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 COMPOUNDS CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 552,942, filed February 13, 2024, which is incorporated herein by reference in its entirety. 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):o u a ( ), or a pharmaceutically acceptable salt solvate or prodrug thereof wherein:R is , , , , , , or ;R1is hydrogen or substituted or unsubstituted C1-C6alkyl;R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; R3is hydrogen 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, or 2; 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; Y1is CR8or N; Y2is C(R8)2or NR8a; x is 0, 1, 2, 3, or 4; each R8is independently hydrogen, 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, substituted or unsubstituted heteroaryl, or -L-R12; R8ais hydrogen, substituted or unsubstituted C1-C6alkyl, or -(substituted or unsubstituted C1- C6alkyl)-CN; or R8aand one or more R8are taken together with the atoms to which they are attached to form a fused substituted or unsubstituted C2-C10heterocycloalkyl or substituted or unsubstituted heteroaryl; L is substituted or unsubstituted C1-C6alkyl, -N(R11)-(substituted or unsubstituted C1-C6alkyl), -O- (substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl; R11is hydrogen or substituted or unsubstituted C1-C6alkyl; R12is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd; R9is substituted or unsubstituted heteroaryl, substituted or unsubstituted C2-C10heterocycloalkyl, -O- substituted or unsubstituted heteroaryl, -O-substituted or unsubstituted C2-C10heterocycloalkyl, - N(R11)-substituted or unsubstituted heteroaryl, -N(R11)-substituted or unsubstituted C2- C10heterocycloalkyl, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd;R10ais halogen, -CN, -OH, -NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; R10bis halogen, -CN, -OH, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbS(=O)2Ra, -C(=O)Ra, -C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl, or -L-R12; R10cis substituted or unsubstituted heteroaryl, substituted or unsubstituted C2-C10heterocycloalkyl, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, or - NRbS(=O)2Ra; 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 (Ia):or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

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

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

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

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

[0011] In some embodiments, described herein is a compound of Formula (VI):Formula (VI), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:; Ring A is C3-C6cycloalkyl or 4 to 6-membered N-containing heterocycloalkyl; L1is absent, -CH2-, -O-, -OCH2-, or -CH2O-; Lais absent, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; R1is hydrogen or substituted or unsubstituted C1-C6alkyl; R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted C1- C6alkyl; R3is hydrogen 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, or 2; 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, or 2; x is 0, 1, 2, 3, or 4; each R8is independently hydrogen, 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 unsubstitutedC2-C10heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -L-R12; R8ais hydrogen, substituted or unsubstituted C1-C6alkyl, -(substituted or unsubstituted C1- C6alkyl)-CN, or -C(=O)-substituted or unsubstituted C1-C6alkyl); or R8aand one or more R8are taken together with the atoms to which they are attached to form a fused substituted or unsubstituted C2-C10heterocycloalkyl or substituted or unsubstituted heteroaryl; L is substituted or unsubstituted C1-C6alkyl, -N(R11)-(substituted or unsubstituted C1-C6alkyl), - O-(substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl; R11is hydrogen or substituted or unsubstituted C1-C6alkyl; R12is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd; 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 (VIa):or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0013] In some embodiments, described herein is a compound of Formula (X):Formula (X), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:R7 is;R1is hydrogen or substituted or unsubstituted C1-C6alkyl; R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted C1- C6alkyl; R3is hydrogen or substituted or unsubstituted C1-C6alkyl; R4is hydrogen or substituted or unsubstituted C1-C6alkyl; R20is hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; R21is 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, or 2; 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; x is 0, 1, 2, 3, or 4; each R8is independently hydrogen, 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, substituted or unsubstituted heteroaryl, or -L-R12;R8ais hydrogen, substituted or unsubstituted C1-C6alkyl, or -(substituted or unsubstituted C1- C6alkyl)-CN; or R8aand one or more R8are taken together with the atoms to which they are attached to form a fused substituted or unsubstituted C2-C10heterocycloalkyl or substituted or unsubstituted heteroaryl; L is substituted or unsubstituted C1-C6alkyl, -N(R11)-(substituted or unsubstituted C1-C6alkyl), - O-(substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl; R11is hydrogen or substituted or unsubstituted C1-C6alkyl; R12is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd; R22ais hydrogen or substituted or unsubstituted C1-C6alkyl; R22is -CH3, -CH2CH3, or -CH2CH2CH3; R23is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, halogen, -CN, -C(=O)Ra, -C(=O)NRcRd, or -NRbC(=O)Ra;R24is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, - NRcRd, or -ORa; R25is substituted or unsubstituted C1-C6alkyl; 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.

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

[0015] In some embodiments, described herein is a compound of Formula (XII):Formula (XII), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:; Ring A is C3-C6cycloalkyl or 4 to 6-membered N-containing heterocycloalkyl; L1is absent, -CH2-, -O-, -OCH2-, or -CH2O-; Lais absent, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; R1is hydrogen or substituted or unsubstituted C1-C6alkyl; R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted C1- C6alkyl; R3is hydrogen or substituted or unsubstituted C1-C6alkyl; R4is hydrogen or substituted or unsubstituted C1-C6alkyl; R20is hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; R21is 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, or 2;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; x is 0, 1, 2, 3, or 4; each R8is independently hydrogen, 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, substituted or unsubstituted heteroaryl, or -L-R12; R8ais hydrogen, substituted or unsubstituted C1-C6alkyl, or -(substituted or unsubstituted C1- C6alkyl)-CN; or R8aand one or more R8are taken together with the atoms to which they are attached to form a fused substituted or unsubstituted C2-C10heterocycloalkyl or substituted or unsubstituted heteroaryl; L is substituted or unsubstituted C1-C6alkyl, -N(R11)-(substituted or unsubstituted C1-C6alkyl), - O-(substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl; R11is hydrogen or substituted or unsubstituted C1-C6alkyl; R12is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd; R22ais hydrogen or substituted or unsubstituted C1-C6alkyl; R22is -CH3, -CH2CH3, or -CH2CH2CH3; R23is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, halogen, -CN, -C(=O)Ra, -C(=O)NRcRd, or -NRbC(=O)Ra;R24is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, - NRcRd, or -ORa; R25is substituted or unsubstituted C1-C6alkyl; R26is substituted or unsubstituted heteroaryl; 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 orunsubstituted 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.

[0016] In some embodiments, described herein is a compound of Formula (XIIa):Formula (XIIa), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0017] 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.

[0018] 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.

[0019] 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 pharmaceutically acceptable 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 someembodiments, 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 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.

[0020] 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.

[0021] 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.

[0022] In any of the aforementioned aspects are further embodiments in which the effective amount of the compound of Formula (I), 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.

[0023] 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 is administered on a continuous dosing schedule. In some embodiments, the compound is administered on a continuous daily dosing schedule.

[0024] In any of the embodiments disclosed herein, the mammal is a human.

[0025] Articles of manufacture, which include packaging material, a compound of Formula (I), 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.

[0026] 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

[0027] 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 INVENTION LpxC, Lipid A and Gram-Negative Bacteria

[0028] 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 gram- negative 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 gram- negative infections. To the contrary, LpxC is not a component of Gram-positive bacteria, such as Staphylococcus aureus.

[0029] 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. There remains a need for metalloprotein modulators of LpxC useful in the field of therapeutics, diagnostics, and research.

[0030] 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).

[0031] In some embodiments provided herein is a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient. Methods of Use

[0032] 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), a pharmaceutical composition comprising a compound of Formula (I), 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), a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0033] 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 gram-negative bacterial infection is hospital-acquired pneumonia (HAP). In some embodiments, the gram-negative bacterial infection is ventilator-associate pneumonia (VAP).

[0034] 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 has emphysema. In some embodiments, the patient has chronic obstructive pulmonary disease (COPD). In some embodiments, the patient has chronic destroyed lung disease.

[0035] In some embodiments the administration is to treat an existing infection.

[0036] In some embodiments the administration is provided as prophylaxis.

[0037] 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 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 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).

[0038] 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.

[0039] 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.

[0040] In some instances, antibiotics have suboptimal concentrations in the lung leading to therapeutic failures for lung infections. In some embodiments, the heterocyclic LpxC inhibitorycompound of Formula (I) 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.

[0041] In some embodiments, disclosed herein is a compound described herein, or a pharmaceutically acceptable salt or solvate thereof, for use as therapeutically active substance.

[0042] 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.

[0043] 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

[0044] 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.

[0045] In some embodiments, compounds of Formula (I), including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof, are UDP-{3-O- [(R)-3-hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) modulators. In some embodiments, the compounds of Formula (I), including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof, are UDP-{3-O-[(R)-3- hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) antagonists. In some embodiments, the compounds of Formula (I), including pharmaceutically acceptable salts, prodrugs, active metabolites, and pharmaceutically acceptable solvates thereof, are UDP-{3-O-[(R)-3- hydroxymyristoyl]}-N-acetylglucosamine deacetylase (LpxC) inhibitors.

[0046] In some embodiments, compounds of Formula (I), or pharmaceutically acceptable salts, solvates, or prodrugs thereof, have lower reactive metabolite formation as compared to known LpxC inhibitors. In some embodiments, compounds of Formula (I), or pharmaceutically acceptable salts, solvates, or prodrugs thereof, have lower glutathione (GSH) conjugate mediated toxicities as compared to known LpxC inhibitors.Compounds

[0047] In some embodiments, described herein is a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:; R1is hydrogen or substituted or unsubstituted C1-C6alkyl; R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; R3is hydrogen 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, or 2; 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; Y1is CR8or N; Y2is C(R8)2 or NR8a; x is 0, 1, 2, 3, or 4; each R8is independently hydrogen, 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, substituted or unsubstituted heteroaryl, or -L-R12;R8ais hydrogen, substituted or unsubstituted C1-C6alkyl, or -(substituted or unsubstituted C1- C6alkyl)-CN; or R8aand one or more R8are taken together with the atoms to which they are attached to form a fused substituted or unsubstituted C2-C10heterocycloalkyl or substituted or unsubstituted heteroaryl; L is substituted or unsubstituted C1-C6alkyl, -N(R11)-(substituted or unsubstituted C1-C6alkyl), -O- (substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl; R11is hydrogen or substituted or unsubstituted C1-C6alkyl; R12is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd; R9is substituted or unsubstituted heteroaryl, substituted or unsubstituted C2-C10heterocycloalkyl, -O- substituted or unsubstituted heteroaryl, -O-substituted or unsubstituted C2-C10heterocycloalkyl, - N(R11)-substituted or unsubstituted heteroaryl, -N(R11)-substituted or unsubstituted C2- C10heterocycloalkyl, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or - C(=O)NRcRd; R10ais halogen, -CN, -OH, -NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; R10bis halogen, -CN, -OH, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbS(=O)2Ra, -C(=O)Ra, -C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl, or -L-R12; R10cis substituted or unsubstituted heteroaryl, substituted or unsubstituted C2-C10heterocycloalkyl, - S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbC(=O)ORb, or - NRbS(=O)2Ra; 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.

[0048] In some embodiments, the compound of Formula (I) is a compound of Formula (Ia), (II), (IIa), (III), (IIIa), (IV), (IVa), (V), or (Va).

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

[0050] In some embodiments, R1is substituted or unsubstituted C1-C6alkyl. In some embodiments, R1is -CH3, -CH2CH3, or -CH(CH3)2. In some embodiments, R1is -CH3.

[0051] In some embodiments, R2aand R2bare each independently hydrogen. In some embodiments, R2ais hydrogen. In some embodiments, R2bis hydrogen.

[0052] In some embodiments, R3is hydrogen; and R4is hydrogen, -CH3, or -CH2CH3. In some embodiments, R3is hydrogen; and R4is hydrogen. In some embodiments, R3is hydrogen. In some embodiments, R4is hydrogen.

[0053] In some embodiments, R7is . In some embodiments, R7. In some embodiments, R7. . some embodiments,. .

[0054] In some embodiments, R7is . In some embodiments, Y1is CR8or N; and Y2is NR8a. In some embodiments, Y1is CR8; and Y2is NR8a. In some embodiments, Y1is N; and Y2is NR8a.,,

[0058] In some embodiments, x is 0, 1, or 2;each R8is independently hydrogen, halogen, -CN, -OH, -ORa, -OC(=O)Ra, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C3-C10cycloalkyl, substituted orunsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -L-R12; or R8aand one or more R8are taken together with the atoms to which they are attached to form a fused substituted or unsubstituted C2-C10heterocycloalkyl or substituted or unsubstituted heteroaryl; L is substituted or unsubstituted C1-C6alkyl, -N(R11)-(substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl; R11is hydrogen or substituted or unsubstituted C1-C6alkyl; R12is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd; each Rais independently substituted or unsubstituted C1-C6alkyl; each Rbis independently hydrogen or substituted or unsubstituted C1-C6alkyl; each Rcand Rdare 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.

[0059] In some embodiments, x is 0, 1, or 2; each R8is independently hydrogen, halogen, -CN, -OH, -ORa, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbS(=O)2Ra, - C(=O)Ra, -C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted heteroaryl, or -L-R12; or R8aand one or more R8are taken together with the atoms to which they are attached to form a fused substituted or unsubstituted C2-C10heterocycloalkyl or substituted or unsubstituted heteroaryl; L is substituted or unsubstituted C1-C6alkyl, -N(H)-(substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl; R12is -CN, -OH, -ORa, or -NRcRd; each Rais independently substituted or unsubstituted C1-C6alkyl; each Rbis independently hydrogen or substituted or unsubstituted C1-C6alkyl; each Rcand Rdare 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.

[0060] In some embodiments, x is 0, 1, or 2; each R8is independently hydrogen, halogen, -CN, -OH, -ORa, - S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbS(=O)2Ra, -C(=O)Ra, - C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted heteroaryl, or -N(R11)-(substituted or unsubstituted C1-C6alkyl)-CN, or -(substituted or unsubstituted C1-C6heteroalkyl)-CN; or R8aand one or more R8are taken together with the atoms to which they are attached to form a fused substituted or unsubstituted C2-C10heterocycloalkyl or substituted or unsubstituted heteroaryl; R11is hydrogen or -CH3; each Rais independently -CH3 or -CH2CH3; each Rbis independently hydrogen, - CH3, or -CH2CH3; each Rcand Rdare independently hydrogen, -CH3, or -CH2CH3; or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C6heterocycloalkyl.

[0061] In some embodiments, R8ais hydrogen or -(substituted or unsubstituted C1-C6alkyl)-CN. In some embodiments, R8ais hydrogen, -CH2CN, -CH2CH2CN, or -CH2CH2CH2CN. In someembodiments, R8ais hydrogen or -CH2CN. In some embodiments, R8ais hydrogen. In some embodiments, R8ais -CH2CN.

[0062] In some embodiments, described herein is a compound of Formula (II):Formula (II), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.e

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

[0064] In some embodiments, each R8is independently hydrogen, halogen, -CN, -OH, -ORa, - OC(=O)Ra, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, - NRbS(=O)2Ra, -C(=O)Ra, -C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted heteroaryl, or -L-CN; L is substituted or unsubstituted C1-C6alkyl, -N(R11)-(substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl; R11is hydrogen or -CH3-; each Rais independently - CH3 or -CH2CH3; each Rbis independently hydrogen, -CH3, or -CH2CH3; each Rcand Rdare independently hydrogen, -CH3, or -CH2CH3; or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C6heterocycloalkyl.

[0065] In some embodiments,.,.

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

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

[0069] In some embodiments, R9is substituted or unsubstituted heteroaryl, substituted or unsubstituted C2-C10heterocycloalkyl, -O-substituted or unsubstituted heteroaryl, -O-substituted or unsubstituted C2-C10heterocycloalkyl, -N(R11)-substituted or unsubstituted heteroaryl, or -N(R11)- substituted or unsubstituted C2-C10heterocycloalkyl; and R11is hydrogen or -CH3. In some embodiments, R9is substituted or unsubstituted monocyclic heteroaryl, -O-substituted orunsubstituted monocyclic heteroaryl, or -N(R11)-substituted or unsubstituted monocyclic heteroaryl, wherein monocyclic heteroaryl is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl; and R11is hydrogen or -CH3. In some embodiments, R9is substituted or unsubstituted monocyclic heteroaryl, -O-substituted or unsubstituted monocyclic heteroaryl, or -N(R11)-substituted or unsubstituted monocyclic heteroaryl, wherein monocyclic heteroaryl is pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl; and R11is hydrogen or -CH3.

[0070] In some embodiments, R9is -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd.

[0071] In some. In some embodiments,,.

[0075] In some embodiments, described herein is a compound of Formula (IV):Formula (IV), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0076] In some embodiments, described herein is a compound of Formula (IVa):Formula (IVa), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0077] In some embodiments, R10ais -F, -Cl, -CN, -OH, -NH2, -CH3, or -CH2CH3; and R10bis halogen, -CN, -S(=O)2NRcRd, -NRbC(=O)Ra, -C(=O)Ra, -C(=O)NRcRd, substituted or unsubstitutedC1-C6alkyl, -N(H)-(substituted or unsubstituted alkyl)-CN, or -(substituted or unsubstituted C1-C6heteroalkyl)-CN. In some embodiments, R10ais -OH, -NH2, or -CH3; and R10bis -CN, - C(=O)NRcRd, -N(H)-(substituted or unsubstituted alkyl)-CN, or -(substituted or unsubstituted C1-C6heteroalkyl)-CN.

[0078] In some embodiments,. ,

[0080] In some embodiments, described herein is a compound of Formula (V):Formula (V), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0081] In some embodiments, described herein is a compound of Formula (Va):Formula (Va), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0082] In some embodiments, R10cis substituted or unsubstituted heteroaryl, substituted or unsubstituted C2-C10heterocycloalkyl, -S(=O)2Ra, -S(=O)2NRcRd, -NRbC(=O)Ra, or -NRbS(=O)2Ra. In some embodiments, R10cis substituted or unsubstituted monocyclic heteroaryl. In some embodiments, R10cis substituted or unsubstituted monocyclic heteroaryl, wherein monocyclicheteroaryl is pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl. In some embodiments, R10cis triazolyl.. .

[0085] In some embodiments, described herein is a compound of Formula (VI):Formula (VI), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:; Ring A is C3-C6cycloalkyl or 4 to 6-membered N-containing heterocycloalkyl; L1is absent, -CH2-, -O-, -OCH2-, or -CH2O-; Lais absent, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; R1is hydrogen or substituted or unsubstituted C1-C6alkyl; R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted C1- C6alkyl; R3is hydrogen 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, or 2; 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, or 2; x is 0, 1, 2, 3, or 4; each R8is independently hydrogen, 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 unsubstitutedC2-C10heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -L-R12; R8ais hydrogen, substituted or unsubstituted C1-C6alkyl, -(substituted or unsubstituted C1- C6alkyl)-CN, or -C(=O)-substituted or unsubstituted C1-C6alkyl); or R8aand one or more R8are taken together with the atoms to which they are attached to form a fused substituted or unsubstituted C2-C10heterocycloalkyl or substituted or unsubstituted heteroaryl; L is substituted or unsubstituted C1-C6alkyl, -N(R11)-(substituted or unsubstituted C1-C6alkyl), - O-(substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl; R11is hydrogen or substituted or unsubstituted C1-C6alkyl; R12is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd; 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.

[0086] In some embodiments, the compound has a structure of Formula (VIa):or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0087] In some embodiments, Lais absent. In some embodiments, Lais substituted or unsubstituted C1-C6alkyl. In some embodiments, Lais -CH2-.

[0088] In some.

[0089] In some embodiments, Ring A is C3-C6cycloalkyl. In some.

[0090] In some embodiments, Ring A is 4 to 6-membered N-containing heterocycloalkyl. In some , ,with the atoms to which they are attached to form a fused substituted or unsubstituted C2- C10heterocycloalkyl or substituted or unsubstituted heteroaryl.

[0093] In some.

[0094] In some embodiments, R8is hydrogen, -OH, -NRbC(=O)Ra, oxo, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, or substituted or unsubstituted heteroaryl;and R8ais hydrogen, substituted or unsubstituted C1-C6alkyl, or -C(=O)-substituted or unsubstituted C1-C6alkyl). In some embodiments, R8is hydrogen, -OH, -CH2OH,-NHC(=O)CH3, oxo, -CH3, substituted or unsubstituted C1-C6heteroalkyl, or substituted or unsubstituted triazole; and R8ais hydrogen, -CH3, or -C(=O)-CH3. In some embodiments, R8is hydrogen; and R8ais hydrogen.

[0095] In some embodiments, L1is absent. In some embodiments, L1is -CH2-, -O-, -OCH2-, or - CH2O-.

[0099] In some embodiments, described herein is a compound of Formula (X):Formula (X), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:;R1is hydrogen or substituted or unsubstituted C1-C6alkyl; R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted C1- C6alkyl; R3is hydrogen or substituted or unsubstituted C1-C6alkyl; R4is hydrogen or substituted or unsubstituted C1-C6alkyl; R20is hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; R21is 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, or 2; 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; x is 0, 1, 2, 3, or 4; each R8is independently hydrogen, 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, substituted or unsubstituted heteroaryl, or -L-R12; R8ais hydrogen, substituted or unsubstituted C1-C6alkyl, or -(substituted or unsubstituted C1- C6alkyl)-CN; or R8aand one or more R8are taken together with the atoms to which they are attached to form a fused substituted or unsubstituted C2-C10heterocycloalkyl or substituted or unsubstituted heteroaryl; L is substituted or unsubstituted C1-C6alkyl, -N(R11)-(substituted or unsubstituted C1-C6alkyl), - O-(substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl; R11is hydrogen or substituted or unsubstituted C1-C6alkyl; R12is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd;R22ais hydrogen or substituted or unsubstituted C1-C6alkyl; R22is -CH3, -CH2CH3, or -CH2CH2CH3;R23is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, halogen, -CN, -C(=O)Ra, -C(=O)NRcRd, or -NRbC(=O)Ra; R24is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, - NRcRd, or -ORa; R25is substituted or unsubstituted C1-C6alkyl; 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.

[0100] In some embodiments, the compound has a structure of Formula (XI):Formula (XI), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0101] In some embodiments, the compound has a structure of Formula (XII):Formula (XII), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:; Ring A is C3-C6cycloalkyl or 4 to 6-membered N-containing heterocycloalkyl; L1is absent, -CH2-, -O-, -OCH2-, or -CH2O-; Lais absent, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; R1is hydrogen or substituted or unsubstituted C1-C6alkyl; R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted C1- C6alkyl; R3is hydrogen or substituted or unsubstituted C1-C6alkyl; R4is hydrogen or substituted or unsubstituted C1-C6alkyl; R20is hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; R21is 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, or 2; 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; x is 0, 1, 2, 3, or 4; each R8is independently hydrogen, 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 unsubstitutedC2-C10heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -L-R12; R8ais hydrogen, substituted or unsubstituted C1-C6alkyl, or -(substituted or unsubstituted C1- C6alkyl)-CN; or R8aand one or more R8are taken together with the atoms to which they are attached to form a fused substituted or unsubstituted C2-C10heterocycloalkyl or substituted or unsubstituted heteroaryl; L is substituted or unsubstituted C1-C6alkyl, -N(R11)-(substituted or unsubstituted C1-C6alkyl), - O-(substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl; R11is hydrogen or substituted or unsubstituted C1-C6alkyl; R12is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd; R22ais hydrogen or substituted or unsubstituted C1-C6alkyl; R22is -CH3, -CH2CH3, or -CH2CH2CH3;R23is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, halogen, -CN, -C(=O)Ra, -C(=O)NRcRd, or -NRbC(=O)Ra; R24is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, - NRcRd, or -ORa; R25is substituted or unsubstituted C1-C6alkyl; R26is substituted or unsubstituted heteroaryl; 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.

[0102] In some embodiments, the compound has a structure of Formula (XIIa):Formula (XIIa), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[00103] In some.

[0104] In some embodiments, Ring A is 4 to 6-membered N-containing heterocycloalkyl..

[0106] In some embodiments, R7. In some embodiments, R26is substituted or unsubstituted 5-6 membered heteroaryl. In some embodiments, R26is substituted or unsubstituted imidazolyl, oxadiazolyl, or triazolyl. In some, ..

[00108] In some embodiments,..

[0110] In some embodiments, R8is hydrogen.

[0111] In some embodiments, R20is hydrogen; and R21is hydrogen..

[0113] In some embodiments, R7is. In someis .

[00114] In some. In some.

[0116] In some embodiments, each R5is independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; s is 0 or 1; each R6is independently hydrogen, halogen, -CN, -OH, -ORa, - NRcRd, or substituted or unsubstituted C1-C6alkyl; and t is 0 or 1. 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.

[0117] In some embodiments, the compound is a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound is a diastereomerof a compound of Table 1, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound is a prodrug of a compound 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 solvate thereof. In some embodiments, the compound is a pharmaceutically acceptable salt of a prodrug of a compound of Table 1, or solvate thereof. Table 1:,*stereochemistry at tail chiral center(s) arbitrarily defined

[0118] In some embodiments, described herein is a compound having the structure:pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0119] In some embodiments, described herein is a compound having the structure:,a pharmaceutically acceptable salt, solvate, or prodrug thereof.

[0120] In some embodiments, described herein is a compound having the structure:prodrug thereof.

[0121] In some embodiments, the compound is a compound of Table 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound is a diastereomer of a compound of Table 2, or a pharmaceutically acceptable salt, solvate, or prodrug thereof. In some embodiments, the compound is a prodrug 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 a solvate thereof. In some embodiments, the compound is a pharmaceutically acceptable salt of a prodrug of a compound of Table 2, or a solvate thereof.Table 2:*stereochemistry at tail chiral center(s) arbitrarily defined

[0122] In some embodiments, described herein is a compound having the structure: ,pharmaceutically acceptable salt, solvate, or prodrug thereof. Prodrugs

[0123] 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.79, 2124 (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 groupthat, 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. Further Forms of Compounds

[0124] 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.

[0125] “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.

[0126] 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 / Zürich: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.

[0127] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I), (VI), (X), or (XII) with an acid. In some embodiments, the compound of Formula (I), (VI), (X), or (XII) (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, 1-hydroxy-2-naphthoic acid; 2,2-dichloroacetic acid; 2-hydroxyethanesulfonic 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-1,5-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 (p); and undecylenic acid.

[0128] In some embodiments, a compound of Formula (I), (VI), (X), or (XII) is prepared as a chloride salt, sulfate salt, bromide salt, mesylate salt, maleate salt, citrate salt or phosphate salt.

[0129] In some embodiments, pharmaceutically acceptable salts are obtained by reacting a compound of Formula (I), (VI), (X), or (XII) with a base. In some embodiments, the compound of Formula (I), (VI), (X), or (XII)is acidic and is reacted with a base. In such situations, an acidic proton of the compound of Formula (I), (VI), (X), or (XII)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. 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.

[0130] 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 with pharmaceutically 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.

[0131] The methods and formulations described herein include the use of N-oxides (if appropriate), or pharmaceutically acceptable salts of compounds having the structure of Formula (I), (VI), (X), or (XII), as well as active metabolites of these compounds having the same type of activity.

[0132] In some embodiments, sites on the organic radicals (e.g., alkyl groups, aromatic rings) of compounds of Formula (I), (VI), (X), or (XII) 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.

[0133] 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.

[0134] 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,17O,35S,18F,36Cl,123I,124I,125I,131I,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.

[0135] In some embodiments, the compounds of Formula (I), (VI), (X), or (XII) 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), (VI), (X), or (XII) exists in the R configuration. In some embodiments, the compound of Formula (I), (VI), (X), or (XII) 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.

[0136] 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), (VI), (X), or (XII) 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 usingcovalent 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.

[0137] 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.

[0138] 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.

[0139] 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

[0140] 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.

[0141] 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.

[0142] As used herein, C1-Cxincludes C1-C2, C1-C3... C1-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, iso-propyl, n-butyl, iso-butyl, sec- butyl, and t-butyl.

[0143] 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 C1-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.

[0144] 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 C1-C4alkylene. Typical alkylene groups include, but are not limited to, -CH2-, -CH2CH2-, - CH2CH2CH2-, -CH2CH2CH2CH2-, and the like. In some embodiments, an alkylene is -CH2-.

[0145] An “alkoxy” group refers to a –O(alkyl) group, where alkyl is as defined herein.

[0146] 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.

[0147] An “hydroxyalkyl” refers to an alkyl in which one hydrogen atom is replaced by a hydroxyl. In some embodiments, a hydroxyalkyl is a C1-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.

[0148] An “aminoalkyl” refers to an alkyl in which one hydrogen atom is replaced by an amino. In some embodiments, aminoalkyl is a C1-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.

[0149] 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)=CR2, 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.

[0150] 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, -C≡CCH3 -C≡CCH2CH3, - CH2C≡CH.

[0151] 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, aheteroalkyl is a C1-C6heteroalkyl where one or two atoms are independently selected from O, NH, and S.

[0152] The term “aromatic” refers to a planar ring having a delocalized ^-electron system containing 4n+2 ^ 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.

[0153] 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.

[0154] 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 C6-C10aryl. Depending on the structure, an aryl group is a monoradical or a diradical (i.e., an arylene group).

[0155] 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, norbornyl and bicyclo[1.1.1]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.

[0156] The term “halo” or, alternatively, “halogen” or “halide” means fluoro, chloro, bromo or iodo. In some embodiments, halo is fluoro, chloro, or bromo.

[0157] 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.

[0158] 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 eachheteroatom 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-1-onyl, isoindoline-1,3-dionyl, 3,4-dihydroisoquinolin-1(2H)-onyl, 3,4-dihydroquinolin- 2(1H)-onyl, isoindoline-1,3-dithionyl, benzo[d]oxazol-2(3H)-onyl, 1H-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-1-yl (N-attached) or pyrrol- 3-yl (C-attached). Further, a group derived from imidazole includes imidazol-1-yl or imidazol-3-yl (both N-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 (=O) moieties, such as pyrrolidin-2-one. In some embodiments, at least one of the two rings of a bicyclic heterocycle is aromatic. In some embodiments, both rings of a bicyclic heterocycle are aromatic.

[0159] 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 someembodiments, 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 O atoms, and 0-1 S atoms in the ring. In some embodiments, a heteroaryl contains 1-4 N atoms, 0-1 O atoms, and 0-1 S atoms in the ring. In some embodiments, heteroaryl is a C1-C9heteroaryl. In some embodiments, monocyclic heteroaryl is a C1-C5heteroaryl. In some embodiments, monocyclic heteroaryl is a 5-membered or 6-membered heteroaryl. In some embodiments, bicyclic heteroaryl is a C6-C9heteroaryl.

[0160] 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.

[0161] 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.

[0162] 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.

[0163] 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(C1-C4alkyl), -C(=O)NH2, -C(=O)NH(C1-C4alkyl), - C(=O)N(C1-C4alkyl)2, -S(=O)2NH2, -S(=O)2NH(C1-C4alkyl), -S(=O)2N(C1-C4alkyl)2, C1-C4alkyl, C3-C6cycloalkyl, C1-C4fluoroalkyl, C1-C4heteroalkyl, C1-C4alkoxy, C1-C4fluoroalkoxy, -SC1-C4alkyl, -S(=O)C1-C4alkyl, and -S(=O)2C1-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 (=O).

[0164] 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- C6heterocycloalkyl, 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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 includetreatment regimens in which the agents are administered by the same or different route of administration or at the same or different time.

[0170] 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.

[0171] 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.

[0172] 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), (VI), (X), or (XII), 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), (VI), (X), or (XII), or a pharmaceutically acceptable salt or solvate thereof, and a co-agent, are administered to a patient as separate entities either simultaneously, concurrently or sequentially with no specific intervening time limits, wherein such administration provides effective levels 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.

[0173] The terms “article of manufacture” and “kit” are used as synonyms.

[0174] 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.

[0175] 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, relievinga secondary condition caused by the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically. Pharmaceutical Compositions

[0176] 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)).

[0177] 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.

[0178] Some embodiments provide a pharmaceutical composition comprising a compound of Formula (I), (VI), (X), or (XII), or a pharmaceutically acceptable salt or solvate thereof, and a pharmaceutically acceptable excipient.

[0179] In certain embodiments, the heterocyclic LpxC inhibitory compound as described by Formula (I), (VI), (X), or (XII)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.

[0180] 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)).

[0181] 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.

[0182] 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 thepatient'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.

[0183] Oral doses typically range from about 1.0 mg to about 1000 mg, one to four times, or more, per day. Preparation of Compounds

[0184] Compounds of Formula (I), (VI), (X), or (XII)described herein are synthesized using standard synthetic techniques or using methods known in the art in combination with methods described herein.

[0185] Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC are employed.

[0186] 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.

[0187] In some embodiments, described herein is a process for the preparation of a compound of Formula (I), comprising: (1) contacting a compound of Formula (A):with a compound of Formula (B):Formula (B), to provide a compound of Formula (C):Formula (C); and (2) removing PG to provide a compound of Formula (I), wherein: R1, R2a, R2b, R3, R4, R5, R6, R7, s, and t are defined in any one of claims 1-52; PG is a protecting group; X is halogen, -OTs, or -OMs; and B is a boronic acid, boronic ester, or trifluoroborate.

[0188] 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 tert- butyldimethylsilyl (TBS).

[0189] In some embodiments, X is a halogen, -OTs, or -OMs. In some embodiments, X is -Cl, -Br, -I, -OTs, or -OMs. In some embodiments, X is -Cl, -Br, or -I. In some embodiments, X is -BR. In some embodiments, X is -OTs. In some embodiments, X is -OMs.

[0190] In some embodiments, B is a boronic acid or boronic ester. In some embodiments, B is. . In some embodiments, B. In some embodiments, B is a trifluoroborate. In some embodiments, B is .

[0191] In some embodiments, compounds described herein are prepared as described in Scheme A.Scheme A:

[0192] An organometallic coupling reaction such as Suzuki–Miyaura reaction between Intermediate A and the appropriate aryl boronic acid or its ester or an organotrifluoroborate (BF3K) B provided Intermediate C. Removal of the protecting group using appropriate deprotection methods yielded final Compound D.

[0193] In some embodiments, compounds are prepared as described in the Examples. EXAMPLES

[0194] 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-butoxycarbonyl; 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); HCl: 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; MeNO2; nitromethane; mg: milligrams; min: minute; mL: milliliter; mmol: millimole; MsCl: methanesulfonyl (mesyl) chloride; MTBE: methyl tert-butyl ether; N: normal; NBS: N-bromosuccinimide; NMR: nuclear magnetic resonance; Pet ether: petroleum ether; PdCl2(dppf): [1,1'‑Bis(diphenylphosphino)ferrocene]palladium(II) dichloride; PdCl2(dtbpf): bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II); Pd(PPh3)4: palladium-tetrakis(triphenylphosphine); POCl3: phosphoryl trichloride; PPTS: pyridinium p-toluenesulfonate; p-TSA: para-toluenesuflonic acid; Py: pyridine; rt: room temperature; SFC: supercritical fluid chromatography; TEA: triethylamine (or Et3N); TFA: trifluoroacetic acid; THF: tetrahydrofuran; THP: tetrahydropyran; TLC: thin layer chromatography; TsCl: para-toluenesulfonyl (tosyl) chloride.

[0195] The following examples are provided for illustrative purposes only and not to limit the scope of the claims provided herein. I. Chemical Synthesis

[0196] 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 (^) 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

[0197] Step 1:

[0198] To a solution of 1 (1.4 g, 4.74 mmol) in DMF (20 mL), were added triethylamine (5.28 mL, 37.9 mmol) and bromoacetonitrile (2, 0.990 mL, 14.21 mmol) at 0 °C, and the resulting reaction mixture stirred at room temperature for 16 h. The reaction mixture was then quenched with water (40 mL) and extracted with EtOAc (60 mL x 3). The combined organic layer was 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; 94% EtOAc in hexanes) to obtain 3 as a white solid. LC-MS: Calculated C17H23BN2O2 is 298.19, Observed: 299.2 [M+1]+. Yield: 700 mg (46%)

[0199] Step 2:

[0200] To a stirred solution of 4 (450 mg, 1.073 mmol) in dioxane (10 mL) and water (2.5 mL), were added 3 (384 mg, 1.288 mmol) and potassium phosphate tribasic (683 mg, 3.22 mmol) at room temperature, and the reaction mixture purged with nitrogen for 5 min. To this reaction mixture, PdCl2(dppf)-DCM adduct (88 mg, 0.107 mmol) was added and the purging continued for another 2min. The resulting reaction mixture was then stirred at 85 °C for 16 h. After the reaction mixture was cooled to room temperature, the inorganic solids were filtered through a Celite pad and washed with EtOAc (80 mL). The combined filtrate was concentrated under reduced pressure. The crude mass, thus obtained, was purified by using MPLC (manually packed SiO2 cartridge, 230-400 mesh size; 6% MeOH in DCM) to afford 5 as a brown gum. LCMS showed 71% purity; this was taken as such to the next step without further purification). Yield: 400 mg (52%). LC-MS: Calculated for C31H34N4O3is 510.64, Observed:^511.3 [M+1]+

[0201] Step 3:

[0202] To a stirred solution of 5 (400 mg, 0.783 mmol) in MeOH (8 mL), was added p- toluenesulfonic acid monohydrate (447 mg, 2.350 mmol) at 0 °C and the reaction mixture stirred at room temperature for 1 h. The volatiles were evaporated under reduced pressure. The resulting residue was basified with 10% NaHCO3solution (8 mL) and extracted with 10% MeOH in DCM (50 mL x 2). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude mass, thus obtained, was purified by reverse phase preparative HPLC (Column: X-select CSH C18 (250*19 mm), 5 µm, Eluents: 10 mM ammonium bicarbonate in water and acetonitrile) to afford Compound 1 as an off-white solid. Yield = 50 mg (13%). LC-MS: Calculated for C26H26N4O2 is 426.52, Observed: 427.3 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.72-7.67 (m, 4H), 7.55 (d, J = 8.40 Hz, 2H), 7.47 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 6.84 (d, J = 0.80 Hz, 1H), 5.70 (t, J = 5.60 Hz, 1H), 5.54 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.38 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.97-4.91 (m, 1H), 3.87 (t, J = 6.00 Hz, 2H), 3.76-3.71 (m, 5H), 3.32 (m, 2H, merges with solvent water), 1.51 (d, J = 6.40 Hz, 3H). SFC: 91.6%, tR = 2.80 min (Column: Whelk-(R,R); Eluents: CO2 and 0.5% isopropyl amine in MeOH)

[0203] Note: SFC purity 91.6%; base line impurities seen in NMR. Example 2: Synthesis of Compound 2

[0204] Step 1:

[0205] To a stirred solution of 1 (300 mg, 0.747 mmol) in DMF (5 mL), was added TEA (0.648 mL, 4.48 mmol) at 0 °C. The reaction mixture was stirred at same temperature for 10 min. Then, methylcarbamic chloride (2, 105 mg, 1.121 mmol) was added and stirred at room temperature for 2 h. The reaction was quenched with water (20 mL), extracted with DCM (20 mL). The combinedorganic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude residue was purified by reversed phase column chromatography using MPLC (Column: Redisep Gold C-18; Eluents: 10 mM ammonium bicarbonate in water and ACN) to get 55 mg of product.1H NMR showed extraneous peaks with SFC purity 93.1%. The product was re-purified by SFC (Column: RR whelk (250*20) mm, 5 μm; Eluents: CO2: 0.5% isopropyl amine in MeOH [60:40]). The fractions were concentrated. The resulting residue dissolved in 10% MeOH in DCM (30 mL) and washed with water (20 mL). The organic layer was dried over anhydrous Na2SO4, filtered, concentrated, and lyophilized to afford Compound 2 as an off-white solid. Yield = 31 mg (25%). LC-MS: Calculated for C27H30N4O3 is 458.56, Observed: 459.2 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.69 (d, J = 1.6, 6.6 Hz, 2H), 7.62 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 1.6, 6.6 Hz, 2H), 7.36 (d, J = 1.2 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 6.84 (d, J = 1.2 Hz, 1H), 6.13 (q, J = 4.8 Hz, 1H, exchanges with D2O), 5.69 (t, J = 6.0 Hz, 1H), 5.54 (t, J = 4.4 Hz, 1H, exchanges with D2O), 5.38 (d, J = 5.6 Hz, 1H, exchanges with D2O), 4.97- 4.92 (m, 1H), 3.87 (t, J = 5.2 Hz, 2H), 3.81(t, J = 6.8 Hz, 2H), 3.52-3.49 (m, 2H), 2.90-2.74 (m, 3H), 2.52 (d, J = 5.2 Hz, 3H), 1.51 (d, J = 6.40 Hz, 3H). SFC: 100%; tR= 2.69 min (Column: Whelk- (R,R); Eluents: CO2 and 0.5% isopropyl amine in MeOH)

[0206] Note: Single isomer with SFC purity = 100% Example 3: Synthesis of Compound 3

[0207] Step 1:

[0208] To a solution of (4-bromophenyl) boronic acid (1, 12.66 g, 63.0 mmol) in DCM (125 mL), were added 2-Boc-2,6-diazaspiro[3.3]heptane (2, 2.5 g, 12.61 mmol) and copper(II) acetate monohydrate (6.29 g, 31.5 mmol) and triethylamine (8.86 mL, 63.0 mmol) under oxygen and theresulting reaction mixture stirred at room temperature for 48 h. The reaction mixture was cooled to room temperature, filtered through the Celite bed. The combined filtrate was concentrated under reduced pressure, and the resulting crude mass purified by using MPLC (manually packed SiO2 cartridge, 100-200 mesh; 22% EtOAc in hexanes) to afford 3 as a colourless liquid. LC-MS: Calculated C16H21BrN2O2 is 353.26, Observed: 353.2 [M]+and 355.2 [M+2]+. Yield: 1.8 g (34%). Two more batches were carried out using 0.5 g and 0.3 g of 2 to get 125 mg and 165 mg of 3 and taken together for the next step.

[0209] Step 2:

[0210] To a solution of 3 (2.09 g, 5.92 mmol) in DCM (22 mL), was added TFA (2.91 mL, 38.0 mmol) at 0 °C, and the resulting reaction mixture stirred at room temperature for 6 h. The reaction mixture was then concentrated under reduced pressure. The crude residue was co-distilled with hexane (2 x 20 mL) under reduced pressure to afford crude 4 as brown gum. LC-MS: Calculated C11H13BrN2is 253.14, Observed: 253.2 [M]+and 255.2 [M+2]+. Yield: 1.8 g (crude).

[0211] Step 3:

[0212] To a solution of 4 (1.8 g, 4.90 mmol) in DMF (20 mL), were added triethylamine (4.13 mL, 29.4 mmol) and bromoacetonitrile (0.512 mL, 7.35 mmol) at 0 °C, and the resulting reaction mixture stirred at room temperature for 2 h .The reaction mixture was quenched with water (100 mL) and extracted with DCM (2 x 100 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude mass was purified by using MPLC (manually packed cartridge; SiO2100-200 mesh; 32% EtOAc in hexanes) to afford 5 as a colourless liquid. LC-MS: Calculated C13H14BrN3 is 292.18, Observed: 292.1 [M]+and 294.1 [M+2]+. Yield: 1.2 g (83%)

[0213] Step 4:

[0214] To a solution of 5 (1.2 g, 4.11 mmol) in 1,4-dioxane (12 mL), were added potassium acetate (1.209 g, 12.32 mmol) and bis(pinacolato)diboron (1.564 g, 6.16 mmol) at room temperature and the resulting mixture purged with nitrogen for 10 min. To this reaction mixture, PdCl2(dppf).DCM adduct (0.168 g, 0.205 mmol) was added and the purging continued for another 2 min. The reaction mixture was stirred at 90 °C for 3 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude mass was purified by using MPLC (manually packed cartridge; SiO2100-200 mesh; 55% EtOAc in hexanes) to afford 6 as a colourless liquid.1H-NMR showed extraneous peaks; product was taken to the next step without further purification. LC-MS: Calculated C19H26BN3O2is 339.25, Observed: 340.2 [M+1]+. Yield: 1.7 g (crude)

[0215] Step 5:

[0216] To a stirred solution of 7 (1.35 g, 3.22 mmol) in THF (22 mL) and water (4 mL), were added 6 (1.638 g, 4.83 mmol) and tripotassium phosphate (2.05 g, 9.66 mmol) at room temperature and the reaction mixture purged with nitrogen for 5 min. To this reaction mixture, Sphos Pd G2 (0.232 g, 0.322 mmol) was added, and the purging continued for another 2 min. The resulting reaction mixture was stirred at 75 °C for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by using MPLC (manually packed SiO2cartridge, 100-200 mesh size; 3% MeOH in DCM) to afford 8 as a colorless liquid. LC-MS: Calculated for C33H37N5O3 is 551.69, Observed:^552.3 [M+1]+. Yield: 410 mg (16%)

[0217] Step 6:

[0218] To a stirred solution of 8 (400 mg, 0.725 mmol) in acetonitrile (6 mL) and water (6 mL), was added acetic acid (1.659 mL, 29.0 mmol) at 0oC, and the resulting reaction mixture stirred at 70oC for 16 h. The reaction mixture was concentrated under reduced pressure and quenched with water (50 mL), neutralized (pH~7) by using sodium bicarbonate. The aqueous layer was extracted with DCM (2 x 50 mL). The combined organic extract was washed with brine solution (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude mass, thus obtained, was purified by preparative HPLC (Column: X-Bridge C18(4.6 x 150 mm), 5 μm; Eluents:10 mM ammonium bicarbonate in water and acetonitrile) to obtain Compound 3 as an off-white solid. Yield: 32 mg (9%). LC-MS: Calculated for C28H29N5O2is 467.57, Observed:^468.2 [M+1]+.1H- NMR (400 MHz, DMSO-d6): δ 7.61 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.8 Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 1.2 Hz, 1H), 6.84 (d, J = 1.2 Hz, 1H), 6.51 (d, J = 8.4 Hz, 2H), 5.68 (t, J = 6.0 Hz, 1H), 5.52 (t, J = 5.6 Hz, 1H, exchanges with D2O), 5.36 (d, J = 5.6 Hz, 1H, exchanges with D2O), 4.98-4.90 (m, 1H), 3.95 (s, 4H), 3.86 (t, J = 5.6 Hz, 2H), 3.64 (s, 2H), 3.45 (s, 4H), 1.51 (d, J = 6.4 Hz, 3H). SFC: 94.9%; tR= 7.77 min (Column: LUX-I-Amylose 3; Eluents: CO2and 0.5% isopropyl amine in MeOH)

[0219] Note: SFC purity = 94.9%Example 4: Synthesis of Compound 4

[0220] Step 1:

[0221] To a stirred solution of methyl 2-(4-bromophenoxy)propanoate ((±)-1, 10 g, 38.6 mmol) in MeOH (60 mL) was added 30% aq. ammonia (55.7 mL, 772 mmol) at 25 ℃, and the reaction mixture stirred at 50 ℃ for 16 h in an autoclave. The volatiles were evaporated under reduced pressure. The crude residue, thus obtained, was triturated with 10% MTBE in hexanes (20 mL). The solid obtained was filtered and dried under vacuum to afford (±)-2 as an off-white solid. Yield: 9.5 g (75%). LCMS: Calculated for C9H10BrNO2 is 244.09, observed: 243.8 [M]+and 245.8 [M+2]+

[0222] Step 2:

[0223] To a stirred solution of (±)-2 (9.5 g, 38.9 mmol) in THF (100 mL), was added borane tetrahydrofuran complex (1.0 M in THF; 156 mL, 156 mmol) at 0 ℃, and the reaction mixture stirred at 70 ℃ for 16 h. The reaction mixture was cooled to 0 ℃, and was quenched with MeOH (150 mL, 16.39 mmol), following which it was stirred at 60 ℃ for 2 h. The residual solvent was removed under reduced pressure, and the crude residue was purified by using reverse phase column chromatography (column: Redisep Gold, C18 SiO2; eluents: 10 mM ammonium bicarbonate in water and acetonitrile) to yield (±)-3 as an off-white solid. Yield: 4.5 g (42%). LCMS: Calculated for C9H12BrNO is 230.11, observed: 230.2 [M]+and 232.0 [M+2]+

[0224] Step 3:

[0225] To a stirred solution of (±)-3 (5.6 g, 24.34 mmol) in THF (60 mL), were added DIPEA (12.75 mL, 73.0 mmol), DMAP (0.297 g, 2.434 mmol) and Boc-anhydride (8.48 mL, 36.5 mmol) at 0 ℃, and the reaction mixture stirred at room temperature for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 x 80 mL). The combined organic layer was washed with brine solution (50 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed SiO2cartridge, 230-400 mesh size; 10% EtOAc in hexanes) to afford (±)-4 as colorless liquid. Yield: 4 g (45%). LCMS: Calculated for C14H20BrNO3is 330.22, observed: 230.2 [M-Boc]+and 232.0 [(M- Boc)+2]+

[0226] Step 4:

[0227] To a stirred solution of (±)-4 (4 g, 12.11 mmol) in 1,4-dioxane (100 mL), were added bis(pinacolato) diboron (4.92 g, 19.38 mmol) and potassium acetate (3.57 g, 36.3 mmol) at 25 ℃, and the reaction mixture degassed with nitrogen for 15 min. To this mixture, PdCl2(dppf).DCM adduct was added (0.989 g, 1.211 mmol), and the reaction mixture stirred at 90 ℃ for 16 h. The reaction mixture was cooled to 25 ℃, diluted with EtOAc (50 mL), filtered through the Celite pad. The pad was washed with EtOAc (50 mL), the filtrate combined and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed SiO2 cartridge, 230-400 mesh, 10% EtOAc in hexanes) to afford (±)-5 as a pale-yellow semi solid. Yield: 4.5 g (92%). LCMS: Calculated for C20H32BNO5is 377.29, observed: 322.2 [(M-tBu)+1]+and 278.2 [(M-Boc)+1]+

[0228] Step 5:

[0229] To a stirred solution of 6 (500 mg, 1.192 mmol) in THF (10 mL) and water (2 mL), were added (±)-5 (540 mg, 1.431 mmol) and potassium phosphate tribasic (623 mg, 2.93 mmol) at 25 ℃. The reaction mixture was degassed using nitrogen for 15 min, after which P(Cy3)Pd G3 (78 mg, 0.119 mmol) was added and the reaction mixture stirred at 80 ℃ for 16 h. The reaction mixture was cooled to 25 ℃ and concentrated under reduced pressure. The crude residue was dissolved in 10% MeOH in DCM (50 mL), washed with water (5 mL), 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 SiO2 cartridge, 230-400 mesh,100% EtOAc) to afford 7 as a pale-brown gum. Yield: 600 mg (84%). LCMS: Calculated for C34H43N3O6 is 589.73, observed: 590.3 [M+1]+

[0230] Step 6:

[0231] To a stirred solution of 7 (500 mg, 0.848 mmol) in trifluoroethanol (5 mL), was added TMSCl (0.323 mL, 2.54 mmol) at 0 ℃, and the reaction mixture stirred at 10 ℃ for 2 h. The reaction mixture was concentrated under reduced pressure to afford 8 as a pale-brown semi solid.The crude product was taken to the next step without any purification. Yield: 350 mg (crude product weight). LCMS: Calculated for C24H28N3O3+is 406.51, observed: 406.21 [M]+

[0232] Step 7:

[0233] To a stirred solution of 8 (0.35 g, 0.792 mmol) in DMF (5 mL), were added Et3N (0.331 mL, 2.376 mmol) and bromoacetonitrile (0.083 mL, 1.188 mmol) at 0 ℃. The reaction mixture was stirred at 10 ℃ for 3 h. The reaction mixture was quenched with ice cold water (20 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with ice cold water (2 x 3 mL), brine solution (3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue thus obtained was purified by preparative HPLC (column: SHIMPACK GIST C18 (10 x 150 nm) 5 μm; eluents: 10 mM ammonium bicarbonate in water and acetonitrile) to afford Compound 4 as an off-white solid. Yield: 22 mg (5%). LCMS: Calculated for C26H28N4O3is 444.54, observed: 445.4 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.66 (d, J = 8.40 Hz, 2H), 7.63 (d, J = 8.80 Hz, 2H), 7.51 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 7.05 (d, J = 8.80 Hz, 2H), 6.84 (d, J = 0.80 Hz, 1H), 5.69 (t, J = 6.00 Hz, 1H), 5.53 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.37 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.96-4.92 (m, 1H), 4.61-4.56 (m, 1H), 3.87 (t, J = 5.60 Hz, 2H), 3.67 (d, J = 6.80 Hz, 2H), 2.87-2.82 (m, 1H), 2.77-2.66 (m, 2H, 1H exchanges with D2O), 1.51 (d, J = 6.40 Hz, 3H), 1.27 (d, J = 6.00 Hz, 3H). SFC: diastereomeric ratio = 48.49 (tR = 3.07 min) : 48.25 (tR = 3.71) (column: LUX-I-Amylose 3; eluents: CO2and 0.5% isopropyl amine in MeOH).

[0234] Note: Diastereomeric ratio = 48.49 (tR = 3.07 min) : 48.25 (tR = 3.71); racemic at tail part. Mixture of diastereomers.Example 5: Synthesis of Compounds 5 and 6

[0235] Step 1:

[0236] To a stirred solution of chlorosulfonyl isocyanate (2, 4.77 mL, 54.6 mmol) in toluene (100 mL), was added 4-bromostyrene (1, 7.14 mL, 54.6 mmol) in toluene (50 mL) at 0 °C and the reaction mixture stirred at room temperature for 16 h. The reaction mixture was added dropwise to the solution of Na2CO3(17.37 g, 164 mmol) and sodium sulfite (4.13 g, 32.8 mmol) in water (50 mL) and stirred for 10 min. The aqueous layer was separated and extracted with toluene (2 x 200 mL). The combined organic layer was dried over anhydrous Na2SO4,filtered, and concentrated under reduced pressure. The resulting crude residue was triturated with hexane (100 mL), filtered, and dried to get 3 as a white solid. Yield: 7.1 g (51%). LC-MS: Calculated for C9H8BrNO is 226.07, Observed: 226.0 [M]+and 228.0 [M+2]+. Reference: Adv. Synth. Catal.2006, 348, 917-923

[0237] Step 2:

[0238] To a stirred solution of 3 (3 g, 13.27 mmol) in dioxane (40 mL), were added bis(pinacolato)diboron (5.05 g, 19.91 mmol) and potassium acetate (3.91 g, 39.8 mmol) at room temperature, and the reaction mixture purged with nitrogen for 10 min. Then, PdCl2(dppf) (0.971 g, 1.327 mmol) was added, and the reaction mixture heated at 85 °C for 16 h. The reaction mixture was cooled to room temperature and filtered through a pad of Celite. The bed was washed with EtOAc (250 mL), the filtrate combined and concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed SiO2cartridge, 100-200 mesh size; 23% EtOAc in hexanes) to get 4 as an off-white solid. Yield: 4.5 g (87%). LC-MS: Calculated for C15H20BNO3 is 273.14, Observed: 274.3 [M+1]+

[0239] Step 3:

[0240] To a stirred solution of 4 (599 mg, 2.194 mmol) and 5 (400 mg, 0.954 mmol) in a mixture of acetonitrile (11 mL) and water (3 mL), was added potassium carbonate (396 mg, 2.86 mmol) at room temperature and the reaction mixture purged with nitrogen for 5 min. Then, PdCl2(dtbpf) (62.2 mg, 0.095 mmol) was added. The reaction mixture was irradiated at 90 °C for 1 h in a microwave reactor. One more batch was carried out using 400 mg of 4. Both batches were mixed for workup and purification. The reaction mixture was filtered through a pad of Celite. The bed was washed with EtOAc (100 mL), the filtrate combined and concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed SiO2cartridge, 230-400 mesh size; 5% MeOH in DCM) to get 6 as a brown solid. Yield: 0.6 g (combined yield for two batches). LC-MS: Calculated for C29H31N3O4 is 485.58, Observed: 486.2 [M+1]+

[0241] Step 4:

[0242] To a stirred solution of 6 (580 mg, 1.194 mmol) in MeOH (10 mL), was added p- toluenesulfonic acid monohydrate (682 mg, 3.58 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (90 mL) and washed with 10% NaHCO3 solution (3 x 20 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by reverse phase purification (Column: Redisp C18; Eluents: 10 mM ammonium bicarbonate in water and ACN) to afford rac-6 as a white solid. Yield = 280 mg (58%)

[0243] The diastereomers were separated using SFC (CHIRAL-PAK ASH -(250*20) mm, 5 μm; Eluents: CO2and 0.5% isopropyl amine in MeOH (50:50)) to get Compound 5 (tR=4.26 min) and Compound 6 (tR=6.50 min) as white solids. Yield: Compound 5 = 90 mg and Compound 6 = 95 mg

[0244] Analytical data for Compound 5: LC MS: Calculated for C24H23N3O3 is 401.47, Observed: 402.2 [M+1]+.1H-NMR (400 MHz, DMSO-d6: δ 8.44 (s, 1H, exchanges with D2O), 7.72 (m, 4H), 7.56 (d, J = 8.40 Hz, 2H), 7.47 (d, J = 8.00 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 6.85 (d, J = 0.80 Hz, 1H), 5.70 (t, J = 6.00 Hz, 1H), 5.55 (t, J = 5.20 Hz, 1H, exchanges with D2O), 5.38 (d, J = 5.20 Hz, 1H, exchanges with D2O), 4.95-4.91 (m, 1H), 4.72-4.70 (m, 1H), 3.87 (t, J = 5.20 Hz, 2H), 3.40-3.38 (m, 1H), 2.71 (dd, J = 2.00, 14.60 Hz, 1H), 1.51 (d, J = 6.40 Hz, 3H). SFC: 100%; tR = 4.26 min (Column: CHIRALPAK-AS-H; Eluents: 0.5% isopropyl amine in MeOH).

[0245] Analytical data for Compound 6: LC MS: Calculated for C24H23N3O3 is 401.47, Observed: 402.3 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 8.44 (s, 1H, exchanges with D2O), 7.72 (m, 4H), 7.56 (d, J = 8.40 Hz, 2H), 7.47 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 6.84 (d, J = 1.20 Hz, 1H), 5.70 (t, J = 6.00 Hz, 1H), 5.54 (t, J = 6.00 Hz, 1H, exchanges with D2O), 5.38 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.96-4.93 (m, 1H), 4.72-4.70 (m, 1H), 3.87 (t, J = 6.00 Hz, 2H), 3.40-3.38 (m, 1H), 2.71 (dd, J = 1.60, 14.60 Hz, 1H), 1.51 (d, J = 6.80 Hz, 3H). SFC: 100%; tR = 6.50 min (Column: CHIRALPAK-AS-H; Eluents: 0.5% isopropyl amine in MeOH)Example 6: Synthesis of Compounds 7 and 8

[0246] Step 1:

[0247] To a stirred the solution of 3,4-epoxytetrahydrofuran (1, 5 g, 58.1 mmol) in 1,4-dioxane (200 mL) and water (50 mL), was added sodium azide (4.53 g, 69.7 mmol) at room temperature, and the reaction mixture stirred at 100 ℃ for 16 h in an autoclave. The reaction mixture was quenched with water (25 mL) and extracted with EtOAc (50 mL x 3). The combined organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 2 as a colourless oil. Yield: 3.5 g (42%). One more batch was performed using 5 g of 1 to get 3.5 g of 2.

[0248] Step 2:

[0249] To a stirred solution of 2 (3.5 g, 27.1 mmol) in DMF (35 mL), was added NaH (60% dispersion in mineral oil; 1.626 g, 40.7 mmol) at 0 ℃, and the reaction mixture stirred at 25 ℃ for 30 min. After the resulting reaction mixture was cooled to 0 ℃, iodomethane (5.06 mL, 81 mmol) was added (dropwise!). After complete addition, the reaction mixture was stirred at 25 ℃ for 4 h. One more batch was performed with 3.5 g of 2. Both the batches were mixed for work-up and purification. The reaction mixture was quenched with ice-cold water (10 mL) and extracted with EtOAc (3 x 35 mL). The combined organic extract was washed with brine solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue thus obtained was purified by using MPLC (manually packed SiO2cartridge, 230-400 mesh size: 15% EtOAc in hexanes) to afford 3 as a yellow solid. Yield : 2.5 g (yield for two batches)

[0250] Step 3:

[0251] To a stirred solution of 3 (2.5 g, 17.46 mmol) in MeOH (100 mL), was added 10% Pd on carbon (1.859 g, 17.46 mmol) at room temperature under nitrogen atmosphere. This reaction mixture was stirred at 25 ℃ for 16 h under a blanket of hydrogen gas (bladder!). The reaction mixture was diluted with MeOH (25 mL) and filtered through the Celite bed. The bed was washed with MeOH (2 x 30 mL), the filtrate combined, and concentrated under reduced pressure to afford 4 as colorless liquid. Yield: 1.8 g (70%)

[0252] Step 4:

[0253] To a stirred solution of 4 (900 mg, 7.68 mmol) in DCM (20 mL), were added pyridine (2.486 mL, 30.7 mmol), (4-bromophenyl)boronic acid (3.086 g, 15.37 mmol) and copper (II) acetate (2.79 g, 15.37 mmol) at 25 ℃, and the reaction mixture stirred at 25 ℃ for 36 h under oxygen atmosphere. The reaction mixture was quenched with water (5 mL) and extracted with DCM (3 x 10 mL). The combined organic extract was washed with brine solution (3 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. One more batch was carried out using 900 mg of 4 to get 3.0 g of crude product. Both batches were mixed for purification. The crude residue thus obtained was purified by using MPLC (manually packed SiO2 cartridge; 230-400 mesh size; 18% EtOAc in hexanes) to afford 5 as yellow semisolid. Yield: 900 mg (yield for two batches). LCMS: calculated for C11H14BrNO2 is 271.02, observed: 272.0 [M]+and 274.0 [M+2]+

[0254] Step 5:

[0255] To a stirred solution 5 (750 mg, 2.76 mmol) in 1,4-dioxane (20 mL), were added potassium acetate (811 mg, 8.27 mmol) and bis(pinacolato)diboron (840 mg, 3.31 mmol) at 25 ℃, and the reaction mixture degassed using nitrogen for 10 min. To this reaction mixture, PdCl2(dppf).DCM adduct (225 mg, 0.276 mmol) was added and the degassing continued for 5 min. The reaction mixture was stirred at 90 ℃ for 16 h. The reaction mixture was cooled to room temperature, filtered through a Celite pad. The pad was washed with EtOAc (10 mL x 2), the filtrate combined and washed with brine solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated. The crude residue thus obtained was purified by using MPLC (manually packed SiO2cartridge; 230-400 mesh size; 20% EtOAc in hexanes) to afford 6 as a yellow solid. Yield: 400 mg (43%). LCMS: Calculated for C17H26BNO4 is 319.22, observed: 320.3 [M+1]+

[0256] Step 6:

[0257] To the stirred solution of 7 (280 mg, 0.668 mmol) in acetonitrile (4 mL) and water (1 mL), were added 6 (320 mg, 1.002 mmol) and potassium carbonate (277 mg, 2.003 mmol) at 25 ℃, and the reaction mixture degassed with nitrogen for 10 min. To this mixture, PdCl2(dtbpf) (43.5 mg, 0.067 mmol) was added and the reaction mixture stirred at 80 ℃ for 16 h. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (10 mL) and filtered through the Celite bed. The Celite bed was washed with EtOAc (3 x 20 mL), the filtrate combined and concentrated under reduced pressure. The crude residue thus obtained was purified by using MPLC (manually packedSiO2cartridge; 230-400 mesh; 5% MeOH in DCM) to afford 8 as a yellow solid. One more batch was performed on 130 mg of 7. Both batches were mixed for work-up and purification. Yield: 250 mg (yield for two batches). LCMS: Calculated for C31H37N3O5 is 531.27. Observed: 532.2 [M+1]+. One more batch was carried out using 130 mg of 7 to yield 80 mg of 8.

[0258] Step 7:

[0259] To the stirred solution of 8 (340 mg, 0.640 mmol) in MeOH (30 mL), was added p- TSA.H2O (365 mg, 1.919 mmol) at 0 ℃, and the reaction mixture stirred at room temperature for 4 h. The reaction mixture was quenched with sat. NaHCO3solution (8 mL) at 0 ℃ and extracted with DCM (3 x 50 mL). The combined organic extract was washed with sat. NaHCO3 solution (2 x 10 mL), brine solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by reversed phase preparative HPLC (column: YMC C18250*20 mm, 5 μm; eluents: 10 mM ammonium bicarbonate in water and acetonitrile) to afford Compounds 7 and 8 as an off-white solid. Yield: 40 mg (14%). LCMS: Calculated for C26H29N3O4is 447.22, observed: 448.2 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.60 (d, J = 8.40 Hz, 2H), 7.50 (d, J = 8.80 Hz, 2H), 7.46 (d, J = 8.40 Hz, 2H), 7.35 (d, J = 1.20 Hz, 1H), 6.84 (d, J = 1.20 Hz, 1H), 6.72 (d, J = 8.80 Hz, 2H), 6.12 (d, J = 6.40 Hz, 1H, exchanges with D2O), 5.68 (t, J = 6.00 Hz, 1H), 5.52 (t, J = 6.00 Hz, 1H, exchanges with D2O), 5.36 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.97-4.91 (m, 1H), 4.03-4.02 (m, 1H), 3.86-3.75 (m, 6H), 3.59 (dd, J = 2.80, 9.00 Hz, 1H), 3.31 (s, 3H, merges with solvent water), 1.51 (d, J = 6.40 Hz, 3H). SFC: 100%; tR = 1.96 min (column: I Cellulose-Z; eluents: CO2and 0.5% isopropyl amine in acetonitrile and MeOH).

[0260] Note: Mixture of diastereomers; racemic at tail part. Example 7: Synthesis of Compound 9

[0261] Step 1:

[0262] To a stirred solution of azetidine-3-carbonitrile hydrochloride (1, 3 g, 25.30 mmol) in DMF (40 mL), were added K2CO3(10.49 g, 76.0 mmol) and 4-Bromobenzyl bromide (2, 7.59 g, 30.40 mmol) at room temperature, and the resulting reaction mixture stirred at 60 °C for 16 h. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (15 mL x 3). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed SiO2cartridge, 230-400 mesh size; 19% EtOAc in hexanes) to obtain 3 as a colorless gum. Yield = 3.9 g (59%) LC-MS: Calculated for C11H11BrN2is 251.13; Observed: 251.0 [M]+and 253.0 [M+2]+

[0263] Step 2:

[0264] To a stirred solution of 3 (2.0 g, 7.96 mmol) in 1,4-dioxane (30 mL), were added potassium acetate (2.34 g, 23.89 mmol) and bis(pinacolato)diboron (2.63 g, 10.35 mmol) at room temperature, and the resulting mixture purged with nitrogen for 10 min. To this reaction mixture, PdCl2(dppf).DCM adduct (0.650 g, 0.796 mmol) was added and the purging continued for 10 min. The reaction mixture was stirred at 90 °C for 16 h. The reaction was cooled to ambient temperature, filtered through a Celite bed. The bed was further washed with EtOAc (100 mL), filtrate combined and concentrated under reduced pressure. The resulting crude mass was purified by using MPLC (manually packed cartridge; SiO2230-400 mesh; 23% EtOAc in hexanes) to afford 4 as a pale- brown solid. Yield: 2.3 g (97%). LC-MS: Calculated for C17H23BN2O2is 298.19, Observed: 299.3 [M+1]+

[0265] Step 3:

[0266] To a stirred solution of 4 (0.533 g, 1.789 mmol) in THF (16 mL) and water (4 mL), were added 5 (0.5 g, 1.192 mmol) and NaHCO3 (0.2 g, 2.385 mmol), and the reaction mixture purged with nitrogen for 10 min. To this reaction mixture, PdCl2(dppf).DCM adduct (0.097 g, 0.119 mmol) was added and the purging continued for another 10 min. The reaction mixture was stirred at 60°C for 16 h. The reaction was cooled to ambient temperature. The inorganic solids were filtered through a Celite pad and washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure. The resulting crude mass was purified by using MPLC (manually packed cartridge; SiO2, 230-400 mesh size; 5% MeOH in EtOAc) to afford 6 as a brown solid. Yield: 0.31 g (48%). LC-MS: Calculated for C31H34N4O3 is 510.63, Observed: 511.3 [M+1]+

[0267] Step 4:

[0268] To a stirred solution of 6 (0.3 g, 0.588 mmol) in MeOH (10 mL), was added p-toluene sulfonic acid monohydrate (0.224 g, 1.175 mmol) at 0 °C and the reaction mixture stirred at room temperature for 3 h. The volatiles were evaporated under reduced pressure. The resulting residue was dissolved in 10% MeOH in DCM (60 mL) and washed with 10% NaHCO3 solution (25 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by reverse phase column chromatography usingMPLC (Column: RediSep Gold, C18reversed phase SiO2, 100 g; Eluents:10 mM ammonium bicarbonate in water and ACN) to obtain Compound 9 as a pale-yellow solid. Yield: 60 mg (24%). LCMS: Calculated for C26H26N4O2 is 426.52; Observed: 427.4 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.71-7.64 (m, 4H), 7.54 (d, J = 8.40 Hz, 2H), 7.38-7.36 (m, 3H), 6.84 (app d, J = 1.20 Hz, 1H), 5.70 (t, J = 6.00 Hz, 1H), 5.54 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.43 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.97-4.92 (m, 1H), 3.87 (t, J = 6.00 Hz, 2H), 3.62 (s, 2H), 3.48-3.46 (m, 3H), 3.31-3.28 (m, 2H), 1.51 (d, J = 6.80 Hz, 3H). SFC: 100%; tR = 1.92 min (Column: I Cellulose- B; Eluents: 0.5% isopropyl amine in MeOH and CO2)

[0269] Note: Single isomer with SFC purity 100% Example 8: Synthesis of Compound 10

[0270] Step 1:

[0271] To a stirred solution of 4-bromobenzyl amine (1, 2 g, 10.75 mmol) in acetonitrile (20 mL), were added K2CO3 (2.97 g, 21.50 mmol) and bromoacetonitrile (2, 1.29 g, 10.75 mmol) at room temperature and the resulting reaction mixture stirred at 50 °C for 16 h. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (20 mL x 2). The combined organic layer was 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; 30% EtOAc in hexanes) to obtain 3 as a pale-brown liquid. Yield = 2 g (79%)

[0272] Step 2:

[0273] To a stirred solution of 3 (2.0 g, 8.89 mmol) in 1,4-dioxane (50 mL), were added potassium acetate (2.62 g, 26.7 mmol) and bis(pinacolato)diboron (2.93 g, 11.55 mmol) at room temperature, and the resulting mixture purged with nitrogen for 10 min. To this reaction mixture, PdCl2(dppf).DCM adduct (0.726 g, 0.889 mmol) was added and the purging continued for 10 min. The reaction mixture was then stirred at 80 °C for 16 h. The reaction was cooled to ambient temperature, filtered through a Celite bed. The bed was washed with EtOAc (50 mL), the filtrate combined and concentrated under reduced pressure. The resulting crude mass was purified by using MPLC (manually packed cartridge; SiO2230-400 mesh; 20% EtOAc in hexanes) to afford 4 as a pale-brown liquid. Yield : 2.20 g (73%)

[0274] Step 3:

[0275] To a stirred solution of 4 (0.454 g, 1.669 mmol) in THF (16 mL) and water (4 mL), were added 5 (0.5 g, 1.192 mmol) and NaHCO3(0.2 g, 2.385 mmol). The reaction mixture was purged with nitrogen for 10 min. To this reaction mixture, PdCl2(dppf).DCM adduct (0.097 g, 0.119 mmol) was added and the purging continued for another 10 min. The reaction mixture was stirred at 60 °C for 16 h. The reaction was cooled to ambient temperature. The inorganic solids were filtered through a Celite pad and washed with EtOAc (30 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude mass was purified by using MPLC (manually packed cartridge; SiO2, 230-400 mesh size; 9% MeOH in EtOAc) to afford 6 as a brown colour liquid. Yield 0.3 g (38%). LC-MS: Calculated for C29H32N4O3is 484.60, Observed: 485.3 [M+1]+

[0276] Step 4:

[0277] To a stirred solution of 6 (0.3 g, 0.458 mmol) in MeOH (10 mL), was added p-toluene sulfonic acid monohydrate (0.174 g, 0.915 mmol) at 0 °C and the reaction mixture stirred at room temperature for 2 h. The volatiles were removed under reduced pressure, the resulting residue dissolved in 10% MeOH in DCM (60 mL) and washed with 10% NaHCO3 solution (25 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced. The crude mass, thus obtained, was purified by reverse phase column chromatography using MPLC (Column: RediSep Gold, C18 reversed phase SiO2; Eluents:10 mM ammonium bicarbonate in water and ACN) to obtain Compound 10 as a white solid. Yield: 65 mg (35%). LC-MS: Calculated for C24H24N4O2 is 400.48; Observed: 401.4 [M+1]+ 1H-NMR (400 MHz, DMSO-d6): δ 7.71 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 8.4 Hz, 2H), 7.56 (d, J = 4.40 Hz, 2H), 7.43 (d, J = 8.00 Hz, 2H), 7.36 (d, J = 0.80 Hz, 1H), 6.84 (d, J = 0.80 Hz, 1H), 5.70 (t, J = 5.60 Hz, 1H), 5.54 (t, J = 6.00 Hz, 1H, exchanges with D2O), 5.38 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.96-4.92 (m, 1H), 3.87 (t, J = 5.60 Hz, 2H), 3.80 (d, J = 6.00 Hz, 2H), 3.61 (d, J = 7.20 Hz, 2H), 3.11-3.08 (m, 1H, exchanges with D2O), 1.51 (d, J = 6.80 Hz, 3H). SFC: 100%; tR = 2.11 min (Column: I Cellulose- B; Eluents: 0.5% isopropyl amine in MeOH and CO2)

[0278] Note: Single isomer with SFC purity 100%Example 9: Synthesis of Compound 11

[0279] Step 1:

[0280] To a stirred solution 1 (5 g, 23.44 mmol) in THF (50 mL), were added triphenylphosphine (7.38 g, 28.1 mmol), imidazole (2.394 g, 35.2 mmol) and iodine (11.90 g, 46.9 mmol) at room temperature, and the resulting mixture stirred at room temperature for 16 h. The reaction mixture was quenched with 10% NaHCO3solution (50 mL) and extracted with DCM (2 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 15% EtOAc in hexanes) to obtain 2 as a white solid. Yield: 3.5 g (46%). LCMS: Calculated for C11H18INO2 is 323.17, Observed: 224.0 [(M-Boc)+1]+

[0281] Step 2:

[0282] A mixture of nickel (II) iodide (0.290 g, 0.928 mmol) and (1R,2R)-trans-2- aminocyclohexanol hydrochloride (0.141 g, 0.928 mmol) in 2-propanol (40 mL) was purged with nitrogen for 5 min. To this reaction mixture, sodium bis(trimethylsilyl)amide (2 M in THF; 4.64 mL, 18.57 mmol), 4-bromophenylboronic acid (3, 2.424 g, 12.07 mmol) and 2 (3 g, 9.28 mmol) were added. The resulting reaction mixture was stirred at 70 °C for 16 h. The volatiles were removed under reduced pressure. The resulting residue was dissolved in DCM (100 mL) and washed with water (100 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 6% EtOAc in hexanes) to obtain 4 as a white solid. Yield: 2.0 g (58%). LCMS: Calculated for C17H22BrNO2 is 352.27, Observed: 252.2 [M-Boc]+and 254.0 [(M-Boc)+2]+

[0283] Step 3:

[0284] To a stirred solution of 4 (2 g, 5.68 mmol) in dioxane (25 mL), were added potassium acetate (1.672 g, 17.03 mmol) and bis(pinacolato)diboron (2.163 g, 8.52 mmol) at room temperature and a stream of nitrogen gas was passed through the reaction mixture for 5 min. To this reaction mixture, PdCl2(dppf)-DCM (0.208 g, 0.284 mmol) was added and stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature, filtered through the Celite pad, and washed with EtOAc (100 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed SiO2cartridge, 100-200 mesh size; 8% EtOAc in hexanes) to obtain 5 as a colorless gum with 67% purity by LCMS; The product was taken to the next step as such without further purification. Yield: 800 mg (24%). LCMS: Calculated for C23H34BNO4 is 399.33, Observed: 300.4 [(M-Boc)+1]+

[0285] Step 4:

[0286] To a solution of 6 (500 mg, 1.192 mmol) in acetonitrile (6 mL) and water (6 mL), were added 5 (714 mg, 1.789 mmol) and K2CO3(494 mg, 3.58 mmol) at room temperature, and a stream of nitrogen gas was passed through the reaction mixture for 10 min. To this reaction mixture, PdCl2(dtbpf) (38.9 mg, 0.060 mmol) was added and irradiated in microwave reactor at 80 °C for 1.5 h. The reaction mixture was then quenched with water (50 mL) and extracted with 10% MeOH in DCM (2 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed SiO2cartridge, 100-200 mesh size; 100% EtOAc) to obtain 7 as pale-brown solid. LCMS showed 74% purity; product was taken to the next step. Yield: 360 mg (36%). LCMS: Calculated for C37H45N3O5 is 611.78, Observed: 612.3 [M+1]+

[0287] Step 5:

[0288] To a stirred solution of 7 (0.2 g, 0.327 mmol) in 2,2,2 trifluoroethanol (4 mL), was added TMSCl (0.063 mL, 0.490 mmol) at 0 °C and the reaction mixture stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to obtain 8 as a brown gum. The crude was taken to the next step without any purification. Yield: 0.14 g (crude product weight). LCMS: Calculated for C27H30N3O2+is 428.56, Observed: 428.3 [M]+

[0289] Step 6:

[0290] To a stirred solution of 8 (130 mg, 0.178 mmol) in DMF (4 mL), were added Et3N (0.149 mL, 1.067 mmol) and 2-bromoacetonitrile (0.025 mL, 0.356 mmol) at 0 °C, and the reaction stirred at room temperature for 2 h. The reaction mixture was quenched with water (25 mL) and extracted with 10% MeOH in DCM (2 x 25 mL). The combined organic layer was dried over anhydrous sodium sulfate, 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 Compound 11 as an off-white solid. Yield: 35 mg (40%). LCMS: Calculated for C29H30N4O2 is 466.58, Observed: 467.2 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.68 (d, J = 8.40 Hz, 2H), 7.62 (d, J = 8.00 Hz, 2H), 7.54 (d, J = 8.00 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 7.31 (d, J = 8.40 Hz, 2H), 6.84 (d, J = 0.80 Hz, 1H), 5.69 (t, J = 6.00 Hz, 1H), 5.54 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.37 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.97-4.91 (m, 1H), 3.87 (t, J = 5.60 Hz, 2H), 3.60 (s, 2H), 3.44-3.41 (m, 3H), 3.21 (s, 2H), 2.50-2.48 (m, 2H, merges with solvent peak), 2.22 (m, 2H), 1.51 (d, J = 6.40 Hz, 3H). SFC: 96.9%; tR = 8.73 min (Column: LUX-I-Amylose 3; Eluents: CO2and 0.5% isopropyl amine in MeOH)

[0291] Note: SFC purity = 96.9% Example 10: Synthesis of Compound 12

[0292] Reference: For synthesis of 2, please refer WO2016009296.

[0293] Step 1:

[0294] To a stirred solution of 3-(benzyloxy)cyclobutan-1-one (1, 5 g, 28.4 mmol) in EtOH (250 mL), was added sodium borohydride (1.073 g, 28.4 mmol) portion wise at 0 °C. After stirring for 1 h at 0 °C, the reaction mixture was quenched with water (100 mL) and extracted with DCM (100 mL x2). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 2 as a colourless oil.

[0295] Note: The stereochemistry was assigned based on the literature (WO2016009296). LC-MS: Calculated for C11H14O2 is 178.2; Desired product mass not observed. Yield: 4.25 g (81%)

[0296] Step 2:

[0297] To a stirred solution of 2 (9.5 g, 53.3 mmol) in DCM (100 mL), were added tosyl chloride (15.24 g, 80 mmol), DMAP (0.651 g, 5.33 mmol) and triethylamine (22.29 mL, 160 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 16 h. The reaction mixture was quenched with water (250 mL) and extracted with DCM (200 mL x 2). The combined organic layer was washed with sat. NaHCO3 solution (100 mL x 2), brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get 3 as a brown solid. The crude product was taken to the next step as such without further purification. LC-MS: Calculated for C18H20O4S is 332.4; Desired product mass not observed. Yield: 15.5 g (85%)

[0298] Step 3:

[0299] To a stirred solution of 3 (15.5 g, 46.6 mmol) in DMF (150 mL), was added potassium thioacetate (10.65 g, 93 mmol) at room temperature and stirred at 70 °C for 16 h. The reaction mixture was quenched with water (400 mL) and extracted with EtOAc (300 mL x 2). The combined organic layer was washed with cold water (150 mL x 2), brine (150 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by using MPLC (manually packed cartridge, SiO2230-400 mesh; 10% EtOAc in hexanes) to afford 4 as a yellow liquid. Yield: 8.5 g (73%)

[0300] Step 4:

[0301] To a stirred solution of N-chlorosuccinimide (14.41 g, 108 mmol) in acetonitrile (85 mL), was added conc. HCl (2.73 mL, 90 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 10 min. After cooling the reaction mixture to 0 °C, a solution of 4 (8.5 g, 36.0 mmol) in acetonitrile (20 mL) was added and the reaction mixture stirred at 0 °C for 30 min. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by using MPLC (manually packed cartridge, SiO2230-400 mesh; 10% EtOAc in hexanes) to obtain 5 as an off-white solid. UPLC-MS: Calculated for C11H13ClO3S is 260.7; observed: 259.0 [M-1]–. Yield: 7.0 g (70%)

[0302] Step 5:

[0303] To a stirred solution of 5 (7.0 g, 26.8 mmol) in a mixture of MeOH (60 mL) and THF (30 mL), was added a solution of methylamine (33 % in in MeOH, 6.44 mL, 53.7 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 was purified by using MPLC (manually packed cartridge, SiO2230-400 mesh; 35% EtOAc in hexanes) to obtain 6 and 6a as white solids. Yield: 6 = 1.4 g and 6a = 1.7 g. LC-MS: Calculated for C12H17NO3S is 255.3, Observed: 256.3 [M+1]+

[0304] The identity of trans-geometry of 6 was established through a lack of the nOe enhancement in the methine (3.81 ppm) ^- to sulfonamide upon irradiation of methine ^- to benzyloxy (4.22 ppm).

[0305] The identity of cis-geometry of 6a was established through the nOe enhancement observed at 3.48 ppm (methine ^- to sulfonamide) upon irradiation of the other methine at 3.96 ppm (methine ^- to benzyloxy).

[0306] The synthesis of Compound 12 was carried out using 6a.

[0307] Step 6:

[0308] To a solution of 6a (1.4 g, 5.48 mmol) in EtOAc (30 mL), was added 20% palladium hydroxide on carbon (0.193 g, 0.274 mmol) at room temperature under nitrogen gas. The reaction mixture was stirred under a blanket of hydrogen gas (70 PSI pressure) at room temperature for 16 h in a tinyclave reactor. The reaction mixture was filtered through the Celite pad, washed with EtOAc (15 mL x 2). The combined filtrate was concentrated under reduced pressure to get 7 as a colorless oil. The crude product was taken to the next step without any purification. LC-MS: Calculated for C5H11NO3S is 165.2; observed: 166.2 [M+1]+. Yield: 0.83 g (90%)

[0309] Step 7:

[0310] To stirred solution of 7 (0.85 g, 5.15 mmol) in DCM (25 mL), were added p-toluenesulfonyl chloride (1.471 g, 7.72 mmol), DMAP (0.063 g, 0.515 mmol) and triethylamine (2.151 mL, 15.44 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with water (30 mL) and extracted with DCM (20 mL x 2). The combined organic layer was washed with sat. NaHCO3 solution (20 mL x 2), brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by using MPLC (manually packed cartridge, SiO2230-400 mesh; 5% MeOH in DCM) to obtain 8 as an off- white solid. LC-MS: Calculated for C12H17NO5S2is 319.3, observed: 318.0 [M-1]-. Yield: 1.6 g (77%)

[0311] Step 8:

[0312] To stirred solution of 8 (1.4 g, 4.38 mmol) in DMF (15 mL), were added 4-bromophenol (9, 0.834 g, 4.82 mmol) and cesium carbonate (4.28 g, 13.15 mmol) at room temperature, and the reaction mixture heated to 100 °C for 16 h. The reaction mixture was then quenched with water (30 mL) and extracted with EtOAc (25 mL x 2). The combined organic layer was washed with cold water (15 mL x 2), brine (10 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; 2% MeOH in DCM) to afford 10 as an off-white solid. LCMSshowed 78% purity; The product was taken to the next step without further purification. LC-MS: Calculated for C11H14BrNO3S is 320.2, observed: 320.0 [M]- and 318.0 [M-2]-. Yield: 0.65 g (36%)

[0313] Step 9:

[0314] To a stirred solution of 10 (0.65 g, 2.030 mmol) in dioxane (10 mL), were added bis(pinacolato)diboron (0.773 g, 3.04 mmol) and potassium acetate (0.598 g, 6.09 mmol) at room temperature and the reaction mixture degassed for 5 min. To this reaction mixture, PdCl2(dppf) (0.074 g, 0.101 mmol) was added. The reaction mixture was heated at 100 °C for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (15 mL x 2). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by using MPLC (manually packed cartridge, SiO2230-400 mesh; 30% EtOAc in hexanes) to obtain 11 as an off-white solid. Yield: 0.750 g (86%). LC-MS: Calculated for C17H26BNO5S is 367.2; Desired product mass not observed.

[0315] Step 10:

[0316] To a stirred solution of 11 (0.723 g, 1.967 mmol) in a mixture of water (5 mL) and acetonitrile (5 mL), were added 12 (0.550 g, 1.312 mmol) and potassium carbonate (0.544 g, 3.93 mmol) at room temperature, and the resulting mixture degassed with nitrogen for 5 min. To this reaction mixture, PdCl2(dtbpf) (0.043 g, 0.066 mmol) was added and the degassing continued for another 2 min. The resulting reaction mixture was heated at 80 °C for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with 10 % MeOH in DCM (15 mL x 2). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed cartridge, SiO2230-400 mesh; 5% MeOH in DCM) to afford 13 as a brown solid. Yield: 460 mg (54%). LC-MS: Calculated for C31H37N3O6S is 579.71, observed: 580.3 [M+1]+

[0317] Step 11:

[0318] To a stirred solution of 13 (450 mg, 0.776 mmol) in MeOH (15 mL), was added p- toluenesulfonic acid monohydrate (443 mg, 2.329 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 2 h. The volatiles in the reaction were concentrated under reduced pressure and the resultant crude residue was basified with sat. NaHCO3 solution (15 mL). The aqueous layer was extracted with 10% MeOH in DCM (10 mL x 2). The combined organic extract was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by preparative HPLC (Column: X-BRIDGE C18(19 x 150 mm) 5 µm; Eluents: 10 mM ammonium bicarbonate in water and acetonitrile) to obtain Compound 12 as a white solid. Yield: 65 mg (16%). LC-MS: Calculated for C26H29N3O5S is 495.59, observed: 496.2 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.66-7.64 (m, 4H), 7.52 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 7.07 (q, J = 4.40 Hz, 1H, exchanges with D2O), 6.92 (d, J = 8.80 Hz, 2H), 6.84 (d, J = 1.20 Hz, 1H), 5.69 (t, J= 5.60 Hz, 1H), 5.53 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.37 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.96-4.90 (m, 2H), 4.00-3.94 (m, 1H), 3.87 (t, J = 5.60 Hz, 2H), 2.86-2.79 (m, 2H), 2.61 (d, J = 4.80 Hz, 3H), 2.55-2.50 (m, 2H, merges with solvent peak), 1.51 (d, J = 6.80 Hz, 3H).

[0319] SFC: 98.9%; tR = 5.36 min (column: l-Amylose-A; eluents: CO2 and 0.5% isopropyl amine in MeOH)

[0320] Note: trans-geometry in the tail, mixture of diastereomers. SFC purity = 98.9 Example 11: Synthesis of Compounds 14 and 15

[0321] Step 1:

[0322] To a stirred solution of methyl (E)-3-(4-bromophenyl)acrylate (1, 7.5 g, 31.1 mmol) in toluene (100 mL), were added benzyltriethylammonium chloride (0.709 g, 3.11 mmol) and K2CO3 (43.0 g, 311 mmol) at room temperature. To this reaction mixture, nitromethane (16.7 mL, 18.99 g, 311 mmol) was added at 0 °C, and the mixture stirred at 50 ℃ for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL), filtered through a Celite pad. The pad was washed with EtOAc (20 mL x 2), the filtrate combined and concentrated under reduced pressure. The crude residue thus obtained was purified by using MPLC (manually packed SiO2 cartridge, 230- 400 mesh size; 10% EtOAc in hexanes) to get (±)-2 as colorless sticky liquid. Yield: 7.2 g (72%). One more batch was carried out using 7.5 g of 1 to get 6.8 g of (±)-2.

[0323] Step 2:

[0324] To a stirred solution of (±)-2 (9 g, 29.8 mmol) in MeOH (150 mL) and water (37.5 mL), were added ammonium chloride (1.770 g, 33.1 mmol) and iron powder (1.848 g, 33.1 mmol) at 25 °C, and the resulting reaction mixture stirred at 80 °C for 16 h. The reaction mixture was cooled to room temperature, filtered through a Celite pad. The pad was washed with MeOH (20 mL x 3), thefiltrate combined and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed SiO2cartridge, 230-400 mesh size; 5% MeOH in DCM) to get (±)-3 as a white solid. LCMS showed 86% purity; product was taken to the next step. Yield: 3.8 g (46%). LCMS: Calculated for C10H10BrNO is 240.10, observed: 240.0 [M]+and 242.0 [M+2]+

[0325] Step 3:

[0326] To a stirred solution of (±)-3 (1 g, 4.16 mmol) in 1,4-dioxane (20 mL), were added potassium acetate (0.818 g, 8.33 mmol) and bis(pinacolato)diboron (1.058 g, 4.16 mmol) at 25 °C, and the mixture degassed with nitrogen for 5 min. To this mixture, PdCl2(dppf).DCM adduct (0.340 g, 0.416 mmol) was added, and the resulting reaction mixture stirred at 90 °C for 16 h. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL), filtered through a Celite pad. The pad was washed with EtOAc (20 mL x 2). The combined filtrate 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 using MPLC (manually packed SiO2cartridge, 230-400 mesh size; 5% MeOH in DCM) to afford (±)-4 as a brown solid. Yield: 460 mg (31%). LCMS: Calculated for C16H22BNO3 is 287.17, observed: 288.2 [M+1]+. One more batch was carried out using 600 mg of (±)-3 to obtain 250 mg of (±)-4.

[0327] Step 4:

[0328] To a stirred solution of (±)-4 (466 mg, 1.622 mmol) in acetonitrile (10 mL) and water (2 mL), were added 5 (400 mg, 0.954 mmol) and potassium carbonate (396 mg, 2.86 mmol) at room temperature, and the reaction mixture degassed with nitrogen for 5 min. To this reaction mixture, PdCl2(dtbpf) (62.2 mg, 0.095 mmol) was added and the degassing continued for 5 min. The resulting reaction mixture was stirred at 80 ℃ for 16 h. The reaction mixture was quenched with ice water (10 mL) and extracted with EtOAc (25 mL x 3). The combined organic extract 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 using MPLC (manually packed SiO2 cartridge; 230-400 mesh size; 7% MeOH in DCM) to get 6 as a brown solid. Yield: 380 mg (69%). LCMS: Calculated for C30H33N3O4is 499.61, observed: 500.3 [M+1]+. One more batch was carried out using 190 mg of 5 to obtain 200 mg of 6.

[0329] Step 5:

[0330] To a stirred solution of 6 (180 mg, 0.360 mmol) in MeOH (25 mL), was added p- toluenesulfonic acid monohydrate (240 mg, 1.261 mmol) at 0 °C. The resulting reaction mixture was stirred at 25 °C for 5 h. Two more batches were carried out using 170 mg of 6. All three batches were mixed for work-up and purification. The reaction mixture was quenched with sat. NaHCO3solution (8 mL) at 0 ℃. This was extracted with DCM (100 mL x 3). The combined organic extract was washed with sat. NaHCO3 solution (2 x 5 mL), brine solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue thus obtained waspurified by using MPLC (manually packed SiO2cartridge, 230-400 mesh size; 5% MeOH in DCM) to afford 260 mg of the racemic compound as brown solid. Yield: 260 mg (combined yield for three batches). LCMS: Calculated for C25H25N3O3 is 415.49. Observed: 416.2 [M+1]+

[0331] Step 6: SFC Purification

[0332] The diastereomers of 260 mg of the racemic compound were separated by SFC (column: Chiralpak ASH-(250*20) mm, 5μm; eluents: CO2and 0.5% isopropyl amine in MeOH) to obtain Compound 14 (tR = 2.46 min) and Compound 15 (tR = 3.28 min) as off-white solids. Yield: Compound 14 = 50 mg and Compound 15 = 70 mg.

[0333] Compound 14 LCMS: Calculated for C25H25N3O3 is 415.49, observed: 416.2 [M+1]+.1H-NMR (400 MHz, DMSO- d6): δ 7.73-7.65 (m, 5H, 1H exchanges with D2O), 7.55 (d, J = 8.40 Hz, 2H), 7.42 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 6.84 (d, J = 1.20 Hz, 1H), 5.70 (t, J = 5.60 Hz, 1H), 5.54 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.38 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.97-4.93 (m, 1H), 3.87 (t, J = 5.60 Hz, 2H), 3.69-3.62 (m, 2H), 3.26-3.22 (m, 1H), 2.58-2.51 (m, 1H, merges with solvent peak), 2.36-2.33 (m, 1H), 1.51 (d, J = 6.40 Hz, 3H). SFC: 100%; tR = 2.46 min (column: CHIRALPAK-AS-H; eluents: CO2 and 0.5% isopropyl amine in MeOH).

[0334] Note: Single isomer with 100% SFC purity; unknown stereochemistry at tail part.

[0335] Compound 15

[0336] LCMS: Calculated for C25H25N3O3is 415.49, observed: 416.2 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.73-7.65 (m, 5H, one proton exchanges with D2O), 7.55 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 1.2 Hz, 1H), 6.84 (d, J = 1.2 Hz, 1H), 5.70 (t, J = 6.0 Hz, 1H), 5.54 (t, J = 5.6 Hz, 1H, exchanges with D2O), 5.38 (d, J = 5.6 Hz, 1H, exchanges with D2O), 4.97-4.91 (m, 1H), 3.87 (t, J = 5.6 Hz, 2H), 3.69-3.62 (m, 2H), 3.26-3.23 (m, 1H), 2.68-2.67 (m, 1H), 2.36-2.30 (m, 1H), 1.51 (d, J = 6.4 Hz, 3H). SFC: diastereomeric ratio = 99.83: 0.16; tR = 3.28 min (for major isomer) (column: CHIRALPAK-AS-H; eluents: CO2and 0.5% isopropyl amine in MeOH).

[0337] Note: Diastereomeric ratio = 99.8: 0.2; unknown stereochemistry at tail part.Example 12: Synthesis of Compound 16

[0338] Step 1:

[0339] To a stirred solution of 1-bromo-4-((methylsulfonyl)methyl)benzene (1, 1 g, 4.01 mmol) in dioxane (15 mL), were added potassium acetate (1.18 g, 12.04 mmol) and bis(pinacolato)diboron (1.53 g, 6.02 mmol) at room temperature and the reaction mixture degassed with nitrogen for 5 min. To this reaction mixture, PdCl2(dppf).DCM complex (0.16 g, 0.20 mmol) was added and stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature, filtered through a Celite pad, and washed with EtOAc (50 mL). The filtrate was washed with water (30 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue was purified using MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 20% EtOAc in hexanes) to obtain 2 as pale-yellow liquid. Yield = 0.68 g (55%)

[0340] Step 2:

[0341] To a solution of 3 (0.5 g, 1.19 mmol) in acetonitrile (15 mL) and water (5 mL), were added 2 (0.53 g, 1.79 mmol) and K2CO3(0.49 g, 3.58 mmol) at room temperature, and the mixture degassed with nitrogen for 10 min. To this reaction mixture, PdCl2(dtbpf) (0.062 g, 0.095 mmol) was added and stirred at 80 °C for 16 h. The reaction mixture was quenched with water (20 mL) and extracted with 10% MeOH in DCM (50 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed SiO2cartridge, 230-400 mesh size; 5% MeOH in DCM) to obtain 4 as pale-brown solid. Yield: 210 mg (26%). LCMS: Calculated for C28H32N2O5S is 508.63; observed: 509.1 [M+1]+

[0342] Step 3:

[0343] To a stirred solution of 4 (0.2 g, 0.39 mmol) in MeOH (10 mL), was added p- toluenesulfonic acid monohydrate (0.22 g, 1.18 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 2 h. The volatiles were removed under reduced pressure. The resulting residuewas dissolved in 10% MeOH in DCM (50 mL), washed with 10% NaHCO3 solution (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude residue was purified by column chromatography (column: Redisep Gold, C18 reverse phase SiO2; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford 60 mg of desired product which was re-purified by SFC (Column: SS Whelk (250*30) mm, 5 μm; Eluents: CO2and 0.5% isopropyl amine in 2-propanol [60:40]) to afford Compound 16 as an off-white solid. Yield: 25 mg (15%). LCMS: Calculated for C23H24N2O4S is 424.52; observed: 425.2 [M+1]+.1H- NMR (400 MHz, DMSO-d6): δ 7.76-7.73 (m, 4H), 7.57 (d, J = 8.40 Hz, 2H), 7.51 (d, J = 8.40 Hz, 2H), 7.37 (d, J = 0.8 Hz, 1H), 6.84 (s, 1H), 5.70 (t, J = 6.00 Hz, 1H), 5.54 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.38 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.98-4.91 (m, 1H), 4.55 (s, 2H), 3.87 (t, J = 5.60 Hz, 2H), 2.94 (s, 3H), 1.51 (d, J = 6.40 Hz, 3H). SFC: 97.1%; tR = 2.43 min (column: I-Cellulose-Z; eluents: CO2 and 0.5% isopropyl amine in MeOH)

[0344] Note: Single isomer with SFC purity = 97% Example 13: Synthesis of Compounds 17 and 18

[0345] Step 1:

[0346] To a stirred solution of 1 (5 g, 22.12 mmol) in THF (50 mL), was added BH3.THF (1 M in THF, 122 mL, 122 mmol) dropwise at 0 °C, and the reaction mixture heated at 70 °C for 16 h. The reaction mixture was cooled to 0 °C and slowly quenched with HCl (6 N, 80 mL). The resulting reaction mixture was heated at 100 °C for 30 min. The volatiles were evaporated under reduced pressure, and the resulting solution basified with NaOH (6 N, 110 mL). The aqueous layer was extracted with EtOAc (3 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get 2 as light- brown oil. The crude product was taken to the next step without any purification. Yield: 4.6 g (87%). LC-MS: Calculated for C9H10BrN is 211.00 (exact mass), observed: 211.2 [M]+and 213.2 [M+2]+

[0347] Step 2:

[0348] To a stirred solution of 2 (4.6 g, 21.69 mmol) and triethylamine (9.07 mL, 65.1 mmol) in THF (50 mL), was added bromoacetonitrile (4.54 mL, 65.1 mmol) dropwise at 0 °C, and the reaction mixture heated at 70 °C for 2 h. The reaction mixture was quenched with water (200 mL). This was extracted with EtOAc (2 x 150 mL). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed SiO2cartridge, 230-400 mesh size; 20% EtOAc in hexanes) to get 3 as a colorless oil. Yield: 3.3 g (57%). LC-MS: Calculated for C11H11BrN2is 251.12, observed: 226.1 [M-CN]+and 228.1 [(M-CN)+2]+

[0349] Step 3:

[0350] To a stirred solution of 3 (3.3 g, 13.14 mmol) and bis(pinacolato)diboron (4.00 g, 15.77 mmol) in 1,4-dioxane (60 mL), was added potassium acetate (3.87 g, 39.4 mmol), and the resulting mixture degassed with nitrogen for 5 min. Then, PdCl2(dppf)-DCM complex (1.073 g, 1.314 mmol) was added and the reaction mixture stirred at 100 °C for 16 h. The reaction mixture was filtered through a pad of Celite. The bed was washed with EtOAc (2 x 30 mL), the filtrate combined and concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed SiO2 cartridge, 230-400 mesh size; 8% EtOAc in hexanes) to get 4 as a light- yellow gum. Yield: 3.2 g (73%). LC-MS: Calculated for C17H23BN2O2 is 298.19; Desired product mass not observed

[0351] Step 4:

[0352] To a stirred solution of 5 (0.58 g, 1.730 mmol) and 4 (0.619 g, 2.076 mmol) in a mixture of THF (10 mL) and water (2 mL), was added potassium phosphate tribasic (0.904 g, 5.19 mmol) at room temperature, and the resulting mixture degassed using nitrogen for 5 min. Then, SPhos Pd G2 (0.062 g, 0.087 mmol) was added under nitrogen, and the reaction mixture s stirred at 70 °C for 18 h. The reaction mixture was filtered through a pad of Celite. The bed was washed with EtOAc (20 mL), the filtrate combined and concentrated under reduced pressure. The resulting crude residue was purified by reverse phase preparative HPLC purification (column: X-select CSH C18(250*19mm) 5μm: eluents: 10 mM ammonium bicarbonate in water and ACN) to afford 5 as a white solid.

[0353] Yield = 230 mg (31%)

[0354] Step 5:

[0355] The diastereomers of 5 were separated using SFC (column: cellulose B (250*30) mm, 5 μm; eluents: CO2and 0.5% isopropyl amine in MeOH (80:20)) to get Compound 17 (tR=5.03 min) and Compound 18 (tR=6.43 min) as white solids. Yield: Compound 17 = 63 mg and Compound 18 = 60 mg

[0356] Analytical data for Compound 17:

[0357] LC MS: Calculated for C26H26N4O2 is 426.52, Observed: 427.4 [M+1]+

[0358] 1H-NMR (400 MHz, DMSO-d6): δ 7.71-7.67 (m, 4H), 7.55 (d, J = 8.40 Hz, 2H), 7.50 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 6.84 (d, J = 0.80 Hz, 1H), 5.70 (t, J = 6.00 Hz, 1H), 5.54 (br s, 1H, exchanges with D2O), 5.38 (d, J = 4.8 Hz, 1H, exchanges with D2O), 4.96-4.93 (m, 1H), 4.31 (t, J = 8.00 Hz, 1H), 3.89-3.86 (m, 2H), 3.74 (d, J = 17.60 Hz, 1H), 3.61 (d, J = 17.60 Hz, 1H), 3.37-3.35 (m, 1H), 3.18-3.14 (m, 1H), 2.40-2.33 (m, 1H), 2.07-2.05 (m, 1H), 1.51 (d, J = 6.40 Hz, 3H).

[0359] SFC: 100%; tR = 5.03 min (column: Cellulose B; eluents: CO2and 0.5% isopropyl amine in MeOH)

[0360] Note: Single isomer with 100% SFC purity.

[0361] Analytical data for Compound 18:

[0362] LC MS: Calculated for C26H26N4O2 is 426.52, Observed: 427.4 [M+1]+

[0363] 1H-NMR (400 MHz, DMSO-d6): δ 7.71-7.67 (m, 4H), 7.55 (d, J = 8.40 Hz, 2H), 7.50 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 6.84 (d, J = 1.20 Hz, 1H), 5.70 (t, J = 6.00 Hz, 1H), 5.54 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.38 (d, J = 5.20 Hz, 1H, exchanges with D2O), 4.96-4.93 (m, 1H), 4.31 (t, J = 8.00 Hz, 1H), 3.87 (t, J = 5.60 Hz, 2H), 3.74 (d, J = 17.60 Hz, 1H), 3.61 (d, J = 17.60 Hz, 1H), 3.37-3.35 (m, 1H), 3.18-3.14 (m, 1H), 2.38-2.33 (m, 1H), 2.11-2.04 (m, 1H), 1.51 (d, J = 6.80 Hz, 3H).

[0364] SFC: 93.4%; tR = 6.43 min (column: Cellulose B; eluents: CO2and 0.5% isopropyl amine in MeOH)

[0365] Note: For Compound 18 the diastereomeric ratio is 93.5 : 4.6 Example 14: Synthesis of Compound 19

[0366] Step 1:

[0367] To a stirred solution of NaH (2.71 g, 67.7 mmol) in THF (25 mL), was added a solution of 4-bromophenol (2, 11.49 g, 66.4 mmol) in THF (25 mL) at 0 °C. The reaction mixture was warmed to room temperature and stirred for 1 h. Then TMEDA (9.94 mL, 66.4 mmol) and methyl 2- cholroacetoacetate (1, 10 g, 66.4 mmol) were added and the reaction mixture heated at 70 °C for 4 h. The reaction mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (2 x 100 mL). 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 cartridge, SiO2100-200 mesh size; 5% EtOAc in hexanes) to get 3 as a colorless liquid. Yield: 8 g (35%). LCMS: Calculated for C11H11BrO4 is 287.11, observed: 287.0 [M]- and 285.0 [M-2]-

[0368] Step 2:

[0369] To a stirred solution of 3 (7 g, 24.38 mmol) in MeOH (35 mL), were added trimethyl orthoformate (53.9 mL, 488 mmol) and p-toluenesulfonic acid monohydrate (0.928 g, 4.88 mmol), and the reaction mixture heated at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed cartridge, SiO2100-200 mesh; 6% EtOAc in hexanes) to get 4 as a colorless liquid. Yield: 7.2 g (62%). LCMS: Calculated for C13H17BrO5 is 333.18; Desired molecular mass not observed.

[0370] Step 3:

[0371] To a stirred solution of 4 (7.2 g, 21.61 mmol) in THF (50 mL), was added lithium aluminum hydride (2 M in THF; 10.81 mL, 21.61 mmol) dropwise at 0 °C. The reaction mixture was slowly warmed to room temperature and stirred for 1 h. The reaction mixture was quenched with saturated NH4Cl (100 mL) and extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get 5 as a colorless liquid. The product was taken to the next step without any purification. Yield: 5.1 g (58%). LCMS: Calculated for C12H17BrO4is 305.17; Desired molecular mass not observed.

[0372] Step 4:

[0373] To a stirred solution of 5 (4 g, 13.11 mmol) in MeOH (80 mL), was added conc. H2SO4(0.8 mL, 15.01 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 4 h. The reaction mixture was quenched with ice-cold water (50 mL). This was extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with saturated sodium bicarbonate solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get the crude residue. The crude residue was purified by using MPLC (manually packed cartridge, SiO2100-200 mesh; 25% EtOAc in hexanes) to get 6 as a colorless liquid. Yield: 2.6 g (69%) LCMS: Calculated for C10H11BrO3 is 259.10; Desired molecular mass not observed.

[0374] Step 5:

[0375] To a stirred solution of 6 (2.8 g, 10.81 mmol) in THF (35 mL), was added methylmagnesium bromide (1.0 M in THF; 43.2 mL, 43.2 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NH4Cl solution (100 mL). This was extracted with EtOAc (2 x 100 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by using MPLC (manually packed cartridge, SiO2100-200 mesh; 25% EtOAc in hexanes) to get 7 as a colorless liquid. Yield: 1.6 g (42%). LCMS: Calculated for C11H15BrO3is 275.14, observed: 257.0 [M-OH]+and 259.0 [(M-OH)+2]+

[0376] Step 6:

[0377] To a stirred solution 7 (1.5 g, 5.45 mmol) in THF (15 mL), was added sodium hydride (60% in mineral oil; 0.240 g, 6.00 mmol) in portions at 0 °C, and the reaction mixture stirred at 0 °C for 40 min. Then, a solution of tosyl chloride (1.039 g, 5.45 mmol) in THF (5 mL) was added and the resulting reaction mixture stirred at 0 °C for 30 min. After this time, another equivalent of sodium hydride (0.240 g, 6.00 mmol) was added in portions. The reaction mixture was slowly warmed to room temperature and heated at 70 °C for 2 h. The reaction mixture was quenched with saturated NH4Cl solution (20 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to get a crude residue, which was purified by using MPLC (manually packed cartridge, SiO2100-200 mesh; 5% EtOAc in hexanes) to get 8 as a colorless liquid. Yield: 1 g (67%). LCMS: Calculated for C11H13BrO2is 257.13; Desired molecular mass not observed.

[0378] Step 7:

[0379] To a stirred solution of 8 (0.55 g, 2.13 mmol) in 1,4-dioxane (10 mL), were added potassium acetate (630 mg, 6.42 mmol) and bis(pinacolato)diboron (815 mg, 3.21 mmol) at a room temperature, and the reaction mixture degassed with nitrogen for 5 min. PdCl2(dppf).CH2Cl2 (175 mg, 0.214 mmol) was added and the reaction mixture was heated at 90 °C for 16 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by MPLC (manually packed cartridge, SiO2100-200 mesh; 5% EtOAc in hexanes) to get 9 as a colorless gum. Yield: 0.4 g (55%). LCMS: Calculated for C17H25BO4 is 304.19, observed: No desired molecular ion

[0380] Step 8:

[0381] To a stirred solution of 10 (290 mg, 0.865 mmol) and 9 (395 mg, 1.298 mmol) in a mixture of water (2 mL) and THF (8 mL), was added potassium phosphate tribasic (551 mg, 2.60 mmol) at room temperature, and the resulting mixture degassed with nitrogen for 5 min. Then, SPhos Pd G2 (31.2 mg, 0.043 mmol) was added and the reaction mixture stirred at 70 °C for 18 h. The reaction mixture was filtered through a pad of Celite. The bed was washed with EtOAc (50 mL), the filtratecombined and concentrated under reduced pressure. The resulting crude residue was purified by preparative HPLC (column: SHIMPACK-GIST, C18(20×150) mm, 5µm; eluents:10 mM ammonium bicarbonate in water and ACN) to obtain Compound 19 as a white solid. Yield: 55 mg (14%). LC- MS: Calculated for C26H28N2O4 is 432.52, observed: 433.2 [M+1]+.1H-NMR (400 MHz, DMSO- d6): δ 7.66-7.64 (m, 4H), 7.52 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 1.60 Hz, 1H), 6.92 (d, J = 9.20 Hz, 2H), 6.84 (d, J = 0.80 Hz, 1H), 5.67 (t, J = 6.0 Hz, 1H), 5.53 (br s, 1H, exchanges with D2O), 5.37 (d, J = 5.60 Hz, 1H, exchanges with D2O), 5.01-4.92 (m, 2H), 4.72 (t, J = 6.80 Hz, 1H), 4.30 (dd, J = 5.60, 7.20 Hz, 1H), 3.87 (t, J = 5.20 Hz, 2H), 1.52-1.50 (m, 6H), 1.35 (s, 3H). SFC: 49.4 : 49.6 ratio; tR = 8.88 min and 10.16 min (column: I-CELLULOSE-B; eluents: CO2 and 0.5% isopropyl amine in MeOH) Example 15: Synthesis of Compound 20

[0382] Step 1:

[0383] To a solution of N-Boc-3-hydroxyazetidine (1, 3 g, 17.32 mmol) in DMF (30 mL), was added sodium hydride (60% dispersion in oil, 0.831 g, 20.78 mmol) in portions at 0 °C. After 1 h, 4- Bromobenzyl bromide (2, 4.76 g, 19.05 mmol) was added under nitrogen, and the reaction mixture stirred at room temperature for 4 h. The reaction mixture was cooled to 0 °C and quenched with MeOH (4 mL) and poured into aq. ammonium chloride solution (50 mL). This was extracted with MTBE (2 x 50 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed SiO2cartridge; 100-200 mesh size; 30% EtOAc in hexane) to obtain 3 as an off-white solid. LC-MS: Calculated C15H20BrNO3is 342.23, observed: 242.0 [M-Boc]+and 244.2 [M-Boc+2]+.Yield: 5.5 g (91%)

[0384] Step 2:

[0385] To a solution of 3 (5 g, 14.61 mmol) in 1,4-dioxane (70 mL), were added potassium acetate (4.30 g, 43.8 mmol) and bis(pinacolato)diboron (5.57 g, 21.91 mmol) at room temperature, and the resulting mixture degassed with nitrogen for 5 min. To this reaction mixture, PdCl2(dppf)-DCM adduct (0.597 g, 0.730 mmol) was added and the degassing continued for another 5 min. The reaction mixture was stirred at 80 °C for 4 h. The reaction mixture was cooled to room temperature, filtered through celite pad. The pad was washed with EtOAc (250 mL), the filtrate combined and concentrated under reduced pressure. The resulting crude mass was purified by using MPLC (manually packed cartridge; SiO2100-200 mesh; 10-25% EtOAc in hexanes) to afford 4 as an orange solid. LC-MS: Calculated C21H32BNO5 is 389.29, observed: 290.3 [(M-Boc)+1]+. Yield: 5.5 g (90%)

[0386] Step 3:

[0387] To a solution of 4 (3 g, 7.71 mmol) in DCM (70 mL), was added HCl (4 M in 1,4-dioxane, 5.78 mL, 23.12 mmol) at 0 °C, and the resulting reaction mixture stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the crude residue triturated with 20% EtOAc in hexane (20 mL) to afford 5 as colorless solid. LC-MS: Calculated C16H25BNO3+is 290.19, observed: 290.2 [M]+. Yield: 2.9 g (96%)

[0388] Step 4:

[0389] To a solution of 5 (2.9 g, 8.01 mmol) in DMF (50 mL), were added triethylamine (6.70 mL, 48.1 mmol) and bromoacetonitrile (6, 0.837 mL, 12.01 mmol) at 0 °C under nitrogen and the resulting reaction mixture stirred at room temperature for 3 h. The reaction mixture was quenched with ice-cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude mass was purified by using MPLC (manually packed cartridge; SiO2100-200 mesh; 10-25% EtOAc in hexanes) to afford 7 as a colourless gum. LC-MS: Calculated C18H25BN2O3is 328.22, Observed: 329.2 [M+1]+. Yield: 750 mg (22%)

[0390] Step 5:

[0391] To a stirred solution of 8 (220 mg, 0.656 mmol) in acetonitrile (5 mL) and water (0.2 mL), were added 7 (259 mg, 0.788 mmol) and potassium phosphate tribasic (343 mg, 1.969 mmol) at room temperature, and the reaction mixture degassed with nitrogen for 5 min. To this reaction mixture, Sphos Pd G2 (23.65 mg, 0.033 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 (20 mL), extracted with DCM (2 x 30 mL). The combined organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude product was purified by reverse phase column chromatography (column: Redisep Gold, C-18 silica gel; eluents: 0.1 mM ammonium bicarbonateand ACN) to afford 8 as an off-white solid. LC-MS: Calculated for C27H28N4O3is 456.55, Observed:^457.2 [M+1]+. Yield: 105 mg (35%).1H-NMR (400 MHz, DMSO-d6): δ 7.73-7.69 (m, 4H), 7.55 (d, J = 8.40 Hz, 2H), 7.44 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 6.84 (d, J = 1.20 Hz, 1H), 5.70 (t, J = 6.00 Hz, 1H), 5.55 (br s, 1H, exchanges with D2O), 5.38 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.96-4.93 (m, 1H), 4.46 (s, 2H), 4.21-4.19 (m, 1H), 3.86 (br s, 2H), 3.66 (s, 2H), 3.53-3.50 (m, 2H), 3.08-3.05 (m, 2H), 1.51 (d, J = 6.40 Hz, 3H).. SFC: 95.4%; tR= 5.14 min (column: LUX-I-Amylose 3; eluents: CO2and 0.5% isopropyl amine in MeOH)

[0392] Note: SFC purity = 95.4% Example 16: Synthesis of Compounds 21 and 22

[0393] Step 1:

[0394] To a stirred solution sodium t-butoxide (4.71 g, 49.0 mmol) in DME (60 mL), was added ethyl 2-(diethoxyphosphoryl)acetate (2, 10.70 g, 47.7 mmol) at 0 ℃. The reaction mixture was stirred at 25 ℃ for 1 h. Then p-Bromostyrene oxide ((±)-1, 5.0 g, 25.1 mmol) was added drop wise manner at 25 ℃, and the reaction mixture stirred at 80 ℃ for 16 h. The reaction mixture was quenched with ice cold water (30 mL) and extracted with EtOAc (2 x 30 mL). The combined organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (SiO2, 230-400 mesh; 8% EtOAc in hexanes) to afford 3 as a colourless gum. The product purity obtained was around 50%; product; This was taken to the next step without further purification. Yield: 3.7 g (27%). LC-MS: Calculated for C12H13BrO2is 269.14, observed: desired molecular ion not observed.

[0395] Step 2:

[0396] To a stirred solution of (±)-3 (3.7 g, 8.25 mmol) in MeOH (20 mL), THF (13.33 mL) and water (6.67 mL), was added lithium hydroxide monohydrate (0.296 g, 12.37 mmol) at 0 ℃, and the reaction mixture stirred at 25 ℃ for 16 h. The reaction mixture was concentrated under reduced pressure. The resulting crude residue was diluted with water (20 mL) and extracted with MTBE (2 x 20 mL). The aqueous layer was acidified (to pH~3) using aqueous 6.0 N HCl solution (5 mL) and extracted with EtOAc (3 x 15 mL). The combined EtOAc layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford (±)-4 as a white solid. Yield: 1.7 g (68%). LC-MS: Calculated for C10H9BrO2 is 241.08, observed: 241.0 [M]- and 239.1 [M-2]-

[0397] Note: The identity of trans-geometry of (±)-4 was established through a lack of the nOe enhancement in the methine (1.8 ppm) ^- to carboxylic acid upon irradiation of methine ^- to phenyl (2.4 ppm).

[0398] Step 3:

[0399] To a stirred solution of (±)-4 (1.7 g, 7.05 mmol) in DMF (10 mL), were added HATU (4.02 g, 10.58 mmol) and DIPEA (3.80 mL, 21.15 mmol) at 0 ℃, and the reaction mixture stirred at room temperature for 1 h, following which methylamine hydrochloride (0.571 g, 8.46 mmol) was added at 0 °C. The resulting reaction mixture was then stirred at room temperature for 16 h. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layer was washed with brine solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (SiO2,230-400 mesh; 20% EtOAc in hexanes) to afford (±)-5 as a white solid. Yield: 1.7 g (81%). LC-MS: Calculated for C11H12BrNO is 254.13, observed: 254.0 [M]+and 256.0 [M+2]+

[0400] Step 4:

[0401] To a stirred solution of (±)-5 (1.7 g, 6.69 mmol) in 1,4-dioxane (15 mL), were added bis(pinacolato)diboron (2.55 g, 10.03 mmol) and potassium acetate (1.970 g, 20.07 mmol) at room temperature, and the reaction mixture degassed with nitrogen for 5 min. To the degassed mixture, PdCl2(dppf)-DCM (0.546 g, 0.669 mmol) was added and the degassing continued for 10 min following which the mixture was stirred at 90 °C for 16 h. The reaction mixture was cooled to 25 ℃, diluted with EtOAc (50 mL), filtered through the Celite pad. The pad was washed with EtOAc (2 x 15 mL), the filtrate combined and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (SiO2, 230-400 mesh; 30% EtOAc in hexanes) to afford (±)-6 as a pale-yellow solid. Yield: 1.7 g (76 %). LC-MS: Calculated for C17H24BNO3 is 301.19, observed: 302.5 [M+1]+

[0402] Step 5:

[0403] To a stirred solution of (±)-6 (512 mg, 1.699 mmol) in THF (4 mL) and water (1 mL), were added 7 (475 mg, 1.133 mmol) and NaHCO3 (238 mg, 2.83 mmol) at room temperature, and thereaction mixture was purged with nitrogen for 10 min, then PdCl2(dppf).DCM complex (93 mg, 0.113 mmol) was added and the degassing continued for 10 min. The reaction mixture was then heated at 90 °C for 16 h. The reaction mixture was cooled to 25 ℃, diluted with EtOAc (100 mL) and filtered through a Celite pad. The pad was washed with EtOAc (2 x 15 mL), the filtrate combined and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (SiO2,230-400 mesh; 5% MeOH in DCM) to afford 8 as a brown colour solid. Yield: 250 mg (40%). LC-MS: Calculated for C31H35N3O4is 513.64, observed: 514.4 [M+1]+

[0404] Step 6:

[0405] To a stirred solution of 8 (250 mg, 0.487 mmol) in MeOH (5 mL), was added p- toluenesulfonic acid monohydrate (185 mg, 0.973 mmol) at 0 °C, and the reaction mixture stirred at 25 °C for 3 h. The reaction mixture was quenched with saturated aqueous NaHCO3 solution (20 mL) and extracted with 10% MeOH in DCM (15 mL x 3). The combined organic extract was dried over anhydrous Na2SO4, filtered and concentrated. The crude residue, thus obtained, was purified by using reverse phase column chromatography (column: RediSep Gold® C18Reverse-Phase column, 100 g; eluents:10 mM ammonium bicarbonate in water and acetonitrile) to afford Compounds 21 and 22 as a white solid. Yield: 50 mg (23%). LC-MS: Calculated for C26H27N3O3 is 429.52, observed: 430.3 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 8.05 (m, J = 4.40 Hz, 1H, exchanges with D2O), 7.68 (d, J = 8.40 Hz, 2H), 7.61 (d, J = 8.40 Hz, 2H), 7.53 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 7.22 (d, J = 8.40 Hz, 2H), 6.84 (d, J = 0.80 Hz, 1H), 5.69 (t, J = 6.00 Hz, 1H), 5.54 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.37 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.96-4.93 (m, 1H), 3.87 (t, J = 5.60 Hz, 2H), 2.62 (d, J = 4.40 Hz, 3H), 2.29-2.26 (m, 1H), 1.87-1.84 (m, 1H), 1.51 (d, J = 6.80 Hz, 3H), 1.40-1.36 (m, 1H), 1.26-1.25 (m, 1H). SFC: 93.69%; tR = 1.80 min (Column: I Cellulose- Z; eluents: 0.5% isopropyl amine in MeOH).

[0406] Note: trans-geometry at tail with 93.69% of SFC purity. Mixture of diastereomers; racemic at tail. The separation of diastereomers is not seen in SFC.Example 17: Synthesis of Compound 23

[0407] Step 1:

[0408] To stirred solution of 1 (6.46 g, 19.42 mmol) in DMF (50 mL), were added 4-bromophenol (2, 2.8 g, 16.18 mmol) and cesium carbonate (4.47 g, 32.4 mmol) at room temperature, and the reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was quenched with water (30 mL) and extracted with EtOAc (50 mL x 2). The combined organic layer was washed with cold water and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue thus obtained was purified by using MPLC (manually packed SiO2 cartridge, 230-400 mesh; 20% EtOAc in hexanes) to afford 3 as an off-white solid. Yield: 4.2 g (70%)

[0409] Step 2:

[0410] To stirred solution of 3 (4.0 g, 12.0 mmol) in DCM (50 mL), was added boron trichloride (1 M in hexane; 24.0 mL, 24.0 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 1 h. The reaction mixture was quenched with MeOH (30 mL); The volatiles were evaporated under reduced pressure. To the resulting residue, NaHCO3 solution was added. This was extracted with DCM (2 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC(manually packed SiO2cartridge, 100-200 mesh; 20% EtOAc in hexanes) to afford 4 as an off-white solid. Yield: 2.4 g (71%)

[0411] Step 3:

[0412] To a stirred solution of 4 (2 g, 8.23 mmol) in DCM (20 mL), were added tosyl chloride (3.14 g, 16.45 mmol), DMAP (0.1 g, 0.82 mmol) and triethylamine (3.47 mL, 24.68 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 16 h. The reaction mixture was quenched with sat. NaHCO3 solution (20 mL) and extracted with DCM (50 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed SiO2 cartridge, 230-400 mesh; 20% EtOAc in hexanes) to afford 5 as a brown solid. Yield: 3 g (83%)

[0413] Step 4:

[0414] To a stirred solution of 5 (3.0 g, 7.55 mmol) in DMSO (20 mL), was added potassium thioacetate (1.72 g, 15.10 mmol) at room temperature, and the reaction mixture heated at 70 °C for 1 h. The reaction mixture was quenched with water (50 mL) and extracted with DCM (100 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed cartridge, SiO2230-400 mesh; 5% EtOAc in hexanes) to afford 6 as an off-white solid. Yield: 1.2 g (48%)

[0415] Step 5:

[0416] To a stirred solution of N-chlorosuccinimide (1.33 g, 9.96 mmol) in acetonitrile (25 mL), was added conc. HCl (0.25 mL, 8.30 mmol) dropwise at room temperature. The reaction mixture was stirred at room temperature for 10 min after which it was cooled to 0 °C and a solution of 6 (1 g, 3.32 mmol) in acetonitrile (5 mL) was added. The reaction mixture was stirred at 0 °C for 30 min. The reaction mixture was concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed cartridge, SiO2230-400 mesh; 5% EtOAc in hexanes) to obtain 7 as an off-white solid. Yield: 0.9 g (75%)

[0417] Step 6:

[0418] To a solution of 7 (900 mg, 2.76 mmol) in THF (1 mL), was added methylamine (2 M in THF; 2.76 mL, 5.53 mmol), 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 MPLC (manually packed cartridge; SiO2230-400 mesh; 5% EtOAc in hexanes) to afford 8 as an off-white solid. LC-MS: Calculated C11H14BrNO3S is 320.20, observed: 320.2 [M]- and 318.2 [M-2]-. Yield: 350 mg (39%)

[0419] The identity of cis-geometry of 8 was established through the nOe enhancement observed at 4.62 ppm (methine ^- to phenoxy) upon irradiation of the other methine at 3.62 ppm (methine ^- to sulfonamide).

[0420] Step 7:

[0421] To a solution of 8 (300 mg, 0.937 mmol) in dioxane (10 mL), were added potassium acetate (276 mg, 2.81 mmol) and bis(pinacolato)diboron (357 mg, 1.405 mmol) at room temperature, and the resulting reaction mixture degassed with nitrogen for 5 min. To this reaction mixture, PdCl2(dppf) (41.1 mg, 0.056 mmol) was added and the resulting reaction mixture was heated at 100 °C for 16 h. The reaction mixture was filtered through Celite bed; The bed was washed with EtOAc (50 mL), the filtrate combined and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed cartridge; SiO2100-200 mesh; 40% EtOAc in hexanes) to afford 9 as an off-white solid. Yield: 330 mg (84%). LC-MS: Calculated C17H26BNO5S is 367.27, observed: 368.3 [M+1]+

[0422] Step 8:

[0423] To a stirred solution of 10 (260 mg, 0.620 mmol) in acetonitrile (3 mL) and water (3 mL), were added 9 (228 mg, 0.620 mmol) and K2CO3(257 mg, 1.680 mmol) at room temperature, and the reaction mixture degassed with nitrogen for 5 min. To this reaction mixture, PdCl2(dtbpf) (20.21 mg, 0.031 mmol) was added and the reaction mixture irradiated in microwave reactor at 80 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 4% MeOH in DCM) to afford 11 as a pale brown solid. Yield: 200 mg (64%). LC-MS: Calculated for C31H37N3O6S is 579.71, observed:^580.4 [M+1]+

[0424] Step 9:

[0425] To a stirred solution of 11 (200 mg, 0.345 mmol) in MeOH (2 mL), was added p-toluene sulfonic acid monohydrate (190 mg, 1.035 mmol) at 0 °C, and the resulting reaction mixture stirred at room temperature for 2 h. The reaction mixture was diluted with DCM (50 mL) and washed with NaHCO3 solution (20 mL). The organic layer was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by reverse phase column chromatography (Column: Redisep C18; Eluents: 10 mM ammonium bicarbonate in water and acetonitrile) to afford product. The product was further repurified by SFC (Column: RR WHELK (250*20) mm, 5 μm; eluents: CO2 and 0.5% isopropyl amine in isopropanol) to afford Compound 23 as an off-white solid. Yield: 35 mg (20%). LCMS: Calculated for C26H29N3O5S is 495.59; observed: 496.2 [M+1]+1H-NMR (400 MHz, DMSO-d6): δ 7.67-7.63 (m, 4H), 7.52 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 7.00-6.95 (m, 3H, 1 H exchanges with D2O), 6.84 (d, J = 1.20 Hz, 1H), 5.69 (t, J = 6.00 Hz, 1H), 5.54 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.38 (d, J = 5.20 Hz, 1H, exchanges with D2O), 4.96-4.93 (m, 1H), 4.74-4.70 (m, 1H), 3.87 (t, J = 6.00 Hz, 2H), 3.68-3.64 (m, 1H), 2.88-2.81 (m, 2H), 2.59 (d, J = 4.80 Hz, 3H), 2.36-2.30 (m, 2H), 1.51 (d, J = 6.40 Hz, 3H). SFC: 99.7%; tR = 7.27 min (Column: RR WHELK; eluents: CO2 and 0.5% isopropyl amine in isopropanol)

[0426] Note: cis-geometry at tail part; mixture of diastereomers. SFC purity = 99.7% Example 18a: Synthesis of Compound 25

[0427] Reference for Step 1: J. Med. Chem.2017, 60,2, 627-640.

[0428] Step 1:

[0429] To a stirred solution of 1-bromo-4-iodobenzene (2, 17.91 g, 63.3 mmol) in THF (90 mL), was added isopropyl magnesium chloride (2M in THF; 34.8 mL, 69.6 mmol) dropwise at 0 °C. The reaction mixture was stirred at 0 °C for 3 h. The reaction mixture was then cooled to -78 °C following which ethyl cyclobutanone-3-carboxylate (1, 7.71 mL, 63.3 mmol) was added dropwise. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with sat. NH4Cl solution (30 mL) and extracted with EtOAc (100 mL x 2). The combined organic layer was 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% EtOAc in hexanes) to afford 3 as a colorless liquid. Yield = 6.0 g (29%)

[0430] Step 2:

[0431] To a solution of 3 (8 g, 26.7 mmol) in TFA (15 mL), was added triethylsilane (8.31 mL, 53.5 mmol) at 0 °C, and the reaction mixture was stirred at room temperature for 3 h. The volatiles were removed under reduced pressure. The crude residue was dissolved in EtOAc (50 mL) andwashed with 10% NaHCO3solution. The pH of aqueous layer was adjusted to 4 with 1.5 N HCl and the resulting solution was extracted with EtOAc (2 x 30 mL). The combined organic layer was 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; 50% EtOAc in hexanes) to afford 4 as a pale-yellow liquid.Yield = 5.0 g (60%)

[0432] Step 3:

[0433] To a stirred solution of 4 (5 g, 17.66 mmol) in MeOH (40 mL), was added methyl amine (33% in MeOH, 10.70 mL, 353 mmol) at room temperature. The resulting reaction mixture was stirred at 80 °C for 16 h in a miniclave reactor. The volatiles were removed under reduced pressure, and the crude residue was purified by MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 95% EtOAc in hexanes) to afford mixture of isomers. The isomers were separated by SFC (column: R, R Whelk (250*30) mm, 5 μm; eluents: CO2and 0.5% isopropyl amine in MeOH) to afford 5 and 6 as off-white solids. Yield: 5 = 600 mg and 6 = 2.0 g

[0434] The identity of trans-geometry of 5 was established through a lack of the nOe enhancement in the methine (3.61 ppm) ^- to carboxamide upon irradiation of methine ^- to phenyl (2.91 ppm). The identity of cis-geometry of 6 was established through the nOe enhancement observed at 3.61 ppm (methine ^- to carboxamide) upon irradiation of the other methine at 2.91 ppm (methine ^- to phenyl). Both cis- and trans- isomers were taken individually for further conversions.

[0435] Step 4:

[0436] To a solution of 5 (1.0 g, 3.73 mmol) in dioxane (20 mL), were added potassium acetate (1.09 g, 11.19 mmol) and bis(pinacolato)diboron (1.13 g, 4.48 mmol) at room temperature, and the reaction mixture degassed using nitrogen for 15 min. To this reaction mixture, PdCl2(dppf).DCM adduct (0.15 g, 0.186 mmol) was added and the degassing continued for 5 min. The reaction mixture was stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature and filtered through Celite pad. The pad was further washed with EtOAc (200 mL), the filtrate combined and washed with water (50 mL). The layers were separated, and the organic layer dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2cartridge, 100-200 mesh size; 70% EtOAc in hexanes) to afford 7 as an off-white solid. Yield = 0.9 g (69%). LC-MS: Calculated for C18H26BNO3is 315.22, observed: 316.4 [M+1]+

[0437] Step 5:

[0438] To a stirred solution of 8 (0.250 g, 0.596 mmol) in THF (4.5 mL) and water (0.5 mL), were added potassium phosphate tribasic (0.380 g, 1.789 mmol) and 7 (0.282 g, 0.894 mmol) at room temperature, and the reaction mixture degassed with nitrogen for 5 min. To this reaction mixture, SPhos Pd G2 (0.43 g, 0.060 mmol) was added and the degassing continued for 5 min. The resulting reaction mixture was irradiated in microwave reactor at 60 °C for 2 h. The reaction mixture wasquenched with water (10 mL) and extracted with 10% MeOH in DCM (25 mL x 2). The combined organic layer was 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; 5% MeOH in DCM) to afford 9 as a pale-yellow solid. Yield = 0.22 g (65%). LC-MS: Calculated for C32H37N3O4 is 527.67, observed: 528.2 [M+1]+

[0439] Step 6:

[0440] To a stirred solution of 9 (0.22 g, 0.417 mmol) in MeOH (5 mL), was added p-toluene sulfonic acid monohydrate (0.238 g, 1.251 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with 10% MeOH in DCM (50 mL) and washed with sat. NaHCO3 solution (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by reverse phase MPLC (column: Redisep Gold, C18SiO2; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 25 as an off-white solid. Yield: 45 mg (24%) LCMS: Calculated for C27H29N3O3is 443.55; observed: 444.2 [M+1]+1H-NMR (400 MHz, DMSO-d6): δ 7.73-7.68 (m, 3H), 7.65 (d, J = 8.40 Hz, 2H), 7.54 (d, J = 8.00 Hz, 2H), 7.39-7.36 (m, 3H), 6.84 (d, J = 1.20 Hz, 1H), 5.70 (t, J = 6.00 Hz, 1H), 5.54 (t, J = 6.00 Hz, 1H, exchanges with D2O), 5.38 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.96-4.93 (m, 1H), 3.87 (t, J = 6.00 Hz, 2H), 3.68-3.64 (m, 1H), 3.02-2.99 (m, 1H), 2.60 (d, J = 6.80 Hz, 3H), 2.52-2.51 (m, 2H, merges with solvent peak), 2.31- 2.23 (m, 2H), 1.51 (d, J = 6.40 Hz, 3H). SFC: 97.9%; tR = 5.33 min (Column: I-Cellulose Z; eluents: CO2and 0.5% isopropyl amine in MeOH)

[0441] Note: trans-geometry at tail part, mixture of diastereomers. dr = 97.9: 0.4 (trans: cis of tail part). Example 18b: Synthesis of Compound 27

[0442] Compound 27 was synthesized in an identical fashion as described in steps 4-6 of Compound 24 using 6 (cis- isomer) as the starting material, however. LCMS: Calculated for C27H29N3O3 is 443.55; observed: 444.2 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.73-7.68 (m,3H), 7.64 (d, J = 8.40 Hz, 2H), 7.54 (d, J = 8.40 Hz, 2H), 7.36-7.33 (m, 3H), 6.84 (d, J = 1.20 Hz, 1H), 5.70 (t, J = 6.00 Hz, 1H), 5.54 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.37 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.96-4.93 (m, 1H), 3.87 (t, J = 5.60 Hz, 2H), 3.43-3.38 (m, 1H), 2.98-2.91 (m, 1H), 2.58 (d, J = 4.80 Hz, 3H), 2.47-2.40 (m, 2H, merges with solvent peak), 2.27-2.22 (m, 2H), 1.51 (d, J = 6.40 Hz, 3H). SFC: 97%; tR = 4.36 min (Column: I-Cellulose Z; eluents: CO2 and 0.5% isopropyl amine in MeOH)

[0443] Note: cis-geometry at tail part, mixture of diastereomers. dr = 97.0: 1.4 (cis: trans of tail part). Example 19: Synthesis of Compound 29

[0444] Step 1:

[0445] To a solution of 1 (8 g, 35.2 mmol) in DCM (150 mL), were added triethylamine (14.72 mL, 10.7 mmol), DMAP (0.43 g, 3.52 mmol) and tosyl chloride (8.73 g, 45.8 mmol) at 0 °C, and the resulting reaction mixture stirred at room temperature for 16 h. The reaction mixture was quenched with 10% NaHCO3 solution (50 mL) and extracted with DCM (100 mL x 2). The combined organic layer was 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; 20% EtOAc in hexanes) to afford 2 as an off-white solid. Yield = 12 g (80%)

[0446] Step 2:

[0447] To a solution of 2 (6.5 g, 17.05 mmol) in DMF (70 mL), was added potassium thioacetate (3.89 g, 34.1 mmol) at room temperature, and the resulting mixture s stirred at 70 °C for 16 h. The reaction mixture was cooled to room temperature, quenched with ice cold water (100 mL) and extracted with MTBE (50 mL x 2). The combined organic layer was washed with brine solution, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2cartridge, 100-200 mesh size; 15% EtOAc in hexanes) to afford 3 as pale-brown solid. Yield = 3.1 g (57%)

[0448] Step 3:

[0449] To a solution of N-chlorosuccinimide (4.21 g, 31.6 mmol) in ACN (20 mL), was added conc. HCl (0.8 mL, 26.3 mmol) at room temperature. The reaction mixture was stirred for 15 min and then cooled to 0 °C. A solution of 3 (3 g, 10.52 mmol) in ACN (10 mL) was added drop wise. The resulting reaction mixture was stirred at 0 °C for 1 h. The volatiles were removed under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2 cartridge, 100-200 mesh size; 10% EtOAc in hexanes) to afford 4 as an off-white solid. Yield: 2.3 g (64%)

[0450] Step 4:

[0451] To a stirred solution of 4 (2.2 g, 7.11 mmol) in mixture of MeOH (20 mL) and THF (10 mL), was added methylamine (33% in MeOH, 1.7 mL, 14.21 mmol) at 0 °C. The 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 MPLC (manually packed SiO2cartridge, 230-400 mesh size; 35% EtOAc in hexanes) to afford mixture of 5 and 6 as white solids. Yield = 5 = 850 mg and 6 = 1.1 g

[0452] The identity of trans-geometry of 5 was established through a lack of the nOe enhancement in the methine (3.91 ppm) ^- to sulfonamide upon irradiation of methine ^- to phenyl (3.69 ppm). The identity of cis-geometry of 6 was established through the nOe enhancement observed at 3.83 ppm (methine ^- to sulfonamide) upon irradiation of the other methine at 3.43 ppm (methine ^- to phenyl). LCMS: Calculated for C11H14BrNO2S is 304.20; observed: 304.0 [M]- and 302.0 [M-2]-. Both cis and trans isomers were taken individually for further conversions.

[0453] Step 5:

[0454] To a stirred solution of 5 (0.8 g, 2.63 mmol) in dioxane (20 mL), were added potassium acetate (1.26 g, 12.85 mmol) and bis(pinacolato)diboron (1 g, 3.94 mmol) at room temperature, and the reaction mixture degassed using nitrogen for 5 min. To this reaction mixture, PdCl2(dppf).DCM complex (0.13 g, 0.158 mmol) was added, and the resulting reaction mixture stirred at 100 °C for 4 h. The reaction mixture was cooled to room temperature and filtered through a Celite bed. The bed 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 SiO2cartridge, 100-200 mesh size; 40% EtOAc in hexanes) to afford boronate 7 as a white solid. Yield: 0.9 g (88%)

[0455] Step 6:

[0456] To a stirred solution of 8 (160 mg, 0.382 mmol) in THF (4.5 mL) and water (0.5 mL), were added boronate 7 (200 mg, 0.572 mmol) and potassium phosphate tribasic (243 mg, 1.14 mmol) at room temperature, and the resulting mixture degassed with nitrogen for 5 min. To this reaction mixture, SPhos Pd G2 (27 mg, 0.038 mmol) was added. The resulting reaction mixture was irradiated in microwave reactor at 60 °C for 2 h. The reaction was quenched with water (10 mL) and extracted with 10% MeOH in DCM (2 x 30 mL). The combined organic layer was 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; 5% MeOH in DCM) to afford 9 as an off-white solid. Yield: 170 mg (77%). LC-MS: Calculated for C31H37N3O5S is 563.71, observed:^564.4 [M+1]+

[0457] Step 7:

[0458] To a solution of 9 (190 mg, 0.337 mmol) in MeOH (8 mL), was added p-toluenesulfonic acid monohydrate (192 mg, 1.01 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 2 h. The reaction mixture was diluted with 10% MeOH in DCM (50 mL) and washed with sat. NaHCO3 solution (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by reverse phase MPLC (column: Redisep Gold, C18SiO2; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 29 as a white solid. Yield = 30 mg (19%). LC-MS: Calculated for C26H29N3O4S is 479.60, observed: 480.3 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.70 (d = 8.40 Hz, 2H), 7.66 (d, J = 8.40 Hz, 2H), 7.55 (d, J = 8.40 Hz, 2H), 7.42 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 7.01 (q, J = 4.80 Hz, 1H, exchanges with D2O), 6.84 (d, J = 0.80 Hz, 1H), 5.70 (t, J = 6.00 Hz, 1H), 5.54 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.37 (d, J = 5.60 Hz, 1H exchanges with D2O), 4.97-4.91 (m, 2H), 4.0-3.93 (m, 1H), 3.87 (t, J = 6.0 Hz, 2H), 3.80-3.72 (m, 1H), 2.77- 2.73 (m, 2H), 2.62 (d, J = 4.80 Hz, 3H), 2.55-2.51 (m, 2H, merges with solvent peak), 1.51 (d, J = 6.40 Hz, 3H). SFC: 99.3%; tR = 3.59 min (column: l-Amylose 3; eluents: CO2 and 0.5% isopropyl amine in MeOH)

[0459] Note: trans-geometry in the tail part, mixture of diastereomers. dr = 99.3 : 0.7 (trans : cis of tail part). Two protons are underneath DMSO peak, confirmed by 1H- NMR which was recorded in CD3OD. Example 20: Synthesis of Compound 31

[0460] Compound 31 was synthesized in an identical fashion as described in steps 5-7 of Compound 29, using 6 as the starting material, however. Yield = 35 mg (20%). LC-MS: Calculated for C26H29N3O4S is 479.60, observed: 480.2 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.71- 7.66 (m, 4H), 7.55 (d, J = 8.40 Hz, 2H), 7.38-7.36 (m, 3H), 6.91 (q, J = 4.80 Hz, 1H, exchanges with D2O), 6.84 (d, J = 1.20 Hz, 1H), 5.70 (t, J = 6.00 Hz, 1H), 5.54 (t, J = 6.00 Hz, 1H, exchanges with D2O), 5.38 (d, J = 5.60 Hz, 1H exchanges with D2O), 4.96-4.93 (m, 1H), 3.99-3.95 (m, 1H), 3.87 (t, J = 5.60 Hz, 2H), 3.53-3.49 (m, 1H), 2.70-2.62 (m, 2H), 2.60 (d, J = 5.20 Hz, 3H), 2.44-2.33 (m, 2H), 1.51 (d, J = 6.40 Hz, 3H). SFC: 98.8%; tR = 5.58 min (column: l-Amylose 3; eluents: CO2 and 0.5% isopropyl amine in MeOH)

[0461] Note: cis-geometry in the tail part, mixture of diastereomers. dr = 98.8 : 1.2 (cis: trans of tail part)Example 21: Synthesis of Compounds 33 and 34

[0462] Step 1:

[0463] To a stirred solution of 4-(4-bromophenyl)pyrrolidin-2-one ((±)-1, 2.5 g, 10.41 mmol) in THF (25 mL), was added borane tetrahydrofuran complex solution (1 M in THF; 15.62 mL, 15.62 mmol) dropwise manner at 0 ℃, and the resulting mixture was stirred at 70 °C for 18 h. The reaction mixture was cooled to 0 ℃ and quenched with MeOH (10 mL). The reaction mixture was again heated at 70 ℃ and for 2 h. The volatiles were evaporated under reduced pressure to get crude (±)-2. The obtained crude residue of (±)-2 was used in the next reaction without any purification. Yield: 1.7 g (crude). LCMS: Calculated for C10H12BrN is 226.12, observed: 226.4 [M]+and 228.4 [M+2]+

[0464] Step 2:

[0465] To a stirred solution of (±)-2 (2.5 g, 11.06 mmol) in DMF (50 mL), were added Et3N (4.62 mL, 33.2 mmol) and iodoacetonitrile (1.2 mL, 16.58 mmol) at 0 ℃, and the reaction mixture stirred at 25 ℃ for 1 h. The reaction mixture was quenched with ice water (50 mL) and extracted with EtOAc (100 mL x 3). The combined organic extract was washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed SiO2 cartridge, 230-400 mesh, 20% EtOAc in hexanes) to afford (±)-3 as colorless liquid. The purity of the product by LC-MS was 70% ; This was taken to the next step as such without further purification. Yield: 1.7 g (41%). LCMS: Calculated for C12H13BrN2is 265.15, observed: 265.1 [M]+and 267.0 [M+2]+

[0466] Step 3:

[0467] To a stirred solution of (±)-3 (1.8 g, 6.79 mmol) in 1,4-dioxane (25 mL), were added potassium acetate (1.332 g, 13.58 mmol) and bis(pinacolato)diboron (1.724 g, 6.79 mmol) at 25 ℃, and the reaction mixture degassed with nitrogen for 5 min, after which PdCl2(dppf)-DCM (0.554 g,0.679 mmol) was added. The reaction mixture was then stirred at 100 ℃ for 16 h. The reaction mixture was cooled to 25 ℃ and concentrated under reduced pressure. The crude residue was dissolved EtOAc (20 mL), filtered through a Celite pad. The pad was washed with EtOAc (20 mL x 2), the filtrate combined and washed with brine solution (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by using MPLC (manually packed SiO2cartridge, 230-400 mesh, 20% EtOAc in hexanes) to afford (±)- 4 as a white solid. Yield: 800 mg (34%)

[0468] Step 4:

[0469] To a stirred solution of (±)-4 (302 mg, 0.966 mmol) in THF (6 mL) and water (1.2 mL), were added 5 (270 mg, 0.644 mmol) and tripotassium phosphate (410 mg, 1.932 mmol) at 25 ℃, and the reaction mixture degassed with nitrogen for 5 min. To this mixture, SPhos Pd G2 (23.20 mg, 0.032 mmol) was added and was stirred at 70 ℃ for 16 h. The reaction mixture was quenched with ice water (10 mL) and extracted with EtOAc (25 mL x 3). The combined organic extract 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 using MPLC (manually packed SiO2 cartridge, 230-400 mesh, 7% MeOH in DCM) to afford 6 as a brown solid. Yield: 220 mg (61%). LCMS: Calculated for C32H36N4O3 is 524.67, observed: 525.2 [M+1]+

[0470] Step 5:

[0471] To a stirred solution of 6 (220 mg, 0.419 mmol) in MeOH (25 mL), was added p- toluenesulfonic acid monohydrate (279 mg, 1.468 mmol) at 0 ℃, and the reaction mixture was stirred for 4 h at room temperature. The reaction mixture was quenched with sat. NaHCO3 solution (8 mL) at 0 ℃. The suspension was extracted with DCM (80 mL x 3). The combined organic extract was washed with sat. NaHCO3 solution (2 x 5 mL), brine solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue thus obtained was purified by using MPLC (manually packed SiO2cartridge, 230-400 mesh size; 5% MeOH in DCM) to afford the racemic compound as a white solid. Yield: 150 mg (81%) LCMS: Calculated for C27H28N4O2is 440.55, observed: 441.2 [M+1]+

[0472] Step 6: SFC Purification

[0473] The diastereomers of 150 mg of the racemic compound were separated by SFC (column: LUX iA3-(250*20) mm, 5 μm; eluents: CO2 and 0.5% isopropyl amine in MeOH and acetonitrile) to obtain Compound 33 (tR = 2.46 min) and Compound 34 (tR = 3.28 min) as off-white solids. Yield: Compound 33 = 40 mg and Compound 34 = 37 mg

[0474] Compound 33

[0475] LCMS: Calculated for C27H28N4O2 is 440.55, observed: 441.5 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.69 (d, J = 8.40 Hz, 2H), 7.64 (d, J = 8.40 Hz, 2H), 7.54 (d, J = 8.40 Hz, 2H), 7.39 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 6.84 (d, J = 0.80 Hz, 1H), 5.70 (t, J = 6.00 Hz, 1H), 5.54(t, J = 5.60 Hz, 1H, exchanges with D2O), 5.37 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.96-4.93 (m, 1H), 3.89-3.45 (m, 4H), 3.42-3.41 (m, 1H), 3.02 (t, J = 8.40 Hz, 1H), 2.84-2.77 (m, 2H), 2.68- 2.60 (m, 1H), 2.34-2.31 (m, 1H), 1.85 (m, 1H), 1.51 (d, J = 6.40 Hz, 3H). SFC: 97.8%; tR = 2.92 min (column: LUX-I-Amylose3; eluents: CO2 and 0.5% isopropyl amine in acetonitrile and MeOH).

[0476] Note: Diastereomeric ratio = 97.8: 1.9; unknown stereochemistry at tail part.

[0477] Compound 34

[0478] LCMS: Calculated for C27H28N4O2is 440.55, observed: 441.1 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.69 (d, J = 6.40 Hz, 2H), 7.64 (d, J = 8.40 Hz, 2H), 7.54 (d, J = 8.40 Hz, 2H), 7.39 (d, J = 8.40 Hz, 2H), 7.36-7.34 (m, 1H), 6.84 (d, J = 1.20 Hz, 1H), 5.70 (t, J = 6.00 Hz, 1H), 5.54 (t, J = 6.00 Hz, 1H, exchanges with D2O), 5.38 (d, J = 5.20 Hz, 1H, exchanges with D2O), 4.96-4.93 (m, 1H), 3.89-3.86 (m, 4H), 3.45-3.36 (m, 1H), 3.02 (t, J = 8.00 Hz, 1H), 2.85-2.77 (m, 2H), 2.64-2.60 (m, 1H), 2.34-2.29 (m, 1H), 1.85-1.82 (m, 1H), 1.51 (d, J = 6.40 Hz, 3H). SFC: 98.79%; tR = 3.82 min (column: LUX-I-Amylose 3; eluents: CO2and 0.5% isopropyl amine in acetonitrile and MeOH).

[0479] Note: Diastereomeric ratio = 98.79 : 1.2; unknown stereochemistry at tail part. Example 22: Synthesis of Compound 35

[0480] Step 1:

[0481] To a solution of 3,4,7,8-tetramethyl-1,10-phenanthroline (Me4Phen, 1.67 g, 7.07 mmol) in toluene (200 mL), was added copper(I) iodide (0.67 g, 3.53 mmol) at room temperature, and the resulting mixture degassed with nitrogen for 5 min. To this reaction mixture, N-Boc-3- hydroxyazetidine (1, 13.47 g, 78 mmol), 1-bromo-4-iodobenzene (2, 20 g, 70.7 mmol) and cesium carbonate (46.1 g, 141 mmol) were added at room temperature and the degassing continued for 5 min. The reaction mixture was stirred at 110oC for 16 h. The reaction was cooled to room temperature, filtered through a pad of Celite. The pad was washed with EtOAc (100 mL), the filtrate combined and concentrated under reduced pressure. The resulting crude residue was purified by MPLC (using manually packed SiO2 cartridge, 100-200 mesh size; 6% EtOAc in hexanes) to obtain 3 as a white solid. Yield: 18 g (72%)

[0482] Reference: J. Org. Chem.2008, 73, 284-286.

[0483] Step 2:

[0484] To a solution of 3 (18 g, 54.8 mmol) in DCM (100 mL), was added HCl (4 M in dioxane, 68.6 mL, 274 mmol) dropwise at 0 °C, and the reaction mixture stirred at room temperature for 2 h. The volatiles were removed under reduced pressure, and the crude residue was dissolved in EtOAc (200 mL), washed with 10% NaHCO3 solution (50 mL). The organic layer was dried over anhydrous Na2SO4 and filtered; the filtrate was concentrated under reduced pressure to afford as 4 pale-yellow solid. Yield: 8.0 g (55%) LC-MS: Calculated for C9H10BrNO is 228.0, observed:^228.1 [M]+and 230.1 [M+2]+

[0485] Step 3:

[0486] To a stirred solution of 4 (4.0 g, 17.54 mmol) in ACN (40 mL), was added triphosgene (5.20 g, 17.54 mmol) at room temperature. The reaction mixture was cooled to 0 °C; triethylamine (7.33 mL, 52.6 mmol) and cyclopropylamine (5, 2.43 mL, 35.1 mmol) were added, and the resulting reaction mixture was 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 layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue was purified by using MPLC (manually packed SiO2cartridge, 230-400 mesh size; 80% EtOAc in hexanes) to afford 6 as an off-white solid. Yield = 2.0 g (32%). LC-MS: Calculated for C13H15BrN2O2 is 311.18, observed: 311.4 [M]+and 313.4 [M+2]+

[0487] Step 4:

[0488] To a stirred solution of 6 (2 g, 6.43 mmol) in dioxane (20 mL), were added potassium acetate (1.26 g, 12.85 mmol) and bis(pinacolato)diboron (2.45 g, 9.64 mmol) at room temperature, and the reaction mixture degassed with nitrogen for 10 min. To this reaction mixture, PdCl2(dppf).DCM complex (0.525 g, 0.643 mmol) was added, and the resulting reaction mixture stirred at 100 °C for 6 h. The reaction mixture was cooled to room temperature, filtered through the Celite pad. The pad was washed with EtOAc (w00 mL), the filtrate combined and concentratedunder reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2cartridge, 100-200 mesh size; 60% EtOAc in hexanes) to afford boronate 7 as an off-white solid (75% purity by LC-MS; The product was taken to the next step without further purification). Yield: 1.5 g (49%). LC-MS: Calculated for C19H27BN2O4 is 358.24, observed:^359.3 [M+1]+

[0489] Step 5:

[0490] To a stirred solution of 8 (400 mg, 0.954 mmol) in THF (5 mL) and water (1 mL), were added boronate 7 (513 mg, 1.431 mmol) and potassium phosphate tribasic (607 mg, 2.86 mmol) at room temperature, and the resulting mixture degassed with nitrogen for 5 min. To this reaction mixture, SPhos Pd G2 (68.7 mg, 0.095 mmol) was added and the resulting reaction mixture was irradiated in microwave reactor at 65 °C for 2 h. The reaction was quenched with water (20 mL) and extracted with 10% MeOH in DCM (2 x 40 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue thus obtained was purified by MPLC (manually packed SiO2cartridge, 230-400 mesh size; 5% MeOH in DCM) to afford 9 as pale-brown solid. Yield: 200 mg (33%). LC-MS: Calculated for C33H38N4O5is 570.69, observed:^571.2 [M+1]+

[0491] Step 6:

[0492] To a solution of 9 (200 mg, 0.35 mmol) in MeOH (5 mL), was added p-toluenesulfonic acid monohydrate (200 mg, 1.05 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with 10% MeOH in DCM (50 mL), washed with sat. NaHCO3 solution (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue thus obtained was purified by reverse phase MPLC (column: Redisep Gold, C18 SiO2; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 35 as a white solid. Yield = 40 mg (23%). LC-MS: Calculated for C28H30N4O4 is 486.57, observed: 487.2 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.67-7.64 (m, 4H), 7.52 (d, J = 8.40 Hz, 2H), 7.35 (d, J = 1.20 Hz, 1H), 6.93 (d, J = 8.40 Hz, 2H), 6.84 (s, 1H), 6.55 (d, J = 2.80 Hz, 1H, exchanges with D2O), 5.69 (t, J = 5.60 Hz, 1H), 5.53 (br s, 1H, exchanges with D2O), 5.37 (d, J = 5.60 Hz, 1H, exchanges with D2O), 5.05-5.01 (m, 1H), 4.96-4.91 (m, 1H), 4.26-4.22 (m, 2H), 3.87 (br s, 2H), 3.75-3.72 (m, 2H), 2.47-2.44 (m, 1H), 1.51 (d, J = 6.40 Hz, 3H), 0.57-0.53 (m, 2H), 0.39-0.35 (m, 2H). SFC: 97.8%; tR = 2.49 min (Column: I-Cellulose B; eluents: CO2 and 0.5% isopropyl amine in MeOH)

[0493] Note: Single isomer with SFC purity = 97.8%Example 23: Synthesis of Compound 37

[0494] Step 1:

[0495] To a stirred solution of methyl 3-methylcyclobutanone-3-carboxylate (1, 5.0 g, 35.2 mmol) in MeOH (100 mL), was added sodium borohydride (0.665 g, 17.59 mmol) portion wise at 0 °C and the reaction mixture stirred at room temperature for 1 h. The volatiles in the reaction mixture were removed under reduced pressure. The reaction was quenched with water (100 mL) and extracted with 10% MeOH in DCM (50 mL x 3). The combined organic layer was washed with brine, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford 2 as colorless liquid. Yield: 4.9 g (92%).1H-NMR showed the product isolated was a mixture of cis- and trans- isomers (the ratio was unidentified). The product was taken to the next steps as a mixture.

[0496] Step 2:

[0497] To a stirred solution 2 (4.9 g, 34.0 mmol) in DCM (100 mL), were added triethylamine (14.23 mL, 102 mmol) and methane sulphonyl chloride (4.00 mL, 51.0 mmol) at 0 °C and the reaction mixture stirred at room temperature for 16 h. The reaction was quenched with water (100 mL) and extracted with DCM (250 mL x 2). The combined organic extract was washed with brine (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford 3 as yellow liquid. Yield: 5.1 g (61%)

[0498] Step 3:

[0499] To a solution of 4-Bromophenol (4, 3.3 g, 19.07 mmol) in DMF (100 mL), were added cesium carbonate (9.32 g, 28.6 mmol) and 3 (5.09 g, 22.89 mmol) at room temperature and thereaction mixture stirred at 90 °C for 16 h. The reaction was quenched with water (100 mL) and extracted with EtOAc (250 mL x 2). The combined organic extract was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude mass was purified by MPLC (manually packed cartridge; SiO2100-200 mesh size; 25% EtOAc in hexanes) to afford 5 as colorless liquid. Yield: 4.0 g (59%)

[0500] Step 4:

[0501] To a stirred solution of 5 (4.0 g, 13.37 mmol) in MeOH (50 mL) and water (10 mL), was added LiOH.H2O (1.685 g, 40.1 mmol) at 0 °C and the reaction mixture stirred at room temperature for 16 h. The volatiles in the reaction mixture were removed under reduced pressure. To the resulting residue, water (100 mL) was added and washed with EtOAc (2 x 100 mL). The aqueous layer was cooled to 0 °C, acidified using 1.5 N HCl and extracted with DCM (2 x 200 mL). The combined DCM layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered and concentrated reduced pressure. The resulting residue was triturated with hexane to afford 6 as a white solid. Yield: 3.5 g (78%). LC-MS: Calculated C12H13BrO3is 285.1, observed: 285.2 [M]- and 283.2 [M-2]-

[0502] Step 5:

[0503] To a stirred solution of 6 (2.0 g, 7.01 mmol) in toluene (50 mL), was added diphenylphosphoryl azide (1.810 mL, 8.42 mmol) followed by triethylamine (3.91 mL, 28.1 mmol) dropwise at room temperature and the reaction mixture stirred at 70 °C for 2 h. Then, 2- (trimethylsilyl)ethanol (3.02 mL, 21.04 mmol) was added at 70 °C. The reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was concentrated under reduced pressure. One more batch was carried out on 1.5 g of 6 to get the crude material. The crude product of both batches combined and purified by using MPLC (manually packed cartridge, SiO2230-400 mesh; 5% EtOAc in hexanes) to get 7 as a white solid. Yield: 2.1 g (combined yield for two batches). The 1H-NMR showed the product obtained was mixture of cis- and trans- isomers.

[0504] Step 6:

[0505] To a stirred solution of 7 (2.1 g, 5.24 mmol) in 1,4-dioxane (80 mL), were added potassium acetate (1.544 g, 15.73 mmol) and bis(pinacolato)diboron (1.998 g, 7.87 mmol) at room temperature and the resulting mixture degassed with nitrogen for 5 min. To this reaction mixture, PdCl2(dppf) (0.192 g, 0.262 mmol) was added, the purging continued for 2 min and the reaction mixture then stirred at 100 °C for 16 h. The inorganic solids were filtered through a Celite pad and washed with EtOAc (30 mL). The filtrate was concentrated under reduced pressure. The reaction was quenched with water (30 mL) and extracted with EtOAc (100 mL x 2). The combined organic layer was washed with brine (25 mL), dried over anhydrous Na2SO4, filtered and concentrated reduced pressure. The resulting crude residue was purified by MPLC (manually packed cartridge; SiO2230- 400 mesh; 20% EtOAc in hexanes) to afford boronate 8 as a colorless liquid. Yield: 2.2 g (80%)

[0506] Step 7:

[0507] To a stirred solution of boronate 8 (2.2 g, 4.92 mmol) in 2,2,2-trifluoroethanol (20 mL), was added TMSCl (0.943 mL, 7.38 mmol) at 0 °C and the reaction mixture stirred at room temperature for 2 h. The volatiles in the reaction mixture were removed under reduced pressure to afford 9 as a white solid. Yield: 1.3 g (70%). LC-MS: Calculated for C17H27BNO3+is 304.22, observed:^304.6 [M]+

[0508] Step 8:

[0509] To a stirred solution of 9 (1.3 g, 3.83 mmol) in DMF (30 mL), were added triethylamine (4.30 mL, 30.6 mmol) and 2-bromoacetonitrile (10, 0.801 mL, 11.48 mmol) at room temperature and the resulting reaction mixture stirred at room temperature for 16 h. The reaction mixture was quenched with water (150 mL) and extracted with EtOAc (200 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by MPLC (using manually packed SiO2cartridge, 230-400 mesh size; 88% EtOAc in hexanes) to obtain 11 as a colorless liquid. Yield: 0.550 g (41%). LC-MS: Calculated for C19H27BN2O3is 342.25, observed:^343.4 [M+1]+

[0510] The identity of cis-relationship between the methyl and hydrogen substituents of the cBu ring of 11 was established through the nOe enhancement observed at 4.58 ppm (methine ^- to phenoxy) upon irradiation of the methyl at 1.40 ppm.

[0511] Note: Over last few steps, the corresponding trans-isomer of 11 got eliminated during purifications.

[0512] Step 9:

[0513] To a solution of 12 (0.380 g, 1.134 mmol) in THF (15 mL) and water (1.5 mL), were added 11 (466 mg, 1.36 mmol) and potassium phosphate tribasic (0.722 g, 3.40 mmol) at room temperature and the resulting mixture purged with nitrogen for 5 min. To this reaction mixture, SPhos Pd G2 (41 mg, 0.057 mmol) was added and irradiated in microwave reactor at 70 °C for 1 h. The reaction mixture was cooled to room temperature, filtered through Celite pad, and washed with THF (30 mL). The filtrate was concentrated under reduced pressure. To the resulting residue, water (15 mL) was added and extracted with EtOAc (20 mL x 2). The combined organic layer was washed with brine (15 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude mass, thus obtained, was purified by reverse phase chromatography (column: Redisep Gold; C18 SiO2; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 37 as a white solid. Yield: 0.159 g (29%). LC-MS: Calculated for C28H30N4O3 is 470.57, Observed: 471.2 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.66-7.61 (m, 4H), 7.51 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 6.95 (d, J = 8.80 Hz, 2H), 6.84 (d, J = 1.20 Hz, 1H), 5.67 (t, J = 6.00 Hz, 1H), 5.53 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.37 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.96-4.92 (m, 1H), 4.66-4.61 (m, 1H), 3.87 (t, J = 6.00 Hz, 2H), 3.57 (d, J = 7.60 Hz, 2H), 3.00 (t, J = 7.20 Hz, 1H, exchanges with D2O), 2.52-2.50 (m, 2H), 2.11-2.06 (m, 2H), 1.51 (d, J = 6.40 Hz, 3H), 1.27 (s,3H). SFC: 92.4%; tR = 3.48 min (column: Whelk-(R, R); eluents: CO2and 0.5% isopropyl amine in MeOH)

[0514] Note: cis-geometry in the tail; mixture of diastereomers. SFC purity = 92.4% Example 24: Synthesis of Compounds 39 and 40

[0515] Step 1:

[0516] To a stirred solution of (±)-1 (0.4 g, 1.353 mmol) in MeOH (40 mL), was added DIPEA (0.709 mL, 4.06 mmol) followed by acrylonitrile (2, 0.142 mL, 2.165 mmol) dropwise at 0 °C. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed cartridge, SiO2100-200 mesh size; 25% EtOAc in hexanes) to get (±)-3 as a light-yellow gum. Yield: 240 mg (58%). LCMS: Calculated for C18H25BN2O2is 312.22, observed: 313.6 [M+1]+

[0517] Step 2:

[0518] To a stirred solution of 4 (0.2 g, 0.597 mmol) and (±)-3 (0.242 g, 0.776 mmol) in a mixture of THF (5 mL) and water (1 mL), was added potassium phosphate tribasic (0.380 g, 1.790 mmol) at room temperature, and the resulting mixture degassed with nitrogen for 5 min. To the mixture, SPhos Pd G2 (0.021 g, 0.030 mmol) was added and the mixture stirred at 70 °C for 18 h. The reaction mixture was quenched with water (10 mL). This was extracted with 10% MeOH in DCM (2 x 10 mL). The combined organic layer was washed with brine (5 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and the filtrate concentrated under reduced pressure. The resulting crude residue was purified by preparative HPLC (column: X-SELECT CSH, C18 (250×19) mm, 5 µm; eluents:10 mM ammonium bicarbonate in water and ACN) to obtain Compounds 39 and 40 as a white solid.Yield: 38 mg (14%). LC-MS: Calculated for C27H28N4O2is 440.55, observed: 441.2 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.67 (d, J = 8.40 Hz, 2H), 7.57 (d, J = 8.40 Hz, 2H), 7.53 (d, J = 8.40 Hz, 2H), 7.35 (d, J = 1.20 Hz, 1H), 7.15 (d, J = 8.40 Hz, 2H), 6.84 (d, J = 1.20 Hz, 1H), 5.69 (t, J = 6.00 Hz, 1H), 5.53 (t, J = 6.00 Hz, 1H, exchanges with D2O),5.37 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.95-4.92 (m, 1H), 3.87 (t, J = 6.00 Hz, 2H), 2.85 (t, J = 6.40 Hz, 2H), 2.75 (br s, 1H, exchanges with D2O), 2.61-2.57 (m, 2H), 2.33-2.30 (m, 1H), 1.89- 1.85 (m, 1H), 1.51 (d, J = 6.40 Hz, 3H), 1.05-1.01 (m, 2H). SFC: Diastereomeric ratio = 47.6 : 48.8; tR = 10.32 min and 12.07 min (column: I-CELLULOSE-J; eluents: CO2 and 0.5% isopropyl amine in MeOH)

[0519] Note: Mixture of diastereomers; racemic at tail. trans-geometry at tail. The diastereomeric ratio = 47.6 : 48.8 Example 25: Synthesis of Compounds 41 and 42

[0520] Step 1:

[0521] To a stirred solution of (±)-1 (1 g, 4.15 mmol) in toluene (25 mL), was added diphenylphosphoryl azide (1.070 mL, 4.98 mmol) followed by triethylamine (0.676 mL, 4.85 mmol) dropwise at room temperature. The reaction mixture was stirred at 70 °C for 2 h. Then, 2- (trimethylsilyl)ethanol (2, 1.784 mL, 12.44 mmol) was added at 70 °C. The reaction mixture was stirred at 70 °C for 18 h. The reaction mixture was concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed cartridge, SiO2230-400 mesh; 5% EtOAc in hexanes) to get (±)-3 as a white solid. Yield: 0.65 g (38%). LCMS: Calculated for C15H22BrNO2Si is 356.33; Desired product mass not observed.

[0522] Step 2:

[0523] To a stirred solution of the trimethylsilylethyl carbamate ((±)-3, 0.65 g, 1.824 mmol) and bis(pinacolato)diboron (0.556 g, 2.189 mmol) in 1,4-dioxane (10 mL), was added potassium acetate (0.537 g, 5.47 mmol) at room temperature, and the resulting mixture degassed with nitrogen for 5min. To the above degassed mixture, PdCl2(dppf) (0.133 g, 0.182 mmol) was added and the mixture stirred at 90 °C for 18 h. The reaction mixture was filtered through a pad of Celite. The Celite bed was washed with EtOAc (10 mL), the filtrate combined and concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed cartridge, SiO2230-400 mesh; 5% EtOAc in hexanes) to get (±)-4 as a light-brown gum. Yield: 0.6 g (57%). LCMS: Calculated for C21H34BNO4Si is 403.40, Observed: 258 (M-Me3SiCH2CH2OCO-)

[0524] Step 3:

[0525] To a stirred solution of (±)-4 (500 mg, 1.239 mmol) in DCM (5 mL), was added HCl (4 M in dioxane, 3.10 mL, 12.39 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 triturated with MTBE (5 mL) to get (±)-5 as a white solid. Yield: 0.18 g (40%). LC-MS: Calculated for C15H23BNO2+is 260.16, Observed: 260.2 [M]+

[0526] Step 4:

[0527] To a stirred solution (±)-5 (400 mg, 1.353 mmol) in DCM (2 mL) was added TEA (0.754 mL, 5.41 mmol) followed by acetyl chloride (6, 0.106 mL, 1.488 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 MPLC (manually packed cartridge, SiO2100- 200 mesh; 2% MeOH in DCM) to get (±)-7 as a white solid. Yield: 0.35 g (67%). LC-MS: Calculated for C17H24BNO3is 301.19, observed: 302.5 [M+1]+

[0528] Step 5:

[0529] To a stirred solution of (±)-7 (205 mg, 0.680 mmol) and 8 (190 mg, 0.567 mmol) in a mixture of water (0.75 mL) and THF (3 mL), was added potassium phosphate tribasic (361 mg, 1.700 mmol) at room temperature, and the resulting mixture degassed with nitrogen for 5 min. To the degassed mixture, SPhos Pd G2 (20.42 mg, 0.028 mmol) was added and the reaction mixture stirred at 70 °C for 18 h. The reaction mixture was filtered through a pad of Celite. The pad was further washed with EtOAc (10 mL), the filtrate combined and concentrated under reduced pressure. The resulting crude residue was purified by reverse phase preparative HPLC (column: X Bridge, C18(19×250) mm, 5 µm; eluents:10 mM ammonium bicarbonate in water and ACN) to obtain Compounds 41 and 42 as a white solid. Yield: 76 mg (31%). LC-MS: Calculated for C26H27N3O3 is 429.52, observed: 430.1 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 8.17 (d, J = 4.40 Hz, 1H, exchanges with D2O), 7.68 (d, J = 8.40 Hz, 2H), 7.59 (d, J = 8.40 Hz, 2H), 7.53 (d, J = 8.00 Hz, 2H), 7.36 (d, J = 0.80 Hz, 1H), 7.20 (d, J = 8.40 Hz, 2H), 6.84 (d, J = 0.80 Hz, 1H), 5.69 (t, J = 6.00 Hz, 1H), 5.54 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.37 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.97-4.91 (m, 1H), 3.87 (t, J = 6.00 Hz, 2H), 2.86-2.81 (m, 1H), 1.97-1.95 (m, 1H), 1.81 (s, 3H), 1.51 (d, J = 6.40 Hz, 3H), 1.20-1.16 (m, 2H). SFC: Diastereomeric ratio = 47.0: 48.3; tR = 2.55 min and 4.40 min (column: R, R-WHELK; eluents: CO2 and 0.5% isopropyl amine in MeOH)

[0530] Note: Mixture of diastereomers; racemic tail. trans-geometry at tail. diastereomeric ratio = 47.0: 48.3 Example 26: Synthesis of Compounds 43 and 44

[0531] Step 1:

[0532] To a stirred solution of 1 (400 mg, 1.353 mmol) in DMF (4 mL), were added triethylamine (0.754 mL, 5.41 mmol) and 2-bromoacetonitrile (0.189 mL, 2.71 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the resulting crude residue purified by using MPLC (manually packed cartridge, SiO2100-200 mesh size; 23% EtOAc in hexanes) to get 3 as a colorless gum. Yield: 320 mg (67%). LCMS: Calculated for C17H23BN2O2 is 298.19, observed: 299.5 [M+1]+

[0533] Step 2:

[0534] A solution of 4 (400 mg, 0.954 mmol), 3 (284 mg, 0.954 mmol) and potassium phosphate tribasic (607 mg, 2.86 mmol) in a mixture of dioxane (3 mL) and water (0.7 mL) was degassed with nitrogen for 5 min. To this reaction mixture, SPhos Pd G2 (34.4 mg, 0.048 mmol) was added, and the resulting reaction mixture was irradiated at 70 °C for 1 h in a microwave reactor. The reaction mixture was quenched with water (10 mL). This was extracted with 10% MeOH in DCM (2 x 15 mL). The combined organic layer was washed with brine (10 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed cartridge, SiO2100-200 mesh size; 5% MeOH in DCM) to get 5 as brown gum. LCMS showed 69% purity; the product was taken to the next step. Yield: 400 mg (56%). LC- MS: Calculated for C31H34N4O3is 510.64, observed: 511.2 [M+1]+

[0535] Step 3:

[0536] To a stirred solution of 5 (400 mg, 0.783 mmol) in MeOH (5 mL) was added p- toluenesulfonic acid monohydrate (596 mg, 3.13 mmol) at 0 °C, and the reaction mixture stirred atroom temperature for 2 h. The reaction mixture was quenched with water (5 mL). This was extracted with 20% MeOH in DCM (2 x 15 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The resulting crude residue was purified by reverse phase preparative HPLC (column: Shim pack, C18 (150×19) mm, 5 µm; eluents:10 mM ammonium bicarbonate in water and ACN) to obtain Compounds 43 and 44 as a white solid. Yield: 55 mg (16%). LC-MS: Calculated for C26H26N4O2is 426.52, observed: 427.2 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.68 (d, J = 8.40 Hz, 2H), 7.59 (d, J = 8.40 Hz, 2H), 7.53 (d, J = 8.80 Hz, 2H), 7.36 (d, J = 1.2 Hz, 1H), 7.19 (d, J = 8.40 Hz, 2H), 6.84 (d, J = 1.20 Hz, 1H), 5.69 (t, J = 6.00 Hz, 1H), 5.54 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.37 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.97-4.91 (m, 1H), 3.87 (t, J = 6.00 Hz, 2H), 3.67 (d, J = 7.20 Hz, 2H), 3.39-3.33 (m, 1H, exchanges with D2O), 2.41-2.35 (m, 1H), 1.99-1.95 (m, 1H), 1.51 (d, J = 6.80 Hz, 3H), 1.09-1.05 (m, 2H). SFC: Diastereomeric ratio = 47: 52; tR = 4.20 min and 4.71 min (column: LUX-I- Amylose3; eluents: CO2 and 0.5% isopropyl amine in MeOH)

[0537] Note: The final compound is a mixture of diastereomers; racemic at tail. trans-geometry at tail. Example 27: Synthesis of Compound 45

[0538] Step 1:

[0539] To a stirred solution 1 (15 g, 80 mmol) in DCM (250 mL), were added triethylamine (33.5 mL, 240 mmol) and methane sulphonyl chloride (9.30 mL, 120 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 16 h. The reaction was quenched with water (150 mL) and extracted with DCM (250 mL x 2). The combined organic extract was washed with brine solution (80 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. Theresulting crude residue was purified by MPLC (using manually packed SiO2cartridge, 230-400 mesh size; 40% EtOAc in hexanes) to obtain 2 as a white solid. Yield: 16 g (64%)

[0540] Step 2:

[0541] To a solution of 4-Bromophenol (3, 4.1 g, 23.70 mmol) in DMF (50 mL), were added cesium carbonate (11.58 g, 35.5 mmol) and 2 (7.55 g, 28.4 mmol) at room temperature, and the reaction mixture stirred at 90 °C for 16 h. The reaction was quenched with water (100 mL) and extracted with EtOAc (250 mL x 2). The combined organic extract was washed with brine (100 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to get the crude residue. One more batch was carried out on 4.1 g of 4-bromophenol (3). The crude product of both batches combined and purified by MPLC (manually packed cartridge; SiO2100-200 mesh size; 25% EtOAc in hexanes) to afford 4 as a white solid. LCMS showed 77% purity; product was taken to the next step. Yield: 5.0 g (combined yield for two batches). LC-MS: Calculated for C15H20BrNO3is 342.23, observed:^ 242.4 [M-Boc]+and 244.4 [(M-Boc)+2]+

[0542] The identity of cis-geometry of 4 was established through the nOe enhancement observed at 3.92 ppm (methine ^- to -NHBoc) upon irradiation of the other methine at 4.34 ppm (methine ^- to phenoxy).

[0543] Step 3:

[0544] To a stirred solution of 4 (2.5 g, 7.30 mmol) in 2,2,2-trifluoroethanol (20 mL), was added TMSCl (1.400 mL, 10.96 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 2 h. The volatiles in the reaction mixture were removed under reduced pressure and washed with (20 mL) n-hexanes to afford 5 as a white solid. Yield: 1.7 g (79%). LC-MS: Calculated for C10H13BrNO+is 242.02, observed: 242.0 [M]+and 244.0^[M+2]+

[0545] Step 4:

[0546] To a stirred solution of 5 (1.45 g, 5.21 mmol) in DCM (50 mL), were added triethylamine (2.195 mL, 15.62 mmol) and acetyl chloride (0.446 mL, 6.25 mmol) at 0 °C, and the resulting reaction mixture stirred at room temperature for 1 h. The reaction mixture was quenched with 10% NaHCO3solution (15 mL) (pH 8-9) and extracted with DCM (20 mL x 2). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. One more batch was carried out on 0.25 g of 5. The crude product of both batches combined and purified by MPLC (manually packed cartridge; SiO2100-200 mesh size; 80% EtOAc in hexanes) to afford 6 as white solid. Yield: 1.45 g (combined yield for two batches). LC-MS: Calculated for C12H14BrNO2 is 284.15, observed: 283.9 [M]+and 285.9 [M+2]+

[0547] Step 5:

[0548] To a stirred solution of 6 (1.4 g, 4.93 mmol) in 1,4-dioxane (50 mL), were added potassium acetate (1.451 g, 14.78 mmol) and bis(pinacolato)diboron (1.877 g, 7.39 mmol) at room temperature, and the resulting mixture degassed with nitrogen for 5 min. To this reaction mixture, PdCl2(dppf)(0.180 g, 0.246 mmol) was added and the degassing continued for 2 min. The reaction mixture was stirred at 100 °C for 16 h. The inorganic solids were filtered through a Celite pad and washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure and the resulting crude residue was purified by MPLC (manually packed cartridge; SiO2230-400 mesh; 0-90% EtOAc in hexanes) to afford boronate 7 as a brown gum. Yield: 1.40 g (82%) LC-MS: Calculated for C18H26BNO4is 331.22, observed:^332.3 [M+1]+

[0549] Step 6:

[0550] To a solution of 8 (0.700 g, 1.669 mmol) in 1,4-dioxane (10 mL) and water (1 mL), were added boronate 7 (0.664 g, 2.003 mmol) and potassium phosphate tribasic (1.063 g, 5.01 mmol) at room temperature, and the resulting mixture degassed with nitrogen for 5 min. To this reaction mixture, PdCl2(dtbpf) (0.109 g, 0.167 mmol) was added and the degassing continued for another 2 min. The reaction mixture was irradiated at 85 °C for 1 h in microwave reactor. The inorganic solids were filtered through a Celite pad and washed with EtOAc (15 mL x 2). The filtrate was concentrated under reduced pressure. To the resulting residue, water (15 mL) was added and extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by MPLC (using manually packed SiO2 cartridge, 230-400 mesh size; 10% MeOH in DCM) to afford 9 as a brown solid. Yield: 0.500 g (45%). LC-MS: Calculated for C32H37N3O5is 543.66, observed:^544.4 [M+1]+

[0551] Step 7:

[0552] To a stirred solution of 9 (0.500 g, 0.920 mmol) in MeOH (10 mL), was added p- toluenesulfonic acid monohydrate (0.525 g, 2.76 mmol) at 0 °C and the mixture stirred at room temperature for 3 h. The reaction mixture was quenched with 10% sodium bicarbonate solution (15 mL) and extracted with DCM (100 mL). The combined organic extract was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude mass, thus obtained, was purified by reversed phase preparative HPLC (column: X-Select-CSH-C18(150*19 mm) 5 µm; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 45 as a white solid. Yield: 59 mg (14%). LC-MS: Calculated for C27H29N3O4 is 459.55, Observed:^460.3 [M+1]+. 1H-NMR (400 MHz, DMSO-d6): δ 8.17 (d, J = 8.00 Hz, 1H), 7.66-7.61 (m, 4H), 7.51 (d, J = 8.40 Hz, 2H), 7.35 (d, J = 1.20 Hz, 1H), 6.95 (d, J = 8.80 Hz, 2H), 6.84 (d, J = 0.80 Hz, 1H), 5.69 (t, J = 6.00 Hz, 1H), 5.53 (t, J = 6.00 Hz, 1H, exchanges with D2O), 5.37 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.96-4.92 (m, 1H), 4.51-4.46 (m, 1H), 4.02-3.92 (m, 1H), 3.87 (t, J = 6.0 Hz, 2H), 2.86- 2.80 (m, 2H), 2.00-1.93 (m, 2H), 1.79 (s, 3H), 1.50 (d, J = 5.6 Hz, 3H). SFC: 98.9%; tR = 3.34 min (column: LUX Amylose-1-(R, R); eluents: CO2 and 0.5% isopropyl amine in MeOH)

[0553] Note: cis-geometry in the tail part; mixture of diastereomers. SFC purity = 98.9% (also contains 1.05% of trans-isomer).Example 28: Synthesis of Compounds 47

[0554] Step 1:

[0555] To a stirred solution of 1 (3.4 g, 9.93 mmol) in 2,2,2-trifluoroethanol (20 mL), was added TMSCl (1.905 mL, 14.90 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The volatiles in the reaction mixture were removed under reduced pressure and washed with n- hexanes (20 mL) to afford 2 as a white solid. Yield: 1.5 g (53%). LC-MS: Calculated for C10H13BrNO+is 242.02, observed: 242.0 [M]+and 244.0^[M+2]+. One more batch was carried out on 200 mg of 1 to get the 70 mg of 2.

[0556] Step 2:

[0557] To a stirred solution of 2 (1.57 g, 5.64 mmol) in DCM (50 mL), were added triethylamine (2.376 mL, 16.91 mmol) and acetyl chloride (0.483 mL, 6.76 mmol) at 0 °C, and the resulting reaction mixture stirred at room temperature for 1 h. The reaction mixture was quenched with 10% NaHCO3 solution (15 mL) (pH 8-9) and extracted with DCM (20 mL x 2). The combined organic layer was washed with brine (10 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by MPLC (manually packed cartridge; SiO2100-200 mesh size; 80% EtOAc in hexanes) to afford 3 as a white solid. Yield: 1.6 g (98%). LC-MS: Calculated for C12H14BrNO2is 284.15, observed: 284.1^[M]+and 286.1 [M+2]+

[0558] The identity of trans-geometry of 3 was established through a lack of the nOe enhancement in the methine (4.80 ppm) ^- to phenoxy upon irradiation of methine ^- to -NHAc (4.23 ppm) and vice-versa.

[0559] Step 3:

[0560] To a stirred solution of 3 (1.6 g, 5.63 mmol) in 1,4-dioxane (50 mL), were added potassium acetate (1.658 g, 16.89 mmol) and bis(pinacolato)diboron (2.145 g, 8.45 mmol) at room temperature, and the resulting mixture degassed with nitrogen for 5 min. To this reaction mixture, PdCl2(dppf) (0.206 g, 0.282 mmol) was added and the purging continued for 2 min. The reaction mixture was then stirred at 100 °C for 16 h. The inorganic solids were filtered through a Celite pad and washed with EtOAc (50 mL). The filtrate was concentrated under reduced pressure afford a crude residue. The resulting crude residue was purified by MPLC (manually packed cartridge; SiO2230-400 mesh; 0-90% EtOAc in hexanes) to afford boronate 4 as a brown gum. Yield: 1.5 g (63%). LC-MS: Calculated for C18H26BNO4 is 331.22, observed:^332.4 [M+1]+

[0561] Step 4:

[0562] To a solution of 5 (0.700 g, 1.669 mmol) in 1,4-dioxane (10 mL) and water (1 mL), were added boronate 4 (0.664 g, 2.003 mmol) and potassium phosphate tribasic (1.063 g, 5.01 mmol) at room temperature, and the resulting mixture degassed with nitrogen for 5 min. To this reaction mixture, PdCl2(dtbpf) (0.109 g, 0.167 mmol) was added and the purging continued for another 2 min. The reaction mixture was irradiated at 85 °C for 1 h in microwave reactor. The inorganic solids were filtered through a celite pad and washed with EtOAc (15 mL x 2). The filtrate was concentrated under reduced pressure afford a crude residue. To the resulting residue, water (15 mL) was added and extracted with EtOAc (30 mL x 2). The combined organic layer was washed with brine (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by MPLC (using manually packed SiO2cartridge, 230-400 mesh size; 10% MeOH in DCM) to afford 6 as a brown solid. Yield: 0.355 g (35%). LC-MS: Calculated for C32H37N3O5 is 543.66, observed:^544.6 [M+1]+

[0563] Step 5:

[0564] To a stirred solution of 6 (0.35 g, 0.644 mmol) in MeOH (10 mL), was added p- toluenesulfonic acid monohydrate (0.367 g, 1.931 mmol) at 0 °C and the reaction mixture stirred at room temperature for 3 h. The reaction mixture was quenched with 10% sodium bicarbonate solution (15 mL) and extracted with DCM (100 mL). The combined organic extract was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by reversed phase preparative HPLC (column: Shimpack GIST-C18 (150*20 mm) 5 µm; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 47 as a white solid. Yield: 0.079 g (26%). LC-MS: Calculated for C27H29N3O4is 459.55, observed:^460.1 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 8.29 (d, J = 6.8 Hz, 1H), 7.67-7.63 (m, 4H), 7.51 (d, J = 8.4 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 6.92 (d, J = 8.40 Hz, 2H), 6.84 (d, J = 0.80 Hz, 1H), 5.69 (t, J = 5.60 Hz, 1H), 5.55 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.39 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.95-4.87 (m, 2H), 4.32-4.27 (m, 1H), 3.86 (t, J = 5.60 Hz, 2H), 2.39-2.34 (m, 4H), 1.82(s, 3H), 1.50 (d, J = 6.40 Hz, 3H). SFC: 98.5%; tR = 3.04 min (column: C-Cellulose-B; eluents: CO2and 0.5% isopropyl amine in MeOH)

[0565] Note: trans-geometry in tail part; mixture of diastereomers. SFC purity = 98.5% (contains 1.47% of cis-isomer). Example 29: Synthesis of Compounds 49 and 50

[0566] Step 1:

[0567] To a solution of (±)-1 (1.5 g, 5.57 mmol) in MeOH (15 mL), was added ammonium hydroxide (15 mL, 385 mmol), and the reaction mixture heated at 55 °C for 18 h in a tiniclave reactor. The reaction mixture was concentrated under reduced pressure. The resulting residue was suspended in water (30 mL), and the solid that precipitated was filtered through Buchner funnel and dried to get (±)-2 as a white solid. Yield: 0.8 g (47%). LCMS: Calculated for C10H10BrNO is 240.10, observed: 240.4 [M]+and 242.4 [M+2]+

[0568] Step 2:

[0569] To a stirred solution of (±)-2 (0.8 g, 3.33 mmol) and bis(pinacolato)diboron (1.015 g, 4.00 mmol) in 1,4-dioxane (15 mL), was added potassium acetate (0.981 g, 10.00 mmol) at room temperature, and the resulting mixture degassed with nitrogen for 5 min. Then, PdCl2(dppf).CH2Cl2 adduct (0.272 g, 0.333 mmol) was added and the reaction mixture was stirred at 90 °C for 18 h. The reaction mixture was filtered through a pad of Celite. The bed was washed with EtOAc (30 mL), the filtrate combined and concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed cartridge, SiO2230-400 mesh; 40% EtOAc in hexanes) to get (±)-3 as a white solid. Yield: 450 mg (40%). LCMS: Calculated for C16H22BNO3is 287.17, observed: 288.4 [M+1]

[0570] Step 3:

[0571] To a solution of 4 (380 mg, 0.906 mmol) and (±)3 (312 mg, 1.087 mmol) in a mixture of dioxane (5 mL) and water (1.25 mL), was added potassium phosphate tribasic (577 mg, 2.72 mmol), and the resulting mixture degassed with nitrogen for 5 min. To this reaction mixture, SPhos Pd G2 (32.7 mg, 0.045 mmol) was added and irradiated with microwave (Biotage microwave irradiator) at 70 °C temperature for 1 h. The reaction mixture was quenched with water (10 mL). This was extracted with 10% MeOH in DCM (2 x 20 mL). The combined organic layer was washed with brine (10 mL). The organic layer was separated and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed cartridge, SiO2100-200 mesh size; 5% MeOH in DCM) to get 5 as a light-brown solid. Yield: 400 mg (83%). LC-MS: Calculated for C30H33N3O4is 499.61, Observed: 500.3 [M+1]+

[0572] Step 4:

[0573] To a stirred solution of 5 (0.4 g, 0.801 mmol) in MeOH (10 mL), was added p- toluenesulfonic acid monohydrate (0.457 g, 2.402 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 1 h. The reaction mixture was quenched with water (15 mL). This was extracted with 10% MeOH in DCM (2 x 15 mL). The combined organic layer was washed with brine (10 mL). The organic layer was separated and dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue thus obtained was purified by reverse phase preparative HPLC (column: X-SELECT CSH C18 (250×19) mm, 5μm; eluents: 10 mM ammonium bicarbonate in water and ACN) to obtain Compounds 49 and 50 as a white solid. Yield: 25 mg (7.4%). LC-MS: Calculated for C25H25N3O3 is 415.49, observed: 416.3 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.68 (d, J = 8.40 Hz, 2H), 7.61 (d, J = 8.00 Hz, 3H), 7.53 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 0.80 Hz, 1H), 7.22 (d, J = 8.40 Hz, 2H), 6.92 (br s, 1H), 6.84 (d, J = 1.20 Hz, 1H), 5.69 (t, J = 6.00 Hz, 1H), 5.54 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.37 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.96-4.92 (m, 1H), 3.87 (t, J = 6.00 Hz, 2H), 2.29-2.24 (m, 1H), 1.90-1.86 (m, 1H), 1.51 (d, J = 6.40 Hz, 3H), 1.38-1.34 (m, 1H), 1.26-1.21 (m, 1H). SFC: Diastereomeric ratio = 50.7: 49.2; tR = 4.11 min and 5.23 min (column: C-Cellulose-B; eluents: CO2 and 0.5% isopropyl amine in IPA)

[0574] Note: Mixture of diastereomers; racemic tail. trans-geometry in the tail.Example 30: Synthesis of Compound 51

[0575] Step 1:

[0576] To a stirred solution of 1 (1.5 g, 5.07 mmol) in DCM (15 mL), was added triethylamine (2.12 mL, 15.22 mmol) at 0 °C and stirred for 15 min. To this reaction mixture, Methylcarbamoyl Chloride (2, 0.57 g, 6.09 mmol) was added at 0 °C and the reaction mixture stirred at room temperature for 2 h. The reaction mixture was quenched with 10% NaHCO3 solution (20 mL) and extracted with DCM (20 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2cartridge, 100-200 mesh size; 2% MeOH in DCM) to obtain 3 as pale-brown solid. Yield = 1.5 g (70%)

[0577] Step 2:

[0578] To a solution of 4 (0.3 g, 0.715 mmol) in THF (15 mL) and water (5 mL), were added 3 (0.294 g, 0.93 mmol) and potassium phosphate tribasic (0.45 g, 2.14 mmol) at room temperature, and the mixture degassed with nitrogen for 10 min. To this reaction mixture, SPhos Pd G2 (0.052 g, 0.072 mmol) was added, and the resulting reaction mixture stirred at 80 °C for 16 h. The reaction was quenched with water (20 mL) and extracted with 10% MeOH in DCM (50 mL x 2). The combined organic layer was 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; 5% MeOH in DCM) to obtain 5 as pale-brown solid. Yield: 0.35 g (90%). LCMS: Calculated for C31H36N4O4 is 528.65; observed: 529.2 [M+1]+

[0579] Step 3:

[0580] To a solution of 5 (0.29 g, 0.55 mmol) in MeOH (15 mL), was added p-toluenesulfonic acid monohydrate (0.31 g, 1.64 mmol) at 0 °C, and the reaction mixture stirred at room temperature for 2 h. To the reaction mixture, DCM (50 mL) was added and washed with 10% NaHCO3 solution (10 mL). The organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue, thus obtained, was purified by column chromatography (column: Redisep Gold, C18reverse phase SiO2; eluents: 10 mM ammonium bicarbonate in water and ACN)to afford Compound 51 as an off-white solid. Yield: 60 mg (24%). LCMS: Calculated for C26H28N4O3is 444.54; observed: 425.2 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.71-7.68 (m, 4H), 7.55 (d, J = 8.40 Hz, 2H), 7.44 (d, J = 8.00 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 6.84 (d, J = 0.80 Hz, 1H), 6.32-6.29 (m, 1H, exchanges with D2O), 5.70 (t, J = 6.00 Hz, 1H), 5.54 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.38 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.96-4.92 (m, 1H), 4.22-4.19 (m, 2H), 3.87 (t, J = 6.40 Hz, 2H), 3.81-3.76 (m, 3H), 2.57 (d, J = 4.40 Hz, 3H), 1.51 (d, J = 6.40 Hz, 3H). SFC: 97.2%; tR = 5.82 min (column: Whelk-(R,R); eluents: CO2and 0.5% isopropyl amine in i-PrOH)

[0581] Note: Single isomer with SFC purity = 97.2% Example 31: Synthesis of Compound 52

[0582] Reference: For amide coupling (Step 1): Bioorg. Med. Chem.2022, 54, 116553.

[0583] Step 1:

[0584] To a solution of 1 (1.2 g, 4.83 mmol) in DCM (15 mL), were added glycolic acid (2, 0.44 g, 5.79 mmol), EDC.HCl (1.39 g, 7.24 mmol) and HOBt (1.1 g, 7.24 mmol) at room temperature, and the resulting reaction mixture stirred at room temperature for 2 h. The volatiles were removed under reduced pressure. The crude residue, thus obtained, was purified by MPLC (manually packed SiO2cartridge, 100-200 mesh size; 3% MeOH in DCM) to obtain 3 as colorless liquid. LCMS showed 72% purity; product was taken to the next step without further purification. Yield = 800 mg (48%). LCMS: Calculated for C11H12BrNO2 is 270.13; Observed: 270.4 [M]+and 272.4 [M+2]+

[0585] Step 2:

[0586] To a stirred solution of 3 (0.8 g, 2.96 mmol) in dioxane (30 mL), were added potassium acetate (0.87 g, 8.88 mmol) and bis(pinacolato)diboron (1.13 g, 4.44 mmol) at room temperature. The resulting mixture was purged with nitrogen for 5 min. To this reaction mixture, PdCl2(dppf) (0.1 g, 0.148 mmol) was added and stirred at 100 °C for 16 h. The reaction mixture was cooled to room temperature, filtered through a Celite pad, and washed with EtOAc (50 mL). The combined filtrate was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The cruderesidue, thus obtained, was purified by MPLC (manually packed SiO2cartridge 100-200 mesh size; 5% MeOH in DCM) to obtain boronate 4 as colorless liquid. LCMS showed 65% purity; product was taken to the next step. LCMS: Calculated for C17H24BNO4 is 317.19; Observed: 318.6 [M+1]+. Yield = 800 mg (55%)

[0587] Step 3:

[0588] To a solution of 5 (0.1 g, 0.298 mmol) in THF (4 mL) and water (1 mL), were added boronate 4 (0.142 g, 0.447 mmol) and potassium phosphate tribasic (0.19 g, 0.895 mmol) at room temperature, and the mixture degassed with nitrogen for 5 min. To this reaction mixture, SPhos Pd G2 (21.5 mg, 0.03 mmol) was added and the resulting mixture irradiated with microwave at 70 °C for 2 h. The reaction was quenched with water (5 mL) and extracted with EtOAc (10 mL x 2). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude residue, thus obtained, was purified by column chromatography (column: Redisep Gold, C18reverse phase SiO2; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 52 as an off-white solid. Yield: 35 mg (26%). LCMS: Calculated for C26H27N3O4 is 445.52; observed: 446.6 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.72-7.69 (m, 4H), 7.55 (d, J = 8.40 Hz, 2H), 7.48 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 6.84 (d, J = 1.20 Hz, 1H), 5.69 (t, J = 6.00 Hz, 1H), 5.54 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.38 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.97-4.91 (m, 2H, 1H exchanges with D2O), 4.59 (t, J = 8.40 Hz, 1H), 4.32 (t, J = 8.40 Hz, 1H), 4.23-4.20 (m, 1H), 3.97-3.86 (m, 6H), 1.51 (d, J = 6.40 Hz, 3H). SFC: 96.6%; tR = 5.54 min (column: I Cellulose-Z; eluents: CO2and 0.5% isopropyl amine in MeOH)

[0589] Note: Final product was single isomer with SFC purity = 96.6%Example 32: Synthesis of Compound 53

[0590] Step 1:

[0591] To a stirred solution of 3-(benzyloxy)cyclobutan-1-one (1, 10 g, 56.7 mmol) in MeOH (100 mL), was added sodium borohydride (3.22 g, 85 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 10 min and further at room temperature for 1 h. The reaction mixture was quenched with saturated ammonium chloride solution (40 mL), the volatiles evaporated under reduced pressure. The obtained solid was taken in water (50 mL) and extracted with DCM (3 x 60 mL). The combined DCM layer was washed with cold water (30 mL), brine (30 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure to afford 2 as a yellow solid. Yield: 9.7 g (86%)

[0592] Step 2:

[0593] To a stirred solution of 2 (9.7 g, 54.4 mmol) in DCM (100 mL), were added triethylamine (22.76 mL, 163 mmol) and DMAP (0.665 g, 5.44 mmol) at room temperature. The reaction mixture was cooled to 0 °C, after which p-toluene sulfonyl chloride (15.56 g, 82 mmol) was added in several portions at 0 °C. The resulting reaction mixture was stirred at room temperature for 16 h. Thereaction mixture was quenched with water (60 mL) and was extracted with DCM (3 x 80 mL). The combined organic layer was washed with cold water (30 mL), followed by brine (30 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The resulting crude mass was purified by MPLC (manually packed cartridge; SiO2230-400 mesh size; 27% in EtOAc in hexane) to afford 3 as a brown solid. Yield: 17 g (85%)

[0594] Step 3:

[0595] To a stirred solution of 4-bromophenol (4, 7.4 g, 42.8 mmol) in DMF (80 mL), were added 3 (17.06 g, 51.3 mmol) and potassium carbonate (11.82 g, 86 mmol) at room temperature. The resulting reaction mixture was stirred at 80 °C for 16 h. The mixture was quenched with ice-cold water (70 mL) and extracted with DCM (2 x 40 mL). The combined organic layer was washed with cold water (60 mL), brine solution (30 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The resulting crude thus obtained was purified by MPLC (manually packed cartridge; SiO2230-400 mesh size; 3% in EtOAc in hexane) to afford 5 as an off- white solid. Yield: 12 g (76%)

[0596] Step 4:

[0597] To a stirred solution of 5 (10.9 g, 32.7 mmol) in DCM (100 mL), was added boron trichloride (1 M in heptane, 45.8 mL, 45.8 mmol) at 0 °C, and the resulting reaction mixture stirred at room temperature for 1 h. The mixture was quenched with water (20 mL) and extracted with 10% MeOH in DCM (3 x 80 mL). The combined organic layer was washed with saturated NaHCO3 (50 mL), followed by brine solution (30 mL), dried over anhydrous sodium sulphate, filtered and concentrated under reduced pressure. The resulting crude mass, thus obtained, was purified by MPLC (manually packed cartridge; SiO2230-400 mesh size; 64% in EtOAc in hexane) to afford 6 as a yellow liquid. Yield: 8 g (91%)

[0598] Step 5:

[0599] To a stirred solution of 6 (4.4 g, 18.1 mmol) in DCM (40 mL), was added Dess-Martin periodinane (9.98 g, 23.53 mmol) portion wise at 0oC under nitrogen for 10 min. The resulting reaction mixture was stirred at room temperature for 1 h. One more batch was carried out using 4.4 g of 6. Both reaction mixtures mixed for workup. The reaction mixture was quenched with saturated sodium bicarbonate solution (40 mL), extracted with DCM (3 x 60 mL). The combined organic layer was washed with brine solution (30 mL), dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure. The obtained crude mass was stirred with water (50 mL), solids were filtered and dried to afford 7 as an off-white solid. Yield: 5 g (combined yield for two batches)

[0600] Step 6:

[0601] To a stirred solution of 7 (2 g, 8.30 mmol) in DCM (30 mL), were added trimethylsilyl cyanide (2.59 mL, 20.74 mmol) and BF3.OEt2 (1.536 mL, 12.44 mmol) at 0 °C. After stirring atroom temperature for 4 h, the reaction mixture was quenched with saturated NaHCO3 (20 mL) and extracted with DCM (3 x 60 mL). The combined organic layer was washed with brine solution (20 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to afford cyanohydrin 8 as a mixture of two compounds (brown liquid). Yield: 2.76 g (crude)

[0602] Note: The mixture of cis- and trans- isomers was taken up to borylation step and separated at that step.

[0603] Step 7:

[0604] To a stirred solution of 8 (2.76 g, 7.21 mmol) in MeOH (30 mL), were added Boc-anhydride (3.31 mL, 14.41 mmol), nickel (II) chloride hexahydrate (0.428 g, 1.801 mmol) and sodium borohydride (1.363 g, 36.0 mmol) in several portions at 0 °C. After stirring for 2 h at room temperature, the reaction mixture was quenched with saturated ammonium chloride solution (20 mL) and extracted with DCM (3 x 15 mL). The combined organic layer was washed with brine solution (10 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude mass was purified by MPLC (manually packed cartridge; SiO2230-400 mesh size; 3% in DCM in EtOAc) to afford aminocarbinol 9 as a colorless solid. Yield: 1.1 g (40%). LC-MS: Calculated for C16H22BrNO4 is 372.25; observed: 272.2 [M-Boc]+and 274.2 [M-Boc+2H]+

[0605] Step 8:

[0606] To a stirred solution of 9 (1.1 g, 2.95 mmol) in 1,4-dioxane (20 mL), were added bis(pinacolato)diboron (1.126 g, 4.43 mmol) and potassium acetate (870 mg, 8.86 mmol) at room temperature, and the reaction mixture degassed with nitrogen for 5 min. To this mixture, PdCl2(dppf).CH2Cl2 complex (0.241 g, 0.295 mmol) was added, and further stirred at 100 °C for 5 h. The reaction mixture was filtered through the Celite bed and washed with EtOAc (100 mL). The combined filtrate was concentrated under reduced pressure. The crude mass was purified by using MPLC (manually packed cartridge; SiO2100-200 mesh size; 18-23% EtOAc in hexane) to afford 10 (non-polar) as an off-white solid and 10a (polar) as a colorless gum. Yield: 10 = 700 mg and 10a = 200 mg. LC-MS: Calculated C22H34BNO6is 419.32, Observed: 320.1 [M-Boc+H]+

[0607] Note: For identification of 10 and 10a please refer note given at the end.

[0608] Step 9:

[0609] To a stirred solution of boronate 10 (700 mg, 1.669 mmol) in 1,4-dioxane (10 mL) and water (3 mL), were added 11 (500 mg, 1.192 mmol) and potassium phosphate tribasic (759 mg, 3.58 mmol) at room temperature, and the reaction mixture degassed with nitrogen for 5 min. To this reaction mixture, SPhos Pd G2 (86 mg, 0.119 mmol) was added and the degassing continued for another 2 min. The resulting reaction mixture was irradiated at 80 °C for 2 h in a microwave reactor. The reaction mixture was quenched with water (40 mL) and extracted with 10% MeOH in DCM (2 x 50 mL). The combined organic layer was washed with water (40 mL), brine solution (40 mL), dried over sodium sulphate, filtered and concentrated under reduced pressure. The crude mass waspurified by using MPLC (manually packed cartridge; SiO2100-200 mesh size; 5% MeOH in DCM) to afford 12 as a brown solid. Yield: 400 mg (46%). LC-MS: Calculated C36H45N3O7is 631.77, observed: 632.4 [M+H]+

[0610] Step 10:

[0611] To a stirred solution of 12 (400 mg, 0.633 mmol) in 2,2,2, trifluoroethanol (5 mL), was added trimethylsilyl chloride (0.162 mL, 1.266 mmol) at 0 °C, and the reaction stirred at room temperature for 3 h. The reaction mixture was quenched with saturated NaHCO3 solution (30 mL) and extracted with 10% MeOH in DCM (2 x 30 mL). The combined organic layer was washed with water (30 mL), brine solution (30 mL), dried over sodium sulfate and concentrated under reduced pressure to afford 13 as a brown solid. Yield: 260 mg (crude product weight). LC-MS: Calculated C26H29N3O4 is 447.53, observed: 448.1 [M+H]+

[0612] Step 11:

[0613] To a solution of 13 (260 mg, 0.581 mmol) in DMF (4 mL), were added triethylamine (0.324 mL, 2.324 mmol) and bromoacetonitrile (0.081 mL, 1.162 mmol) at 0 °C. The reaction was stirred at room temperature for 3 h. The reaction mixture was quenched with water (30 mL) and extracted with 10% MeOH in DCM (2 x 30 mL). The combined organic layer was washed with water (30 mL), brine (30 mL), dried over sodium sulfate, filtered and the filtrate concentrated under reduced pressure. The crude material, thus obtained, was purified by reverse phase column chromatography (column: Redisep Gold, C18-reversed phase silica; eluents: Redisep Gold, C-18silica gel; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 53 as an off-white solid. Yield: 50 mg (17%). LC-MS: Calculated C28H30N4O4 is 486.57, observed: 487.3 [M+H]+.1H-NMR (400 MHz, DMSO-d6): δ 7.67-7.59 (m, 4H), 7.52 (d, J = 6.80 Hz, 2H), 7.36 (d, J = 1.60 Hz, 1H), 6.93 (d, J = 8.80 Hz, 2H), 6.84 (d, J = 1.20 Hz, 1H), 5.69 (t, J = 6.00 Hz, 1H), 5.54 (t, J = 5.20 Hz, 1H, exchanges with D2O), 5.38 (d, J = 6.00 Hz, 1H, exchanges with D2O), 5.32 (s, 1H, exchanges with D2O), 4.99-4.89 (m, 1H), 4.42-4.34 (m, 1H), 3.87 (t, J = 5.60 Hz, 2H), 3.69 (d, J = 7.20 Hz, 2H), 2.74-2.69 (m, 2H), 2.63 (d, J = 6.40 Hz, 2H), 2.51-2.07 (m, 1H), 2.07-2.02 (m, 2H), 1.51 (d, J = 6.40 Hz, 3H). SFC: 93.3%; tR = 3.05 min (column: I Cellulose C; eluents: CO2and 0.5% isopropyl amine in MeOH)

[0614] Note: Mixture of diastereomers; cis-geometry (cis with respect to -OH and phenoxy substituents) in tail part. SFC purity = 93.3%Example 33: Synthesis of Compound 55

[0615] Step 1:

[0616] To a stirred solution of 1 (5 g, 20.74 mmol) in DCM (60 mL), were added trimethylsilyl cyanide (3.9 mL, 31.1 mmol) and BF3.OEt2 (3.0 mL, 24.89 mmol) at 0 °C. After stirring for 30 min, the reaction mixture was quenched with saturated NaHCO3 (50 mL) and extracted with DCM (3 x 60 mL). The combined organic layer was washed with brine solution (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude mass was purified by using MPLC (manually packed cartridge; SiO2230-400 mesh size; 10% EtOAc in hexane) to afford cyanohydrins 2 (non-polar fraction) and 2a (polar fraction), both as off-white solids.Yield: 2 = 3.8 g and 2a = 800 mg

[0617] Note: 2 and 2a isomers were separated and analyzed in another batch.

[0618] The identity of 2 cis-geometry (with respect to -OH and bromophenoxy substituents) was established through the absence of nOe enhancement in the hydroxy proton (7.11 ppm) upon irradiation of methine at (4.63 ppm) ^- to bromophenoxy and vice versa.The identity of 2a trans- geometry (with respect to -OH and bromophenoxy substituents) was established through the nOe enhancement observed at 7.02 ppm (-OH) upon irradiation of the methine at 4.90 ppm (methine a- phenoxy) and vice versa.

[0619] Step 2:

[0620] A solution of 2 (2.8 g, 10.44 mmol) in con. HCl (49.6 mL, 522 mmol), was stirred at 100oC for 3 h. The reaction mixture was cooled to room temperature to obtain a solid. This solid was filtered and dried in vacuum. Yield of 3: 2.5 g (62%)

[0621] Step 3:

[0622] To a stirred solution of 3 (2 g, 6.97 mmol) in DMF (40 mL), was added DIPEA (3.65 mL, 20.9 mmol), EDC.HCl (1.602 g, 8.36 mmol), HOAt (1 M in DMA, 8.36 mL, 8.36 mmol) and methylamine hydrochloride (0.470 g, 6.97 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with ice-cold water (30 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude mass was purified by using MPLC (manually packed cartridge; SiO2230-400 mesh size;66% EtOAc in hexane) to afford 4 as an off- white solid. Yield: 1.8 g (91%). LC-MS: Calculated for C12H14BrNO3is 300.15; observed: 300.0 [M]+and 302.0 [M+2]+

[0623] Step 4:

[0624] To a stirred solution of 4 (800 mg, 2.67 mmol) in 1,4-dioxane (20 mL), were added bis(pinacolato)diboron (1.015 g, 4.00 mmol) and potassium acetate (785 mg, 8.00 mmol) at room temperature. The reaction mixture was purged with nitrogen for 5 min. To this reaction mixture, PdCl2(dppf) (0.195 g, 0.267 mmol) was added and the mixture stirred at 100 °C for 16 h. The reaction mixture was filtered through a Celite bed. The bed was washed with EtOAc (50 mL), the filtrate combined and concentrated under reduced pressure. The crude mass was purified by using MPLC (manually packed cartridge; SiO2100-200 mesh size; 35% EtOAc in hexane) to afford 5 as a brown solid. Yield: 900 mg (70%) LC-MS: Calculated C18H26BNO5is 347.2, Observed: 348.4 [M+H]+

[0625] Step 5:

[0626] To a stirred solution of 6 (150 mg, 0.447 mmol) in THF (3 mL) and water (1 mL), were added 5 (186 mg, 0.537 mmol) and potassium phosphate tribasic (285 mg, 1.342 mmol) at room temperature, and the reaction mixture degassed with nitrogen for 5 min. To this reaction mixture, SPhos Pd G2 (32.2 mg, 0.045 mmol) was added and the degassing continued for another 2 min. The resulting reaction mixture was heated to 80 °C for 2 h in a microwave reactor. The reaction mixture was filtered through a Celite bed and washed with EtOAc (10 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude was purified by reverse phase MPLC (column: Redisep Gold, C-18 silica gel; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 55 as an off-white solid. Yield: 87 mg (40%). LC-MS: Calculated C27H29N3O5 is 475.5, observed: 476.2 [M+H]+.1H-NMR (400 MHz, DMSO-d6): δ 7.75 (q, J = 4.80 Hz, 1H, exchanges with D2O), 7.68-7.62 (m, 4H), 7.51 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 6.91 (d, J = 8.80 Hz, 2H), 6.84 (d, J = 0.80 Hz, 1H), 6.32 (s, 1H, exchanges with D2O), 5.69 (t, J = 6.00 Hz, 1H), 5.53 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.37 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.96-4.93 (m, 1H), 4.61-4.57 (m, 1H), 3.87 (t, J = 6.00 Hz, 2H), 2.94-2.89 (m, 2H), 2.64 (d, J = 4.80 Hz, 3H), 2.22 (t, J = 2.80 Hz, 2H), 1.51 (d, J = 6.40 Hz, 3H). SFC: 93.1%; tR= 3.997 min (column: LUX-I-Amylose3; eluents: CO2 and 0.5% isopropyl amine in MeOH)

[0627] Note: Mixture of diastereomers; cis-geometry (with respect to -CONHMe and -H) in tail part. NMR showed only mixture of cis-diastereomers, however, SFC showed 93.1% purity. Example 34: Synthesis of Compound 57

[0628] Step 1:

[0629] To 1 (2 g, 8.1 mmol) was basified with sat. NaHCO3solution (10 mL) and extracted with 10% MeOH in DCM (50 mL x 2). The combined organic layer was dried over anhydrous sodium sulphate, filtered, and concentrated under reduced pressure to afford 2 as a colorless liquid. The crude product was used as such in the next step.Yield = 1.1 g (64%)

[0630] Step 2:

[0631] To a solution of 2 (1 g, 4.71 mmol) in MeOH (15 mL), were added 1-methyl-1H-pyrazole- 4-carbaldehyde (3, 0.57 g, 5.19 mmol) and acetic acid (0.027 mL, 0.47 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h. The reaction mixture was cooled to 0 °C, following which sodium cyanoborohydride (0.44 g, 7.07 mmol) was added and the resulting reaction mixture stirred at room temperature for 3 h. The reaction was quenched with water. The volatiles were removed 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 4 as a pale-brown liquid. Yield = 0.9 g (59%). LCMS: Calculated for C14H16BrN3is 306.20; observed: 306.2 [M]+and 308.2 [M+2]+

[0632] Step 3:

[0633] To a solution of the 4 (0.9 g, 2.94 mmol) in dioxane (30 mL), were added potassium acetate (0.86 g, 8.82 mmol) and bis(pinacolato)diboron (1.12 g, 4.41 mmol) at room temperature, and the mixture degassed using nitrogen for 5 min. To this mixture, PdCl2(dppf) (0.1 g, 0.147 mmol) was added and the reaction mixture stirred at 90 °C for 3 h. The reaction mixture was cooled to room temperature, filtered through the Celite pad and washed with EtOAc (50 mL). The combined filtrate was concentrated under reduced pressure. The crude residue, thus obtained, was purified by reversephase column chromatography (column: Redisep Gold, C18SiO2; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford 5 as a pale-brown liquid. Yield = 0.52 g (47%). LCMS: Calculated for C20H28BN3O2 is 353.27; observed: 354.2 [M+1]+

[0634] Step 4:

[0635] To a solution of 6 (0.15 g, 0.447 mmol) in THF (8 mL) and water (2 mL), were added 5 (0.237 g, 0.671 mmol) and potassium phosphate tribasic (0.285 g, 1.342 mmol) at room temperature, and the mixture degassed using nitrogen for 5 min. To this reaction mixture, SPhos Pd G2 (0.032 g, 0.045 mmol) was added. The resulting reaction mixture was irradiated in a microwave reactor at 80 °C for 2 h. The volatiles were removed under reduced pressure, and 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 Compound 57 as a white solid.Yield: 45 mg (21%). LCMS: Calculated for C29H31N5O2 is 481.60; observed: 482.2 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.69 (d, J = 8.40 Hz, 2H), 7.64 (d, J = 8.00 Hz, 2H), 7.57-7.53 (m, 3H), 7.42 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 7.30-7.32 (m, 1H), 6.84 (d, J = 1.20 Hz, 1H), 5.70 (t, J = 6.00 Hz, 1H), 5.54 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.38 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.97-4.91 (m, 1H), 3.87 (t, J = 6.40 Hz, 2H), 3.79 (s, 3H), 3.62-3.56 (m, 3H), 3.44 (s, 2H), 3.08-3.06 (m, 2H), 1.51 (d, J = 6.80 Hz, 3H). SFC: 98.2%; tR = 2.62 min (column: C- Cellulose-B; eluents: CO2 and 0.5% isopropyl amine in MeOH)

[0636] Note: Single isomer with SFC purity = 98.2% Example 35: Synthesis of Compound 58

[0637] Step 1:

[0638] To a solution of 1 (1 g, 4.02 mmol) in DMF (10 mL), were added 2-Bromoethyl Methyl Sulfone (2, 0.83 g, 4.43 mmol) and trimethylamine (1.68 mL, 12.07 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 16 h. The volatiles were removed under reduced pressure. The crude residue thus obtained was purified by reverse phase column chromatography (column: Redisep Gold, C18SiO2; eluents: 10 mM ammonium bicarbonate in waterand ACN) to afford 3 as an off-white solid. Yield = 0.52 g (35%). LCMS: Calculated for C12H16BrNO2S is 318.22; observed: 318.2 [M]+and 320.2 [M+2]+

[0639] Step 2:

[0640] To a solution of the 3 (0.5 g, 1.57 mmol) in dioxane (15 mL), were added potassium acetate (0.46 g, 4.71 mmol) and bis(pinacolato)diboron (0.6 g, 2.35 mmol) at room temperature, and the mixture degassed with nitrogen for 5 min. To this reaction mixture, PdCl2(dppf) (0.09 g, 0.126 mmol) was added and the reaction mixture stirred at 90 °C for 4 h. The reaction mixture was cooled to room temperature and filtered through the Celite pad. The filtrate was washed with EtOAc (50 mL), the filtrate combined and concentrated under reduced pressure. The crude residue, thus obtained, was purified by column chromatography (column: Redisep Gold, C18 SiO2; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford 4 as a pale-brown liquid. Yield = 0.5 g (73%). LCMS: Calculated for C18H28BNO4S is 365.29; observed: 366.2 [M+1]+

[0641] Step 3:

[0642] To a solution of 5 (0.2 g, 0.597 mmol) in dioxane (8 mL) and water (2 mL), were added the boronate (4, 0.327 g, 0.895 mmol) and potassium phosphate tribasic (0.38 g, 1.79 mmol) at room temperature. The mixture was purged with nitrogen for 5 min. To this reaction mixture, SPhos Pd G2 (0.043 g, 0.06 mmol) was added and the resulting mixture was irradiated in microwave reactor at 80 °C 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, C18SiO2; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 58 as a white solid.Yield: 70 mg (22%). LCMS: Calculated for C27H31N3O4S is 493.62; observed: 494.3 [M+1]+.1H-NMR (400 MHz, DMSO-d6): δ 7.70 (d, J = 8.40 Hz, 2H), 7.66 (d, J = 8.40 Hz, 2H), 7.55 (d, J = 8.40 Hz, 2H), 7.45 (d, J = 8.0 Hz, 2H),7.36 (d, J = 0.8 Hz, 1H), 6.84 (d, J = 0.8 Hz, 1H), 5.70 (t, J = 6.00 Hz, 1H), 5.54 (t, J = 5.60 Hz, 1H, exchanges with D2O), 5.38 (d, J = 5.60 Hz, 1H, exchanges with D2O), 4.96-4.93 (m, 1H), 3.87 (t, J = 5.60 Hz, 2H), 3.67-3.66 (m, 3H), 3.17-3.14 (m, 4H), 3.06 (s, 3H), 2.86-2.82 (m, 2H), 1.51 (d, J = 6.80 Hz, 3H). SFC: 99%; tR = 3.41 min (column: I-Cellulose-Z; eluents: CO2 and 0.5% isopropyl amine in MeOH)

[0643] Note: Single isomer with SFC purity = 99%Example 36: Synthesis of Compound 59

[0644] Step 1:

[0645] To a stirred solution of 1 (8 g, 35.5 mmol) in DCM (40 mL), were added trimethylsilyl cyanide (11.16 mL, 89 mmol) and BF3.OEt2 (4.50 mL, 35.5 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 4 h. The obtained solid was filtered through Buchner funnel, washed with n-hexane (20 mL) and dried in vacuum to obtain 2 (major product) as a pale-yellow solid. Yield: 2.6 g (27%)

[0646] Step 2:

[0647] A solution of 2 (2 g, 7.93 mmol) in con HCl (0.78 mL, 159 mmol) was stirred at 100°C for 3 h following which the reaction mixture was cooled to room temperature. The obtained solid was filtered and dried in vacuum to afford 3 as a pale brown solid. Yield: 1.4 g (62%). LC-MS: Calculated for C11H11BrO3 is 269.9; observed: 271.0 [M]- and 269.0 [M-2]-

[0648] Step 3:

[0649] To a stirred solution of 3 (400 mg, 1.475 mmol) in DMF (4 mL), were added DIPEA (0.77 mL, 4.43 mmol), EDC.HCl (0.339 g, 1.770 mmol), HOAt (1 M in DMA, 1.770 mL, 1.770 mmol), and methylamine hydrochloride (0.100 g, 1.475 mmol) at room temperature. The mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with ice-cold water (50 mL) and extracted with EtOAc (2 x 50 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The crude mass was purified by using MPLC (manually packed cartridge; SiO2230-400 mesh size;70% EtOAc in hexane) to afford 4 as an off- white solid. Yield: 250 mg (58%). LC-MS: Calculated for C12H14BrNO2is 283.0; observed: 284.1 [M+H]+and 286.0 [(M+2)]+

[0650] Step 4:

[0651] To a stirred solution of 4 (250 mg, 0.880 mmol) in 1,4-dioxane (5 mL), were added bis(pinacolato)diboron (335 mg, 1.320 mmol) and potassium acetate (259 mg, 2.64 mmol) at room temperature, and the reaction mixture degassed with nitrogen for 5 min. To this reaction mixture, PdCl2(dppf).CH2Cl2 adduct (71.8 mg, 0.088 mmol) was added, and the mixture stirred at 100 °C for 5 h. The reaction mixture was filtered through a Celite bed; The bed was washed with EtOAc (50 mL), the filtrate combined and concentrated under reduced pressure. The crude mass was purified by using MPLC (manually packed cartridge; SiO2100-200 mesh size; 80% EtOAc in hexane) to afford 5 as a brown solid. Yield: 150 mg (44%). LC-MS: Calculated C18H26BNO4is 331.2, observed: 332.4 [M+H]+

[0652] Step 5:

[0653] To a stirred solution of 6 (100 mg, 0.298 mmol) in THF (1.5 mL) and water (0.5 mL), were added 5 (148 mg, 0.447 mmol) and potassium phosphate tribasic (190 mg, 0.895 mmol) at room temperature, and the reaction mixture degassed with nitrogen for 5 min. To this reaction mixture, SPhos Pd G2 (21.5 mg, 0.030 mmol) was added and the degassing continued for another 2 min. The resulting reaction mixture was heated to 70 °C for 4 h in a microwave reactor. The reaction was quenched with water (15 mL) and extracted with 10% MeOH in DCM (2 x 15 mL). The combined organic layer was washed with water (10 mL), brine solution (10 mL), dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude mass was purified by reverse phase MPLC (column: Redisep Gold, C-18silica gel; eluents: 10 mM ammonium bicarbonate in water and ACN) to afford Compound 59 as an off-white solid. Yield: 40 mg (28%). LC-MS: Calculated C27H29N3O4 is 459.2, observed: 460.2 [M+H]+.1H-NMR (400 MHz, DMSO-d6): δ 7.74- 7.52 (m, 5H), 7.54 (d, J = 8.00 Hz, 2H), 7.44-7.35 (m, 3H), 6.87 (s, 1H, exchanges with D2O), 6.15 (br s, 1H, exchanges with D2O), 5.70 (t, J = 5.60 Hz, 1H), 5.55 (br s, 1H, exchanges with D2O), 5.41 (br s, 1H, exchanges with D2O), 5.01-4.91 (m, 1H), 3.88 (bs, 2H), 3.41-3.34 (m, 1H), 2.79 (td, J = 2.40, 9.00 Hz, 2H), 2.65 (d, J = 4.80 Hz, 3H), 2.21 (td, J = 2.40, 9.60 Hz, 2H), 1.51 (d, J = 6.80 Hz, 3H). SFC: 97.8%; tR= 3.35 min (column: I-Cellulose-Z; eluents: CO2and 0.5% isopropyl amine in MeOH)

[0654] Note: Unknown geometry in tail part. Mixture of diastereomers; SFC purity = 97.Example 37: Synthesis of Compounds 60

[0655] Step 1:

[0656] To a solution of 1 (10 g, 28.3 mmol) in DCM (100 mL), was added DIBAL-H (1 M in hexanes, 28.3 mL, 28.3 mmol) dropwise at -78°C, and the reaction mixture stirred at -78°C for 1 h. The reaction mixture was quenched with saturated potassium sodium tartrate solution (50 mL) at -78°C. The resulting reaction mixture was slowly warmed to room temperature and extracted with DCM (2 x 100 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed cartridge, SiO2100-200 mesh; 15% EtOAc in hexanes) to get 2 (as a mixture of two compounds) as a yellow liquid. Yield: 4 g (47%) LCMS: Calculated for C11H11BrO is 238.0, observed: 238.9 [M+H]+and 240.9 [(M+2)+H]+

[0657] Step 2:

[0658] To a stirred solution of 2 (a mixture of two compounds, 4 g, 13.38 mmol) in MeOH (30 mL), was added ammonium acetate (4.13 g, 53.5 mmol) and stirred for 10 min. To this reaction mixture, aq. glyoxal (3, ca.8.8 M, 2.293 mL, 20.07 mmol) was added at room temperature, and the reaction mixture stirred at 80°C for 2 h. The reaction mixture was cooled to room temperature and concentrated under reduced pressure. This was suspended in saturated sodium bicarbonate solution (30 mL). The resulting mixture 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; C18silica gel; eluents:10 mM ammonium bicarbonate in water and ACN) to afford 4 (as a mixture oftwo compounds) as a colorless liquid. Yield: 1.4 g (36%). LC-MS: Calculated for C13H13BrN2is 276.0, observed: 277.0 [M+H]+and 279.0 [(M+2)+H]+

[0659] Step 3:

[0660] To a stirred solution of 4 (mixture of two compounds, 1.3 g, 4.55 mmol) and triethylamine (1.902 mL, 13.65 mmol) in DCM (15 mL), was added Boc-anhydride (1.585 mL, 6.82 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (manually packed cartridge, SiO2100-200 mesh; 13% EtOAc in hexanes) to get colorless gum (1.5 g) as a mixture of cis-trans isomers. The cis-trans mixture (1.5 g) was separated by SFC (column: CHIRAL-PAK IK (250*30) mm, 5 μm; eluents: CO2 and 0.5% isopropyl amine in isopropyl alcohol) to get 5a and 5b as off-white solids. Yield: 5a (tR = 3.62 min) = 0.35 g and 5b (tR = 4.20 min) = 0.8 g. LC-MS: Calculated for C18H21BrN2O2is 376.0, observed: 377.4 [M]+and 379.4 [(M+2)+H]+

[0661] The structures of the 5a and 5b were confirmed by nOe studies using another batch. The identity of trans-geometry of 5a was established through a lack of the nOe enhancement at 3.71 ppm (methine α- to phenyl) upon irradiation of 4.0 ppm (methine α- to -imidazole) and vice versa.

[0662] The identity of cis-geometry of 5b was established through the nOe enhancement observed at 3.48 ppm (methine α- to phenyl) upon irradiation of the methine at 4.0 ppm (methine α- to - imidazole) and vice versa. Compound 5b was taken further to complete the synthesis of Compound 60.

[0663] Step 4:

[0664] To a stirred solution of 5b (800 mg, 1.993 mmol) in 1,4-dioxane (8 mL), were added bis(pinacolato)diboron (759 mg, 2.99 mmol) and potassium acetate (587 mg, 5.98 mmol) at room temperature, and the reaction mixture degassed with nitrogen for 15 min. Then, PdCl2(dppf) (146 mg, 0.199 mmol) was added, and the reaction mixture stirred at 90°C for 16 h. The reaction mixture was filtered through a Celite bed. The bed was washed with EtOAc (50 mL), the filtrate combined and concentrated under reduced pressure. The resulting crude thus obtained was purified by MPLC (manually packed cartridge, SiO2100-200 mesh; 12% EtOAc in hexanes) to get 6 as a colorless gum. Yield: 0.7 g (76%). LC-MS: Calculated for C24H33BN2O4 is 424.2, observed: 425.3 [M+H]+

[0665] Step 5:

[0666] To a stirred solution of 6 (250 mg, 0.542 mmol)) in DCM (4 mL) was added HCl (4 M in dioxane, 0.678 mL, 2.71 mmol) at 0°C, and the reaction mixture stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure to get 7 as a white solid. Yield: 0.18 g (90%). LC-MS: Calculated for C + 19H26BN2O2 is 325.2, observed: 325.4 [M]+

[0667] Step 6:

[0668] A solution of 8 (100 mg, 0.280 mmol), 7 (155 mg, 0.421 mmol), potassium phosphate tribasic (238 mg, 1.122 mmol) in a mixture of THF (4 mL) and water (1 mL). The mixture was degassed with nitrogen for 5 min, following which SPhos Pd G2 (10.10 mg, 0.014 mmol) was added and the mixture irradiated at 80 °C in a microwave irradiator for 1 h. The reaction mixture was quenched with water (2 mL) and extracted with 10% MeOH in DCM (2 x 10 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The resulting crude residue was purified by using reverse phase preparative HPLC (column: CSH C18(150×19) mm, 5μm; eluents:10 mM formic acid in water and ACN) to afford Compound 60 as a white solid. Yield: 35 mg (27%). LC-MS: Calculated for C28H28N4O2 is 452.2, observed: 453.2 [M+H]+.1H-NMR (400 MHz, DMSO-d6): δ 11.80 (br s, 1H, exchanges with D2O), 7.70 (d, J = 8.8 Hz, 2H), 7.66 (d, J = 8.0 Hz, 2H), 7.55 (d, J = 8.4 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.36 (d, J = 1.2 Hz, 1H), 6.89 (br s, 2H), 6.84 (d, J = 0.8 Hz, 1H), 5.70 (t, J = 6.4 Hz, 1H), 5.56 (br s, 1H, exchanges with D2O), 5.39-5.38 (d, J = 5.6 Hz, 1H, exchanges with D2O), 4.96-4.93 (m, 1H), 3.87 (br s, 2H), 3.51-3.46 (m, 2H), 2.69-2.63 (m, 2H), 2.41-2.33 (m, 2H), 1.50 (d, J = 6.4 Hz, 3H). SFC: 99.5%; tR = 5.64 min (column: LUX-I-Amylose 3; eluents: CO2 and 0.5% isopropyl amine in i-PrOH)

[0669] Note: Mixture of diastereomers; cis-geometry in tail part. dr = 99.5 : 0.5 (corresponding to cis- and trans- geometry in tail) Example 38: Synthesis of Compound 62

[0670] Step 1:

[0671] To a stirred solution of 1H-imidazol-2-amine (1, 5 g, 60.2 mmol) in DCM (30 mL), was added aq.NaOH (1 N in water, 60.2 mL, 60.2 mmol) followed by Boc-anhydride (22.47 mL, 97 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h. The aqueous layer was separated and extracted with DCM (2 x 100 mL). The combined organic layer was dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude residue thus obtained, was purified by using MPLC (SiO2100-200 mesh; 30% EtOAc in hexanes) to afford 2 as a yellow solid. Yield: 8 g (67%). LC-MS: Calculated for C8H13N3O2is 183.1, observed: 184.1 [M+H]+

[0672] Step 2:

[0673] To a stirred solution of 3-(4-bromophenyl)cyclobutanone (3, 2.0 g, 8.80 mmol) and 2 (1.733 g, 8.80 mmol) in DCM (30 mL), was added titanium (IV) isopropoxide (7.73 mL, 26.4 mmol) at room temperature. The reaction mixture was stirred at 50 °C for 18 h. To this reaction mixture, sodium borohydride (0.998 g, 26.4 mmol) was added in portions at 0 °C. The resulting reaction mixture was stirred at room temperature for 18 h. The reaction mixture was quenched with water (60 mL), solids were filtered, and the filtrate was extracted with 10% MeOH in DCM (2 x 80 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; C18silica gel; eluents:10 mM ammonium bicarbonate in water and ACN) to afford 4 as a light-brown solid. Yield: 1.35 g (51%). LC-MS: Calculated for C13H14BrN3is 291.04, observed: 292.0 [M+H]+

[0674] Step 3:

[0675] To a stirred solution of 4 (1.1 g, 3.76 mmol) and triethylamine (1.587 mL, 11.29 mmol) in DCM (12 mL), was added Boc-anhydride (1.311 mL, 5.65 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. Thereafter, the reaction mixture was concentrated. The resulting crude residue was purified by using MPLC (SiO2230-400 mesh; 18% EtOAc in hexanes) to get 5 and 6 as off-white solids.Yield: 5 = 0.35 g and 6 = 0.72 g. LC-MS: Calculated for C18H22BrN3O2is 391.09, observed: 392.0 [M+H]+

[0676] Note: The structures of the 5 and 6 were confirmed by nOe studies using another batch.

[0677] The identity of trans-geometry of 5 was established through a lack of the nOe enhancement in the methine (3.55 ppm) ^- to phenyl upon irradiation of methine (4.33 ppm) ^- to -NH-imidazole and vice versa.

[0678] The identity of cis-geometry of 6 was established through the nOe enhancement observed at 3.19 ppm (methine ^- to phenyl) upon irradiation of the methine at 4.40 ppm (methine ^- to -NH- imidazole) and vice versa.

[0679] Step 4:

[0680] To a stirred solution of 6 (680 mg, 1.647 mmol) in 1,4-dioxane (10 mL), were added bis(pinacolato)diboron (502 mg, 1.976 mmol) and potassium acetate (485 mg, 4.94 mmol) at room temperature. The reaction mixture was purged with nitrogen for 5 min, then PdCl2(dppf).CH2Cl2 adduct (67.2 mg, 0.082 mmol) was added. The reaction mixture was stirred at 90 °C for 4 h. The reaction mixture was filtered through a pad of Celite bed. The Celite bed was washed with EtOAc (30 mL). The combined filtrate was concentrated under reduced pressure. The resulting crude residue was purified by using MPLC (SiO2230-400 mesh; 18% EtOAc in hexanes) to afford 7 as a light-brown gum. Yield: 600 mg (74%). LC-MS: Calculated for C24H34BN3O4is 439.26, observed: 440.0 [M+H]+

[0681] Step 5:

[0682] A solution of 7 (605 mg, 1.240 mmol), 8 (408 mg, 0.954 mmol), potassium phosphate tribasic (607 mg, 2.86 mmol) in a mixture of THF (10 mL) and water (2.5 mL) was purged with nitrogen for 5 min, after which SPhos Pd G2 (34.3 mg, 0.048 mmol) was added. The reaction mixture was irradiated at 70 °C in a microwave irradiator for 1 h. The reaction mixture was filtered through a pad of Celite bed. The Celite bed was washed with EtOAc (20 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 (SiO2230-400 mesh; 8% MeOH in DCM) to afford 9 as a pale-yellow gum. Yield: 400 mg (60%). LC-MS: Calculated for C38H45N5O5is 651.34, observed: 652.2 [M+H]+

[0683] Step 6:

[0684] To a stirred solution of 9 (350 mg, 0.502 mmol) in trifluoroethanol (5 mL), was added TMSCl (0.128 mL, 1.004 mmol) dropwise at 0 °C, and the reaction mixture stirred at room temperature for 2 h. The reaction mass was concentrated under reduced pressure. The resulting residue was suspended in an aqueous 10% NaHCO3 solution (6 mL). This was extracted with 20% MeOH in DCM (3 x 10 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 preparative HPLC (column: Evoke C18 (250×30) mm, 5μm; eluents:10 mM formic acid in water and ACN) to afford Compound 62 as a white solid. Yield: 4 mg (1.7%). LC-MS: Calculated for C28H29N5O2 is 467.23, observed: 468.2 [M+H]+.1H-NMR (400 MHz, DMSO-d6): δ 8.24 (s, 1H), 7.69 (d, J = 8.40 Hz, 2H), 7.64 (d, J = 8.40 Hz, 2H), 7.54 (d, J = 8.40 Hz, 2H), 7.40 (d, J = 8.40 Hz, 2H), 7.36 (d, J = 1.20 Hz, 1H), 6.84 (d, J = 0.80 Hz, 1H), 6.51 (s, 1H), 6.27 (d, J = 7.60 Hz, 1H, exchanges with D2O), 5.70 (t, J = 5.60 Hz, 1H), 5.55 (br s, 1H, exchanges with D2O), 5.38 (br s, 1H, exchanges with D2O), 4.97-4.92 (m, 1H), 4.02-3.96 (m, 1H), 3.87 (d, J = 6.00 Hz, 2H), 3.15- 3.08 (m, 2H), 2.74-2.67 (m, 2H), 2.06-1.98 (m, 2H), 1.51 (d, J = 6.40 Hz, 3H) . SFC: 100%; tR = 2.07 min (column: I Cellulose- Z; eluents: CO2 and 0.5% isopropyl amine in MeOH)

[0685] Note: One exchangeable proton not seen in NMR. The product was formate salt.Example 39: Synthesis of Compounds 64 and 65

[0686] Step 1:

[0687] To a stirred solution of 4-(4-bromophenyl)pyrrolidin-2-one ((±)-1, 1 g, 4.16 mmol) in 1,4- dioxane (12 mL), was added Lawesson’s reagent (2.53 g, 6.25 mmol) at 25 ℃, and the resulting reaction mixture stirred at 90 ℃ for 16 h. The reaction mixture w...

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:R1is hydrogen or substituted or unsubstituted C1-C6alkyl; R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted C1- C6alkyl; R3is hydrogen 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, or 2; 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, or 2; Y1is CR8or N; Y2is C(R8)2 or NR8a; x is 0, 1, 2, 3, or 4; each R8is independently hydrogen, 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, substituted or unsubstituted heteroaryl, or -L-R12; R8ais hydrogen, substituted or unsubstituted C1-C6alkyl, or -(substituted or unsubstituted C1- C6alkyl)-CN; or R8aand one or more R8are taken together with the atoms to which they are attached to form a fused substituted or unsubstituted C2-C10heterocycloalkyl or substituted or unsubstituted heteroaryl; L is substituted or unsubstituted C1-C6alkyl, -N(R11)-(substituted or unsubstituted C1-C6alkyl), - O-(substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl; R11is hydrogen or substituted or unsubstituted C1-C6alkyl; R12is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd; R9is substituted or unsubstituted heteroaryl, substituted or unsubstituted C2-C10heterocycloalkyl, -O-substituted or unsubstituted heteroaryl, -O-substituted or unsubstituted C2- C10heterocycloalkyl, -N(R11)-substituted or unsubstituted heteroaryl, -N(R11)-substituted or unsubstituted C2-C10heterocycloalkyl, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, - C(=O)ORb, or -C(=O)NRcRd; R10ais halogen, -CN, -OH, -NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; R10bis halogen, -CN, -OH, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl, or -L-R12; R10cis substituted or unsubstituted heteroaryl, substituted or unsubstituted C2- C10heterocycloalkyl, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRbC(=O)NRcRd, - NRbC(=O)Ra, -NRbC(=O)ORb, or -NRbS(=O)2Ra; 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 orunsubstituted 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 has a structure of Formula (Ia):or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

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

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

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

6. The compound of any one of claims 1-5, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R2aand R2bare each independently hydrogen.

7. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R3is hydrogen; and R4is hydrogen, -CH3, or -CH2CH3.

8. The compound of any one of claims 1-6, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R3is hydrogen; and R4is hydrogen.

9. The compound of any one of claims 1-8, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:R7is .

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

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

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

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

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

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

16. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: Y1is CR8or N; and Y2is NR8a.

17. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: Y1is CR8; and Y2is NR8a.

18. The compound of claim 15, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: Y1is N; and Y2is NR8a.

19. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: x is 0, 1, or 2; each R8is independently hydrogen, halogen, -CN, -OH, -ORa, -OC(=O)Ra, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbS(=O)2Ra, -C(=O)Ra, - 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, substituted or unsubstituted heteroaryl, or -L-R12; or R8aand one or more R8are taken together with the atoms to which they are attached to form a fused substituted or unsubstituted C2-C10heterocycloalkyl or substituted or unsubstituted heteroaryl; L is substituted or unsubstituted C1-C6alkyl, -N(R11)-(substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl; R11is hydrogen or substituted or unsubstituted C1-C6alkyl; R12is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd; each Rais independently substituted or unsubstituted C1-C6alkyl; each Rbis independently hydrogen or substituted or unsubstituted C1-C6alkyl; each Rcand Rdare 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.

20. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: x is 0, 1, or 2; each R8is independently hydrogen, halogen, -CN, -OH, -ORa, -S(=O)2Ra, -S(=O)2NRcRd, - NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl,substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted heteroaryl, or -L-R12; or R8aand one or more R8are taken together with the atoms to which they are attached to form a fused substituted or unsubstituted C2-C10heterocycloalkyl or substituted or unsubstituted heteroaryl; L is substituted or unsubstituted C1-C6alkyl, -N(H)-(substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl; R12is -CN, -OH, -ORa, or -NRcRd; each Rais independently substituted or unsubstituted C1-C6alkyl; each Rbis independently hydrogen or substituted or unsubstituted C1-C6alkyl; each Rcand Rdare 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.

21. The compound of any one of claims 1-18, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: x is 0, 1, or 2; each R8is independently hydrogen, halogen, -CN, -OH, -ORa, - S(=O)2NRcRd, -NRcRd, - NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbS(=O)2Ra, -C(=O)Ra, -C(=O)NRcRd, oxo, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted heteroaryl, or -N(R11)-(substituted or unsubstituted C1-C6alkyl)-CN, or - (substituted or unsubstituted C1-C6heteroalkyl)-CN; or R8aand one or more R8are taken together with the atoms to which they are attached to form a fused substituted or unsubstituted C2-C10heterocycloalkyl or substituted or unsubstituted heteroaryl; R11is hydrogen or -CH3; each Rais independently -CH3or -CH2CH3; each Rbis independently hydrogen, -CH3, or -CH2CH3; each Rcand Rdare independently hydrogen, -CH3, or -CH2CH3; or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C6heterocycloalkyl.

22. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R8ais hydrogen or -(substituted or unsubstituted C1-C6alkyl)-CN.

23. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R8ais hydrogen, -CH2CN, -CH2CH2CN, or -CH2CH2CH2CN.

24. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R8ais hydrogen or -CH2CN.

25. The compound of any one of claims 1-21, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R8ais hydrogen.

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

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

29. The compound of any one of claims 1-9 or 19-21, wherein the compound has a structure of Formula (II):Formula (II), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

30. The compound of claim 26, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: each R8is independently hydrogen, halogen, -CN, -OH, -ORa, -OC(=O)Ra, -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -NRcRd, -NRbC(=O)NRcRd, -NRbC(=O)Ra, -NRbS(=O)2Ra, -C(=O)Ra, - C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C2-C10heterocycloalkyl, substituted or unsubstituted heteroaryl, or -L-CN; L is substituted or unsubstituted C1-C6alkyl, -N(R11)-(substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl; R11is hydrogen or -CH3-; each Rais independently -CH3 or -CH2CH3; each Rbis independently hydrogen, -CH3, or -CH2CH3; each Rcand Rdare independently hydrogen, -CH3, or -CH2CH3; or Rcand Rdare taken together with the atom to which they are attached to form a substituted or unsubstituted C2-C6heterocycloalkyl.

31. The compound of claim 29 or 30, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

32. The compound of any one of claims 29-31, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

33. The compound of any one of claims 1-8, 10, or 19-21, wherein the compound has a structure of Formula (III):Formula (III), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

34. The compound of claim 33, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R9is substituted or unsubstituted heteroaryl, substituted or unsubstituted C2-C10heterocycloalkyl, -O-substituted or unsubstituted heteroaryl, -O-substituted or unsubstituted C2- C10heterocycloalkyl, -N(R11)-substituted or unsubstituted heteroaryl, or -N(R11)-substituted or unsubstituted C2-C10heterocycloalkyl; and R11is hydrogen or -CH3.

35. The compound of claim 33 or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R9is substituted or unsubstituted monocyclic heteroaryl, -O-substituted or unsubstituted monocyclic heteroaryl, or -N(R11)-substituted or unsubstituted monocyclic heteroaryl, wherein monocyclic heteroaryl is furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, or triazinyl; and R11is hydrogen or -CH3.

36. The compound of claim 33, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R9is substituted or unsubstituted monocyclic heteroaryl, -O-substituted or unsubstituted monocyclic heteroaryl, or -N(R11)-substituted or unsubstituted monocyclic heteroaryl,wherein monocyclic heteroaryl is pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl; and R11is hydrogen or -CH3.

37. The compound of claim 33, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R9is -S(=O)Ra, -S(=O)2Ra, -S(=O)2NRcRd, -C(=O)Ra, -C(=O)ORb, or -C(=O)NRcRd.

38. The compound of any one of claims 33-37, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

39. The compound of claim 38, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: ,40. The compound of claim 38, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:,.

41. The compound of any one of claims 1-8, 12, or 19-21, wherein the compound has a structure of Formula (IV):Formula (IV), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

42. The compound of claim 41, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R10ais -F, -Cl, -CN, -OH, -NH2, -CH3, or -CH2CH3; and R10bis halogen, -CN, -S(=O)2NRcRd, -NRbC(=O)Ra, -C(=O)Ra, -C(=O)NRcRd, substituted or unsubstituted C1-C6alkyl, -N(H)-(substituted or unsubstituted alkyl)-CN, or -(substituted or unsubstituted C1-C6heteroalkyl)-CN.

43. The compound of claim 41, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R10ais -OH, -NH2, or -CH3; and R10bis -CN, -C(=O)NRcRd, -N(H)-(substituted or unsubstituted alkyl)-CN, or -(substituted or unsubstituted C1-C6heteroalkyl)-CN.

44. The compound of any one of claims 41-43, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

45. The compound of any one of claims 41-44, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

46. The compound of any one of claims 1-11, 15, or 19-21, wherein the compound has a structure of Formula (V):Formula (V), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

47. The compound of claim 46, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R10cis substituted or unsubstituted heteroaryl, substituted or unsubstituted C2- C10heterocycloalkyl, -S(=O)2Ra, -S(=O)2NRcRd, -NRbC(=O)Ra, or -NRbS(=O)2Ra.

48. The compound of claim 46, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R10cis substituted or unsubstituted monocyclic heteroaryl 49. The compound of any one of claims 42-46, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

50. The compound of claim 49, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R10cis substituted or unsubstituted monocyclic heteroaryl, wherein monocyclic heteroaryl is pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, or thiadiazolyl.

51. The compound of claim 49, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R10cis substituted or unsubstituted monocyclic heteroaryl, wherein monocyclic heteroaryl is imidazolyl, triazolyl, or tetrazolyl.

52. The compound of any one of claims 42-46, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

53. The compound of any one of claims 42-46, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

54. The compound of any one of claims 42-46, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

55. The compound of any one of claims 42-46, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

56. A compound of Formula (VI):Formula (VI), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:; Ring A is C3-C6cycloalkyl or 4 to 6-membered N-containing heterocycloalkyl; L1is absent, -CH2-, -O-, -OCH2-, or -CH2O-; Lais absent, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; R1is hydrogen or substituted or unsubstituted C1-C6alkyl; R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted C1- C6alkyl; R3is hydrogen 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, or 2; 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, or 2; x is 0, 1, 2, 3, or 4; each R8is independently hydrogen, 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 unsubstitutedC2-C10heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -L-R12; R8ais hydrogen, substituted or unsubstituted C1-C6alkyl, -(substituted or unsubstituted C1- C6alkyl)-CN, or -C(=O)-substituted or unsubstituted C1-C6alkyl); or R8aand one or more R8are taken together with the atoms to which they are attached to form a fused substituted or unsubstituted C2-C10heterocycloalkyl or substituted or unsubstituted heteroaryl; L is substituted or unsubstituted C1-C6alkyl, -N(R11)-(substituted or unsubstituted C1-C6alkyl), - O-(substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl; R11is hydrogen or substituted or unsubstituted C1-C6alkyl; R12is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd; 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.

57. The compound of claim 56, wherein the has a structure of Formula (VIa):or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

58. The compound of any one of claims 56-57, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:Lais absent.

59. The compound of any one of claims 56-57, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: Lais substituted or unsubstituted C1-C6alkyl.

60. The compound of any one of claims 56-57, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: Lais -CH2-.

61. The compound of any one of claims 56-60, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

62. The compound of any claim 61, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: Ring A is C3-C6cycloalkyl.

63. The compound of any one of claims 56-60, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

64. The compound of any claim 61, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: Ring A is 4 to 6-membered N-containing heterocycloalkyl.

65. The compound of any one of claims 56-60, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:prodrug thereof, wherein:,67. The compound of any one of claims 56-60, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:, wherein R8a and one or more R8 are taken together with the atoms to whichthey are attached to form a fused substituted or unsubstituted C2-C10heterocycloalkyl or substituted or unsubstituted heteroaryl.

68. The compound of any one of claims 56-60, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

69. The compound of any one of claims 56-68, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R8is hydrogen, -OH, -NRbC(=O)Ra, oxo, substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, or substituted or unsubstituted heteroaryl; and R8ais hydrogen, substituted or unsubstituted C1-C6alkyl, or -C(=O)-substituted or unsubstituted C1-C6alkyl).

70. The compound of any one of claims 56-68, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R8is hydrogen, -OH, -CH2OH, -NHC(=O)CH3 , oxo, -CH3, substituted or unsubstituted C1-C6heteroalkyl, or substituted or unsubstituted triazole; and R8ais hydrogen, -CH3, or -C(=O)-CH3.

71. The compound of any one of claims 56-68, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R8is hydrogen; and R8ais hydrogen.

72. The compound of any one of claims 56-60, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: L1is absent.

73. The compound of any one of claims 56-60, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: L1is -CH2-, -O-, -OCH2-, or -CH2O-.

74. The compound of any one of claims 56-60 or 72-73, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

75. The compound of any one of claims 56-60 or 72-73, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

76. The compound of any one of claims 56-60 or 72-73, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

77. The compound of any one of claims 56-60 or 72-73, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

78. The compound of any one of claims 56-60 or 72-73, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: , .

79. The compound of any one of claims 56-60 or 72-73, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

80. The compound of any one of claims 56-79, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R1is substituted or unsubstituted C1-C6alkyl.

81. The compound of any one of claims 56-79, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R1is -CH3, -CH2CH3, or -CH(CH3)2.

82. The compound of any one of claims 56-79, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R1is -CH3.

83. The compound of any one of claims 56-82, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R2aand R2bare each independently hydrogen.

84. The compound of any one of claims 56-83, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R3is hydrogen; and R4is hydrogen, -CH3, or -CH2CH3.

85. The compound of any one of claims 56-83, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R3is hydrogen; and R4is hydrogen.

86. The compound of any one of claims 1-85, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: each R5is independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; s is 0 or 1; each R6is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or substituted or unsubstituted C1-C6alkyl; and t is 0 or 1.

87. The compound of any one of claims 1-85, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: each R5is independently hydrogen; and each R6is independently hydrogen, -F, -Cl, -CH3, -CH2CH3, or -CH(CH3)2.

88. The compound of any one of claims 1-85, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:each R5is independently hydrogen; and each R6is independently hydrogen or -F.

89. The compound of any one of claims 1-85, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: each R5is independently hydrogen; and each R6is independently hydrogen.

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

91. A compound selected from:, ,,, , or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

92. A compound selected from:, ,, ,,, , ,, ,, ,or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

93. A compound of FormulaFormula (X), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R7 is;R1is hydrogen or substituted or unsubstituted C1-C6alkyl; R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted C1- C6alkyl; R3is hydrogen or substituted or unsubstituted C1-C6alkyl;R4is hydrogen or substituted or unsubstituted C1-C6alkyl; R20is hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; R21is 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, or 2; 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; x is 0, 1, 2, 3, or 4; each R8is independently hydrogen, 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, substituted or unsubstituted heteroaryl, or -L-R12; R8ais hydrogen, substituted or unsubstituted C1-C6alkyl, or -(substituted or unsubstituted C1- C6alkyl)-CN; or R8aand one or more R8are taken together with the atoms to which they are attached to form a fused substituted or unsubstituted C2-C10heterocycloalkyl or substituted or unsubstituted heteroaryl; L is substituted or unsubstituted C1-C6alkyl, -N(R11)-(substituted or unsubstituted C1-C6alkyl), - O-(substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl; R11is hydrogen or substituted or unsubstituted C1-C6alkyl; R12is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd; R22ais hydrogen or substituted or unsubstituted C1-C6alkyl; R22is -CH3, -CH2CH3, or -CH2CH2CH3; R23is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, halogen, -CN, -C(=O)Ra, -C(=O)NRcRd, or -NRbC(=O)Ra;R24is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, - NRcRd, or -ORa; R25is substituted or unsubstituted C1-C6alkyl;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.

94. The compound of claim 93, wherein the compound has a structure of Formula (XI):Formula (XI), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

95. The compound of claim 93 or 94, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

96. The compound of claim 95, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

97. The compound of claim 95, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

98. The compound of claim 95, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

99. The compound of claim 95, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

100. The compound of claim 95, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

101. The compound of claim 93 or 94, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

102. The compound of claim 101, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

103. A compound ofFormula (XII), or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:; Ring A is C3-C6cycloalkyl or 4 to 6-membered N-containing heterocycloalkyl; L1is absent, -CH2-, -O-, -OCH2-, or -CH2O-; Lais absent, substituted or unsubstituted C1-C6alkyl, or substituted or unsubstituted C1-C6heteroalkyl; R1is hydrogen or substituted or unsubstituted C1-C6alkyl; R2aand R2bare each independently hydrogen, halogen, or substituted or unsubstituted C1- C6alkyl; R3is hydrogen or substituted or unsubstituted C1-C6alkyl; R4is hydrogen or substituted or unsubstituted C1-C6alkyl; R20is hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; R21is 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, or 2; 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; x is 0, 1, 2, 3, or 4; each R8is independently hydrogen, 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, substituted or unsubstituted heteroaryl, or -L-R12; R8ais hydrogen, substituted or unsubstituted C1-C6alkyl, or -(substituted or unsubstituted C1- C6alkyl)-CN;or R8aand one or more R8are taken together with the atoms to which they are attached to form a fused substituted or unsubstituted C2-C10heterocycloalkyl or substituted or unsubstituted heteroaryl; L is substituted or unsubstituted C1-C6alkyl, -N(R11)-(substituted or unsubstituted C1-C6alkyl), - O-(substituted or unsubstituted C1-C6alkyl), or substituted or unsubstituted C1-C6heteroalkyl; R11is hydrogen or substituted or unsubstituted C1-C6alkyl; R12is -CN, -OH, -ORa, -NRcRd, -C(=O)Ra, -C(=O)NRcRd, or -S(=O)2NRcRd; R22ais hydrogen or substituted or unsubstituted C1-C6alkyl; R22is -CH3, -CH2CH3, or -CH2CH2CH3; R23is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, halogen, -CN, -C(=O)Ra, -C(=O)NRcRd, or -NRbC(=O)Ra; R24is substituted or unsubstituted C1-C6alkyl, substituted or unsubstituted C1-C6heteroalkyl, - NRcRd, or -ORa; R25is substituted or unsubstituted C1-C6alkyl; R26is substituted or unsubstituted heteroaryl; 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.

104. The compound of claim 103, wherein the compound has a structure of Formula (XIIa):Formula (XIIa), or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

105. The compound of claim 103 or 104, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: Lais absent.

106. The compound of claim 103 or 104, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: Lais substituted or unsubstituted C1-C6alkyl.

107. The compound of claim 103 or 104, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: Lais -CH2-.

108. The compound of any one of claims 103-107, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

109. The compound of claim 108, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: Ring A is 4 to 6-membered N-containing heterocycloalkyl.

110. The compound of any one of claims 103-108, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

111. The compound of any one of claims 103-108, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

112. The compound of any one of claims 103-108, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R8is hydrogen; and R8ais hydrogen.

113. The compound of any one of claims 103-108, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

114. The compound of claim 113, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R26is substituted or unsubstituted 5-6 membered heteroaryl.

115. The compound of claim 113, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R26is substituted or unsubstituted imidazolyl, oxadiazolyl, or triazolyl.

116. The compound of any one of claims 103-108, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: ,, .

117. The compound of any one of claims 103-108, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: L1is absent.

118. The compound of any one of claims 103-108, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: L1is -CH2-, -O-, -OCH2-, or -CH2O-.

119. The compound of any one of claims 103-108 or 117-118, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

120. The compound of any one of claims 103-108 or 117-118, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:.

121. The compound of any one of claims 103-108 or 117-118, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein:

122. The compound of any one of claims 93-121, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R8is hydrogen.

123. The compound of any one of claims 93-122, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R1is substituted or unsubstituted C1-C6alkyl.

124. The compound of any one of claims 93-122, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R1is -CH3, -CH2CH3, or -CH(CH3)2.

125. The compound of any one of claims 93-122, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R1is -CH3.

126. The compound of any one of claims 93-125, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R2aand R2bare each independently hydrogen.

127. The compound of any one of claims 93-126, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R3is hydrogen; and R4is hydrogen, -CH3, or -CH2CH3.

128. The compound of any one of claims 93-126, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R3is hydrogen; and R4is hydrogen.

129. The compound of any one of claims 93-128, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: R20is hydrogen; and R21is hydrogen.

130. The compound of any one of claims 93-129, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: each R5is independently hydrogen, halogen, or substituted or unsubstituted C1-C6alkyl; s is 0 or 1; each R6is independently hydrogen, halogen, -CN, -OH, -ORa, -NRcRd, or substituted orunsubstituted C1-C6alkyl; and t is 0 or 1.

131. The compound of any one of claims 93-129, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: each R5is independently hydrogen; and each R6is independently hydrogen, -F, -Cl, -CH3, -CH2CH3, or -CH(CH3)2.

132. The compound of any one of claims 93-129, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: each R5is independently hydrogen; and each R6is independently hydrogen or -F.

133. The compound of any one of claims 93-129, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein: each R5is independently hydrogen; and each R6is independently hydrogen.

134. The compound of any one of claims 93-123, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, wherein the compound is selected from: , ,,, , , , , ,,, , , , ,, or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

135. A compound selected from:,, ,, , or a pharmaceutically acceptable salt, solvate, or prodrug thereof.

136. A pharmaceutical composition comprising the compound of any one of claims 1-135, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, and a pharmaceutically acceptable excipient.

137. 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 1-135, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or the pharmaceutical composition of claim 136.

138. The method of claim 137, wherein the gram-negative bacterial infection is associated with Pseudomonas aeruginosa.

139. The method of claim 137, wherein the gram-negative bacterial infection is a respiratory infection.

140. The method of claim 137, wherein the gram-negative bacterial infection is pneumonia.

141. The method of claim 140, 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.

142. 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 1-135, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or the pharmaceutical composition of claim 136.

143. The method of any one of claims 137-142, wherein the patient has been identified as having a lung disease.

144. The method of claim 143, wherein the lung disease is a structural lung disease.

145. The method of claim 143 or claim 144, wherein the lung disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic destroyed lung disease, or a combination thereof.

146. The method of any one of claims 137-145, wherein the administration is to treat an existing infection.

147. The method of any one of claims 137-145, wherein the administration is provided as prophylaxis.

148. The method of any one of claims 137-145, wherein the compound of any one of claims 1-135, or a pharmaceutically acceptable salt, solvate, or prodrug thereof, or the pharmaceutical composition of claim 136, is administered in a solution by inhalation, intravenous injection, or intraperitoneal injection.

149. A compound of any one of claims 1-135 for use as therapeutically active substance.

150. A compound of any one of claims 1-135 for use in treating or preventing a gram-negative bacterial infection.

151. The compound for use of claim 150, wherein the gram-negative bacterial infection is associated with Pseudomonas aeruginosa.

152. The compound for use of claim 150, wherein the gram-negative bacterial infection is a respiratory infection.

153. The compound for use of claim 150, wherein the gram-negative bacterial infection is pneumonia.

154. The compound for use of claim 153, 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.

155. A compound of any one of claims 1-135 for use in treating or preventing a P. aeruginosa infection.

156. The compound for use of any one of claims 149-155, wherein the patient has been identified as having a lung disease.

157. The compound for use of claim 156, wherein the lung disease is a structural lung disease.

158. The compound for use of claim 156 or claim 157, wherein the lung disease is cystic fibrosis, bronchiectasis, emphysema, chronic obstructive pulmonary disease (COPD), chronic destroyed lung disease, or a combination thereof.

159. The use of a compound of any one of claims 1-135 for the preparation of a medicament for treating or preventing a gram-negative bacterial infection.

160. The use of a compound of any one of claims 1-135 for treating or preventing a gram-negative bacterial infection.

161. A process for the preparation of a compound of Formula (I), comprising:(1) contacting a compound of Formula (A):Formula (A), with a compound of Formula (B):Formula (B), to provide a compound of Formula (C):Formula (C); and (2) removing PG to provide a compound of Formula (I), wherein: R1, R2a, R2b, R3, R4, R5, R6, R7, s, and t are defined in any one of claims 1-133; PG is a protecting group; X is a halogen, -OTs, or -OMs; and B is a boronic acid, boronic ester, or trifluoroborate.

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