Antibacterial compounds

Abstract

Provided herein are heterocyclic compounds and pharmaceutical compositions comprising said compounds that are useful for inhibiting the growth of gram-negative bacteria. The subject compounds and compositions are useful for the treatment of bacterial infections, such as pneumonia

Description

ANTIBACTERIAL COMPOUNDSCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 552,933, filed February 13, 2024, and U.S. Provisional Patent Application No. 63 / 552,937, filed February 13, 2024, which are incorporated herein by reference in their entireties.STATEMENT AS TO FEDERALLY SPONSORED RESEARCH

[0002] This invention was made with government support under Agreement HHS0100201600038C, awarded by HHS. The government has certain rights in the invention.BACKGROUND OF THE INVENTION

[0003] A need exists in the medicinal arts for the effective treatment of illness caused by bacterial infection.SUMMARY OF THE INVENTION

[0004] Provided herein are heterocyclic compounds and pharmaceutical compositions comprising said compounds that are useful for inhibiting the growth of gram-negative bacteria. The subject compounds and compositions are useful for the treatment of bacterial infection, such as pneumonia and the like. In some embodiments, compounds described herein are UDP-{3-O-[(R)-3- hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) modulator compounds. In some embodiments, the compounds described herein are UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N- acetylglucosamine deacetylase (LpxC) antagonists. In some embodiments, the compounds described herein are UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) inhibitors.

[0005] In some embodiments, described herein is a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein:Lais absent, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; each R3is independently hydrogen or substituted or unsubstituted C1-C6alkyl;R1is hydrogen or substituted or unsubstituted C1-C6alkyl;R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl;R4is hydrogen or substituted or unsubstituted C1-C6alkyl; each R5is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; s is 0, 1, 2, 3, or 4; each R6is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; t is 0, 1, 2, 3, or 4;L1is absent, -O, -N(R9), -S, substituted or unsubstituted C1-C6alkyl, -O-(substituted or unsubstituted C1-C6alkyl), -(substituted or unsubstituted C1-C6alkyl)-O, -N(R9)-(substituted or unsubstituted C1-C6alkyl), -(substituted or unsubstituted C1-C6alkyl)-N(R9), -S-(substituted or unsubstituted C1-C6alkyl), or -(substituted or unsubstituted C1-C6alkyl)-S;R9is hydrogen or substituted or unsubstituted C1-C6alkyl;R7is absent, substituted or unsubstituted C3-C10cycloalkyl or substituted or unsubstituted C2- C10heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R10aand n R10groups; n is 1, 2, 3, 4, 5, or 6; each R10is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or -L2-Rn;R10ais hydrogen, substituted or unsubstituted C1-C6alkyl, -C(=O)Ra, -C(=O)NRcRd, or -L2-Rn;L2is substituted or unsubstituted C1-C6alkyl, -N(R9)-(substituted or unsubstituted C1-C6alkyl), -O- (substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl;R11is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd; or L1-R7is absent and two R6on adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C10cycloalkyl or substituted or unsubstituted C2-C10heterocycloalkyl; each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rcand Rdare independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C10heterocycloalkyl.

[0006] In some embodiments, described herein is a compound of Formula (la):Formula (la), or a pharmaceutically acceptable salt or solvate thereof.

[0007] In some embodiments, described herein is a compound of Formula (II):Formula (II), or a pharmaceutically acceptable salt or solvate thereof.

[0008] In some embodiments, described herein is a compound of Formula (III):Formula (III), or a pharmaceutically acceptable salt or solvate thereof.

[0009] In some embodiments, described herein is a compound of Formula (IV):or a pharmaceutically acceptable salt or solvate thereof.

[0010] In some embodiments, described herein is a compound of Formula (V):Formula (V), or a pharmaceutically acceptable salt or solvate thereof.

[0011] In some embodiments, described herein is a compound of Formula (VI):Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein:Ring A is heterocycloalkyl or heteroaryl; each R12is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; p is 0, 1, 2, 3, or 4;Lais absent, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; each R3is independently hydrogen or substituted or unsubstituted C1-C6alkyl;R1is hydrogen or substituted or unsubstituted C1-C6alkyl;R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl;R4is hydrogen or substituted or unsubstituted C1-C6alkyl; each R5is independently hydrogen, halogen, -CN, -OH, -0Ra, -NRcRd, -C(=0)Ra, -C(=0)0Rb, - C(=0)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; s is 0, 1, 2, 3, or 4; each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rcand Rdare independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C10heterocycloalkyl.

[0012] In some embodiments, described herein is a compound of Formula (XI):Formula (XI), or a pharmaceutically acceptable salt or solvate thereof, wherein:Lais absent, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; each R3is independently hydrogen or substituted or unsubstituted C1-C6alkyl;R1is hydrogen or substituted or unsubstituted C1-C6alkyl;R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl;R4is hydrogen or substituted or unsubstituted C1-C6alkyl;R12is hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl;R13is hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; each R5is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; s is 0, 1, 2, 3, or 4; each R6is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; t is 0, 1, 2, 3, or 4;L1is absent, -O, -N(R9), -S, substituted or unsubstituted C1-C6alkyl, -O-(substituted or unsubstituted C1-C6alkyl), -(substituted or unsubstituted C1-C6alkyl)-O, -N(R9)-(substituted or unsubstituted C1-C6alkyl), -(substituted or unsubstituted C1-C6alkyl)-N(R9), -S-(substituted or unsubstituted C1-C6alkyl), or -(substituted or unsubstituted C1-C6alkyl)-S;R9is hydrogen or substituted or unsubstituted C1-C6alkyl;R7is absent, substituted or unsubstituted C3-C10cycloalkyl or substituted or unsubstituted C2-C10heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R10aand n R10groups; n is 1, 2, 3, 4, 5, or 6;each R10is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or -L2-Rn;R10ais hydrogen, substituted or unsubstituted C1-C6alkyl, -C(=O)Ra, -C(=O)NRcRd, or -L2-Rn;L2is substituted or unsubstituted C1-C6alkyl, -N(R9)-(substituted or unsubstituted C1-C6alkyl), -O- (substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl;R11is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd; or L1-R7is absent and two R6on adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C10cycloalkyl or substituted or unsubstituted C2-C10heterocycloalkyl; each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rcand Rdare independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C10heterocycloalkyl.

[0013] In some embodiments, described herein is a compound of Formula (Xia):Formula (Xia),or a pharmaceutically acceptable salt or solvate thereof.

[0014] In some embodiments, described herein is a compound of Formula (XII):Formula (XII), or a pharmaceutically acceptable salt or solvate thereof.

[0015] In some embodiments, described herein is a compound of Formula (XIV):Formula (XIV), or a pharmaceutically acceptable salt or solvate thereof.

[0016] Any combination of the groups described above for the various variables is contemplated herein. Throughout the specification, groups and substituents thereof are chosen by one skilled in the field to provide stable moieties and compounds.

[0017] Also described herein is a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by intravenous administration, subcutaneous administration, oral administration, inhalation, nasal administration, dermal administration, or ophthalmic administration. In some embodiments, the pharmaceutical composition is formulated for administration to a mammal by oral administration. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, a capsule, a liquid, a suspension, a gel, a dispersion, a solution, an emulsion, an ointment, or a lotion. In some embodiments, the pharmaceutical composition is in the form of a tablet, a pill, or a capsule.

[0018] In another aspect provided herein is a method of treating or preventing a gram-negative bacterial infection in a patient in need thereof comprising administering to the patient a pharmaceutical composition comprising a compound described herein, or a pharmaceuticallyacceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the gram-negative bacterial infection is associated with Pseudomonas aeruginosa. In some embodiments, the gram-negative bacterial infection is a respiratory infection. In some embodiments, the gram-negative bacterial infection is pneumonia. In some embodiments, the gramnegative bacterial infection is community-acquired pneumonia (CAP), health care-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), ventilator-associate pneumonia (VAP), or a combination thereof. In some embodiments, the patient has been identified as having a lung disease. In some embodiments, the lung disease is a structural lung disease. In some embodiments, the lung disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic destroyed lung disease, or a combination thereof. In some embodiments, the administration is to treat an existing infection. In some embodiments, the administration is provided as prophylaxis. In some embodiments, a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered in a solution by inhalation, intravenous injection, or intraperitoneal injection. In some embodiments, a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, is administered in a solution by inhalation, intravenous injection, or intraperitoneal injection.

[0019] In another aspect provided herein is a method of inhibiting UDP-{3-O-[(R)-3- hydroxymyristoyl]}-N-acetylglucosamine deacetylase enzyme comprising contacting the enzyme with a compound described herein.

[0020] In another aspect provided herein is a method for treating bacterial infection in a patient in need thereof comprising administering to the patient a composition comprising a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0021] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound of Formula (I) or (XI), or a pharmaceutically acceptable salt or solvate thereof, is: (a) systemically administered to the mammal; and / or (b) administered orally to the mammal; and / or (c) intravenously administered to the mammal; and / or (d) administered by inhalation; and / or (e) administered by nasal administration; or and / or (f) administered by injection to the mammal; and / or (g) administered topically to the mammal; and / or (h) administered by ophthalmic administration; and / or (i) administered rectally to the mammal; and / or (j) administered non-systemically or locally to the mammal.

[0022] In any of the aforementioned aspects are further embodiments comprising single administrations of the effective amount of the compound, including further embodiments in which the compound is administered once a day to the mammal or the compound is administered to the mammal multiple times over the span of one day. In some embodiments, the compound isadministered on a continuous dosing schedule. In some embodiments, the compound is administered on a continuous daily dosing schedule.

[0023] In any of the embodiments disclosed herein, the mammal is a human.

[0024] Articles of manufacture, which include packaging material, a compound of Formula (I) or (XI), or a pharmaceutically acceptable salt or solvate thereof, within the packaging material, and a label that indicates that the compound or composition, or pharmaceutically acceptable salt, tautomers, pharmaceutically acceptable N-oxide, pharmaceutically active metabolite, pharmaceutically acceptable prodrug, or pharmaceutically acceptable solvate thereof, is used for modulating UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC), or for the treatment, prevention or amelioration of one or more symptoms of a disease or condition that would benefit from modulating UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC), are provided.

[0025] Other objects, features and advantages of the compounds, methods and compositions described herein will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples, while indicating specific embodiments, are given by way of illustration only, since various changes and modifications within the spirit and scope of the instant disclosure will become apparent to those skilled in the art from this detailed description.INCORPORATION BY REFERENCE

[0026] All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference for the specific purposes identified herein.DETAILED DESCRIPTION OF THE INVENTIONLpxC, Lipid A and Gram-Negative Bacteria

[0027] Metalloproteins influence a vast diversity of biological systems, biological processes, and diseases. For example, UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) is an essential enzyme involved in the first committed step in lipid A biosynthesis for gramnegative bacteria. Lipid A is an essential component of the outer membrane of gram-negative bacteria. LpxC is a zinc(II)-dependent metalloenzyme, with two histidines and an aspartic acid residue bound to the zinc(II) ion. Structures of LpxC show the zinc(II) ion is bound to two water molecules, both of which have been implicated in the mechanism of the enzyme. LpxC is highly conserved across strains of gram-negative bacteria, making LpxC an attractive target to treat gramnegative infections. To the contrary, LpxC is not a component of Gram-positive bacteria, such as Staphylococcus aureus.

[0028] In recent years, there has been an increase in resistant and multi-drug resistant strains of bacteria. Thus, there is a need for new antibiotics, especially with new mechanisms of action. Thereremains a need for metalloprotein modulators of LpxC useful in the field of therapeutics, diagnostics, and research.

[0029] Some embodiments provide a method of inhibiting UDP-{3-O-[(R)-3-hydroxymyristoyl]}- N-acetylglucosamine deacetylase enzyme comprising contacting the enzyme with a compound of Formula (I) or (XI).

[0030] In some embodiments provided herein is a pharmaceutical composition comprising a compound of Formula (I) or (XI), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.Methods of Use

[0031] Disclosed herein are methods of treating disease wherein the inhibition of bacterial growth is indicated. Such disease includes gram-negative bacterial infection. In some embodiments, the gram-negative bacterial infection is associated with Pseudomonas aeruginosa. In some embodiments, the method of treating a gram-negative bacterial infection in a patient in need thereof comprises administering to the patient a compound of Formula (I) or (XI), a pharmaceutical composition comprising a compound of Formula (I) or (XI), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In some embodiments, the method of treating a Pseudomonas aeruginosa infection in a patient in need thereof comprises administering to the patient the compound of Formula (I) or (XI), a pharmaceutical composition comprising a compound of Formula (I) or (XI), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0032] In some embodiments, the gram-negative bacterial infection is associated with Pseudomonas aeruginosa. In some embodiments, the gram-negative bacterial infection is a respiratory infection. In some embodiments, the gram-negative bacterial infection is pneumonia. In some embodiments, the gram-negative bacterial infection is community-acquired pneumonia (CAP), health care-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), ventilator-associate pneumonia (VAP), or a combination thereof. In some embodiments, the gram-negative bacterial infection is community-acquired pneumonia (CAP). In some embodiments, the gram-negative bacterial infection is health care-associated pneumonia (HCAP). In some embodiments, the gramnegative bacterial infection is hospital -acquired pneumonia (HAP). In some embodiments, the gramnegative bacterial infection is ventilator-associate pneumonia (VAP).

[0033] In some embodiments, the patient has been identified as having a lung disease. In some embodiments, the lung disease is a structural lung disease. In some embodiments, the lung disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic destroyed lung disease, or a combination thereof. In some embodiments, the patient has cystic fibrosis. In some embodiments, the patient has bronchiectasis. In some embodiments, the patient hasemphysema. In some embodiments, the patient has chronic obstructive pulmonary disease (COPD). In some embodiments, the patient has chronic destroyed lung disease.

[0034] In some embodiments the administration is to treat an existing infection.

[0035] In some embodiments the administration is provided as prophylaxis.

[0036] In some embodiments, the LpxC inhibitory compound as described herein is used for treating or preventing conditions caused by the bacterial production of endotoxin and, in particular, by gram-negative bacteria and bacteria that use LpxC in the biosynthesis of lipopolysaccharide (LPS) or endotoxin. In some embodiments, the method of treating or preventing a condition caused by endotoxin or LPS in a patient in need thereof comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I) or (XI), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. In another embodiment, the heterocyclic LpxC inhibitory compounds as described herein are useful in the treatment of conditions that are caused or exacerbated by the bacterial production of lipid A and LPS or endotoxin, such as chronic obstructive pulmonary disease (COPD) and acute exacerbations of chronic bronchitis (AECB). In some embodiments, the method of treating or preventing a condition caused by endotoxin or LPS in a patient in need thereof comprises administering to the patient a pharmaceutical composition comprising a compound of Formula (I) or (XI), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient, wherein the condition caused by endotoxin or LPS is selected from chronic obstructive pulmonary disease (COPD) and acute exacerbations of chronic bronchitis (AECB).

[0037] In other embodiments, the compounds of the disclosure can be used for the treatment of a serious or chronic respiratory tract infection including serious lung and nosocomial infections such as those caused by Enterobacter aerogenes, Enterobacter cloacae, Escherichia coli, Klebsiella pneumoniae, Klebsiella oxytoca, Kuyvera ascorbata, Kuyvera cryocrescense, Shigella sonnei, Proteus mirabilis, Serratia marcescens, Stenotrophomonas maltophilia, Pseudomonas aeruginosa, Burkholderia cepacia, Acinetobacter baumannii, Alcaligenes xylosoxidans, Flavobacterium meningosepticum, and Citrobacter freundi, Haemophilus influenzae, Kluyvera species, Legionella species, Moraxella catarrhalis, Enterobacter species, Acinetobacter species, Klebsiella species, Burkholderia species and Proteus species, and infections caused by other bacterial species such as Neisseria species, Shigella species, Salmonella species, Helicobacler pylori, Vibrionaceae and Bordetella species as well as the infections caused by a Brucella species, Francisella tularensis and / or Yersinia pestis. In some embodiments, the infection is associated with a Pseudomonas species. In some embodiments, the infection is associated with Pseudomonas aeruginosa. In some embodiments, the compounds of the disclosure do not inhibit the growth of Gram-positive bacteria, such as Staphylococcus aureus.

[0038] In some embodiments, the LpxC inhibitory compound as described herein is used in a method of preventing growth of a Pseudomonas species. In some embodiments, the Pseudomonas species is Pseudomonas aeruginosa.

[0039] In some instances, antibiotics have suboptimal concentrations in the lung leading to therapeutic failures for lung infections. In some embodiments, the heterocyclic LpxC inhibitory compound of Formula (I) or (XI) have optimal concentrations in the lung for treating or preventing a gram-negative bacterial infection in the lung. In some embodiments, the compounds are present in the lung in a therapeutically effective amount after administration.

[0040] In some embodiments, disclosed herein is a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, for use as therapeutically active substance.

[0041] In some embodiments, disclosed herein is a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, for use in treating or preventing a gram-negative bacterial infection. In some embodiments, the gram-negative bacterial infection is associated with Pseudomonas aeruginosa. In some embodiments, the gram-negative bacterial infection is a respiratory infection. In some embodiments, the respiratory infection is pneumonia.

[0042] In some embodiments, disclosed herein is the use of a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, for the preparation of a medicament for treating or preventing a gram-negative bacterial infection. In some embodiments, the gram-negative bacterial infection is associated with Pseudomonas aeruginosa. In some embodiments, the gram-negative bacterial infection is a respiratory infection. In some embodiments, the respiratory infection is pneumonia.LpxC Inhibitory Compounds

[0043] Provided herein, in some embodiments, are heterocyclic LpxC inhibitory compounds and pharmaceutical compositions comprising said compounds. The subject compounds and compositions are useful for inhibiting UDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) and for the treatment of bacterial infection.

[0044] In some embodiments, compounds of Formula (I) or (XI), including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof, are LTDP-{3-O-[(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) modulators. In some embodiments, the compounds of Formula (I) or (XI), including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof, are UDP-{3-0- [(R)-3 -hydroxymyristoyl] }-N-acetylglucosamine deacetylase (LpxC) antagonists. In some embodiments, the compounds of Formula (I) or (XI), including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof, are UDP-{3-O-[(R)- 3 -hydroxymyristoyl] }-N-acetyl glucosamine deacetylase (LpxC) inhibitors.

[0045] In some embodiments, compounds of Formula (I) or (XI), or pharmaceutically acceptable salts or solvates thereof, described herein have increased solubility compared to corresponding compounds without a phosphate ester. In some embodiments, compounds of Formula (I) or (XI), or pharmaceutically acceptable salts or solvates thereof, described herein have increased bioavailability compared to corresponding compounds without a phosphate ester.Compounds

[0046] In some embodiments, described herein is a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein:Lais absent, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; each R3is independently hydrogen or substituted or unsubstituted C1-C6alkyl;R1is hydrogen or substituted or unsubstituted C1-C6alkyl;R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl;R4is hydrogen or substituted or unsubstituted C1-C6alkyl; each R5is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; s is 0, 1, 2, 3, or 4; each R6is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; t is 0, 1, 2, 3, or 4;L1is absent, -O, -N(R9), -S, substituted or unsubstituted C1-C6alkyl, -O-(substituted or unsubstituted C1-C6alkyl), -(substituted or unsubstituted C1-C6alkyl)-O, -N(R9)-(substituted or unsubstituted C1-C6alkyl), -(substituted or unsubstituted C1-C6alkyl)-N(R9), -S-(substituted or unsubstituted C1-C6alkyl), or -(substituted or unsubstituted C1-C6alkyl)-S;R9is hydrogen or substituted or unsubstituted C1-C6alkyl;R7is absent, substituted or unsubstituted C3-C10cycloalkyl or substituted or unsubstituted C2-C10heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R10aand n R10groups; n is 1, 2, 3, 4, 5, or 6; each R10is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or -L2-Rn;R10ais hydrogen, substituted or unsubstituted C1-C6alkyl, -C(=O)Ra, -C(=O)NRcRd, or -L2-Rn;L2is substituted or unsubstituted C1-C6alkyl, -N(R9)-(substituted or unsubstituted C1-C6alkyl), -O- (substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl;R11is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd; or L1-R7is absent and two R6on adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C10cycloalkyl or substituted or unsubstituted C2-C10heterocycloalkyl; each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rcand Rdare independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C10heterocycloalkyl.

[0047] In some embodiments, the compound of Formula (I) is a compound of Formula (la), (lb), (Ic), (II), (Ila), (III), (Illa), (IV), (IVa), (V), or (Va).

[0048] In some embodiments, described herein is a pharmaceutically acceptable salt of a compound of Formula (I).

[0049] In some embodiments, described herein is a compound of Formula (la):Formula (la), or a pharmaceutically acceptable salt or solvate thereof.

[0050] In some embodiments, described herein is a compound of Formula (lb):Formula (lb), or a pharmaceutically acceptable salt or solvate thereof.

[0051] In some embodiments, described herein is a compound of Formula (Ic):Formula (Ic), or a pharmaceutically acceptable salt or solvate thereof.

[0052] In some embodiments, R2aand R2bare each independently hydrogen.

[0053] In some embodiments, R1is substituted or unsubstituted C1-C6alkyl. In some embodiments, R1is -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, R1is -CH3.

[0054] In some embodiments, R4is hydrogen, -CH3, or -CH2CH3. In some embodiments, R4is hydrogen.

[0055] In some embodiments, L1-R7is absent and two R6on adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C10cycloalkyl. In some embodiments, L1-R7is absent and two R6on adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C2-C10heterocycloalkyl. In some embodiments, L1-R7is absent and two R6on adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C2-C6monocyclic heterocycloalkyl.

[0057] In some embodiments, R7is substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted C2-C6heterocycloalkyl. In some embodiments, R7is substituted or unsubstituted monocyclic C3-C6cycloalkyl or substituted or unsubstituted monocyclic C2-C6heterocycloalkyl. In some embodiments, R7is substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted C2-C6heterocycloalkyl, wherein heterocycloalkyl contains 0-2 N atoms or 0-2 O atoms in the ring. In some embodiments, R7is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted aziridinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperazinyl, or substitituted or unsubstituted tetrahydrothiophene 1 -oxide. In some embodiments, R7is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted aziridinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, or substituted or unsubstituted piperazinyl.

[0058] In some embodiments, R7is substituted or unsubstituted pyrrolidinyl or substituted or unsubstituted azetidinyl. In some embodiments, R7is substituted or unsubstituted tetrahydrofuranyl or substituted or unsubstituted tetrahydropyranyl. In some embodiments, R7is substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl. In some embodiments, R7is substituted or unsubstituted cyclobutyl. In some embodiments, R7is substituted or unsubstituted tetrahydrofuranyl. In some embodiments, R7is substituted or unsubstituted tetrahydropyranyl. In some embodiments, R7is substituted or unsubstituted azetidinyl.

[0059] In some embodiments, described herein is a compound of Formula (II):Formula (II), or a pharmaceutically acceptable salt or solvate thereof.

[0060] In some embodiments, described herein is a compound of Formula (Ila):Formula (Ila), or a pharmaceutically acceptable salt or solvate thereof.

[0062] In some embodiments,embodiments,some embodiments,

[0063] In some embodiments, described herein is a compound of Formula (III):Formula (III), or a pharmaceutically acceptable salt or solvate thereof.

[0064] In some embodiments, described herein is a compound of Formula (Illa):Formula (Illa), or a pharmaceutically acceptable salt or solvate thereof.

[0067] In some embodiments, described herein is a compound of Formula (IV):or a pharmaceutically acceptable salt or solvate thereof.

[0068] In some embodiments, described herein is a compound of Formula (IVa):or a pharmaceutically acceptable salt or solvate thereof.In some embodiments,

[0071] In some embodiments, described herein is a compound of Formula (V):Formula (V), or a pharmaceutically acceptable salt or solvate thereof.

[0072] In some embodiments, described herein is a compound of Formula (Va):or a pharmaceutically acceptable salt or solvate thereof.

[0073] In some embodiments,

[0074] In some embodiments,

[0075] In some embodiments, Lais absent or substituted or unsubstituted C1-C6alkyl)-; and each R3is independently hydrogen, -CH3, -CH2CH3, or -CH(CH3)2.. In some embodiments, -La-O- P(=O)(OR3)2is -O-P(=O)(OR3)2or -O-CH2-O-P(=O)(OR3)2; and each R3is independently hydrogen, -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, -La-O-P(=O)(OR3)2is -O-P(=O)(OH)2or -O- CH2-O-P(=O)(OH)2. In some embodiments, -La-O-P(=O)(OR3)2is -O-P(=O)(OH)2. In some embodiments, -La-O-P(=O)(OR3)2is -CH2-O-P(=O)(OH)2.

[0076] In some embodiments, each R5is independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; s is 0, 1, or 2; each R6is independently hydrogen, halogen, -CN, -OH, - ORa, -NRcRd, or substituted or unsubstituted C1-C6alkyl; and t is 0, 1, or 2. In some embodiments, each R5is independently hydrogen or halogen; s is 0, 1, or 2; each R6is independently hydrogen,halogen, or substituted or unsubstituted C1-C6alkyl; and t is 0, 1, or 2. In some embodiments, each R5is independently hydrogen; and each R6is independently hydrogen, -F, -Cl, -CH3, -CH2CH3, or - CH(CH3)2. In some embodiments, each R5is independently hydrogen; and each R6is independently hydrogen, -F, -Cl, or -CH3. In some embodiments, each R5is independently hydrogen; and each R6is independently hydrogen or -F. In some embodiments, each R5is independently hydrogen; and each R6is independently hydrogen.

[0077] In some embodiments, each R5is independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl. In some embodiments, each R5is independently hydrogen or halogen. In some embodiments, each R5is independently hydrogen. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2.

[0078] In some embodiments, each R6is independently hydrogen, halogen, -CN, -OH, -ORa, - NRcRd, or substituted or unsubstituted C1-C6alkyl. In some embodiments, each R6is independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl. In some embodiments, each R6is independently hydrogen, -F, -Cl, -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, each R6is independently hydrogen. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2.

[0079] In some embodiments, L1is absent, -O-, -N(R9)-, -(substituted or unsubstituted Ci- Cealkyl)-, -O-(substituted or unsubstituted C1-C6alkyl)-, -(substituted or unsubstituted C1-C6alkyl)- O-, -N(R9)-(substituted or unsubstituted C1-C6alkyl)-, or -(substituted or unsubstituted C1-C6alkyl)- N(R9)-; and R9is hydrogen or -CH3.

[0080] In some embodiments, L1is absent, -O-, -N(H)-, -N(CH3)-, -CH2-, -O-CH2-, -CH2-O-, - N(H)-CH2-, -CH2-N(H)-, -N(CH3)-CH2-, or -CH2-N(CH3)-. In some embodiments, L1is absent, -O-, -N(H)-, -O-CH2-, -CH2-O-, -N(H)-CH2-, or -CH2-N(H)-. In some embodiments, L1is absent, -O-, - N(H), -CH2-, -O-CH2- -CH2-O-, -N(H)-CH2-, or -CH2-N(H)-. In some embodiments, L1is absent, - O-, -O-CH2, or -CH2-O. In some embodiments, L1is absent, -N(H), -N(H)-CH2, or -CH2-N(H). In some embodiments, L1is absent. In some embodiments, L1is -O-. In some embodiments, L1is - N(H). In some embodiments, L1is -CH2-. In some embodiments, L1is -O-CH2- or-CH2-O-. In some embodiments, L1is -O-CH2-. In some embodiments, L1is -CH2-O-. In some embodiments, L1is a - N(H)-CH2- or -CH2-N(H)-.

[0081] In some embodiments, each R10is independently halogen, -CN, -OH, -ORa, -OC(=O)Ra, - S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)Ra, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, or -L2-Rn; R10ais hydrogen, substituted or unsubstituted C1-C6alkyl, -C(=O)Ra, - C(=O)NRcRd, or -L2-Rn; L2is substituted or unsubstituted C1-C6alkyl; R11is -CN, -OH, -ORa, - NRcRd; n is 1, 2, 3, or 4; each Rais independently substituted or unsubstituted C1-C6alkyl; each Rbis independently hydrogen or substituted or unsubstituted C1-C6alkyl; each Rcis independentlyhydrogen or substituted or unsubstituted C1-C6alkyl; each Rdis independently hydrogen or substituted or unsubstituted C1-C6alkyl; or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C10heterocycloalkyl. In some embodiments, each R10is independently halogen, -CN, -OH, -ORa, -S(=O)2Ra, -S(=0)2NRcRd, -NRcRd, - NRbC(=O)Ra, -NRbS(=0)2Ra, -C(=O)Ra, -C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, or -L2-Rn; R10ais hydrogen, substituted or unsubstituted C1-C6alkyl, -C(=O)Ra, -C(=O)NRcRd, or - L2-R"; L2is substituted or unsubstituted C1-C6alkyl; R11is -CN; n is 1, 2, 3, or 4; each Rais independently substituted or unsubstituted C1-C6alkyl; each Rbis independently hydrogen or substituted or unsubstituted C1-C6alkyl; each Rcis independently hydrogen or substituted or unsubstituted C1-C6alkyl; each Rdis independently hydrogen or substituted or unsubstituted C1-C6alkyl; or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C10heterocycloalkyl. In some embodiments, each R10is independently halogen, -CN, -OH, -ORa, -S(=O)2NRcRd, -NRcRd, -NRbS(=0)2Ra, -C(=O)Ra, - C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, or -L2-R11; R10ais hydrogen, substituted or unsubstituted C1-C6alkyl, -C(=0)Ra, -C(=0)NRcRd, or -L2-Rn; L2is substituted or unsubstituted C1-C6alkyl; R11is -CN; n is 1, 2, or 3; each Rais independently -CH3or -CH2CH3; each Rbis independently hydrogen, -CH3, or-CH2CH3; each Rcis independently hydrogen, -CH3, or-CH2CH3; and each Rdis independently hydrogen, -CH3, or-CTfcCHs. In some embodiments, each R10is independently -CN, -OH, -0CH3, oxo, -CH3, -S(=O)2NHCH3, -NH2, -NHS(=O)2CH3, -C(=0)CH3, C(=0)NH2, -C(=0)NHCH3, -C(=O)N(CH3)2, -CH2CH2CN, -NHCH2CN; R10ais hydrogen, - C(=0)NH2, -C(=O)N(CH3)2, -CH2CN, -CH2CH2CN; and n is 1, 2, or 3. In some embodiments, each R10is independently -OH; and n is i.

[0084] In some embodiments, described herein is a compound of Formula (VI):Formula (VI), or a pharmaceutically acceptable salt or solvate thereof, wherein:Ring A is heterocycloalkyl or heteroaryl; each R12is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; p is 0, 1, 2, 3, or 4;Lais absent, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; each R3is independently hydrogen or substituted or unsubstituted C1-C6alkyl;R1is hydrogen or substituted or unsubstituted C1-C6alkyl;R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl;R4is hydrogen or substituted or unsubstituted C1-C6alkyl; each R5is independently hydrogen, halogen, -CN, -OH, -0Ra, -NRcRd, -C(=0)Ra, -C(=0)0Rb, - C(=0)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; s is 0, 1, 2, 3, or 4; each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rcand Rdare independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C10heterocycloalkyl.

[0085] In some embodiments, the compound of Formula (VI) is a compound of Formula (Via).

[0086] In some embodiments, described herein is a pharmaceutically acceptable salt of a compound of Formula (VI).

[0087] In some embodiments, described herein is a compound of Formula (Via):Formula (Via), or a pharmaceutically acceptable salt or solvate thereof.

[0088] In some embodiments, Ring A is heterocycloalkyl. In some embodiments, Ring A is heteroaryl.

[0089] In some embodiments, each R5is independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; s is 0, 1, or 2; each R12is independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; and p is 0, 1, or 2. In some embodiments, each R5is independently hydrogen, -F, -Cl, -CH3, -CH2CH3, or -CH(CH3)2; and each R12is independently hydrogen, -F, -Cl, - CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, each R5is independently hydrogen; and each R12is independently hydrogen.

[0090] In some embodiments, described herein is a compound of Formula (XX):Formula (XX),, or a pharmaceutically acceptable salt or solvate thereof, wherein:Lais absent, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; each R3is independently hydrogen or substituted or unsubstituted C1-C6alkyl;R1is hydrogen or substituted or unsubstituted C1-C6alkyl;R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl;R4is hydrogen or substituted or unsubstituted C1-C6alkyl; each R5is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl;s is 0, 1, 2, 3, or 4; each R6is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; t is 0, 1, 2, 3, or 4;L1is absent, -O, -N(R9), -S, substituted or unsubstituted C1-C6alkyl, -O-(substituted or unsubstituted C1-C6alkyl), -(substituted or unsubstituted C1-C6alkyl)-O, -N(R9)-(substituted or unsubstituted C1-C6alkyl), -(substituted or unsubstituted C1-C6alkyl)-N(R9), -S-(substituted or unsubstituted C1-C6alkyl), or -(substituted or unsubstituted C1-C6alkyl)-S;R9is hydrogen or substituted or unsubstituted C1-C6alkyl;R7is absent, substituted or unsubstituted C3-C10cycloalkyl or substituted or unsubstituted C2-C10heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R10aand n R10groups; n is 1, 2, 3, 4, 5, or 6; each R10is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or -L2-Rn;R10ais hydrogen, substituted or unsubstituted C1-C6alkyl, -C(=O)Ra, -C(=O)NRcRd, or -L2-Rn;L2is substituted or unsubstituted C1-C6alkyl, -N(R9)-(substituted or unsubstituted C1-C6alkyl), -O- (substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl;R11is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd; or L1-R7is absent and two R6on adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C10cycloalkyl or substituted or unsubstituted C2-C10heterocycloalkyl; each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;each Rcand Rdare independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C10heterocycloalkyl.

[0091] In some embodiments, the compound is a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound is a diastereomer of a compound of Table 1, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound is a pharmaceutically acceptable salt of a compound of Table 1, or or solvate thereof.Table 1:

[0092] In some embodiments, described herein is a compound of Formula (XI):Formula (XI), or a pharmaceutically acceptable salt or solvate thereof, wherein:Lais absent, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; each R3is independently hydrogen or substituted or unsubstituted C1-C6alkyl;R1is hydrogen or substituted or unsubstituted C1-C6alkyl;R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl;R4is hydrogen or substituted or unsubstituted C1-C6alkyl;R12is hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl;R13is hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; each R5is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; s is 0, 1, 2, 3, or 4; each R6is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; t is 0, 1, 2, 3, or 4;L1is absent, -O, -N(R9), -S, substituted or unsubstituted C1-C6alkyl, -O-(substituted or unsubstituted C1-C6alkyl), -(substituted or unsubstituted C1-C6alkyl)-O, -N(R9)-(substituted or unsubstituted C1-C6alkyl), -(substituted or unsubstituted C1-C6alkyl)-N(R9), -S-(substituted or unsubstituted C1-C6alkyl), or -(substituted or unsubstituted C1-C6alkyl)-S;R9is hydrogen or substituted or unsubstituted C1-C6alkyl;R7is absent, substituted or unsubstituted C3-C10cycloalkyl or substituted or unsubstituted C2-C10heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R10aand n R10groups; n is 1, 2, 3, 4, 5, or 6; each R10is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo,substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or -L2-Rn;R10ais hydrogen, substituted or unsubstituted C1-C6alkyl, -C(=O)Ra, -C(=O)NRcRd, or -L2-Rn;L2is substituted or unsubstituted C1-C6alkyl, -N(R9)-(substituted or unsubstituted C1-C6alkyl), -O- (substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl;R11is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd; or L1-R7is absent and two R6on adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C10cycloalkyl or substituted or unsubstituted C2-C10heterocycloalkyl; each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rcand Rdare independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C10heterocycloalkyl.

[0093] In some embodiments, the compound of Formula (XI) is a compound of Formula (Xia), (Xlb), (XIc), (XII), (Xna), (XIV), or (XlVa).

[0094] In some embodiments, described herein is a pharmaceutically acceptable salt of a compound of Formula (XVI).

[0095] In some embodiments, described herein is a compound of Formula (Xia):Formula (Xia), or a pharmaceutically acceptable salt or solvate thereof.

[0096] In some embodiments, described herein is a compound of Formula (Xlb):Formula (Xlb), or a pharmaceutically acceptable salt or solvate thereof.

[0097] In some embodiments, described herein is a compound of Formula (XIc):Formula (XIc), or a pharmaceutically acceptable salt or solvate thereof.

[0098] In some embodiments, R2aand R2bare each independently hydrogen.

[0099] In some embodiments, R1is substituted or unsubstituted C1-C6alkyl. In some embodiments, R1is -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, R1is -CH3.

[0100] In some embodiments, R4is hydrogen, -CH3, or -CH2CH3. In some embodiments, R4is hydrogen.

[0101] In some embodiments, R12is hydrogen or halogen; and R13is hydrogen or halogen. In some embodiments, R12is hydrogen; and R13is hydrogen.

[0102] In some embodiments, R7is substituted or unsubstituted Cs-Cgcycloalkyl or substituted or unsubstituted C2-C6heterocycloalkyl. In some embodiments, R7is substituted or unsubstituted monocyclic C3-C6cycloalkyl or substituted or unsubstituted monocyclic C2-C6heterocycloalkyl. In some embodiments, R7is substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted C2-C6heterocycloalkyl, wherein C2-C6heterocycloalkyl contains 0-2 N atoms or 0-2 O atoms in the ring. In some embodiments, R7is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstitutedaziridinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperazinyl, or substitituted or unsubstituted tetrahydrothiophene 1- oxide. In some embodiments, R7is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted aziridinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, or substituted or unsubstituted piperazinyl. In some embodiments, R7is substituted or unsubstituted cyclobutyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted azetidinyl, or substitituted or unsubstituted tetrahydrothiophene 1 -oxide.

[0103] In some embodiments, R7is substituted or unsubstituted pyrrolidinyl or substituted or unsubstituted azetidinyl. In some embodiments, R7is substituted or unsubstituted tetrahydrofuranyl or substituted or unsubstituted tetrahydropyranyl. In some embodiments, R7is substituted or unsubstituted cyclopropyl or substituted or unsubstituted cyclobutyl. In some embodiments, R7is substituted or unsubstituted tetrahydropyranyl. In some embodiments, R7is substituted or unsubstituted cyclobutyl.

[0104] In some embodiments, described herein is a compound of Formula (XII):Formula (XII), or a pharmaceutically acceptable salt or solvate thereof.

[0105] In some embodiments, described herein is a compound of Formula (Xlla):Formula (Xlla), or a pharmaceutically acceptable salt or solvate thereof.

[0106] In some embodiments,

[0107] In some embodiments,

[0108] In some embodiments, described herein is a compound of Formula (XIV):Formula (XIV), or a pharmaceutically acceptable salt or solvate thereof.

[0109] In some embodiments, described herein is a compound of Formula (XlVa):Formula (XlVa), or a pharmaceutically acceptable salt or solvate thereof.

[0112] In some embodiments, Lais absent or substituted or unsubstituted C1-C6alkyl)-; and each R3is independently hydrogen, -CH3, -CH2CH3, or -CH(CH3)2.. In some embodiments, -La-O- P(=O)(OR3)2is -O-P(=O)(OR3)2or -O-CH2-O-P(=O)(OR3)2; and each R3is independently hydrogen, -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, -La-O-P(=O)(OR3)2is -O-P(=O)(OH)2or -O- CH2-O-P(=O)(OH)2. In some embodiments, -La-O-P(=O)(OR3)2is -O-P(=O)(OH)2.

[0113] In some embodiments, each R5is independently hydrogen or halogen; s is 0, 1, or 2; each R6is independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; and t is 0, 1, or 2. In some embodiments, each R5is independently hydrogen; and each R6is independently hydrogen, - F, -Cl, -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, each R5is independently hydrogen; and each R6is independently hydrogen. In some embodiments, each R5is independently hydrogen; and each R6is independently hydrogen or -F.

[0114] In some embodiments, each R5is independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl. In some embodiments, each R5is independently hydrogen or halogen. In some embodiments, each R5is independently hydrogen. In some embodiments, s is 0. In some embodiments, s is 1. In some embodiments, s is 2.

[0115] In some embodiments, each R6is independently hydrogen, halogen, -CN, -OH, -ORa, - NRcRd, or substituted or unsubstituted C1-C6alkyl. In some embodiments, each R6is independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl. In some embodiments, each R6is independently hydrogen, -F, -Cl, -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, each R6is independently hydrogen, -F, or -Cl. In some embodiments, each R6is independently hydrogen or -F. In some embodiments, each R6is independently hydrogen. In some embodiments, t is 0. In some embodiments, t is 1. In some embodiments, t is 2.

[0116] In some embodiments, L1is absent, -O-, -N(R9)-, -(substituted or unsubstituted Ci- Cealkyl)-, -O-(substituted or unsubstituted C1-C6alkyl)-, -(substituted or unsubstituted C1-C6alkyl)- O-, -N(R9)-(substituted or unsubstituted C1-C6alkyl)-, or -(substituted or unsubstituted C1-C6alkyl)- N(R9)-; and R9is hydrogen or -CH3.

[0117] In some embodiments, L1is absent, -O-, -N(H)-, -N(CH3)-, -CH2-, -O-CH2-, -CH2-O-, - N(H)-CH2-, -CH2-N(H)-, -N(CH3)-CH2-, or -CH2-N(CH3)-. In some embodiments, L1is absent, -O-, -N(H)-, -O-CH2-, -CH2-O-, -N(H)-CH2-, or -CH2-N(H)-. In some embodiments, L1is absent, -O-, or - N(H)-. In some embodiments, L1is absent, -O-, -O-CH2-, or-CIL-O-. In some embodiments, L1is absent, -N(H)-, -N(H)-CH2-, or -CH2-N(H)-. In some embodiments, L1is absent, -O-, -CH2-O-, or - N(H)-. In some embodiments, L1is absent. In some embodiments, L1is -O-. In some embodiments, L1is -N(H)-. In some embodiments, L1is -O-CH2- or-CIfc-O-. In some embodiments, L1is a -N(H)- CH2- or -CH2-N(H)-.

[0118] In some embodiments, each R10is independently halogen, -CN, -OH, -ORa, -OC(=O)Ra, - S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)Ra, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, or -L2-Rn; R10ais hydrogen, substituted or unsubstituted C1-C6alkyl, -C(=O)Ra, - C(=O)NRcRd, or -L2-R11; L2is substituted or unsubstituted C1-C6alkyl or -N(R9)-(substituted or unsubstituted C1-C6alkyl); R11is -CN, -OH, -ORa, -NRcRd; n is 1, 2, 3, or 4; each Rais independently substituted or unsubstituted C1-C6alkyl; each Rbis independently hydrogen or substituted or unsubstituted C1-C6alkyl; each Rcis independently hydrogen or substituted or unsubstituted C1-C6alkyl; each Rdis independently hydrogen or substituted or unsubstituted C1-C6alkyl; or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C10heterocycloalkyl.

[0119] In some embodiments, each R10is independently halogen, -CN, -OH, -ORa, -S(=O)2NRcRd, -NRcRd, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, or - L2-R"; R10ais hydrogen or substituted or unsubstituted C1-C6alkyl; L2is substituted or unsubstituted C1-C6alkyl or -N(R9)-(substituted or unsubstituted C1-C6alkyl); R11is -CN; n is 1, 2, or 3; each Rais independently -CH3or -CH2CH3; each Rbis independently hydrogen, -CH3, or-CH2CH3; each Rcis independently hydrogen, -CH3, or-CH2CH3; and each Rdis independently hydrogen, -CH3, or- CH2CH3.

[0120] In some embodiments, each R10is independently -CN, -OH, -OCH3, -CH3, - S(=O)2NHCH3, -NH2, -NHS(=O)2CH3, -C(=O)CH3, C(=O)NH2J-C(=O)NHCH3, -C(=O)N(CH3)2, - CH2CH2CN, -NHCH2CN; and n is 1, 2, or 3. In some embodiments, each R10is independently -OH, -0CH3, -CH3, -NHS(=O)2CH3, or -NHCH2CN; and n is 1 or 2

[0121] In some embodiments, each R10is independently -OH, -OCH3, -NHS(=O)2CH3, or - NHCH2CN; and n is 1 or 2.some embodiments,some embodiments, R7is. In some embodiments, R7is. In some embodiments, R7is

[0124] In some embodiments, described herein is a compound of Formula (XXI):Formula (XXI), , or a pharmaceutically acceptable salt or solvate thereof, wherein:Lais absent, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; each R3is independently hydrogen or substituted or unsubstituted C1-C6alkyl;R1is hydrogen or substituted or unsubstituted C1-C6alkyl;R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl;R4is hydrogen or substituted or unsubstituted C1-C6alkyl;R12is hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl;R13is hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; each R5is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; s is 0, 1, 2, 3, or 4; each R6is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; t is 0, 1, 2, 3, or 4;L1is absent, -O, -N(R9), -S, substituted or unsubstituted C1-C6alkyl, -O-(substituted or unsubstituted C1-C6alkyl), -(substituted or unsubstituted C1-C6alkyl)-O, -N(R9)-(substituted or unsubstituted C1-C6alkyl), -(substituted or unsubstituted C1-C6alkyl)-N(R9), -S-(substituted or unsubstituted C1-C6alkyl), or -(substituted or unsubstituted C1-C6alkyl)-S;R9is hydrogen or substituted or unsubstituted C1-C6alkyl;R7is absent, substituted or unsubstituted C3-C10cycloalkyl or substituted or unsubstituted C2-C10heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R10aand n R10groups; n is 1, 2, 3, 4, 5, or 6; each R10is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or -L2-Rn;R10ais hydrogen, substituted or unsubstituted C1-C6alkyl, -C(=O)Ra, -C(=O)NRcRd, or -L2-Rn;L2is substituted or unsubstituted C1-C6alkyl, -N(R9)-(substituted or unsubstituted C1-C6alkyl), -O- (substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl;R11is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd;or L1-R7is absent and two R6on adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C10cycloalkyl or substituted or unsubstituted C2-C10heterocycloalkyl; each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rcand Rdare independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C10heterocycloalkyl

[0125] In some embodiments, the compound is a compound of Table 2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound is a diastereomer of a compound of Table 2, or a pharmaceutically acceptable salt or solvate thereof. In some embodiments, the compound is a pharmaceutically acceptable salt of a compound of Table 2, or or solvate thereof.Table 2:* stereochemistry at chiral center(s) corresponding to L1-R7of Formula (XI) arbitrarily definedProdrugs

[0126] The term “prodrug” is meant to indicate a compound that is, in some embodiments, converted under physiological conditions or by solvolysis to a biologically active compound. Thus, the term “prodrug” refers to a precursor of a biologically active compound that is pharmaceutically acceptable. A prodrug is typically inactive when administered to a subject, but is converted in vivo to an active compound, for example, by hydrolysis. The prodrug compound often offers advantages of solubility, tissue compatibility or delayed release in a mammalian organism (see, e.g., Bundgard, H., Design of Prodrugs (1985), pp. 7 9, 21 24 (Elsevier, Amsterdam). A discussion of prodrugs is provided in Higuchi, T., et al., “Prodrugs as Novel Delivery Systems,” A.C.S. Symposium Series, Vol. 14, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987. The term “prodrug” is also meant to include any covalently bonded carriers, which release the active compound in vivo when such prodrug is administered to a mammalian subject. Prodrugs of an active compound, as described herein, are prepared by modifying functional groups present in the active compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent active compound.Prodrugs include compounds wherein a hydroxy, amino or mercapto group is bonded to any group that, when the prodrug of the active compound is administered to a mammalian subject, cleaves to form a free hydroxy, free amino or free mercapto group, respectively. In some embodiments, the prodrug moeity comprises a phosphate group.

[0127] In some embodiments, the phosphate ester compounds of Formula (I) or (XI), or pharmaceutically acceptable salts or solvates thereof, described herein function as prodrugs of the corresponding compounds without a phosphate ester (e.g., the corresponding free alcohol compounds).Further Forms of Compounds

[0128] In one aspect, compounds described herein are in the form of pharmaceutically acceptable salts. As well, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like. The solvated forms of the compounds presented herein are also considered to be disclosed herein.

[0129] “Pharmaceutically acceptable,” as used herein, refers a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic at the concentration or amount used, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0130] The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation. Handbook of Pharmaceutical Salts: Properties, Selection and Use. International Union of Pure and Applied Chemistry, Wiley -VCH 2002. S.M. Berge, L.D. Bighley, D.C. Monkhouse, J. Pharm. Sci. 1977, 66, 1-19. P. H. Stahl and C. G. Wermuth, editors, Handbook of Pharmaceutical Salts: Properties, Selection and Use, Weinheim / Ziiri ch: Wiley - VCH / VHCA, 2002. Pharmaceutical salts typically are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this capability can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt-forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.

[0131] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I) or (XI) with an acid. In some embodiments, the compound of Formula (I)or (XI) (i.e. free base form) is basic and is reacted with an organic acid or an inorganic acid. Inorganic acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid, and metaphosphoric acid. Organic acids include, but are not limited to, l-hydroxy-2-naphthoic acid; 2, 2-di chloroacetic acid; 2 -hydroxy ethanesulfonic acid; 2-oxoglutaric acid; 4-acetamidobenzoic acid; 4-aminosalicylic acid; acetic acid; adipic acid; ascorbic acid (L); aspartic acid (L); benzenesulfonic acid; benzoic acid; camphoric acid (+); camphor- 10-sulfonic acid (+); capric acid (decanoic acid); caproic acid (hexanoic acid); caprylic acid (octanoic acid); carbonic acid; cinnamic acid; citric acid; cyclamic acid; dodecylsulfuric acid; ethane- 1,2-disulfonic acid; ethanesulfonic acid; formic acid; fumaric acid; galactaric acid; gentisic acid; glucoheptonic acid (D); gluconic acid (D); glucuronic acid (D); glutamic acid; glutaric acid; glycerophosphoric acid; glycolic acid; hippuric acid; isobutyric acid; lactic acid (DL); lactobionic acid; lauric acid; maleic acid; malic acid (- L); malonic acid; mandelic acid (DL); methanesulfonic acid; naphthalene-l,5-disulfonic acid; naphthalene-2-sulfonic acid; nicotinic acid; oleic acid; oxalic acid; palmitic acid; pamoic acid; phosphoric acid; proprionic acid; pyroglutamic acid (- L); salicylic acid; sebacic acid; stearic acid; succinic acid; sulfuric acid; tartaric acid (+ L); thiocyanic acid; toluenesulfonic acid ( / ?); and undecylenic acid.

[0132] In some embodiments, a compound of Formula (I) or (XI) is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.

[0133] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I) or (XI) with a base. In some embodiments, the compound of Formula (I) or (XI) is acidic and is reacted with a base. In such situations, an acidic proton of the compound of Formula (I) or (XI) is replaced by a metal ion, e.g., lithium, sodium, potassium, magnesium, calcium, or an aluminum ion. In some cases, compounds described herein coordinate with an organic base, such as, but not limited to, ethanolamine, diethanolamine, triethanolamine, tromethamine, meglumine, N-methylglucamine, dicyclohexylamine, tris(hydroxymethyl)methylamine. In other cases, compounds described herein form salts with amino acids such as, but not limited to, arginine, lysine, and the like. Acceptable inorganic bases used to form salts with compounds that include an acidic proton, include, but are not limited to, aluminum hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium hydroxide, lithium hydroxide, and the like.

[0134] In some embodiments, the compounds provided herein are prepared as a sodium salt, calcium salt, potassium salt, magnesium salt, meglumine salt, N-methylglucamine salt or ammonium salt.

[0135] It should be understood that a reference to a pharmaceutically acceptable salt includes the solvent addition forms. In some embodiments, solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and are formed during the process of crystallization withpharmaceutically acceptable solvents such as water, ethanol, and the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol. Solvates of compounds described herein are conveniently prepared or formed during the processes described herein. In addition, the compounds provided herein optionally exist in unsolvated as well as solvated forms.

[0136] The methods and formulations described herein include the use of X-oxides (if appropriate), or pharmaceutically acceptable salts of compounds having the structure of Formula (I) or (XI), as well as active metabolites of these compounds having the same type of activity.

[0137] In some embodiments, sites on the organic radicals (e.g., alkyl groups, aromatic rings) of compounds of Formula (I) or (XI) are susceptible to various metabolic reactions. Incorporation of appropriate substituents on the organic radicals will reduce, minimize or eliminate this metabolic pathway. In specific embodiments, the appropriate substituent to decrease or eliminate the susceptibility of the aromatic ring to metabolic reactions is, by way of example only, a halogen, deuterium, an alkyl group, a haloalkyl group, or a deuteroalkyl group.

[0138] In another embodiment, the compounds described herein are labeled isotopically (e.g., with a radioisotope) or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels.

[0139] Compounds described herein include isotopically-labeled compounds, which are identical to those recited in the various formulae and structures presented herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into the present compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine chlorine, iodine, phosphorus, such as, for example,2H,3H,13C,14C,15N,18O,170,35S,18F,36C1,123I,1241,125I,1311,32P and33P. In one aspect, isotopically-labeled compounds described herein, for example those into which radioactive isotopes such as3H and14C are incorporated, are useful in drug and / or substrate tissue distribution assays. In one aspect, substitution with isotopes such as deuterium affords certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements.

[0140] In some embodiments, the compounds of Formula (I) or (XI) possess one or more stereocenters and each stereocenter exists independently in either the R or S configuration. In some embodiments, the compound of Formula (I) or (XI) exists in the R configuration. In some embodiments, the compound of Formula (I) or (XI) exists in the S configuration. The compounds presented herein include all diastereomeric, individual enantiomers, atropisomers, and epimeric forms as well as the appropriate mixtures thereof. The compounds and methods provided herein include all cis, trans, syn, anti, entgegen (E), and zusammen (Z) isomers as well as the appropriate mixtures thereof.

[0141] Individual stereoisomers are obtained, if desired, by methods such as, stereoselective synthesis and / or the separation of stereoisomers by chiral chromatographic columns or the separation of diastereomers by either non-chiral or chiral chromatographic columns or crystallization and recrystallization in a proper solvent or a mixture of solvents. In certain embodiments, compounds of Formula (I) or (XI) are prepared as their individual stereoisomers by reacting a racemic mixture of the compound with an optically active resolving agent to form a pair of diastereoisomeric compounds / salts, separating the diastereomers and recovering the optically pure individual enantiomers. In some embodiments, resolution of individual enantiomers is carried out using covalent diastereomeric derivatives of the compounds described herein. In another embodiment, diastereomers are separated by separation / resolution techniques based upon differences in solubility. In other embodiments, separation of stereoisomers is performed by chromatography or by the forming diastereomeric salts and separation by recrystallization, or chromatography, or any combination thereof. Jean Jacques, Andre Collet, Samuel H. Wilen, “Enantiomers, Racemates and Resolutions”, John Wiley And Sons, Inc., 1981. In some embodiments, stereoisomers are obtained by stereoselective synthesis.

[0142] In additional or further embodiments, the compounds described herein are metabolized upon administration to an organism in need to produce a metabolite that is then used to produce a desired effect, including a desired therapeutic effect.

[0143] A “metabolite” of a compound disclosed herein is a derivative of that compound that is formed when the compound is metabolized. The term “active metabolite” refers to a biologically active derivative of a compound that is formed when the compound is metabolized. The term “metabolized,” as used herein, refers to the sum of the processes (including, but not limited to, hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance is changed by an organism. Thus, enzymes may produce specific structural alterations to a compound. For example, cytochrome P450 catalyzes a variety of oxidative and reductive reactions while uridine diphosphate glucuronyltransferases catalyze the transfer of an activated glucuronic -acid molecule to aromatic alcohols, aliphatic alcohols, carboxylic acids, amines and free sulfhydryl groups. Metabolites of the compounds disclosed herein are optionally identified either by administration of compounds to a host and analysis of tissue samples from the host, or by incubation of compounds with hepatic cells in vitro and analysis of the resulting compounds.

[0144] In some instances, heterocyclic rings may exist in tautomeric forms. In such situations, it is understood that the structures of said compounds are illustrated or named in one tautomeric form but could be illustrated or named in the alternative tautomeric form. The alternative tautomeric forms are expressly included in this disclosure, such as, for example, the structures illustrated below. For example, benzimidazoles or imidazoles could exist in the following tautomeric forms:Certain Terminology

[0145] As used herein and in the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality of cells) and equivalents thereof known to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or chemical properties, such as chemical formulae, all combinations and subcombinations of ranges and specific embodiments therein are intended to be included. The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary between 1% and 15% of the stated number or numerical range. The term “comprising” (and related terms such as “comprise” or “comprises” or “having” or “including”) is not intended to exclude that in other certain embodiments, for example, an embodiment of any composition of matter, composition, method, or process, or the like, described herein, “consist of’ or “consist essentially of’ the described features.

[0146] Unless otherwise stated, the following terms used in this application have the definitions given below. The use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0147] As used herein, Ci-Cxincludes C1-C2, C1-C3 . . . Ci-Cx. By way of example only, a group designated as “C1-C6” indicates that there are one to six carbon atoms in the moiety, i.e. groups containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms or 4 carbon atoms. Thus, by way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl group, i.e., the alkyl group is selected from among methyl, ethyl, propyl, / .so-propyl, w-butyl, iso-butyl, secbutyl, and / -butyl.

[0148] An “alkyl” group refers to an aliphatic hydrocarbon group. The alkyl group is branched or straight chain. In some embodiments, the “alkyl” group has 1 to 10 carbon atoms, i.e. a Ci-C10alkyl. Whenever it appears herein, a numerical range such as “1 to 10” refers to each integer in the given range; e.g., “1 to 10 carbon atoms” means that the alkyl group consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 10 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated. In some embodiments, an alkyl is a C1-C6alkyl. In one aspect the alkyl is methyl, ethyl, propyl, iso-propyl, n- butyl, iso-butyl, sec-butyl, or t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tertiary butyl, pentyl, neopentyl, or hexyl. In some embodiments, an alkyl is methyl.

[0149] An “alkylene” group refers to a divalent alkyl radical. Any of the above-mentioned monovalent alkyl groups may be an alkylene by abstraction of a second hydrogen atom from the alkyl. In some embodiments, an alkylene is a C1-C6alkylene. In other embodiments, an alkylene is a Ci-C4alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, - CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, an alkylene is -CH2-.

[0150] An “alkoxy” group refers to a -O(alkyl) group, where alkyl is as defined herein.

[0151] The term “alkylamine” refers to the -N(alkyl)xHygroup, where x is 0 and y is 2, or where x is 1 and y is 1, or where x is 2 and y is 0.

[0152] An “hydroxyalkyl” refers to an alkyl in which one hydrogen atom is replaced by a hydroxyl. In some embodiments, a hydroxyalkyl is a Ci-C4hydroxyalkyl. Typical hydroxyalkyl groups include, but are not limited to, -CH2OH, -CH2CH2OH, -CH2CH2CH2OH, - CH2CH2CH2CH2OH, and the like. In some embodiments, a hydroxyalkyl is -CH2OH or - CH2CH2OH. In some embodiments, a hydroxyalkyl is -CH2OH. In some embodiments, a hydroxyalkyl is -CH2CH2OH.

[0153] An “aminoalkyl” refers to an alkyl in which one hydrogen atom is replaced by an amino. In some embodiments, aminoalkyl is a Ci-C4aminoalkyl. Typical aminoalkyl groups include, but are not limited to, -CH2NH2, -CH2CH2NH2, -CH2CH2CH2NH2, -CH2CH2CH2CH2NH2, and the like. In some embodiments, an amino alkyl is -CH2NH2 or -CH2CH2NH2. In some embodiments, a hydroxyalkyl is -CH2NH2. In some embodiments, a hydroxyalkyl is -CH2CH2NH2.

[0154] The term “alkenyl” refers to a type of alkyl group in which at least one carbon-carbon double bond is present. In one embodiment, an alkenyl group has the formula -C(R)=CR.2, wherein R refers to the remaining portions of the alkenyl group, which may be the same or different. In some embodiments, R is H or an alkyl. In some embodiments, an alkenyl is selected from ethenyl (i.e., vinyl), propenyl (i.e., allyl), butenyl, pentenyl, pentadienyl, and the like. Non-limiting examples of an alkenyl group include -CH=CH2, -C(CH3)=CH2, -CH=CHCH3, -C(CH3)=CHCH3, and - CH2CH=CH2.

[0155] The term “alkynyl” refers to a type of alkyl group in which at least one carbon-carbon triple bond is present. In one embodiment, an alkynyl group has the formula -C=C-R, wherein R refers to the remaining portions of the alkynyl group. In some embodiments, R is H or an alkyl. In some embodiments, an alkynyl is selected from ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like. Non-limiting examples of an alkynyl group include -C=CH, -OCCH3-OCCH2CH3, - CH2C=CH.

[0156] The term “heteroalkyl” refers to an alkyl group in which one or more skeletal atoms of the alkyl are selected from an atom other than carbon, e.g., oxygen, nitrogen (e.g., -NH-, -N(alkyl)-, sulfur, or combinations thereof. A heteroalkyl is attached to the rest of the molecule at a carbon atom of the heteroalkyl. In one aspect, a heteroalkyl is a C1-C6heteroalkyl. In some embodiments, a heteroalkyl is a C1-C6heteroalkyl where one or two atoms are independently selected from O, NH, and S.

[0157] The term “aromatic” refers to a planar ring having a delocalized 7t-electron system containing 4n+2 it electrons, where n is an integer. The term “aromatic” includes both carbocyclic aryl (“aryl”, e.g., phenyl) and heterocyclic aryl (or “heteroaryl” or “heteroaromatic”) groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups.

[0158] The term “carbocyclic” or “carbocycle” refers to a ring or ring system where the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from “heterocyclic” rings or “heterocycles” in which the ring backbone contains at least one atom which is different from carbon. In some embodiments, at least one of the two rings of a bicyclic carbocycle is aromatic. In some embodiments, both rings of a bicyclic carbocycle are aromatic. Carbocycles include aryls and cycloalkyls.

[0159] As used herein, the term “aryl” refers to an aromatic ring wherein each of the atoms forming the ring is a carbon atom. In one aspect, aryl is phenyl or a naphthyl. In some embodiments, an aryl is a phenyl. In some embodiments, an aryl is a phenyl, naphthyl, indanyl, indenyl, or tetrahydronaphthyl. In some embodiments, an aryl is a phenyl. In some embodiments, an aryl is a Ce-C10aryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).

[0160] The term “cycloalkyl” refers to a monocyclic or polycyclic aliphatic, non-aromatic radical, wherein each of the atoms forming the ring (i.e. skeletal atoms) is a carbon atom. In some embodiments, cycloalkyls are spirocyclic or bridged compounds. In some embodiments, cycloalkyls are optionally fused with an aromatic ring, and the point of attachment is at a carbon that is not an aromatic ring carbon atom. Cycloalkyl groups include groups having from 3 to 10 ring atoms. In some embodiments, cycloalkyl groups are selected from among cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, spiro[2.2]pentyl,norbomyl and bicyclo [l.l.l]pentyl. In some embodiments, a cycloalkyl is a C3-C6cycloalkyl. In some embodiments, a cycloalkyl is a C3-C4cycloalkyl. In some embodiments, a cycloalkyl is a cyclopropyl. In some embodiments, a cycloalkyl is a cyclobutyl.

[0161] The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0162] The term “fluoroalkyl” refers to an alkyl in which one or more hydrogen atoms are replaced by a fluorine atom. In one aspect, a fluoroalkyl is a C1-C6fluoroalkyl. In some embodiments, a fluoroalkyl is -CF3.

[0163] The term “heterocycle” or “heterocyclic” refers to heteroaromatic rings (also known as heteroaryls) and heterocycloalkyl rings containing one to four heteroatoms in the ring(s), where each heteroatom in the ring(s) is selected from O, S and N, wherein each heterocyclic group has from 3 to 10 atoms in its ring system, and with the proviso that any ring does not contain two adjacent O or S atoms. Non-aromatic heterocyclic groups (also known as heterocycloalkyls) include rings having 3 to 10 atoms in its ring system and aromatic heterocyclic groups include rings having 5 to 10 atoms in its ring system. The heterocyclic groups include benzo-fused ring systems. Examples of non- aromatic heterocyclic groups are pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothienyl, oxazolidinonyl, tetrahydropyranyl, dihydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, thioxanyl, piperazinyl, aziridinyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1,2,3,6-tetrahydropyridinyl, pyrrolin-2-yl, pyrrolin-3-yl, indolinyl, 2H-pyranyl, 4H-pyranyl, dioxanyl, 1,3-dioxolanyl, pyrazolinyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, dihydrofuranyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, 3 -azabicyclo [3.1.0]hexanyl, 3-azabicyclo[4.1.0]heptanyl, 3H-indolyl, indolin-2-onyl, isoindolin-l-onyl, isoindoline-l,3-dionyl, 3,4-dihydroisoquinolin-l(2H)-onyl, 3,4-dihydroquinolin- 2(lH)-onyl, isoindoline-l,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, lH-benzo[d]imidazol-2(3H)- onyl, benzo[d]thiazol-2(3H)-onyl, and quinolizinyl. Examples of aromatic heterocyclic groups are pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, quinolinyl, isoquinolinyl, indolyl, benzimidazolyl, benzofuranyl, cinnolinyl, indazolyl, indolizinyl, phthalazinyl, pyridazinyl, triazinyl, isoindolyl, pteridinyl, purinyl, oxadiazolyl, thiadiazolyl, furazanyl, benzofurazanyl, benzothiophenyl, benzothiazolyl, benzoxazolyl, quinazolinyl, quinoxalinyl, naphthyridinyl, and furopyridinyl. The foregoing groups are either C-attached (or C-linked) or N-attached where such is possible. For instance, a group derived from pyrrole includes both pyrrol-l-yl (N-attached) or pyrrol- 3-yl (C-attached). Further, a group derived from imidazole includes imidazol-l-yl or imidazol-3-yl (both ^-attached) or imidazol-2-yl, imidazol-4-yl or imidazol-5-yl (all C-attached). The heterocyclic groups include benzo-fused ring systems. Non-aromatic heterocycles are optionally substituted with one or two oxo (=0) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of thetwo rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0164] The terms “heteroaryl” or, alternatively, “heteroaromatic” refers to an aryl group that includes one or more ring heteroatoms selected from nitrogen, oxygen and sulfur. Illustrative examples of heteroaryl groups include monocyclic heteroaryls and bicyclic heteroaryls. Monocyclic heteroaryls include pyridinyl, imidazolyl, pyrimidinyl, pyrazolyl, triazolyl, pyrazinyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazolyl, isothiazolyl, pyrrolyl, pyridazinyl, triazinyl, oxadiazolyl, thiadiazolyl, and furazanyl. Monocyclic heteroaryls include indolizine, indole, benzofuran, benzothiophene, indazole, benzimidazole, purine, quinolizine, quinoline, isoquinoline, cinnoline, phthalazine, quinazoline, quinoxaline, 1,8-naphthyridine, and pteridine. In some embodiments, a heteroaryl contains 0-4 N atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms in the ring. In some embodiments, a heteroaryl contains 0-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 0 atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a Ci-Cyheteroaryl. In some embodiments, monocyclic heteroaryl is a Ci-Csheteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a Ce-Cgheteroaryl.

[0165] A “heterocycloalkyl” group refers to a cycloalkyl group that includes at least one heteroatom selected from nitrogen, oxygen and sulfur. In some embodiments, a heterocycloalkyl is fused with an aryl or heteroaryl. In some embodiments, the heterocycloalkyl is oxazolidinonyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, piperidin-2-onyl, pyrrolidine-2, 5-dithionyl, pyrrolidine-2, 5-dionyl, pyrrolidinonyl, imidazolidinyl, imidazolidin-2-onyl, or thiazolidin-2-onyl. In one aspect, a heterocycloalkyl is a C2-C10heterocycloalkyl. In another aspect, a heterocycloalkyl is a C4-C10heterocycloalkyl. In some embodiments, a heterocycloalkyl is monocyclic or bicyclic. In some embodiments, a heterocycloalkyl is monocyclic and is a 3, 4, 5, 6, 7, or 8 -membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3, 4, 5, or 6-membered ring. In some embodiments, a heterocycloalkyl is monocyclic and is a 3 or 4-membered ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms in the ring. In some embodiments, a heterocycloalkyl contains 0-2 N atoms, 0-2 O atoms and 0-1 S atoms in the ring.

[0166] The term “bond” or “single bond” refers to a chemical bond between two atoms, or two moieties when the atoms joined by the bond are considered to be part of larger substructure. In one aspect, when a group described herein is a bond, the referenced group is absent thereby allowing a bond to be formed between the remaining identified groups.

[0167] The term “moiety” refers to a specific segment or functional group of a molecule. Chemical moieties are often recognized chemical entities embedded in or appended to a molecule.

[0168] The term “optionally substituted” or “substituted” means that the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from halogen, -CN, -NH2, -NH(alkyl), -N(alkyl)2, -OH, -CO2H, -CO2alkyl, -C(=O)NH2, - C(=O)NH(alkyl), -C(=O)N(alkyl)2, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, alkyl, cycloalkyl, fluoroalkyl, heteroalkyl, alkoxy, fluoroalkoxy, heterocycloalkyl, aryl, heteroaryl, aryloxy, alkylthio, arylthio, alkylsulfoxide, arylsulfoxide, alkylsulfone, and arylsulfone. In some other embodiments, optional substituents are independently selected from halogen, -CN, -NH2, - NH(CH3), -N(CH3)2, -OH, -CO2H, -CO2(Ci-C4alkyl), -C(=O)NH2, -C(=O)NH(Ci-C4alkyl), - C(=O)N(Ci-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(Ci-C4alkyl), -S(=O)2N(Ci-C4alkyl)2, Ci-C4alkyl, C3-C6cycloalkyl, Ci-C4fluoroalkyl, Ci-C4heteroalkyl, Ci-C4alkoxy, Ci-C4fluoroalkoxy, -SCi- C4alkyl, -S(=O)Ci-C4alkyl, and -S(=O)2Ci-C4alkyl. In some embodiments, optional substituents are independently selected from halogen, -CN, -NH2, -OH, -NH(CH3), -N(CH3)2, -CH3, -CH2CH3, - CHF2, -CF3, -OCH3, -OCHF2, and -OCF3. In some embodiments, substituted groups are substituted with one or two of the preceding groups. In some embodiments, an optional substituent on an aliphatic carbon atom (acyclic or cyclic) includes oxo (=0).

[0169] In some embodiments, each substituted alkyl, substituted fluoroalkyl, substituted heteroalkyl, substituted carbocycle, and substituted heterocycle is substituted with one or more Rsgroups independently selected from the group consisting of halogen, C1-C6alkyl, monocyclic carbocycle, monocyclic heterocycle, -CN, -OR21, -CO2R21, -C(=O)N(R21)2, -N(R21)2, - NR21C(=O)R22, -SR21, -S(=O)R22, -SO2R22, and -SO2N(R21)2; each R21is independently selected from hydrogen, C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2- Cgheterocycloalkyl, phenyl, benzyl, 5 -membered heteroaryl and 6-membered heteroaryl; or two R21groups are taken together with the N atom to which they are attached to form a N-containing heterocycle; each R22is independently selected from C1-C6alkyl, C1-C6fluoroalkyl, C1-C6heteroalkyl, C3-C6cycloalkyl, C2-C6heterocycloalkyl, phenyl, benzyl, 5-membered heteroaryl and 6-membered heteroaryl.

[0170] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0171] The term “modulate” as used herein, means to interact with a target either directly or indirectly so as to alter the activity of the target, including, by way of example only, to enhance the activity of the target, to inhibit the activity of the target, to limit the activity of the target, or to extend the activity of the target.

[0172] The term “modulator” as used herein, refers to a molecule that interacts with a target either directly or indirectly. The interactions include, but are not limited to, the interactions of an agonist,partial agonist, an inverse agonist, antagonist, degrader, or combinations thereof. In some embodiments, a modulator is an antagonist. In some embodiments, a modulator is an inhibitor.

[0173] The terms “administer,” “administering”, “administration,” and the like, as used herein, refer to the methods that may be used to enable delivery of compounds or compositions to the desired site of biological action. These methods include, but are not limited to oral routes, intraduodenal routes, parenteral injection (including intravenous, subcutaneous, intraperitoneal, intramuscular, intravascular or infusion), topical and rectal administration. Those of skill in the art are familiar with administration techniques that can be employed with the compounds and methods described herein. In some embodiments, the compounds and compositions described herein are administered orally.

[0174] The terms “co-administration” or the like, as used herein, are meant to encompass administration of the selected therapeutic agents to a single patient, and are intended to include treatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0175] The terms “effective amount” or “therapeutically effective amount,” as used herein, refer to a sufficient amount of an agent or a compound being administered, which will relieve to some extent one or more of the symptoms of the disease or condition being treated. The result includes reduction and / or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. For example, an “effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to provide a clinically significant decrease in disease symptoms. An appropriate “effective” amount in any individual case is optionally determined using techniques, such as a dose escalation study.

[0176] The terms “enhance” or “enhancing,” as used herein, means to increase or prolong either in potency or duration a desired effect. Thus, in regard to enhancing the effect of therapeutic agents, the term “enhancing” refers to the ability to increase or prolong, either in potency or duration, the effect of other therapeutic agents on a system. An “enhancing-effective amount,” as used herein, refers to an amount adequate to enhance the effect of another therapeutic agent in a desired system.

[0177] The term “pharmaceutical combination” as used herein, means a product that results from the mixing or combining of more than one active ingredient and includes both fixed and non-fixed combinations of the active ingredients. The term “fixed combination” means that the active ingredients, e.g., a compound of Formula (I) or (XI), or a pharmaceutically acceptable salt or solvate thereof, and a co-agent, are both administered to a patient simultaneously in the form of a single entity or dosage. The term “non-fixed combination” means that the active ingredients, e.g., a compound of Formula (I) or (XI), or a pharmaceutically acceptable salt or solvate thereof, and a coagent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effectivelevels of the two compounds in the body of the patient. The latter also applies to cocktail therapy, e.g., the administration of three or more active ingredients.

[0178] The terms “article of manufacture” and “kit” are used as synonyms.

[0179] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0180] The terms “treat,” “treating” or “treatment,” as used herein, include alleviating, abating or ameliorating at least one symptom of a disease or condition, preventing additional symptoms, inhibiting the disease or condition, e.g., arresting the development or progression of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a secondary condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically.Pharmaceutical Compositions

[0181] In certain embodiments, the heterocyclic LpxC inhibitory compound as described herein is administered as a pure chemical. In other embodiments, the heterocyclic LpxC inhibitory compound described herein is combined with a pharmaceutically suitable or acceptable carrier (also referred to herein as a pharmaceutically suitable (or acceptable) excipient, physiologically suitable (or acceptable) excipient, or physiologically suitable (or acceptable) carrier) selected on the basis of a chosen route of administration and standard pharmaceutical practice as described, for example, in Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0182] Provided herein is a pharmaceutical composition comprising at least one heterocyclic LpxC inhibitory compound as described herein, or a stereoisomer, pharmaceutically acceptable salt, or N-oxide thereof, together with one or more pharmaceutically acceptable carriers. The carrier(s) (or excipient(s)) is acceptable or suitable if the carrier is compatible with the other ingredients of the composition and not deleterious to the recipient (i.e., the subject or patient) of the composition.

[0183] Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I) or (XI), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0184] In certain embodiments, the heterocyclic LpxC inhibitory compound as described by Formula (I) or (XI) is substantially pure, in that it contains less than about 5%, or less than about 1%, or less than about 0.1%, of other organic small molecules, such as unreacted intermediates or synthesis by-products that are created, for example, in one or more of the steps of a synthesis method.

[0185] Suitable oral dosage forms include, for example, tablets, pills, sachets, or capsules of hard or soft gelatin, methylcellulose or of another suitable material easily dissolved in the digestive tract. In some embodiments, suitable nontoxic solid carriers are used which include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. (See, e.g., Remington: The Science and Practice of Pharmacy (Gennaro, 21stEd. Mack Pub. Co., Easton, PA (2005)).

[0186] The dose of the composition comprising at least one heterocyclic LpxC inhibitory compound as described herein differ, depending upon the patient’s condition, that is, stage of the disease, general health status, age, and other factors.

[0187] Pharmaceutical compositions are administered in a manner appropriate to the disease to be treated (or prevented). An appropriate dose and a suitable duration and frequency of administration will be determined by such factors as the condition of the patient, the type and severity of the patient’s disease, the particular form of the active ingredient, and the method of administration. In general, an appropriate dose and treatment regimen provides the composition(s) in an amount sufficient to provide therapeutic and / or prophylactic benefit (e.g., an improved clinical outcome), or a lessening of symptom severity. Optimal doses are generally determined using experimental models and / or clinical trials. The optimal dose depends upon the body mass, weight, or blood volume of the patient.

[0188] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day.Preparation of Compounds

[0189] Compounds of Formula (I) or (XI) described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.

[0190] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC are employed.

[0191] Compounds are prepared using standard organic chemistry techniques such as those described in, for example, March’s Advanced Organic Chemistry, 6thEdition, John Wiley and Sons, Inc. Alternative reaction conditions for the synthetic transformations described herein may be employed such as variation of solvent, reaction temperature, reaction time, as well as different chemical reagents and other reaction conditions.

[0192] In some embodiments, described herein is a process for the preparation of a compound of Formula (I), comprising:(1) contacting a phosphorylating reagent with a compound of Formula (A):Formula (A), or a pharmaceutically acceptable salt or solvate thereof, wherein PG is a protecting group;R1, R2a, R2b, R4, R5, R6, R7, L1, La, s, and t are defined in any one of claims 1-43; and (2) removing PG to provide the compound of Formula (I).

[0193] In some embodiments, the compound of Formula (A) is a compound of Formula (B):Formula (B), or a pharmaceutically acceptable salt or solvate thereof.

[0194] In some embodiments, described herein is a process for the preparation of a compound of Formula (XI), comprising:(1) contacting a phosphorylating reagent with a compound of Formula (X-A):Formula (X-A), or a pharmaceutically acceptable salt or solvate thereof, wherein PG is a protecting group;R1, R2a, R2b, R4, R5, R6, R7, R12, R13, L1, La, s, and t are defined herein; and(2) removing PG to provide the compound of Formula (XI).

[0195] In some embodiments, the compound of Formula (X-A) is a compound of Formula (X-B):Formula (X-B), or a pharmaceutically acceptable salt or solvate thereof.

[0196] In some embodiments, the phosphorylating reagent is phosphoryl trichloride (POCI3). In some embodiments, the phosphorylating reagent is di-tert-butyl N,N-diisopropylphosphoramidite. In some embodiments, the phosphorylating reagent is a phosphite, phosphoramidite, or phosphorus oxyhalide. In some embodiments, the phosphorylating reagent is a phosphorus (III) reagent. In some embodiments, the phosphorylating reagent is a phosphorus (V) reagent.

[0197] In some embodiments, PG is tetrahydropyranyl (THP). In some embodiments, PG is acetyl (Ac), benzoyl (Bz), benzyl (Bn), methoxyethoxymethyl ether (MEM), methoxymethyl ether (MOM), pivaloyl (Piv), tert-butyl (tBu), tetrahydropyranyl (THP), trimethylsilyl (TMS), or tertbutyldimethylsilyl (TBS).

[0198] In some embodiments, compounds described herein are prepared as described in Scheme A.Scheme A:a) Pd catalyst, base; b) P0CI3, base c) deprotectionPG = protecting groupX = Cl, Br, I, OMs, OTsB = boronic acid or ester, or trifluoroborate (BF3K)

[0199] An organometallic coupling reaction such as Suzuki-Miyaura reaction betweenIntermediate A and the appropriate aryl boronic acid or its ester or an organotrifluoroborate (BF3K) B provided Intermediate C. Reaction with POCI3 and then removal of the protecting group using appropriate deprotection methods yielded final Compound E.

[0200] In some embodiments, compounds described herein are prepared as described in Scheme B.Scheme B:a) Pd catalyst, base; b) POCI3, base c) deprotectionPG = protecting groupX = Cl, Br, I, OMs, OTsB = boronic acid or ester, or trifluoroborate (BF3K)

[0201] An organometallic coupling reaction such as Suzuki-Miyaura reaction between Intermediate 2-A and the appropriate aryl boronic acid or its ester or an organotrifluoroborate (BF3K) 2-B provided Intermediate 2-C. Reaction with POCI3 and then removal of the protecting group using appropriate deprotection methods yielded final Compound 2-E.

[0202] In some embodiments, compounds are prepared as described in the Examples.EXAMPLES

[0203] As used above, and throughout the description of the invention, the following abbreviations, unless otherwise indicated, shall be understood to have the following meanings:Abbreviations:ACN or MeCN: acetonitrile; aq: aqueous;Boc or BOC: tert-butoxy carbonyl;B2pin2: bis(pinacolato)diboron;DCM: dichloromethane;DHP: 3,4-dihydro-2H-pyran;DIAD: diisopropyl azodicarboxylate;DMAP: 4-dimethylaminopyridine;DMF: dimethylformamide;DMP: Dess-Martin periodinane;DPPA: diphenylphosphoryl azide;Eq. or equiv: equivalents;EtOAc: ethyl acetate; g: grams; h or hr(s): hour(s);HC1: hydrochloric acid;HPLC: high-performance liquid chromatography;H2O: water;(i-Pr)2NP(OCH2CH=CH2)2: diallyl N,N-diisopropylphosphoramidite;KOAc: potassium acetate;K2CO3: potassium carbonate;LC-MS, LC MS, or LCMS: liquid chromatography-mass spectrometry;LDA: lithium diisopropylamide;M: molar;MeOH: methanol;MeNCh; nitromethane; mg: milligrams; min: minute; mL: milliliter; mmol: millimole;MsCl: methanesulfonyl (mesyl) chloride;MTBE: methyl tert-butyl ether;N : normal ;NBS : A-bromosuccinimide ;NMR: nuclear magnetic resonance;Pet ether: petroleum ether;PdCh(dppf): [l,r-Bis(diphenylphosphino)ferrocene]palladium(II) dichloride;PdCh(dtbpf): bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II);Pd(PPhs)4: palladium-tetrakis(triphenylphosphine);POCI3: phosphoryl trichloride;PPTS: pyridinium p-toluenesulfonate;p-TSA: para-toluenesuflonic acid;Py: pyridine; rt: room temperature;SFC: supercritical fluid chromatography;TEA: triethylamine (or EtsN);TFA: trifluoroacetic acid;THF: tetrahydrofuran;THP: tetrahydropyran;TLC: thin layer chromatography;TsCl: para-toluenesulfonyl (tosyl) chloride.

[0204] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein.I. Chemical Synthesis

[0205] Unless otherwise noted, reagents and solvents were used as received from commercial suppliers. Anhydrous solvents and oven-dried glassware were used for synthetic transformations sensitive to moisture and / or oxygen. Yields were not optimized. Reaction times are approximate and were not optimized. Column chromatography and thin layer chromatography (TLC) were performed on silica gel unless otherwise noted. Spectra are given in ppm (5) and coupling constants, J are reported in Hertz. For proton spectra the solvent peak was used as the reference peak.Example 1: Synthesis of Compound 1

[0206] Step 4:

[0207] The diastereomers of (±)-4 (5 g, 17.41 mmol) were separated by using SFC (column: CHIRAL-PAK ASH (250*20) mm, 5 pm; eluents: CO2and 0.5% isopropyl amine in MeOH) to get 4_Isomer-l and 4_Isomer-2 as pale-brown solids. Yield: 4_Isomer-l (tR=3.0 min) =1.5 g and 4_Isomer-2 (tR=4.7 min) = 1.7 g. LC-MS: Calculated for C16H22BNO3 is 287.17, observed: 288.2 [M+l]+

[0208] Step 5:

[0209] To a solution of 5 (740 mg, 1.7 mmol) and 4_Isomer-2 (608 mg, 2.1 mmol) in THF (10 mL) and water (2.5 mL), was added potassium phosphate tribasic (1.1 g, 5.3 mmol) at room temperature. The reaction mixture was purged with nitrogen for 10 min. Then, Sphos Pd G2 (59.1 mg, 0.082 mmol) was added. The reaction mixture was irradiated in a micro wave reactor at 70 °C for 1 h. One more batch was carried out using 740 mg of 5. Both batches were mixed for workup andpurification. The reaction mixture was filtered through a pad of Celite. The Celite bed was washed with EtOAc (200 mL). The combined filtrate was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (SiC>2230-400 mesh; 8% MeOH in DCM) to afford 6 as a pale-yellow solid. Yield: 910 mg (combined yield for two batches). LC-MS: Calculated for C30H33N3O4 is 499.61, observed: 500.2 [M+l]+

[0210] Step 6:

[0211] To a stirred solution of 6 (1.2 g, 2.282 mmol) in DCM (25 mL), were added Diallyl N,N- diisopropylphosphoramidite (7, 1.095 mL, 4.11 mmol) and l / 7-tetrazole (0.480 g, 6.85 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C, 30 % hydrogen peroxide in water (0.337 mL, 3.42 mmol) was added and the resulting reaction mixture stirred at room temperature for 30 min. The reaction mixture was quenched with 10% NaHCCL solution (10 mL). This was extracted with DCM (3 x 15 mL). The combined organic layer was dried over anhydrous ISfeSCL, filtered and concentrated under reduced pressure. The resulting crude residue was purified by using reverse phase column chromatography (column: RediSep Gold; C18 silica gel; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford 8 as a brown gum. Yield: 0.85 g (56%). LC-MS: Calculated for C36H42N3O7P is 659.28 Observed: 660.0 [M+l]+

[0212] Step 7:

[0213] To a stirred solution of 8 (850 mg, 1.277 mmol) in MeOH (25 mL) was added p- toluenesulfonic acid monohydrate (243 mg, 1.277 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous NaHCO? solution (10 mL). This was extracted with 10% MeOH in DCM (3 x 20 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 9 as a light-brown solid. The crude product was taken to the next step without any purification. Yield: 750 mg (crude product weight). LCMS: Calculated for C31H34N3O6P is 575.2, observed: 576.4 [M+l]+

[0214] Step 8:

[0215] To a stirred solution of 9 (620 mg, 1.048 mmol) in MeOH (10 mL), were added 1,3- dimethylbarbituric acid (327 mg, 2.095 mmol) and Pd(PPhs)4 (60.5 mg, 0.052 mmol) at room temperature, and the mixture stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting crude residue was purified by using reverse phase column chromatography (column: RediSep Gold, C18 silica gel; eluents: 10 mM ammonium bicarbonate in water and ACN) to obtain Compound 1 as a pale-yellow solid. Yield: 260 mg (50%). LCMS: Calculated for C25H26N3O6P is 495.2, observed: 496.2 [M+l]+. 1H-NMR (400 MHz, DMSO- d6): 5 7.74 (brs, 1H, exchanges with D2O), 7.69-7.64 (m, 4H), 7.55 (d, J = 8.00 Hz, 2H), 7.40 (d, J =8.40 Hz, 2H), 7.35 (d, J = 0.80 Hz, 1H), 7.22 (br s, 2H, exchanges with D2O), 6.88 (s, 1H), 5.98 (t, J = 6.40 Hz, 1H), 4.94-4.91 (m, 1H), 4.19-4.04 (m, 2H), 3.68-3.62 (m, 2H), 3.26-3.20 (m, 1H), 2.57- 2.55 (m, 1H), 2.34-2.30 (m, 1H), 1.48 (d, J = 6.40 Hz, 3H). 31P-NMR (162 MHz, DMSO-d6): 5 - 0.402. SFC: 100%; tR = 5.24 min (column: I Cellulose- Z; eluents: CO2and 0.5% isopropyl amine in ACN and MeOH)

[0216] Note: One exchangeable proton not seen in NMRExample 2: Synthesis of Compound 3Step 1

[0217] Step l:

[0218] To a solution of 1 (1 g, 1.24 mmol) in DCM (20 mL), were added diallyl diisopropylphosphoramidite (2, 0.7 g, 2.84 mmol) and IH-Tetrazole (0.4 g, 5.69 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. After cooling the reaction mixture to 0 °C, hydrogen peroxide (30% in water; 1.95 mL, 18.95 mmol) was added and the resulting reaction mixture stirred at room temperature for 1 h. The reaction was quenched with 10% NaHCO3 solution (25 mL) and extracted with DCM (50 mL x 2). The combined organic layer was dried over anhydrous Na2SC>4, concentrated under reduced pressure. One more batch was carried out on 1 g of 1 to get the crude product. Both batches were mixed and purified by reverse phase column chromatography (column: Redisep Gold, Cis reverse phase SiO2; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford 3 as a pale-brown solid. Yield: 1.3 g (corresponds to two batches). LCMS: Calculated for C38H46N3O7P is 687.77, observed: 688.4 [M+l]+

[0219] Step 2:

[0220] To a solution of 3 (1.3 g, 1.89 mmol) in MeOH (20 mL), was added p-toluenesulfonic acid monohydrate (1.08 g, 5.67 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 4 h. The reaction mixture was diluted with DCM (50 mL), washed with 10% NaHCO3 solution (20 mL). The organic layer was dried over anhydrous ISfeSCL, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by column chromatography (column: Redisep Gold, Cis reverse phase SiO2; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford 4 as pale-brown solid. Yield: 0.85 g (70%). LCMS: Calculated for C33H38N3O6P is 603.66, observed: 604.2 [M+l]+

[0221] Step 3:

[0222] To a solution of 4 (0.85 g, 1.40 mmol) in DCM (10 mL), were added pyrrolidine (0.2 mL, 2.39 mmol) and tetrakis(triphenylphosphine)palladium (0) (81 mg, 0.07 mmol) at 0 °C, and the resulting reaction mixture stirred at room temperature for 4 h. The volatiles were removed under reduced pressure. The crude residue thus obtained was purified by reverse phase column chromatography (column: Redisep Gold, Cis reverse phase SiO2; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 3 as white solid. Yield: 198 mg (26%) . LCMS: Calculated for C27H30N3O6P is 523.52, observed: 524.2 [M+l]+. 1H-NMR (400 MHz, DMSO-d6): δ 7.73-7.68 (m, 3H, one proton exchanges with D2O), 7.64 (d, J = 8.0 Hz, 2H), 7.56 (d, J = 8.40 Hz, 2H), 7.47 (s, 1H), 7.33 (d, J = 8.40 Hz, 2H), 7.01 (s, 1H), 6.01 (t, J = 6.00 Hz, 1H), 5.04-4.99 (m, 1H), 4.23-4.15 (m, 2H), 3.47-3.38 (m, 1H), 3.01-2.91 (m, 1H), 2.58 (d, J = 4.80 Hz, 3H), 2.47-2.44 (m, 2H), 2.27-2.22 (m, 2H), 1.50 (d, J = 6.40 Hz, 3H). Due to more moisture content the exchangeable protons not seen properly. 31P-NMR (162 MHz, DMSO-d6): δ - 0.766. SFC: 99.8%; tR = 1.29 min (column: CHIRALPAK AS-H; eluents: CO2and 0.5% isopropyl amine in ACN and MeOH)

[0223] Note: Mixture of diastereomers; cis-geometry in tail part. SFC purity = 99.8%. Due to more moisture content the exchangeable protons not seen properly.Example 3: Synthesis of Compounds 5 and 6

[0224] Step 1:

[0225] To a stirred solution of 1 (1.3 g, 2.53 mmol) in DCM (25 mL), were added Diallyl N,N- diisopropylphosphoramidite (2, 1.082 mL, 4.06 mmol) and IH-tetrazole (0.474 g, 6.76 mmol) at room temperature, and the resulting reaction mixture stirred at room temperature for 1 h. To the mixture cooled to 0 °C, 30% hydrogen peroxide in water (0.333 mL, 3.38 mmol) was added and the mixture then stirred at room temperature for 30 min. The reaction mixture was quenched with 10% NaHCCh solution (10 mL), extracted with DCM (15 mL x 3). The combined organic extract was washed with brine solution (8 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The crude mass, thus obtained, was purified by using reverse phase column chromatography (column: Redisep Cis column; eluents: 10 mM ammonium bicarbonate in water and acetonitrile) to afford 3 as a brown gum. Yield: 0.75 g (48%). LCMS: Calculated for C37H44N3O7P is 673.2, observed: 674.4 [M+H]+.

[0226] Step 2:

[0227] To a stirred solution of 3 (1.4 g, 2.078 mmol) in MeOH (25 mL), was added p- toluenesulfonic acid monohydrate (0.790 g, 4.16 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 3 h. The reaction was quenched with saturated NaHCO? solution (10 mL) and extracted with 10% MeOH in DCM (3 x 20 mL). The combined organic layer was washed with brine solution (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 4 as a brown gum. Yield: 1 g (74%). LCMS: Calculated for C32H36N3O6P is 589.6, observed: 590.4 [M+H]+

[0228] Step 3:

[0229] To a stirred solution of 4 (1 g, 1.696 mmol) in DCM (20 mL), were added pyrrolidine (0.281 mL, 3.39 mmol) and Pd(PhsP)4 (0.098 g, 0.085 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 1 h. The volatiles were removed under reduced pressure. One more batch was performed on 340 mg of 4. Both batches were mixed and purified. The crude residue, thus obtained, was purified by using reverse phase column chromatography (column: Redisep Cis column; eluents: 10 mM ammonium bicarbonate in water and acetonitrile) to obtain Compounds 5 and 6 as a white solid. Yield: 160 mg (combined yield of two batches). LCMS: Calculated for C26H28N3O6P is 509.1, observed: 510.4 [M+H]+. 'H-NMR (400 MHz, DMSO-r / 6): 8 8.06 (q, J = 4.4 Hz, 1H, exchanges with D2O), 7.68 (d, J = 8.4 Hz, 2H), 7.60 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.47 (s, 1H), 7.21 (d, J = 8.4 Hz, 2H), 7.01 (s, 1H), 6.00 (t, J = 6.0 Hz, 1H), 5.02 (q, J = 6.4 Hz, 1H), 4.25-4.13 (m, 2H), 2.62 (d, J = 4.8 Hz, 3H), 2.28-2.26 (m, 1H), 1.87-1.85 (m, 1H), 1.49 (d, J = 6.4 Hz, 3H), 1.25-1.23 (m, 1H), 1.15-1.14 (m, 1H). Three exchangeable protons not seen. SFC purity = 100% (column: LAMYLOSE-A; eluents: CO2and 0.5% isopropyl amine in MeOH).

[0230] Note: / ra / r.s-geometry in the tail; mixture of diastereomers.Example 4: Synthesis of Compound 7

[0231] Step l:

[0232] To a solution of 1 (1.0 g, 1.725 mmol) in DCM (15 mL), were added diallyl N,JV- diisopropylphosphoramidite (2, 0.821 mL, 3.10 mmol) and l / 7-tetrazole (0.363 g, 5.17 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. Then, the reaction was cooled to 0 °C, and 30% hydrogen peroxide in water (0.264 mL, 2.59 mmol) was added. The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with 10% NaHCCh solution (30 mL). This was extracted with DCM (2 x 30 mL). The combined organic layer was dried over anhydrous ISfeSCL, fdtered and concentrated. The resulting crude residue was purified by using reverse phase column chromatography (column: RediSep Gold; Cis silica gel; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford 3 as a brown gum. Yield: 0.75 g (58%). LC-MS: Calculated for C37H46N3O9PS is 739.8, observed: 740.2 [M+H]+

[0233] Step 2:

[0234] To a stirred solution of 3 (1.4 g, 1.892 mmol) in MeOH (25 mL), was added p- toluenesulfonic acid monohydrate (1.440 g, 7.57 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 4 h. The reaction was quenched with saturated NaHCO? solution (50 mL). This was extracted with 10% MeOH in DCM (2 x 40 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 4 as a brown gum. Yield: 1.1 g (84 %). LCMS: Calculated for C32H38N3O8PS is 655.7, observed: 656.2 [M+H]+

[0235] Step 3:

[0236] To a solution of 4 (1.4 g, 2.135 mmol) in DCM (15 mL), were added pyrrolidine (0.298 mL, 3.63 mmol) and Pd(PPh3)4 (0.123 g, 0.107 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting crude residue was purified by using reverse phase column chromatography (column: RediSep Gold, C18 silica gel; eluents:10 mM ammonium bicarbonate in water and ACN) to obtainCompound 7 as a white solid. Yield: 210 mg (17%). LCMS: Calculated for C26H30N3O8PS is 575.6, observed: 576.1 [M+H]+. 1H-NMR (400 MHz, DMSO-d6): δ 7.65-7.62 (m, 4H), 7.51 (d, J = 8.4 Hz, 2H), 7.34 (d, J = 1.2 Hz, 1H), 7.08- 7.04 (m, 3H), 6.90 (d, J = 8.0 Hz, 2H), 6.86 (d, J = 0.8 Hz, 1H), 5.99 (t, J = 6.8 Hz, 1H), 4.93-4.89 (m, 2H), 4.13- 3.93 (m, 3H), 2.87-2.79 (m, 2H), 2.60 (d, J = 4.8 Hz, 3H), 1.48 (d, J = 6.4 Hz, 3H). One exchangeable proton not seen in NMR. Two protons are merged in DMSO peak (clear from the NMR recorded in MeOD). 1H-NMR (400 MHz, MeOD): 8 7.60-7.52 (m, 7H), 7.14 (s, 1H), 6.92 (d, J = 8.80 Hz, 2H), 5.99-5.96 (m, 1H), 5.27-5.21 (m, 1H), 5.01-4.98 (m, 1H), 4.39-4.36 (m, 1H), 4.29-4.27 (m, 1H), 4.01-3.97 (m, 1H), 2.96-2.89 (m, 2H), 2.75 (s, 3H), 2.65-2.57 (m, 2H), 1.64 (d, J = 6.80 Hz, 3H). 31P-NMR (162 MHz, DMSO-d6): δ -1.544. SFC: 99.68%; tR = 1.60 min (column: CHIRALPAK AS; eluents: CO2and 0.5% isopropyl amine in ACN and MeOH)

[0237] Note: trans-geometry in the tail; mixture of diastereomers.Example 5: Synthesis of Compound 9Step 1

[0238] Step l:

[0239] To a stirred solution of 1 (0.750 g, 1.469 mmol) in THF (30 mL), were added triethylamine (0.614 mL, 4.41 mmol) and POC13 (0.274 mL, 2.94 mmol) at -78 °C, and the resulting reaction mixture stirred at room temperature for 1 h. To this reaction mixture, water (10 mL) was added at 0 °C and stirred for 1 h at room temperature. The volatiles were evaporated under reduced pressure to get the crude residue. The crude mass, thus obtained was purified by reverse phase chromatography (column: Redisep Gold; Cis SiCL; eluents: 10 mM formic acid in water and ACN) to afford 161 mg as a white solid. One more batch was carried out using 0.6 g of 1 to yield 66 mg of product as a white solid. Both the batches were mixed and lyophilized to get Compound 9 a white solid. Yield: 217 mg (combined yield for two batches). LC-MS: Calculated C26H27N4O5P is 506.49, observed: 507.2 [M+l]+. 1H-NMR (400 MHz, DMSO-d6): δ 7.71-7.66 (m, 4H), 7.56 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.4 Hz, 2H), 7.39 (s, 1H), 7.16 (bs, 2H, exchanges with D2O), 6.92 (s, 1H), 6.01 (t, J = 6.4 Hz, 1H), 4.98-4.93 (m, 1H), 4.21-4.07 (m, 2H), 3.75-3.68 (m, 5H), 3.34 (s, 2H), 1.49 (d, J = 6.40 Hz, 3H). One exchangeable proton less in 1H-NMR. 31P-NMR (162 MHz, DMSO-d6): δ -0.624. SFC: 100%; tR = 1.07 min (column: CHIRALPAK-IH; eluents: CO2and 0.5% isopropyl amine in MeOH).

[0240] Note: Single isomer with 100% SFC purityExample 6: Synthesis of Compound 10

[0241] Step l:

[0242] To a solution of 1 (1 g, 1.839 mmol) in DCM (40 mL), were added Diallyl N,N- diisopropylphosphoramidite (2, 0.883 mL, 3.31 mmol) and IH-tetrazole (0.387 g, 5.52 mmol) at room temperature and stirred for 1 h. The reaction mixture was cooled to 0 °C, following which 30% hydrogen peroxide in water (0.272 mL, 2.76 mmol) was added and stirred at 25 °C for 1 h. The reaction mixture was quenched with 10% NaHCCh solution (30 mL), extracted with DCM (60 mL x 2). The combined organic extract was washed with brine solution (10 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure crude product. One more batch was performed on 1 g of 1 to get 1.2 g crude of 3. Both batches were mixed and purified using reverse phase column chromatography (column: Redisep Cis column; eluents: 10 mM ammonium bicarbonate in water and acetonitrile) to afford 3 as a brown gum. Yield: 1.5 g (combined yield for both batches). LCMS: Calculated for CssILeNsOsP is 703.3, observed: 704.4 [M+l]+

[0243] Step 2:

[0244] To a stirred solution of 3 (750 mg, 1.066 mmol) in MeOH (10 mL), was added p- toluenesulfonic acid monohydrate (608 mg, 3.20 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 4 h. The reaction was quenched with saturated NaHCO? solution (40 mL) and extracted with 10% MeOH in DCM (3 x 40 mL). The combined organic layer was washed with brine solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford 4 as a brown gum. Yield: 620 mg (89%). LCMS: Calculated for C33H38N3O7P is 619.24, observed: 620.4 [M+l]+

[0245] Step 3:

[0246] To a stirred solution of 4 (1.2 g, 1.937 mmol) in DCM (50 mL), were added pyrrolidine (0.320 mL, 3.87 mmol) and Pd(PhsP)4 (0.112 g, 0.097 mmol) at 25 °C, and the reaction mixture stirred at room temperature for 1 h. The volatiles were removed under reduced pressure and the crude residue, thus obtained, was purified by preparative HPLC (Column: Zorbax Cis; eluents: 10 mM ammonium bicarbonate in water and acetonitrile) to obtain Compound 10 as white solid. Yield:320 mg (30%). LCMS: Calculated for C27H30N3O7P is 539.52, observed: 540.4 [M+l]+. 'H-NMR (400 MHz, DMSO-c4>): 8 7.82 (q, J = 4.4 Hz, 1H, exchanges with D2O), 7.67-7.61 (m, 5H), 7.55 (d, J = 8.4 Hz, 2H), 7.18 (br s, 1H), 6.95 (d, J = 8.8 Hz, 2H), 6.04 (t, J = 5.6 Hz, 1H), 5.10 (q, J = 6.4, 13.2 Hz, 1H), 4.71-4.66 (m, 1H), 4.25-4.19 (m, 2H), 2.69-2.61 (m, 6H), 2.20-2.14 (m, 2H), 1.51 (d, J = 6.8 Hz, 3H). SFC purity = 100% (column: LUX-I-Amylose 3; eluents: CO2and 0.5% isopropyl amine in MeOH).

[0247] Note: Mixture of diastereomers; c / .s-geometry at tail part. SFC purity = 100%. Downfield shifts seen for imidazole protons.Example 7: Synthesis of Compounds 12 and 13Step 1 Step 2 Step 3

[0248] Step l:

[0249] To a solution of 3,4-epoxytetrahydrofuran (1, 10.60 mL, 148 mmol) in a mixture of dioxane (385 mL) and water (96 mL), was added 4-bromobenzylamine (2, 11 g, 59.1 mmol) at room temperature, and the reaction mixture heated at 100 °C for 16 h in an autoclave. The reaction mixture was quenched with water (500 mL) and extracted with EtOAc (200 mL x 2). The combined organic layer was washed with water (500 mL x 2), brine (50 mL), dried over anhydrous Na2SC>4,filtered, and concentrated under reduced pressure. The crude residue was purified by using MPLC (manually packed SiCh cartridge, 230-400 mesh; 80% ACN in DCM) to afford (±)-3 as a paleyellow solid. Yield: 9.3 g (57%). LC-MS: Calculated for CnHuBrNCh is 272.1; observed: 272.0 [M]+and 274.0 [M+2]+

[0250] Step 2:

[0251] To a stirred solution of (±)-3 (9.3 g, 34.2 mmol)) in DCM (200 mL), were added di-tert- butyl dicarbonate (39.3 mL, 171 mmol), DMAP (0.417 g, 3.42 mmol) and triethylamine (47.6 mL, 342 mmol) at 0 °C, and the reaction stirred at room temperature for 16 h. The reaction mixture was quenched with water (150 mL) and extracted with 10% MeOH in DCM (100 mL x 2). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced to get (±)-4 as a brown oil. Yield: 15 g (84%)

[0252] Step 3:

[0253] To a stirred solution of (±)-4 (15 g, 31.8 mmol) in MeOH (200 mL), was added potassium carbonate (8.78 g, 63.5 mmol) at room temperature, and the reaction mixture stirred for 16 h. The reaction mixture was quenched with water (300 mL) and extracted with EtOAc (200 mL x 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by using MPLC (manually packed SiO2 cartridge, 230-400 mesh; 50% EtOAc in hexanes) to afford (±)-5 as a yellow solid. Yield: 1.5 g (12%). LC-MS: Calculated for Ci6H22BrNO4is 372.26, observed: 372.0 [M]’ and 370.0 [M-2]-

[0254] Step 4:

[0255] To a stirred solution of (±)-5 (1.5 g, 4.03 mmol) in DCM (20 mL), were added DHP (1.103 mL, 12.09 mmol) and PPTS (0.101 g, 0.403 mmol) at room temperature, and the reaction mixture stirred at room temperature for 48 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (50 mL x 2). The combined organic layer was washed with NaHCO3 solution (30 mL x 2), brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by using MPLC (manually packed SiCL cartridge, 230-400 mesh; 15% EtOAc in hexane) to afford 6 as a colorless oil. Yield: 1.4 g (76%). LC-MS: Calculated for C2iH3oBrNOs is 456.3, observed: 356.4 [M-Boc]+and 358.4 [(M-Boc)+2]+

[0256] Step 5:

[0257] To a stirred solution of 6 (1.4 g, 3.07 mmol) in dioxane (20 mL), were added bis(pinacolato)diboron (1.168 g, 4.60 mmol) and potassium acetate (0.903 g, 9.20 mmol) at room temperature, and the reaction mixture degassed using nitrogen for 5 min. To this reaction mixture, PdC12(dppf) (0.112 g, 0.153 mmol) was added and stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature, quenched with water (50 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4,filtered, and concentrated under reduced pressure. The crude residue was purified by using MPLC (manually packed SiCh cartridge, 230-400 mesh; 20% EtOAc in hexanes) to afford boronate 7 as a colorless oil. Yield: 1.4 g (87%). LC-MS: Calculated for C27H42BNO7 is 503.44, Observed: 502.4 [M-l]-

[0258] Step 6:

[0259] To a stirred solution of 8 (0.8 g, 1.908 mmol) in acetonitrile (10 mL) and water (10 mL), were added boronate 7 (1.441 g, 2.86 mmol) and K2CO3 (0.791 g, 5.72 mmol) at room temperature, and the reaction mixture degassed using nitrogen for 5 min. To this reaction mixture, PdC12(dtbpf) (0.062 g, 0.095 mmol) was added and the mixture stirred at 80 °C for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with 10% MeOH in DCM (30 mL x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed SiCL cartridge, 230-400 mesh; 4% MeOH in DCM) to afford 9 as a brown solid. Yield: 1.0 g (72%). LC-MS: Calculated for C41H53N3O8 is 715.89, observed: 716.3 [M+l]+

[0260] Step 7:

[0261] To a stirred solution of 9 (1.0 g, 1.397 mmol) in acetonitrile (20 mL), were added pyridine (0.338 mL, 4.19 mmol) and phosphoryl trichloride (0.392 mL, 4.19 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 2 h. To the reaction mixture aq. HC1 (1.5 N, 16 mL) was added and the stirring continued for 30 min. It was then concentrated under reduced pressure and the crude residue, thus obtained, was purified by preparative HPLC (column: X-Select CSH Cis (4.6 x 150 mm) 5pm; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compounds 12 and 13 as an off-white solid. Yield: 0.180 g (24%). LC-MS: Calculated for C26H30N3O7P is 527.5, observed: 528.4 [M+l]+. 1H-NMR (400 MHz, DMSO-d6): δ 7.70 (d, J = 8.40 Hz, 2H), 7.65 (d, J = 8.00 Hz, 2H), 7.55 (d, J = 8.40 Hz, 2H), 7.43 (d, J = 8.00 Hz, 2H), 7.33 (d, J = 1.20 Hz, 1H), 6.85 (d, J = 1.20 Hz, 1H), 6.10 (br s, 1H, exchanges with D2O), 6.03 (t, J = 6.40 Hz, 1H), 4.88 (q, J = 6.40 Hz, 1H), 4.54 (br s, 4H, exchanges with D2O), 4.16-4.09 (m, 1H), 4.04-3.98 (m, 3H), 3.85-3.82 (m, 2H), 3.76 (s, 2H), 3.51-3.47 (m, 2H), 3.02 (t, J = 2.00 Hz, 1H), 1.47 (d, J = 6.40 Hz, 3H). 31P-NMR (162 MHz, DMSO-d6): δ - 0.272. SFC: 100%; tR = 1.31 mm (column: CHIRALPAK-AS-H; eluents: CO2and 0.5% isopropyl amine in ACN and MeOH)

[0262] Note: The final compound was mixture of diastereomers; racemic in the tail part. SFC showed 100% purity.Example 8: Synthesis of Compound 14

[0263] Step l:

[0264] To a solution of 1 (1.2 g, 2.261 mmol) in DCM (30 mL), were added Diallyl N,N- diisopropylphosphoramidite (2, 1.206 mL, 4.52 mmol) and IH-tetrazole (0.475 g, 6.78 mmol) at room temperature, and the resulting mixture stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C, then 30% H2O2 in H2O (0.231 mL, 2.261 mmol) was added and the resulting mixture stirred at room temperature for 1 h. The reaction was quenched with 10% NaHCO3 solution (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude material was purified by reverse phase column chromatography (Column: Redisep Gold, C-is SiCL; Eluents: 10 mM ammonium bicarbonate in water and ACN) to obtained 3 as a pale-brown gum. Yield: 1.1 g (69%). LCMS: Calculated for C36H43N4O8P is 690.73; Observed: 691.2 [M+l]+

[0265] Step 2:

[0266] To a stirred solution of 3 (1.1 g, 1.593 mmol) in MeOH (10 mL), was added p- toluenesulfonic acid monohydrate (0.29 g, 1.54 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 4 h. The reaction mixture was quenched with 10% NaHCO3 solution (100 mL). This was extracted with 10% MeOH in DCM (2 x 100 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to obtain 4 as a brown gum as a crude residue. The crude product was taken to the next step without any purification. Yield: 0.9 g (89%). LCMS: Calculated for C31H35N4O7P is 606.62, observed: 607.5 [M+l]+

[0267] Step 3:

[0268] To a stirred solution of 4 (900 mg, 1.484 mmol) in DCM (15 mL), were added tetrakis(triphenylphosphine)palladium (0) (86 mg, 0.074 mmol) and pyrrolidine (0.123 mL, 1.484 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure. The obtained solid was triturated with EtOAc (20 mL) and dried under vacuum. The crude material was purified by reverse phase column chromatography (Column: Redisep Gold, Cis SiCL; Eluents: 10 mM ammonium bicarbonate in water and ACN) to obtained Compound 14 as an off-white solid. Yield: 170 mg (21%). LCMS: Calculated for C25H27N4O7P is 526.49; Observed: 527.2 [M+l]+. 1H-NMR (400 MHz, DMSO-d6): δ 7.65 (d, J = 8.00 Hz, 4H), 7.53 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 0.80 Hz, 1H), 7.18 (br s, 2H, exchanges with D2O), 6.93 (d, J = 8.80 Hz, 2H), 6.89 (s, 1H), 6.01-5.97 (m, 3H, 2H exchanges with D2O), 5.00-5.05 (m, 1H), 4.95-4.94 (m, 1H), 4.27-4.23 (m, 2H), 4.19-4.06 (m, 2H), 3.75 (dd, J = 3.60, 9.20 Hz, 2H), 1.48 (d, J = 6.40 Hz, 3H). One exchangeable proton not seen in 1H NMR. SFC: 100%; tR = 1.72 min (column: LAmylose-A; eluents: CO2and 0.5% isopropyl amine in MeOH)

[0269] Note: Single isomer with 100% SFC purity. One exchangeable proton not seen in 1H NMR.Example 9: Synthesis of Compound 15

[0270] Step l:

[0271] To a stirred solution of 1 (4.5 g, 11.56 mmol) in 2,2,2-trifluoroethanol (40 mL), was addedTMSC1 (4.14 mL, 32.4 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 1 h.The volatiles were removed under reduced pressure to afford 2 as an off-white solid. Yield = 3.4 g (crude product weight). LC-MS: Calculated for CielfeBNCh is 290.19, Observed: 290.3 [M]+

[0272] Step 2:

[0273] To a stirred solution of 2 (3.4 g, 10.44 mmol) in DMF (20 mL), were added triethylamine (12.07 mL, 84 mmol) and bromoacetonitrile (2.184 mL, 31.3 mmol) at room temperature, and the resulting reaction mixture stirred at room temperature for 3 h. The reaction mixture was quenched with water (250 mL) and extracted with EtOAc (100 mL x 2). The combined organic layer was dried over anhydrous ISfeSCL, filtered and concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed SiCL cartridge, 230-400 mesh size; 10% MeOH in EtOAc) to obtain 4 as a white solid. Yield: 2 g (56%). LC-MS: Calculated for C18H25BN2O3 is 328.22, observed: 329.2 [M+l]+

[0274] Step 3:

[0275] To a solution of 5 (600 mg, 1.431mmol) in DMA (12 mL) and water (3 mL), were added 4 (517 mg, 1.574 mmol) and potassium phosphate tribasic (607 mg, 2.86 mmol) at room temperature, and the resulting mixture degassed using nitrogen for 5 min. To this degassed mixture, PdCb(dtbpf) (93 mg, 0.143 mmol) was added and stirred at 65 °C for 16 h. The reaction mixture was cooled to room temperature and filtered through a Celite pad. The pad was washed with THF (20 mL), the filtrate combined and concentrated under reduced pressure. The residue was diluted with water (20 mL) and extracted with EtOAc (100 mL x 2). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Three more batches on 0.6 g of 5 were carried out to get the crude material. The crude product of all four batches combined and purified by using MPLC (manually packed SiO2 cartridge, 230-400 mesh size; 15% MeOH in EtOAc) to obtain 6 as a brown solid. Yield = 1.4 g (combined yield for four batches).LC-MS: Calculated C32H36N4O4 is 540.66, Observed: 541.3 [M+l]+

[0276] Step 4:

[0277] To a stirred solution of 6 (1.3 g, 2.404 mmol) in THF (13 mL), were added triethylamine (0.456 mL, 7.21 mmol) and POC13 (1.053 mL, 4.81 mmol) at -78 °C, and the reaction mixture stirred at -78 °C for 1 h. To the reaction mixture, water (10 mL) was added at 0 °C and stirred for 30 min at room temperature. The volatiles were evaporated under reduced pressure. The crude residue thus obtained was purified by reversed phase preparative HPLC (Column: X-Bridge Cs (4.6 X 150 mm, 5 pm); eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 15 as an off-white solid. Yield: 180 mg. LC-MS: Calculated C27H29N4O6P is 536.52, Observed: 537.2 [M+l]+. 1H-NMR (400 MHz, DMSO-d6): δ 7.65-7.62 (m, 4H), 7.52 (d, J = 8.4 Hz, 2H), 7.32 (d, J = 1.2 Hz, 1H), 7.12 (br s, 2H, exchanges with D2O), 6.90 (d, J = 8.8 Hz, 2H), 6.85 (d, J = 0.8 Hz, 1H), 6.01 (t, J = 6.8 Hz, 1H), 4.90-4.84 (m, 2H), 4.16-4.09 (m, 1H), 4.05-3.97 (m, 1H), 3.60 (s, 2H), 3.49- 3.45 (m, 2H, exchanges with D2O), 2.34-2.25 (m, 4H), 1.47 (d, J = 6.40 Hz, 3H). One exchangeableproton less in 1H-NMR. 31P-NMR (400 MHz, DMSO-d6): δ -0.349. SFC: 99.8%; tR = 1.43 mm (column: CHIRALPAK-AS-H; eluents: CCL and 0.5% isopropyl amine in MeOH)

[0278] Note: Single isomer with 99.8% SFC purityExample 10: Synthesis of Compound 17Ste -1

[0279] Step l:

[0280] To a stirred solution 1 (600 mg, 0.976 mmol) in ACN (10 mL), were added pyridine (0.158 mL, 1.952 mmol) and POC13 (0.274 mL, 2.93 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was cooled to 0 °C, and water (10 mL) was added slowly and stirred for 30 min at room temperature. The volatiles were removed under reduced pressure. The crude residue was purified by reverse phase preparative HPLC (Column: X-BRIDGE Cis OBD (250*19 mm) 5 pm; Eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 17 as a white solid. Yield = 210 mg (41%). LC-MS: Calculated for C26H27N4O5P is 506.49, Observed: 507.4 [M+l]+. 1H-NMR (400 MHz, DMSO-d6): δ 7.69-7.64 (m, 4H), 7.55 (d, J =8.40 Hz, 2H), 7.41 (d, J = 8.40 Hz, 2H), 7.33 (s, 1H), 7.20-7.00 (m, 1H, exchanges with D2O), 6.86 (s, 1H), 6.00 (t, J = 6.40 Hz, 1H), 4.93-4.88 (m, 1H), 4.17-4.11 (m, 1H), 4.08-4.02 (m, 1H), 3.47-3.41 (m, 1H), 2.92-2.87 (m, 2H), 2.30-2.24 (m, 2H), 1.47 (d, J = 6.40 Hz, 3H). 4H not observed.31P-NMR (400 MHz, DMSO-d6): δ -0.375. SFC: 100%; tR = 2.19 mm (Column: I Cellulose- Z; Eluents: CO2and 0.5% isopropyl amine in ACN and MeOH)

[0281] Note: Exchangeable protons not seen in 1H-NMR; mixture of diastereomers (racemic at tail). Cis-geometry at tail part.Example 11: Synthesis of Compound 19

[0282] Step l:

[0283] To a solution of 1 (1 g, 1.79 mmol) in acetonitrile (10 mL), were added triethylamine (0.734 mL, 5.37 mmol) followed by phosphoryl trichloride (0.34 mL, 3.58 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooledto 0 °C; water (10 mL) was added and stirred at room temperature for 30 min. The volatiles were removed under reduced pressure. The crude residue, thus obtained, was purified by column chromatography (column: Redisep Gold, Cis reverse phase Si O2; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 19 as an off-white solid. Yield: 230 mg (23%). LCMS: Calculated for C27H31N4O7P is 554.5; observed: 555.6 [M+l]+. 1H-NMR (400 MHz, DMSO-d6): δ 7.66-7.63 (m, 4H), 7.52 (d, J = 8.40 Hz, 2H), 7.32 (app d, J = 0.80 Hz, 1H), 6.93 (d, J = 8.80 Hz, 2H), 6.85 (app d, J = 1.20 Hz, 1H), 5.99 (t, J = 6.40 Hz, 1H), 5.04-5.02 (m, 1H), 4.91- 4.89 (m, 1H), 4.35 (dd, J = 6.40, 9.20 Hz, 2H), 4.15-4.10 (m, 1H), 4.07-4.01 (m, 1H), 3.89 (dd, J = 3.60, 31.00 Hz, 2H), 2.77 (s, 6H), 1.47 (d, J = 6.40 Hz, 3H). Three exchangeable protons not seen in 1H-NMR. 31P-NMR (162 MHz, DMSO-d6): δ - 0.347. SFC: 100%; tR = 2.36 mm (column: I- Cellulose-B; eluents: CO2and 0.5% isopropyl amine in MeOH)

[0284] Note: Single isomer with SFC purity = 100%Example 12: Synthesis of Compound 20

[0285] Step l:

[0286] To a solution of 1 (1 g, 1.850 mmol) in acetonitrile (25 mL) were added Et3N (0.77 mL, 5.55 mmol) followed by POCh (0.34 mL, 3.70 mmol) at 0 °C. After complete addition, the reaction mixture was stirred at 25 °C for 40 min. To the reaction mixture water (30 mL) was added and stirred for 30 min. at 25 °C. The volatiles were evaporated under reduced pressure. One more batch was carried out using 750 mg of 1 to get 1.2 g of crude product. Both batches were mixed for purification. The crude residue thus obtained was purified by reverse phase (column: redisef Cis, 20x150 mm, 5pm; eluents: 10 mM ammonium bicarbonate in water and acetonitrile) to afford Compound 20 as a white solid. Yield: 600 mg (combined yield for two batches). LCMS: Calculated for C27H29N4O6P is 536.52, observed: 537.2 [M+l]+. 1H-NMR (400 MHz, DMSO-d6): δ 7.66-7.62 (m, 4H), 7.52 (d, J = 8.40 Hz, 2H), 7.32 (app d, J = 1.20 Hz, 1H), 7.05 (br s, 3H, exchanges with D2O), 6.93 (d, J = 8.80 Hz, 2H), 6.85 (app d, J = 0.80 Hz, 1H), 6.02 (t, J = 6.40 Hz, 1H), 4.87-4.85 (m, 2H), 4.15-4.08 (m, 1H), 4.03-3.96 (m, 1H), 3.81 (dd, J = 6.40, 8.40 Hz, 2H), 3.10-3.07 (m, 2H), 2.71-2.68 (m, 2H), 2.56-2.50 (m, 2H, merges with the solvent peak), 1.47 (d, J = 6.40 Hz, 3H). 31P- NMR (162 MHz, DMSO-d6, DMSO-d6): δ -0.285. SFC: 100%; tR = 1.79 mm (column: I Cellulose- Z; eluents: CO2and 0.5% isopropyl amine in MeOH).

[0287] Note: Single isomer with 10% SFC purity.Example 13: Synthesis of Compounds 21 and 22OH Compounds 21 and 22

[0288] Step 1:

[0289] To a stirred solution of (±)-l (0.248 g, 0.572 mmol) in water (2.5 mL) and acetonitrile (2.5 mL), were added 2 (0.20 g, 0.477 mmol) and potassium carbonate (0.198 g, 1.431 mmol) at room temperature and the resulting reaction mixture was purged with nitrogen for 5 min. To this reaction mixture, PdC12(dtbpf) (0.016 g, 0.024 mmol) was added and the purging continued for another 2 min. The resulting reaction mixture was irradiated at 60 °C for 4 h in a microwave reactor. The reaction mixture was quenched with water (10 mL) and extracted with 10 % MeOH in DCM (10 mL x 2). The combined organic layer was washed with brine (5 mL), dried over anhydrous ISfeSCL, fdtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed SiCL cartridge; 230-400 mesh size; 5% MeOH in DCM) to afford 3 as a brown solid. LCMS showed 77% purity; product was taken to the next step. LC-MS: Calculated for C37H51N3O5S1 is 645.36, Observed: 646.4 [M+l]+Yield: 0.2 g (55%)

[0290] Step 2:

[0291] To a stirred solution of 3 (0.6 g, 0.929 mmol) in acetonitrile (15 mL), were added pyridine (0.224 mL, 2.79 mmol) and POCI3 (0.174 mL, 1.858 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. To the reaction mixture, water (10 mL) was added and stirred for 30 min. The reaction mixture was concentrated. The crude material, thus obtained, was purified using reverse phase column chromatography (Column: Redisep, Cis silica gel; Eluents: 10 mM ammonium bicarbonate in water and acetonitrile) to afford Compounds 21 and 22 as a white solid. Yield: 0.160 g (31%). LC-MS: Calculated for C26H30N3O7P is 527.51, Observed: 528.3 [M+l]+. 1H- NMR (400 MHz, DMSO-d6): δ 7.58 (d, J = 8.40 Hz, 2H), 7.48-7.42 (m, 4H), 7.36 (s, 1H), 7.12 (br s, 2H, exchanges with D2O), 6.90 (s, 1H), 6.66 (d, J = 8.80 Hz, 2H), 6.02-5.98 (m, 2H, 1H exchanges with D2O), 5.01 (br s, 1H, exchanges with D2O), 4.95-4.90 (m, 1H), 4.16-4.07 (m, 3H), 3.90 (dd, J = 6.80, 8.40 Hz, 1H), 3.83 (dd, J = 4.80, 9.20 Hz, 1H), 3.52 (dd, J = 4.40, 8.60 Hz, 1H),3.48 (dd, J = 2.80, 9.20 Hz, 1H), 3.10-3.06 (m, 1H), 2.97-2.94 (m, 1H), 2.33-2.31 (m, 1H), 1.48 (d, J = 6.40 Hz, 3H). 31P-NMR (400 MHz, DMSO-d6): 5 -0.641. SFC: 100%; tR = 2.21 mm (Column: 1- Cellulose- Z; Eluents: CO2and 0.5% isopropyl amine in MeOH)

[0292] Note: Final product was mixture of diastereomers; racemic in the tail partExample 14: Synthesis of Compound 23

[0293] Step l:

[0294] To a stirred solution of 1 (0.75 g, 1.416 mmol) in THF (8 mL), were added triethylamine (0.597 mL, 4.25 mmol) and POCI3 (0.265 mL, 2.83 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 1 h. To the reaction mixture water (8 mL) was added at 0 °C and stirred for 0.5 h at room temperature. The volatiles were evaporated under reduced pressure to get the crude residue. Two more batches on 0.5 g and 0.75 g of 1 were carried out to get crude material.

[0295] The crude product of all three batches combined and purified by reversed phase preparative HPLC (Column: Shimpack Cis (20*150) 5 um; Eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 23 as an off-white solid. Yield: 0.265 g (35%). LC-MS: Calculated for C26H28N3O7P is 525.49, Observed: 526.3 [M+H]+. 1H-NMR (400 MHz, DMSO-d6): 5 7.66 (d, J = 8.00 Hz, 4H), 7.53 (d, J = 8.00 Hz, 2H), 7.34 (app d, J = 1.20 Hz, 1H), 7.16 (br s, 3H, exchanges with D2O), 6.95 (d, J = 8.80 Hz, 2H), 6.87 (s, 1H), 6.00 (t, 1H), 5.09-5.06 (m, 1H), 4.92- 4.89 (m, 1H), 4.59-4.55 (m, 1H), 4.32-4.28 (m, 1H), 4.17-4.03 (m, 3H), 3.80-3.77 (m, 1H), 1.80 (s, 3H), 1.47 (d, J = 6.40 Hz, 3H). 31P-NMR (400 MHz, DMSO-d6): 5 -0.375. SFC: Purity = 100% (Method: LAmylose-A O.5% IP Am in MeOH); tR = 1.80 min.

[0296] Note: Single isomer with SFC purity 100%Example 15: Synthesis of Compounds 24 and 25

[0297] Both the isomers (1-Isomer-l and l-Isomer-2) were taken independently for further conversions.

[0298] The synthesis of Compound 25 was carried out using l-Isomer-2.

[0299] Step 1:

[0300] y0 a stirrec[ solution of l-Isomer-2 (2.008 g, 5.37 mmol) in acetonitrile (20 mL) and water (15 mL), were added K2CO3 (1.483 g, 10.73 mmol) and 2 (1.5 g, 3.58 mmol) at room temperature and the reaction mixture purged with nitrogen for 5 min. To this reaction mixture, PdC12(dtbpf) (0.117 g, 0.179 mmol) was added and the resulting reaction mixture was heated to 80 °C for 16 h. The reaction mixture was then quenched with ice water (100 mL) and extracted with 10% MeOH in DCM (50 mL x 3). The combined organic extract was washed with brine solution (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The obtained crude residue was purified by MPLC (using manually packed SiCL cartridge, 230-400 mesh size; 13% MeOH in DCM) to get 3-Isomer-2 as brown solid. Yield: 1.2 g (53%). LCMS: Calculated for C35H42N2O6 is 586.73, Observed: 587.0 [M+l]+

[0301] Step 2:

[0302] To a stirred solution of 3-Isomer-2 (1.2 g, 2.045 mmol) in acetonitrile (20 mL), were added pyridine (0.496 mL, 6.14 mmol) and POCh (0.381 mL, 4.09 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. To the reaction mixture, aq. HC1 (1.5 N, 20 mL) was added and stirred for 30 min. The reaction mixture was concentrated under reduced pressure. The crude material, thus obatined, was purified by using reverse phase column chromatography using MPLC (Column: Redisep, C18 silica gel; Eluents: 10 mM ammonium bicarbonate in water and acetonitrile) to afford Compound 25 as a white solid. Yield: 180 mg (17%). By using the above procedure, another 65 mg of Compound 25 was synthesized. LC-MS: Calculated for C25H27N2O7P is 498.47, Observed: 499.2 [M+l]+. 1H-NMR (400 MHz, DMSO-d6): δ 7.68 (d, J = 8.40 Hz, 2H), 7.65 (d, J = 8.40 Hz, 2H), 7.55 (d, J = 8.40 Hz, 2H), 7.37-7.35 (m, 3H), 7.20 (br s, 2H, exchange with D2O), 6.88 (s, 1H), 6.00 (t, J = 6.40 Hz, 1H), 4.98-4.90 (m, 1H), 4.25-4.24 (m, 1H), 4.18-4.12 (m, 2H), 4.09-4.04 (m, 1H), 3.98 (dd, J = 5.60, 9.20 Hz, 1H), 3.75 (dd, J = 6.00, 8.40 Hz, 1H), 3.58 (dd, J = 3.60, 9.20 Hz, 1H), 3.25-3.21 (m, 1H), 1.48 (d, J = 6.40 Hz, 3H). (Two protons not observed). 31P-NMR (400 MHz, DMSO-d6): δ -0.428. SFC: 100%; tR = 3.20 mm (Column: Lux I- Amylose-3; Eluents: 0.5% isopropyl amine in MeOH and CO2).

[0303] Note: Single isomer with SFC purity = 100%.

[0304] Compound 24 was synthesized by using the same procedure as outlined above for Compound 25. SFC: 100%; tR = 2.0 min (Column: Lux I-Amylose-3; Eluents: 0.5% isopropyl amine in MeOH and CO2). 1H-NMR (400 MHz, DMSO-d6): δ 7.68 (d, J = 8.40 Hz, 2H), 7.65 (d, J = 8.40 Hz, 2H), 7.56 (d, J = 8.40 Hz, 2H), 7.41 (d, J = 1.20 Hz, 1H), 7.36 (d, J = 8.40 Hz, 2H), 7.17 (br s, 2H, exchange with D2O), 6.94 (s, 1H), 6.00 (t, J = 6.40 Hz, 1H), 4.99-4.94 (m, 1H), 4.27-4.21 (m, 1H), 4.19-4.08 (m, 3H), 3.98 (dd, J = 5.60, 9.20 Hz, 1H), 3.75 (dd, J = 6.40, 8.60 Hz, 1H), 3.58 (dd, J = 4.00, 9.00 Hz, 1H), 3.26-3.21 (m, 1H), 1.49 (d, J = 6.40 Hz, 3H) (Two protons notobserved). 31P-NMR (400 MHz, DMSO-d6): δ -0.473. LUX-l-Amylose3_0.5%IPAm in MeOH tR = 2 min

[0305] Note: Single isomer with SFC purity = 100%Example 16: Synthesis of Compounds 26 and 27

[0306] Step 3:

[0307] 7 g of (±)-4a was separated by using SFC (Column: LUX A3 (250 x 30) mm, 5 pm; Eluents: CO2: 0.2% formic acid in IPA: ACN [70:30]) to get 5-Isomer-l (tR = 1.73 min) and 5- Isomer-2 (tR = 3.10 min) as colorless liquid.JH NMR complies with desired product along with minor formic acid. Yield: 5-Isomer-l = 3.6 g and 5-Isomer-2 = 3.4 g. SFC: 5-Isomer-l: 96.2% (ee = 100%) and 5-Isomer-2: 100% (ee = 100%). One more batch was carried out to get 800 mg of each isomer. The respective isomers from both batches were mixed, dissolved in DCM (50 mL), washed with 10% sodium bicarbonate solution (20 mL x 3), brine (25 mL), dried over anhydrous Na2SO4, fdtered and concentrated under reduced pressure to get 4 g of each isomer as a colorless liquid. Both the isomers (5-Isomer-l and 5-Isomer-2) were taken independently for further conversion. The synthesis of Compound 27 was carried out using 5-Isomer-2.

[0308] Step 4:

[0309] To a stirred solution of 5-Isomer-2 (4 g, 14.65 mmol) in DCM (50 mL), were added 3,4- Dihydro-2H-pyran (4.02 mL, 43.9 mmol), pyridinium p-toluenesulfonate ( PPTS) (0.368 g, 1.465 mmol) at room temperature and stirred for 16 h. The reaction mixture was quenched with water (150 mL) and extracted with 5% EtOAc in hexanes (50 mL x 3). The combined organic layer was washed with brine (25 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to get 6-Isomer-2 as a colorless oil. Yield: 5 g (91%). LC-MS: Calculated for CieLbiBrCL is 357.24; Observed: Desired product mass not observed.

[0310] Step 5:

[0311] To a stirred solution of 6-Isomer-2 (5 g, 14.00 mmol) in 1,4-dioxane (50 mL), were added bis(pinacolato)diboron (5.33 g, 20.99 mmol), potassium acetate (4.12 g, 42.0 mmol). The reaction mixture was degassed for 5 mm, following which PdC12(dppf) (0.512 g, 0.700 mmol) was added. The mixture was again degassed with nitrogen for 2 min and then stirred at 100 °C for 16 h. The reaction mixture was quenched with water (500 mL) and extracted with EtOAc (200 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed SiO2 cartridge, 230-400 mesh size; 15% EtOAc in hexanes) to afford 7-Isomer-2 as a yellow oil. Yield: 6 g (95%)

[0312] Step 6:

[0313] To a stirred solution of 7-Isomer-2 (2.89 g, 7.15 mmol) in mixture of acetonitrile (20 mL) and water (20 mL), were added 8 (2 g, 4.77 mmol) and K2CO3 (1.978 g, 14.31 mmol) at room temperature. The resulting reaction mixture was purged with nitrogen for 5 min. To this reaction mixture, PdC12(dtbpf) (0.155 g, 0.238 mmol) was added and purging continued for another 2 min. The resulting reaction mixture was then stirred at 80 °C for 16 h. The reaction mixture was quenched with water (500 mL) and extracted with 10% MeOH in DCM (200 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed SiC>2 cartridge 230-400 mesh size; 4% MeOH in DCM) to afford 9-Isomer-2 as a brown gum. Yield: 1.6 g (52%). LC-MS: Calculated for C36H44N2O7 is 616.75; Observed: 617.4 [M+l]+

[0314] Step 7:

[0315] To a stirred solution of 9-Isomer-2 (1.6 g, 2.59 mmol) in acetonitrile (20 mL), were added pyridine (0.629 mL, 7.78 mmol) and POC13 (0.484 mL, 5.19 mmol) at 0 °C and the reaction mixture stirred at RT for 2 h. To the reaction mixture, water (10 mL) was added and stirred for 30 min. The reaction mixture was concentrated and the crude material, thus obatined, was purified by using reverse phase column chromatography using MPLC (Column: Redisep, Cis silica gel; Eluents: 10 mM ammonium bicarbonate in water and acetonitrile) to afford Compound 27 as an off-white solid. Yield: 330 mg (24%). LC-MS: Calculated for C26H29N2O8P is 528.50, Observed: 529.2 [M+l]+. 1H-NMR (400 MHz, DMSO-d6): δ 7.66-7.61 (m, 4H), 7.52 (d, J = 8.40 Hz, 2H), 7.34 (app d, J = 1.20 Hz, 1H), 7.18 (br s, 2H, exchange with D2O), 7.10 (d, J = 8.80 Hz, 2H), 6.87 (app d, J = 0.80 Hz, 1H), 6.00 (t, J = 6.40 Hz, 1H), 5.28 (br s, 1H, exchanges with D2O), 4.94-4.89 (m, 1H), 4.34-4.31 (m, 1H), 4.15-4.05 (m, 2H), 3.83-3.77 (m, 2H), 3.59-3.57 (m, 1H), 3.48-3.42 (m, 1H), 3.18 (t, J = 8.80 Hz, 1H), 2.12-2.09 (m, 1H), 1.52-1.47 (m, 4H). (1H not observed). 31P-NMR (162.07 MHz, DMSO-d6): δ -0.420. SFC: 99.8%; tR = 1.87 min (Column: 1- Cellulose- Z; Eluents: 0.5% isopropyl amine in MeOH and CO2)

[0316] Note: Single isomer with SFC purity = 99.8%

[0317] Compound 26 was synthesized in an identical fashion starting with 5-Isomer-l by using the steps detailed for Compound 27. 1H-NMR (400 MHz, DMSO-d6): δ 7.66-7.61 (m, 4H), 7.52 (d, J = 8.40 Hz, 2H), 7.36 (s, 1H), 7.17 (br s, 2H, exchange with D2O), 7.10 (d, J = 8.80 Hz, 2H), 6.89 (s, 1H), 5.99 (t, J = 6.40 Hz, 1H), 5.29 (br s, 1H, exchanges with D2O), 4.94-4.92 (m, 1H), 4.34-4.31 (m, 1H), 4.15-4.06 (m, 3H), 3.83-3.78 (m, 1H), 3.59-3.53 (m, 1H), 3.53-3.42 (m, 1H), 3.17 (t, J = 8.80 Hz, 1H), 2.13-2.09 (m, 1H), 1.52-1.47 (m, 4H). (1H not observed). 31P-NMR (162.07 MHz, DMSO-d6): δ -0.474. SFC: 100%; tR = 1.94 min (Column: I Cellulose- Z; Eluents: 0.5% isopropyl amine in MeOH and CO2)

[0318] Note: Single isomer with SFC purity = 100%Example 17: Synthesis of Compound 28Step-1

[0319] Step l:

[0320] To a stirred solution of 1 (1.0 g, 1.836 mmol) in ACN (10 mL), were added pyridine (0.45 mL, 5.51 mmol) followed by phosphoryl trichloride (0.343 mL, 3.67 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C, water (15 mL) was added and stirred at room temperature for 30 min. The volatiles were removed under reduced pressure and the crude residue was purified by reverse phase column chromatography (Column: Redisep Cis-reversed phase SiCL; Eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 28 as an off-white solid. Yield = 175 mg (17%). LC-MS: Calculated for C26H29N4O7P is 540.51 Observed: 540.8 [M+l]+. 1H-NMR (400 MHz, DMSO-d6): δ 7.65 (d, J = 8.40 Hz, 4H), 7.56-7.52 (m, 2H), 7.33 (app d, J = 0.80 Hz, 1H), 7.17-7.10 (br s, 2H, exchanges with D2O), 6.93 (d, J = 8.80 Hz, 2H), 6.86 (s, 1H), 6.35 (t, J = 4.40 Hz, 1H, exchanges with D2O), 6.00(t, J = 6.40 Hz, 1H), 5.05-5.02 (m, 1H), 4.93-4.88 (m, 1H), 4.25 (dd, J = 6.80, 9.00 Hz, 2H), 4.15- 4.11 (m, 1H), 4.10-4.04 (m, 1H), 3.74 (dd, J = 4.00, 9.20 Hz, 2H), 2.55 (d, J = 4.80 Hz, 3H), 1.50- 1.46 (m, 3H). 1H not observed. 31P-NMR (400 MHz, DMSO-d6): δ -0.331

[0321] Note: Single isomer with SFC purity = 98% (Lcellulose B O.5% IP Am in MeOH tR = 1.86 min).Example 18: Synthesis of Compound 29

[0322] Step l:

[0323] To a stirred solution of 1 (1.2 g, 2.253 mmol) in ACN (20 mL), were added pyridine (0.421 mL, 4.51 mmol) and phosphoryl trichloride (0.547 mL, 6.76 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C, quenched with water (4 mL) and stirred at room temperature for 30 min. The volatiles were removed under reduced pressure and the crude residue purified by reversed phase preparative HPLC (Column: shimpack Cis (150*20) 5um; Eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 29 as an off-white solid. Yield = 270 mg (22%). LC-MS: Calculated for C26H29N2O8P is 528.4, Observed: 529.3 [M+l]+. 1H-NMR (400 MHz, DMSO-d6): δ 7.67-7.65 (m, 4H), 7.54 (d, J = 8.40 Hz, 2H), 7.41 (d, J = 0.80 Hz, 1H), 7.14 (br s, 2H), 7.07 (d, J = 8.80 Hz, 2H), 6.95 (s, 1H), 6.00 (t, J = 6.00 Hz, 1H), 4.95 (m, 2H), 4.18-4.10 (m, 2H), 4.05-3.99 (m, 2H), 3.95-3.91 (m, 1H), 3.78- 3.74 (m, 2H), 3.34 (s, 3H), 1.49 (d, J = 6.40 Hz, 3H). 1H not observed. 1H-NMR (400 MHz, DMSO-d6 : D2O (~ 20: 1 v / v)): 8 7.67-7.65 (m, 4H), 7.55-7.53 (m, 3H), 7.07-7.05 (m, 3H), 5.97 (dd, J = 5.60, 7.60 Hz, 1H), 5.05-5.03 (m, 1H), 4.93 (d, J = 3.60 Hz, 1H), 4.19-4.15 (m, 1H), 4.10-4.01 (m, 3H), 3.98-3.89 (m, 1H), 3.78-3.73 (m, 2H), 3.68 (s, 3H), 1.50-1.47 (m, 3H). 31P-NMR (400 MHz, DMSO-d6): δ -0.496.

[0324] Note: Single isomer with unknown stereochemistry at tail part; SFC purity = 100% (1- Cellulose- B O.5%IPAm in MeOH tR = 1.17 min).Example 19: Synthesis of Compound 30

[0325] Step l:

[0326] To a stirred solution of 1 (1.4 g, 2.63 mmol) in ACN (20 mL), were added pyridine (0.638 mL, 7.89 mmol) and phosphoryl trichloride (0.49 mL, 5.26 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C, quenched with water (4 mL) and stirred at room temperature for 30 min. The volatiles were removed under reduced pressure and the crude residue purified by reversed phase preparative HPLC (Column: shimpack Cis (150*20) 5um; Eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 30 as an off-white solid. Yield = 223 mg (16%). LC-MS: Calculated for C26H29N2O8P is 528.4, Observed: 529.2 [M+l]+. 1H-NMR (400 MHz, DMSO-d6): δ 7.67-7.65 (m, 4H), 7.53 (dd, J = 2.00, 6.60 Hz, 2H), 7.41 (d, J = 1.20 Hz, 1H), 7.17 (br s, 2H), 7.09-7.05 (m, 2H), 6.94 (d, J = 1.20 Hz, 1H), 5.99 (t, J = 6.00 Hz, 1H), 4.98-4.95 (m, 2H), 4.19-4.10 (m, 2H), 4.08-4.01 (m, 2H), 3.99-3.92 (m, 1H), 3.78-3.74 (m, 2H), 3.34 (s, 3H), 1.49 (d, J = 6.40 Hz, 3H). IH not observed. 1H-NMR (400 MHz, DMSO-d6 : D2O (~ 20:1 v / v)): 8 7.66-7.64 (m, 4H), 7.55-7.53 (m, 3H), 7.11 (s, 1H), 7.05 (d, J = 8.80 Hz, 2H), 5.93 (dd, J = 5.20, 8.00 Hz, 1H), 5.10-5.05 (m, 1H), 4.91 (d, J = 4.00 Hz, 1H), 4.22-4.16 (m, 1H), 4.10-4.01 (m, 3H), 4.00-3.89 (m, 1H), 3.78-3.73 (m, 2H), 3.68 (s, 3H), 1.50-1.47 (m, 3H). 31P-NMR (400 MHz, DMSO-d6): δ -0.513.

[0327] Note: Single isomer with unknown stereochemistry at tail part; SFC purity = 100% (1- cellulose B O.5% IP Am in MeOH tR = 1.11 minExample 20: Synthesis of Compound 31

[0328] Step-1:

[0329] To a stirred solution of 1 (3 g, 9.20 mmol) in THF (30 mL), were added triethylamine (1.329 mL, 9.20 mmol) and di-tert-butyl dicarbonate (2.113 mL, 9.20 mmol) in dropwise manner, and the reaction mixture stirred at room temperature for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 100 mL). The combined organic extract was dried over anhydrous ISfeSCL, filtered and concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed SiCL cartridge, 230-400 mesh size; 35% EtOAc in hexanes) to afford 2 as a pale-yellow solid. Yield = 3 g (72%). LC-MS: Calculated C24H35BN2O4 is 426.36, Observed: 327.3 [(M-Boc)+1]+

[0330] Step-2:

[0331] To a stirred solution of 3 (500 mg, 1.192 mmol) in dioxane (10 mL) and water (2.5 mL), were added 2 (610 mg, 1.431 mmol) and potassium phosphate tribasic (759 mg, 3.58 mmol) at room temperature, and the reaction mixture purged with nitrogen for 5 min. To this reaction mixture, PdC12(dtbpf) (78 mg, 0.119 mmol) was added and the purging continued for 2 min. The resulting reaction mixture was stirred at 85 °C for 16 h. The reaction mixture was cooled to room temperature, quenched with water (20 mL) and extracted with DCM (2 x 100 mL). The combined organic extract was washed with brine solution (50 mL), dried over anhydrous ISfeSCL, fdtered, and concentrated under reduced pressure. Three more batches on 0.5 g of 3 were carried out to get the crude material. The crude product of all four batches were combined and purified by using MPLC (manually packed SiO2 cartridge, 230-400 mesh size; 6% MeOH in DCM) to afford 4 as a brown solid. Yield = 2.1 g (combined yield of four batches). LC-MS: Calculated C38H46N4O5 is 638.80, Observed: 639.2 [M+l]+

[0332] Step-3:

[0333] To a stirred solution of 4 (600 mg, 0.939 mmol) in THF (6 mL), were added tri ethylamine (0.407 mL, 2.82 mmol) and POCI3 (0.180 mL, 1.878 mmol) at -78 °C, and the reaction mixture stirred at for 1 h at the same temperature. To the reaction mixture, water (8 mL) was added at 0 °C and stirred for 0.5 h at room temperature. The volatiles were evaporated under reduced pressure. The crude residue, thus obtained, was purified by reversed phase column chromatography (Column: Redisep Gold; Cis SiCL; Eluents: 10 mM ammonium bicarbonate in water and ACN) to afford 100 mg of Compound 31 (HC1 salt) as a white solid. 1H-NMR (400 MHz, DMSO-d6): δ 7.46-7.40 (m, 4H), 7.36-7.34 (m, 3H), 7.21 (d, J = 8.40 Hz, 2H), 6.87 (app d, J = 1.20 Hz, 1H), 5.99 (t, J = 6.40 Hz, 1H), 4.96-4.93 (m, 1H), 4.23-4.11 (m, 2H), 3.79-3.71 (m, 1H), 3.66-3.64 (m, 1H), 3.00-2.97 (m, 2H), 2.87-2.84 (m, 2H), 2.57-2.50 (m, 2H, merges with solvent peak), 2.38-2.34 (m, 2H), 1.50 (d, J = 6.40 Hz, 3H). 4 protons not observed. 31P-NMR (400 MHz, DMSO-d6): δ -0.506. Both the batches were mixed, treated with saturated NH4HCO3 solution (5 mL) and purified by reverse phase column chromatography (Column: Redisep Gold; Cis SiCL; Eluents: 10 mM ammonium bicarbonatein water and ACN) to afford Compound 31 as a white solid. Yield: 204 mg (combined yield for two batches). LC-MS: Calculated C28H31N4O5P is 534.55, Observed: 535.3 [M+l]+. 1H-NMR (400 MHz, DMSO-d6): δ 7.68 (d, J = 8.00 Hz, 2H), 7.63 (d, J = 8.40 Hz, 2H), 7.54 (d, J = 8.40 Hz, 2H), 7.37 (d, J = 8.40 Hz, 2H), 7.33 (app d, J = 1.20 Hz, 1H), 6.85 (app d, J = 0.80 Hz, 1H), 5.99 (t, J = 6.40 Hz, 1H), 4.91-4.90 (m, 1H), 4.15-4.08 (m, 1H), 4.06-4.03 (m, 1H), 3.60-3.52 (m, 1H), 3.44-3.38 (m, 1H), 2.72 (t, J = 6.40 Hz, 2H), 2.58 (t, J = 6.80 Hz, 2H), 2.30-2.25 (m, 2H), 2.23-2.18 (m, 2H), 1.48 (d, J = 6.80 Hz, 3H). ). 4 exchangeable protons not observed. 31P-NMR (400 MHz, DMSO-d6): 8 - 0.421. SFC: 100%, tR = 2.14 min (Column: I Cellulose- Z; Eluents: CO2and 0.5% isopropyl amine in MeOH).

[0334] Note: Single isomer with SFC purity 100%; exchangeable protons not seen in 1H-NMRExample 21: Synthesis of Compound 33

[0335] Step l:

[0336] To a stirred solution of tert-butyl 3 -hydroxyazetidine-1 -carboxylate (1, 33 g, 191 mmol) in DCM (330 mL), were added EtsN (57.8 g, 572 mmol), DMAP (2.328 g, 19.05 mmol) and tosyl chloride (47.2 g, 248 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with water (150 mL) and extracted with DCM (250 mL x 3). The combined organic extract was washed with brine solution (50 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by MPLC (manually packed cartridge; SiCL 100-200 mesh size; 15% EtOAc in hexanes) to afford 57.5 g of 2 as a yellow liquid. Yield: 57.7 g (88%). LC-MS: Calculated for C15H21NO5S is 327.11;Observed: 228.2 [M-Boc+1]+

[0337] Step 2:

[0338] To a solution of 2 (50.0 g, 153 mmol) in DMF (330 mL), were added caesium carbonate (83 g, 254 mmol) and 4-bromophenol (3, 22 g, 127 mmol) at room temperature. The reaction mixture was stirred at 100 °C for 16 h. Two more batches were performed with 22 g of 3. All three batches were mixed for work-up and purification. The reaction mixture was cooled to room temperature, quenched with ice-cold water (500 mL) and extracted with EtOAc (500 mL x 3). The combined organic extract was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by MPLC (manually packed cartridge; SiO2100-200 mesh size; 10% EtOAc in hexanes) to afford 4 as white solid. Yield: 85 g (combined yield for three batches). LC-MS: Calculated for CuHisBrNOs is 328.2, Observed: 228.0 [M-Boc]+and 230.0 [M-Boc+2]+

[0339] Step 3:

[0340] To a stirred solution of 4 (50 g, 152 mmol) in DCM (100 mL), was added HC1 (4 M in 1,4- di oxane, 76 mL, 305 mmol) in a dropwise manner at 0 °C. The reaction mixture was allowed to attain room temperature and stirred for 16 h. The solid formed was filtered, washed with DCM (50 mL), and dried under reduced pressure to afford 5 as an off-white solid. Yield: 37 g (84%). LC-MS: Calculated for CLHioBrNO is 228.09, Observed: 228.0 [M]+and 230.0 [M+2]+

[0341] Step 4:

[0342] To a stirred solution of 5 (5 g, 18.90 mmol) in DMF (50 mL), were added triethylamine (13.17 mL, 95 mmol) and iodoacetonitrile (6, 2.74 mL, 37.8 mmol) at 0 °C and the resulting reaction mixture stirred at room temperature for 2 h. The reaction was quenched with ice-water (25 mL) and stirred for 10 min. The solid otained was filtered, washed with hexanes (10 mL), and dried under reduced pressure to afford 7 as an off-white solid. Yield: 4.2 g (80%). LC-MS: Calculated for CnHnBrN2O is 267.13, Observed: 267.1 [M]+and 269.1 [M+2]+

[0343] Step 5:

[0344] To a stirred solution of 7 (4.2 g, 15.72 mmol) in 1,4-dioxane (100 mL), were added bis(pinacolato)diboron (5.99 g, 23.58 mmol) and potassium acetate (3.86 g, 39.3 mmol) at room temperature. The resulting mixture was purged with nitrogen for 5 min. To this reaction mixture, PdC12(dppf).DCM (1.284 g, 1.572 mmol) was added. The resulting reaction mixture was stirred at 90 °C for 16 h. The reaction mixture was filtered through Celite bed. The bed was washed with EtOAc (2 x 20 mL) and the combined filtrate concentrated under reduced pressure. The resulting crude residue was purified by MPLC (manually packed cartridge, SiO2gel 230-400 mesh size; 25% EtOAc in hexanes) to afford 8 as an off-white solid. Yield: 5.42 g (99%). LC-MS: Calculated for Ci7H23BN2O3 is 314.18, Observed: 315.3 [M+l]+

[0345] Step 6:

[0346] To a solution of 8 (1.124 g, 3.58 mmol) in acetonitrile (16 mL) and water (4 mL), were added 9 (1 g, 2.385 mmol) and K2COs (0.989 g, 7.15 mmol) at room temperature. The resultingmixture was purged with nitrogen for 5 min. To this reaction mixture, PdC12(dtbpf) (0.155 g, 0.238 mmol) was added, and the resulting mixture stirred at 80 °C for 16 h. The reaction was quenched with water (50 mL) and extracted with EtOAc (3 x 90 mL). The combined organic extract was washed with brine (50 mL), dried over sodium sulphate, fdtered and the filtrate was concentrated. The crude residue was purified by MPLC (manually packed SiCL cartridge, 230-400 mesh size; 5% MeOH in DCM) to afford 10 as a brown solid. Yield: 560 mg (43%). LC-MS: Calculated for C31H34N4O4 is 526.26, Observed: 527.2 [M+l]+

[0347] Step 7:

[0348] To a stirred solution of 10 (1.25 g, 2.374 mmol) in acetonitrile (15 mL), were added pyridine (0.575 mL, 7.12 mmol) followed by POCI3 (0.455 mL, 4.75 mmol) at 0 °C. After complete addition, the resulting reaction mixture was allowed to stir at room temperature for 40 min. The reaction mixture was quenched with water (50 mL) at 0 °C, and slowly allowed to attain room temperature and stirred for an additional 30 min. The volatiles were removed under reduced pressure. Another batch was performed on 100 mg of 10, to get 180 mg of crude product which was mixed with this batch for work-up and purification. The crude residue was purified by reverse phase preparative HPLC (Column: SHIMPACK, Cis, 20 * 150 mm, 5 pm; Eluents: 10 mM ammonium bicarbonate in water and acetonitrile), to afford Compound 33 as an off-white solid. Yield: 507 mg (40%). LC-MS: Calculated for C26H27N4O6P is 522.17, Observed: 523.3 [M+l]+. 1H-NMR (400 MHz, DMSO-d6): δ 7.66-7.62 (m, 4H), 7.52 (d, J = 8.40 Hz, 2H), 7.32 (d, J = 1.20 Hz, 1H), 6.95 (d, J = 8.80 Hz, 2H), 6.85 (d, J = 1.20 Hz, 1H), 6.00 (t, J = 6.80 Hz, 1H), 4.90-4.88 (m, 2H), 4.15-4.09 (m, 1H), 4.04-3.99 (m, 1H), 3.84-3.80 (m, 2H), 3.81 (s, 2H), 3.26-3.23 (m, 2H), 1.47 (t, J = 6.40 Hz, 3H). 31P-NMR (400 MHz, DMSO-d6): δ -0.316.

[0349] Note: Single isomer; exchangeable protons not seen in 1H NMRExample 22: Synthesis of Compound 34Step 1

[0350] Step l:

[0351] To the stirred solution of 1-Isomer-l (1.85 g, 2.90 mmol) in acetonitrile (25 mL), were added pyridine (0.468 mL, 5.81 mmol) and POCI3 (0.814 mL, 8.71 mmol) at 0 °C. After the complete addition, the resulting reaction mixture was allowed to attain room temperature and stirred for 4 h. To the reaction mixture, water (30 mL) was added and stirred for 30 min. The reaction mixture was then extracted with EtOAc (4 x 100 mL). The combined organic extract was washedwith brine solution (5 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified by preparative HPLC (Column: X-BRIDGE Cs (19*150 mm)5 pm; Eluents: 10 mm ammonium bicarbonate in water and ACN) to obtain Compound 34 as an off-white solid. Yield: 125 mg (8%). LCMS: Calculated for C25H26CIN2O8P is 548.11, Observed: 549.3 [M+l]+. 1H-NMR (400 MHz, DMSO-r / 6): 8 7.55 (d, J = 8.0 Hz, 2H), 7.44-7.41 (m, 2H), 7.36 (d, J = 8.8 Hz, 1H), 7.32 (d, J = 1.2 Hz, 1H), 7.23 (d, J = 2.8 Hz, 1H), 7.07 (dd, J = 2.4, 8.8 Hz, 1H), 6.85 (d, J = 0.8 Hz, 1H), 6.64 (br s, 3H, exchanges with D2O), 6.02 (t, J = 6.4 Hz, 1H), 5.60 (br s, 1H, exchanges with D2O), 4.89 (q, J = 6.4 Hz, 1H), 4.74 (d, J = 4.0 Hz, 1H), 4.23 (M, 1H), 4.16- 3.96 (m, 3H), 3.92 (dd, J = 4.8, 9.4 Hz, 1H), 3.80 (d, J = 10.0 Hz, 1H), 3.60 (dd, J = 2.0, 9.4 Hz, 1H), 1.47 (d, J = 6.8 Hz, 3H). 31P-NMR (400 MHz, DMSO-d6): δ -1.142. SFC: 99.89%; tR = 2.02 mm (Column: I Cellulose-Z; Eluents: 0.5% isopropyl amine in MeOH)

[0352] Note: Single isomer with SFC purity 99.89%Example 23: Synthesis of Compound 35Step 1

[0353] Step l:

[0354] 185 mg of Compound 35 was synthesized by using 1.6 g of l-Isomer-2 by using the above procedure of Compound 34. LCMS: Calculated for C25H26CIN2O8P is 548.11, Observed:549.4 [M+l]+. 1H-NMR (400 MHz, DMSO-r / 6): 8 7.55 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.37-7.35 (m, 2H), 7.23 (d, J = 2.8 Hz, 2H), 7.16 (br s, 2H, exchanges with D2O), 7.06 (dd, J = 2.8, 8.6 Hz, 1H), 6.90 (s, 1H), 6.01 (t, J = 6.4 Hz, 1H), 5.99 (br s, 1H, exchanges with D2O), 4.92 (q, J =6.4 Hz, 1H), 4.74 (d, J = 4.0 Hz, 1H), 4.23 (d, J = 2.8 Hz, 1H), 4.18-4.12 (m, 1H), 4.10-4.02 (m, 2H), 3.92 (dd, J = 4.4, 9.2 Hz, 1H), 3.80 (d, J = 10.0 Hz, 1H), 3.60 (dd, J = 1.6, 9.4 Hz, 1H), 1.48 (d, J =6.4 Hz, 3H). 31P-NMR (400 MHz, DMSO-d6): δ -0.411. SFC: 99.5%; tR = 2.00 min (Column: I Cellulose- Z; Eluents: 0.5% isopropyl amine in MeOH)

[0355] Note: One of the exchangeable proton not seen in NMR; Single isomer with SFC purity99.5%Example 24: Synthesis of Compounds 36 and 37

[0356] Step 2:

[0357] The enantiomers of (±)-3 (9 g) were separated by SFC (PIC -22-027, IZ (250*30) mm, 5 pm; Eluents: CO2: 0.5% isopropyl amine in MeOH [75:25]). The fractions were concentrated under reduced pressure to afford 3-Isomer-l (tR = 3.0 min) and 3- Isomer-2 (tR = 1.90 min). Yield: 3- Isomer-1 (tR = 3.0 min) = 5 g (ee = 99%) and 3- Isomer-2 (tR = 1.90 min) = 3 g (ee = 98%). Both the isomers were taken individually for further conversions.

[0358] Compound 36

[0359] Step 3:

[0360] To a stirred solution of 3-Isomer-l (5.5 g, 18.02 mmol) in DCM (75 mL), were added 3,4- dihydro-2H-pyran (2.466 mL, 27.0 mmol) and pyridinium p-toluenesulfonate (0.906 g, 3.60 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic extract was washed with brine solution (50 mL), dried over anhydrous ISfeSCL, fdtered and concentrated under reduced pressure. The resulting crude mass was purified by MPLC (using manually packed SiO2 cartridge, 100-200 mesh size; 10% EtOAc in hexanes) to afford 4-Isomer-l as yellow viscous liquid. Yield: 5.98 g (68%). LC-MS: Calculated for C21H32BNO5 is 389.30, Observed: 390.2 [M+l]+

[0361] Step 4:

[0362] To a stirred solution of 5 (2.5 g, 5.96 mmol) in acetonitrile (50 mL) and water (10 mL), were added 4-Isomer-l (2.79 g, 7.15 mmol) and potassium carbonate (2.472 g, 17.89 mmol) at room temperature. The reaction mixture was purged with nitrogen for 5 min. To this reaction mixture,PdCb(dtbpf) (0.389 g, 0.596 mmol) was added and the purging continued for another 2 min. The reaction mixture was stirred at 85 °C for 16 h. To the reaction cooled to ambient temperature, water (20 mL) was added and extracted with EtOAc (2 x 100 mL). The combined organic extract was washed with brine (10 mL), dried over anhydrous Na2SC>4, fdtered and concentrated under reduced pressure. The resulting crude mass was purified by MPLC (using manually packed Si O2 cartridge, 230-400 mesh size; 5% MeOH in DCM) to afford 6-Isomer-l as a pale-brown solid. Yield: 1.5 g (39%). LC-MS: Calculated for C35H43N3O6IS 601.74, Observed: 602.4 [M+l]+

[0363] Step 5:

[0364] To a stirred solution of 6-Isomer-l (1.5 g, 2.493 mmol) in THF (50 mL), were added triethylamine (1.212 mL, 8.70 mmol) and POCI3 (0.540 mL, 5.80 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 1 h. The reaction was quenched with water (2 mL) and concentrated under reduced pressure. The resulting crude mass was purified by reversed phase preparative HPLC (Column: Shimpack C18 150 mm; Eluents: 10 mM formic acid in water and ACN) to afford 400 mg Compound 36 (as a salt) as a white solid. Note: 1H NMR showed downfield shifts for imidazole protons. The above 400 mg of compound was taken in 10 mM ammonium bicarbonate solution in water (6 mL) and stirred for 2 h at room temperature. The resulting mixture was purified by reversed phase column chromatography (column: CIS-reversed phase SiCL; Eluents: water and ACN) to afford Compound 36 as a white solid. Yield: 175 mg (42%). LC-MS: Calculated for C25H28N3O7P is 513.48, Observed: 514.3 [M+l]+. 1H-NMR (4OO MHz, DMSO-d6): δ 7.58 (d, J = 8.40 Hz, 2H), 7.46 (t, J = 6.00 Hz, 4H), 7.20 (br s, 2H), 7.32 (app d, J = 1.20 Hz, 1H), 6.90 (s, 1H), 6.73 (d, J = 8.40 Hz, 2H), 6.07 (br s, 1H, exchanges with D2O), 5.96 (t, J = 6.40 Hz, 1H), 4.97-4.95 (m, 1H), 4.04-4.02 (m, 4H), 3.86 (dd, J = 4.00, 9.40 Hz, 1H), 3.69 (br s, 1H), 3.62 (d, J = 2.40, 8.80 Hz, 1H), 3.57 (dd, J = 1.20, 9.20 Hz, 1H), 1.48 (d, J = 6.40 Hz, 3H). (2H not observed). 31P-NMR (400 MHz, DMSO-d6): δ -1.120

[0365] Note: The product was single isomer with unknown stereochemistry at tail part (LUX-L Amylose3_0.5%IPAm in MeOH tR=2.66 min)

[0366] Compound 37

[0367] Step 3:

[0368] To a stirred solution of 3-Isomer-2 (3 g, 9.83 mmol) in DCM (45 mL), were added 3,4- dihydro-2H-pyran (1.348 mL, 14.75 mmol) and pyridinium p-toluenesulfonate (0.494 g, 1.966 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction was quenched with water (10 mL) and extracted with DCM (2 x 100 mL). The combined organic extract was washed with brine solution (10 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The resulting crude mass was purified by MPLC (using manually packed SiO2 cartridge, 100-200 mesh size; 10-20% EtOAc in hexanes) to afford 4-Isomer-2 as pale-yellow solid. Yield: 2.8 g (71%). LC-MS: Calculated for C21H32BNO5 is 389.30, Observed: 390.2 [M+l]+

[0369] Step 4:

[0370] To a stirred solution of 5 (2.0 g, 4.77 mmol) in 1,4-dioxane (50 mL) and water (12 mL), were added 4-Isomer-2 (2.228 g, 5.72 mmol) and potassium carbonate (1.977 g, 14.31 mmol) at room temperature. The reaction mixture was purged with nitrogen for 5 min. To this reaction mixture, PdC12(dtbpf) (0.933 g, 1.431 mmol) was added and the purging continued for another 2 min. The reaction mixture was stirred at 85 °C for 16 h. To the reaction cooled to ambient temperature, water (50 mL) was added and extracted with EtOAc (2 x 150 mL). The combined organic extract was washed with brine (10 mL), dried over anhydrous Na2SC>4, fdtered and concentrated under reduced pressure. The resulting crude mass was purified by MPLC (using manually packed SiCLcartridge, 230-400 mesh size; 10% MeOH in EtOAc) to afford 6-Isomer-2 as a yellow solid. Yield: 1.2 g (34%). LC-MS: Calculated for C35EI43N3O6 is 601.74, Observed: 602.4 [M+l]+.

[0371] Step 5:

[0372] To a stirred solution of 6-Isomer-2 (1.4 g, 2.327 mmol) in THF (70 mL), were added triethylamine (1.134 mL, 8.11 mmol) and POC13 (0.505 mL, 5.41 mmol) at -78 °C. The reaction mixture was stirred at -78 °C for 1 h. The reaction was quenched with water (1.5 mL) and concentrated under reduced pressure. The resulting crude mass was purified by reversed phase preparative HPLC (Column: X bridge 5 mm Cs (150*19) um; Eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 37 as a white solid. Yield: 220 mg (15%). LC- MS: Calculated for C25H28N3O7P is 513.48, Observed: 514.3 [M+l]+. 1H-NMR (400 MHz, DMSO- d6): 8 7.59 (d, J = 8.40 Hz, 2H), 7.47 (t, J = 8.00 Hz, 4H), 7.32 (app d, J = 1.20 Hz, 1H), 6.85 (app d, J = 1.20 Hz, 1H), 6.73 (d, J = 8.80 Hz, 2H), 6.08 (d, J = 5.60 Hz, 1H, exchanges with D2O), 5.98 (t, J = 6.40 Hz, 1H), 4.91-4.89 (m, 1H), 4.04-4.02 (m, 4H), 3.86 (dd, J = 4.00, 9.40 Hz, 1H), 3.69 (br s, 1H), 3.63 (dd, J = 2.40, 8.80 Hz, 1H), 3.57 (dd, J = 1.20, 9.60 Hz, 1H), 1.47 (d, J = 6.40 Hz, 3H). (4H not observed). 31P-NMR (400 MHz, DMSO-d6): δ 0.098

[0373] Note: The product was single isomer with unknown stereochemistry at tail part (LUX-L Amylose3_0.5%IPAm in MeOH tR=2.36 min)Example 25: Synthesis of Compound 38

[0374] Step l:

[0375] To a stirred solution of 1 (1.2 g, 1.475 mmol) in ACN (20 mL), were added pyridine (0.355 ml, 4.42 mmol) followed by phosphoryl trichloride (0.275 mL, 2.95 mmol) at 0 °C. The resulting reaction mixture was allowed to stir at 25 °C for 30-40 min. To the reaction mixture, water (4 mL) was added and stirred for 30 min at 25 °C. Excess solvent was distilled out under reduced pressure to afford a crude mass which was further purified by reversed phase preparative HPLC (Column: shimpack Cl 8 (150*20) 5 pm; Eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 38 as an off-white solid. Yield = 210 mg (32%). LC-MS: Calculated for C21H22N3O6P is 443.40, Observed: 444.0 [M+l]+

[0376] Note: Exchangeable protons not seen in 1HNMR.Example 26: Synthesis of Compound 39

[0377] Step l:

[0378] To a solution of 1-Isomer-l (1 g, 1.621 mmol) in acetonitrile (10 mL), were added pyridine (0.393 mL, 4.86 mmol) followed by POCI3 (0.302 mL, 3.24 mmol) at 0 °C. After addition, the resulting reaction mixture was allowed to attain room temperature and stirred for 40 min. To the reaction mixture, water (20 mL) was added and stirred for 30 min at 25 °C. The reaction mixture was extracted with EtOAc (3 x 60 mL). The combined organic layer was washed with cold brine solution (60 mL), dried over anhydrous sodium sulfate, fdtered, and concentrated under reduced pressure.The crude residue, thus obtained, was purified by reverse phase preparative HPLC (Column: ZORBAX C18 150*21.2 pm, 7 pm; Eluents: 10 mM ammonium bicarbonate in water and acetonitrile) to afford Compound 39 as an off-white solid. Yield: 320 mg (37%). LCMS: Calculated for C26H29N2O8P is 528.17, Observed: 529.4 [M+l]+. 1H-NMR (400 MHz, DMSO-r / 6): 8 7.66-7.64 (m, 2H), 7.53-7.49 (m, 4H), 7.38 (d, J = 1.2 Hz, 1H), 7.19 (br s, 2H, exchanges with D2O), 7.11 (d, J = 8.8 Hz, 1H), 6.91 (d, J = 1.2 Hz, 1H), 5.99 (t, J = 6.4 Hz, 1H), 4.94 (q, J = 6.4 Hz, 1H), 4.72 (d, J = 4.0 Hz, 1H), 4.23 (d, J = 3.6 Hz, 1H), 4.19-4.04 (m, 3H), 3.92 (dd, J = 4.4, 9.4 Hz, 1H), 3.79 (d, J = 9.6 Hz, 1H), 3.62 (dd, J = 1.6, 9.2 Hz, 1H), 2.18 (s, 3H), 1.48 (d, J = 6.4 Hz, 3H); (2 more exchangeable protons not observed). 31P-NMR (400 MHz, DMSO-r / g): 8 -0.393. SFC: 98.4%; tR = 1.19 min (Column: CHIRALPAK-IH; Eluents: 0.5% isopropyl amine in MeOH).

[0379] Note: Single isomer with SFC purity = 98.4%Example 27: Synthesis of Compound 40

[0380] 170 mg of Compound 40 was synthesized from l-Isomer-2 by using the procedure detailed above for Compound 39. LCMS: Calculated for C26H29N2O8P is 528.50, Observed: 529.4 [M+l]+. 1H-NMR (400 MHz, DMSO-r / 6): 8 7.66 (d, J = 8.4 Hz, 2H), 7.53-7.50 (m, 4H), 7.37 (s, 1H), 7.12-7.10 (m, 4H; two protons exchanges with D2O), 6.91 (s, 1H), 6.01 (t, J = 6.4 Hz, 1H), 5.49 (br s, 1H, exchanges with D2O), 4.93 (q, J = 6.4 Hz, 1H), 4.72 (d, J = 3.6 Hz, 1H), 4.23 (br s, 1H), 4.19-4.10 (m, 1H), 4.07 (dd, J = 8.8, 11.8 Hz, 2H), 3.93 (dd, J = 4.0, 9.4 Hz, 1H), 3.79 (d, J = 10.0 Hz, 1H), 3.63 (d, J = 9.6 Hz, 1H), 2.19 (s, 3H), 1.48 (d, J = 6.4 Hz, 3H). 31P-NMR (400 MHz, DMSO-d6): δ -1.216. SFC: 98.2%; tR = 1.29 mm (Column: CHIRALPAK-IH; Eluents: 0.5% isopropyl amine in MeOH)

[0381] Note: Single isomer with SFC purity = 98.19%Example 28: Synthesis of Compound 41

[0382] Step l:

[0383] To a stirred solution of 6-bromooxindole (1, 2 g, 9.43 mmol) and bis(pinacolato)diboron (3.59 g, 14.15 mmol) in dioxane (40 mL), was added potassium acetate (2.78 g, 28.3 mmol) at room temperature following which a stream of nitrogen gas was bubbled through the reaction mixture for 5 min. To this reaction mixture, PdCh(dppf) (0.690 g, 0.943 mmol) was added and the mixture was stirred at 100 °C for 16 h. The reaction was quenched with water (100 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SC>4, fdtered, and concentrated under reduced pressure to get the crude product. The crude residue was purified by MPLC (manually packed cartridge, SiCL 230-400 mesh; 30% EtOAcin hexanes) to obtain 2 as a pale yellow solid. Yield: 2.5 g (51%). UPLC-MS: Calculated for CuHisBNOs is 259.1, Observed: 260.1 [M+l]+

[0384] Step 2:

[0385] To a stirred solution of 2 (2.5 g, 9.65 mmol) in water (15 mL) and acetonitrile (15 mL), were added 3 (2.7 g, 6.44 mmol) and K2CO3 (2.67 g, 19.32 mmol) at room temperature following which a stream of nitrogen gas was bubbled through the mixture for 5 min. To this reaction mixture, PdC12(dtbpf) (0.420 g, 0.644 mmol) was added and the bubbling of nitrogen continued for another 2 min. The resulting reaction mixture was stirred at 80 °C for 16 h. The reaction was quenched with water (100 mL) and extracted with 10% MeOH in DCM (80 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SC>4, filtered, and concentrated under reduced pressure to get the crude product. The crude product was purified by MPLC (manually packed cartridge, SiCL 230-400 mesh; 5% MeOH in DCM) to obtain 4 as a brown color solid. Yield: 1.1 g (35%). UPLC-MS: Calculated for C28H29N3O4 is 471.55, Observed: 472.2 [M+l]+

[0386] Step 3:

[0387] To a stirred solution of 4 (1 g, 2.121 mmol) in THF (15 mL), were added pyridine (0.335 g, 4.24 mmol) and POCI3 (0.593 mL, 6.36 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 2 h. To the reaction mixture, water (15 mL) was added and stirred for 30 min. The reaction mixture was concentrated under reduced pressure. The resulting crude residue was purified by preparative HPLC (Column: X-BRIDGE Cs (19 x 150mm) 5 pm; Eluents: 10 mM ammonium bicarbonate in water and ACN) to obtain Compound 41 as a white solid. Yield: 165 mg (17%). LC- MS: Calculated for C23H22N3O6P is 467.4, Observed: 468.2 [M+l]+. 1H-NMR (400 MHz, DMSO- d6): 5 10.49 (s, 1H), 7.64 (d, J = 8.40 Hz, 2H), 7.57 (d, J = 8.40 Hz, 2H), 7.47 (s, 1H), 7.30 (d, J = 7.60 Hz, 1H), 7.24 (dd, J = 1.60, 7.80 Hz, 1H), 7.20-7.10 (br s, 1H, exchanges with D2O), 7.05-7.01 (m, 2H), 6.01 (t, J = 6.00 Hz, 1H), 5.03-0.98 (m, 1H), 4.21-4.14 (m, 2H), 3.52 (s, 2H), 1.49 (d, J = 6.80 Hz, 3H). 2H not observed. SFC = > 99 % (1-cellulose B O.5% IP Am in MeOH; tR = 1.65 min)

[0388] Note: Exchangeable proton not seen in 1HNMR; single isomer. Due to the polar nature of the compound, SFC showed a broad peak.Example 29: Synthesis of Compound 42

[0389] Step l:

[0390] To a stirred solution of 6-bromo-3,4-dihydro-2H-benzo[b][l,4]oxazine (1, 500 mg, 2.336 mmol) in 1,4-dioxane (10 mL), were added potassium acetate (917 mg, 9.34 mmol) and bis(pinacolato)diboron (1186 mg, 4.67 mmol). The reaction mixture was degassed for 5 min by using nitrogen gas, then PdC12(dppf).DCM (171 mg, 0.234 mmol) was added and the degassing continued for 2 min. The reaction mixture was stirred at 90 °C for 6 h. The reaction mixture was fdtered through Celite pad, washed with EtOAc (50 mL) and then concentrated under reduced pressure to obtain brown gum. The crude residue was purified by MPLC (using manually packed cartridge; SiCL 230-400 mesh; 18% EtOAc in hexane) to obtain boronate 2 as a colourless gum. Yield: 530 mg (86%). LCMS: Calculated for C14H2OBNO3 is 261.12, Observed: 262.2 [M+l]+

[0391] Step 2:

[0392] To a stirred solution of 2 (467 mg, 1.789 mmol) and 3 (500 mg, 1.192 mmol) in acetonitrile (7 mL) and water (7 mL), was added K2CO3 (494 mg, 3.58 mmol). The reaction mixture was degassed for 5 min by using nitrogen gas, then PdC12(dtbpf) (78 mg, 0.119 mmol) was added under continuous bubbling of nitrogen. The reaction mixture was stirred at 80 °C for 16 h during which time the progress of the reaction was monitored by TLC (DCM : MeOH = 1:19). The reaction was quenched with water (50 mL) and extracted with 10% MeOH in DCM (2 x 50 mL). The combined organic layer was washed with water (50 mL), brine (50 mL), dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The crude residue was purified by MPLC (using manually packed cartridge; SiO2230-400 mesh; 6% MeOH in DCM) to obtain 4 as a pale-brown solid. Yield: 130 mg (23%). LCMS: Calculated for C28H31N3O4 is 473.57, Observed: 474.4 [M+l]+

[0393] Step 3:

[0394] To a stirred solution of 4 (1.1 g, 2.323 mmol) in acetonitrile (12 mL), were added pyridine (0.564 mL, 6.97 mmol) and POCI3 (0.433 mL, 4.65 mmol) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 2 h. After 2 h, an aliquot was withdrawn and analysedby LCMS. The analysis indicated complete consumption of the starting material and formation of 32% product mass [M+H]+ = 470.1 at / R = 1.39 min. To the reaction mixture, water (5 mL) was added and concentrated under reduced pressure to obtain a dark brown gum. The crude residue was purified by reversed phase preparative HPLC (Column: Shimpack Cis (150*199 mm) 5 pm; Eluents: 10 mM ammonium bicarbonate in water and acetonitrile) to obtain Compound 42 as an off-white solid. Yield: 165 mg (14%). LCMS: Calculated for C23H24N3O6P is 469.43, Observed: 470.1 [M+l]+

[0395] Note: Exchangeable proton not seen in 1HNMR; Single isomer. Due to polar nature of compound SFC showed broad peak.Example 30: Synthesis of Compound 431

[0396] Step l:

[0397] To a stirred solution of 1 (1.0 g, 1.997 mmol) in ACN (20 mL), were added pyridine (0.5 mL, 5.99 mmol) followed by phosphoryl trichloride (0.373 mL, 3.99 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C, water (4 mL) was added and stirred at room temperature for 30 min. The volatiles were removed under reduced pressure and the crude residue purified by reversed phase preparative HPLC (Column: Gemini nx Cis (250*20 mm) 5 pm; Eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 43 as white solid. Yield = 300 mg (30%). LC-MS: Calculated for C26H29N2O6P is 496.50 Observed: 497.0 [M+l]+

[0398] Note: cA-geometry at tail; SFC purity = 99%. Two exchangeable protons were not observed in 1H NMRExample 31: Synthesis of Compounds 45 and 46

[0399] Step l:

[0400] To a suspension of Copper(II) tetrafluoroborate (45% in water, 4.54 mL, 13.37 mmol) in DCM (250 mL), were added 4-Bromobenzyl alcohol (2, 25 g, 134 mmol) and 3,4- epoxytetrahydrofuran (1, 19.18 mL, 267 mmol) at room temperature. The reaction was stirred at room temperature for 16 h. The reaction mixture was quenched with water (200 mL) and extracted with DCM (200 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SC>4, fdtered and concentrated under reduced pressure. The crude product was purified by using MPLC (manually packed cartridge; SiCL 100-200 mesh; 70% EtOAc in hexanes) to afford (±)-3 as an off-white solid. Yield: 3.75 g (10%)

[0401] Step 2:

[0402] 18.5 g of (±)-3 was separated by using SFC (Column: I Amylose A (250x30)mm, 5 pm; Eluents: CO2: Methanol [85:15]) to get 3_Isomer-l (retention time: 3.76 min) and 3_Isomer-2 (retention time: 4.60 min) as an off-white solids. Yield: 3_Isomer-l: 8 g and 3_Isomer-2: 6.9 g. SFC purity = 3_Isomer-l (ZR = 3.74 min): 99.7% and 3_Isomer-2 (ZR = 4.55 min): 97.2%. Both the isomers (3-Isomer-l and 3-Isomer-2) were taken independently for further conversion.

[0403] Step 3: using 3-Isomer-l:

[0404] To a stirred solution of 3-Isomer-l (3.0 g, 10.98 mmol) in DCM (30 mL), was added 3,4- dihydro-2H-pyran (1.848 g, 21.97 mmol) followed by pyridinium p-toluenesulfonate (0.055 g, 0.220 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. Thereaction was quenched by the addition of a saturated solution of sodium bicarbonate (100 mL) and extracted with DCM (100 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by using MPLC (manually packed cartridge, SiO2230-400 mesh; 10% EtOAc in hexanes) to afford 4-Isomer-l as a colorless oil. Yield: 3.8 g (92%)

[0405] Step 4: Using 4-Isomer-l

[0406] To a solution of 4-Isomer-l (3.8 g, 10.64 mmol) and bis(pinacolato)diboron (4.05 g, 15.96 mmol) in dioxane (38 mL) was added potassium acetate (3.13 g, 31.9 mmol). The reaction mixture was degassed for 5 min and PdCL(dppf) (0.778 g, 1.064 mmol) was added. The mixture was heated at 100 °C for 16 h. The reaction mixture was quenched with water (100 mL) and extracted with EtOAc (100 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get the crude product. The crude residue was purified by MPLC (manually packed cartridge, SiO2230-400 mesh; 10% EtOAc in hexanes) to obtain 5-Isomer-l as an off-white solid. Yield: 2.9 g (64%)

[0407] Step 5: Using 5-Isomer-l

[0408] To a stirred solution of 5-Isomer-l (1.018 g, 2.52 mmol) in water (5 mL) and acetonitrile (5 mL), were added 6 (0.88 g, 2.099 mmol) and potassium carbonate (0.870 g, 6.30 mmol) at room temperature. The reaction mixture was purged with nitrogen for 5 min. To this reaction mixture, PdC12(dtbpf) (0.137 g, 0.210 mmol)) was added and the purging continued for another 2 min. The resulting reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with 10 % MeOH in DCM (50 mL x 2). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get the crude product. The crude product was purified by MPLC (manually packed cartridge, SiCL 230-400 mesh; 5% MeOH in DCM) to obtain 7-Isomer-l as a brown color solid. Yield: 730 mg (52%). LC-MS: Calculated for C36H44N2O7 is 616.75, Observed: 617.2 [M+l]+

[0409] Step 6: Using 7-Isomer-l

[0410] To a stirred solution of 7-Isomer-l (0.680 g, 1.103 mmol) in acetonitrile (8 mL), were added pyridine (0.266 mL, 3.31 mmol) and phosphoryl trichloride (0.215 mL, 2.205 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with water (15 mL) and stirred for 30 min. The reaction mixture was concentrated to get crude. The crude residue was purified by preparative HPLC (Column: X-BRIDGE Cs (19 x 150mm) 5 pm; Eluents: 10 mM ammonium bicarbonate in water and ACN) to obtain Compound 45 as a white solid. Yield: 150 mg (30%). LC-MS: Calculated for C26H29N2O8P is 528.4, Observed: 529.0 [M+l]+LC-MS: Calculated for C26H29N2O8P is 528.4, Observed: 529.0 [M+l]+1H-NMR (400 MHz, DMSO-d6): δ 7.71-7.68 (m, 4H), 7.56 (d, J = 8.40 Hz, 2H), 7.42 (d, J = 8.40 Hz,2H), 7.34 (s, 1H), 7.18 (br s, 2H), 6.87 (s, 1H), 6.01 (t, J = 6.80 Hz, 1H), 4.91-4.89 (m, 1H), 4.60 (d, J = 12.40 Hz, 1H), 4.56 (d, J = 12.40 Hz, 1H), 4.20-4.16 (m, 1H), 4.14-4.10 (m, 1H), 4.07-4.02 (m, 1H), 3.91-3.90 (m, 1H), 3.85-3.81 (m, 2H), 3.72 (d, J = 9.60 Hz, 1H), 3.53 (d, J = 9.20 Hz, 1H), 1.47 (d, J = 6.40 Hz, 3H). 2H not observed.31P-NMR (400 MHz, DMSO-d6): δ -0.338.CHIRALPAK-IH (0.5% IPAm in MeOH) tR = 1.06 mm

[0411] By using the same procedure of Step 3 to Step 6, Compound 46 was synthesized from 3- Isomer-2 as a white solid. LC-MS: Calculated for C26H29N2O8P is 528.4, Observed: 529.0 [M+l]+LC-MS: Calculated for C26H29N2O8P is 528.4, Observed: 529.0 [M+l]+1H-NMR (400 MHz, DMSO-d6): δ 7.71-7.68 (m, 4H), 7.56 (d, J = 8.40 Hz, 2H), 7.42 (d, J = 8.00 Hz, 2H), 7.33 (s, 1H), 6.84 (d, J = 12.40 Hz, 1H), 6.01 (t, J = 6.40 Hz, 1H), 4.90-4.89 (m, 1H), 4.60 (d, J = 12.40 Hz, 1H), 4.56 (d, J = 12.40 Hz, 1H), 4.21-4.20 (m, 1H), 4.17-4.11 (m, 1H), 4.10-3.98 (m, 1H), 3.91-3.90 (m, 1H), 3.86-3.81 (m, 2H), 3.72 (d, J = 9.20 Hz, 1H), 3.53 (d, J = 9.20 Hz, 1H), 1.47 (d, J = 6.40 Hz, 3H).31P-NMR (400 MHz, DMSO-d6): δ -0.330.CHIRALPAK-IH 0.5% IPAm in MeOH tR = 1.02 mmExample 32: Synthesis of Compound 47

[0412] Step l:

[0413] To a solution of boronate 1 (3.0 g, 9.80 mmol; in DCM (60 mL), were added 3,4-dihydro- 2H-pyran (1.16 mL, 12.74 mmol) and pyridinium p-toluene sulphonate (0.24 g, 0.98 mmol) at room temperature and stirred for 36 h. The reaction was monitored by TLC. After complete consumptionof starting material, the reaction was quenched with water (50 mL) and extracted with DCM (70 mL X 2). The combined organic layer was washed with water (50 mL) and brine solution (50 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to get crude product. The crude was purified by flash column chromatography (SiCL 230-400 mesh; 15-20% EtOAc in petroleum ether) to afford 3 as colorless liquid. Yield: 2.0 g (52%). LC-MS: Calculated for C2iH3iBO6 is 390.28, Observed: No ionization observed.

[0414] Step 2:

[0415] To a stirred solution of boronate 2 (2.0 g, 4.77 mmol) in ACN (10 mL) and water (10 mL), were added 3 (2.79 g, 7.15 mmol) and K2CO3 (1.98 g, 14.31 mmol). The reaction mixture was degassed with nitrogen for 5 min. To this reaction mixture, was added PdC12(dtbpf) (0.31 g, 0.47 mmol) and the degassing was continued for another 2 min. The pressure tube was capped and heated at 80 °C for 16 h. The progress of the reaction was monitored by TLC. After completion, the reaction mixture was mixed with quenched with water (10 mL), extracted with DCM (20 mL X 2). The combined organic layer was washed with brine solution (10 mL), dried over anhydrous Na2SC>4, fdtered and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (SiO2 230-400 mesh size; 5% MeOH in DCM) to afford 4 as a brown solid. Yield: 1.0 g (35%). LC-MS: Calculated for C35H42N2O7is 602.78, Observed: 603 [M+l]+

[0416] Step 3:

[0417] To a solution of 4 (0.3 g, 0.498 mmol) in ACN (10 mL), were added pyridine (0.120 mL, 1.493 mmol) and phosphoryl trichloride (0.093 mL, 0.995 mmol) at 0 °C. The reaction mixture was stirred at 25 °C for 2 h. The reaction was followed by TLC. After complete consumption of starting material, the reaction mixture was quenched with water (10 mL) and stirred for 30 min. The reaction mixture was concentrated to get 250 mg of crude material which was taken for next step as such without further purification. (UPLC showed mono- and di-THP deprotected compound mass m / z = 599 and 515). Yield: 250 mg (Crude). LC-MS: Calculated for C35H43N2O10P is 682.70, Observed: 683 [M+l]+

[0418] Step 4:

[0419] To a solution of 5 (0.25 g, 0.366 mmol) in MeOH (10 mL), was added 1.5 N HC1 in water (1 mL, 0.366 mmol) at 0 °C. The resulting reaction mixture was stirred at 0 °C for 30 min. The reaction was followed by UPLC; showed formation of desired product. The reaction mixture was concentrated at 35 °C to get crude compound which was purified by reversed phase preparative HPLC (10 mM ammonium bicarbonate buffer and acetonitrile) to afford Compound 47 as white solid. Yield: 80 mg (42%). LC-MS: Calculated for C25H27N2O8P is 514.47, Observed: 515.2 [M+1]+Example 33: Synthesis of Compound 60

[0420] Step-1 & 2:

[0421] To a solution of (4-bromo-3-fluorophenyl)methanol (1, 10 g, 48.8 mmol) in DCE (150 mL), were added 3,4-Epoxytetrahydrofuran (2, 8.75 mL, 122 mmol) and copper(II) tetrafluoroborate (3.31 mL, 9.75 mmol) at room temperature, and the resulting reaction mixture stirred at 85 °C for 16 h. The reaction was quenched with water (100 mL) and extracted with DCM (100 mL x 2). The combined organic layer was washed with brine, dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure.

[0422] Three more batches were carried out on 10 g of 1 to get crude residue.

[0423] The combined crude residue from all the four batches were mixed and purified by MPLC (manually packed SiO2 cartridge; 100-200 mesh size; 30% EtOAc in hexanes) to afford (±)-3 as an off-white solid.

[0424] The isomers of (±)-3 were separated by SFC (column: Chiral Pak -IH (250*21) mm, 5pm; eluents: CO2and 0.5% isopropyl amine in isopropanol). The fractions were concentrated under reduced pressure to afford 3-Isomer-l (retention time = 5.76 min) and 3-Isomer-2 (retention time = 8.25 min). Yield: 3-Isomer-l (tR = 5.76 min) = 4.2 g (ee = 99%) and 3-Isomer-2 (tR = 8.25 min) = 4.0 g (ee = 99.7%)

[0425] 3-Isomer-2 was taken for further conversions.

[0426] Based on the experimental procedure carried out to determine the stereochemistry of isomers of 3 (3-Isomer-l and 3-Isomer-2), the stereochemistry of the 3-Isomer-2 was found to be (R, R).

[0427] Step-3:

[0428] To a solution of 3-Isomer-2 (4.0 g, 13.74 mmol) in DCM (50 mL), were added 3,4- dihydropyran (2.51 mL, 27.5 mmol) and pyridinium p-toluenesulfonate (0.345 g, 1.374 mmol) at 0 °C, and the resulting reaction mixture stirred at room temperature for 16 h. The reaction was quenched with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was dried over anhydrous Na2SC>4, fdtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 230-400 mesh size; 10% EtOAc in hexanes) to afford 4 as a colorless liquid. Yield: 4.5 g (86%)

[0429] Step-4:

[0430] To a solution of 4 (4.5 g, 11.99 mmol) in dioxane (50 mL), were added potassium acetate (3.53 g, 36.0 mmol) and bis(pinacolato)diboron (4.57 g, 17.99 mmol) at room temperature, and the resulting mixture degassed with nitrogen for 10 min. To this mixture, PdC12(dppf) (0.877g, 1.199 mmol) was added and degassed again for another 2 min. The resulting reaction mixture was stirred at 100 °C for 16 h. The inorganic solids were filtered through a Celite pad. The Celite pad was washed with EtOAc (150 mL), the filtrate combined and concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 230-400 mesh size; 15% EtOAc in hexanes) to afford 5 as yellow liquid.

[0431] Yield = 4.0 g (71%)

[0432] Step-5:

[0433] To a solution of 6 (2.7 g, 6.44 mmol) in acetonitrile (15 mL) and water (15 mL), were added 5 (4.08 g, 9.66 mmol) and potassium carbonate (2.67 g, 19.32 mmol) at room temperature, and the resulting mixture degassed with nitrogen for 5 min. To this reaction mixture, PdC12(dtbpf) (0.42 g, 0.644 mmol) was added, and the resulting reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with 10% MeOH in DCM (100 mL x 2). The combined organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue, thus obtained ,was purified by MPLC (manually packed SiO2 cartridge, 230-400 mesh size; 4% MeOH in DCM) to afford 7 as a pale-brown solid. Yield: 1.6 g (39%)

[0434] LC-MS: Calculated for C36H43FN2O7 is 634.31, observed: 635.2 [M+H]+

[0435] Step-6:

[0436] To a solution of 7 (0.75 g, 1.182 mmol) in acetonitrile (10 mL), were added pyridine (0.28 mL, 3.54 mmol) and phosphoryl trichloride (0.36 mL, 2.363 mmol) at 0 °C, and the resulting mixture stirred at the room temperature for 1 h. The reaction mixture was cooled to 0 °C, water (5 mL) was added dropwise and stirred at room temperature for 30 min. The volatiles were removed under reduced pressure. One more batch was carried out on 0.75 g of 7 to get the crude residue.

[0437] The combined crude residue was purified by reversed phase column chromatography (column: Redisep Gold, C-18 silica gel; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 60 as a white solid. Yield: 400 mg (61%)[°°438] LCMS: Calculated for C26H28FN2O8P is 546.16; observed: 547.0 [M+H]+

[0439] 1H-NMR (400 MHz, DMSO-d6): δ 7.61-7.52 (m, 5H), 7.43 (d, J = 1.20 Hz, 1H), 7.29- 7.26 (m, 2H), 7.17 (br s, 1H, exchangeable with D2O), 6.96 (s, 1H), 6.00 (t, J = 6.0 Hz, 1H), 5.01 - 4.95 (m, 1H), 4.60-4.55 (m, 2H), 4.20-4.13 (m, 3H), 3.91 (d, J = 4.0 Hz, 1H), 3.86-3.82 (m, 2H), 3.74 -3.71 (m, 1H), 3.55-3.52 (m, 1H), 1.49 (d, J = 6.80 Hz, 3H) (three exchangeable protons were not observed).

[0440] 31P-NMR (162 MHz, DMSO-d6): δ -0.498

[0441] SFC: 100%; tR = 3.34 min (column: I-Cellulose-Z; eluents: CO2and 0.5% isopropyl amine in ACN and MeOH)

[0442] Note: Single isomer with (R, R) stereochemistry in the tail. SFC purity = 100%Example 34: Synthesis of Compound 58

[0443] Synthesis of 5

[0444] Step-1:

[0445] To a solution of LiHMDS (1.0 M in THF, 73.5 mL, 73.5 mmol) in THF (40 mL), was added (S)-4-hydroxydihydrofuran-2(3H)-one (1, 3 g, 29.4 mmol) at -45 °C under nitrogen atmosphere. After stirring for 30 min at the same temperature, 1 -bromo-4-(bromomethyl)benzene (8.81 g, 35.3 mmol) and l,3-dimethyl-2-imidazolidinone (8.7 mL, 80 mmol) in THF (20 mL) wasdropped thereto. After stirring for additional 30 min at the same temperature, the reaction mixture was quenched by the addition of saturated NILC1 solution (50 mL) and extracted with EtOAc (50 mL X 3). The combined organic phase weas washed with brine (120 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The resulting crude product was purified by flash column chromatography (Si O2 100-200 mesh; 50% EtOAc in petroleum ether) to obtain 2 as a white solid.

[0446] Yield: 5.5 g (69%)

[0447] Step-2:

[0448] To a solution of 2 (2 g, 7.38 mmol) in DCM (20 mL), was added imidazole (1.256 g, 18.44 mmol) followed by TBDPS-C1 (2.84 mL, 11.07 mmol) at 0 °C and the reaction mixture stirred at room temperature for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (50 mL X 3). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product, thus obtained, was purified by flash column chromatography (SiCL 100-200 mesh; 20% EtOAc in hexane) to get 3 as a colorless liquid.

[0449] Yield: 3.6 g (96%)

[0450] Step-3:

[0451] To a stirred solution of 3 (3.0 g, 5.89 mmol) in DCM (30 mL), was added DIBAL-H (1.2 M in toluene, 7.36 mL, 8.83 mmol) at -78 °C under nitrogen atmosphere and the resulting reaction mixture stirred for 1 h. The reaction mixture was quenched with aqueous NH4CI solution (30 mL) at -78 °C and allowed to room temperature. The reaction mixture was diluted with DCM (80 mL), filtered through the Celite bed and the Celite bed further washed with DCM (40 mL). The combined filtrate was washed with brine (20 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude product, thus obtained, was purified by flash column chromatography (SiCL 100-200 mesh; 20% EtOAc in hexane) to get 4 as a colourless gum.

[0452] Yield: 1.7 g (56%)

[0453] Note: One more batch was carried out on 1.3 g scale to yield 0.73 g of 4 as a colourless gum. Both batches were mixed and taken up for next step.

[0454] Step-4:

[0455] To a solution of 4 (2.3 g, 4.50 mmol) in DCM (20 mL), was added TFA (0.693 mL, 8.99 mmol) at 0 °C and the reaction mixture was stirred at the same temperature for 30 min before the addition of tri ethyl silane (3.59 mL, 22.48 mmol). The reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with water (100 mL) and extracted with DCM (100 mL X 2). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The resulting crudeproduct was purified by flash column chromatography (SiO2100-200 mesh; 10% EtOAc in Hexane) to get 5 as a colourless gum.

[0456] Yield: 1.4 g (63%)

[0457] Synthesis of Compound 58

[0458] Step 5:

[0459] To a stirred solution of 5 (2.0 g, 4.04 mmol) in 1,4-di oxane (20 mL), were added and bis(pinacolato)diboron (1.230 g, 4.84 mmol) and potassium acetate (1.188 g, 12.11 mmol), and the mixture degassed with nitrogen for 5 min. Then, PdC12(dppf) (0.295 g, 0.404 mmol) was added, and the reaction mixture stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (50 mL), and filtered through a pad of Celite. The bed was washed with EtOAc (50 mL), the filtrate combined and concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 10% EtOAc in hexanes) to get 6 as a colorless gum. Yield: 1.9 g (85%)

[0460] LC-MS: Calculated for C33H43BO4S1 is 542.30, observed: 560.2 [M+H20]+

[0461] Step 6:

[0462] To a stirred solution of 7 (0.6 g, 1.431 mmol) and 6 (0.932 g, 1.717 mmol) in a mixture of THF (6 mL) and water (2 mL), was added potassium phosphate tribasic (0.911 g, 4.29 mmol), and the mixture degassed using nitrogen gas for 5 min. Then, SPhos Pd G2 (0.052 g, 0.072 mmol) was added. The reaction mixture was irradiated at 80 °C for 1 h in a microwave reactor. The reaction mixture was quenched with water (20 mL). This was extracted with 10% MeOH in DCM (2 x 20 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed SiO2 cartridge, 230-400 mesh size; 5% MeOH in DCM) to get 8 as a light-brown solid. Yield: 900 mg (80%)

[0463] LCMS: Calculated for C47H54N2O5S1 is 754.38, observed: 755.2 [M+H]+

[0464] Step 7:

[0465] To a solution of 8 (1.3 g, 1.722 mmol) in DCM (20 mL), were added diallyl N,N- diisopropylphosphoramidite (9, 0.817 mL, 3.10 mmol) and IH-tetrazole (0.362 g, 5.17 mmol) at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C, and 30% hydrogen peroxide in water (0.202 mL, 2.58 mmol) was added. The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with 10% NaHCCE solution (30 mL). This was extracted with DCM (3 x 30 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by using reverse phase column chromatography (column: RediSep Gold; C18 silica gel; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford 10 as a brown gum. Yield: 1.0 g (61%)

[0466] LC-MS: Calculated for C53H53N2O8PSI is 914.4, observed: 915.3 [M+H]+

[0467] Step 8:

[0468] To a stirred solution of 10 (1.0 g, 1.060 mmol) in MeOH (10 mL), was added HC1 (4 M in MeOH, 2.65 mL, 10.60 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. The resulting crude residue was purified by using reverse phase column chromatography (column: Redisep Gold, Cl 8 silica gel; eluents: 10 mM ammonium bicarbonate in water and ACN) to obtain Ila and 11b as brown gums.

[0469] Yield: Ila = 220 mg and 11b = 400 mg

[0470] LCMS: Calculated for Ila C32H37N2O7P is 592.2, observed: 593.2 [M+H]+

[0471] LCMS: Calculated for 11b C29H33N2O7P is 552.2, observed: 553.0 [M+H]+

[0472] Step 9:

[0473] To a stirred solution of 11b (0.400 g, 0.507 mmol) in MeOH (10 mL), were added 1,3- dimethylbarbituric acid (0.158 g, 1.013 mmol) and Pd(PPhs)4 (0.029 g, 0.025 mmol), and the reaction mixture stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to get 350 mg of crude product. Another batch was carried out using 220 mg of Ila. The crude product of both batches were mixed and purified by using reverse phase preparative HPLC (column: XTIMATE C18 (21 x250) mm, 5pm; eluents:10 mM ammonium bicarbonate in water and ACN) to obtain Compound 58 as an off-white solid.

[0474] Yield: 185 mg (combined yield for both batches)

[0475] LCMS: Calculated for C26H29N2O7P is 512.17, observed: 513.2 [M+H]+

[0476] 1H-NMR (400 MHz, DMSO-d6): δ 7.70 (d, J = 8.00 Hz, 2H), 7.63 (d, J = 8.00 Hz, 2H), 7.56 (d, J = 8.40 Hz, 2H), 7.47 (s, 1H), 7.32 (d, J = 8.00 Hz, 2H), 7.01 (s, 1H), 6.01 (t, J = 6.40 Hz, 1H), 5.02-4.99 (m, 1H), 4.21-4.15 (m, 2H), 3.98-3.96 (m, 1H), 3.87 (dd, J = 4.80, 9.20 Hz, 1H), 3.82 (dd, J = 6.40, 8.40 Hz, 1H), 3.493.42 (m, 1H), 3.42 (dd, J = 4.40, 8.20 Hz, 1H), 2.75-2.68 (m, 1H), 2.57-2.54 (m, 1H), 2.34-2.31 (m, 1H), 1.50 (d, J = 6.40 Hz, 3H). Four exchangeable protons not seen.

[0477] 31P-NMR (162 MHz, DMSO-d6): δ -0.690

[0478] SFC: 100%; tR = 1.47 min (column: I Amylose- A; eluents: CO2and 0.5% isopropyl amine in MeOH).

[0479] Note: Single isomer with 100% SFC purity. Four exchangeable protons were not seen in NMR.Example 35: Synthesis of Compound 63

[0480] Step l:

[0481] To a suspension of Copper(II) tetrafluoroborate (45% in water, 4.54 mL, 13.37 mmol) in DCM (250 mL), were added 4-Bromobenzyl alcohol (2, 25 g, 134 mmol) and 3,4- epoxytetrahydrofuran (1, 19.18 mL, 267 mmol) at room temperature. The reaction was stirred at room temperature for 16 h. The reaction mixture was quenched with water (200 mL) and extracted with DCM (200 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SC>4, fdtered and concentrated under reduced pressure. The crude product was purified by using MPLC (manually packed cartridge; SiCL 100-200 mesh; 70% EtOAc in hexanes) to afford (±)-3 as an off-white solid. Yield: 3.75 g (10%)

[0482] Step 2:

[0483] 18.5 g of (±)-3 was separated by using SFC (Column: I Amylose A (250x30)mm, 5 pm; Eluents: CO2: Methanol [85: 15]) to get 3_Isomer-l (retention time: 3.76 min) and 3_Isomer-2 (retention time: 4.60 min) as an off-white solids.

[0484] Step 3:

[0485] To a stirred solution of 3-Isomer-l (4.0 g, 14.65 mmol) in dioxane (80 mL), were added bis(pinacolato)diboron (4.46 g, 17.57 mmol) and potassium acetate (4.31 g, 43.9 mmol) at room temperature, and the resulting mixture degassed with nitrogen for 5 min. Then, PdC12(dppf) (1.072 g, 1.465 mmol) was added and the reaction mixture stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL), fdtered through a Celite pad. The Celite pad was washed with EtOAc (150 mL), the fdtrate combined and concentrated under reduced pressure. The resulting crude mass, thus obtained, was purified by using MPLC (manually packed SiO2 cartridge, 230-400 mesh; 40 % EtOAc in hexene) to get 4 as a pale-yellow gum.

[0486] Yield = 5.0 g (91%)

[0487] Step 4:

[0488] To a stirred solution of 5 (0.6 g, 1.124 mmol) and 4 (0.468 g, 1.462 mmol) in a mixture of THF (6 mL) and water (3 mL), was added potassium phosphate tribasic (0.716 g, 3.37 mmol) and the reaction mixture degassed with nitrogen gas for 5 min. Then, SPhos Pd G2 (0.081 g, 0.112 mmol) was added to the reaction mixture and irradiated at 80 °C for 1 h in a microwave reactor. The reaction mixture was quenched with water (20 mL), extracted with 10% MeOH in DCM (2 x 20 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The resulting crude residue, thus obtained, was purified by using MPLC (manually packed SiO2 cartridge, 230-400 mesh size; 5% MeOH in DCM) to get 6 as brown gum. Yield: 0.6 g (76%)

[0489] LC-MS: Calculated for C37H50N2O6S1 is 646.34, observed: 647.2 [M+H]+

[0490] Another batch was carried out using 0.6 g of 5 to get 0.6 g of 6.

[0491] Step 5:

[0492] To a solution of 6 (0.4 g, 0.618 mmol) in acetonitrile (5 mL), were added pyridine (0.149 mL, 1.855 mmol) followed by phosphoryl trichloride (0.115 mL, 1.237 mmol) at 0 °C and the resulting reaction mixture stirred at room temperature for 2 h. To this reaction mixture, water (3 mL) was added dropwise and stirred at room temperature for 5 h. The reaction mixture was kept in the cold room (5-8 °C) overnight.

[0493] Two more batches were carried out on 0.4 g of 6 to get the crude residue.

[0494] The combined crude residue was purified by using reverse phase preparative HPLC (column: X-BRIDGE C8 (150x19) mm, 5 pm; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford 180 mg (yield for three batches) of Compound 63 as a white solid.

[0495] Another batch was carried out on 0.3 g of 6 to get 70 mg of Compound 63 as a white solid.

[0496] All the batches were combined and lyophilized to get Compound 63 as a white solid. Yield: 260 mg (combined yield for four batches)

[0497] LCMS: Calculated for C26H29N2O8P is 528.17, observed: 529.0 [M+H]+

[0498] 1H-NMR (400 MHz, DMSO-d6): δ 7.69 (d, J = 8.00 Hz, 2H), 7.66 (d, J = 8.00 Hz, 2H), 7.54 (d, J = 8.40 Hz, 2H), 7.43 (d, J = 8.00 Hz, 2H), 7.37 (d, J = 1.20 Hz, 1H), 7.14 (br s, 1H, exchanges with D2O ), 6.85 (d, J = 0.80 Hz, 1H), 5.70 (t, J = 6.00 Hz, 1H), 4.98-4.92 (m, 1H), 4.68- 4.65 (m, 2H), 4.57 (d, J = 12.40 Hz, 1H), 4.17 (d, J = 4.00 Hz, 1H), 3.88-3.84 (m, 4H), 3.74 (d, J = 9.60 Hz, 1H), 3.68 (d, J = 9.20 Hz, 1H), 1.51 (d, J = 6.40 Hz, 3H). Three exchangeable protons not seen in NMR.

[0499] 31P-NMR (162 MHz, DMSO-d6): δ -0.920

[0500] SFC: 100%; tR = 2.09 min (column: I Amylose- 3; eluents: CO2and 0.5% isopropyl amine in MeOH-ACN)Example 36: Synthesis of Compound 62

[0501] Step-3:

[0502] To a solution of 3-Isomer-2 (5 g, 17.18 mmol) in dioxane (50 mL), were added potassium acetate (5.06 g, 51.8 mmol) and bis(pinacolato)diboron (6.54 g, 25.8 mmol) at room temperature and the resulting mixture degassed with nitrogen for 10 min. To this reaction mixture, PdC12(dppf) (1 g, 1.374 mmol) was added. The resulting reaction mixture was stirred at 100 °C for 16 h. The inorganic solids were filtered through a Celite pad. The Celite pad was washed with EtOAc (2 x 60 mL), the filtrate combined and concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 60% EtOAc in hexanes) to afford 4 as pale-brown solid. Yield = 4.8 g (74%)

[0503] Step-4:

[0504] To a solution of 5 (1 g, 1.87 mmol) in THF (5 mL) and water (2.5 mL), were added 4 (0.95 g, 2.81 mmol) and potassium phosphate tribasic (1.19 g, 5.62 mmol) at room temperature and the reaction mixture degassed with nitrogen for 10 min. To this reaction mixture, SPhosPdG2 (0.135 g, 0.187 mmol) was added and the reaction mixture irradiated in micro wave reactor at 70 °C for 1.5 h. The reaction mixture was quenched with water (10 mL), extracted with 10% MeOH in DCM (2 x 25 mL). The combined organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 6% MeOH in DCM) to afford 6 as a pale-brown solid.

[0505] Yield: 0.85 g (63%)

[0506] LC-MS: Calculated for C37H49FN2O6S1 is 664.33, observed: 665.2 [M+H]+

[0507] Step-5:

[0508] To a solution of 6 (0.4 g, 0.6 mmol) in acetonitrile (6 mL), were added pyridine (0.145 mL, 1.80 mmol) followed by phosphoryl trichloride (0.112 mL, 1.20 mmol) at 0 °C. The resulting reaction mixture was stirred at the room temperature for 2 h. To this reaction mixture, water (4 mL) was added dropwise and stirred at room temperature for 4 h. The reaction mixture was kept in cold room for overnight.

[0509] One more batch was carried out on 0.4 g of 6 to get the crude residue.

[0510] The combined crude residue was purified by reversed phase column chromatography (column: Redisep Gold, C-18 silica gel; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 62 as an off-white solid.

[0511] Yield: 260 mg (combined yield for two batches) l°0512l LCMS: Calculated for C26H28FN2O8P is 546.16; observed: 547.2 [M+H]+

[0513] 'H-NMR (400 MHz, DMSO-d6): δ 7.55 (s, 4H), 7.49 (t, J = 8.4 Hz, 1H), 7.36 (d, J = 1.20 Hz, 1H), 7.28-7.25 (m, 2H), 6.84 (d, J = 0.80 Hz, 1H), 5.71 (t, J = 6.0 Hz, 1H), 4.97-4.92 (m, 1H), 4.71-4.58 (m, 3H), 4.17 (d, J = 4.0 Hz, 1H), 3.88-3.83 (m, 4H), 3.73-3.66 (m, 2H), 1.51 (d, J = 6.40 Hz, 3H) (four exchangeable protons not observed).

[0514] 31P-NMR (162 MHz, DMSO-d6): 8 -1.206

[0515] SFC: 100%; tR = 3.63 min (column: Lux I-Amylose-3; eluents: CO2and 0.5% isopropyl amine in ACN and MeOH)

[0516] Note: Single isomer with (R, R) stereochemistry in tail. SFC purity = 100%Example 37: Synthesis of Compound 57

[0517] Step-5:

[0518] To a solution of 6 (1 g, 2.38 mmol) in THF (8 mL) and water (2 mL), were added 5- Isomer-1 (1.06 g, 3.34 mmol) and potassium phosphate tribasic (1.52 g, 7.15 mmol) at room temperature and the reaction mixture degassed with nitrogen for 5 min. To this reaction mixture, SPhos Pd G2 (0.17 g, 0.23 mmol) was added and the reaction mixture irradiated in microwave reactor at 80 °C for 2 h. The reaction mixture was quenched with water (30 mL), extracted with 10% MeOH in DCM (2 x 50 mL). The combined organic layer was dried over anhydrous Na2SC>4, fdtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 6% MeOH in DCM) to afford 7 as a palebrown solid. Yield: 800 mg (55%)

[0519] LC-MS: Calculated for C31H35N3O5 is 529.26, observed: 530.8 [M+H]+

[0520] Step-6:

[0521] To a solution of 7 (1.6 g, 3.02 mmol) in DCM (15 mL), were added diallyl N, N- diisopropylphosphoramidite (8, 1.2 mL, 4.53 mmol) and IH-tetrazole (0.42 g, 6.04 mmol) at room temperature. The resulting mixture was stirred at room temperature for 3 h. The reaction mixture was cooled to 0 °C, hydrogen peroxide (30% in water; 1.18 mL, 15.1 mmol) was added and the resulting reaction mixture stirred at room temperature for 30 min. The reaction was quenched with 10% NaHCCh solution (60 mL) and extracted with DCM (2 x 80 mL). The combined organic layer was dried over anhydrous Na2SC>4, concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 6% MeOH in DCM) to afford 9 as a pale-brown gum. Yield: 1.5 g (63%)

[0522] LCMS: Calculated for C37H44N3O8P is 689.29, observed: 690.8 [M+H]+

[0523] Step-7:

[0524] To a solution of 9 (1.5 g, 2.17 mmol) in MeOH (20 mL), was added p-toluenesulfonic acid monohydrate (1.24 g, 6.52 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with DCM (80 mL), washed with 10% NaHCO? solution (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 10 as a pale-brown gum. Yield: 1.1 g (77%)

[0525] LCMS: Calculated for C32H36N3O7P is 605.23, observed: 606.6 [M+H]+

[0526] Step-8:

[0527] To a solution of 10 (1.1 g, 1.81 mmol) in MeOH (10 mL), were added 1,3- dimethylbarbituric acid (0.28 g, 1.81 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.1 g, 0.09 mmol) at 0 °C and the resulting reaction mixture stirred at room temperature for 3 h. The volatiles were removed under reduced pressure. The crude residue was triturated with EtOAc (80 mL), the supernatant layer was decanted. The crude residue, thus obtained, was purified by reverse phase

[0528] column chromatography using MPLC (column: Redisep Gold, C18 silica; eluents: 10 mM ammonium bicarbonate in water and ACN). The product was further re-purified by reverse phase preparative HPLC (column: EVOKE (30*250 mm) 5 pm; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 57 as an off- white solid.

[0529] Yield: 250 mg (26%)[°o53°] LCMS: Calculated for C26H28N3O7P is 525.17, observed: 526.3 [M+H]+

[0531] 'H-NMR (400 MHz, DMSO-d6): 5 7.66-7.63 (m, 4H), 7.59 (s, 1H, exchanges with D2O), 7.52 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 1.2 Hz, 1H), 7.19 (br s, 2H, exchanges with D2O), 7.04 (d, J = 8.8 Hz, 2H), 6.84 (d, J = 0.8 Hz, 1H), 5.99 (t, J = 6.0 Hz, 1H), 4.94-4.89 (m, 1H), 4.01-3.97 (m, 4H), 3.43 (t, J = 8.8 Hz, 1H), 3.11 (dd, J = 5.6, 9.6 Hz, 1H), 2.89-2.83 (m, 1H), 2.34 (dd, J = 8.8, 16.4 Hz , 1H), 2.05 (dd, J= 6.8, 16.8 Hz, 1H), 1.48 (d, J = 6.4 Hz, 3H). One exchangeable proton was not seen.

[0532] 31P-NMR (162 MHz, DMSO-d6): 5 - 0.371

[0533] SFC: 100%; tR = 2.02 min (column: Lux Amylose-A; eluents: CO2and 0.5% isopropyl amine in MeOH)

[0534] Note: Single isomer with unknown stereochemistry in tail part. SFC purity = 100%Example 38: Synthesis of Compound 56

[0535] 13 was synthesized in an identical fashion starting with 4-Isomer-2, by using the steps 4 to 7 followed for Compound 57.

[0536] Step-5:

[0537] To a solution of 13 (0.75 g, 1.17 mmol) in MeOH (10 mL), were added 1,3- dimethylbarbituric acid (0.36 g, 2.35 mmol) and tetrakis(triphenylphosphine)palladium (0) (68 mg, 0.06 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 3 h. The volatiles were removed under reduced pressure. The crude residue was triturated with EtOAc (80mL), the supernatant layer was decanted. The crude residue, thus obtained, was purified by reverse phase column chromatography using MPLC (column: Redisep Gold, C18 silica; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 56 as an off-white solid. Yield: 190 mg (33%)[°°538] LCMS: Calculated for C26H28N3O7P is 525.17, observed: 526.1 [M+H]+

[0539] 'H-NMR (400 MHz, DMSO-d6): 8 7.66-7.63 (m, 4H), 7.59 (s, 1H, exchanges with D2O), 7.52 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 1.2 Hz, 1H), 7.17 (br s, 2H, exchanges with D2O), 7.04 (d, J = 8.8 Hz, 2H), 6.89 (s, 1H), 5.99 (t, J = 6.4 Hz, 1H), 4.95-4.90 (m, 1H), 4.0-4.16 (m, 4H), 3.43 (t, J = 8.8 Hz, 1H), 3.11 (dd, J = 5.6, 9.6 Hz, 1H), 2.83-2.87 (m, 1H), 2.34 (dd, J = 8.8, 16.4 Hz, 1H), 2.05 (dd, J= 6.8, 16.8 Hz, 1H), 1.48 (d, J = 6.4 Hz, 3H). One exchangeable proton was not seen.

[0540] 31P-NMR (162 MHz, DMSO-d6): δ - 0.478

[0541] SFC: 100%; tR = 2.56 min (column: I Amylose-A; eluents: CO2and 0.5% isopropyl amine in MeOH).

[0542] Note: Single isomer with unknown stereochemistry in tail part. SFC purity = 100%Example 39: Synthesis of Compound 55

[0543] Step 1:

[0544] To a stirred solution of 4-bromophenol (1, 15 g, 87 mmol) in 1,4-dioxane (150 mL), were added 3,4-epoxytetrahydrofuran (2, 6.22 mL, 87 mmol), cesium carbonate (42.4 g, 130 mmol) and benzyltriethylammonium chloride (3.95 g, 17.34 mmol) at room temperature and the reaction mixture heated at 120 °C for 16 h. The reaction mixture was cooled to room temperature, quenchedwith water (100 mL) and extracted with EtOAc (200 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 40% EtOAc in hexane) to afford (±)-3 as an off-white solid. Yield: 17.0 g (68%)

[0545] Step 2:

[0546] To a stirred solution of (±)-3 (17 g, 65.6 mmol) in MTBE (100 mL), was added vinyl acetate (18.1 mL, 197 mmol) followed by Amano Lipase PS (3.0 g) and the reaction mixture stirred at room temperature for 5 h. The reaction mixture was filtered through Buchner funnel and the solid was washed with MTBE (150 mL). The combined filtrate was concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 60-80% EtOAc in hexane) to afford 3-Isomer-2 (tR = 5.00 min; LUX-1- Amylose-3, 0.5% IP Am in MeOH).and 4 as off-white solids. Yield: 3-Isomer-2 = 6 g and 4 = 6.2 g

[0547] Step 3:

[0548] To a solution of 3-Isomer-2 (6.2 g, 23.93 mmol) in DCM (60 mL), were added 3,4- dihydropyran (4.38 mL, 47.9 mmol) and pyridinium p-toluenesulfonate (0.601 g, 2.393 mmol) at 0 °C and the reaction mixture stirred at room temperature for 16 h. The reaction was quenched with water (60 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 50% EtOAc in hexane) to obtain 5 as a colorless liquid. Yield: 8.5 g (93%)

[0549] Step 4:

[0550] To a stirred solution of 5 (8.2 g, 23.9 mmol) in 1,4-dioxane (80 mL), were added potassium acetate (7.03 g, 71.7 mmol) and bis(pinacolato)diboron (9.10 g, 35.8 mmol) and the reaction mixture degassed with nitrogen for 5 min. To this reaction mixture, PdC12(dppf) (1.748 g, 2.389 mmol) was added and degassing continued for 2 min. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature and filtered through a Celite pad. The Celite pad was washed with EtOAc and concentrated under reduced pressure. The resulting crude mass, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 70% EtOAc in hexanes) to obtain 6 as a pale-yellow liquid. Yield: 9 g (87%)

[0551] Step 5:

[0552] To a stirred solution of 7 (1.5 g, 3.46 mmol) and 6 (2.026 g, 5.19 mmol) in acetonitrile (15 mL) and water (15 mL), was added potassium carbonate (1.435 g, 10.38 mmol) and the reaction mixture degassed with nitrogen for 5 min. To this reaction mixture, PdC12(dtbpf) (0.226 g, 0.346 mmol) was added, and the reaction mixture heated at 80 °C for 16 h. The reaction mixture was cooled to room temperature, quenched with water (20 mL) and extracted with 10% MeOH in DCM (2 x 15 mL). The combined organic layer was dried over sodium sulphate, filtered and concentratedunder reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 5% MeOH in DCM) to obtain 8 as pale-brown gum.

[0553] Yield: 1.3 g (55%). LC-MS: Calculated for C36H44N2O7 is 616.31, observed: 617.6 [M+H]+

[0554] Step 6:

[0555] To a stirred solution of 8 (1.3 g, 2.108 mmol) in DCM (15 mL), were added ? / , N- diallyl diisopropylphosphoramidite (9, 1.089 mL, 4.22 mmol) and IH-tetrazole (0.443 g, 6.32 mmol) at room temperature and the reaction mixture stirred for 1 h. To this reaction mixture, 30% hydrogen peroxide in water (0.824 mL, 10.54 mmol) was added at 0 °C and the reaction mixture stirred for 30 min at room temperature. The reaction was quenched with saturated sodium thiosulphate solution (10 mL) and extracted with DCM (2 x 15 mL). The combined organic layer was washed with sodium bicarbonate solution (10 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude residue thus obtained, was purified by using MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 4% MeOH in DCM) to obtain 10 as a pale-yellow gum.

[0556] Yield: 1.1 g (65%). LC-MS: Calculated for C42H53N2O10P is 776.3, observed: 777.6 [M+H]+

[0557] Step 7:

[0558] To a stirred solution of 10 (2.5 g, 3.22 mmol) in MeOH (15 mL), was added p- toluenesulfonic acid monohydrate (1.836 g, 9.65 mmol) at 0 °C and the reaction mixture stirred at room temperature for 2 h. The reaction mixture was cooled to 0 °C, quenched with saturated NaHCO3 solution (10 mL) and extracted with 10% MeOH in DCM (2 x 20 mL). The combined organic layer was dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by reverse phase column chromatography (column: Redisep Gold, C18 SiO2; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford 11 as pale-yellow gum.

[0559] Yield: 1.1 g (56%). LC-MS: Calculated for C32H37N2O8P is 608.2, observed: 609.5 [M+H]+

[0560] Step 8:

[0561] To a stirred solution of 11 (1.1 g, 1.807 mmol) in MeOH (10 mL), was added 1,3- dimethylbarbituric acid (0.564 g, 3.61 mmol) and tetrakis(triphenylphosphine) palladium (0) (0.104 g, 0.090 mmol) at 0 °C and the reaction mixture stirred at room temperature for 2 h. The volatiles were evaporated under reduced pressure and the resulting residue triturated with EtOAc (50 mL). The supernatant solvent was decanted and the resulting crude, thus obtained purified by reverse phase column chromatography (column: Redisep Gold, Cl 8 SiO2; 10 mM ammonium bicarbonate in water and ACN) to afford 250 mg of product. The product was re-purified using RP-MPLC (column: Redisep Gold, Cl 8 SiO2; water and ACN) to afford Compound 55 as an off-white solid.Yield: 220 mg (23%)1005621LC-MS: Calculated for C26H29N2O8P is 528.2, observed: 529.4 [M+H]

[0563] 'H-NMR (400 MHz, DMSO-d6): 5 7.65-7.63 (m, 4H), 7.52 (d, J = 8.4 Hz, 2H), 7.42 (s, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.93 (s, 1H), 5.81 (t, J = 6.8 Hz, 1H), 4.97-4.93 (m, 1H), 4.70 (d, J = 4.0 Hz, 1H), 4.23 (d, J = 3.2 Hz, 1H), 4.07 (dd, J = 4.0 Hz, 10.0 Hz, 1H), 3.96-3.88 (m, 3H), 3.77 (d, J = 10.4 Hz, 1H), 3.60 (dd, J = 1.6, 9.2 Hz, 1H), 2.45-2.39 (m, 1H), 2.29-2.24 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H). Four exchangeable protons not seen in NMR.

[0564] 31P-NMR (162 MHz, DMSO-d6): 5 -1.152

[0565] SFC: 100%; tR = 1.80 min (column: I Cellulose J; eluents: CO2and 0.5% isopropyl amine in MeOH).

[0566] Note: Hygroscopic in nature. SFC purity is 100% and unknown stereochemistry in tail part. Four exchangeable protons not seen in NMR.Example 40: Synthesis of Compound 54

[0567] Step 10:

[0568] To a stirred solution of 4-bromophenol (12, 15 g, 87 mmol) in 1,4-dioxane (150 mL), were added 3,4-epoxytetrahydrofuran (13, 6.22 mL, 87 mmol), cesium carbonate (42.4 g, 130 mmol) and benzyltriethylammonium chloride (3.95 g, 17.34 mmol) at room temperature and the reaction mixture heated at 120 °C for 16 h. The reaction mixture was cooled to room temperature, quenched with water (100 mL) and extracted with EtOAc (200 mL). The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 40% EtOAc in hexane) to afford (±)-14 as an off-white solid. Yield: 17.0 g (68%)

[0569] Step 11:

[0570] To a stirred solution of (±)-14 (17 g, 65.6 mmol) in MTBE (100 mL), was added vinyl acetate (18.1 mL, 197 mmol) followed by Amano Lipase PS (3.0 g) and the reaction mixture stirred at room temperature for 5 h. The reaction mixture was fdtered through Buchner funnel and the solid was washed with MTBE (150 mL). The combined filtrate was concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 60-80% EtOAc in hexane) to afford 14-Isomer-2 (tR = 5.00 min; LUX-1- Amylose-3, 0.5% IP Am in MeOH).and 15 as off-white solids.

[0571] Yield: 14-Isomer-2 = 6 g and 15 = 6.2 g

[0572] Step 12:

[0573] To a solution of 15 (6.2 g, 20.59 mmol) in MeOH (60 mL), were added potassium carbonate (5.69 g, 41.2 mmol) and water (20 mL) at room temperature and the resulting reaction mixture stirred at room temperature for 2 h. The volatiles were evaporated under reduced pressure. To the resulting residue, water (50 mL) was added and extracted with DCM (2 x 20 mL). The combined organic layer was dried over sodium sulphate, filtered, and concentrated under reduced pressure to obtain 14-Isomer-l as an off-white solid (tR = 3.70 min; LUX-1- Amylose-3, 0.5% IP Am in MeOH). Yield: 5.5 g (98%)

[0574] Step 13:

[0575] To a solution of 14-Isomer-l (5.5 g, 21.23 mmol) in DCM (60 mL), were added 3,4- dihydropyran (3.87 mL, 42.5 mmol) and pyridinium p-toluenesulfonate (0.533 g, 2.12 mmol) at 0 °C and the reaction mixture stirred at room temperature for 16 h. The reaction was quenched with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was washed with brine solution (30 mL), dried over sodium sulphate, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 20% EtOAc in hexane) to obtain 16 as a pale-brown gum.

[0576] Yield: 6.8 g (89%)

[0577] Step 14:

[0578] To a stirred solution of 16 (6.7 g, 19.5 mmol) in 1,4-di oxane (80 mL), were added potassium acetate (5.75 g, 58.6 mmol) and bis(pinacolato)diboron (7.44 g, 29.3 mmol) and the reaction mixture degassed with nitrogen for 10 min. To this reaction mixture, PdC12(dppf) (0.86 g, 1.17 mmol) was added and the reaction mixture stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature and filtered through a Celite pad. The Celite pad was washed with EtOAc (100 mL), and the filtrate combined and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 30% EtOAc in hexane) to obtain 17 as a pale-brown gum. Yield: 5.6 g (70%)

[0579] Step 15:

[0580] To a stirred solution of 11 (1.5 g, 3.46 mmol) and boronate 17 (2.026 g, 5.19 mmol) in acetonitrile (15 mL) and water (5 mL), was added potassium carbonate (1.435 g, 10.38 mmol) and the reaction mixture degassed with nitrogen for 5 min. To this reaction mixture, PdC12(dtbpf) (0.226 g, 0.346 mmol) was added and the reaction mixture heated at 80 °C for 4 h. The reaction mixture was cooled to room temperature, quenched with water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed SiO2 cartridge, 230-400 mesh size; 6% MeOH in DCM) to obtain 18 as a brown solid. Yield: 1.1 g (46%)

[0581] LC-MS: Calculated for C36H44N2O7 is 616.31, observed: 617.3 [M+H]+

[0582] Step 16:

[0583] To a stirred solution of 18 (1.7 g, 2.76 mmol) in DCM (30 mL), were added diallyl diisopropylphosphoramidite (19, 1.5 mL, 5.51 mmol) and IH-tetrazole (0.58 g, 8.27 mmol) at room temperature and the reaction mixture stirred for 3 h. To this reaction mixture, 30% hydrogen peroxide in water (0.422 mL, 13.78 mmol) was added at 0 °C and the reaction mixture stirred at room temperature for 1 h. The reaction was quenched with saturated sodium thiosulphate solution (30 mL) and extracted with DCM (2 x 15 mL). The combined organic layer was washed with sodium bicarbonate solution (30 mL), brine (50 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 6% MeOH in DCM) to obtain 20 as a palebrown liquid. Yield: 1.8 g (80%)

[0584] LC-MS: Calculated for C42H53N2O10P is 776.3, observed: 777.6 [M+H]+

[0585] Step 17:

[0586] To a stirred solution of 20 (1.8 g, 2.3 mmol) in MeOH (30 mL), was added p- toluenesulfonic acid monohydrate (1.54 g, 8.11 mmol) at 0 °C and the reaction mixture stirred at room temperature for 3 h. The reaction mixture was quenched with saturated NaHCO? solution (30 mL) and extracted with 5% MeOH in DCM (2 x 80 mL). The combined organic layer was washed with brine (20 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by reverse phase column chromatography (column: Redisep Gold, C18 SiO2; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford 21 as a pale-brown gum. Yield: 0.9 g (63%)

[0587] LC-MS: Calculated for C32H37N2O8P is 608.2, observed: 609.6 [M+H]+

[0588] Step 18:

[0589] To a stirred solution of 21 (0.9 g, 1.5 mmol) in MeOH (15 mL), was added 1,3- dimethylbarbituric acid (0.462 g, 2.96 mmol) and tetrakis(triphenylphosphine) palladium (0) (0.085 g, 0.074 mmol) at 0 °C and the reaction mixture stirred at room temperature for 3 h. The volatileswere evaporated under reduced pressure and the resulting residue triturated with EtOAc (50 mL). The supernatant solvent was decanted and the resulting crude, thus obtained was purified by reverse phase column chromatography (column: Redisep Gold, Cl 8 SiO2; 10 mM ammonium bicarbonate in water and ACN) to afford 260 mg of product. The resulting product was passed through RP- MPLC (column: Redisep Gold, Cl 8 SiO2; water and ACN) to afford Compound 54 as an off-white solid. Yield: 230 mg (29%)[°059°l LC-MS: Calculated for C26H29N2O8P is 528.2, observed: 529.4 [M+H]+

[0591] 'H-NMR (400 MHz, DMSO-d6): δ 7.65-7.63 (m, 4H), 7.52 (d, J = 8.0 Hz, 2H), 7.43 (s, 1H), 7.07 (d, J = 8.8 Hz, 2H), 6.93 (s, 1H), 5.82 (t, J = 6.8 Hz, 1H), 4.94 (q, J = 4.6 Hz, 1H), 4.71 (d, J = 3.6 Hz, 1H), 4.23 (d, J = 3.2 Hz, 1H), 4.07 (dd, J = 4.0 Hz, 10.2 Hz, 1H), 3.93-3.87 (m, 3H), 3.79 (d, J = 10.0 Hz, 1H), 3.60 (dd, J = 1.6, 9.2 Hz, 1H), 2.45-2.39 (m, 1H), 2.29-2.24 (m, 1H), 1.50 (d, J = 6.4 Hz, 3H). Four exchangeable protons not seen in 1HNMR.

[0592] 31P-NMR (162 MHz, DMSO-d6): δ -1.181

[0593] SFC: 100%; tR = 1.76 min (column: I Cellulose J; eluents: CO2and 0.5% isopropyl amine in MeOH).

[0594] Note: Hygroscopic in nature. SFC purity 100% and unknown stereochemistry in tail part.Example 41: Synthesis of Compound 52

[0595] Step l:

[0596] To a stirred solution of 2 (2.0 g, 4.77 mmol) and 1 (3.02 g, 7.15 mmol) in a mixture of THF (50 mL) and water (5 mL), was added potassium phosphate tribasic (3.04 g, 14.31 mmol) and the reaction mixture purged with nitrogen for 5 min. Then, SPhos Pd G2 (0.344 g, 0.477 mmol) was added, and the reaction mixture stirred at 80 °C for 2 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over anhydrous sodium sulphate, fdtered, and concentrated under reduced pressure. The crude mass, thus obtained, was purified by using MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 1% MeOH in DCM) to get 3 as a brown solid. Yield: 2.2 g (66%)

[0597] LCMS: Calculated for C35H42N2O7S is 634.27, observed: 635.2 [M+H]+

[0598] Step 2:

[0599] To a solution of 3 (2.0 g, 3.15 mmol) in DCM (30 mL), were added? / , N- diallyl diisopropylphosphoramidite (4, 2.498 mL, 9.45 mmol) and IH-tetrazole (0.772 g, 11.03 mmol) at room temperature and the resulting mixture stirred at same temperature for 5 h. The reaction mixture was cooled to 0 °C, 30% hydrogen peroxide in water (1.725 mL, 22.05 mmol) added and the resulting mixture stirred at room temperature for 22 h. The reaction mixture was quenched with saturated sodium thiosulphate solution (30 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was washed with saturated sodium bicarbonate solution (20 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 4% MeOH in DCM) to get 5 as a pale-yellow gum. Yield: 1.8 g (67%)

[0600] LC-MS: Calculated for C41H51N2O10PS is 794.30, observed: 795.2 [M+H]+

[0601] Step 3:

[0602] To a stirred solution of 5 (1.7 g, 2.139 mmol) in MeOH (20 mL), was added p- toluenesulfonic acid monohydrate (1.424 g, 7.49 mmol) at 0 °Cand the reaction mixture stirred at room temperature for 16 h. The reaction mixture was cooled to 0 °C, quenched with saturated sodium bicarbonate solution (20 mL) and extracted with 10% MeOH in DCM (2x 50 mL). The combined organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude mass, thus obtained, was purified by using RP-MPLC (column: Redisep Gold, Cl 8 SiO2; eluents: 10 mM ammonium bicarbonate in water and ACN) to obtain 6 as an off-white solid. Yield: 1.0 g (69%)

[0603] LCMS: Calculated for C31H35N2O8PS is 626.19, observed: 627.1 [M+H]+

[0604] Step 4:

[0605] To a stirred solution of 6 (1.0 g, 1.596 mmol) in MeOH (10 mL), were added 1,3- dimethylbarbituric acid (0.498 g, 3.19 mmol) and Pd(PPhs)4 (0.092 g, 0.080 mmol) and the reaction mixture stirred at room temperature for 5 h. The reaction mixture was concentrated under reduced pressure. The crude mass, thus obtained, was triturated with EtOAc (10 mL), and the obtainedresidue further purified by using RP-MPLC (column: Redisep Gold, C18 SiO2; eluents: 10 mM ammonium bicarbonate in water and ACN) to obtain Compound 52 (mixture of diastereomers) as an off-white solid. Yield: 500 mg (57%)

[0606] LCMS: Calculated for C25H27N2O8PS is 546.12, observed: 547.1 [M+H]+

[0607] 1H-NMR (400 MHz, DMSO-d6) for major isomer: 8 7.68-7.64 (m, 4H), 7.53 (d, J = 8.4 Hz, 2H), 7.39 (s, 1H), 7.17-7.06 (m, 4H, two protons exchanges with D2O), 6.92 (s, 1H), 5.99 (t, J = 6.0 Hz, 1H), 5.25-5.24 (m, 1H), 4.97-4.93 (m, 1H), 4.54-4.52 (m, 1H), 4.18-4.11 (m, 2H), 3.65 (dd, J = 13.8, 3.6 Hz, 1H), 3.51 (dd, J = 8.8, 5.6 Hz, 1H), 3.18 (dd, J = 13.6, 4.4 Hz, 1H), 2.73-2.68 (m, 1H), 1.48 (d, J = 6.4 Hz, 3H). Two exchangeable protons not seen in NMR

[0608] 31P-NMR (162 MHz, DMSO-d6): δ -0.548

[0609] SFC: 100%; tR = 2.59 min (column: CHIRALPAK IJ; elunets: CO2and 0.5% isopropyl amine in CAN and MeOH)Example 42: Synthesis of Compound 51

[0610] Step 7:

[0611] To a stirred solution of 11 (5 g, 16.28 mmol) in DCM (50 mL), was added Boc anhydride (4.86 mL, 21.16 mmol) and the reaction mixture stirred at 50 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC(manually packed SiO2 cartridge, 230-400 mesh size; 4% MeOH in DCM) to get 12 as a white solid. Yield: 5.8 g (87%)

[0612] LC-MS: Calculated for Ci9H23BrN2O3 is 406.09, observed: 307.0 [(M-Boc)+H]+and 309.2 [((M+2)-Boc)+H]+

[0613] Step 8:

[0614] To a stirred solution of 12 (5.8 g, 12.82 mmol) in 1,4-di oxane (60 mL), were added bis(pinacolato)diboron (4.23 g, 16.66 mmol) and potassium acetate (3.77 g, 38.4 mmol), and the mixture degassed with nitrogen for 5 min. Then, PdC12(dppf) (0.938 g, 1.282 mmol) was added, and the reaction mixture stirred at 90 °C for 7 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (100 mL), and filtered through a pad of Celite. The Celite bed was washed with EtOAc (300 mL) and the filtrate combined and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 13% EtOAc in hexanes) to get 13 as a white solid.

[0615] Yield: 5.7 g (95%). LCMS: Calculated for C25H35BN2O5is 454.3, observed: 355.2 [(M- Boc)+H]+

[0616] Step 9:

[0617] To a stirred solution of 14 (1 g, 2.385 mmol) and boronate 13 (1.300 g, 2.86 mmol) in a mixture of THF (15 mL) and water (5 mL), was added potassium phosphate tribasic (1.519 g, 7.15 mmol), and the mixture degassed using nitrogen for 5 min. Then, SPhos Pd G2 (0.172 g, 0.238 mmol) was added, and the reaction mixture stirred at 80 °C for 4 h. The reaction mixture was quenched with water (60 mL). This was extracted with 10% MeOH in DCM (2 x 50 mL). The combined organic layer was washed with brine (40 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to get 1.3 g of crude product.

[0618] Another batch was carried out using 3.3 g of 14.

[0619] The crude product of both batches was mixed and purified by using MPLC (manually packed SiO2 cartridge, 230-400 mesh size; 5% MeOH in DCM) to get 15 as a yellow solid.

[0620] Yield: 5 g (combined yield for both batches)

[0621] LC-MS: Calculated for C39H46N4O6 is 666.34, observed: 667.6 [M+H]+

[0622] Step 10:

[0623] To a solution of 15 (2 g, 2.55 mmol) in DCM (25 mL), were added diallyl N,N- diisopropylphosphoramidite (16, 1.224 mL, 4.59 mmol) and IH-tetrazole (0.357 g, 5.10 mmol) at room temperature, and the resulting mixture stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C, and 30% hydrogen peroxide in water (0.997 mL, 12.75 mmol) was added. The resulting mixture was stirred at room temperature for 30 min. The reaction mixture was quenched with saturated sodium thiosulphate solution (15 mL). This was extracted with DCM (3 x 40 mL). The combined organic layer was washed with 10% NaHCCE solution (2 x 10 mL), driedover anhydrous Na2SC>4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed SiO2 cartridge, 230-400 mesh size; 4% MeOH in DCM) to get 17 as a light-yellow gum.

[0624] LCMS: Calculated for C45H55N4O9P is 826.37, observed: 827.2 [M+H]+

[0625] Step 11:

[0626] To a stirred solution of 17 (2.2 g, 2.66 mmol) in 2-2-2, trifluoroethanol (20 mL), was added trimethylsilyl chloride (0.680 mL, 5.32 mmol) at 0 °C and the reaction mixture stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure. The crude residue, thus obtained, was purified by using RP-MPLC (column: RediSep Gold; Cl 8 silica gel; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford a mixture of 18a and 18b as a brown gum. Yield: 1.1 g (51%)1006271LCMS: Calculated for 18a C35H39N4O6P is 642.26, observed: 643.2 [M+H]+

[0628] LCMS: Calculated for 18b C32H35N4O6P is 602.23, observed: 603.2 [M+H]+

[0629] Step 12:

[0630] To a stirred solution of a mixture of 18a and 18b (0.6 g, 0.934 mmol) in MeOH (10 mL), were added 1,3 -dimethylbarbituric acid (0.292 g, 1.867 mmol) and Pd(PPhs)4 (0.054 g, 0.047 mmol), and the reaction mixture stirred at room temperature for 4 h. The reaction mixture was concentrated under reduced pressure to get 800 mg of crude product.

[0631] Another two batches were carried out using 240 mg of 18a and 18b.

[0632] The crude product of three batches were mixed and purified by using RP-MPLC (column: RediSep Gold; C18 silica gel; eluents:10 mM ammonium bicarbonate in water and ACN) to obtain Compound 51 as a pale-yellow solid

[0633] Yield: 230 mg (combined yield for three batches)

[0634] LCMS: Calculated for C29H31N4O6P is 562.20, observed: 563.3 [M+H]+

[0635] 1H-NMR (400 MHz, DMSO-d6): 5 8.43 (s, 1H), 8.19 (s, 1H), 7.58-7.54 (m, 4H), 7.43- 7.38 (m, 4H), 7.30 (d, J = 0.80 Hz, 1H), 6.84 (s, 1H), 5.98 (t, J = 6.40 Hz, 1H), 4.92 (q, J = 6.40 Hz, 1H), 4.19-4.14 (m, 1H), 4.11-4.03 (m, 1H), 3.86 (s, 2H), 3.53-3.50 (m, 1H), 3.21-3.16 (m, 1H), 2.61- 2.56 (m, 2H), 2.21-2.16 (m, 2H), 1.48 (d, J = 6.40 Hz, 3H). Four exchangeable protons not seen.

[0636] 31P-NMR (162 MHz, DMSO-d6): 5 -0.287

[0637] SFC: 100%; tR = 2.98 min (column: I Amylose- A; eluents: CO2and 0.5% isopropyl amine in ACN and MeOH)

[0638] Note: Single isomer with 100% SFC purity. Four exchangeable protons were not seen in NMR. cis-geometry in tail part.Example 43: Synthesis of Compound 50

[0639] Step-1:

[0640] To a stirred solution of 1 -bromo-4-iodobenzene (2, 20 g, 70.7 mmol), 1-Boc-azeti din-3 -ol (1, 13.47 g, 78 mmol) in toluene (100 mL) was added cesium carbonate (46.1 g, 141 mmol), 3, 4,7,8- tetramethyl- 1,10-phenanthroline (1.671 g, 7.07 mmol) and degassed with nitrogen for 5 min. To this reaction mixture, copper (I) iodide (0.673 g, 3.53 mmol) was added and the resulting reaction mixture stirred at for 110 °C for 16 h. The reaction mixture was cooled to room temperature and fdtered through a Celite pad. The Celite pad was washed with EtOAc (100 mL) and the combined fdtrate concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiCL cartridge, 100-200 mesh size; 15% EtOAc in hexanes) to afford 3 as a white solid. Yield = 19 g (69%)

[0641] Step-2:

[0642] To a stirred solution of 3 (19 g, 57.9 mmol) in DCM (100 mL), were added HC1 (4 M in dioxane, 72.4 mL, 289 mmol) at 0 °C and the resulting reaction mixture stirred at room temperature for 3 h. The volatiles were evaporated under reduced pressure, the crude obtained was dissolved in 20% isopropanol in chloroform (100 mL) and washed with 10% sodium bicarbonate solution (50 mL). The combined organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford 4 as an off-white solid. Yield = 13 g (82%)

[0643] LC-MS: Calculated for C9Hi0BrNO is 226.99, observed: 227.9 [M+H]+and 229.9 [(M+2)+H]+

[0644] Step-3:

[0645] To a solution of (R)-(2,2-dimethyl-l,3-dioxolan-4-yl)methanol (5, 10 g, 76 mmol) in DCM (50 mL), were added tosyl chloride (17.3 g, 91 mmol), triethylamine (31.6 mL, 227 mmol) and DMAP (1.84 g, 15.13 mmol) at 0 °C and the resulting reaction mixture stirred at room temperature for 16 h. The reaction mixture was quenched water (25 mL) and extracted with DCM (3 x 50 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous ISfeSCL, filtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiCL cartridge, 100-200 mesh size; 50% EtOAc in hexanes) to afford tosylate 6 as a yellow liquid. Yield = 19 g (75%)

[0646] Step-4:

[0647] To a stirred solution of 4 (13 g, 57.0 mmol) in DMF (100 mL), were added 6 (17.9 g, 62.7 mmol) and potassium carbonate (19.6 g, 142 mmol) at 0 °C and the resulting reaction mixture stirred at 80 °C for 16 h. The reaction was quenched with ice cold water (25 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 10% MeOH in DCM) to afford 7 as a yellow liquid. Yield = 13 g (48%)

[0648] Step-5:

[0649] To as solution of 7 (13 g, 38.0 mmol) in 1,4-dioxane (100 mL), were added potassium acetate (11.18 g, 114 mmol) and bis(pinacolato)diboron (14.47 g, 57.0 mmol) at room temperature and the resulting reaction mixture degassed with nitrogen for 5 min. To this reaction mixture, PdC12(dppf).CH2C12 adduct (3.1 g, 3.80 mmol) was added and degassing continued for 2 min. The resulting reaction mixture was stirred at 100 °C for 16 h. The reaction was filtered through a Celite pad and the Celite pad washed with EtOAc (100 mL). The combined filtrate was concentrated under reduced pressure. To the resulting crude residue, water (50 mL) was added and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine solution (15 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 230-400 mesh size; 8% MeOH in DCM) to afford boronate 8 as a brown gum. Yield = 10 g (53%)

[0650] Step-6:

[0651] To a solution of 9 (1.0 g, 2.38 mmol) in THF (10 mL) and water (2 mL), were added boronate 8 (1.4 g, 3.58 mmol) and potassium phosphate tribasic (1.26 g, 5.96 mmol) at room temperature and the resulting mixture degassed with nitrogen for 5 min. To this reaction mixture, SPhos Pd G2 (0.172 g, 0.23 mmol) was added and the reaction mixture irradiated in a microwavereactor at 80 °C for 2 h. The reaction mixture was quenched water (10 mL) and extracted with 10% MeOH in DCM (2 x 25 mL). The combined organic layer was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to get the crude product.

[0652] Three more batches were done using 1 g of 9 to give the crude product. All the batches were mixed and purified together.

[0653] The crude residue, thus obtained, from all the batches was purified by MPLC (manually packed SiCL cartridge, 100-200 mesh size; 8% MeOH in DCM) to afford 10 as a brown solid.

[0654] Yield = 1.4 g (combined yield for four batches)

[0655] Step-7:

[0656] To a solution of 10 (1.4 g, 2.32 mmol) in acetonitrile (20 mL), were added pyridine (0.565 mL, 6.98 mmol) followed by phosphoryl trichloride (0.434 mL, 4.65 mmol) at 0 °C and the reaction mixture stirred at the room temperature for 30 min. Then, to the reaction mixture water (8 mL) was added in dropwise manner at 0 °C and the reaction mixture stirred at room temperature for 40 min. The volatiles were evaporated under reduced pressure (at 35 °C) to afford crude product. The resulting crude was purified by RP-MPLC (column: RediSep Gold, Cl 8 silica; eluents: 10 mM ammonium bicarbonate in water and acetonitrile). The obtained product was re-purified RP-HPLC (column: Xtimate C18 (19 x 250) mm, 5 pm; eluents: 10 mM ammonium bicarbonate in water and acetonitrile) to afford Compound 50 as a white solid. Yield: 290 mg (22%) l°0657l LC-MS: Calculated for C27H33N3O8P+is 558.20, observed: 558.2 [M+H]+

[0658] 1H-NMR (400 MHz, DMSO-d6): δ 7.59-7.56 (m, 4H), 7.48 (d, J = 8.40 Hz, 2H), 7.35 (d, J = 0.80 Hz, 1H), 6.90 (d, J = 8.80 Hz, 2H), 6.87 (d, J = 0.80 Hz, 1H), 5.99 (t, J = 6.40 Hz, 1H), 4.96- 4.91 (m, 2H), 4.18-4.09 (m, 4H), 3.54-3.60 (m, 1H), 3.49-3.50 (m, 2H), 3.36-3.29 (m, 2H), 2.89 (d, J = 9.20 Hz, 1H), 2.72-2.67 (m, 1H), 1.48 (d, J = 6.40 Hz, 3H). Exchangeable protons not seen in NMR.

[0659] 31P-NMR (162 MHz, DMSO-d6): δ -0.081

[0660] SFC: 100%; tR= 1.55 min (column: I-AMYLOSE-A; eluents: CO2and 0.5% isopropyl amine in MeOH).

[0661] Note: Hygroscopic in nature. The product was shipped as HC1 salt. Single compound with SFC purity 100%; (R)-isomer in the tail.Example 44: Synthesis of Compound 49

[0662] Note: For synthesis of 10, please refer the synthetic procedure of Compound 50.

[0663] Step-1:

[0664] To a solution of 10 (0.7 g, 1.163 mmol) in acetonitrile (14 mL), were added pyridine (0.28 mL, 3.49 mmol) followed by phosphoryl trichloride (0.22 mL, 2.327 mmol) at 0 °C. After addition, the reaction mixture was stirred at room temperature for 30 min. To the reaction mixture, water (8 mL) was added in dropwise manner at 0 °C and the reaction mixture stirred at room temperature for 40 min. The volatiles were evaporated under reduced pressure (at 35 °C) to afford crude product. The resulting crude, thus obtained, was purified by RP-MPLC (column: RediSep Gold, Cl 8 SiO2; eluents: 10 mM ammonium bicarbonate in water and acetonitrile) to afford Compound 49 as a white solid. Yield: 160 mg

[0665] LC-MS: Calculated for C27H33N3O8P+is 558.20, observed: 558.2 [M+H]+

[0666] 1H-NMR (400 MHz, DMSO-d6): δ 7.59-7.55 (m, 4H), 7.48 (d, J = 8.40 Hz, 2H), 7.35 (d, J = 1.20 Hz, 1H), 6.90 (d, J = 8.80 Hz, 2H), 6.87 (d, J = 0.80 Hz, 1H), 5.99 (t, J = 6.40 Hz, 1H), 4.96- 4.92 (m, 2H), 4.21-4.07 (m, 4H), 3.69-3.53 (m, 4H), 3.36-3.28 (m, 2H), 2.92 (d, J = 9.60 Hz, 1H), 2.75-2.51 (m, 1H), 1.49 (d, J = 6.40 Hz, 3H). Exchangeable protons not seen in 1HNMR.

[0667] 31P-NMR (162 MHz, DMSO-d6): δ -0.090

[0668] SFC: 100%; tR= 1.92 min (column: EP-1; eluents: CO2and 0.5% isopropyl amine in MeOH)

[0669] Note: Hygroscopic in nature. Based on the downfield shift in 1H NMR for tail part protons, the product was shipped as HC1 salt. Single compound with SFC purity 100%; (S)-isomer in the tail.Example 45: Synthesis of Compound 64Step 8

[0670] Step l:

[0671] To a cooled solution of 3-(4-bromophenyl)cyclobutan-l-one (1, 8 g, 35.5 mmol) in MeOH (100 mL), was added NaBH4 (0.672 g, 17.77 mmol) in portions at 0 °C. After the complete addition, the resulting reaction mixture was allowed to room temperature and stirred for 2 h. The reaction was cooled to 0 °C and quenched with sat. NH4CI solution (20 mL). The reaction mixture was evaporated to remove methanol and extracted with EtOAc (250 mL x 2). The combined organic extract was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to afford crude as a pale-yellow liquid, which was purified by MPLC (manually packed cartridge; SiO2 230- 400 mesh size; 20% EtOAc in hexanes) to get 2 as a yellow solid.

[0672] Yield: 6 g (72%)

[0673] Step 2:

[0674] To a cooled solution of 2 (6 g, 25.6 mmol) in THF (100 mL), were added 4-nitrobenzoic acid (3, 4.71 g, 28.2 mmol), triphenylphosphine (8.07 g, 30.8 mmol) and DIAD (5.41 mL, 30.8 mmol) at 0 °C. The resulting reaction mixture was allowed to warm to room temperature and stirred for 16 h. The reaction mixture was quenched with water (40 mL) and extracted with EtOAc (100 mL x 2). The combined organic extract was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a crude residue, which waspurified by MPLC (manually packed cartridge; SiO2 230-400 mesh size; 10% EtOAc in hexanes) to get 4 as a white solid. Yield: 6.5 g (60%).

[0675] LC-MS: Calculated for C17H14BrNO4 is 376.21, Observed: 376.8 [M]’ and 374.8 [M-2]’

[0676] Step 3:

[0677] To a solution of 4 (6.5 g, 15.55 mmol) in a mixture of THF (10 mL), water (2.5 mL) and MeOH (10 mL), was added lithium hydroxide monohydrate (1.958 g, 46.6 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 3 h. The reaction mixture was evaporated to remove volatiles. To the obtained residue, water (15 mL) was added and extracted with EtOAc (50 mL x 5). The combined organic extract was washed with brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford crude residue, which was purified by MPLC (manually packed cartridge; SiO2230-400 mesh size; 30% EtOAc in hexanes) to get 5 as a white solid. Yield: 3.0 g (68%)

[0678] Step-4:

[0679] The isomers (trans and cis) of 5 (7.2 g) were separated by chiral SFC (column: Lux A3 (250*30) mm, 5 pm; eluents: CO2: 0.5% isopropyl amine in MeOH [80:20]). The fractions were concentrated under reduced pressure to afford 5a as a pale-yellow solid. Yield = 5.0 g

[0680] Step 5:

[0681] To the stirred solution of sodium hydride (1.014 g, 21.14 mmol) in THF (30 mL), was added 5a (3 g, 10.57 mmol) at 0 °C and stirred for 10 min. Then, iodomethane (1.32 mL, 21.14 mmol) was added dropwise at 0 °C. After the complete addition, the resulting reaction mixture was warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with ice-cold water and sat. NH4CI solution (15 mL). This was extracted with EtOAc (30 mL x 3). The combined organic extract was washed with brine (15 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford a crude residue, which was purified by MPLC (manually packed cartridge; SiO2 230-400 mesh size; 20% EtOAc in hexanes) to get 6 as white solid. Yield: 2.5 g (78%)

[0682] Step 6:

[0683] To the stirred solution of 6 (2.5 g, 10.37 mmol) in 1,4-dioxane (15 mL), were added bis(pinacolato)diboron (3.42 g, 13.48 mmol) and KOAc (2.035 g, 20.74 mmol) at 0 °C. The reaction mixture was purged with nitrogen for 5 min. To this reaction mixture, PdCh(dppf) (0.759 g, 1.037 mmol) was added. The resulting reaction mixture was heated to 90 °C for 2 h. The reaction mixture was diluted with water (8 mL) and extracted with EtOAc (2 x 20 mL). The combined organic extract was washed with brine (8 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude residue, which was purified by MPLC (manually packed cartridge; SiO2 230-400 mesh size; 10% EtOAc in hexanes) to get 7 as a white solid. Yield: 2.2 g (73%)

[0684] Step 7:

[0685] To the stirred solution of 7 (0.973 g, 3.04 mmol) in MeCN (4 mL) and water (4 mL), were added K2CO3 (0.969 g, 7.01 mmol) and 8 (1.0 g, 2.337 mmol) at room temperature. The reaction mixture was purged with nitrogen for 2 min. To this reaction mixture, PdC12(dtbpf) (0.152 g, 0.234 mmol) was added. The resulting reaction mixture was heated to 80 °C and stirred for 16 h. The reaction mixture was diluted with ice-cold water (8 mL) and extracted with 5% MeOH in DCM (16 mL x 3). The combined organic extract was washed with brine (8 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford crude residue, which was purified by MPLC (manually packed cartridge; SiO2 230-400 mesh size; 5% MeOH in DCM) to get 9 as brown sticky solid. Yield: 405 mg (32%)[°0686l LC MS: Calculated for C31H36N2O4 is 500.27, Observed: 501.2 [M+l]+

[0687] Step-8:

[0688] To a solution of 9 (1.5 g, 3.0 mmol) in acetonitrile (10 mL), were added pyridine (0.73 mL, 8.99 mmol) and phosphoryl trichloride (0.56 mL, 5.99 mmol) at 0 °C and the resulting reaction mixture stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C after which water (5 mL) was added dropwise and stirred at room temperature for 15 min. The volatiles were removed under reduced pressure. The crude residue, thus obtained, was purified by reversed phase column chromatography (column: Redisep Gold, C-18 silica gel; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 64 as a white solid. Yield: 285 mg (61%) l°0689l LCMS: Calculated for C26H29N2O6P is 496.18, observed: 497.2 [M+H]+

[0690] 1H-NMR (400 MHz, DMSO-d6): δ 7.68 (d, J = 8.40 Hz, 2H), 7.63 (d, J = 8.40 Hz, 2H), 7.55 (d, J = 8.40 Hz, 2H), 7.42 (s, 1H), 7.36 (d, J = 8.40 Hz, 2H), 7.16 (bs, 1H, exchangeable with D2O), 6.95 (s, 1H), 6.00 (t, J = 6.0 Hz, 1H), 4.99-4.97 (m, 1H), 4.21-4.13 (m, 2H), 4.09 -4.03 (m, 1H), 3.61-3.53 (m, 1H), 3.18 (s, 3H), 2.41-2.30 (m, 4H), 1.49 (d, J = 6.40 Hz, 3H). Two exchangeable protons not seen.

[0691] 31P-NMR (162 MHz, DMSO-d6): δ -0.611

[0692] SFC: 100%; tR = 1.82 min (column: I Amylose-A; eluents: CO2and 0.5% isopropyl amine in ACN and MeOH)

[0693] Note: trans-geometry in tail part; mixture of diastereomers. SFC purity = 100%; Two exchangeable protons not seen in NMR.Example 46: Synthesis of Compound 66

[0694] Step l:

[0695] To a stirred solution of (R)-3 -aminopropane- 1,2-diol (1, 5 g, 54.9 mmol) in water (60 mL), were added sodium bicarbonate (16.14 g, 192 mmol), and triphosgene (8.14 g, 27.4 mmol) portion wise, and stirred at room temperature for 16 h. The reaction mixture was neutralized with 1.5 N HC1 (15 mL) at 0 °C and concentrated under reduced pressure. The obtained solid was diluted with EtOH (100 mL) and fdtered through Buchner funnel, the solid washed with EtOH (100 mL). The combined filtrate was concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge; 230-400 mesh size; 10% MeOH in DCM) to get 2 as a colorless gum. Yield: 4.5 g (61%)

[0696] LC-MS: Calculated for C4H7NO3 is 117.04, observed: 118.1 [M+H]+

[0697] Step 2:

[0698] To a stirred solution of 2 (2 g, 17.08 mmol) in DCM (30 mL), were added TEA (7.14 mL, 51.2 mmol), DMAP (0.417 g, 3.42 mmol), and tosyl chloride (3.58 g, 18.79 mmol) at 0 °C and allowed to stir at room temperature for 18 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (50 mL x 3). The combined organic extract was washed with brine (40 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiCL cartridge; 100-200 mesh size; 5% MeOH in DCM) to afford 3 as a colorless gum. Yield: 0.65 g (13%)[°06"] LC-MS: Calculated for C11H13NO5S is 271.05, observed: 272.2 [M+H]+

[0700] Step-3:

[0701] To a solution of 4-bromophenol (4, 3.5 g, 20.23 mmol) in DMF (50 mL), were added tosylate 3 (6.6 g, 24.28 mmol) and cesium carbonate (19.77 g, 60.7 mmol) at room temperature and the resulting reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (2 x 80 mL). The combined organic layer was washed with brine solution (50 mL), dried over anhydrous ISfeSCL, fdtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 80% EtOAc in hexanes) to afford 5 as a white solid.

[0702] Yield: 2.8 g (49%)

[0703] LC-MS: Calculated for C10HioBrN03is 270.98, observed: 271.8 [M+H]+and 273.8 [(M+2)+H]+

[0704] Step-4:

[0705] To a solution of 5 (3 g, 11.03 mmol) in 1,4-dioxane (50 mL), were added potassium acetate (3.25 g, 33.1 mmol) and bis(pinacolato)diboron (3.64 g, 14.33 mmol) at room temperature and the reaction mixture degassed with nitrogen for 5 min. To this reaction mixture, PdC12(dppf) (0.48 g, 0.66 mmol) was added and the resulting reaction mixture stirred at 100 °C for 16 h. The reaction mixture was filtered through a pad of Celite. The Celite pad was washed with EtOAc (50 mL), the filtrate combined and concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 90% EtOAc in hexanes) to afford 6 as a pale-brown gum. Yield = 2.7 g (70%)

[0706] LC-MS: Calculated for C16H22BNO5 is 319.16, observed: 318.0 [M-H]’

[0707] Step-5:

[0708] To a stirred solution of 7 (1.5 g, 3.58 mmol) in THF (6 mL) and water (2 mL), were added boronate 6 (1.49 g, 3.65 mmol) and potassium phosphate tribasic (2.28 g, 10.73 mmol) at room temperature and the resulting mixture degassed with nitrogen for 10 min. To this reaction mixture, SPhos Pd G2 (0.26 g, 0.36 mmol) was added and the resulting reaction mixture irradiated in a micro wave reactor at 80 °C for 2 h. The reaction mixture was quenched with water (30 mL), extracted with 10% MeOH in DCM (2 x 50 mL). The combined organic layer was dried over anhydrous ISfeSCL, filtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 6% MeOH in DCM) to afford 8 as a pale-brown solid. Yield: 1.2 g (62%)

[0709] LC-MS: Calculated for C30H33N3O6 is 531.24, observed: 532.1 [M+H]+

[0710] Step-6:

[0711] To a stirred solution of 8 (1.2 g, 2.26 mmol) in DCM (20 mL), were added diallyl N, N- diisopropylphosphoramidite (9, 0.9 mL, 3.39 mmol) and IH-tetrazole (0.31 g, 4.51 mmol) at room temperature and the resulting mixture stirred at room temperature for 3 h. The reaction mixture was cooled to 0 °C, hydrogen peroxide (30% in water; 1.15 mL, 11.29 mmol) was added and theresulting reaction mixture stirred at room temperature for 30 min. The reaction was quenched with 10% NaHCCh solution (60 mL) and extracted with DCM (2 x 80 mL). The combined organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SC>4, fdtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 6% MeOH in DCM) to afford 10 as a pale-brown gum.

[0712] Yield: 1.2 g (69%). LCMS: Calculated for C36H42N3O9P is 691.27, observed: 692.6 [M+H]+

[0713] Step-7:

[0714] To a solution of 10 (1.5 g, 1.73 mmol) in MeOH (20 mL), was added p-toluenesulfonic acid monohydrate (0.99 g, 5.2 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with DCM (80 mL), washed with saturated NaHCO? solution (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 11 as a pale-brown gum. Yield: 900 mg (76%)

[0715] LCMS: Calculated for C31H34N3O8P is 607.21, observed: 608.0 [M+H]+

[0716] Step-8:

[0717] To a solution of 11 (0.9 g, 1.48 mmol) in MeOH (10 mL), were added 1,3- dimethylbarbituric acid (0.23 g, 1.48 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.068 g, 0.06 mmol) at 0 °C and the resulting reaction mixture stirred at room temperature for 3 h. The reaction mixture was filtered through a pad of Celite and the Celite pad washed with MeOH (10 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude residue was triturated with EtOAc (80 mL), the supernatant layer was decanted. The solid residue, thus obtained, was purified by reverse phase column chromatography using MPLC (column: Redisep Gold, Cl 8 SiO2; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 66 as a white solid. Yield: 290 mg (37%)

[0718] LCMS: Calculated for C25H26N3O8P is 527.15, observed: 528.1 [M+H]+

[0719] 'H-NMR (400 MHz, DMSO-d6): 7.68-7.65 (m, 4H), 7.61 (s, 1H, exchanges with D2O), 7.54 (d, J = 8.4 Hz, 2H), 7.51 (d, J = 1.2 Hz, 1H), 7.10-7.05 (m, 4H, one proton exchanges with D2O), 6.01 (t, J =5.6 Hz, 1H), 5.06-5.01 (m, 1H), 4.96-4.91 (m, 1H), 4.25-4.19 (m, 4H), 3.63 (t, J = 8.8 Hz, 1H), 3.39-3.34 (m, 1H), 1.5 (d, J = 6.4 Hz, 3H). Two exchangeable protons not seen.

[0720] 31P-NMR (162 MHz, DMSO-d6): 5 - 0.648

[0721] SFC: 100%; tR = 1.25 min (column: Chiralpak-AS-H; eluents: CO2and 0.5% isopropyl amine in MeOH)Example 47: Synthesis of Compound 65

[0722] Step-1:

[0723] To a solution of 1 (1 g, 1.77 mmol) in DCM (10 mL), were added diallyl N, N- diisopropylphosphoramidite (2, 0.7 mL, 2.66 mmol) and IH-tetrazole (0.37 g, 5.23 mmol) at room temperature, and the resulting mixture stirred at room temperature for 1 h. After the reaction was cooled to 0 °C, hydrogen peroxide (30% in water; 0.9 mL, 8.87 mmol) was added and the resulting reaction mixture stirred at room temperature for 1 h. The reaction was quenched with 10% NaHCO3 solution (20 mL) and extracted with DCM (50 mL x 2). The combined organic layer was dried over anhydrous ISfeSCL, concentrated under reduced pressure.

[0724] One more batch was carried out on 1 g of 1 to get the crude product.

[0725] Both batches were mixed and purified by reverse phase column chromatography (column: Redisep Gold, Cl 8 SiO2 gel; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford 3 as a pale-brown solid. Yield: 1.8 g (corresponds to two batches). Yield: 0.85 g (49%)

[0726] LCMS: Calculated for C37H46N3O8PS is 723.27, observed: 724.1 [M+H]+

[0727] Step-2:

[0728] To a solution of 3 (1.8 g, 2.487 mmol) in MeOH (10 mL), was added p-toluenesulfonic acid monohydrate (1.41 g, 7.46 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (50 mL), washed with 10% NaHCO3 solution (20 mL). The organic layer was dried over anhydrous ISfeSCL, filtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by column

[0729] chromatography (column: Redisep Gold, C18 reverse phase SiO2; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford 4 as pale-brown solid. Yield: 1.3 g (78%)

[0730] LCMS: Calculated for C32H38N3O7PS is 639.22, observed: 640.1 [M+H]+

[0731] Step-3:

[0732] To a solution of 4 (1.1 g, 1.72 mmol) in MeOH (10 mL), were added 1,3- dimethylbarbituric acid (0.6 mL, 3.44 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.1 g, 0.086 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature for 2 h. The volatiles were removed under reduced pressure. The crude residue, thus obtained, was purified by reverse phase column chromatography (column: Redisep Gold, Cl 8 reverse phase SiO2; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 65 as white solid. Yield: 470 mg (49%)

[0733] LCMS: Calculated for C26H30N3O7PS is 559.15, observed: 560.1 [M+H]+

[0734] 1H-NMR (400 MHz, DMSO-d6): 5 7.70-7.64 (m, 4H), 7.57-7.55 (m, 3H), 7.41-7.39 (m, 3H), 7.17 (br s, 2H, exchangeable with D2O), 6.93 (s, 1H), 5.99 (t, J = 6.40 Hz, 1H), 4.98-4.95 (m, 1H), 4.19-4.11 (m, 2H), 4.0 -3.94 (m, 1H), 3.57 -3.50 (m, 1H), 2.88 (s, 3H), 2.51-2.46 (m, 4H), 1.49 (d, J = 6.80 Hz, 3H). One exchangeable proton not seen.

[0735] 31P-NMR (162 MHz, DMSO-d6): 5 -0.443

[0736] SFC: 100%; tR = 1.40 min (column: I-Amylose-A; eluents: CO2and 0.5% isopropyl amine in MeOH). Note: Mixture of diastereomers; trans-geometry in tail part. SFC purity = 100%.Example 101: Synthesis of Compounds 101 and 1027-lsomer-17-lsomer-2 Compound 102

[0737] Both the isomers (3-Isomer-l (tR = 3.0 min) and 3-Isomer-2 (tR = 4.7 min) were taken independently for further conversion. The synthesis of Compound 1 was carried out using 3- Isomer-1 (tR = 3.0 min).

[0738] Step 3:

[0739] To a stirred solution of 3_Isomer_l (8.7 g, 35.8 mmol) in DCM (90 mL), were added 3,4- dihydro-2H-pyran (6.53 mL, 71.6 mmol) and PPTS (1.349 g, 5.37 mmol) at 0 °C, and the reaction mixture stirred at 25 °C for 8 h. The reaction mixture was quenched with 10% NaHCO? (200 mL) and extracted with 20% MeOH in DCM (50 mL x 2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure to afford 4_Isomer_l as a pale-yellow liquid. Yield: 11.7 g (91%). LC-MS: Calculated for CisHigBrChis 327.22, Observed: No desired product mass.

[0740] Step 4:

[0741] To a stirred solution of 4_Isomer_l (11.7 g, 35.8 mmol) in dioxane (250 mL), were added bis(pinacolato)diboron (13.62 g, 53.6 mmol) and potassium acetate (10.53 g, 107 mmol) at room temperature. The reaction mixture was degassed with nitrogen for 5 min, following which PdC12(dppf) (1.308 g, 1.788 mmol) was added. The mixture was degassed with nitrogen for 2 min and then stirred at 100 °C for 16 h. The reaction mixture was quenched with water (300 mL) and extracted with EtOAc (150 mL x 2). The combined organic layer was washed with brine (150 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The crude residue was purified by MPLC (using manually packed SiCL cartridge, 230-400 mesh; 60% EtOAc in hexanes) to afford 5_Isomer_l as a brown solid. Yield: 7.9 g (58%) LC-MS: Calculated for C21H31BO5 is 374.28, Observed: No desired product mass.

[0742] Step 5:

[0743] To a stirred solution of 5_Isomer_l (2.398 g, 6.41 mmol), in acetonitrile (50 mL) and water (10 mL), were added 6 (2 g, 4.27 mmol) and K2CO3 (1.77 g, 12.81 mmol) at 25 °C. The reaction mixture was degassed for 5 min. To this reaction mixture, PdC12(dtbpf) (0.139 g, 0.214 mmol) was added. The mixture was again degassed with nitrogen for 2 min and then stirred at 80 °C for 16 h. The reaction mixture was quenched with water (100 mL) and extracted with 20 % MeOH in DCM (30 mL x 3). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue thus obtained, was purified by using MPLC (using manually packed SiO2 cartridge, 230-400 mesh; 3% MeOH in DCM) to afford 7_Isomer_l as a pale-yellow solid. Yield: 2 g (70%) LC-MS: Calculated for C35H44N2O6 IS 588.75, Observed: 589.5 [M+l]+

[0744] Step 6:

[0745] To a stirred solution of 7_Isomer_l (2 g, 3.40 mmol) in acetonitrile (20 mL), were added pyridine (0.823 mL, 10.19 mmol) and POCI3 (0.635 mL, 6.79 mmol) at 0 °C. The reaction mixturewas stirred at 25°C for 2 h. To this reaction mixture was added aq. HC1 (1.5 N, 25 mL) at 0 °C, and the reaction mixture maintained at 25°C for 30 min. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by reverse phase purification (Column : Redisep reverse phase C-18 silica gel; Eluents: 10 mM ammonium bicarbonate and acetonitrile) to obtain Compound 101 as a white solid. Yield: 220 mg (13%). UPLC-MS: Calculated for C25H29N2O7P is 500.48, Observed: 501.3 [M+l]+. 1H-NMR (400 MHz, DMSO-d6): δ 7.62 (app d, J = 8.00 Hz, 4H), 7.50 (d, J = 8.00 Hz, 2H), 7.34 (d, J = 8.40 Hz, 2H), 7.27 (app d, J = 0.80 Hz, 1H), 7.16 (br s, 2H, exchange with D2O), 6.85 (s, 1H), 6.56-6.45 (m, 2H), 5.55-5.54 (m, 1H), 4.89-4.86 (m, 1H), 4.27- 4.23 (m, 1H), 4.17 (dd, J = 7.60, 8.40 Hz, 1H), 4.17-3.97 (m, 3H), 3.75 (dd, J = 6.00, 8.60 Hz, 1H), 3.58 (dd, J = 4.00, 9.00 Hz, 1H), 3.25-3.22 (m, 1H), 1.47 (d, J = 6.40 Hz, 3H). (Two protons not observed) 31P-NMR (400 MHz, DMSO-d6): δ -0.698.

[0746] Note: Single isomer with SFC purity = 99.7% (LUX Amylose-l_0.5%IPAm in MeOH tR= 1.49 min)

[0747] Compound 102 was synthesized by using the same procedure as detailed above for Compound 102 (Step-3 to Step-6). UPLC-MS: Calculated for C25H29N2O7P is 500.48, Observed: 501.3 [M+l]+. 1H-NMR (400 MHz, DMSO-d6): δ 7.63 (app d, J = 8.40 Hz, 4H), 7.51 (d, J = 8.00 Hz, 2H), 7.34 (d, J = 8.40 Hz, 2H), 7.28 (app d, J = 0.80 Hz, 1H), 7.15 (br s, 2H, exchange with D2O), 6.86 (s, 1H), 6.56-6.47 (m, 2H), 5.62-5.58 (m, 1H), 5.34 (br s, 1H, exchange with D2O), 4.91-4.86 (m, 1H), 4.24-4.22 (m, 1H), 4.17-4.15 (m, 1H), 4.10-4.00 (m, 2H), 3.97 (dd, J = 5.60, 9.20 Hz, 1H), 3.75 (dd, J = 6.00, 8.60 Hz, 1H), 3.58 (dd, J = 3.60, 9.00 Hz, 1H), 3.25-3.20 (m, 1H), 1.47 (d, J = 6.40 Hz, 3H). (1 H not observed). 31P-NMR (400 MHz, DMSO-d6): δ -0.691.

[0748] Note: Single isomer with SFC purity 97.6% (CHIRALPAK-AS-H_0.5%IPAm in MeOH tR = 1.96 min)Example 102: Synthesis of Compounds 103 and 104Step-1

[0749] Step l:

[0750] To a solution of 1-Isomer-l (1 g, 1.87 mmol) in acetonitrile (10 mL), were added pyridine (0.43 mL, 5.30 mmol) and phosphoryl trichloride (0.45 mL, 5.61 mmol) at 0 °C. The resulting reaction mixture was stirred at the room temperature for 1 h. The reaction mixture was cooled to 0 °C, water (5 mL) was added drop wise and stirred at room temperature for 30 min. The volatiles were removed under reduced pressure. The crude residue was purified by reverse phase preparativeHPLC (Column: Shimpack-Cis (150*20 mm) 5 pm; Eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 103 as a white solid. SFC: ZR = 2.07 min. Yield: 220 mg (22%). LCMS: Calculated for C26H31N2O8P is 530.51; Observed: 531.2 [M+l]+. 1H-NMR (4OO MHz, DMSO-d6): δ 7.64 (d, J = 8.80 Hz, 2H), 7.61 (d, J = 8.40 Hz, 2H), 7.49 (d, J = 8.40 Hz, 2H), 7.31 (s, 1H), 7.11 (br s, 1H, exchanges with D2O), 7.06 (d, J = 8.80 Hz, 2H), 6.90 (s, 1H), 6.51 (s, 2H), 5.60 (app t, 1H), 4.94-4.88 (m, 2H), 4.13-4.00 (m, 4H), 3.95-3.91 (m, 1H), 3.78-3.74 (m, 2H), 3.35 (s, 3H, merges with solvent water), 1.50 (d, J = 6.40 Hz, 3H). 31P ( MHz, DMSO-d6): 8 -0.647

[0751] Note: Single isomer with unknown stereochemistry in tail part.

[0752] Step l:

[0753] To a solution of l-Isomer-2 (1 g, 1.87 mmol) in acetonitrile (10 mL), were added pyridine (0.43 mL, 5.30 mmol) and phosphoryl trichloride (0.45 mL, 5.61 mmol) at 0 °C. The resulting reaction mixture was stirred at the room temperature for 1 h. The reaction mixture was cooled to 0 °C, water (10 mL) was added drop wise and stirred at room temperature for 30 min. The volatiles were removed under reduced pressure. The crude residue was purified by reversed phase preparative HPLC (Column: YMC C is (250*20 mm) 5 pm; Eluents: 10 mM ammonium bicarbonate in water and ACN) to afford 80 mg of Compound 104 as a white solid. SFC: ZR = 2.60 min. LCMS: Calculated for C26H31N2O8P is 530.51; Observed: 531.0 [M+l]+. 1H-NMR (400 MHz, DMSO-d6): 8 7.63 (d, J = 8.80 Hz, 2H), 7.60 (d, J = 8.40 Hz, 2H), 7.49 (d, J = 8.40 Hz, 2H), 7.36 (s, 1H), 7.18 (br s, 1H, exchanges with D2O), 7.05 (d, J = 8.80 Hz, 2H), 6.95 (s, 1H), 6.57-6.52 (m, 2H), 5.58 (br s, 1H), 4.95-4.94 (m, 2H), 4.14-3.99 (m, 4H), 3.92 (dd, J = 4.40, 10.00 Hz, 1H), 3.78-3.74 (m, 2H), 3.34 (s, 3H), 1.48 (d, J = 6.40 Hz, 3H). 31P ( MHz, DMSO-d6): δ -0.535

[0754] Note: Single isomer with unknown stereochemistry in tail part; SFC purity = 99.6%Example 103: Synthesis of Compound 105

[0755] Step l:

[0756] To a stirred solution of 1 (1.2 g, 1.910 mmol) in ACN (10 mL), were added pyridine (0.463 mL, 5.73 mmol) and phosphoryl trichloride (0.356 mL, 3.82 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. To the reaction mixture cooled to 0 °C, water (4 mL) was added and stirred at room temperature for 30 min. The volatiles were removed under reduced pressure. The crude residue was purified by reverse phase preparative HPLC (Column: Gemini nx Cis (250*20 mm) 5 pm; Eluents: 10 mM ammonium bicarbonate in water and ACN) toafford Compound 105 as a white solid. Yield = 400 mg (42%). LC-MS: Calculated forC26H31N2O6P is 498.52, Observed: 499.4 [M+l]+Note: cis- geometry at tail; SFC purity = 98.9%. Two exchangeable protons not seen in 1H NMR.Example 104: Synthesis of Compound 107

[0757] Step l:

[0758] To a solution of 1 (1 g, 1.768 mmol) in acetonitrile (10 mL), were added pyridine (0.427 mL, 5.30 mmol) followed by phosphoryl trichloride (0.427 mL, 3.54 mmol) at 0 °C. The resulting reaction mixture was stirred at the room temperature for 1 h. The reaction mixture was cooled to 0 °C, water (5 mL) was added drop wise and stirred at room temperature for 30 min. The volatiles were removed under reduced pressure. The crude residue was purified by reversed phase preparative HPLC (Column: Shimpack-Cis (150*20 mm) 5 pm; Eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 107 as a white solid. Yield: 300 mg (30%). LCMS: Calculated for C26H32N3O7PS is 561.59; Observed: 562.2 [MT1]+

[0759] Note: / raw.s-geometry at tail; racemic tail part. One of the exchangeable protons not observed in 1H NMR.Example 105: Synthesis of Compounds 9 and 10Step 1 Step 2

[0760] Step l:

[0761] To a stirred solution of 1-Isomer-l (3.0 g, 9.25 mmol) in DCM (40 mL), were added DHP(1.1 mL, 12.03 mmol) and PPTS (0.233 g, 0.925 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (100 mL). The organic extract was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The resulting crude mass was purified by MPLC (manually packed cartridge; SiO2 (100-200 mesh size); 10% EtOAc in hexanes) to afford 2-Isomer-l as colourless liquid. Yield: 2.5 g (60%)

[0762] Step 2:

[0763] To a solution of 3 (1.0 g, 2.135 mmol) in acetonitrile (10 mL) and water (10 mL), were added boronate ester 2-Isomer-l (1.3 g, 3.20 mmol) and potassium carbonate (885 mg, 6.41 mmol). The resulting reaction mixture was purged with nitrogen for 5 min. To this reaction mixture,PdCb(dtbpf) (139 mg, 0.214 mmol) was added and the purging continued for 2 min. The reaction mixture was stirred at 80 °C for 16 h. The reaction was cooled to room temperature, water (50 mL) was added and extracted with 10% MeOH in DCM (50 mL x 2). The combined organic extract was washed with brine (50 mL), dried over anhydrous ISfeSCL, fdtered and concentrated under reduced pressure. The resulting crude mass was purified by MPLC (manually packed cartridge; SiCL (230- 400 mesh size); 5% MeOH in DCM) to afford 4-Isomer-l as pale-brown solid. Yield: 1.2 g (88%). LC-MS: Calculated for C35H43FN2O7 is 622.73, Observed: 623.2 [M+l]+

[0764] Step 3:

[0765] To a stirred solution of 4-Isomer-l (1.2 g, 1.927 mmol) in ACN (20 mL), were added pyridine (0.467 mL, 5.78 mmol) and phosphoryl trichloride (0.360 mL, 3.85 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 40 min. The reaction mixture was cooled to 0°C after which water (10 mL) was added and stirred for 30 min. The volatiles were removed under reduced pressure to afford the crude residue. The crude residue was purified by reversed phase preparative HPLC (Column: Shimpack Cis (150*20) 5pm; Eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 109 as off white solid. Yield = 300 mg (29%). LC-MS: Calculated for C25H28FN2O8P is 534.48, Observed: 535.3 [MT1]+

[0766] Note: Single isomer with unknown stereochemistry at tail; all exchangeable protons not seen in NMR.

[0767] Step l:

[0768] To a stirred solution of l-Isomer-2 (2 g, 6.17 mmol) in DCM (40 mL), were added DHP (0.675 g, 8.02 mmol) and PPTS (0.155 g, 0.617 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (100 mL) The organic extract was dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The resulting crude mass was purified by MPLC (manually packed cartridge; SiO2 (100-200 mesh size); 10% EtOAc in hexanes) to afford 2-Isomer-2 as colourless liquid. Yield: 1.7 g (57%)

[0769] Step 2:

[0770] To a solution of 3 (0.8 g, 1.708 mmol) in acetonitrile (15 mL) and water (15 mL), were added boronate ester 2-Isomer-2 (1.05 g, 2.56 mmol) and potassium carbonate (0.708 g, 5.12 mmol) and the resulting mixture purged with nitrogen for 5 min. To this reaction mixture, PdC12(dtbpf) (0.11 g, 0.171 mmol) was added and the purging continued for 2 min. The reaction mixture was stirred at 80 °C for 16 h. The reaction was cooled to room temperature, water (50 mL) was added and extracted with 10% MeOH in DCM (50 mL x 2). The combined organic extract was washed with brine (50 mL), dried over anhydrous Na2SC>4, filtered and concentrated under reduced pressure. The resulting crude was purified by MPLC (manually packed cartridge; SiO2 230-400 mesh size;5% MeOH in DCM) to afford 4-Isomer-2 as pale-brown solid. Yield: 1.2 g (87%). LC-MS: Calculated for C35H43FN2O7 is 622.73, Observed: 623.1 [M+l]+

[0771] Step 3:

[0772] To a stirred solution of 4-Isomer-2 (1 g, 1.236 mmol) in ACN (30 mL), were added pyridine (0.3 mL, 3.71 mmol) followed by phosphoryl trichloride (0.231 mL, 2.473 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 40 min. The reaction mixture was cooled to 0 °C after which water (5 mL) was added and stirred for 30 min. The volatiles were removed under reduced pressure to afford the crude residue. The crude residue was purified by reversed phase preparative HPLC (Column: Shimpack Cis (150*20) 5pm; Eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 110 as white solid. Yield = 170 mg (26%). LC-MS: Calculated for C25H28FN2O8P is 534.48, Observed: 535.3 [M+l]+

[0773] Note: Single isomer with unknown stereochemistry at tail; all exchangeable protons not seen in NMR. 19F showed presence of TFA and imidazole protons showed downfield shift compared to Compound 109.Example 106: Synthesis of Compound 111

[0774] Step l:

[0775] To a solution of 1 (0.55 g, 1.24 mmol) in DCM (25 mL), di-tert-butyl N,N- diisopropylphosphoramidite (2, 0.69 g, 2.48 mmol) and IH-tetrazole (0.26 g, 3.73 mmol) were added at room temperature. The resulting mixture was stirred at room temperature for 1 h. The reaction was cooled to 0 °C, hydrogen peroxide (30% in water) (2.069 mL, 26.5 mmol) was added and the resulting mixture stirred at room temperature for 1 h. The reaction mixture was quenched with 10% sodium metabisulphite (25 mL) and extracted with DCM (50 mL x 2). The combined organic layer was washed with 10% NaHCCh solution and dried over anhydrous ISfeSCL, concentrated under reduced pressure. The crude residue was purified by reversed phase column on Grace Reveleris X2 (Column: Redisep, Cis-reversed phase silica, 40 g; Eluents: 10 mM ammonium bicarbonate in water and ACN) to afford 3 as an off-white solid. Yield: 400 mg (41%). LCMS: Calculated for C35H47N4O5P is 634.75, Observed: 635.3 [M+l]+

[0776] Step 2:

[0777] To a solution of 3 (0.35 g, 0.55 mmol) in DCM (15 mL), was added TFA (0.34 mL, 4.41 mmol) at 0 °C. The resulting mixture was stirred at room temperature for 1 h. The volatiles were removed under reduced pressure and the resulting crude residue purified by reversed phasepreparative HPLC (Column: YMC C18 250*20 mm, 5 pm; Eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 111 as white solid. Yield: 135 mg (45%). LCMS: Calculated for C27H31N4O5P is 522.54, Observed: 523.3 [M+l]+Note: The final compound has / rans-geometry at cyclobutane ring.Example 107: Synthesis of Compound 115Step 1 Step 2

[0778] Step l:

[0779] To a stirred solution of 3-(4-bromophenyl)cyclobutan-l-one (1, 4.0 g, 17.77 mmol) in THF (50 mL), was added methylmagnesium bromide (1.0 M in THF; 39.1 mL, 39.1 mmol) dropwise at - 30 °C. After complete addition, the resulting reaction mixture was stirred for 15 min. then slowly warmed to room temperature and stirred for 1 h. The reaction mixture was cooled to 0 °C and quenched with sat. NH4CI solution (15 mL) and extracted with EtOAc (30 mL x 2). The combined organic extract was washed with brine solution (15 mL), dried over anhydrous sodium sulphate, and concentrated under reduced pressure to afford crude residue. The crude residue was purified by MPLC (manually packed cartridge, SiCL 230-400 mesh size; 0-10% EtOAc in hexanes) to afford 2 as an off-white solid. Yield: 1.7 g (35%)

[0780] Step 2:

[0781] To a solution of 2 (3.7 g, 13.81 mmol) in DCM (40 mL), were added 3,4-dihydro-2H- pyran (1.532 mL, 27.6 mmol) and PPTS (0.347 g, 1.381 mmol) at 0 °C and the reaction mixture stirred for 16 h. The reaction mixture was quenched with water (15 mL) and extracted with DCM (3 x 30 mL). The combined organic layer was washed with brine solution (15 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed SiCL cartridge: 230-400 mesh size; 10% EtOAc in hexanes) to afford 3 as a yellow gum. Yield: 3 g (60%). LC-MS: Calculated for CieEEiBrCL is 325.24; observed: no desired molecular ion

[0782] Step 3:

[0783] To a solution of 3 (3 g, 8.30 mmol) in 1,4-dioxane (40 mL), were added potassium acetate (2.444 g, 24.9 mmol) and bis(pinacolato)diboron (3.16 g, 12.45 mmol) at 25 °C, and the reaction mixture purged with nitrogen for 5 min. To this reaction mixture, PdCb(dppf) (0.607 g, 0.830 mmol) was added, and the reaction mixture stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature and filtered through a Celite pad. The Celite pad was washed with EtOAc (40 mL). The combined filtrate was concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 10% EtOAc in hexanes) to afford 4 as a white solid. Yield: 3.3 g (91%)

[0784] LC-MS: Calculated for C22H33BO4 is 372.25; observed: no desired molecular ion

[0785] Step 4:

[0786] To a stirred solution of 5 (1.0 g, 2.135 mmol) in 1,4-dioxane (10 mL) and water (2.5 mL), were added boronate 4 (1.148 g, 2.78 mmol) and potassium carbonate (0.885 g, 6.41 mmol) at 25 °C, and the reaction mixture purged with nitrogen for 5 min. To this reaction mixture, PdCL (dtbpf) (0.070 g, 0.107 mmol) was added and the reaction mixture irradiated in a microwave reactor at 80 °C for 1 h. The reaction mixture was concentrated under reduced pressure. The reaction mixture quenched with water (10 mL) and extracted with 10% MeOH in DCM (3 x 15 mL). The combined organic extract was washed with brine solution (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed SiCL cartridge, 230-400 mesh size; 7% MeOH in DCM) to afford 6 as pale-brown solid. Yield: 860 mg (51%)

[0787] LC-MS: Calculated for C36H46N2O5 is 586.3; observed: 587.5 [M+H]+

[0788] Another batch was carried out using 1 g of 5 to get 900 mg of 6.

[0789] Step 5:

[0790] To a solution of 6 (1.6 g, 2.181 mmol) in DCM (25 mL), were added phosphoramidite 7 (0.880 mL, 3.93 mmol) and IH-tetrazole (0.458 g, 6.54 mmol) at room temperature and the reaction mixture stirred at room temperature for 1 h. The reaction mixture was cooled to 0 °C, 30% of H2O2 in water (0.330 mL, 3.27 mmol) was added, and the reaction mixture stirred for 30 min at roomtemperature. The reaction was quenched with 10% NaHCO? solution (15 mL) and extracted with DCM (3 x 20 mL). The combined organic extract was dried over anhydrous sodium sulphate, fdtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using reverse phase MPLC (column: Redisep Gold, C18 SiCL gel; eluents: 10 mM ammonium bicarbonate in water and acetonitrile) to afford 8 as a brown gum. Yield: 1 g ...

Claims

CLAIMSWHAT IS CLAIMED IS:

1. A compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt or solvate thereof, wherein:Lais absent, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; each R3is independently hydrogen or substituted or unsubstituted C1-C6alkyl;R1is hydrogen or substituted or unsubstituted C1-C6alkyl;R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted Ci- Cealkyl;R4is hydrogen or substituted or unsubstituted C1-C6alkyl; each R5is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; s is 0, 1, 2, 3, or 4; each R6is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; t is 0, 1, 2, 3, or 4;L1is absent, -O, -N(R9), -S, substituted or unsubstituted C1-C6alkyl, -O-(substituted or unsubstituted C1-C6alkyl), -(substituted or unsubstituted C1-C6alkyl)-O, -N(R9)-(substituted or unsubstituted C1-C6alkyl), -(substituted or unsubstituted C1-C6alkyl)-N(R9), -S- (substituted or unsubstituted C1-C6alkyl), or -(substituted or unsubstituted C1-C6alkyl)-S;R9is hydrogen or substituted or unsubstituted C1-C6alkyl;R7is absent, substituted or unsubstituted C3-C10cycloalkyl or substituted or unsubstituted C2-C10heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R10aand n R10groups; n is 1, 2, 3, 4, 5, or 6;each R10is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or -L2-Rn;R10ais hydrogen, substituted or unsubstituted C1-C6alkyl, -C(=O)Ra, -C(=O)NRcRd, or -L2-Rn;L2is substituted or unsubstituted C1-C6alkyl, -N(R9)-(substituted or unsubstituted C1-C6alkyl), - O-(substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl;R11is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd; or L1-R7is absent and two R6on adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C10cycloalkyl or substituted or unsubstituted C2-C10heterocycloalkyl; each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rcand Rdare independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C10heterocycloalkyl.

2. The compound of claim 1, wherein the compound has a structure of Formula (la):or a pharmaceutically acceptable salt or solvate thereof.

3. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein:R2aand R2bare each independently hydrogen.

4. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein:R1is substituted or unsubstituted C1-C6alkyl.

5. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein:R1is -CH3, -CH2CH3, or -CH(CH3)2.

6. The compound of claim 1 or claim 2, or a pharmaceutically acceptable salt or solvate thereof, wherein:R1is -CH3.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein:R4is hydrogen, -CH3, or -CH2CH3.

8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt or solvate thereof, wherein:R4is hydrogen.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt or solvate thereof, wherein:IAR7is absent and two R6on adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C2-C10heterocycloalkyl.

10. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein:R7is substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted C2-Ceheterocycloalkyl.

11. The compound of any one of claims 1 -9, or a pharmaceutically acceptable salt or solvate thereof, wherein:R7is substituted or unsubstituted monocyclic C3-C6cycloalkyl or substituted or unsubstituted monocyclic C2-C6heterocycloalkyl.

12. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein:R7is substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted C2-Ceheterocycloalkyl, wherein heterocycloalkyl contains 0-2 N atoms or 0-2 O atoms in the ring.

13. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein:R7is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted aziridinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperazinyl, or substitituted or unsubstituted tetrahydrothiophene 1 -oxide.

14. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein:R7is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted aziridinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, or substituted or unsubstituted piperazinyl.

15. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein:R7is substituted or unsubstituted cyclobutyl.

16. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein:R7is substituted or unsubstituted azetidinyl.

17. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein:R7is substituted or unsubstituted tetrahydrofuranyl.

18. The compound of any one of claims 1-9, or a pharmaceutically acceptable salt or solvate thereof, wherein:R7is substituted or unsubstituted tetrahydropyranyl.

19. The compound of any one of claims 1-18, wherein the compound has a structure of Formula (II):Formula (II), or a pharmaceutically acceptable salt or solvate thereof.

20. The compound of any one of claims 1-19, or a pharmaceutically acceptable salt or solvate thereof, wherein:

21. The compound of any one of claims 1-19 or a pharmaceutically acceptable salt or solvate thereof, wherein:Formula (III), or a pharmaceutically acceptable salt or solvate thereof.

23. The compound of any one of claims 1-18 or 22, or a pharmaceutically acceptable salt or solvate thereof, wherein:

24. The compound of any one of claims 1-18 or 22, or a pharmaceutically acceptable salt or solvate thereof, wherein:

25. The compound of any one of claims 1-18, wherein the compound has a structure of Formula (IV):Formula (IV), or a pharmaceutically acceptable salt or solvate thereof.

26. The compound of any one of claims 1-18 or 25, or a pharmaceutically acceptable salt or solvate thereof, wherein:

27. The compound of any one of claims 1-18 or 25, or a pharmaceutically acceptable salt or solvate thereof, wherein:

28. The compound of any one of claims 1-18 or 25, or a pharmaceutically acceptable salt or solvate thereof, wherein:

29. The compound of any one of claims 1-18 or 25, or a pharmaceutically acceptable salt or solvate thereof, wherein:

30. The compound of any one of claims 1-18 or 25, or a pharmaceutically acceptable salt or solvate thereof, wherein:

31. The compound of any one of claims 1-18 or 25, or a pharmaceutically acceptable salt or solvate thereof, wherein:

32. The compound of any one of claims 1-18 or 25, or a pharmaceutically acceptable salt or solvate thereof, wherein:

33. The compound of any one of claims 1-18 or 25, or a pharmaceutically acceptable salt or solvate thereof, wherein:

34. The compound of any one of claims 1-18, wherein the compound has a structure of Formula (V):or a pharmaceutically acceptable salt or solvate thereof.

35. The compound of any one of claims 1-18 or 34, or a pharmaceutically acceptable salt or solvate thereof, wherein:

36. The compound of any one of claims 1-18 or 34, or a pharmaceutically acceptable salt or solvate thereof, wherein:

37. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt or solvate thereof, wherein:Lais absent or substituted or unsubstituted C1-C6alkyl; and each R3is independently hydrogen, -CH3, -CH2CH3, or -CH(CH3)2.

38. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt or solvate thereof, wherein:-La-O-P(=O)(OR3)2is -O-P(=O)(OR3)2or -O-CH2-O-P(=O)(OR3)2; and each R3is independently hydrogen, -CH3, -CH2CH3, or -CH(CH3)2.

39. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt or solvate thereof, wherein:-La-O-P(=O)(OR3)2is -O-P(=O)(OH)2or -O-CH2-O-P(=O)(OH)2.

40. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt or solvate thereof, wherein:-La-O-P(=O)(OR3)2is -O-P(=O)(OH)2.

41. The compound of any one of claims 1-36, or a pharmaceutically acceptable salt or solvate thereof, wherein:-La-O-P(=O)(OR3)2is -CH2-O-P(=O)(OH)2.

42. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R5is independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; s is 0, 1, or 2; each R6is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or substituted or unsubstituted C1-C6alkyl; and t is 0, 1, or 2.

43. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R5is independently hydrogen or halogen; s is 0, 1, or 2; each R6is independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; and t is 0, 1, or 2.

44. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R5is independently hydrogen; and each R6is independently hydrogen, -F, -Cl, -CH3, -CH2CH3, or -CH(CH3)2.

45. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R5is independently hydrogen; and each R6is independently hydrogen, -F, -Cl, or -CH3.

46. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R5is independently hydrogen; and each R6is independently hydrogen or -F.

47. The compound of any one of claims 1-41, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R5is independently hydrogen; and each R6is independently hydrogen.

48. The compound of any one of claims 1-18, 22, 25, 34, or 37-47, or a pharmaceutically acceptable salt or solvate thereof, wherein:L1is absent, -O-, -N(R9)-, -(substituted or unsubstituted C1-C6alkyl)-, -O-(substituted or unsubstituted C1-C6alkyl)-, -(substituted or unsubstituted C1-C6alkyl)-O-, -N(R9)-(substituted or unsubstituted C1-C6alkyl)-, or -(substituted or unsubstituted C1-C6alkyl)-N(R9)-; andR9is hydrogen or -CH3.

49. The compound of any one of claims 1-18, 22, 25, 34, or 37-47, or a pharmaceutically acceptable salt or solvate thereof, wherein:L1is absent, -O-, -N(H)-, -N(CH3)-, -CH2-, -O-CH2-, -CH2-O-, -N(H)-CH2-, -CH2-N(H)-, -N(CH3)- CH2-, or -CH2-N(CH3)-.

50. The compound of any one of claims 1-18, 22, 25, 34, or 37-47, or a pharmaceutically acceptable salt or solvate thereof, wherein:L1is absent, -O-, -N(H), -CH2-, -O-CH2-, -CH2-O-, -N(H)-CH2-, or -CH2-N(H)-.

51. The compound of any one of claims 1-18, 22, 25, 34, or 37-47, or a pharmaceutically acceptable salt or solvate thereof, wherein:

52. L1is absent, -O-, -N(H)-, -O-CH2-;-CH2-O-, -N(H)-CH2-, or -CH2-N(H)-. The compound of any one of claims 1-18, 22, 25, 34, or 37-47, or a pharmaceutically acceptable salt or solvate thereof, wherein:L1is absent, -O-, -O-CH2-, or-CH2-O-.

53. The compound of any one of claims 1-18, 22, 25, 34, or 37-47, or a pharmaceutically acceptable salt or solvate thereof, wherein:L1is absent.

54. The compound of any one of claims 1-18, 22, 25, 34, or 37-47, or a pharmaceutically acceptable salt or solvate thereof, wherein:L1is -O-.

55. The compound of any one of claims 1-18, 22, 25, 34, or 37-47, or a pharmaceutically acceptable salt or solvate thereof, wherein:L1is -CH2-.

56. The compound of any one of claims 1-18, 22, 25, 34, or 37-47, or a pharmaceutically acceptable salt or solvate thereof, wherein:L1is -CH2-O-.

57. The compound of any one of claims 1-18, 22, 25, 34, or 37-47, or a pharmaceutically acceptable salt or solvate thereof, wherein:

58. L1is -O-CH2-.The compound of any one of claims 1-19, 22, 23, 25-27, 34, 35, or 37-57, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R10is independently halogen, -CN, -OH, -ORa, -OC(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)Ra, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, or -L2-Rn;R10ais hydrogen, substituted or unsubstituted C1-C6alkyl, -C(=O)Ra, -C(=O)NRcRd, or -L2-Rn;L2is substituted or unsubstituted C1-C6alkyl;R11is -CN, -OH, -ORa, -NRcRd; n is 1, 2, 3, or 4;each Rais independently substituted or unsubstituted C1-C6alkyl; each Rbis independently hydrogen or substituted or unsubstituted C1-C6alkyl; each Rcis independently hydrogen or substituted or unsubstituted C1-C6alkyl; each Rdis independently hydrogen or substituted or unsubstituted C1-C6alkyl; or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C10heterocycloalkyl.

59. The compound of any one of claims 1-19, 22, 23, 25-27, 34, 35, or 37-57, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R10is independently halogen, -CN, -OH, -ORa, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, - NRbC(=O)Ra, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)NRcRd, oxo, substituted or unsubstituted Ci-C6alkyl, or -L2-Rn;R10ais hydrogen, substituted or unsubstituted C1-C6alkyl, -C(=O)Ra, -C(=O)NRcRd, or -L2-Rn;L2is substituted or unsubstituted C1-C6alkyl;R11is -CN; n is 1, 2, 3, or 4; each Rais independently substituted or unsubstituted C1-C6alkyl; each Rbis independently hydrogen or substituted or unsubstituted C1-C6alkyl; each Rcis independently hydrogen or substituted or unsubstituted C1-C6alkyl; each Rdis independently hydrogen or substituted or unsubstituted C1-C6alkyl or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C10heterocycloalkyl.

60. The compound of any one of claims 1-19, 22, 23, 25-27, 34, 35, or 37-57, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R10is independently halogen, -CN, -OH, -ORa, -S(=O)2NRcRd, -NRcRd, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, or -L2-Rn;R10ais hydrogen, substituted or unsubstituted C1-C6alkyl, -C(=0)Ra, -C(=0)NRcRd, or -L2-Rn;L2is substituted or unsubstituted C1-C6alkyl;R11is -CN; n is 1, 2, or 3; each Rais independently -CH3or -CH2CH3; each Rbis independently hydrogen, -CH3, or-CH2CH3; each Rcis independently hydrogen, -CH3, or-CH2CH3; and each Rdis independently hydrogen, -CH3, or-CH2CH3.

61. The compound of any one of claims 1-15, 17, 18, 20, 21, 23, 24, or 26-37, or a pharmaceutically acceptable salt or solvate thereof, wherein:each R10is independently -CN, -OH, -OCH3, oxo, -CH3, -S(=O)2NHCH3, -NH2, -NHS(=O)2CH3, - C(=O)CH3, -C(=O)NH2J-C(=O)NHCH3, -C(=O)N(CH3)2, -CH2CH2CN, -NHCH2CN;; and n is 1, 2, or 3.

62. The compound of any one of claims 1-19, 22, 23, 25-27, 34, 35, or 37-57, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R10is independently -OH; and n is 1.

63. The compound of any one of claims 1-18 or 37-62, or a pharmaceutically acceptable salt or solvate thereof, wherein:

64. The compound of any one of claims 1-18 or 37-62, or a pharmaceutically acceptable salt or solvate thereof, wherein:

65. The compound of any one of claims 1-18 or 37-62, or a pharmaceutically acceptable salt or solvate thereof, wherein:

66. The compound of any one of claims 1-18 or 37-62, or a pharmaceutically acceptable salt or solvate thereof, wherein:

67. The compound of any one of claims 1-18 or 37-62, or a pharmaceutically acceptable salt or solvate thereof, wherein:

68. The compound of any one of claims 1-18 or 37-62, or a pharmaceutically acceptable salt or solvate thereof, wherein:or a pharmaceutically acceptable salt or solvate thereof, wherein:Ring A is heterocycloalkyl or heteroaryl; each R12is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; p is 0, 1, 2, 3, or 4;Lais absent, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; each R3is independently hydrogen or substituted or unsubstituted C1-C6alkyl;R1is hydrogen or substituted or unsubstituted C1-C6alkyl;R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted Ci- Cealkyl;R4is hydrogen or substituted or unsubstituted C1-C6alkyl;each R5is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; s is 0, 1, 2, 3, or 4; each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rcand Rdare independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C10heterocycloalkyl.

70. The compound of claim 69, or a pharmaceutically acceptable salt or solvate thereof, wherein: Ring A is heterocycloalkyl.

71. The compound of claim 69, or a pharmaceutically acceptable salt or solvate thereof, wherein: Ring A is heteroaryl.

72. The compound of any one of claims 69-71, or a pharmaceutically acceptable salt or solvate thereof, wherein:R2aand R2bare each independently hydrogen.

73. The compound of any one of claims 69-72, or a pharmaceutically acceptable salt or solvate thereof, wherein:R1is substituted or unsubstituted C1-C6alkyl.

74. The compound of any one of claims 69-72, or a pharmaceutically acceptable salt or solvate thereof, wherein:R1is -CH3, -CH2CH3, or -CH(CH3)2.

75. The compound of any one of claims 69-72, or a pharmaceutically acceptable salt or solvate thereof, wherein:R1is -CH3.

76. The compound of any one of claims 69-75, or a pharmaceutically acceptable salt or solvate thereof, wherein:R4is hydrogen, -CH3, or -CH2CH3.

77. The compound of any one of claims 69-75, or a pharmaceutically acceptable salt or solvate thereof, wherein:R4is hydrogen.

78. The compound of any one of claims 69-77, or a pharmaceutically acceptable salt or solvate thereof, wherein:-La-O-P(=O)(OR3)2is -O-P(=O)(OR3)2or -O-CH2-O-P(=O)(OR3)2; and each R3is independently hydrogen, -CH3, -CH2CH3, or -CH(CH3)2.

79. The compound of any one of claims 69-77, or a pharmaceutically acceptable salt or solvate thereof, wherein:-La-O-P(=O)(OR3)2is -O-P(=O)(OH)2or -O-CH2-O-P(=O)(OH)2.

80. The compound of any one of claims 69-77, or a pharmaceutically acceptable salt or solvate thereof, wherein:-La-O-P(=O)(OR3)2is -O-P(=O)(OH)2.

81. The compound of any one of claims 69-80, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R5is independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; s is 0, 1, or 2; each R12is independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; and p is 0, 1, or 2.

82. The compound of any one of claims 69-80, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R5is independently hydrogen, -F, -Cl, -CH3, -CH2CH3, or -CH(CH3)2; and each R12is independently hydrogen, -F, -Cl, -CH3, -CH2CH3, or -CH(CH3)2.

83. The compound of any one of claims 69-80, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R5is independently hydrogen; and each R12is independently hydrogen.

84. The compound of any one of claims 1-83, wherein the compound is selected from:, p y ate thereof.

85. The compound of any one of claims 1-83, wherein the compound is selected from:or a pharmaceutically acceptable salt or solvate thereof.

86. The compound of any one of claims 1-83, wherein the compound is selected from:

87. The compound of any one of claims 1-83, wherein the compound is:or a pharmaceutically acceptable salt or solvate thereof.

88. The compound of any one of claims 1-83, wherein the compound is:or a pharmaceutically acceptable salt or solvate thereof.

89. The compound of any one of claims 1-83, wherein the compound is:or a pharmaceutically acceptable salt or solvate thereof.

90. The compound of any one of claims 1-83, wherein the compound is:or a pharmaceutically acceptable salt or solvate thereof.

91. The compound of any one of claims 1-83, wherein the compound is:solvate thereof.

92. A compound having the structure:or a pharmaceutically acceptable salt or solvate thereof.

93. A pharmaceutical composition comprising the compound of any one of claims 1-92, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

94. A method of treating or preventing a gram-negative bacterial infection in a patient in need thereof comprising administering to the patient the compound of any one of claims 1-92, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 93.

95. The method of claim 93, wherein the gram-negative bacterial infection is associated with Pseudomonas aeruginosa.

96. The method of claim 93, wherein the gram-negative bacterial infection is a respiratory infection.

97. The method of claim 93, wherein the gram-negative bacterial infection is pneumonia.

98. The method of claim 97, wherein the pneumonia is community-acquired pneumonia (CAP), health care-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), ventilator-associate pneumonia (VAP), or a combination thereof.

99. A method of treating or preventing aP. aeruginosa infection in a patient in need thereof comprising administering to the patient the compound of any one of claims 1-92, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 64.

100. The method of any one of claims 94-99, wherein the patient has been identified as having a lung disease.

101. The method of claim 100, wherein the lung disease is a structural lung disease.

102. The method of claim 100 or claim 101, wherein the lung disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic destroyed lung disease, or a combination thereof.

103. The method of any one of claims 94-102, wherein the administration is to treat an existing infection.

104. The method of any one of claims 94-102, wherein the administration is provided as prophylaxis.

105. The method of any one of claims 94-102, wherein the compound of any one of claims 1-92, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 93, is administered in a solution by inhalation, intravenous injection, or intraperitoneal injection.

106. A compound of any one of claims 1-92 for use as therapeutically active substance.

107. A compound of any one of claims 1-92 for use in treating or preventing a gram-negative bacterial infection.

108. The compound for use of claim 107, wherein the gram-negative bacterial infection is associated with Pseudomonas aeruginosa.

109. The compound for use of claim 107, wherein the gram-negative bacterial infection is a respiratory infection.

110. The compound for use of claim 107, wherein the gram-negative bacterial infection is pneumonia.

111. The compound for use of claim 110, wherein the pneumonia is community-acquired pneumonia (CAP), health care-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), ventilatorassociate pneumonia (VAP), or a combination thereof.

112. A compound of any one of claims 1 -92 for use in treating or preventing a P. aeruginosa infection.

113. The compound for use of any one of claims 106-112, wherein the patient has been identified as having a lung disease.

114. The compound for use of claim 113, wherein the lung disease is a structural lung disease.

115. The compound for use of claim 113 or claim 114, wherein the lung disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic destroyed lung disease, or a combination thereof.

116. The use of a compound of any one of claims 1-92 for the preparation of a medicament for treating or preventing a gram-negative bacterial infection.

117. The use of a compound of any one of claims 1-92 for treating or preventing a gram-negative bacterial infection.

118. A process for the preparation of a compound of Formula (I), comprising:(1) contacting a phosphorylating reagent with a compound of Formula (A):Formula (A), or a pharmaceutically acceptable salt or solvate thereof, wherein PG is a protecting group;R1, R2a, R2b, R4, R5, R6, R7, L1, La, s, and t are defined in any one of claims 1-83; and(2) removing PG to provide the compound of Formula (I).

119. The process of claim 118 wherein the phosphorylating reagent is phosphoryl trichloride (POCh).

120. The process of claim 118 or 119, wherein PG is tetrahydropyranyl (THP).

121. A compound of Formula (XI):Formula (XI), or a pharmaceutically acceptable salt or solvate thereof, wherein:Lais absent, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; each R3is independently hydrogen or substituted or unsubstituted C1-C6alkyl;R1is hydrogen or substituted or unsubstituted C1-C6alkyl;R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted Ci- Cealkyl;R4is hydrogen or substituted or unsubstituted C1-C6alkyl;R12is hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl;R13is hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; each R5is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; s is 0, 1, 2, 3, or 4; each R6is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)ORb, - C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; t is 0, 1, 2, 3, or 4;L1is absent, -O, -N(R9), -S, substituted or unsubstituted C1-C6alkyl, -O-(substituted or unsubstituted C1-C6alkyl), -(substituted or unsubstituted C1-C6alkyl)-O, -N(R9)-(substituted or unsubstituted C1-C6alkyl), -(substituted or unsubstituted C1-C6alkyl)-N(R9), -S- (substituted or unsubstituted C1-C6alkyl), or -(substituted or unsubstituted C1-C6alkyl)-S;R9is hydrogen or substituted or unsubstituted C1-C6alkyl;R7is absent, substituted or unsubstituted C3-C10cycloalkyl or substituted or unsubstituted C2-C10heterocycloalkyl, wherein substituted cycloalkyl and substituted heterocycloalkyl are substituted with R10aand n R10groups; n is 1, 2, 3, 4, 5, or 6; each R10is independently halogen, -CN, -NO2, -OH, -ORa, -OC(=O)Ra, -OC(=O)ORb, - OC(=O)NRcRd, -SRb, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl, or -L2-Rn;R10ais hydrogen, substituted or unsubstituted C1-C6alkyl, -C(=O)Ra, -C(=O)NRcRd, or -L2-Rn;L2is substituted or unsubstituted C1-C6alkyl, -N(R9)-(substituted or unsubstituted C1-C6alkyl), - O-(substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl;R11is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd; or L1-R7is absent and two R6on adjacent carbon atoms are taken together with the carbon atoms to which they are attached to form a substituted or unsubstituted C3-C10cycloalkyl or substituted or unsubstituted C2-C10heterocycloalkyl; each Rais independently substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rbis independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; each Rcand Rdare independently hydrogen, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6haloalkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C10heterocycloalkyl.

122. The compound of claim 121, wherein the compound has a structure of Formula (Xia):Formula (Xia), or a pharmaceutically acceptable salt or solvate thereof.

123. The compound of claim 121 or claim 122, or a pharmaceutically acceptable salt or solvate thereof, wherein:R2aand R2bare each independently hydrogen.

124. The compound of claim 121 or claim 122, or a pharmaceutically acceptable salt or solvate thereof, wherein:R1is substituted or unsubstituted C1-C6alkyl.

125. The compound of claim 121 or claim 122, or a pharmaceutically acceptable salt or solvate thereof, wherein:R1is -CH3, -CH2CH3, or -CH(CH3)2.

126. The compound of claim 121 or claim 122, or a pharmaceutically acceptable salt or solvate thereof, wherein:R1is -CH3.

127. The compound of any one of claims 121-126, or a pharmaceutically acceptable salt or solvate thereof, wherein:R4is hydrogen, -CH3, or -CH2CH3.

128. The compound of any one of claims 121-126, or a pharmaceutically acceptable salt or solvate thereof, wherein:R4is hydrogen.

129. The compound of any one of claims 121-128, or a pharmaceutically acceptable salt or solvate thereof, wherein:R12is hydrogen or halogen; andR13is hydrogen or halogen.

130. The compound of any one of claims 121-128, or a pharmaceutically acceptable salt or solvate thereof, wherein:R12is hydrogen; andR13is hydrogen.

131. The compound of any one of claims 121-130, or a pharmaceutically acceptable salt or solvate thereof, wherein:R7is substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted C2- Ceheterocycloalkyl.

132. The compound of any one of claims 121-130, or a pharmaceutically acceptable salt or solvate thereof, wherein:R7is substituted or unsubstituted monocyclic C3-C6cycloalkyl or substituted or unsubstituted monocyclic C2-C6heterocycloalkyl.

133. The compound of any one of claims 121-130, or a pharmaceutically acceptable salt or solvate thereof, wherein:R7is substituted or unsubstituted C3-C6cycloalkyl or substituted or unsubstituted C2- Ceheterocycloalkyl, wherein C2-C6heterocycloalkyl contains 0-2 N atoms or 0-2 O atoms in the ring.

134. The compound of any one of claims 121-130, or a pharmaceutically acceptable salt or solvate thereof, wherein:R7is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted aziridinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted piperazinyl, or substitituted or unsubstituted tetrahydrothiophene 1 -oxide.

135. The compound of any one of claims 121-130, or a pharmaceutically acceptable salt or solvate thereof, wherein:R7is substituted or unsubstituted cyclopropyl, substituted or unsubstituted cyclobutyl, substituted or unsubstituted cyclopentyl, substituted or unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted aziridinyl, substituted or unsubstituted azetidinyl, substituted or unsubstituted pyrrolidinyl, or substituted or unsubstituted piperazinyl.

136. The compound of any one of claims 121-130, or a pharmaceutically acceptable salt or solvate thereof, wherein:R7is substituted or unsubstituted cyclobutyl, substituted or unsubstituted tetrahydropyranyl, substituted or unsubstituted pyrrolidinyl, substituted or unsubstituted azetidinyl, or substitituted or unsubstituted tetrahydrothiophene 1 -oxide.

137. The compound of any one of claims 121-136, wherein the compound has a structure of Formula (XII):Formula (XII), or a pharmaceutically acceptable salt or solvate thereof.

138. The compound of any one of claims 121-137, or a pharmaceutically acceptable salt or solvate thereof, wherein:

139. The compound of any one of claims 121-137, or a pharmaceutically acceptable salt or solvate thereof, wherein:

140. The compound of any one of claims 121-136, wherein the compound has a structure of Formula (XIV):or a pharmaceutically acceptable salt or solvate thereof.

141. The compound of any one of claims 121-136 or 140, or a pharmaceutically acceptable salt or solvate thereof, wherein:

142. The compound of any one of claims 121-136 or 140, or a pharmaceutically acceptable salt or solvate thereof, wherein:

143. The compound of any one of claims 121-136 or 140, or a pharmaceutically acceptable salt or solvate thereof, wherein:

144. The compound of any one of claims 121-136 or 140, or a pharmaceutically acceptable salt or solvate thereof, wherein:

145. The compound of any one of claims 121-144, or a pharmaceutically acceptable salt or solvate thereof, wherein:Lais absent or substituted or unsubstituted C1-C6alkyl)-; and each R3is independently hydrogen, -CH3, -CH2CH3, or -CH(CH3)2.

146. The compound of any one of claimsl21-144, or a pharmaceutically acceptable salt or solvate thereof, wherein:-La-O-P(=O)(OR3)2is -O-P(=O)(OR3)2or -O-CH2-O-P(=O)(OR3)2; and each R3is independently hydrogen, -CH3, -CH2CH3, or -CH(CH3)2.

147. The compound of any one of claims 121-144, or a pharmaceutically acceptable salt or solvate thereof, wherein:-La-O-P(=O)(OR3)2is -O-P(=O)(OH)2or -O-CH2-O-P(=O)(OH)2.

148. The compound of any one of claims 121-144, or a pharmaceutically acceptable salt or solvate thereof, wherein:-La-O-P(=O)(OR3)2is -O-P(=O)(OH)2.

149. The compound of any one of claims 121-148, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R5is independently hydrogen or halogen; s is 0, 1, or 2; each R6is independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; and t is 0, 1, or 2.

150. The compound of any one of claims 121-148, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R5is independently hydrogen; each R6is independently hydrogen, -F, -Cl, -CH3, -CH2CH3, or -CH(CH3)2.

151. The compound of any one of claims 121-148, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R5is independently hydrogen; and each R6is independently hydrogen or -F.

152. The compound of any one of claims 121-148, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R5is independently hydrogen; and each R6is independently hydrogen.

153. The compound of any one of claims 121-137, 140, or 145-152, or a pharmaceutically acceptable salt or solvate thereof, wherein:L1is absent, -O-, -N(R9)-, -(substituted or unsubstituted C1-C6alkyl)-, -O-(substituted or unsubstituted C1-C6alkyl)-, -(substituted or unsubstituted C1-C6alkyl)-O-, -N(R9)-(substituted or unsubstituted C1-C6alkyl)-, or -(substituted or unsubstituted C1-C6alkyl)-N(R9)-; andR9is hydrogen or -CH3.

154. The compound of any one of claims 121-137, 140, or 145-152, or a pharmaceutically acceptable salt or solvate thereof, wherein:L1is absent, -O-, -N(H), -N(CH3)-, -CH2-, -O-CH2-, -CH2-O-, -N(H)-CH2-, -CH2-N(H)-, - N(CH3)-CH2-, or -CH2-N(CH3)-.

155. The compound of any one of claimsl21-137, 140, or 145-152, or a pharmaceutically acceptable salt or solvate thereof, wherein:L1is absent, -O-, -N(H), -O-CH2-, -CH2-O-, -N(H)-CH2, or -CH2-N(H)-.

156. The compound of any one of claims 121-137, 140, or 145-152, or a pharmaceutically acceptable salt or solvate thereof, wherein:L1is absent, -O-, -CH2-O-, or -N(H)-.

157. The compound of any one of claims 121-137, 140, or 145-152, or a pharmaceutically acceptable salt or solvate thereof, wherein:L1is absent, -O-, or -N(H)-.

158. The compound of any one of claims 121-138, 140-142, or 145-157, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R10is independently halogen, -CN, -OH, -ORa, -OC(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, - NRcRd, -NRbC(=O)Ra, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)ORb, -C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, or -L2- R11;R10ais hydrogen, substituted or unsubstituted C1-C6alkyl, -C(=O)Ra, -C(=O)NRcRd, or -L2-Rn;L2is substituted or unsubstituted C1-C6alkyl or -N(R9)-(substituted or unsubstituted C1-C6alkyl);R11is -CN, -OH, -ORa, -NRcRd; n is 1, 2, 3, or 4; each Rais independently substituted or unsubstituted C1-C6alkyl; each Rbis independently hydrogen or substituted or unsubstituted C1-C6alkyl; each Rcis independently hydrogen or substituted or unsubstituted C1-C6alkyl; each Rdis independently hydrogen or substituted or unsubstituted C1-C6alkyl; or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C10heterocycloalkyl.

159. The compound of any one of claims 121-138, 140-142, or 145-157, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R10is independently halogen, -CN, -OH, -ORa, -S(=O)2NRcRd, -NRcRd, -NRbS(=O)2Ra, - C(=O)Ra, -C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, or -L2-Rn;R10ais hydrogen or substituted or unsubstituted C1-C6alkyl;L2is substituted or unsubstituted C1-C6alkyl or -N(R9)-(substituted or unsubstituted C1-C6alkyl);R11is -CN; n is 1, 2, or 3; each Rais independently -CH3or -CH2CH3; each Rbis independently hydrogen, -CH3, or-CH2CH3; each Rcis independently hydrogen, -CH3, or-CH2CH3; and each Rdis independently hydrogen, -CH3, or-CH2CH3.

160. The compound of any one of claims 121-138, 140-142, or 145-157, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R10is independently -CN, -OH, -OCH3, -CH3, -S(=O)2NHCH3, -NH2, -NHS(=O)2CH3, - C(=O)CH3, C(=0)NH2J-C(=0)NHCH3, -C(=O)N(CH3)2, -CH2CH2CN, -NHCH2CN; and n is 1, 2, or 3.

161. The compound of any one of claims 121-138, 140-142, or 145-157, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R10is independently -OH, -OCH3, -CH3, -NHS(=O)2CH3, or -NHCH2CN; and n is 1 or 2.

162. The compound of any one of claims 121-138, 140-142, or 145-157, or a pharmaceutically acceptable salt or solvate thereof, wherein: each R10is independently -OH, -OCH3, -NHS(=O)2CH3, or -NHCH2CN; and n is 1 or 2.

163. The compound of any one of claims 121-162, or a pharmaceutically acceptable salt or solvate thereof, wherein:

164. The compound of any one of claims 121-162, or a pharmaceutically acceptable salt or solvate thereof, wherein:

165. The compound of any one of claims 121-162, or a pharmaceutically acceptable salt or solvate thereof, wherein:

166. The compound of any one of claims 121-162, or a pharmaceutically acceptable salt or solvate thereof, wherein:

167. The compound of any one of claims 121-166, wherein the compound is selected from:or a pharmaceutically acceptable salt or solvate thereof.

168. The compound of any one of claims 121-167, wherein the compound is selected from:or a pharmaceutically acceptable salt or solvate thereof.

169. The compound of any one of claims 121-167, wherein the compound is selected from:

170. The compound of any one of claims 121-167, wherein the compound is:or a pharmaceutically acceptable salt or solvate thereof.

171. The compound of any one of claims 121-167, wherein the compound is:or a pharmaceutically acceptable salt or solvate thereof.

172. The compound of any one of claims 121-167, wherein the compound is:or a pharmaceutically acceptable salt or solvate thereof.

173. The compound of any one of claims 121-167, wherein the compound is:or a pharmaceutically acceptable salt or solvate thereof.

174. A compound having the structure:or a pharmaceutically acceptable salt or solvate thereof.

175. A pharmaceutical composition comprising the compound of any one of claims 121-174, or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

176. A method of treating or preventing a gram-negative bacterial infection in a patient in need thereof comprising administering to the patient the compound of any one of claims 121-174, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 175.

177. The method of claim 176, wherein the gram-negative bacterial infection is associated with Pseudomonas aeruginosa.

178. The method of claim 176, wherein the gram-negative bacterial infection is a respiratory infection.

179. The method of claim 176, wherein the gram-negative bacterial infection is pneumonia.

180. The method of claim 179, wherein the pneumonia is community-acquired pneumonia (CAP), health care-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), ventilatorassociate pneumonia (VAP), or a combination thereof.

181. A method of treating or preventing a P. aeruginosa infection in a patient in need thereof comprising administering to the patient the compound of any one of claims 121-174, or apharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 175.

182. The method of any one of claims 176-181, wherein the patient has been identified as having a lung disease.

183. The method of claim 182, wherein the lung disease is a structural lung disease.

184. The method of claim 182 or claim 183, wherein the lung disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic destroyed lung disease, or a combination thereof.

185. The method of any one of claims 176-184, wherein the administration is to treat an existing infection.

186. The method of any one of claims 176-184, wherein the administration is provided as prophylaxis.

187. The method of any one of claims 176-184, wherein the compound of any one of claims 121-174, or a pharmaceutically acceptable salt or solvate thereof, or the pharmaceutical composition of claim 175, is administered in a solution by inhalation, intravenous injection, or intraperitoneal injection.

188. A compound of any one of claims 121-174 for use as therapeutically active substance.

189. A compound of any one of claims 121-174 for use in treating or preventing a gram-negative bacterial infection.

190. The compound for use of claim 189, wherein the gram-negative bacterial infection is associated with Pseudomonas aeruginosa.

191. The compound for use of claim 189, wherein the gram-negative bacterial infection is a respiratory infection.

192. The compound for use of claim 189, wherein the gram-negative bacterial infection is pneumonia.

193. The compound for use of claim 192, wherein the pneumonia is community-acquired pneumonia (CAP), health care-associated pneumonia (HCAP), hospital-acquired pneumonia (HAP), ventilator-associate pneumonia (VAP), or a combination thereof.

194. A compound of any one of claims 121-174 for use in treating or preventing aP. aeruginosa infection.

195. The compound for use of any one of claims 188-194, wherein the patient has been identified as having a lung disease.

196. The compound for use of claim 195, wherein the lung disease is a structural lung disease.

197. The compound for use of claim 195 or claim 196, wherein the lung disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic destroyed lung disease, or a combination thereof.

198. The use of a compound of any one of claims 121-174 for the preparation of a medicament for treating or preventing a gram-negative bacterial infection.

199. The use of a compound of any one of claims 121-174 for treating or preventing a gram-negative bacterial infection.

200. A process for the preparation of a compound of Formula (XI), comprising:(1) contacting a phosphorylating reagent with a compound of Formula (X-A):Formula (X-A), or a pharmaceutically acceptable salt or solvate thereof, wherein PG is a protecting group;R1, R2a, R2b, R4, R5, R6, R7, R12, R13, L1, La, s, and t are defined in any one of claims 121-166; and(2) removing PG to provide the compound of Formula (XI).

201. The process of claim 200, wherein the phosphorylating reagent is phosphoryl trichloride (POCh).

202. The process of claim 200 or 201, wherein PG is tetrahydropyranyl (THP).

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