Antiviral agents against hepatitis B

Abstract

The present invention describes compounds of formula (I), or their pharmaceutically acceptable salts, esters, or prodrugs, that inhibit the protein(s) encoded by the hepatitis B virus (HBV) or interfere with the HBV life cycle, and that are also useful as antiviral agents. The present invention further relates to pharmaceutical compositions comprising the aforementioned compounds for administration to a subject suffering from an HBV infection. The invention also relates to methods for treating an HBV infection in a subject by administering a pharmaceutical composition comprising the compounds of the present invention.

Description

Antiviral agents against hepatitis B Technical field The present invention is defined in the claims and relates generally to novel antiviral agents. Specifically, the present invention relates to compounds that can inhibit the protein(s) encoded by the hepatitis B virus (HBV) or interfere with its functioning in the HBV life cycle, compositions comprising such compounds, methods for inhibiting HBV viral replication, methods for treating or preventing HBV infection, and processes for producing the compounds. Background of the Invention HBV infection remains a major public health problem, affecting approximately 2 billion people worldwide. Among them, 350 million people globally and 1.4 million in the United States develop chronic infection, which can lead to chronic persistent hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). Each year, 500,000 to 1 million people die from end-stage liver disease caused by HBV infection. Despite the availability of a prophylactic vaccine against HBV, HBV infection remains a significant global health concern due to suboptimal treatment options and high rates of reinfection in most of the developing world. Current treatments do not provide a cure and are limited to only two classes of agents (interferon and viral polymerase analogues / nucleoside inhibitors); drug resistance, low efficacy, and tolerability issues limit their effectiveness. Low HBV cure rates are attributed, at least in part, to the presence and persistence of covalently bound circular DNA (cccDNA) in the nuclei of infected hepatocytes. However, persistent suppression of HBV DNA slows the progression of liver disease and helps prevent hepatocyte cholangiocarcinoma (HCC).Current therapeutic goals for HBV-infected patients are aimed at reducing serum HBV DNA content to low or undetectable levels and, ultimately, reducing or preventing the development of cirrhosis and HCC. HBV is an enveloped, partially double-stranded DNA (dsDNA) virus belonging to the hepadnavirus family (Hepadnaviridae). The HBV capsid or core protein (CP) plays an essential role in HBV replication. The primary biological function of the capsid protein is to act as a structural protein to encapsulate the pregenomic RNA and form immature capsid particles, which spontaneously self-assemble from multiple copies of core dimers in the cytoplasm. The capsid protein also regulates viral DNA synthesis through different phosphorylation states at its C-terminal phosphorylation sites.Additionally, the capsid protein may facilitate the nuclear translocation of the relaxed viral circular genome through nuclear localization signals in the arginine-rich domain of the capsid protein's C-terminal region. In the nucleus, as a component of the viral cccDNA minichromosome, the capsid protein may play a structural and regulatory role in cccDNA minichromosome function. The capsid protein also interacts with the large viral envelope protein in the endoplasmic reticulum (ER), triggering the release of intact viral particles from hepatocytes. Capsid-related anti-HBc inhibitors have been reported. For example, phenylpropenamide derivatives, including compounds called AT-61 and AT-130 (Feld J. et al., Antiviral Res. 2007, 76, 168), and a class of thiazolidine-4-ones from Valeant (WO2006 / 033995), have been shown to inhibit pregenomic RNA (pgRNA) packaging. Heteroaryldihydropyrimidines, or PAHs, were discovered in a tissue culture-based assay (Weber et al., Antiviral Res. 2002, 54, 69). These PAH analogs act as synthetic allosteric activators and are capable of inducing aberrant capsid formations that lead to coat protein degradation. A subclass of sulfamoilarylamides exhibits activity against HBV (WO2013 / 006394, WO2013 / 096744, WO2014 / 184365 and WO 2017 / 136403). The small molecule bis-ANS was also seen to act as a molecular wedge and interfere with the normal geometry of the capsid protein and capsid formation (Zlotnick A.and others J. Virol.2002, 4848) . The field requires new therapeutic agents to treat, alleviate, or prevent HBV infection. Administering these agents to an HBV-infected patient, either as monotherapy or in combination with other HBV treatments or secondary therapies, will lead to a significant improvement in prognosis, a reduction in disease progression, and increased seroconversion rates. Summary of the invention References to treatment methods in the abstract and detailed description shall be construed as references to the compounds, pharmaceutical compositions, and medicaments of the present invention for use in a method for treating the human (or animal) body therapeutically (or for diagnosis). The present invention relates to novel antiviral compounds, pharmaceutical compositions comprising such compounds, and methods for treating or preventing viral infection (particularly by HBV) in a subject requiring therapy with such compounds. The compounds of the present invention inhibit the protein(s) encoded by the hepatitis B virus (HBV) or interfere with the HBV life cycle and are also useful as antiviral agents. Furthermore, the present invention includes the process for preparing such compounds. Here is a description of a main aspect of a compound of formula (I): XAYLR (I) or an acceptable pharmaceutical-grade salt thereof, where: X and Y are each independently selected from optionally substituted aryl or optionally substituted heteroaryl; in one disclosure one of X and Y is optionally substituted phenyl; in another disclosure both X and Y are optionally substituted phenyl; A is selected from the group consisting of -NHC (O) -, and preferably A is -NHC(O)-; L is S (O) 2, S (O) , S u O; and R is connected to L through a carbon atom and is independently selected from the group consisting of optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, optionally substituted C2-C10 alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C3-C12 cycloalkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted 3- to 12-membered heterocyclic ring; in one disclosure, R is optionally substituted C5-C12 cycloalkyl or optionally substituted 5- to 12-membered heterocyclic ring, each of which is optionally substituted with one or more of the following: fused rings, one or more spiro rings, or one or more bridging ring groups.In another disclosure, R is optionally substituted C3-C12 cycloalkyl, optionally substituted C1-C6 alkyl, optionally substituted C3-C12 cycloalkenyl, optionally substituted C1-C6 alkyl, C1-C6 alkyl, optionally substituted 3- to 12-membered heterocyclic ring. The appearance according to the present invention provides a compound of Formula: where R21 is hydrogen or fluorine. Detailed description of the invention In a disclosure of the present invention, it is a compound of the formula described above or an acceptable pharmaceutical-use salt thereof. This description covers compounds of Formula (I) and their pharmaceutically acceptable salts, where X is optionally substituted phenyl. In certain disclosures, X is phenyl substituted with one or more substituents, such as 1, 2, 3, 4, or 5 substituents. Preferably, the substituents are independently selected from halogen, CN, optionally substituted C1-C3 alkoxy, optionally substituted C1-C3 alkyl, and optionally substituted C3-C6 cycloalkyl. In certain disclosures, X is phenyl substituted with one or more substituents independently selected from fluoro, chloro, bromo, methyl, difluoromethyl, trifluoromethyl, CN, and cyclopropyl. In certain disclosures, X is selected from the following groups: In certain disclosures, compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where X is an optionally substituted monocyclic heteroaryl. In certain disclosures, compounds of Formula (I) or, and pharmaceutically acceptable salts thereof, are compounds where X is an optionally substituted thiophenyl, optionally substituted thiazolyl, optionally substituted pyridyl, or optionally substituted pyrimidinyl. In certain disclosures, compounds of Formula (I) or, and pharmaceutically acceptable salts thereof, are compounds where X is an optionally substituted pyrimidinyl, optionally substituted pyridacil, or optionally substituted pyracyl, as illustrated below: In certain disclosures, the compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where X is an optionally substituted bicyclic heteroaryl. In certain disclosures, the compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where X is an optionally substituted 5 / 6 bicyclic heteroaryl and is connected to A through a carbon or nitrogen atom, preferably a carbon atom, of the 6-membered ring of said 5 / 6 bicyclic heteroaryl. In certain disclosures, the compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where X is optionally substituted benzimidazolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinolyl, isoquinolyl, or quinazolyl. In certain disclosures, compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where Y is optionally substituted phenyl. In certain disclosures, compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where Y is halogen-substituted phenyl, CN, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkenyl, optionally substituted C3-C6 cycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl. In certain disclosures, compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where Y is optionally substituted 1,3-phenylene, for example. In certain disclosures, the compounds of Formula (I), and the pharmaceutically acceptable salts thereof, are compounds where Y is optionally substituted 1,3-phenylene, for example In certain disclosures, the compounds of Formula (I), and the pharmaceutically acceptable salts thereof, are compounds where Y is optionally substituted 2,4-pyrrolylene, for example In certain disclosures, compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where Y is an optionally substituted monocyclic heteroaryl. In certain disclosures, compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where Y is optionally substituted thiophenyl, optionally substituted thiazolyl, optionally substituted pyrrolyl, optionally substituted pyrazolyl, optionally substituted imidazolyl, optionally substituted pyridyl, or optionally substituted pyrimidinyl. In certain disclosures, compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where Y is optionally substituted pyrrolyl with a halogen, CN, and optionally substituted C1-C3 alkyl. In certain disclosures, compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where Y is an optionally substituted bicyclic heteroaryl. In certain disclosures, compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where Y is an optionally substituted 5 / 6 bicyclic heteroaryl and is connected to A through a carbon or nitrogen atom of the 5-membered ring of said 5 / 6 bicyclic heteroaryl. In certain disclosures, compounds of Formula (I), and pharmaceutically acceptable salts thereof, where Y is optionally substituted benzimidazolyl, benzothiazolyl, benzoxazolyl, indazolyl, quinolyl, isoquinolyl, or quinazolyl. In certain disclosures, the compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where X and Y are each independently optionally substituted monocyclic heteroaryl. In certain disclosures, the compounds of Formula (I), and the pharmaceutically acceptable salts thereof, are compounds where X is optionally substituted phenyl and Y is optionally substituted monocyclic heteroaryl. In certain disclosures, the compounds of Formula (I), and the pharmaceutically acceptable salts thereof, are compounds where X is optionally substituted monocyclic heteroaryl and Y is optionally substituted phenyl. In certain disclosures, the compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where X and Y are each independently phenyl or monocyclic heteroaryl, each optionally substituted with 1- to 3- substituents selected from the group comprising halogen, CN, optionally substituted methyl, optionally substituted methoxy, and optionally substituted cyclopropyl. In certain disclosures, the compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where X and Y are each independently selected from the group comprising optionally substituted phenyl, optionally substituted thiophenyl, optionally substituted pyridyl, and optionally substituted pyrimidiyl. In certain disclosures, the compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where X and Y are each independently optionally substituted phenyl. In certain disclosures, the compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where X is optionally substituted phenyl and Y is optionally substituted pyrrolyl. In certain disclosures, the compounds of Formula (I) , and the pharmaceutically acceptable salts thereof, are compounds where A is -NHC (O) -. In certain disclosures, the compounds of Formula (I), and the pharmaceutically acceptable salts thereof, are compounds where A is -NHC (O) -, either and said nitrogen of -NHC (O) -, is connected to X. In certain disclosures, the compounds of Formula (I), and the pharmaceutically acceptable salts thereof, are compounds where A is -NHC (O) -, either and said nitrogen of -NHC (O) -, It is connected to Y. In certain disclosures, the compounds of Formula (I), and the pharmaceutically acceptable salts thereof, are compounds where L is S(O)2. In certain disclosures, the compounds of Formula (I) , and the pharmaceutically acceptable salts thereof, are compounds where L is S (O) . In certain disclosures, the compounds of Formula (I), and the pharmaceutically acceptable salts thereof, are compounds where L is S. In certain disclosures, the compounds of Formula (I), and the pharmaceutically acceptable salts thereof, are compounds where L is O. In certain disclosures, the compounds of Formula (I), and acceptable pharmaceutical salts thereof, are compounds where R is optionally substituted C1-C10 alkyl, optionally substituted C2-C10 alkenyl, or optionally substituted C2-C10 alkynyl. In certain disclosures, compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where R is optionally substituted aryl or optionally substituted heteroaryl. In certain disclosures, compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where R is optionally substituted C3-C12 cycloalkyl or optionally substituted 3- to 12-membered heterocyclic ring. In certain disclosures, the compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where R is optionally substituted cycloalkyl, C3-C12 alkyl, C1-C6 cycloalkyl, optionally substituted cycloalkenyl, C3-C12 alkyl, optionally substituted C1-C6 alkyl, or optionally substituted 3- to 12-membered C1-C6 alkyl heterocyclic ring. In certain disclosures, the compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where R is an optionally substituted C5-C12 cycloalkyl or optionally substituted 5- to 12-membered heterocyclic ring, each of which is optionally substituted with one or more fused rings. In certain disclosures, the compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where R is optionally substituted C5-C12 cycloalkyl or optionally substituted 5- to 12-membered heterocyclic ring, each of which is optionally substituted with one or more spiro rings. In certain disclosures, the compounds of Formula (I), and pharmaceutically acceptable salts thereof, are compounds where R is optionally substituted C5-C12 cycloalkyl or 5- to 12-membered ring, each of which optionally comprises a bridging group. In certain disclosures, the compounds of Formula (I), and the pharmaceutically acceptable salts thereof, are compounds where R is -C (R10) 3, where n in each occurrence is independently selected from 0, 1, 2 or 3; T in each occurrence is independently selected from C(R10) and N; E in each occurrence is independently selected from -C(R10)2-, -N(R10)-, O, S, S(O) and S(O)2; where R10 in each occurrence is independently selected from the group comprising hydrogen, halo, -CN, -NO2, optionally substituted C1-C6 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, optionally substituted heteroaryl and -L1-R1; where L1 is -O-, -S-, -NR1-, -C (O) -, -C (O) O-, -OC (O) -, -C (O) N (R1) -, -N (R1) C (O) -, -OC (O) N (R1) -, -N (R1) C (O) O-, -N (R1) C (O) N (R1) -, -S (O) -, -S (O) 2-, -S(O)2N(R1)-, -N(R1)S(O)2-;R1 in each occurrence is independently selected from the group comprising hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted aryl, and optionally substituted heteroaryl. In certain disclosures, each R10 is independently selected from hydrogen, halo, hydroxy, protected hydroxy, -CN, -NO2, amino, protected amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and -O- (prodrug hydroxy group). In certain disclosures, the prodrug hydroxy group is phosphate or sulfamate. In certain disclosures, such prodrug hydroxy groups are acyl groups derived from an amino acid, preferably an amino acid. In certain disclosures, each R10 is independently C1-C6 alkyl optionally substituted with one or more substituents selected from the group comprising halo, hydroxy, hydroxy protected, amino, amino protected, and optionally substituted heteroaryl. In certain disclosures, two adjacent R10 groups are taken together with the carbon or nitrogen atoms to which they are attached to form an olefinic or iminic double bond or a fused ring. In certain disclosures, two geminal R10 groups together form an oxo, an optionally substituted olefin, an optionally substituted oxime, or a spiro ring. In certain disclosures, two remote R10 groups are taken together with the atoms to which they are attached and any intervening atoms to form a bridging group. In certain disclosures, the compounds of Formula (I), and the pharmaceutically acceptable salts thereof, are compounds where R is - (CH2) 0-4-C (R10) 3 optionally substituted, where n, E, T, and R10 are previously defined; v is selected from 1, 2, 3, or 4. In certain disclosures, each R10 is independently selected from hydrogen, halo, hydroxy, protected hydroxy, -CN, -NO2, amino, protected amino, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted aryl, optionally substituted heteroaryl, and -O- (prodrug hydroxy group). In certain disclosures, the prodrug hydroxy group is phosphate or sulfamate. In certain disclosures, said prodrug hydroxy group is an acyl group derived from an amino acid, preferably an amino acid. In certain disclosures, each R10 is independently C1-C6 alkyl optionally substituted with one or more substituents selected from the group comprising halo, hydroxy, protected hydroxy, amino, protected amino, and optionally substituted heteroaryl.In certain disclosures, two adjacent R10 groups are taken together with the carbon or nitrogen atoms to which they are attached to form an olefinic double bond, an imine double bond, or a fused carbocyclic or heterocyclic ring. In certain disclosures, two geminal R10 groups together form an oxo, an optionally substituted olefin, an optionally substituted oxime, or a spiro ring. In certain disclosures, two remote R10 groups are taken together with the atoms to which they are attached and any intervening atoms to form a bridging group. In certain disclosures, R is selected from the groups listed below and is optionally substituted: In certain disclosures, R is selected from the groups listed below and is optionally substituted: In another disclosure, the compound of formula (I) is represented by Formula (Ia), (Ib), (Ic) or (Id) or an acceptable pharmaceutical salt thereof: where X, A, Y and R are previously defined. In another disclosure, the compound of formula (I) is represented by Formula (IIa), (IIb), (IIc), (IId), (IIe), (IIIf), (IIg), or (IIh) or an acceptable pharmaceutical-use salt thereof: where X, Y and R are previously defined. In certain disclosures, the compounds of Formula (I) are represented by Formula (IIa), (IIb), (IIc), (IId), (IIe), (IIIf), (IIg), or (IIh), or pharmaceutically acceptable salts thereof, wherein X and Y are each independently optionally substituted phenyl or optionally substituted monocyclic heteroaryl. In certain disclosures, the compounds of Formula (I) are represented by Formula (IIa), (IIb), (IIc), (IId), (IIe), (IIIf), (IIg) or (IIh), or pharmaceutically acceptable salts thereof, where X is optionally substituted phenyl and Y is optionally substituted 5-membered heteroaryl. In certain disclosures, the compounds of Formula (I) are represented by Formula (IIa), (IIb), (IIc), (IId), (IIe), (IIf), (IIg) or (IIh), or pharmaceutically acceptable salts thereof, where X is optionally substituted 5-membered heteroaryl and Y is optionally substituted phenyl. In certain disclosures, the compounds of Formula (I) are represented by Formula (IIa), (IIb), (IIc), (IId), (IIe), (IIIf), (IIg) or (IIh), or pharmaceutically acceptable salts thereof, where X is optionally substituted phenyl and Y is optionally substituted pyrrolyl. In certain disclosures, the compounds of Formula (I) are represented by Formula (IIa), (IIb), (IIc), (IId), (IIe), (IIIf), (IIg) or (IIh), or pharmaceutically acceptable salts thereof, where X and Y are each optionally substituted phenyl, optionally substituted naphthyl, optionally substituted pyridyl, optionally substituted pyrimidinyl, optionally substituted thiophenyl, optionally substituted pyrrolyl, optionally substituted thiazolyl, optionally substituted thiadiazolyl, optionally substituted oxazolyl, optionally substituted isoxazolyl, optionally substituted oxadiazolyl, optionally substituted imidiazolyl, optionally substituted pyrazolyl, optionally substituted triazolyl or optionally substituted quinolinyl. In another disclosure, the compound of formula (I) is represented by Formula (IIIa), (IIIb), (IIIc) or (IIId), or an acceptable pharmaceutical-use salt thereof: where m in each occurrence is independently 0, 1, 2, 3 or 4; R14 in each occurrence is independently selected from the group comprising hydroxy, hydroxy protected, halogen, -CN, -NO2, optionally substituted amino, N3, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic ring, optionally substituted C1-C6 alkoxy, C(O)2-C1-C6 alkyl, C(O)NH-C1-C6 alkyl and optionally substituted C(O)-C1-C6 alkyl; and R is as previously defined. In another disclosure, the compound of formula (I) is represented by Formula (IIIa-1), (IIIb-1), (IIIc-1) or (IIId-1), or an acceptable pharmaceutical-use salt thereof: , where X, R, R14 and m are as previously defined. In another disclosure, the compound of formula (I) is represented by Formula (IIIa-2), (IIIb-2), (IIIc-2) or (IIId-2), or an acceptable pharmaceutical-use salt thereof: where Y, R, R14 ym are as previously defined. In another disclosure, the compound of formula (I) is represented by Formula (IVa), (IVb), (IVc), (IVd), or (IVe) or an acceptable pharmaceutical-use salt thereof: where E, T, m, n, R10, and R14 are as previously defined. In another disclosure, the compound of formula (I) is represented by Formula (Va), (Vb), (Vc), (Vd), or (Ve), or an acceptable pharmaceutical salt thereof: where m1 in each occurrence is independently 1, 2 or 3; m2 in each occurrence is independently 0, 1 or 2; m3 in each occurrence is independently 0, 1, 2 or 3; R21 in each occurrence is independently selected from the group comprising halogen, CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy and optionally substituted C3-C8 cycloalkyl; R22 in each occurrence is independently selected from the group comprising halogen, CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted aryl and optionally substituted heteroaryl; E, n and R10 are as previously defined. In another disclosure, the compound of formula (I) is represented by Formula (Vf), (Vg), (Vh), or (Vj), or an acceptable pharmaceutical salt thereof: where m4 in each occurrence is independently 0, 1, or 2; R30 is hydrogen, optionally substituted C1-C6 alkyl, hydroxyl protecting group, or prodrug hydroxy group; m1, m2, n, E, R10, R21, and R22 are as previously defined. In certain disclosures, R30 is phosphate or sulfamate. In certain disclosures, R30 is an acyl group derived from an amino acid, preferably an amino acid. In another disclosure, the compound of formula (I) is represented by Formula (VIa), (VIb), (VIc), (VId), (VIe) or (VIf), or an acceptable pharmaceutical salt thereof: where m1 in each occurrence is independently 1, 2, or 3; m2 in each occurrence is independently 1 or 2; n, R21, R22, and R30 are as previously defined. In certain disclosures, R30 is phosphate or sulfamate. In certain disclosures, R30 is an acyl group derived from an amino acid, preferably an amino acid. In another disclosure, the compound of formula (I) is represented by Formula (VIa), (VIb), (VIc), (VId), (VIe), or (VIf), or a pharmaceutically acceptable salt thereof, where m1 in each occurrence is independently 2 or 3; m2 in each occurrence is 1; n in each occurrence is independently 0, 1, or 2; R21 is halogen, CN, optionally substituted methyl, optionally substituted methoxy, and optionally substituted cyclopropyl; R22 is halogen, CN, optionally substituted methyl and optionally substituted methoxy; R30 is an acyl group derived from an amino acid.In some disclosures, R30 is an acyl group derived from an amino acid containing an aliphatic side chain. In some disclosures, R30 is an acyl group derived from alanine or valine. In another disclosure, the compound of formula (I) is represented by Formula (VIIa), (VIIb), (VIIc), (VIId) or (VIIe), or an acceptable pharmaceutical-use salt thereof: where m1, m3, n, E, R10, R21 and R22 are as previously defined. In another disclosure, the compound of formula (I) is represented by Formula (VIIa-1), (VIIb-1), (VIIc-1), (VIId-1) or (VIIe-1), or an acceptable pharmaceutical-use salt thereof: where R23 in each occurrence is independently selected from group comprising hydrogen, halogen, CN, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, and optionally substituted C3-C8 cycloalkyl; m3, n, E, R10, R21, and R22 are as previously defined. In another disclosure, the compound of formula (I) is represented by Formula (VIIa-2), (VIIb-2), (VIIc-2) or (VIId-2), or an acceptable pharmaceutical-use salt thereof: where m4, n, E, R10, R21, R22, R23, and R30 are as previously defined. In some disclosures, R30 is hydrogen. In some disclosures, R30 is an acyl group derived from an amino acid, preferably an amino acid. In another disclosure, the compound of formula (I) is represented by Formula (VIIa-2), (VIIb-2), (VIIc-2), or (VIId-2), or an acceptable pharmaceutical salt thereof, wherein n in each occurrence is independently 0, 1, or 2; R21 in each occurrence is independently halogen, CN, optionally substituted methyl, optionally substituted methoxy, or optionally substituted cyclopropyl; R22 is halogen, CN, optionally substituted methyl, or optionally substituted methoxy; R23 is hydrogen or halogen; R10 is hydrogen, halogen, hydroxyl, or optionally substituted C1-C6 alkyl; R30 is hydrogen or an acyl group derived from an amino acid. In certain disclosures, R21 in each occurrence is fluorine. In certain disclosures, R22 is fluorine or chlorine. In certain disclosures, R10 is hydrogen, halogen, hydroxyl, C1-C6 alkyl optionally substituted with one or more groups selected from halogen, hydroxy, and C1-C6 alkoxy optionally substituted.In some disclosures, R23 is hydrogen or fluorine. In some disclosures, R30 is an acyl group derived from alanine or valine. In another disclosure, the compound of formula (I) is represented by Formula (VIIIa), (VIIIb), (VIIIc) or (VIIId), or an acceptable pharmaceutical-use salt thereof: where R11 in each occurrence is independently selected from the group comprising hydrogen, halogen, hydroxy, protected hydroxy, -CN, amino, protected amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted C1-C6 alkoxy, optionally substituted NH-C1-C6 alkyl, optionally substituted -N(C1-C6 alkyl)2, -CO2H, optionally substituted C(O)2-C1-C6 alkyl, optionally substituted C(O)NH-C1-C6 alkyl, and optionally substituted C(O)-C1-C6 alkyl; m, n, E, T, R10 and R14 are as previously defined.In certain disclosures, the preferred R11 groups include hydrogen, halogen, hydroxy, protected hydroxy, protected amino, optionally substituted aryl, optionally substituted heteroaryl, -CO2H, optionally substituted C1-C6 alkyl, optionally substituted NHC(O)2-C1-C6 alkyl, and optionally substituted C1-C6 alkoxy. In certain disclosures, R11 is optionally substituted C1-C6 alkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted C1-C6 alkoxy. In another disclosure, the compound of formula (I) is represented by Formula (VIIIa-1), (VIIIb-1), (VIIIc-1), or (VIIId-1), or an acceptable pharmaceutical salt thereof. where m, n, E, R10, R11 and R14 are as previously defined. In another disclosure, the compound of formula (I) is represented by Formula (IXa), (IXb), (IXc) or (IXd) or an acceptable pharmaceutical salt thereof: where m4, n, R10, R21, R22, R23 and R30 are as previously defined. In another disclosure, the compound of formula (I) is represented by Formula (Xa), (Xb), (Xc) or (Xd), or an acceptable pharmaceutical-use salt thereof: where m4, n, R10, R21, R22, R23 and R30 are as previously defined. In another disclosure, the compound of formula (I) is represented by Formula (XIa), (XIb), (XIc) or (XId), or an acceptable pharmaceutical-use salt thereof: where m4, n, R10R21, R22, R23 and R30 are as previously defined. In another disclosure, the compound of formula (I) is represented by Formula (XIIa), (XIIb), (XIIc) or (XIId), or an acceptable pharmaceutical-use salt thereof: where R31 in each occurrence is independently selected from group comprising hydrogen, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted C1-C6 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, and optionally substituted 3- to 8-membered heterocyclic ring; m1, m2, m4, n, R10, R11, R21, R22, and R30 are as previously defined. In certain disclosures, R31 is C1-C6 alkyl optionally substituted with one or more groups selected from halogen, hydroxy, C1-C6 alkoxy optionally substituted, amino, NH-C1-C6 alkyl, -N (C1-C6 alkyl ) 2 optionally substituted, CO2-C1-C6 alkyl optionally substituted, C (O) NH-C1-C6 alkyl optionally substituted, NHC (O) -C1-C6 alkyl optionally substituted, C (O) -C1-C6 alkyl and NHS (O) 2-C1-C6 alkyl optionally substituted. In another disclosure, the compound of formula (I) is represented by Formula (XIIIa), (XIIIb), (XIIIc) or (XIIId), or an acceptable pharmaceutical-use salt thereof: where R32 in each occurrence is independently selected from the group comprising hydrogen, optionally substituted C1-C6 alkyl, C(O)-optionally substituted C1-C6 alkyl, C(O)-optionally substituted C2-C8 alkenyl, C(O)-optionally substituted C2-C8 alkynyl, C(O)-optionally substituted C3-C8 cycloalkyl, C(O)-optionally substituted aryl, -C(O)-(3-to-8-membered heterocyclic ring) optionally substituted, C(O)-optionally substituted C1-C6 alkyl, CO2-optionally substituted C1-C6 alkyl, S(O)-optionally substituted C1-C6 2-alkyl, S(O)-C2-C6 2-alkenyl;preferably when one R32 is C(O)-C1-C6 optionally substituted alkyl, C(O)-C2-C8 optionally substituted alkenyl, C(O)-C2-C8 optionally substituted alkynyl, C(O)-C3-C8 optionally substituted cycloalkyl, C(O)-C(O)-optionally substituted aryl -C(O)-(3- to 8-membered heterocyclic ring) optionally substituted, C(O)-C1-C6 optionally substituted alkyl, CO2-C1-C6 optionally substituted alkyl, S(O)-C1-C6 optionally substituted alkyl, S(O)-C2-C6 optionally substituted alkyl, the other R32 is hydrogen or C1-C6 optionally substituted alkyl; m1, m2, m4, n, R10, R11, R21, R22, and R30 are as previously defined. In some disclosures, two R32 groups are taken together with the nitrogen atom to which they are attached to form a 3- to 8-membered heterocyclic ring. In another disclosure, the compound of formula (I) is represented by Formula (XIVa), (XIVb), (XIVc) or (XIVd), or an acceptable pharmaceutical-use salt thereof: where R33 in each occurrence is independently selected from the group comprising hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted 3- to 8-membered heterocyclic, optionally substituted C1-C6 alkoxy, -NH- optionally substituted C1-C6 alkyl, -NH- optionally substituted C1-C6 alkenyl, -NH- (3- to 8-membered heterocyclic ring); m1, m2, m4, n, R10, R11, R21, R22 and R30 are as previously defined. In another disclosure, the compound of formula (I) is represented by Formula (XVa), (XVb), (XVc) or (XVd), or an acceptable pharmaceutical-use salt thereof: where R34 in each occurrence is independently selected from group comprising hydrogen, optionally substituted C1-C6 alkyl, optionally substituted C2-C8 alkenyl, optionally substituted C2-C8 alkynyl, optionally substituted C3-C8 cycloalkyl and 3- to 8-membered heterocyclic; m1, m2, m4, n, R10, R11, R21, R22, R30 and R31 are as previously defined. In another disclosure, the compound of formula (I) is represented by Formula (XVI), or an acceptable pharmaceutical-use salt thereof: where R21, R21 and R21" are independently selected from hydrogen, fluorine, methyl, difluoromethyl and trifluoromethyl; and R35 is -[CH(R36)]pC(R37)(R38)OH or -CH2-O-CH2-[CH(R36)]pC(R37)(R38)OH, where p is 0 or 1; R36 is hydrogen, methyl or hydroxyl; and R37 and R38 are independently selected from hydrogen or methyl. Preferably, at least two of R21, R21 and R21" are not hydrogen. More preferably, (i) none of R21, R21 and R21" are hydrogen; or (ii) R21 is hydrogen and R21 and R21" are not hydrogen. In preferred disclosures, at least two of R21, R21, and R21" are fluorine. In other disclosures, each of R21, R21, and R21" is fluorine. In one embodiment of the invention, R35 is CHOH-CH(CH3)OH, i.e., R36 is hydrogen, p is 1, R37 is hydrogen, and R38 is methyl, and R21 is either hydrogen or fluorine, and R21' and R21" are fluorine. In another disclosure, the compound of formula (I) is represented by Formula (XVII), or an acceptable pharmaceutical-use salt thereof: where R21, R21 and R21" are independently selected from hydrogen, fluorine, methyl, difluoromethyl and trifluoromethyl; R39 is hydrogen or hydroxyl; and R40 is -[C (R41) (R42) ]q-R43, where q is 0, 1 or 2; R41 and R42 are each independently hydrogen, methyl or hydroxyl; or alternatively, R41 and R42 can be taken together to form an oxo; and R43 is hydrogen, hydroxyl, optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 12-membered heterocyclic, optionally substituted aryl or optionally substituted heteroaryl. Preferably, at least two of R21, R21 and R21" are not hydrogen. More preferably, (i) none of R21, R21 and R21" is hydrogen; or (ii) R21 is hydrogen and R21 and R21" are not hydrogen. In preferred disclosures, at least two of R21, R21 and R21" are fluorine. In other disclosures, each of R21, R21 and R21" is fluorine.Preferably, R39 is hydroxyl; q is 1 or 2; R41 and R42 are each independently hydrogen or hydroxyl; and R43 is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 12-membered heterocyclic, optionally substituted aryl, or optionally substituted heteroaryl. More preferably, R39 is hydroxyl; q is 1 or 2; R41 is hydrogen; R42 is hydroxyl; and R43 is optionally substituted C1-C6 alkyl, optionally substituted C3-C6 cycloalkyl, optionally substituted 3- to 12-membered heterocyclic, or optionally substituted heteroaryl. In preference disclosures, R39 is hydrogen or hydroxyl; q is 1 or 2; R41 is hydrogen or methyl; R42 is hydroxyl; and R43 is optionally substituted C1-C6 alkyl or optionally substituted C3-C6 cycloalkyl.In other disclosures, R39 is hydrogen or hydroxyl; q is 1 or 2; R41 is hydrogen or methyl; R42 is hydroxyl; and R43 is optionally substituted 3- to 12-membered heterocyclic or optionally substituted heteroaryl. In preferred disclosures, R43 is methyl, ethyl, propyl, isopropyl, cyclopropyl, cyclobutyl, pyridyl, pyrimidinyl, oxazolyl, thiazolyl, oxazolyl, or isoxazolyl. It will be appreciated if the description is constructed in accordance with the laws and principles of chemical bonding. In some cases, it may be necessary to remove a hydrogen atom in order to accommodate a substituent at any other given location. It will be further appreciated that the compounds described herein may contain one or more asymmetric carbon atoms and that racemic, diastereomeric, and optically active forms may exist. It will be highly appreciated that certain compounds may exist in different tautomeric forms. It is anticipated that all tautomers will be included within the scope described herein. In one aspect, the compounds of the invention are useful in the treatment against HBV by altering, accelerating, reducing, delaying and / or inhibiting the normal functioning of the viral core protein, among other forms of action, by direct or indirect interaction with relaxed circular viral DNA (rc) DNA, cccDNA, or with reverse transcriptase, direct or indirect interaction with host proteins such as histones or associated host proteins such as kinase, the assembly and / or disassembly of the capsid of immature or mature particles, inducing an aberrant capsid morphology and leading to antiviral effects such as the alteration of virion assembly and / or disassembly, virion maturation and / or virus release. In one embodiment, a capsid assembly disruptor interacts with a mature or immature viral capsid to disrupt capsid stability and thus affect assembly and / or disassembly.In another embodiment, a capsid assembly disruptor disrupts the protein folding and / or salt bridges necessary for the normal stability, function, and / or morphology of the viral capsid, thereby affecting and / or accelerating capsid assembly and / or disassembly. In another embodiment, the compounds of the invention bind to the capsid and alter the metabolism of polyproteins and precursors, leading to an abnormal accumulation of protein monomers and / or oligomers and / or abnormal particles, resulting in cellular toxicity and death of infected cells. In another embodiment, the compounds of the invention affect the formation of the optimally stable capsid by disrupting the efficient uncoating and / or disassembly of the viruses (e.g., during infectivity). In one embodiment, the compounds of the invention affect and / or accelerate the assembly and / or disassembly of the capsid when the capsid protein is immature. In another embodiment, the compounds of the invention affect and / or accelerate the assembly of the capsid when the capsid protein is mature. In another embodiment, the compounds of the invention affect and / or accelerate the assembly and / or disassembly of the capsid during vial infectivity. In another embodiment, the alteration and / or acceleration of the assembly and / or disassembly of the capsid attenuates the viral infectivity of HBV and / or reduces the viral load. In another embodiment, the alteration, acceleration, inhibition, delay, and / or reduction of the assembly and / or disassembly of the capsid eradicates the virus from the host organism. In another embodiment, the compounds of the invention alter and / or modulate the interaction between the coat protein and viral rcDNA, cccDNA, or revert to transcriptase during viral infectivity.In another embodiment, the compounds of the invention alter and / or modulate the interaction between the nuclear protein and host proteins or associations during viral infectivity. In another embodiment, eradication of HBV from a host advantageously avoids the need for long-term chronic therapies and / or reduces the duration of long-term therapies. In one embodiment, the compounds of the invention are suitable for monotherapy and are effective against wild-type or native HBV strains and against HBV strains resistant to currently known drugs. In another embodiment, the compounds of the invention are suitable for use in combination therapy. In another embodiment, the compounds of the invention can be used in methods of modulating (e.g., inhibiting, altering, or accelerating) HBV cccDNA activity. In another embodiment, the compounds of the invention can be used in methods of decreasing or preventing HBV cccDNA formation. In another embodiment, the additional therapeutic agent is selected from immunomodulatory or immunostimulatory therapies, including the T-cell response activator AIC649 and biological agents belonging to the interferon class, such as interferon alpha 2a or 2b or modified interferons such as pegylated interferon alpha 2a, alpha 2b, or lambda; or STING modulator (interferon gene stimulator); or TLR modulators such as TLR-7 agonists, TLR-8 agonists, or TLR-9 agonists.or therapeutic vaccines to stimulate a specific immune response to HBV such as viral-like particles composed of HBcAg and HBsAg, immune complexes of HBsAg and HBsAb, or recombinant proteins comprising HBx, HBsAg, and HBcAg in the context of a yeast vector; or an immune activator such as SB-9200 of certain cellular sensors of viral RNA such as the RIG-I protein, NOD2, and MDA5; or interfering RNA (RNAi) or small interfering RNA (pRNAi) such as ARC-520, ARC-521, ARB-1467, and ALN-HBV RNAi; or another inhibitor or modulator of the envelope protein;or antiviral agents that block viral entry or maturation or that target HBV polymerase such as nucleoside or nucleotide or non-nucleoside / nucleotide polymerase inhibitors and agents with different or unknown mechanisms including agents that alter the function of other essential viral protein(s) or host proteins required for HBV replication or persistence such as REP 2139 and RG7834. In one embodiment of the combination therapy, the reverse transcriptase inhibitor is at least one of Zidovudine, Didanosine, Zalcitabine, ddA, Stavudine, Lamivudine, Abacavir, Emtricitabine, Entecavir, Apricitabine, Atevirapine, ribavirin, acyclovir, famciclovir, valacyclovir, ganciclovir, valganciclovir, Tenofovir, Adefovir, PMPA, cidofovir, Efavirenz, Nevirapine, Delavirdine or Etravirine.; In another embodiment of combination therapy, the TLR-7 agonist is selected from the group consisting of SM360320 (9-benzyl-8-hydroxy-2-(2-methoxy-ethoxy)adenine), AZD 8848 ([3-({[3-(6-amino-2-butoxy-8-oxo-7,8-dihydro-9H-purin-9-yl)propyl][3-(4-morpholinyl)propyl]aminomethyl)phenyl]methyl acetate, GS-9620 (4-Amino-2-butoxy-8-[3-(1-pyrrolidinylmethyl)benzyl]-7,8-dihydro-6(5H)-pteridinone), and RO6864018. In another embodiment of the combination therapy, the TLR-8 agonist is GS-9688. In one embodiment of these combination therapies, the compound and the additional therapeutic agent are co-formulated. In another embodiment, the compound and the additional therapeutic agent are co-administered. In another embodiment of combination therapy, the administration of the compound of the invention allows the additional therapeutic agent to be administered at a lower dose or frequency compared to the administration of at least one additional therapeutic agent needed to achieve similar results in the prophylactic treatment of an HBV infection in an individual who requires it. In another embodiment of the combination therapy, prior to administering the effective therapeutic amount of the compound of the invention, the individual is known to be refractory to a compound selected from the group comprising an HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, a modulator other than capsid assembly, antiviral compounds of different or unknown mechanisms, and combinations thereof. In another embodiment of the method, administration of the compound of the invention reduces the viral load in the individual to a greater degree compared to the administration of a compound selected from the group comprising an HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, a modulator other than capsid assembly, antiviral compounds of a different or unknown mechanism, and combinations thereof. In another embodiment, administration of the compound of the invention causes a lower incidence of viral mutation and / or viral resistance than with the administration of a compound selected from the group comprising an HBV polymerase inhibitor, interferon, viral entry inhibitor, viral maturation inhibitor, a modulator other than capsid assembly, antiviral compounds of a different or unknown mechanism, and combinations thereof. It should be understood that the compounds included in the present invention are adequately stable for use as a pharmaceutical agent. Definitions The following are definitions of several terms used to describe the present invention. These definitions apply to these terms as they are used throughout this specification and in the claims, unless otherwise limited in specific examples, either individually or as part of a larger group. The term "aryl," as used herein, refers to a mono- or polycyclic carbocyclic ring system comprising at least one aromatic ring, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. A polycyclic aryl is a polycyclic ring system comprising at least one aromatic ring. Polycyclic aryls may comprise fused rings, covalently bonded rings, or a combination thereof. The term "heteroaryl," as used herein, refers to a mono- or polycyclic aromatic radical having one or more ring atoms selected from S, O, and N; the remaining ring atoms being carbon, where any N or S contained within the ring may be optionally oxidized. Heteroaryl includes, among others, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isoxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, and quinoxalinyl. A polycyclic heteroaryl may comprise fused rings, covalently bonded rings, or a combination thereof. Aromatic groups can be substituted or not substituted. The term "bicyclic aryl" or "bicyclic heteroaryl" refers to a ring system comprising two or more rings where at least one ring is aromatic; and the two rings may be fused or covalently bonded. The term "alkyl," as used here, refers to saturated hydrocarbon radicals with linear or branched chains. "C1-C3 alkyl," "C1-C6 alkyl," "C1-C10 alkyl," "C2-C4 alkyl," or "C3-C6 alkyl" refers to alkyl groups containing one to three, one to six, one to ten, two to four, and three to six carbon atoms, respectively. Examples of C1-C8 alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, tert-butyl, neopentyl, n-hexyl, heptyl, and octyl. The term "alkenyl," as used here, refers to linear or branched hydrocarbon radicals containing at least one carbon-carbon double bond formed by the removal of a single hydrogen atom. "C2-C10 alkenyl," "C2-C8 alkenyl," "C2-C4 alkenyl," and "C3-C6 alkenyl" refer to alkenyl groups containing two to ten, two to eight, two to four, or three to six carbon atoms, respectively. Examples of alkenyl groups include, but are not limited to, ethenyl, propenylol, butenyl, 1-methyl-2-buten-1-yl, heptenyl, octenyl, and similar groups. The term "alkynyl," as used here, refers to linear or branched hydrocarbon radicals that have at least one carbon-carbon triple bond formed by the removal of a single hydrogen atom. "C2-C10 alkynyl," "C2-C8 alkynyl," "C2-C4 alkynyl," or "C3-C6 alkynyl" refer to alkynyl groups containing two to ten, two to eight, two to four, or three to six carbon atoms, respectively. Representative alkynyl groups include, but are not limited to, ethynyl, 1-propynyl, 1-butynyl, heptynyl, octinyl, and the like. The term "cycloalkyl," as used here, refers to a saturated monocyclic or polycyclic, bicyclic or tricyclic, fused, bridged, or spiro carbocyclic ring, and the carbon atoms may be optionally oxo-substituted or optionally substituted with an olefinic, iminic, or oximic exocyclic double bond. Cycloalkyl groups include C3-C12 cycloalkyl, C3-C6 cycloalkyl, C3-C8 cycloalkyl, and C4-C7 cycloalkyl. Examples of C3-C12 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene-cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, spiro[2.5]octyl, 3-methylene bicyclo[3.2.1]octyl, spiro[4.4]nonanyl and the like. The term "cycloalkenyl," as used herein, refers to a saturated monocyclic or polycyclic, bi- or tricyclic, fused, bridged, or spiro carbocyclic ring having at least one carbon-carbon double bond, and the carbon atoms may be optionally oxo-substituted or optionally substituted with an olefinic, iminic, or oximic exocyclic double bond. Preferred cycloalkenyl groups include C3-C12 cycloalkenyl, C3-C8 cycloalkenyl, or C5-C7 cycloalkenyl. Examples of C3-C12 cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[3.1.0]hex-2-enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-1-enyl, bicyclo[4.2.1]non-3-en-9-yl and the like. As used here, the term "arylalkyl" means a functional group in which an alkyl chain is attached to an aryl group, e.g., phenyl CH2CH2. The term "substituted arylalkyl" means a functional group in which the aryl group is substituted. Similarly, the term "heteroarylalkyl" means a functional group in which an alkyl chain is attached to a heteroaryl group. The term "substituted heteroarylalkyl" means a heteroarylalkyl functional group in which the heteroaryl group is substituted. As used herein, the term "alkoxy" employed alone or in combination with other terms means, unless otherwise specified, an alkyl group having the designated number of carbon atoms connected to the rest of the molecule through an oxygen atom, such as methoxy, ethoxy, 1-propoxy, 2-propoxy (isopropoxy), and higher homologues and isomers. The preferred alkoxy is (C1-C3) alkoxy. It is understood that any alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic ring or cycloalkenyl group described herein may also be an aliphatic group or an alicyclic group. An "aliphatic" group is a non-aromatic group comprising any combination of carbon atoms, hydrogen atoms, oxygen, nitrogen, or other atoms and optionally containing one or more units of unsaturation, e.g., double and / or triple bonds. Examples of aliphatic groups are functional groups, such as alkyl, alkenyl, alkynyl, O, OH, NH, NH2, C(O) , S(O) 2, C(O) O, C(O) NH, OC(O) O, OC(O) NH, OC(O) NH2, S(O) 2NH, S(O) 2NH2, NHC(O) NH2, NHC(O) C(O) NH, NHS(O) 2NH, NHS(O) 2NH2, C(O) NHS(O) 2, C(O) NHS(O) 2NH or C(O) NHS(O) 2NH2, and the like comprising one or more functional groups, non-aromatic (optionally substituted) hydrocarbons, and groups where one or more carbons of a non-aromatic (optionally substituted) hydrocarbon are replaced by a functional group. The carbon atoms of an aliphatic group can be optionally oxo-substituted.An aliphatic group can be linear, branched, cyclic, or a combination thereof, and preferably contains between approximately 1 and approximately 24 carbon atoms, more typically between approximately 1 and approximately 12 carbon atoms. In addition to aliphatic hydrocarbon groups, as used here, aliphatic groups expressly include, for example, alkoxyalkyls, polyalkoxyalkyls such as polyalkylene glycols, polyamines, and polyimines. Aliphatic groups may be optionally substituted. The terms "heterocyclic" or "heterocycloalkyl" may be used interchangeably and refer to a non-aromatic ring or a fused, bridged, or spiro bi- or tricyclic group, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur, and nitrogen, (ii) each ring system may be saturated or unsaturated, (iii) the nitrogen and sulfur heteroatoms may be optionally oxidized, (iv) the nitrogen heteroatom may be optionally quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms that may be optionally oxo-substituted or optionally substituted with an olefinic, iminic, or oxymic exocyclic double bond.Representative heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidonyl, pyrazolinyl, imidazolinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]heptyl, 8-azabicyclo[3.2.1]octyl, 5-azaspiro[2.5]octyl, 1-oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepan-4-yl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted. Heteroaryl groups or heterocyclic rings may be attached to C- or N-bonds (where possible). It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic ring, aliphatic, or similar group described herein may also be a divalent or multivalent group when used as a link to connect two or more groups or substituents, which may be on the same atom(s) or on different atom(s). Those versed in the art can readily determine the valency of any such group from the context in which it occurs. The term "substituted" refers to substitution by independent replacement of one, two, or three or more hydrogen atoms with substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, C1-C12 alkyl; C2-C12 alkenyl, C2-C12 alkynyl, hydroxy protected, -NO2, -N3, -CN, -NH2, amino protected, oxo, thioxo, C1-C12 NH-alkyl, C2-C8 NH-alkenyl, C2-C8 NH-alkynyl, C3-C12 NH-cycloalkyl, NH-aryl, NH-heteroaryl, NH-heterocycloalkyl, dialkylamino, -diarylamino, -diheteroarylamino, O-C1-C12 alkyl, O-C2-C8 alkenyl, C2-C8 O-alkynyl, C3-C12 O-cycloalkyl, O-aryl, O-heteroaryl, O-heterocycloalkyl, C(O)-C1-C12 alkyl, C(O)-C2-C8 alkenyl, C (O) -C2-C8 alkynyl-, C (O) -C3-C12 cycloalkyl-, C (O) -aryl, C (O) -heteroaryl, C (O) -heterocycloalkyl, -CONH2, CONH-C1-C12 alkyl-, CONH-C2-C8 alkenyl-, CONH-C2-C8 alkynyl-, CONH-C3-C12 cycloalkyl-, CONH-aryl, CONH-heteroaryl, CONH-heterocycloalkyl-, OCO2 -C1-C12 alkyl-, OCO2-C2-C8 alkenyl-,OCO2-alkynyl C2-C8-, OCO2-cycloalkyl C3-C12-, OCO2-aryl, OCO2-heteroaryl, OCO2-heterocycloalkyl, CO2-alkyl C1-C12, CO2-alkenyl C2-C8, CO2-alkynyl C2-C8, CO2-cycloalkyl C3-C12-, CO2-aryl, CO2-heteroaryl, CO2-heterocycloalkyl, -OCONH2, OCONH-alkyl C1-C12-, OCONH-alkenyl C2-C8-, OCONH-alkynyl C2-C8-, OCONH-cycloalkyl C3-C12-, OCONH-aryl, OCONH-heteroaryl, OCONH-heterocycloalkyl, -NHC(O) H, NHC(O) -alkyl C1-C12-, NHC(O) -alkenyl C2-C8-, NHC(O) -alkynyl C2-C8-, NHC(O) -cycloalkyl C3-C12-, NHC(O) -aryl, NHC(O) -heteroaryl, -NHC(O) NHCO2-alkyl C1-C12-, NHCO2-alkenyl C2-C8-, NHCO2-alkynyl C2-C8-, NHCO2-cycloalkyl C3-C12-, NHCO2-aryl, NHCO2-heteroaryl, NHCO2-heterocycloalkyl, -NOH NH-alkyl C1-C12-, NHC (O) NH-alkenyl C2-C8-, NHC (O) NH-alkynyl C2-C8-, NHC (O) NH-cycloalkyl C3-C12-, NHC (O) NH-aryl, NHC (O) NH-heteroaryl, NHC-O (S) NH2, NHC (S) NH-alkyl C1-C12-, NHC (S) NH-alkenyl C2-C8-, NHC (S) NH-alkynyl C2-C8-, NHC (S) NH-cycloalkyl C3-C12-, NHC (S) NH-aryl, NHC (S) NH-hetero (NHCS) NH-heterocycloalkyl, -NHC (NH) NH2, NHC (NH) NH-alkyl C1-C12-, NHC (NH) NH-alkenyl C2-C8-, NHC (NH) NH-alkynyl C2-C8-, NHC (NH) NH-cycloalkyl C3-C12-, NHC (NH) NH-heteroaryl, NHC (NH) NH-heterocycloalkyl, NHC (NH) -alkyl C1-C12-, NHC (NH) -alkenyl C2-C8-, NHC (NH) -alkynyl C2-C8-, NHC (NH) -cycloalkyl C3-C1-C8-, NHC (NH) -cycloalkyl C3-C1-, NH -heteroaryl, NHC (NH) -heterocycloalkyl, C (NH) NH-alkyl C1-C12-, C (NH) NH-alkenyl C2-C8-, C (NH) NH-alkynyl C2-C8-, C (NH) NH-cycloalkyl C3-C12-, C (NH) (NH NH-heteroaryl, C (NH) NH-heterocycloalkyl, S (O) -alkyl C1-C12-, S (O) -alkenyl C2-C8-, S (O) -alkynyl C2-C8-, S (O) -cycloalkyl C3-C12-, S (O) -aryl, S(O) -heterocycloalkyl, -SO2NH2, -SO2NH-alkyl C1-C12-, SO2NH-alkenyl C2-C8-, SO2NH-alkynyl C2-C8-, SO2NH-cycloalkyl C3-C12-, SO2NH-cycloalkyl C3-C12-, SO2NH-aryl, SO2NH-aryl, SO2NH-heterocycloalkyl, NHSO2-alkyl C1-C12-, NHSO2-alkenyl C2-C8-, NHSO2-alkynyl C2-C8-,NHSO2-C3-C12-cycloalkyl, NHSO2-aryl, NHSO2-heteroaryl, NHSO2-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroarylalkyl, -heterocycloalkyl, C3-C12-cycloalkyl, polyalkoxyalkyl, polyalkoxy, -methoxymethoxy, -methoxyethoxy, -SH, S-C1-C12-alkyl, S-C2-C8-alkenyl, S-C2-C8-alkynyl, S-C3-C12-cycloalkyl, S-aryl, S-heteroaryl, -S-heterocycloalkyl or methylthio-methyl. Optionally, the substituents are independently selected from halo, preferably Cl and F; C1-C4-alkyl, preferably methyl and ethyl; C2-C4 alkenyl; C1-C4 haloalkyl, such as fluoromethyl, difluoromethyl, and trifluoromethyl; C2-C4 haloalkenyl; C3-C6 cycloalkyl, such as cyclopropyl; -CN; -OH; NH2; C1-C4 alkylamino; di(C1-C4 alkyl)amino; and NO2. It is understood that substituents, such as aryls, heteroaryls, alkyls, and the like, may be optionally further substituted. In some cases,Each substituent on a substituted group is additionally optionally substituted with one or more groups, each group being independently selected from C1-C4- alkyl; CF3, C1-C4- alkoxy; -OCF3, -F, -Cl, -Br, -I, -OH, -NO2, -CN and -NH2. It is understood that aryls, heteroaryls, alkyls, cycloalkyls and the like may be further substituted. The term "halo" or "halogen" alone or as part of another substituent, as used here, refers to an atom of fluorine, chlorine, bromine, or iodine. The term "optionally substituted," as used here, means that the reference group may be substituted or unsubstituted. The reference group is optionally substituted with zero substituents; that is, the reference group is unsubstituted. The reference group is optionally substituted with one or more additional groups individually and independently selected from among the groups described herein. The term "hydrogen" includes hydrogen and deuterium. Furthermore, the mention of an atom includes other isotopes of that atom, provided the resulting compound is pharmaceutically acceptable. The compounds in each Formula herein are defined to include isotope-labeled compounds. An "isotope-labeled compound" is a compound in which at least one atomic position is enriched in a specific isotope of the designated element to a level significantly greater than that of the naturally occurring abundance of that isotope. For example, one or more hydrogen atom positions in a compound may be enriched with deuterium to a level significantly greater than that of deuterium's naturally occurring abundance. For example, enrichment to a level of at least 1%, preferably at least 20% or at least 50%. Such a deuterated compound may, for example, be metabolized more slowly than its non-deuterated analogue and thus exhibit a longer half-life when administered to a subject. Such compounds may be synthesized using methods known in the art, for example, using deuterated raw materials.Unless otherwise stated, isotopically labeled compounds are of acceptable pharmaceutical use. The term "hydroxyl activating group," as used here, refers to a labile chemical group known in the art to activate a departing hydroxyl group during synthetic procedures such as substitution or elimination reactions. Examples of hydroxyl activating groups include, but are not limited to, mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate, and similar compounds. The term "activated hydroxyl," as used herein, refers to an activated hydroxyl group with a hydroxyl activator group, as defined above, including mesylate, tosylate, triflate, p-nitrobenzoate, phosphonate groups, for example. The term "hydroxyl protecting group," as used here, refers to a labile chemical group known in the art to protect a hydroxyl group from unwanted reactions during synthesis procedures. Following such synthesis procedures, the hydroxyl protecting group, as described here, can be selectively removed. Hydroxyl protecting groups, as known in the art, are generally described in the work of T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999).Examples of hydroxyl protecting groups include benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, tert-butoxycarbonyl, isopropoxycarbonyl, diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, allyloxycarbonyl, acetyl, formyl, chloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl, benzoyl, methyl, t-butyl, 2,2,2-trichloroethyl, 2-trimethylosiliyl, ethyl, allyl, benzyl, triphenylmethyl (trityl), methoxymethyl, methylthiomethyl, benzyloxymethyl, 2-(trimethylsilyl)-ethoxymethyl, methanesulfonyl, trimethylsilyl, triisopropylsilyl, and the like. The term "hydroxy protected," as used herein, refers to a hydroxyl group protected with a hydroxyl protecting group, as defined above, including benzoyl, acetyl, trimethylsilyl, triethylsilyl, methoxymethyl, for example. The term "prodrug hydroxy group," as used herein, refers to the functional group protecting group known to the art to transiently alter the physicochemical and, consequently, biological properties of a precursor drug by covering or masking the hydroxy group. Following such synthesis procedures, the prodrug hydroxy group as described herein must be capable of regenerating the hydroxy group in vivo. The hydroxy groups of prodrugs known in the art are generally described in the work of Kenneth B. Sloan, Prodrugs, Topical and Ocular Drug Delivery, (Drugs and the Pharmaceutical Sciences; Volume 53), Marcel Dekker, Inc., New York (1992) and in "Prodrugs of Alcohols and Phenols" by SS Dhareshwar and VJ Stella, in Prodrugs Challenges and Rewards Part-2, (Biotechnology: Pharmaceutical Aspects), edited by VJ Stella, et al, Springer and AAPSPress, 2007, pp 31-99. The term "amino protecting group," as used here, refers to a labile chemical group known in the art to protect an amino group from unwanted reactions during synthesis procedures. After such synthesis procedures, the amino protecting group described here can be selectively removed. Amino protecting groups as known in the art are generally described in the work of T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd edition, John Wiley & Sons, New York (1999). Examples of amino protecting groups include, but are not limited to, methoxycarbonyl, tert-butoxycarbonyl, 9-fluorenyl-methoxycarbonyl, benzyloxycarbonyl, and similar groups. The term "amino protected," as used herein, refers to an amino group protected with an amino protecting group as defined above. The term "amino acid" refers to naturally occurring or synthetic amino acids and includes, among others, amino acids found in proteins or intermediates in amino acid or protein metabolism, namely glycine, alanine, valine, leucine, isoleucine, methionine, phenylalanine, tryptophan, proline, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartate, glutamate, lysine, citrulline, arginine, and histidine. In some disclosures, the amino acid has the L configuration. In some disclosures, the amino acid has the D configuration.In some disclosures, the amino acid is provided as a substituent of a compound described herein, where the amino acid is a residue selected from the group comprising alanyl, valinyl, leucinyl, isoleucinyl, prolinyl, phenylalanine, tryptophanyl, methionynyl, glycinyl, serinyl, threonine, cysteinyl, tyrosinyl, asparaginyl, glutamyl, aspartoyl, glutaroyl, lysine, arginine, histidine, β-alanyl, β-valinyl, β-leucinyl, β-isoleucinyl, β-prolinyl, β-phenylalanine, β-tryptophanyl, β-methionynyl, β-glycinyl, β-serinyl, β-threonine, β-cysteinyl, β-tyrosinyl, ß-asparaginyl, ß-glutaminyl, ß-aspartoyl, ß-glutaroyl, ßlysinyl, ß-argininyl and ß-histidinyl. The term "amino acid derivative" refers to a group of an amino acid, whether naturally occurring or not, as exemplified and described herein. Amino acid derivatives are obvious to those skilled in the art and include, but are not limited to, ester, amino alcohol, amino aldehyde, amino lactone, and N-methyl derivatives of naturally occurring and non-naturally occurring amino acids. Optionally, an amino acid derivative is provided as a substituent of a compound described herein, wherein the substituent is -NRu-G(Sc)-C(O)-Q1, where Q1 is -SRv, -NRvRv, or alkoxy, Rv is hydrogen or alkyl, Sc is a side chain of a naturally occurring or non-naturally occurring amino acid, G is C1-C2 alkyl, and Ru is hydrogen; or Ru and Sc are taken together with the atoms to which they are attached to form a five-membered heterocyclic ring.Optionally, an amino acid derivative is provided as a substituent on a compound described herein, wherein the substituent is -OC(O)-G(Sc)-NH-Q2, where Q2 is hydrogen or alkoxy, Sc is a naturally occurring or non-naturally occurring amino acid side chain, and G is a C1-C2 alkyl group. Optionally, Q2 and Sc are taken together with the atoms to which they are attached to form a five-membered heterocyclic ring. Optionally, G is an optionally substituted methylene group, and Sc is selected from the group consisting of hydrogen, alkyl, arylalkyl, heterocycloalkyl, carboxyalkyl, heteroarylalkyl, aminoalkyl, hydroxylalkyl, aminoiminoaminoalkyl, aminocarbonylalkyl, sulfanylalkyl, carbamoylalkyl, alkylsulfanylalkyl, and hydroxylarylalkyl. Optionally, an amino acid derivative is provided as a substituent of a compound described herein, wherein the amino acid derivative has the D configuration.Optionally, an amino acid derivative is provided as a substituent of a compound described herein, wherein the amino acid derivative has the L configuration. The term "leaving group" means a functional group or atom that can be displaced by another functional group or atom in a substitution reaction, such as a nucleophilic substitution reaction. Representative leaving groups include chlorine, bromine, and iodine; sulfonic ester groups, such as mesylate, tosylate, brosylate, and the like; and acyloxy groups, such as acetoxy, trifluoroacetoxy, and the like. The term "aprotic solvent," as used here, refers to a solvent that is relatively inert to proton activity, that is, it does not act as a proton donor. Examples include, but are not limited to, hydrocarbons such as hexane and toluene; halogenated hydrocarbons such as methylene chloride, ethylene chloride, chloroform, and the like; heterocyclic compounds such as tetrahydrofuran and N-methylpyrrolidone; and ethers such as diethyl ether and bis-methoxymethyl ether. Such compounds are well known to those skilled in the art, and it will be obvious to them that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending on factors such as the solubility and reactivity of the reactants and preferred temperature ranges.Further discussions of aprotic solvents can be found in organic chemistry texts or specialized monographs, for example: Organic Solvents Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986. The term "protic solvent," as used here, refers to a solvent that tends to donate protons, such as an alcohol, for example, methanol, ethanol, propanol, isopropanol, butanol, t-butanol, and the like. Such solvents are well known to those skilled in the art, and it will be obvious to them that individual solvents or mixtures thereof may be preferred for specific compounds and reaction conditions, depending on factors such as reactant solubility, reactant reactivity, and preferred temperature ranges. Further discussions of protogenic solvents can be found in organic chemistry textbooks or specialized monographs, for example: Organic Solvents: Physical Properties and Methods of Purification, 4th ed., edited by John A. Riddick et al., Vol. II, in the Techniques of Chemistry Series, John Wiley & Sons, NY, 1986. The combinations of substituents and variables provided for in this disclosure are only those that result in the formation of stable compounds. The term "stable," as used herein, refers to compounds that possess sufficient stability to permit manufacture and that maintain the integrity of the compound for a period of time sufficient to be useful for the purposes detailed herein (e.g., therapeutic or prophylactic administration to a subject). The synthesized compounds can be separated from a reaction mixture and further purified by methods such as column chromatography, high-performance liquid chromatography, or recrystallization. As those skilled in the art will appreciate, more methods of synthesis for the compounds in the present formula will be evident to them. Furthermore, the various synthetic steps can be carried out in an alternating sequence or order to yield the desired compounds. Chemical transformations of synthesis and protection group methodologies (protection and deprotection) useful for synthesizing the compounds described here are known to those skilled in the art and include, for example, those described in R. Larock's *Comprehensive Organic Transformations*, 2nd ed., Wiley-VCH (1999); T.W. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); L. Fieser and M. Fieser, Fieser and Fieser's Reagents for Organic Synthesis, John Wiley and Sons (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995), and subsequent editions thereof. The term "subject," as used here, refers to an animal. Preferably, the animal is a mammal. More preferably, the mammal is a human. A subject can also refer, for example, to dogs, cats, horses, cows, pigs, guinea pigs, fish, birds, and the like. Compounds can be modified by adding appropriate functionalities to enhance selective biological properties. Such modifications, known to experts in the field, can include those that increase biological penetration within a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility, or allow administration by injection, modify metabolism, and alter the rate of excretion. The compounds described herein contain one or more asymmetric centers and give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stoichiometry, as (R)- or (S)-, or as (D)- or (L)- for amino acids. This disclosure is intended to include all such possible isomers, as well as their racemic and optically pure forms. Optical isomers may be prepared from their respective optically active precursors described above, or by the procedures described above, or by resolving racemic mixtures. Resolution may be carried out in the presence of a resolving agent, by chromatography, by repeated crystallization, or by some combination of these techniques known to those skilled in the art. Further details on resolutions can be found in Jacques et al., Enantiomers, Racemates, and Resolutions (John Wiley & Sons, 1981).When the compounds described herein contain olefinic double bonds, other unsaturation, or other centers of geometric asymmetry, and unless otherwise stated, the compounds are intended to include both the E and Z geometric isomers or the cis- and trans- isomers. Likewise, all tautomeric forms are also intended to be included. Tautomers may be cyclic or acyclic. The configuration of any carbon-carbon double bond appearing herein is selected only for convenience and is not intended to designate a particular configuration unless the text so states; hence, a carbon-carbon double bond or a carbon-heteroatom double bond arbitrarily represented here as trans may be cis, trans, or a mixture of the two in any proportion. Certain compounds described here can also exist in different stable conformational forms that can be separated. Torsional asymmetry due to restricted rotation around an asymmetric single bond, for example, due to ring strain, can allow the separation of different conformers. The disclosure includes each conformational isomer of these compounds and mixtures thereof. As used herein, the term "pharmaceutical-acceptable salt" refers to those salts that fall within the scope of sound medical judgment, are suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, or allergic response, and are proportionate with a reasonable benefit-risk ratio. Pharmaceutical-acceptable salts are well known in the art. For example, S.M. Berge et al. describe pharmaceutical-acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts may be prepared in situ during the isolation and final purification of the compounds of the invention, or separated by reaction of the free base with a suitable organic acid.Examples of acceptable pharmaceutical salts include, but are not limited to, non-toxic addition salts of acids, which are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or using other methods employed in the art such as ion exchange.Other acceptable pharmaceutical use sales include, among others, sales of adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanpropionate, digluconate, dodecylsulfate, ethansulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroioduro, 2-hydroxy-ethansulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methansulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluensulfonate, undecanoate, valerate and the like. Representative sales of alkali or alkaline earth metals include sodium, lithium, potassium, calcium, magnesium and the like.Other pharmaceutically acceptable salts include, where appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl containing 1 to 6 carbon atoms, sulfonate, and aryl sulfonate. As used here, the term "pharmaceutically acceptable ester" refers to esters that hydrolyze in vivo and includes those that rapidly degrade in the human body to leave the parent compound or its salt. Suitable ester groups include, for example, pharmaceutically acceptable aliphatic carboxylic acid derivatives, particularly alkanoic, alkenoic, cycloalkanoic, and alkandioic acids, in which each alkyl or alkenyl group advantageously has no more than six carbon atoms. Examples of particular esters include, but are not limited to, esters of C1-C6 alkanoic acids such as acetate, propionate, butyrate, and pivalate. Pharmaceutical compositions The pharmaceutical compositions of the present invention comprise a therapeutically effective amount of a compound of the present invention formulated together with one or more vehicles or excipients of acceptable pharmaceutical use. As used herein, the term "pharmaceutical-acceptable vehicle or excipient" means any nontoxic, inert solid, semisolid, or liquid filler, diluent, encapsulating material, or formulation aid that may serve as a pharmaceutical-acceptable vehicle. Examples of materials that may serve as pharmaceutical-acceptable vehicles include sugars such as lactose, glucose, and sucrose; starches such as corn and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; and alginic acid. pyrogen-free water;isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffer solutions, as well as other compatible non-toxic lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavorings and aromas, preservatives and antioxidants may also be present in the composition, at the formulator's discretion. The pharmaceutical compositions of this invention can be administered orally, parenterally, by inhalation of a spray, topically, rectally, nasally, buccally, vaginally as an implanted reservoir, preferably orally or by injection. The pharmaceutical compositions of this invention may contain any conventional, non-toxic, pharmaceutically acceptable vehicle, adjuvant, or carrier. In some cases, the pH of the formulation may be adjusted with pharmaceutically acceptable acids, bases, or buffers to increase the stability of the formulated compound or its delivery form. The term "parenteral" as used herein includes injections or infusion techniques via subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, intralesional, and intracranial routes. Liquid dosage forms for oral administration include emulsions, microemulsions, solutions, suspensions, syrups, and elixirs of acceptable pharmaceutical use. In addition to the active compounds, liquid dosage forms may contain inert diluents commonly used in the art, such as water or other solvents, and solubilizing and emulsifying agents such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (particularly cottonseed, peanut, corn, wheat germ, olive, castor, and sesame), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions may also include adjuvants such as wetting agents, emulsifiers and suspending agents, sweeteners, flavorings and aromas. Injectable preparations, such as sterile aqueous injectables or oil suspensions, may be formulated according to known best practices using suitable dispersing or wetting agents and suspending agents. A sterile injectable preparation may also be a sterile injectable solution, suspension, or emulsion in an acceptable nontoxic parenteral diluent or solvent, such as a solution in 1,3-butanediol. Acceptable vehicles and solvents include water, Ringer's solution, and isotonic or USP sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any soft fixed oil may be used, including synthetic mono- or diglycerides. Furthermore, fatty acids such as oleic acid are used in the preparation of injectables. Injectable formulations can be sterilized, for example, by filtration through a bacteria retention filter or by incorporating sterilizing agents in the form of sterile solid compositions that can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use. To prolong the effect of a drug, it is often desirable to slow its absorption from a subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of drug absorption then depends on its dissolution rate, which, in turn, may depend on the crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered dosage form is achieved by dissolving or suspending the drug in an oily vehicle. Injectable depot dosage forms are made by forming microencapsulation matrices of the drug in biodegradable polymers such as polylactic-polyglycolic acid (PLA). Depending on the drug-to-polymer ratio and the nature of the particular polymer used, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations are also prepared by encapsulating the drug in liposomes or microemulsions that are compatible with body tissues. The compositions for rectal or vaginal administration are preferably suppositories that can be prepared by mixing the compounds of this invention with suitable and non-irritating excipients or vehicles such as cocoa butter, polyethylene glycol, or suppository wax that are solid at room temperature but liquid at body temperature and, consequently, melt in the rectal or vaginal cavity and release the active compound. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active ingredient is mixed with at least one excipient or inert vehicle of acceptable pharmaceutical use, such as sodium citrate or dicalcium phosphate, and / or: a) fillers or diluents such as starches, lactose, sucrose, glucose, mannitol, and silicic acid; b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato starch or tapioca, alginic acid, certain silicates, and sodium carbonate; e) dissolution retarders such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as, for example, cetyl alcohol and glyceryl monostearate.(h) absorbents such as kaolin and bentonite clay, (i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the pharmaceutical form may also include buffering agents. Solid compositions of a similar type can also be used as fillings in soft and hard gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. Solid dosage forms such as tablets, coated tablets, capsules, and granules may be prepared with coatings and sheaths, including enteric coatings and other well-known coatings used in pharmaceutical formulation. They may optionally contain opacifying agents and may also be composed to release the active ingredient(s) only, or preferentially, in a specific part of the intestinal tract, optionally in a delayed manner. Examples of integrated compositions that may be used include polymeric substances and waxes. Pharmaceutical forms for the topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with an acceptable pharmaceutical vehicle and any necessary preservatives or buffers. Ophthalmic formulations, ear drops, eye ointments, powders, and solutions are also contemplated within the scope of this invention. Ointments, pastes, creams and gels may contain, in addition to an active ingredient of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide or mixtures thereof. The powders and sprays may contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates, and polyamide powder, or mixtures of these substances. The sprays may also contain common propellants such as hydrochlorofluorocarbons. Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispersing the compound in an appropriate medium. Absorption enhancers can also be used to increase the flow of the compound through the skin. The rate can be controlled by providing a rate-control membrane or by dispersing the compound in a polymer matrix or gel. For pulmonary administration, a therapeutic composition of the invention is formulated and administered to the patient in solid or liquid particulate form by direct administration, e.g., inhalation into the respiratory system. The solid or liquid particulate forms of the active ingredient prepared to carry out the present invention include respirable-sized particles: that is, particles of a size small enough to pass through the mouth and larynx upon inhalation and into the bronchi and alveoli of the lungs. The administration of aerosolized therapeutic products, particularly aerosolized antibiotics, is known in the art (see, for example, U.S. Patent No. 5,767,068 to Van Devanter et al., U.S. Patent No. 5,508,269 to Smith et al. at WO 98 / 43650 to Montgomery et al.). Antiviral activity An inhibitory amount or dose of the compounds of the present invention may vary from approximately 0.01 mg / kg to approximately 500 mg / kg, or alternatively from approximately 1 mg / kg to approximately 50 mg / kg. The inhibitory amounts or doses will also vary depending on the route of administration, as well as the possibility of use in combination with other agents. Based on the treatment methods of the present invention, viral infection conditions are treated or prevented in a patient, such as a human or other animal, by administering to the patient a therapeutically effective amount of a compound of the invention, in such amounts and for such a period of time as is necessary to achieve the desired result. A "therapeutically effective amount" of a compound of the invention means an amount of the compound that confers a therapeutic effect on the treated subject, at a reasonable benefit / risk ratio applicable to any medical treatment. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject provides an indication or feels an effect). An effective amount of the compound described above may range from approximately 0.1 mg / kg to approximately 500 mg / kg, preferably from approximately 1 mg / kg to approximately 50 mg / kg. Effective doses will also vary depending on the route of administration, as well as the possibility of use in combination with other agents. However, it is understood that the total daily use of the compounds and compositions of the present invention will be determined by the treating physician within the scope of sound medical judgment.The specific therapeutically effective dose level for any particular patient will depend on a variety of factors, including the disorder being treated and its severity; the activity of the specific compound used; the specific composition used; the patient's age, body weight, general health, sex, and diet; the time of administration and the rate of excretion of the specific compound used; the duration of treatment; drugs used in combination with or concurrently with the specific compound used; and similar factors well known in the medical arts. The total daily dose of the compounds of this invention administered to a human or other animal in single or divided doses may consist of amounts, for example, ranging from 0.01 to 50 mg / kg of body weight or, more commonly, from 0.1 to 25 mg / kg of body weight. Single-dose compositions may contain such amounts or submultiples thereof to complete the daily dose. In general, treatment regimens according to the present invention comprise the administration to a patient requiring such treatment of amounts ranging from approximately 10 mg to approximately 1000 mg of the compound(s) of this invention per day in single or multiple doses. The compounds of the present invention can, for example, be administered by injection, intravenously, intra-arterially, subdermally, intraperitoneally, intramuscularly or subcutaneously; or orally, buccally, nasally, transmucosally, topically, in an ophthalmic preparation or by inhalation, with a dose ranging from approximately 0.1 to approximately 500 mg / kg of body weight, alternatively doses between 1 mg and 1000 mg / dose, every 4 to 120 hours, or according to the requirements of the particular drug. These methods involve administering an effective amount of the compound or compound composition to achieve the desired or established effect. Typically, the pharmaceutical compositions of this invention are administered approximately 1 to approximately 6 times daily or, alternatively, as a continuous infusion. Such administration may be used as chronic or acute therapy. The amount of active ingredient that may be combined with excipients or pharmaceutical vehicles to produce a unique pharmaceutical form will vary depending on the host being treated and the particular mode of administration. A typical preparation will contain from approximately 5% to approximately 95% of the active ingredient (w / w). Alternatively, such preparations may contain from approximately 20% to approximately 80% of the active ingredient. Lower or higher doses than those mentioned above may be required. The specific dosages and treatment regimens for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health status, sex, diet, time of administration, rate of excretion, drug combination, severity and course of the disease, condition, or symptoms, the patient's predisposition to the disease, condition, or symptoms, and the treating physician's judgment. Upon improvement of the patient's condition, a maintenance dose of a compound, composition, or combination of this invention may be administered, if necessary. Subsequently, the dose or frequency of administration, or both, may be reduced according to the symptoms, to a level at which the improvement is maintained once the desired level of symptom relief has been reached. However, patients may require long-term intermittent treatment if symptoms of the disease recur. When the compositions of this invention comprise a combination of a compound of the formula described herein and one or more additional therapeutic or prophylactic agents, both the compound and the additional agent shall be present at dose levels of between approximately 1% and 100%, and more preferably between approximately 5% and 95%, of the dose normally administered in a monotherapy regimen. The additional agents may be administered separately, as part of a multiple-dose regimen, from the compounds of this invention. Alternatively, such agents may be part of a unique pharmaceutical form, mixed together with the compounds of this invention in a single composition. These "additional therapeutic or prophylactic agents" include, among others, immunotherapies (e.g., interferon), therapeutic vaccines, antifibrotic agents, anti-inflammatory agents such as corticosteroids or NSAIDs, bronchodilators such as beta-2 adrenergic agonists and xanthines (e.g., theophylline), mucolytic agents, antimuscarinics, antileukotrienes, adhesion cell inhibitors (e.g., ICAM antagonists), antioxidants (e.g., N-acetylcysteine), cytokine agonists, cytokine antagonists, pulmonary surfactants, and / or antimicrobial and antiviral agents (e.g., ribavirin and amantadine). The compositions according to the invention may also be used in combination with gene replacement therapy. Combination and Alternating Therapy for HBV It has been recognized that drug-resistant variants of HIV, HBV, and HCV can emerge following prolonged treatment with an antiviral agent. The most typical drug resistance occurs through mutation of a gene encoding a protein, such as an enzyme used in viral replication—most typically, in the case of HIV, reverse transcriptase, protease, or DNA polymerase; in the case of HBV, DNA polymerase; or in the case of HCV, RNA polymerase, protease, or helicase. Recently, it has been shown that the efficacy of a drug against HIV infection can be prolonged, increased, or restored by administering the compound in combination or alternation with a second, and perhaps a third, antiviral compound that induces a different mutation than the one caused by the active ingredient.The compounds may be used in combinations and are selected from the group comprising an HBV polymerase inhibitor, interferon, TLR modulators such as TLR-7 or TLR-9 agonists, therapeutic vaccines, an immune activator of certain viral RNA cellular sensors, an inhibitor of viral entry, an inhibitor of viral maturation, a modulator other than capsid assembly, antiviral compounds of distinct or unknown mechanism, and combinations thereof. Alternatively, the pharmacokinetics, biodistribution, or other parameters of the drug may be altered by such combination or alternating therapy. In general, combination therapy is typically preferred over alternating therapy because it induces simultaneous multiple stressors on the virus. Preferred compounds for combination or alternating therapy for the treatment of HBV include 3TC, FTC, L-FMAU, interferon, adefovir, dipivoxil, entecavir, telbivudine (L-dT), valtorcitabine (3'-valinyl L-dC), β-D-dioxolanyl-guanine (DXG), β-D-dioxolanyl-2,6-diaminopurine (DAPD) and Ο-D-dioxolanyl-6-chloropurine (ACP), famciclovir, penciclovir, lobucavir, ganciclovir, and ribavirin. Abbreviations The abbreviations that may be used in the descriptions of the scheme and the examples that follow are: Ac for acetyl; AcOH for acetic acid; AIBN for azobisisobutyronitrile; BINAP for 2,2-bis(diphenylphosphino)-1,1-binaphthyl; Boc2O for di-tert-butyl dicarbonate; Boc for t-butoxycarbonyl; Bpoc for 1-methyl-1-(4-biphenylyl)ethyl carbonyl; Bz for benzoyl; Bn for benzyl; BocNHOH for tert-butyl N-hydroxycarbamate; t-BuOK for potassium tert-butoxide; Bu3SnH for tributiltyne hydride; BOP for (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; Brine for sodium chloride in water; BSA for N,O-bis-(trimethylsilyl)acetamide; CDI for carbonyldiimidazole; CH2Cl2 for dichloromethane; CH3 for methyl; CH3CN for acetonitrile; Cs2CO3 for cesium carbonate; CuCl for copper(I) chloride; CuI for copper(I) iodide; dba for dibenzilidene acetone; dppb for diphenylphosphinobutane; DBU for 1,8-diazabicyclo[5.4.0]-undec-7-ene;DCC for N,N-dicyclohexyl-carbodiimida; DEAD for diethylazodicarboxylate; DIAD for diisopropyl azodicarboxylate; DIPEA or (i-Pr)2EtN for N,N,-diisopropylethyl amine; Dess-Martin periodinane for 1, 1, 1-tris(acetyloxy)-1, 1-dihydro-1, 2-benziodoxol-3-(1H)-one; DMAP for 4-dimethylaminopyridine; DME for 1, 2-dimethoxyethane; DMF for N,N-dimethylformamide; DMSO for dimethyl sulfoxide; DMT for di(p-methoxyphenyl)-phenylmethyl or dimethoxytrityl; DPPA for diphenylphosphoryl azide; EDC para N-(3-dimethylaminopropyl)-N-ethylcarbodiimida; EDC HCl para chlorhihydrate de N-(3-dimethylaminopropyl)-N-ethylcarbodiimida; EtOAc for ethyl acetate; EtOH for ethanol; Et2O for diethyl ether; HATU para O- (7-azabenzotriazol-1-yl) -N, N, N, N, -tetramethyluronium, Hexafluorophosphate; HCl for hydrogen chloride; HOBT para 1-hidroxybenzotriazol; K2CO3 for potassium carbonate; n-BuLi para n-butyl lithium; i-BuLi para i-butyl lithium; t-BuLi para t-butyl lithium; PhLi para phenyl lithium;LDA for lithium diisopropylamide; LiTMP for lithium 2,2,6,6-tetramethylpiperidinate; MeOH for methanol; Mg for magnesium; MOM for methoxymethyl; Ms for mesyl or -SO2-CH3; Ms2O for methanesulfonic anhydride or mesyl anhydride; MTBE for t-butyl methyl ether; NaN(TMS)2 for sodium bis(trimethylsilyl)amide; NaCl for sodium chloride; NaH for sodium hydride; NaHCO3 for sodium bicarbonate or sodium hydrogen carbonate; Na2CO3 for sodium carbonate; NaOH for sodium hydroxide; Na2SO4 for sodium sulfate; NaHSO3 for sodium bisulfite or sodium hydrogen sulfite; Na2S2O3 for sodium thiosulfate; NH2NH2 for hydrazine; NH4HCO3 for ammonium bicarbonate; NH4Cl for ammonium chloride; NMO for N-methyl-morpholine N-oxide; NaIO4 for sodium per and odate; Not even for nickel; NSFI for N-fluorobenzene-sulfonimide; OH for hydroxyl; o / n during the night; OsO4 for osmium tetroxide; PTSA for p-toluenesulfonic acid; PPTS for pyridinium p-toluenesulfonate;TBAF para fluoruro de tetrabutyl-ammonio; TEA o Et3N para trietilamina; TES para trietilsilil; TESCl para cloruro de trietilsililo; TESOTf para trietilsilil trifluorometansulfonato; TFA para ácido trifluoroacetico; THF para tetrahidrofurano; TMEDA para N,N,N,N-tetrametiletilendiamina; TPP o PPh3 para triphenylphosfina; Troc para 2, 2, 2-trichloroetil carbonilo; Ts para tosilo o -SO2-C6H4CH3; Ts2O para anídrido tolilsulfónico o anhídrido tosilo; TsOH para ácido p-tolilsulfónico; Pd para paladio; Ph para fenilo; POPd para dihidrogeno dichlorobis (di-ter-butylphosphinito-P) paladato (II); Pd2 (dba) 3 para tris (dibenzilidenacetona) dipaladio (0) ; Pd (PPh3) 4 para tetraquis (triphenylphosphino) palladio (0) ; PdCl2(PPh3)2 para trans-diclorobis-(triphenylphosphino)palladio(II); Pt for platinum; Rh for rodeo; rt for ambient temperature; Ru for routine; SFC for supercritical liquid chromatography; TBS for ter-butyl dimethylsilyl; TMS for trimethylsilyl;or TMSCl for trimethylsilyl chloride.; Synthesis Methods The compounds and processes described here will be better understood in relation to the following synthesis schemes, which illustrate the methods by which the compounds described here can be prepared. These schemes are for illustrative purposes only. Equivalent, similar, or suitable solvents, reagents, or reaction conditions may be substituted for the particular solvents, reagents, or reaction conditions described here. Certain reactions may be carried out as generally described in WO 2017 / 136403. Compounds of Formula I can be prepared via several different synthetic routes starting from a variety of phenyl, heteroaryl, fused bicyclic aryl, or optionally substituted heteroaryl precursors using chemical transformations known to those skilled in the art. Strategically, a compound of Formula I can be constructed to form the sulfonyl group at the right end followed by the formation of group A at the left end. Alternatively, a compound of Formula I can be constructed to form group A at the left end followed by the formation of the sulfonyl group at the right end. The preparation of sulfones can be carried out by sulfide oxidation (review of K. Schank, The Chemistry of Sulfones and Sulfoxides, Wiley, New York, 1988, Chap. 7) or by alkylation / arylation of a novel low-valence sulfur species such as sulfinate salts (review of G. Liu, C. Fan, J. Wu, Org. Biomol. Chem.2015, 13, 1592). A sulfide can be synthesized from a thiol precursor through nucleophilic substitution to an organic halide or sulfonate ester or nucleophilic addition to an epoxide, aziridine or unsaturated substrate (review by G. Solladie, Comprehensive Organic Synthesis, 1991, Vol 6, 133), or radical addition of thiol to an unsaturated substrate. A sulfinate salt can be obtained by reduction of a sulfonyl halide (review of Schubart, R. Sulfinic Acids and Derivatives, Ullmanns Encyclopedia of Industrial Chemistry, 2000, 677) or by transition-metal catalyzed reaction of an aryl or heteroaryl halide (A. Shavnya, SS Coffey, AC Smith, V. Mascitti, Org. Lett., 2013, 15, 6226) or boronic acid (A. Shavnya, KD Hesp, V. Mascitti, AC Smith, Angew. Chem. Int. Ed., 2015, 54, 13571) with potassium metabisulfite.A sulfone compound can be further functionalized by deprotonation with a strong base followed by reaction of the resulting anion with an electrophile such as a halide, aldehyde, ketone, electrophilic reagent, halogenation, or an unsaturated substrate such as a Michael addition acceptor; a tertiary sulfone can be prepared from a primary sulfone through sequential two-step deprotonation and anionic nucleophilic reaction. An amide bond can be formed by reaction of an acid halide or anhydride with an amine or by direct coupling of a carboxylic acid with an amine in the presence of a coupling reagent such as DCC, EDC, or HATU. As illustrated in Scheme 1, where X, Y, and R are as defined above; LG1 and LG2 in each occurrence are leaving groups and are each independently selected from halogen, tosylate, mesylate, and triflate. In one approach, an optionally substituted 1-1 aryl or heteroaryl amine can react selectively with various 1-2 acid chlorides in a solvent such as, among others, toluene, tetrahydrofuran, dichloromethane, or a mixture thereof, optionally in the presence of a base such as, among others, triethylamine, DIPEA, or pyridine, to give a variety of 1-3 amide intermediates.1-3 then treated with a reducing reagent such as, among others, triphenylphosphine, SnCl2, Sn / HCl, Zn / HCl or Pd / HCOOH, to provide the thiol intermediate 1-4, which reacts with the intermediate 1-5 by nucleophilic displacement optionally in the presence of a base such as, among others, potassium carbonate, sodium carbonate, triethylamine or DIPEA to obtain a sulfide intermediate that is transformed to a compound of formula IIa in a suitable solvent in the presence of an oxidizing reagent such as, among others, hydrogen peroxide, methchloroperbenzoic acid, perbenzoic acid or tert-butyl peroxide. Alternatively, the carboxylic ester 1-6 is converted to the sulfone intermediate 1-7 using chemistry similar to that described above or by nucleophilic substitution with an organometallic agent (RM, where M is a Mg- or Zn- species).1-7 can be saponified with a base, such as, among others, lithium hydroxide, sodium hydroxide, or potassium hydroxide to yield carboxylic acid 1-8. Acid 1-8 can react with amine 1-1 in the presence of a coupling reagent such as, among others, DCC, EDC, or HATU, in a suitable solvent, optionally in the presence of a base such as, among others, triethylamine, DIPEA, or pyridine to yield the compound of formula IIa. The preparation of the compound of formula IIb is described below in Scheme 2. A 2-1 aldehyde reacts with TMSCF3 to give the 2-2 trifluoroethyl alcohol, which is converted to a triflate by reacting with Tf2O in the presence of a base such as DIPEA, followed by displacement with an amine X-NH2 to yield the compound of formula IIb. The synthesis of the compound of formula IIc containing an aminoxetanyl group is exemplified in Scheme 3. An arylamine or heteroarylamine 3-1 is condensed with oxetan-3-one in the presence of an acid such as acetic acid or p-TsA to give the imine 3-2, which is treated with a nucleophilic reagent 3-3, where M1 is an organometallic species including, among others, a boronic acid / ester related species or an organothin, organozinc, organolithium, or organomagnesium group to obtain the compound of formula IIc. As shown in Scheme 4, the compound of formula IId can be prepared from the compound of formula IIa. IIa can be reacted with benzyl bromide in the presence of a base such as, among others, NaH or LDA, to give compound 4-1, which is converted to compound 4-2 by reaction with oxalyl chloride, followed by treatment with a fluorinating reagent such as, among others, DAST, SF4, or Et3N-HF. Compound 4-2 can be treated with hydrogen gas in the presence of a suitable catalyst such as, among others, Pd / C, PtO2, or Pd(OH)2 / C, to obtain the compound of formula IId. It will be observed that, with the appropriate manipulation and protection of any chemical functional group, the synthesis of Formula I compounds is achieved using methods analogous to those described in the Experimental section. Protecting groups can be found, among others, like those found in TW Greene and PGM Wuts "Protective Groups in Organic Synthesis", 3rd Ed (1999), J Wiley and Sons. Examples The compounds and processes described here will be better understood in connection with the following examples, which are intended for illustrative purposes only. Several changes and modifications to the disclosure will be obvious to those skilled in the art. Intermediary 1 (not according to the invention) Intermediate step 1a. A mixture of 4-chloro-3-(chlorosulfonyl)-benzoic acid (0.86 g, 3.4 mmol) in SOCl2 (5.0 mL) was heated under reflux overnight. It was concentrated to give the desired crude product, which was used directly for the next step. Intermediate Step 1b. The compound from Intermediate Step 1a (0.91 g, 3.3 mmol) and 3,4,5-trifluoroaniline (0.49 g, 3.3 mmol) in toluene (10 mL) was stirred at 90 °C overnight. It was concentrated to give the desired crude compound, which was used directly for the next step. Intermediate step 1c. The compound from Intermediate step 1b (0.89 g, 2.3 mmol) and triphenylphosphine (3.4 g, 13 mmol) in toluene (12 mL) was stirred at 80 °C for 4 h. It was diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine. The organic phase was dried (Na2SO4), filtered, and concentrated. Chromatography of the residue (silica, hexanes / EtOAc) was performed to give the desired compound as a white solid (0.49 g, 71%). ESI-MS m / z = 316, 0, 318, 0 [MH]-. Intermediary 2 (not according to the invention) Intermediate step 2a. A mixture of 2-methylenepropane-1,3-diyl diacetate (2.69 g, 15.62 mmol), Pd(OAc)2 (0.210 g, 0.937 mmol), Ph3P (0.983 g, 3.75 mmol), and 1-(cyclopent-1-en-1-yl)pyrrolidine (3.19 mL, 21.86 mmol) in acetonitrile (89 mL) was heated and held at 65 °C for 18 hours. Water (45 mL) was added and the reaction mixture was stirred for 1 hour. Saturated brine was added and the mixture was extracted with ethyl acetate. The organic phase was dried (Na2SO4), filtered, and concentrated. Chromatography was performed on the residue (silica, hexanes / EtOAc) to give the desired compound (1.53 g, 71.9% yield) in the form of a colorless oil. Intermediate step 2b. A solution of the compound from intermediate step 2a (41.25 g, 306 mmol) in THF (300 mL) was cooled to -78 °C followed by the addition of LiAlH4 (1M in THF, 92 mL, 92 mmol). After stirring for 15 minutes, the reaction was stopped with water (3.4 mL), NaOH (1M, 3.4 mL), and water (10.2 mL). The organic phase was dried (Na2SO4), filtered with Celite, and concentrated to give the desired crude compound (48.4 g, 97%, containing 15% THF w / w), which was used for the next step. Intermediate step 2c. To a stirred compound from Intermediate step 2b (50.7 g, 367 mmol) and imidazole (62.4 g, 58.8 mmol) in DMF (400 mL) at 0 °C, TBSCl (66.3 g, 440 mmol) was added. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction was diluted with hexanes and the mixture was washed with water and brine. The organic layer was dried (Na₂SO₄), filtered, and concentrated to give the desired compound in the form of a white solid (101.0 g, 100%). Intermediate Step 2d. A suspension of the compound from intermediate step 2c (101 g, 368 mmol) in dioxane water (1.1 L / 0.36 L) was mixed with 2,6-dimethylpyridine (86 mL, 735 mmol), osmium(VIII) oxide (1.87 g, 7.35 mmol), and sodium peroxide (280 g, 1.31 mol), and the mixture was stirred for 20 h. The reaction was stopped with aqueous Na2S2O3, the mixture was extracted with MBTE, washed with water and brine, dried over Na2SO4, filtered, and concentrated to give the desired product as a white solid (100 g, 99%). Intermediate step 2e. To a solution of the compound from intermediate step 2d (118.5 g, 466 mmol) in MTBE (1.2 L) at 0 °C, LiBH4 (314 mL, 629 mmol, 2 M in THF) was added. The resulting reaction mixture was dried at 0 °C for 2 h. The reaction was deactivated with aqueous NH4Cl, and the mixture was extracted with MTBE and washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was used without further purification (117 g, 98%, 10:1 dr favoring the desired isomer). Intermediate step 2f. To a stirred solution of intermediate step 2e (315 mg, 1.23 mmol) and the compound from step 1c (390 mg, 1.23 mmol) in toluene (5 mL), 2-(tributyl-15-phosphanylidene)acetonitrile (0.81 mL, 3.07 mmol) was added, and the mixture was stirred at 100 °C for 60 h. It was cooled to room temperature, diluted with MBTE, washed with NaOH (0.5 N) brine, dried over Na₂SO₄, filtered, and concentrated on a silica column to give the desired compound (362 mg, 53%). ESI-MS m / z = 554.15, 556.15 [MH]-. Intermediate step 2g. A suspension of the compound from intermediate step 2f (0.53 g, 0.95 mmol) in MeOH (11 mL) at room temperature was added with HCl (1.0 mL) and stirred at room temperature for 24 h. It was concentrated under vacuum to remove most of the MeOH, and the residue was extracted with EtOAc. The organic phase was washed with 10% K2CO3, brine, dried over Na2SO4, filtered, concentrated, and recrystallized from EtOAc / hexanes to give the desired product as a white solid (0.33 g, 78%). ESI-MS m / z = 440.07, 442.07 [MH]-. Intermediate step 2 h. To a solution of the intermediate step compound (1.8 g, 3.8 mmol) in DMSO (10 mL) at room temperature, IBX (4.3 g, 15.3 mmol) was added and the mixture was stirred at room temperature for 20 h. Aqueous Na₂S₂O₃, NaHCO₃, and a few drops of Et₃N were added and stirred at room temperature for 1 h. The mixture was extracted with EtOAc, washed with water and brine, dried over Na₂SO₄, filtered, and concentrated to give the title compound (1.65 g, 92%). ESI-MS m / z = 470.04, 472.04 [MH]⁻. Intermediary 3 (not according to the invention) Intermediate Step 3a. To a solution of Intermediate 2 (1.76 g, 4.0 mmol) and trimethylsulfoxonium iodide (1.76 g, 8.0 mmol) in DMSO (20 mL) at 0 °C, t-BuOK (1.12 g, 10 mmol) was added. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction was deactivated with aqueous NH4Cl, and the mixture was extracted with EtOAc and washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was analyzed by chromatography (silica, hexanes / EtOAc) to give the desired compound as a white solid (1.36 g, 75%). ESI-MS m / z = 452.07, 454.07 [MH]-. Intermediate step 3b. To a stirred solution of the compound from intermediate step 3a (78 mg, 0.17 mmol) in DMF (2.5 mL), NH4Cl (17 mg, 0.32 mmol) and NaN3 (44 mg, 0.67 mmol) were added, then stirred at 60 °C for 24 h. It was diluted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and then chromatography (silica, hexanes / EtOAc) was performed to give the desired compound as a white solid (73 mg, 88%). ESI-MS m / z = 495.08, 497.08 [MH]-. Intermediate step 3c. To a solution of the compound from intermediate step 3b (0.20 g, 0.40 mmol) in MPN (2.0 mL), m-CPBA (0.27 g, 77%, 1.2 mmol) was added and stirred at room temperature. Aqueous Na₂S₂O₃, NaHCO₃, and a few drops of Et₃N were added and stirred at room temperature for 1 h. The mixture was extracted with EtOAc, washed with water and brine, dried over Na₂SO₄, filtered, concentrated, and chromatographed (silica, hexanes / EtOAc) to give the desired compound as a white solid (0.21 g, 98%). ESI-MS m / z = 527.07, 529.07 [MH]⁻. Intermediate step 3d. To the solution of example 257 (540 mg, 1.02 mmol) in MeOH (2 mL) and THF (1 mL), Raney nickel was added (washed with MeOH, 50 mg). A flask filled with hydrogen was introduced. It was shaken for 2 hours at room temperature. The mixture was filtered through a Celite bed and washed with MeOH. The filtrate was concentrated to give the title compound (440 mg, 86%). ESI-MS m / z = 501.08, 503.08 [MH]-. Intermediary 4 (not according to the invention) Intermediate step 4a. To a solution of the compound from intermediate step 2b (7.7 g, 77.18% in THF, 43 mmol) in anhydrous dichloromethane (20 mL) at 0 °C, DBU (7.9 g, 5.2 mmol) and 1,1,2,2,3,3,4,4,4-nonafluorobutan-1-sulfonyl fluoride (14.4 g, 48 mmol) were added. The reaction was maintained at 0 °C for 0.5 h before being concentrated to dryness. The residue was dissolved in hexane (70 mL). The solution was washed with HCl (0.5 M), water, NaHCO3, brine, and dried with Na2SO4. It was filtered through a silica gel layer, washed with hexane (300 mL) and concentrated to give a colorless oil (16.8 g 92%) .1HNMR (400 MHz, CDCl3) 5.13 (t, 1H) , 4.85 (s, 2H) , 2.67 (d, 2H) , 2.46 (brs, 2H) , 2.04 (dd, 2H) , 1.72 (m, 2H) , 1.58 (m, 2H) . Intermediate step 4b. A mixture of the compound from intermediate step 4a (2.101 g, 5 mmol) and 4-methylmorpholino4-oxide (0.703 g, 6.00 mmol) in acetone-water (4.5 mL / 0.5 mL) was mixed with osmium(VIII) oxide (0.628 mL, 2.5% in t-BuOH) and stirred continuously. Na2S2O3 (1.58 g, 10 mmol) and water (2 mL) were added and stirred continuously for 30 mins. The mixture was partitioned (EtOAc / water). The organic phase was washed with 1N HCl, aqueous NaHCO3 solution, brine, and dried (Na2SO4). After filtering, the crude product was concentrated to give the desired product (2.24 g, 99%). 1HNMR (400 MHz, CDCl3) 5.03 (t, 1H) , 3.60 (s, 2H) , 2.44 (brs, 2H) , 1.99 (ddd, 4H) , 1.82 (m, 4H) , 1.61 (m, 2H) . Intermediate step 4c. To a suspension of the compound from intermediate step 4b (1.84 g, 5.81 mmol), triphenylphosphine (0.063 g, 0.024 mmol) was degassed in THF (4 mL) to 1 / 4, followed by the addition of tert-potassium butoxide (1 M in THF, 5.32 mL, 5.32 mmol). After 5 minutes, the compound from step 1c (2.2 g, 4.84 mmol) in THF (9 mL) was added, and the mixture was stirred at 60 °C for 24 h. After cooling, it was diluted with MTBE (60 mL), filtered, and washed with MTBE. The combined solution was washed with 0.5 N NaOH, brine, and dried with Na₂SO₄. It was filtered through a short silica plug (10 g silica gel) and washed with EtOAc (50 mL). The combined organic phase was concentrated under vacuum to give the crude compound 2.5 g (110%). Intermediate step 4d. To a solution of the compound from intermediate step 4c (1.80 g, 3.81 mmol) in NMP (5 mL), m-CPBA (77 wt.%, 2.14 g, 9.54 mmol) was added. The mixture was stirred at room temperature for 20 hours before adding aqueous NaS₂O₃ (3 mL), followed by aqueous NaHCO₃ (3 mL) and MeOH (5 mL). The white solid was collected under vacuum and washed with aqueous NaHCO₃ and water. This mixture was recrystallized from MeOH to give the title compound (1.7 g, 87%). ESI-MS m / z = 502.07, 504.07 [MH]⁻. Intermediary 5 (not according to the invention) To a mixture of intermediate compound 4 (2.00 g, 3.97 mmol), DIPEA (3.47 mL, 19.84 mmol), and DMSO (6.2 mL, 87 mmol) in DCM (12 mL), pyridine SO3 complex (1.895 g, 11.9 mmol) was added. The reaction was stirred at room temperature for 3 h. It was diluted with EtOAc and washed with 1 M HCl and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was chromatographed (silica, hexanes / acetone) to give the title compound (1.59 g, 3.18 mmol, 80% yield). ESI-MS m / z = 500.05, 502.05 [MH]-. Intermediary 6 (not according to the invention) The title compound was prepared using procedures similar to those described in Intermediate 1, ESI-MS m / z = 297, 99, 299, 99 [MH]-. Example 1 (not according to the invention) Step 1a. To a solution of Intermediate 3 (50 mg, 0.10 mmol) and (tert-butoxycarbonyl)-L-proline (26 mg, 0.12 mmol) in DMF (1.0 mL), DIPEA (0.051 mL, 0.30 mmol) and HATU (45 mg, 0.12 mmol) were added. The mixture was stirred for 2 hours at room temperature and purified by preparative HPLC (C-18, Acetonitrile / water) to obtain the desired compound as a white solid (20 mg, 29%). ESI-MS m / z = 698.19, 700.19 [MH]-. Step 1b To a solution of the compound from step 1a (16 mg, 0.023 mmol) in THF (0.4 mL) HCl (4M in dioxane, 0.4 mL, 1.6 mmol) was added. It was stirred for 3 hours at room temperature and concentrated to obtain the desired compound in the form of a white solid (14 mg, 99%). ESI-MS m / z = 598, 14, 600, 14 [MH]-. Step 1c. To a solution of the compound from step 1b (12 mg, 0.019 mmol), formaldehyde (0.1 mL 37% aqueous solution), and DIPEA (0.033 mL, 0.019 mmol), and a few drops of acetic acid in THF (0.5 mL), NaBH(OAc)3 (12 mg, 0.057 mmol) was added. The mixture was stirred for 2 hours at room temperature and then diluted with saturated aqueous NaHCO3. It was extracted with EtOAc, washed with water and brine, dried over anhydrous Na2SO4, filtered, concentrated, and the crude was purified by preparative HPLC (C-18, Acetonitrile / water) to obtain the title compound as a white solid (8.2 mg, 71%). ESI-MS m / z = 612, 12, 614, 12 [MH]-. Example 3 (not according to the invention) To a solution of intermediate 4 compound (30 mg, 0.06 mmol), sulfamoyl chloride (8.5 mg, 0.072 mmol) in THF (0.5 mL) at room temperature, TEA (4 drops) was added and the mixture was stirred at room temperature for 3 hours. It was concentrated and purified by preparative HPLC (C18 column, acetonitrile / water) as eluent to give the title compound (13.5 mg, 38%). ESI-MS m / z = 581.04, 583.04 [MH]-. Example 4 (not according to the invention) Step 4a. To the intermediate 2 solution (880 mg, 2.0 mmol) in THF (10 mL) at 0 °C, prop-1-en-1-yl magnesium chloride (0.5 M, 12 mL) was added, and the solution was stirred at this temperature for 30 minutes before inactivation with NH4Cl (20 mL). Extraction was performed using EtOAc, the organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated. The crude was chromatographed (silica, ethyl acetate / hexanes) to give the desired compound: the Z isomer (252 mg, 26% yield) as a white solid and the E isomer (596 mg, 61%) ESI-MS m / z = 502.09, 504.07 [MH]-. Step 4b. To the solution of the Z isomer from step 4a (252 mg, 0.523 mmol) and NMO (123 mg, 1.05 mmol) in acetone (5 mL) / water (1 mL), OsO4 (4% in t-BuOH, 0.066 mL, 0.01 mmol) was added, and the solution was stirred at room temperature. It was diluted with EtOAc, washed with Na2S2O3, NaHCO3, water, and brine, and concentrated. The crude was dissolved in THF (3 mL). m-CPBA (77 wt%, 234 mg, 1.1 mmol) was added, and the mixture was stirred at room temperature. After inactivation with aqueous Na2SO3 and aqueous NaHCO3, it was extracted with EtOAc before drying and concentrating. The crude was crystallized from hot MeOH to give the title compound (223 mg, 78%, racemic) as a white solid. ESI-MS m / z = 546.06, 548.06 [MH]-. Example 5 (not according to the invention) The title compound (racemic, white solid) is prepared from the E isomer of Step 4a following similar procedures described in Step 4b. ESI-MS m / z = 546.06, 548.06 [MH]-. Example 6 (not according to the invention) Step 6a. To a mixture of the compound from Intermediate Step 2b (1.400 g, 4.67 mmol) and Intermediate 6 (0.922 g, 5.14 mmol) in toluene (30 mL) at room temperature, triphenylphosphine (1.715 g, 6.54 mmol) was added, followed by DIAD (1.181 mL, 6.07 mmol) dropwise. The mixture was stirred at 95 °C overnight before being allowed to cool to room temperature and purified directly by column chromatography (silica, hexanes / EtOAc) to obtain the desired product in the form of a white crystal (1.760 g, 90%). ESI-MS m / z = 418.07, 420.06 [MH]-. Step 6b. To a clear solution of the compound from step 6a (1.760 g, 4.19 mmol) in THF (40 mL) and water (0.5 mL) at room temperature, NMO (2.455 g, 20.96 mmol) was added, followed by osmium tetroxide (4 wt. in water, 1.644 mL, 0.210 mmol) dropwise. The mixture was stirred at room temperature overnight. More osmium tetroxide (4 wt. in water, 1.644 mL, 0.210 mmol) was added. The yellow solution was stirred at room temperature overnight. Saturated Na₂S₂O₃ solution was added to deactivate the reaction. After 20 min at room temperature, the mixture was diluted with THF. The aqueous layer was re-extracted with THF (*1). The combined organic layers were washed with brine (*2), dried over Na2SO4 (s), filtered, and concentrated. The residual solid was recrystallized from boiling MeOH (40 mL) to obtain the desired product in the form of a white crystal (1,620 g, 80%). ESI-MS m / z = 484.04, 486.04 [MH]-. Step 6c. To a solution of the compound from step 6b (1.320 g, 2.72 mmol) and DIPEA (2.467 mL, 14.13 mmol) in DCM (8 mL) and DMSO (4.24 mL) cooled to 0 °C, pyridine sulfur trioxide complex (1.340 g, 8.42 mmol) was added. The resulting solution was stirred at 0 °C for 4 h. The mixture was diluted with EtOAc / THF and then washed with 0.1 N aqueous HCl (*2), water (*1), and brine (*1). The organic layer was dried over Na2SO4 (s), filtered, and concentrated. The solid was dissolved in DCM / THF (1 / 1) and purified by filtration through a short column (silica, hexanes / THF) to obtain the desired product in the form of a whitish foam (1, 420 g, quantitative yield). ESI-MS m / z = 482, 04, 484, 04 [MH]-. Step 6d. To a solution of the compound from step 6c (0.150 g, 0.310 mmol) in DMSO (3 mL) and 7 N ammonia in methanol (1.328 mL, 9.30 mmol) at room temperature, glyoxal (40% in water, 0.071 mL, 0.620 mmol) was added. The resulting solution was stirred overnight. The mixture was freed of volatile substances. The remaining solution was purified directly by HPLC (40–90% CH3CN in H2O) to obtain the title compound as a white solid (42.0 mg, 26%). ESI-MS m / z = 520.07, 522.07 [MH]-. Example 7 (not according to the invention) Step 7a. To a solution of the compound from step 6c (0.120 g, 0.248 mmol) in THF (4 mL) cooled to -78 °C, methylmagnesium bromide (3 M in Et₂O, 0.413 mL, 1.240 mmol) was added dropwise. The reaction mixture was stirred at -78 °C for 30 min. More methylmagnesium bromide (3 M in Et₂O, 0.413 mL, 1.240 mmol) was added. The reaction mixture was stirred at -78 °C for 2 h before being allowed to heat to room temperature and deactivated with saturated NH₄Cl solution. The mixture was diluted with THF and water. The organic layer was washed with brine (*2), dried over Na2SO4 (s), filtered, and concentrated. The residue was dissolved in DMSO (4 mL) and purified by HPLC (40–90% ACN in water) to obtain the title compound as a white solid (39.0 mg, 31%, racemic). ESI-MS m / z = 498.07, 500.07 [MH]-. Example 9 (not according to the invention) Step 9a. A solution of 2-(diethoxyphosphoryl)ethyl acetate (673 mg, 3.0 mmol) in THF (10 mL) was treated with NaH (60% w / w, 120 mg, 3.0 mmol) at room temperature for 30 minutes before adding intermediate 5 (502 mg, 1.0 mmol). The mixture was stirred at room temperature. It was diluted with EtOAc and washed with aqueous NH4Cl and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The residue was chromatographed (silica, hexanes / acetone) to give the desired compound (280 mg, 49%). ESI-MS m / z = 570.09, 572.09 [MH]-. Step 9b. To the solution from step 9a (80 mg, 0.14 mmol) in THF (1 mL) / EtOH (1 mL), NaBH4 (16 mg, 0.42 mmol) was added and stirred at room temperature for 2 hours before adding the second portion of NaBH4 (20 mg). It was stirred for another 3 hours before being deactivated with water and extracted with EtOAc. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude was purified by preparative HPLC (C18 column, acetonitrile / water) to give the title compound (13.5 mg, 38%). ESI-MS m / z = 530.08, 532.08 [MH]-. Example 10 (not according to the invention) Step 10a. To a solution of triethyl phosphonoacetate (0.520 mL, 2.60 mmol) in THF (5.0 mL) at 0 °C, NaH (0.104 g, 60%, 2.6 mmol) was added. The resulting reaction mixture was stirred at 0 °C for 30 mins. A solution of intermediate 2 (0.15 g, 0.34 mmol) was added to THF (2.0 mL) and stirred at room temperature for 2 h. The reaction was deactivated with aqueous NH4Cl, and the mixture was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed (silica, hexanes / EtOAc) to give the desired compound in the form of a white solid (0.50 g, 98%). ESI-MS m / z = 508.10, 510.10 [MH]-. Step 10b. To a solution of the compounds from step 10a (0.32 g, 0.627 mmol) in THF (5.0 mL) at -78 °C, DibAL-H (2.5 mL, 1.0 M solution in hexanes, 2.5 mmol) was added. The resulting reaction mixture was stirred at -78 °C for 1 h. The reaction was treated with aqueous sodium potassium tartrate solution for 3 h, and the mixture was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na₂SO₄), filtered, and concentrated. The crude product was chromatographed (silica, hexanes / EtOAc) to give the desired compound as a white solid (132 mg, 45%). ESI-MS m / z = 466.06, 468.07 [MH]-. Step 10c. To a mixture of the compound from step (43 mg, 0.092 mmol) and NMO (64 mg, 0.55 mmol) in acetone (3.0 mL) at room temperature, osmium tetroxide (0.58 mL 4% in water, 0.092 mmol) was added and the mixture was stirred at room temperature for 16 h. It was deactivated with aqueous Na2SO3, extracted with EtOAc, washed with water, 3N HCl, NaHCO3, brine, dried over Na2SO4, filtered, concentrated and purified by preparative HPLC (C18 column, acetonitrile / water) to give the title compound (18 mg, 37% racemic). ESI-MS m / z = 578.07, 580.07 [M+HCO2]-. Example 11 (not according to the invention) Step 11a. Vinylmagnesium chloride (1.6 M in 3.75 mL, 6.0 mmol) was added to a solution of intermediate 2 (880 mg, 2.0 mmol) in THF (10 mL). The mixture was stirred for 30 minutes before adding aqueous NH4Cl. It was extracted twice with EtOAc. The organic layer was washed with brine and dried (Na2SO4). After being concentrated to 10 mL, the mixture was filtered under vacuum to provide the desired product (616 mg, 66%). ESI-MS m / z = 466.08, 468.08 [MH]-. Step 11b. To the solution from step 11a (94 mg, 0.2 mmol) in THF (2 mL), m-CPBA (77 wt.%, 224 mg, 1.0 mmol) was added and stirred at room temperature. After deactivation with aqueous Na₂SO₃ and aqueous NaHCO₃, it was extracted with EtOAc, dried, and concentrated. The crude was chromatographed (silica, ethyl acetate / hexanes) to give the desired compound (75 mg, 73% yield) as a white solid. ESI-MS m / z = 514.08, 516.08 [MH]⁻. Step 11c. To the solution from step 11b (75 mg, 0.14 mmol) in DMF (1 mL), NaN3 (29 mg, 0.44 mmol) and NH4Cl (8 mg, 1.5 mmol) were added, and the mixture was stirred at 55 °C o / n. After cooling, it was diluted with EtOAc and filtered. After concentrating the solution, it was purified by preparative HPLC (C18 column, acetonitrile / water) as the eluent to give the title compound (13.5 mg, 38%, racemic) as a white solid. ESI-MS m / z = 557.04, 559.04 [MH]-. Example 14 (not according to the invention) To a solution of Intermediate 3 (50 mg, 0.10 mmol) and (S)-tetrahydrofuran-2-carboxylic acid (14.43 µl, 0.149 mmol) in DMF (1 mL), EDC (38 mg, 0.20 mmol) and DMAP (36 mg, 0.30 mmol) were added. The reaction was stirred at room temperature for 2 h. The reaction was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na₂SO₄), filtered, and concentrated. The crude product was chromatographed (silica, hexane / acetone) to give the title compound as a white solid (14 mg, 23%, single enantiomer). ESI-MS m / z = 599, 125, 601, 122 [MH]-. Example 18 (not according to the invention) To the solution of Intermediate 3 (75 mg, 0.15 mmol) and DIPEA (52.1 µl, 0.298 mmol) and cyclohex-3-en-1-carboxylic acid (18.8 mg, 0.15 mmol) in DMF (1 mL) at room temperature, HATU (68.0 mg, 0.18 mmol) was added and the mixture was stirred at room temperature for 4 days. It was purified by preparative HPLC (C-18, Acetonitrile / water) to obtain the title compound as a white solid (65 mg, 71%). ESI-MS m / z = 609.14, 611.14 [MH]-. Example 19 (not according to the invention) A mixture of the compound from example 18 (40 mg, 0.065 mmol) and NMO (23 mg, 0.196 mmol) in acetone / water (2.0 / 0.2 mL) at rt was treated with osmium tetroxide (0.042 mL 4% in water, 0.0065 mmol) at rt for 16 h. It was deactivated with aqueous Na2SO3 and extracted with EtOAc, washed with water, 3N HCl, NaHCO3, brine, dried over Na2SO4, filtered, concentrated and purified by preparative HPLC (C18 column, acetonitrile / water) to give the title compound (26 mg, 61%, single isomer, stereochemistry not determined). ESI-MS m / z = 643, 15, 645, 15[MH]-. Example 20 (not according to the invention) Step 20a. To a suspension of (methoxymethyl)triphenylphosphonium chloride (3.43 g, 10 mmol) in THF (16 mL) at 0 °C, t-BuOK (1.68 g, 15 mmol) was added. The resulting mixture was stirred at room temperature for 30 mins. A solution of intermediate 2 (2.2 g, 5.0 mmol) was added to THF (4.0 mL) and stirred at room temperature for 20 h. It was deactivated with aqueous NH4Cl and the mixture was extracted with EtOAc, washed with water, and then brine. The organic layer was dried over Na2SO4, filtered, and concentrated. The crude product was chromatographed (silica, hexanes / EtOAc) to give the desired compound in the form of a white solid (2.08 g, 89%). ESI-MS m / z = 466.13, 468.13 [MH]-. Step 20b. To a solution of the compound from step 20a (1.1 g, 2.35 mmol) in THF (10 mL) at room temperature, concentrated HCl (1.5 mL) was added and stirred at room temperature for 2 h. It was concentrated under vacuum to remove most of the THF, and the residue was extracted with EtOAc. The organic phase was washed with water, 10% K2CO3, brine, dried over Na2SO4, filtered, and concentrated to give the desired compound (0.95 g, 89%). ESI-MS m / z = 452.07, 454.07 [MH]-. Step 20c. To a solution of the compound from step 20b (0.27 g, 0.59 mmol) in THF (6.0 mL) at 0 °C, vinylmagnesium bromide (2.37 mL, 1 M in THF, 2.37 mmol) was added. The resulting reaction mixture was stirred at 0 °C for 1 h. The reaction was deactivated with aqueous NH4Cl, and the mixture was extracted with EtOAc and washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed (silica, hexanes / EtOAc) to give the desired compound as a mixture of diastereomers (50 mg, 17%). ESI-MS m / z = 480.08, 482.08 [MH]-. Step 20d. To a mixture of the compound from step 20c (50 mg, 0.104 mmol) and NMO (73 mg, 0.62 mmol) in acetone (3.0 mL) at room temperature, osmium tetroxide (0.66 mL 4% in water, 0.104 mmol) was added and the mixture was stirred at room temperature for 16 h. It was deactivated with aqueous Na2SO3, extracted with EtOAc, washed with water, 3N HCl, NaHCO3, brine, dried over Na2SO4, filtered and concentrated, and purified by preparative HPLC using a C18 column and acetonitrile / water as eluent to give the title compound as a mixture of diastereomers (21 mg, 37%). ESI-MS m / z = 546, 06, 548, 06[MH]-. Example 21 (not according to the invention) Step 21a. To a clear solution of 2-methylbut-3-yn-2-ol (0.115 g, 1.364 mmol) in THF (5 mL) at -78 °C, BuLi (2.6 M in hexanes, 1.091 mL, 2.73 mmol) was added dropwise. The resulting clear solution was stirred at -78 °C for 1 h. A solution of Intermediate 2 (0.150 g, 0.341 mmol) in THF (1 mL) at -78 °C was added. The mixture was stirred at -78 °C for 1 h before allowing heating to 1 / 3°C and stirring at 1 / 3°C for 30 min. Saturated NH4Cl solution was added to deactivate the reaction. The mixture was diluted with EtOAc and water. The organic layer was washed with brine (*2), dried over Na2SO4 (s), filtered, and concentrated. The residue was purified by column chromatography (silica, hexanes / EtOAc) to obtain the desired product as a yellow solid (0.152 g, 85%). ESI-MS m / z = 522.11, 524.11 [MH]-. Step 21b. Lindlar catalyst (114 mg, 0.053 mmol) was added to a solution of the compound from step 21a (140 mg, 0.267 mmol) in ethyl acetate (12 mL) at room temperature. The suspension was stirred at room temperature with a hydrogen flask overnight. LC-MS showed a conversion of approximately 20%. The mixture was filtered through a short bed of Celite. The filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes / acetone) to obtain the desired product as a white solid (23.5 mg, 17%). ESI-MS m / z = 524.11, 526.11 [MH]-. Step 21c. To a solution of the compound from step 21b (23.5 mg, 0.045 mmol) in THF (2.80 mL) and water (0.200 mL) at room temperature, NMO (26.2 mg, 0.223 mmol) was added, followed by osmium tetroxide (4% in water, 0.057 mL, 8.94 µmol). The solution was stirred at room temperature overnight before stirring at 55 °C for 2 nights. More osmium tetroxide (4% in water, 0.057 mL, 8.94 µmol) was added. The mixture was stirred at 55 °C overnight before being deactivated with saturated Na₂S₂O₃ solution and diluted with THF. The organic layer was washed with brine (*2), dried over Na2SO4 (s), filtered, and concentrated. The residue was dissolved in DMSO (2 mL) and purified by HPLC (40–90% ACN in water) to obtain the title compound as a white solid (3.5 mg, 14%). ESI-MS m / z = 556.12, 558.11 [MH]-. Example 22 (not according to the invention) The title compound (44 mg, 84%) was prepared following the procedure described in Example 14 for intermediate 3 and cyclopent-3-ene-1-carboxylic acid. ESI-MS m / z = 641.13, 643.13 (M+HCO2) -. Example 26 (not according to the invention) Step 26a. The desired compound was prepared from the compound of example 11 following a procedure similar to that described in intermediate step 3d, ESI-MS m / z = 531, 09, 533, 09 [MH]-. Step 26b. A solution of the compound from step 26a (50 mg, 0.091 mmol) and DMAP (60 mg, 0.49 mmol) in THF-water (1.0 / 0.1 mL) was treated with MsCl (38 mg, 0.33 mmol) for 1 h. It was concentrated under vacuum and purified by preparative HPLC (C18, acetonitrile / water) to give the title compound (13 mg, 23%). ESI-MS m / z = 609.07, 611.07 [MH]-. Example 27 (not according to the invention) Step 27a. The desired compound was prepared using a procedure similar to that described in Example 14 for intermediate 3 and (tert-butoxycarbonyl)-L-asparagine ESI-MS. m / z = 715, 18, 717, 18 [MH]-. Step 27b. The compound from step 27a was treated with HCl (4 M in dioxane) for two hours at room temperature. It was concentrated to give the title compound in the form of a white solid as an HCl salt. ESI-MS m / z = 615, 12, 617, 12 [MH-56]-. Example 28 (not according to the invention) Step 28a Pure Adonitol (1.0 g, 6.57 mmol) and pyridine hydrochloride (1.215 g, 10.52 mmol) were mixed and heated to 150C for 4h. The crude product was chromatographed (silica, EtOAc / MeOH) to give the desired compound as a colorless gum (882 mg, 100%). Step 28b. To a solution of the compound from step 28a and 2,2-dimethoxypropane (3.23 mL, 26.3 mmol) in acetone (26.303 mL), PTSA (250 mg, 1.315 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction was quelled with aqueous NaHCO3, and the mixture was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed (silica, dichloromethane / MeOH) to give the desired compound as a colorless oil (852 mg, 74%). Step 28c. To a solution of the compound from step 28b (327 mg, 1.88 mmol) in acetonitrile (2 mL) and water (2 mL), TEMPO (59 mg, 0.375 mmol) and iodobenzene diacetate (1.21 g, 3.75 mmol) were added. The reaction was stirred at room temperature for 1 h. The reaction was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude acid was used without further purification (454 mg, 50% purity, 64%). Step 28d. To a solution of Intermediate 3 (150 mg, 0.30 mmol) and the compound from step 28c (168 mg, 0.447 mmol, 50% purity) in DMF (3 mL), EDC (114 mg, 0.60 mmol) and DMAP (109 mg, 0.90 mmol) were added. The reaction was stirred at room temperature for 2 h. The reaction was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na₂SO₄), filtered, and concentrated. The crude product was chromatographically analyzed (silica, hexane / acetone) to give the title compound as a white solid (117 mg, 58%). ESI-MS m / z = 717, 153, 719, 151 [M+CO₂H]⁻. Example 29 (not according to the invention) To a solution of the compound from Example 28 (115 mg, 0.171 mmol) in THF (5 mL) and methanol (10 mL), HCl (4 mL, 2M aqueous, 8 mmol) was added. The reaction was heated to 60°C for 1 h. The reaction was extracted with EtOAc, washed with NaHCO3, water, and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed (silica, hexane / acetone) to give the title compound as a white solid (76 mg, 70%). ESI-MS m / z = 677, 119, 679, 117 [M+CO2H]-. Example 32 (not according to the invention) Step 32a. To the solution of Intermediate 2 (3.20 g, 7.27 mmol) and tert-butyl ((1-methoxyvinyl)-oxy)dimethylsilane (1.905 mL, 8.73 mmol) in THF (36 mL) at -78°C, diethyl etherate, BF3 (1.11 mL, 8.73 mmol), was added. Stir for 1 h at -78°C, then heat to room temperature for 1 h. The reaction was stopped with aqueous NaHCO3. The crude was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed (silica, hexane / EtOAc) to give the desired compound in the form of a white solid (2, 976 g, 80%). ESI-MS m / z = 511, 8, 513, 8 [MH]-. Step 32b. To a solution of the material from step 32a (2.976 g, 5.79 mmol) in NMP (29 mL), m-CPBA (3.89 g, 17.37 mmol, 77%) was added. The reaction was stirred at room temperature for 18 h. The reaction was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na₂SO₄), filtered, and concentrated. The residue was ground with methanol and filtered to give the title compound as a white solid (2.50 g, 4.58 mmol). ESI-MS m / z = 544,076,546,074 [MH]⁻. Example 33 (not according to the invention) To the solution of the compound of Example 32 (2.50 g, 4.58 mmol) in THF (27 mL) and methanol (18 mL), LiOH (9.16 mL, 18.32 mmol, 2M aqueous) was added. The mixture was stirred at room temperature for 6 h. The reaction was acidified to pH 3 with HCl (2M aqueous). The crude was extracted with EtOAc and washed with brine. The organic layer was dried (Na₂SO₄), filtered, and concentrated to give the title compound (2.40 g, 99%). ESI-MS m / z = 498,068,500,066 [MH]⁻. Example 34 (not according to the invention) Step 34a. To a solution of intermediate compound 2 (1.76 g, 4.0 mmol) and trimethylsulfoxonium iodide (1.76 g, 8.0 mmol) in DMSO (20 mL) at 0°C, t-BuOK (1.12 g, 10 mmol) was added. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction was deactivated with aqueous NH4Cl, and the mixture was extracted with EtOAc and washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed (silica, hexanes / EtOAc) to give the desired compound as a white solid (1.36 g, 75%). ESI-MS m / z = 452.07, 454.07 [MH]-. Step 34b. Potassium tert-butoxide (297 mg, 2.64 mmol) was added to a mixture of the compound from step 34a (0.12 g, 0.264 mmol) and cyclopent-3-en-1-ol (0.523 mL, 6.61 mmol) at room temperature and heated to 80°C for 1 h, then to 50°C for 16 h. The reaction was deactivated with aqueous NH4Cl, and the mixture was extracted with EtOAc and washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed (silica, hexanes / EtOAc) to give the desired compound (82 mg, 57%). ESI-MS m / z = 536.11, 538.11 [MH]-. Step 34c. To a mixture of the compound from step 34b (50 mg, 0.093 mmol) and NMO (65.3 mg, 0.558 mmol) in acetone (2.0 mL) at rt, osmium tetroxide (0.29 mL 4% in water, 0.046 mmol) was added and the mixture was stirred at rt for 2 days.Aqueous Na2SO3 was deactivated, extracted with EtOAc, washed with water, 3N HCl, NaHCO3, brine, dried over Na2SO4, filtered and concentrated, and purified by preparative HPLC using a C18 column and acetonitrile / water as eluent to give the title compound, whose structure was tentatively assigned (11 mg, 19%). ESI-MS m / z = 602, 12, 604, 12 [MH]-. Example 35 (not according to the invention) The title compound (12 mg, 21%) was isolated from example 34. ESI-MS m / z = 602, 12, 604, 12 [MH]-. Example 36 (not according to the invention) Step 36a. Crotyl alcohol (341 µl, 4.00 mmol) was added to a suspension of NaH (160 mg, 60%, 4.00 mmol) in DMF (5.0 mL) at 0 °C and stirred for 30 mins at room temperature. The compound from step 34a (182 mg, 0.40 mmol) was added and stirred at room temperature for 16 h. It was deactivated with aqueous NH4Cl, extracted with EtOAc, washed with water and brine, and dried over Na2SO4. It was filtered and concentrated, and chromatographed (silica, hexanes / EtOAc) to give the desired product (195 mg, 93%). ESI-MS m / z 524, 11, 526, 11 [MH]-. Step 36b. To a mixture of the compound from step 36a (190 mg, 0.36 mmol) and NMO (254 mg, 2.17 mmol) in acetone (2.5 mL) at room temperature, osmium tetroxide (1.15 mL 4% in water, 0.181 mmol) was added, and the mixture was stirred at room temperature for 2 days. It was deactivated with aqueous Na2SO3, extracted with EtOAc, washed with water, 3N HCl, NaHCO3, and almuria, dried over Na2SO4, filtered and concentrated, and purified by preparative HPLC using a C18 column and acetonitrile / water as the eluent to give the title compound whose structure was tentatively assigned (36 mg, 17%). ESI-MS m / z = 590, 11, 592, 11 [MH]-. Example 37 (not according to the invention) Step 37a. To a solution of the compound from Intermediate Step 2 g (1.9 g, 4.30 mmol) in NMP (12 mL), m-CPBA (2.89 g, 12.90 mmol) was added at room temperature. The mixture was stirred at room temperature overnight. It was deactivated with aqueous Na₂S₂O₃ and NaHCO₃ with a few drops of triethylamine. The mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated. The residual solid was recrystallized from MeOH to obtain the desired product as a white solid (1.8 g, 88%). ESI-MS m / z = 472.06, 474.06 [MH]⁻. Step 37b. To a solution of the compound from step 37a (1.8 g, 3.8 mmol) in DMSO (10 mL) at room temperature, IBX (4.3 g, 15.3 mmol) was added. The mixture was stirred at 45 °C for 20 h. Aqueous solutions of Na₂S₂O₃ and NaHCO₃ with a few drops of Et₃N were added. The mixture was stirred at room temperature for 1 h. It was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated to give the desired compound (1.65 g, 92%). ESI-MS m / z = 470.04, 472.04 [MH]⁻. Step 37c. To a solution of the compound from step 37b (104 mg, 0.220 mmol) in THF (2 mL) at 5–10 °C, methylmagnesium bromide (3 M in ether, 367 µL, 1.102 mmol) was added dropwise. More THF (2.5 mL) was added, and the mixture was stirred at room temperature for 1 h. It was diluted with EtOAc, washed with water, aqueous Na₂SO₃, and brine. The organic layer was dried (Na₂SO₄), filtered, and concentrated. The crude product was purified by preparative TLC (silica, hexanes / EtOAc) to give the desired compound (85 mg, 79%). ESI-MS m / z = 486.08, 488.08 [MH]⁻. Step 37d. To a clear solution of the compound from step 37c (30.0 mg, 0.061 mmol) in THF / MeOH (1 / 1, 2.0 mL) at room temperature, 10% Pd / C (6.5 mg, 6.15 µmol) was added in one portion. The suspension was purged with H2 three times and then stirred at room temperature with an H2 flask overnight. The suspension was then stirred at room temperature under H2 (60 psi (414 kPa)) for 4 h. More 10% Pd / C (13.0 mg, 12.3 µmol) was added.The suspension was purged with H2 three times and then stirred at room temperature under H2 (~15 psi (103 kPa)) over the weekend. The mixture was filtered through a short bed of Celite. The filtrate was freed of volatile substances. The solid residue was ground with DCM to obtain the title compound as a white solid (20.0 mg, 72%). ESI-MS m / z = 452.11, 453.11 [MH]-. Example 38 (not according to the invention) Step 38a. A solution of the compound from Intermediate Step 3a (214 mg, 0.47 mmol) in THF / water (3.0 / 1.0 mL) was treated with TFA (0.40 mL) for 6 h. It was concentrated under vacuum to remove most of the THF. The residue was extracted with EtOAc. The organic phase was washed with water, 10% K2CO3, brine, dried over Na2SO4, filtered, and concentrated to give the desired compound (0.20 g, 90%). ESI-MS m / z = 470.08, 472.08 [MH]-. Step 38b. To a solution of the compound from step 38a (0.340 g, 0.720 mmol) in DMSO (6 mL) at room temperature, IBX (0.303 g, 1.081 mmol) was added. The resulting milky mixture was stirred at room temperature for 2 h. The mixture was diluted with EtOAc and water. The organic layer was washed with brine (*2), dried over Na2SO4 (s), filtered, and concentrated. The residue was dried under vacuum to obtain the desired product in the form of a white solid (0.324 g, 96%). ESI-MS m / z = 468.05, 470.05 [MH]-. Step 38c. To a suspension of the compound from step 38b (0.324 g, 0.690 mmol) in t-BuOH (6.0 mL) and water (2.0 mL) at room temperature, monobasic potassium phosphate (0.657 g, 4.83 mmol) was added, followed by 2-methyl-2-butene (1.826 mL, 17.24 mmol). Sodium chlorite (80%, 0.702 g, 6.21 mmol) was added to the suspension in one portion. The resulting clear solution was stirred at room temperature for 1 h. It was diluted with MTBE and 1.0 M NaOH (8 mL). The organic layer was diluted with EtOAc, washed with 0.5 M aqueous HCl (*1), and then with brine (*1). The organic phases were dried over Na2SO4 (s), filtered, and concentrated. The residue was dried under vacuum to obtain the desired product in the form of a white solid (0.306 g, 91%). ESI-MS m / z = 484.05, 486.05 [MH]-. Step 38d.To a suspension of the compound from step 38c (50.0 mg, 0.103 mmol), but-2-en-1-amine hydrochloride (12.18 mg, 0.113 mmol), and DIPEA (0.054 mL, 0.309 mmol) in acetonitrile (3 mL), HATU (47.0 mg, 0.123 mmol) was added in one portion. The resulting slightly milky solution was stirred overnight. More DIPEA (0.054 mL, 0.309 mmol) and HATU (47.0 mg, 0.123 mmol) were added. The resulting solution was stirred for 4 h and then at 55 °C for 2 h. The mixture was freed of volatile substances. The residue was purified by column chromatography (silica, hexanes / EtOAc) to obtain the desired product in the form of a white solid (7.0 mg, 12%). ESI-MS m / z = 583.11, 585.11 [MH]-Step 38e. To a clear solution of compound 38d (7.0 mg, 0.013 mmol) in THF (2.0 mL) and water (0.14 mL) NMO (7.61 mg, 0.065 mmol) was added, followed by osmium tetroxide (0.083 mL, 0.013 mmol). The solution was stirred at 50 °C overnight.The mixture was deactivated with saturated Na₂S₂O₃ solution and diluted with THF. The organic layer was washed with brine (*2), dried over Na₂SO₄ (s), filtered, and concentrated. The residue was dissolved in DMSO (1 mL) and purified by HPLC (40–90% ACN in water) to obtain the title compound as a white solid (3.0 mg, 38%, racemic mixture of diastereomers). ESI-MS m / z = 649.13, 651.13 [M+HCO₂]⁻. Example 42 (not according to the invention) Step 42a. To a solution of the compound from step 82a (173 mg, 0.37 mmol) in CH2Cl2 (3.7 mL) a rt, (Z)-but-2-en-1,4-diyl diacetate (234 µl, 1.479 mmol) and Grubbs-Hoveyda Second Generation catalyst (23.1 mg, 0.037 mmol) were added, then the mixture was degassed and maintained under reflux for 24 h. The mixture was concentrated and the residue was chromatographed (silica, hexanes / EtOAc) to give the desired compound in the form of a white solid (160 mg, 80%). ESI-MS m / z = 584.10, 586.10 (M+HCO2)-. Step 42b. Potassium carbonate (10.5 mg, 0.076 mmol) was added to a solution of the compound from step 42a (20.5 mg, 0.038 mmol) in MeOH (1.3 mL) at room temperature, and the mixture was then maintained at room temperature for 1 h. The reaction mixture was diluted with water and extracted with CH2Cl2. The organic phases were dried over concentrated Na2SO4 to give the desired product (19 mg) without further purification. ESI-MS m / z = 542.10, 544.10 (M+HCO2) -. Step 42c. To a solution of the compound from step 42b (18.9 mg, 0.038 mmol) in Acetone / H2O (0.8 mL, 4:1), NMO (26.7 mg, 0.228 mmol) and Osmium Tetroxide (298 µl, 0.038 mmol) were added. The mixture was maintained at 50°C for 2 days. It was deactivated with aqueous Na2S2O3, extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated and purified by preparative HPLC using a C18 column and acetonitrile / water as the eluent to give the title compound (3.9 mg, 18%). ESI-MS m / z = 608, 10, 610, 10 (M+HCO2) -. Example 51 (not according to the invention) Step 51a. To a clear solution of 1-methoxy-4-((prop-2-yn-1-yloxy)methyl)benzene (801 mg, 4.55 mmol) in THF (15 mL) at -78 °C, BuLi (2.6 M in hexanes, 1.819 mL, 4.55 mmol) was added dropwise. The resulting clear solution was stirred at -78 °C for 0.5 h. A solution of Intermediate 2 (500 mg, 1.137 mmol) in THF (3 mL) at -78 °C was added dropwise. The mixture was stirred at -78 °C for 1 h before deactivation with saturated NH4Cl solution. Heating was allowed to rt and the mixture was diluted with EtOAc and water. The organic layer was washed with brine (*1), dried over Na2SO4 (s), filtered, and concentrated. The residue was purified by column chromatography (silica, hexanes / EtOAc) to obtain the desired product in the form of a white solid (0.440 g, 63%). ESI-MS m / z = 614.14, 616.14 [MH]-. Step 51b. Lindlar catalyst (0.097 g, 0.045 mmol) was added to a solution of the compound from step 51a (0.140 g, 0.227 mmol) in ethyl acetate (10 mL) at room temperature. The suspension was stirred at room temperature with a hydrogen peroxide flask for 2 h. The mixture was filtered through a short bed of Celite. The filtrate was concentrated. The residue was purified by column chromatography (silica, hexanes / EtOAc) to obtain the desired product as a white solid (96.0 mg, 68%). ESI-MS m / z = 616.15, 618.15 [MH]-. Step 51c. To a clear solution of the compound from step 51c (46.0 mg, 0.074 mmol) in DCM (2 mL) at room temperature, pH 7 buffer (0.4 mL) was added, followed by DDQ (33.8 mg, 0.149 mmol). The biphasic mixture was stirred at room temperature for 3 h. It was deactivated with saturated NaHCO3 solution and diluted with DCM. The organic layer was dried over Na2SO4 (s), filtered, and concentrated. The residue was purified by chromatography (silica, hexanes / EtOAc) to obtain the desired product as a white solid (20.2 mg, 54%). ESI-MS m / z = 496.09, 498.09 [MH]-. Step 51d. To a clear solution of the compound from step 51c (45.6 mg, 0.092 mmol) in THF (5.60 mL) and water (0.56 mL) at room temperature, NMO (53.6 mg, 0.458 mmol) was added, followed by osmium tetroxide in tert-butanol (2.5%, 0.186 mL, 0.018 mmol). The solution was stirred at room temperature for 4 h and then at 50 °C for 2 h overnight. The mixture was deactivated with saturated Na₂S₂O₃ solution and diluted with THF. The organic layer was washed with brine (*2), dried over Na₂SO₄ (s), filtered, and concentrated. The residue was dissolved in DMSO (2 mL) and purified by HPLC (30~90% ACN in water) to obtain the title compound in the form of a white solid (15.0 mg, 29%). ESI-MS m / z = 608.09, 610.08 [M+HCO2]-. Example 52 (not according to the invention) A solution of the compound from Example 33 (50 mg, 0.094 mmol), 3-methylbut-2-en-1-amide hydrochloride (12.6 mg, 0.103 mmol), and DIPEA (0.5 mL, 0.282 mmol) in DMF (0.9 mL) was mixed with a solution of HATU (54 mg, 0.141 mmol) in DMF (0.5 mL). The mixture was shaken for 2 hours. The crude reaction mixture was chromatographed (silica, hexane / acetone) to give the title compound as a white solid (40 mg, 71%). ESI-MS m / z = 596.8, 598.8 [MH]-. Example 56 (not according to the invention) To a solution of Example 52 (40 mg, 0.067 mmol) in acetone (5 mL) were added OsO4 (0.085 mL, 4% w / w in water, 0.013 mmol) and NMO (19.6 mg, 0.167 mmol). It was stirred for 48 h and then evaporated over silica. The residue was chromatographed (silica, hexane / acetone) to give the title compound as a white solid (18 mg, 43%). ESI-MS m / z = 630.8, 632.8 [MH]-. Example 61 (not according to the invention) Step 61a. To a mixture of the compound from Example 34 (0.030 g, 0.050 mmol) and sodium bicarbonate (8.4 mg, 0.10 mmol) in THF-water (1.5 / 0.5 mL), sodium peroxide (0.032 g, 0.150 mmol) was added and stirred for 16 h. It was extracted with EtOAC, washed with water, brine, dried over Na2SO4, filtered and concentrated and used in the next step without further purification. ESI-MS m / z = 600, 10, 602, 10 [MH]-. Step 61b. To a solution of the compound from step 61a (30 mg, 0.050 mmol) in THF-MeOH (1.5 / 0.5 mL), NaBH4 (7.57 mg, 0.20 mmol) was added at 0 °C, then stirred at 0 °C for 30 mins. It was deactivated with aqueous NH4Cl, extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, concentrated, and purified by preparative HPLC using a C18 column and acetonitrile / water as the eluent to give the title compound (7.6 mg, 25%). ESI-MS m / z = 604.13, 606.13 [MH]-. Example 64 (not according to the invention) Step 64a. Vinylmagnesium chloride in THF (1.6 M, 1.25 mL, 2.0 mmol) was added to a solution of intermediate 5 (250 mg, 0.50 mmol) in THF (5 mL) in an ice-water bath and stirred at room temperature for 1 h before deactivation with aqueous NH4Cl. It was extracted with EtOAc and washed with brine. After drying (Na2SO4), it was concentrated to give the desired crude compound, which was used in the next step without further purification. ESI-MS m / z = 528.07, 530.07 [MH]-. Step 64b. To a solution of the crude compound from step 64a (maximum 0.3 mmol) in acetone (5 mL) and water (1 mL), NMO (67 mg, 0.57 mmol) was added, and OsO4 (4% in water, 0.12 mL, 0.02 mmol) was added and stirred at room temperature for 2 days. After deactivation with aqueous Na2S2O3, it was extracted with EtOAc before drying and concentrating. The crude was chromatographed (silica, acetone / hexanes) to give the title compound as a mixture of two pairs of racemic products (122 mg, 57%, white solid). ESI-MS m / z = 562.08, 564.08 [MH]-. Example 70 (not according to the invention) Step 70a. HATU (135 mg, 0.355 mmol) was added to a solution of Intermediate 3 (119 mg, 0.237 mmol), Boc-(L)-alanine (49 mg, 0.260 mmol), and DIPEA (0.124 mL, 0.71 mmol) in DMF (2.4 mL). The reaction was stirred at room temperature for 3 h. The reaction was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na₂SO₄), filtered, and concentrated. The crude product was chromatographed (silica, hexane / acetone) to give the desired product as a white solid (54 mg, 34%). Step 70b. To a solution of the compound from step 70a (54 mg, 0.08 mmol) in THF (2 mL) HCl (2 mL, 8 mmol, 4M in dioxane) was added. The reaction was stirred for 2 h then evaporated to give the crude product used without further purification. Step 70c. Isopropyl chloroformate (0.048 mL, 0.048 mmol, 1M toluene) was added to a solution of the compound from step 70b (23 mg, 0.04 mmol) and DIPEA (0.017 mL, 0.1 mmol) in DMF. The mixture was stirred for 15 minutes at room temperature. The crude reaction mixture was chromatographically analyzed (preparative HPLC, acetonitrile / water) to give the title compound as a white solid (3.8 mg, 14%). ESI-MS m / z = 660, 0, 662, 0 [M+H]+. Example 74 (not according to the invention) To a solution of the compound from Example 8 (62 mg, 0.092 mmol) in DMSO (0.6 mL) at room temperature, IBX (38.6 mg, 0.138 mmol) was added and the mixture was stirred at 45 °C for 16 h. It was deactivated with MeOH and purified by reparative HPLC using a C18 column and acetonitrile / water as the eluent to give the title compound (11 mg, 18%). ESI-MS m / z = 670, 13, 672, 13 [MH]-. Example 76 (not according to the invention) Step 76. To a solution of Intermediate 3 (95.0 mg, 0.189 mmol) and (2S,3R)-1-(tert-butoxycarbonyl)-3-hydroxypyrrolidine-2-carboxylic acid (43.0 mg, 0.189 mmol) in DMF (3 mL) at room temperature, DIPEA (0.099 mL, 0.567 mmol) was added, followed by HATU (108 mg, 0.283 mmol). The resulting clear solution was stirred at room temperature for 1 h. The mixture was freed of volatile substances. The residue was dissolved in DCM with THF and purified by column chromatography (silica, DCM / MeOH) to obtain the title compound in the form of a colorless sticky oil (128 mg, 95%). ESI-MS m / z = 760, 20, 762, 20 [M+HCO2]-. Example 78 Step 78a. To a solution of the compound from Example 76 (0.064 g, 0.090 mmol) in THF (2 mL) at room temperature, HCl (4 M in 1,4-dioxane, 0.900 mL, 3.60 mmol) was added. The resulting clear solution was stirred at room temperature for 3 h. It transformed into a suspension. The mixture was concentrated. The residual solid was used directly for the next step. ESI-MS m / z = 660.15, 662.15 [M+HCO2]-. Step 78b. To a solution of the compound from step 78a (0.090 mmol) in DMF (2.0 mL) at room temperature, DIPEA (0.157 mL, 0.900 mmol) was added, followed by a solution of methyl chloroformate (6.97 µl, 0.090 mmol) in DMF (0.1 mL). The resulting yellow solution was stirred at room temperature for 1 h before being cleared of volatile substances. The residue was dissolved in DMSO (2 mL) and purified by HPLC (40–90% ACN in water) to obtain the title compound as a white solid (20.0 mg, 33% in 2 steps). ESI-MS m / z = 718.16, 720.16 [M+HCO2]-. Example 82 (not according to the invention) Step 82a. Vinylmagnesium chloride in THF (1.6 M, 0.94 mL, 1.5 mmol) was added to a solution of the compound from step 150d (210 mg, 0.50 mmol) in THF (5 mL) in an ice-water bath. The mixture was stirred at room temperature for 1 h before deactivation with aqueous NH4Cl. It was extracted with EtOAc and washed with brine. After drying (Na2SO4), it was concentrated, and the residue was chromatographed (silica, EtOAc / hexanes) to give the desired compound (201 mg, 94%) as a white solid. ESI-MS m / z = 448.08, 450.08 [MH]-. Step 82b. To a solution of the compound from 82a (152 mg, 0.34 mmol) in acetone (1 mL) and water (0.2 mL), NMO (79 mg, 0.68 mmol) was added, and OsO4 (2.5% in t-BuOH, 0.12 mL, 0.007 mmol) was added. It was stirred at room temperature before deactivating with aqueous Na2S2O3. It was extracted with EtOAc, dried, and concentrated. The crude was crystallized from MeOH to give the title compound (141 mg, 84%, racemic) as a white solid. ESI-MS m / z = 514.08, 516.08 [MH]-. Example 106 (not according to the invention) The title compound (single enantiomer) was isolated from the preparation of the compound in example 13. ESI-MS m / z = 645, 11, 647, 11 [MH]-. Example 108 (not according to the invention) The title compound (single enantiomer, tentatively assigned) was isolated from the compound in example 4 via SFC chromatography. Example 109 (not according to the invention) The title compound (single enantiomer, tentatively assigned) was isolated from the compound in example 5 via SFC chromatography. Example 120 (not according to the invention) To a solution of the compound from Example 119 (50 mg, 0.083 mmol) in THF (1 mL) and water (0.67 mL), LiOH (0.33 mL, 0.67 mmol, 2 M aqueous) was added to 1 M. The reaction was stirred for 1 h, then acidified to pH 3 with 2 M HCl. The reaction was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na₂SO₄), filtered, and concentrated to give the title compound as a white solid (40 mg, 82%). ESI-MS m / z = 586.8, 588.8 [MH]⁻. Example 121 (not according to the invention) Step 121a. To a solution of the compound from step 34a (170 mg, 0.375 mmol) and 1,3-dimethoxypropan-2-ol (900 mg, 7.49 mmol) in THF (2 mL), potassium 2-methylpropan-2-olate (630 mg, 5.62 mmol) was added to 1 / 4 mL. The mixture was then stirred at 60 °C for 20 h. It was cooled to 1 / 4 mL, deactivated with aqueous NH4Cl, extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, concentrated, and chromatographed (silica, hexanes / EtOAc) to give the desired product (98 mg, 45%). ESI-MS m / z 572, 15, 574, 15 [MH]-. Step 121b. To a solution of the compound from step 121a (95 mg, 0.165 mmol) in MPN (1.5 mL), mCPBA (0.167 g, 77%, 0.745 mmol) was added and stirred at room temperature for 20 h. Aqueous Na₂S₂O₃, NaHCO₃, and a few drops of Et₃N were added and stirred at room temperature for 1 h. The solution was extracted with EtOAc, washed with water and brine, dried over Na₂SO₄, filtered, concentrated, and purified by preparative HPLC using a C18 column and acetonitrile / water as the eluent to give the title compound (44 mg, 44%). ESI-MS m / z = 604, 14, 606, 14 [MH]⁻. Example 124 (not according to the invention) Step 124a. To a suspension of methyltriphenylphosphonium bromide (0.24 g, 0.67 mmol) in THF (1.0 mL) at 0 °C, t-BuOK (0.11 g, 1.0 mmol) was added. The resulting reaction mixture was stirred at room temperature for 30 mins. A solution of the intermediate compound 2 (0.15 g, 0.34 mmol) was added to THF (1.0 mL) and stirred at room temperature for 24 h. The reaction was deactivated with aqueous NH4Cl, and the mixture was extracted with EtOAc, washed with water, and then brine. The organic layer was dried with Na2SO4, filtered, and concentrated. The crude product was chromatographed (silica, hexanes / EtOAc) to give the desired compound in the form of a white solid (1.36 g, 75%). ESI-MS m / z = 436.08, 438.07 [MH]-. Step 124b. To a suspension of the compound from step 124a (0.35 g, 0.80 mmol) and NMO (0.375 g, 3.2 mmol) in acetone-water (6 mL / 1 mL) at room temperature, osmium tetroxide (1.0 mL, 0.080 mmol) was added and the mixture was stirred at room temperature for 18 h. It was deactivated with aqueous Na2SO3, extracted with EtOAc, washed with water, 3N HCl, NaHCO3, brine, dried over Na2SO4, filtered and concentrated to give a mixture of sulfone and sulfoxide. Step 124c. To a solution of the compound from step 124b (156 mg, 0.32 mmol) in DMF (1.5 mL) at 0 °C, NaH (45 mg, 60%, 1.12 mmol) and MeI (45 mg, 0.32 mmol) were added. After 1.5 h at 0 °C, the reaction was deactivated with aqueous NH4Cl solution, extracted with EtOAc, and the organic layer was washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated, then purified by preparative HPLC (C-18, Acetonitrile / water) to obtain the title compound as a white solid (61 mg, 38%). ESI-MS m / z = 500.09, 502.09 [MH]-. Step 124d. To a solution of the compound from step 124c (61 mg, 0.122 mmol) in MPN (1.5 mL), mCPBA (0.11 g, 77%, 0.49 mmol) was added and stirred at room temperature for 20 h. Na₂S₂O₃, aqueous NaHCO₃, and a few drops of Et₃N were added and stirred at room temperature for 1 h. The mixture was extracted with EtOAc, washed with water and brine, dried over Na₂SO₄, filtered, and concentrated to give the title compound (63 mg, 100%). ESI-MS m / z = 516.08, 518.08 [MH]⁻. Example 125 (not according to the invention) Step 125a. To a solution of the compound from intermediate step 3a (91 mg, 0.2 mmol) in DMF (1 mL), (S)-1-aminopropan-2-ol (45 mg, 0.6 mmol) was added and stirred at 90 °C for 20 hours before cooling. It was concentrated to give the desired crude compound, which was used in the next step without further purification. ESI-MS m / z = 527.12, 529.12 [MH]-. Step 125b. To a solution containing half the compound from step 125a (~0.1 mmol) in CH2Cl2 (1 mL), TEA (3 drops) and acetic anhydride (20 mg) were added. The solution was shaken for 2 hours before concentration. NMP (1 mL) was added, followed by m-CPBA (13.5 mg, 6 mmol), and the solution was shaken at room temperature for 20 hours. The crude was purified by preparative HPLC (C18, acetonitrile / water) to give the title compound (18 mg, 30%, three steps). ESI-MS m / z = 601, 13, 603, 13 [MH]-. Example 130 (not according to the invention) Step 130a. To a solution of (R)-propane-1,2-diol (168 mg, 2.20 mmol) in DMF (3 mL) NaH (88 mg, 60%, 2.20 mmol) at 0°C was added and stirred at room temperature for 30 mins. The compound from step 34a (100 mg, 0.220 mmol) was added and heated to 55°C for 20 h. It was cooled to room temperature, deactivated with aqueous NH4Cl, extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated, and chromatographed (silica, hexanes / EtOAc) to give the desired product (65 mg, 56%). ESI-MS m / z 528, 12, 530, 12 [MH]-. Step 130b. To a solution of the compound from step 130a (80 mg, 0.15 mmol) in MPN (1.5 mL), mCPBA (0.169 g, 77%, 0.75 mmol) was added and stirred at room temperature for 20 h. Aqueous Na₂S₂O₃, NaHCO₃, and a few drops of Et₃N were added, and the mixture was stirred at room temperature for 1 h. The solution was extracted with EtOAc, washed with water and brine, dried over Na₂SO₄, filtered, concentrated, and purified by preparative HPLC using a C18 column and acetonitrile / water as the eluent to give the title compound (65 mg, 77%, single enantiomer). ESI-MS m / z = 560, 11, 562, 11 [MH]⁻. Example 136 (not according to the invention) The title compound (single enantiomer, tentatively assigned) was isolated from the compound of example 4 by SFC chromatography. ESI-MS m / z = 546, 10 [M+H]+. Example 137 (not according to the invention) The title compound (single enantiomer, tentatively assigned) was isolated from the compound of example 5 by SFC chromatography. ESI-MS m / z = 546.05[M+H]+. Example 141 (not according to the invention) Step 141a. A solution of Intermediate 1 (1.23 g, 3.88 mmol), tert-butyl ester of 3-exo-Hydroxy-8-azabicyclo[3.2.1]octan-8-carboxylic acid (801 mg, 3.52 mmol) in 50 mL toluene was mixed with 2-(tributyl-15-phosphanylidene)acetonitrile (2.13 g, 8.81 mmol), then stirred at 85 °C O / N. It was diluted with methyl tert-butyl ether, washed with aqueous solution of 0.5 N NaOH, water, brine, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed (silica, hexanes / EtOAc) to give the desired compound in the form of a white solid (1.63 g, 86%). ESI-MS m / z = 525.12, 527.12 (MH) -. Step 141b. To the solution of the compound from step 141a (1.31 g, 2.48 mmol) in N-Methyl-2-pyrrolidinone (8.29 mL) at room temperature, mCPBA (1.95 g, 8.70 mmol) was added, and the mixture was then incubated overnight. The reaction was deactivated with aqueous Na₂S₂O₃. The mixture was extracted with EtOAc, and the combined organic phases were dried over Na₂SO₄, filtered, and concentrated. The residue was chromatographed (silica, hexanes / EtOAc) to give the desired compound as a white solid (1.28 g, 92%). ESI-MS m / z = 557.11, 559.11 (MH). Step 141c. To a solution of the compound from step 141b (131 mg, 0.234 mmol) 2N HCl in dioxane was added at room temperature, then the mixture was maintained at room temperature for 4 h. The solution was concentrated to give a white solid (106 mg, 99%). ESI-MS m / z = 457.06, 459.06 (MH) -. Step 141d. To a solution of the compound from step 141c (45 mg, 0.091 mmol) in DMF (1.8 mL) at room temperature, iPr2EtN (63.5 µl, 0.363 mmol), (methoxycarbonyl)-L-alanine (13.4 mg, 0.091 mmol), and HATU (51.8 mg, 0.136 mmol) were added. The mixture was kept at room temperature overnight. The mixture was partitioned between EtOAc and water. The organic phase was washed with aqueous NaHCO3, water, and brine, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed (silica, CH2Cl2 / MeOH) to give the title compound as a white solid (37 mg, 69%, single enantiomer). ESI-MS m / z = 586.10, 588.10 (MH) -. Example 144 (not according to the invention) To a solution of the compound from step 141c (49 mg, 0.099 mmol) in MeOH (0.99 mL) at room temperature, (R)-2,2-dimethyl-1,3-dioxolan-4-carbaldehyde (19.31 mg, 0.148 mmol) and NaCNBH4 (12.4 mg, 0.198 mmol) were added, and the mixture was then kept at room temperature overnight. The reaction was deactivated with aqueous NH4Cl solution at room temperature. The reaction mixture was partitioned between EtOAc and water, then the organic phase was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed (silica, CH2Cl2 / MeOH) to give the title compound as a white solid (45 mg, 79%, single enantiomer). ESI-MS m / z = 571, 12, 573, 12 (MH) -. Example 150 (not according to the invention) Step 150a. To a solution of the compound from intermediate step 2e (246 g, 959 mmol) and pyridine (155 mL, 1.92 mol) in DCM (1 L) at 0°C, 3-nitrobenzenesulfonyl chloride (217 g, 978 mmol) was added. The reaction mixture was stirred at 0°C for 30 mins and stirred at room temperature for 2 days. It was deactivated with water (100 mL) and stirred at room temperature for 1 r followed by extraction with MBTE (4 L). The organic layer was washed with water (2 x 1 L), 1 N HCl (1 L), water (500 mL), saturated NaHCO3 solution (500 mL), and brine (500 mL), dried over Na2SO4, filtered through Celite and concentrated to approximately 500 mL, then hexanes (500 mL) were added. The mixture was concentrated under vacuum to induce precipitation, cooled to room temperature and filtered, washed with cold hexanes to give the desired product (321 g, 76%). Step 150b. Cesium carbonate (96 g, 295 mmol) was added to a solution of the compound from step 150a (108.6 g, 246 mmol) and Intermediate 4 (70 g, 234 mmol) in DMF (250 mL). The reaction mixture was degassed and slowly heated to 70 °C, stirred at 70 °C for 14 h. It was cooled to room temperature, diluted with MBTE, washed with water and brine, dried over Na2SO4, filtered, and concentrated to give the desired product (123 g, 98%), which was used without further purification. Step 150c. To a suspension of the compound from step 150b (50 g, 93 mmol) in MeOH (1.6 L) in a cold water bath, concentrated HCl (200 mL) was added slowly to maintain the temperature below 30°C, and the mixture was stirred overnight. The reaction mixture was concentrated under vacuum to a volume of approximately 700 mL, cooled to 0°C, and then filtered to collect the solid, which was washed with cold MeOH. The mother liquor was then concentrated to 300 mL, cooled to 0°C, and filtered to collect the solid. The solid was air-dried for 14 h to give the desired product (36 g, 91%). Step 150d. To a solution of the compound from step 150c (36 g, 85 mmol) in DMSO (150 mL), IBX (30.9 g, 110 mmol) was added, and the mixture was stirred at 50°C for 2 h. The mixture was poured over 1.2 L of cold water and extracted with EtOAc (2 x 500 mL). A white solid was removed by filtration. The EtOAc extracts were washed with saturated NaHCO3 solution in brine and dried over Na2SO4. Filtration and concentration were carried out to approximately 150 mL, then cooled to 0°C to yield the desired solid, which was collected by filtration. The mother liquors were concentrated to 50 mL to give the second harvest of the desired product (34.1 g, 95%). Step 150e. Potassium tert-butoxide (18.51 g, 165 mmol, 1.6 eq) was added to a suspension of trimethylsulfoxonium iodide (36.3 g, 165 mmol) in DMF (180 mL) at 0°C and then stirred at room temperature for 30 mins. A solution of the compound from step 150d (43.5 g, 103 mmol) in DMF (120 mL) was added to the reaction mixture through a cannula (temperature below 10°C) and stirred at room temperature for 16 h. The reaction mixture was poured into cold saturated solution of NH4Cl (500 mL) and MBTE (1.2 L). The organic layer was washed with water (3 x 500 mL) and saturated NaCl solution (2 x 300 mL). The organic layer was dried with Na2SO4, filtered through a silica plug, washed with MBTE, and concentrated to obtain the desired crude product, which was used without further purification. Step 150f. To a solution of the raw material from step 150e in THF / water (220 / 70 mL) in an ice / water bath, TFA (30.8 mL, 400 mmol) was added, then stirred at room temperature for 6.5 hours, cooled to 0C, and 20 mL of saturated NaHCO3 solution was slowly added, followed by solid NaOH (16.00 g, 400 mmol). EtOAc (800 mL) and water (600 mL) were added. The organic layer was washed with a mixture of NaHCO3 solution and brine, then brine, dried over (Na2SO4), filtered and concentrated to approximately 150 mL, then 450 mL of cyclohexane was added, cooled to 0C, and filtered with cyclohexane / EtOAc (3 / 1) to give the desired product (39 g, 83 mmol, 81% yield during 2 steps). Step 150g. To a solution of the compound from step 150f (5.75 g, 12.67 mmol) in NMP (40 mL) at 0 °C, m-CPBA (8.52 g, 38.0 mmol, 77%) was added in one portion. The mixture was stirred at room temperature. It was diluted with EtOAc, washed with Na2S2O3, NaHCO3, water, and brine. It was dried over Na2SO4, filtered, and concentrated. The crude product was recrystallized from MeOH. It was dried at room temperature under vacuum to give the title compound (4.10 g, 8.44 mmol, 66.6% yield). ESI-MS m / z = 484.08, 486.08 [MH]-. Example 153 (not according to the invention) A solution of the compound from step 144a in AcOH (500 µl, 8.73 mmol) was stirred overnight. The reaction mixture was concentrated and the residue was chromatographed (silica, CH2Cl2 / MeOH) to give the title compound as a white solid (17 mg, 88%, single enantiomer). ESI-MS m / z = 577.10, 579.10 (M+HCO2)-. Example 156 (not according to the invention) Intermediate 3 (78 mg, 0.155 mmol) and sulfuric diamide (44.7 mg, 0.465 mmol) in dioxane (0.5 mL) were stirred at 105 °C for 3 h. The mixture was cooled to room temperature and purified by preparative HPLC using a C18 column and acetonitrile / water as the eluent to give the title compound (42 mg, 46%). ESI-MS m / z = 580.06, 582.06 [MH]-. Example 163 (not according to the invention) Two enantiomers of Example 36 were separated by chiral SFC. The title compound (tentatively assigned) was eluted first. ESI-MS m / z = 590, 11, 592, 11 [MH]-. Example 164 (not according to the invention) Two enantiomers of Example 36 were separated by chiral SFC. The title compound (tentatively assigned) was subsequently eluted. ESI-MS m / z = 590, 11, 592, 11 [MH]-. Example 174 (not according to the invention) The title compound (single enantiomer, tentatively assigned, first eluted) was isolated from the compound of example 82 by SFC chromatography. ESI-MS m / z = 514.09, 516.09 [MH]-. Example 175 (not according to the invention) The title compound (single enantiomer, tentatively assigned, subsequently eluted) was isolated from the compound of example 82 by SFC chromatography. ESI-MS m / z = 514.09, 516.09 [MH]-. Example 180 (not according to the invention) The title compound (single enantiomer, tentatively assigned, eluted first) was isolated from the compound of example 172 by SFC chromatography. ESI-MS m / z = 528, 10, 530, 10[MH]-. Example 181 (not according to the invention) The title compound (single enantiomer, tentatively assigned, subsequently eluted) was isolated from the compound of example 172 by SFC chromatography. ESI-MS m / z = 528, 10, 530, 10[MH]-. Example 182 (not according to the invention) The title compound (single enantiomer, eluted first) was isolated from the compound of example 173 by SFC chromatography. ESI-MS m / z = 528, 10, 530, 10[MH]-. Example 183 (not according to the invention) The title compound (single enantiomer, subsequently eluted) was isolated from the compound of example 173 by SFC chromatography. ESI-MS m / z = 528, 10, 530, 10[MH]-. Example 202 (not according to the invention) Step 202a. To a solution of (R)-2,2-dimethyl-1,3-dioxolan-4-carboxylate methyl (55 mg, 0.35 mmol) in THF (1 mL), freshly prepared LDA (0.34 mmol) in THF was added to The mixture was cooled to -78 °C and stirred at the same temperature for 15 minutes before adding a solution of intermediate 2 (100 mg, 0.23 mmol) in THF (1 mL). It was heated to 0 °C in one hour and deactivated using aqueous NH4Cl. It was extracted with EtOAc, washed with brine, and dried with Na2SO4. After concentration, the crude was chromatographed (silica, EtOAc / hexanes) to give the desired compound (79 mg, contaminated with intermediate 2). ESI-MS m / z = 598, 12, 600, 12[MH]-. Step 125b. To a solution of the compound from step 202a (79 mg, 0.13 mmol) in THF (2 mL), m-CPBA (112 mg, 0.5 mmol) was added and stirred to room temperature. The crude was purified by preparative HPLC (C18, acetonitrile / water) to give the title compound (13 mg, 10%, two steps). ESI-MS m / z = 630, 11, 632, 11 [MH]-. Example 203 (not according to the invention) IBX (179 mg, 0.639 mmol) was added to a solution of the compound from Example 150 (207 mg, 0.426 mmol) in DMSO (2.1 mL). The reaction was stirred at room temperature for 2 h. The reaction was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na₂SO₄), filtered, and concentrated. The crude product was chromatographed (silica, hexane / acetone) to give the title compound as a white solid (175 mg, 85%). ESI-MS m / z = 481.6, 483.6 [MH]⁻. Example 204 (not according to the invention) To a solution of the compound from Example 150 (103 mg, 0.212 mmol) in THF (2 mL) and saturated aqueous NaHCO3 (1 mL) NaIO4 (140 mg, 0.655 mmol) was added. The reaction was stirred at room temperature for 2 h. The reaction was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed (silica, hexane / acetone) to give the title compound as a white solid (60 mg, 62%). ESI-MS m / z = 452.05, 454.05 [MH]-. Example 205 (not according to the invention) To a solution of the compound from Example 203 (140 mg, 0.289 mmol), 2-methyl-2-butene (0.77 mL, 7.23 mmol), and KH₂PO₄ (276 mg, 2.025 mmol) in THF (3 mL) and water (1 mL), NaClO₂ (294 mg, 2.60 mmol) was added. The reaction was stirred at room temperature for 1 h. The reaction was acidified to pH 4 with 1 M HCl, then extracted with EtOAc, washed with water and brine. The organic layer was dried (Na₂SO₄), filtered, and concentrated. The crude product was chromatographed (silica, hexane / acetone) to give the title compound as a white solid (109 mg, 75%). ESI-MS m / z = 497.7, 499.6 [MH]-. Example 206 (not according to the invention) To a solution of the compound from Example 204 (22 mg, 0.048 mmol) in THF (0.5 mL) and MeOH (0.5 mL) NaBH4 (9 mg, 0.244 mmol) was added. The reaction was stirred at room temperature for 15 minutes. The reaction was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated to give the title compound as a white solid (21 mg, 95%, stereochemistry not determined). ESI-MS m / z = 453.6, 455.6 [MH]-. Example 210 (not according to the invention) A solution of the compound from step 11b (47 mg, 0.091 mmol) in THF (911 µl) was mixed with 2N LiBH4 solution (22.77 µl, 0.046 mmol) at room temperature, and the mixture was then held at room temperature overnight. The reaction was stopped with aqueous NH4Cl solution, and the mixture was extracted with EtOAc. The combined organic phases were washed with water and brine, dried over Na2SO4, filtered, and concentrated. The residue was chromatographed (silica, CH2Cl2 / MeOH) to give the title compound as a white solid (14 mg, 30%). ESI-MS m / z = 562.09, 564.09, (M+HCO2) - Example 272 (not according to the invention) Step 272a. To a suspension of Me3SOI (1.98 g, 9.0 mmol.) in DMF (5.0 mL) at 0 oC, t-BuOK (1.01 g, 9.0 mmol.) was added and shaken at room temperature for one hour. The reaction was cooled to 0°C. (1R, 5S)-3-methylenebicyclo[3.2.1]octan-8-one-6,6,7,7-d4 (in DMF (2.0 mL)), which was prepared using procedures similar to those described in intermediate step 2a, was added dropwise to the reaction mixture. The reaction was stirred for 2 hours. 15% NH4Cl was added dropwise to the reaction mixture and extracted with MTBE. The aqueous phase was then re-extracted using MTBE. The entire organic phase was then combined and washed with water and brine. The organic phase was dried over Na2SO4, filtered, and concentrated to dryness to give the desired product (0.59 g, 64%). Step 272b. To a solution of the compound from step 272a (0.59 g, 3.83 mmol) in THF / water (3.9 / 1.3 mL) at 0°C, TFA (0.589 mL, 7.65 mmol) was added. The reaction was stirred at room temperature for 20 hours. The reaction was cooled to 0°C, and Na₂CO₃ was slowly added, adjusting the pH to 7–8. EtOAc and water were added. The two layers were separated (brine was added to aid separation), and the organic layer was washed with water and brine. The organic phase was dried over Na₂SO₄, filtered, and concentrated to dryness to give the desired product (0.50 g, 76%). Step 272c. To a solution of the compound from step 272b (0.48 g, 2.8 mmol), imidazole (0.57 g, 8.4 mmol) in DMF (4.0 mL), TBSCl (0.63 g, 4.2 mmol) was added and stirred at room temperature for 18 h. It was deactivated by pouring it into cold water. The product was extracted with hexanes. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product (0.97 g, 100%). Step 272d. To a solution of the compound from step 272c (1.43 g, 5.0 mmol) in dioxane-water (18 / 6.0 mL), 2,6-lutidine (1.16 mL, 10 mmol) and OsO4 (0.78 mL, 2.5% solution in tert-butanol, 0.05 mmol) were added. The mixture was cooled to 0°C and NaIO4 (3.21 g, 15 mmol) was added. The suspension was stirred at room temperature for 16 hours. Aqueous Na2S2O3 solution was added. The mixture was stirred for 1 hour and filtered through Celite. The mixture was extracted with MBTE / Hexanes. The organic phase was washed with water, 1 N HCl, saturated NaHCO3 solution, and brine. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give the crude product (1.0 g, 69%). Step 272e. To a solution of LiBD4 (0.108 g, 4.2 mmol), the compound from step 272d (0.577 g, 2.0 mmol) was added dropwise in MBTE (12 mL) at 0°C. The resulting solution was stirred for 2 hours at 0°C. The reaction was stopped by the slow addition of aqueous NH4Cl solution, maintaining the temperature below 15°C. The reaction mixture was diluted with MBTE and water. The mixture was separated, and the organic layer was washed with brine. The mixture was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was chromatographed (silica, hexanes / EtOAc) to give the desired compound as a white solid (0.39, 67%). Step 272f. To a solution of the compound from step 272e (0.39 g, 1.34 mmol) and pyridine (0.216 mL, 2.68 mmol) in DCM (2 mL) at room temperature, TsCl (0.306 g, 1.60 mmol) was added and stirred at room temperature for 40 h. It was deactivated with H2O and extracted with EtOAc. The mixture was washed with H2O, 1M HCl, saturated NaHCO3 solution, and brine. The organic phase was collected, dried over Na2SO4, filtered, and concentrated. The crude product was chromatographed (silica, hexanes / EtOAc) to give the desired compound as a white solid (0.59, 99%). Step 272g. Concentrated HCl (1.0 mL) was added to a solution of the compound from step 272f (1.7 g, 3.81 mmol) in MeOH (22 mL) and stirred at room temperature for 16 h. It was diluted with EtOAc and the mixture was washed with water, saturated NaHCO3 solution, brine, dried over Na2SO4, filtered, and concentrated. The crude product was recrystallized from hexanes / MBTE to give the desired product (1.1 g, 87%). Step 272h. A solution of the compound from step 272 (0.16 g, 0.48 mmol), intermediate 6 (0.12 g, 0.40 mmol), and Cs₂CO₃ (0.128 g, 0.392 mmol) in DMF (1.0 mL) was stirred at 75 °C for 16 h. It was diluted with EtOAc, and the mixture was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated. The crude product was chromatographed (silica, hexanes / EtOAc) to give the desired compound as a white solid (0.162 g, 88%). ESI-MS m / z = 457.12, 459.12 [MH]⁻. Step 272i. A solution of the compound from step 272h (0.16 g, 0.35 mmol) and m-CPBA (253 mg, 1.13 mmol, 77%) in MPN (2.0 mL) was stirred at room temperature for 24 h. Aqueous Na2S2O3, NaHCO3, and a few drops of Et3N were added, and the mixture was stirred at room temperature for 1 h. It was extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and recrystallized from MeOH to give the title compound (118 mg, 68%). ESI-MS m / z = 489.11, 491.11 [MH]-. Example 279 (not according to the invention) Step 279a. To a suspension of Me3SOI (48.5 g, 220 mmol) in DMF (120 mL) at 0°C, t-BuOK (24.72 g, 220 mmol) was added and stirred at room temperature for one hour. The reaction was cooled to 0°C. Intermediate 2a (20 g, 147 mmol) in DMF (80 mL) was added dropwise to the reaction mixture. The reaction was stirred for two hours. 15% NH4Cl was added dropwise to the reaction mixture and extracted with MTBE. The aqueous phase was re-extracted using MTBE. The combined organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to give the desired product (19.9 g, 90%). Step 279b. To a solution of the compound from step 279a (20 g, 133 mmol) in THF / water (150 / 50 mL) at 0°C, TFA (30.8 mL, 399 mmol) was added. The reaction was stirred at room temperature for 3 hours, then cooled to 0°C and Na2CO3 was slowly added and the pH adjusted to 7-8. EtOAc and water were added. The two layers were separated (brine was added to aid separation), the organic layer was washed with water and brine, dried over Na2SO4, filtered, and concentrated to provide the desired product (17.7 g, 79%). Step 279c. To a solution of the compound from step 279b (10 g, 59.4 mmol), imidazole (10.2 g, 148 mmol) in DMF (80 mL), TBSCl (10.7 g, 71.3 mmol) was added and stirred at room temperature for 18 h. It was deactivated by pouring cold water over it. The product was extracted with hexanes. The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give the crude product (18.1 g, 100%). Step 279d. To a solution of the compound from step 279c (16.8 g, 59.4 mmol) in dioxane-water (170 / 60 mL), 2,6-lutidine (13.8 mL, 119 mmol) and OsO4 (9.3 mL, 2.5% solution in tert-butanol, 0.59 mmol) were added. The mixture was cooled, and NaIO4 (37.1 g, 178.2 mmol) was added. The suspension was stirred at room temperature for 16 hours. Aqueous Na2S2O3 solution was added. The mixture was stirred for 1 hour and filtered through Celite. The mixture was extracted with MBTE / Hexanes. The organic phase was washed with water, 1N HCl, saturated NaHCO3 solution, and brine. The organic phase was separated, dried over Na2SO4, filtered and concentrated to give the crude product (16.6 g, 94%). Step 279f. To a solution of the compound from step 279d (143 mg, 0.503 mmol) in CD3OD (3.0 mL), MeONa (5.4 mg, 0.10 mmol) was added, and the mixture was stirred at room temperature for 3 h. It was concentrated, and the residue was dissolved in CD3OD (3.0 mL) and stirred for 3 h. The same reaction cycle was repeated two more times, and the solution was cooled to 0°C and portions of NaBD4 (0.10 g, 2.4 mmol) were added. After 1 h, the reaction was stopped by slowly adding aqueous NH4Cl, MBTE, and water. The mixture was separated, and the organic layer was washed with brine. The mixture was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was chromatographed (silica, hexanes / EtOAc) to give the desired compound in the form of a white solid (0.070 g, 50%). Step 279g. To a mixture of intermediate 6 (73 mg, 0.24 mmol) and compounds from step 279f (71 mg, 0.24 mmol) in toluene (1.5 mL) at room temperature, cyanomethylenetributylphosphoran (176 mg, 0.73 mmol) was added and stirred at 75°C for 16 h. The mixture was cooled to room temperature and chromatographed (silica, hexanes / EtOAc) to give the desired compound as a white solid (0.11 g, 79%). ESI-MS m / z = 571.21, 573.21 [MH]-. Step 279h. To a solution of the compound from step 279 (0.11 g, 0.19 mmol) in MeOH (3.0 mL), concentrated HCl solution (0.3 mL) was added and stirred at room temperature for 2 h. It was diluted with EtOAc and the mixture was washed with water, saturated NaHCO3 solution, brine, dried over Na2SO4, filtered, and concentrated. The crude product was recrystallized from hexanes / MBTE to give the desired product (0.083 g, 94%). ESI-MS m / z = 457.12, 459.12 [MH]-. Step 279i. A solution of the compound from step 279h (0.083 g, 0.18 mmol) and m-CPBA (0.14 g, 0.63 mmol, 77%) in MPN (2.0 mL) was stirred at room temperature for 24 h. Aqueous solution of Na2S2O3, NaHCO3, and a few drops of Et3N were added, and the mixture was stirred at room temperature for 1 h. The solution was extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered and concentrated, and purified by preparative HPLC (C18, acetonitrile / water) to give the title compound (48 mg, 54%). ESI-MS m / z = 489.11, 491.11 [MH]-. Example 281 (not according to the invention) Step 281a. To a solution of the compound from step 150f (4.0 g, 8.11 mmol) in DMSO (22 mL), IBX (3.70 g, 13.22 mmol) was added. The reaction mixture was heated to 50°C for 3 h. The reaction mixture was cooled to 1 / 4°C and diluted with EtOAc. The reaction mixture was filtered, the solid was discarded, and the filtrate was washed with water and saturated NaCl solution. The organic layer was dried with Na₂SO₄, filtered, and concentrated to obtain the desired crude product, which was used without further purification (3.90 g, 98%). Step 281b. Isopropylmagnesium chloride-lithium chloride complex (237 mL, 0.243 mmol, 1.3 M in THF) was added to a solution of the compound from step 281a (50 mg, 0.111 mmol) in THF (0.53 mL) at -78°C. The reaction mixture was stirred for 30 minutes, and the reaction was stopped using aqueous NH₄Cl. The solution was extracted with EtOAc, washed with brine, and dried with Na₂SO₄. After concentration, the crude was chromatographed (silica, EtOAc / hexanes) to give the desired compound (18 mg, 33%). ESI-MS m / z = 540.14, 542.14[M+HCO₂]⁻. Step 281c. To a solution of the compound from step 281b (18 mg, 0.01 mmol) in MPN (0.5 mL), m-CPBA (24 mg, 0.096 mmol, 77%) was added and stirred at room temperature. The reaction was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed (silica, hexane / acetone) to give the title compound as a white solid (14 mg, 73%). ESI-MS m / z = 572.13, 574.13[M+HCO2]-. Example 283 (not according to the invention) Step 283a. Phenylmagnesium bromide (237 L, 0.243 mmol, 1 M in THF) was added to a solution of the compound from step 281a (50 mg, 0.111 mmol) in THF (0.53 mL) at -78°C. The reaction mixture was stirred for 30 minutes and deactivated using aqueous NH4Cl. It was extracted with EtOAc, washed with brine, and dried (Na2SO4). After concentration, the crude was chromatographed (silica, EtOAc / hexanes) to give the desired compound (17 mg, 29%). ESI-MS m / z = 574.13, 576.13[M+HCO2]-. Step 283b. To a solution of the compound from step 283a (17 mg, 0.03 mmol) in MPN (0.5 mL), m-CPBA (22 mg, 0.096 mmol, 77%) was added and stirred at room temperature. The crude was purified by preparative HPLC (C18, acetonitrile / water) to give the title compound (3 mg, 17%). ESI-MS m / z = 606, 12, 608, 12 [M+HCO2]-. Example 284 (not according to the invention) Step 284a. Isopropylmagnesium chloride and lithium chloride complex (0.49 mL, 0.49 mmol, 1.3 M in THF) were added to a solution of 2-bromopyridine (46 L, 0.49 mmol) in THF (1 mL) at 0°C. The reaction mixture was heated to 1°C and stirred for 30 minutes, then cooled to -78°C followed by the addition of a solution of the compound from step 281a (100 mg, 0.221 mmol) in THF (1 mL). The reaction mixture was stirred for 18 h, heated slowly to 1°C, and deactivated using aqueous NH4Cl. It was extracted with EtOAc, washed with brine, and dried with Na2SO4. After concentration, the crude was chromatographed (silica, acetone / hexanes) to give the desired compound (11 mg, 9%). ESI-MS m / z = 575, 12, 577, 12 [M+HCO2]-. Step 284b. To a solution of the compound from step 284a (11 mg, 0.02 mmol) in MPN (1 mL), p-TSA (20 mg, 0.105 mmol) and m-CPBA (20 mg, 0.089 mmol, 77%) were added and stirred at room temperature. The reaction was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed (silica, hexane / acetone) to give the title compound as a white solid (6 mg, 51%). ESI-MS m / z = 607.13, 609.13 [M+HCO2]-. Example 284a (not according to the invention) The title compound (single enantiomer, tentatively assigned) was isolated from the compound in example 284 by SFC chromatography, the compound that eluted first. Example 284b (not according to the invention) The title compound (single enantiomer, tentatively assigned) was isolated from the compound in example 284 via SFC chromatography, and subsequently eluted. Example 285 (not according to the invention) Step 285a. Isopropylmagnesium chloride and lithium chloride complex (0.49 mL, 0.49 mmol, 1.3 M in THF) were added to a solution of 3-bromopyridine (46 L, 0.49 mmol) in THF (1 mL) at 0°C. The reaction mixture was heated to 1°C and stirred for 30 minutes, then cooled to -78°C followed by the addition of a solution of the compound from step 281a (100 mg, 0.221 mmol) in THF (1 mL). The reaction mixture was stirred for 18 h, heated slowly to 1°C, and deactivated using aqueous NH4Cl. It was extracted with EtOAc, washed with brine, and dried with Na2SO4. After concentration, the crude was chromatographed (silica, acetone / hexanes) to give the desired compound (15 mg, 13%). ESI-MS m / z = 575, 12, 577, 12 [M+HCO2]-. Step 285b. To a solution of the compound from step 285a (15 mg, 0.028 mmol) in MPN (1 mL), p-TSA (20 mg, 0.105 mmol) and m-CPBA (20 mg, 0.089 mmol, 77%) were added and stirred at room temperature. The reaction was extracted with EtOAc, washed with water and brine.The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed (silica, hexane / acetone) to give the title compound as a white solid (8 mg, 50%). ESI-MS m / z = 607.13, 609.13 [M+HCO2]-. Example 285a (not according to the invention) The title compound (single enantiomer, tentatively assigned) was isolated from the compound in example 285 by SFC chromatography, the compound that eluted first. Example 285b (not according to the invention) The title compound (single enantiomer, tentatively assigned) was isolated from the compound in example 285 by SFC chromatography, and subsequently eluted. Example 286 (not according to the invention) Step 286a. To a solution of 4-iodopyridine (159 mg, 0.774 mmol) in THF (1.5 mL) at 0°C, n-Butyllithium (0.31 mL, 0.774 mmol, 25 M in hexanes) was added. This reaction mixture was heated to 1°C and stirred for 30 minutes, then cooled to -78°C followed by the addition of a solution of the compound from step 281a (100 mg, 0.221 mmol) in THF (1 mL). The reaction mixture was stirred for 18 h, heated slowly to 1°C, and deactivated using aqueous NH4Cl. It was extracted with EtOAc, washed with brine, and dried with Na2SO4. After concentration, the crude was chromatographed (silica, acetone / hexanes) to give the desired compound (45 mg, 38%). ESI-MS m / z = 575, 30, 577, 30[M+HCO2]-. Step 286b. To a solution of the compound from step 286a (45 mg, 0.085 mmol) in MPN (2 mL), p-TSA (48 mg, 0.254 mmol) and m-CPBA (57 mg, 0.254 mmol, 77%) were added and stirred at room temperature. The reaction was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed (silica, hexane / acetone) to give the title compound as a white solid (8 mg, 17%). ESI-MS m / z = 607.29, 609.29 [M+HCO2]-. Example 287 (not according to the invention) Step 287a. To a solution of 1-(dietoxy)-1H-imidazole (159 mg, 0.487 mmol) in THF (1 mL) at -78°C, n-Butyllithium (0.195 mL, 0.487 mmol, 2.5 M in hexanes) was added. The reaction mixture was stirred for 30 minutes, followed by the addition of a solution of the compound from step 281a (100 mg, 0.221 mmol) in THF (1 mL). The reaction mixture was stirred for 18 h, heated slowly to 100°C, and deactivated using aqueous NH4Cl. It was extracted with EtOAc, washed with brine, and dried with Na2SO4. After concentration, the crude was chromatographed (silica, acetone / hexanes) to give the desired compound (22 mg, 38%). ESI-MS m / z = 564, 29, 566, 29[M+HCO2]-. Step 287b. To a solution of the compound from step 287a (22 mg, 0.042 mmol) in NMP (2 mL), p-TSA (50 mg, 0.263 mmol) and m-CPBA (50 mg, 0.223 mmol, 77%) were added and stirred at room temperature. The reaction was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed by preparative HPLC (C18, acetonitrile / water) to give the title compound as a white solid (6 mg, 26%). ESI-MS m / z = 596.28, 598.28 [M+HCO2]-. Example 288 (not according to the invention) Step 288a. To a solution of 1-methyl-1H-pyrazole (64 L, 0.774 mmol) in THF (1.5 mL) at 0°C, n-Butyllithium (0.31 mL, 0.774 mmol, 2.5 M in hexanes) was added. The reaction mixture was stirred for 30 minutes followed by the addition of a solution of the compound from step 281a (100 mg, 0.221 mmol) in THF (1 mL). The reaction mixture was stirred for 18 h, heated slowly to 1°C, and deactivated using aqueous NH4Cl. It was extracted with EtOAc, washed with brine, and dried with Na2SO4. After concentration, the crude was chromatographed (silica, acetone / hexanes) to give the desired compound (79 mg, 67%). ESI-MS m / z = 578, 32, 580, 31 [M+HCO2]-. Step 288b. To a solution of the compound from step 288a (79 mg, 0.148 mmol) in MPN (2 mL), m-CPBA (99 mg, 0.444 mmol, 77%) was added and stirred at room temperature. The reaction was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed (silica, acetone / hexanes) to give the title compound as a white solid (65 mg, 78%). ESI-MS m / z = 610, 30, 612, 30 [M+HCO2]-. Example 289 (not according to the invention) Step 289a. To a solution of 4-bromo-1-methyl-1H-pyrazole (69 L, 0.664 mmol) in THF (2 mL) at -78°C, n-Butyllithium (0.266 mL, 0.664 mmol, 2.5 M in hexanes) was added. The reaction mixture was stirred for 30 minutes, followed by the addition of a solution of the compound from step 281a (100 mg, 0.221 mmol) in THF (1 mL). The reaction mixture was stirred for 18 h, heated slowly to 100°C, and deactivated using aqueous NH4Cl. It was extracted with EtOAc, washed with brine, and dried with Na2SO4. After concentration, the crude was chromatographed (silica, acetone / hexanes) to give the desired compound (23 mg, 19%). ESI-MS m / z = 578, 31, 580, 31 [M+HCO2]-. Step 289b. To a solution of the compound from step 289a (23 mg, 0.148 mmol) in MPN (2 mL), m-CPBA (29 mg, 0.444 mmol, 77%) was added and stirred at room temperature. The reaction was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed (silica, acetone / hexanes) to give the title compound as a white solid (22 mg, 90%). ESI-MS m / z = 610, 30, 612, 31 [M+HCO2]-. Example 290 (not according to the invention) Step 290a. To a solution of oxazole (76 L, 1,162 mmol) in THF (1,5 mL) at 0°C, i-PrMgCl-LiCl (0,894 mL, 1,162 mmol, 1,3M in THF) was added. The reaction mixture was stirred for 30 minutes followed by the addition of a solution of the compound from step 281a (150 mg, 0,332 mmol) in THF (1,5 mL). The reaction mixture was stirred for 3 h, heated slowly to room temperature, and deactivated using aqueous NH4Cl. It was extracted with EtOAc, washed with brine, and dried with Na2SO4. After concentration, the crude was chromatographed (silica, acetone / hexanes) to give the desired compound (22 mg, 38%). ESI-MS m / z = 565, 28, 567, 28 [M+HCO2]-. Step 290b. To a solution of the compound from step 290a (133 mg, 0.042 mmol) in MPN (2.5 mL), p-TSA (243 mg, 1.276 mmol) and m-CPBA (172 mg, 0.766 mmol, 77%) were added and stirred at room temperature. The reaction was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed by preparative HPLC (C18, acetonitrile / water) to give the title compound as a white solid (20 mg, 14%). ESI-MS m / z = 597.26, 599.26 [M+HCO2]-. Example 291 (not according to the invention) Step 291a. To a solution of 2-bromo-5-fluoropyridine (302 mg, 1.715 mmol) in THF (3 mL), n-Butyllithium (0.730 mL, 1.826 mmol, 2.5 M in THF) was added dropwise at -78 °C. After stirring for 1 h at the same temperature, a solution of the compound from step 281a (250 mg, 0.553 mmol) in THF (1.5 mL) was added to the mixture at -78 °C. The reaction was heated slowly to 100°C and stirred for 16 h. Saturated NH4Cl solution was added. The mixture was extracted with EtOAc, dried over Na2SO4, and purified by column chromatography (silica. MeOH / DCM) to give the desired compound (70 mg, 0.128 mmol, 23% yield) in the form of a pale brown solid. Step 291b. To a solution of the compound from step 291a (70 mg, 0.128 mmol), p-TSA (72.8 mg, 0.383 mmol) in MPN (1 mL), m-CPBA (86 mg, 0.383 mmol, 77%) was added at 0 °C. The reaction was heated slowly to 100 °C and stirred for 16 h. Saturated Na₂S₂O₃ and NaHCO₃ solution was added, and the resulting mixture was stirred for 1 h. The mixture was extracted with EtOAc, washed with saturated Na₂S₂O₃ and NaHCO₃ solution (x2), brine, and dried over Na₂SO₄. The crude material was purified by column chromatography (silica, MeOH / DCM) to give the title compound (17.0 mg, 0.128 mmol, 23% yield) as a light brown solid. ESI-MS m / z = 580.00, 582.01 [MH]-. Example 291a (not according to the invention) The title compound (single enantiomer, tentatively assigned) was isolated from the compound in example 291 by SFC chromatography, the compound that eluted first. Example 291b (not according to the invention) The title compound (single enantiomer, tentatively assigned) was isolated from the compound in example 291 by SFC chromatography, and subsequently eluted. Example 292 (not according to the invention) The crude material from step 291b was purified by column chromatography (0-20% MeOH in DCM) to give the title compound (9.3 mg, 0.016 mmol, 12% yield) as a light brown solid. ESI-MS m / z = 596.00, 598.01 [MH]-. Example 293 (not according to the invention) Step 293a. To a solution of 2-bromo-5-methylpyridine (200 mg, 1.16 mmol) in THF (1.5 mL) at -78°C, n-Butyllithium (0.465 mL, 1.16 mmol, 2.5 M in hexane) was added. The reaction mixture was stirred for 30 minutes, followed by the addition of a solution of the compound from step 281a (150 mg, 0.332 mmol) in THF (1.5 mL). The reaction mixture was stirred for 1 h, heated slowly to 100°C, and deactivated using aqueous NH4Cl. It was extracted with EtOAc, washed with brine, and dried with Na2SO4. After concentration, the crude was chromatographed (silica, acetone / hexanes) to give the desired compound (129 mg, 71%). ESI-MS m / z = 589.14, 591.14 [M+HCO2]-. Step 293b. To a solution of the compound from step 293a (129 mg, 0.24 mmol) in MPN (2.4 mL), p-TSA (225 mg, 1.18 mmol) and m-CPBA (159 mg, 0.71 mmol, 77%) were added and stirred at room temperature. The reaction was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed (silica, hexane / acetone) to give the title compound as a white solid (109 mg, 80%). ESI-MS m / z = 621.13, 623.13 [M+HCO2]-. Example 297 (not according to the invention) Step 297a. To a solution of 2-bromo-3-fluoropyridine (204 mg, 1.16 mmol) in THF (1.5 mL) at -78°C, n-Butyllithium (0.465 mL, 1.16 mmol, 2.5 M in hexane) was added. The reaction mixture was stirred for 30 minutes, followed by the addition of a solution of the compound from step 281a (150 mg, 0.332 mmol) in THF (1.5 mL). The reaction mixture was stirred for 1 h, heated slowly to 1°C, and deactivated using aqueous NH4Cl. It was extracted with EtOAc, washed with brine, and dried with Na2SO4. After concentration, the crude was chromatographed (silica, acetone / hexanes) to give the desired compound (10 mg, 5.5%). ESI-MS m / z = 563, 12, 565, 10 [M+HCO2]-. 3-(((1R,3r,5S,8r)-8-((2-bromo-3-fluoropyridin-4-yl)(hydroxy)methyl)-8-hydroxybicyclo[3.2.1]octan-3-yl)thio)-4-chloro-N-(3,4-difluorophenyl)benzamide (77 mg, 37%). ESI-MS m / z = 671, 03, 673, 04 [M+HCO2]-Step 297b.To a solution of the compound from step 297a (10 mg, 0.018 mmol) in MPN (0.2 mL), p-TSA (17 mg, 0.09 mmol) and m-CPBA (12 mg, 0.055 mmol, 77%) were added and stirred at room temperature. The reaction was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was chromatographed (silica, hexane / acetone) to give the title compound as a white solid (4.7 mg, 44%). ESI-MS m / z = 625.11, 627.11 [M+HCO2]-. Example 298 (not according to the invention) Step 298. To a solution of the byproduct of step 297a (3-(((1R,3r,5S,8r)-8-((2-bromo-3-fluoropyridin-4-yl)(hydroxy)methyl)-8-hydroxybicyclo[3,2.1]octan-3-yl)thio)-4-chloro-N-(3,4-difluorophenyl)benzamide (77 mg, 0.123 mmol) in MPN (1.3 mL), p-TSA (117 mg, 0.613 mmol) and m-CPBA (82 mg, 0.368 mmol, 77%) were added and the mixture was stirred at room temperature. The reaction was extracted with EtOAc, washed with water and brine. The organic layer was dried (Na2SO4), filtered, and concentrated. The crude product was Chromatography (silica, hexane / acetone) was performed to give the title compound as a white solid (64 mg, 79%). ESI-MS m / z = 703, 01, 705, 12 [M+HCO2]-. Example 307 (not according to the invention) Step 307a. To the mixture of the compound from Example 150d (7.04 g, 16.61 mmol) in ACN (70 mL) and DBU (3.25 mL, 21.59 mmol) at 0 °C, nonafluorobutan-1-sulfonyl fluoride (5.52 g, 18.27 mmol) was added by pipette over one minute and stirred at that temperature for 1 h. While still cold, 200 mL of MTBE was added. The solution was washed with water, twice with 1N HCl, then with water, twice with aqueous NaHCO3 solution, and twice with brine. After drying (Na2SO4) and concentrating, 13.5 g of a light yellow solid were obtained. To this, MTBE / Hexanes ~ 1:10 (200 mL) was added and the mixture was stirred at room temperature for 30 mins before filtration under vacuum. The collected solid was washed with MTBE / hexanes (1:10, 100 mL) to give (10.1 g, 86%) a whitish solid. ESI-MS m / z = 704.02, 706.02 [MH]-. Step 307b. To a solution of the compound from step 307a (200 mg, 0.283 mmol) in DMF (2 mL), methylisopropylamine (0.15 mL) was added and the mixture was stirred at 75 °C for two days. The crude was diluted with EtOAc, washed twice with water, twice with brine, dried with Na₂SO₄, and concentrated. The crude was chromatographed (silica, MeOH / DCM) to give the desired compound as a mixture with other impurities. ESI-MS m / z = 477.15, 479.15 [MH]⁻. Step 307c. The title compound was obtained from the compound of step 307b following the procedure described in Example 284b and was purified by preparative HPLC. ESI-MS m / z = 509, 14, 511, 14 [MH]-. Example 308 (not according to the invention) The compound from step 82a (570 mg, 1.27 mmol) in THF (10 mL) was added to m-CPBA (77% w / w, 1.42 g, 6.33 mmol) and stirred at room temperature. Aqueous solutions of Na₂S₂O₃ (10 mL) and NaHCO₃ (10 mL) were added, followed by 4 drops of TEA and EtOAc (50 mL). The mixture was stirred at room temperature for 1.5 hours before separation. The aqueous phase was extracted with EtOAc. The combined organic phase was washed with NaHCO₃ and brine, and dried with Na₂SO₄. After concentration, the crude pale yellow solid was dissolved in MeOH (50 mL) under heat (heat gun) and cooled slowly to room temperature before being held at 0 °C for 30 minutes. The crystals formed were collected from empty garlic to obtain the titer compound (510 mg, 81%) in the form of a white solid. ESI-MS m / z = 496, 20, 498, 20 [MH]-. Example 309 (not according to the invention) To a solution of the compound of Example 308 (50 mg, 0.10 mmol) in DMF (0.5 mL), 1,1-Dioxoisothiazolidine (18.3 mg, 0.15 mmol) was added, followed by K₂CO₃ (14 mg, 0.1 mmol), and the mixture was stirred at 50 °C o / n. The crude was purified by preparative HPLC (C-18, Acetonitrile / water) to give the title compound (16 mg, 26%) as a white solid. ESI-MS m / z = 617.25, 619.25 [MH]-. Example 314 (not according to the invention) Step 314a. Potassium tert-butoxide (186 mg, 1.66 mmol) was added to a slurry of Me3SOI (365 mg, 1.66 mmol) in DMF (1 mL) at 0 °C. The mixture was heated to 1 °C and stirred for 45 min. The compound from step 281a (150 mg, 0.33 mmol) in DMF (2 mL) was added dropwise to the reaction mixture. After stirring for 4 h, the reaction mixture was cooled to 0 °C, saturated NH4Cl solution was added, the mixture was extracted with MTBE, and dried over Na2SO4. The crude product was purified by column chromatography (0-50% EtOAc in Hex) to give the desired compound (42.0 mg, 0.090 mmol, 27% yield) in the form of a white solid. Step 314b. To a solution of the compound from step 314a (42 mg, 0.090 mmol) in DMF (2 mL) were added 1H-pyrazole (12.27 mg, 0.180 mmol) and potassium carbonate (18.69 mg, 0.135 mmol). The reaction was stirred at 65 °C for 15 h. The mixture was extracted with EtOAc, dried over Na2SO4, and purified by column chromatography (0-70% EtOAc in Hex) to give the desired compound (30.0 mg, 0.056 mmol, 62% yield) as a whitish solid. Step 314c. To a solution of the compound from step 314b (30 mg, 0.056 mmol) and camphorsulfonic acid (CSA) (19.57 mg, 0.084 mmol) in MPN (0.2 mL), m-CPBA (37.8 mg, 0.169 mmol, 77%) was added at 0 °C. The reaction was heated slowly to rt and stirred for 15 h. Saturated Na₂S₂O₃ solution and NaHCO₃ solution were added to the mixture, and it was stirred for 1 h. The reaction was extracted with EtOAc, washed with saturated Na₂S₂O₃ solution and NaHCO₃ solution (x2), brine, and dried over Na₂SO₄. The crude material was purified by column chromatography (silica, hexanes / acetone) to give the title compound (20 mg, 0.035 mmol, 63% yield) as a whitish solid. ESI-MS m / z = 565, 30, 567, 29 [MH]. Example 315 (not according to the invention) Step 315a. Sodium hydride (17.38 mg, 0.435 mmol) was added to a solution of oxazolidin-2-one (42.0 mg, 0.483 mmol) in DMF (1 mL) at 0 °C. The mixture was stirred for 1 h and cooled to 0 °C. The compound from step 314a (45 mg, 0.097 mmol) in DMF (1 mL) was added to the reaction. The mixture was heated to 55 °C for 15 h. The reaction was cooled to 0 °C and saturated NH4Cl solution was added. The mixture was extracted with EtOAc, dried over Na2SO4, and purified by column chromatography (silica, hexanes / EtOAc) to give the desired compound (40mg, 0.072 mmol, 75% yield) in the form of a white solid. Step 315b. To a solution of the compound from step 315a (38 mg, 0.069 mmol) in MPN (1 mL), m-CPBA (46.2 mg, 0.206 mmol, 77%) was added at 0 °C. The reaction was heated slowly to rt and stirred for 16 h. The mixture was extracted with EtOAc, washed with saturated Na₂S₂O₃ and NaHCO₃ (x2) solution, brine, and dried over Na₂SO₄. The crude material was purified by column chromatography (silica, MeOH / DCM) to give the title compound (14.0 mg, 0.024 mmol, 35% yield) as a whitish solid. ESI-MS m / z = 584.02, 586.02 [MH]-. Example 316 (not according to the invention) Step 316a. To a solution of 1-(diethoxymethyl)-1H-imidazole (0.053 mL, 0.322 mmol) in THF (2 mL), n-Butyllithium (0.116 mL, 0.290 mmol, 2.5 M in THF) was added at -78 °C. The mixture was heated to 0 °C and stirred for 45 min, then cooled to -78 °C. The compound from step 314a (30 mg, 0.064 mmol) in THF (1 mL) was added to the reaction mixture. The reaction was heated to 50 °C and stirred for 16 h. The reaction was cooled to room temperature, and saturated NH4Cl solution was added. The mixture was extracted with EtOAc, dried over Na2SO4, and purified by column chromatography (silica, hexanes / acetone) to give the desired compound (13 mg, 0.024 mmol, 38% yield) in the form of a whitish solid. Step 316b. To a solution of the compound from step 316a (13 mg, 0.024 mmol), CSA (8.48 mg, 0.037 mmol) in MPN (1 mL) m-CPBA (16.37 mg, 0.073 mmol, 77%) was added at 0 °C. The reaction was heated slowly to rt and stirred for 15 h. The mixture was extracted with EtOAc, washed with saturated Na2S2O3 solution and NaHCO3 solution (x2), brine, and dried over Na2SO4. The crude material was purified by column chromatography (silica, hexanes / acetone) to give the title compound (5.8 mg, 0.010 mmol, 42% yield) as a whitish solid. ESI-MS m / z = 565.02, 566.02 [MH]-. Example 317 (not according to the invention) Step 317a. Lithium diisopropylamide (1.372 mL, 1.372 mmol, 1M in THF) was added dropwise to a solution of 4-methylopyridine (0.134 mL, 1.372 mmol) in THF (3 mL) at -78 °C. The mixture was stirred for 1 h at the same temperature. A solution of the compound from step 281a (200 mg, 0.443 mmol) in THF (1.5 mL) was added to the mixture at -78 °C. The reaction was heated slowly to 100 °C and stirred for 16 h. Saturated NH4Cl solution was added. The mixture was extracted with EtOAc, dried over Na2SO4, and purified by column chromatography (silica, MeOH / DCM) to give the desired compound (91 mg, 0.167 mmol, 38% yield) in the form of a sticky oil. Step 317b. To a solution of the compound from step 317a (91 mg, 0.167 mmol), p-TSA (95 mg, 0.501 mmol) in MPN (1 mL), m-CPBA (112 mg, 0.501 mmol, 77%) was added at 0 °C. The reaction was heated slowly to rt and stirred for 16 h. The mixture was extracted with EtOAc, washed with saturated Na₂S₂O₃ solution and NaHCO₃ (x2) solution, brine, and dried over Na₂SO₄. The crude material was purified by column chromatography (silica, hexanes / acetone) to give the title compound (61.0 mg, 0.106 mmol, 63% yield) as a white solid. ESI-MS m / z = 576.04, 578.04 [MH]-. Example 318 (not according to the invention) Step 318a. Lithium diisopropylamide (1.372 mL, 1.372 mmol, 1 M in THF) was added dropwise to a solution of 3-methylopyridine (0.134 mL, 1.372 mmol) in THF (3 mL) at -78 °C. After stirring for 30 min at the same temperature, the mixture was heated to 0 °C, stirred for 30 min, and cooled to -78 °C. A solution of the compound from step 281a (200 mg, 0.443 mmol) in THF (1.5 mL) was added to the mixture at -78 °C. The reaction was heated slowly to 100 °C and stirred for 15 h. Saturated NH4Cl solution was added. The mixture was extracted with EtOAc, dried over Na2SO4, and purified by column chromatography (silica, MeOH / DCM) to give the desired compound (70 mg, 0.128 mmol, 29% yield) in the form of a pale yellow solid. Step 318b. To a solution of the compound from step 318a (70 mg, 0.128 mmol), p-TSA (73.3 mg, 0.385 mmol) in MPN (1 mL), m-CPBA (86 mg, 0.385 mmol, 77%) was added at 0 °C. The reaction was heated slowly to 100 °C and stirred for 16 h. Saturated Na₂S₂O₃ solution and NaHCO₃ solution were added, and the resulting mixture was stirred for 1 h. The mixture was extracted with EtOAc, washed with saturated Na₂S₂O₃ and NaHCO₃ solution (x2), brine, and dried over Na₂SO₄. The crude material was purified by column chromatography (silica, hexanes / acetone) to give the title compound (27.0 mg, 0.047 mmol, 36% yield) as a white solid. ESI-MS m / z = 576.04, 578.04 [MH]-. Example 319 (not according to the invention) Step 319a. Lithium diisopropylamide (0.549 mL, 1.372 mmol, 1M in THF) was added dropwise to a solution of 2-methylopyridine (0.135 mL, 1.372 mmol) in THF (3 mL) at -78 °C. After stirring for 1 h at the same temperature, a solution of the compound from step 281a (200 mg, 0.443 mmol) in THF (1.5 mL) was added to the mixture at -78 °C. The reaction was heated slowly to 100°C and stirred for 16 h. Saturated NH4Cl solution was added. The mixture was extracted with EtOAc, dried over Na2SO4, and purified by column chromatography (silica, MeOH / DCM) to give the desired compound (130 mg, 0.239 mmol, 54% yield) in the form of a pale yellow solid. Step 319b. To a solution of the compound from step 319a (130 mg, 0.239 mmol), p-TSA (136 mg, 0.716 mmol) in MPN (1 mL) m-CPBA (160 mg, 0.716 mmol, 77%) was added at 0 °C. The reaction was heated slowly to rt and stirred for 16 h. Saturated Na2S2O3 solution and NaHCO3 solution were added and the resulting mixture was stirred for 1 h rt. The mixture was extracted with EtOAc, washed with saturated Na2S2O3 solution and NaHCO3 solution (x2), brine, and dried over Na2SO4. The crude material was purified by column chromatography (silica, hexanes / acetone) to give the title compound (80.0 mg, 0.139 mmol, 58% yield) as a white solid. ESI-MS m / z = 576.04, 578.04 [MH]-. Example 320 (not according to the invention) Step 320a. To a solution of the compound from Example 82a (450 mg, 1.00 mmol) in DCM (5 mL), allyl bromide (363 mg, 3.0 mmol) was added, followed by a second-generation Hoveyda-Grubbs catalyst (12.5 mg, 0.2 mmol), and the mixture was stirred at room temperature. The reaction was concentrated. The crude was chromatographed (silica, EtOAc / hexanes) to give the desired compound (410 mg, a mixture of desired and starting material in a 1.1:1 ratio) as a whitish solid. ESI-MS m / z = 542.16, 544.16[MH]-. Step 320b. To a solution of the compound from step 320a (170 mg, 0.31 mmol) in DMF (2 mL), Dioxoisothiazolidine (38 mg, 0.31 mmol) was added, followed by K₂CO₃ (44 mg, 0.31 mmol), and the mixture was stirred at 65 °C o / n. The crude was diluted with EtOAc, washed twice with water, twice with brine, dried (Na₂SO₄), and concentrated. The crude was chromatographed (silica, MTBE / hexanes) to give the desired compound (59 mg, 32%) as a whitish solid. ESI-MS m / z = 627.12, 629.12 [M-H+HCOOH]-. Step 320c. The title compound was obtained from the compound of step 320b following the procedure described in example 4b. ESI-MS m / z = 693, 30, 695, 30 [M-H+HCOOH]-. Example 321 (not according to the invention) Step 321a. To a solution of the compound from step 82a (100 mg, 0.222 mmol) and 3-bromopyridine (26 L, 0.267 mmol) in DMF (2 mL) were added Et3N (62 L, 0.445 mmol), tri-o-tolylphosphine (6.8 mg, 0.022 mmol), and palladium acetate (2.5 mg, 0.011 mmol). The reaction mixture was stirred at 120 °C for 18 h. The reaction mixture was cooled, then extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by column chromatography (silica, hexane / acetone) to give the desired compound (100 mg, 0, 190 mmol, 85% yield). ESI-MS m / z = 571, 30, 573, 30 [MH]-. Step 321b. To a solution of the compound from step 321a (52 mg, 0.099 mmol) in acetone (1 mL) and water (0.2 mL), OsO4 (25 L, 4.93 mol, 5% in water) and NMO (58 mg, 0.493 mmol) were added. The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with ethyl acetate and then washed with saturated Na2S2O3 and saturated NaCl. The organic layer was dried with Na2SO4, filtered, and concentrated. The crude material was used without further purification. Step 321c. To a solution of the crude material from step 321b in MPN (2 mL), p-TSA (56 mg, 0.294 mmol) and m-CPBA (110 mg, 0.49 mmol, 77%) were added and stirred at room temperature. The reaction was extracted with EtOAc, washed with water and brine. The organic layer (Na2SO4) was dried, filtered, and concentrated. The crude product was chromatographed (silica, hexane / acetone) to give the title compound as a white solid. ESI-MS m / z = 637.32, 639.32 [M+HCO2]-. Example 322 (not according to the invention) Step 322a. To a solution of the compound from step 82a (100 mg, 0.222 mmol) and 4-bromo-1-methyl-1H-pyrazole (28 L, 0.267 mmol) in DMF (2 mL) were added Et3N (62 L, 0.445 mmol), tri-o-tolylphosphine (6.8 mg, 0.022 mmol), and palladium acetate (2.5 mg, 0.011 mmol). The reaction mixture was stirred at 120 °C for 18 h. The reaction mixture was cooled, then extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated. The crude material was purified by column chromatography (silica, hexane / acetone) to give the desired compound (12 mg, 0.023 mmol, 10% yield). ESI-MS m / z = 574.32, 576.32 [MH]-. Step 322b. To a solution of the compound from step 322a (12 mg, 0.099 mmol) in acetone (0.5 mL) and water (0.1 mL), OsO4 (6 L, 1.13 mol, 5% in water) and NMO (13 mg, 0.113 mmol) were added. The reaction mixture was stirred at room temperature for 72 h. The reaction mixture was diluted with ethyl acetate and then washed with saturated Na2S2O3 and saturated NaCl.The organic layer was dried with Na2SO4, filtered, and concentrated. The crude mixture was used without further purification. Step 322c. To a solution of the crude material from step 322b in MPN (1 mL), m-CPBA (16 mg, 0.069 mmol, 77%) was added and stirred at room temperature. The reaction was extracted with EtOAc, washed with water and brine. The organic layer (Na2SO4) was dried, filtered, and concentrated. The crude product was chromatographed (silica, hexane / acetone) to give the title compound as a white solid. ESI-MS m / z = 640.33, 642.33 [M+HCO2]-. Example 323 (not according to the invention) Step 323a. To a solution of trimethylosylacetylene (0.50 mL, 3.56 mmol) in THF (1.66 mL), n-BuLi (1.426 mL, 3.56 mmol, 2.5 M in THF) was added at -78 °C. The resulting mixture was stirred for 1 h at the same temperature. A solution of the compound from step 281a (0.3 g, 0.664 mmol) in THF (1.66 mL) was added to the reaction at -78 °C. The resulting pale yellow solution was heated slowly to 1 h and stirred for 3 h. Saturated NH4Cl solution was added. The mixture was extracted with EtOAc, dried over Na2SO4, and used without further purification. Step 323b. Potassium carbonate (459 mg, 3.32 mmol) was added to a solution of the compound from step 323a (365 mg, 0.664 mmol) in MeOH (3 mL) and water (0.3 mL). The mixture was stirred for 15 h. The solvent was removed by vacuum, and the resulting mixture was extracted with EtOAc, dried over Na2SO4, and then purified by column chromatography (silica, hexanes / EtOAc) to give the desired compound (204.9 mg, 0.429 mmol, 65% yield) in the form of a white solid. Step 323c. A mixture of formaldehyde (109 µl, 1.465 mmol), acetic acid (12.58 µl, 0.220 mmol), and THF (1 mL) was stirred for 15 min at room temperature. Sodium azide (14.28 mg, 0.220 mmol) was added, followed by the compound from step 323b (70 mg, 0.146 mmol). The mixture was stirred for 10 min, and sodium ascorbate (5.80 mg, 0.029 mmol) was added, followed by copper(II) sulfate (1.169 mg, 7.32 µmol) in 150 µL of water. The reaction was heated to 50°C and stirred for 16h, then extracted with EtOAc, dried over Na2SO4, and then purified by column chromatography (silica, MeOH / DCM) to give the desired compound (53.4 mg, 0.103 mmol, 70% yield) in the form of a greenish solid. Step 323d. To a solution of the compound from step 323c (53.4 mg, 0.102 mmol) and p-TsOH (97 mg, 0.512 mmol) in MPN (1 mL), m-CPBA (68.9 mg, 0.307 mmol, 77%) was added at 0 °C. The reaction was heated slowly to 100 °C and stirred for 15 h. Saturated Na2S2O3 solution and NaHCO3 solution were added, and the resulting mixture was stirred for 1 h. The mixture was extracted with EtOAc, washed with saturated Na2S2O3 solution and NaHCO3 solution (x2), brine, and dried over Na2SO4. The crude material was purified by column chromatography (silica, MeOH / DCM with 0.1% NH3) to give the title compound (15.0 mg, 0.027 mmol, 27% yield) as a whitish solid. ESI-MS m / z = 549.95, 551.97 [MH]-. Example 327 (not according to the invention) Step 327a. Treatment of the compound from step 279d with the condition described in intermediate step 2e gave the desired product.1H NMR (400 MHz, Chloroform-d) 3, 90 (m, 1H) , 3, 43 (s, 2H) , 2, 69 (s, 1H) , 1, 84 (m, 4H) , 1, 70 (m 2H) , 1, 57 (m, 2H) , 1, 45 (t, J = 6, 7 Hz, 3H) , 0, 83 (s, 9H) , 0, 00 (s, 6H) . Step 327b. To a solution of the compound from step 327a (10.6 g, 37.0 mmol) in CH2Cl2 (74.0 mL) at 0 °C, pyridine (8.98 mL, 111 mmol), DMAP (0.226 g, 1.850 mmol), and benzenesulfonyl chloride (5.19 mL, 40.7 mmol) were added. After stirring at room temperature, water (15 mL) was added, and the mixture was stirred for 30 min. The solution was concentrated and then diluted with EtOAc (400 mL) and washed with saturated aqueous NaHCO3, water, 1M HCl, water, and brine. The organic layer (Na2SO4) was dried and concentrated to give the crude product, which was used for the next step without further purification. Step 327c. To a solution from step 327b (15.60 g, 36.6 mmol) in 2-methyl-THF (58.5 mL) at room temperature, concentrated HCl (11.70 mL, 140 mmol) was added. The resulting clear solution was stirred at room temperature for 3 h. The mixture was poured in portions into a mixture of saturated aqueous NaHCO3 and DCM. The aqueous layer was extracted with DCM twice. The combined organic phase was washed with brine, dried (Na2SO4), filtered, and concentrated. The residue was dried under vacuum to obtain a white solid, which was used directly for the next step. Step 327d. To a solution of the compound from step 327c (11.42 g, 36.6 mmol) in CH2Cl2 (122 mL) at 0 °C, DMAP (0.447 g, 3.66 mmol), pyridine (8.87 mL, 110 mmol), and acetic anhydride (3.79 mL, 40.2 mmol) were added. The reaction was stirred at room temperature. Saturated aqueous NaHCO3 (30 mL) was added, and the mixture was stirred for 15 minutes. After separation, the aqueous phase was extracted with CH2Cl2 (100 mL x 2), and the combined organic phases were dried (Na2SO4) and concentrated. The crude was chromatographed to give the desired compound (11.4 g, 93% in three steps) in the form of a whitish solid. Step 327e. To a solution of the compound from step 327d (4.000 g, 11.29 mmol) in acetic acid (45 mL) at room temperature, manganese bis(trifluoromethansulfonate) (0.91 mL, 0.011 mmol) (0.0125 M in acetic acid / water 9 / 1) and 2,2'-bipyridine (0.018 g, 0.113 mmol) were added. After stirring for 10 min at room temperature, a peracetic acid / KOH mixture (prepared by adding 10% KOH (3.0 mL) to 35% peracetic acid (10.0 mL), 11.79 mL, 39.5 mmol) was added dropwise for ~10 min. The mixture was stirred for an additional 15 minutes at room temperature, followed by the addition of 130 mL of acetone. After 1 minute at room temperature, the slightly turbid solution was filtered through a short bed of Celite and washed with acetone. The filtrate was concentrated. The crude residue was chromatographed (silica, EtOAc / hexanes) to obtain the desired compound (2, 130 g, 51%) in the form of a colorless oil. Step 327f. To a clear solution of step 327e (2.130 g, 5.78 mmol) and intermediate 6 (1.820 g, 6.07 mmol) in DMF (5.78 mL), potassium carbonate (0.799 g, 5.78 mmol) was added. The mixture was stirred at 70 °C for 12 h before cooling. The mixture was diluted with EtOAc and saturated NH4Cl solution. The organic layer was washed with water / brine (1 / 1, *2), brine (*1), dried, and concentrated. The crude residue was chromatographed (silica, EtOAc / DCM) to obtain the desired compound (2.10 g, 70%). ESI-MS m / z = 508.07, 510.07 [MH]-. Step 327g. To a solution of the compound from step 327f (40 mg, 0.078 mmol) in EtOH at 0 °C, NaBH4 (6 mg, 0.16 mmol) was added. 30 minutes later, a second portion of 2 eq. of NaBH4 was added and stirred at room temperature for 3 hours. A total of ~10 eq. of NaBH4 was added. Concentrated to remove the volatile.The crude compound was dissolved in EtOAc and washed with NH4Cl and brine, dried, and concentrated to give the desired crude compound (60 mg) as a white solid. This material was used in the next step without further purification. ESI-MS m / z = 468.08, 470.08 [MH]-. Step 327h. The title compound was obtained from step 327g, following the procedure described in example 130b. ESI-MS m / z = 500, 07, 502, 07 [MH]-. Example 328 (not according to the invention) Step 328a. To the compound from step 327f (610 mg, 1.2 mmol) in EtOH (50 mL) / MeOH (15 mL) at 0 °C, NaBH4 (360 mg, 9.6 mmol) was added. Fifteen minutes later, a second portion of NaBH4 (200 mg) was added. Ten minutes later, a third portion of NaBH4 (100 mg) was added, and the mixture was stirred for another 10 minutes. While still cold, dilute HCl (0.5 M) was added dropwise until bubbling ceased. EtOAc (200 mL) was added, followed by 50 mL of water. The organic layer was washed with water and brine, dried with Na2SO4, and concentrated. The crude residue was chromatographed (silica, EtOAc / hexanes) to obtain the desired compound (410 mg, 67%) as a white solid. ESI-MS m / z = 510.09, 512.09[MH]-. Step 328b. To the compound solution of step 328a (382 mg, 0.77 mmol) in toluene (1 mL), 2-(tributyl-15-phosphanylidene)acetonitrile (647 mg, 2.68 mmol) in toluene (3 mL) was added. It was heated to 95 to 100 °C for 1 h, a second portion of 2-(tributyl-15-phosphanylidene)acetonitrile (400 mg) was added and it was heated for another 1.5 h. A third portion of 2-(tributyl-15-phosphanylidene)acetonitrile (500 mg) was added, and the mixture was heated for another 1.5 h before being cooled and concentrated. The crude product was chromatographed (silica, MTBE / hexanes) to give the desired compound (302 mg 80%) as a white solid. ESI-MS m / z = 492.08, 494.08[MH]-. Step 328c. To the compound from step 328b (295 mg, 0.60 mmol) in acetic anhydride (5 mL), BF3 etherate (0.6 mL, 4.8 mmol) was added and stirred at room temperature for 30 minutes. The reaction was added to aqueous NaHCO3 (40 mL) slowly in an ice-cold water bath. It was extracted twice with EtOAc. The combined organic layer was washed with water and brine and dried (Na2SO4). After concentration, the crude residue was chromatographed (silica, EtOAc / hexanes) to obtain the desired compound (245 mg, 69%) as a white solid, a mixture of bis-acetates and tri-acetates. ESI-MS m / z = 552, 10, 554, 10[MH]- (bis-acetates), m / z = 594, 11, 596, 11[MH]- (tri-acetates). Step 328d. K₂CO₃ (183 mg, 1.33 mmol) was added to the solution of the compound from step 328c (245 mg, 0.44 mmol) in MeOH (3 mL). Two hours later, an additional 25 mg of K₂CO₃ was added, and the mixture was stirred for another 1 h before being diluted with EtOAc and washed with water. The aqueous phase was extracted with EtOAc. The combined organic phase was washed with brine, dried (Na₂SO₄), and concentrated. The crude was chromatographed (silica, MTBE / hexanes) to give the desired compound (148 mg, 71%) as a whitish solid. ESI-MS m / z = 468.08, 470.08[MH]⁻. Step 328e. The title compound was obtained from the compound of step 328d following the procedure described in example 130b. ESI-MS m / z = 500, 07, 502, 07 [MH]-. Example 329 (not according to the invention) To a solution of compound from example 150 (250 mg, 0.514 mmol) in acetonitrile (5 mL) were added (2R, 3R, 4S, 5S, 6S)-2-bromo-6-(methoxycarbonyl) tetrahydro-2H-pyran-3,4,5-triyl triacetate (613 mg, 1.543 mmol) and Ag2CO3 (1.42 g, 2.57 mmol, 50% w / w on celite). The reaction mixture was heated at 80 °C for 18 h. The crude reaction mixture was filtered through celite, concentrated, and purified by chromatography (silica, acetone / hexanes) to give the title compound (195 mg, 47%). ESI-MS m / z = 846, 17, 848, 16 (M+HCO2) -. Example 330 (not according to the invention) To a solution of the compound from Example 329 (195 mg, 0.243 mmol) in THF (3 mL), methanol (1 mL), and water (2 mL), LiOH (50 mg, 2.09 mmol) was added. The reaction mixture was heated at 40 °C for 1 h. The crude reaction mixture was diluted with EtOAc and acidified to pH 4 with 1 M HCl. The organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by preparative HPLC (C₁₈, acetonitrile / water) to give the title compound (10 mg, 6%). ESI-MS m / z = 660.11, 662.11 (MH) -. Example 331 (not according to the invention) A mixture of example 182 (159 mg, 0.30 mmol) and IBX (101 mg, 0.36 mmol) in DMSO (1.5 mL) was stirred at room temperature for 4 h. Aqueous Na₂S₂O₃ solution was added, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na₂SO₄, filtered, concentrated, and purified by preparative HPLC (C₁₈ column, acetonitrile / water) to give the title compound (58 mg, 36%). ESI-MS m / z = 572.27, 574.27 (M+HCO₂)⁻. Example 332 (not according to the invention) To a solution of the compound from step 331 (230 mg, 0.436 mmol) in THF (5 mL), methylmagnesium bromide (0.508 mL, 1.525 mmol) was added at -78 °C. The mixture was stirred for 3 h at the same temperature. Water was added, and the mixture was extracted with EtOAc, dried over Na₂SO₄, and the crude material was purified by column chromatography (silica, hexanes / acetone) to the title compound (34.3 mg, 0.063 mmol, 15% yield) as a white solid. ESI-MS m / z = 541.01, 543.01 [MH]-. Example 333 (not according to the invention) Step 333a. A mixture of the compound from step 82a (112 mg, 0.25 mmol), E-hex-3-ene (630 mg, 7.5 mmol), and Grubbs-Hoveyda 2nd generation catalyst (15.7 mg, 0.025 mmol) in DCM (2.0 mL) was stirred at room temperature for 20 h. The mixture was purified by column chromatography (silica, hexanes / EtOAc) to give the desired compound as a white solid (78 mg, 65%). ESI-MS m / z = 476.13, 478.13 [MH]-. Step 333b. To a suspension of the compound from step 333a (78 mg, 0.163 mmol) and NMO (0.115 g, 0.98 mmol) in acetone-water (2.1 mL / 0.3 mL) at room temperature, osmium tetroxide (0.205 mL 2.5% in t-butanol, 0.016 mmol) was added and the mixture was stirred at room temperature for 20 h. It was deactivated with aqueous Na2SO3, extracted with EtOAc, washed with water, 3N HCl, NaHCO3, brine, dried over Na2SO4, filtered and concentrated to give a mixture of sulfone and sulfoxide, used without further purification. Step 333c. To a solution of the compound from step 333b in MPN (2 mL), m-CPBA (0.183 g, 0.85 mmol, 77%) was added and stirred at room temperature for 20 h. Aqueous Na₂S₂O₃, NaHCO₃, and a few drops of Et₃N were added and stirred at room temperature for 1 h. The mixture was extracted with EtOAc, washed with water and brine, dried over Na₂SO₄, filtered, concentrated, and purified by preparative HPLC (C₁₈, acetonitrile / water) to give the racemic product. The racemic product was separated by chiral SFC using MeOH as the eluent to give the title compound (18 mg, 20%). ESI-MS m / z = 542.29, 544.29 [MH]⁻. Example 334 (not according to the invention) Step 334, The title compound (18 mg, 20%) was isolated from example 333, ESI-MS m / z = 542, 29, 544, 29 [MH]-. Example 336 (not according to the invention) A solution of the compound from Example 182 (1.05 g, 1.98 mmol) and IBX (0.777 g, 2.77 mmol) in DMSO (5 mL) was stirred overnight. It was deactivated with aqueous Na₂S₂O₃ and aqueous NaHCO₃. The reaction mixture was extracted with EtOAc, washed with water and brine, dried over Na₂SO₄, filtered, and concentrated. The resulting crude product was purified by preparative HPLC (C18, acetonitrile / water) to give the title compound (32 mg, 3.1%) as a white solid. ESI-MS m / z = 570.26, 572.26 [M+HCO₂]⁻. Example 337 (not according to the invention) Step 337a. To a solution of the compound from intermediate step 2a (92.0 g, 676 mmol) in THF (135 mL) at 0 °C, a solution of prop-1-yn-1-ylmagnesium bromide (1554 mL, 777 mmol) was added through a cannula for 30 minutes. The mixture was stirred for 5 minutes before removing the ice bath. The mixture was heated to 100 °C and held at 100 °C for 30 minutes. The reaction mixture was cooled to 0 °C, and saturated aqueous NH4Cl (500 mL) was added, followed by MTBE (500 mL). The aqueous phase was separated and extracted with MTBE (500 mL). The combined organic phases were washed with brine and dried with Na2SO4. The solution was passed through a short silica gel column and concentrated to give a yellow oil (125 g, 105% yield). Step 337b. To a solution of the compound from step 337a (50.0 g, 284 mmol) in dioxane (400 mL) and water (133 mL) at 0 °C, 2,6-lutidine (66.1 mL, 567 mmol) and sodium peroxide (212 g, 993 mmol) were added, followed by the addition of a solution of OsO4 (1.803 mL, 0.284 mmol, 4% in water). This mixture was heated to 1 °C and stirred at 1 °C for 2 days, then cooled to 0 °C and deactivated with saturated aqueous Na2S2O3 solution. The mixture was stirred at 0 °C for 1 h, then diluted with 1 L of water, and extracted with MTBE (1 L x 3). The combined organic phases were washed twice with 1N HCl, water, aqueous NaHCO3 solution, water, and brine, dried (Na2SO4), and concentrated. The crude residue was chromatographed to obtain the desired product (40.2 g, 80%) in the form of a whitish solid. Step 337c. A solution of LAH (1M in THF, 265 mL, 265 mmol) and DME (430 mL) was cooled to 0°C. A solution of the compound from step 337b (18.9 g, 106 mmol) in DME (80 mL) was added dropwise over approximately 0.5 hours and stirred for one more hour. It was heated to and held at 80°C for 2 hours before being cooled to 0°C. It was carefully deactivated with 10 mL of water and 10 mL of 15% NaOH solution, followed by the addition of 72 g of solid Na₂SO₄ and stirred for 1 hour before filtration. After concentration, the crude residue was chromatographed to obtain the desired product (12.6 g, 65%) in the form of a whitish solid. Step 337d. To a solution from step 337c (4.58 g, 25.1 mmol) in dichloromethane (50 mL), pyridine (4.1 mL, 50 mmol) and benzenesulfonyl chloride (5.33 g, 30.2 mmol) were added. The reaction was stirred before adding water (30 mL). The mixture was stirred for 1 h. After separation, the aqueous phase was extracted with DCM (100 mL). The combined organic phase was washed with HCl (1 M, 20 mL), water, NaHCO3, brine, and dried with Na2SO4. After concentration, the crude residue was chromatographed to obtain the desired product (6.67 g, 82%) in the form of a whitish solid. Step 337e. To a solution of K2OsO6•2H2O (381 mg, 1.03 mmol), (DHQ) 2PHAL (1.61 mg, 2.07 mmol), K2CO3 (8.58 g, 62.1 mmol), and K3FeCN6 (20.4 g, 62.1 mmol) in t-BuOH (40 mL) / water (40 mL) at 0 °C, the compound from step 337d (6.67 g, 20.69 mmol) and MeSO2NH2 (5.90 g, 62.1 mmol) were added. The reaction was heated to 1 °C and stirred for 1 day. It was cooled to 0 °C and Na2SO3 (30 g) was added. The mixture was stirred for 15 minutes at 0°C, then for 1 hour at room temperature before partitioning with EtOAc (50 mL). The aqueous phase was re-extracted with EtOAc. The combined organic layer was washed with aqueous Na₂S₂O₃, water, 1N HCl (20 mL), water, 2M KOH (10 mL), water, and almuria. It was dried with Na₂SO₄ and concentrated to give the desired product (7.20 g, 97%) in the form of a whitish solid. This material was used in the next step without further purification. Step 337f. To a solution of the compound from step 337e (7.20 g, 20.20 mmol) in CH2Cl2 (50 mL) at 0 °C, DIPEA (14.11 mL, 81 mmol) and acetic anhydride (5.72 mL, 60.6 mmol) were added. The reaction was stirred overnight. Saturated aqueous NaHCO3 (30 mL) was added and stirred for 15 minutes. After separation, the aqueous phase was extracted with CH2Cl2 (100 mL x 2), the combined organic phases were dried (Na2SO4), and concentrated. The crude was chromatographed to give the desired compound (8.2 g, 100%) as a whitish solid. Step 337g. To a clear solution of the compound from step 337f (5.09 g, 11.55 mmol) in hexafluoroisopropanol (40 mL) at 1 / 4 volume, manganese bis(trifluoromethansulfonate) (20 mg / mL, 0.058 mmol) and 2,2'-bipyridine (0.09 g, 0.58 mmol) were added. After stirring for 10 min at 1 / 4 volume, a peracetic acid / KOH mixture (prepared by adding 10% KOH (3.0 mL) to 35% peracetic acid (10.0 mL), 11.79 mL, 39.5 mmol) was added using a syringe pump for 1 h. Acetone (100 mL) was added. After stirring for 10 min, the solution was concentrated. The crude residue was chromatographed (silica, EtOAc / hexanes) to obtain the recovered starting material 3.1 g and the highly polar mixture 1.79 g. This highly polar mixture was used directly in the next step. Step 337h. To a solution of the highly polar mixture from step 337g, intermediate 6 was added following step 327f to obtain two-component mixtures. One component of the mixture contains the ketone product; ESI-MS m / z = 640, 31, 642, 31 [M+HCOO-]-. The other component contains the alcohol product. ESI-MS m / z = 642, 32, 644, 32 [M+HCOO-]-. Step 337i. The alcohol product from step 337h was treated under the conditions described in steps 328d and 328e sequentially and purified by preparative HPLC (C-18, Acetonitrile / water) to yield the title compound as a white solid. ESI-MS m / z = 590, 27, 592, 27 [M+HCOO-]-. Example 339 (not according to the invention) Step 339a. To a solution of intermediate 2a (2.29 g, 16.8 mmol) in THF (18 mL) at 0 °C, ethinylmagnesium bromide (40.4 mL, 20.2 mmol, 0.5 M in THF) was added and stirred at 0 °C for 30 minutes. The reaction was deactivated by the slow addition of aqueous NH4Cl. MBTE and water were added. The mixture was separated, and the organic layer was washed with water and brine. The mixture was dried over Na2SO4, filtered, and concentrated under vacuum to give the desired product (2.73 g, 100%). Step 339b. To a solution of the compound from step 339a (1.7 g, 8.38 mmol) in THF (12 mL) at 0 °C, n-BuLi (7.38 mL, 18.4 mmol, 2.5 M in hexanes) was added dropwise. After 20 minutes at 0 °C, CD3I (0.69 mL, 10.9 mmol) was added, and the mixture was stirred at room temperature for 20 h. The reaction was stopped by the slow addition of aqueous NH4Cl. MBTE and water were added. The mixture was separated, and the organic layer was washed with water and brine. The mixture was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was chromatographed (silica, hexanes / MBTE) to give the desired product (1.09 g, 65%). Step 339c. To a solution of the compound from step 339b (0.986 g, 5.5 mmol) in dioxane-water (12.4 mL), 2,6-lutidine (1.45 mL, 11 mmol) and OsO4 (0.18 mL 2.5% solution in tert-butanol, 0.017 mmol) were added. The mixture was cooled and NaIO4 (4.12 g, 19.25 mmol) was added. The suspension was stirred at room temperature for 16 hours. Aqueous Na2S2O3 solution was added. The mixture was stirred for 1 hour and filtered through Celite. The mixture was extracted with MBTE / Hexanes. The organic phase was washed with water, 1N HCl, Sat.NaHCO3 and brine, dried over Na2SO4, filtered and concentrated to give the crude product (0.64 g, 64.2%). Step 339d. To a solution of the compound from step 339c (0.64 g, 3.53 mmol) in CD3OD (10 mL), MeONa (23 mg, 0.42 mmol) was added, and the mixture was stirred at room temperature for 3 h. It was concentrated, and the residue was redissolved in CD3OD (5 mL) and stirred for 3 h. The same reaction cycle was repeated two more times, and the solution was deactivated with D2O. The mixture was extracted using MBTE. The organic layer was washed with D2O and a saturated solution of NaCl in D2O, dried over Na2SO4, filtered, and concentrated under vacuum to give the desired compound (0.62 g, 95%). Step 339e. To a LiBH4 solution (3.35 mL, 6.70 mmol, 2M solution in THF) at -40 °C, the compound from step 339d (0.62 g, 3.35 mmol) was added in MBTE (20 mL). The resulting solution was heated to 0 °C for 1 h. The reaction was deactivated by the slow addition of aqueous NH4Cl. MBTE and water were added. The mixture was separated, and the organic layer was washed with brine. The mixture was dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was chromatographed (silica, hexanes / MBTE) to give the desired compound as a white solid (0.45 g, 72%). Step 339f. A solution of the compound from step 339e (0.45 g, 2.40 mmol), LAH (6.01 mL, 6.01 mmol, 1M in THF), and MeONa (26 mg, 0.48 mmol) in DME (12 mL) was heated to and held at 80 °C for 2 h. The reaction mixture was cooled to 0 °C, carefully deactivated with 0.23 mL of water and 0.23 mL of 15% NaOH solution, held for 10 min, then 0.69 mL of water, followed by the addition of 5 g of solid Na2SO4, and stirred for 1 h before filtration. The filtrate was concentrated. The crude product was chromatographed (silica, hexanes / MBTE) to give the desired compound (0.32 g, 70%). Step 339g. To a solution of the compound from step 339f (0.32 g, 1.69 mmol) in dichloromethane (3.5 mL) at room temperature, pyridine (0.33 mL, 4.3 mmol) and 4-toluenesulfonyl chloride (0.387 g, 2.02 mmol) were added. The reaction was stirred at room temperature. Water was added. The mixture was stirred for 1 h. After separation, the aqueous phase was extracted with DCM. The combined organic phase was washed with 1N HCl, water, NaHCO3, brine, dried over Na2SO4, and concentrated. The crude product was chromatographed (silica, hexanes / MBTE) to give the desired compound (0.52 g, 90%). Step 339h. To a solution of K2OsO6•2H2O (27 mg, 0.073 mmol), (DHQ) 2PHAL (85 mg, 0.109 mmol), K2CO3 (0.604 g, 4.37 mmol), and K3FeCN6 (1.44 g, 4.37 mmol) in t-BuOH (7.0 mL) / water (7.0 mL) at 0 °C, compound from step 339 g (0.50 g, 1.46 mmol) and MeSO2NH2 (0.277 g, 2.91 mmol) were added. The reaction was allowed to heat slowly to rt and was stirred for 3 days. The mixture was cooled to 0°C followed by the addition of Na₂SO₃. The mixture was stirred for 15 minutes at 0°C, then for 1 hour at room temperature before partitioning with EtOAc. The aqueous phase was re-extracted with EtOAc. The combined organic layer was washed with aqueous Na₂S₂O₃, water, 1N HCl, water, 2M KOH, water, and brine, dried with Na₂SO₄, filtered, and concentrated. The crude product was chromatographed (silica, hexanes / EtOAc), then suspended in MeOH (5.6 mL) for 16 minutes and filtered to collect the desired product as a white solid (0.39 g, 70%). Step 339i. A solution of compound from step 339h (0.39 g, 1.03 mmol), intermediate 6 (0.316 g, 1.06 mmol), and K₂CO₃ (0.143 g, 1.03 mmol) in DMF (1.1 mL) was stirred at 70 °C for 16 h. It was diluted with EtOAc, and the mixture was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated. The crude product was chromatographed (silica, hexanes / EtOAc) to give the desired compound as a white solid (0.37 g, 71%). ESI-MS m / z = 503.16, 505.16 [MH]-. Step 339j. A solution of the compound from step 339i (0.37 g, 0.73 mmol) and m-CPBA (0.575 g, 2.56 mmol, 77%) in NMP (3.0 mL) was stirred at room temperature for 24 h. Aqueous Na2S2O3, NaHCO3, and a few drops of Et3N were added, and the mixture was stirred at room temperature for 1 h. The solution was extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and recrystallized from MeOH to give the title compound (0.33 g, 84%). ESI-MS m / z = 535.15, 537.15 [MH]-. Example 340 (not according to the invention) Step 340a. A mixture of the compound from step 337c (3.2 g, 17.6 mmol) and IBX (6.8 g, 24.3 mmol) in DMSO (20 mL) was stirred at 45 °C for 14 h. Aqueous Na₂S₂O₃ solution was added to 1 / 3 and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated. The crude product was chromatographed (silica, hexanes / MBTE) to give the desired product (2.3 g, 72%). Step 340b. To a solution of the compound from step 340a (2.3 g, 12.8 mmol) in CD3OD (20 mL), MeONa (138 mg, 2.55 mmol) was added, and the mixture was stirred at room temperature for 3 h. It was concentrated, and the residue was redissolved in CD3OD (20 mL) and stirred for 3 h. The same reaction cycle was repeated two more times, and the solution was deactivated with D2O. The mixture was extracted using MBTE. The organic layer was washed with D2O and a saturated solution of NaCl in D2O, dried over Na2SO4, filtered, and concentrated under vacuum to give the desired compound (2.0 g, 85%). Step 340c. To a LiBH4 solution (10.8 mL, 21.6 mmol, 2M solution in THF) at -40 °C, the compound from step 340b (2.0 g, 10.8 mmol) was added in MBTE (60 mL). The resulting solution was heated to 0 °C for 1 h. The reaction was deactivated by the slow addition of aqueous NH4Cl, then diluted with MBTE and water. The mixture was separated, and the organic layer was washed with brine. The mixture was dried over Na2SO4, filtered, and concentrated. The crude product was chromatographed (silica, hexanes / MBTE) to give the desired compound as a white solid (1.4 g, 69%). Step 340d. To a solution of the compound from step 340c (0.216 g, 1.16 mmol) in dichloromethane (1.5 mL) at room temperature, pyridine (0.28 mL, 3.48 mmol) and 3-nitrobenzenesulfonyl chloride (0.385 g, 1.74 mmol) were added. The reaction was stirred at room temperature. Water was added, and the mixture was stirred for 1 h. After separation, the aqueous phase was extracted with DCM. The combined organic phase was washed with 1N HCl, water, NaHCO3, and brine, dried over Na2SO4, filtered, and concentrated. The crude product was chromatographed (silica, hexanes / MBTE) to give the desired compound (0.37 g, 86%). Step 340e. A solution of the compound from step 340d (0.36 g, 0.97 mmol), methyl 4-chloro-3-mercaptobenzoate (0.206 g, 1.02 mmol), and Cs₂CO₃ (0.316 g, 0.97 mmol) in DMF (1.1 mL) was stirred at 80 °C for 16 h. It was diluted with EtOAc, and the mixture was washed with water and brine, dried over Na₂SO₄, filtered, and concentrated. The crude product was chromatographed (silica, hexanes / EtOAc) to give the desired compound as a white solid (0.25 g, 69%). Step 340f. To a solution of the compound from step 340e (0.25 g, 0.674 mmol) in THF (3.0 mL), LiOH (2.7 mL, 1.35 mmol, 0.5 M solution in water) was added, and the mixture was stirred at room temperature for 3 h. The reaction was deactivated by the addition of 1 N HCl. EtOAc and water were added. The mixture was separated, and the organic layer was washed with brine. The mixture was dried over Na₂SO₄, filtered, and concentrated under vacuum to give the desired compound as a white solid (0.23 g, 96%). ESI-MS m / z = 355.24, 357.24 [MH]⁻. Step 340g. To a solution of the compound from step 340f (0.23 g, 0.644 mmol), 3,4-difluorobenzene-2,6-D2-amine (0.127 g, 0.967 mmol), DMAP (0.039 g, 0.322 mmol) in DMF (2.5 mL), EDC (0.185 g, 0.967 mmol) was added and the mixture was stirred at room temperature for 16 h. It was diluted with EtOAc and the mixture was washed with water and brine, dried over Na2SO4, filtered, and concentrated. The crude product was chromatographed (silica, hexanes / EtOAc) to give the desired compound (0.26 g, 86%). ESI-MS m / z = 468, 31, 470, 31 [MH]-. Step 340h. To a suspension of the compound from step 340 g (260 mg, 0.553 mmol) and NMO (0.324 g, 2.77 mmol) in acetone-water (2.1 mL / 0.3 mL) at room temperature, osmium tetroxide (0.28 mL, 0.055 mmol, 5% in water) was added and the mixture was stirred at room temperature for 20 h. It was inactivated with aqueous Na2SO3, extracted with EtOAc, washed with water, 1N HCl, NaHCO3, brine, dried over Na2SO4, filtered and concentrated to give a used sulfone and sulfoxide mixture without further purification. Step 340i. To a solution of the compound from step 340h in MPN (2.5 mL), m-CPBA (0.41 g, 1.83 mmol, 77%) was added and stirred at room temperature for 20 h. Aqueous Na2S2O3, NaHCO3, and a few drops of Et3N were added and stirred at room temperature for 1 h. The mixture was extracted with EtOAc, washed with water and brine, dried over Na2SO4, filtered, and concentrated to give the desired product (0.27 g, 96%). ESI-MS m / z = 580.33, 582.33 (M+HCO2)-. Step 340j. A mixture of the compound from step 340i (362 mg, 0.675 mmol) and IBX (227 mg, 0.81 mmol) in DMSO (5.0 mL) was stirred at room temperature for 4 h. Aqueous Na₂S₂O₃ solution was added, and the mixture was extracted with EtOAc. The organic layer was washed with water and brine, dried over Na₂SO₄, filtered, concentrated, and purified by preparative HPLC (C18 column, acetonitrile / water) to give the title compound (150 mg, 41%). ESI-MS m / z = 578.32, 580.32 (M+HCO₂)⁻. Example 341 (not according to the invention) Step 341a. 1-Methyl-1H-pyrrole-2-carboxylic acid (3 g, 23.98 mmol) was dissolved in portions in chlorosulfonic acid (12 mL, 179 mmol) in an ice bath. The reaction was stirred for 70 min at the same temperature. The mixture was slowly deactivated by the addition of ice / water (100 mL) (very reactive!!) and stirred for 15 min. The precipitate was filtered, rinsed with water, and the resulting solid was dissolved in EtOAc, dried over NaSO4, the solvent was removed under vacuum, and it was dried overnight under vacuum to give the desired compound (3.60 g, 16.10 mmol, 67% yield) in the form of a whitish solid. Step 341b. Oxalyl chloride (11.18 mL, 22.36 mmol) was added to a mixture of the compound from step 341a (1 g, 4.47 mmol) in DCM (20 mL) and DMF (0.02 mL). The reaction was stirred for 5 h. The solvent was removed under vacuum and taken with benzene (x3) to give the desired compound (1.08 g, 100% yield) in the form of a pale yellow solid. Step 341c. To a solution of the compound from step 341b (400 mg, 1.652 mmol) in toluene (15 mL) was added 3,4-Difluoroaniline (0.164 mL, 1.652 mmol) in toluene (1 mL) to 1°C. The mixture was heated to 110 °C and stirred for 1 h, then cooled to 1°C and stirred for 16 h. The solid was filtered and the resulting filtrate was removed under vacuum, which was used without further purification (553 mg, 100% yield). Step 341d. To a suspension of the compound from step 341c (550 mg, 1.643 mmol) in toluene (10 mL), triphenylphosphine (2.16 g, 8.22 mmol) was added. The reaction was heated to 85 °C and stirred for 6 h. The reaction was cooled to 100 °C and 10 mL of H₂O was added. The organic layer was washed twice with water (5 mL), followed by 1 N NaOH. The aqueous layer was collected. The aqueous layer was acidified with 1 N HCl to pH 4; it became a white emulsion as HCl was added. It was extracted with EtOAc, and the resulting mixture became a clear, colorless solution. The organic layer was collected and dried over Na2SO4 to give the desired compound (220mg, 0.820 mmol, 50% yield) in the form of a white solid. Step 341e. Cesium carbonate (197 mg, 0.606 mmol) was added to a solution of the compound from step 341d (130 mg, 0.485 mmol) and the compound from step 337d (187 mg, 0.505 mmol) in DMF (0.5 mL). The reaction was heated to 70 °C and stirred for 17 h. The mixture was extracted with EtOAc, dried over Na2SO4, and then purified by column chromatography (silica, hexanes / EtOAc) to give the desired compound (170 mg, 0.364 mmol, 72% yield) as a white solid. Step 341f. To a solution of the compound from step 341e (35 mg, 0.075 mmol) in NMP (0.3 mL), m-CPBA (50.4 mg, 0.225 mmol, 77%) was added at 0 °C. The reaction was heated slowly to rt and stirred for 15 h. Saturated Na2S2O3 solution and NaHCO3 solution were added, and the resulting mixture was stirred for 1 h rt. The mixture was extracted with EtOAc, washed with saturated Na2S2O3 solution and NaHCO3 solution (x2), brine, and dried over Na2SO4. The crude material was purified by column chromatography (silica, hexanes / EtOAc) to give the title compound (24.0 mg, 0.048 mmol, 64% yield) as a white solid. ESI-MS m / z = 497.52, 499.53 [MH]-. Example 344 (not according to the invention) Step 344a. To the compound solution from step 307a (500 mg, 0.71 mmol) in 2-methyltetrahydrofuran (3 mL), (R)-1-aminopropan-2-ol (160 mg, 2.12 mmol) was added, and the mixture was stirred at 75 °C for one day. The crude was diluted with EtOAc, washed twice with water, twice with brine, dried (Na₂SO₄), and concentrated. The crude was chromatographed (silica, MeOH / DC) to give the desired compound (255 mg) as a mixture of the desired compound with other impurities. ESI-MS m / z = 479.27, 481.27 [MH]-. Step 344b. To the mixture solution from step 344a (255 mg, 0.53 mmol) in 2-methyltetrahydrofuran (2 mL), CDI (112 mg, 0.69 mmol) and TEA (0.15 mL, 1.06 mmol) were added. The reaction mixture was heated to 50 °C for 1 h before cooling and concentrating. The crude was chromatographed (silica, EtOAc / hexanes) to give the desired compound as a mixture with other impurities. ESI-MS m / z = 505, 26, 507, 26 [MH]-. Step 344c. The compound from step 344b was treated under the conditions described in 130b and purified by preparative HPLC (C-18, acetonitrile / water) to obtain the title compound as a white solid. ESI-MS m / z = 537.26, 539.26 [MH]-. Example 345 (not according to the invention) Step 345a. To a solution of the compound from step 182 (1.046 g, 2.100 mmol) in CH2Cl2 (21 mL) at room temperature, triethylamine (0.586 mL, 4.20 mmol) and Ac2O (0.238 mL, 2.52 mmol) were added, and the mixture was then maintained at room temperature overnight. The reaction mixture was then partitioned between aqueous NaHCO3 and CH2Cl2 solutions. The combined organic phases were dried over Na2SO4, concentrated, and the crude product was purified by flash column chromatography to give a mixture (415 mg) of two inseparable monoacylated products. ESI-MS m / z = 584.13, 586.13 [M+HCO2]-. Step 345b. To a solution of the compound from step 345a (415 mg, 0.768 mmol) in CH2Cl2, 2-iodoxybenzoic acid (430 mg, 1.54 mmol) was added. The mixture was maintained at room temperature, then saturated aqueous Na2S2O3 solution was added. The mixture was partitioned between EtOAc and water. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated. The resulting crude product was chromatographed (silica, hexanes / EtOAc) to give the desired product (39 mg, 8.2% over 2 steps) as a white solid. ESI-MS m / z = 582.12, 584.12 [M+HCO2]-. Step 345c. To a solution of the compound from step 345b (39.1 mg, 0.073 mmol) in THF (0.3 mL) and MeOH (1.1 mL) at room temperature, K2CO3 (10 mg, 0.073 mmol) was added. The mixture was then maintained at room temperature for 1 h. The reaction mixture was diluted with MTBE, washed with water, dried over Na2SO4, and concentrated to give the desired crude product (19 mg, 53%) as a white solid, which was taken in the next step without further purification. ESI-MS m / z = 540.11, 542.11 [M+HCO2]-. Step 345d. To a solution of the compound from step 345c (19 mg, 0.038 mmol) in CH2Cl2 (1.9 mL) at room temperature, m-CPBA (34.3 mg, 0.153 mmol, 77%) was added and stirred at room temperature. The reaction was inactivated with saturated aqueous Na2S2O3 and aqueous NaHCO3. The reaction mixture was partitioned between EtOAc and the aqueous phase. The combined organic phases were washed with brine, dried over Na2SO4, and concentrated. The resulting crude product was chromatographed to give the desired product (11 mg, 29% over 2 steps) as a white solid. ESI-MS m / z = 572.09, 574.09 [M+HCO2]-. Example 346 (not according to the invention) Step 346a. To a solution of ethinylcyclopropane (1.864 mL, 22.03 mmol) in THF (4.50 mL), n-BuLi (8.81 mL, 22.03 mmol, 2.5 M in THF) was added at -78 °C. The resulting mixture was stirred for 1 h at the same temperature. A solution of the compound from intermediate step 2a (2.0 g, 14.68 mmol) in THF (9 mL) was added to the reaction at -78 °C. The resulting light yellow solution was heated slowly to 1 h and stirred for 2 h. Saturated NH4Cl solution was added. The mixture was extracted with MTBE and dried over Na2SO4 to give 2.95 g (99% yield) of the desired compound in the form of a yellow oil, which was used without further purification. Step 346b. To a solution of the compound from step 346a (2.97 g, 14.68 mmol) in dioxane (122 mL) and water (25 mL) at 5 °C, 2,6-lutidine (3.42 mL, 29.4 mmol) and sodium peroxide (10.99 g, 51.4 mmol) were added. OsO4 (0.921 mL, 0.073 mmol, 2.5% in t-BuOH) was added, and the resulting mixture was stirred for 15 h. Na2S2O3 (50 mL) and EtOAc (100 mL) were added. The mixture was stirred for 30 min and then filtered. The solid was washed with EtOAc (x3). The filtrate was collected and washed with 0.5N HCl (x4). The aqueous layer was re-extracted with EtOAc and the combined organic layer was dried over Na2SO4. The crude material was chromatographed (silica, hexanes / acetone) to give the desired compound (2.25 g, 11.01 mmol, 75% yield) in the form of a yellow oil. Step 346c. A solution of LiBH4 (13.77 mL, 27.5 mmol, 2M in THF) in MTBE (22.03 mL) at -50 °C was mixed with a solution of the compound from step 346b (2.25 g, 11.01 mmol) in MTBE (5 mL).The reaction was stirred at -50 °C for 3 h. NH4Cl (50 mL) was added. The mixture was extracted with EtOAc (100 mL), washed with brine, dried over Na2SO4 and chromatographed (silica, hexanes / EtOAc) to give the desired compound (1.62 g, 7.85 mmol, 71% yield) as a white solid. Step 346d. A mixture of LAH (13.77 mL, 13.77 mmol, 1M in THF) and NaOMe (0.074 g, 1.377 mmol) in DME (15 mL) was gradually mixed with a solution of the compound from step 346c (1.42 g, 6.88 mmol) in DME (2 mL). The reaction was heated to 80 °C and stirred for 3 h. The reaction was cooled to 0 °C and carefully deactivated with water and 1N NaOH solution. The mixture was filtered. The filtrate was extracted with MTBE and dried over Na₂SO₄. Recrystallization of the resulting material with MTBE and Hex yielded the desired compound (1.30 g, 6.24 mmol, 91% yield) as a white solid. Step 346e. To a solution of the compound from step 346d (1.6 g, 7.68 mmol) in DCM (10 mL), pyridine (1.243 mL, 15.36 mmol) was added at 0 °C. 4-Methylbenzenesulfonyl chloride (1.904 g, 9.99 mmol) was added. The mixture was heated slowly to 10 °C and stirred for 16 h. Water was added, and the mixture was extracted with DCM and dried over Na₂SO₄. The crude material was purified by column chromatography (silica, hexanes, EtOAc) to give the desired compound (2.10 g, 5.79 mmol, 75% yield) in the form of a colorless oil. Step 346f. To a mixture of t-BuOH (29.0 mL) and water (29.0 mL) at 0 °C, potassium osmate dihydrate (0.064 g, 0.174 mmol), (DHQ) 2PHAL (0.203 g, 0.261 mmol), potassium hexacyanoferrate (III) (5.72 g, 17.38 mmol), and potassium carbonate (2.402 g, 17.38 mmol) were added, followed by methanesulfonamide (3.31 g, 34.8 mmol) and the compound from step 346e (2.1 g, 5.79 mmol). The reaction was heated slowly to rt and stirred for 50 h. Na2SO3 (3.7 g) was added at 0 °C and the resulting mixture was stirred for 1 h. EtOAc was added, the solid was filtered through Celite, and washed with EtOAc (x2). The organic layer was extracted with EtOAc, and washed with 1N HCl (x3), followed by 2N K2CO3 solution and brine, and dried over Na2SO4 to give 1.85 g (4.67 mmol, 81% yield) of the desired product in the form of a whitish solid, which was used without further purification. Step 346g. To a solution of the compound from step 346f (1.85 g, 4.67 mmol) in DMF (15.55 mL), K2CO3 (0.632 g, 4.57 mmol) was added to 1 / 4. 4-Chloro-N-(3,4-difluorophenyl)-3-mercaptobenzamide (1.468 g, 4.90 mmol) was added. The resulting mixture was heated to 75 °C and stirred for 15 h. The reaction was cooled to 1 / 4, water was added, and the mixture was extracted with EtOAc (x3), washed with brine, and dried over Na2SO4. The raw material was chromatographed (silica, hexanes / EtOAc) to give the desired compound (1.91 g, 3.64 mmol, 75% yield) in the form of a whitish solid. Step 346h. To a solution of the compound from step 346 g (1.91 g, 3.64 mmol) in NMP (10 mL) m-CPBA (2.451 g, 10.93 mmol, 77%) was added at 0 °C. The mixture was heated to rt and stirred for 15 h. The reaction was inactivated with saturated Na2S2O3 solution and NaHCO3 solution, and stirred for 1 h. The mixture was extracted with EtOAc, washed with saturated Na2S2O3 solution and NaHCO3 solution (x2), brine, and dried over Na2SO4. The crude material was chromatographed (silica, hexanes / acetone) to give the desired compound (1.26 g, 2.27 mmol, 42% yield) as a white solid. ESI-MS m / z = 555.02, 557.02 [MH]-. Example 347 (not according to the invention) Step 347a. To a solution of 3-methylbut-1-yne (2.253 mL, 22.03 mmol) in THF (4.50 mL), n-BuLi (8.81 mL, 22.03 mmol, 2.5 M in THF) was added at -78 °C. The resulting mixture was stirred for 1 h at the same temperature. A solution of the compound from intermediate step 2a (2.0 g, 14.68 mmol) in THF (10 mL) was added to the reaction at -78 °C. The resulting pale yellow solution was heated slowly to 1 hr and stirred for 2 h. NH4Cl solution was added. The mixture was extracted with MTBE, dried over Na2SO4 to give 3.0 g (99% yield) of the desired compound in the form of a yellow oil, which was used without further purification. Step 347b. To a solution of the compound from step 347a (3.0 g, 14.68 mmol) in dioxane (122 mL) and water (25 mL) at 5 °C, 2,6-lutidine (3.42 mL, 29.4 mmol) and sodium peroxide (10.99 g, 51.4 mmol) were added. Osmium tetroxide (0.921 mL, 0.073 mmol, 2.5% in tBuOH) was added, and the resulting mixture was stirred for 16 h. Na2S2O3 (50 mL) and EtOAc (100 mL) were added. The mixture was stirred for 30 min and then filtered. The solid was washed with EtOAc (x3). The filtrate was collected and washed with 0.5N HCl (x4). The aqueous layer was re-extracted with EtOAc and the combined organic layer was dried over Na2SO4. The crude material was chromatographed (silica, hexanes / acetone) to give the desired compound (1.60 g, 7.76 mmol, 53% yield) in the form of a yellow oil. Step 347c. A solution of LiBH4 (9.70 mL, 19.39 mmol, 2M in THF) in MTBE (15.51 mL) at -50 °C was mixed with a solution of the compound from step 347b (1.60 g, 7.76 mmol) in MTBE (5 mL). The reaction was stirred at -50 °C for 3 h. NH4Cl (50 mL) was added. The mixture was extracted with EtOAc (100 mL), washed with brine, dried over Na2SO4, and the crude material was chromatographed (silica, hexanes / EtOAc) to give the desired compound (1.16 g, 5.58 mmol, 72% yield) as a foamy solid. Step 347d. A mixture of LAH (11.16 mL, 11.16 mmol, 1M in THF) and sodium methoxide (0.060 g, 1.116 mmol) in DME (15 mL) was gradually mixed with a solution of the compound from step 347c (1.162 g, 5.58 mmol) in DME (2 mL). The reaction was heated to 80 °C and stirred for 3 h. The reaction was cooled to 0 °C and carefully deactivated with water and 1N NaOH solution. The mixture was filtered. The filtrate was extracted with MTBE and dried over Na₂SO₄. Recrystallization of the resulting material with MTBE and Hex gives the desired compound (1.06 g, 5.02 mmol, 90% yield) as a white solid. Step 347e. The desired compound was obtained from the compound of step 347d following the procedure described in example 346e in the form of a cloudy oil (1.51g, 4.14 mmol, 87% yield). Step 347f. The desired compound was obtained from the compound of step 347e by following the procedure described in example 346f in the form of an off-white solid (1.01g, 2.53 mmol, 61% yield). Step 347g. The desired compound was obtained from the compound of step 347f by following the procedure described in example 346g in the form of an off-white solid (0.87g, 1.65 mmol, 65% yield). Step 347h. The desired compound was obtained from the compound of step 347 g following the procedure described in example 346 h in the form of a white solid (0.74 g, 1.32 mmol, 80% yield). ESI-MS m / z = 557.03, 559.02 [MH]-. Example 348 (not according to the invention) Step 348a. To a solution of the compound from Example 82a (50 mg, 0.111 mmol) in DCE (2 mL) at room temperature, tert-butyl 2-oxo-5-vinyloxazolidine-3-carboxylate (71.1 mg, 0.333 mmol) Grubbs-Hoveyda 2nd generation catalyst (6.96 mg, 0.011 mmol) was added. The mixture was degassed by bubbling N2 for 5 min and heated to 60 °C and stirred for 15 h. The reaction was cooled to room temperature. Water was added. The mixture was extracted with DCM and dried over Na2SO4. The raw material was chromatographed (silica, hexanes / EtOAc) to give the desired compound (45 mg, 0.071 mmol, 64% yield) in the form of a whitish solid. Step 348b. To a solution of the compound from step 348a (45 mg, 0.071 mmol) in acetone (3 mL) and water (0.8 mL), NMO (33.2 mg, 0.283 mmol) and OsO4 (178 µl, 0.014 mmol, 2.5% in t-BuOH) were added to 100%. The reaction was stirred for 16 h. The reaction was deactivated with saturated Na2S2O3 solution and extracted with EtOAc, washed with brine, and dried over Na2SO4. The crude material was used without further purification. Step 348c. To a solution of the compound from step 348b (50 mg, 0.071 mmol) in DCM (1 mL), TFA (0.027 mL, 0.355 mmol) was added to 1 mL. The reaction was stirred for 2 h. The solvent was removed. The mixture was extracted with DCM, washed with saturated NaHCO3 solution, and dried over Na2SO4. The crude material was purified by column chromatography (silica, MeOH / DCM) to give the desired compound (2:1 isomeric mixture, 14.5 mg, 0.024 mmol, 34% yield) as a whitish solid. ESI-MS m / z = 600.02, 602.02 [MH]-. The following examples were prepared using procedures similar to those described. The following are the following: Biological activity Methods: HepAD38 cells are maintained as previously reported (Ladner et al., Antimicrob. Agents Chemother. 1997, 4, 1715). Briefly, cells are passaged to confluence in DMEM / F12 media in the presence of 10% FBS, Penn / Strep, 250 µg / mL G418, and 1 µg / mL tetracycline. New compounds are analyzed by first washing the cells three times with PBS to remove tetracycline and seeding them in 96-well plates at 35,000 cells / well. The compounds, dissolved in DMSO, are then diluted 1:200 into the wells containing the cells. Five days after compound addition, the material is harvested for analysis. During an extended analysis period of 8 days, the cells are seeded and treated as described above, but the media and compound are renewed on days d2 and d5 after the initial treatment. On harvest day, DNA virions were obtained by lysis using Sidepaso Lysis and Stabilization Buffer and then quantified by real-time quantitative PCR. Commercially available ELISA kits were used to quantify the viral proteins HBsAg (Alpco) or HbeAg (US Biological) following the manufacturer's recommended protocol after diluting the samples to match the linear range of their respective assays. Regardless of the assay used, the concentrations of the compound that reduce viral product accumulation in lysates or cell supernatants by 50% relative to drug-free controls (EC50) are reported; the EC50 ranges are as follows: A < 0.1 µM; B 0.1–0.2 µM; C > 0.2 µM. The toxicity of the compound is assessed by culturing cells at 15,000 cells / well and treating them with the compound as described above. Three days after the addition of the compound, the cells are treated with ATPLite reagent, and the concentrations of the compound that reduce total ATP levels in the wells by 50% relative to drug-free controls (CC50) are reported; the CC50 ranges are as follows: A > 25 µM; B 10–25 µM; C < 10 µM. Table 1 Summary of Activities Table 2. Cytotoxicity Summary ATPlite Compound Number CC50 (µM) ATPlite Compound Number CC50 (µM)

Claims

1. A compound represented by the formula where R21 is hydrogen or fluorine.

2. The compound of claim 1, which is:

3. The compound of claim 1, which is:

4. The compound of claim 1, which is:

5. The compound of claim 1, which is:

6. The compound of claim 1, which is:

7. The compound of claim 1, which is:

8. The compound of claim 1, which is:

9. The compound of claim 1, which is:

10. A pharmaceutical composition comprising a compound according to any one of claims 1 to 9 and an acceptable pharmaceutical vehicle or excipient.

11. The compound of any one of claims 1 to 9 for use in the treatment or prevention of hepatitis B virus infection.