, and S, substituted with one to four RA4 atoms, wherein each RA4 is independently a halogroup or a C1-4 alkyl group. In some embodiments, W2 is -CR6a=CR6b-, wherein R6a and R6b, together with their respective attached carbon atoms, form a 5- to 10-membered fused aromatic ring, substituted with one to four RA4 atoms, wherein each RA4 is independently a halogroup or a C1-4 alkyl group. In some embodiments, W2 is -CR 6a=CR 6b-, wherein R 6a and R 6b, together with their respective attached carbon atoms, form a 5- to 10-membered fused heteroaromatic ring containing one to two heteroatoms selected from N, O, and S, substituted with one to four RA4 atoms as appropriate, wherein each RA4 is independently a halogroup or a C1-4 alkyl group. In some embodiments, W2 is -CR 6a=CR 6b-, wherein R 6a and R 6b, together with their respective attached atoms, form a fused 1,2-benzene ring, substituted with one to four RA4 atoms as appropriate, wherein each RA4 is independently a halogroup or a C1-4 alkyl group. In some embodiments, W2 is , where p is 0, 1, 2, 3, or 4. In some embodiments, W2 is Each RA4 group is independently a halogen group. In some embodiments, W2 is... Each RA4 group is independently a halogenated group and p is 0, 1, 2, or 3. In some embodiments, W2 is... Each RA4 group is independently a halogen group and p is 0, 1, or 2. In some embodiments, W2 is... In some embodiments, W2 is In some embodiments, W2 is -N(R7)-. In some embodiments, W2 is -N(R7)-, wherein R7 is H, C1-4 alkyl, C1-4 haloalkyl, C(O)Rc, or SO2Rc. In some embodiments, W2 is -N(R7)-, wherein R7 is H, C1-4 alkyl, C(O)Rc, or SO2Rc. In some embodiments, W2 is -NH-. In some embodiments, W2 is -N(CH3)-. In some embodiments, W2 is -N(CH(CH3)2)-. In some embodiments, W2 is -N(C(O)Rc)-. In some embodiments, W2 is -N(C(O)CH3)-. In some embodiments, W2 is -N(SO2Rc)-. In some embodiments, W2 is -N(SO2CH3)-. In some embodiments, W2 is -O-. In some embodiments, W2 is -CR 5aR 5b-N(R 7)-. In some embodiments, W2 is -CH 2-N(R 7)-. In some embodiments, W2 is -CR 5aR 5b-O-. In some embodiments, W2 is -CH 2-O-. In some embodiments, W2 is -CH 2-, -CH 2CH 2-, -CH=CH-, , -NH-, -N(CH 3)-, -N(CH(CH 3) 2)-, -N(C(O)CH 3)-, -N(SO 2CH 3)-, -O- or -CH 2-O-.

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

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

[0083] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va] or In some embodiments of the [Vb] compound, the compound has the formula ( [Xb]): Mode( [Xb]).

[0084] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va] or In some embodiments of the [Vb] compound, the compound has the formula ( [XI]): Mode( [XI]).

[0085] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb] or In some embodiments of compound [X], the compound has the formula ( [XIa]): Mode( [XIa]).

[0086] In some embodiments, the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb] or [X] compounds have the formula ( [XIb]): Mode( [XIb]).

[0087] In the formula [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, X is a bond or -CR 8aR 8b-; wherein R 8a and R 8b are each independently H, hydroxyl, -OC 1-4 alkyl, C 1-4 alkyl-OC 1-4 alkyl, C 1-6 alkyl, C 1-4 haloalkyl, cyano, or halo. In some embodiments, X is a bond. In some embodiments, X is -CR 8aR 8b-; wherein R 8a and R 8b are each independently H, hydroxyl, -OC 1-4 alkyl, C 1-4 alkyl-OC 1-4 alkyl, C 1-6 alkyl, C 1-4 haloalkyl, cyano, or halo. In some embodiments, X is -CR 8aR 8b-; wherein R 8a and R 8b are each independently H, C 1-6 alkyl, C 1-4 haloalkyl, or halo. In some embodiments, R8a and R8b are each independently H, -CH3, -CHF2, -CH2F, or a halogen group.

[0088] In the formula [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, Z is -CR 9aR 9b- or -CR 9aR 9bCR 9cR 9d-; wherein R 9a, R 9b, R 9c and R 9d are each independently H, a C1-6 alkyl or a C1-4 haloalkyl. In some embodiments, Z is -CR 9aR 9b-. In some embodiments, Z is -CR 9aR 9bCR 9cR 9d-. In some embodiments, R 9a, R 9b, R 9c and R 9d are each independently H, -CH 3, -CHF 2 or -CH 2F.

[0089] In the formula [XI]、 [XIa] or In some examples of the [XIb] compound or its pharmaceutically acceptable salt, each R6a and R6b is independently H, a halogroup, a C1-4 haloalkyl group, or a C1-6 alkyl group.

[0090] In the formula [X]、 [Xa] or In some examples of the [Xb] compound or its pharmaceutically acceptable salt, each of R5a, R5b, R5c and R5d is independently H, a halogen, a C1-4 haloalkyl or a C1-6 alkyl.

[0091] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, X is a bond. In some embodiments, X is -CR 8aR 8b-. In some embodiments, X is -CR 8aR 8b-, wherein R 8a and R 8b are independently H, hydroxyl, C1-4 alkyl, or halogroup. In some embodiments, X is -CR 8aR 8b-, wherein R 8a is H, fluorine, or hydroxyl, and R 8b is H or fluorine. In some embodiments, X is -CH 2-. In some embodiments, X is -CF 2-. In some embodiments, X is -CH(F)-. In some embodiments, X is -CH(OH)-. In some embodiments, X is -CH(CH 3)-. In some embodiments, X is -CF(CH 3)-. In some embodiments, X is -CH 2-, -CF 2-, -CH(F)-, -CH(OH)-, -CH(CH 3)-, or -CF(CH 3)-. In some embodiments, X is -CR 8aR 8b-, wherein R 8a and R 8b, together with the carbon atoms to which they are attached, form a 3-, 4-, or 5-membered saturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spirocyclic ring is optionally substituted with one to four RA5 groups, each RA5 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group. In some embodiments, X is -CR 8aR 8b-, wherein R 8a and R 8b, together with the carbon atoms to which they are attached, form a 3- to 5-membered saturated spirocyclic ring containing 0 heteroatoms, wherein the spirocyclic ring is optionally substituted with one to four RA5 groups, each RA5 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group. In some embodiments, X is -CR 8aR 8b-, wherein R 8a and R 8b, together with the carbon atoms to which they are attached, form a spirocyclic propane ring.

[0092] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, X is a bond or -CR 8aR 8b-, wherein R 8a and R 8b are independently H, hydroxyl, -OC 1-4 alkyl, C 1-4 alkyl, C 1-4 haloalkyl or halo, or wherein R 8a and R 8b together with the carbon atom to which they are attached form a 3- to 5-membered saturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O and S, wherein the spirocyclic ring is, as appropriate, substituted with one to four RA5s, wherein each RA5 is independently a halo, C 1-4 alkyl or C 1-4 haloalkyl.

[0093] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, X is a bond or -CR 8aR 8b-, wherein R 8a and R 8b are independently H, hydroxyl, -OC 1-4 alkyl, C 1-4 alkyl, C 1-4 haloalkyl or halo, or wherein R 8a and R 8b together with the carbon atom to which they are attached form a 3- to 5-membered saturated spirocyclic ring containing one or two heteroatoms selected from N, O and S, wherein the spirocyclic ring is, as appropriate, substituted with one to four RA5s, wherein each RA5 is independently a halo, C 1-4 alkyl or C 1-4 haloalkyl. In some embodiments, X is a bond or -CR 8aR 8b-, wherein R 8a and R 8b are independently H, hydroxyl, -OC 1-4 alkyl, C 1-4 alkyl, C 1-4 haloalkyl or halo, or wherein R 8a and R 8b together with the carbon atom to which they are attached form a 3- to 5-membered saturated spirocyclic ring containing one or two heteroatoms selected from N, O and S.

[0094] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, X is a bond or -CR 8aR 8b-, wherein R 8a and R 8b are independently H, hydroxyl, -OC 1-4 alkyl, C 1-4 alkyl, C 1-4 haloalkyl, or halo, or wherein R 8a and R 8b together with the carbon to which they are attached form a 3- to 5-membered saturated spirocyclic ring, wherein the 3- to 5-membered saturated spirocyclic ring is optionally substituted by one to four RA5s, wherein each RA5 is independently a halo, C 1-4 alkyl, or C 1-4 haloalkyl. In some embodiments, X is a bond or -CR 8aR 8b-, wherein R 8a and R 8b are independently H, hydroxyl, -OC 1-4 alkyl, C 1-4 alkyl, C 1-4 haloalkyl, or halo, or wherein R 8a and R 8b together with the carbon to which they are attached form a 3- to 5-membered saturated spirocyclic ring.

[0095] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, X is a bond or -CR 8aR 8b-, wherein R 8a and R 8b are independently H, hydroxyl, -OC 1-4 alkyl, C 1-4 alkyl, C 1-4 haloalkyl, or halo, or wherein R 8a and R 8b together with the carbon to which they are attached form a 3-membered saturated spirocyclic ring, wherein the 3-membered saturated spirocyclic ring is optionally substituted with one to four RA5s, wherein each RA5 is independently a halo, C 1-4 alkyl, or C 1-4 haloalkyl. In some embodiments, X is a bond or -CR 8aR 8b-, wherein R 8a and R 8b are independently H, hydroxyl, -OC 1-4 alkyl, C 1-4 alkyl, C 1-4 haloalkyl, or halo, or wherein R 8a and R 8b together with the carbon to which they are attached form a 3-membered saturated spirocyclic ring.

[0096] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] In some embodiments of the compound or its pharmaceutically acceptable salt, X is a bond, -CH 2-, -CF 2-, -CH(F)-, -CH(Cl)-, -CH(OH)-, -C(CH 2F)(OH)-, -C(CH 3)(OH)-, -CH(OCH 3)-, -C(CH 2CH 3)(OCH 3)-, -C(CH 2CH 3)(OH)-, -CH(CH 3)-, -CH(CH 2CH 3)-, -CF(CH 3)-, -CF(CH 2CH 3)- or -CR 8aR 8b-, wherein R 8a and R 8b together with the carbon to which they are attached form a 3-membered saturated spirocarbocyclic ring. In some embodiments, X is a bond, -CH 2-, -CF 2-, -CH(F)-, -CH(Cl)-, -CH(OH)-, -C(CH 2F)(OH)-, -C(CH 3)(OH)-, -CH(OCH 3)-, -C(CH 2CH 3)(OCH 3)-, -C(CH 2CH 3)(OH)-, -CH(CH 3)-, -CH(CH 2CH 3)-, -CF(CH 3)-, or -CF(CH 2CH 3)-.

[0097] In some embodiments, X is a bond, -CH 2-, -CF 2-, -CH(F)-, -CH(Cl)-, -CH(OH)-, -C(CH 2F)(OH)-, -C(CH 3)(OH)-, -CH(OCH 3)-, -C(CH 2CH 3)(OCH 3)-, -C(CH 2CH 3)(OH)-, -CH(CH 3)-, -CH(CH 2CH 3)-, -CF(CH 3)-, -CF(CH 2CH 3)-, -C(CH 2F)(H)-, or -CR 8aR 8b-, wherein R 8a and R 8b together with the carbon atoms they are attached to form a 3-membered saturated spirocarbocyclic ring. In some embodiments, X is a bond, -CH 2-, -CF 2-, -CH(F)-, -CH(Cl)-, -CH(OH)-, -C(CH 2F)(OH)-, -C(CH 3)(OH)-, -CH(OCH 3)-, -C(CH 2CH 3)(OCH 3)-, -C(CH 2CH 3)(OH)-, -CH(CH 3)-, -CH(CH 2CH 3)-, -CF(CH 3)-, -C(CH 2F)(H)-, or -CF(CH 2CH 3)-.

[0098] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, X is -CR 8aR 8b-, wherein R 8a and R 8b, together with the carbon atom to which they are attached, form a 3- to 5-membered saturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spirocyclic ring is optionally substituted with one to four RA5s, each RA5 being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group. In some embodiments, X is -CR 8aR 8b-, wherein R 8a and R 8b, together with the carbon atom to which they are attached, form a 3- to 5-membered saturated spirocyclic ring, wherein the 3- to 5-membered saturated spirocyclic ring is optionally substituted with one to four RA5s, each RA5 being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group. In some embodiments, X is -CR 8aR 8b-, wherein R 8a and R 8b, together with the carbon atoms to which they are attached, form a 3-membered spirocyclic ring. In some embodiments, X is -CR 8aR 8b-, wherein R 8a and R 8b, together with the carbon atoms to which they are attached, form a 3- to 5-membered saturated spirocyclic ring containing one or two heteroatoms selected from N, O, and S, wherein the 3- to 5-membered saturated spirocyclic ring is optionally substituted by one to four RA5 groups, wherein each RA5 group is independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group. In some embodiments, X is -CR 8aR 8b-, wherein R 8a and R 8b, together with the carbon atoms to which they are attached, form a 3- to 5-membered saturated spirocyclic ring containing one or two heteroatoms selected from N, O, and S.

[0099] In some embodiments, the formula [I] or [II] The compound is of formula ( [VIII]) Compound: [] Or a medically acceptable salt thereof, wherein R1, L, W1, W2 and Z are as follows: Defined in [I].

[0100] In formula [I], [II], [IIIa], [IIIb], [IV], [Va], [Vb], [VI], [VIIa], [VIIb], [VIII], [X], [Xa], [Xb], [XI], [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, Z is -CR 9aR 9b-. In some embodiments, Z is -CR 9aR 9b-, wherein R 9a and R 9b are independently H, C1-4 alkyl, C1-4 haloalkyl, or halogroup. In some embodiments, Z is -CR 9aR 9b-, wherein R 9a and R 9b are independently H or C1-4 alkyl. In some embodiments, Z is -CH 2-. In some embodiments, Z is -CH(CH 3)-. In some embodiments, Z is -CR 9aR 9b-CR 9cR 9d-. In some embodiments, Z is -CR 9aR 9b-CR 9cR 9d-, wherein R 9a, R 9b, R 9c, and R 9d are independently H, C1-4 alkyl, C1-4 haloalkyl, or halogroup. In some embodiments, Z is -CH 2-CH 2-. In some embodiments, Z is -CR 10a=CR 10b-. In some embodiments, Z is -CR 10a=CR 10b-, wherein R 10a and R 10b together with their respective attached carbon atoms form a 5- to 10-membered partially unsaturated fused ring, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing 0 heteroatoms selected from N, O, and S or 1 heteroatomium selected from N, O, and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is, as appropriate, substituted by one to four RA7 groups, wherein each RA7 group is independently a halogroup or a C1-4 alkyl group. In some embodiments, Z is -CR 10a=CR 10b-, wherein R 10a and R 10b, together with their respective attached carbon atoms, form a 5- to 10-membered partially unsaturated fused ring containing 0 heteroatoms selected from N, O, and S or 1 heteroatomum selected from N, O, and S, substituted with one to four RA7 atoms, wherein each RA7 is independently a halogroup or a C1-4 alkyl group. In some embodiments, Z is -CR 10a=CR 10b-, wherein R 10a and R 10b, together with their respective attached carbon atoms, form a 5- to 10-membered fused aromatic ring, substituted with one to four RA7 atoms, wherein each RA7 is independently a halogroup or a C1-4 alkyl group. In some embodiments, Z is -CR 10a=CR 10b-, wherein R 10a and R 10b together with their respective attached carbon atoms form, as appropriate, a 5- to 10-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O and S, substituted with one to four RA7s, wherein each RA7 is independently a halogroup or a C1-4 alkyl group.In some embodiments, Z is -CR 10a=CR 10b-, wherein R 10a and R 10b, together with their respective attached atoms, form a fused 1,2-benzene ring, which may be substituted with one to four RA7 groups, wherein each RA7 group is independently a halogroup or a C1-4 alkyl group. In some embodiments, Z is... Where q is 0, 1, 2, 3, or 4. In some embodiments, Z is... Each RA4 group is independently a halogen group. In some embodiments, Z is... Each RA4 group is independently a halogenated group and q is 0, 1, 2, or 3. In some embodiments, Z is... Each RA4 group is independently a halogenated group and q is 0, 1, or 2. In some embodiments, Z is... In some embodiments, Z is In some embodiments, Z is In some embodiments, Z is -CH2-, -CH(CH3)-, -CH2-CH2-, .

[0101] In the formula [I]、 [II] [IIIa]、 [IIIb] or In some embodiments of the [VIII] compound or its pharmaceutically acceptable salt, L is -CR3aR3b- and R3a and R3b are independently H, C1-4 alkyl, C1-4 haloalkyl, or -OC1-4 alkyl. In some embodiments, R3a and R3b are independently H or C1-4 alkyl. In some embodiments, R3a and R3b are H. In some embodiments, R3a and R3b are C1-4 alkyl. In some embodiments, R3a is H and R3b is C1-4 alkyl. In some embodiments, R3a is H and R3b is methyl. In some embodiments, R3a and R3b, together with the carbon atom to which they are attached, form a 3- to 7-membered saturated or partially unsaturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spirocyclic ring is optionally substituted with one to three RA2 groups, each RA2 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group. In some embodiments, R3a and R3b, together with the carbon atom to which they are attached, form a 3-, 4-, or 5-membered saturated or partially unsaturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spirocyclic ring is optionally substituted with one to three RA2 groups, each RA2 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group. In some embodiments, R3a and R3b, together with the carbon atom to which they are attached, form a 3- or 4-membered saturated spirocyclic ring containing 0 heteroatoms selected from N, O, and S or 1 heteroatomide selected from N, O, and S, wherein the spirocyclic ring is optionally substituted with one to three RA2 groups, each RA2 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group. In some embodiments, R3a and R3b, together with the carbon atom to which they are attached, form a 3-membered saturated spirocyclic ring containing 0 heteroatoms selected from N, O, and S or 1 heteroatomide selected from N, O, and S, wherein the spirocyclic ring is optionally substituted with one to three RA2 groups, each RA2 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group. In some embodiments, R3a and R3b, together with the carbon atom to which they are attached, form a spirocyclic propane ring.

[0102] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb] or [VIII] In some embodiments of the compound or its pharmaceutically acceptable salt, W1 is -CR4aR4b- and R4a and R4b are independently H, C1-4 alkyl, C1-4 haloalkyl, or halogroup. In some embodiments, R4a and R4b are independently H or halogroup. In some embodiments, R4a and R4b are H. In some embodiments, R4a and R4b are halogroups. In some embodiments, R4a and R4b are fluorine. In some embodiments, R4a is H and R4b is a halogroup. In some embodiments, R4a is H and R4b is fluorine.

[0103] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, W2 is -CR5aR5b- and R5a and R5b are independently H, C1-4 alkyl, C1-4 haloalkyl, halogen, hydroxyl, cyano, -OC1-4 alkyl, or C1-4 alkyl-OC1-4 alkyl. In some embodiments, R5a and R5b are independently H, C1-4 alkyl, C1-4 haloalkyl, halogen, or hydroxyl. In some embodiments, R5a and R5b are independently H or halogen. In some embodiments, R5a and R5b are H. In some embodiments, R5a and R5b are halogen. In some embodiments, R5a and R5b are fluorine. In some embodiments, R5a is H and R5b is halogen. In some embodiments, R5a is H and R5b is fluorine. In some embodiments, R5a and R5b, together with the carbon atom to which they are attached, form a 3- to 7-membered saturated or partially unsaturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spirocyclic ring is optionally substituted with one to three RA3 groups, each RA3 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group. In some embodiments, R5a and R5b, together with the carbon atom to which they are attached, form a 3-, 4-, or 5-membered saturated or partially unsaturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spirocyclic ring is optionally substituted with one to three RA3 groups, each RA3 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group. In some embodiments, R5a and R5b, together with the carbon atom to which they are attached, form a 3- or 4-membered saturated spirocyclic ring containing 0 heteroatoms selected from N, O, and S or 1 heteroatomide selected from N, O, and S, wherein the spirocyclic ring is optionally substituted with one to three RA3 groups, each RA3 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group. In some embodiments, R5a and R5b, together with the carbon atom to which they are attached, form a 3-membered saturated spirocyclic ring containing 0 heteroatoms selected from N, O, and S or 1 heteroatomide selected from N, O, and S, wherein the spirocyclic ring is optionally substituted with one to three RA3 groups, each RA3 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group. In some embodiments, R5a and R5b, together with the carbon atom to which they are attached, form a spirocyclic propane ring.

[0104] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, W2 is -CR5aR5bCR5cR5d- and R5a, R5b, R5c, and R5d are independently H, C1-4 alkyl, C1-4 haloalkyl, halogen, hydroxyl, cyano, -OC1-4 alkyl, or C1-4 alkyl-OC1-4 alkyl. In some embodiments, R5a, R5b, R5c, and R5d are independently H, C1-4 alkyl, C1-4 haloalkyl, halogen, or hydroxyl. In some embodiments, R5a, R5b, R5c, and R5d are independently H or halogen. In some embodiments, R5a, R5b, R5c, and R5d are H. In some embodiments, R5a and R5c are independently H or halogroups, and R5b and R5d, together with their respective attached carbon atoms, form 3- to 7-membered saturated or partially unsaturated fused carbocyclic rings, which may be substituted with one to three RA3 groups, wherein each RA3 group is independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group. In some embodiments, R5a and R5c are independently H or halogroups, and R5b and R5d, together with their respective attached carbon atoms, form 3-, 4-, or 5-membered saturated fused carbocyclic rings. In some embodiments, R5a and R5c are H, and R5b and R5d, together with their respective attached carbon atoms, form 3-, 4-, or 5-membered saturated fused carbocyclic rings. In some embodiments, R5a and R5c are H, and R5b and R5d, together with their respective attached carbon atoms, form fused cyclopropane rings.

[0105] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, W2 is -CR 6a=CR 6b- and R 6a and R 6b are independently H, a halogroup, a C1-4 haloalkyl, or a C1-4 alkyl. In some embodiments, R 6a and R 6b are independently H or a halogroup. In some embodiments, R 6a and R 6b are H. In some embodiments, R 6a and R 6b together with their respective attached atoms form, as appropriate, a 5- to 10-membered fused aromatic ring substituted with one to four RA4s, wherein each RA4 is independently a halogroup or a C1-4 alkyl. In some embodiments, R 6a and R 6b together with their respective attached atoms form, as appropriate, a fused 1,2-benzene ring substituted with one to four RA4s, wherein each RA4 is independently a halogroup or a C1-4 alkyl. In some embodiments, R 6a and R 6b together with their respective attached atoms form Where p is 0, 1, 2, 3, or 4. In some embodiments, R 6a and R 6b, together with the atoms they are attached to, form Each RA4 group is independently a halogroup. In some embodiments, R6a and R6b, together with the atoms they are attached to, form Each RA4 group is independently a halogroup with p being 0, 1, 2, or 3. In some embodiments, R6a and R6b, together with the atoms they are attached to, form Each RA4 group is independently a halogroup with p = 0, 1, or 2. In some embodiments, R6a and R6b, together with the atoms to which they are attached, form In some embodiments, R6a and R6b, together with the atoms to which they are attached, form .

[0106] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, W2 is -N(R7)- and R7 is H, C1-4 alkyl, C1-4 haloalkyl, C(O)Rc, or SO2Rc. In some embodiments, R7 is H, C1-4 alkyl, C(O)Rc, or SO2Rc. In some embodiments, R7 is H. In some embodiments, R7 is C1-4 alkyl. In some embodiments, R7 is methyl or 1-methylethyl. In some embodiments, R7 is C(O)Rc. In some embodiments, R7 is -C(O)-C1-4 alkyl. In some embodiments, R7 is -C(O)CH3. In some embodiments, R7 is SO2Rc. In some embodiments, R7 is -SO2-C1-4 alkyl. In some embodiments, R7 is -SO2CH3.

[0107] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, W2 is selected from the group consisting of: -CR5aR5b-, -CR5aR5bCR5cR5d-, -CR6a=CR6b-, -N(R7)-, -O-, -S(O)n-, -C(O)-, -CR5aR5b-C(O)- and -CR5aR5b-O-; wherein each R5a, R5b, R5c and R5d is independently H, C1-4 alkyl, C1-4 haloalkyl, halogen, hydroxyl, cyano, -OC1-4 alkyl or C1-4 alkyl-OC1-4 alkyl; or R5a and R5b, R5c and R5d, R5a and R5c or R5b and R R6a and R6b together with their respective attached carbon atoms form, as appropriate, 3- to 7-membered saturated or partially unsaturated carbocyclic rings substituted with one to three RA3s, wherein each RA3 is independently a halogroup, C1-4 alkyl, or C1-4 haloalkyl; each R6a and R6b is independently H, a halogroup, C1-4 haloalkyl, or C1-4 alkyl; or R6a and R6b together with their respective attached atoms form (i) 5- to 10-membered fused aromatic rings or (ii) 5- to 10-membered fused heteroaromatic rings containing one to two heteroatoms selected from N, O, and S, wherein the 5- to 10-membered fused aromatic ring or the 5- to 10-membered fused heteroaromatic ring is, as appropriate, substituted with one to four RA4s, wherein each RA4 is independently a halogroup or C1-4 alkyl; R7 is H, C1-4 alkyl, C1- 4-Hydroalkyl, C(O)Rc or SO2Rc; Rc is C1-4 alkyl; and n is 0, 1 or 2.

[0108] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, W2 is selected from the group consisting of: -CR5aR5b-, -CR5aR5bCR5cR5d-, -CR6a=CR6b-, -N(R7)-, -O-, -S(O)n-, -C(O)-, -CR5aR5b-C(O)- and -CR5aR5b-O-; wherein each R5a, R5b, R5c and R5d is independently H, C1-4 alkyl, C1-4 haloalkyl, halogen, hydroxyl, cyano, -OC1-4 alkyl or C1-4 alkyl-OC1-4 alkyl; or R5a and R5b, R5c and R5d, R5a and R5c or R5b and R 5d, together with the carbon atoms to which they are attached, forms a 3-membered carbon ring, which may be substituted with one to three RA3s, wherein each RA3 is independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group; each R6a and R6b is independently H, a halogroup, a C1-4 haloalkyl group, or a C1-4 alkyl group; or R6a and R6b, together with the atoms to which they are attached, form (i) a fused benzene ring or (ii) a 5- to 6-membered fused heteroaromatic ring containing one to two heteroatoms selected from N, O, and S, wherein the fused benzene ring or the 5- to 6-membered fused heteroaromatic ring is substituted with one to four RA4s, wherein each RA4 is independently a halogroup or a C1-4 alkyl group; R7 is H, a C1-4 alkyl group, a C1-4 haloalkyl group, C(O)Rc, or SO2Rc; Rc is C1- 4 alkyl groups; and n is 0, 1 or 2.

[0109] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, W2 is selected from the group consisting of: -CR5aR5b-, -CR5aR5bCR5cR5d-, -CR6a=CR6b-, -N(R7)-, -O-, -S(O)n-, -C(O)-, -CR5aR5b-C(O)- and -CR5aR5b-O-; wherein each R5a, R5b, R5c and R5d is independently H, C1-4 alkyl, halogen, hydroxyl or -OC1-4 alkyl; or R5a and R5b, R5c and R5d, R5a and R5c or R5b and R5d together with the carbon atom to which they are attached form a 3-membered carbon ring; each R6a and R R6b is independently H, a halogroup, or a C1-4 alkyl group; or R6a and R6b together with the atoms to which they are attached form (i) a fused benzene ring or (ii) a 5- or 6-membered fused heteroaromatic ring containing one or two heteroatoms selected from N and O, wherein the fused benzene ring or the 5- or 6-membered fused heteroaromatic ring is, as appropriate, substituted by one or two RA4 groups, wherein each RA4 group is independently a halogroup or a C1-4 alkyl group; R7 is H, a C1-4 alkyl group, a C1-4 haloalkyl group, C(O)Rc, or SO2Rc; Rc is a C1-4 alkyl group; and n is 0 or 1.

[0110] In some embodiments, W2 is selected from the group consisting of: -CR5aR5b-, -CR5aR5bCR5cR5d-, -CR6a=CR6b-, -N(R7)-, -O-, -S(O)n-, -C(O)-, -CR5aR5b-C(O)-, and -CR5aR5b-O-; wherein each R5a, R5b, R5c, and R5d is independently H, -CH3, a halogen, a hydroxyl group, or -OCH3; or R5a and R5b, R5c and R5d, R5a and R5c, or R5b and R5d together with the carbon atoms to which they are attached form a 3-membered carbon ring; each R6a and R6b is independently H, a halogen, or CH3; or R6a and R6b are independently H, a halogen, or CH3; 6b, together with the atoms to which they are attached, forms (i) a fused benzene ring or (ii) a 5-membered fused heteroaromatic ring containing one or two heteroatoms selected from N and O, wherein the fused benzene ring or the 5-membered fused heteroaromatic ring is, as appropriate, substituted by one or two RA4 groups, wherein each RA4 group is independently a halogen or CH3; R7 is H, -CH3, -CH(CH3)2, -CF3, -C(O)Rc or -SO2Rc; Rc is -CH3; and n is 0 or 1.

[0111] In some embodiments, W2 is selected from the group consisting of: -CR5aR5b-, -CR5aR5bCR5cR5d-, -CR6a=CR6b-, -N(R7)-, -O-, -S(O)n-, -C(O)-, -CR5aR5b-C(O)- and -CR5aR5b-O-; wherein each R5a, R5b, R5c and R5d is independently H, -CH3, a halogen, a hydroxyl group or -OCH3; each R6a and R6b is independently H, a halogen or -CH3; R7 is H, -CH3, -CH(CH3)2, -CF3, -C(O)Rc or -SO2Rc; Rc is -CH3; and n is 0 or 1.

[0112] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, X is -CR8aR8b- and R8a and R8b are independently H, hydroxyl, -OC1-4 alkyl, C1-4 alkyl-OC1-4 alkyl, C1-4 alkyl, C1-4 haloalkyl, cyano, or halo. In some embodiments, R8a and R8b are independently H, hydroxyl, C1-4 alkyl, or halo. In some embodiments, R8a is H, fluorine, or hydroxyl and R8b is H or fluorine. In some embodiments, R8a and R8b are H. In some embodiments, R8a and R8b are fluorine. In some embodiments, R8a is H and R8b is halo. In some embodiments, R8a is H and R8b is fluorine. In some embodiments, R8a is H and R8b is hydroxyl. In some embodiments, R8a is H and R8b is C1-4 alkyl. In some embodiments, R8a is H and R8b is methyl. In some embodiments, R8a is a halogroup and R8b is a C1-4 alkyl group. In some embodiments, R8a is fluorine and R8b is methyl. In some embodiments, R8a and R8b, together with the carbon atom to which they are attached, form a 3-, 4-, or 5-membered saturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spirocyclic ring is substituted by one to four RA5 groups, each RA5 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group. In some embodiments, R8a and R8b, together with the carbon atom to which they are attached, form a 3-, 4-, or 5-membered saturated spirocyclic ring containing 0 heteroatoms, wherein the spirocyclic ring is substituted by one to four RA5 groups, each RA5 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group. In some embodiments, R8a and R8b, together with the carbon atom to which they are attached, form a spirocyclic propane ring.

[0113] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, Z is -CR 9aR 9b- and R 9a and R 9b are independently H, C1-4 alkyl, C1-4 haloalkyl, or halogroup. In some embodiments, R 9a and R 9b are independently H or C1-4 alkyl. In some embodiments, R 9a and R 9b are H. In some embodiments, R 9a and R 9b are C1-4 alkyl. In some embodiments, R 9a is H and R 9b is C1-4 alkyl. In some embodiments, R 9a is H and R 9b is methyl.

[0114] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, Z is -CR 9aR 9b-CR 9cR 9d- and R 9a, R 9b, R 9c, and R 9d are independently H, C1-4 alkyl, C1-4 haloalkyl, or halogroup. In some embodiments, R 9a, R 9b, R 9c, and R 9d are independently H or C1-4 alkyl. In some embodiments, R 9a, R 9b, R 9c, and R 9d are H.

[0115] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, Z is -CR 10a=CR 10b- and R 10a and R 10b are independently H, a halogroup, a C1-4 haloalkyl, or a C1-4 alkyl. In some embodiments, R 10a and R 10b together with their respective attached atoms form a 5- to 10-membered fused aromatic ring or a heteroaromatic ring containing one to two heteroatoms selected from N, O, and S, wherein the aromatic ring or heteroaromatic ring is optionally substituted with one to four RA7s, wherein each RA7 is independently a halogroup or a C1-4 alkyl. In some embodiments, R 10a and R 10b together with their respective attached atoms form a 5- to 10-membered fused aromatic ring optionally substituted with one to four RA7s, wherein each RA7 is independently a halogroup or a C1-4 alkyl. In some embodiments, R10a and R10b, together with their respective attached atoms, form a fused 1,2-phenylene ring, optionally substituted with one to four RA7 groups, wherein each RA7 group is independently a halogroup or a C1-4 alkyl group. In some embodiments, R10a and R10b, together with their respective attached atoms, form Where q is 0, 1, 2, 3, or 4. In some embodiments, R 10a and R 10b, together with the atoms they are attached to, form Each RA4 group is independently a halogroup. In some embodiments, R10a and R10b, together with the atoms to which they are attached, form Each RA4 group is independently a halogroup and q is 0, 1, 2, or 3. In some embodiments, R10a and R10b, together with the atoms they are attached to, form Each RA4 group is independently a halogroup and q is 0, 1, or 2. In some embodiments, R10a and R10b, together with the atoms they are attached to, form In some embodiments, R10a and R10b, together with the atoms to which they are attached, form In some embodiments, R10a and R10b, together with the atoms to which they are attached, form .

[0116] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, Z is -CR 9aR 9b-, -CR 9aR 9bCR 9cR 9d-, or -CR 10a=CR 10b-; wherein R 9a, R 9b, R 9c, and R 9d are each independently H, C1-6 alkyl, C1-4 haloalkyl, or halo; or R 9a and R 9b or R 9c and R 9d together with the carbon atom to which they are attached form a 3- to 7-membered saturated or partially unsaturated ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spirocyclic ring is substituted by one to three RA6, wherein each RA6 is independently halo, C1-4 alkyl, or C1-4 haloalkyl; R 10a and R 10b are independently H, halo, C1-4 haloalkyl, or C1-6 alkyl; or R 10a and R 10b, together with the carbon atoms to which they are attached, form (i) a 5- to 10-member partially unsaturated fused ring containing 0 heteroatoms selected from N, O and S or 1 heteroatom selected from N, O and S, (ii) a 5- to 10-member fused aromatic ring or (iii) a 5- to 10-member fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O and S, wherein the 5- to 10-member partially unsaturated fused ring, 5- to 10-member fused aromatic ring or 5- to 10-member fused heteroaromatic ring is, as appropriate, substituted by one to four RA7s, wherein each RA7 is independently a halogroup or a C1-4 alkyl group.

[0117] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb] or [VIII] In some embodiments of the compound or its pharmaceutically acceptable salt, Z is -CR 9aR 9b-, -CR 9aR 9bCR 9cR 9d-, or -CR 10a=CR 10b-; wherein R 9a, R 9b, R 9c, and R 9d are each independently H, CH 3, CH 2CH 3, CHF 2, or a halogen; or R 9a and R 9b or R 9c and R 9d together with the carbon atom to which they are attached form a 3-membered carbon ring; R 10a and R 10b are independently H, a halogen, or CH 3; or R 10a and R 10b together with the carbon atom to which they are attached form (i) a fused benzene ring or (ii) a 5- to 6-membered fused heteroaromatic ring containing 1 to 2 heteroatoms selected from N, O, and S, wherein the fused benzene ring or the fused heteroaromatic ring is, as appropriate, via one or two R A7 substitution, wherein each RaA7 is independently a halogen or CH3.

[0118] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb] or In some examples of compound [VIII] or its pharmaceutically acceptable salt, wherein R1 is a phenyl group that is mono-, di-, tri-, or tetra-substituted with R1, wherein each R1 is independently a halogroup or a -OC1-4 alkyl group; X is a bond or CR 8aR 8b-, wherein R 8a and R 8b are independently H, hydroxyl, -OC 1-4 alkyl, C 1-4 alkyl, C 1-4 haloalkyl or halo, or R 8a and R 8b together with the carbon they are attached to form a 3-membered saturated spirocarbocyclic ring; W1 is a bond or -CR4aR4b-; wherein R4a and R4b are independently H, C1-6 alkyl or halogroup; W2 is selected from the group consisting of: -CR5aR5b-, -CR5aR5bCR5cR5d-, -CR6a=CR6b-, -N(R7)-, -O-, -S(O)n-, -C(O)-, -CR5aR5b-C(O)-, and -CR5aR5b-O-; wherein each R5a, R5b, R5c, and R5d is independently H, C1-4 alkyl, halogroup, hydroxyl group, or -OC1-4 alkyl; each R6a and R6b is independently H, halogroup, or C1-4 alkyl; R7 is H, C1-4 alkyl, C1-4 haloalkyl, C(O)Rc, or SO2Rc; Rc is C1-4 alkyl; and n is 0 or 1; and Z is -CR 9aR 9b-, -CR 9aR 9bCR 9cR 9d-, or -CR 10a=CR 10b-; wherein R 9a, R 9b, R 9c, and R 9d are each independently H, C1-6 alkyl, C1-4 haloalkyl, or halogroup; or R 9a and R 9b or R 9c and R 9d together with the carbon atom to which they are attached form a 3-membered carbon ring; and R 10a and R 10b are independently H, halogroup, C1-4 haloalkyl, or C1-6 alkyl.

[0119] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb] or In some examples of compound [VIII] or its pharmaceutically acceptable salt, R1 is a phenyl group that is mono-, di-, tri-, or tetra-substituted with R1, wherein each R1 is independently a halogroup or a -OC1-4 alkyl group; X is a bond or CR 8aR 8b-, wherein R 8a and R 8b are independently H, hydroxyl, -OC 1-4 alkyl, C 1-4 alkyl, C 1-4 haloalkyl, or halogroup; W1 is a bond or -CR4aR4b-; wherein R4a and R4b are independently H, C1-6 alkyl or halogroup; W2 is -CR5aR5b-; wherein each R5a and R5b is independently H, C1-4 alkyl, halogroup, hydroxyl group, or -OC1-4 alkyl; and Z is -CR 9aR 9b-; where R 9a and R 9b are each independently H, C 1-6 alkyl, C 1-4 haloalkyl or halogroup.

[0120] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some examples of the [XIb] compound or its pharmaceutically acceptable salt, Ra is independently H, C1-4 alkyl, C1-6 haloalkyl, C(O)Rc or SO2Rc.

[0121] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, Rb is H. In some embodiments, Rb is a C1-4 alkyl group. In some embodiments, Rb is a methyl group.

[0122] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or a pharmaceutically acceptable salt thereof, Rc is a C1-4 alkyl group. In some embodiments, Rc is a methyl group. In some embodiments, Rc is an -OC1-4 alkyl group.

[0123] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb] or [VIII]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or a pharmaceutically acceptable salt thereof, n is 0. In some embodiments, n is 1. In some embodiments, n is 2.

[0124] In some embodiments, the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb] or [VIII] Compounds are of formula ( [IX]) Compound: [] Or a pharmaceutically acceptable salt thereof, wherein R1 is H or C6-10 aryl, wherein the C6-10 aryl is substituted by one to four RA1s as appropriate, wherein each RA1 is independently a halogroup, C1-6 alkyl, C1-4 haloalkyl, cyano, -OC1-4 alkyl or C1-4 alkyl-OC1-4 alkyl.

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

[0126] In some embodiments, the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII] or [IX] The compound is of formula ( [IXb]) compound: [] Or a pharmaceutically acceptable salt thereof, wherein R1 is H or C6-10 aryl, wherein the C6-10 aryl is substituted by one to four RA1s as appropriate, wherein each RA1 is independently a halogroup, C1-6 alkyl, C1-4 haloalkyl, cyano, -OC1-4 alkyl or C1-4 alkyl-OC1-4 alkyl.

[0127] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa] or [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound or its pharmaceutically acceptable salt, R1 is H. In some embodiments, R1 is a C6-10 aryl group. In some embodiments, R1 is a phenyl group substituted with one to four R1s, wherein each R1 is independently a halogroup, C1-4 alkyl, C1-4 haloalkyl, cyano, -OC1-4 alkyl, or C1-4 alkyl-OC1-4 alkyl. In some embodiments, R1 is a phenyl group substituted with one, two, three, or four R1s. In some embodiments, R1 is a phenyl group substituted with one, two, three, or four R1s. In some embodiments, R1 is a phenyl group substituted with one, two, three, or four R1s, wherein each R1 is independently a halogroup, C1-4 alkyl, C1-4 haloalkyl, or -OC1-4 alkyl. In some embodiments, R1 is a phenyl group substituted with one, two, three, or four R1 groups, wherein each R1 group is independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group. In some embodiments, R1 is a phenyl group substituted with one, two, three, or four R1 groups, wherein each R1 group is independently a halogroup or a C1-4 alkyl group. In some embodiments, R1 is a phenyl group substituted with one, two, three, or more halogens. In some embodiments, R1 is a phenyl group substituted with two or three halogens selected from chlorine and fluorine. In some embodiments, R1 is... .

[0128] In the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or In some embodiments of the [XIb] compound, R1 is selected from the group consisting of: In the formula [I] or [II] In some embodiments of the compound, R1 is selected from the group consisting of: .

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

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

[0131] In some embodiments, the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [Xia] or [XIb] compounds are selected from the following groups: or a medically acceptable salt thereof.

[0132] In some embodiments, the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa] or [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [Xia] or [XIb] compounds are selected from the following groups: or a medically acceptable salt thereof.

[0133] Mode [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds can be described with reference to rings A, B, and C, as follows, referring to formulas... [I] describes: Wherein A indicates a bridged ring relative to ring B, B indicates a bridged ring relative to ring A and a fused ring relative to ring C, and C indicates a fused ring relative to ring B. As mentioned above, the compound may have one or more additional fused rings or spirocyclic rings.

[0134] When any variable is an asymmetric group, unless otherwise specified, it is intended to cover both orientations of the group. For example, when W2 is -CR5aR5b-N(R7)-, it includes both orientations of -CR5aR5b-N(R7)- (i.e., both ZW1-CR5aR5b-N(R7)-X and ZW1-N(R7)-CR5aR5b-X), and when Z is When, including The two orientations (i.e., including) Both).

[0135] It should be understood that, as explained above, the formula... [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or Any embodiment of the compound of any of [XIb] and the formula as described above [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] Any specific group or substituent described herein (e.g., R1, R2, L, W1, W2, X, Y, Z and their substituents) in the compound may independently interact with the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or Other embodiments and / or combinations of substituents of any of the compounds in [XIb] may be used to form embodiments not specifically described above. Furthermore, where a list of substituents is not provided for any specific R1, R2, L, W1, W2, X, Y, and Z groups in a particular embodiment and / or technical solution, it should be understood that each individual substituent may be removed from the particular embodiment and / or technical solution, and the remaining list of substituents is considered to be within the scope of the embodiments disclosed herein. Pharmaceutical Composition []

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

[0137] In some embodiments, the pharmaceutical composition further comprises one, two, three, or four additional therapeutic agents. In some embodiments, the additional therapeutic agent is an anti-HIV agent. In specific embodiments, the additional therapeutic agent is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitor, an HIV nucleoside or nucleotide reverse transcriptase inhibitor, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latency reversal agent, a capsid polymerization inhibitor, an HIV bNAb, a TLR7 agonist, a pharmacokinetic enhancer, other medicines for treating HIV, or combinations thereof. In one embodiment, the additional therapeutic agent is abacavir, tenofovir alafenamide, tenofovir disoproxil, N-((S)-l-(3-(4-chloro-3-(methanesulfonamide)-l-(2,2,2-trifluoroethyl)-lH-indazol-7-yl)-6-(3-methyl-3-(methanesulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-lH-cyclopropano[3,4]cyclopentano[l,2-c]pyrazol-l-yl)acetamide, or a pharmaceutically acceptable salt thereof. Sets and products []

[0138] In some embodiments, the present invention relates to inclusion. [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] A kit of compounds or their pharmaceutically acceptable salts. In one embodiment, the kit may contain one, two, three, or four additional therapeutic agents as described above. The kit may further contain, for example, instructions for use for inhibiting HIV integrase, such as for treating HIV infection or AIDS, or as a research tool. Instructions for use are generally written instructions, but electronic storage media containing instructions (e.g., magnetic disks or optical discs) are also acceptable.

[0139] In some embodiments, the present invention also relates to a pharmaceutical kit comprising one or more containers, the one or more containers being contained in a manner that allows for... [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] The compound or a pharmaceutically acceptable salt thereof. Associated with the container(s) may be a notification in the form prescribed by the government agency regulating the manufacture, use, or sale of the drug, reflecting the agency's approval for manufacture, use, or sale for human administration. Components (if more than one component is present) may be packaged in separate containers, or, where cross-reactivity and shelf life permit, some components may be combined in one container. Kits may be in unit dosage form, bulk packaging (e.g., multi-dose packaging), or subunit doses. Kits may also include multiple unit doses of the compound and instructions for use, packaged in an amount sufficient for storage and use by a pharmacy (e.g., hospital pharmacies and dispensing pharmacies).

[0140] In some embodiments, this document discloses a formula for a unit dose contained in an encapsulation applicable to the methods described herein. [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] Articles of compounds or their pharmaceutically acceptable salts. Suitable packaging is as known in this art and includes, for example, vials, containers, ampoules, bottles, cans, flexible packaging and similar packaging. Articles may be further sterilized and / or sealed. Treatment []

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

[0142] In some embodiments, these methods further comprise administering to a human one, two, three, or four additional therapeutic agents in a therapeutically effective amount. In some embodiments, the additional therapeutic agent is an anti-HIV agent. In specific embodiments, the additional therapeutic agent is an HIV protease inhibitor, an HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitor, an HIV nucleoside or nucleotide reverse transcriptase inhibitor, an HIV capsid inhibitor, a gp41 inhibitor, a CXCR4 inhibitor, a gp120 inhibitor, a CCR5 inhibitor, a latency reversal agent, a capsid polymerization inhibitor, an HIV bNAb (broadly neutralizing HIV antibody), a TLR7 agonist, a pharmacokinetic enhancer, other drugs for treating HIV, or combinations thereof. In one embodiment, the additional therapeutic agent is abacavir, tenofovir alafenamide, tenofovir disoproxil fumarate, N-((S)-l-(3-(4-chloro-3-(methanesulfonamide)-l-(2,2,2-trifluoroethyl)-lH-indazole-7-yl)-6-(3-methyl-3-(methanesulfonyl)but-l-yn-l-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)-2-((3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-lH-cyclopropano[3,4]cyclopentano[l,2-c]pyrazol-l-yl)acetamide or a pharmaceutically acceptable salt thereof.

[0143] In another embodiment, the provision is... [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their pharmaceutically acceptable salts or having the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or The use of a pharmaceutical composition of a [XIb] compound or a pharmaceutically acceptable salt thereof for the treatment of infection in humans who have or are at risk of having HIV (e.g., HIV-1 and / or HIV-2) infection.

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

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

[0146] In another embodiment, the provision is... [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their pharmaceutically acceptable salts or having the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] A pharmaceutical composition of a compound or a pharmaceutically acceptable salt thereof, used in a method of treating infection in humans who are infected with HIV or at risk of being infected with HIV.

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

[0148] In another embodiment, the provision is... [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their pharmaceutically acceptable salts or having the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or A pharmaceutical composition of a [XIb] compound or a pharmaceutically acceptable salt thereof, used for treating infection in humans who are infected with HIV or at risk of HIV infection, wherein the method further comprises administering to a human one, two, three, or four additional therapeutic agents selected from the group consisting of: HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV capsid inhibitors, gp41 inhibitors, CXCR4 inhibitors, gp120 inhibitors, CCR5 inhibitors, latency reversal agents, capsid polymerization inhibitors, HIV bNAb, 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 reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, latency reversal agents, HIV capsid inhibitors, HIV bNAb, TLR7 agonists, and combinations thereof.

[0149] In another embodiment, the provision is... [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their pharmaceutically acceptable salts or having the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or A pharmaceutical composition of a [XIb] compound or a pharmaceutically acceptable salt thereof, used for the treatment of infection in humans who are infected with HIV or at risk of being infected with HIV, wherein the method further comprises administering to a human a therapeutically effective amount of tenofovir disoproxil fumarate and emtricitabine.

[0150] In another embodiment, the provision is... [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their pharmaceutically acceptable salts or having the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or A pharmaceutical composition of a [XIb] compound or a pharmaceutically acceptable salt thereof, used for the treatment of infection in humans who are infected with HIV or at risk of being infected with HIV, wherein the method further comprises administering to a human a therapeutically effective amount of tenofovir alafenamide and dromizine.

[0151] In another embodiment, the provision is... [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their pharmaceutically acceptable salts or having the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or A pharmaceutical composition of a [XIb] compound or a pharmaceutically acceptable salt thereof, used for treating infection in humans who are infected with HIV or at risk of being infected with HIV, wherein the method further comprises administering to a human a therapeutically effective amount of tenofovir disoproxil fumarate.

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

[0153] In another embodiment, a formula for use in therapy is provided. [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or Methods for [XIb] compounds. Specifically, methods are provided for treating HIV viral replication, treating AIDS, or delaying the onset of AIDS or ARC symptoms in mammals (e.g., humans), comprising administering [XIb] compounds to mammals. [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their pharmaceutically acceptable salts and pharmaceutically acceptable excipients.

[0154] In another embodiment, a containing [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb]A combination of a compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient, used in a method of treating HIV viral replication, treating AIDS, or delaying the onset of AIDS or ARC symptoms in mammals (e.g., humans).

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

[0156] For example, in one embodiment, the provision is... [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their pharmaceutically acceptable salts or having the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or pharmaceutical compositions of pharmaceutically acceptable salts thereof, used in pre-exposure prophylaxis (PrEP), i.e., before an individual is exposed to HIV, to prevent the spread of HIV infection and / or to prevent the establishment of permanent infection and / or to prevent the onset of disease symptoms and / or to prevent the viral load in the blood from reaching a detectable level.

[0157] In another embodiment, the revealing [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] The use of a compound or a pharmaceutically acceptable salt thereof in the manufacture of a medicine for treating infection in humans who are infected with HIV or at risk of being infected with HIV.

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

[0159] In another embodiment, an article comprising: a composition effective in treating HIV infection; and an encapsulating substance comprising a label indicating the composition for treating HIV infection. Exemplary compositions include... [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their pharmaceutically acceptable salts.

[0160] In yet another embodiment, a method for inhibiting HIV replication is disclosed. This method involves exposing the virus to an effective amount under conditions where HIV replication is inhibited. [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their salts.

[0161] In another embodiment, the revealing [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds are used to inhibit HIV integrase activity.

[0162] In another embodiment, the revealing [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or The use of [XIb] compounds or their salts for inhibiting HIV replication. invest

[0163] In some embodiments, the compounds described herein are administered or formulated into pharmaceutical compositions for administration purposes. Pharmaceutical compositions falling within the scope of the embodiments disclosed herein include... [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] Compounds and pharmaceutically acceptable excipients. Formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds are present in the composition in an amount sufficient to effectively treat the specific disease or condition of interest. [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or The activity of [XIb] compounds can be determined as described in the examples below.

[0164] The administration of the compounds of the embodiments disclosed herein, either in pure form or in the form of a suitable pharmaceutical composition, or of a pharmaceutically acceptable salt thereof, may be carried out via any of the methods of administration of a receiving agent for serving a similar effect. The pharmaceutical compositions of the embodiments disclosed herein may be prepared by combining the compounds of the embodiments disclosed herein with a suitable pharmaceutically acceptable excipient, and may be formulated into formulations in solid, semi-solid, liquid, or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalers, gels, microspheres, and sprays. Typical routes of administration of these pharmaceutical compositions include, but are not limited to, oral, topical, transdermal, inhalation, non-enteric, injection, sublingual, buccal, rectal, vaginal, and intranasal administration. The pharmaceutical compositions of the embodiments disclosed herein are formulated to allow the active ingredient contained therein to be biologically usable after administration to a patient. Compositions administered to an individual or patient are in the form of one or more dose units, wherein, for example, a tablet may be a single dose unit, and a container for a compound having the embodiments disclosed herein, in the form of a spray, may contain a plurality of dose units. Practical methods for preparing such dosage forms are known or will be obvious to those skilled in the art; for example, see Remington: The Science and Practice of Pharmacy, 20th edition (Philadelphia College of Pharmacy and Science, 2000). According to the teachings of the invention, in any case, the composition to be administered should contain a therapeutically effective amount of the compound of the embodiments disclosed herein or a pharmaceutically acceptable salt thereof for the treatment of the disease or condition of interest.

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

[0166] In one embodiment, the pharmaceutical composition is a non-enteric dosing unit. In one embodiment, the pharmaceutical composition is a subcutaneous, intramuscular, intravenous, intradermal, intrathecal, or epidural dosing unit. In one embodiment, the pharmaceutical composition is a subcutaneous, intramuscular, or intravenous dosing unit. In one embodiment, the pharmaceutical composition is injectable.

[0167] The pharmaceutical compositions disclosed herein can be prepared using methods well-known in pharmaceutical technology. For example, a pharmaceutical composition intended for injection can be prepared by combining the compounds of the examples disclosed herein with sterile distilled water to form a solution. Surfactants may be added to promote the formation of a homogeneous solution or suspension. Surfactants are compounds that do not covalently interact with the compounds of the examples disclosed herein to promote the dissolution or homogeneous suspension of the compounds in an aqueous delivery system.

[0168] The compounds or their pharmaceutically acceptable salts disclosed in the embodiments herein are administered in a therapeutically effective amount, which shall vary depending on various factors including: the activity of the specific compound used; the metabolic stability and duration of action of the compound; the patient's age, weight, general health, sex, and diet; the administration method and time; the rate of excretion; the combination of drugs; the severity of the specific disease or condition; and the individual undergoing the therapy. Combination therapy

[0169] In some embodiments, a method is provided for treating HIV infection in humans who are infected with HIV or at risk of HIV infection, comprising administering to a human 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 in therapeutically effective amounts. In one embodiment, a method is provided for treating HIV infection in humans who are infected with HIV or at risk of HIV infection, comprising administering to a human 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 in therapeutically effective amounts.

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

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

[0172] 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 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 still other 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 of therapeutic agents, and / or may be selected from different classes of therapeutic agents. HIV combination therapy administration

[0173] In some embodiments, the compounds disclosed herein are administered co-administered with one, two, three, or four additional therapeutic agents. Co-administration of the compounds disclosed herein with one, two, three, or four additional therapeutic agents generally refers to the simultaneous or sequential administration of the compounds disclosed herein with one, two, three, or four additional therapeutic agents, such that a therapeutically effective amount of the compounds disclosed herein and one, two, three, or four additional therapeutic agents are present in the patient. When administered sequentially, the combination may be administered in two or more doses.

[0174] Co-administration includes administering a unit dose of the compound disclosed herein before or after administering one, two, three, or four additional therapeutic agents. For example, the compound disclosed herein may be administered within seconds, minutes, or hours after administering 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 after a period of several hours (e.g., 1-12 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 after a period of several hours (e.g., 1-12 hours).

[0175] In some embodiments, the compounds disclosed herein are combined with one, two, three, or four additional therapeutic agents in unit dosage forms, such as solid dosage forms for oral administration, to be simultaneously administered to the patient.

[0176] In some embodiments, a compound comprising the compounds disclosed herein (e.g., formula...) is provided. [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or A combination of [XIb] compounds or their pharmaceutically acceptable salts with one or more (e.g., one, two, three or four) additional therapeutic agents.

[0177] In some embodiments, formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds are formulated into tablets, which may, where appropriate, contain one or more other compounds suitable for treating HIV. In some embodiments, the tablets may contain another active ingredient for treating HIV, such as HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, pharmacokinetic enhancers, and combinations thereof.

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

[0179] In the above embodiments, the additional therapeutic agent may be an anti-HIV agent selected from the following: HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editing agents (such as CRISPR / Cas9, zinc finger nucleases, homing nucleases, synthetic nucleases, TALEN), cell therapies (such as chimeric antigen receptor T-cell therapy, CAR-T and engineered T-cell receptor therapy, TCR-T therapy, autologous T-cell therapy), latency reversal agents, compounds targeting the HIV capsid, capsid polymerization inhibitors, HIV bNAb, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, broadly neutralizing HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV viral infection 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, reverse cyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 capture non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase activation complex inhibitors, G6PD-oxidase inhibitors and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines and combinations thereof.

[0180] In some embodiments, the additional therapeutic agent is selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immunotherapy-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof. HIV combination therapy

[0181] Examples of combination therapies include ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and duracil); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and duracil); STRIBILD® (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and duracil); TRUVADA® (tenofovir disoproxil fumarate and duracil; TDF+FTC); DESCOVY® (tenofovir alafenamide and duracil); ODEFSEY® (tenofovir alafenamide, duracil, and rilpivirine); GENVOYA® (tenofovir alafenamide, duracil, cobicistat, and elvitegravir); SYMTUZA® (darunavir, tenofovir alafenamide, and dromizine and cobicidazole); BIKTARVY® (bictegravir, tenofovir alafenamide and dromizine); bictegravir, tenofovir disoproxil fumarate and dromizine; bictegravir, tenofovir alafenamide and lamivudine; bictegravir, tenofovir disoproxil fumarate and lamivudine; bictegravir, abacavir and lamivudine; efavirenz, lamivudine and tenofovir fumarate. Tenofovir disoproxil fumarate; Lamivudine and Tenofovir disoproxil fumarate; Tenofovir and Lamivudine; Tenofovir alafenamide and Andrositidine; Tenofovir alafenamide and Andrositidine; Tenofovir alafenamide, Andrositidine and Rilpivirine; Tenofovir alafenamide, Andrositidine, Cobicistat and Eticagvir; COMBIVIR ® (zidovudine and lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; abacavir sulfate and lamivudine; ABC+3TC); KALETRA® (ALUVIA®; lopinavir and ritonavir); TRIUMEQ® (dolutegravir, abacavir, and lamivudine); JULUCA® (dolutegravir, rilpivirine); TRIZIVIR ® (Abacavir sulfate, Zidovudine, and Lamivudine; ABC+AZT+3TC); Dorugvir and Lamivudine; Dorugvir and Abacavir; Cabotegravir and Lamivudine; Cabotegravir and Abacavir; Cabotegravir and Rilpivirine; Atazanavir and Cobicistat; Atazanavir sulfate and Cobicistat; Atazanavir sulfate and Ritonavir;Darunavir and Cobicista; Dorugvir and Rilpivirine; Dorugvir and Rilpivirine Hydrochloride; Dorugvir, Abacavir Sulfate and Lamivudine; Lamivudine, Nevirapine and Zidovudine; Raltegravir and Lamivudine; Doravirine, Lamivudine and Tenofovir Dimethicone Fumarate; Doravirine, Lamivudine and Tenofovir Dimethicone Fumarate; Lugvir + Lamivudine; Lamivudine + Abacavir + Zidovudine; Lamivudine + Abacavir; Lamivudine + Tenofovir Disoproxil Fumarate; Lamivudine + Zidovudine + Nevirapine; Ropinavir + Ritonavir; Ropinavir + Ritonavir + Abacavir + Lamivudine; Ropinavir + Ritonavir + Zidovudine + Lamivudine; Tenofovir + Lamivudine; and Tenofovir Disoproxil Fumarate + Andrositidine + Rilpivirine Hydrochloride. Other HIV medications

[0182] Examples of other medications used to treat HIV include acemannan, alisporivir, BanLec, deferiprone, gamimune, metenkefalin, naltrexone, prolastin, and REP. 9. RPI-MN, VSSP, H1 virus, SB-728-T, 1,5-dicaffeoylquinic acid, rHIV7-shl-TAR-CCR5RZ, MazF gene therapy, BlockAide, ABX-464, AG-1105, APH-0812, BIT-225, CYT-107, HGTV-43, HPH-116, HS-10234, IMO-3100, IND-02, MK-1376, MK-2048, MK-4250, MK-8507, MK-8591, NOV-205, PA-1050040 (PA-040), PGN-007, SCY-635, SB-9200, SCB-719, TR-452, TEV-90110, TEV-90112, TEV-90111, TEV-90113, RN-18, Immuglo and VIR-576. HIV protease inhibitors

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

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

[0185] Examples of HIV nucleoside or nucleotide reverse transcriptase inhibitors include adefovir, adefovir dipivoxil, azvudine, andrositidine, tenofovir, tenofovir alafenamide, tenofovir alafenamide fumarate, tenofovir alafenamide hemistranylpyrate, tenofovir disoproxil fumarate, tenofovir alafenamide fumarate, tenofovir alafenamide hemistranylpyrate, VIDEX® and VIDEX EC® (didanosine, ddl), abacavir, abacavir sulfate, alovudine, apricitabine, censavudine, doxorubicin, elvucitabine, festinavir, and fosalvudine. tidoxil), CMX-157, dapoxil, doravirine, ectavirine, OCR-5753, tenofovir disoproxil flotinib, fozivudine tidoxil, lamivudine, phosphazid, stavudine, zalcitabine, zidovudine, rovafovir etalafenamide (GS-9131), GS-9148, MK-8504, MK-8591, MK-858, VM-2500 and KP-1461. HIV integrase inhibitors

[0186] Examples of HIV integrase inhibitors include erticagvir, curcumin, curcumin derivatives, chicoric acid, chicoric acid derivatives, 3,5-dicaffeoylquinic acid, 3,5-dicaffeoylquinic acid derivatives, aurantium tricarboxylic acid, aurantium tricarboxylic acid derivatives, caffeic acid phenylethyl ester, caffeic acid phenylethyl ester derivatives, tyrphostin, tyramine phosphorylation inhibitor derivatives, quercetin, quercetin derivatives, retigvir, dorugvir, JTK-351, and biticagvir. AVX-15567, diketoquinoline-4-1 derivatives, integrase-LEDGF inhibitors, ledgin, M-522, M-532, NSC-310217, NSC-371056, NSC-48240, NSC-642710, NSC-699171, NSC-699172, NSC-699173, NSC-699174, stilbene disulfonic acid, T-169, VM-3500, and cabergovir.

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

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

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

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

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

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

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

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

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

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

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

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

[0199] Examples of immunotherapy include TLR1 receptor modulators, such as TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13; planned cell death protein 1 (Pd-1) modulators; planned death-ligand 1 (PDL-1) modulators; IL-15 modulators; DermaVir; interleukin-7; plaquenil (hydroxychloroquine); and proleukin. (Adeleukin, IL-2); Interferon α; Interferon α-2b; Interferon α-n3; Pegylated Interferon α; Interferon γ; Hydroxyurea; Mycophenolic acid (MPA) and its ester derivative mycophenolic acid ester (MMF); Ribavirin; Polyethylene imine (PEI); Gepon; IL-12; WF-10; VGV-1; MOR-22; BMS-936559; CYT-107, Interleukin-15 / Fc fusion protein, AM-0015, ALT-803, NIZ-985, NKTR-255, Normferon, Pegylated Interferon α-2a, Pegylated Interferon α-2b, Recombinant Interleukin-15, RPI-MN, STING regulator, RIG-I regulator, NOD2 regulator, SB-9200 and IR-103.

[0200] Examples of TLR agonists include vesatolimod (GS-9620), lefitolimod, tilsotolimod, rintatolimod, DSP-0509, AL-034, G-100, cobitolimod, AST-008, motolimod, GSK-1795091, GSK-2245035, VTX-1463, GS-9688, LHC-165, BDB-001, RG-7854, and telratolimod. Phosphatidylinositol 3-kinase (PI3K) inhibitors

[0201] Examples of PI3K inhibitors include idelalisib, alpelisib, buparlisib, orotic acid (CAI), copanlisib, duvelisib, gedatolisib, neratinib, panulisib, perifosine, pictilisib, pilaralisib, and puquitinib mesylate. mesylate), rigosertib, rigosertib sodium, sonoxixib, taselisib, AMG-319, AZD-8186, BAY-1082439, CLR-1401, CLR-457, CUDC-907, DS-7423, EN-3342, GSK-2126458, GSK-22 69577, GSK-2636771, INCB-040093, LY-3023414, MLN-1117, PQR-309, RG-7666, RP-6530, RV- 1729, SAR-245409, SAR-260301, SF-1126, TGR-1202, UCB-5857, VS-5584, XL-765 and ZSTK-474. α-4 / β-7 antagonists

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

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

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

[0205] Examples of in vivo delivered bNAb include AAV8-VRC07; and the anti-HIV antibody VRC01 encoding mRNA. Pharmacokinetic enhancers

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

[0207] Examples of additional therapeutic agents include the compounds disclosed below: WO 2004 / 096286 (Gilead Sciences), WO 2006 / 015261 (Gilead Sciences), WO 2006 / 110157 (Gilead Sciences), WO 2012 / 003497 (Gilead Sciences), WO 2012 / 003498 (Gilead Sciences), WO 2012 / 145728 (Gilead Sciences), WO 2013 / 006738 (Gilead Sciences), WO 2013 / 159064 (Gilead Sciences), WO 2014 / 100323 (Gilead Sciences), US 2013 / 0165489 (University of Pennsylvania), US 2014 / 0221378 (Japan Tobacco), US 2014 / 0221380 (Japan The following references are incorporated herein by reference in their entirety: Tobacco, WO 2009 / 062285 (Boehringer Ingelheim), WO 2010 / 130034 (Boehringer Ingelheim), WO 2013 / 006792 (Pharma Resources), US 20140221356 (Gilead Sciences), US 20100143301 (Gilead Sciences), WO 2013 / 091096 (Boehringer Ingelheim), WO 2018 / 145021 (Gilead Sciences), and WO2017 / 106346 (Gilead Sciences). HIV vaccine

[0208] Examples of HIV vaccines include peptide vaccines, recombinant subunit protein vaccines, live vector vaccines, DNA vaccines, CD4-derived peptide vaccines, vaccine combinations, rgp120 (AIDSVAX), ALVAC HIV (vCP1521) / AIDSVAX B / E (gp120) (RV144), monomeric gp120 HIV subtype C vaccine, Remune, ITV-1, Contre Vir, Ad5-ENVA-48, DCVax-001 (CDX-2401), Vacc-4x, Vacc-C5, VAC-3S, multibranched DNA recombinant adenovirus-5 (rAd5), rAd5 gag-pol env A / B / C vaccine, Pennvax-G, Pennvax-G / MVA-CMDR, HIV-TriMix-mRNA vaccine, HIV-LAMP-vax, Ad35, Ad35-GRIN, and NAcGM3 / VSSP. ISA-51, Poly-ICLC Adjuvanted Vaccine, TatImmune, GTU-multiHIV (FIT-06), gp140[δ]V2.TV1+MF-59, rVSVIN HIV gag vaccine, SeV-Gag vaccine, AT-20, DNK-4, ad35-Grin / ENV, TBC-M4, HIVAX, HIVAX-2, NYVAC-HIV-PT1, NYVAC-HIV-PT4, DNA-HIV-PT123, rAAV1-PG9DP, GOVX-B11, GOVX-B21, TVI-HIV, Ad-4 (Ad4-env branch line C+Ad4-mGag), Paxvax, EN41-UGR7C, EN41-FPA2, PreVaxTat, AE-H, MYM-V101, CombiHIVvac, ADVAX, MYM-V201, MVA-CMDR, DNA-Ad5 gag / pol / nef / nev (HVTN505), MVATG-17401, ETV-01, CDX-1401, rcAD26.MOS1.HIV-Env, Ad26.Mod.HIV vaccine, Ad26.Mod.HIV + MVA mosaic vaccine + gp140, AGS-004, AVX-101, AVX-201, PEP-6409, SAV-001, ThV-01, TL-01, TUTI-16, VGX-3300, IHV-001 and virus-like particle vaccines (such as pseudovirus particle vaccines), CombiVICHvac, LFn-p24 B / C fusion vaccine, GTU-based DNA vaccine, HIV gag / pol / nef / env DNA vaccine, anti-TAT HIV vaccine, conjugate peptide vaccine, dendritic cell vaccine, gag-based DNA vaccine, GI-2010, gp41 HIV vaccine, HIV vaccine (PIKA adjuvant), I i-key / MHC Type II antigen determinant hybrid peptide vaccines, ITV-2, ITV-3, ITV-4, LIPO-5, multi-branched Env vaccine, MVA vaccine, Pennvax-GP, HCMV vector HIV gag vaccine lacking pp71, recombinant peptide vaccine (HIV infection), NCI, rgp160 HIV vaccine, RNActive HIV vaccine, SCB-703, Tat Oyi vaccine, TBC-M4, therapeutic HIV vaccine, UBI HIV gp120, Vacc-4x + romidepsin, variant gp120 peptide 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; based on eOD-GT8 60-mer vaccines, PD-201401, env (A, B, C, A / E) / gag (C) DNA vaccines, gp120 (A, B, C, A / E) protein vaccines, PDPHV-201401, Ad4-EnvCN54, EnvSeq-1 Envs HIV vaccines (containing GLA-SE adjuvant), HIV p24gag primary / boost (pri, me-boost) plasmid DNA vaccines, isanoid viral vector-based immunotherapy (Vaxwave, TheraT), MVA-BN HIV vaccine therapy, UBI HIV gp120, mRNA-based prophylactic vaccines, and TBL-1203HI. HIV combination therapy

[0209] In one particular embodiment, the compounds disclosed herein or their pharmaceutically acceptable salts are combined with one, two, three, four or more additional therapeutic agents selected from: ATRIPLA® (efavirenz, tenofovir disoproxil fumarate, and dromalacin); COMPLERA® (EVIPLERA®; rilpivirine, tenofovir disoproxil fumarate, and dromalacin); STRIBILD® (etigavir, cobicistat, tenofovir disoproxil fumarate, and dromalacin); TRUVADA® (tenofovir disoproxil fumarate and dromalacin; TDF + FTC); DESCOVY® (tenofovir alafenamide and dromalacin); ODEFSEY® (tenofovir alafenamide, dromalacin, and rilpivirine); GENVOYA® (Tenofovir Alamonamide, Andrositol, Cobicistat, and Eticagvir); Adefovir; Adefovir Dipipride; Cobicistat; Andrositol; Tenofovir; Tenofovir Dipipride; Tenofovir Dipipride Fumarate; Tenofovir Alamonamide; Tenofovir Hemibutenedioic Alamonamide; TRIUMEQ® (Dorugvir, Abacavir, and Lamivudine); Dorugvir, Abacavir Sulfate, and Lamivudine; Retegvir; Retegvir and Lamivudine; Malawiro; Enfuvirta; ALUVIA® (KALETRA®; Lopinavir and Ritonavir); COMBIVIR® (Zidovudine and Lamivudine; AZT+3TC); EPZICOM® (LIVEXA®; Abacavir Sulfate and Lamivudine; ABC+3TC); TRIZIVIR ® (Abacavir sulfate, Zidovudine, and Lamivudine; ABC+AZT+3TC); Rilpivirine; Rilpivirine hydrochloride; Atazanavir sulfate and Cobicistat; Atazanavir and Cobicistat; Darunavir and Cobicistat; Atazanavir; Atazanavir sulfate; Dorugvir; Eticagvir; Ritonavir; Atazanavir sulfate and Ritonavir; Darunavir; Lamivudine; Prastin; Fusana Viagra; fusanavir calcium, efavirenz; ectavirin; nelfinavir; nelfinavir mesylate; interferon; doxorinosine; stavudine; indinavir; indinavir sulfate; tenofovir and lamivudine; zidovudine; nevirapine; saquinavir; saquinavir mesylate; adeleukin; zalcitabine; telanavir; ampravir; deravirin; deravirin mesylate; Radha-108 (recipotropin); lamivudine and tenofovir disoproxil fumarate; efavirenz, lamivudine and tenofovir disoproxil fumarate; fosfilz; lamivudine, nevirapine and zidovudine; abacavir; and abacavir sulfate.

[0210] Those familiar with this technique should understand that the additional therapeutic agents listed above may be included in more than one of the categories listed above. Specific categories are not intended to limit the functionality of the compounds listed in those categories.

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

[0212] As disclosed in this article, compounds (e.g., any formula) [I] compound) can be combined with one, two, three or four additional therapeutic agents in formula [I] Any combination of doses of compounds (e.g., 1 mg to 500 mg of compounds).

[0213] In one embodiment, a kit is provided comprising the compounds disclosed herein or their medically acceptable salts, and one or more (e.g., one, two, three, one or two, or one to three) additional therapeutic agents.

[0214] In one embodiment, the additional therapeutic agent in the kit is an anti-HIV agent selected from: HIV protease inhibitors, HIV non-nucleoside or non-nucleotide reverse transcriptase inhibitors, HIV nucleoside or nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry inhibitors, HIV maturation inhibitors, immunomodulators, immunotherapeutic agents, antibody-drug conjugates, gene modifiers, gene editing agents (such as CRISPR / Cas9, zinc finger nucleases, guide nucleases, synthetic nucleases, TALEN), cell therapies (such as chimeric antigen receptor T cells, CAR-T and engineered T cell receptors, TCR-T, autologous T cell therapy), compounds targeting the HIV capsid, latency reversal agents, capsid polymerization inhibitors, HIV bNAb, immunotherapy, phosphatidylinositol 3-kinase (PI3K) inhibitors, HIV antibodies, broad-spectrum neutralizing HIV antibodies, bispecific antibodies and "antibody-like" therapeutic proteins, HIV p17 matrix protein inhibitors, IL-13 antagonists, peptidyl-prolyl cis-trans isomerase A modulators, protein disulfide isomerase inhibitors, complement C5a receptor antagonists, DNA methyltransferase inhibitors, HIV vif gene modulators, Vif dimerization antagonists, HIV viral infection 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, reverse cyclin modulators, CDK-9 inhibitors, dendritic ICAM-3 capture non-integrin 1 inhibitors, HIV GAG protein inhibitors, HIV POL protein inhibitors, complement factor H regulators, ubiquitin ligase inhibitors, deoxycytidine kinase inhibitors, cyclin-dependent kinase inhibitors, proprotein convertase PC9 stimulators, ATP-dependent RNA helicase DDX3X inhibitors, reverse transcriptase activation complex inhibitors, G6PD-oxidase inhibitors and NADH-oxidase inhibitors, pharmacokinetic enhancers, HIV gene therapy, HIV vaccines and combinations thereof.

[0215] In some embodiments, the additional therapeutic agents in the kit are selected from combination drugs for HIV, other drugs for treating HIV, HIV protease inhibitors, HIV reverse transcriptase inhibitors, HIV integrase inhibitors, HIV non-catalytic site (or ectopic) integrase inhibitors, HIV entry (fusion) inhibitors, HIV maturation inhibitors, latency reversal agents, capsid inhibitors, immunotherapy-based therapies, PI3K inhibitors, HIV antibodies and bispecific antibodies and "antibody-like" therapeutic proteins, and combinations thereof.

[0216] In one specific embodiment, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, and an HIV nucleoside or nucleotide reverse transcriptase inhibitor. In another specific embodiment, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, and an HIV nucleoside or nucleotide reverse transcriptase inhibitor and an HIV non-nucleoside reverse transcriptase inhibitor. In another specific embodiment, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide reverse transcriptase inhibitor, and an HIV protease inhibitor. In yet another embodiment, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, an HIV nucleoside or nucleotide reverse transcriptase inhibitor, an HIV non-nucleoside reverse transcriptase inhibitor, and a pharmacokinetic enhancer. In some embodiments, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, at least one HIV nucleoside reverse transcriptase inhibitor, an integrase inhibitor, and a pharmacokinetic enhancer. In yet another embodiment, the kit includes a compound disclosed herein or a pharmaceutically acceptable salt thereof, and two HIV nucleoside or nucleotide reverse transcriptase inhibitors. In one specific embodiment, the kit includes the compounds disclosed herein or their pharmaceutically acceptable salts, HIV nucleoside or nucleotide reverse transcriptase inhibitors, and HIV capsid inhibitors or HIV capsid polymerization inhibitors. In one specific embodiment, the kit includes the compounds disclosed herein or their pharmaceutically acceptable salts, and HIV capsid inhibitors or HIV capsid polymerization inhibitors. In one specific embodiment, the kit includes the compounds disclosed herein or their pharmaceutically acceptable salts, and one, two, three, or four HIV bNAbs. In one specific embodiment, the kit includes the compounds disclosed herein or their pharmaceutically acceptable salts, one, two, three, or four HIV bNAbs, and HIV capsid inhibitors or HIV capsid polymerization inhibitors. In one specific embodiment, the kit includes the compounds disclosed herein or their pharmaceutically acceptable salts, one, two, three, or four HIV bNAbs, HIV capsid inhibitors or HIV capsid polymerization inhibitors, and HIV nucleoside or nucleotide reverse transcriptase inhibitors. Fertility control (contraception) combination therapy

[0217] Therapeutic agents used for fertility control (contraception) include cyproterone acetate, desogestrel, dienogest, drospirenone, estradiol valerate, ethinylestradiol, norethindrone, etonogestrel, levomefolate, levonorgestrel, linegestrel, medroxyprogesterone acetate, estradiol methyl ether, mifepristone, misoprostol, noremeticone, norethindrone, isethindrone, norethindrone acetate, ormeloxifene, segestersone acetate, ulipristal acetate, and any combination thereof. Gene therapy and cell therapy

[0218] Gene therapy and cell therapy include gene modification for silencing genes; gene methods for directly killing infected cells; infusion of immune cells designed to replace most of a patient’s own immune system to enhance the immune response to infected cells, or to activate the patient’s own immune system to kill infected cells, or to find and kill infected cells; and gene methods for modifying cell activity to further alter the endogenous immune response to infection.

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

[0220] Examples of CCR5 gene-editing drugs include SB-728T.

[0221] Examples of CCR5 gene inhibitors include Cal-1.

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

[0223] Autologous T-cell therapy transduced with AGT-103.

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

[0225] Genome editing systems are selected from the following groups: CRISPR / Cas9 system, zinc finger nuclease system, TALEN system, guide endonuclease system, and macronuclease system.

[0226] Examples of CRISPR / Cas9 systems targeting HIV include EBT-101. CAR-T cell therapy

[0227] The immune effector cell population is engineered to represent a chimeric antigen receptor (CAR), wherein the CAR contains an HIV antigen-binding domain. The HIV antigen includes an HIV envelope protein or a portion thereof, gp120 or a portion thereof, a CD4 binding site on gp120, a CD4-induced binding site on gp120, an N-glycan on gp120, a V2 region of gp120, and a juxtamembranous 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 may be autologous or allogeneic.

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

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

[0230] Examples of drugs developed as long-acting therapies include cabozanthivir, rilpivirine, any integrase LA, VM-1500 LAI, malaviro (LAI), tenofovir implant, MK-8591 implant, doravirine, retegvir, and long-acting dorugvir.

[0231] In some embodiments, when the compounds disclosed herein are combined with one, two, three, or four additional therapeutic agents as described above, the components of the composition are administered as simultaneous or sequential therapy. When administered sequentially, the combination may be administered in two or more doses. Investment channels

[0232] Mode [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] The compound or a pharmaceutically acceptable salt thereof (also referred to herein as the active ingredient) may be administered by any route suitable for the condition to be treated. Suitable routes include oral, rectal, nasal, local (including buccal and sublingual), percutaneous, vaginal, and non-enteric routes (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal, and epidural) and similar routes. It should be understood that the suitable route may vary depending on, for example, the condition of the recipient. In some embodiments, the disclosed compound may be administered non-enterically. In some embodiments, the disclosed compound may be administered intravenously, subcutaneously, or intramuscularly. In some embodiments, the disclosed compound is orally bioavailable and may be administered orally.

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

[0234] In some embodiments, the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] The compound or its pharmaceutically acceptable salt is administered using an auto-injector comprising a syringe. In some embodiments, the syringe is disposable. In some embodiments, the syringe is reusable. In some embodiments, the syringe is pre-filled with a... [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their pharmaceutically acceptable salts. Dosing regimen

[0235] In some embodiments, such as the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] The compound or a pharmaceutically acceptable salt thereof is administered to an individual according to an effective dosing regimen for the desired time period or duration such as: at least once daily, at least once weekly, at least once monthly, at least once every two months, at least once every three months, at least once every four months, at least once every six months, or at least once every twelve months or longer. In some embodiments, the compound is administered on a daily or intermittent schedule. In some embodiments, the compound is administered on a weekly schedule. In some embodiments, the compound is administered on a monthly schedule. In some embodiments, the compound is administered every two months. In some embodiments, the compound is administered every three months. In some embodiments, the compound is administered every four months. In some embodiments, the compound is administered every five months. In some embodiments, the compound is administered every six months.

[0236] In some embodiments, such as the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] The compound or its pharmaceutically acceptable salts are administered subcutaneously or intramuscularly to the individual at least once a month. In some embodiments, the compound (e.g., formula...) [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] The compound or its pharmaceutically acceptable salt) is administered subcutaneously or intramuscularly to an individual at least once every two months, at least once every three months, at least once every four months, or at least once every six months. In some embodiments, the compound (e.g., formula...) [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] The compound or its pharmaceutically acceptable salt is administered subcutaneously to the individual at least once a month. In some embodiments, the compound (e.g., formula...) [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] The compound or its pharmaceutically acceptable salt is administered subcutaneously to the individual at least once every two months. In some embodiments, the compound (e.g., formula...) [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their pharmaceutically acceptable salts are administered subcutaneously to an individual at least once every 3 months.

[0237] In some embodiments, the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or The dosage or frequency of administration of [XIb] compounds or their pharmaceutically acceptable salts shall be adjusted during treatment based on the physician’s judgment.

[0238] In some embodiments, compounds such as those disclosed herein (e.g., formula...) [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds) or their pharmaceutically acceptable salts may be administered in effective doses. For example, doses may range from 1 mg to 1000 mg of the compound. []

[0239] In some embodiments, the methods disclosed herein include performing a process on individuals. [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] Event-driven administration of a compound or a pharmaceutically acceptable salt thereof.

[0240] As used herein, the terms “event-driven” and “event-driven investment” refer to (1) events prior to an individual’s exposure to HIV (or otherwise increasing the individual’s risk of contracting HIV) (e.g., 2 hours, 1 day, 2 days, 5 days, or 7 days or more prior to the event); and / or (2) events during which an individual is exposed to HIV (or otherwise increases the individual’s risk of contracting HIV) (or more than one cycle of events); and / or (3) events after which an individual is exposed to HIV (or otherwise increases the individual’s risk of contracting HIV) (or after the final event in a series of cycle of events). [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] Administered compound or a pharmaceutically acceptable salt thereof. In some embodiments, event-driven administration is performed before an individual is exposed to HIV. In some embodiments, event-driven administration is performed after an individual is exposed to HIV. In some embodiments, event-driven administration is performed both before and after an individual is exposed to HIV.

[0241] In some embodiments, the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their pharmaceutically acceptable salts are administered to an individual prior to exposure to HIV.

[0242] Examples of event-driven dosing regimens include administering an injection 24 to 2 hours prior to HIV exposure (e.g., first sexual activity with a known HIV-positive partner, including intercourse). [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compound or a pharmaceutically acceptable salt thereof, administered every 24 hours during the period of exposure (e.g., sexual activity with a known HIV-positive sexual partner). [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or medically acceptable salts, administered again after the last exposure (e.g., sexual activity with a known HIV-positive partner). [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compound or its pharmaceutically acceptable salt, and the last administration 24 hours later. [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their pharmaceutically acceptable salts.

[0243] Another example of an event-driven dosing regimen includes administering an injection within 24 hours prior to HIV exposure (e.g., sexual activity with a known HIV-positive partner). [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compound or a pharmaceutically acceptable salt thereof, subsequently administered daily during the exposure period (e.g., sexual activity with a known HIV-positive sexual partner, including the last sexual intercourse), followed by a final administration approximately 24 hours after the last exposure (the dose may be increased, such as by doubling the dose).

[0244] In some embodiments, such as when delivered in the form of PrEP, the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] The compound or its pharmaceutically acceptable salt is administered daily. In some embodiments, such as when administered in the form of an event-driven PrEP, the formula is... [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their pharmaceutically acceptable salts are administered 1 hour to 10 days, 1 hour to 7 days, 1 hour to 5 days, 1 hour to 72 hours, 1 hour to 48 hours, 1 hour to 24 hours, or 1 hour to 12 hours prior to events that increase an individual's risk of HIV infection (e.g., prior to sexual activity or other exposure to HIV). In some embodiments, the formula... [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their pharmaceutically acceptable salts are administered 10 days, 7 days, 5 days, 72 hours, 60 hours, 48 ​​hours, 24 hours, 12 hours, 9 hours, 6 hours, 4 hours, 3 hours, 2 hours, or 1 hour prior to an event that increases an individual's risk of HIV (e.g., prior to sexual activity or other exposure to HIV). In some embodiments, when the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their pharmaceutically acceptable salts are administered prior to an event, such as prior to an event that increases an individual's risk of contracting HIV, administered daily prior to the event (e.g., sexual activity). In some embodiments, when the formula... [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or When a [XIb] compound or a pharmaceutically acceptable salt thereof is administered before an event that increases an individual's risk of contracting HIV, it is administered one to three times before the event.

[0245] In some embodiments, such as when part of an event-driven PrEP scheme is deployed, the formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their pharmaceutically acceptable salts are administered during HIV exposure. In which the formula... [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] The compound is given to the individual prior to exposure in certain embodiments, as shown in the formula... [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their pharmaceutically acceptable salts are administered daily (e.g., in a single dose) during the period of HIV exposure (e.g., during periods of sexual activity with a known HIV-positive partner). In some embodiments, formula [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their pharmaceutically acceptable salts are administered daily (e.g., for 1 to 7 days) after final exposure to HIV (e.g., after a period of sexual activity with a known HIV-positive partner). In some embodiments, administration continues for 1 or 2 days after final exposure to HIV.

[0246] Additional examples of PrEP and / or PEP can be found, for example, in the following: a summary of a clinical trial entitled "On Demand Antiretroviral Pre-exposure Prophylaxis for HIV Infection in Men Who Have Sex With Men" (Clinical Trial No. NCT01473472); a summary of a clinical trial entitled "Prevention of HIV in Île-de-France" (Clinical Trial No. NCT03113123); and Molina et al. N. Engl. J. Med. 2015, 353:2237-2246, the contents of which are incorporated herein by reference in their entirety.

[0247] In some embodiments, methods for reducing the risk of contracting HIV (e.g., HIV-1 and / or HIV-2) include dosing [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds or their pharmaceutically acceptable salts and safety specifications. In some embodiments, methods for reducing the risk of HIV (e.g., HIV-1 and / or HIV-2) include administration to individuals at risk of contracting HIV. Examples of individuals at high risk of contracting HIV include, but are not limited to, individuals at risk of sexual transmission of HIV.

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

[0249] Suitable for non-enteral administration of formulations include aqueous and non-aqueous sterile injectable solutions containing antioxidants, buffers, antibacterial agents, and solutes that make the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions that may include suspending agents and thickeners. In some embodiments, the suspension is a microsuspension. In some embodiments, the suspension is a nanosuspension.

[0250] In some embodiments, formulations suitable for non-enteral administration (e.g., intramuscular (IM) and subcutaneous (SC) administration) include one or more excipients. The excipients should be compatible with the other components of the formulation and physiologically harmless to their receptors. Examples of suitable excipients are well known to those skilled in the art of non-enteral formulations and can be found, for example, in Handbook of Pharmaceutical Excipients (editors Rowe, Sheskey, and Quinn), 6th edition, 2009.

[0251] In some embodiments, the active ingredient (e.g., formula...) [I]、 [II] [IIIa]、 [IIIb] [IV] [Va]、 [Vb]、 [VI]、 [VIIa]、 [VIIb]、 [VIII]、 [IX]、 [IXa]、 [IXb]、 [X]、 [Xa]、 [Xb]、 [XI]、 [XIa] or [XIb] compounds exist as free acids. []

[0252] In some embodiments, the pharmaceutical compositions disclosed herein are non-enteric formulations. In some embodiments, the formulation is administered subcutaneously to the individual in need. In some embodiments, the formulation is administered intramuscularly to the individual in need. []

[0253] The amount of active ingredient that can be combined with an inactive ingredient to produce a dosage form may vary depending on the intended individual being treated and the specific administration method. For example, in some embodiments, a dosage form for oral administration to humans may contain about 1 mg to 1000 mg of active ingredient formulated with an appropriate and suitable amount of a carrier substance (e.g., an inactive ingredient or excipient substance). In some embodiments, the carrier substance varies from about 5% to about 95% (by weight) of the total composition.

[0254] It should be understood that, in addition to the ingredients specifically mentioned above, the compositions of these embodiments may also include other pharmaceutical agents known in the art for the type of composition discussed, such as flavoring agents suitable for oral administration. abbreviation []

[0255] The abbreviations used in this article have the following individual meanings: [] ACN Acetonitrile aq. Aqueous solution AXI isocratic anion exchange AZ-H Amylose (3-chloro-4-tolylcarbamate) AZT Azidovudine or zidovudine atm Atmospheric pressure Bn benzyl bNAbs Broad-spectrum neutralizing HIV antibodies Boc or BOC Tertiary butoxycarbonyl Boc 2O Dibutyl dicarbonate Cbz Benzoxycarbonyl CbzCl or Cbz-Cl benzyl chloroformate Cp Cyclopentadienyl CC 50 50% cytotoxic concentration CCM Cell culture medium Cp 2TiMe 2 Dimethyldicenetate or bis(cyclopentadienyl)dimethyltitanium or Petasis reagent DBU 1,8-Diazobicyclo[5.4.0]undec-7-ene DCE dichloroethane DCM dichloromethane dd Double peak ddd Double double peak dddd Double double peak ddq Double quadruple peak ddt Double double triple peak DIPEA N,N-Diisopropylethylamine DMF dimethylformamide DMP Dess Martin periodinane DMSO Dimethicone dpm Di-apartylmethyl or 2,2,6,6-tetramethyl-3,5-heptanedionyl dq Double Quadruple Peak dt Double Triple Peak dtd Double triplet peak EC 50 Half of the maximum effective concentration Et Ethyl Et 2O Diethyl ether Et 3N Triethylamine EtOAc Ethyl acetate EtOH ethanol FBS Fetal bovine serum (culture medium) Gen generation Grubbs Gen 1 Grubbs Catalyst™ Generation 1 h Hour HATU 2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethylhexafluorophosphate HPLC High-performance liquid chromatography HS Human serum Hz hertz IA Amylose (3,5-dimethylaminocarbamate) IB Cellulose ginseng (3,5-dimethylaminocarbamate) IPA Isopropanol LA Long-lasting LCMS or LC-MS Liquid chromatography-mass spectrometry m Multiplets M Mo Er Me methyl MeCN Acetonitrile MeI Iodomethane MeLi Methyllithium MeMgBr Methylmagnesium bromide MeOH methanol Me 2S Dimethyl sulfide Me 3SiCHN 2 (trimethylsilyl)diazomethane MHz megahertz min. minute mmol Momo μM Micromer μmol Micromer mL milliliters Mn(dpm) 3 San(diterpentylmethane)manganese MS Mass spectrometry MT-4 or MT4 Metallothionein 4 human T cell line m / z mass versus charge N Equivalent concentration NMR Nuclear magnetic resonance OAc Acetate OD-H Cellulose ginseng (3,5-dimethylaminocarbamate) p Five Peaks PA Protein-modified Ph Phenyl PhCHO benzaldehyde PhSiH 3 Phenylsilane ppm parts per million prep. Preparative q Four Peaks qd Four times double peak rac racemic rel Relative (stereochemistry or configuration) RLuc Renilla luciferase or Renilla-luciferin 2-monooxygenase RP Reverse phase RPMI Roswell Park Memorial Institute (culture medium) RT or RT room temperature s Single peak SFC Supercritical fluid chromatography SGC Solvated gas chromatography STAB Sodium triethoxyborohydride t Triple Peak td Triple double peak tdd Triple Double Peak TFA Trifluoroacetic acid THF Tetrahydrofuran Ti(OEt) 4 Titanium ethoxide (IV) TMS trimethylsilyl TLR Tridacoid receptors tt Triple peak UV Ultraviolet rays wt weight The following examples are provided for illustrative purposes and not for limitation. Example 1: Preparation of (S)- and (R)-N-(2,4-difluorobenzyl)-13-hydroxy-1,12-disideloxy-1,4,5,7,8,12-hexahydro-3H-2,8-methylbridged pyrido[1,2-d][1,4,7]oxazacyclodecavene-11-methamide (1-1, 1-2): [synthesis] [3-] [Methylene] [-1,5-] [Oxy-nitrogen heterocyclic octane] [-5-] [Tributyl formate] [(1a)] [:] []

[0256] When mineral oil containing 60% sodium hydride (~526 mg, 13.2 mmol) was added in batches, a solution of N-(3-hydroxypropyl)aminocarbamate tributyl ester (1005.4 mg, 5.74 mmol) in DMF (20 mL) was stirred in an ice-salt bath. After stirring in a cold bath for ~30 min, 3-chloro-2-(chloromethyl)prop-1-ene (0.61 mL, 5.80 mmol) was added over 15 min using a syringe driver. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched by slow addition of ice water and diluted with water (~100 mL), followed by extraction with ethyl acetate (2 × ~100 mL). After washing the organic extract with water (~100-150 mL × 1), the organic solvents were combined, dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel column chromatography by dissolving hexane containing 0–70% ethyl acetate to obtain the title compound. MS (m / z) 171.74 [M+HC 4H 8]+. [synthesis] [3-] [Side group] [-1,5-] [Oxy-nitrogen heterocyclic octane] [-5-] [Tributyl formate] [(1b)] [:] []

[0257] When ozone is bubbled through the mixture until a blue color appears, it contains tert-butyl 3-methylene-1,5-oxazine-octane-5-carboxylate ( [1a], 339 mg, 1.49 mmol) in methanol (10 mL) was stirred in a -78°C bath. When blue ozone appeared, dimethyl sulfide (5 mL) was added and the resulting solution was stirred at room temperature for 2 h. The solution was concentrated and the residue was purified by silica gel column chromatography by dissolution of hexane containing 0-100% ethyl acetate to obtain the title compound. MS (m / z) 251.96 [M+Na]+. [synthesis] [3-((] [Third-term butylsulfoxide] [)] [Amine] [)-1,5-] [Oxy-nitrogen heterocyclic octane] [-5-] [Tributyl formate] [(1c)] [:] []

[0258] Will [1b] A solution of racemic-2-methylpropane-2-sulfinamide (170.3 mg, 1.41 mmol) and titanium ethoxide (IV) (0.59 mL, 2.81 mmol) in THF (5.5 mL) was refluxed at 70 °C for 1 h. The reaction mixture was cooled to room temperature and further cooled to approximately -50 °C, and then THF (5.5 mL) containing 1 M tributylborohydride was added. After 30 min, the reaction mixture was slowly heated to room temperature over 2 h. The reaction mixture was cooled to 0 °C again and methanol was added until no gas was released. Brine was added to the solution under vigorous stirring, and the resulting mixture was filtered through Celite® and the solids were washed with ethyl acetate. After extracting the filtrate with ethyl acetate (× 3), the combined organic solvents were washed with brine (× 1), combined, dried over MgSO4, filtered, and concentrated. Hexane containing 50-100% ethyl acetate was dissolved by silicone column chromatography, followed by purification of the residue with ethyl acetate containing 0-20% methanol to obtain the title compound. MS (m / z) 334.94 [M+H]+. [synthesis] [13-] [Methoxy] [-1,12-] [Dilateral oxygen group] [-1,4,5,7,8,12-] [Hexahydrogen] [-3H-2,8-] [Methioninated pyridyl] [[1,2-d][1,4,7]] [Oxadiazine-decacyclic decpentene] [-11-] Methyl formate [(1d)] [:] []

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

[0260] The reaction mixture was cooled to room temperature, concentrated, and the residue was dissolved in an aqueous DMF solution. The solution was filtered and purified by precipitating a 10–60% acetonitrile (0.1% TFA) aqueous solution (0.1% TFA) by preparative HPLC (column, Gemini 10 μC18 110A, AXI / ; 250 × 21.2 mm) over 20 minutes. The combined elutions were lyophilized to obtain the title compound. MS (m / z) 323.16 [M+H]+. [synthesis] [N-(2,4-)] [Difluorobenzyl] [)-13-] [Methoxy] [-1,12-] [Dilateral oxygen group] [-1,4,5,7,8,12-] [Hexahydrogen] [-3H-2,8-] [Methioninated pyridyl] [[1,2-d][1,4,7]] [Oxadiazine-decacyclic decpentene] [-11-] [Methionine] [(1e)] [:] []

[0261] Methyl 13-methoxy-1,12-di-side-oxy-1,4,5,7,8,12-hexahydro-3H-2,8-methylbridged pyrido[1,2-d][1,4,7]oxadiazepine-decavene-11-carboxylate ( A solution of [1d] (30.8 mg, 95.6 μmol) in methanol (0.5 mL) was mixed with 1 N lithium hydroxide (0.2 mL) and stirred at room temperature for 1 h. After acidifying the reaction mixture with 1 N HCl (~0.2 mL), the resulting solution was concentrated to dryness and co-evaporated with toluene (× 3). To the previous residue, (2,4-difluorophenyl)methylamine (26.1 mg, 182 μmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 62.2 mg, 163.5 μmol) and DMF (1 mL) were added and stirred at room temperature to N,N-diisopropylethylamine (0.1 mL, 574.1 μmol). After 1 h, the reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution (× 2), saturated sodium bicarbonate solution (× 2), and brine (× 1). After extraction of the aqueous solution of the combined organic solvents with ethyl acetate (× 1), the two organic solvents were combined, dried over MgSO4, filtered, and concentrated. The residue was dissolved in DMF, filtered, and purified by precipitating a 10-60% acetonitrile (0.1% TFA) aqueous solution (0.1% TFA) by preparative HPLC (column, Gemini 10 μC18 110A, AXI / ; 250 × 21.2 mm) for 20 min. The combined solvents were lyophilized to obtain the title compound. MS (m / z) 434.22 [M+H]+. [synthesis] [(] [racemic] [)] [、] [( , S, )- ] [and] [( , R , )-N-(2,4- ] [Difluorobenzyl] [)-13-] [Hydroxy] [-1,12-] [Dilateral oxygen group] [-1,4,5,7,8,12-] [Hexahydrogen] [-3H-2,8-] [Methioninated pyridyl] [[1,2-d][1,4,7]] [Oxadiazine-decacyclic decpentene] [-11-] [Methionine] [(1)] [、] [1-1] [、] [1-2)] [:] []

[0262] At room temperature, N-(2,4-difluorobenzyl)-13-methoxy-1,12-disideloxy-1,4,5,7,8,12-hexahydro-3H-2,8-methylbridged pyrido[1,2-d][1,4,7]oxadiazepine-11-methamide ( [1e], 13.7 mg, 31.6 μmol) was added to a solution of magnesium bromide (16.2 mg, 88.5 μmol) in acetonitrile (1 mL), and the mixture was stirred in a 50 °C bath. After 1 h, the reaction mixture was concentrated and the residue was ground together with 2 N HCl (~0.5 mL) and water (~1.5 mL) at 0 °C. After sonication, the suspension was diluted with DMF (3 mL) to form a solution and then filtered. The filtered solution was purified by elution of a 10-60% acetonitrile (0.1% TFA) aqueous solution (0.1% TFA) by preparative HPLC (column, Gemini 10 μ C18 110A, AXI / ; 250 × 21.2 mm) for 20 min. The combined elution fractions were lyophilized to give the title compound. MS (m / z) 420.23 [M+H]+. 1H NMR (400 MHz, acetonitrile-d 3 ) δ 10.31 (s, 1H), 8.40 (s, 1H), 7.40 (td, J= 8.8, 6.4 Hz, 1H), 6.93 (ddq, J= 10.8, 5.8, 2.8 Hz, 2H), 4.57 (d, J= 5.2 Hz, 2H), 4.43 - 4.26 (m, 2H), 4.07 (d, J= 33.0 Hz, 4H), 3.95 (dd, J= 14.9, 1.7 Hz, 1H), 3.75 (s, 1H), 3.13 (ddd, J= 13.9, 7.5, 4.6 Hz, 1H), 2.06 - 1.96 (m, 1H), 1.86 (s, 1H). 19F NMR (376 MHz, acetonitrile-d3) δ -114.07 (p, J = 7.6 Hz), -116.55 (q, J = 8.7 Hz).

[0263] Preparative AZ-H column SFC chromatography was used with ethanol-TFA co-solvent to separate N-(2,4-difluorobenzyl)-13-hydroxy-1,12-disideloxy-1,4,5,7,8,12-hexahydro-3H-2,8-methylbridgedpyrido[1,2-d][1,4,7]oxadiazepine-11-methamide. [1], 15 mg) was isolated into its individual enantiomers, yielding [1-1] and [1-2]. Example 2: Preparation of 13-hydroxy-1,12-disideroxy-N-(2,4,6-trifluorobenzyl)-1,4,5,7,8,12-hexahydro-3H-2,8-methylbridgedpyrido[1,2-d][1,4,7]oxadiazepinene-11-methamide (2): [synthesis] [13-] [Methoxy] [-1,12-] [Dilateral oxygen group] [-N-(2,4,6-)] [Trifluorobenzyl] [)-1,4,5,7,8,12-] [Hexahydrogen] [-3H-2,8-] [Methioninated pyridyl] [[1,2-d][1,4,7]] [Oxadiazine-decacyclic decpentene] [-11-] [Methionine] [(2a)] [:] []

[0264] Methyl 13-methoxy-1,12-di-side-oxy-1,4,5,7,8,12-hexahydro-3H-2,8-methylbridged pyrido[1,2-d][1,4,7]oxadiazepine-decavene-11-carboxylate ( A solution of [1d] (32.7 mg, 101.5 μmol) in methanol (0.5 mL) was mixed with 1 N lithium hydroxide (0.2 mL) and stirred at room temperature for 1 h. After acidifying the reaction mixture with 1 N HCl (~0.2 mL), the resulting solution was concentrated to dryness and co-evaporated with toluene (× 3). To the previous residue, (2,4,6-trifluorophenyl)methylamine (30.8 mg, 191.15 μmol), 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 57.9 mg, 152.2 μmol) and DMF (1 mL) were added and stirred at room temperature to N,N-diisopropylethylamine (0.1 mL, 574.1 μmol). After 1 h, the reaction mixture was dissolved in ethyl acetate and washed with saturated ammonium chloride solution (× 2), saturated sodium bicarbonate solution (× 2), and brine (× 1). After extraction of the aqueous solution of the combined organic solvents with ethyl acetate (× 1), the two organic solvents were combined, dried over MgSO4, filtered, and concentrated. The residue was dissolved in DMF, filtered, and purified twice over 20 min by preparative HPLC (column, Gemini 10 μC18 110A, AXI / ; 250 × 21.2 mm) by dissolution in an aqueous solution of 10-60% acetonitrile (0.1% TFA) (0.1% TFA). The combined solvents were lyophilized to obtain the title compound. MS (m / z) 452.23 [M+H]+. [synthesis] [13-] [Hydroxy] [-1,12-] [Dilateral oxygen group] [-N-(2,4,6-)] [Trifluorobenzyl] [)-1,4,5,7,8,12-] [Hexahydrogen] [-3H-2,8-] [Methioninated pyridyl] [[1,2-d][1,4,7]] [Oxadiazine-decacyclic decpentene] [-11-] [Methionine] [(2)] [:] []

[0265] At room temperature, 13-methoxy-1,12-di-side-oxy-N-(2,4,6-trifluorobenzyl)-1,4,5,7,8,12-hexahydro-3H-2,8-methylbridged pyrido[1,2-d][1,4,7]oxadiazepine-decavene-11-methamide ( [2a] Magnesium bromide (16.2 mg, 88.0 μmol) was added to a solution of [2a] in acetonitrile (1 mL) and stirred in a 50 °C bath. After 30 min, the reaction mixture was cooled and concentrated, and the residue was dissolved in DMF (0.5 mL) and 2 N HCl (0.1 mL). After filtration, the filtrate was purified by precipitating a 10-60% acetonitrile (0.1% TFA) aqueous solution (0.1% TFA) by preparative HPLC (column, Gemini 10 μC18 110A, AXI / ; 250 × 21.2 mm) for 20 min. The combined elution fractions were lyophilized to obtain the title compound. MS (m / z) 420.23 [M+H]+. 1H NMR (400 MHz, acetonitrile-d 3 ) δ 10.31 (s, 1H), 8.40 (s, 1H), 7.40 (td, J= 8.8, 6.4 Hz, 1H), 6.93 (ddq, J= 10.8, 5.8, 2.8 Hz, 2H), 4.57 (d, J= 5.2 Hz, 2H), 4.43 - 4.26 (m, 2H), 4.07 (d, J= 33.0 Hz, 4H), 3.95 (dd, J= 14.9, 1.7 Hz, 1H), 3.75 (s, 1H), 3.13 (ddd, J= 13.9, 7.5, 4.6 Hz, 1H), 2.06 - 1.96 (m, 1H), 1.86 (s, 1H). 19F NMR (376 MHz, acetonitrile-d3) δ -114.07 (p, J = 7.6 Hz), -116.55 (q, J = 8.7 Hz). Example 3: Preparation of (R)- and (S)-(7R)-4,4-difluoro-12-hydroxy-1,11-di-side-oxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide (3-1, 3-2): [synthesis] [1-] [Benzyl] [-5,5-] [Difluoropiperidine] [-2-] [Formate esters] [(3b)] [:] []

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

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

[0268] A solution of methyl 5,5-difluoropiperidine-2-carboxylate (962 mg, 5.37 mmol) in DMF (15 mL) was added in portions at 0 °C with stirring. After 30 minutes at 0 °C, bromotoluene (0.96 mL, 8.1 mmol) was added. After stirring the reaction mixture at 0 °C for 1 h and then at room temperature for 1 h, additional mineral oil containing 60% sodium hydride (150 mg, 3.75 mmol) and bromotoluene (0.5 mL, 4.20 mmol) were added at room temperature and stirred for 2.5 h. The reaction mixture was quenched with 2 N HCl (~4 mL) at 0 °C and diluted with saturated sodium bicarbonate solution (~100 mL), followed by extraction with ethyl acetate (~100 mL × 2). The organic extract was washed with water (150 mL × 1), combined, dried over MgSO4, filtered, concentrated, and purified by silica gel column chromatography by dissolving hexane containing 0-100% ethyl acetate to obtain the title compound. MS (m / z) 270.10 [M+H]+. [synthesis] [6-] [Azide group] [-1-] [Benzyl] [-3,3-] [Difluorozaheptanane] [(3c)] [:] []

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

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

[0271] DMSO (4 mL) containing unpurified chloride and sodium azide (187 mg, 2.88 mmol) was stirred in a 90 °C bath for 4 h and then cooled to room temperature. The reaction mixture was diluted with water (~50 mL) and saturated sodium bicarbonate solution (~5 mL), and the product was extracted with ethyl acetate (~30 mL × 3). The extract was washed with water (~50 mL × 1), combined, dried (Na₂SO₄), and concentrated. The residue was purified by silica gel column chromatography by dissolution with hexane containing 0-10% ethyl acetate to obtain the title compound. MS (m / z) 267.06 [M+H]⁺. [synthesis] [12-(] [Benzyloxy] [)-4,4-] [Difluoride] [-1,11-] [Dilateral oxygen group] [-N-(2,4,6-)] [Trifluorobenzyl] [)-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(3d)] [:] []

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

[0273] Unpurified 6,6-difluoroazacycloheptane-3-amine dihydrochloride (119.9 mg, 0.54 mmol), methyl 3-(benzyloxy)-4-sideoxy-5-((2,4,6-trifluorobenzyl)aminomethyl)-4H-piperan-2-carboxylate (280.8 mg, 0.63 mmol), and sodium bicarbonate (238.7 mg, 2.84 mmol) were dissolved in methanol (5 mL) and water (1 mL), and the resulting solution was stirred at 55 °C for 20 h. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate and water. After separating the two solvent fractions, the aqueous solution of the solvent fractions was extracted with ethyl acetate (× 1), and the two organic solvent fractions were washed with water (× 1), combined, dried over MgSO4, filtered, and concentrated. The residue was purified by dissolving dichloromethane containing 0-5% methanol using silicone column chromatography to obtain a partially purified product.

[0274] The partially purified product was dissolved in DMF, filtered, and purified by precipitating a 30-90% acetonitrile (0.1% TFA) aqueous solution (0.1% TFA) with preparative HPLC (column, Gemini 10 μC18 110A, AXI / ; 250 × 21.2 mm) for 20 min. The collected solvent was freeze-dried to obtain the title compound. MS (m / z) 548.14 [M+H]+. [synthesis] [( , R , )- ] [and] [( , S , )-(7R)-4,4- ] [Difluoride] [-12-] [Hydroxy] [-1,11-] [Dilateral oxygen group] [-N-(2,4,6-)] [Trifluorobenzyl] [)-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(3-1. 3-2)]

[0275] Preparative IA column SFC chromatography was used with methanol as a co-solvent to separate 12-(benzyloxy)-4,4-difluoro-1,11-di-side-oxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4]diazanol-10-methamide. [3d], 140.7 mg) was isolated into enantiomers, yielding 47.4 mg. [3d-1] and 46.9 mg [3d-2]. The separated enantiomers were dissolved in toluene (0.5 mL) and trifluoroacetic acid (3 mL) and stirred at room temperature for 30 min. The individual reactants were concentrated and the residues were purified by silica gel column chromatography by dissolution with dichloromethane containing 0-14% methanol to give the individual title compounds. MS (m / z) 458.16 [M+H]+. 1H NMR (400 MHz, acetonitrile-d 3 ) δ 12.34 (s, 1H), 10.38 (s, 1H), 8.27 (s, 1H), 7.02 - 6.66 (m, 2H), 5.45 (s, 2H), 4.70 (ddt, J= 14.4, 11.6, 2.8 Hz, 1H), 4.59 (d, J= 5.8 Hz, 1H), 4.37 (dd, J= 13.5, 4.2 Hz, 1H), 4.04 (dd, J= 13.6, 8.2 Hz, 1H), 3.89 (ddt, J= 11.8, 7.8, 3.7 Hz, 1H), 3.19 (ddd, J= 31.8, 14.2, 1.9 Hz, 1H), 2.42 - 2.22 (m, 1H), 2.22 - 2.06 (m, 1H), 2.06 - 1.98 (m, 1H), 1.80 - 1.62 (m, 1H). Example 4: Preparation of (R)- and (S)-(7R)-N-(2,4-difluorobenzyl)-4,4-difluoro-12-hydroxy-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide (4-1, 4-2): [synthesis] [12-(] [Benzyloxy] [)-N-(2,4-] [Difluorobenzyl] [)-4,4-] [Difluoride] [-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(4a)] [:] []

[0276] Unpurified 6,6-difluoroazacycloheptane-3-amine dihydrochloride (116.7 mg, 0.52 mmol), methyl 3-(benzyloxy)-4-sideoxy-5-((2,4,6-trifluorobenzyl)aminomethyl)-4H-piperan-2-carboxylate (273.2 mg, 0.64 mmol), and sodium bicarbonate (225.7 mg, 2.69 mmol) were dissolved in methanol (5 mL) and water (1 mL), and the resulting solution was stirred in a 55°C bath for 20 h. The reaction mixture was concentrated, and the residue was dissolved in ethyl acetate and water. After separating the two solvent fractions, the aqueous solution of the solvent fractions was extracted with ethyl acetate (× 1), and the two organic solvent fractions were washed with water (× 1), combined, dried over MgSO4, filtered, and concentrated. The residue was purified by dissolving dichloromethane containing 0-5% methanol using silicone column chromatography to obtain a partially purified product.

[0277] The partially purified product was dissolved in DMF, filtered, and purified by precipitating a 30-90% acetonitrile (0.1% TFA) aqueous solution (0.1% TFA) with preparative HPLC (column, Gemini 10 μC18 110A, AXI / ; 250 × 21.2 mm) for 20 min. The collected solvent was freeze-dried to obtain the title compound. MS (m / z) 530.12 [M+H]+. [synthesis] [( , R , )- ] [and] [( , S , )-(7R)-N-(2,4- ] [Difluorobenzyl] [)-4,4-] [Difluoride] [-12-] [Hydroxy] [-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(4-1, 4-2)] [:] []

[0278] Preparative IA column SFC chromatography was used with methanol as a co-solvent to separate 12-(benzyloxy)-N-(2,4-difluorobenzyl)-4,4-difluoro-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide. [4a], 133 mg) was isolated into its individual enantiomers, yielding [4a-1] and [4a-2]. The separated enantiomers were dissolved in toluene (0.5 mL) and trifluoroacetic acid (3 mL) and stirred at room temperature for 30 min. The reactants were concentrated individually, and the residues were purified by silica gel column chromatography by dissolution with dichloromethane containing 0-14% methanol to give the title compound. MS (m / z) 440.19 [M+H]+. 1H NMR (400 MHz, acetonitrile-d 3 ) δ 12.36 (s, 1H), 10.40 (s, 1H), 8.28 (s, 1H), 7.47 - 7.31 (m, 1H), 6.94 (ddq, J= 11.0, 5.2, 2.8 Hz, 2H), 4.71 (tt, J= 11.7, 2.8 Hz, 1H), 4.57 (d, J= 6.0 Hz, 2H), 4.38 (dd, J= 13.5, 4.2 Hz, 1H), 4.06 (dd, J= 13.6, 8.1 Hz, 1H), 3.90 (td, J= 8.2, 4.2 Hz, 1H), 3.20 (ddd, J= 31.8, 14.2, 1.9 Hz, 1H), 2.38 - 2.22 (m, 1H), 2.19 - 2.08 (m, 1H), 2.07 - 1.98 (m, 1H), 1.80 - 1.63 (m, 1H). Example 5: Preparation of (R)- and (S)-N-(2,4-difluorobenzyl)-13-hydroxy-1,12-disideloxy-1,3,4,5,6,7,8,12-octahydro-2,8-methylbridged pyrido[1,2-a][1,4]diazacyclodecavene-11-methamide (5-1, 5-2): [synthesis] [13-] [Methoxy] [-1,12-] [Dilateral oxygen group] [-1,3,4,5,6,7,8,12-] [Octahydrogen] [-2,8-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazacyclodecavene] [-11-] Methyl formate [(5a)] [:] []

[0279] A vial was packed with azircyclooctane-3-amine (0.13 g, 1.0 mmol), sodium bicarbonate (66 mg, 0.79 mmol), methanol (3 mL), and water (0.3 mL). Dimethyl 3-methoxy-4-sideoxy-4H-piperan-2,5-dicarboxylate (100 mg, 0.41 mmol) was added, and the mixture was stirred at 30 °C. After 2 h, the mixture was concentrated to dryness and purified by rapid column chromatography (hexane / EtOAc / MeOH) to give the title compound. MS (m / z) 321.1 [M+H]+. 1H NMR (400 MHz, acetonitrile-d3) δ 8.07 (s, 1H), 4.43 (ddd, J = 13.6, 8.8, 4.4 Hz, 1H), 4.18 (ddt, J = 7.9, 5.3, 2.2 Hz, 1H), 4.05 (s, 3H), 3.94 (dd, J = 14.4, 2.7 Hz, 1H), 3.85 (s, 3H), 3.65 (dd, J = 14.5, 2.1 Hz, 1H), 2.86 (ddd, J = 14.0, 6.2, 4.2 Hz, 1H), 2.16 (ddd, J = 15.1, 8.7, 5.4 Hz, 1H), 2.00 - 1.56 (m, 6H), 1.57 - 1.45 (m, 1H). [synthesis] [N-(2,4-)] [Difluorobenzyl] [)-13-] [Methoxy] [-1,12-] [Dilateral oxygen group] [-1,3,4,5,6,7,8,12-] [Octahydrogen] [-2,8-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazacyclodecavene] [-11-] [Methionine] [(5b)] [:] []

[0280] 13-Methoxy-1,12-di-side-oxy-1,3,4,5,6,7,8,12-octahydro-2,8-methylbridged pyrido[1,2-a][1,4]diazacyclodecavene-11-carboxylate (80 mg, 0.25 mmol) was dissolved in methanol (3 mL), and 1M NaOH (0.75 mL, 0.75 mmol) was added. After 25 minutes, the reaction mixture was quenched by adding 2M HCl and concentrated to dryness. The residue was dissolved in DCM (2 mL) and (2,4-difluorophenyl)methylamine (54 mg, 0.37 mmol) and triethylamine (0.10 mL, 0.75 mmol). HATU (114 mg, 0.30 mmol) was added, and the mixture was stirred at room temperature. After 15 minutes, the reactants were concentrated to dryness, purified by preparative HPLC (MeCN / water with 0.1% TFA), and lyophilized to give the title compound. MS (m / z) 432.2 [M+H]+. [synthesis] [( , 8R , )- ] [and] [( , 8S , )-N-(2,4- ] [Difluorobenzyl] [)-13-] [Hydroxy] [-1,12-] [Dilateral oxygen group] [-1,3,4,5,6,7,8,12-] [Octahydrogen] [-2,8-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazacyclodecavene] [-11-] [Methionine] [(5-1)] [、] [5-2)] [:] []

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

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

[0283] (3R)-3-(dibenzylamino)azacycloheptan-2-one ( [7a] 637 mg, 2.07 mmol) was suspended in toluene (20 mL) and triethylamine (0.57 mL, 4.1 mmol). Toluene (3 mL) containing trimethylsilane (0.29 mL, 2.3 mmol) was added dropwise. After 5 minutes, the mixture was heated to 50 °C and stirred for 3 h. The slurry was cooled to 5 °C, and the precipitate was removed by filtration and the mixture was forward washed with a 1:1 hexane:ether solution. The supernatant was concentrated to dryness and placed under high vacuum overnight. The residue was dissolved in ether (30 mL), cooled to -78 °C, and 1.6 M MeLi (2.84 mL) was slowly added. The reaction mixture was heated to room temperature and an additional 1.6 M MeLi (1 mL) was added. After 3 h, the reaction mixture was cooled to 5 °C, quenched with an aqueous ammonium chloride solution, and diluted with an aqueous sodium bicarbonate solution and ethyl acetate. The organic layer was removed, dried over Na₂SO₄, filtered, and concentrated. The unpurified mixture was dissolved in DCM (50 mL) and 5 g of 3 Å molecular sieve at 5 °C. After stirring for 5 min, sodium triethoxyborohydride (0.88 g, 4.1 mmol) was added, and the reaction mixture was stirred overnight and slowly heated to room temperature. The reaction mixture was quenched with an aqueous sodium bicarbonate solution and filtered. The organic layer was separated, dried over Na₂SO₄, filtered, concentrated, and purified by rapid column chromatography (hexane / EtOAc) to give the title compound. MS (m / z) 309.2 [M+H]⁺. 1H NMR (400 MHz, chloroform-d) δ 7.48 (d, J = 7.2 Hz, 4H), 7.33 (dd, J = 8.3, 6.8 Hz, 4H), 7.24 (t, J = 7.2 Hz, 2H), 4.15 (d, J = 14.3 Hz, 2H), 3.53 (d, J = 14.3 Hz, 2H), 3.19 - 3.01 (m, 1H), 2.96 - 2.79 (m, 1H), 2.69 (dt, J = 10.4, 6.1 Hz, 1H), 2.45 (td, J = 12.3, 3.1 Hz, 1H), 2.13 - 2.00 (m, 1H), 1.94 - 1.68 (m, 3H), 1.58 - 1.38 (m, 1H), 1.28 (d, J = 6.9 Hz, 3H), 1.26 - 1.11 (m, 1H). [synthesis] [(7R,13R)-12-(] [Benzyloxy] [)-N-(2,4-] [Difluorobenzyl] [)-13-] [methyl] [-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(7c)] [:] []

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

[0285] (2R,3R)-2-methylazacycloheptane-3-amine dihydrochloride (58 mg, 0.29 mmol) was dissolved in methanol (3 mL), water (0.5 mL), and sodium bicarbonate (151 mg, 1.79 mmol). Methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)aminomethyl)-4-sideoxy-4H-piperan-2-carboxylate (110 mg, 0.26 mmol) was added, and the mixture was stirred at 65 °C for 4 h. The mixture was cooled to room temperature, concentrated, dissolved in DCM, filtered, concentrated, purified by preparative HPLC (MeCN / water with 0.1% TFA), and lyophilized to give the title compound. MS (m / z) 508.6 [M+H]+. [synthesis] [(1R,14R)-N-[(2,4-] [Difluorophenyl] [)] [methyl] []-6-] [Hydroxy] [-14-] [methyl] [-5,8-] [Dilateral oxygen group] [-2,9-] [Dazatricyclic] [[7.4.1.02,7]] [Carbon 14] [-3,6-] [Diene] [-4-] [Methionine] [(7)] [:] []

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

[0287] With (7R,13R)-N-(2,4-difluorobenzyl)-12-hydroxy-13-methyl-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide ( [7] Similarly, (7S,13S)-12-hydroxy-13-methyl-1,11-di-sideoxy-N-(2,4,6-trifluorobenzyl)aminomethyl)-4H-piperan-2-carboxylate was prepared using (S)-3-aminoazacycloheptan-2-one as the starting material and methyl 3-(benzyloxy)-4-sideoxy-5-((2,4,6-trifluorobenzyl)aminomethyl)-4-sideoxy-4H-piperan-2-carboxylate instead of methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)aminomethyl)-4-sideoxy-4H-piperan-2-carboxylate as the starting material. [8]). HPLC analysis indicated an enantiomer mixture. MS (m / z) 436.2 [M+H]+. ¹H NMR (400 MHz, acetonitrile-d³) δ 10.40 (s, 1H), 8.43 (s, 1H), 6.98 - 6.79 (m, 2H), 4.62 (d, J = 5.5 Hz, 2H), 4.52 - 4.37 (m, 1H), 4.24 (ddd, J = 13.3, 8.9, 7.5 Hz, 1H), 3.86 (qd, J = 6.9, 1.7 Hz, 1H), 3.20 (ddd, J = 13.4, 7.4, 2.9 Hz, 1H), 2.06 - 2.00 (m, 1H), 1.88 - 1.66 (m, 2H), 1.34 - 1.13 (m, 4H). Example 8: Preparation of (7R,13S)-N-(2,4-difluorobenzyl)-12-hydroxy-13-methyl-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide (9): [synthesis] [(R)-3-(] [Dibenzylamino] [)-2-] [Methylenezacycloheptanane] [-1-] [Tributyl formate] [(9a)] [:] []

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

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

[0290] (3R)-3-(dibenzylamino)-2-methylene-azacycloheptan-1-carboxylic acid tert-butyl ester ( [9a], 256 mg, 0.63 mmol) was combined with tributyl hydroperoxide (5-6 M, 214 µl in decane) and phenylsilane (78 µl, 0.63 mmol) in isopropanol (3 mL). Tris(di-p-pentylmethyl)manganese (34 mg, 0.056 mmol) was added and the reaction mixture was stirred at room temperature. After 1 h, additional tris(p-p-pentylmethyl)manganese (11 mg, 0.019 mmol) was added and stirring continued. After an additional 30 min, the reaction mixture was concentrated and purified by rapid column chromatography (hexane / EtOAc) to give the title compound as a diastereomeric mixture. MS (m / z) 319.3 [M+H]+. [synthesis] [(7R)-12-(] [Benzyloxy] [)-N-(2,4-] [Difluorobenzyl] [)-13-] [methyl] [-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(9c)] [:] []

[0291] (3R)-3-(benzylamino)-2-methyl-azacycloheptane-1-carboxylic acid tributyl ester (138 mg, 433 µmol) was combined with ethanol (10 mL) containing Pd / C (10 wt%, wet, E101 NE / W, 138 mg) and stirred vigorously overnight. The reactants were filtered through Celite® and concentrated to dryness to give unpurified (3R)-3-amino-2-methyl-azacycloheptane-1-carboxylic acid tributyl ester. MS (m / z) 229.0 [M+H]+. The material was dissolved in methanol (5 mL) and water (0.5 mL), and sodium bicarbonate (146 mg, 1.73 mmol) was added, followed by methyl 3-benzyloxy-5-[(2,4-difluorophenyl)methylaminomethoxy]-4-sideoxy-piperan-2-carboxylate (186 mg, 0.43 mmol). The mixture was stirred at 45 °C for 5 minutes, then heated to 65 °C and stirred for 40 minutes. The reaction mixture was cooled to room temperature, concentrated to dryness, dissolved in DCM, dried over Na₂SO₄, filtered, and concentrated. The residue was dissolved in toluene (4 mL), and TFA (2 mL) was added. The reaction mixture was concentrated to dryness, dissolved in methanol (5 mL), and triethylamine (2 mL) was added. The mixture was heated to 60 °C and stirred overnight. The reactants were concentrated to dryness, purified by preparative HPLC (MeCN / water with 0.1% TFA), and lyophilized to give the title compound as a mixture of diastereomers, the major isomer being (7R,13S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-13-methyl-1,11-di-side-oxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide. MS (m / z) 508.4 [M+H]+. [synthesis] [(7R,13S)-N-(2,4-] [Difluorobenzyl] [)-12-] [Hydroxy] [-13-] [methyl] [-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(9)] [:] []

[0292] (1R)-6-benzyloxy-N-[(2,4-difluorophenyl)methyl]-14-methyl-5,8-dioxy-2,9-diazatricyclo[7.4.1.02,7]tetradec-3,6-diene-4-methylamine (99 mg, 0.20 mmol) was dissolved in 4 mL toluene and 2 mL TFA and stirred at 30 °C. After 1 h, the reaction mixture was concentrated, purified by preparative HPLC (MeCN / water with 0.1% TFA), and lyophilized to give the title compound. MS (m / z) 418.3 [M+H]+. 1H NMR (400 MHz, acetonitrile-d3) δ 10.42 (s, 1H), 8.38 (s, 1H), 7.51 - 7.35 (m, 1H), 7.09 - 6.91 (m, 2H), 4.60 (d, J = 5.8 Hz, 2H), 4.44 (d, J = 4.4 Hz, 1H), 4.37 (dt, J = 14.3, 9.4 Hz, 1H), 4.24 - 4.14 (m, 1H), 2.23 - 2.05 (m, 2H), 2.04 - 1.98 (m, 1H), 1.78 - 1.62 (m, 2H), 1.50 (d, J = 7.4 Hz, 3H), 1.19 - 1.02 (m, 1H). Example 9: Preparation of (7S- and 7R-)-6,6-difluoro-12-hydroxy-1,11-di-sideoxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide (10⁻¹, 10⁻²): [synthesis] [12-(] [Benzyloxy] [)-6-] [Hydroxy] [-1,11-] [Dilateral oxygen group] [-N-(2,4,6-)] [Trifluorobenzyl] [)-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(10a)] [:] []

[0293] A vial was filled with methyl 3-(benzyloxy)-4-sideoxy-5-((2,4,6-trifluorobenzyl)aminomethyl)-4H-piperan-2-carboxylate (350 mg, 0.78 mmol), tributyl 3-amino-4-hydroxyazine-1-heptane-carboxylate (180 mg, 0.78 mmol), and sodium bicarbonate (131 mg, 1.56 mmol). Methanol (3.5 mL), water (3.5 mL), and 2-methyltetrahydrofuran (2 mL) were added. The reaction mixture was stirred overnight at room temperature and partitioned between 1 N HCl and ethyl acetate. The organic layer was separated and concentrated to dryness. The residue was dissolved in 1 mL DCM and 3 mL dioxane containing 4 N HCl, and the solution was stirred at room temperature for 2 h to remove the Boc protecting group and concentrated to dryness. 10 mL ethanol and DBU (0.47 mL, 3.12 mmol) were added to the residue. The reaction mixture was heated in a microwave oven to 120 °C for 30 minutes. After cooling to room temperature, the reaction mixture was partitioned between 1 N HCl and ethyl acetate. The organic layer was separated and concentrated to dryness to give the title compound. MS (m / z) 528.17 [M+H]+. [synthesis] [12-(] [Benzyloxy] [)-1,6,11-] [Trilateral oxygen group] [-N-(2,4,6-)] [Trifluorobenzyl] [)-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(10b)] [:] []

[0294] To 12-(benzyloxy)-6-hydroxy-1,11-di-sideoxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4]diazanol-10-methamide ( [10a]) (320 mg, 0.61 mmol) was added to a solution of Desmartin periodane in anhydrous DCM (15 mL), and the mixture was stirred at room temperature for 20 minutes. DCM was added, and the organic phase was washed twice with 10% sodium thiosulfate solution, twice with 0.5 N NaOH and twice with brine. The organic phase was dried and evaporated. The residue was purified by silica gel chromatography by dissolution with methanol-containing DCM to obtain the title compound. MS (m / z) 526.28 [M+H]+. [synthesis] [12-(] [Benzyloxy] [)-6,6-] [Difluoride] [-1,11-] [Dilateral oxygen group] [-N-(2,4,6-)] [Trifluorobenzyl] [)-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(10c)] [:] []

[0295] 12-(benzyloxy)-1,6,11-trisyloxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4]diazidine-10-methamide ( ) was cooled to -78°C under argon atmosphere. [10b]) 200 mg, 0.38 mmol) of Deoxo-Fluor® (1.1 mmol, 0.42 mL, 50% in toluene) was added to a solution in DCM (5 mL). The mixture was stirred at -78 °C and gradually heated to room temperature overnight. The mixture was cooled at -78 °C and Deoxo-Fluor® (0.76 mmol, 0.28 mL, 50% in toluene) was added under argon atmosphere. The reaction mixture was stirred at room temperature for 1 day and diluted with DCM. The mixture was cooled in an ice / water bath and quenched by dropwise addition of a saturated sodium bicarbonate aqueous solution. The resulting mixture was stirred for 1 h, and more saturated sodium bicarbonate aqueous solution was added, and stirring was continued for 10 minutes until bubbling stopped. The organic layer was separated, dried over Na₂SO₄ and filtered. The filtrate was concentrated to dryness. The residue was purified by silica gel chromatography with EtOAc / hexane dissolution and by preparative HPLC (MeCN / water with 0.1% TFA), followed by lyophilization to obtain the title compound. MS (m / z) 548.25 [M+H]+. [synthesis] [(7S-)] [and] [7R-)-6,6-] [Difluoride] [-12-] [Hydroxy] [-1,11-] [Dilateral oxygen group] [-N-(2,4,6-)] [Trifluorobenzyl] [)-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(10-1)] [、] [10-2)] [:] []

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

[0297] 12-(benzyloxy)-6-hydroxy-1,11-di-sideoxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4]diazidine-10-methamide ( [10a]) (20 mg) was dissolved in 0.3 mL toluene and 0.6 mL TFA and stirred at room temperature for 30 minutes. The reaction mixture was concentrated to dryness and the residue was purified by RP-HPLC with ACN / water (0.1% TFA) to give the title compound. MS (m / z) 438.18 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.74 (s, 1H), 10.44 (t, J = 5.8 Hz, 1H), 8.28 (s, 1H), 7.28 - 7.15 (m, 2H), 4.57 (d, J = 5.6 Hz, 3H), 4.13 (dt, J = 13.2, 9.2 Hz, 1H), 3.91 - 3.78 (m, 2H), 3.62 (dd, J = 15.0, 1.6 Hz, 1H), 3.12 (dt, J = 13.1, 4.5 Hz, 1H), 1.84 (d, J = 6.8 Hz, 2H), 1.66 (d, J = 14.5 Hz, 1H), 1.02 (td, J = 14.4, 13.5, 5.8 Hz, 1H). Example 11: Preparation of N-(2,4-difluorobenzyl)-6,12-dihydroxy-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide (12): [synthesis] [12-(] [Benzyloxy] [)-N-(2,4-] [Difluorobenzyl] [)-6-] [Hydroxy] [-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(12a)] [:] []

[0298] With compounds [10a] Similarly, methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)aminomethyl)-4-sideoxy-4H-piperan-2-carboxylate was used to prepare 12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-1,11-sideoxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-carboxamide ( [12a]). MS (m / z) 510.23 [M+H] +. [synthesis] [N-(2,4-)] [Difluorobenzyl] [)-6,12-] [Dihydroxy] [-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(12)] [:] []

[0299] With compounds

[11] Similarly, using compounds [12a] was used to prepare the title compound. MS (m / z) 420.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.77 (s, 1H), 10.43 (t, J = 5.9 Hz, 1H), 8.31 (s, 1H), 7.41 (td, J = 8.7, 6.6 Hz, 1H), 7.25 (ddd, J = 10.6, 9.3, 2.6 Hz, 1H), 7.12 - 7.02 (m, 1H), 5.37 (s, 1H), 4.61 - 4.52 (m, 3H), 4.20 - 4.08 (m, 1H), 3.86 (td, J = 14.0, 13.0, 4.4 Hz, 2H), 3.68 - 3.59 (m, 1H), 3.17 - 3.09 (m, 1H), 1.85 (d, J = 7.4 Hz, 2H), 1.68 (d, J = 14.9 Hz, 1H), 1.04 (s, 1H). Example 12: Preparation of N-(2,4-difluorobenzyl)-6-fluoro-12-hydroxy-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide (13): [synthesis] [12-(] [Benzyloxy] [)-N-(2,4-] [Difluorobenzyl] [)-6-] [fluorine] [-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(13a)] [:] []

[0300] 12-(benzyloxy)-N-(2,4-difluorobenzyl)-6-hydroxy-1,11-dioxy-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4]diazidine-10-methamide ( ) was cooled to -78°C under argon atmosphere. [12a], 47 mg, 0.092 mmol) was added to a solution of Deoxo-Fluor® (0.14 mmol, 0.05 mL, 50% in toluene) in DCM (3 mL). The mixture was stirred at -78 °C and gradually heated to room temperature overnight. The mixture was cooled at -78 °C and Deoxo-Fluor® (0.14 mmol, 0.05 mL, 50% in toluene) was added under argon atmosphere. The reaction mixture was stirred at room temperature for 2 h and diluted with DCM. The mixture was cooled in an ice / water bath and the reactants were quenched by adding saturated sodium bicarbonate aqueous solution dropwise. The mixture was stirred for 1 h and more saturated sodium bicarbonate aqueous solution was added, and stirring was continued for 10 min until bubbling stopped. The organic layer was separated, dried over Na₂SO₄ and filtered. The filtrate was concentrated to dryness to give the title compound. MS (m / z) 512.22 [M+H]⁺. [synthesis] [N-(2,4-)] [Difluorobenzyl] [)-6-] [fluorine] [-12-] [Hydroxy] [-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(13)] [:] []

[0301] With compounds

[11] Similarly, using [13a] was used to prepare the title compound. MS (m / z) 422.18 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 10.33 (t, J = 5.9 Hz, 1H), 8.60 (s, 1H), 7.41 (td, J = 8.7, 6.6 Hz, 1H), 7.25 (td, J = 9.6, 2.6 Hz, 1H), 7.07 (td, J = 8.7, 2.5 Hz, 1H), 5.10 - 5.03 (m, 1H), 4.98 - 4.89 (m, 1H), 4.56 (d, J = 6.0 Hz, 2H), 4.13 (dt, J = 13.2, 7.9 Hz, 1H), 3.90 (d, J = 15.0 Hz, 1H), 3.83 (dd, J = 15.1, 2.0 Hz, 1H), 3.13 (ddd, J = 13.2, 7.1, 2.9 Hz, 1H), 2.18 - 2.05 (m, 1H), 2.04 (s, 1H), 1.82 - 1.64 (m, 1H), 1.53 - 1.20 (m, 1H). Example 13: Preparation of (6S,7R)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-6-methyl-1,11-disideoxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide and (6R,7S)-N-(2,4-difluorobenzyl)-6,12-dihydroxy-6-methyl-1,11-disideoxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide (14-1, 14-2): [synthesis] [3-((()] [Benzyloxy] [)] [Carbonyl] [)] [Amine] [)-4-] [Hydroxyazine heptane] [-1-] [Benzyl formate] [(14b)] [:] []

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

[0303] benzyl 3-(((benzyloxy)carbonyl)amino)-4-hydroxyazine-heptane-1-carboxylate ( [14b]) (760 mg, 1.9 mmol) was added to a solution of Desmartin periodane (1.2 g, 2.8 mmol) in 5 mL of DCM. The reaction mixture was stirred at room temperature for 30 minutes. DCM was added and the organic phase was washed twice with 10% sodium thiosulfate solution, twice with 0.5 M NaOH and twice with brine. The organic phase was dried and evaporated. The residue was purified by dissolution with EtOAc / hexane by SGC to give benzyl 3-(((benzyloxy)carbonyl)amino)-4-hydroxyazine-heptane-1-carboxylate ( [14c]). MS (m / z) 397.53 [M+H]+. The compound was obtained by preparative IA column SFC chromatography using MeOH co-solvent. [14c] Separated into individual enantiomers, yielding [14c-1] and [14c-2]. [synthesis] [((3S,4R)] [and] [(3R,4S)-4-] [Hydroxy] [-4-] [Methylazacycloheptane] [-3-] [base] [)] [Benzyl carbamate] [(14d-1)] [、] [14d-2)] [:] []

[0304] Add methyl gramine (1.02 mL, 3.05 mmol [in Et 2O, 3 M]) to the flask at 0 °C. Add slowly. [14c-1] or A solution of [14c-2] (302 mg, 0.76 mmol) in 1 mL THF was prepared with stirring. The reaction mixture was heated to room temperature and stirred overnight. The reaction mixture was quenched with NH4Cl and extracted to ethyl acetate, washed with brine, dried over MgSO4, filtered, and the solvent was removed under vacuum to give either ((3S,4R)-4-hydroxy-4-methylazheptan-3-yl)aminocarbamate or ((3R,4S)-4-hydroxy-4-methylazheptan-3-yl)aminocarbamate. MS (m / z) 413.50 [M+H]+.

[0305] The residue was dissolved in absolute ethanol and purged under an argon atmosphere. Palladium hydroxide (101 mg, 20 wt% Pd) was added and the mixture was purged under a hydrogen atmosphere (1 atm, balloon). The mixture was vigorously stirred for one weekend and purged under an argon atmosphere. It was then filtered through a Celite® pad. Celite® was washed with absolute ethanol and the filtrate was concentrated under vacuum to obtain the title compound. MS (m / z) 145.16 [M+H]+. [synthesis] [(6S,7R)] [and] [(6R,7S)-N-(2,4-] [Difluorobenzyl] [)-6,12-] [Dihydroxy] [-6-] [methyl] [-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(14-1)] [、] [14-2)] [:] []

[0306] With compounds

[12] Similarly, using compounds [14d-1] [and] The title compound was prepared using [14d-2]. MS (m / z) 434.15 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.80 (s, 1H), 10.46 (t, J = 6.0 Hz, 1H), 8.34 (s, 1H), 7.41 (td, J = 8.7, 6.6 Hz, 1H), 7.25 (ddd, J = 11.7, 9.4, 2.6 Hz, 1H), 7.08 (td, J = 8.6, 2.7 Hz, 1H), 4.99 (s, 1H), 4.56 (d, J = 5.9 Hz, 2H), 4.30 (s, 1H), 4.15 (dt, J = 13.0, 8.8 Hz, 1H), 3.85 (dd, J = 15.2, 3.0 Hz, 1H), 3.68 (dd, J = 15.2, 1.7 Hz, 1H), 3.10 (dt, J = 13.0, 4.8 Hz, 1H), 1.81 (d, J = 7.2 Hz, 2H), 1.47 (d, J = 15.4 Hz, 1H), 1.35 (s, 3H), 1.23 (dt, J = 14.4, 6.5 Hz, 1H). Example 14: Preparation of (6R,7S)- and (6S,7R)-6-fluoro-12-hydroxy-1,11-di-sideoxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide (15-1, 15-2): [synthesis] [(7S)-] [and] [(7R)-12-(] [Benzyloxy] [)-1,6,11-] [Trilateral oxygen group] [-N-(2,4,6-)] [Trifluorobenzyl] [)-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(15a-1)] [、] [15a-2)] [:] []

[0307] Preparative IA column SFC chromatography was performed using MeOH co-solvent to separate 12-(benzyloxy)-1,6,11-trisyloxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide. [10b]) (350 mg) was isolated into its individual enantiomers, yielding [15a-1] and [15a-2]. MS (m / z) 526.00 [M+H] +. [synthesis] [(6S,7S)-] [and] [(6R,7R)-12-(] [Benzyloxy] [)-6-] [Hydroxy] [-1,11-] [Dilateral oxygen group] [-N-(2,4,6-)] [Trifluorobenzyl] [)-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(15b-1)] [、] [15b-2)] [:] []

[0308] At 0℃ [15a-1] or [15a-2] (150 mg, 0.285 mmol) was dissolved in 7 mL of methanol with NaBH₄ (21.6 mg, 0.57 mmol). The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with 1 N HCl and extracted with DCM. The organic phase was dried over MgSO₄ and concentrated to dryness to give the title compound. MS (m / z) 528.26 [M+H]⁺. [synthesis] [(6R,7S)-] [and] [(6S,7R)-6-] [fluorine] [-12-] [Hydroxy] [-1,11-] [Dilateral oxygen group] [-N-(2,4,6-)] [Trifluorobenzyl] [)-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(15-1)] [、] [15-2)] [:] []

[0309] With compounds

[13] Similarly, using compounds [15b-1] [and] [15b-2] was used to prepare the title compound. [15-1]: MS (m / z) 440.22 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 10.35 (t, J = 5.8 Hz, 1H), 8.58 (s, 1H), 7.28 - 7.15 (m, 2H), 5.12 - 4.78 (m, 2H), 4.65 - 4.50 (m, 2H), 4.18 - 4.06 (m, 1H), 3.89 - 3.80 (m, 2H), 3.12 (ddd, J = 13.2, 7.2, 2.9 Hz, 1H), 2.19 - 1.95 (m, 2H), 1.79 - 1.70 (m, 1H), 1.56 - 1.21 (m, 1H). [15-2]: MS (m / z) 440.20 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.57 (s, 1H), 10.35 (t, J = 5.8 Hz, 1H), 8.58 (s, 1H), 7.28 - 7.15 (m, 2H), 5.12 - 4.81 (m, 2H), 4.65 - 4.50 (m, 2H), 4.12 (dt, J = 13.3, 8.1 Hz, 1H), 3.89 (d, J = 15.0 Hz, 1H), 3.86 - 3.77 (m, 1H), 3.12 (ddd, J = 13.1, 7.0, 2.9 Hz, 1H), 2.22 - 1.95 (m, 2H), 1.79 - 1.70 (m, 1H), 1.50 - 1.28 (m, 1H). Example 15: Preparation of (7S)- and (7R)-N-(2,4-difluorobenzyl)-6,6-difluoro-12-hydroxy-1,11-dioxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylpyridino[1,2-a][1,4]diazamine-10-methamide (16-1, 16-2): [synthesis] [(7S)-] [and] [(7R)-12-(] [Benzyloxy] [)-N-(2,4-] [Difluorobenzyl] [)-1,6,11-] [Trilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(16a-1)] [、] [16a-2)] [:] []

[0310] With compounds [10b] Similarly, methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)aminomethyl)-4-sideoxy-4H-piperan-2-carboxylate was used. [16a]) to prepare 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,6,11-trisphenoxy-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4]diazanol-10-methamide ( [16a]). MS (m / z) 508.15 [M+H]+. The compound was obtained by preparative OD-H column SFC chromatography using IPA-NH3 co-solvent. [16a] Separated into its individual enantiomers, we obtain [16a-1] and [16a-2]. [synthesis] [(7S)-] [and] [(7R)-N-(2,4-] [Difluorobenzyl] [)-6,6-] [Difluoride] [-12-] [Hydroxy] [-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(16-1)] [、] [16-2)] [:] []

[0311] With compounds [10-1] and [10-2] Similarly, using [16a-1] and [16a-2] was used to prepare the title compound. [16-1]: MS (m / z) 440.20 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 10.24 (t, J = 6.0 Hz, 1H), 8.50 (s, 1H), 7.42 (td, J = 8.6, 6.6 Hz, 1H), 7.26 (ddd, J = 10.5, 9.4, 2.6 Hz, 1H), 7.07 (td, J = 8.5, 7.6, 4.2 Hz, 1H), 5.24 (s, 1H), 4.56 (d, J = 5.8 Hz, 2H), 4.27 - 4.15 (m, 1H), 4.04 (d, J = 16.5 Hz, 1H), 3.92 - 3.83 (m, 1H), 3.19 (dd, J = 13.2, 6.8 Hz, 1H), 2.22 (s, 1H), 1.96 (d, J = 21.8 Hz, 2H), 1.71 - 1.54 (m, 1H). [16-2]: MS (m / z) 440.27 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.64 (s, 1H), 10.24 (t, J = 5.9 Hz, 1H), 8.50 (s, 1H), 7.42 (td, J = 8.7, 6.6 Hz, 1H), 7.31 - 7.20 (m, 1H), 7.07 (td, J = 8.4, 2.7 Hz, 1H), 5.24 (s, 1H), 4.56 (d, J = 5.9 Hz, 2H), 4.21 (q, J = 10.2, 9.7 Hz, 1H), 4.04 (d, J = 15.8 Hz, 1H), 3.88 (dd, J = 15.4, 2.0 Hz, 1H), 3.18 (dd, J = 13.1, 6.7 Hz, 1H), 2.22 (s, 1H), 1.97 (d, J = 22.4 Hz, 2H), 1.62 (dd, J = 35.1, 14.3 Hz, 1H). Example 16: Preparation of N-(2,4-difluorobenzyl)-6-fluoro-12-hydroxy-6-methyl-1,11-disideoxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide (17-1a) and N-(2,4-difluorobenzyl)-12-hydroxy-6-methyl-1,11-disideoxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide (17-1b, 17-2b): [synthesis] [12-(] [Benzyloxy] [)-N-(2,4-] [Difluorobenzyl] [)-6-] [fluorine] [-6-] [methyl] [-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(17a-1a)] [、] [17a-2a)] [and] [12-(] [Benzyloxy] [)-N-(2,4-] [Difluorobenzyl] [)-6-] [Methylene] [-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(17a-1b)] [、] [17a-2b)] [:] []

[0312] With compounds [13a] Similarly, using compounds [14e-1] and [14e]- [2] to prepare the title compound. MS (m / z) 526.16 [M+H]+. Byproducts were generated ( [17a]- [1b] [、] [17a]- [2b]). MS (m / z) 506.13 [M+H] +. [synthesis] [N-(2,4-)] [Difluorobenzyl] [)-6-] [fluorine] [-12-] [Hydroxy] [-6-] [methyl] [-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(17-1a)] [and] [N-(2,4-)] [Difluorobenzyl] [)-12-] [Hydroxy] [-6-] [methyl] [-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(17-1b)] [、] [17-2b)] [:] []

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

[0314] Titanium ethoxide (IV) (1.03 mL, 4.91 mmol) was added to a solution of 0.52 g (2.44 mmol) of 3-oxazacycloheptan-1-carboxylic acid tributyl ester and 0.35 g (2.93 mmol) of 2-methylpropane-2-sulfinamide (10 mL) in THF at room temperature. The resulting solution was stirred overnight at room temperature.

[0315] The reaction mixture was diluted with ethyl acetate (10 mL) and quenched with an aqueous solution of NaHCO3 (~5 mL). Celite® was added to the mixture, and the solids were filtered off. The filter cake was washed with ethyl acetate (10 mL × 2). The washes were concentrated and combined under vacuum. The residue was purified by CombiFlash® using EtOAc / hexane to obtain the title compound. MS (m / z) 317.2 [M+H]+. [synthesis] [3-((] [Third-term butylsulfoxide] [)] [Amine] [)-3-] [Methylazacycloheptane] [-1-] [Tributyl formate] [(18b)] [:] []

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

[0317] The reaction mixture was diluted with ethyl acetate and washed with saturated NH₄Cl and brine. The mixture was dried over MgSO₄ and the solvent was removed under vacuum. The residue was purified by column chromatography with ethyl acetate / hexane to give the title compound. MS (m / z) 333.2 [M+H]⁺. [synthesis] [3-] [Methylazacycloheptane] [-3-] [amine] [(18c)] [:] []

[0318] Dioxane containing 4M HCl (0.07 mL) was added to 3-(tert-butylsulfinylamino)-3-methyl-azacycloheptane-1-carboxylic acid tert-butyl ester at room temperature. [18b], 0.03 g, 0.1 mmol) was added to a solution in DCM (2 mL). After 2 h, the solvent was removed under vacuum, and the unpurified material was used directly in the next step. MS (m / z) 129.2 [M+H]+. [synthesis] [12-(] [Benzyloxy] [)-7-] [methyl] [-1,11-] [Dilateral oxygen group] [-N-(2,4,6-)] [Trifluorobenzyl] [)-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(18d)] [:] []

[0319] At room temperature, 3-methylazine-heptane-3-amine ( Methyl 3-benzyloxy-4-sideoxy-5-[(2,4,6-trifluorophenyl)methylaminomethoxy]piperan-2-carboxylate (30 mg, 0.07 mmol) was added to a mixture of [18c], 0.013 g, 0.1 mmol) and sodium bicarbonate (45.07 mg, 0.54 mmol) in MeOH (2 mL) and water (2 mL). The mixture was stirred at 60 °C for 3 h. The reaction mixture was diluted with ethyl acetate and washed with water and brine, and dried over MgSO4. The solvent was removed under vacuum and the residue was purified to give the title compound. MS (m / z) 526.2 [M+H]+. [synthesis] [12-] [Hydroxy] [-7-] [methyl] [-1,11-] [Dilateral oxygen group] [-N-(2,4,6-)] [Trifluorobenzyl] [)-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(18)] [:] []

[0320] 12-(benzyloxy)-7-methyl-1,11-di-sideoxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide (0.03 g, 0.06 mmol) was dissolved in toluene (2 mL) and TFA (2 mL) was added. The reaction mixture was stirred at room temperature for 1 h. The solvent was removed under vacuum and the residue was purified by HPLC to give the title compound. MS (m / z) 436.1 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ 10.46 (s, 1H), 8.57 (s, 1H), 6.74 - 6.62 (m, 2H), 4.69 (m, 1H), 4.47 (m, 1H), 4.30 - 4.14 (m, 1H), 3.65-3.77 (m, 3H), 3.40 (m, 1H), 3.09 (m, 1H), 2.15 - 1.7 (m, 7H). Example 18: Preparation of (7S)-12-hydroxy-1,11-di-side-oxy-N-(2,4,6-trifluorobenzyl)-1,3,4,6,7,11-hexahydro-2,7-methylbridged pyrido[1,2-d][1,4,7]oxadazonine-10-methamide (19): []

[0321] With 12-hydroxy-7-methyl-1,11-disideoxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide (

[18] Similarly, (7S)-12-hydroxy-1,11-disidero-N-(2,4,6-trifluorobenzyl)-1,3,4,6,7,11-hexahydro-2,7-methylbridgedpyrido[1,2-d][1,4,7]oxadazine-10-methamide was prepared by replacing 3-methylazacycloheptane-3-amine with (S)-1,4-oxadazine-6-amine.

[19] ). 1H NMR (400 MHz, DMSO-d6) δ 10.41 (t, J = 5.8 Hz, 1H), 8.51 (s, 1H), 7.35 - 6.97 (m, 2H), 4.71 (s, 1H), 4.57 (d, J = 5.7 Hz, 2H), 4.28 (ddd, J = 13.1, 9.4, 7.3 Hz, 1H), 4.11 (d, J = 13.9 Hz, 1H), 4.07 - 3.78 (m, 6H). MS (m / z) 514.2 [M+H] +. Example 19: Preparation of (7R)-12-hydroxy-1,11-disideoxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide (20): []

[0322] With 12-hydroxy-7-methyl-1,11-disideoxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide (

[18] Similarly, (7R)-12-hydroxy-1,11-disidero-N-(2,4,6-trifluorobenzyl)-1,3,4,6,7,11-hexahydro-2,7-methylbridgedpyrido[1,2-d][1,4,7]oxadazine-10-methamide was prepared by replacing 3-methylazacycloheptane-3-amine with (R)-1,4-oxadazine-6-amine.

[20] ). 1H NMR (400 MHz, DMSO-d6) δ 10.41 (s, 1H), 8.51 (s, 1H), 7.22 (dd, J = 9.2, 8.0 Hz, 2H), 4.71 (d, J = 3.1 Hz, 1H), 4.57 (d, J = 5.7 Hz, 2H), 4.27 (ddd, J = 12.9, 9.1, 7.1 Hz, 1H), 4.16 - 3.62 (m, 6H). MS (m / z) 514.2 [M+H] +. Example 20: Preparation of N-(2,4-difluorobenzyl)-11-hydroxy-1,10-disideloxy-1,3,4,5,6,10-hexahydro-2,6-ethbridged pyrido[1,2-a][1,4]1,4-diaza-9-methamide (23): [synthesis] [1-(] [Zyrocycloheptane] [-4-] [base] [)-3-(] [Benzyloxy] [)-4-] [Side group] [-1,4-] [Dihydropyridine] [-2,5-] Diethyl diformate [(23a)] [:] []

[0323] The reactor was packed with tert-butyl 3-aminoazacycloheptan-1-carboxylate (588 mg, 3 mmol), EtOH / water (9 mL / 6 mL) containing NaHCO3 (576 mg, 7 mmol), and diethyl 3-(benzyloxy)-4-sideoxy-4H-piperan-2,5-dicarboxylate (950 mg, 3 mmol). The reaction mixture was heated to 50°C overnight. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (100 mL). The organic layer was concentrated under vacuum. The residue was used in the next step without purification.

[0324] Add 3 mL of dioxane solution containing 4 N HCl to 10 mL of DCM containing the residue described above. After incubation at room temperature for 2 h, remove the solvent under vacuum to obtain the title compound, which was used in the next step without purification. MS (m / z) 442.945 [M+H]+. [synthesis] [11-(] [Benzyloxy] [)-1,10-] [Dilateral oxygen group] [-1,3,4,5,6,10-] [Hexahydrogen] [-2,6-] [Ethyl-bridged pyridyl] [[1,2-a][1,4] 1,4-] [Dazonium chloride] [-9-] Ethyl formate [(23b)] [:] []

[0325] EtOH (20 mL) and DBU (2.2 g, 15 mmol) were added to the residue. The mixture was heated to 110 °C for 1 h in a microwave reactor, then cooled to room temperature and extracted with ethyl acetate (100 mL). The organic layer was concentrated under vacuum. The residue was purified by silica gel chromatography to give the title compound. MS (m / z) 397.113 [M+H]+. [synthesis] [11-(] [Benzyloxy] [)-1,10-] [Dilateral oxygen group] [-1,3,4,5,6,10-] [Hexahydrogen] [-2,6-] [Ethyl-bridged pyridyl] [[1,2-a][1,4] 1,4-] [Dazonium chloride] [-9-] [Formic acid] [(23c)] [:] []

[0326] 2 N LiOH (1 mL) was added to MeOH (6 mL) containing the above residue (114 mg, 0.288 mmol) at room temperature. After 2 h, the reaction mixture was diluted with ethyl acetate (100 mL) and 1 N HCl (20 mL). The organic layer was dried and concentrated under vacuum. The resulting residue was used in the next reaction without purification. MS (m / z) 369.131 [M+H]+. [synthesis] [11-(] [Benzyloxy] [)-N-(2,4-] [Difluorobenzyl] [)-1,10-] [Dilateral oxygen group] [-1,3,4,5,6,10-] [Hexahydrogen] [-2,6-] [Ethyl-bridged pyridyl] [[1,2-a][1,4] 1,4-] [Dazonium chloride] [-9-] [Methionine] [(23d)] [:] []

[0327] (2,4-Difluorophenyl)methylamine (27.4 mg, 0.17 mmol), DIPEA (60 mg, 0.46 mmol), and HATU (60.2 mg, 0.186 mmol) were added to DCM (5 mL) containing the residue described above (57 mg, 0.155 mmol) at room temperature. After 1 h, the reaction mixture was diluted with ethyl acetate (100 mL) and washed with brine. The organic layer was dried and concentrated under vacuum. The resulting residue was used in the next step. MS (m / z) 512.147 [M+H]+. [synthesis] [11-] [Hydroxy] [-1,10-] [Dilateral oxygen group] [-N-(2,4-)] [Difluorobenzyl] [)-1,3,4,5,6,10-] [Hexahydrogen] [-2,6-] [Ethyl-bridged pyridyl] [[1,2-a][1,4] 1,4-] [Dazonium chloride] [-9-] [Methionine] [(twenty three)] [:] []

[0328] TFA (1 mL) was added to a solution of 11-(benzyloxy)-1,10-di-side-oxy-N-(2,4-difluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethbridged pyrido[1,2-a][1,4]1,4-diaza-9-methoxyamine (163 mg) in DCM (2 mL). After 4 h, the solvent was removed. The resulting residue was purified by RP-HPLC by precipitation with ACN / water (0.1% TFA) to give the title compound as a TFA salt. MS (m / z) 404.154 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.41 (t, J = 5.9 Hz, 1H), 8.33 (s, 1H), 7.39 (dd, J = 8.6, 6.6 Hz, 2H), 7.22 (ddd, J = 10.7, 9.3, 2.6 Hz, 1H), 7.07 - 7.01 (m, 1H), 4.99 (d, J = 11.6 Hz, 1H), 4.59 - 4.46 (m, 2H), 4.30 - 4.19 (m, 1H), 3.15 - 3.07 (m, 1H), 2.42 - 2.15 (m, 3H), 2.07 - 1.91 (m, 2H), 1.73 (d, J = 46.6 Hz, 3H). Example 21: Preparation of racemic- and (R)- or (S)-11-hydroxy-1,10-di-sideoxy-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethbridged pyrido[1,2-a][1,4]1,4-diaza-9-methamide (24 and 24-1): [Synthetic racemic mixture] [-11-] [Hydroxy] [-1,10-] [Dilateral oxygen group] [-N-(2,4,6-)] [Trifluorobenzyl] [)-1,3,4,5,6,10-] [Hexahydrogen] [-2,6-] [Ethyl-bridged pyridyl] [[1,2-a][1,4] 1,4-] [Dazonium chloride] [-9-] [Methionine] [(twenty four)] [:] []

[0329] With compounds [5] The synthesis is similar, using 11-(benzyloxy)-1,10-disideoxy-1,3,4,5,6,10-hexahydro-2,6-ethbridged pyrido[1,2-a][1,4]1,4-diaza-9-carboxylic acid and (2,4,6-trifluorophenyl)methylamine to synthesize racemic 11-hydroxy-1,10-disideoxy-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethbridged pyrido[1,2-a][1,4]1,4-diaza-9-methylamine. [twenty four]). MS (m / z) 422.089 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.41 (t, J = 5.9 Hz, 1H), 8.33 (s, 1H), 7.39 (dd, J = 8.6, 6.6 Hz, 2H), 7.22 (ddd, J = 10.7, 9.3, 2.6 Hz, 1H), 7.07 - 7.01 (m, 1H), 4.99 (d, J = 11.6 Hz, 1H), 4.59 - 4.46 (m, 2H), 4.30 - 4.19 (m, 1H), 3.15 - 3.07 (m, 1H), 2.42 - 2.15 (m, 2H), 2.07 - 1.91 (m, 2H), 1.73 (d, J = 46.6 Hz, 2H). [synthesis] [(R)-] [or] [(S)-11-] [Hydroxy] [-1,10-] [Dilateral oxygen group] [-N-(2,4,6-)] [Trifluorobenzyl] [)-1,3,4,5,6,10-] [Hexahydrogen] [-2,6-] [Ethyl-bridged pyridyl] [[1,2-a][1,4] 1,4-] [Dazonium chloride] [-9-] [Methionine] [(24-1)] [:] []

[0330] The peak of (R)- or (S)-11-(benzyloxy)-1,10-di-side-oxy-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethbridged pyrido[1,2-a][1,4]1,4-diaza-9-methamide was separated by palmar HPLC (IB 4.6 × 100 mm 5 mic column SFC chromatography, using MeOH(20) cosolvent) [24a-1]) and racemic-11-(benzyloxy)-1,10-di-side-oxy-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethionized pyrido[1,2-a][1,4] 1,4-diaza-9-methamide ( [24a]) separation. The separated peak 1 was used to prepare 11-hydroxy-1,10-di-sideoxy-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,10-hexahydro-2,6-ethionized pyrido[1,2-a][1,4]1,4-diaza-9-methamide ( [24-1]). MS (m / z) 422.124 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.45 (t, J = 5.8 Hz, 1H), 8.31 (s, 1H), 7.28 - 7.10 (m, 2H), 4.97 (d, J = 11.3 Hz, 2H), 4.61 (dd, J = 14.5, 6.1 Hz, 1H), 4.48 (dd, J = 14.6, 5.5 Hz, 1H), 4.24 (d, J = 13.0 Hz, 2H), 3.11 (dd, J = 13.5, 8.3 Hz, 1H), 2.37 - 2.21 (m, 2H), 2.00 (d, J = 40.1 Hz, 2H), 1.70 (d, J = 31.2 Hz, 2H). Example 22: Preparation of racemic and (7R)- and (7S)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide (25, 25-1, 25-2): [synthesis] [12-(] [Benzyloxy] [)-N-(2,4-] [Difluorobenzyl] [)-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(25d)] [:] []

[0331] Follow with compounds [24a] A similar procedure is used to synthesize 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-di-side-oxy-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4]diazanol-10-methamide from diethyl 3-(benzyloxy)-4-side-oxy-4H-piperanol-2,5-dicarboxylate and tributyl 3-aminoazacycloheptan-1-carboxylate as starting materials. [25d]). MS (m / z) 494.181 [M+H] +. [Synthetic racemic mixture] [N-(2,4-)] [Difluorobenzyl] [)-12-] [Hydroxy] [-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(25)] [:] []

[0332] At room temperature, 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide ( [25d]) (5.5 mg) was added to a solution of toluene (0.2 mL) with TFA (0.2 mL). After 4 h, the solvent was removed. The residue was purified by RP-HPLC with ACN / water (0.1% TFA) to give the title compound as a TFA salt. MS (m / z) 404.134 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 10.38 (t, J = 6.0 Hz, 1H), 8.47 (s, 1H), 7.38 (td, J = 8.7, 6.6 Hz, 1H), 7.22 (ddd, J = 10.6, 9.3, 2.6 Hz, 1H), 7.04 (td, J = 8.6, 2.6 Hz, 1H), 4.75 (dd, J = 5.9, 2.8 Hz, 1H), 4.53 (d, J = 5.9 Hz, 2H), 4.12 (d, J = 13.3 Hz, 1H), 3.90 - 3.84 (m, 1H), 3.65 (dd, J = 14.7, 1.9 Hz, 1H), 3.07 (td, J = 6.6, 3.6 Hz, 1H), 2.02 - 1.94 (m, 1H), 1.89 - 1.74 (m, 3H), 1.62 (d, J = 7.6 Hz, 1H), 1.12 (d, J = 12.1 Hz, 1H). [synthesis] [(7R)-12-(] [Benzyloxy] [)-N-(2,4-] [Difluorobenzyl] [)-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methamide and] [(7S)-12-(] [Benzyloxy] [)-N-(2,4-] [Difluorobenzyl] [)-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(25d-1)] [、] [25d-2)] [:] []

[0333] The (7R)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-di-side-oxy-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4]diazine-10-methamide ( ) was separated by palmar HPLC (IB 4.6 × 100 mm 5 mic column SFC chromatography, using MeOH (20) as a co-solvent) to separate the peak 1. [25d-1]) and as peak 2, (7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4]diazanol-10-methamide ( [25d-2]) and the racemic compound 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4]diazanol-10-methamide ( [25d]) separation. The structure of peak 1 was confirmed by synthesis using (R)-azacycloheptane-3-amine as the starting material. [synthesis] [(7R)-N-(2,4-] [Difluorobenzyl] [)-12-] [Hydroxy] [-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(25-1)] [and] [(7S)-N-(2,4-] [Difluorobenzyl] [)-12-] [Hydroxy] [-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(25-2)] [:] []

[0334] Follow and use for preparing compounds

[25] Under similar reaction conditions, (7R)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-dioxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazidine-10-methamide was synthesized from peaks 1 and 2, respectively. [25-1]) and (7S)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-disiderol-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-pyrido[1,2-a][1,4]diazidine-10-methamide ( [25-2]). Compounds [25-1]: MS (m / z) 404.186 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.59 (s, 1H), 10.38 (t, J = 5.9 Hz, 1H), 8.47 (s, 1H), 7.38 (td, J = 8.7, 6.6 Hz, 1H), 7.22 (ddd, J = 10.6, 9.3, 2.6 Hz, 1H), 7.04 (tdd, J = 8.6, 2.6, 1.1 Hz, 1H), 4.75 (d, J = 5.4 Hz, 1H), 4.53 (d, J = 5.9 Hz, 2H), 4.17 - 4.05 (m, 1H), 3.86 (d, J = 14.6 Hz, 1H), 3.65 (dd, J = 14.7, 1.9 Hz, 1H), 3.06 (ddd, J = 13.1, 6.9, 3.6 Hz, 1H), 1.99 (s, 1H), 1.89 - 1.74 (m, 3H), 1.62 (d, J = 8.0 Hz, 1H). Compound [25-2]: MS (m / z) 404.165 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.61 (s, 1H), 10.38 (t, J = 5.9 Hz, 1H), 8.47 (s, 1H), 7.38 (td, J = 8.7, 6.6 Hz, 1H), 7.22 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.09 - 6.99 (m, 1H), 4.75 (s, 1H), 4.53 (d, J = 5.9 Hz, 2H), 4.12 (d, J = 13.3 Hz, 1H), 3.86 (d, J = 14.6 Hz, 1H), 3.69 - 3.60 (m, 1H), 3.06 (ddd, J = 13.1, 6.8, 3.6 Hz, 1H), 1.99 (s, 1H), 1.83 (d, J = 13.3 Hz, 3H), 1.67 - 1.60 (m, 1H). Example 23: Preparation of racemic-12-hydroxy-1,11-disideoxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide (26), (7R)-12-hydroxy-1,11-disideoxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6, 7,11-Hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide (26-1) and (7S)-12-hydroxy-1,11-disideoxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide (26-2): [synthesis] [12-] [Hydroxy] [-1,11-] [Dilateral oxygen group] [-N-(2,4,6-)] [Trifluorobenzyl] [)-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(26)] [:] []

[0335] 12-(benzyloxy)-1,11-di-side-oxy-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4]diazanol-10-carboxylic acid (57 mg, 0.155 mmol) was dissolved in DCM (2 mL) and (2,4,6-trifluorophenyl)methylamine (27 mg, 0.17 mmol) and triethylamine (60 mg, 0.464 mmol). HATU (60 mg, 0.186 mmol) was added and the mixture was stirred at room temperature. After an overnight reaction, the reactants were concentrated to dryness and purified by silica gel chromatography to obtain compound 12-(benzyloxy)-1,11-di-sideoxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4]diazanol-10-methamide. [26a]). MS (m / z) 512.06 [M+H]+.

[0336] The compound 12-(benzyloxy)-1,11-di-sideoxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4]diazidine-10-methamide ( [26a]) (7 mg, 0.014 mmol) was dissolved in toluene (1 mL), followed by the addition of TFA (1 mL). The resulting mixture was stirred overnight at rt. The solvent was removed under vacuum, and the residue was purified by HPLC to obtain the title compound (

[26] ). MS (m / z) 422.091 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.39 (t, J = 5.8 Hz, 1H), 8.45 (s, 1H), 7.24 - 7.11 (m, 2H), 4.72 (dd, J = 5.9, 2.9 Hz, 1H), 4.54 (dd, J = 6.0, 2.4 Hz, 2H), 4.11 (d, J = 13.3 Hz, 1H), 3.88 - 3.79 (m, 1H), 3.64 (dd, J = 14.7, 1.9 Hz, 1H), 3.05 (dq, J = 9.5, 3.4 Hz, 1H), 2.06 - 1.91 (m, 1H), 1.89 - 1.74 (m, 3H), 1.61 (d, J = 7.7 Hz, 1H), 1.11 (d, J = 12.7 Hz, 1H). [synthesis] [(7S)-12-] [Hydroxy] [-1,11-] [Dilateral oxygen group] [-N-(2,4,6-)] [Trifluorobenzyl] [)-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(26-2)] [and] [(7R)-12-] [Hydroxy] [-1,11-] [Dilateral oxygen group] [-N-(2,4,6-)] [Trifluorobenzyl] [)-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4]] [Dazazine] [-10-] [Methionine] [(26-1)] [:] []

[0337] Racemic 12-(benzyloxy)-1,11-di-side-oxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4]diazidine-10-methamide was separated by palmar HPLC separation (IB 4.6 × 100 mm 5mic column SFC chromatography, using MeOH(20) as a co-solvent). [26a]), to obtain compound (7R)-12-(benzyloxy)-1,11-di-side-oxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4]diazanol-10-methamide ( [26a-1]) and (7S)-12-(benzyloxy)-1,11-di-side-oxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4]diazanol-10-methamide ( [26a-2]).

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

[0339] The compound (7R)-12-(benzyloxy)-1,11-di-side-oxy-N-(2,4,6-trifluorobenzyl)-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4]diazidine-10-methamide ( [26a-1] (20 mg, 0.039 mmol) was dissolved in toluene (1 mL), followed by the addition of TFA (1 mL). The resulting mixture was stirred overnight at rt. The solvent was removed under vacuum, and the residue was purified by HPLC to obtain the title compound ( [26-1]). MS (m / z) 422.116 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.58 (s, 1H), 10.39 (t, J = 5.8 Hz, 1H), 8.45 (s, 1H), 7.18 (dd, J = 9.2, 8.0 Hz, 2H), 4.73 (s, 1H), 4.58 - 4.49 (m, 2H), 4.11 (d, J = 13.3 Hz, 1H), 3.85 (d, J = 14.6 Hz, 1H), 3.65 (d, J = 14.2 Hz, 1H), 3.10 - 3.00 (m, 1H), 1.96 (m, 1H), 1.82 (d, J = 12.2 Hz, 3H), 1.61 (d, J = 7.4 Hz, 1H), 1.18 - 1.05 (m, 1H). Example 24: Preparation of N-(2,4-difluorobenzyl)-7-hydroxy-6,8,15-trilateral-oxy-6,8,13,14-tetrahydro-12H-5,12-methylbridged benzo[e]pyrido[1,2-a][1,4]diazanol-9-methamide (27): [synthesis] [3-] [Amine] [-1,3,4,5-] [Tetrahydrogen] [-2H-] [Benzoan] [b] [Nitrogen Boom] [-2-] [ketone] [TFA] [Salt] [(27a)] [:] []

[0340] TFA (1 mL) was added to a solution of (2-sidekto-2,3,4,5-tetrahydro-1H-benzo[b]azinon-3-yl)aminocarbamate (55 mg, 0.02 mmol) in DCM (3 mL) at room temperature. After 4 h, the solvent and excess TFA were removed to give 3-amino-1,3,4,5-tetrahydro-2H-benzo[b]azinon-2-one. MS (m / z) 276.676 [M+H]+. [synthesis] [7-(] [Benzyloxy] [)-N-(2,4-] [Difluorobenzyl] [)-6,8,15-] [Trilateral oxygen group] [-6,8,13,14-] [Tetrahydrogen] [-12H-5,12-] [Methaprisified Benzo[]] [[e]] [pyrido] [[1,2-a][1,4]] [Dazazine] [-9-] [Methionine] [(27b)] [:] []

[0341] Follow with compounds

[25] A similar procedure was used to prepare 7-(benzyloxy)-N-(2,4-difluorobenzyl)-6,8,15-trisyloxy-6,8,13,14-tetrahydro-12H-5,12-methylbridged benzo[e]pyrido[1,2-a][1,4]diazanine-9-methamide from 3-amino-1,3,4,5-tetrahydro-2H-benzo[b]azopyridine TFA salt (45 mg, 0.163 mmol) and methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)aminomethoxy)-4-sideoxy-4H-piperan-2-carboxylate (70 mg, 0.163 mmol). MS (m / z) 555.034 [M+H]+. [synthesis] [N-(2,4-)] [Difluorobenzyl] [)-7-] [Hydroxy] [-6,8,15-] [Trilateral oxygen group] [-6,8,13,14-] [Tetrahydrogen] [-12H-5,12-] [Methaprisified Benzo[]] [[e]] [pyrido] [[1,2-a][1,4]] [Dazazine] [-9-] [Methionine] [(27)] [:] []

[0342] Follow with compounds

[26] A similar procedure was followed to prepare N-(2,4-difluorobenzyl)-7-hydroxy-6,8,15-trisyloxy-6,8,13,14-tetrahydro-12H-5,12-methylbridged benzo[e]pyrido[1,2-a][1,4]diazine-9-methamide (11 mg) as the starting material.

[27] ). MS (m / z) 465.05 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.25 (t, J = 5.9 Hz, 1H), 8.61 (s, 1H), 7.42 (d, J = 7.1 Hz, 1H), 7.29 (ddd, J = 12.1, 9.4, 2.8 Hz, 1H), 7.25 - 7.18 (m, 2H), 7.14 - 7.01 (m, 3H), 5.74 (s, 2H), 5.45 (s, 1H), 4.54 (d, J = 5.8 Hz, 1H), 3.68 (s, 2H), 3.64 (d, J = 2.8 Hz, 1H). Example 25: Preparation of (7S)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-disideloxy-1,3,4,6,7,11-hexahydro-2,7-methylbridged pyrido[1,2-d][1,4,7]oxadazonine-10-methamide (28): [synthesis] [(7S)-12-(] [Benzyloxy] [)-N-(2,4-] [Difluorobenzyl] [)-1,11-] [Dilateral oxygen group] [-1,3,4,6,7,11-] [Hexahydrogen] [-2,7-] [Methioninated pyridyl] [[1,2-d][1,4,7]] [Oxadiazepines] [-10-] [Methionine] [(28a)] [:] []

[0343] Sodium bicarbonate (109.6 mg, 1.3 mmol) and methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)aminomethyl)-4-sideoxy-4H-piperan-2-carboxylate (70 mg, 0.163 mmol) were added to a solution of 1,4-oxazacycloheptan-6-amine (18.9 mg, 0.16 mmol) in MeOH (6 mL) and water (1 mL). The reaction mixture was heated to 50 °C overnight. The reaction mixture was cooled to room temperature and extracted with ethyl acetate (100 mL). The organic layer was concentrated under vacuum. The residue was used in the next step without purification. MS (m / z) 496.016 [M+H]+. [synthesis] [(7S)-N-(2,4-] [Difluorobenzyl] [)-12-] [Hydroxy] [-1,11-] [Dilateral oxygen group] [-1,3,4,6,7,11-] [Hexahydrogen] [-2,7-] [Methioninated pyridyl] [[1,2-d][1,4,7]] [Oxadiazepines] [-10-] [Methionine] [(28)] [:] []

[0344] To the (7S)-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-disideloxy-1,3,4,6,7,11-hexahydro-2,7-methylbridged pyrido[1,2-d][1,4,7]oxadazine-10-methamide from the above reaction ( Toluene (1 mL) and TFA (1 mL) were added to the solution of [28a]. After 4 h at room temperature, the solvent and excess TFA were removed under vacuum. The residue was dissolved in DMF and purified by preparative HPLC to give the title compound. MS (m / z) 406.83 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (t, J = 5.9 Hz, 1H), 8.50 (s, 1H), 7.39 (td, J = 8.7, 6.6 Hz, 1H), 7.27 - 7.20 (m, 1H), 7.05 (td, J = 7.6, 6.7, 4.0 Hz, 1H), 5.73 (s, 2H), 4.54 (d, J = 5.9 Hz, 2H), 4.34 - 4.23 (m, 1H), 4.10 (d, J = 14.3 Hz, 2H), 4.00 - 3.82 (m, 4H). Example 26: Preparation of (7R)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-disideloxy-1,3,4,6,7,11-hexahydro-2,7-methylbridgedpyrido[1,2-d][1,4,7]oxadazonine-10-methamide (29):

[0345] Follow with compounds (

[28] ) A similar procedure was used to synthesize (7R)-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-disidel-1,3,4,6,7,11-hexahydro-2,7-methyl-bridged pyrido[1,2-d][1,4,7]oxadazine-10-methamide from (R)-1,4-oxazacycloheptan-6-amine (18.9 mg, 0.163 mmol) and methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)aminomethoxy)-4-sidel-4H-piperan-2-carboxylate (70 mg, 0.163 mmol).

[29] ). MS (m / z) 406.136 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (t, J = 5.9 Hz, 1H), 8.51 (s, 1H), 7.42 - 7.37 (m, 1H), 7.21 (dd, J = 9.9, 2.5 Hz, 1H), 7.07 - 7.02 (m, 1H), 4.70 (s, 1H), 4.54 (d, J = 5.9 Hz, 2H), 4.30 - 4.23 (m, 1H), 4.09 (d, J = 5.8 Hz, 1H), 4.00 (d, J = 12.0 Hz, 1H), 3.89 (t, J = 8.9 Hz, 3H), 3.66 (d, J = 10.0 Hz, 2H). Example 27: Preparation of N-(2,4-difluorobenzyl)-12-hydroxy-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4,7]triazonine-10-methamide (30):

[0346] Follow with compounds

[28] A similar procedure was used to synthesize N-(2,4-difluorobenzyl)-12-hydroxy-1,11-disidel-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4,7]triazine-10-methamide from 1,4-diazacycloheptan-6-amine (75.1 mg, 0.652 mmol) and methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)aminomethoxy)-4-sidel-4H-piperan-2-carboxylate (140 mg, 0.326 mmol).

[30] ). MS (m / z) 405.183 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.70 (s, 1H), 10.37 (s, 1H), 8.52 (s, 1H), 7.42 - 7.34 (m, 1H), 7.22 (s, 1H), 7.05 (d, J = 2.6 Hz, 1H), 4.72 (s, 1H), 4.54 (d, J = 5.7 Hz, 2H), 4.16 (d, J = 12.8 Hz, 2H), 3.92 (d, J = 14.8 Hz, 2H), 3.72 (d, J = 15.0 Hz, 2H), 3.15 (s, 2H). Example 28: Preparation of 5-acetyl-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4,7]triazonine-10-methamide (31): [synthesis] [5-] [acetyl] [-12-(] [Benzyloxy] [)-N-(2,4-] [Difluorobenzyl] [)-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4,7]] [Triazine] [-10-] [Methionine] [(31)] [:] []

[0347] Under ice-water bath cooling, 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-di-side-oxy-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4,7]triazine-10-methamide ( [30a], 26 mg, 0.053 mmol) was added to a solution of DCM (5 mL) containing DIPEA (27.2 mg, 0.21 mmol) and acetyl chloride (6.2 mg, 0.079 mmol). After stirring for 4 h, the reaction mixture was extracted with ethyl acetate (100 mL). The organic layer was concentrated under vacuum. The residue was used in the next step without purification. MS (m / z) 537.013 [M+H]+.

[0348] Follow and use for preparing compounds

[30] The debenzylation conditions are similar to those of 5-acetyl-12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-di-side-oxy-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4,7]triazine-10-methamide ( [31a]) Synthesis of 5-acetylated-N-(2,4-difluorobenzyl)-12-hydroxy-1,11-disiderol-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4,7]triazine-10-methamide (

[31] ). MS (m / z) 447.159 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (t, J = 5.9 Hz, 1H), 8.59 (d, J = 19.5 Hz, 1H), 7.39 (td, J = 8.7, 6.6 Hz, 1H), 7.22 (ddd, J = 10.6, 9.4, 2.7 Hz, 1H), 7.05 (ddt, J = 10.0, 7.4, 1.3 Hz, 1H), 5.73 (s, 2H), 4.54 (d, J = 6.0 Hz, 2H), 4.42 - 4.32 (m, 1H), 3.97 - 3.88 (m, 2H), 3.78 (d, J = 15.1 Hz, 2H), 3.20 - 3.15 (m, 1H), 1.86 (s, 3H). Example 29: Preparation of N-(2,4-difluorobenzyl)-12-hydroxy-5-(methylsulfonyl)-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4,7]triazonine-10-methamide (32):

[0349] Follow and use for preparing compounds

[31] A similar procedure was used, but with the addition of methanesulfonyl chloride (9 mg, 0.079 mmol), to synthesize N-(2,4-difluorobenzyl)-12-hydroxy-5-(methanesulfonyl)-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4,7]triazine-10-methamide (26 mg, 0.053 mmol) from 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4,7]triazine-10-methamide.

[32] ). MS (m / z) 483.083 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (t, J = 6.0 Hz, 1H), 8.56 (s, 1H), 7.38 (dd, J = 8.7, 6.7 Hz, 1H), 7.22 (ddd, J = 10.5, 9.3, 2.6 Hz, 1H), 7.14 - 6.96 (m, 1H), 4.54 (d, J = 5.9 Hz, 2H), 4.21 (dd, J = 6.6, 3.3 Hz, 1H), 3.98 (s, 2H), 3.90 - 3.75 (m, 4H), 3.45 (d, J = 15.0 Hz, 1H), 3.29 (d, J = 9.2 Hz, 1H), 3.23 - 3.10 (m, 1H), 2.88 (s, 3H). Example 30: Preparation of N-(2,4-difluorobenzyl)-12-hydroxy-5-methyl-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4,7]triazonine-10-methamide (33): [synthesis] [12-(] [Benzyloxy] [)-N-(2,4-] [Difluorobenzyl] [)-5-] [methyl] [-1,11-] [Dilateral oxygen group] [-1,4,5,6,7,11-] [Hexahydrogen] [-3H-2,7-] [Methioninated pyridyl] [[1,2-a][1,4,7]] [Triazine] [-10-] [Methionine] [(33)] [:] []

[0350] DIPEA (25.1 mg, 0.194 mmol) and MeI (10.3 mg, 0.073 mmol) were added to a solution of 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-di-side-oxy-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4,7]triazine-10-methamide (24 mg, 0.049 mmol) in DMF (1.5 mL) at room temperature. After stirring for 4 h, the reaction mixture was extracted with ethyl acetate (100 mL). The organic layer was concentrated under vacuum. The residue was used in the next step without purification. MS (m / z) 509.11 [M+H]+.

[0351] Follow and use for preparing compounds

[30] The debenzylation conditions are the same as those for 12-(benzyloxy)-N-(2,4-difluorobenzyl)-5-methyl-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4,7]triazine-10-methamide ( [33a]) Synthesis of N-(2,4-difluorobenzyl)-12-hydroxy-5-methyl-1,11-disiderol-1,4,5,6,7,11-hexahydro-3H-2,7-methyl-bridged pyrido[1,2-a][1,4,7]triazine-10-methamide (

[33] ). MS (m / z) 419.2 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 8.60 - 8.18 (m, 2H), 7.40 (td, J = 8.6, 6.6 Hz, 1H), 7.23 (td, J = 9.9, 2.6 Hz, 1H), 7.05 (td, J = 8.5, 2.5 Hz, 1H), 4.54 (d, J = 5.9 Hz, 2H), 4.17 (dt, J = 13.1, 8.1 Hz, 1H), 3.89 - 3.77 (m, 3H), 3.71 - 3.60 (m, 1H), 3.28 (d, J = 7.3 Hz, 3H), 2.78 (s, 3H), 2.27 (s, 1H). Example 31: Preparation of N-(2,4-difluorobenzyl)-12-hydroxy-5-isopropyl-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4,7]triazonine-10-methamide (34):

[0352] Follow and use for preparing compounds

[33] A similar procedure was used, employing 2-iodopropane (12.38 mg, 0.073 mmol), to synthesize N-(2,4-difluorobenzyl)-12-hydroxy-5-isopropyl-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4,7]triazine-10-methamide (24 mg, 0.049 mmol) from 12-(benzyloxy)-N-(2,4-difluorobenzyl)-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4,7]triazine-10-methamide.

[34] ). MS (m / z) 447.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.43 (s, 1H), 10.40 - 10.30 (m, 1H), 8.58 (d, J = 17.2 Hz, 1H), 8.50 (s, 1H), 7.81 (d, J = 12.3 Hz, 1H), 7.38 (dd, J = 9.0, 6.8 Hz, 2H), 7.22 (ddd, J = 10.7, 9.3, 2.6 Hz, 2H), 7.05 (td, J = 8.5, 2.5 Hz, 2H), 4.53 (d, J = 5.7 Hz, 5H), 4.26 (s, 2H), 4.08 (s, 3H), 3.97 - 3.80 (m, 3H), 3.04 (s, 4H), 2.71 (s, 2H), 0.83 (s, 3H), 0.66 (s, 3H). Example 32: Preparation of (7R)-N-(3-chloro-2,4-difluorobenzyl)-12-hydroxy-1,11-disideloxy-1,4,5,6,7,11-hexahydro-3H-2,7-methylbridged pyrido[1,2-a][1,4]diazanol-10-methamide (35):

[0353] Follow and use for preparing compounds

[28] A similar procedure was used to synthesize (7R)-N-(3-chloro-2,4-difluorobenzyl)aminomethyl)-4-sideoxy-4H-piperan-2-carboxylic acid ethyl ester (170 mg, 0.356 mmol) and (R)-azacycloheptane-3-amine (48.7 mg, 0.427 mmol) from 3-(benzyloxy)-5-((3-chloro-2,4-difluorobenzyl)aminomethyl)-4-sideoxy-4H-piperan-2-carboxylic acid ethyl ester (170 mg, 0.356 mmol) and (R)-azacycloheptane-3-amine (48.7 mg, 0.427 mmol).

[35] ). MS (m / z) 438.1 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.42 (t, J = 6.0 Hz, 1H), 8.47 (s, 1H), 7.37 (td, J = 8.4, 6.2 Hz, 1H), 7.27 (td, J = 8.8, 1.6 Hz, 1H), 4.78 - 4.70 (m, 1H), 4.57 (d, J = 5.9 Hz, 2H), 4.16 - 4.08 (m, 2H), 3.86 (d, J = 14.9 Hz, 1H), 3.65 (dd, J = 14.7, 1.8 Hz, 1H), 3.06 (ddd, J = 13.2, 6.9, 3.5 Hz, 1H), 1.98 (dd, J = 7.5, 4.4 Hz, 1H), 1.90 - 1.70 (m, 3H), 1.62 (d, J = 7.5 Hz, 1H), 1.12 (d, J = 12.7 Hz, 1H). Example 33: Preparation of N-(2,4-difluorobenzyl)-7-hydroxy-6,8-disideloxy-6,8,13,14-tetrahydro-12H-5,12-methylbridged benzo[e]pyrido[1,2-a][1,4]diazanol-9-methamide (36): [synthesis] [(2,3,4,5-] [Tetrahydrogen] [-1H-] [Benzoan] [b] [Nitrogen Boom] [-3-] [base] [)] [Tributyl carbamate] [(36b)] [:] []

[0354] At room temperature, the third butyl ester of (2-sideoxy-2,3,4,5-tetrahydro-1H-benzo[b]azapyr-3-yl)aminocarbamate ( [36a]) 300 mg, 1.086 mmol) was added to a solution of BH 3-THF (6 mL, 1 N, 6 mmol) in THF (5 mL). After stirring overnight, the reaction mixture was quenched by adding MeOH and an aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate (100 mL). The organic layer was concentrated under vacuum. The residue was purified by silica gel chromatography to give tributyl (2,3,4,5-tetrahydro-1H-benzo[b]azido-3-yl)aminocarbamate. MS (m / z) 262.897 [M+H]+. [synthesis] [2,3,4,5-] [Tetrahydrogen] [-1H-] [Benzoan] [b] [Nitrogen Boom] [-3-] [amine] [(36c)] [:] []

[0355] At room temperature, the third butyl of (2,3,4,5-tetrahydro-1H-benzo[b]azapyron-3-yl)aminoformate ( [36b]) 13 mg, 0.05 mmol) was added to a solution of TFA (1 mL) in DCM (1 mL). After 2 h, the solvent and excess TFA were removed. The residue was used in the next step without purification. MS (m / z) 162.952 [M+H]+. [synthesis] [N-(2,4-)] [Difluorobenzyl] [)-7-] [Hydroxy] [-6,8-] [Dilateral oxygen group] [-6,8,13,14-] [Tetrahydrogen] [-12H-5,12-] [Methaprisified Benzo[]] [[e]] [pyrido] [[1,2-a][1,4]] [Dazazine] [-9-] [Methionine] [(36)] [:] []

[0356] Follow and use for preparing compounds

[28] A similar procedure was used to synthesize N-(2,4-difluorobenzyl)-5-((2,4-difluorobenzyl)aminomethyl)-4-sideoxy-4H-piperan-2-carboxylic acid methyl ester (30 mg, 0.07 mmol) and 2,3,4,5-tetrahydro-1H-benzo[b]azinon-3-amine.

[36] ). MS (m / z) 452.152 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.34 (t, J = 5.9 Hz, 1H), 8.59 (s, 1H), 7.41 (s, 1H), 7.36 - 7.16 (m, 5H), 7.05 (tdd, J = 8.5, 2.7, 1.1 Hz, 1H), 4.89 (s, 1H), 4.55 (d, J = 6.0 Hz, 2H), 4.18 (s, 1H), 3.74 (d, J = 2.1 Hz, 1H), 2.83 - 2.67 (m, 2H), 2.24 (s, 1H), 2.10 (s, 1H). Example 34: Preparation of (12R)- and (12S)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-di-side-oxy-6,8,13,14-tetrahydro-12H-5,12-methylbridged benzo[e]pyrido[1,2-a][1,4]diazanol-9-methamide (37-1, 37-2):

[0357] Follow and use for preparing compounds

[28] A similar procedure was performed by separation by diaphragmatic HPLC (IB 4.6 × 100 mm 5 mic column SFC chromatography, using EtOH (15%) as a co-solvent and racemic (2,3,4,5-tetrahydro-1H-benzo[b]azapyr-3-yl)aminocarbamate tributyl ester ( [36b]) Separation of (R)- and (S)-(2,3,4,5-tetrahydro-1H-benzo[b]azido-3-yl)aminocarbamate tributyl ester ( [37a-1]、 [37a-2], for each enantiomer, 164 mg, 0.625 mmol) synthesized (12R)- and (12S)-N-(2,4-difluorobenzyl)-7-hydroxy-6,8-dioxy-6,8,13,14-tetrahydro-12H-5,12-methylbridged benzo[e]pyrido[1,2-a][1,4]diazanol-9-methamide ( [37-1]、 [37-2]). Peak 1 ( [37a-1]) obtained [37-1]. MS (m / z) 452.16 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (t, J = 5.9 Hz, 1H), 8.62 (s, 1H), 7.48 - 7.21 (m, 7H), 7.13 - 7.03 (m, 1H), 4.91 (dq, J = 4.9, 2.5 Hz, 1H), 4.58 (d, J = 5.9 Hz, 2H), 4.23 - 4.14 (m, 1H), 3.75 (dd, J = 14.8, 2.1 Hz, 1H), 2.79 (dtd, J = 17.3, 14.5, 9.6 Hz, 2H), 2.27 (td, J = 12.1, 11.6, 4.8 Peak 2 (Hz, 1H), 2.15 - 2.05 (m, 1H). [37a-2]) obtained [37-2]. MS (m / z) 452.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 10.33 (t, J = 5.9 Hz, 1H), 8.59 (s, 1H), 7.40 (d, J = 6.9 Hz, 1H), 7.36 - 7.18 (m, 5H), 7.05 (td, J = 8.4, 2.5 Hz, 1H), 4.89 (s, 1H), 4.55 (d, J = 5.9 Hz, 2H), 4.16 (d, J = 14.5 Hz, 1H), 3.86 (s, 1H), 2.81 - 2.70 (m, 2H), 2.24 (d, J = 3.5 Hz, 1H), 2.09 (d, J = 8.4 Hz, 1H). Example 35: Preparation of (12R)- and (12S)-7-hydroxy-6,8-di-side-oxy-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methylbridged benzo[e]pyrido[1,2-a][1,4]diazanol-9-methamide (38-1, 38-2):

[0358] and [37-1] and [37-2] Similarly, methyl 3-(benzyloxy)-4-sideoxy-5-((2,4,6-trifluorobenzyl)aminomethyl)-4H-piperan-2-carboxylate was used instead of methyl 3-(benzyloxy)-5-((2,4-difluorobenzyl)aminomethyl)-4-sideoxy-4H-piperan-2-carboxylate to synthesize (12R)- and (12S)-7-hydroxy-6,8-disideoxy-N-(2,4,6-trifluorobenzyl)-6,8,13,14-tetrahydro-12H-5,12-methylbridged benzo[e]pyrido[1,2-a][1,4]diazidine-9-carboxylamine ( [38-1] and [38-2]). MS (m / z) 470.1 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.36 (t, J = 5.8 Hz, 1H), 10.25 (s, 1H), 8.57 (s, 1H), 7.36 - 7.24 (m, 4H), 7.19 (t, J = 8.6 Hz, 2H), 4.86 (s, 1H), 4.56 (d, J = 5.8 Hz, 2H), 4.14 (d, J = 14.5 Hz, 1H), 3.71 (dd, J = 14.8, 2.0 Hz, 1H), 2.81 - 2.69 (m, 2H), 2.27 - 2.17 (m, 1H), 2.08 (d, J = 9.7 Hz, 1H). Example 37: Preparation of (4R,7S,8S)- and (4S,7R,8R)-13-hydroxy-1,12-disideloxy-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,12-octahydro-2,8:4,7-dimethylbridged pyrido[1,2-a][1,4]diazacyclodecavene-11-methamide (40-1, 40-2): [synthesis] [4-] [bromine] [-2-] [Nitrogen-based bicyclic] [[4.2.1]] [the ninth of the ten Heavenly Stems] [-3-] [ketone] [(40a)] [:] []

[0359] PCl 5 (1.496 g, 7 mmol) was added to a solution of 2-azabicyclo[4.2.1]non-3-one (1 g, 7.18 mmol) in DCM (30 mL) under ice-water bath cooling. After stirring at 0–5 °C for 1 h, iodine (18.2 mg, 0.7 mmol) was added and the mixture was stirred for 5 min. Bromine (1.148 g, 7 mmol) was added to a solution of DCM (5 mL) at -5 °C and the mixture was stirred at room temperature for 1.5 h. Ice-water was added and stirring was continued for 30 min. The mixture was extracted with ethyl acetate (100 mL) and washed with aqueous Na₂S₂O₃ solution and brine. After drying and removal of solvent, the residue was crystallized from DCM and hexane to give the title compound. MS (m / z) 218.1 [M+H]⁺. [synthesis] [4-] [Azide group] [-2-] [Nitrogen-based bicyclic] [[4.2.1]] [the ninth of the ten Heavenly Stems] [-3-] [ketone] [(40b)] [:] []

[0360] 4-bromo-2-azabicyclo[4.2.1]non-3-one ( A mixture of [40a)] (330 mg, 1.513 mmol) and NaN 3 (394 mg, 6 mmol) in DMF (10 mL) was heated overnight at 120 °C in a microwave reactor. The reaction mixture was extracted with ethyl acetate (100 mL), and the extract was washed with brine, dried, and the solvent was removed. The residue was purified by silica gel chromatography to give 4-azido-2-azabicyclo[4.2.1]non-3-one ( [40b]). MS (m / z) 181.12 [M+H] +. [synthesis] [((1R,4S,6S)-3-] [Side group] [-2-] [Nitrogen-based bicyclic] [[4.2.1]] [the ninth of the ten Heavenly Stems] [-4-] [base] [)] [Aminocarboxylic acid, relative , ] [-] [Tributyl ester] [(40c)] [and] [((1R,4R,6S)-3-] [Side group] [-2-] [Nitrogen-based bicyclic] [[4.2.1]] [the ninth of the ten Heavenly Stems] [-4-] [base] [)] [Aminocarboxylic acid, relative , ] [-] [Tributyl ester] [(40d)] [:] []

[0361] The reactor was packed with 4-azido-2-azabicyclo[4.2.1]non-3-one under argon atmosphere. [40b]) (500 mg, 2.775 mmol), ditert-butyl dicarbonate (1.21 g, 6 mmol) and palladium / carbon (10 wt%, wet, 296 mg) in EtOH (30 mL). The reaction mixture was placed under vacuum and backfilled with hydrogen. After vigorous stirring for two hours, the reaction mixture was diluted with EtOH (50 mL), filtered through Celite®, and washed with ethyl acetate. The solvent was removed and the residue was purified by silica gel chromatography to obtain two diastereomers of the product, peak 1 and peak 2. Peak 1, ((1R,4S,6S)-3-sideoxy-2-azabicyclo[4.2.1]non-4-yl)aminocarbamate relative to ditert-butyl dicarbonate ( [40c]). MS (m / z) 255.02 [M+H]+. 1H NMR (400 MHz, chloroform-d) δ 6.10 - 5.84 (m, 2H), 4.12 (d, J = 4.9 Hz, 1H), 3.25 (dd, J = 14.6, 3.1 Hz, 1H), 3.10 (dddd, J = 14.8, 8.4, 6.9, 1.4 Hz, 1H), 2.53 (s, 1H), 2.36 (d, J = 6.2 Hz, 1H), 1.99 - 1.82 (m, 2H), 1.73 - 1.58 (m, 3H), 1.50 (d, J = 1.9 Hz, 1H), 1.45 (s, 9H). Peak 2, ((1R,4R,6S)-3-sideoxy-2-azabicyclo[4.2.1]non-4-yl)aminocarbamate relative to tertiary butyl ester ( [40d]). MS (m / z) 277.2 [M+Na] +. 1H NMR (400 MHz, chloroform-d) δ 5.89 (s, 1H), 5.56 (s, 1H), 4.02 (dd, J = 6.9, 4.5 Hz, 1H), 3.36 (ddd, J = 15.3, 7.6, 6.0 Hz, 1H), 2.76 (dt, J = 15.4, 6.5 Hz, 1H), 2.42 - 2.31 (m, 1H), 2.17 (s, 1H), 1.97 (s, 2H), 1.75 (d, J = 12.7 Hz, 2H), 1.67 - 1.55 (m, 1H), 1.45 (s, 9H), 1.41 (d, J = 5.7 Hz, 1H). [synthesis, relative , ] [-(1R,4S,6R)-2-] [Nitrogen-based bicyclic] [[4.2.1]] [the ninth of the ten Heavenly Stems] [-4-] [amine] [(40f)] [:] []

[0362] With (2-sideoxy-2,3,4,5-tetrahydro-1H-benzo[b]azinon-3-yl)aminocarbamate tributyl ester ( [36a]) proceeding to 2,3,4,5-tetrahydro-1H-benzo[b]azapyr-3-amine ( [36c]) is synthesized similarly, from ((1R,4S,6S)-3-sideoxy-2-azabicyclo[4.2.1]non-4-yl)aminoformic acid relative to tertiary butyl ester ( [40c]) Synthesis of relative -(1R,4S,6R)-2-azabicyclo[4.2.1]non-4-amine ( [40f]). [synthesis] [(4S,7R,8R)-] [and] [(4R,7S,8S)-13-(] [Benzyloxy] [)-1,12-] [Dilateral oxygen group] [-N-(2,4,6-)] [Trifluorobenzyl] [)-1,3,4,5,6,7,8,12-] [Octahydrogen] [-2,8:4,7-] [Dimethyl-bridged pyridyl] [[1,2-a][1,4]] [Dazacyclodecavene] [-11-] [Methionine] [(40g-1)] [、] [40g-2)] [:] []

[0363] By means of preparing compounds

[28] A similar procedure is used, consisting of a relative -(1R,4S,6R)-2-azabicyclo[4.2.1]non-4-amine ( [40f]) and methyl 3-(benzyloxy)-4-sideoxy-5-((2,4,6-trifluorobenzyl)aminomethyl)-4H-piperan-2-carboxylate synthesized relative-(4R,7S,8S)-13-(benzyloxy)-1,12-sideoxy-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,12-octahydro-2,8:4,7-dimethylbridged pyrido[1,2-a][1,4]diazacyclodecavene-11-methylamine ( [40g]), followed by palmar HPLC separation to obtain peak 1 ( [40g-1]) and peak 2 ( [40g-2]). MS (m / z) 538.2 [M+H] +. [synthesis] [(4R,7S,8S)-] [and] [(4S,7R,8R)-13-] [Hydroxy] [-1,12-] [Dilateral oxygen group] [-N-(2,4,6-)] [Trifluorobenzyl] [)-1,3,4,5,6,7,8,12-] [Octahydrogen] [-2,8:4,7-] [Dimethyl-bridged pyridyl] [[1,2-a][1,4]] [Dazacyclodecavene] [-11-] [Methionine] [(40-1)] [and] [40-2)] [:] []

[0364] Follow and use for preparing compounds

[28] is a similar procedure to that of the compound [40h-1] and [40h-2] Synthesis of (4R,7S,8S)- and (4S,7R,8R)-13-hydroxy-1,12-disideloxy-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,12-octahydro-2,8:4,7-dimethylbridged pyrido[1,2-a][1,4]diazacyclodecavene-11-methamide ( [40-1]、 [40-2]). MS (m / z) 448.2 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.37 (t, J = 5.8 Hz, 1H), 8.50 (s, 1H), 7.19 (t, J = 8.6 Hz, 2H), 4.55 (dd, J = 5.9, 2.8 Hz, 2H), 4.51 - 4.38 (m, 1H), 4.21 (dd, J = 13.4, 7.0 Hz, 1H), 3.80 (d, J = 15.1 Hz, 1H), 2.90 - 2.68 (m, 2H), 2.68 - 2.59 (m, 1H), 2.57 - 2.50 (m, 1H), 2.15 - 1.99 (m, 1H), 1.74 (d, J = 7.0 Hz, 2H), 1.49 (dd, J = 14.1, 6.9 Hz, 2H), 1.16 (d, J = 14.4 Hz, 1H). Example 38: Preparation of (4S,7R,8S)- and (4R,7S,8R)-13-hydroxy-1,12-disideloxy-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,12-octahydro-2,8:4,7-dimethylbridged pyrido[1,2-a][1,4]diazacyclodecavene-11-methamide (41-1 and 41-2):

[0365] With compounds [40-1] and [40-2] is prepared similarly, from ((1R,4R,6S)-3-sideoxy-2-azabicyclo[4.2.1]non-4-yl)aminoformic acid relative-tertiary butyl ester ( [40d]) Synthesis of (4S,7R,8S)- and (4R,7S,8R)-13-hydroxy-1,12-disideloxy-N-(2,4,6-trifluorobenzyl)-1,3,4,5,6,7,8,12-octahydro-2,8:4,7-dimethylbridged pyrido[1,2-a][1,4]diazacyclodecavene-11-methamide ( [41-1] and [41-2]). MS (m / z) 448.2 [M+H] +. 1H NMR (400 MHz, DMSO-d6) δ 10.38 (t, J = 5.8 Hz, 1H), 8.48 (s, 1H), 7.19 (t, J = 8.6 Hz, 2H), 4.78 (d, J = 9.2 Hz, 1H), 4.55 (t, J = 5.7 Hz, 2H), 4.08 (d, J = 13.3 Hz, 1H), 3.82 (d, J = 2.5 Hz, 1H), 3.05 - 2.88 (m, 2H), 2.42 (s, 1H), 2.19 (d, J = 14.0 Hz, 1H), 1.63 (dd, J = 13.2, 7.2 Hz, 3H), 1.40 (d, J = 11.9 Hz, 1H), 0.92 (d, J = 3.7 Hz, 1H). Example 39a: Preparation of N-(2,4-difluorobenzyl)-5-hydroxy-4,6-disideloxy-1,1a,2,4,6,10,11,11a-octahydro-3,10-methylbridged cyclopropenzo[f]pyrido[1,2-a][1,4]diazanol-7-methamide (42-1): [synthesis] [(1-] [Hydroxypentyl] [-4-] [ene] [-2-] [base] [)] [Benzyl carbamate] [(42a)] [:] []

[0366] Add 2-aminopent-4-en-1-ol (2000 mg, 19.8 mmol), 100 mL of water, and anhydrous potassium carbonate (2.5 g, 40 mmol) to a round-bottom flask. Add 100 mL of dioxane and benzyl chloroformate (3.1 mL, 22 mmol) to a second round-bottom flask. Stir the mixtures to dissolve. Cool the amine mixture in an ice bath and add the dioxane mixture. Slowly heat the reaction mixture to room temperature while stirring overnight. Dilute the reaction mixture with DCM and extract twice with DCM. Wash the organic extract with NH4Cl, dry over sodium sulfate, and concentrate. Purify the residue by silica gel chromatography to give the title compound. MS (m / z) 235.9 [M+H]+. [synthesis] [(1-] [Side-oxypentyl] [-4-] [ene] [-2-] [base] [)] [Benzyl carbamate] [(42b)] [:] []

[0367] Add (1-hydroxypent-4-en-2-yl)aminobenzyl formate to a round-bottom flask. [42a], 3 g, 13 mmol) and 200 mL DCM, followed by Desmartin periodane (6 g, 14.2 mmol). After stirring for 1 h, more Desmartin periodane (2 g, 4.7 mmol) was added to the reaction mixture and stirring was continued for another 30 min. The mixture was diluted with DCM, saturated NaHCO3 solution and 11 g sodium thiosulfate was added. The resulting mixture was stirred for about 10 min and extracted twice with DCM. The organic extract was washed with a mixture of brine, water and NaHCO3, dried over sodium sulfate and concentrated to give the title compound. MS (m / z) 234.0 [M+H]+. [synthesis] [(1-() [Allylamino] [)] [E] [-4-] [ene] [-2-] [base] [)] [Benzyl carbamate] [(42c)] [:] []

[0368] Add (6 g, 26 mmol) benzyl (1-semi-oxypent-4-en-2-yl)aminocarbamate and THF (100 mL) to a round-bottom flask. Add allylamine (2.1 mL, 28.3 mmol) and sodium triacetoxyborohydride (8.2 g, 39 mmol), and stir the reaction mixture overnight. Quench the reaction mixture with a saturated aqueous solution of NaHCO3 (20 mL) and extract the mixture with EtOAc (100 mL × 3). Dry the combined organic extracts over anhydrous sodium sulfate and concentrate under vacuum to give the title compound. MS (m / z) 275.2 [M+H]+. [Synthetic allyl] [(2-((()] [Benzyloxy] [)] [Carbonyl] [)] [Amine] [)] [E] [-4-] [ene] [-1-] [base] [)] [Benzyl carbamate] [(42d)] [:] []

[0369] Add (1-(allylamino)pent-4-en-2-yl)aminobenzyl formate to a round-bottom flask. [42c], 6.3 g, 23.1 mmol), 120 mL of water and anhydrous potassium carbonate (2.9 g, 46.2 mmol). Add 120 mL of dioxane and benzyl chloroformate (3.6 mL, 25.4 mmol) to a second round-bottom flask. Stir the mixtures to dissolve. Cool the amine mixture in an ice bath and add the dioxane mixture. Slowly heat the reaction mixture to room temperature while stirring overnight. Dilute the reaction mixture with DCM and extract twice with DCM. Wash the organic ...

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, wherein R1 is H or a C6-10 aryl group, wherein the C6-10 aryl group is substituted by one to four RA1 groups, wherein each RA1 group is independently a halogroup, a C1-6 alkyl group, a C1-4 haloalkyl group, a cyano group, an O-C1-4 alkyl group, or a C1-4 alkyl-O-C1-4 alkyl group; R2 is H, a C1-6 alkyl group, or a C1-4 haloalkyl group; L is -CH2-, -CH(CH3)-, -C(O)-, or -CH2-CH2-; W1 is a bond or -CR4aR4b-; W2 is -CR5aR5b-, -CR5aR5bCR5cR5d-, -N(R7)-, -CR5aR5b-O-, or -CR5aR5b-C(O)-; X is -CR8aR8b-; Y is -C(O)NH- or Q, where Q is; Z is -CR9aR9b-, -CR9aR9bCR9cR9d-, or -CR10a=CR10b-; R4a and R4b are independently H, C1-6 alkyl, C1-4 haloalkyl, or halogroup; R5a, R5b, R5c, and R5d are independently H, C1-6 alkyl, C1-4 haloalkyl, halogroup, hydroxyl, cyano, -O-C1-4 alkyl, or C1-4 alkyl-O-C1-4 alkyl; or as appropriate: R5a and R5b or R5c and R5d, together with the carbon atoms they are attached to, form a 3- to 7-membered saturated or partially unsaturated spirocyclic ring, wherein the spirocyclic ring is optionally substituted by one to three RA3 groups, each RA3 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group; or R5a and R5c or R5b and R5d, together with the carbon atoms they are attached to, form a 3- to 7-membered saturated or partially unsaturated fused cyclic ring, wherein the fused ring is optionally substituted by one to three RA3 groups, each RA3 group being independently a halogroup, a C1-4 alkyl group, or a C1-4 haloalkyl group; R7 is H, a C1-6 alkyl group, a C1-4 haloalkyl group, a C(O)Rc group, or a SO2Rc group; R8a is H, hydroxyl, -O-C1-4 alkyl, C1-4 alkyl, C1-4 haloalkyl, or halo; and R8b and one of R5a, R5b, R5c, R5d, and R7, together with the atoms to which they are attached, form a 3- to 7-membered saturated fused carbide ring, wherein the fused carbide ring is optionally substituted by one to four RA5s, wherein each RA5 is independently a halo or C1-4 alkyl; or R9a, R9b, R9c, and R9d are each independently H, C1-6 alkyl, C1-4 haloalkyl, or halo; or, as appropriate: R9a and R9b or R9c and R9d, together with the carbon atoms to which they are attached, form a 3- to 7-membered saturated or partially unsaturated spirocyclic ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the spirocyclic ring is optionally substituted by one to three RA6s, wherein each RA6 is independently a halo, C1-4 alkyl, or C1-4 haloalkyl;Alternatively, R9a and R9c or R9b and R9d, together with their respective attached carbon atoms, form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 heteroatoms selected from N, O, and S or 1 heteroatom selected from N, O, and S, wherein the fused ring is optionally substituted by one to three RA6 groups, each RA6 group being independently a halogroup, C1-4 alkyl group, or C1-4 haloalkyl group; or one of R9a, R9b, R9c, and R9d, and one of R4a, R4b, R5a, R5b, and R7, together with their respective attached atoms, form a 3- to 7-membered saturated or partially unsaturated fused ring containing 0 to 2 heteroatoms selected from N, O, and S, wherein the fused ring is optionally substituted by one to four RA6 groups, each RA6 group being independently a halogroup or C1-4 alkyl group; R10a and R10b are independently H, halogroup, C1-4 haloalkyl group, or C1-6 alkyl group; or, as appropriate: R10a and R10b, together with their respective attached carbon atoms, form a 5- to 10-membered partially unsaturated fused ring, or a 5- to 10-membered fused aromatic ring, or a 5- to 10-membered fused heteroaromatic ring containing 0 heteroatoms selected from N, O, and S, or 1 heteroatomium selected from N, O, and S, wherein the partially unsaturated fused ring, fused aromatic ring, or fused heteroaromatic ring is, as appropriate, substituted by one to four RA7 groups, each RA7 group being independently a halogroup or a C1-4 alkyl group; Rb is H or a C1-4 alkyl group; Rc is a C1-4 alkyl group; and n is 0, 1, or 2.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R2 is H or a C1-4 alkyl group.

3. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein Y is -C(O)NH-.

4. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, having formula (II): .

5. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R1 is a phenyl group substituted with one, two, three or four RA1 groups, wherein each RA1 group is independently a halogroup or an -O-Cl-4 alkyl group.

6. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, wherein R1 is selected from the group consisting of:

7. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R1 is a phenyl substituted with one, two, three or four halogens.

8. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R1 is...

9. The compound of claim 1 or 2 or its pharmaceutically acceptable salt has the following formula: .

10. The compound of claim 1 or 2 or its pharmaceutically acceptable salt, having formula (IV): .

11. The compound of claim 1 or 2 or its pharmaceutically acceptable salt has the following formula: .

12. A compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein W1 is a bond or -CR4aR4b-; wherein R4a and R4b are independently H, C1-6 alkyl or halogroup.

13. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R8a is H, C1-4 alkyl, C1-4 haloalkyl or halogen.

14. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein R8a is H.

15. The compound of claim 1 or 2 or a pharmaceutically acceptable salt thereof, wherein Z is -CR9aR9b-.

16. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of: , , and.

17. A pharmaceutical composition comprising a therapeutically effective amount of any one of claims 1 to 16 of the compound or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipient.

18. The pharmaceutical composition of claim 17, further comprising one, two, three or four additional therapeutic agents.

19. The pharmaceutical composition of claim 17 or 18, wherein the pharmaceutical composition is for oral or non-enteral administration.

20. A kit comprising a compound as claimed in any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, and instructions for use.

21. The kit as requested in item 20 may further include one, two, three or four additional therapeutic agents.

22. Use of a compound of any one of claims 1 to 16 or a pharmaceutically acceptable salt thereof or a pharmaceutical composition of any one of claims 17 to 19, for the manufacture of an agent for treating HIV infection in humans who are infected with HIV or at risk of HIV infection.

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