Monomeric and multimeric anti-HBV drugs

Abstract

The present invention relates to compounds, compositions and methods for preventing, treating or curing Hepatitis B (HBV) infection in human subjects or other animal hosts. The compounds are also used as pharmaceutically acceptable salts, prodrugs and other derivatives thereof in pharmaceutical compositions and methods for treating, preventing or eradicating HBV infection.

Description

[Technical Field]

[0001] The present invention relates to compounds, methods, and compositions for preventing, treating, and / or curing Hepatitis B virus (HBV) infection. More specifically, the present invention describes, inter alia, substituted aromatic / heteroaromatic compounds, pharmaceutically acceptable salts, or other derivatives thereof, and their use as monomeric or conjugated multimeric agents in the treatment or cure of HBV infection. [Background technology]

[0002] Hepatitis B virus (HBV) poses a serious human health problem and is second only to tobacco as a cause of human cancer. The mechanism by which HBV induces cancer is unclear. It is speculated that HBV may directly induce tumorigenesis or indirectly induce tumorigenesis through the chronic inflammation, cirrhosis, and cellular regeneration associated with this infection.

[0003] After an incubation period of 2 to 6 months, during which the host is usually unaware of the infection, HBV infection can cause acute hepatitis and liver damage, resulting in abdominal pain, jaundice, and high blood levels of certain enzymes. HBV can also cause fulminant hepatitis, a rapidly progressive and often fatal form of the disease in which large parts of the liver are destroyed.

[0004] Subjects usually recover from the acute phase of HBV infection. However, in some people, the virus continues to replicate for a long or indeterminate period, causing chronic infection. Chronic infection can lead to chronic persistent hepatitis. Subjects infected with chronic persistent HBV are most prevalent in developing countries. By mid-1991, there were approximately 225 million chronic carriers in Asia alone and nearly 300 million worldwide. Chronic persistent hepatitis can lead to fatigue, cirrhosis, and hepatocellular carcinoma, a primary liver cancer.

[0005] In industrialized countries, high-risk groups for HBV infection include those who have contact with HBV carriers or their blood samples. The epidemiology of HBV is very similar to that of HIV / AIDS, which is why HBV infection is common among people infected with HIV or with AIDS. However, HBV is much more infectious than HIV. 3TC (lamivudine), interferon alfa-2b, pegylated interferon alfa-2a, Hepsera (adefovir pivoxil), Baraclude (entecavir), Taizeka (telbivudine), and Viread (tenofovir disoproxil fumarate) are currently FDA-approved drugs for the treatment of HBV infection. Another nucleoside, tenofovir alafenamide fumarate (TAF) (formerly GS-7340), was also recently approved. All of these drugs are highly effective in reducing viral load, but none of them can provide high remission rates. In addition, their effectiveness is limited due to problems of drug resistance, low efficacy, and poor tolerability. The low cure rate of HBV is mainly due to the presence and persistence of covalently closed circular DNA (cccDNA) in the nuclei of infected hepatocytes.

[0006] Therefore, there is an urgent need for novel HBV drugs that are highly potent, safe, act by a mechanism different from nucleoside analogues, and can reduce the inactive form of HBV known as cccDNA.

[0007] It would be beneficial to provide novel antiviral agents, compositions containing these agents, and methods of treatment using these agents to treat HBV and prevent the development of drug-resistant HBV. The present invention provides such agents, compositions, and methods. Summary of the Invention

[0008] The present invention provides compounds, methods, and compositions for preventing, treating, and / or curing HBV infection in a host, or reducing the activity of HBV in a host, comprising administering a therapeutically or prophylactically effective amount of at least one compound described herein to treat, cure, or prevent infection by HBV infection, or administering an amount sufficient to reduce the biological activity of HBV infection.

[0009] The pharmaceutical compositions comprise one or more compounds described herein in combination with a pharmaceutically acceptable carrier or excipient for treating HBV-infected hosts. These compounds can be used in combination with nucleoside and non-nucleoside inhibitors of HBV. The formulations can further comprise at least one other therapeutic agent. Additionally, the present invention includes a process for preparing such compounds.

[0010] Also disclosed are pharmaceutical compositions comprising one or more compounds of Formulas 1-10 and a pharmaceutically acceptable carrier. The carrier can be, for example, an oral composition, an injectable composition, a transdermal composition, or a nanoparticle composition. The composition can further comprise a second antiviral agent, particularly if that agent is active against HBV infection, and more particularly if that second antiviral agent is active against HBV infection via a different mechanism than the compounds described herein.

[0011] Representative types of second antiviral agents include polymerase inhibitors, viral entry inhibitors, viral maturation inhibitors, capsid assembly modulators, IMPDH inhibitors, protease inhibitors, immune-based therapeutics, reverse transcriptase inhibitors, TLR agonists, and agents with different or unknown mechanisms. Combinations of these agents can be used.

[0012] The compounds described herein can be used to prepare a medicament for treating, preventing, or reducing the biological activity of HBV infection. The medicament can further comprise another anti-HBV drug.

[0013] The compounds and compositions can be used in methods for treating a host infected with HBV, preventing HBV infection, and reducing the biological activity of HBV infection in a host. The methods can also include co-administration with another anti-HBV agent, which can be simultaneous or sequential.

[0014] These and other aspects of the present invention are further described in the detailed description that follows. DETAILED DESCRIPTION OF THE INVENTION

[0015] Compounds and compositions useful for treating, preventing, or curing HBV infection are disclosed. Methods for treating, preventing, or curing HBV infection are also disclosed.

[0016] The compounds described herein exhibit inhibitory activity against HBV in cell-based assays. Therefore, the compounds can be used to treat or prevent HBV in a host, or to reduce the biological activity of the virus. The host can be a mammal, particularly a human, infected with HBV. The method includes administering an effective amount of one or more of the compounds described herein.

[0017] Also disclosed are pharmaceutical formulations comprising one or more of the compounds described herein in combination with a pharmaceutically acceptable carrier or excipient. In one embodiment, the formulation comprises at least one compound described herein and at least one additional therapeutic agent. The invention will be better understood with reference to the following definitions.

[0018] I. Definition Hepatitis B virus (HBV) capsid assembly is a critical step in virus production. As used herein, an "HBV capsid assembly effector" is a compound that inhibits HBV capsid assembly. In some embodiments, these compounds target or misdirect capsid assembly and / or disrupt preformed capsids, resulting in the inhibition of HBV replication and virion production.

[0019] As used herein, the term "inhibition of assembly" of an HBV capsid assembly effector includes, but is not limited to, modulating the rate of capsid assembly, stabilizing or destabilizing assembly, and disrupting preformed capsids.

[0020] Small molecule compounds, or capsid assembly effectors, that target the HBV core can be divided into two major classes based on their effect on assembly: the phenylpropenamide and sulfamoylbenzamide chemical families accelerate the formation of capsid-like particles (Campagna et al., “Sulfamoylbenzamide derivatives inhibit the assembly of hepatitis B virus nucleocapsids,” J Virol 87:6931-6942 (2013); Katen et al., “Trapping of hepatitis B virus capsid assembly intermediates by phenylpropenamide assembly accelerators,” ACS Chem Biol 5:1125-1136 (2010)), while the heteroaryldihydropyrimidine (HAP) compound family induces the formation of aggregated, abnormal capsid structures (Stray and Zlotnick, “BAY 41-4109 has multiple effects on hepatitis B virus capsid assembly,” J Mol Recognit 19:542-548(2006), Wang et al., “In vitro inhibition of HBV replication by a novel compound,GLS4, and its efficacy against adefovir-dipivoxil-resistant HBV mutations“.Antivir Ther 17:793-803(2012)).

[0021] Representative examples include AB-506 (Arbutus Biopharma), JNJ-379 (also known as JNJ-56136379, which binds to HBV core protein, disrupts early and late steps in the viral life cycle, interferes with RNA encapsidation, and blocks hepatitis B virus replication), AT-61, AT-130, Bay41-4109, NVR3-778, GLS4, HAP-12, bis-ANS, and RO7049389 (core allosteric modulator (Roche)). Additional HBV capsid assembly inhibitors are described, for example, in U.S. Patent Application Publication No. 20180000824, which identifies the following HBV capsid assembly inhibitor: 3-[(8aS)-7-[[(4R)-4-(2-chloro-3-fluorophenyl)-5-ethoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1, 5-a]pyrazin-2-yl]-2,2-dimethyl-propanoic acid;3-[(8aS)-7-[[(4S)-5-ethoxycarbonyl-4-(3-fluoro-2-methyl-phenyl)-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-3-oxo-5,6,8,8a-tetrahydro-1H-imidazo[1,5-a]pyrazin-2-yl]-2,2-dimethylpropanoic acid;2-[(1R,3S,5S )-8-[[(4R)-4-(2-chloro-3-fluorophenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1,4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]octan-3-yl]-acetic acid;2-[(1S,3R,5R)-8-[[(4R)-4-(2-chloro-3-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-1, 4-dihydropyrimidin-6-yl]methyl]-6,6-difluoro-8-azabicyclo[3.2.1]-octan-3-yl]acetic acid; or (S)-4-[(R)-6-(2-chloro-4-fluoro-phenyl)-5-methoxycarbonyl-2-thiazol-2-yl-3,6-dihydropyrimidin-4-ylmethyl]morpholine-3-carboxylic acid; or a pharmaceutically acceptable salt, enantiomer or diastereomer thereof.It also has the following formula: [ka] (In the formula, R 9 is C 1-6 alkyl; R 10 is phenyl, which is a halogen or C 1-6 substituted once, twice or three times by alkyl; R 11 is hydrogen or C 1-6 alkyl; R 12 is a monocyclic, bicyclic, or bicyclic bridged heterocyclyl. ) or a pharmaceutically acceptable salt, enantiomer, or diastereomer thereof.

[0022] Another representative HBV capsid inhibitor disclosed in Wang et al., Antimicrob. Agents Chemother. November 2015 vol. 59, no. 11, 7061-7072, has the following structure: [ka]

[0023] The term "independently" is used herein to indicate that the variables being independently applied vary independently from application to application. Thus, in a compound such as R"XYR", where R" is "independently carbon or nitrogen", both R" can be carbon, both R" can be nitrogen, or one R" can be carbon and the other R" can be nitrogen.

[0024] As used herein, the term "enantiomerically pure" means a compound composition that contains at least about 95%, and preferably about 97%, 98%, 99% or 100%, of a single enantiomer of that compound.

[0025] As used herein, the terms "substantially free" or "substantially in the absence" refer to a compound composition that contains at least 85% to 90%, preferably 95% to 98%, and even more preferably 99% to 100% by weight of a specified enantiomer of that compound. In preferred embodiments, the compounds described herein are substantially free of enantiomers.

[0026] Similarly, the term "isolated" refers to a compound composition that contains at least 85% to 90% by weight, preferably 95% to 98% by weight, and even more preferably 99% to 100% by weight of the compound, with the remainder containing other chemical species or enantiomers.

[0027] As used herein, the term "alkyl," unless otherwise specified, refers to a saturated, linear, branched, or cyclic primary, secondary, or tertiary hydrocarbon, including both substituted and unsubstituted alkyl groups. The alkyl group may be optionally substituted with any moiety that does not otherwise interfere with the reaction or that results in a process improvement, including, but not limited to, halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphonate, optionally unprotected or protected, as known to those skilled in the art, for example, as taught in Greene, et al., Protective Groups in Organic Synthesis, John Wiley and Sons, Second Edition, 1991. Specifically included are CF3 and CH2CF3.

[0028] In the description, whenever the term C (alkyl range) is used, this term includes each member of that class independently as if specifically and separately stated. The term "alkyl" refers to C 1-22 The term "lower alkyl" includes C 1-6 It is understood by those skilled in the art that related alkyl radicals are designated by replacing the suffix "-ane" with the suffix "-yl".

[0029] As used herein, "bridged alkyl" means a bicyclo or tricycloalkane, for example, 2:1:1 bicyclohexane.

[0030] As used herein, "spiroalkyl" means two rings joined at a single (quaternary) carbon atom.

[0031] The term "alkenyl" refers to a straight- or branched-chain unsaturated hydrocarbon radical containing one or more double bonds. The alkenyl groups disclosed herein may be optionally substituted with any moiety that does not adversely affect the reaction process, including, but not limited to, those listed as substituents for the alkyl moiety. Non-limiting examples of alkenyl groups include ethylene, methylethylene, isopropylidene, 1,2-ethanediyl, 1,1-ethanediyl, 1,3-propanediyl, 1,2-propanediyl, 1,3-butanediyl, and 1,4-butanediyl.

[0032] The term "alkynyl" refers to a straight- or branched-chain unsaturated acyclic hydrocarbon radical containing one or more triple bonds. Alkynyl groups may be optionally substituted with any moiety that does not adversely affect reaction processes, including, but not limited to, those described above for alkyl moieties. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, hydroxypropynyl, butyn-1-yl, butyn-2-yl, pentyn-1-yl, pentyn-2-yl, 4-methoxypentyn-2-yl, 3-methylbutyn-1-yl, hexyn-1-yl, hexyn-2-yl, and hexyn-3-yl, 3,3-dimethylbutyn-1-yl radicals.

[0033] The terms "alkylamino" or "arylamino" refer to an amino group having one or two alkyl or aryl substituents, respectively.

[0034] As used herein, unless otherwise specified, the term "protected" means a group added to an oxygen, nitrogen, or phosphorus atom to prevent it from further reaction or for other purposes. A wide variety of oxygen and nitrogen protecting groups are known to those skilled in the art of organic synthesis and are described, for example, in Greene et al., Protective Groups in Organic Synthesis (ibid.).

[0035] The term "aryl," alone or in combination, refers to a carbocyclic aromatic system containing one, two, or three rings, which may be linked together in a pendant manner or may be fused. Non-limiting examples of aryl include phenyl, biphenyl, or naphthyl, or other aromatic groups remaining after removing a hydrogen from an aromatic ring. The term aryl includes both substituted and unsubstituted moieties. Aryl groups may be optionally substituted with any moiety that does not adversely affect the process, including, but not limited to, those listed above for alkyl moieties. Non-limiting examples of substituted aryls include heteroarylamino, N-aryl-N-alkylamino, N-heteroarylamino-N-alkylamino, heteroaralkoxy, arylamino, aralkylamino, arylthio, monoarylamidosulfonyl, arylsulfonamido, diarylamidosulfonyl, monoarylamidosulfonyl, arylsulfinyl, arylsulfonyl, heteroarylthio, heteroarylsulfinyl, heteroarylsulfonyl, aroyl, heteroaroyl, aralkanoyl, heteroaralkanoyl, hydroxyaralkyl, hydroxyheteroaralkyl, haloalkoxyalkyl, aryl, aralkyl, aryloxy, aralkoxy, aryloxyalkyl, saturated heterocyclyl, partially saturated heterocyclyl, heteroaryl, heteroaryloxy, heteroaryloxyalkyl, arylalkyl, heteroarylalkyl, arylalkenyl, and heteroarylalkenyl, carboaralkoxy.

[0036] The terms "alkaryl" or "alkylaryl" refer to an alkyl group with an aryl substituent. The terms "aralkyl" or "arylalkyl" refer to an aryl group with an alkyl substituent.

[0037] As used herein, the term "halo" includes chloro, bromo, iodo or fluoro.

[0038] The term "acyl" refers to a carboxylic acid ester in which the non-carbonyl portion of the ester group is selected from the group consisting of linear, branched, or cyclic alkyl or lower alkyl; alkoxyalkyl, including but not limited to, methoxymethyl; aryl, including but not limited to, phenyl optionally substituted with halogen (F, Cl, Br, or I); alkyl (including but not limited to, C1, C2, C3, and C4) or alkoxy (including but not limited to, C1, C2, C3, and C4); sulfonate esters such as alkyl or aralkylsulfonyl, including but not limited to, methanesulfonyl; mono-, di-, or triphosphate esters; trityl or monomethoxytrityl; substituted benzyl; trialkylsilyl (e.g., dimethyl-t-butylsilyl); or diphenylmethylsilyl. The aryl group in the ester most suitably comprises a phenyl group. The term "lower acyl" refers to an acyl group in which the non-carbonyl portion is lower alkyl.

[0039] The term "aliphatic" refers to hydrocarbons that are not aromatic and includes those with open chain structures such as alkanes, alkenes, and alkynes, ideally having 1 to 10 carbons, and cyclic hydrocarbons, ideally having 3 to 10 carbons.

[0040] The terms "alkoxy" and "alkoxyalkyl" encompass straight- or branched-chain oxy-containing radicals having an alkyl moiety, such as a methoxy radical. The term "alkoxyalkyl" similarly encompasses alkyl radicals having one or more alkoxy radicals attached to the alkyl radical (i.e., forming monoalkoxyalkyl and dialkoxyalkyl radicals). An "alkoxy" radical may be further substituted with one or more halo atoms, such as fluoro, chloro, or bromo, to provide a "haloalkoxy" radical. Examples of such radicals include fluoromethoxy, chloromethoxy, trifluoromethoxy, difluoromethoxy, trifluoroethoxy, fluoroethoxy, tetrafluoroethoxy, pentafluoroethoxy, and fluoropropoxy.

[0041] The term "alkylamino" refers to "monoalkylamino" and "dialkylamino," each containing one or two alkyl radicals attached to an amino radical. The term arylamino refers to "monoarylamino" and "diarylamino," each containing one or two aryl radicals attached to an amino radical. The term "aralkylamino" encompasses an aralkyl radical attached to an amino radical. The term aralkylamino refers to "monoaralkylamino" and "diaralkylamino," each containing one or two alkyl radicals attached to an amino radical. The term aralkylamino encompasses one aralkyl radical and one alkyl radical attached to an amino radical.

[0042] As used herein, the term "heteroatom" means oxygen, sulfur, nitrogen, and phosphorus.

[0043] As used herein, "heteroaryl" or "heteroaromatic" means an aromatic group that contains at least one of sulfur, oxygen, nitrogen, or phosphorus in the aromatic ring.

[0044] The terms "heterocycle," "heterocyclyl," and cycloheteroalkyl refer to a non-aromatic cyclic group in which at least one heteroatom is present, such as oxygen, sulfur, nitrogen, or phosphorus.

[0045] Non-limiting examples of heteroaryl and heterocyclic groups include furyl, furanyl, pyridyl, pyrimidyl, thienyl, isothiazolyl, imidazolyl, tetrazolyl, pyrazinyl, benzofuranyl, benzothiophenyl, quinolyl, isoquinolyl, benzothienyl, isobenzofuryl, pyrazolyl, indolyl, isoindolyl, benzimidazolyl, purinyl, carbazolyl, oxazolyl, thiazolyl, isothiazolyl, 1,2,4-thiadiazolyl, isoxazolyl, pyrrolyl, quinazolinyl, cinnolinyl, phthalazinyl, xanthinyl, hypoxanthinyl, thiophene, furan, pyrrole, isopyrrole, pyrazole, imidazole, 1 , 2,3-triazole, 1,2,4-triazole, oxazole, isoxazole, thiazole, isothiazole, pyrimidine or pyridazine, and pteridinyl, aziridinyl, thiazole, isothiazole, 1,2,3-oxadiazole, thiazine, pyridine, pyrazine, piperazine, pyrrolidine, oxaziranes, phenazine, phenothiazine, morpholinyl, pyrazolyl, pyridazinyl, pyrazinyl, quinoxalinyl, xanthinyl, hypoxanthinyl, pteridinyl, 5-azacytidinyl, 5-azauracilyl, triazolopyridinyl, imidazolopyridinyl, pyrrolopyrimidinyl, pyrazolopyrimidinyl, adenine, N 6 -Alkylpurines, N 6 -Benzylpurine, N 6 -Haloprin, N 6 -Viniprine, N 6 -acetylene purine, N 6 -Acylpurines, N 6 -Hydroxyalkylpurine, N 6 -thioalkylpurine, thymine, cytosine, 6-azapyrimidine, 2-mercaptopyrimidin, uracil, N 5 -Alkylpyrimidine, N 5 -benzylpyrimidine, N 5 -halopyrimidines, N 5 -vinylpyrimidine, N 5 -acetylenepyrimidine, N 5 -Acylpyrimidine, N 5 -hydroxyalkylpurines, and N 6Examples of suitable protecting groups include -thioalkylpurines, and isoxazolyl. Heteroaromatic groups may be optionally substituted as described above for aryl. Heteroaromatic or heteroaromatic groups may be optionally substituted with one or more substituents selected from the group consisting of halogen, haloalkyl, alkyl, alkoxy, hydroxy, carboxyl derivatives, amide, amino, alkylamino, and dialkylamino. Heteroaromatics may be partially or fully hydrogenated, as desired. As a non-limiting example, dihydropyridine may be used in place of pyridine. Functional oxygen and nitrogen groups on heteroaromatic or heteroaryl groups can be protected as necessary or desired. Suitable protecting groups are well known to those skilled in the art and include trimethylsilyl, dimethylhexylsilyl, t-butyldimethylsilyl, trityl or substituted trityl, alkyl groups, acyl groups such as acetyl and propionyl, methanesulfonyl, and p-toluenesulfonyl. Heteroaromatic or heteroaromatic groups may be substituted with any moiety that does not adversely affect the process, including, but not limited to, those described above for aryl.

[0046] As used herein, the term "host" refers to a unicellular or multicellular organism in which a virus can replicate, including, but not limited to, cell lines and animals, preferably humans. Alternatively, the host can harbor a portion of the viral genome, the replication or function of which can be altered by the compounds of the present invention. The term host specifically refers to infected cells, cells transfected with all or part of the viral genome, and animals, particularly primates (including, but not limited to, chimpanzees) and humans. In most animal applications of the present invention, the host is a human. In certain indications, however, veterinary applications are expressly contemplated by the present invention (such as for use in treating chimpanzees).

[0047] The term "peptide" refers to a natural or synthetic compound containing 2 to 100 amino acids linked by the carboxyl group of one amino acid to the amino group of another.

[0048] The term "pharmaceutically acceptable salt or prodrug" is used throughout this specification to describe any pharmaceutically acceptable form of a compound (such as an ester) that, upon administration to a patient, provides the compound. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals, such as potassium and sodium, alkaline earth metals, such as calcium and magnesium, among many other acid salts well known in the pharmaceutical art.

[0049] The term "pharmaceutically acceptable salt or prodrug" is used throughout this specification to describe any pharmaceutically acceptable form (e.g., ester) of a compound that provides the compound upon administration to a patient. Pharmaceutically acceptable salts include those derived from pharmaceutically acceptable inorganic or organic bases and acids. Suitable salts include those derived from alkali metals, such as potassium and sodium, and alkaline earth metals, such as calcium and magnesium, among many other acids well known in the pharmaceutical art. A pharmaceutically acceptable prodrug refers to a compound that is metabolized, e.g., hydrolyzed or oxidized, in the host to form a compound of the present invention. Typical examples of prodrugs include compounds that have biologically labile protecting groups on functional moieties of the active compound. Prodrugs include compounds that can be oxidized, reduced, aminated, deaminated, hydroxylated, dehydroxylated, hydrolyzed, dehydrolyzed, alkylated, dealkylated, acylated, deacylated, phosphorylated, and / or dephosphorylated to produce the active compound. Prodrug forms of the compounds of the invention may possess antiviral activity, may be metabolized to form compounds that exhibit such activity, or may possess both of these properties.

[0050] II. Active Compounds HBV is an enveloped, partially double-stranded DNA (dsDNA) virus of the Hepadnavirus family (Hepadnaviridae). Its genome contains four overlapping reading frames: the precore / core gene, the polymerase gene, the L, M, and S genes (which encode three envelope proteins), and the X gene.

[0051] During infection, the partially double-stranded DNA genome (relaxed circular closed DNA; rcDNA) is converted to covalently closed circular DNA (cccDNA) in the host cell nucleus, and viral mRNA is transcribed. Upon encapsidation, pregenomic RNA (pgRNA), which also encodes core proteins and Pol, serves as a template for reverse transcription, regenerating the partially double-stranded DNA genome (rcDNA) within the nucleocapsid.

[0052] After hepatitis B infection, cccDNA can persist in hepatocytes and reactivate after clinical treatment. The relative amount of cccDNA present is an indicator of HBV treatment (Bourne, et al., (January 2007) "Quantitative analysis of HBV cccDNA from clinical specimens: correlation with clinical and virological response during antiviral therapy." Journal of Viral Hepatitis 14(1):56-63).

[0053] A capsid is the protein shell of a virus, containing oligomeric structural subunits made up of proteins called protomers. The observable three-dimensional morphological subunits, which may or may not correspond to individual proteins, are called capsomers. The capsid encloses the genetic material of the virus.

[0054] HBV capsid assembly around the RNA reverse transcriptase complex in vivo. Capsid assembly is required for reverse transcription of the RNA pregenome into its mature DNA form. In HBV, the predominant form of the capsid consists of 120 copies of a capsid protein dimer. Even slight mutations in the capsid protein can have dramatic effects on the viability of progeny viruses.

[0055] Most of the compounds described herein are active as capsid inhibitors. For example, inhibiting capsid assembly by disrupting or negatively affecting capsid assembly can reduce cccDNA, the main reservoir of HBV, and can also reduce the levels of HBV DNA, HBeAg, and HBsAg. Compounds that do not necessarily inhibit capsid formation, but rather regulate or affect capsid formation, are also known as capsid assembly regulators or capsid assembly effectors, and their use in the formation of dimers and trimers described herein is intended to be within the scope of the present invention.

[0056] In one embodiment, the compound has the formula: [ka] (In the formula, A 1 , B 1 and C 1 are independently HBV capsid assembly effectors, Each A 1 , and B 1 , and C 1 may be the same or different; L 1 -W 1 -(C 3-6 Alkyl-O) s -C 1-6 Alkyl-W 1 -;-W 1 -(CH2-CH2-O) t -C 1-6 Alkyl-W 1 -;-W 1 -((CH2-CH2-O)s ) m -;W 1 -C 1-30 Alkyl-W 1 -;W 1 -(C 3-6 Alkyl-O) s -C 1-6 Alkyl-X-(C 3-6 Alkyl-O) s -C 1-6 Alkyl-W 1 ;-W 1 -(CH2-CH2-O) t -C 1-6 Alkyl-X-(CH2-CH2-O) t -C 1-6 Alkyl-W 1 -, W 1 -C 1-30 Alkyl-XC 1-30 Alkyl-W 1 -; [ka] -NR'-;-N(R')C(O)-;-C(O)N(R')-;-N(R')SO2-;-SO2N(R')-;-O-;-C(O)-;-OC(O)-;-C(O)O-;-S-;-S(O)-;-SO2-;-C(=S)-;-C(=NR')-;-Si(R 7 )(R 8 )-;-Si(R 7 )(R 8 )-O-;-O-Si(R 7 )(R 8)-;-NR'-;-N(R')C(O)-;-C(O)N(R')-;-N(R')SO2-;-SON(R')-;-O-;-C(O)-;-OC(O)-;-C(O)O-;-S-;-S(O)-;-SO2-;-C(=S)-;-C(=NR')-; an optionally substituted unsaturated or partially saturated aliphatic moiety, an optionally substituted unsaturated or partially saturated cycloalkyl moiety; an optionally substituted unsaturated or partially saturated heteroaliphatic moiety; an optionally substituted unsaturated or partially saturated heterocycloalkyl moiety; an optionally substituted aryl, an optionally substituted heteroaryl, and covalently bonded combinations thereof; X is Si(R 7 )(R 8 )-;-Si(R 7 )(R 8 )-O-;-O-Si(R 7 )(R 8 )-;-NR'-;-N(R')C(O)-;-C(O)N(R')-;-N(R')SO2-;-SO2N(R')-;-O-;-C(O)-;-OC(O)-;-C(O)O-;-S-;-S(O)-;-SO2-;-C(=S)-; or -C(=NR')-; R" is independently H, alkylene, arylene, -C(O)-, -(C 3-6 Alkyl-O) s -C 1-6 Alkyl-;-(CH2-CH2-O) s -;C(O)N(R')-;-SON(R')-;-C(O)-;-OC(O)-;-C(O)O-;-S(O)-;-SO-;-C(=S)-;-C(=NR')-; or an optionally substituted unsaturated or partially saturated aliphatic moiety or an optionally substituted unsaturated or partially saturated heteroaliphatic moiety; only one of R" may be H; Optional substituents for heteroaliphatic, aliphatic, aryl, and heteroaryl moieties are selected from the group consisting of halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, silyl ether, boronic ester, boronic acid, phosphonic acid, phosphonamidate, and phosphonate; W 1 is independently at each occurrence aryl, heteroaryl, CHR', NR', N, O, or S; s and m are integers from 1 to 15; t is an integer from 3 to 15; R' is H, C 1-6 Alkyl, optionally unsaturated C 3-8 Cycloalkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, or arylalkyl; R 7 and R 8 are independently -OH, optionally unsaturated -OC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally unsaturated C 3-8 is cycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl; and Alternatively, R 7 and R 8together with the silicon to which they are attached form a 4-7 membered ring optionally containing one or more heteroatoms, each independently O, S, or N, which 4-7 membered ring may be optionally substituted with one or more substituents selected from the group consisting of C1-C3 alkyl, halogen, cyano, oxo, and OH, or an enantiomer, diastereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof.

[0057] In another embodiment, the compound has the following formula: [ka] (In the formula, R 1 is one or more R a C may be optionally substituted with 2-6 alkenyl, or one or more R a C may be optionally substituted with 2-6 is alkynyl, R a is C optionally substituted with one or more R' 1-6 alkyl, C optionally substituted with one or more R' 2-6 alkenyl, optionally substituted with one or more R' 2-6 Alkynyl, one or more R b , N3, -OR', -C(O)OR', oxo, -SF5, [ka] N(R')S(O)2R';-S-R';S(O)2R';S(O)2N(R')2, [ka] C may be optionally substituted with 3-6 is cycloalkyl, R b are independently cyano, N3, -O-R', -C(O)O-R', oxo, -SF5, [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] C may be optionally substituted with 1-6 alkyl; or containing one or more heteroatoms selected from the group consisting of N, O, and S, and one or more R d , optionally substituted with cycloalkylalkynyl, cycloalkyloxyl, or halocycloalkylalkyl; 5-8 is heteroaryl, R d is independently cyclopropanyl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyl, cyclopropanyloxy, halocyclopropanyl, or halocyclopropanyloxy; A is pyrrolidine or has one nitrogen and one or more R 2 is an optionally substituted 5- to 7-membered bicyclic heterocycle; R 2 are independently hydrogen, halogen, OH, C 1-6 Alkyl, C 2-6 Alkene, C 2-6 alkyne, haloalkyl, cycloalkyl, CN, amino, alkoxy, alkylsulfonylamino, azido, or cycloalkyloxyl; R 3 is hydrogen, halogen, C 1-6 alkyl, haloalkyl, alkyloxy, haloalkyloxy, or cycloalkyl; R 4 is 1 to 5 R 4a C may be optionally substituted with 6-10 aryl or one or more heteroatoms selected from the group consisting of N, O, and S, and one or more R 4b is a 5- to 12-membered heteroaryl optionally substituted with R 4a and R 4b are independently H, CN, halogen, -OC1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyl, cyclopropanyloxy, halocyclopropanyl, or halocyclopropanyloxy; R' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; R 10 and R 11 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; Alternatively, R 10 and R 11may together form a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; or a 3-membered ring containing 0 heteroatoms, and R 10 and R 11 The groups may independently be halo, C 1-6 Haloalkyl, C 1-6 or an enantiomer, diastereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, or a compound having the formula: (R) optionally substituted with one or more of the following substituents: hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivative, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate.

[0058] In another embodiment, the compound has the same general formula as Formula 2 above, or an enantiomer, diastereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, but with the variables defined as follows: R 1 is one or more R a C replaced with 1-6 alkyl, one or more R b C replaced with 3-6 cycloalkyl or one or more heteroatoms selected from the group consisting of N, O, and S, and one or more R c is a mono- or bicyclic heterocyclyl optionally substituted with R ais C optionally substituted with one or more R' 1-6 alkyl, C optionally substituted with one or more R' 2-6 alkenyl, optionally substituted with one or more R' 2-6 alkynyl, one or more R b , N3, -OR', -C(O)OR', oxo, -SF5, [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] C may be optionally substituted with 3-6 is cycloalkyl, R b are independently cyano, N3, -O-R', -C(O)O-R', oxo, -SF5, [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] C may be optionally substituted with 1-6 alkyl; or containing one or more heteroatoms selected from the group consisting of N, O, and S, and one or more R d , optionally substituted with cycloalkylalkynyl, cycloalkyloxyl, or halocycloalkylalkyl; 5-8 is heteroaryl, R c is one or more R a C may be optionally substituted with 2-6 alkenyl, one or more R a C may be optionally substituted with 2-6 Alkynyl, one or more R b , N3, -O-R', -SF5, [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] or -C(O)N(R')2 optionally substituted 3-6 is cycloalkyl, R d is independently cyclopropanyl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyl, cyclopropanyloxy, halocyclopropanyl, or halocyclopropanyloxy; A is pyrrolidine; or has one nitrogen and one or more R 2 is an optionally substituted 5- to 7-membered bicyclic heterocycle; R 2 are independently hydrogen, halogen, OH, C 1-6 Alkyl, C 2-6 Alkene, C 2-6 alkyne, haloalkyl, cycloalkyl, CN, amino, alkoxy, alkylsulfonylamino, azido, or cycloalkyloxyl; R 3 is hydrogen, halogen, C 1-6 alkyl, haloalkyl, alkyloxy, haloalkyloxy, or cycloalkyl; R 4 is 1 to 5 R 4a C may be optionally substituted with 6-10 aryl or one or more heteroatoms selected from the group consisting of N, O, and S, and one or more R 4b is a 5- to 12-membered heteroaryl optionally substituted with R 4a and R 4b are independently H, CN, halogen, -OC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6cycloalkyl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyl, cyclopropanyloxy, halocyclopropanyl, or halocyclopropanyloxy; R' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl; a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; R 10 and R 11 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; Alternatively, R 10 and R 11may together form a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; or a 3-membered ring containing 0 heteroatoms, and R 10 and R 11 The groups may independently be halo, C 1-6 Haloalkyl, C 1-6 optionally substituted with one or more of the following substituents: hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate; R 2 , R', R a , or R c At least one of the 2-6 Alkenyl or C 2-6 is alkynyl, or R 1 C 1-6 If it is alkyl, R a is OR 1 rather than, or R 1 When is cycloalkyl, R b is unsubstituted C 1-6 It is not alkyl or unsubstituted heteroaryl.

[0059] In one aspect of this embodiment, R 3 is haloalkyl, alkyloxyl, haloalkyloxy, or cycloalkyl.

[0060] In another aspect of this embodiment, R 1 is one or more R a C replaced with 1-6 alkyl, one or more R b C replaced with 3-6 cycloalkyl, or one or more heteroatoms selected from the group consisting of N, O, and S, and one or more R c is an optionally substituted monocyclic or bicyclic heterocyclyl; R a is C optionally substituted with one or more R' 1-6 alkyl, C optionally substituted with one or more R' 2-6 alkenyl, optionally substituted with one or more R' 2-6 Alkynyl, one or more R b , N3, -OR', -C(O)OR', oxo, -SF5, [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] C may be optionally substituted with 3-6 is cycloalkyl, R b are independently cyano, N3, -O-R', -C(O)O-R', oxo, -SF5, [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] C may be optionally substituted with 1-6 alkyl; or containing one or more heteroatoms selected from the group consisting of N, O, and S, and one or more R d, optionally substituted with cycloalkylalkynyl, cycloalkyloxyl, or halocycloalkylalkyl; 5-8 is heteroaryl, R c are independently one or more R a C may be optionally substituted with 2-6 alkenyl, one or more R a C may be optionally substituted with 2-6 Alkynyl, one or more R b , N3, -O-R', -SF5, [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] or -C(O)N(R')2 optionally substituted 3-6 is cycloalkyl, R d is independently cyclopropanyl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyl, cyclopropanyloxy, halocyclopropanyl, or halocyclopropanyloxy; A is pyrrolidine; or has one nitrogen and one or more R 2 is an optionally substituted 5- to 7-membered bicyclic heterocycle; R 2 are independently hydrogen, halogen, OH, C 1-6 Alkyl, C 2-6 Alkene, C 2-6 alkyne, haloalkyl, cycloalkyl, CN, amino, alkoxy, alkylsulfonylamino, azido, or cycloalkyloxyl; R 3 is hydrogen, halogen, C 1-6 alkyl, haloalkyl, alkyloxyl, haloalkyloxy, or cycloalkyl; R 4 is 1 to 5 R 4aC may be optionally substituted with 6-10 aryl or one or more heteroatoms selected from the group consisting of N, O, and S, and one or more R 4b is a 5- to 12-membered heteroaryl optionally substituted with R 4a and R 4b are independently H, CN, halogen, -OC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 Cycloalkyl, C 3-6 cycloalkyl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyl, cyclopropanyloxy, halocyclopropanyl, or halocyclopropanyloxy; R' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl; a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; R 10 and R 11 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; Alternatively, R 10 and R 11 may together form a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; or a 3-membered ring containing 0 heteroatoms, and R 10 and R 11 The groups may independently be halo, C 1-6 Haloalkyl, C 1-6 optionally substituted with one or more of the following substituents: hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate; R 2 , R', R a , or R c At least one of the 2-6 Alkenyl or C 2-6 is alkynyl, or R 1C 1-6 If it is alkyl, R a is OR 1 rather than, or R 1 When is cycloalkyl, R b is unsubstituted C 1-6 It is not alkyl or unsubstituted heteroaryl.

[0061] In one aspect of this embodiment, R 3 is haloalkyl, alkyloxyl, haloalkyloxyl, or cycloalkyl.

[0062] In another aspect of this embodiment, R 1 is C 1-6 alkyl, and R a is C optionally substituted with one or more R' 1-6 alkyl, C optionally substituted with one or more R' 2-6 alkenyl, optionally substituted with one or more R' 2-6 Alkynyl, one or more R b , N3, -OR', -C(O)O-R', oxo, -SF5, [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] C may be optionally substituted with 3-6 is cycloalkyl, R b are independently cyano, N3, -O-R', -C(O)O-R', oxo, -SF5, [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] C may be optionally substituted with 1-6 alkyl, or one or more heteroatoms selected from the group consisting of N, O, and S, and one or more R d , optionally substituted with cycloalkylalkynyl, cycloalkyloxyl, or halocycloalkylalkyl; 5-8 It is heteroaryl.

[0063] In another aspect of this embodiment, R 1 is cycloalkyl, R b are cyano, N3, -O-R', -C(O)O-R', oxo, -SF5, [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] C replaced with 1-6 alkyl; or containing one or more heteroatoms selected from the group consisting of N, O, and S, and one or more R d , cycloalkylalkynyl, cycloalkyloxyl, or halocycloalkylalkyl-substituted C 5-8 It is heteroaryl.

[0064] In still a further aspect of any of these embodiments, R 2 , R', R a , or R c At least one of the 2-6 Alkenyl or C 2-6 It is alkynyl.

[0065] In another embodiment, the compound has the formula: [ka] (In the formula, W 1 and W is N, NR m , C.R.m , O and S, with the proviso that W and W 1 If one of is O or S, the other is CR m and W 1 Or if one of W is N, the other is NR m It is assumed that X is N or CR n and Y is a bond, —C(O)—, or —SO—; Z is NH or -(CR 6 R 7 ) m -NH-, n is 0, 1, 2, or 3; m is 0, 1, 2, 3, or 4; R m and R n are independently H, C 1-6 Alkyl, C 2-6 Alkynyl, or C 2-6 is alkenyl, R 1 is one or more R z C may be optionally substituted with 2-6 is alkynyl, R z is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OH, aryl, heteroaryl, C 3-6 Cycloalkyl, C 3-6 Halocycloalkyl, C 3-6 heterocyclyl, CN, -C(O)R', -C(O)O-R', [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] and R 2 , R 3 and R 4H, OH, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, C 3-6 Halocycloalkyl, C 3-6 Heterocyclyl, -CN, OC 3-6 Cycloalkyl, and OC 3-6 independently selected from the group consisting of halocycloalkyl; Alternatively, R 2 and R 3 may together form a 5- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S; Alternatively, R 2 and R 4 together contain 1 to 3 heteroatoms selected from the group consisting of N, O, and S. 3-6 may form a cycloalkyl ring or a 3- to 7-membered heterocycle, R 5 is one or more R a C may be optionally substituted with 1-6 alkyl, one or more R a C may be optionally substituted with 2-6 alkenyl, one or more R a C may be optionally substituted with 2-6 Alkynyl, one or more R b C may be optionally substituted with 3-6 cycloalkyl, or one or more heteroatoms selected from the group consisting of N, O, and S, and one or more R c is a monocyclic or bicyclic heterocyclyl optionally substituted with R 6 is independently selected at each occurrence from the group consisting of H, —OH, halo, C-C alkyl, C-C haloalkyl, —O—C-C alkyl, and C-C alkyl-OH; R 7is selected from the group consisting of H, C1-C6 alkyl, and C1-C6 alkyl-OH; R a is C optionally substituted with one or more R' 1-6 alkyl, C optionally substituted with one or more R' 2-6 alkenyl, optionally substituted with one or more R' 2-6 Alkynyl, one or more R b , N3, -OR', -C(O)O-R', oxo, -SF5, [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] C may be optionally substituted with 3-6 is cycloalkyl, R b are independently cyano, N3, -O-R', -C(O)O-R', oxo, -SF5, [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] C may be optionally substituted with 1-6 alkyl; containing one or more heteroatoms selected from the group consisting of N, O, and S, and one or more R d , optionally substituted with cycloalkylalkynyl, cycloalkyloxyl, or halocycloalkylalkyl; 5-8 It is heteroaryl. R c are independently one or more R a C may be optionally substituted with 2-6 alkenyl, one or more R a C may be optionally substituted with 2-6Alkynyl, one or more R b , N3, -O-R', -SF5, [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] C optionally substituted with -C(O)N(R')2 3-6 is cycloalkyl, R d are independently cyclopropanyl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyl, cyclopropanyloxy, halocyclopropanyl, halocyclopropanyloxy; R' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; R 10 and R 11 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently N, O, or S; or R 10 and R 11 may together form a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; or a 3-membered ring containing 0 heteroatoms, R 10 and R 11 The groups may independently be halo, C 1-6 Haloalkyl, C 1-6 or an enantiomer, diastereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, or a compound having the formula: (R) optionally substituted with one or more of the following substituents: hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivative, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate.

[0066] In another embodiment, the compound has the same Formula 3 as above, or an enantiomer, diastereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, but with the variables defined as follows: W 1 and W is N, NR m , C.R. m , O and S, with the proviso that W and W 1 If one of is O or S, the other is CR m and W 1 Or if one of W is N, the other is NR m It is assumed that X is N or CR n and Y is a bond, —C(O)—, or —SO—; Z is NH or -(CR 6 R 7 ) m -NH-, n is 0, 1, 2, or 3; m is 0, 1, 2, 3, or 4; R m and R n are independently H, C 1-6 Alkyl, C 2-6 Alkynyl, or C 2-6 is alkenyl, R 1 is one or more R y C replaced with 2-6 alkenyl, one or more R y C replaced with 3-8 cycloalkyl, one or more R y C replaced with 3-6 heterocyclyl, or one or more R y C replaced with 1-6 is alkyl, R y is C 2-6 Alkynyl, C 2-6 Alkenyl, aryl, heteroaryl, C 3-6 Cycloalkyl, C 3-6 Halocycloalkyl, C3-6 heterocyclyl, -CN, -C(O)R', -C(O)O-R', [ka] -N(R')S(O)2R', -SR';-S(O)2R', -S(O)2N(R')2, [ka] and R 2 , R 3 and R 4 H, OH, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, OC 1-6 Alkyl, -OC 1-6 Haloalkyl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, C 3-6 Halocycloalkyl, C 3-6 Heterocyclyl, -CN, OC 3-6 Cycloalkyl, and OC 3-6 independently selected from the group consisting of halocycloalkyl; Alternatively, R 2 and R 3 may together form a 5- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S; Alternatively, R 2 and R 4 together contain 1 to 3 heteroatoms selected from the group consisting of N, O, and S. 3-6 may form a cycloalkyl ring or a 3- to 7-membered heterocycle, R 5 is one or more R a C may be optionally substituted with 1-6 alkyl, one or more R a C may be optionally substituted with 2-6 alkenyl, one or more R a C may be optionally substituted with 2-6 Alkynyl, one or more R bC may be optionally substituted with 3-6 cycloalkyl, or one or more heteroatoms selected from the group consisting of N, O, and S, and one or more R c is a monocyclic or bicyclic heterocyclyl optionally substituted with R 6 is independently selected at each occurrence from the group consisting of H, —OH, halo, C-C alkyl, C-C haloalkyl, —O—C-C alkyl, and C-C alkyl-OH; R 7 is selected from the group consisting of H, C1-C6 alkyl, and C1-C6 alkyl-OH; R a is C optionally substituted with one or more R' 1-6 alkyl, C optionally substituted with one or more R' 2-6 alkenyl, optionally substituted with one or more R' 2-6 Alkynyl, one or more R b , N3, -OR', -C(O)O-R', oxo, -SF5, [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] C may be optionally substituted with 3-6 is cycloalkyl, R b are independently cyano, N3, -O-R', -C(O)O-R', oxo, -SF5, [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] C may be optionally substituted with 1-6alkyl; containing one or more heteroatoms selected from the group consisting of N, O, and S, and one or more R d , optionally substituted with cycloalkylalkynyl, cycloalkyloxyl, or halocycloalkylalkyl; 5-8 It is heteroaryl. R c are independently one or more R a C may be optionally substituted with 2-6 alkenyl, one or more R a C may be optionally substituted with 2-6 Alkynyl, one or more R b , N3, -O-R', -SF5, [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] C optionally substituted with -C(O)N(R')2 3-6 is cycloalkyl, R d are independently cyclopropanyl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyl, cyclopropanyloxy, halocyclopropanyl, halocyclopropanyloxy; R' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; R 10 and R 11 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently N, O, or S; or R 10 and R 11 may together form a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; or a 3-membered ring containing 0 heteroatoms, R 10 and R 11 The groups may independently be halo, C 1-6 Haloalkyl, C 1-6It may be optionally substituted with one or more of the following substituents: hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate.

[0067] In yet another embodiment, the compound has the formula: [ka] (In the formula, W 1 and W each independently represent N, NR m , C.R. m , O or S, except for W and W 1 If one of is O or S, the other is CR m and W 1 Or if one of W is N, the other is NR m It is assumed that X is NR m or CR n and Y is a bond, —C(O)—, or —SO—; Z is NH or -(CR 6 R 7 ) m -NH-, n is 0, 1, 2, or 3; m is 0, 1, 2, 3, or 4; R m and R n are independently H, C 1-6 Alkyl, C 2-6 Alkynyl, or C 2-6 is alkenyl, R 2 , R 3 and R4 are independently, -OC 1-6 Haloalkyl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, C 3-6 Halocycloalkyl, C 3-6 Heterocyclyl, -CN, -OC 3-6 Cycloalkyl, or OC 3-6 halocycloalkyl, Alternatively, R 2 and R 3 may together form a 5- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S; Alternatively, R 2 and R 4 together contain 1 to 3 heteroatoms selected from the group consisting of N, O, and S. 3-6 may form a cycloalkyl ring or a 3- to 7-membered heterocycle, R 1 is C 3-6 Cycloalkyl, C 3-6 Heterocyclyl, C 1-6 alkyl, halo, one or more R z C may be optionally substituted with 2-6 Alkynyl, one or more R y C may be optionally substituted with 2-6 alkenyl, one or more R y C may be optionally substituted with 3-8 cycloalkyl, or one or more R y C may be optionally substituted with 3-6 heterocyclyl, or one or more R y C may be optionally substituted with 1-6 is alkyl, R z is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OH, C 2-6 Alkynyl, C 2-6 Alkenyl, aryl, heteroaryl, C 3-6 Cycloalkyl, C 3-6Halocycloalkyl, C 3-6 heterocyclyl, CN, -C(O)R', -C(O)O-R', [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] and R y is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkyl-OH, C 2-6 Alkynyl, C 2-6 Alkenyl, aryl, heteroaryl, C 3-6 Cycloalkyl, C 3-6 Halocycloalkyl, C 3-6 Heterocyclyl, —CN, —C(O)R′, —C(O)O-R′, [ka] -N(R')S(O)2R', -SR';-S(O)2R', -S(O)2N(R')2, [ka] and R 5 is one or more R a C may be optionally substituted with 1-6 alkyl, one or more R a C may be optionally substituted with 2-6 alkenyl, one or more R a C may be optionally substituted with 2-6 Alkynyl, one or more R b C may be optionally substituted with 3-6 cycloalkyl, or one or more heteroatoms selected from the group consisting of N, O, and S, and one or more R c is a monocyclic or bicyclic heterocyclyl optionally substituted with R6 is independently selected at each occurrence from the group consisting of H, —OH, halo, C-C alkyl, C-C haloalkyl, —O—C-C alkyl, and C-C alkyl-OH; R 7 is selected from the group consisting of H, C1-C6 alkyl, and C1-C6 alkyl-OH; R a is C optionally substituted with one or more R' 1-6 alkyl, C optionally substituted with one or more R' 2-6 alkenyl, optionally substituted with one or more R' 2-6 alkynyl, or one or more R b , N3, -OR', -C(O)O-R', oxo, -SF5, [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] C may be optionally substituted with 3-6 is cycloalkyl, R b are independently cyano, N3, -OR', -C(O)O-R', oxo, -SF5, [ka] N(R')S(O)2R', -SR', -S(O)2R', -S(O)2N(R')2, [ka] C may be optionally substituted with 1-6 alkyl; or containing one or more heteroatoms selected from the group consisting of N, O, and S, and one or more R d , optionally substituted with cycloalkylalkynyl, cycloalkyloxyl, halocycloalkylalkyl 5-8 is heteroaryl, R c are independently one or more R a C may be optionally substituted with 2-6 alkenyl, one or more R a C may be optionally substituted with 2-6 Alkynyl, one or more R b , -N3, -OR', -SF5, [ka] -N(R')S(O)2R', -SR', -S(O)2R', -S(O)2N(R')2, [ka] or -C(O)N(R')2 optionally substituted 3-6 is cycloalkyl, R d is independently cyclopropanyl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyl, cyclopropanyloxy, halocyclopropanyl, or halocyclopropanyloxy; R' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl; a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; R 10 and R 11 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; Alternatively, R 10 and R 11 may together form a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; or a 3-membered ring containing 0 heteroatoms, R 10 and R 11 The groups may independently be halo, C 1-6 Haloalkyl, C 1-6 or an enantiomer, diastereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, or a compound having the formula: (R) optionally substituted with one or more of the following substituents: hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivative, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate.

[0068] In one aspect of this embodiment, R′, R a , R c, R m , R n , R y , R z , R 1 , R 2 , R 3 , R 4 , or R 5 At least one of 2-6 It is alkynyl.

[0069] In yet another embodiment, the compound has the formula: [ka] (In the formula, W 1 and W each independently represent N, NR m , C.R. m , O or S, except for W and W 1 If one of is O or S, the other is CR m and W 1 Or if one of W is N, the other is NR m It is assumed that X is N or CR n and Y is a bond, —C(O)—, or —SO2—; Z is NH or -(CR 6 R 7 ) m -NH-, n is 0, 1, 2, or 3; m is 0, 1, 2, 3, or 4; R m and R n are independently H, C 1-6 Alkyl, C 2-6 Alkynyl, or C 2-6 is alkenyl, R 5 is one or more R b C may be optionally substituted with 1-4 alkyl, one or more R a C may be optionally substituted with 2-6 alkenyl, one or more R aC may be optionally substituted with 2-6 Alkynyl, one or more R a C may be optionally substituted with 3-6 cycloalkyl, or one or more heteroatoms selected from the group consisting of N, O, and S, and one or more R c is a monocyclic or bicyclic heterocyclyl optionally substituted with R 6 is independently selected at each occurrence from the group consisting of H, —OH, halo, C-C alkyl, C-C haloalkyl, —O—C-C alkyl, and C-C alkyl-OH; R 7 is selected from the group consisting of H, C1-C6 alkyl, and C1-C6 alkyl-OH; R a is C optionally substituted with one or more R' 1-6 alkyl, C optionally substituted with one or more R' 2-6 alkenyl, optionally substituted with one or more R' 2-6 Alkynyl, one or more R', N3, -O-R', -C(O)O-R', oxo, -SF5, [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] C may be optionally substituted with 3-6 is cycloalkyl, R b are independently one or more R a , N3, -OR', -C(O)O-R', oxo, -SF5, [ka] -N(R')S(O)2R', -SR', -S(O)2R', -S(O)2N(R')2, [ka] C may be optionally substituted with 1-6 is alkyl, R c are independently one or more R a C may be optionally substituted with 2-6 alkenyl, one or more R a C may be optionally substituted with 2-6 Alkynyl, one or more R b , -N3, -OR', -SF5, [ka] -N(R')S(O)2R', -SR', -S(O)2R', -S(O)2N(R')2, [ka] or -C(O)N(R')2 optionally substituted 3-6 is cycloalkyl, R d is independently cyclopropanyl, alkylaminocarbonyl, aminocarbonyl, alkylcarbonyl, cyclopropanyloxy, halocyclopropanyl, or halocyclopropanyloxy; R' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl; a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; R 10 and R 11 are independently H, C1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; Alternatively, R 10 and R 11 may together form a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; or a 3-membered ring containing 0 heteroatoms, R 10 and R 11 The groups may independently be halo, C 1-6 Haloalkyl, C 1-6 optionally substituted with one or more of the following substituents: hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate; R 1 is C 1-6 alkyl, halo, one or more R zC may be optionally substituted with 2-6 Alkynyl, one or more R y C may be optionally substituted with 2-6 alkenyl, one or more R y C may be optionally substituted with 3-8 cycloalkyl, one or more R y C may be optionally substituted with 3-6 heterocyclyl, one or more R y C may be optionally substituted with 1-6 is alkyl, R z is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkynyl, C 2-6 Alkenyl, aryl, heteroaryl, C 3-6 Cycloalkyl, C 3-6 Halocycloalkyl, C 3-6 heterocyclyl, -CN, -C(O)R', -C(O)O-R', [ka] N(R')S(O)2R', -S-R', S(O)2R', S(O)2N(R')2, [ka] and R y is C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Hydroxyalkyl, C 2-6 Alkynyl, C 2-6 Alkenyl, aryl, heteroaryl, C 3-6 Cycloalkyl, C 3-6 Halocycloalkyl, C 3-6 heterocyclyl, CN, -C(O)R', -C(O)O-R', [ka] -N(R')S(O)2R', -SR', -S(O)2R', -S(O)2N(R')2, [ka] and R 2 , R 3 and R 4 are independently H, OH, halo, C 1-6 Alkyl, C 1-6 Haloalkyl, OC 1-6 Alkyl, C 1-6 Alkyl-OH, -OC 1-6 Haloalkyl, C 2-6 Alkynyl, C 2-6 Alkenyl, C 3-6 Cycloalkyl, C 3-6 Halocycloalkyl, C 3-6 Heterocyclyl, -CN, OC 3-6 Cycloalkyl, or OC 3-6 halocycloalkyl, Alternatively, R 2 and R 3 may together form a 5- to 7-membered heterocycle containing 1 to 3 heteroatoms selected from the group consisting of N, O, and S, and Alternatively, R 2 and R 4 together contain 1 to 3 heteroatoms selected from the group consisting of N, O, and S. 3-6 may form a cycloalkyl ring or a 3- to 7-membered heterocycle, R', R a , R c , R m , R n , R y , R z , R 1 , R 2 , R 3 , R 4 , or R 5 At least one of 2-6 or an enantiomer, diastereoisomer, tautomer, pharmaceutically acceptable salt or prodrug thereof.

[0070] In yet another embodiment, the compound has the formula: [ka] (In the formula, A is H, CN, OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 is a thioalkyl or halogen; R 1 teeth, [ka] or optionally substituted C 1-6 is alkyl, R 2 is C, which may be optionally substituted with hydrogen, deuterium, or one or more fluoro atoms; 1-3 is alkyl, or R 2 and A, together with the carbons to which they are attached, optionally form a 4-7 membered ring containing one or more heteroatoms which are each independently O, S, or N, which 4-7 membered ring may be optionally substituted with one or more substituents selected from the group consisting of C1-C3 alkyl, halogen, oxo, and OH; R respectively 3 are independently H, -CN, OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 is a thioalkyl or halogen; R 6 is H, C 1-3 Alkyl, or C 1-3 is haloalkyl, B is -(CR 7 R 7a ) n - or -C(O)-, n is 0, 1, 2 or 3; each a is independently 0, 1, 2, 3, or 4; R respectively 7 and R7a are independently H, C 1-6 Alkyl or C 1-6 is haloalkyl, Alternatively, R 7 and R 7a may, together with the carbons to which they are attached, form a 6- to 10-membered bicyclic or bridged ring, a 3- to 8-membered saturated ring, or a 5-membered unsaturated ring, and such bicyclic, bridged, saturated, and unsaturated rings optionally contain one or more additional heteroatoms, each independently O, S, or N, and may further include halogen (F, Cl, Br, I), CF, hydroxy, -N(R')S(O)R', -S(O)R', -S(O)N(R'), C 1-6 Alkoxy, cyano, azido, C 2-6 Alkynyl, C 3-6 Alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 1-6 Alkyl, arylalkoxycarbonyl, carboxy, C 1-6 haloalkyl, heterocyclylalkyl, or C 1-6 each optionally substituted with one or more substituents independently selected from hydroxyalkyl; R' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; R 4 may be optionally substituted C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; optionally substituted C 1-6 The alkyl substituents are independently halo, C 1-6 Haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amide, carboxyl derivative, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate; R 5 H, -OR 10 , [ka] and R 10 and R 11 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; -COOR', -(C=O)-R', -S(O)R', -S(O)N(R')C(=O)NR'; -S(=O)-NR'; or -P(=O)(OR') R 10 and R 11 may together form a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; or a 3-membered ring containing 0 heteroatoms, R 10 and R 11 The groups may independently be halo, C 1-6 Haloalkyl, C 1-6 optionally substituted with one or more of the following substituents: hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate; R 12 and R 12a are independently H, F, C 1-6 Alkyl, C1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 3-membered ring containing 0 or 1 heteroatom, independently N, O, or S; -COOR 10 , -(CO)-R 10 , -N(R')S(O)2R', -S(O)2R', -S(O)2N(R')2, -C(=O)NR 10 R 11 ;-NR'-S(O)2-R 10 ;-NR'-S(O)2-NR 10 R 11 ; or -NR 10 -P(O)(OR 10 )2, Alternatively, R 12 and R 12a may together form a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; or a 3-membered ring containing 0 heteroatoms, R 12 and R 12a are on the same carbon, they may form -C=O together with the carbon to which they are attached; R 12 and R 12a The groups are independently halogen, C 1-6 Haloalkyl, C 1-6optionally substituted with one or more of the following substituents: hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, azide, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate; b is 0, 1, 2 or 3; c is independently 0, 1, 2, 3, 4, or 5; C is O, S, NR 10 , -C(O), or -C(R 12 R 12a )- and d is 0, 1, 2 or 3; F is sulfonyl or -C(R 12 R 12a )- and D is -C(R 12 R 12a )- or -O-, E is NR 10 , -C=O, or -C(R 12 R 12a )- and e is 0 or 1, R 14 , R 15 and R 16 are independently H, optionally substituted C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 3-membered ring containing 0 or 1 heteroatom, independently N, O, or S; -COOR 10 , -(C=O)-R 10 , -N(R')S(O)2R', -S(O)2R', -S(O)2N(R')2, -C(=O)NR 10 R 11 ;-NR'-S(=O)2-R 10 ;-NR'-S(=O)2-NR 10 R 11 ;-P(=O)(OR 10 )2 or -NR 10 -P(=O)(OR 10 )2, C 1-6 Optional substituents on alkyl are halogen, C 1-6 Haloalkyl, C 1-6 selected from the group consisting of hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amide, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, and phosphonate; R 14 , R 15 and R 16 is a halogen, C 1-6 Haloalkyl, C 1-6optionally substituted independently with one or more substituents selected from the group consisting of hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, and phosphonate; Alternatively, R 14 and R 16 may, together with the carbons to which they are attached, form a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring, R 3 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, or C 1-3 is thioalkyl, or R 4 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, or C 2-6 or an enantiomer, diastereoisomer, tautomer, pharmaceutically acceptable salt or prodrug thereof.

[0071] In one aspect of this embodiment, R 4 is C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6Alkenyl, or C 2-6 alkynyl, and in another embodiment, R 4 is C 2-6 It is alkynyl.

[0072] In another aspect of this embodiment, R 3 is C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, or C 1-3 It is a thioalkyl.

[0073] In another embodiment, the compound has the formula: [ka] (In the formula, A is H, CN, OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 is a thioalkyl or halogen; R 1 teeth, [ka] or optionally substituted C 1-6 is alkyl, R 2 is C, which may be optionally substituted with hydrogen, deuterium, or one or more fluoro atoms; 1-3 is alkyl, or R 2 and A, together with the carbons to which they are attached, optionally form a 4-7 membered ring containing one or more heteroatoms which are each independently O, S, or N, which 4-7 membered ring may be optionally substituted with one or more substituents selected from the group consisting of C1-C3 alkyl, halogen, oxo, and OH; R respectively 3 are independently H, -CN, -OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3is a thioalkyl or halogen; R 6 is H, C 1-3 Alkyl, or C 1-3 is haloalkyl, B is -(CR 7 R 7a ) n - or -C(O)-, n is 0, 1, 2 or 3; each a is independently 0, 1, 2, 3, or 4; R respectively 7 and R 7a are independently H, C 1-6 Alkyl or C 1-6 is haloalkyl, Alternatively, R 7 and R 7a may, together with the carbons to which they are attached, form a 6- to 10-membered bicyclic or bridged ring, a 3- to 8-membered saturated ring, or a 5-membered unsaturated ring, and such bicyclic, bridged, saturated, and unsaturated rings optionally contain one or more additional heteroatoms, each independently O, S, or N, and may further include halogen (F, Cl, Br, I), —CF, hydroxy, —N(R′)S(O)R′, —S(O)R′, —S(O)N(R′), C 1-6 Alkoxy, cyano, azido, C 2-6 Alkynyl, C 3-6 Alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 1-6 Alkyl, arylalkoxycarbonyl, carboxy, C 1-6 haloalkyl, heterocyclylalkyl, or C 1-6 each optionally substituted with one or more substituents independently selected from hydroxyalkyl; R' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl; a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; R 4 may be optionally substituted C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; optionally substituted C 1-6 The alkyl substituents are independently halo, C 1-6 Haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amide, carboxyl derivative, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate; R 5 H, -OR10 , [ka] and R 10 and R 11 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; -COOR', -(C=O)-R', -S(O)R', -S(O)N(R')C(=O)NR'; -S(=O)-NR'; or -P(=O)(OR') R 10 and R 11 may together form a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; or a 3-membered ring containing 0 heteroatoms, R 10 and R 11 The groups may independently be halo, C 1-6 Haloalkyl, C 1-6optionally substituted with one or more of the following substituents: hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate; R 12 and R 12a are independently H, F, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 3-membered ring containing 0 or 1 heteroatom, independently N, O, or S; -COOR 10 , -(CO)-R 10 , -N(R')S(O)2R', -S(O)2R', -S(O)2N(R')2, -C(=O)NR 10 R 11 ;-NR'-S(O)2-R 10 ;-NR'-S(O)2-NR 10 R 11 ; or -NR 10 -P(O)(OR 10 )2, Alternatively, R 12 and R 12amay together form a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; or a 3-membered ring containing 0 heteroatoms, R 12 and R 12a are on the same carbon, they may form -C=O together with the carbon to which they are attached; R 12 and R 12a The groups are independently halogen, C 1-6 Haloalkyl, C 1-6 optionally substituted with one or more of the following substituents: hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, azide, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate; b is 0, 1, 2 or 3; c is independently 0, 1, 2, 3, 4, or 5; C is O, S, NR 10 , -C(O), or -C(R 12 R 12a )- and d is 0, 1, 2 or 3; F is sulfonyl or -C(R 12 R 12a )- and D is -C(R 12 R 12a )- or -O-, E is NR 10 , -C=O, or -C(R12 R 12a )- and e is either 0 or 1, R 14 , R 15 and R 16 are independently H, optionally substituted C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 3-membered ring containing 0 or 1 heteroatom, independently N, O, or S; -COOR 10 , -(C=O)-R 10 , -N(R')S(O)2R', -S(O)2R', -S(O)2N(R')2, -C(=O)NR 10 R 11 ;-NR'-S(=O)2-R 10 ;-NR'-S(=O)2-NR 10 R 11 ;-P(=O)(OR 10 )2 or -NR 10 -P(=O)(OR 10 )2, C 1-6 Optional substituents on alkyl are halogen, C 1-6 Haloalkyl, C 1-6selected from the group consisting of hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amide, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, and phosphonate; R 14 , R 15 and R 16 is a halogen, C 1-6 Haloalkyl, C 1-6 optionally substituted independently with one or more substituents selected from the group consisting of hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, and phosphonate; Alternatively, R 14 and R 16 may, together with the carbons to which they are attached, form a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring.

[0074] In yet another embodiment, the compound has the formula: [ka] (In the formula, A is H, CN, OH, C 1-3 Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 is a thioalkyl or halogen; R 1 teeth, [ka] or optionally substituted C 1-6 is alkyl, optionally substituted C 1-6 Alkyl substituents include halogen, C 1-6 Haloalkyl, C 1-6 selected from the group consisting of hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amide, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, and phosphonate; R 2 is a C optionally substituted with hydrogen or one or more fluoro atoms 1-3 is alkyl, or R 2 and A, together with the carbons to which they are attached, optionally form a 4-7 membered ring containing one or more heteroatoms which are each independently O, S, or N, which 4-7 membered ring may be optionally substituted with one or more substituents selected from the group consisting of C1-C3 alkyl, halogen, oxo, and OH; R respectively 3 are independently H, -CN, OH, C 1-3Alkyl, C 1-3 Haloalkyl, C 1-3 Hydroxyalkyl, C 1-3 is a thioalkyl or halogen; each a is independently 0, 1, 2, 3, or 4; R 4 may be optionally substituted C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; optionally substituted C 1-6 Alkyl substituents include halogen, C 1-6 Haloalkyl, C 1-6 selected from the group consisting of hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amide, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, and phosphonate; R 12 and R 12a are independently H, F, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6Alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 3-membered ring containing 0 or 1 heteroatom, independently N, O, or S; -COOR 10 , -(C=O)-R 10 , -N(R')S(O)2R', -S(O)2R', -S(O)2N(R')2, -C(=O)NR 10 R 11 ;-NR'-S(=O)2-R 10 ;-NR'-S(O)2-NR 10 R 11 ; or -NR 10 -P(O)(OR 10 )2, R 10 and R 11 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; -COOR', -(CO)-R', -S(O)R', -S(O)N(R')C(=O)NR'; -S(O)-NR'; or -P(=O)(OR') R 10 and R 11may together form a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; or a 3-membered ring containing 0 heteroatoms, R 10 and R 11 The groups may independently be halo, C 1-6 Haloalkyl, C 1-6 optionally substituted with one or more of the following substituents: hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate; Alternatively, R 12 and R 12a may together form a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; or a 3-membered ring containing 0 heteroatoms, R 12 and R 12a are on the same carbon, they may form -C=O together with the carbon to which they are attached; R 12 and R 12a The groups are independently halogen, C 1-6 Haloalkyl, C 1-6optionally substituted with one or more of the following substituents: hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, azide, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, or phosphonate; R' is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; s is 0, 1, 2, or 3; t is 1, 2, 3, or 4; X is -C(R 12 R 12a )-, -C(=O)N(R 10 )-, -N(R 10 )-, -C(=NR 10 )-, -S(=O)N(R 10 )-, -O-, -S-, -C(=O)O-, -C(=O)-;-C(=S)-;-S(=O)-; or -S(=O)2-, u is independently 0, 1, 2, 3, 4, 6, or 7. or an enantiomer, diastereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof.

[0075] In one aspect of this embodiment, R 1 teeth, [ka] is.

[0076] In yet another embodiment, the compound has the formula: [ka] (In the formula, R 1 and R 1’ When attached to carbon, they are independently hydrogen, halogen, CF3, hydroxy, SF5, N(R')S(O)2R', S(O)2R', S(O)2N(R')2, C 1-6 Alkoxy, Cyano, C 2-6 Alkynyl, C 3-6 Alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 1-6 Alkyl, arylalkoxycarbonyl, carboxy, C 1-6 haloalkyl, heterocyclylalkyl, or C 1-6 is a hydroxyalkyl, R 1 and R 1’ When attached to nitrogen, they are independently hydrogen, C 1-6 Alkoxy, C 3-6 Alkoxyalkyl, alkoxycarbonyl, carbonylalkyl, carbonylaryl, C 1-6 Alkyl, C 2-6 Alkynyl, C 2-6 Alkenyl, heterocyclylalkyl, C 1-6 hydroxyalkyl, or S(O)R'; Each R' is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6cycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, or when two R' are on the same nitrogen atom, they together form a C 3-6 may form an alkyl ring, and the R' groups may be one or more substituents as defined above, for example C 1-6 optionally substituted with hydroxyalkyl, aminoalkyl, and alkoxyalkyl; u and v are independently 0, 1, 2, 3, 4, or 5; C is phenyl; a 6-membered heteroaromatic ring containing 1, 2, or 3 nitrogen atoms; a 5-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms which are independently N, O, or S; C 4-14 alkylheteroaryl, or alkylaryl; B is selected from the group consisting of a 5-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms which are independently N, O, or S; a 6- or 7-membered ring or a 6- or 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms which are independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms which are independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms which are independently N, O, or S; W is [ka] and R 12 is H, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, or C 2-6 is alkynyl, R 13 is C 7-20 Alkyl, C 7-20 Alkenyl, C 7-20 Alkynyl, [ka] and n is 1, 2, 3, 4, 5, 6, 7, or 8; R 13 are hydrogen, halogens (F, Cl, Br, I), CF3, SF5, hydroxy, [ka] -NH-C(O)-N(R 10 )2, -N(R 10 )2, -OR 11 , -C(O)OR 10 , -C(O)-N(R 10 )2, -C(O)-NHOH, oxo, [ka] -SR 10 , [ka] N(R 10 )S(O)2R 10 , S(O)2R 10 , S(O)2N(R 10 )2, C(O)R 10 a saturated or unsaturated 5-, 6-, or 7-membered ring or a 6- or 7-membered bridged or spiro-fused ring containing one or two heteroatoms, independently N, S, Se, or Si; C 1-6 Alkoxy, C 1-6 Haloalkoxy, Cyano, Azido, C 2-6 Alkynyl, C 3-6 Alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 1-6 Alkyl, cycloalkyl, arylalkoxycarbonyl, carboxyl, haloalkyl, heterocyclylalkyl, C 1-6 optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; The substituents of the substituted aryl and substituted heteroaryl are halogen, SF5, CF3, hydroxy, [ka] -NH-C(O)-N(R 10 )2, -N(R 10 )2, -OR 11 , -C(O)OR 10 , -C(O)-N(R 10 )2, -C(O)-NHOH, oxo, [ka] -SR 10 , [ka] N(R 10 )S(O)2R 10 , S(O)2R 10 , S(O)2N(R 10 )2, C(O)R 10 a saturated or unsaturated 5-, 6-, or 7-membered ring or a 6- or 7-membered bridged or spiro-fused ring containing one or two heteroatoms, independently N, S, Se, or Si; C3-C7 cycloalkyl; C 1-6 Alkoxy, cyano, azido, C 2-6 Alkynyl, C 3-6 Alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, and C 1-6 is selected from the group consisting of alkyl, Or, R 12 and R 13 together with the nitrogen to which they are attached, hydrogen, halogens (F, Cl, Br, I), CF3, hydroxy, [ka] -NH-C(O)-N(R 10 )2, -N(R 10 )2, -OR 11 , -C(O)OR 10 , -C(O)-N(R 10 )2, -C(O)-NHOH, oxo, [ka] -SR 10 , [ka] N(R 10 )S(O)2R 10 , S(O)2R 10 , S(O)2N(R 10 )2, C(O)R 10 , C 1-6 Alkoxy, cyano, azido, C 2-6 Alkynyl, C 3-6 Alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 1-6 Alkyl, arylalkoxycarbonyl, carboxy, C 1-6 Haloalkyl, heterocyclylalkyl, and C 1-6 a saturated or unsaturated 4- to 7-membered ring which may be optionally substituted with one or more substituents independently selected from the group consisting of hydroxyalkyl, R 10 and R 11 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; Alternatively, R 10 and R 11may together form a 5- to 8-membered ring or a 6-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused saturated or partially unsaturated ring containing zero, one, or two heteroatoms, independently N, O, or S; a 5-membered ring containing zero, one, or two heteroatoms, independently N, O, or S; a 4-membered ring containing zero, one, or two heteroatoms, independently N, O, or S; or a 3-membered ring containing zero heteroatoms; a saturated or partially unsaturated 6- to 12-membered heterobicyclic ring; a saturated or partially unsaturated 6- to 12-membered heterotricyclic ring, and R 10 and R 11 The groups may independently be halo, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 or an enantiomer, diastereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, or a compound having the formula: (I) optionally substituted with one or more of the following substituents: hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivative, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphoramidate, or phosphonate.

[0077] In still further embodiments, the compound has the following formula: [ka] (In the formula, R 1 and R 1’ When attached to carbon, they are independently hydrogen, halogen, CF3, hydroxy, SF5, N(R')S(O)2R', S(O)2R', S(O)2N(R')2, C1-6 Alkoxy, Cyano, C 2-6 Alkynyl, C 3-6 Alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 1-6 Alkyl, arylalkoxycarbonyl, carboxy, C 1-6 haloalkyl, heterocyclylalkyl, or C 1-6 is a hydroxyalkyl, R 1 and R 1’ When attached to nitrogen, they are independently hydrogen, C 1-6 Alkoxy, C 3-6 Alkoxyalkyl, alkoxycarbonyl, carbonylalkyl, carbonylaryl, C 1-6 Alkyl, C 2-6 Alkynyl, C 2-6 Alkenyl, heterocyclylalkyl, C 1-6 hydroxyalkyl, or S(O)R'; Each R' is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, or when two R' are on the same nitrogen atom, they together form a C 3-6 may form an alkyl ring, and the R' groups may be one or more substituents as defined above, for example C 1-6 optionally substituted with hydroxyalkyl, aminoalkyl, and alkoxyalkyl; u and v are independently 0, 1, 2, 3, 4, or 5; E is phenyl; a 6-membered heteroaromatic ring containing 1, 2, or 3 nitrogen atoms; a 5-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms which are independently N, O, or S; C 4-14 alkylheteroaryl, or alkylaryl; D is selected from the group consisting of a 5-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms, which are independently N, O, or S; a 6- or 7-membered ring or a 6- or 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, which are independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, which are independently N, O, or S; and a 4-membered ring containing 0, 1, or 2 heteroatoms, which are independently N, O, or S; W is [ka] and R 12 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, or C 2-6 is alkynyl, R 13 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, C 4-14 a bicyclic ring; a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, which are independently N, O, or S; or a 3- to 7-membered saturated or partially unsaturated ring containing one or more heteroatoms, each independently selected from the group N, O, or S; R 13 teeth, [ka] -NH-C(O)-N(R 10 )2, -N(R 10 )2, -OR 11 , -C(O)OR 10 , -C(O)-N(R 10 )2, -C(O)-NHOH, oxo, [ka] -SR 10 , [ka] and optionally substituted with one or more substituents each independently selected from the group consisting of: The substituents of the substituted aryl and substituted heteroaryl are: [ka] -NH-C(O)-N(R 10 )2, -N(R 10 )2, -OR 11 , -C(O)OR 10 , -C(O)-N(R 10 )2, -C(O)-NHOH, oxo, [ka] -SR 10 , [ka] selected from the group consisting of Or, R 12 and R 13 together with the nitrogen to which they are attached, [ka] -NH-C(O)-N(R 10 )2, -N(R 10 )2, -OR 11 , -C(O)OR 10 , -C(O)-N(R 10 )2, -C(O)-NHOH, oxo, [ka] -SR 10 , [ka] and forming a saturated or unsaturated 4- to 7-membered ring which may be optionally substituted with one or more substituents independently selected from the group consisting of: R 10 and R 11 are independently H, C 1-6 Alkyl, C1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; Alternatively, R 10 and R 11 may together form a 5- to 8-membered ring or a 6-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused saturated or partially unsaturated ring containing zero, one, or two heteroatoms, independently N, O, or S; a 5-membered ring containing zero, one, or two heteroatoms, independently N, O, or S; a 4-membered ring containing zero, one, or two heteroatoms, independently N, O, or S; or a 3-membered ring containing zero heteroatoms; or a saturated or partially unsaturated 6- to 12-membered heterobicyclic ring; or a saturated or partially unsaturated 6- to 12-membered heterotricyclic ring, and R 10 and R 11 The groups may independently be halo, C 1-6 Alkyl, C 3-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6or an enantiomer, diastereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof, or a compound having the formula: (I) optionally substituted with one or more of the following substituents: hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivative, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphoramidate, or phosphonate.

[0078] In still further embodiments, the compound has the following formula: [ka] (In the formula, R 1 and R 1’ When attached to carbon, they are independently hydrogen, halogen, CF3, hydroxy, SF5, N(R')S(O)2R', S(O)2R', S(O)2N(R')2, C 1-6 Alkoxy, Cyano, C 2-10 Alkynyl, C 3-6 Alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C 1-6 Alkyl, C 1-6 Haloalkyl, arylalkoxycarbonyl, carboxy, C 1-6 haloalkyl, heterocyclylalkyl, or C 1-6 is a hydroxyalkyl, R 1 and R 1’ When attached to nitrogen, they are independently hydrogen, C 1-6 Alkoxy, C 3-6 Alkoxyalkyl, alkoxycarbonyl, carbonylalkyl, carbonylaryl, C 1-6 Alkyl, C 2-10 Alkynyl, C 2-6Alkenyl, heterocyclylalkyl, C 1-6 hydroxyalkyl, or S(O)R'; Each R' is independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 1-6 Alkoxy, C 2-6 Alkenyl, C 2-6 Alkynyl, C 3-6 cycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, or when two R' are on the same nitrogen atom, they together form a C 3-6 may form an alkyl ring, and the R' groups may be one or more substituents as defined above, for example C 1-6 optionally substituted with hydroxyalkyl, aminoalkyl, and alkoxyalkyl; u and v are independently 0, 1, 2, 3, 4, or 5; G is a phenyl; a 6-membered heteroaromatic ring containing 1, 2, or 3 nitrogen atoms; a 5-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms which are independently N, O, or S; C 4-14 bicyclic; cubane, alkylheteroaryl, or alkylaryl; F is selected from the group consisting of a 5-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms, which are independently N, O, or S; a 6- or 7-membered ring or a 6- or 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, which are independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, which are independently N, O, or S; and a 4-membered ring containing 0, 1, or 2 heteroatoms, which are independently N, O, or S; W is [ka] and R 12 is H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, or C 2-6 is alkynyl, R13 is C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, C 4-14 a bicyclic ring; a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, each independently selected from the group consisting of cubane, N, O, and S; or a 3- to 7-membered saturated or partially unsaturated ring containing one or more heteroatoms, each independently selected from the group consisting of N, O, or S; R 13 teeth, [ka] -NH-C(O)-N(R 10 )2, -N(R 10 )2, -OR 11 , -C(O)OR 10 , -C(O)-N(R 10 )2, -C(O)-NHOH, oxo, [ka] -SR 10 , [ka] and —OS(O)—OH, When G is a substituted aryl or F is a substituted 5-membered heteroaryl, the substituents are [ka] -NH-C(O)-N(R 10 )2, -N(R 10 )2, -OR 11 , -C(O)OR 10 , -C(O)-N(R 10 )2, -C(O)-NHOH, oxo, [ka] -SR 10 , [ka] and —OS(O)—OH, Or, R 12 and R 13 together with the nitrogen to which they are attached, [ka] -NH-C(O)-N(R 10 )2, -N(R 10 )2, -OR 11 , -C(O)OR 10 , -C(O)-N(R 10 )2, -C(O)-NHOH, oxo, [ka] -SR 10 , [ka] and -OS(O)2-OH, R 10 and R 11 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently, N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom, independently, N, O, or S; Alternatively, R 10 and R 11may together form a 5- to 8-membered ring or a 6-membered bridged or spiro-fused ring containing zero, one, or two heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused saturated or partially unsaturated ring containing zero, one, or two heteroatoms, independently N, O, or S; a 5-membered ring containing zero, one, or two heteroatoms, independently N, O, or S; a 4-membered ring containing zero, one, or two heteroatoms, independently N, O, or S; or a 3-membered ring containing zero heteroatoms; or a saturated or partially unsaturated 6- to 12-membered heterobicyclic ring; or a saturated or partially unsaturated 6- to 12-membered heterotricyclic ring, and R 10 and R 11 The groups may independently be halo, C 1-6 Alkyl, C 3-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, C 1-6 optionally substituted with one or more of the following substituents: hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphoramidate or phosphonate; R 14 and R 15 are independently H, C 1-6 Alkyl, C 1-6 Haloalkyl, C 2-6 Alkenyl, C 2-6 is alkynyl, R 14 and R 15 may together form an optionally substituted 3- to 5-membered ring, and R 16 is H or C 1-6or a pharmaceutically acceptable salt or prodrug thereof.

[0079] In one aspect of this embodiment, G is phenyl.

[0080] In another aspect of this embodiment, F is pyrrolyl. [ka] can be attached directly to the ring nitrogen.

[0081] In one aspect of this embodiment, R 1’ is selected from the group consisting of F, CN and OH.

[0082] In one aspect of this embodiment, R 1 is methyl.

[0083] In one aspect of this embodiment, R 16 is H.

[0084] In addition to the monomers, dimers, and trimers described above, in another embodiment, the compounds have the following formula: [ka] (In the formula, A 1 , B 1 , C 1 and D 1 are independently HBV capsid assembly effectors, A respectively 1 , B 1 , C 1 and D 1 may be the same or different; L 1 is -C-((C 2-6 Alkyl-O) p)4 -, -C-(C 1-16 Alkyl-)4, -C(NR')3-)4, C(C 1-6 Alkyl-W 1 -)4, -C((CH2-CH2-O)t -C 1-6 Alkyl-W 1 -)4, -C((CH2-CH2-O) s )4-, C(C 1-30 Alkyl-W 1 -)4, C-((C 3-6 Alkyl-O) s -C 1-6 Alkyl-X-(C 3-6 Alkyl-O) s -C 1-6 Alkyl-)4, C((CH2-CH2-O) t -C 1-6 Alkyl-X-(CH2-CH2-O) t -C 1-6 Alkyl-W 1 -)4, or C(C 1-30 Alkyl-XC 1-30 Alkyl-W 1 -) a chemical linker selected from the group consisting of 4, p, s, and m are integers from 1 to 15; t is an integer from 3 to 15; X is Si(R 7 )(R 8 )-;-Si(R 7 )(R 8 )-O-;-O-Si(R 7 )(R 8 )-;-NR'-;-N(R')C(O)-;-C(O)N(R')-;-N(R')SO2-;-SO2N(R')-;-O-;-C(O)-;-OC(O)-;-C(O)O-;-S-;-S(O)-;-SO2-;-C(=S)-; or -C(=NR')-; Optional substituents for heteroaliphatic, aliphatic, aryl, and heteroaryl moieties are selected from the group consisting of halo, haloalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, carboxyl derivatives, alkylamino, dialkylamino, arylamino, alkoxy, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, silyl ether, boronic ester, boronic acid, phosphonic acid, phosphonamidate, and phosphonate; W 1 is independently at each occurrence aryl, heteroaryl, CHR', NR', N, O, or S; R' is H, C 1-6 Alkyl, optionally unsaturated C 3-8 Cycloalkyl, C 1-6 Haloalkyl, C 2-8 Alkoxyalkyl, C 2-6 Alkenyl, C 2-6 alkynyl, aryl, heteroaryl, alkylaryl, or arylalkyl; R 7 and R 8 are independently -OH, optionally unsaturated -OC 1-6 Alkyl, C 1-6 Alkyl, C 2-6 Alkenyl, C 2-6 Alkynyl, optionally unsaturated C 3-8 is cycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl; and Alternatively, R 7 and R 8together with the silicon to which they are attached form a 4-7 membered ring optionally containing one or more heteroatoms, each independently O, S, or N, which 4-7 membered ring may be optionally substituted with one or more substituents selected from the group consisting of C1-C3 alkyl, halogen, cyano, oxo, and OH; or an enantiomer, diastereoisomer, tautomer, pharmaceutically acceptable salt, or prodrug thereof.

[0085] Specific compounds include the following: and tautomers, stereoisomers, diastereomers, pharmaceutically acceptable salts or prodrugs of these compounds: [ka] TIFF0007648528000113.tif235158TIFF0007648528000114.tif219158TIFF0007648528000115.tif227158TIFF0007648528000116.tif23615 8TIFF0007648528000117.tif236158TIFF0007648528000118.tif204158TIFF0007648528000119.tif221158TIFF0007648528000120.tif2361 58TIFF0007648528000121.tif228158TIFF0007648528000122.tif218158TIFF0007648528000123.tif237158TIFF0007648528000124.tif236158TIFF0007648528000125.tif236158TIFF0007648528000126.tif231158TIFF0007648528000127.tif114158 and pharmaceutically acceptable salts or prodrugs thereof.

[0086] In another embodiment, the compound is selected from the group consisting of: [ka] TIFF0007648528000129.tif220158TIFF0007648528000130.tif216158TIFF0007648528000131.tif142158 and pharmaceutically acceptable salts and prodrugs thereof.

[0087] Examples of compounds of formula 11 include: [ka] TIFF0007648528000133.tif192158 and pharmaceutically acceptable salts, tautomers, and prodrugs thereof.

[0088] Additional compounds include: [ka] TIFF0007648528000135.tif216158TIFF0007648528000136.tif194158TIFF0007648528000137.tif221158TIFF0007648528000138.tif235158TIFF0007648528000139.tif221158 and pharmaceutically acceptable salts or prodrugs thereof.

[0089] III Stereoisomerism and Polymorphism The compounds described herein may have asymmetric centers and may occur as racemates, racemic mixtures, individual diastereomers, or enantiomers, and all isomeric forms are encompassed by the present invention. Compounds of the present invention having chiral centers may exist in optically active and racemic forms and may be isolated in such forms. Some compounds may exhibit polymorphism. The present invention encompasses racemates, optically active forms, polymorphs, or stereoisomers of the compounds described herein, or mixtures thereof, which possess the useful properties described herein. Optically active forms can be prepared, for example, by recrystallization techniques, by synthesis from optically active starting materials, by chiral synthesis, or by resolution of a racemate by chromatographic separation using chiral stationary phases or enzymatic resolution. After purification of each compound, the compound can be derivatized to form a compound described herein, or the compound itself can be purified.

[0090] Optically active forms of compounds can be prepared using any method known in the art, including, but not limited to, recrystallization techniques, synthesis from optically active starting materials, chiral synthesis, or resolution of racemates by chromatographic separation using chiral stationary phases.

[0091] Examples of methods for obtaining optically active substances include at least the following. i) Physical separation of crystals: A technique in which macroscopic crystals of individual enantiomers are manually separated. This technique can be used when separate enantiomers exist, i.e., the material is a conglomerate and the crystals are visually distinguishable. ii) Simultaneous crystallization: A technique in which the individual enantiomers are separately crystallized from a solution of the racemate, which is only possible if the latter is a conglomerate in the solid state. iii) Enzymatic resolution: A technique for partial or complete separation of a racemate based on the different rates of reaction of an enzyme with the enantiomers. iv) Enzymatic Asymmetric Synthesis: A synthetic technique in which at least one synthetic step uses an enzymatic reaction to obtain a synthetic precursor that is enantiomerically pure or enriched in the desired enantiomer. v) Chemical asymmetric synthesis: A synthetic technique in which the desired enantiomer is synthesized from an achiral precursor under conditions that can be achieved using a chiral catalyst or chiral auxiliary that results in asymmetry (i.e., chirality) in the product. vi) Diastereomeric separation: A technique in which an enantiomerically pure reagent (chiral auxiliary) is reacted with a racemate to convert the individual enantiomers into diastereomers. The resulting diastereomers are then separated by chromatography or crystallization on the basis of their now more distinct structural differences, and the chiral auxiliary is later removed to yield the desired enantiomer. vii) First and second order asymmetric transformations: techniques in which diastereomers from a racemate are equilibrated to give a predominance of the diastereomer from the desired enantiomer, or, in principle, techniques in which the preferential crystallization of the diastereomer from the desired enantiomer disrupts the equilibrium so that all material is ultimately converted to the crystalline diastereomer from the desired enantiomer, which is then separated from the diastereomers. viii) Kinetic Resolution: This technique involves achieving partial or complete resolution of a racemate (or further resolution of a partially resolved compound) based on the unequal reaction rates of enantiomers with a chiral, non-racemic reagent or catalyst under kinetic conditions. ix) Enantiospecific synthesis from non-racemic precursors: A synthetic technique in which the desired enantiomer is obtained from non-chiral starting materials and the stereochemical integrity during the synthesis is not compromised or is only minimally compromised. x) Chiral liquid chromatography: a technique (including but not limited to chiral HPLC) in which the enantiomers of a racemate are separated in a liquid mobile phase based on their different interactions with a stationary phase. The stationary phase can be made of a chiral material, or the mobile phase can contain additional chiral material to induce the different interactions. xi) Chiral gas chromatography: A technique in which the racemate is volatilized and the enantiomers are separated on the basis of their different interactions in gas with a column containing a fixed non-racemic chiral adsorbent phase. xii) Chiral solvent extraction: A technique in which enantiomers are separated based on the preferential dissolution of one enantiomer in a particular chiral solvent. xiii) Transport through chiral membranes: a technique in which a racemate is placed in contact with a thin membrane barrier. Typically, the barrier separates two miscible fluids, one of which contains the racemate, and a driving force such as a concentration or pressure difference results in preferential transport through the membrane barrier. Separation occurs as a result of the non-racemic chiral nature of the membrane, which allows only one enantiomer of the racemate to pass through.

[0092] In one embodiment, chiral chromatography, including but not limited to simulated moving bed chromatography, is used. A wide variety of chiral stationary phases are commercially available.

[0093] IV. Salt or Prodrug Formulations When a compound is sufficiently basic or acidic to form a non-toxic acid or base salt, it may be appropriate to administer the compound as a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include organic acids that form physiologically acceptable anions, such as tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Suitable inorganic salts can also be formed, including but not limited to sulfate, nitrate, bicarbonate, and carbonate. In certain transdermal applications, it may be preferable to use fatty acid salts of the compounds described herein. Fatty acid salts can aid in penetration into the stratum corneum. Examples of suitable salts include salts of the compounds with stearic acid, oleic acid, linoleic acid, palmitic acid, caprylic acid, and capric acid.

[0094] Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example, by reacting a sufficiently basic compound, such as an amine, with a suitable acid to provide a physiologically acceptable anion. If the compound contains multiple amine groups, salts can be formed with any number of amine groups. Alkali metal (e.g., sodium, potassium, or lithium) or alkaline earth metal (e.g., calcium) salts of carboxylic acids can also be made.

[0095] A prodrug is a pharmacological agent that is administered in an inactive (or significantly less active) form and then metabolized in vivo to an active metabolite. Delivering more drug to the desired target at a lower dose is often the rationale behind the use of prodrugs, which is usually due to better absorption, distribution, metabolism, and / or excretion (ADME) properties. Prodrugs are typically designed to improve oral bioavailability, where poor absorption from the gastrointestinal tract is often a limiting factor. Furthermore, the use of prodrug strategies can increase the selectivity of the drug for the intended target, thus reducing the likelihood of off-target effects.

[0096] V. Isotope The compounds described herein include isotopically labeled compounds, which are identical to the descriptions in the various formulas and structures set forth herein except for the fact that one or more atoms have been replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number normally found in nature. In other embodiments, examples of isotopes incorporated in the compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, and chlorine, e.g., 2 H, 3 H, 13 C. 14 C. 15 N, 18 O. 17 O. 35 S, 18 F, 36 Certain isotopically labeled compounds described herein, for example, 2Compounds incorporating radioactive isotopes such as 3H are useful in drug and / or substrate tissue distribution assays. Further, in some embodiments, isotopes such as deuterium (i.e., 2 H), may confer certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements.

[0097] VI. Treatment method The compounds described herein can be used to prevent, treat or cure HBV infection. Hosts, including but not limited to humans, suffering from one of these cancers or infected with one of these viruses, such as HBV, or a genetic fragment thereof, can be treated by administering to the patient an effective amount of an active compound or a pharmaceutically acceptable prodrug or salt thereof in the presence of a pharmaceutically acceptable carrier or diluent. The active agent can be administered in liquid or solid form by any suitable route, for example, orally, parenterally, intravenously, intradermally, transdermally, subcutaneously, or topically.

[0098] VII. Alternation Therapy Combinations In one embodiment, the compounds described herein can be used in combination with at least one other antiviral agent. Representative antiviral agents include, but are not limited to, polymerase inhibitors, anti-HBV nucleosides and their prodrugs, viral entry inhibitors, viral maturation inhibitors, literature-described capsid assembly regulators, IMPDH inhibitors, protease inhibitors, immune-based therapeutics, reverse transcriptase inhibitors, TLR agonists, and agents with different or unknown mechanisms. They can also be used in conjunction with CRISPR / Cas9 technology, for example, using AAV as a human delivery vector.

[0099] For example, when used to treat or prevent HBV infection, the active compound or its prodrug or pharmaceutically acceptable salt can be administered in combination with or alternating with another anti-HBV drug, including, but not limited to, those of the above formula. Generally, in combination therapy, effective dosages of two or more drugs are administered together, while in alternation therapy, effective dosages of each drug are administered sequentially. Dosages depend on the absorption, inactivation, and excretion rates of the drugs, as well as other factors known to those skilled in the art. It should be noted that dosage values ​​also vary with the severity of the condition to be alleviated. It should be further understood that the specific dosing regimen and schedule for each particular subject should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the composition.

[0100] Non-limiting examples of antiviral agents that can be used in combination with the compounds disclosed herein include those in the table below. [Table 1] JPEG0007648528000141.jpg236158JPEG0007648528000142.jpg236158JPEG0007648528000143.jpg236158JPEG0007648528000144.jpg41158

[0101] Additional anti-HBV drugs that can be used in combination or alternation therapy In addition to the compounds described herein that function by cccDNA inhibition and the above-mentioned combination therapies that combine the compounds described herein with approved anti-HBV drugs such as TAF, approaches such as siRNA, shRNA, Talen, Crisper / Cas9, ARCUS and mir (microRNA) compounds can be used as well.

[0102] siRNA and shRNA therapy siRNA therapy for treating HBV is described, for example, in Chen and Mahato, "siRNA Pool Targeting Different Sites of Human Hepatitis B Surface Antigen Efficiently Inhibits HBV Infection;" J Drug Target. 2008 Feb;16(2):140-148 and Morrissey et al., "Potent and persistent in vivo anti-HBV activity of chemically modified siRNAs," Nature Biotechnology 23,1002-1007(2005).

[0103] RNAi is a sequence-specific, post-transcriptional gene silencing mechanism that is mediated by double-stranded synthetic siRNA or short hairpin RNA (shRNA) expressed intracellularly from a vector. HBV replication and expression can be inhibited by administering synthetic siRNA or endogenously expressed shRNA. See, for example, Giladi et al., "Small interfering RNA inhibits hepatitis B virus replication in mice," Mol Ther. 2003;8(5):769-76; McCaffrey et al., "Inhibition of hepatitis B virus in mice by RNA interference," Nat Biotechnol. 2003;21(6):639-44; and Shlomai and Shaul, "Inhibition of hepatitis B virus expression and replication by RNA interference," Hepatology. 2003;37(4):764-70). HBV gene silencing can depend, for example, on siRNA dosage and sequence, and targets of gene silencing include, for example, inhibition of viral replication and suppression of HBsAg expression.

[0104] In one embodiment, a combination of several siRNAs and / or shRNAs is used to target two or more of the HBV S, C, P and X genes, thus providing multiple targets for inhibiting HBV replication and gene expression.

[0105] Once a suitable target, e.g., human hepatitis B virus surface antigen (HBsAg) (GeneBank accession number #NM_U95551), has been identified, siRNAs can be designed following the guidance provided by Ambion (http: / / www.ambion.com / techlib / misc / siRNA_finder.html) and Invitrogen (https: / / rnaidesigner.invitrogen.com / rnaiexpress / design.do). The sequence specificity of the siRNA can be checked by performing a BLAST search (www.ncbi.nlm.nih.gov).

[0106] Once the siRNA sequences are identified, they can be converted into shRNAs. To express shRNAs, a control vector can be constructed using, for example, psiSTRIKE™, a linearized plasmid containing a U6 RNA polymerase promoter. These shRNAs contain two complementary oligonucleotides that can anneal to form double-stranded DNA, which can be ligated to the corresponding sites of the psiSTRIKE™ vector using an appropriate ligase, such as T4 DNA ligase, under a suitable promoter, such as the U6 promoter. The plasmid can be purified, for example, using the QIAGEN® Plasmid Mini Kit (QIAGEN, Valencia, CA).

[0107] Talen / CRISPR As discussed above, chronic HBV viral infections often persist due to the presence of long-lived forms of viral DNA in infected cells. Current therapeutic agents can suppress viral replication but have little or no effect on the long-lived DNA forms, so viral replication resumes as soon as treatment is stopped.

[0108] In addition to targeting long-lived DNA forms using capsid inhibitors as described herein, targeting endonucleases such as homing endonucleases, zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and CRISPR (clustered regularly interspaced short palindromic repeats) systems can be used. The use of TALENs to target HBV is described, for example, in Weber et al., "TALENs Targeting HBV: Designer Endonuclease Therapies for Viral Infections," Molecular Therapy (2013); 21 10, 1819-1820.

[0109] These nucleases function by specifically recognizing and cleaving select DNA sequences, which results in gene disruption upon imprecise DNA repair. TALEN targeting of the hepatitis B virus (HBV) genome can generate TALEN-induced mutations in the long-lived HBV covalently closed circular DNA (cccDNA). Mutation and / or disruption of cccDNA prevents functional viral replication by preventing the expression of functional viral proteins.

[0110] CRISPR CRISPR, or clustered regularly interspaced short palindromic repeats, is another method for mutating HBV DNA by providing targeted genome editing. In addition to programmable editing tools such as zinc finger nucleases and transcription activator-like effector nucleases (TALENs), CRISPR (clustered regularly interspaced short palindromic repeats) / Cas9 technology also allows genome editing and site-specific genome targeting in HBV.

[0111] The type II CRISPR / Cas system is a prokaryotic adaptive immune response system that uses non-coding RNA to guide the Cas9 nuclease to cause site-specific DNA cleavage, which is then repaired by cellular DNA repair mechanisms via the non-homologous end joining (NHEJ) or homology-directed repair (HDR) pathways.

[0112] The CRISPR / Cas9 system provides a simple, RNA-programmable method to generate gene knockouts (by insertion / deletion) or knock-ins (by HDR), allowing site-specific genome targeting in HBV. The type II CRISPR / Cas system is a prokaryotic adaptive immune response system that uses non-coding RNA to guide the Cas9 nuclease to cause site-specific DNA cleavage.

[0113] To generate a gene disruption, a single guide RNA (sgRNA) is generated to target the Cas9 nuclease to a specific genomic location. The Cas9-induced double-strand break is repaired via the NHEJ DNA repair pathway. Repair is error-prone, and therefore insertions and deletions (indels) can be introduced, which can disrupt gene function. Therefore, targeting hepatitis B virus using CRISPR / Cas9 nuclease can efficiently inhibit viral replication.

[0114] ARCUS ARCUS is a next-generation genome editing platform derived from naturally occurring genome editing enzymes called homing endonucleases. These are site-specific DNA cleavage enzymes encoded in the genomes of many eukaryotic species. Homing endonucleases have the unique ability to precisely recognize long DNA sequences (12–40 base pairs) that are typically sufficiently rare to occur only once in complex genomes. These non-destructive enzymes trigger gene conversion events that modify the genome with the insertion of novel DNA sequences in a highly precise manner and at maximum frequency. The backbone of the ARCUS technology is the ARC nuclease, a fully synthetic enzyme similar to homing endonucleases but significantly improved to serve as the starting point for the first therapeutic-grade genome editing platform. ARC nucleases are small, have unparalleled specificity, and can be customized to recognize DNA sequences within any target gene. ARC nucleases are engineered using a series of proprietary in silico and lab-based technologies to ensure maximum gene editing efficiency with minimal off-target activity. Importantly, ARC nuclease can be optimized to control potency and specificity based on analysis of cleavage activity in relevant model organisms such as HBV.

[0115] Mir / microRNA MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression primarily at the post-transcriptional level by binding to mRNA. miRNAs contribute to various physiological and pathological processes. Many miRNAs have been shown to play important roles in host-HBV interactions. HBV infection can alter cellular miRNA expression patterns, and different HBV-associated disease stages exhibit distinctive miRNA profiles. Differentially expressed miRNAs are involved in the progression of HBV-associated disease. For example, some miRNAs are involved in liver tumorigenesis and tumor metastasis. Circulating miRNAs in serum or plasma can be highly useful biomarkers for the diagnosis and prognosis of HBV-associated disease. In addition, miRNA-based therapies can be used to treat, prevent, or cure HBV-associated disease. See, e.g., Ying-Feng Wei, “MicroRNAs may solve the mystery of chronic hepatitis B virus infection,” World J Gastroenterol.2013 Aug 14;19(30):4867-4876.http: / / www.ncbi.nlm.nih.gov / pmc / articles / PMC3740416 / .

[0116] In the interaction between viruses and hosts, miRNAs can be divided into cellular miRNAs and viral miRNAs. The expression profile of cellular miRNAs changes with the infection state, and abnormal miRNAs are often closely related to the virus life cycle and host disorders. Viral miRNAs can evolve to regulate both viral and cellular gene expression.

[0117] Sometimes, viruses exploit cellular miRNAs to promote specific steps in their life cycle. For example, miR-122 plays an antiviral role in the HBV life cycle. MiR-122 overexpression suppresses HBV expression, while depletion of endogenous miR-122 leads to increased HBV production in transfected cells. MiR-122 inhibitors increase cellular heme oxygenase-1, which can reduce HBV covalently closed circular DNA (cccDNA) levels by reducing the stability of HBV core protein. MiR-122 expression in the liver can be significantly downregulated in patients with HBV infection compared to healthy controls. MiR-122 is significantly upregulated in HBV-infected patients and can suppress HBV replication in Huh7 and HepG2 cells. Cyclin G1 is a miR-122 target that specifically interacts with p53, resulting in the specific binding of p53 to HBV enhancer sequences and the simultaneous abrogation of p53-mediated inhibition of HBV transcription.

[0118] HBV is a non-cytopathogenic virus that replicates preferentially in hepatocytes. The cccDNA serves as a template for transcription of all viral RNAs synthesized after HBV DNA enters the hepatocyte nucleus. The HBV genome is 3.2 kb long and contains four overlapping open reading frames. It can reverse transcribe to synthesize the viral DNA genome and transcribe viral pregenomic RNA encoding hepatitis B virus surface antigen (HBsAg), hepatitis B virus core protein, viral reverse DNA polymerase (Pol), and X protein.

[0119] Hsa-miR-125a-5p disrupts HBV translation and downregulates HBV surface antigen expression. Thus, cellular miRNAs can alter HBV gene expression by targeting HBV transcripts.

[0120] Cellular miRNAs can affect viral translation and alter viral replication. In addition to the example of miR-122 inhibition of HBV replication, there are other examples of host miRNAs altering HBV replication. MiR-141 suppresses HBV replication by reducing HBV promoter activity and downregulating peroxisome proliferator-activated receptor alpha. DNA hypermethylation may be closely related to the suppression of HBV cccDNA transcription, and miR-152 may be a factor involved in regulating HBV cccDNA methylation.

[0121] Therefore, miRNAs can directly or indirectly alter HBV replication. The close association between miRNAs and HBV-related diseases provides an opportunity to use miRNAs or antagomirs in combination therapy to treat, cure, or prevent HBV.

[0122] VIII. Pharmaceutical Compositions Hosts, including but not limited to humans, infected with HBV can be treated by administering to the patient an effective amount of an active compound or a pharmaceutically acceptable prodrug or salt thereof in the presence of a pharmaceutically acceptable carrier or diluent. The active agent can be administered in liquid or solid form by any suitable route, for example, orally, parenterally, intravenously, intradermally, subcutaneously, or topically.

[0123] Preferred dosages of the compounds range from about 0.01 to about 10 mg / kg, more usually from about 0.1 to about 5 mg / kg, and preferably from about 0.5 to about 2 mg / kg (of recipient body weight) per day. Effective dosage ranges of pharmaceutically acceptable salts and prodrugs can be calculated based on the weight of the parent compound delivered. If the salt or prodrug is active in its own right, the effective dosage can be estimated using the weight of the salt or prodrug as described above, or by other means known to those skilled in the art.

[0124] Conveniently, the compounds are administered in any suitable unit dosage form, including but not limited to, containing 7 to 600 mg, preferably 60 to 600 mg, of active ingredient per unit dosage form. An oral dosage of 1 to 400 mg is usually convenient.

[0125] The concentration of the active compound in the drug composition depends on the absorption, inactivation and excretion rate of the drug, as well as other factors known to those skilled in the art.It should be noted that dosage values ​​also vary with the severity of the condition to be alleviated.It should be further understood that the specific dosage regimen for each specific subject should be adjusted over time according to individual needs and the professional judgment of the person administering or supervising the administration of the composition, and the concentration ranges described herein are merely illustrative and are not intended to limit the scope or implementation of the claimed compositions.The active ingredient can be administered at once, or can be divided into multiple smaller doses and administered at various time intervals.

[0126] The preferred method of administration of the active compound is oral, but for certain patients, it can be administered sc, ip or iv in a sterile injectable form. Oral compositions generally contain an inert diluent or an edible carrier. They can be enclosed in gelatin capsules or compressed into tablets. For the purpose of oral therapeutic administration, the active compound can be incorporated with excipients and used in the form of tablets, lozenges, or capsules. Pharmaceutically compatible binders and / or auxiliary substances can be included as part of the composition.

[0127] Tablets, pills, capsules, troches, etc. may contain any of the following ingredients or compounds: binders such as microcrystalline cellulose, tragacanth gum, or gelatin; excipients such as starch or lactose; disintegrants such as alginic acid, Primogel, or corn starch; lubricants such as magnesium stearate or sterol; glidants such as colloidal silicon dioxide; sweeteners such as sucrose or saccharin; or flavorings such as peppermint, methyl salicylate, or orange flavor. When the dosage unit is a capsule, it can contain, in addition to the above-mentioned types of materials, a liquid carrier such as fatty oil. In addition, dosage unit forms can contain various other materials that modify the physical form of the dosage unit, for example, sugar, shellac, or other enteric coatings.

[0128] The compounds can be administered as a component of an elixir, suspension, syrup, wafer, chewing gum, etc. A syrup may contain, in addition to the active compounds, sucrose as a sweetening agent and certain preservatives, dyes and colorings and flavors.

[0129] The compound or its pharmaceutically acceptable prodrug or salt can also be mixed with other active substances that do not reduce the desired effect, or with substances that supplement the desired effect, such as antibiotics, antifungals, anti-inflammatory agents, or other antiviral compounds. Solutions or suspensions used for parenteral, intradermal, subcutaneous, or topical administration can include sterile diluents such as distilled water for injection, saline, fixed oils, polyethylene glycol, glycerin, propylene glycol, or other synthetic solvents; antibacterial agents such as benzyl alcohol or methylparabens; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetate, citrate, or phosphate, and tonicity adjusting agents such as sodium chloride or dextrose. Parenteral preparations can be enclosed in glass or plastic ampoules, disposable syringes, or multiple-dose vials. If administered intravenously, preferred carriers are physiological saline or phosphate buffered saline (PBS).

[0130] Transdermal preparations In some embodiments, the composition is in the form of a transdermal formulation, such as the FDA-approved agonist transdermal formulation rotigotine transdermal formulation (Neupro Patch). Another suitable formulation is described in U.S. Patent Application Publication No. 20080050424, entitled "Transdermal Therapeutic System for Treating Parkinsonism." The formulation may include a silicone or acrylate adhesive and may further include an additive that enhances the solubility of the active agent in an amount effective to enhance the dissolution capacity of the matrix for the active agent.

[0131] The transdermal formulation may be a single-phase matrix comprising a backing layer, an active substance-containing self-adhesive matrix, and a protective coating to be removed prior to use. More complex embodiments include multi-layer matrices that may include an adhesive layer and a control membrane. When a polyacrylate adhesive is used, it can be crosslinked with polyvalent metal ions such as zinc, calcium, aluminum, or titanium ions, such as aluminum acetylacetonate and titanium acetylacetonate.

[0132] When silicone adhesives are used, they are usually polydimethylsiloxanes.However, in principle, other organic residues, such as ethyl or phenyl groups, can be present instead of methyl groups.Because the active compound is amine, it can be advantageous to use amine-resistant adhesives.Representative amine-resistant adhesives are described in EP0180377.

[0133] Representative acrylate-based polymeric adhesives include acrylic acid, acrylamide, hexyl acrylate, 2-ethylhexyl acrylate, hydroxyethyl acrylate, octyl acrylate, butyl acrylate, methyl acrylate, glycidyl acrylate, methacrylic acid, methacrylamide, hexyl methacrylate, 2-ethylhexyl methacrylate, octyl methacrylate, methyl methacrylate, glycidyl methacrylate, vinyl acetate, vinyl pyrrolidone, and combinations thereof.

[0134] The adhesive must have a suitable dissolving ability for the active substance, and the active substance must be able to migrate through the matrix and pass through the skin contact surface. Those skilled in the art can easily formulate transdermal formulations with suitable active substance transdermal transport properties.

[0135] Certain pharmaceutically acceptable salts tend to be more suitable for use in transdermal formulations.This is because they can help active substance to pass through the barrier of the stratum corneum.Examples include fatty acid salts such as stearic acid and acid salts.Oleic acid salt and stearate salt are relatively lipophilic and can also function as skin penetration enhancers.

[0136] Penetration enhancers can also be used, and representative examples of penetration enhancers include fatty alcohols, fatty acids, fatty acid esters, fatty acid amides, glycerin or glycerin fatty acid esters, N-methylpyrrolidone, terpenes such as limonene, α-pinene, α-terpineol, carvone, carveol, limonene oxide, pinene oxide, or 1,8-eucalyptol.

[0137] Patches can typically be prepared by dissolving or suspending the active agent in ethanol or another suitable organic solvent, followed by adding the adhesive solution with stirring. Additional auxiliary substances can be added to the adhesive solution, the active agent solution, or the active agent-containing adhesive solution. The solution can then be coated onto a suitable sheet, the solvent removed, a backing layer laminated onto the matrix layer, and patches can be punched out from the entire laminate.

[0138] Nanoparticle Composition The compounds described herein can also be administered in the form of nanoparticle compositions.

[0139] In one embodiment, the sustained-release nanoparticle formulation comprises a nanoparticle active agent and a rate-controlling polymer that functions to sustain the release of the agent after administration. In this embodiment, the composition can release the active agent over a period of time after administration ranging from about 2 to about 24 hours, or up to 30 days or more. Exemplary controlled-release formulations containing nanoparticle active agents are described, for example, in U.S. Patent No. 8,293,277.

[0140] The nanoparticle composition comprises particles of an active agent as described herein having noncrosslinked surface stabilizers adsorbed or bound on their surfaces.

[0141] The average particle size of the nanoparticles is typically less than about 800 nm, more typically less than about 600 nm, and even more typically less than about 400 nm, less than about 300 nm, less than about 250 nm, less than about 100 nm, or less than about 50 nm. In one aspect of this embodiment, at least 50% of the active agent particles have an average particle size of less than about 800, 600, 400, 300, 250, 100, or 50 nm, as measured by light scattering techniques.

[0142] Various surface stabilizers are commonly used with nanoparticle compositions to prevent particle aggregation or agglomeration. Representative surface stabilizers include gelatin, lecithin, dextran, gum arabic, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, polyethylene glycol, polyoxyethylene stearate, colloidal silicon dioxide, phosphate, sodium dodecyl sulfate, carboxymethylcellulose calcium, carboxymethylcellulose sodium, methylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, amorphous cellulose, and aluminum magnesium silicate. ammonium, triethanolamine, polyvinyl alcohol, polyvinylpyrrolidone, tyloxapol, poloxamer, poloxamine, poloxamine 908, dialkyl ester of sodium sulfosuccinate, p-isononylphenoxypoly-(glycidol), SA9OHCO, decanoyl-N-methylglucamide, n-decyl-D-glucopyranoside, n-decyl-D-maltopyranoside, n-decyl-D-glucopyranoside These include lanosides, n-decyl-D-maltoside, heptanoyl-N-methylglucamide, n-heptyl-D-glucopyranoside, n-heptyl-D-thioglucoside, n-hexyl-D-glucopyranoside, nonanoyl-N-methylglucamide, n-nonyl-D-glucopyranoside, octanoyl-N-methylglucamide, n-octyl-D-glucopyranoside, and octyl-D-thioglucopyranoside. Lysozyme can also be used as a surface stabilizer in nanoparticle compositions. Certain nanoparticles, such as polylactic-co-glycolic acid (PLGA) nanoparticles, are known to target the liver when administered intravenously (IV) or subcutaneously (SQ).

[0143] Because HBV causes damage to the liver and resides in the liver, in one embodiment, nanoparticles or other drug delivery carriers target the liver.One such type of liver-targeting drug delivery carrier is described in Park, et al., Mol Imaging.Feb 2011;10(1):69-77, and uses glypican-3 (GPC3) as molecular target.Park taught the use of this target for hepatocellular carcinoma (HCC), which is a primary liver cancer frequently caused by chronic persistent hepatitis.

[0144] In one aspect of this embodiment, the drug delivery vehicle can also be used to target therapeutic agents to the liver to treat viral infections. Furthermore, because the compounds described herein have indirect anticancer applications, this type of system can target compounds to the liver to treat or reverse liver cancer. GPC3 is not expressed in normal adult tissues, but is significantly overexpressed in up to 80% of human HCC tissues. GPC3 can be targeted, for example, using antibody-mediated targeting and conjugation (see Hsu, et al., Cancer Res. 1997;57:5179-84).

[0145] Another type of drug delivery system for liver targeting is described in U.S. Patent No. 7,304,045. U.S. Patent No. 7,304,045 discloses a dual-particle tumor or cancer targeting system comprising a first ligand-mediated targeting galactosamine-conjugated nanoparticle, the ligand being located on the target cell. The first nanoparticle comprises a poly(γ-glutamic acid) / poly(lactide) block copolymer and an antiviral compound, in this case a compound described herein, which in U.S. Patent No. 7,304,045 is ganciclovir. The second nanoparticle comprises a poly(γ-glutamic acid) / poly(lactide) block copolymer, an endothelial cell-specific promoter, and a (herpes simplex virus)-(thymidine kinase) gene construct plasmid to provide vascular permeability and retention enhancement-mediated targeting. The first and second nanoparticles are mixed in a solution configured for delivery to the liver. When the disorder being treated is a liver tumor or liver cancer, delivery can be directly to or adjacent to the liver tumor or liver cancer.

[0146] Representative rate-controlling polymers from which nanoparticles can be formulated include chitosan, polyethylene oxide (PEO), polyvinyl acetate phthalate, gum arabic, agar, guar gum, cereal gum, dextran, casein, gelatin, pectin, carrageenan, wax, shellac, hydrogenated vegetable oil, polyvinylpyrrolidone, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hydroxypropyl methylcellulose (HPMC), sodium carboxymethylcellulose (CMC), poly(ethylene) oxide, alkylcelluloses, ethylcellulose, methylcellulose, carboxymethylcellulose, hydrophilic cellulose, and the like. Examples of suitable acrylic or methacrylic acid derivatives include cellulose acetate derivatives, polyethylene glycol, polyvinylpyrrolidone, cellulose acetate butyrate, cellulose acetate phthalate, cellulose acetate trimellitate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, polyvinyl acetal diethylaminoacetate, poly(alkyl methacrylates), poly(vinyl acetate), polymers derived from acrylic or methacrylic acid and their respective esters, and copolymers derived from acrylic or methacrylic acid and their respective esters.

[0147] Methods for preparing nanoparticle compositions are described, for example, in U.S. Pat. Nos. 5,518,187 and 5,862,999, both under the heading "Method of Grinding Pharmaceutical Substances"; U.S. Pat. No. 5,718,388, under the heading "Continuous Method of Grinding Pharmaceutical Substances"; and U.S. Pat. No. 5,510,118, under the heading "Process of Preparing Therapeutic Compositions Containing Nanoparticles."

[0148] Nanoparticle compositions may also be used in a variety of applications, including, for example, U.S. Pat. No. 5,298,262, entitled "Use of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization"; U.S. Pat. No. 5,302,401, entitled "Method to Reduce Particle Size Growth During Lyophilization"; U.S. Pat. No. 5,318,767, entitled "X-Ray Contrast Compositions Useful in Medical Imaging"; U.S. Pat. No. 5,326,552, entitled "Novel Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants"; U.S. Pat. No. 5,328,404, entitled "Method of X-Ray Imaging Using Iodinated Aromatic Propanedioates"; U.S. Pat. No. 5,336,507, entitled "Use of Charged Phospholipids to Reduce Nanoparticle Aggregation"; and U.S. Pat. No. 5,340,564, entitled "Formulations Comprising Olin 10-G to Prevent Particle Aggregation and Increase Stability”; U.S. Patent No. 5,346,702, “Use of Non-Ionic Cloud Point Modifiers to Minimize Nanoparticulate Aggregation During Sterilization”; U.S. Patent No. 5,349,957, “Preparation and Magnetic Properties of Very Small Magnetic-Dextran Particles”; U.S. Patent No. 5,352,459, “Use of Purified Surface Modifiers to Prevent Particle Aggregation During Sterilization”;U.S. Patent Nos. 5,399,363 and 5,494,683, both for "Surface Modified Anticancer Nanoparticles"; U.S. Patent No. 5,401,492, for "Water Insoluble Non-Magnetic Manganese Particles as Magnetic Resonance Enhancement Agents"; U.S. Patent No. 5,429,824, for "Use of Tyloxapol as a Nanoparticulate Stabilizer"; U.S. Patent No. 5,447,710, for "Method for Making Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic Surfactants"; U.S. Patent No. 5,451,393, for "X-Ray Contrast Compositions Useful in Medical Imaging"; and U.S. Patent No. 5,466,440, for "Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with Pharmaceutically Acceptable Clays”; U.S. Patent No. 5,470,583, “Method of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation”; U.S. Patent No. 5,472,683, “Nanoparticulate Diagnostic Mixed Carbamic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging”; U.S. Patent No. 5,500,204, “Nanoparticulate Diagnostic Dimers as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging”;U.S. Patent No. 5,518,738, entitled "Nanoparticulate NSAID Formulations"; U.S. Patent No. 5,521,218, entitled "Nanoparticulate Iododipamide Derivatives for Use as X-Ray Contrast Agents"; U.S. Patent No. 5,525,328, entitled "Nanoparticulate Diagnostic Diatrizoxy Ester X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging"; U.S. Patent No. 5,543,133, entitled "Process of Preparing X-Ray Contrast Compositions Containing Nanoparticles"; U.S. Patent No. 5,552,160, entitled "Surface Modified NSAID Nanoparticles"; U.S. Patent No. 5,560,931, entitled "Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids"; and U.S. Patent No. 5,565,188, entitled "Polyalkylene Block Copolymers as Surface Modifiers" for Nanoparticles”; U.S. Patent No. 5,569,448, “Sulfated Non-ionic Block Copolymer Surfactant as Stabilizer Coatings for Nanoparticle Compositions”; U.S. Patent No. 5,571,536, “Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids”; U.S. Patent No. 5,573,749, “Nanoparticulate Diagnostic Mixed Carboxylic Acids as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging”;U.S. Patent No. 5,573,750, "Diagnostic Imaging X-Ray Contrast Agents"; U.S. Patent No. 5,573,783, "Redispersible Nanoparticulate Film Matrices With Protective Overcoats"; U.S. Patent No. 5,580,579, "Site-Specific Adhesion Within the GI Tract Using Nanoparticles Stabilized by High Molecular Weight, Linear Poly(ethylene Oxide) Polymers"; U.S. Patent No. 5,585,108, "Formulations of Oral Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically Acceptable Clays"; U.S. Patent No. 5,587,143, "Butylene Oxide-Ethylene Oxide Block Copolymers Surfactants as Stabilizer Coatings for Nanoparticulate Compositions"; U.S. Patent No. 5,591,456, "Milled Naproxen with Hydroxypropyl Cellulose as Dispersion "Novel Barium Salt Formulations Stabilized by Non-ionic and Anionic Stabilizers" in U.S. Patent No. 5,593,657; "Sugar-Based Surfactant for Nanocrystals" in U.S. Patent No. 5,622,938; "Improved Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal Therapeutic Agents" in U.S. Patent No. 5,628,981;U.S. Patent No. 5,643,552, entitled "Nanoparticulate Diagnostic Mixed Carbonic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging"; U.S. Patent No. 5,718,388, entitled "Continuous Method of Grinding Pharmaceutical Substances"; U.S. Patent No. 5,718,919, entitled "Nanoparticles Containing the R(-) Enantiomer of Ibuprofen"; U.S. Patent No. 5,747,001, entitled "Aerosols Containing Beclomethasone Nanoparticle Dispersions"; U.S. Patent No. 5,834,025, entitled "Reduction of Intravenously Administered Nanoparticulate Formulation Induced Adverse Physiological Reactions"; and U.S. Patent No. 6,045,829, entitled "Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surfaces." No. 6,068,858, "Methods of Making Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers"; U.S. Patent No. 6,153,225, "Injectable Formulations of Nanoparticulate Naproxen"; U.S. Patent No. 6,165,506, "New Solid Dose Form of Nanoparticulate Naproxen";U.S. Patent No. 6,221,400, entitled "Methods of Treating Mammals Using Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors"; U.S. Patent No. 6,264,922, entitled "Nebulized Aerosols Containing Nanoparticle Dispersions"; U.S. Patent No. 6,267,989, entitled "Methods for Preventing Crystal Growth and Particle Aggregation"; No. 6,270,806, "Use of PEG-Derivatized Lipids as Surface Stabilizers for Nanoparticulate Compositions"; U.S. Patent No. 6,316,029, "Rapidly Disintegrating Solid Oral Dosage Form," U.S. Patent No. 6,375,986, "Solid Dose Nanoparticulate Compositions Comprising a Synergistic Combination of a Polymeric Surface Stabilizer and Dioctyl Sodium Sulfosuccinate"; U.S. Patent No. 6,428,814, "Bioadhesive nanoparticulate compositions having cationic surface stabilizers"; U.S. Patent No. 6,431,478, "Small Scale Mill"; and U.S. Patent No. 6,432,381, "Methods for Targeting Drug Delivery to the Upper and / or Lower Gastrointestinal Tract." tract," all of which are specifically incorporated by reference. Additionally, U.S. Patent Application Publication No. 20020012675A1, published January 31, 2002, entitled "Controlled Release Nanoparticulate Compositions," describes nanoparticulate compositions and is specifically incorporated by reference.

[0149] Nanoparticle formulations comprising the compounds described herein, and prodrug or salt forms of the compounds, can be used to treat or prevent infection with the Hepatitis B virus.

[0150] Amorphous small particle compositions are described, for example, in U.S. Pat. No. 4,783,484, entitled "Particulate Composition and Use Thereof as an Antimicrobial Agent"; U.S. Pat. No. 4,826,689, entitled "Method for Making Uniformly Sized Particles from Water-Insoluble Organic Compounds"; U.S. Pat. No. 4,997,454, entitled "Method for Making Uniformly-Sized Particles From Insoluble Compounds"; U.S. Pat. No. 5,741,522, entitled "Ultrasmall, Non-aggregated Porous Particles of Uniform Size for Entrapping Gas Bubbles Within and Methods"; and U.S. Pat. No. 5,776,496, entitled "Ultrasmall Porous Particles for Enhancing Ultrasound Backscatter."

[0151] Sustained-release formulations In a preferred embodiment, the active compound is prepared with a carrier that prevents the compound from being rapidly excreted from the body, such as a sustained-release formulation, including but not limited to implants and microencapsulated delivery systems.Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid.For example, enteric-coated compounds can be used to prevent digestion by stomach acid.The preparation method of such formulations is clear to those skilled in the art.Suitable materials can also be commercially available.

[0152] Liposomal suspensions (including liposomes targeted to infected cells using monoclonal antibodies against viral antigens) are also preferred as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art, for example, as described in U.S. Pat. No. 4,522,811 (incorporated by reference). For example, liposomal formulations can be prepared by dissolving a suitable lipid (e.g., stearoylphosphatidylethanolamine, stearoylphosphatidylcholine, arachidonoylphosphatidylcholine, and cholesterol) in an inorganic solvent, followed by evaporation, leaving a thin film of dry lipid on the surface of the container. An aqueous solution of the active compound is then introduced into the container. The container is then manually agitated to free lipid material from the sides of the container and disperse lipid aggregates, thereby forming a liposomal suspension.

[0153] The terms used in describing the present invention are those commonly used and known to those skilled in the art. As used herein, the following abbreviations have the indicated meanings: Boc2O di-tert-butyl dicarbonate CDI Carbonyldiimidazole DCC N,N-dicyclohexylcarbodiimide DIPEA Diisopropylethylamine (Hunig's base) DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EDC 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride EtOAc ethyl acetate h time HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate M mole min RT room temperature TFA trifluoroacetic acid THF tetrahydrofuran DMA Dimethylacetamide

[0154] IX. General Methods for Preparing Active Compounds The easy preparation of the active compounds is known in the art and can be obtained by selectively combining known methods. The compounds disclosed herein can be prepared as described in detail below or by other methods known to those skilled in the art. It will be understood by those skilled in the art that modifications in detail can be made without departing from the spirit of the invention and without limiting the scope of the invention in any way.

[0155] The various reaction schemes are summarized below. Scheme 1 is a non-limiting example of the synthesis of intermediates IX and X. Scheme 2 is a non-limiting example of a method for synthesizing active compounds of the present invention, particularly compounds of Formulae AC. Scheme 3 is an alternative synthesis of intermediate IV. Scheme 4 is an alternative synthesis of intermediate IV. Scheme 5 shows the synthesis of intermediate XXIII. Scheme 6 shows the synthesis of intermediate XXIV. Scheme 7 shows the synthesis of intermediate XXVII. Scheme 8 is a synthesis of compound D, which can be used to make compounds of formula 8. Scheme 9 is a non-exhaustive list of reagents that can be used to bind HBV capsid assembly effectors ("CAEs"). Schemes 10 and 11 show the synthesis of diazo linkers. Scheme 12 is a synthesis of compounds of formula HD, a dimer in which a central linker moiety is attached to two CAEs via heteroaryl moieties formed by coupling of an azide and an alkyne. Scheme 13 is a synthetic method for forming compounds of formula DAM (a dimer in which a central linker moiety is attached to two CAE moieties via amide bonds). Scheme 14 illustrates the synthesis of compounds of formula DHAR (dimers in which a central linker moiety is attached to two CAEs via heteroaryl-alkenyl or alkynyl moieties) formed by coupling a heteroaryl ring to an alkene or alkyne moiety attached to a CAE, and compounds of formula DHAR2 (dimers in which a central linker moiety is attached to two CAEs via heteroaryl-alkyl moieties) formed by reducing a double or triple bond in a compound of formula DHAR using transition metal catalyzed coupling chemistry. Scheme 15 is a method for the synthesis of compounds of formula LO and LA, dimers in which a central linker moiety containing two double bonds (formula LDB) is attached to two CAEs via olefinic (LO) or alkyl (LA) bonds. Scheme 16 is a method for synthesizing compounds C5 to C7. Scheme 17 is a method for synthesizing compounds A2 to A9. Scheme 18 is a method for synthesizing compounds of formula B1, B2, B3, B3B, B4, B5, B6, B6B, and B7. Scheme 19 shows the synthesis of compound 8. Scheme 20 shows the synthesis of compound 17. Scheme 21 shows the synthesis of compound 9. Scheme 22 shows the synthesis of compound 16a. Scheme 23 shows the synthesis of compound 17c. Scheme 24 shows the synthesis of compound 20. Scheme 25 shows the synthesis of compound 23. Scheme 26 shows the synthesis of compound 28. Scheme 27 shows the synthesis of compound 33. Scheme 28 shows the synthesis of compound 45. Scheme 29 shows the synthesis of compound 50. Scheme 30 shows the synthesis of compound 53. Scheme 31 shows the synthesis of compounds 58 and 60. Scheme 32 shows the synthesis of compounds 62 and 64.

[0156] Compounds of general formulas A, B, and C can be synthesized from a common intermediate IX or X. As outlined in Scheme 1, intermediates IX and X can be prepared by first reacting ketoester II with an aldehyde or ketone of general formula III and an amine of general formula I to generate a dihydropyrimidine of general formula IV. Halogenation of the 6-methyl group, for example, by treatment with N-bromosuccinimide (NBS) or other N-halosuccinimide (NXS), followed by reaction with an amine of general formula V in the presence of an organic base such as pyridine, provides compounds of general formula VI. Deprotection of this intermediate, for example, with BCl or by hydrogenation, followed by decarboxylative halogenation, for example, with NaI, oxone, and KCO, and final N-protection with carbobenzoxychloride (CBzCl) in the presence of a base such as KHMDS (potassium bis(trimethylsilyl)amide), provides compounds of general formula IX or X. Scheme 1A. Synthesis of Intermediates IX and X [ka]

[0157] Compounds of general formula A-C can be prepared from intermediates IX and X via a Sonogashira-type reaction with alkynes of general formula XI followed by a subsequent deprotection step. For example, when carbobenzoxy (Cbz) is used as a protecting group, BCl3 can be used. Compounds of general formula B can be obtained by reduction of compound A with H2 in the presence of a Lindlar catalyst. Compounds of general formula C can be synthesized by a palladium-catalyzed reaction with alkenes of general formula XIV under Heck, Suzuki-Miyaura, or Stille coupling conditions. Scheme 2A. Synthesis of Compounds A, B, and C [ka]

[0158] Alternatively, intermediate IV can be prepared by first reacting a ketone or aldehyde of general formula II with a keto acid I in the presence of a Lewis acid, e.g., TiCl, followed by reaction with an amidine XIV to form a thioether intermediate of general formula XV, which can finally be reacted via a transition metal catalyzed C-C bond forming reaction, e.g., a Heck-type coupling. Scheme 3. Alternative synthesis of intermediate IV [ka]

[0159] Key intermediate IV can also be synthesized by reacting compound XIII with urea, followed by halogenation of intermediate XVII with, for example, POCl 3 , and finally by a transition metal catalyzed coupling reaction such as those previously described. Scheme 4. Alternative synthesis of intermediate IV [ka]

[0160] Intermediates of general formula XXIII can be synthesized from compound IV by first halogenating it with, for example, N-bromosuccinimide (NBS) in 1,2-dichloroethane and then reacting the halogenated compound with a protected amine of general formula XX in the presence of a base such as KCO. The hydroxyl group in compound XXI can be converted to a leaving group by reaction with, for example, an organic base such as mesyl chloride (MsCl) and triethylamine (EtN), followed by cyclization in the presence of an inorganic base such as KCO. Other leaving groups can also be used, including tosylate, triflate, brosylate, nosylate, and the like. Deprotection of bicyclic compounds of general formula XXII, for example with 1-chloroethyl chloroformate when PMB (p-methoxybenzyl) is used as the protecting group, and finally reaction with an electrophile, for example ethyl chloroformate, in the presence of an organic base such as EtN, gives intermediates of general formula XXIII. Scheme 5A: Synthesis of Intermediate XXIII [ka]

[0161] Intermediates of general formula XXIV can be prepared from compounds XIX by first reacting compound XIX with an amine such as N-methylamine in the presence of a base such as t-BuOK, followed by reaction with 2-chloroacetyl chloride in the presence of an organic base such as EtN and final cyclization under basic conditions. Scheme 6A: Synthesis of Intermediate XXIV [ka]

[0162] Activated compounds of general formula XIX can be reacted with malonate in the presence of a base such as NaH to form intermediates XXV, which can then be reduced, for example, with NaBH. Reaction of the resulting diol with MsCl in the presence of an organic base can provide cyclized derivatives of general formula XXVI, which can finally be reacted with a nucleophile such as NaSMe to produce compounds of general formula XXVII. Scheme 7A: Synthesis of Intermediate XXVII [ka]

[0163] Bicyclic compounds of general structure D can be prepared, for example, from intermediates XXIII, XXIV, or XXVII by first deprotecting the ester group with, for example, BCl in dichloromethane, followed by decarboxylative halogenation using, for example, NaI, oxone, and KCO, and a final transition metal-catalyzed coupling reaction such as the Sonogashira, Heck, Suzuki-Miyaura, or Stille reaction. Scheme 8A Synthesis of Compound D [ka]

[0164] Conjugated HBV capsid assembly effectors (CAEs) of general formula 1 can be prepared using bi- or trifunctional, homo- or heterofunctional linkers and cross-linking reagents. Preparation of such compounds of general formula 1 can be achieved by those skilled in the art using methods and linkers outlined, for example, in ThermFisher Scientific Crosslinking Reagents Technical Handbook by Greg T. Hermanson (https: / / tools.thermofisher.com / content / sfs / brochures / 1602163-Crosslinking-Reagents-Handbook.pdf); Bioconjugate Techniques, 3rd Edition (Academic Press, 2013, ISBN: 978-0-12-382239-0).

[0165] As shown in Scheme 9 below, there are many types of reagents that can be used to couple the HBV CAE to the central linker. For example, an amine (i.e., X = NH) on the linker moiety can react with a leaving group (LG) on the HBV CAE or on a moiety coupled to the HBV CAE, or vice versa. An azide on the linker moiety can react with a leaving group (LG) on the HBV CAE or on a moiety coupled to the HBV CAE, or vice versa. A carboxylic acid group on the linker moiety can react with a hydroxyl, thiol, or amine group on the HBV CAE or on a moiety coupled to the HBV CAE, or vice versa. An alkene or alkyne moiety on the linker moiety can react with a halide on the HBV CAE or on a moiety coupled to the HBV CAE, for example, by a transition metal-catalyzed coupling reaction, or vice versa. Any double or triple bond remaining after the coupling step can be reduced, if desired, using, for example, hydrogen and an appropriate catalyst. Scheme 9A. Non-Comprehensive List of Reagents that Can Be Used to Bind to HBV CAE [ka]

[0166] Diazido linkers of formula DAL can be prepared by activation of diols of general formula DOL, for example with mesyl chloride (MsCl) in the presence of an organic base such as pyridine, followed by displacement with NaN3 in a polar solvent such as DMF. Scheme 10A. Synthesis of Compounds of Formula DAL [ka]

[0167] Diazide linkers of general formula DAL2 can be prepared by activation of diols of general formula DOL2, for example with triflic anhydride (TfO) in the presence of an organic base such as pyridine, followed by displacement with an azide salt such as NaN in a polar solvent such as DMF. Scheme 11A. Synthesis of a linker of formula DAL2 [ka]

[0168] Dimers or heterodimers of general formula HD can be prepared, for example, by copper(I)-catalyzed alkyne-azide cycloaddition using an alkyne derivative of HBV CAE of a diazide linker of general formula LAZ (azide linker) in the presence of CuSO4 and sodium ascorbate in a mixture of water and tBuOH. Scheme 12A. Synthesis of Compounds of Formula HD [ka]

[0169] Dimers or heterodimers of the general formula DAM (dimers with an amide bond) can be prepared, for example, by coupling a diamino linker of the general formula LAM (linker with an amine group) with a carboxylic acid derivative of the HBV CAE in the presence of a peptide coupling agent such as HATU (1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate, hexafluorophosphate azabenzotriazole tetramethyluronium) in the presence of an organic amine base such as DIPEA (also known as Hunig's base, N,N-diisopropylethylamine). Dimers or heterodimers of the general formula DAM can also be prepared, for example, by coupling a diamino linker of the general formula LAM with an N-hydroxysuccinimide ester derivative of the HBV CAE in the presence of an organic amine base such as DIPEA. Scheme 13A. Synthesis of compounds of formula DAM (dimer linked to CAE via an amide bond) [ka]

[0170] Dimers or heterodimers of the general formula DHAR (dimers linked by a heteroaryl-alkenyl or alkynyl bond to the HBV CAE) can be prepared, for example, by transition metal-catalyzed coupling, such as the Heck or Sonogashira reaction, between a properly functionalized HBV CAE of the general formula AC (alkene / alkyne-functionalized CAE) and two aromatic or heteroaromatic rings substituted with leaving groups such as I, Br, Cl, mesylate, tosylate, or triflate. Reduction of the resulting unsaturated bond, for example, with H2 and Pd / C in MeOH, can produce compounds of the general formula DHAR2 (dimers linked to the CAE via a heteroaryl-alkyl linker). Scheme 14A. Synthesis of compounds of formula DHAR and DHAR2 [ka]

[0171] Dimers or heterodimers of general formula DO (dimers linked to the HBV CAE via an olefinic bond) can be prepared, for example, by ruthenium- or tungsten-catalyzed cross-metathesis between a properly functionalized HBV CAE of general formula CO (CAE linked to an olefin) and a linker bearing two vinyl or allylic substitutions (formula LO, linker linked to an olefin). Reduction of the formed unsaturation, for example, with H and Pd / C in MeOH, can produce compounds of general formula DA (dimers linked to the CAE via an alkyl linker). Scheme 15A: Synthesis of compounds ?? and ?? [ka]

[0172] Compounds of general formula C5-7 can be prepared, for example, by first reacting a properly functionalized and protected piperidinone or a properly functionalized and protected bicyclic piperidinone of general structure C1 with a functionalized acyl chloride derivative in the presence of a base such as LiHMDS in a solvent such as THF. Reaction of the diketo intermediate C2 with hydrazine forms intermediate C3, followed by deprotection of the amino group to provide key intermediate C4. Reaction of C4 with a properly functionalized isocyanate, acyl chloride, or sulfonyl chloride reagent, such as Et3N, in the presence of an organic base provides compounds of structures C5, C6, and C7. In the generalized reaction scheme shown below, the dotted line indicates the R 2 and R 3 represents an optional ring formed by bonding through an alkyl bridge to 1 ~R 5 is as defined in the Compounds section. Scheme 16A: Synthesis of compounds C5-7 [ka]

[0173] In Schemes 17 and 18 shown below, R, R 1 , R 3 , R 4 and A are as defined in the Compounds section herein. Scheme 17: Synthesis of compounds A2-A9 [ka]

[0174] As shown in Scheme 17, A1 can be converted to A2 by treatment with an appropriate alkyl halide, such as (3-bromopropoxy)(tert-butyl)diphenylsilane, in the presence of a suitable catalyst, such as palladium dichloride bis(acetonitrile). A2 can be converted to A3 by deprotection with a suitable reagent, such as tetrabutylammonium fluoride, and further halogenated to A4 with carbon tetrabromide and triphenylphosphine. Cyclization to A5 can be achieved with a suitable radical initiator, such as 2,2'-azobis(2-methylpropionitrile), in the presence of other reagents, such as tributyltin hydride. Ester hydrolysis with a suitable reagent, such as lithium hydroxide, followed by amide formation via treatment with a suitable coupling agent, such as HATU, and an appropriate aniline, or conversion to the acid chloride with a reagent, such as thionyl chloride or oxalyl chloride, followed by treatment with an appropriate aniline, provides A6. The aniline can be modified based on the R4 group disclosed herein. Formation of A7 can be achieved by treatment with a suitable reagent such as oxalyl chloride or ethyl 2-chloro-2-oxoacetate, with or without the addition of a catalyst such as aluminum chloride. Hydrolysis to AS with a suitable reagent such as lithium hydroxide is followed by the preparation of A9 by coupling with an appropriate amine such as 1,1,1-trifluoropropan-2-amine in the presence of a coupling agent such as HATU. The amine may vary for the specific R1 groups disclosed herein. Scheme 18: Synthesis of compounds B2, B3, B3B, B4, B5, B6, B6B, and B7 [ka]

[0175] As shown in Scheme 18, B1 can be converted to B2 by treatment with, for example, methyl 2-chloro-2-oxoacetate. Conversion to B3 can be achieved using a suitable hydroxide reagent, such as lithium hydroxide, or in some cases, if the ester is a benzyl ester, using hydrogen gas and a suitable catalyst. B3 can be converted to B4 by treatment with a suitable reagent, such as N,N-diisopropylcarbodiimide and the alkyne reagent B3B, at elevated temperature. Alternatively, B3 can be treated with oxalyl chloride, followed by workup, and treatment with B3B and a suitable base, such as 2,6-ditertbutylpyridine, to give B4. Hydrolysis to B5 can be achieved with a suitable reagent, such as lithium hydroxide. Conversion to B6 is achieved by addition of an appropriate amine (e.g., R1-NH2) and an amide coupling agent, such as HATU. B6 can be converted to the desired B7 by treatment with a suitable reagent such as lithium hydroxide at elevated temperature, followed by a second amide coupling using an appropriate aniline or heteroarylamine (e.g., R4-NH2) and a coupling agent such as HATU. Alternatively, B5 can be treated with an aniline or heteroarylamine in the presence of a reagent such as lithium bis(trimethylsilyl)amide to give B6B, which can then be treated with an appropriate amine and a coupling agent such as HATU to give the desired B7.

[0176] As shown in Scheme 18A, it is relatively straightforward to obtain esters such as amino acid esters, sulfates, phosphates, and phosphoramidate-terminated alkynes. Reaction of the acid with an acetylene functionalized with both a hydroxyl and an amine moiety results in the formation of an amide bond to the core molecule, retaining the hydroxyl group at the end of the alkyne. This hydroxyl group can then be esterified, sulfated, or phosphorylated using known chemical methods.

[0177] Representative compounds are shown below, but the synthesis is applicable to other compounds described herein, so long as any groups that would react with the amine moiety on the alkyne are appropriately protected, or so long as such groups are added to the molecule after coupling chemistry, in this case amidation chemistry, has been performed. Scheme 18A: Synthesis of ester, sulfate, phosphate, and phosphoramidate terminated acetylenes. [ka]

[0178] As shown in Scheme 18B, W1 can be converted to W2 by reaction with a base such as KOH in the presence of a suitable alkylating agent such as MeI. W2 can then be saponified, for example, in the presence of NaOH, followed by reaction with a substituted aniline in the presence of a coupling agent such as HATU and a base such as DIPEA. Conversion of W4 to W5 can be achieved by treatment with a suitable reagent such as oxalyl chloride or ethyl 2-chloro-2-oxoacetate, with or without the addition of a catalyst such as aluminum chloride. Hydrolysis to W6 with a suitable reagent such as lithium hydroxide is followed by the preparation of W7 by coupling with an appropriate amine, such as propargylamine, in the presence of a coupling agent such as HATU. Scheme 18B: Synthesis of compound W7. [ka]

[0179] Deuterium incorporation: Single or multiple substitutions of hydrogen with deuterium (from carbon-hydrogen bonds to carbon-deuterium bonds) at metabolic positions on HBV CAE, homo- or hetero-HBV CAE dimers, and homo- or hetero-HBV CAE trimers are predicted to slow their metabolic rate, which may result in a longer half-life and slower clearance from the body. The slow metabolism of HBV CAE, homo- or hetero-HBV CAE dimers, and homo- or hetero-HBV CAE trimers is predicted to add additional value to potential therapeutic agents, while other physical or biochemical properties are unaffected.

[0180] Methods for incorporating deuterium into organic derivatives are well known to those skilled in the art. Representative methods are disclosed in Angew. Chem. Int. Ed. Engl. 2007, 46, 7744-7765. Thus, these techniques can be used to introduce one or more deuterium atoms into HBV CAE, homo- or hetero-HBV CAE dimers, or homo- or hetero-HBV CAE trimers.

[0181] Specific Examples Specific compounds representative of the present invention were prepared according to the following examples and reaction sequences. The examples and reaction sequences are provided as illustrative examples to aid in the understanding of the invention and should not be construed as limiting in any way the invention described in the claims that follow. Compounds of the present invention can also be used as intermediates in subsequent examples to make additional compounds of the invention. No attempt has necessarily been made to optimize the yields obtained in any reaction. One of ordinary skill in the art would know how to increase such yields through routine variations in reaction times, temperatures, solvents and / or reagents.

[0182] Anhydrous solvents were purchased from Aldrich Chemical Company, Inc. (Milwaukee, WI) and EMD Chemicals Inc. (Gibbstown, NJ). Reagents were purchased from commercial sources. Unless otherwise noted, materials used in the examples were obtained from readily available commercial sources or synthesized using standard methods known to those skilled in the art of chemical synthesis. 1 H and 13 C NMR spectra were acquired at room temperature on a Bruker Ascend™ 400 MHz Fourier transform spectrometer and are reported in ppm downfield from internal tetramethylsilane. Deuterium exchange, decoupling experiments, or 2D-COSY were performed to confirm proton assignments. Peak multiplicities are designated as follows: s (singlet), d (doublet), dd (double doublet), t (triplet), q (quartet), br (broad), bs (broad singlet), and m (multiplet). All J values ​​are in Hz. Mass spectra were measured on a Micromass Platform LC spectrometer using electrospray technology. Analytical TLC was performed on Sigma-Aldrich® aluminum-backed silica gel (25 μm) plates. Column chromatography was performed by silica gel or reverse-phase high-performance liquid chromatography.

[0183] Example 1 Scheme 19 [ka] Reagents and conditions: a) i) benzyl 3-oxobutanoate, AcOH, iPrOH, piperidine, 50°C, 1 hour; ii) pyridine-2-carboxamidine hydrochloride, 125°C, 3 days; b) i) NBS, AcOH, DCE, 50°C, 30 minutes; ii) morpholine, EtN, DMF, RT, 18 hours; c) H2, Pd / C, EtOH, RT, 1 hour; d) NaI, NaCO 3、Oxone, MeOH / H2O, 1 h, RT; e) CbzCl, KHMDS, THF, -78 °C to RT, 15 h; f) ethynylcyclopropane, PdCl2(PPh3)2, CuI, Et3N, DMF, RT, 4 h; g) BCl3, DCM, -78 °C, 3 h.

[0184] 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate benzyl (2) To a suspension of 2-chloro-4-fluorobenzaldehyde (6 g, 37.8 mmol), piperidine (3 mL), and acetic acid (1 mL) in anhydrous isopropanol (60 mL) was added benzyl 3-oxobutanoate (10.9 g, 56.8 mmol). The mixture was heated at 50 °C for 1 h, and then pyridine-2-carboxamidine hydrochloride (5.96 g, 37.8 mmol) was added. The resulting solution was heated at 125 °C for 3 days and then concentrated under reduced pressure. The residue was washed with MeOH (50 mL) to give compound 2 as a yellow solid (3.8 g, 8.7 mmol). 1 H NMR(400MHz,chloroform-d)δ8.64(s,1H),8.54(dt,J=4.9,1.2Hz,1H),8.20(d,J =8.0Hz,1H),7.76(t,J=7.8Hz,1H),7.42-7.31(m,2H),7.28(dd,J=4.2,2.3Hz ,3H),7.12(dt,J=8.5,3.1Hz,3H),6.90(td,J=8.3,2.6Hz,1H),6.33(s,1H),5 .13(d,J=12.6Hz,1H),5.04(d,J=12.6Hz,1H),2.58(s,3H).MS(ESI)m / z[M+H] + C 24 H 20 Calculated for ClFN3O2: 436.9; Found: 436.3, 438.4.

[0185] 4-(2-chloro-4-fluorophenyl)-6-(morpholinomethyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid (4) To a solution of 2 (1.65 g, 3.7 mmol) in dichloroethane (30 mL) and acetic acid (1 mL) was added N-bromosuccinimide (0.67 g, 3.8 mmol) at 50 °C. The mixture was stirred at 50 °C for 30 min and then poured into a saturated solution of sodium thiosulfate (50 mL). The aqueous phase was extracted with dichloromethane (3 × 50 mL), and the combined organic layers were washed with saturated sodium carbonate solution (2 × 50 mL), dried over sodium sulfate, and concentrated under reduced pressure. Finally, the residue was purified by flash chromatography (hexane / AcOEt) to give the desired brominated intermediate. To a solution of this intermediate in N,N-dimethylformamide (60 mL), morpholine (0.97 mL, 11.3 mmol) and triethylamine (1.54 mL, 11.3 mmol) were added. The mixture was stirred at room temperature for 18 h and then poured into a saturated solution of ammonium chloride (50 mL). The mixture was extracted with ethyl acetate (3 x 50 mL), and the combined organic phases were dried over sodium sulfate. After concentration under reduced pressure, the residue was finally purified by flash chromatography (hexane / EtOAc) to give compound 3 (0.8 g, 1.5 mmol) as a yellow foam. After argon was bubbled through a solution of intermediate 3 (0.8 g, 1.5 mmol) in EtOH (100 mL) for 5 minutes, palladium on carbon (10%) (0.13 g) was added. The reaction mixture was then stirred under a hydrogen atmosphere for 2 hours and then filtered through Celite. After concentration under reduced pressure, the carboxylic acid derivative 4 (0.64 g, 1.5 mmol) was obtained in 98% yield. 1 H NMR (400MHz, chloroform-d) δ8.60-8.54(m,1H),8.36-8.26(m,1H),7.81(t,J=7.8Hz,1H),7.45-7.38(m,1H),7.35-7.29(m,1H),7.16(dd,J =8.4,2.6Hz,1H),6.93(td,J=8.2,2.6Hz,1H),6.25(s,1H),3.84(brs,4H),3.73(s,2H),3.18(brs,1H),3.03(brs,1H),2.72(brs,2H). MS(ESI)m / z[M+H] + C 21 H 21Calculated for ClFN4O3: 431.9; Found: 431.4, 433.4.

[0186] 4-((6-(2-chloro-4-fluorophenyl)-5-iodo-2-(pyridin-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine (5) A suspension of carboxylic acid 4 (0.5 mg, 1.2 mmol), sodium iodide (0.87 mg, 5.8 mmol), and sodium carbonate (184 mg, 1.7 mmol) in water (35 mL) and methanol (35 mL) was stirred and sonicated until a clear, colorless solution was obtained. To the solution, protected from light, was added oxone (159 mg, 1.0 mmol). After stirring at room temperature for 20 min, a saturated solution of sodium thiosulfate (50 mL) was added. The reaction was then extracted with ethyl acetate (3 × 50 mL), and the combined organic phases were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (hexane / ethyl acetate: 8 / 2) to give 5 (435 mg, 73%) as a yellow solid. 1 H NMR(400MHz,chloroform-d)δ9.25(s,1H),8.59(d,J=4.8Hz,1H),8.18(d,J=8.0Hz,1H),7.76(td,J=7.7,1.7Hz,1H),7.47-7.34(m,2H),7.17(d d,J=8.6,2.6Hz,1H),6.99(td,J=8.3,2.6Hz,1H),6.08(s,1H),3.81(t,J=4.6Hz,4H),3.41(s,2H),2.60(d,J=5.4Hz,4H).MS(ESI)m / z[M+H] + C 20 H 20 Calculated for ClFIN4O: 513.7; Found: 513.2.

[0187] Benzyl 4-(2-chloro-4-fluorophenyl)-5-iodo-6-(morpholinomethyl)-2-(pyridin-2-yl)pyrimidine-1(4H)-carboxylate (6) To a solution of 5-iodo-dihydropyrimidine 5 (0.4 g, 0.8 mmol) in THF (20 mL) at 0 °C was added KHMDS (1 M in THF, 1.16 mL, 1.16 mmol) and benzyl chloroformate (0.22 mL, 1.6 mmol). The mixture was stirred at 0 °C for 1 h and then at room temperature for 15 h. The reaction was quenched with a saturated solution of ammonium chloride (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (hexane / ethyl acetate: 8 / 2) to give 6 (0.3 g, 0.5 mmol, 59%) as a yellow solid. 1 H NMR (400MHz, chloroform-d) δ8.44(d,J=4.8Hz,1H),7.69(dt,J=15.3,7.8Hz,2H),7.41-7.12(m,7H),6.89(dd,J=19 .7,7.9Hz,3H),6.52(s,1H),5.06-4.93(m,2H),3.77(t,J=4.6Hz,4H),3.64-3.47(m,2H),2.66(t,J=4.6Hz,4H). 19 F NMR (377 MHz, chloroform-d) δ -111.32 (q, J = 7.1 Hz). MS (ESI) m / z [M+H] + C 28 H 26 Calculated for ClFIN4O3: 647.9; Found: 647.3, 649.3.

[0188] 4-((6-(2-chloro-4-fluorophenyl)-5-(cyclopropylethynyl)-2-(pyridin-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine (8) Argon was bubbled through a solution of 6 (50 mg, 77 μmol), copper iodide (3 mg, 15.4 μmol), and triethylamine (30 μL, 232 μmol) in DMF (2 mL) for 5 min. After the addition of bis(triphenylphosphine)palladium dichloride (5.4 mg, 8 μmol), the reaction mixture was stirred at room temperature for 4 h. The reaction mixture was then diluted with ethyl acetate (50 mL) and washed with a saturated solution of ammonium chloride (50 mL). The organic layer was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography to give compound 7. To a solution of 7 in dichloromethane (20 mL) was added boron trichloride (1 M in dichloromethane, 232 μL, 232 μmol) at −78° C. The mixture was stirred for 3 h, quenched with methanol (2 mL), and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (DCM / MeOH: 95:5) to give compound 8 (10 mg, 22 μmol, 29%). 1 H NMR (400MHz, chloroform-d) δ9.10(s,1H),8.58(d,J=4.8Hz,1H),8.18(d,J=7.9Hz,1H),7.74(td,J=7. 8,1.8Hz,1H),7.37(ddd,J=8.2,5.4,3.0Hz,2H),7.11(dd,J=8.7,2.6Hz,1H),6.95(td,J=8.3,2.6H z,1H),5.82(s,1H),3.76(t,J=4.6Hz,4H),3.48-3.34(m,2H),2.52(q,J=4.1Hz,4H),1.30-1.22(m, 1H),0.90-0.66(m,2H),0.59(dt,J=8.5,3.6Hz,1H),0.52(dt,J=6.1,3.6Hz,1H).MS(ESI)m / z[M+H] + C 25 H 25 Calculated for ClFN4O: 451.9; Found: 451.4, 453.3.

[0189] Scheme 20 [ka] Reagents and conditions: a) benzyl 3-oxobutanoate, iPrOH, AcOH, piperidine, RT, 24 h; b) pyridine-2-carboxamidine hydrochloride, NMI, MeOH, reflux, 18 h; c) i) NBS, AcOH, DCE, 50 °C, 30 min; ii) morpholine, EtN, DMF, RT, 18 h; d) BCl, DCM, -78 °C, 1 h; e) NaI, NaCO, oxone, MeOH / H2O, 1 h, RT; f) CbzCl, KHMDS, THF, -78 °C to RT, 15 h; g) ethynylcyclopropane, PdCl2(PPh3)2, CuI, EtN, DMF, MW, 90 °C, 30 min; h) KOH, MeOH / THF, 0 °C, 1 h.

[0190] Benzyl 2-(2-bromo-4-fluorobenzylidene)-3-oxobutanoate (10) To a solution of 2-bromo-4-fluorobenzaldehyde (5 g, 24.6 mmol) in iPrOH (60 mL) was added benzyl 3-oxobutanoate (5.2 g, 27.1 mmol), piperidine (1 mL), and acetic acid (1 mL). The reaction mixture was stirred at room temperature for 24 hours and then concentrated under reduced pressure. The reaction mixture was solubilized in ethyl acetate (100 mL) and washed with a saturated solution of ammonium chloride (50 mL) and a saturated solution of sodium carbonate (50 mL). The organic layer was then dried over sodium sulfate and concentrated under reduced pressure. The resulting oil was purified by flash chromatography (hexane / EtOAc: 9 / 1) to give compound 10 (7.5 g, 19.9 mmol, 80%) as a 2.3 / 1 mixture of E and Z isomers. 1 H NMR (400MHz, chloroform-d) δ7.89(s,1H),7.77(s,2H),7.45-7.30(m,18H),7.30-7.23(m,7H),7.19(dd,J=8.7,5.8Hz, 3H),7.04(td,J=8.3,2.6Hz,1H),6.69(td,J=8.3,2.6Hz,3H),5.32(s,2H),5.24(s,5H),2.47(s,8H),2.24(s,3H).

[0191] Benzyl 4-(2-bromo-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (11) A solution of 10 (2.54 g, 6.7 mmol), NMI (977 μL, 12.2 mmol), and thiazole-2-carboxamidine hydrochloride (1 g, 6.1 mmol) in THF (30 mL) was refluxed for 18 h. After concentration under reduced pressure, the residue was diluted with EtOAc (50 mL), and the organic layer was washed with a saturated solution of ammonium chloride (50 mL). Finally, the aqueous phase was extracted with ethyl acetate (2 × 50 mL), and the combined organic layers were dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by flash chromatography (hexane / EtOAc: 7 / 3) to give compound 10 as a 2.6 / 1 tautomeric mixture (1.5 g, 3.1 mmol, 50%). 1 H NMR (400MHz, chloroform-d) δ7.86(d,J=3.1Hz,4H),7.82(d,J=3.1Hz,3H),7.55(s,1H),7.53(d,J=3.1Hz,1H),7.46(d,J=3.1Hz,3H),7.37-7.24(m,21H),7. 16-7.06(m,8H),6.97(dtd,J=11.1,8.3,2.6Hz,4H),6.23(s,3H),6.09(d,J =2.5Hz,1H),5.19-4.98(m,8H),2.61(s,3H),2.55(s,8H).MS(ESI)m / z[M+H] + C 22 H 18 Calculated for BrFN3O2S: 487.4; Found: 486.3, 488.2.

[0192] Benzyl 4-(2-bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (12) To a solution of 11 (1.5 g, 3.1 mmol) in dichloroethane (15 mL) and acetic acid (1.5 mL) was added N-bromosuccinimide (0.55 g, 3.1 mmol) at 50 °C. The mixture was stirred at 50 °C for 30 min and then poured into a saturated solution of sodium thiosulfate (50 mL). The aqueous phase was extracted with dichloromethane (3 × 50 mL), and the combined organic layers were washed with saturated sodium carbonate solution (2 × 50 mL), dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc) to give the desired brominated intermediate. To a solution of this intermediate in DMF (5 mL) was added morpholine (0.41 mL, 4.6 mmol) and triethylamine (1.26 mL, 9.3 mmol). The mixture was stirred at room temperature for 18 h and then poured into a saturated solution of ammonium chloride (50 mL). The aqueous layer was extracted with ethyl acetate (3x50 mL), and the combined organic phases were dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by flash chromatography (hexane / EtOAc) to give compound 12 (0.75 g, 1.3 mmol, 43%) as a yellow foam. 1 H NMR(400MHz,chloroform-d)δ9.73(s,1H),7.87(d,J=3.1Hz,1H),7.46(d,J=3.1Hz,1H),7.35-7.22(m,5H),7.11(dd,J=6.6,2.9Hz,2H), 6.95(td,J=8.3,2.6Hz,1H),6.25(s,1H),5.15-4.98(m,2H),4.12-3.87(m,2H),3.84(dd,J=5.7,3.7Hz,4H),2.63(t,J=4.7Hz,4H). 19 F NMR (377 MHz, chloroform-d) δ −114.77.

[0193] 4-(2-Bromo-4-fluorophenyl)-6-(morpholinomethyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylic acid (13) To a solution of 12 (0.9 g, 1.6 mmol) in dichloromethane (30 mL) was added boron trichloride (1 M in dichloromethane, 6.3 mL, 6.3 mmol) at −78° C. The mixture was stirred at room temperature for 2 h and then quenched with MeOH (2 mL). After concentration under reduced pressure, the resulting solid was washed with diethyl ether to give compound 13 as a yellow solid (0.5 g, 1.0 mmol, 66%). 1 H NMR (400MHz, chloroform-d) δ7.89(d,J=3.1Hz,1H),7.57(d,J=3.1Hz,1H),7.42-7.30(m,2H),7.01(dd,J=8.9,6.4Hz,1H),6.1 5(s,1H),4.61(d,J=14.8Hz,1H),4.38(d,J=14.8Hz,1H),4.09(brs,5H),3.72(brs,2H),3.19(brs,2H).MS(ESI)m / z[M+H] + C 19 H 19 Calculated for BrFN4O3S: 481.4; Found: 481.3, 483.2.

[0194] 4-((6-(2-bromo-4-fluorophenyl)-5-iodo-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine (14) A suspension of carboxylic acid 13 (346 mg, 1.0 mmol), sodium iodide (750 mg, 5.0 mmol), and sodium carbonate (106 mg, 1.0 mmol) in water (8 mL) and methanol (8 mL) was stirred and sonicated until a clear, colorless solution was obtained. To the solution, protected from light, was added oxone (431 mg, 0.7 mmol). After stirring at room temperature for 20 min, a saturated solution of sodium thiosulfate (50 mL) was added. The reaction was then extracted with ethyl acetate (3 × 25 mL), and the combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (hexane / ethyl acetate: 8 / 2) to give 14 (290 mg, 68% yield) as a yellow solid. 1H NMR(400MHz,chloroform-d)δ8.62(s,1H),7.84(d,J=3.0Hz,1H),7.42(d,J=3.1Hz,1H),7.41-7.29(m,2H),7 .02(td,J=8.3,2.7Hz,1H),5.99(s,1H),3.78(t,J=4.6Hz,4H),3.41-3.28(m,2H),2.55(d,J=4.9Hz,4H). 19 F NMR (377 MHz, chloroform-d) δ −113.92 (q, J = 7.5 Hz).

[0195] Benzyl 4-(2-bromo-4-fluorophenyl)-5-iodo-6-(morpholinomethyl)-2-(thiazol-2-yl)pyrimidine-1(4H)-carboxylate (15) To a solution of 5-iodo-dihydropyrimidine 14 (0.15 g, 0.26 mmol) in THF (10 mL) at 0 °C, KHMDS (1 M in THF, 0.53 mL, 0.53 mmol) and benzyl chloroformate (0.57 mL, 0.39 mmol) were added. The mixture was stirred at 0 °C for 1 h and then at room temperature for 15 h. The reaction was quenched with a saturated solution of ammonium chloride (50 mL) and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel flash chromatography (hexane / ethyl acetate: 8 / 2) to give product 15 (0.11 g, 0.16 mmol, 59%) as a yellow solid. 1 H NMR (400MHz, chloroform-d) δ7.85(d,J=3.2Hz,1H),7.41(d,J=3.1Hz,1H),7.40-7.33(m,3H),7.33-7.24(m,2H),7.10-7.03(m,2H),6.93(td,J =8.3,2.6Hz,1H),5.77(s,1H),5.10(dd,J=15.3,3.0Hz,2H),4.03-3.88(m,2H),3.76-3.66(m,4H),2.51(t,J=4.6Hz,4H).MS(ESI)m / z[M+H] + C 31 H 29Calculated for BrFN4O3S: 636.5; Found: 635.4, 637.4.

[0196] 4-((6-(2-bromo-4-fluorophenyl)-5-(cyclopropylethynyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholine (17) Argon was bubbled through a solution of 15 (80 mg, 114 μmol), copper iodide (2 mg, 11 μmol), and triethylamine (47 μL, 344 μmol) in DMF (2 mL) for 5 minutes. After adding bis(triphenylphosphine)palladium dichloride (16 mg, 22 μmol), the reaction was heated to 90 °C under microwave irradiation. The reaction was then diluted with ethyl acetate (50 mL) and washed with a saturated solution of ammonium chloride (50 mL). The organic phase was dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (hexane / ethyl acetate) to give compound 16 (0.02 mg, 31 μmol, 27%). To a solution of intermediate 16 (40 mg, 63 μmol) in MeOH (2 mL) and THF (2 mL) was added 20% aqueous potassium hydroxide solution (2 mL). The reaction mixture was stirred at room temperature for 1 hour, neutralized to pH 7 with saturated ammonium chloride solution, and extracted with ethyl acetate (3 x 50 mL). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography (hexane / ethyl acetate: 7 / 3) to give compound 17 (31 mg, 61 μmol, 98% yield). 1H NMR (400 MHz, chloroform-d) δ 8.47 (s, 1H), 7.85 (d, J = 3.2 Hz, 1H), 7.43 (d, J = 3.2 Hz, 1H), 7.39-7.34 (m, 1H), 7.29 (dd, J = 8.4, 2.6 Hz, 1H), 7.01 (td, J = 8.3, 2.7 Hz, 1H), 5.77 ( s,1H),3.75(t,J=4.6Hz,4H),3.42-3.30(m,2H),2.51(q,J=4.1Hz,4H),1.31-1.20 (m,1H),0.78-0.67(m,2H),0.64-0.57(m,1H),0.55-0.47(m,1H).MS(ESI)m / z[M+H] + C 23 H 23 Calculated for BrFN4OS: 502.4; Found: 501.3, 503.3. Scheme 21 [ka] Reagents and conditions: (a) NaN3, DMF, 80°C, 24 hours, 70%; e) CuSO4.5H2O, Na ascorbate, 80°C, microwave, 20 minutes, 50%.

[0197] 1,8-Diazidooctane (2a) To a solution of compound 1a (544 mg, 2 mmol) in DMF (3 mL) was added NaN3 (400 mg, 6.2 mmol, 3.1 equiv.). The resulting mixture was stirred at 80 °C for 24 h and quenched with cold water. The aqueous layer was then extracted with ethyl acetate (3 × 20 mL). Finally, the combined organic layers were washed with water, brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / ethyl acetate, 30:0 to 3:1) to give product 2a (275 mg, 70%). 1 H NMR(400MHz,CDCl3)δ3.28-3.25(m,4H),1.64-1.56(m,4H),1.39-1.31(m,8H).

[0198] 4,4'-(2,2'-(((octane-1,8-diylbis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(azanediyl))bis(2-oxoacetyl))bis(N-(3,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide) (9) To a mixture of compound 2a (8 mg, 0.13 mmol) and compound 7a (37 mg, 0.10 mmol) in HO / CHCN (0.3 mL / 0.5 mL) was added CuSO 5HO (6 mg) and Na ascorbate (12 mg) under an Ar atmosphere. The resulting mixture was stirred at 80 °C for 20 min under microwave irradiation. The mixture was diluted with 20 mL of cold HO and extracted with ethyl acetate (3 × 30 mL). The combined organic layer was washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH, 50:1 to 5:1) to give product 9 (19 mg, 50%). 1 H NMR(400MHz,CDCl3)δ8.86(s,2H),8.09(s,2H),7.75-7.70(m,2H),7.60(s,2H),7.34-7.32(m,2H),7.11-7.04(m,2H) ,4.45(s,4H),4.27(t,J=6.2Hz,4H),3.57(s,6H),2.25(s,6H),2.15(s,6H),1.80(t,J=6.6Hz,4H),1.23-1.19(m,8H). 19 F NMR (377MHz, CDCl3) δ -135.95(t, J=12.25Hz), δ -142.57(t, J=11.08Hz.MS(ESI)m / z[M+H] + C 46 H 51 F4N 12 Calculated value for O6: 944.0; Measured value: 943.7.

[0199] Scheme 22 [ka] Reagents and conditions: (a) NaOH, MeI, DMSO, rt, 12 h, 94%; (b) 20% NaOH, EtOH, 100°C, 6 h, 40%; (c) difluoroaniline, HATU, DIPEA, DMF, 80°C, 24 h; (d) ClCOCOOEt, AlCl3, DCM, 0°C-rt, 16 h, 72%; (e) 5% NaOH, MeOH, rt, 15 min, 70%; (f) tris(3-aminopropyl)amine, CDI, DMF, rt, 24 h, 40%.

[0200] Ethyl 1,3,5-trimethyl-1H-pyrrole-2-carboxylate (11a) To a solution of 10a (10.4 g, 62.2 mmol) in anhydrous DMSO (120 mL) was added KOH (10.5 g, 186.6 mmol). The resulting mixture was stirred at room temperature for 45 min. MeI (26.5 g, 186.6 mmol) was added slowly, maintaining the temperature below 25 °C (ice bath control). After the addition of MeI, the ice bath was removed and the reaction was stirred at room temperature for 6 h. Cold water containing 10a (400 mL) was added, and the mixture was extracted with EtO (4 x 150 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / EtOAc, 20: to 3:1) to give product 11a (83%, 9.4 g). 1 H NMR(400MHz,CDCl3)δ5.76(s,1H),4.28(dd,J=14.2Hz,J=7.1Hz,2H),3.76(s,3H),2.29(s,3H),2.19(s,3H),1.35(t,J=7.1Hz,3H).MS(ESI)m / z[M+H] + C 10 H 16 Calculated value as NO2: 182.2; Measured value: 182.5.

[0201] 1,3,5-Trimethyl-1H-pyrrole-2-carboxylic acid (12a) To a solution of 11a (3 g, 72 mmol) in EtOH (100 mL) was added NaOH 20% (70 mL). The reaction was heated at 100 °C for 6 h. EtOH was evaporated under reduced pressure, and the mixture was washed with DCM (3 × 30 mL). The aqueous layer was carefully acidified to pH 3–4 with 1 M HCl. The mixture was extracted with DCM (3 × 30 mL). The combined organic layers were dried over MgSO and concentrated under reduced pressure. The resulting solid was washed with cold EtO to give 12a as a pink solid in 61% yield (6.7 g). 1 H NMR(400MHz,DMSO-d6)δ11.88(s,1H),5.75(s,1H),3.68(s,3H),2.19(s,3H),2.15(s,3H).MS(ESI)m / z[M+H] + C8H 12 Calculated value as NO2: 154.1; Measured value: 154.5.

[0202] N-(3,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide (13a) To a solution of 12a (2.9 g, 18.9 mmol) in DMF (20 mL) was added 3,4-difluoroaniline (4.5 mL, 22.7 mmol), HATU (8.6 g, 22.7 mmol), and DIPEA (6.6 mL, 37.8 mmol) at 0 °C. The mixture was heated at 60 °C for 2 days. The reaction mixture was then diluted with EtOAc and washed with 1 M HCl, water, and brine. The organic layer was dried over Na SO and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:EtOAc, 8:2) to give 13a (1.85 g) in 37% yield. 1 H NMR(400MHz,CDCl3)δ7.76-7.65(m,1H),7.19-7.07(m,2H),5.80(s,1H),3.77(s,3H),2.38(s,3H),2.24(s,3H).MS(ESI)m / z[M+H] + C 14 H 14 Calculated value for F2N2O: 264.1; Found value: 265.5.

[0203] 2-(5-((3,4-difluorophenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetic acid (15a) To a solution of 13a (860 mg, 3.26 mmol) in DCM (30 mL) was added ethyl oxalyl chloride (980 μL, 8.80 mmol) and AlCl (1.08 g, 8.15 mmol) at 0 °C. The mixture was stirred at room temperature for 16 h and poured into crushed ice. The mixture was extracted with DCM, and the combined organic layers were filtered through Celite. The filtrate was concentrated, and the resulting residue was used in the next step without further purification. To a solution of crude 14a in EtOH, NaOH 10% (25 mL) was added. The mixture was stirred at room temperature for 1 h. EtOH was evaporated under reduced pressure, and the mixture was extracted with EtOAc (3 × 10 mL). The aqueous layer was acidified with 1 M HCl. The mixture was extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over MgSO and concentrated under reduced pressure. The resulting solid was washed with Et2O to give 646 mg of 15a in 59% yield over the two steps. 1 H NMR(400MHz,DMSO-d6)δ14.13(s,1H),10.46(s,1H),8.04-7.71(m,1H),7.59-7.28(m,2H),3.60(s,3H),2.46(s,3H),2.26(s,3H).MS(ESI)m / z[M+H] + C 16 H 15 Calculated for F2N2O4: 337.1; Found: 337.5.

[0204] 4,4',4''-(2,2',2''-((nitrilotris(propane-3,1-diyl))tris(azanediyl))tris(2-oxoacetyl))tris(N-(3,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide) (16a) To a solution of 15a (75 mg, 0.22 mmol) in anhydrous DMF (5 mL) was added CDI (72 mg, 0.45 mmol) at room temperature. After 15 min, tri(3-aminopropyl)amine (25 mg, 0.13 mmol) was added, and the mixture was stirred at room temperature for 24 h. The reaction mixture was quenched with cold HO (20 mL) and extracted with CHCl (3 × 30 mL). The organic layer was dried over NaSO and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH, 30:1 to 5:1) to give 16a in 40% yield (34 mg). 1 H NMR(400MHz,DMSO-d6)δ10.32(s,3H),8.62(t,J=5.4Hz,3H),7.82-7.76(m,3H),7.36-7.30(m,6H) ,3.50(s,9H),3.17-3.12(m,6H),2.39-2.36(m,6H),2.30(s,9H),2.15(s,9H),1.58-1.55(m,6H). 19 F NMR(377MHz, DMSO-d6)δ -137.22(m),δ -144.30(m).MS(ESI)m / z[M+H] + C 57 H 61 F6N 10 Calculated for O9: 1144.2; Found: 1144.5.

[0205] Scheme 23 [ka] Reagents and conditions: a) propargylamine, Et3N, DMF, rt, 1 h; b) diazidooctane, sodium ascorbate, CuSO4·5H2O, ACN / H2O, rt, 2 h;

[0206] Ethyl 4-(2-bromo-4-fluorophenyl)-6-((prop-2-yn-1-ylamino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (17b) Propargylamine (0.09 mL, 1.34 mmol) and triethylamine (0.25 mL, 1.78 mmol) were added to a solution of compound 17a (450 mg, 0.89 mmol) in DMF (15 mL). The mixture was stirred at room temperature for 1 hour, then poured into water and extracted three times with AcOEt. The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (6:4 hexane:AcOEt) gave compound 17b (190 mg, 85%). 1 H NMR(400MHz,CDCl3)δ9.52(s,1H),7.84(d,J=3.1Hz,1H),7.42(d,J=3.1Hz,1H),7.34-7.28(m,2H),6.95(td,J=8.3,2.6Hz,1H),6.19(s,1H),4.3 4(d,J=17.7Hz,1H),4.24(d,J=17.8Hz,1H),4.11-4.00(m,2H),3.53(d, J=2.4Hz,2H),2.28(t,J=2.4Hz,1H),1.79(s,1H),1.14(t,J=7.1Hz,3H). 13 C NMR(101MHz,CDCl3)δ166.2,163.1,162.6,160.1,147.2,144.2,143.1,140.0,130.6(d,J=8.5Hz),123 .0,120.0(d,J=24.2Hz),114.9(d,J=20.8Hz),97.33,81.16,72.29,59.84,58.73,46.78,38.42,14.17. 19 F NMR (377 MHz, CDCl3) δ -113.5.

[0207] Diethyl 6,6'-((((octane-1,8-diylbis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis-(azanediyl))bis(methylene))bis(4-(2-bromo-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate) (17c) A mixture of compound 17b (136 mg, 0.30 mmol), 1,8-diazidooctane (23 mg, 0.12 mmol), CuSO₄·5H₂O (90 mg, 0.36 mmol), and sodium ascorbate (142 mg, 0.72 mmol) in acetonitrile (8 mL) and H₂O (6 mL) was stirred at room temperature for 2 h. The mixture was diluted with DCM and washed twice with a solution of NH₄OH / NH₄Cl, pH 9. The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification by column chromatography (95:5 DCM:MeOH) gave compound 17c (22 mg, 17%) as a mixture of two isomers (85:15 ratio). NMR of the major compound: 1 H NMR(400MHz,CDCl3)δ9.73(s,1H),7.90-7.77(m,2H),7.64(s,1H),7.59-7.4 1(m,4H),7.37-7.20(m,4H),7.08-6.92(2H),6.16(s,2H),4.82(d,J=15.4Hz ,1H),4.60(d,J=15.3Hz,1H),4.38-4.12(m,6H),4.12-3.94(m,4H),3.72(q, J=7.0Hz,2H),1.99-1.70(m,6H),1.38-1.18(m,11H),1.12(t,J=7.1Hz,3H). 13 C NMR(101MHz, CDCl3)δ169.2,166.3,160.2,151.3,143.9,143.1,131.5,130.8,124.5,123.2,122.4,120.8,120. 0,115.7,115.2,109.6,59.9,58.9,58.6,52.4,51.8,50.4,47.6,45.0,37.4,30.3,28.8,28.8,26.5,14.3,14.3. 19 F NMR(377MHz,CDCl3)δ -110.8,-113.5.

[0208] Scheme 24 [ka] Reagents and conditions: c) diazidooctane, sodium ascorbate, CuSO4·5H2O, ACN / H2O, microwave at 80 °C, 20 min; d) sodium ascorbate, CuSO4·5H2O, ACN / H2O, rt, 1 h;

[0209] 4-(2-(((1-(8-azidooctyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide (19) A mixture of 18 (40 mg, 0.10 mmol), 1,8-diazidooctane (30 mg, 0.15 mmol), CuSO 5HO (4 mg), and sodium ascorbate (8 mg) in acetonitrile (1 mL) and HO (0.5 mL) was stirred at 80 °C for 20 min under microwave irradiation. The mixture was diluted with AcOEt and washed with a saturated solution of NaCl. The organic phase was dried over NaSO, filtered, and concentrated under reduced pressure. Purification by column chromatography (98:2 DCM:MeOH) gave 19 (24 mg, 42%). 1 H NMR(400MHz,CDCl3)δ7.91(s,1H),7.78-7.68(m,1H),7.60-7.54(m,1H),7.53-7.46(m,1H),7.24-7.08(m,2H),4.64-4.53(m,2H),4.38-4. 26(m,2H),3.68(s,3H),3.31-3.19(m,2H),2.36(s,3H),2.32(s,3H), 1.96-1.81(m,2H),1.73(s,1H),1.64-1.51(m,2H),1.42-1.22(m,8H). 13 C NMR(101MHz,CDCl3)δ186.7,164.7,160.2,143.8,142.0,126.2,123.5,122.3,117.9,117.3, 115.6,109.9,109.7,51.5,50.5,35.1,32.5,30.3,29.0,28.9,28.9,26.7,26.5,12.5,12.2. 19F NMR(377MHz,CDCl3)δ -135.4~-135.5(m),-142.2~-142.3(m).LC-MS(ESI)m / z:570.5[M+H] + .

[0210] Ethyl 4-(2-bromo-4-fluorophenyl)-6-((((1-(8-(4-((2-(5-((3,4-difluorophenyl)-carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetamido)methyl)-1H-1,2,3-triazol-1-yl)octyl)-1H-1,2,3-triazol-4-yl)methyl)amino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (20) A mixture of compound 17b (19 mg, 0.04 mmol), compound 19 (24 mg, 0.04 mmol), CuSO₄·5H₂O (42 mg, 0.17 mmol), and sodium ascorbate (50 mg, 0.25 mmol) in acetonitrile (2 mL) and H₂O (1.5 mL) was stirred at room temperature for 1 h. The mixture was diluted with DCM and washed twice with a solution of NH₄OH / NH₄Cl, pH 9. The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification by column chromatography (95:5 DCM:MeOH) afforded compound 20 (19 mg, 43%) as a yellowish solid. 1 H NMR(400MHz,CDCl3)δ9.74(s,1H),8.03-7.97(m,1H),7.86-7.81(m,1H),7.77-7.70(m,1H),7.65(s, 1H),7.63-7.59(m,1H),7.57(s,1H),7.47-7.42(m,1H),7.33-7.28(m,1H),7.25-7.18(m,2H),7.17-7 .08(m,1H),7.01-6.93(m,1H),6.12(s,1H),4.65-4.60(m,2H),4.35-4.10(m,6H),4.04-3.95(m,4H) ,3.67(s,3H),2.36(s,3H),2.30(s,3H),1.91-1.76(m,4H),1.32-1.17(m,8H),1.10(t,J=7.1Hz,3H). 13C NMR(101MHz,CDCl3)δ187.4,186.6,173.8,166.2,164.7,163.2,160.1,146.1,1 43.8,143.0,141.9,134.29,130.7,130.7,126.1,123.4,123.1,122.2,122.0,12 0.1,117.7,117.4,117.2,115.6,109.8,109.6,97.0,59.8,58.7,50.3,50.2,47.5,46.1,44.9,35.07,32.3,30.1,30.0,28.5,28.4,26.1,26.1,14.2,12.3,12.2. 19 F NMR(377MHz,CDCl3)δ -110.8,-113.4,-135.6,-142.3.

[0211] Scheme 25 [ka] Reagents and conditions: e) NaN3, DMF, 80 °C, 18 h; f) sodium ascorbate, CuSO4·5H2O, ACN / H2O, 80 °C microwave, 20 min; d) 17b, sodium ascorbate, CuSO4·5H2O, ACN / H2O, rt, 1 h;

[0212] 1,12-Diazidododecane Sodium azide (590 mg, 9.1 mmol) was added to a solution of 1,12-dibromododecane (600 mg, 1.83 mmol) in DMF (4 mL) under a nitrogen atmosphere. The mixture was stirred at 80 °C overnight. Water was added and extracted three times with hexane. The combined organic phases were dried over Na SO , filtered, and concentrated under reduced pressure to give 1,12-diazidododecane as a colorless liquid (420 mg, 91%). 1 H NMR(400MHz, CDCl3)δ3.24(t,J=7.0Hz,4H),1.64-1.54(m,4H),1.42-1.22(m,16H). 13 C NMR(101MHz,CDCl3)δ51.4,29.5,29.4,29.1,28.9,26.7.

[0213] 4-(2-(((1-(12-azidododecyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide (22) A mixture of 21 (50 mg, 0.13 mmol), 1,12-diazidododecane (68 mg, 0.27 mmol), CuSO 5HO (4 mg), and sodium ascorbate (8 mg) in acetonitrile (1 mL) and HO (0.5 mL) was stirred at 80 °C for 20 min under microwave irradiation. The mixture was diluted with AcOEt and washed with a saturated solution of NaCl. The organic phase was dried over NaSO, filtered, and concentrated under reduced pressure. Purification by column chromatography (98:2 DCM:MeOH) gave 22 (44 mg, 54%) as an oil. 1 H NMR(400MHz,CDCl3)δ8.26(s,1H),7.74(ddd,J=12.1,7.2,2.4Hz,1H),7.67-7 .61(m,1H),7.58(s,1H),7.26-7.23(m,1H),7.12(q,J=8.9Hz,1H),4.54(d,J= 5.6Hz,2H),4.31(t,J=7.3Hz,2H),3.66(s,3H),3.25(t,J=7.0Hz,2H),2.33(s ,3H),2.28(s,3H),1.91-1.82(m,2H),1.64-1.55(m,2H),1.39-1.21(m,16H). 13 C NMR(101MHz,CDCl3)δ186.7,165.0,160.2,151.3(d,J=13.2Hz),148.9(d,J=13.1Hz),148. 2(d,J=12.8Hz),145.8(d,J=12.7Hz),143.7,141.8,134.4(dd,J=8.7,3.2Hz),126.3,123. 4,122.3,117.6,117.2(d,J=18.1Hz),115.6(dd,J=5.8,3.6Hz),109.7(d,J=21.8Hz),51.5 ,50.5,34.9,32.3,30.3,29.4,29.4,29.4,29.3,29.1,29.0,28.8,26.7,26.5,12.2,12.1. 19F NMR(377MHz,CDCl3)δ -135.56~-135.73(m),-142.32~-142.48(m).LC-MS(ESI)m / z:626.4[M+H] + .

[0214] Ethyl 4-(2-bromo-4-fluorophenyl)-6-((((1-(12-(4-((2-(5-((3,4-difluorophenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetamido)methyl)-1H-1,2,3-triazol-1-yl)dodecyl)-1H-1,2,3-triazol-4-yl)methyl)amino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (23)

[0215] A mixture of compound 17b (31 mg, 0.07 mmol), compound 22 (43 mg, 0.07 mmol), CuSO₄·5H₂O (70 mg, 0.28 mmol), and sodium ascorbate (83 mg, 0.42 mmol) in acetonitrile (4 mL) and H₂O (3 mL) was stirred at room temperature for 1 h. The mixture was diluted with DCM and washed twice with a solution of NH₄OH / NH₄Cl (pH 9). The organic phase was dried over Na₂SO₄, filtered, and concentrated under reduced pressure. Purification by column chromatography (96:4 DCM:MeOH) afforded compound 23 (15 mg, 19%) as a yellowish solid. Two isomers were observed by NMR (9:1 ratio), and only one major isomer is described: 1H NMR (400MHz, CDCl3) δ9.74(s,1H),7.91(s,1H),7.83(d,J=3.1Hz,1H),7.73(ddd,J=12.2,7.2,2.5Hz,1H),7.65( s,1H),7.56(s,1H),7.52-7.47(m,1H),7.47-7.42(m,1H),7.30(dd,J=8.4,2.6Hz,1H),7.22-7.17(m,1H),7.17-7 .09(m,1H),7.01-6.93(m,1H),6.14(s,1H),4.61(d,J=5.9Hz,2H),4.35-4.28(m,4H),4.27-4.12(m,2H),4.06-3 .94(m,4H),3.68(s,3H),2.36(s,3H),2.31(s,3H),1.92-1.82(m,4H),1.32-1.19(m,16H),1.11(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ186.6,164.5,160.1,143.7,141.9,134.3,130.6,126.1,123.4,122.2,121.9,117.8,117.3(d,J=18.4Hz ),115.4,114.9,109.7(d,J=21.8Hz),50.4,50.4,35.0,32.4,30.2,29.3,29.3,29.2,28.9,28.9,26.4,26.4,14.2,12.4,12.2. 19 F NMR(377MHz, CDCl3)δ -110.8,-113.5,-135.4~-135.5(m,F),-142.2~-142.3(m,F).

[0216] スキーム26

change

[0217] 2-(4-Ditronic acid) anhydrous acid (24) To a solution of glycine (0.963 g, 12.8 mmol) in 10 mL of 10% sodium hydroxide was added 4-nitrobenzoyl chloride (2 g, 10.7 mmol). The reaction was stirred at 0°C for 30 min and then acidified by adding 1 M HCl solution. The precipitated solid was filtered off, and the solid was recrystallized from water to give 24 as a yellow solid (1.8 g, 75%). 1 H NMR (400MHz, DMSO-d6): δ12.72(s,1H),9.21(t,J=5.9Hz,1H),8.33(d,J=8.9Hz,2H),8.10(d,J=8.9Hz,2H),3.98(d,J=5.9Hz,2H); 13 C NMR (101MHz, DMSO): δ171.1,165.0,149.2,139.5,128.8,123.7,41.4,40.1.

[0218] 2,2'-(dodecane-1,12-diylbis(oxy))dibenzaldehyde (25) A solution of 1,12-dibromododecane (1.34 g, 4.09 mmol), salicylaldehyde (1 g, 8.18 mmol), and KCO (1.13 g, 8.18 mmol) in 12 mL of DMF was stirred at 60 °C for 24 h. The mixture was quenched with water. After extraction with AcOEt, the combined organic layers were dried over MgSO and evaporated. The crude residue was purified by silica gel column chromatography (hexane / EtOAc 95:5) to give 25 as a white solid (750 mg, 56%). 1 H NMR (400MHz, CDCl3): δ10.52(d,J=1.8Hz,2H),7.83(dd,J=7.3,1.8Hz,2H),7.53(ddd,J=8.4,7.3,1.9Hz, 2H),7.02-6.96(m,4H),4.07(t,J=6.4Hz,4H),1.88-1.83(m,4H),1.54-1.43(m,4H),1.37-1.30(m,13H); 13C NMR(101MHz,CDCl3):δ190.0,161.7,136.0,128.3,125.0,120.8,112.6,68.7,29.7,29.4,29.2,26.2;SM(IS):m / z=411[M+1];

[0219] (4Z,4'E)-4,4'-(((dodecane-1,12-diylbis(oxy))bis(2,1-phenylene))bis(methanylylidene))bis(2-(4-nitrophenyl)oxazol-5(4H)-one) (26) A mixture of 25 (0.552 g, 1.34 mmol), 2-(4-nitrobenzamido)acetic acid (24) (0.652 mg, 2.68 mmol), sodium acetate (0.22 g, 2.69 mmol), and acetic anhydride (0.6 mL) was heated at 100 °C for 2 h. After cooling to room temperature, the precipitate was triturated with ethanol, washed with water, and dried under vacuum to give 26 as a yellow solid (0.8 g, 76%). 1 H NMR (400MHz, CDCl3): δ8.82(d,J=7.6Hz,2H),8.34(q,J=8.7Hz,8H),7.98(s,1H),7.44(t,J=7.6Hz,2H),7.08(t,J= 7.6Hz,2H),6.93(d,J=8.4Hz,2H),4.06(t,J=6.5Hz,4H),2.08-1.71(m,4H),1.71-1.36(m,4H),1.50-1.34(m,13H); 13 C NMR (101MHz, CDCl3): δ167.1,160.9,159.5,150.3,134.0,133.2,131.7,131.6,129.1,129 .1,124.2,122.5,121.0,112.0,69.0,29.6,29.4,29.2,26.2.SM(IS):M / Z=787[M+1];HRMS

[0220] N,N'-((1E,1'E)-((dodecane-1,12-diylbis(oxy))bis(2,1-phenylene))bis(3-oxo-3-(piperidin-1-yl)prop-1-ene-2,1-diyl))bis(4-nitrobenzamide) (27) To a solution of 26 (0.8 g, 1.01 mmol) in chloroform (3 mL) was added a solution of piperidine (0.2 mL, 2.035 mmol) in chloroform (2 mL) dropwise. The reaction was stirred at room temperature for 1 h. After removal of volatiles under reduced pressure, the crude residue was purified by silica gel column chromatography (DCM / MeOH 99:1 to 95:5) to give 27 as a yellow solid (710 mg, 73%). 1 H NMR (400MHz, CDCl3): δ10.10(s,2H),8.10(d,J=8.9Hz,4H),7.98(d,J=8.9Hz,4H),7.47(s,1H),7.32-7.27(m,3H),7.02-6.94(m,4H),6.31( s,2H),3.98(t,J=6.6Hz,4H),3.77(s,4H),3.49(d,J=6.4Hz,4H),1.66(dt,J=18.8,6.7Hz,12H),1.36(q,J=7.1Hz,5H),1.29-1.17(m,15H); 13 C NMR(101MHz,CDCl3):δ167.8,163.8,155.9,149.5,138.6,130.1,129.7,128.8,123.5,123.3,121.0, 117.6,113.1,69.5,49.3,43.4,29.6,29.4,29.3,26.1,25.8,25.5,24.8;SM(IS):m / z=957[M+1];HRMS

[0221] N,N'-((dodecane-1,12-diylbis(oxy))bis(2,1-phenylene))bis(1-bromo-3-oxo-3-(piperidin-1-yl)prop-1-ene-2,1-diyl))bis(4-nitrobenzamide) (28) To a solution of 27 (0.3 g, 0.313 mmol) in chloroform (1 mL) was added dropwise a solution of Br2 (0.1 mg, 0.626 mmol) in chloroform (1 mL). The reaction was stirred at room temperature for 24 h. After removal of volatiles under reduced pressure, the crude residue was purified by silica gel column chromatography (DCM / hexane / MeOH 80 / 20 / 1 to 80 / 20 / 5) to give 28 as a yellow solid (40 mg, 9%). 1H NMR (400MHz, CDCl3): δ8.44(s,2H),8.33(d,J=8.9Hz,4H),8.08(d,J=8.9Hz,4 H),7.35-7.26(m,4H),6.96-6.88(m,4H),4.01(dt,J=6.3,3.9Hz,4H),3.55-3 .45(m,2H),3.35-3.23(m,4H),3.16(t,J=10.6Hz,2H),1.80(p,J=6.3Hz,4H), 1.66(dt,J=18.8,6.3Hz,8H),1.41(q,J=5.5,3.9Hz,5H),1.30-1.21(m,15H); 13 C NMR (101MHz, CDCl3): δ162.2,157.2,150.2,138.4,131.5,131.2,130.7,128.8,124.1,120.3,111. 5,110.2,68.3,47.8,42.7,29.7,29.4,29.3,26.3,25.2,25.0,24.3;SM(IS):m / z=1115[M+1];HRMS

[0222] Scheme 27 (R=3-chloro, 4-fluorophenyl) [ka]

[0223] (Tert-butyl(1S,5R)-3-oxo-2-(thiazole-4-carbonyl)-8-azabicyclo[3.2.1]octane-8-carboxylic acid) (30) To a solution of tert-butyl (1R,5S)-3-oxo-8-azabicyclo[3.2.1]octane-8-carboxylic acid 29 (1.05 g, 4.66 mmol) in THF (14 mL) was added LiHMDS (1.5 M in THF, 4.6 mL, 6.9 mmol) at −75° C. After 30 min at this temperature, thiazole-4-carbonyl chloride (0.7 g, 4.74 mmol) was added to the solution. The reaction mixture was stirred at −75° C. for 2 h, quenched with a saturated solution of ammonium chloride (20 mL), and extracted with ethyl acetate (10 mL × 3). The combined organic layers were dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (hexane / ethyl acetate: 100 / 30 to 100 / 50) to give 30 (0.75 g, 48%) as a white solid. 1 H-NMR(CDCl3,400MHz):δ8.86(s,1H),8.22(d,J=2.0Hz,1H),6.04(s,1H),4.44(s,1H),3.01(s,1H),2.40 and 2.35(2s,1H),2.22-2.32(m,2H),2.02-2.04(m,1H),1.70-1.74(m,1H),1.25-1.52(m,10H). 13 C-NMR(CDCl3,400MHz):δ197.8,169.8,168.7,154.6,152.47,125.5,114.0,79.7,55.6,52.5,51.5,44.0,34.8,29.4,28.3.LC-MS m / z(M+H) + :337.4.

[0224] (Tert-butyl (4S,7R)-3-(thiazol-4-yl)-1,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxylate) (31) To a solution of 30 (200 mg, 0.59 mmol) in MeOH, hydrazine monohydrate (0.05 mL) was added. The mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol v / v; 100:1 to 100:10) to give 31 as a white solid (170 mg, 86%). 1H-NMR(CDCl3,400MHz):δ8.97(s,1H),7.47(s,1H),5.36(m,1H),4.55(m,1H),3.24-3.38(m, 1H),2.59(m,1H),2.15-2.23(m,1H),1.88(t,J=10Hz,1H),1.67(m,1H),1.35-1.44(m,10H). 13 C-NMR(CDCl3,100MHz):δ171.1,153.5,146.5,144.2,132.7,118.4,113.0,79.7,51.4,34.7,30.9,29.2,28.4.LC-MS m / z(M+H) + :333.4.

[0225] ((4S,7R)-N-(3-chloro-4-fluorophenyl)-3-(thiazol-4-yl)-1,4,5,6,7,8-hexahydro-4,7-epiminocyclohepta[c]pyrazole-9-carboxamide) (33) To a solution of 31 (200 mg, 0.6 mmol) in dichloromethane (3 mL) was added TFA (0.5 mL). The reaction mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The residue was azeotroped with ethyl acetate (3 mL) and washed with ether (2 mL × 2) to give 32 as a white solid (0.23 g, 85%). To a solution of 32 (0.23 g, 0.5 mmol) in dichloromethane (2 mL) was added triethylamine (0.28 mL, 2 mmol) and 3-chloro-4-fluorophenyl isocyanate (0.09 g, 0.52 mmol). The reaction mixture was stirred at room temperature overnight and then poured into water (3 mL). The mixture was extracted with ethyl acetate (5 mL × 3). The combined organic layers were washed with water and saturated sodium chloride solution, then dried over sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane:methanol (v / v) = 100:1 to 100:10) to give 33 as a white solid (0.13 g, 65%). 1H-NMR (DMSO-d6 + DO, 400 MHz): δ 9.18 and 9.22 (2s, 1H), 7.83 and 7.90 (2s, 1H), 7.69 (d, J = 4.8 Hz, 1H), 7.35 (d, J = 7.6 Hz, 1H), 7.20 (t, J = 8.8 Hz, 1H), 5.62 (s, 1H), 4.72 (s, 1H), 3.21 (m, 1H), 2.51 (m, 2H), 2.28 (m, 1H), 2.10 (m, 1H), 1.82 (m, 1H), 1.67 (m, 1H). 19 F-NMR(DMSO-d6,376MHz):δ125.4. 13 C-NMR(DMSO-d6,100MHz):δ 154.6,153.7,151.0,145.8,141.1,137.8,136.6,131.1,120.9,119.7,118.7,116.7,113.8,52.1,51.5,35.1,31.6,29.1.LC-MS m / z(M+H) + :404.3.

[0226] Scheme 28: [ka] Reagents and conditions: a) piperidine, AcOH, iPrOH, 24 h; b) thiazole-2-carboximidamide hydrochloride, NMI, THF, 60 °C, 65 h; c) N-bromosuccinimide, 1,2-DCE, 55 °C, 2 h; d) ethyl nitroacetate, Cs2CO3, DMF, rt, 1.5 h; e) H2, Raney Ni, Boc2O, EtOH, rt, 48 h; f) NaBH4, EtOH, 50 °C, 4 h; g) methanesulfonyl chloride, Et3N, DCM, 40 °C, 24 h; h) NaOH, EtOH / H2O 1:1, 60 °C, 48 h; i) sodium iodide, Na2CO3, oxone, MeOH / H2O 1:1, rt, 18 h; j) cyclopropylacetylene, PdCl2(PPh3)2, CuI, Et3N, DMF, rt, 4 h; k) HCl / dioxane 4M, DCM, rt, 18 h; l) cyclopropanesulfonyl chloride, pyridine, rt, 4 h.

[0227] Ethyl 2-(2-chloro-4-fluorobenzylidene)-3-oxobutanoate (35) To a solution of 2-chloro-4-fluorobenzaldehyde (5 g, 31.5 mmol) in isopropanol (50 mL) was added ethyl 3-oxobutanoate (4.83 mL, 37.9 mmol), piperidine (0.62 mL, 6.3 mmol), and acetic acid (0.9 mL, 15.8 mmol). The mixture was stirred at room temperature for 24 h and then concentrated under reduced pressure. The residue was then diluted with AcOEt (100 mL) and washed with a saturated solution of Na2CO3. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (9:1 hexane:AcOEt) gave 35 (6.56 g, 77%) as a 6:4 mixture of isomers. 1 H NMR(400MHz,CDCl3)δ7.87(s,0.4H),7.80(s,0.6H),7.46(dd,J=8.7,5.9Hz,0.6H),7.35(dd,J=8.7,5.9Hz,0.4H),7.24-7.18(m,1H),7.03-6. 94(m,1H),4.32(q,J=6.9Hz,0.8H),4.25(q,J=7.1Hz,1.2H),2.46(s,1.8H),2.26(s,1.2H),1.35(t,J=7.1Hz,1.2H),1.21(t,J=7.1Hz,1.8H). 13 C NMR(101MHz,CDCl3)δ202.1,194.5,166.8,164.6,164.5,163.9,162.1,161.9,137.0, 136.6,136.4,135.9(d,J=10.5Hz),135.6(d,J=10.4Hz),131.5(d,J=9.1Hz),130.7(d, J=9.1Hz),128.3(d,J=3.8Hz),128.0(d,J=3.7Hz),117.5(d,J=24.9Hz),117.5(d,J=2 4.9Hz),114.6(d,J=21.4Hz),114.5(d,J=21.5Hz),61.8,61.8,31.3,26.8,14.1,13.9. 19 F NMR(377MHz,CDCl3)δ -107.3~-107.4(m,F),-107.7~-107.7(m,F).HRMS(ESI)m / z C13 H 13 ClFO3[M+H] + Calculated value: 271.0459; Measured value: 271.0526.

[0228] Ethyl 4-(2-chloro-4-fluorophenyl)-6-methyl-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (36) A mixture of compound 35 (6.56 g, 24.2 mmol), thiazole-2-carboximidamide hydrochloride (4.74 g, 29.1 mmol), and N-methylimidazole (3.84 mL, 48.4 mmol) in THF (70 mL) was stirred at 60 °C for 65 h under a nitrogen atmosphere. The mixture was then poured into an aqueous solution of NH4Cl (200 mL) and extracted with AcOEt (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (7:3 hexane:AcOEt) gave compound 36 (8.56 g, 93%) as a yellow solid. 1 H NMR(400MHz,CDCl3)δ7.83(d,J=3.1Hz,0.25H),7.80(d,J=3.1Hz,0.75H),7 .50(d,J=3.1Hz,0.25H),7.43(d,J=3.1Hz,0.75H),7.37-7.32(m,1H),7.15 -7.10(m,1H),6.97-6.88(m,1H),6.20(s,0.75H),6.08(d,J=2.4Hz,0.25H) ,4.09-4.00(m,2H),2.57(s,0.75H),2.51(s,2.25H),1.13(t,J=7.1Hz,3H). 13C NMR(101MHz,CDCl3)δ166.3,166.1,163.2,162.8,162.7,162.5,160.7,160.2,157.7,149.2,145.1, 143.9,143.8,142.8,138.3(d,J=3.5Hz),136.7(d,J=3.5Hz),133.7(d,J=10.3Hz),132.5(d,J=10.5 Hz),130.7(d,J=8.9Hz),130.6(d,J=9.0Hz),124.2,123.2,117.0(d,J=24.8Hz),116.8(d,J=24.5Hz ),114.8(d,J=21.0Hz),114.3(d,J=20.9Hz),104.6,98.9,60.1,59.9,56.2,49.4,23.2,18.7,14.1. 19 F NMR(377MHz,CDCl3)δ -111.6~-111.7(m,F),-113.4 to~-113.5(m,F).HRMS(ESI)m / z C 17 H 16 ClFN3O2S[M+H] + Calculated value: 380.0558; Measured value: 380.0621.

[0229] Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (37) Compound 36 (8.56 g, 22.5 mmol) was dissolved in a solution of 1,2-DCE (50 mL) and acetic acid (35 mL) at 55 °C. A solution of N-bromosuccinimide (4.41 g, 24.8 mmol) in 1,2-DCE (150 mL) and acetic acid (35 mL) was added dropwise to the above solution at 55 °C over 1.5 h. After the addition, the mixture was stirred for an additional 30 min and then cooled to room temperature. The mixture was then poured into a saturated solution of Na2CO3 (300 mL) and extracted with DCM (3 x 50 mL). The combined organic phases were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (9:1 hexane:AcOEt) gave compound 37 as a yellow oil (6.73 g, 65%). 1H NMR(400MHz,CDCl3)δ8.23(s,0.3H),7.84(d,J=3.1Hz,1H),7.54(d,J=3.1Hz,0.7H), 7.48(s,0.7H),7.46(d,J=3.2Hz,0.3H),7.44-7.34(m,1H),7.14(dd,J=8.3,2.5Hz,1H ),7.01-6.90(m,1H),6.20(s,0.3H),6.11(d,J=2.5Hz,0.7H),4.98-4.90(m,1H),4.7 5(d,J=11.3Hz,0.3H),4.59(d,J=8.4Hz,0.7H),4.17-4.04(m,2H),1.19-1.12(m,3H). 13 C NMR(101MHz,CDCl3)δ165.3,164.7,163.3,162.0,160.8,155.7,150.3,143.9,143.0(d,J=11.9Hz),136.2,132.5(d,J=10.5Hz),130.5(d, J=9.2Hz),124.6,123.4,117.1(d,J=24.8Hz),115.1(d,J=21.1Hz),114.5(d,J=21.4Hz),106.0,60.7,60.6,56.1,49.2,31.8,26.1,14.0. 19 F NMR(377MHz,CDCl3)δ -110.94~-111.0(m,F),-112.7~-112.8(m,F).HRMS(ESI)m / z C 17 H 15 BrClFN3O2S[M+H] + Calculated value: 457.9663; Measured value: 457.9726.

[0230] Ethyl 4-(2-chloro-4-fluorophenyl)-6-(3-ethoxy-2-nitro-3-oxopropyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (38) Cesium carbonate (14.2 g, 43.5 mmol) was added to a solution of 37 (6.60 g, 14.4 mmol) and ethyl nitroacetate (3.2 mL, 28.8 mmol) in DMF (50 mL). The mixture was stirred at room temperature for 1.5 h, then poured into water (500 mL) and extracted with DCM (3 × 100 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. Purification by column chromatography (9:1 hexane:AcOEt) gave 38 as a yellow oil (5.19 g, 71%). NMR spectrum indicated two isomers (5:5). 1 H NMR(400MHz,CDCl3)δ7.82(d,J=3.1Hz,1H),7.56-7.49(m,2H),7.39-7.32(m,1H) ,7.17-7.11(m,1H),6.99(qd,J=7.8,2.6Hz,1H),6.12(d,J=10.5Hz,1H),6.01-5. 93(m,1H),4.38-4.16(m,3H),4.08(q,J=7.1Hz,2H),3.82(dd,J=17.6,4.8Hz,0.5 H),3.66(dd,J=17.5,4.4Hz,0.5H),1.33(t,J=7.2Hz,3H),1.13(t,J=7.1Hz,3H). 13 C NMR (101MHz, CDCl3) δ165.3,165.2,163.3,161.9,160.8,153.8,153.5,149.6,143.9,136.3,132.5,130.8(t,J=8.9Hz),125.0,124. 9,117.3,117.1(d,J=24.7Hz),117.0(d,J=24.9Hz),115.1(t,J=22Hz),104.9,85.4,77.4,63.0,60.5,49.4,35.0,35.0,14.0,14.0. 19 F NMR(377MHz,CDCl3)δ -110.95~-111.03(m,F).HRMS(ESI)m / z C 21 H 21 ClFN4O6S[M+H] + Calculated value: 511.0776; Measured value: 511.0841.

[0231] Ethyl 6-(2-((tert-butoxycarbonyl)amino)-3-ethoxy-3-oxopropyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (39) A solution of commercially available Raney nickel in water (5 mL) was washed three times with EtOH. The Raney nickel was then suspended in EtOH (50 mL), followed by the addition of a solution of 38 (5.19 g, 10.2 mmol) in EtOH (150 mL) and di-tert-butyl dicarbonate (4.45 g, 20.4 mmol). The mixture was stirred under hydrogen (1 atm) at room temperature for 48 h. The mixture was then filtered through Celite and concentrated under reduced pressure. Purification by column chromatography (7:3 hexane:AcOEt) afforded 39 as a yellow oil (5.46 g, 92%). 1 H NMR(400MHz,CDCl3)δ7.86-7.80(m,1H),7.55-7.33(m,3H),7.16-7.09(m,1H),7.01-6.88(m,1H),6.21(d,J=12.4Hz,0.3H), 6.13-6.08(m,0.9H),6.01(d,J=8.4Hz,0.3H),4.75-4.65(m,0.5H),4.56(d,J=17.2Hz,0.3H),4.45(d,J=17.2Hz,0.3H),4.3 9-4.30(m,0.5H),4.26-4.15(m,1.75H),4.15-4.00(m,2.8H),3.70(dd,J=14.6,7.4Hz,0.3H),3.61(dd,J=14.9,7.4Hz,0.3H ),3.38(dd,J=15.0,4.2Hz,0.3H),3.18(dd,J=14.6,4.5Hz,0.3H),1.56-1.39(m,9H),1.30-1.23(m,3H),1.18-1.09(m,3H). 13C NMR(101MHz,CDCl3)δ172.5,172.3,171.5,171.4,171.1,165.8,165.7,165.3,163.2,162.5,162.27,162.2,162.1,160.8, 156.9,156.2,155.8,151.1,149.5,149.3,149.1,143.9,142.9,136.5(d,J=8.5Hz),133.6(d,J=10.5Hz),132.5(d,J=10.2H z),131.0(d,J=8.4Hz),130.8(d,J=10.9Hz),124.7(d,J=10.2Hz),123.2,117.1,117.1,116.9,116.8,115.1,114.9,106.4 2,106.2,104.4,79.3,62.3,61.9,61.1,60.4,56.2,56.0,52.6,52.6,49.6,49.4,36.2,36.0,32.9,28.4,28.3,27.7,14.2. 19 F NMR(377MHz,CDCl3)δ -111.13~-111.45(m,F),-113.22~-113.33(m,F).HRMS(ESI)m / z C 26 H 31 ClFN4O6S[M+H] + Calculated value: 581.1559; Measured value: 581.1623.

[0232] Ethyl 6-(2-((tert-butoxycarbonyl)amino)-3-hydroxypropyl)-4-(2-chloro-4-fluorophenyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (40) Sodium borohydride (1.39 g, 36.9 mmol) was added to a solution of 39 (5.36 g, 9.2 mmol) in ethanol (150 mL) under a nitrogen atmosphere. The mixture was stirred at 50 °C for 4 h and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 mL) and washed with water (200 mL) and brine (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (10:0 to 0:10 hexane:AcOEt) gave 40 as a yellow oil (3.17 g, 64%).1 H NMR(400MHz,CDCl3)δ7.86-7.79(m,1H),7.57-7.49(m,1H),7.44-7.40(m,0.5H),7.40-7.31(m,1H),7.17-7.09(m,1H),7.01-6.87(m,1H),6.22(s,0.25H),6.17(s,0.2H),6.11(d,J=2.4Hz,0.2H),6.09(d,J=2.5Hz,0.25H),5.92(d,J=7.4Hz,0.2H),5.80(d,J=7.4Hz,0.25H),5.67(d,J=7.2Hz,0.2H),5.51(d,J=9.3Hz,0.25H),4.24-3.83(m,3.7H),3.83-3.60(m,2.3H),3.47(dd,J=13.2,8.9Hz,0.3H),3.41-3.27(m,0.7H),3.11-2.98(m,0.5H),2.93(dd,J=12.5,6.6Hz,0.25H),2.77(dd,J=13.2,5.9Hz,0.25H),2.43(s,0.2H),1.44(s,9H),1.16-1.08(m,3H). 13C NMR(101MHz,CDCl3)δ163.3,162.8,162.7,162.5,161.9,161.8,160.8,160.3,15 8.6,158.1,157.0,156.7,156.1,154.8,151.0,149.3,149.2,148.3,147.5,146.6 ,145.8,144.0,144.0,143.3,142.9,142.0,141.9,138.4,136.5,136.4,133.6,133.5,132.6,131.0,130.6,130.6,130.5,130.5,124.6,124.5,123.1,117.3,117.3 ,117.1,117.0,117.0,116.8,116.7,115.1(d,J=21.9Hz),114.5(d,J=20.8Hz),1 06.7(d,J=16.1Hz),79.8,79.8,79.1,79.1,65.5,65.4,65.3,65.2,63.5,63.2,63 .1,62.8,60.8,60.8,60.6,60.6,60.4,59.6,58.0,57.9,56.4,55.9,53.4,52.2,52.1,52.1,51.5,51.5,49.7,49.6,36.0,36.0,35.8,32.9,32.2,28.5,28.4,28.4. 19 F NMR(377MHz,CDCl3)δ -110.8~-111.0(m,F),-113.0~-113.0(m,F),-113.1~-113.2(m,F).HRMS(ESI)m / z C 24 H 29 ClFN4O5S[M+H] + Calculated value: 539.1453; Measured value: 539.1518.

[0233] Ethyl 6-((tert-butoxycarbonyl)amino)-3-(2-chloro-4-fluorophenyl)-1-(thiazol-2-yl)-3,5,6,7-tetrahydropyrrolo[1,2-c]pyrimidine-4-carboxylate (41) Methanesulfonyl chloride (0.91 mL, 11.8 mmol) was added to a solution of 39 (3.17 g, 5.9 mmol) and trimethylamine (1.6 mL, 5.9 mmol) in dichloromethane (150 mL) under a nitrogen atmosphere. The mixture was stirred at 40 °C for 24 h until mixing was complete. The mixture was then poured into an aqueous solution of NH4Cl (200 mL) and extracted with DCM (2 × 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (7:3 hexane:AcOEt) gave 41 as a yellow solid (2.00 g, 65%). 1 H NMR(400MHz,CDCl3)δ7.81(d,J=3.2Hz,0.6H),7.80(d,J=3.2Hz,0.4H),7.37(d,J=3.2Hz,0.6H),7.36(d,J=3.2Hz,0.4H),7. 32(dd,J=8.6,6.1Hz,0.6H),7.28-7.23(m,0.4H),7.16-7.10(m,1H),6.97-6.89(m,1H),6.18(s,0.6H),6.17(s,0.4H),4.87- 4.78(m,1H),4.50-4.30(m,3H),4.09-4.01(m,2H),3.56(dd,J=18.0,7.2Hz,0.4H),3.41-3.34(m,0.6H),3.28(dd,J=18.4,6. 3Hz,0.6H),3.08(dd,J=18.0,6.1Hz,0.4H),1.47(s,5.4H),1.46(s,3.6H),1.15(t,J=7.1Hz,1.8H),1.13(t,J=7.1Hz,1.2H). 13C NMR(101MHz,CDCl3)δ166.0,166.0,164.3,164.2,162.7,162.7,160.3,160.2,155.2,155.2,151 .9,151.5,144.7,144.2,143.2,143.1,138.2(d,J=3.4Hz),138.0(d,J=3.5Hz),133.9(dd,J=12. 4,10.5Hz),130.8(t,J=9.3Hz),122.80,117.2(d,J=10.4Hz),117.0(d,J=10.4Hz),114.3,114.1 ,96.5,96.3,80.2,60.0,59.9,57.9,56.6,56.4,56.2,48.0,37.6,37.1,28.4,28.4,14.2,14.2. 19 F NMR(377MHz,CDCl3)δ -113.3~-113.5(m,F).HRMS(ESI)m / z C 24 H 27 ClFN4O4S[M+H] + Calculated value: 521.1347; Measured value: 521.1413.

[0234] 6-((tert-butoxycarbonyl)amino)-3-(2-chloro-4-fluorophenyl)-1-(thiazol-2-yl)-3,5,6,7-tetrahydropyrrolo[1,2-c]pyrimidine-4-carboxylic acid (42) A solution of sodium hydroxide (456 mg, 11.4 mmol) in water (50 mL) was added to a solution of 41 (2.00 g, 3.8 mmol) in ethanol (150 mL). After stirring at 60 °C for 48 h, the mixture was poured into an aqueous solution of ammonium chloride (200 mL) and extracted with ethyl acetate (3 × 50 mL). The combined layers were dried over NaSO, filtered, and concentrated under reduced pressure. Purification by column chromatography (6:4 to 0:10 hexane:AcOEt) gave 42 as an orange solid (1.48 g, 79%). 1H NMR(400MHz,CDCl3)δ7.82-7.77(m,1H),7.38-7.34(m,1H),7.33-7.27(m,0.45H),7.24-7.17(m,0.55),7.15-7.09(m,1H),6.96- 6.87(m,1H),6.14(s,0.55H),6.11(s,0.45H),4.98-4.80(m,1H),4.48-4.17(m,3H),3.56-2.99(m,2H),1.46(s,5H),1.45(s,4H). 13 C NMR(101MHz,CDCl3)δ164.1,144.6,144.1,143.2,143.2,137.1,134.1,130.5,123.0,117.5,117.2, 114.2(d,J=7.7Hz),114.0(d,J=7.5Hz),94.7,58.1,56.4,56.1,56.1,47.8,37.4,28.4,28.4,14.2. 19 F NMR(377MHz,CDCl3)δ -113.3.HRMS(ESI)m / z C 23 H 23 ClFN4O4S[M+H] + Calculated value: 493.1034; Measured value: 493.1099.

[0235] tert-Butyl (3-(2-chloro-4-fluorophenyl)-4-iodo-1-(thiazol-2-yl)-3,5,6,7-tetrahydropyrrolo-[1,2-c]pyrimidin-6-yl)carbamate (43) Sodium iodide (2.25 g, 15.0 mmol) was added to a solution of 42 (1.48 g, 3.0 mmol) and Na2CO3 (350 mg, 3.3 mmol) in methanol (70 mL) and water (70 mL). After protecting the flask from light with aluminum foil, Oxone® (1.94 g, 3.15 mmol) was added to the mixture, and the reaction was stirred for 18 h. The mixture was poured into a saturated solution of Na2SO3 (200 mL) and extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (6:4 hexane:AcOEt) gave 43 as a yellow solid (926 mg, 54%).1 H NMR(400MHz,CDCl3)δ7.80(d,J=3.2Hz,1H),7.41-7.34(m,2H),7.17-7.11(m,1H),7.04-6.96(m,1H),6.01(s,1H),4.86-4.76( m,1H),4.58-4.49(m,0.5H),4.49-4.44(m,1H),4.44-4.30(m,1.5H),3.04-2.93(m,1H),2.66-2.56(m,1H),1.50-1.43(m,9H). 13 C NMR(101MHz,CDCl3)δ164.4,163.0,163.2,160.5,160.5,155.1,155.1,145.3,144.9,14 3.2,143.2,141.5,141.4,137.3,137.2,136.9,136.9,134.0(d,J=8.6Hz),133.9(d,J=8 .6Hz),131.5(d,J=1.9Hz),131.4(d,J=1.7Hz),122.5,117.2(d,J=20.5Hz),117.0(d,J= 20.1Hz),114.6,114.4,80.2,65.5,65.1,64.7,58.7,57.8,47.2,40.6,40.4,28.4,28.4. 19 F NMR(377MHz,CDCl3)δ -112.6~-112.7(m,F).HRMS(ESI)m / z C 21 H 22 ClFIN4O2S[M+H] + Calculated value: 575.0102; Measured value: 575.0169.

[0236] tert-Butyl (3-(2-chloro-4-fluorophenyl)-4-(cyclopropylethynyl)-1-(thiazol-2-yl)-3,5,6,7-tetrahydropyrrolo[1,2-c]pyrimidin-6-yl)carbamate (44) To a solution of 43 (100 mg, 0.17 mmol) in DMF (5 mL) under a nitrogen atmosphere, cyclopropylacetylene (22 μL, 0.26 mmol), trimethylamine (0.07 mL, 0.51 mmol), copper iodide (2 mg, 0.01 mmol), and PdCl(PPh) (21 mL, 0.03 mmol) were added. The mixture was stirred at room temperature for 4 h and then quenched by the addition of an aqueous solution of NHCl (50 mL). The solution was extracted with ethyl acetate (3 × 20 mL), and the combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. Purification by column chromatography (8:2 hexane:AcOEt) afforded 44 as a yellow oil (69 mg, 79%). 1 H NMR(400MHz,CDCl3)δ7.84-7.79(m,1H),7.39-7.32(m,2H),7.14-7.08(m,1H),7.02-6.96(m,1H),5.82(s,1H),4.86-4.70(m,1H) ,4.45-4.27(m,3H),3.05-2.93(m,1H),2.70-2.59(m,1H),1.46(s,9H),1.31-1.18(m,1H),0.78-0.66(m,2H),0.63-0.45(m,2H). 13 C NMR(101MHz,CDCl3)δ164.9,164.9,162.8,162.8,160.4,160.3,155.2,145.4,143.3,142.6 ,138.1,138.0,133.8,133.7,131.4(d,J=8.9Hz),131.2(d,J=8.9Hz),122.6,122.5,116.8(d ,J=24.6Hz),116.4(d,J=24.6Hz),114.4(d,J=20.9Hz),114.4(d,J=20.9Hz),96.8,96.7,90. 7,90.5,80.2,71.9,71.8,59.4,58.7,57.8,57.7,48.1,35.8,28.5,14.3,8.8,8.8,0.5,0.5. 19 F NMR(377MHz,CDCl3)δ -113.8~-113.9(m,F),-114.0~-114.0(m,F).HRMS(ESI)m / z C 26 H 27 ClFN4O2S[M+H] +Calculated value: 513.1449; Measured value: 513.1516.

[0237] N-(3-(2-chloro-4-fluorophenyl)-4-(cyclopropylethynyl)-1-(thiazol-2-yl)-3,5,6,7-tetrahydropyrrolo[1,2-c]pyrimidin-6-yl)cyclopropanesulfonamide (45) A solution of HCl in dioxane (4 M, 1.5 mL) was added to a solution of 44 (69 mg, 0.13 mmol) in DCM (10 mL) at 0° C. The mixture was stirred at room temperature for 18 h and then concentrated under reduced pressure. The crude compound (LC-MS (ESI) m / z: 413 [M+H] + To a solution of 45 (C13H2O, 4H2O) in pyridine (2 mL) under a nitrogen atmosphere, cyclopropanesulfonyl chloride (20 μL, 0.2 mmol) was added. The mixture was stirred at room temperature for 2 h. To complete the reaction, cyclopropanesulfonyl chloride (20 μL, 0.2 mmol) was added again every 2 h for 4 h. The mixture was then poured into a saturated solution of Na2CO3 (30 mL) and extracted with DCM (3 × 10 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), then dried over Na2SO4, filtered, and concentrated under reduced pressure. Purification by column chromatography (8:2 hexane:AcOEt) gave 45 (25 mg, 37%). 1 H NMR(400MHz,CDCl3)δ7.82(d,J=3.2Hz,1H),7.40-7.31(m,2H),7.11(dd,J=8.6,2.6Hz,1H),7.00 (dt,J=8.3,2.6Hz,1H),5.81(s,1H),4.81(d,J=7.7Hz,1H),4.49(dd,J=11.7,5.7Hz,1H),4.44(dd ,J=12.1,4.0Hz,1H),4.25-4.16(m,1H),3.07(dd,J=16.3,7.3Hz,1H),2.75(dd,J=16.9,4.5Hz,1H ),2.50-2.41(m,1H),1.23-1.16(m,3H),1.06-1.00(m,2H),0.77-0.70(m,2H),0.62-0.49(m,2H). 13C NMR(101MHz,CDCl3)δ164.7,162.8,160.4,145.1,143.3,141.7,137.8(d,J=3.4Hz),133.8(d,J=10.4Hz),131.4(d ,J=8.8Hz),122.7,116.8,116.6,114.5,114.3,97.1,91.0,71.6,59.2,57.8,50.9,36.4,31.4,8.8,6.0,5.9,0.5. 19 F NMR(377MHz,CDCl3)δ -113.62(q,J=7.9Hz).HRMS(ESI)m / z C 24 H 23 ClFN4O2S2[M+H] + Calculated value: 517.0857; Measured value: 517.0922.

[0238] Scheme 29: [ka] Reagents and conditions: a) tosyl chloride, triethylamine, CHCl3, RT 2 h; b) sodium azide, DMF, 80 °C, 24 h; c) 48, sodium ascorbate, CuSO4·5H2O, ACN / H2O, 80 °C microwave, 20 min; d) sodium ascorbate, CuSO4·5H2O, ACN / H2O, RT, 3 h.

[0239] 3,6,9,12,15-Pentaoxaheptadecane-1,17-diyl bis(4-methylbenzenesulfonate) (47) Triethylamine (0.92 mL, 6.4 mmol) and tosyl chloride (0.91 g, 4.8 mmol) were added to a solution of 3,6,9,12,15-pentaoxaheptadecane-1,17-diol (46) (0.4 mL, 1.6 mmol) in chloroform (10 mL) at 0 °C. The mixture was then stirred at room temperature for 2 h, quenched with a saturated solution of NaCO (100 mL), and extracted with DCM (2 × 50 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure. Purification by column chromatography (7:3 hexane:AcOEt) gave 47 as an oil (870 mg, 92%). 1 H NMR(400MHz,CDCl3)δ7.79(d,J=8.3Hz,4H),7.34(d,J=8.1Hz,4H),4.17-4.13(m,4H),3.70-3.66(m,4H),3.62(s,8H),3.58(s,8H),2.45(s,6H). 13 C NMR(101MHz, CDCl3)δ144.8,133.0,129.8,128.0,70.7,70.6,70.5,70.5,69.3,68.7,21.6.

[0240] 1,17-Diazido-3,6,9,12,15-pentaoxaheptadecane (48) Sodium azide (385 mg, 5.9 mmol) was added to a solution of 47 (870 mg, 1.47 mmol) in DMF (8 mL) under a nitrogen atmosphere. The mixture was stirred at 80 °C for 24 h. Water (100 mL) was added, followed by extraction with hexane (3 × 30 mL). The combined organic layers were dried over NaSO, filtered, and concentrated under reduced pressure to give 48 (430 mg, 88%). 1 H NMR(400MHz,CDCl3)δ3.70-3.64(m,20H),3.41-3.37(m,4H). 13 C NMR(101MHz,CDCl3)δ70.4,70.4,70.3,69.8,50.5.LC-MS(ESI)m / z:333.5[M+H] + .

[0241] 4-(2-(((1-(17-azido-3,6,9,12,15-pentaoxaheptadecyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide (49) A mixture of 7a (50 mg, 0.13 mmol), 48 (95 mg, 0.26 mmol), CuSO 5HO (4 mg), and sodium ascorbate (8 mg) in acetonitrile (1 mL) and HO (0.5 mL) was stirred at 80 °C for 20 min under microwave irradiation. The mixture was diluted with ethyl acetate and washed with a saturated solution of NaCl. The organic layer was dried over NaSO, filtered, and concentrated under reduced pressure. Purification by column chromatography (98:2 DCM:MeOH) gave 49 (36 mg, 40%). 1 H NMR(400MHz,CDCl3)δ8.06(s,1H),7.80(s,1H),7.72(ddd,J=12.2,7.2,2.4Hz,1H),7.57(s,1H),7.26-7.20(m,1H),7.13(q,J=8.8Hz,1H ),4.64-4.56(m,2H),4.53(t,J=4.9Hz,2H),3.85(t,J=4.0Hz,2H),3.70-3.56(m,20H),3.37(t,J=6.0Hz,2H),2.36(s,3H),2.29(s,3H). 13 C NMR (101MHz, CDCl3) δ186.8,164.8,160.2,151.3(d,J=13.2Hz),148.9(d,J=13.0Hz ),148.2(d,J=12.9Hz),145.8(d,J=12.8Hz),141.9,134.4(dd,J=8.6,3.1Hz),126.1 ,123.7,123.4,117.7,117.3(d,J=18.0Hz),115.6(dd,J=5.8,3.5Hz),109.8(d,J=21 .8Hz),70.6,70.6,70.5,70.5,70.4,70.0,69.3,50.7,50.4,34.9,32.3,12.3,12.0. 19F NMR(377MHz,CDCl3)δ -135.6~-135.7(m,F),-142.4~-142.5(m,F).HRMS(ESI)m / z C 31 H 42 F2N9O8[M+H] + Calculated value: 706.3046; Measured value: 706.3102.

[0242] Ethyl 4-(2-bromo-4-fluorophenyl)-6-((((1-(17-(4-((2-(5-((3,4-difluorophenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetamido)methyl)-1H-1,2,3-triazol-1-yl)-3,6,9,12,15-pentaoxaheptadecyl)-1H-1,2,3-triazol-4-yl)methyl)amino)methyl)-2-(thiazol-2-yl)-1,4-dihydropyrimidine-5-carboxylate (50) A mixture of 7a (22 mg, 0.05 mmol), 49 (36 mg, 0.05 mmol), CuSO 5HO (50 mg, 0.2 mmol), and sodium ascorbate (60 mg, 0.3 mmol) in acetonitrile (4 mL) and HO (3 mL) was stirred at room temperature for 3 h. The mixture was diluted with DCM and washed twice with a solution of NH OH / NH Cl, pH 9. The organic phase was dried over Na SO , filtered, and concentrated under reduced pressure. Purification by column chromatography (96:4 DCM:MeOH) gave 50 (10 mg, 17%). 1H NMR(400MHz,CDCl3)δ9.81(s,0.5H),8.22-8.15(m,1H),7.86-7.83(m,1.4H),7.82(s,0.4H),7.79(s,0.6H),7.77-7.71(m,1H),7.69(s,0.4H),7.64-7.59(m,0.6H),7.58-7.50(m,1H),7.43(d,J=3.1Hz,0.6H),7.33-7.20(m,2.6H),7.17-7.07(m,1H),7.02(dt,J=8.2,2.5Hz,0.4H),6.96(dt,J=8.3,2.6Hz),6.14-6.08(m,1H),4.79-4.72(m,0.4H),4.66-4.60(m,1.6H),4.55-4.46(m,4H),4.27-4.19(m,1H),4.16-4.07(m,1.4H),4.03-3.96(m,0.6H),3.91(s,1H),3.88-3.79(m,4H),3.75-3.69(m,0.6H),3.67(s,3H),3.64-3.51(m,16H),2.37(s,1.8H),2.36(s,1.2H),2.31(s,1,2H),2.26(s,1,8H),1.29-1.22(m,1.2H),1.10(t,J=7.1Hz,1.8H). 13C NMR(101MHz,CDCl3)δ186.8,169.1,166.1,164.8,164.7,163.1,162.2,1 60.2,160.2,160.1,160.1,151.1,147.8,145.9,144.3,143.8,143.7,14 3.6,143.2,141.8,141.8,140.1,140.0,134.5,131.4(d,J=9.0Hz),130. 7(d,J=8.6Hz),126.2,126.1,124.3,123.6,123.6,123.3,123.3,123.1,1 23.1,120.5(d,J=24.7Hz),120.0(d,J=24.2Hz),117.7,117.7,117.3,11 7.3,117.1,117.1,115.6,115.5,115.1,114.9,109.9,109.8,109.7,109 .3,97.1,70.5,70.4,69.5,69.4,60.4,59.8,58.6,52.1,51.6,50.3,50. 2,47.4,44.8,37.1,35.0,32.3,29.7,14.2,14.1,12.3,12.2,12.1,12.1. 19 F NMR(377MHz,CDCl3)δ -110.7(q,J=7.5Hz,0.4F),-113.4(q,J=8.1Hz,0.6F),-135.6~-135.7(m,F),-142.4~-142.7(m,F).HRMS(ESI)m / z C 51 H 60 BrF3N 13 O 10 S[M+H] + Calculated value: 1182.3364; Measured value: 1182,3429.

[0243] Scheme 30: [ka] Reagents and conditions: a) sodium azide, DMF, 80 °C, overnight; b) 7a, sodium ascorbate, CuSO 4 ·5H 2 O, ACN / H 2 O, 80 °C microwave, 10 min.

[0244] 1,10-Diazidododecane (52) Sodium azide (260 mg) was added to a solution of 1,10-dibromododecane 51 (340 mg) in DMF (2 mL) under a nitrogen atmosphere. The mixture was stirred at 80 °C overnight. Water was added and extracted three times with hexane. The combined organic phases were dried over Na SO , filtered, and concentrated under reduced pressure to give 1,10-diazidododecane 52.

[0245] 4,4'-(2,2'-(((dodecane-1,12-diylbis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(azanediyl))bis(2-oxoacetyl))bis(N-(3,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide) (53) A mixture of 7a (92 mg, 0.25 mmol), 1,12-diazidododecane 52 (25 mg, 0.1 mmol), CuSO 5HO (4 mg), and sodium ascorbate (8 mg) in acetonitrile (0.5 mL) and HO (0.3 mL) was stirred at 80 °C for 10 min under microwave irradiation. The mixture was diluted with AcOEt and washed with a saturated solution of NaCl. The organic phase was dried over NaSO, filtered, and concentrated under reduced pressure. Purification by column chromatography (98:2 DCM:MeOH) gave 53 (55 mg). 1 H NMR(400MHz,CDCl3)δ8.69(s,2H),7.88(s,2H),7.78-7.73(m,2H),7.61(s,2H),7.34-7.31(m,2H),7.14-7.07(m,2H), 4.48(s,4H),4.30(t,J=7.2Hz,4H),3.62(s,6H),2.29(s,6H),2.21(s,6H),1.85(t,J=6.4Hz,4H),1.27-1.21(m,16H); 19 F NMR(377MHz,CDCl3)δ -135.8~-135.9(m),δ-142.5~-142.6(m);MS(ESI):m / z[M+H] + C 50 H 59 F4N 12 Calculated O6: 999.5; Measured: 999.6.

[0246] Scheme 31 [ka] Reagents and conditions: (b) CDI, DMF, 45°C, 24 hours, 52%; t BuMgCl, THF, rt, 24 h, 40%; (c) HATU, DIPEA, DMF, 45°C, 24 h, 50%.

[0247] N-(3,4-difluorophenyl)-4-(2-((4-hydroxybutyl)amino)-2-oxoacetyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide (56) To a solution of 2-(5-((3,4-difluorophenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetic acid (54) (75 mg, 0.22 mmol) in DMF (4 mL) was added CDI (90 mg, 0.56 mmol) and 4-aminobutan-1-ol (55) (50 mg, 0.56 mmol). After stirring at room temperature for 24 h, the reaction mixture was poured into saturated NH4Cl (20 mL) and extracted with CHCl3 (3 x 50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure, and the residue was purified by Combi-flash chromatography to give N-(3,4-difluorophenyl)-4-(2-((4-hydroxybutyl)amino)-2-oxoacetyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide (56) (69 mg, 52% yield). 1 H NMR(400MHz,DMSO-d6)δ10.34(s,1H),8.60(t,J=5.8Hz,1H),7.82-7.77(m,1H),7.38-7.33(m,2H),4.37(t,J=5.1Hz,1 H),3.51(s,3H),3.34-3.33(m,2H),3.11-3.09(m,2H),2.32(s,3H),2.15(s,3H),1.47-1.36(m,4H);MS(ESI):m / z[M+H] + C 20 H 24 Calculated F2N3O4: 408.4; Found: 408.4.

[0248] Isopropyl((S)-(4-(2-(5-((3,4-difluorophenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetamido)butoxy)(phenoxy)phosphoryl)-L-alaninate (58) To a solution of N-(3,4-difluorophenyl)-4-(2-((4-hydroxybutyl)amino)-2-oxoacetyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide (56) (10 mg, 0.025 mmol) in anhydrous THF (2 mL) was added a 1.0 M solution of tert-butylmagnesium chloride in THF (74 μL, 0.074 mmol) at 0° C. The resulting mixture was stirred at room temperature for 30 minutes. After cooling the reaction mixture to 0° C., a solution of (S)-2-[(S)-(2,3,4,5,6-pentafluorophenoxy)phenoxyphosphorylamino]propionic acid isopropyl ester (57) (17 mg, 0.037 mmol) in THF (1.0 mL) was added over 2 minutes. The mixture was stirred at room temperature for 24 h, cooled to 0 °C, and quenched with a saturated solution of NH Cl (0.1 mL). The solvent was evaporated, and the residue was purified by Combi-flash chromatography (DCM / MeOH = 30:1 to 10:1) to give 58 (6.6 mg, 40% yield) as a foam. 1 H NMR(400MHz,MeOH-d4)δ7.83-7.77(m,1H),7.38-7.34(m,3H),7.27-7.17(m,4H),5.02-4.95(m,2H),4.18-4.11(m,2H),3.92-3.88(m,1H) ),3.67(s,3H),3.38-3.34(m,1H),2.46(s,3H),2.34(s,3H),1.78-1.69(m,4H),1.36-1.31(m,3H),1.26-1.23(m,6H).MS(ESI):m / z[M+H] + C 32 H 40 F2N4O8P calculated value: 677.7; found value: 677.5.

[0249] N-(3,4-difluorophenyl)-4-(2-(8-hydroxyoctylamino)-2-oxoacetyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide (60) To a solution of 2-(5-((3,4-difluorophenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetic acid 54 (100 mg, 0.30 mmol) in DMF (4 mL) was added HATU (283 mg, 0.74 mmol), 8-amino-1-octanol 59 (86 mg), and DIPEA (208 μL, 0.59 mmol). After stirring at 45 °C for 24 h, the reaction mixture was poured into saturated NH 4 Cl (30 mL) and extracted with EtOAc (3 × 50 mL). The combined organic layers were dried over Na 2 SO 4 and concentrated under reduced pressure. The residue was purified by Combi-flash chromatography (DCM / MeOH = 100:1 to 10:1) to give 60 (69 mg, 50% yield). 1 H NMR(400MHz,MeOH-d4)δ7.83-7.78(m,1H),7.36-7.33(m,1H),7.30-7.23(m,1H),3.67(s,3H),3.57-3.54(m,2H),3. 35-3.31(m,2H),2.46(s,3H),2.34(s,3H),1.66-1.59(m,2H),1.57-1.52(m,2H),1.38(brs,8H);MS(ESI):m / z[M+H] + C 24 H 32 Calculated F2N3O4: 464.5; Found: 464.5.

[0250] Scheme 32: [ka] Reagents and conditions: (a) HATU, DIPEA, DMF, rt, 24 h, 45%; (b) 1 N HCl, HO, THF, 60 °C, 24 h, 70%.

[0251] N-(3,4-Difluorophenyl)-1,3,5-trimethyl-4-(2-oxo-2-((3-(3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)propyl)amino)acetyl)-1H-pyrrole-2-carboxamide (62) To a solution of 2-(5-((3,4-difluorophenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetic acid (54) (600 mg, 1.78 mmol) in DMF (40 mL) was added HATU (1.70 g, 4.46 mmol), DIPEA (1.25 mL, 7.14 mmol), and 3-(3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)propan-1-amine (61) (508 mg, 2.14 mmol). After stirring at room temperature for 24 h, the reaction mixture was poured into saturated NH4Cl (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over NaSO and concentrated under reduced pressure, and the residue was purified by Combi-flash chromatography (hexane / EtOAc = 10:1 to 1:3) to give N-(3,4-difluorophenyl)-1,3,5-trimethyl-4-(2-oxo-2-((3-(3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)propyl)amino)acetyl)-1H-pyrrole-2-carboxamide (62) (446 mg, 45% yield). 1H NMR(400MHz,CH3COCH3-d6)δ9.52(s,1H),8.00-7.95(m,1H),7.81-7.85(m,1H),7.53-7.49(m,1H),7.34-7 .27(m,1H),4.29(dd,J=8.7Hz,1.92Hz,1H),3.67(s,3H),3.32(dd,J=13.7Hz,6.5Hz,2H),2.39(s,3H),2.39 -2.31(m,1H),2.27(s,3H),2.22-2.18(m,1H),2.00-1.97(m,1H),1.88-1.86(m,1H),1.81-1.76(m,1H),1. 72-1.69(m,2H),1.35(s,3H),1.27(s,3H),1.11(d,J=10.8Hz,1H),0.86-0.82(m,5H).HRMS(ESI):m / z[M+H] + C 29 H 37 BF2N3O5 Calculated: 556.27943; Found: 556.2786.

[0252] (3-(2-(5-((3,4-difluorophenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetamido)propyl)boronic acid (64) To a solution of N-(3,4-difluorophenyl)-1,3,5-trimethyl-4-(2-oxo-2-((3-(3a,5,5-trimethylhexahydro-4,6-methanobenzo[d][1,3,2]dioxaborol-2-yl)propyl)amino)acetyl)-1H-pyrrole-2-carboxamide (62) (30 mg, 0.054 mmol) and phenylboronic acid (13 mg, 0.108 mmol) in EtO (2 mL) and HO (2 mL) was added 1N HCl (0.5 mL) was added, and the resulting mixture was stirred at 50° C. for 48 hours. Then, it was concentrated under reduced pressure, and the residue was purified by Combi-flash chromatography (DCM / MeOH=100:1 to 5:1) to give (3-(2-(5-((3,4-difluorophenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetamido)propyl)boronic acid (64) (16 mg, 70% yield). 1H NMR(400MHz,CH3COCH3-d6)δ9.48(s,1H),8.01-7.96(m,1H),7.81-7.78(m,1H),7.53-7.49(m,1H),7.36-7.29(m,1H),6.77(s ,2H),3.68(s,3H),3.34-3.29(m,2H),2.42(s,3H),2.28(s,3H),1.73-1.69(m,2H),0.79(t,J=8.0Hz,2H);MS(ESI):m / z[M+H] + C 19 H 23 Calculated BF2N3O5: 422.2; Found: 422.3.

[0253] Scheme 33 [ka] Reagents and conditions: (a) TsCl, Et3N, DCM, 0 °C to rt, 24 h; (b) NaN3, (NH4)2SO4, MeOH, 65 °C, 4 h; (c) CuSO4.5H2O, sodium ascorbate, 100 °C, 2 h.

[0254] (Diethoxyphosphoryl)methyl 4-methylbenzenesulfonate (66) To a solution of compound 65 (3.0 g, 17.8 mmol, 1 equiv.) and EtN (5.0 mL, 35.6 mmol, 2 equiv.) in DCM (90 mL) was added TsCl (3.4 g, 17.8 mmol, 1.0 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 24 h and quenched with cold saturated NaSO. The aqueous layer was then extracted with DCM (3 × 80 mL). Finally, the combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / ethyl acetate, 3:1 to 1:2) to give product 66 (4.0 g, 70%). 1 H NMR(400MHz,CDCl3)δ7.80(d,J=8.0Hz,2H),7.37(d,J=8.0Hz,2H),4.20-4.13(m,6H),2.46(s,3H),1.32(t,J=7.0Hz,6H).

[0255] Diethyl(azidomethyl)phosphonate (67) To a solution of compound 66 (2.4 g, 7.45 mmol, 1.0 equiv.) and (NH)SO (1.97 g, 14.89 mmol, 2.0 equiv.) in MeOH (50 mL) was added NaN (0.97 g, 14.89 mmol, 2.0 equiv.). The resulting mixture was stirred at 65 °C for 24 h and quenched with cold HO (100 mL). The aqueous layer was then extracted with EtOAc (2 × 200 mL). Finally, the combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / ethyl acetate, 10:1 to 1:4) to give product 67 (1.18 g, 82%). 1 H NMR(400MHz, CDCl3)δ4.25-4.18(m,4H),3.48(d,J=11.6Hz,2H),1.38(t,J=6.8Hz,6H).

[0256] Diethyl ((4-((2-(5-((3,4-difluorophenyl)carbamoyl)-1,2,4-trimethyl-1H-pyrrol-3-yl)-2-oxoacetamido)methyl)-1H-1,2,3-triazol-1-yl)methyl)phosphonate (68) To a mixture of compound 67 (103 mg, 0.54 mmol, 2 equiv.) and compound 7a (100 mg, 0.27 mmol, 1.0 equiv.) in HO / CHCN (3 mL / 6.0 mL) was added CuSO 5HO (15 mg) and Na ascorbate (30 mg) under an Ar atmosphere. The resulting mixture was stirred at 100 °C overnight. The mixture was diluted with 20 mL of cold HO and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH, 100:1 to 5:1) to give product 68 (138 mg, 91%). 1H NMR(400MHz,DMSO-d6)δ10.42(s,1H),9.25(t,J=5.6Hz,1H),7.94(s,1H),7.90-7.85(m,1H),7.44-7.38(m,2H),5.10(d ,J=13.0Hz,2H),4.48(d,J=5.6Hz,2H),4.10-4.03(m,4H),3.59(s,3H),2.36(s,3H)2.20(s,3H),1.21(t,J=7.0Hz,6H). 19 F NMR(377MHz,DMSO-d6)δ -137.2~-137.3(m,1F),-144.2~-144.3(m,1F).HRMS(ESI)m / z C 24 H 30 F2N6O6P[M+H] + Calculated value: 567.1933; Measured value: 567.1918.

[0257] Scheme 34 [ka] Reagents and conditions: (a) NaN3, DMF / H2O, 90 °C, overnight; (b) CuSO4·5H2O, Na ascorbate, CH3CN / H2O, 90 °C, 8 h.

[0258] 1,6-Diazidohexane(70) To a solution of compound 69 (2.5 g, 10.25 mmol, 1.0 equiv.) in DMF / HO (54 mL / 6 mL) was added NaN (1.3 g, 20.49 mmol, 2.0 equiv.). The resulting mixture was stirred at 90 °C overnight and quenched with cold HO (50 mL). The aqueous layer was then extracted with EtOAc (2 × 100 mL). Finally, the combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / ethyl acetate, 10:1 to 1:4) to give product 70 (1.4 g, 82%). 1 H NMR(400MHz,DMSO-d6)δ3.33(d,J=6.8Hz,4H),1.58-1.51(m,4H),1.39-1.33(m,4H).

[0259] 4,4'-(2,2'-(((hexane-1,6-diylbis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(azanediyl))bis(2-oxoacetyl))bis(N-(3,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide) (71) To a mixture of compound 70 (100 mg, 0.27 mmol, 1.0 equiv.) and compound 7a (22.5 mg, 0.13 mmol, 0.5 equiv.) in HO / CHCN (3 mL / 5 mL) was added CuSO 5HO (24 mg) and Na ascorbate (48 mg) under an Ar atmosphere. The resulting mixture was stirred at 90 °C for 8 h. The mixture was diluted with 40 mL of cold HO and extracted with ethyl acetate (3 × 50 mL). The combined organic layer was washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH, 100:1 to 5:1) to give product 71 (62 mg, 51%). 1 H NMR(400MHz,DMSO-d6)δ10.42(s,2H),9.18(t,J=5.6Hz,2H),7.99(s,2H),7.90-7.84(m,2H),7.46-7.38(m,4H),4.4 4(d,J=5.6Hz,4H),4.31(t,J=7.0Hz,4H),3.58(s,6H),2.18(s,6H),2.34(s,6H).1.77(t,J=6.6Hz,4H),1.23(s,4H). 19 F NMR(377MHz,DMSO-d6)δ -137.1~-137.2(m,1F),-144.2~-144.4(m,1F).LCMS(ESI):m / z[M+H] + C 44 H 47 F4N 12 Calculated O6: 915.9; Measured: 915.2.

[0260] Scheme 35 [ka] Reagents and conditions: (a) NaN3, DMF, 80 °C, overnight; (b) CuSO4·5H2O, Na ascorbate, CH3CN / H2O, 80 °C, microwave, 20 min.

[0261] 1,8-Diazidooctane (73) To a solution of compound 72 (544 mg, 2.0 mmol, 1.0 equiv) in DMF (9 mL) was added NaN (400 mg, 6.2 mmol, 3.1 equiv). The resulting mixture was stirred at 80 °C overnight and quenched with cold HO (50 mL). The aqueous layer was then extracted with EtOAc (2 × 50 mL). Finally, the combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / ethyl acetate, 10:1 to 1:4) to give product 73 (275 mg, 70%). 1 H NMR(400MHz, CDCl3)δ3.26(t,J=6.8Hz,4H),1.64-1.57(m,4H),1.39-1.31(m,8H).

[0262] 4,4'-(2,2'-(((octane-1,8-diylbis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(azanediyl))bis(2-oxoacetyl))bis(N-(3,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide) (74) To a mixture of compound 73 (8 mg, 0.04 mmol, 0.4 equiv.) and compound 7a (38 mg, 0.1 mmol, 1.0 equiv.) in HO / CHCN (0.6 mL / 1 mL) was added CuSO 5HO (6 mg) and Na ascorbate (12 mg) under an Ar atmosphere. The resulting mixture was heated in a microwave oven at 80 °C for 20 min. The mixture was diluted with 30 mL of cold HO and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH, 100:1 to 5:1) to give product 74 (19 mg, 50%). 1H NMR(400MHz,CDCl3)δ8.87(s,2H),8.09(s,2H),7.75-7.70(m,2H),7.61(s,2H),7.33(d,J=8.0Hz,2H),7.11-7.04(m,2H) ),4.45(s,4H),4.27(t,J=6.2Hz,4H),3.57(s,6H),2.25(s,6H),2.15(s,6H),8.09(t,J=6.6Hz,4H),1.23-1.19(m,8H). 19 F NMR(377MHz,CDCl3)δ -135.9~-136.0(m,1F),-142.5~-142.6(m,1F).LCMS(ESI)m / z[M+H] + C 46 H 51 F4N 12 O6 [M+H] + Calculated value: 944.0; Measured value: 943.7.

[0263] Scheme 36 [ka] Reagents and conditions: (a) NaN3, DMF, 60 °C, overnight; (b) CuSO4·5H2O, Na ascorbate, CH3CN / H2O, 100 °C, overnight.

[0264] 1,10-Diazidododecane(76) To a solution of compound 75 (2.5 g, 8.33 mmol, 1.0 equiv.) in DMF (100 mL) was added NaN (1.6 g, 24.99 mmol, 3.0 equiv.). The resulting mixture was stirred at 60 °C overnight and quenched with cold HO (50 mL). The aqueous layer was then extracted with EtOAc (2 × 100 mL). Finally, the combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / ethyl acetate, 20:1 to 1:4) to give product 76 (1.68 g, 90%). 1 H NMR(400MHz, CDCl3)δ3.31(t,J=6.8Hz,4H),1.57-1.50(m,4H),1.34-1.28(m,12H).

[0265] 4,4'-(2,2'-(((decane-1,10-diylbis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(azanediyl))bis(2-oxoacetyl))bis(N-(3,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide) (77) To a mixture of compound 76 (30 mg, 0.134 mmol, 0.5 equiv) and compound 7a (100 mg, 0.268 mmol, 1.0 equiv) in HO / CHCN (5 mL / 10 mL) was added CuSO 5HO (20 mg) and Na ascorbate (40 mg) under an Ar atmosphere. The resulting mixture was stirred at 100 °C overnight. The mixture was diluted with 30 mL of cold HO and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH, 100:1 to 5:1) to give product 77 (52 mg, 40%). 1 H NMR(400MHz,CDCl3)δ8.66(s,2H),7.99(s,2H),7.75-7.66(m,4H),7.31-7.30(m,2H),7.11-7.05(m,2 H),4.51(s,4H),4.30(s,4H),3.59(s,6H),2.27(s,6H),2.18(s,6H),1.83(s,4H),1.24-1.19(m,12H). 19 F NMR(377MHz,CDCl3)δ -135.8~-135.9(m,1F),-142.5~-142.6(m,1F).LCMS(ESI)m / z[M+H] + C 48 H 55 F4N 12 O6 [M+H] + Calculated value: 972.0; Measured value: 971.3.

[0266] Scheme 37 [ka] Reagents and conditions: (a) NaN3, DMF, 90 °C, 24 h; (b) CuSO4·5H2O, Na ascorbate, CH3CN / H2O, 100 °C, overnight.

[0267] 1,14-Diazidotetradecane(79) To a solution of compound 78 (500 mg, 1.4 mmol, 1.0 equiv) in DMF (20 mL) was added NaN (274 mg, 4.21 mmol, 3.0 equiv). The resulting mixture was stirred at 90 °C for 24 h and quenched with cold HO (40 mL). The aqueous layer was then extracted with EtOAc (2 × 50 mL). Finally, the combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / ethyl acetate, 20:1 to 1:4) to give product 79 (339 mg, 86%). 1 H NMR(400MHz, CDCl3)δ3.26(t,J=7.2Hz,4H),1.62-1.56(m,4H),1.38-1.27(m,20H).

[0268] 4,4'-(2,2'-(((tetradecane-1,14-diylbis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(azanediyl))bis(2-oxoacetyl))bis(N-(3,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide) (80) To a mixture of compound 79 (30 mg, 0.107 mmol, 0.5 equiv) and compound 7a (80 mg, 0.214 mmol, 1.0 equiv) in HO / CHCN (8 mL / 12 mL) was added CuSO 5HO (20 mg) and Na ascorbate (40 mg) under an Ar atmosphere. The resulting mixture was stirred at 100 °C overnight. The mixture was diluted with 30 mL of cold HO and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH, 100:1 to 5:1) to give product 80 (55 mg, 50%). 1H NMR(400MHz,CDCl3)δ8.08(s,2H),7.76-7.71(m,2H),7.57(s,2H),7.54(t,J=5.9Hz,2H),7.24-7.22(m,2H),7.22-7.09(m,2H), 4.56(d,J=5.9Hz,4H),4.32(t,J=7.2Hz,4H),3.67(s,6H),2.34(s,6H),2.29(s,6H),1.87(t,J=7.2Hz,4H),1.29-1.22(m,20H). 19 F NMR(377MHz,CDCl3)δ -135.8~-135.9(m,1F),-142.5~-142.6(m,1F).LCMS(ESI)m / z[M+H] + C 52 H 63 F4N 12 O6 [M+H] + Calculated value: 1028.1; Measured value: 1027.3.

[0269] Scheme 38 [ka] Reagents and conditions: (a) TsCl, Et3N, DCM, 0 °C to room temperature, overnight; (b) NaN3, DMF, 80 °C, overnight; CuSO4·5H2O, Na ascorbate, 100 °C, overnight.

[0270] 1-Azido-2-(2-azidoethoxy)ethane (83) To a solution of compound 81 (2.1 g, 19.79 mmol, 1 equiv.) and EtN (8.3 mL, 59.37 mmol, 3 equiv.) in DCM (60 mL) was added TsCl (8.3 g, 43.54 mmol, 2.2 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 24 h and quenched with cold saturated NaSO solution. The aqueous layer was then extracted with DCM (3 × 100 mL). The final organic layers were combined, washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure to give crude compound 82 (10 g). To a solution of compound 82 (7.5 g, 18.09 mmol, 1 equiv.) in DMF (150 mL) was added NaN (2.6 g, 39.8 mmol, 2.2 equiv.). The resulting mixture was stirred at 80 °C overnight and quenched with cold HO (100 mL). The aqueous layer was then extracted with EtOAc (2 × 200 mL). Finally, the combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / ethyl acetate, 20:1 to 1:1) to give product 83 (1.2 g, 52% over two steps). 1 H NMR(400MHz,CD3COCD3)δ3.73-3.71(m,4H),3.43(t,J=7.2Hz,4H).

[0271] 4-(2-(((1-(2-(2-azidoethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide (84) and 4,4'-(2,2'-((((oxybis(ethane-2,1-diyl))bis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(azanediyl))bis(2-oxoacetyl))bis(N-(3,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide) (85). To a mixture of compound 83 (16.7 mg, 0.107 mmol, 0.5 equiv.) and compound 7a (80 mg, 0.214 mmol, 1.0 equiv.) in HO / CHCN (8 mL / 12 mL) was added CuSO 5HO (20 mg) and Na ascorbate (40 mg) under an Ar atmosphere. The resulting mixture was stirred at 100 °C overnight. The mixture was diluted with 30 mL of cold HO and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH, 100:1 to 5:1) to give product 84 (28 mg, 25%): 1 H NMR(400MHz,DMSO-d6)δ10.42(s,1H),9.20(t,J=5.8Hz 1H),7.98(s,1H),7.91-7.85(m,1H),7.47-7.38(m,2H),4.56(t,J=5.2Hz,2H),4.46(d,J=5.7Hz ,2H),3.85(t,J=5.2Hz,2H),3.59(t,J=4.4Hz,5H),3.39-3.36(m,2H),2.36(s,3H),2.20(s,3H). 19 F NMR(377MHz,DMSO-d6)δ -137.1~-137.3(m,1F),-144.2~-144.4(m,1F).LCMS(ESI)m / z C 23 H 26 F2N9O4[M+H] + Calculated: 530.5; Found: 530.1; and Product 85 (58 mg, 60%): 1 H NMR(400MHz,DMSO-d6)δ10.41(s,2H),9.19(t,J=5.7Hz,2H),7.91(s,2H),7.90-7.84(m,2H),7.45-7.38(m,4H) ),4.50(t,J=5.0Hz,4H),4.45(d,J=5.7Hz,4H),3.79(t,J=5.2Hz,4H),3.58(s,6H),2.34(s,6H),2.20(s,6H). 19 F NMR(377MHz,DMSO-d6)δ -137.1~-137.2(m,1F),-144.2~-144.4(m,1F).LCMS(ESI)m / z[M+H] + C42 H 43 F4N 12 O7 [M+H] + The calculated value was 903.9; the measured value was 903.1.

[0272] Scheme 39 [ka] Reagents and conditions: (a) TsCl, Et3N, DCM, 0 °C to room temperature, 16 h; (b) NaN3, DMF, 100 °C, overnight; (b) CuSO4·5H2O, Na ascorbate, CH3CN / H2O, 100 °C, 8 h.

[0273] (Ethan-1,2-diylbis(oxy))bis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate) (87) To a solution of compound 86 (2.0 g, 13.3 mmol, 1 equiv.) and EtN (4.6 mL, 33.3 mmol, 2.5 equiv.) in DCM (50 mL) was added TsCl (5.6 g, 29.3 mmol, 2.2 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 16 h and quenched with cold saturated NaSO solution. The aqueous layer was then extracted with DCM (3 × 100 mL). Finally, the combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / ethyl acetate, 3:1 to 1:2) to give product 87 (5.2 g, 85%).

[0274] 1,2-Bis(2-azidoethoxy)ethane (88) To a solution of compound 87 (5.8 g, 12.65 mmol, 1.0 equiv) in DMF (120 mL) was added NaN (1.64 g, 25.30 mmol, 2.0 equiv). The resulting mixture was stirred at 100 °C overnight and quenched with cold HO (40 mL). The aqueous layer was then extracted with EtOAc (2 × 100 mL). Finally, the combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / ethyl acetate, 20:1 to 1:4) to give product 88 (2.0 g, 80%). 1 H NMR(400MHz, CDCl3)δ3.71-3.68(m,8H),3.39(t,J=5.2Hz,4H).

[0275] 4,4'-(2,2'-(((((ethane-1,2-diylbis(oxy))bis(ethane-2,1-diyl))bis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(azanediyl))bis(2-oxoacetyl))bis(N-(3,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide) (89) To a mixture of compound 88 (13.4 mg, 0.067 mmol, 0.5 equiv) and compound 7a (50 mg, 0.134 mmol, 1.0 equiv) in HO / CHCN (4 mL / 6 mL) was added CuSO 5HO (15 mg) and Na ascorbate (30 mg) under an Ar atmosphere. The resulting mixture was stirred at 100 °C for 8 h. The mixture was diluted with 30 mL of cold HO and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH, 100:1 to 5:1) to give product 89 (39 mg, 61%). 1H NMR(400MHz,DMSO-d6)δ10.42(s,2H),9.21(t,J=5.8Hz,2H),7.96(s,2H),7.90-7.85(m,2H),7.46-7.38(m,4H),4.5 0(d,J=5.1Hz,4H),4.45(d,J=5.7Hz,4H),3.76(t,J=5.1Hz,4H),3.58(s,6H),3.48(s,4H),2.35(s,6H),2.19(s,6H). 19 F NMR(377MHz,DMSO-d6)δ -137.1~-137.2(m,1F),-144.2~-144.4(m,1F).HRMS(ESI)m / z C 44 H 47 F4N 12 O8[M+H] + Calculated value: 947.3576; Measured value: 947.3555.

[0276] Scheme 40 [ka] Reagents and conditions: (a) TsCl, Et3N, DCM, 0 °C to room temperature, 16 h; (b) NaN3, DMF, 100 °C, 24 h; (b) CuSO4·5H2O, Na ascorbate, 100 °C, 2 h.

[0277] ((oxybis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl)bis(4-methylbenzenesulfonate) (92) To a solution of compound 90 (2.0 g, 10.30 mmol, 1 equiv.) and EtN (3.6 mL, 25.74 mmol, 2.5 equiv.) in DCM (50 mL) was added TsCl (4.3 g, 22.65 mmol, 2.2 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 16 h and quenched with cold saturated NaSO solution. The aqueous layer was then extracted with DCM (3 × 100 mL). Finally, the combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / ethyl acetate, 3:1 to 1:2) to give product 91 (4.7 g, 90%). To a solution of compound 91 (4.5 g, 8.95 mmol, 1.0 equiv) in DMF (100 mL) was added NaN (1.16 g, 17.91 mmol, 2.0 equiv). The resulting mixture was stirred at 100 °C for 24 h and quenched with cold HO (40 mL). The aqueous layer was then extracted with EtOAc (2 × 100 mL). Finally, the combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / ethyl acetate, 20:1 to 1:4) to give product 92 (2.0 g, 80%). 1 H NMR(400MHz, CDCl3)δ3.72-3.62(m,12H),3.39(t,J=6.4Hz,4H).

[0278] 4-(2-(((1-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide (93) and 4,4'-(2,2'-(((((o bis(ethane-2,1-diyl))bis(oxy))bis(ethane-2,1-diyl))bis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(azanediyl))bis(2-oxoacetyl))bis(N-(3,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide) (94) To a mixture of compound 92 (16.4 mg, 0.067 mmol, 0.5 equiv) and compound 7a (50 mg, 0.134 mmol, 1.0 equiv) in HO / CHCN (4 mL / 6 mL) was added CuSO 5HO (20 mg) and Na ascorbate (40 mg) under an Ar atmosphere. The resulting mixture was stirred at 100 °C for 2 h. The mixture was diluted with 30 mL of cold HO and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH, 100:1 to 5:1) to give product 93 (17 mg, 20%). 1 H NMR(400MHz,DMSO-d6)δ10.42(s,1H),9.20(t,J=5.8Hz,1H),7.97(s,1H),7.90-7.85(m,1H),7.45-7.38(m,2H),4.52(t,J=5.1Hz,2 H),4.45(d,J=5.8Hz,2H),3.81(t,J=5.3Hz,2H),3.60-3.57(m,5H),3.55-3.48(m,8H),3.39-3.36(m,2H),2.35(s,3H),2.19(s,3H). 19 F NMR(377MHz,DMSO-d6)δ -137.2~-137.3(m,1F),-144.3~-144.4(m,1F).HRMS(ESI)m / z C 27 H 34 F2N9O6[M+H] + Calculated: 618.2600; Found: 618.2587. and product 94 (41 mg, 61%): 1 H NMR(400MHz,DMSO-d6)δ10.42(s,2H),9.19(t,J=5.8Hz,2H),7.96(s,2H),7.90-7.84(m,2H),7.45-7.38(m,4H),4.51(t,J=5.1Hz ,4H),4.44(d,J=5.8Hz,4H),3.79(t,J=5.2Hz,4H),3.58(s,6H),3.52-3.49(m,4H),3.45-3.43(m,4H),2.34(s,6H),2.19(s,6H). 19F NMR(377MHz,DMSO-d6)δ -137.1~-137.2(m,1F),-144.3~-144.4(m,1F).HRMS(ESI)m / z C 46 H 51 F4N 12 O9 [M+H] + The calculated value was 991.3838; the measured value was 991.3814.

[0279] Scheme 41 [ka] Reagents and conditions: (a) CuSO4·5H2O, Na ascorbate, 90°C, overnight.

[0280] 4,4'-(2,2'-((((3,6,9,12,15-pentaoxaheptadecane-1,17-diyl)bis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(azanediyl))bis(2-oxoacetyl))bis(N-(3,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide) (95) To a mixture of compound 48 (45 mg, 0.134 mmol, 0.5 equiv) and compound 7a (100 mg, 0.268 mmol, 1.0 equiv) in HO / CHCN (6 mL / 10 mL) was added CuSO 5HO (28 mg) and Na ascorbate (60 mg) under an Ar atmosphere. The resulting mixture was stirred at 90 °C overnight. The mixture was diluted with 30 mL of cold HO and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH, 100:1 to 5:1) to give product 95 (65 mg, 45%): 1H NMR(400MHz,CDCl3)δ8.72(s,2H),7.93(t,J=5.7Hz,2H),7.81(s,2H),7.76-7.71(m,2H),7.33-7.28(m,2H),7 .13-7.06(m,2H),4.48(t,J=3.9Hz,8H),3.81(t,J=4.8Hz,4H),3.59-3.54(m,22H),2.29(s,6H),2.18(s,6H). 19 F NMR(377MHz,CDCl3)δ -135.9~-136.0(m,1F),-142.5~-142.7(m,1F).LCMS(ESI)m / z C 50 H 59 F4N 12 O 11 [M+H] + The calculated value was 1080.1; the measured value was 1079.4.

[0281] Scheme 42 [ka] Reagents and conditions: (a) NaN3, DMF, 95 °C, overnight; (b) TsCl, Et3N, CHCl3, 0 °C–rt, 16 h; (c) NaH, DMF, 0 °C–rt, 4 h; (d) CuSO4·5H2O, Na ascorbate, 100 °C, 4 h.

[0282] 2-(2-(2-azidoethoxy)ethyl)ethan-1-ol (97) To a solution of compound 96 (2.5 g, 14.8 mmol, 1.0 equiv) in DMF / HO (60 mL / 1.5 mL) was added NaN (1.0 g, 15.4 mmol, 1.05 equiv). The resulting mixture was stirred at 95 °C overnight and quenched with cold HO (50 mL). The aqueous layer was then extracted with EtOAc (2 × 100 mL). Finally, the combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / ethyl acetate, 10:1 to 1:4) to give product 97 (2.5 g, 95%). 1H NMR(400MHz,CDCl3)δ3.76-3.72(m,2H),3.71-3.67(m,6H),3.63-3.61(m,2H),3.41(t,J=5.2Hz,2H),2.86-2.85(m,1H).

[0283] 2-(2-(2-azidoethoxy)ethoxy)ethyl 4-methylbenzenesulfonate (98) To a solution of compound 97 (1.8 g, 10.28 mmol, 1 equiv.) and EtN (2.9 mL, 30.83 mmol, 2.0 equiv.) in DCM (60 mL) was added TsCl (2.4 g, 12.33 mmol, 1.2 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 16 h and quenched with cold saturated NaSO. The aqueous layer was then extracted with DCM (3 × 100 mL). Finally, the combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / ethyl acetate, 3:1 to 1:2) to give product 98 (3.8 g, 90%). 1 H NMR(400MHz,CDCl3)δ7.80(d,J=8.4Hz,2H),7.35(d,J=8.4Hz,2H),4.18-4.15(m,2H), 3.71-3.69(m,2H),3.66-3.63(m,2H),3.60(s,4H),3.37(t,J=5.2Hz,2H),2.45(s,3H).

[0284] 3-(2-(2-(2-azidoethoxy)ethoxy)ethyl)-2-((2-(2-(2-azidoethoxy)ethyl)ethyl)methyl)propan-1-ol (100) Compound 99 (200 mg, 1.88 mmol, 1.0 equiv) was dissolved in anhydrous DMF (30 mL), and powdered NaH (60% in oil, 407 mg, 10.18 mmol, 5.4 equiv) was added to the reaction mixture in several portions under argon. The reaction was stirred for 30 minutes, after which compound 98 (1.86 g, 5.65 mmol, 3.0 equiv) was added dropwise. After the reaction was complete, the mixture was filtered, and the organic phase was carefully quenched with cold HO and ice. The aqueous layer was then extracted with EtOAc (3 x 100 mL). Finally, the combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / ethyl acetate, 3:1 to 1:10) to give product 100 (3.8 g, 90%). 1 H NMR(400MHz,CD3COCD3)δ3.69-3.68(m,4H),3.64-3.58(m,15H),3.56-3.51(m,9H),3.39(t,J=5.0Hz,4H).LCMS(ESI)m / z C 16 H 33 N6O7[M+H] + Calculated value: 421.5; Measured value: 421.4.

[0285] 4,4'-(2,2'-((((11-(hydroxymethyl)-3,6,9,13,16,19-hexaoxahenicosan-1,21-diyl)bis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(azanediyl))bis(2-oxoacetyl))bis(N-(3,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide) (101) To a mixture of compound 100 (30 mg, 0.071 mmol, 1.0 equiv.) and compound 7a (58 mg, 0.156 mmol, 3.0 equiv.) in HO / CHCN (3 mL / 3 mL) was added CuSO 5HO (15 mg) and Na ascorbate (30 mg) under an Ar atmosphere. The resulting mixture was stirred at 100 °C for 4 h. The mixture was diluted with 30 mL of cold HO and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH, 100:1 to 5:1) to give product 101 (33 mg, 40%). 1 H NMR(400MHz,DMSO-d6)δ10.41(s,2H),9.19(t,J=5.8Hz,2H),7.97(s,2H),7.90-7.84(m,2H),7.45-7.38(m,4H),4.52(t,J=5.1Hz,4H),4.4 4(d,J=5.8Hz,4H),3.80(t,J=5.2Hz,4H),3.58(s,6H),3.53-3.43(m,15H),3.41-3.35(m,8H),2.35(s,6H),2.19(s,6H),1.89-1.83(m,1H). 19 F NMR(377MHz,DMSO-d6)δ -137.1~-137.2(m,1F),-144.2~-144.4(m,1F).HRMS(ESI)m / z C 54 H 67 F4N 12 O 13 [M+H] + Calculated value: 1167.4887; Measured value: 1167.4870.

[0286] Scheme 43 [ka] Reagents and conditions: (a) NaN3, DMF / H2O (40:1), 80 °C, 18 h; (b) TsCl, Et3N, DCM, 0 °C–rt, 24 h; (c) NaH, DMF, 0 °C–rt, 24 h; (d) CuSO4·5H2O, Na ascorbate, 100 °C, 16 h.

[0287] 2-(2-azidoethoxy)ethan-1-ol (103) To a solution of compound 102 (2.5 g, 20.0 mmol, 1.0 equiv) in DMF / HO (60 mL / 1.5 mL) was added NaN (1.4 g, 21.1 mmol, 1.05 equiv). The resulting mixture was stirred at 80 °C overnight and quenched with cold HO (50 mL). The aqueous layer was then extracted with EtOAc (3 × 50 mL). Finally, the combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (hexane / ethyl acetate, 10:1 to 1:4) to give product 103 (2.3 g, 88%). 1 H NMR(400MHz,CDCl3)δ3.78-3.75(m,2H),3.74-3.69(m,2H),3.63-3.61(m,2H),3.42(t,J=5.1Hz,2H),2.77(t,J=6.0Hz,1H).

[0288] 2-(2-Azidoethoxy)ethyl 4-methylbenzenesulfonate (105) To a solution of compound 103 (1.4 g, 10.7 mmol, 1 equiv.) and EtN (3.0 mL, 21.4 mmol, 2.0 equiv.) in DCM (60 mL) was added TsCl (2.4 g, 12.8 mmol, 1.2 equiv.) at 0 °C. The resulting mixture was stirred at room temperature for 24 h and quenched with cold saturated NaSO. The aqueous layer was then extracted with DCM (3 × 50 mL). Finally, the combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / ethyl acetate, 3:1 to 1:2) to give product 105 (2.7 g, 90%). 1 H NMR(400MHz,CDCl3)δ7.81(d,J=8.3Hz,2H),7.35(d,J=8.0Hz,2H),4.18-4.16(m ,2H),3.71-3.69(m,2H),3.62-3.59(m,2H),3.32(t,J=5.1Hz,2H),2.45(s,3H).

[0289] 1,15-Diazido-8,8-bis((2-(2-azidoethoxy)ethoxy)methyl)-3,6,10,13-tetraoxapentadecane (106) Compound 104 (260 mg, 1.91 mmol, 1.0 equiv) was dissolved in anhydrous DMF (25 mL), and powdered NaH (60% in oil, 367 mg, 9.2 mmol, 4.8 equiv) was added to the reaction mixture in several portions under argon. The reaction was stirred for 30 minutes, and then compound 105 (2.18 g, 7.64 mmol, 4.0 equiv) was added dropwise. After the reaction was complete, the mixture was filtered, and the organic phase was carefully quenched with cold HO and ice. The aqueous layer was then extracted with EtOAc (3 x 100 mL). Finally, the combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / ethyl acetate, 3:1 to 1:10) to give product 106 (910 mg, 81%). 1 H NMR(400MHz,CDCl3)δ3.69-3.66(m,8H),3.64-3.62(m,8H),3.59-3.56(m,8H),3.47(s,8H),3.74(t,J=5.2Hz,8H).

[0290] 4-(2-(((1-(15-azido-8,8-bis((2-(2-azidoethoxy)ethoxy)methyl)-3,6,10,13-tetraoxapentadecyl)-1H-1,2,3-triazol-4-yl)methyl)amino)-2-oxoacetyl)-N-(3,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide (107) and 4,4'-(2,2'-(( ((8,8-bis((2-(2-azidoethoxy)ethoxy)methyl)-3,6,10,13-tetraoxapentadecane-1,15-diyl)bis(1H-1,2,3-triazole-1,4-diyl))bis(methylene))bis(azanediyl))bis(2-oxoacetyl))bis(N-(3,4-difluorophenyl)-1,3,5-trimethyl-1H-pyrrole-2-carboxamide) (108) To a mixture of compound 106 (426 mg, 0.723 mmol, 4.5 equiv.) and compound 7a (60 mg, 0.161 mmol, 1.0 equiv.) in HO / CHCN (4 mL / 4 mL), CuSO 5HO (20 mg) and Na ascorbate (40 mg) were added under an Ar atmosphere. The resulting mixture was stirred at 100 °C for 16 h. The mixture was diluted with 30 mL of cold HO and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH, 100:1 to 5:1) to give product 107 (46 mg, 30%) and product 108 (48 mg, 45%). For compound 107: 1 H NMR(400MHz,DMSO-d6)δ10.41(s,1H),9.19(t,J=5.7Hz,1H),7.96(s,1H),7.91-7.85(m,2H),4.53(t,J=5.2Hz,2 H),4.46(d,J=5.7Hz,2H),3.84-3.82(m,2H),3.63-3.44(m,26H),3.39-3.33(m,14H),2.36(s,3H),2.20(s,3H). 19 F NMR(377MHz,DMSO-d6)δ -137.2~-137.3(m,1F),-144.3~-144.4(m,1F).HRMS(ESI)m / z C 40 H 58 F2N 15 O 11 [M+H] + Calculated: 962.4408; Found: 962.4393. For compound 108: 1 H NMR(400MHz,DMSO-d6)δ10.42(s,2H),9.20(t,J=5.7Hz,2H),7.97(s,2H),7.91-7.86(m,2H),7.48-7.37(m,4H),4.53(t,J=5.1Hz,4H) ,4.46(d,J=18.6Hz,4H),3.83(t,J=5.2Hz,4H),3.63-3.60(m,10H),3.56-3.51(m,16H),3.50-3.31(m,12H),2.36(s,6H),2.21(s,6H). 19F NMR(377MHz,DMSO-d6)δ -137.1~-137.2(m,1F),-144.2~-144.4(m,1F).HRMS(ESI)m / z C 59 H 75 F4N 18 O 14 [M+H] + Calculated value: 1335.5646; Measured value: 1335.5639.

[0291] Scheme 44 [ka] Reagents and conditions: (a) CuSO4·5H2O, Na ascorbate, 100°C, 4 hours.

[0292] Trimer (109) and tetramer (110) To a mixture of compound 106 (32 mg, 0.0544 mmol, 1 equiv.) and compound 7a (162 mg, 0.4349 mmol, 8.0 equiv.) in HO / CHCN (4 mL / 4 mL), CuSO 5HO (20 mg) and Na ascorbate (40 mg) were added under an Ar atmosphere. The resulting mixture was stirred at 100 °C for 4 h. The mixture was diluted with 30 mL of cold HO and extracted with ethyl acetate (3 × 50 mL). The combined organic layers were washed with water, brine, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography (DCM / MeOH, 100:1 to 5:1) to give product 109 (trimer, 33 mg, 35%) and product 110 (tetramer, 52 mg, 46%). For trimer 109: 1H NMR(400MHz,DMSO-d6)δ10.42(s,3H),9.21(t,J=5.7Hz,3H),7.98(s,3H), 7.91-7.86(m,3H),7.48-7.37(m,6H),4.53(t,J=5.0Hz,6H),4.47(d,J=5. 6Hz,6H),3.83(t,J=5.1Hz,6H),3.62-3.60(s,10H),3.56-3.44(m,17H),3 .38(dd,J=4.2Hz,9.3Hz,3H),3.31-3.29(m,7H),2.37(s,9H),2.21(s,9H). 19 F NMR(377MHz,DMSO-d6)δ -137.1~-137.2(m,1F),-144.2~-144.3(m,1F).HRMS(ESI)m / z C 78 H 92 F6N 21 O 17 [M+H] + Calculated value: 1708.6884; measured value: 1708.6865.テトラマー110 occasions: 1 H NMR(400MHz,DMSO-d6)δ10.41(s,4H),9.19(t,J=5.7Hz,4H),7.95(s,4H),7.89-7.84(m,4H),7.45-7.37(m,8H),4.50(t,J=5.1Hz,8H),4. 44(d,J=5.7Hz,8H),3.80(t,J=5.2Hz,8H),3.57(s,12H),3.50-3.48(m,8H),3.42-3.39(m,8H),3.24(s,8H),2.34(s,12H),2.18(s,12H). 19 F NMR(377MHz,DMSO-d6)δ -137.1~-137.2(m,1F),-144.2~-144.4(m,1F).HRMS(ESI)m / z C 97 H 109 F8N 24 O 20 [M+H] + Calculated value: 2081.8122; Measured value [M+H] 2+ :1041.9089.

[0293] スキーム45

change

[0294] Ethyl 3,5-dimethyl-1-(prop-2-yn-1-yl)-1H-pyrrole-2-carboxylate (111) A solution of ethyl 3,5-dimethyl-1H-pyrrole-2-carboxylate (10a) (1.76 g, 10.5 mmol, 1 equiv.) in DMSO (10 mL) was treated with KOH (1.46 g, 26.0 mmol, 2.5 equiv.) and propargyl bromide (80% in toluene, 12.0 mL). After stirring at ambient temperature for 24 h, the solution was poured into water (150 mL) and extracted three times with EtOAc (50 mL). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by SiO chromatography using hexane:EtOAc (90:10) as the eluent to give ethyl 3,5-dimethyl-1-(prop-2-yn-1-yl)-1H-pyrrole-2-carboxylate (111) (64.9% yield) as a white solid. 1 H NMR(CDCl3)δppm 5.79(s,1H),5.10(d,J=2.4Hz,2H),4.29(q,J=7.2Hz,2H),2.28(s,3H),2.27(s,3H),2.23(t,J=2.4Hz,1H),1.35(t,J=7.2Hz,3H). 13 C NMR(CDCl3)δ161.97,135.50,118.16,111.46,79.33,71.50,59.51,34.46,14.15,14.33,12.12.LC-MS(ES + ) m / z: 206.3 [M+H].

[0295] N-(3,4-difluorophenyl)-3,5-dimethyl-1-(prop-2-yn-1-yl)-1H-pyrrole-2-carboxamide (112) A solution of ethyl 3,5-dimethyl-1-(prop-2-yn-1-yl)-1H-pyrrole-2-carboxylate (111) (1.37 g, 6.67 mmol, 1 equiv.) and 3,4-difluoroaniline (1.40 mL, 13.7 mmol, 2 equiv.) in dichloroethane (40 mL) was cooled to 0 °C and treated with trimethylaluminum (2.0 M in toluene) (6.70 mL, 13.4 mmol, 2 equiv.). The solution was allowed to slowly warm to ambient temperature over 2 h, then heated to reflux under nitrogen for 24 h. After that, the solution was poured into water (150 mL) and extracted three times with dichloromethane (50 mL). The combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO chromatography using hexane:EtOAc (80:20) as the eluent to afford N-(3,4-difluorophenyl)-3,5-dimethyl-1-(prop-2-yn-1-yl)-1H-pyrrole-2-carboxamide (112) (89.3% yield) as an off-white solid. 1 H NMR(CDCl3)δppm 7.72-7.67(m,1H),7.37(s,1H),7.10-7.07(m,2H),5.81(s,1H),5.07(d,J=2.4Hz,2H),2.34(s,3H),2.30(s,3H),2.27(t,J=2.4Hz,1H). 19 F NMR(CDCl3)δppm-135.79(d,J=24Hz,1F),-143.23(d,J=24Hz,1F). 13 C NMR(CDCl3)δppm 160.31,151.46,151.33,149.00,148.87,148.06,147.93,145.63,145.50,134.95,134.73,134.70,134.64,134.61, 123.37,121.91,117.25,117.08,115.32,111.21,109.74,109.52,79.24,71.94,34.24,13.85,11.99.LC-MS(ES+)m / z 289.3[M+H].

[0296] Ethyl 2-(5-((3,4-difluorophenyl)carbamoyl)-2,4-dimethyl-1-(prop-2-yn-1-yl)-1H-pyrrol-3-yl)-2-oxoacetate (113) A solution of N-(3,4-difluorophenyl)-3,5-dimethyl-1-(prop-2-yn-1-yl)-1H-pyrrole-2-carboxamide (112) (2.05 g, 7.11 mmol, 1 equiv.) and aluminum trichloride (2.85 g, 21.4 mmol, 3 equiv.) in DCM (70 mL) was cooled to 0 °C, and ClCOCOEt (2.38 mL, 21.3 mmol, 3 equiv.) was added dropwise over 30 min. The solution was slowly brought to ambient temperature and stirred under nitrogen for 24 h. The solution was then poured into cold water (200 mL). The aqueous phase was extracted three times with DCM (50 mL). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by SiO chromatography using hexane:EtOAc (80:20) as the eluent to afford ethyl 2-(5-((3,4-difluorophenyl)carbamoyl)-2,4-dimethyl-1-(prop-2-yn-1-yl)-1H-pyrrol-3-yl)-2-oxoacetate (113) (66% yield) as a white solid. 1 H NMR(CDCl3)δppm 7.82(s,1H),7.73(dd,J=7.2,2.4Hz,1H),7.22-7.10(m,2H),4.99(d,J=2.4Hz,2H),2.52(s,3H),2.36(s,4H),1.39(t,J=7.2Hz,3H). 19 F NMR(CDCl3)δppm-135.29(d,J=24Hz,1F),-141.80(d,J=24Hz,1F). 13C NMR(CDCl3)δppm 165.55,159.69,151.46,151.33,149.00,148.87,148.54,148.41,146.09,145.97,142.34,134.03,134.00,133.94,133.91,125.33,1 LC-MS(ES + ) m / z 389.4 [M+H].

[0297] N-(3,4-difluorophenyl)-3,5-dimethyl-4-(2-oxo-2-(prop-2-yn-1-ylamino)acetyl)-1-(prop-2-yn-1-yl)-1H-pyrrole-2-carboxamide (114) A solution of ethyl 2-(5-((3,4-difluorophenyl)carbamoyl)-2,4-dimethyl-1-(prop-2-yn-1-yl)-1H-pyrrol-3-yl)-2-oxoacetate (113) (0.780 g, 2.00 mmol, 1 equiv.) in MeOH (10 mL) and THF (2 mL) was cooled to 0 °C, and 5% aqueous NaOH (10 mL) was slowly added. The solution was stirred at 0 °C for 20 min, after which the pH of the solution was adjusted to 4-5 by the addition of 1 N HCl. The solution was partitioned between water (50 mL) and EtOAc (25 mL). The aqueous phase was extracted twice with EtOAc (25 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was dissolved in DMF (20 mL) and CDI (1.62 g, 9.99 mmol, 10 equiv.) was added. After stirring the solution under nitrogen at ambient temperature for 30 minutes, propargylamine (0.380 mL, 5.93 mmol, 3 equiv.) was added and the reaction was stirred for 24 hours. The solution was then poured into water (150 mL) and extracted three times with EtOAc (30 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by SiO chromatography using hexane:EtOAc (65:35) as the eluent to afford N-(3,4-difluorophenyl)-3,5-dimethyl-4-(2-oxo-2-(prop-2-yn-1-ylamino)acetyl)-1-(prop-2-yn-1-yl)-1H-pyrrole-2-carboxamide (114) (35% yield) as a white solid. 1 H NMR(DMSO-d6)δppm 10.53(s,1H),9.21(t,J=5.6Hz,1H),7.90-7.85(m,1H),7.47-7.42(m,2H),5.03(d,J=2Hz,2),4. 02(dd,J=2.4,5.6Hz,2H),3.42(t,J=2.4Hz,1H),3.2(t,J=2.4Hz,1H),2.47(s,3H),2.26(s,3H). 19 F NMR(DMSO-d6)δppm -137.15(d,J=28Hz,1F),-144.14(d,J=24Hz,1F). 13C NMR(DMSO-d6)δppm 187.93,167.31,160.30,150.68,150.55,148.26,148.13,147.33,147.19,144.91,144.79,141.23,136.28,136.20,126.17,12 3.69,118.05,117.87,117.26,116.51,109.29,109.08,80.50,78.99,76.07,73.86,34.06,28.12,11.97,11.69.LC-MS(ES+)m / z 398.3[M+H].

[0298] Scheme 46 [ka]

[0299] N-(3,4-difluorophenyl)-4-(2-((3-ethylpent-1-yn-3-yl)amino)-2-oxoacetyl)-3,5-dimethyl-1-(prop-2-yn-1-yl)-1H-pyrrole-2-carboxamide (115) A solution of ethyl 2-(5-((3,4-difluorophenyl)carbamoyl)-2,4-dimethyl-1-(prop-2-yn-1-yl)-1H-pyrrol-3-yl)-2-oxoacetate (113) (0.450 g, 1.16 mmol, 1 equiv) in MeOH (11 mL) and THF (1 mL) was cooled to 0 °C, and 5% aqueous NaOH (11 mL) was slowly added. The solution was stirred at 0 °C for 20 min, after which the pH of the solution was adjusted to 4-5 by the addition of 1 N HCl. The solution was partitioned between water (100 mL) and EtOAc (50 mL). The aqueous phase was extracted twice with EtOAc (25 mL). The combined organic phases were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was then dissolved in DMF (11 mL) and treated with HATU (1.33 g, 3.50 mmol, 3 equiv.) and DIPEA (0.610 mL, 3.50 mmol, 3 equiv.) and stirred under nitrogen at ambient temperature for 30 minutes. 3-Ethylpent-1-yn-3-amine (0.520 g, 4.68 mmol, 4 equiv.) was then added and the reaction was continued for 2 hours. The solution was then heated to 65° C. and stirred under nitrogen for 24 hours. The solution was then poured into water (150 mL) and extracted three times with EtOAc (30 mL). The combined organic phases were dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by SiO chromatography using hexane:EtOAc (65:35) as the eluent to give N-(3,4-difluorophenyl)-4-(2-((3-ethylpent-1-yn-3-yl)amino)-2-oxoacetyl)-3,5-dimethyl-1-(prop-2-yn-1-yl)-1H-pyrrole-2-carboxamide (115) (35.7% yield) as a white solid. 1 H NMR(CDCl3)δppm 7.73-7.69(m,1H),7.65(s,1H),7.17-7.09(m,2H),6.88(s,1H),5.01(d,J=2.4Hz,2H),.45(s,3H),2.43 (s,1H),2.37(s,3H),2.31(t,J=2.4Hz,1H),2.21-2.13(m,2H),1.96-1.87(m,2H),1.04(t,J=7.2Hz,6H). 19F NMR(CDCl3)δppm -135.31(...

Claims

1. The formula: 【Chemistry 1】 (In the formula, R １ and R １’ When attached to carbon, they are independently hydrogen, halogen, CF ３ , Hydroxy, SF ５ , N(R')S(O) ２ R', S(O) ２ R', S(O) ２ N(R') ２ , C １－６ Alkoxy, Cyano, C ２－６ Alkynyl, C ３－６ Alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C １－６ Alkyl, C １－６ Haloalkyl, arylalkoxycarbonyl, carboxy, C １－６ haloalkyl, heterocyclylalkyl, or C １－６ is hydroxyalkyl, R １ and R １’ When attached to nitrogen, they are independently hydrogen, C １－６ Alkoxy, C ３－６ Alkoxyalkyl, alkoxycarbonyl, carbonylalkyl, carbonylaryl, C １－６ Alkyl, C ２－６ Alkynyl, C ２－６ Alkenyl, heterocyclylalkyl, C １－６ Hydroxyalkyl, or S(O) ２ R′, Each R' is independently H, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ cycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, or when two R' are on the same nitrogen atom, they together represent a C ３－６ may form an alkyl ring, said R' groups being optionally substituted with one or more substituents; u and v are independently 0, 1, 2, 3, 4 or 5; C is phenyl; a 6-membered heteroaromatic ring containing 1, 2, or 3 nitrogen atoms; a 5-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms which are independently N, O, or S; C ４－１４ bicyclic; alkylheteroaryl, or alkylaryl; B is selected from the group consisting of a 5-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms which are independently N, O or S; a 6- or 7-membered ring or a 6- or 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms which are independently N, O or S; a 5-membered ring containing 0, 1, or 2 heteroatoms which are independently N, O or S; a 4-membered ring containing 0, 1, or 2 heteroatoms which are independently N, O or S; W is 【Chemistry 2】 and R １２ is H, C １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, or C ２－６ is alkynyl, R １３ is C ７－２０ Alkyl, C ７－２０ Alkenyl, or C ７－２０ is alkynyl, R １３ is hydrogen, halogen, CF ３ , S.F. ５ , hydroxy, 【Chemistry 3】 -NH-C(O)-N(R １０ ) ２ 、-N(R １０ ) ２ 、-OR １１ 、-C(O)OR １０ 、-C(O)-N(R １０ ) ２ 、-C(O)-NHOH、オキソ、 【Chemistry 4】 -S-R １０ 、 【Chemistry 5】 N (R １０ ) S (O) ２ R １０ , S(O) ２ R １０ , S(O) ２ N (R １０ ) ２ , C(O)R １０ a saturated or unsaturated 5-, 6- or 7-membered ring or a 6- or 7-membered bridged or spiro-fused ring containing 1 or 2 heteroatoms which are independently N, S, Se or Si; １－６ Alkoxy, C １－６ Haloalkoxy, cyano, azido, C ２－６ Alkynyl, C ３－６ Alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C １－６ Alkyl, cycloalkyl, arylalkoxycarbonyl, carboxyl, haloalkyl, heterocyclylalkyl, C １－６ optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; The substituents of the substituted aryl and substituted heteroaryl are halogen, SF ５ , C.F. ３ , hydroxy, 【Chemistry 6】 -NH-C(O)-N(R １０ ) ２ 、-N(R １０ ) ２ 、-OR １１ 、-C(O)OR １０ 、-C(O)-N(R １０ ) ２ 、-C(O)-NHOH、オキソ、 【Chemistry 7】 -S-R １０ 、 【Chemistry 8】 N (R １０ ) S (O) ２ R １０ , S(O) ２ R １０ , S(O) ２ N (R １０ ) ２ , C(O)R １０ a saturated or unsaturated 5-, 6- or 7-membered ring or a 6- or 7-membered bridged or spiro-fused ring containing 1 or 2 heteroatoms, which are independently N, S, Se or Si; ３ -C ７ Cycloalkyl, C １－６ Alkoxy, cyano, azido, C ２－６ Alkynyl, C ３－６ Alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, and C １－６ is selected from the group consisting of alkyl, R １０ and R １１ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms which are independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms which are independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms which are independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms which are independently N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom which is independently N, O, or S, Or, R １０ and R １１ may together form a 5- to 8-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused saturated or partially unsaturated ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; or a 3-membered ring containing 0 heteroatoms; a saturated or partially unsaturated 6- to 12-membered heterobicyclic ring; a saturated or partially unsaturated 6- to 12-membered heterotricyclic ring, and R １０ and R １１ The groups are independently halo, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ or a pharmaceutically acceptable salt thereof, or a compound of the formula: hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphoramidate, or phosphonate.

2. The formula: 【Chemistry 9】 (In the formula, R １ and R １’ When attached to carbon, they are independently hydrogen, halogen, CF ３ , Hydroxy, SF ５ , N(R')S(O) ２ R', S(O) ２ R', S(O) ２ N(R') ２ , C １－６ Alkoxy, Cyano, C ２－６ Alkynyl, C ３－６ Alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C １－６ Alkyl, C １－６ Haloalkyl, arylalkoxycarbonyl, carboxy, C １－６ haloalkyl, heterocyclylalkyl, or C １－６ is hydroxyalkyl, R １ and R １’ When attached to nitrogen, they are independently hydrogen, C １－６ Alkoxy, C ３－６ Alkoxyalkyl, alkoxycarbonyl, carbonylalkyl, carbonylaryl, C ２－６ Alkynyl, C ２－６ Alkenyl, heterocyclylalkyl, C １－６ Hydroxyalkyl, or S(O) ２ R′, Each R' is independently H, C １－６ Alkyl, C １－６ Haloalkyl, C １－６ Alkoxy, C ２－６ Alkenyl, C ２－６ Alkynyl, C ３－６ cycloalkyl, aryl, heteroaryl, alkylaryl, or arylalkyl, or when two R' are on the same nitrogen atom, they together represent a C ３－６ may form an alkyl ring, said R' groups being optionally substituted with one or more substituents; u and v are independently 0, 1, 2, 3, 4 or 5; C is phenyl; a 6-membered heteroaromatic ring containing 1, 2, or 3 nitrogen atoms; a 5-membered heteroaromatic ring containing 1, 2, or 3 heteroatoms which are independently N, O, or S; C ４－１４ bicyclic; alkylheteroaryl, or alkylaryl; B is selected from the group consisting of a 5-membered heteroaromatic ring containing 1, 2 or 3 heteroatoms which are independently N, O or S; a 6- or 7-membered ring or a 6- or 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms which are independently N, O or S; a 5-membered ring containing 0, 1, or 2 heteroatoms which are independently N, O or S; a 4-membered ring containing 0, 1, or 2 heteroatoms which are independently N, O or S; W is 【Chemistry 10】 and R １２ is H, C １－６ Alkyl, C ３－７ Cycloalkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, or C ２－６ is alkynyl, R １３ is C ７－２０ Alkyl, C ７－２０ Alkenyl, C ７－２０ Alkynyl, 【Chemistry 11】 and n is 1, 2, 3, 4, 5, 6, 7 or 8; R １３ is hydrogen, halogen, CF ３ , S.F. ５ , hydroxy, 【Chemistry 12】 -NH-C(O)-N(R １０ ) ２ 、-N(R １０ ) ２ 、-OR １１ 、-C(O)OR １０ 、-C(O)-N(R １０ ) ２ 、-C(O)-NHOH、オキソ、 【Chemistry 13】 -S-R １０ 、 【Chemistry 14】 N (R １０ ) S (O) ２ R １０ , S(O) ２ R １０ , S(O) ２ N (R １０ ) ２ , C(O)R １０ a saturated or unsaturated 5-, 6- or 7-membered ring or a 6- or 7-membered bridged or spiro-fused ring containing 1 or 2 heteroatoms which are independently N, S, Se or Si; １－６ Alkoxy, C １－６ Haloalkoxy, cyano, azido, C ２－６ Alkynyl, C ３－６ Alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C １－６ Alkyl, cycloalkyl, arylalkoxycarbonyl, carboxyl, haloalkyl, heterocyclylalkyl, C １－６ optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyalkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl; The substituents of the substituted aryl and substituted heteroaryl are halogen, SF ５ , C.F. ３ , hydroxy, 【Chemistry 15】 -NH-C(O)-N(R １０ ) ２ 、-N(R １０ ) ２ 、-OR １１ 、-C(O)OR １０ 、-C(O)-N(R １０ ) ２ 、-C(O)-NHOH、オキソ、 【Chemistry 16】 -S-R １０ 、 【Chemistry 17】 N (R １０ ) S (O) ２ R １０ , S(O) ２ R １０ , S(O) ２ N (R １０ ) ２ , C(O)R １０ a saturated or unsaturated 5-, 6- or 7-membered ring or a 6- or 7-membered bridged or spiro-fused ring containing 1 or 2 heteroatoms, which are independently N, S, Se or Si; ３ -C ７ Cycloalkyl, C １－６ Alkoxy, cyano, azido, C ２－６ Alkynyl, C ３－６ Alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, and C １－６ is selected from the group consisting of alkyl, Or, R １２ and R １３ together with the nitrogen to which they are attached, hydrogen, halogens, CF ３ , hydroxy, 【Chemistry 18】 -NH-C(O)-N(R １０ ) ２ 、-N(R １０ ) ２ 、-OR １１ 、-C(O)OR １０ 、-C(O)-N(R １０ ) ２ 、-C(O)-NHOH、オキソ、 【Chemistry 19】 -S-R １０ 、 【Chemistry 20】 N (R １０ ) S (O) ２ R １０ , S(O) ２ R １０ , S(O) ２ N (R １０ ) ２ , C(O)R １０ , C １－６ Alkoxy, cyano, azido, C ２－６ Alkynyl, C ３－６ Alkoxyalkyl, alkoxycarbonyl, alkoxycarbonylalkyl, C １－６ Alkyl, arylalkoxycarbonyl, carboxy, C １－６ Haloalkyl, heterocyclylalkyl, and C １－６ forming a saturated or unsaturated 4- to 7-membered ring which may be optionally substituted with one or more substituents each independently selected from the group consisting of hydroxyalkyl, R １０ and R １１ are independently H, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ alkynyl, aryl, heteroaryl, alkylaryl, arylalkyl, a 6-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms which are independently N, O, or S; a 7-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms which are independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms which are independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms which are independently N, O, or S; or a 3-membered ring containing 0 or 1 heteroatom which is independently N, O, or S, Or, R １０ and R １１ may together form a 5- to 8-membered ring or a 6-membered bridged or spiro-fused ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 7-membered bridged or spiro-fused saturated or partially unsaturated ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 5-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; a 4-membered ring containing 0, 1, or 2 heteroatoms, independently N, O, or S; or a 3-membered ring containing 0 heteroatoms; a saturated or partially unsaturated 6- to 12-membered heterobicyclic ring; a saturated or partially unsaturated 6- to 12-membered heterotricyclic ring, and R １０ and R １１ The groups are independently halo, C １－６ Alkyl, C １－６ Haloalkyl, C ２－６ Alkenyl, C ２－６ Alkynyl, C １－６ or a pharmaceutically acceptable salt thereof, or a compound of the formula: hydroxyalkyl, hydroxyl, carboxyl, acyl, aryl, acyloxy, amino, amido, alkylamino, dialkylamino, arylamino, alkoxy, alkoxyalkyl, aryloxy, nitro, cyano, sulfonic acid, thiol, imine, sulfonyl, sulfanyl, sulfinyl, sulfamonyl, ester, carboxylic acid, amide, phosphonyl, phosphinyl, phosphoryl, phosphine, thioester, thioether, oxime, hydrazine, carbamate, phosphonic acid, phosphoramidate, or phosphonate. 【Request 3】 【Chemical 21】 【change】 【change】 or an enantiomer, diastereoisomer, tautomer or pharma- ceutically acceptable salt thereof.

4. 4. A pharmaceutical composition comprising a compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, for use in treating an HBV infection, preventing an HBV infection, or reducing the biological activity of an HBV infection.

5. The pharmaceutical composition of claim 4 , wherein the composition is a transdermal composition or a nanoparticle composition.

6. 5. The pharmaceutical composition of claim 4, further comprising a second antiviral agent selected from the group consisting of a polymerase inhibitor, a viral entry inhibitor, a viral maturation inhibitor, a literature-described capsid assembly modulator, an IMPDH inhibitor, a protease inhibitor, an immune-based therapeutic, a reverse transcriptase inhibitor, a TLR agonist, an siRNA, shRNA, Talen, Crisper / Cas9, mir (microRNA), and any combination thereof.

7. The pharmaceutical composition of claim 4, further comprising the use of another anti-HBV drug.

8. 4. Use of a compound according to any one of claims 1 to 3 in the preparation of a medicament for treating HBV.

9. 9. The use of claim 8, wherein the medicament further comprises a second antiviral agent selected from the group consisting of a polymerase inhibitor, a viral entry inhibitor, a viral maturation inhibitor, a literature-described capsid assembly modulator, an IMPDH inhibitor, a protease inhibitor, an immune-based therapeutic, a reverse transcriptase inhibitor, a TLR agonist, an siRNA, shRNA, Talen, Crisper / Cas9, mir (microRNA), and any combination thereof.

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