STAT6 modulators and uses thereof

Abstract

The present disclosure relates generally to STAT6 modulators and uses thereof, and more specifically to compounds, salts, and compositions thereof useful for treating conditions associated with STAT6.

Description

Attorney Docket No.: 183952036340 STAT6 MODULATORS AND USES THEREOF CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority benefit to U.S. Provisional Application Nos. 63 / 670,686, filed July 12, 2024, and 63 / 743,999, filed January 10, 2025, the disclosures of each of which are hereby incorporated herein by reference in their entireties for all purposes. FIELD

[0002] The present disclosure relates generally to STAT6 modulators and uses thereof, and more specifically to compounds, salts, and compositions thereof useful for treating conditions associated with STAT6. BACKGROUND

[0003] The Signal Transducer and Activator of Transcription (STAT) family of proteins consists of transcription factors that play an essential role in the regulation of cell processes, such as proliferation, differentiation, apoptosis and angiogenesis. Seven STAT genes have been identified in the human genome: STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, and STAT6.

[0004] Recent studies have shown that STAT6 signaling is essential for IL-4- and IL-13- induced epithelial mesenchymal transition (EMT) and aggressiveness of colorectal cancer cells (CRC) cells. STAT6 is involved in several aspects of inflammatory disease and other related conditions.

[0005] Given their role in the regulation of cell processes, modulating the activity of one or more STAT proteins, particularly STAT6, represent a pivotal area of investigation for the treatment of cancer, inflammatory conditions, and other therapeutic needs. Therefore, there is a substantial need to supply modulators of STAT, particularly STAT6 modulators. BRIEF SUMMARY

[0006] The present disclosure provides compounds of Formula (I), compositions thereof, and methods of using these compounds and compositions thereof for the treatment of diseases or conditions associated with STAT, in particular STAT6.

[0007] In one aspect, provided is a compound of Formula (I): 1MOFO-358009544Attorney Docket No.: 183952036340or a pharmaceutically acceptable salt thereof, wherein: R1aand R1bare each independently H or halogen; R2is H, (C1-C6)alkyl, or (C3-C6)cycloalkyl; R3is (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, 3- to 7-membered heterocyclyl, -(C1-C6)alkylene-(C3-C6)cycloalkyl, or - (C1-C6)alkylene-(3- to 7-membered heterocyclyl), wherein (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl of -(C1-C6)alkylene-(C3-C6)cycloalkyl, or (3- to 7-membered heterocyclyl) of -(C1-C6)alkylene-(3- to 7-membered heterocyclyl) is each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of (C1-C6)alkyl, (C1- C6)alkoxy, cyano, halogen, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy, or R2and R3together with the nitrogen atom to which they are attached form 5- to 7-membered heterocyclyl substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, cyano, halogen, halo(C1-C6)alkyl, and halo(C1- C6)alkoxy; R4is H, (C6-C10)aryl, or 5- to 10-membered heteroaryl, wherein (C6-C10)aryl or 5- to 10-membered heteroaryl is each substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halogen, cyano, (C1-C6)alkyl, (C1- C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, and -NR4aR4b, wherein: each R4aand R4bis independently H or (C1-C6)alkyl; R5 is H, cyano, or (C1-C6)alkoxy; and RPis phosphonic acid, phosphonate, phosphonamidate, or phosphondiamidate. DETAILED DESCRIPTION

[0008] The following description is presented to enable a person of ordinary skill in the art to make and use the various embodiments. Descriptions of specific methods, techniques, and applications are provided only as examples. Various modifications to the examples described herein will be readily apparent to those of ordinary skill in the art, and the general principles defined herein may be applied to other examples and applications without departing from the spirit and scope of the various embodiments. Thus, the various 2MOFO-358009544Attorney Docket No.: 183952036340 embodiments are not intended to be limited to the examples described herein and shown, but are to be accorded the scope consistent with the claims. Definitions

[0009] As used in the present specification, the following words and phrases are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0010] Throughout this application, unless the context indicates otherwise, references to a compound of Formula (I) include all subgroups defined herein, such as Formula (I-A-1), (I- A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-B-5), (I-B-6), (I- C-1), (I-C-2), (I-C-3), (I-C-4), (I-C-5), (I-C-6), (I-D-1), (I-D-2), (I-D-3), (I-D-4), (I-D-5), (I- D-6), (I-E-1), (I-E-2), (I-E-3), (I-E-4), (I-E-5), (I-E-6), (I-F-1), (I-F-2), (I-F-3), (I-F-4), (I-F- 5), (I-F-6), (I-G-1), (I-G-2), (I-G-3), (I-G-4), (I-G-5), (I-G-6), (I-H-1), (I-H-2), (I-H-3), (I-H- 4), (I-H-5), (I-H-6), (I-J-1), (I-J-2), (I-J-3), (I-J-4), (I-J-5), or (I-J-6) including all substructures, subgenera, preferences, embodiments, examples, and particular compounds defined and / or described herein. In some embodiments, references to a compound of Formula (I) and subgroups thereof include ionic forms, stereoisomers, rotamers, tautomers, oxides (e.g., N-oxides, S-oxides), esters, prodrugs, isotopologues, and / or protected forms thereof.

[0011] When used in connection to describe a chemical group that may have multiple points of attachment, a hyphen (-) designates the point of attachment(s) of that group. For example, -NHC(O)OH means that the point of attachment for this group occurs on the nitrogen atom.

[0012] As used herein, “CX-CY” or “(Cx-Cy)” in reference to or preceding the name of a chemical group (e.g., alkyl, alkoxy, cycloalkyl, aryl) refers to the group having from X to Y carbon atoms, for example a (C1-C6)alkyl refers to an alkyl having 1, 2, 3, 4, 5, or 6 carbon atoms. The terms “halo” and “halogen” refer to an atom selected from fluorine (fluoro, -F), chlorine (chloro, -Cl), bromine (bromo, -Br), and iodine (iodo, -I).

[0013] Unless otherwise specified, the term “alkyl” when used alone or as part of a larger moiety, such as “haloalkyl”, and the like, means saturated straight-chain or branched monovalent hydrocarbon radical. For example, “(C1-C6)alkyl” includes methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, isobutyl, tert-butyl, pentyl, isopentyl, neopentyl, and 3MOFO-358009544Attorney Docket No.: 183952036340 hexyl. The term “alkylene” when used alone or as part of a larger moiety, such as “alkylene- cycloalkyl”, and the like, means saturated straight-chain or branched divalent hydrocarbon radical, for example, -CH2-, -CH2CH2-, -CH2CH2CH2-, -CH2CH2CH2CH2-, -CH(CH3)-, and - C(CH3)2-.

[0014] The term “haloalkyl” includes mono, poly, and perhaloalkyl groups where the halogens are independently selected from fluorine, chlorine, bromine, and iodine. In some embodiments, the halogen is fluorine. For example, haloalkyl includes chloromethyl, dichloromethyl, trichloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, 1,2- difluoroethyl, 2,2,2-trifluoroethyl, and 1,1,2,2-tetrafluoroethyl.

[0015] “Alkoxy” means an alkyl radical attached through an oxygen linking atom, represented by –O-alkyl. For example, “(C1-C4)alkoxy” includes methoxy, ethoxy, proproxy, and butoxy.

[0016] “Haloalkoxy” is a haloalkyl group which is attached to another moiety via an oxygen atom such as, e.g., –OCHF2or –OCF3.

[0017] The term “oxo” means the group =O.

[0018] The term “imino” means the group =NH.

[0019] Unless otherwise specified, the term “heteroaryl” refers to a 5- to 12-membered aromatic radical containing 1-4 heteroatoms selected from N, O, and S. In some instances, nitrogen atoms in a heteroaryl may be quaternized. The term “heteroaryl” may be used interchangeably with the terms “heteroaryl ring”, “heteroaryl group”, or “heteroaromatic”. A heteroaryl group may be mono- or bi-cyclic. Monocyclic heteroaryl includes, for example, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl,etc. Bi-cyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Nonlimiting examples include indolyl, benzooxazolyl, benzooxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothiopheneyl, quinolinyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, purinyl, cinnolinyl, naphthyridinyl, and pteridinyl. It will be understood that when specified, optional substituents on a heteroaryl 4MOFO-358009544Attorney Docket No.: 183952036340 group may be present on any substitutable position and, include, e.g., the position at which the heteroaryl is attached (where valency permits).

[0020] Unless otherwise specified, the term “heterocyclyl” means a 4- to 12-membered saturated or partially unsaturated heterocyclic ring containing 1 to 4 heteroatoms independently selected from N, O, and S. The terms “heterocycle”, “heterocyclyl”, “heterocyclyl ring”, “heterocyclic group”, “heterocyclic moiety”, and “heterocyclic radical”, are used interchangeably herein. A heterocyclyl ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. A heterocyclyl group may be mono- or bicyclic (e.g., a bridged, fused, or spiro bicyclic ring). Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, without limitation, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, terahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydrooxadizolyl, and dihydroisoxazolyl. Bi-cyclic heterocyclyl groups include, e.g., unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical, cycloalkyl, aryl, or heteroaryl ring, such as for example, benzodioxolyl, dihydrobenzodioxinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, 5-oxa-2,6- diazaspiro[3.4]oct-6-enyl, 6-thia-2,7-diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.3]heptanyl, spiro[indoline-3,3'-pyrrolidine]-yl, thiochromanyl, and the like. It will be understood that when specified, optional substituents on a heterocyclyl group may be present on any substitutable position and, include, e.g., the position at which the heterocyclyl is attached (where valency permits).

[0021] The term “spiro” refers to two rings that shares one ring atom (e.g., carbon).

[0022] The term “fused” refers to two rings that share two adjacent ring atoms with one another.

[0023] The term “bridged” refers to two rings that share three adjacent ring atoms with one another.

[0024] The term “aryl” refers to an aromatic carbocyclic single ring or two fused ring system containing 6 to 10 carbon atoms. Examples include phenyl, indanyl, tetrahydronaphthalene, and naphthyl. In some embodiments, the aryl is phenyl or naphthyl. In some embodiments, the aryl is phenyl. 5MOFO-358009544Attorney Docket No.: 183952036340

[0025] The term “cycloalkyl”, used alone or as part of a larger moiety, refers to a saturated cyclic aliphatic monocyclic or bicyclic ring system, including spirocyclic ring system that may be referred to as “spirocycloalkyl”, having from, unless otherwise specified, 3 to 10 carbon ring atoms. Monocyclic cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. It will be understood that when specified, optional substituents on a cycloalkyl or cycloaliphatic group may be present on any substitutable position and, include, e.g., the position at which the cycloalkyl group is attached.

[0026] The term “N-linked amino acid” refers to an amino acid that is attached to the indicated moiety via the main-chain amino group. For example, N-linked alanine can be represented by -NHCH(CH3)C(O)OH. N-linked amino acids can be substituted or unsubstituted.

[0027] The term “N-linked amino acid ester” refers to an N-linked amino acid where the main-chain carboxylic acid group and / or any other carboxylic acid group(s) has been converted to an ester group. N-linked amino acid esters can be substituted or unsubstituted.

[0028] The term “amino acid” refers to any amino acid (both standard and non-standard amino acids, and both natural and non-natural amino acids), including, but not limited to, α- amino acids, β-amino acids, g-amino acids, and δ-amino acids. Examples of suitable amino acids include, but are not limited to, alanine, asparagine, aspartate, cysteine, glutamate, glutamine, glycine, proline, serine, tyrosine, arginine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. Additional examples of suitable amino acids include, but are not limited to, ornithine, hypusine, 2-aminoisobutyric acid, dehydroalanine, gamma-aminobutyric acid, citrulline, beta-alanine, alpha-ethyl-glycine, alpha-propyl-glycine and norleucine.

[0029] Non-natural amino acids are known in the art and include, e.g., alpha-alkyl amino acids (e.g., alpha methyl), alpha-alkylalkoxy amino acids (e.g., alpha -CH2OCH3), N-methyl amino acids, homo-amino acids, etc.

[0030] The term “phosphonic acid,” as used herein, refers to an organophosphorous group containing a P(=O) moiety where the phosphorous atom is bonded to a carbon atom (herein the point of attachment of RP) and two hydroxy groups, i.e., -P(=O)(OH)2. The term “phosphonate,” as used herein, refers to an organophosphorous group containing a P(=O) 6MOFO-358009544Attorney Docket No.: 183952036340 moiety where the phosphorous atom is bonded to a carbon atom (herein the point of attachment of RP) and two monovalent oxygen-linked groups, up to one of which may be hydroxy, and the other or both of which may be a non-hydroxy group, such as alkyloxy, aryloxy, cycloalkyloxy, heteroaryloxy, or heterocyclyloxy. The term “phosphonamidate,” as used herein, refers to an organophosphorous group containing a P(=O) moiety where the phosphorous atom is bonded to a carbon atom (herein the point of attachment of RP), one monovalent oxygen-linked group, such as hydroxy, alkyloxy, aryloxy, cycloalkyloxy, heteroaryloxy, or heterocyclyloxy, and one monovalent nitrogen-linked group, such as alkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, N-linked amino acid, N-linked amino acid ester, N-linked heteroaryl, or N-linked heterocyclyl. The term “phosphondiamidate,” as used herein, refers to an organophosphorous group containing a P(=O) moiety where the phosphorous atom is bonded to a carbon atom (herein the point of attachment of RP) and two monovalent nitrogen-linked group, such as alkylamino, arylamino, cycloalkylamino, heteroarylamino, heterocyclylamino, N-linked amino acid, N-linked amino acid ester, N-linked heteroaryl, or N-linked heterocyclyl.

[0031] The term “substituted” refers to one or more hydrogen radical of the designated group being replaced with the radical(s) of a moiety other than hydrogen. Unless otherwise noted, the substituent(s) can be in any position(s), provided that the respective compound is sufficiently stable and pharmaceutically acceptable. Reference to a group being substituted by, for example, 0, 1, 2, or 3 substituents indicates the group is optionally substituted, that is the group may be unsubstituted (have zero substituents) or may be substituted with one, two, or three substituents.

[0032] Compounds having one or more chiral centers can exist in various stereoisomeric forms. Stereoisomers are compounds that differ only in their spatial arrangement. Stereoisomers include all diastereomeric, enantiomeric, and epimeric forms as well as racemates and mixtures thereof. A “geometric isomer” refers to stereoisomers that differ in the orientation of substituent group in relationship to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. Atoms (other than H) on each side of a carbon- carbon double bond may be in an E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. “Cis” refers to substituents oriented on the same side of a double bond or ring, whereas “trans” refers to substituents oriented on opposite sides of a double bond or ring. 7MOFO-358009544Attorney Docket No.: 183952036340

[0033] When the stereochemical configuration at a chiral center in a compound having one or more chiral centers is depicted by its chemical name (e.g., where the configuration is indicated in the chemical name by “R” or “S”) or structure (e.g., the configuration is indicated by “wedge” bonds), the enrichment of the indicated configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. “Enrichment of the indicated configuration relative to the opposite configuration” is a mole percent and is determined by dividing the number of compounds with the indicated stereochemical configuration at the chiral center(s) by the total number of all of the compounds with the same or opposite stereochemical configuration in a mixture.

[0034] When a geometric isomer is depicted by name or structure, the enrichment of the indicated isomer relative to the opposite isomer is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. “Enrichment of the indicated isomer relative to the opposite isomer” is a mole percent and is determined by dividing the number of compounds with the indicated geometrical configuration by the total number of all of the compounds with the same or opposite geometrical configuration in a mixture.

[0035] When a disclosed compound is named or depicted by structure without indicating stereochemistry, it is understood that the name or the structure encompasses one of the possible stereoisomers or geometric isomers free of the others, or a mixture of the encompassed stereoisomers or geometric isomers.

[0036] The terms “subject” and “patient” may be used interchangeably, and means a mammal in need of treatment, e.g., companion animals (e.g., dogs, cats, and the like), farm animals (e.g., cows, pigs, horses, sheep, goats and the like) and laboratory animals (e.g., rats, mice, guinea pigs and the like). Typically, the subject is a human in need of treatment.

[0037] The term “inhibit,” “inhibition” or “inhibiting” includes a decrease in the baseline activity of a biological activity or process.

[0038] The term “pharmaceutically acceptable excipient” refers to a compound suitable for use in contact with recipient animals, particularly mammals, and more particularly humans, and having a toxicity, irritation, or allergic response commensurate with a reasonable benefit / risk ratio, and effective for their intended use. 8MOFO-358009544Attorney Docket No.: 183952036340

[0039] As used herein, the term “pharmaceutically acceptable salt” refers to salts that are, within the scope of sound medical judgment, suitable for administration to a subject without undue toxicity, irritation, allergic response, or other undesired effect, commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts of the compounds describe herein include those derived from suitable inorganic and organic acids and bases.

[0040] The term “effective amount” or “therapeutically effective amount” refers to an amount of a compound described herein that is sufficient to achieve the desired biological effect. In some embodiments, the effective amount is sufficient to achieve the desired therapeutic effect (such as treatment of a condition recited herein) under the conditions of administration by modulating, e.g., inhibiting STAT, in particular STAT6. The therapeutically effective amount will vary depending on the compound, the disease or condition and its severity and the age, weight, or other characteristics of the subject to be treated.

[0041] The term “administer,” “administering,” and “administration,” refer to contacting a subject with a compound or composition, or to prescribing, instructing, managing, or supervising the contacting of a subject with a compound or a composition by the subject or by another. Compounds

[0042] Compounds and salts thereof (such as pharmaceutically acceptable salts) are detailed herein, including in the Brief Summary and in the appended claims. Also provided are the use of all of the compounds described herein, including any and all stereoisomers, including geometric isomers (e.g., cis / trans, E / Z isomers), enantiomers, diastereomers, and mixtures thereof in any ratio including racemic mixtures, and salts of the compounds described herein, as well as methods of making such compounds. Any compound described herein may also be referred to as a drug.

[0043] In one aspect, provided is a compound of Formula (I): 9MOFO-358009544Attorney Docket No.: 183952036340or a pharmaceutically acceptable salt thereof, wherein: R1aand R1bare each independently H or halogen; R2is H, (C1-C6)alkyl, or (C3-C6)cycloalkyl; R3is (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, 3- to 7-membered heterocyclyl, -(C1-C6)alkylene-(C3-C6)cycloalkyl, or -(C1-C6)alkylene-(3- to 7- membered heterocyclyl), wherein (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3- C6)cycloalkyl of -(C1-C6)alkylene-(C3-C6)cycloalkyl, or (3- to 7-membered heterocyclyl) of -(C1-C6)alkylene-(3- to 7-membered heterocyclyl) is each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, cyano, halogen, halo(C1- C6)alkyl, and halo(C1-C6)alkoxy, or R2and R3together with the nitrogen atom to which they are attached form 5- to 7- membered heterocyclyl substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, cyano, halogen, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy; R4is H, (C6-C10)aryl, or 5- to 10-membered heteroaryl, wherein (C6-C10)aryl or 5- to 10-membered heteroaryl is each substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, and -NR4aR4b, wherein: each R4aand R4bis independently H or (C1-C6)alkyl; R5is H, cyano, or (C1-C6)alkoxy; and RPis phosphonic acid, phosphonate, phosphonamidate, or phosphondiamidate.

[0044] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), or (I-A-6), or a pharmaceutically acceptable salt thereof: 10MOFO-358009544Attorney Docket No.: 18395203634011MOFO-358009544Attorney Docket No.: 183952036340

[0045] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-B-5), or (I-B-6), or a pharmaceutically acceptable salt thereof:12MOFO-358009544Attorney Docket No.: 183952036340wherein RPaa2is H or (C1-C6)alkyl; and RPaa3is H, (C1-C6)alkyl, -(C1-C6)alkylene-(C1- C6)alkoxy, or -(C1-C6)alkylene-(C6-C10)aryl; or RPaa2and RPaa3, together with the carbon atom to which they are attached form (C3-C6)cycloalkyl.

[0046] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-C-1), (I-C-2), (I-C-3), (I-C-4), (I-C-5), or (I-C-6), or a pharmaceutically acceptable salt thereof:13MOFO-358009544Attorney Docket No.: 183952036340wherein RPais (C1-C6)alkyl, halo(C1-C6)alkyl, (C6-C10)aryl, or (C3-C6)cycloalkyl, wherein (C1-C6)alkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo and (C1-C6)alkoxy; RPaa2is H or (C1-C6)alkyl; RPaa3is H, (C1- C6)alkyl, -(C1-C6)alkylene-(C1-C6)alkoxy, or -(C1-C6)alkylene-(C6-C10)aryl; or RPaa2and RPaa3, together with the carbon atom to which they are attached form (C3-C6)cycloalkyl; and RPaa4is (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylene-(C1-C6)alkoxy, (C3-C6)cycloalkyl, (C5- C8)spirocycloalkyl, -(C1-C6)alkylene-(C6-C10)aryl, -(C1-C6)alkylene-(C1-C6)alkoxy, -(C1- C6)alkylene-(C3-C7)cycloalkyl, 3- to 7-membered heterocyclyl, or -(C1-C6)alkylene-(3- to 7- membered heterocyclyl), wherein (C1-C6)alkyl, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, or (C3-C7)cycloalkyl of -(C1-C6)alkylene-(C3-C7)cycloalkyl is each substituted with 0, 1, 2, or 3 independently selected halogen. 14MOFO-358009544Attorney Docket No.: 183952036340

[0047] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-D-1), (I-D-2), (I-D-3), (I-D-4), (I-D-5), or (I-D-6), or a pharmaceutically acceptable salt thereof:15MOFO-358009544Attorney Docket No.: 183952036340(C1-C6)alkyl, -(C1-C6)alkylene-(C1-C6)alkoxy, or -(C1-C6)alkylene-(C6-C10)aryl; or RPaa2and RPaa3, together with the carbon atom to which they are attached form (C3-C6)cycloalkyl.

[0048] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-E-1), (I-E-2), (I-E-3), (I-E-4), (I-E-5), or (I-E-6), or a pharmaceutically acceptable salt thereof:16MOFO-358009544Attorney Docket No.: 183952036340

[0049] wherein RPaa2is H or (C1-C6)alkyl; RPaa3is H, (C1-C6)alkyl, -(C1-C6)alkylene-(C1- C6)alkoxy, or -(C1-C6)alkylene-(C6-C10)aryl; or RPaa2and RPaa3, together with the carbon atom to which they are attached form (C3-C6)cycloalkyl; and RPaa4is (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylene-(C1-C6)alkoxy, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, -(C1-C6)alkylene- (C6-C10)aryl, -(C1-C6)alkylene-(C1-C6)alkoxy, -(C1-C6)alkylene-(C3-C7)cycloalkyl, 3- to 7- membered heterocyclyl, or -(C1-C6)alkylene-(3- to 7-membered heterocyclyl), wherein (C1- C6)alkyl, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, or (C3-C7)cycloalkyl of -(C1-C6)alkylene- (C3-C7)cycloalkyl is each substituted with 0, 1, 2, or 3 independently selected halogen.In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-F-1), (I-F-2), (I-F-3), (I-F-4), (I-F-5), or (I-F-6), or a pharmaceutically acceptable salt thereof: 17MOFO-358009544Attorney Docket No.: 183952036340wherein RPaa2is H or (C1-C6)alkyl; RPaa3is H, (C1-C6)alkyl, -(C1-C6)alkylene-(C1-C6)alkoxy, or -(C1-C6)alkylene-(C6-C10)aryl; or RPaa2and RPaa3, together with the carbon atom to which 18MOFO-358009544Attorney Docket No.: 183952036340they are attached form (C3-C6)cycloalkyl; and Ring A issubstituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo, oxo, COOH, and -C(O)ORPE; and each RPEis independently (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylene- (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, -(C1-C6)alkylene-(C6-C10)aryl, -(C1-C6)alkylene-(C1-C6)alkoxy, -(C1-C6)alkylene-(C3-C7)cycloalkyl, 3- to 7-memberedheterocyclyl, or -(C1-C6)alkylene-(3- to 7-membered heterocyclyl), wherein (C1-C6)alkyl, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, or (C3-C7)cycloalkyl of -(C1-C6)alkylene-(C3- C7)cycloalkyl is each substituted with 0, 1, 2, or 3 independently selected halogen.

[0050] In some embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is a compound of Formula (I-G-1), (I-G-2), (I-G-3), (I-G-4), (I-G-5), or (I-G-6), or a pharmaceutically acceptable salt thereof:19 MOFO-358009544Attorney Docket No.: 183952036340wherein RPaa2is H or (C1-C6)alkyl; RPaa3is H, (C1-C6)alkyl, -(C1-C6)alkylene-(C1-C6)alkoxy, or -(C1-C6)alkylene-(C6-C10)aryl; or RPaa2and RPaa3, together with the carbon atom to which they are attached form (C3-C6)cycloalkyl; RPaa4is (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1- C6)alkylene-(C1-C6)alkoxy, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, -(C1-C6)alkylene-(C6-C10)aryl, -(C1-C6)alkylene-(C1-C6)alkoxy, -(C1-C6)alkylene-(C3-C7)cycloalkyl, 3- to 7-membered heterocyclyl, or -(C1-C6)alkylene-(3- to 7-membered heterocyclyl), wherein (C1-C6)alkyl, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, or (C3-C7)cycloalkyl of -(C1-C6)alkylene- (C3-C7)cycloalkyl is each substituted with 0, 1, 2, or 3 independently selected halogen; and Ring A issubstituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo, oxo, COOH, and -C(O)ORPE; and each RPEis independently (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylene-(C1-C6)alkoxy, (C3-C6)cycloalkyl, (C5- C8)spirocycloalkyl, -(C1-C6)alkylene-(C6-C10)aryl, -(C1-C6)alkylene-(C1-C6)alkoxy, -(C1- 20 MOFO-358009544Attorney Docket No.: 183952036340C6)alkylene-(C3-C7)cycloalkyl, 3- to 7-membered heterocyclyl, or -(C1-C6)alkylene-(3- to 7-membered heterocyclyl), wherein (C1-C6)alkyl, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, or (C3-C7)cycloalkyl of -(C1-C6)alkylene-(C3-C7)cycloalkyl is each substituted with 0, 1, 2, or 3 independently selected halogen.

[0051] In some embodiments, the compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, is a compound of Formula (I-H-1), (I-H-2), (I-H-3), (I-H-4), (I-H-5), or (I-H-6), or a pharmaceutically acceptable salt thereof:21 MOFO-358009544Attorney Docket No.: 183952036340substituents each independently selected from the group consisting of halo, oxo, COOH, and -C(O)ORPE; RPais independently (C1-C6)alkyl, halo(C1-C6)alkyl, (C6-C10)aryl, or (C3- C6)cycloalkyl, wherein (C1-C6)alkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo and (C1-C6)alkoxy; each RPEis independently (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylene-(C1-C6)alkoxy, (C3- C6)cycloalkyl, (C5-C8)spirocycloalkyl, -(C1-C6)alkylene-(C6-C10)aryl, -(C1-C6)alkylene-(C1-C6)alkoxy, -(C1-C6)alkylene-(C3-C7)cycloalkyl, 3- to 7-membered heterocyclyl, or -(C1-C6)alkylene-(3- to 7-membered heterocyclyl), wherein (C1-C6)alkyl, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, or (C3-C7)cycloalkyl of -(C1-C6)alkylene-(C3-C7)cycloalkyl is each substituted with 0, 1, 2, or 3 independently selected halogen; each RPaa1is independently H or (C1-C6)alkyl; each RPaa2is independently H or (C1-C6)alkyl; each RPaa3is independently H, (C1-C6)alkyl, -(C1-C6)alkylene-(C1-C6)alkoxy, or -(C1-C6)alkylene-(C6-C10)aryl; or RPaa2and RPaa3, together with the carbon atom to which they are attached form (C3-C6)cycloalkyl; and each RPaa4is independently (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylene-(C1-C6)alkoxy, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, -(C1-C6)alkylene-(C6-C10)aryl, -(C1-C6)alkylene-(C1-C6)alkoxy, -(C1-C6)alkylene-(C3-C7)cycloalkyl, 3- to 7-membered heterocyclyl, or -(C1-C6)alkylene-(3- to 7-membered heterocyclyl), wherein (C1-C6)alkyl, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, or (C3-C7)cycloalkyl of -(C1-C6)alkylene-(C3-C7)cycloalkyl is each substituted with 0, 1, 2, or 3 independently selected halogen. 22 MOFO-358009544Attorney Docket No.: 183952036340

[0052] In some embodiments, R1aand R1bare each independently H or halogen. In some embodiments, R2is H, (C1-C6)alkyl, or (C3-C6)cycloalkyl. In some embodiments, R3is (C1- C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, 3- to 7-membered heterocyclyl, -(C1- C6)alkylene-(C3-C6)cycloalkyl, or -(C1-C6)alkylene-(3- to 7-membered heterocyclyl), wherein (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3-C6)cycloalkyl of -(C1-C6)alkylene-(C3-C6)cycloalkyl, or (3- to 7-membered heterocyclyl) of -(C1-C6)alkylene-(3- to 7-membered heterocyclyl) is each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, cyano, halogen, halo(C1-C6)alkyl, and halo(C1- C6)alkoxy. In some embodiments, R2and R3together with the nitrogen atom to which they are attached form 5- to 7-membered heterocyclyl substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, cyano, halogen, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy. In some embodiments, R4is H, (C6- C10)aryl, or 5- to 10-membered heteroaryl, wherein (C6-C10)aryl or 5- to 10-membered heteroaryl is each substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, and -NR4aR4b, wherein: each R4aand R4bis independently H or (C1- C6)alkyl. In some embodiments, R5 is H, cyano, or (C1-C6)alkoxy. In some embodiments, RPis phosphonic acid, phosphonate, phosphonamidate, or phosphondiamidate.

[0053] In some embodiments, R1ais F. In some embodiments, R1bis H. In some embodiments, R1ais F and R1bis H. In some embodiments, R1aand R1bare each F.

[0054] In some embodiments, R2is methyl or ethyl.

[0055] In some embodiments, R3is (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, 3- to 7-membered heterocyclyl, or -(C1-C6)alkylene-(3- to 7-membered heterocyclyl). In some embodiments, R3is halo(C1-C6) alkyl. In some embodiments, R3is (C3-C6)cycloalkyl substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halogen, cyano, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy. In some embodiments, R3is 3-to 7-membered heterocyclyl. In some embodiments, R3is -(C1- C6)alkylene-[3-to 7-membered heterocyclyl substituted with 0 or 1 (C1-C6)alkyl]. In some embodiments, R3is (C1-C6)alkyl substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of halo, (C1-C6)alkoxy, and halo(C1- 23MOFO-358009544Attorney Docket No.: 183952036340 C6)alkoxy. In some embodiments, R3is, , ,

[0057] In some embodiments, R2and R3together with the nitrogen atom to which they are attached form 6-membered heterocyclyl. 24MOFO-358009544Attorney Docket No.: 183952036340

[0058] In some embodiments, of Formula

[0059] In some embodiments, R4 is H. In some embodiments, R4 is (C6-C10)aryl or 5- to10-membered heteroaryl. In some embodiments, R4 is phenyl substituted with 0, 1, 2, or 3halogen. In some embodiments, R4 is. In some embodiments,some embodiments, R4 is pyridinyl substituted with 0 or 1 -NR4aR4b. In some embodiments,

[0060] In some embodiments, R5 is H. In some embodiments, R5 is cyano. In someembodiments, R5is methoxy.

[0061] In some embodiments, RP is , wherein RP1 and RP2 are eachindependently -OH, -ORPa, N-linked amino acid, N-linked amino acid ester, or Ring A. In some embodiments, Ring A issubstituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo, oxo, COOH, and -C(O)ORPE. Insome embodiments, RPa is independently (C1-C6)alkyl, halo(C1-C6)alkyl, (C6-C10)aryl, or (C3-C6)cycloalkyl, wherein (C1-C6)alkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo and (C1-C6)alkoxy. In some embodiments, each RPEis independently (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylene-(C1- C6)alkoxy, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, -(C1-C6)alkylene-(C6-C10)aryl, -(C1-C6)alkylene-(C1-C6)alkoxy, -(C1-C6)alkylene-(C3-C7)cycloalkyl, 3- to 7-memberedheterocyclyl, or -(C1-C6)alkylene-(3- to 7-membered heterocyclyl), wherein (C1-C6)alkyl, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, or (C3-C7)cycloalkyl of -(C1-C6)alkylene-(C3- C7)cycloalkyl is each substituted with 0, 1, 2, or 3 independently selected halogen. 25 MOFO-358009544Attorney Docket No.: 183952036340

[0062] In some embodiments, RP is, wherein RP1 and RP2 are eachindependently -OH, -ORPa, -NRPaa1CRPaa2RPaa3C(O)OH, -NRPaa1CRPaa2RPaa3C(O)ORPaa4, or Ring A. In some embodiments, Ring A issubstituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo, oxo, COOH, and -C(O)ORPE. In some embodiments, RPais independently (C1-C6)alkyl, halo(C1-C6)alkyl, (C6-C10)aryl, or (C3-C6)cycloalkyl, wherein (C1-C6)alkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo and (C1-C6)alkoxy. In some embodiments, each RPEis independently (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylene- (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, -(C1-C6)alkylene-(C6-C10)aryl, -(C1-C6)alkylene-(C1-C6)alkoxy, -(C1-C6)alkylene-(C3-C7)cycloalkyl, 3- to 7-memberedheterocyclyl, or -(C1-C6)alkylene-(3- to 7-membered heterocyclyl), wherein (C1-C6)alkyl,(C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, or (C3-C7)cycloalkyl of -(C1-C6)alkylene-(C3-C7)cycloalkyl is each substituted with 0, 1, 2, or 3 independently selected halogen. In someembodiments, each RPaa1is independently H or (C1-C6)alkyl. In some embodiments, each RPaa2is independently H or (C1-C6)alkyl, and each RPaa3is independently H, (C1-C6)alkyl, - (C1-C6)alkylene-(C1-C6)alkoxy, or -(C1-C6)alkylene-(C6-C10)aryl; or RPaa2and RPaa3, together with the carbon atom to which they are attached form (C3-C6)cycloalkyl. In some embodiments, each RPaa4is independently (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylene- (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, -(C1-C6)alkylene-(C6-C10)aryl, -(C1-C6)alkylene-(C1-C6)alkoxy, -(C1-C6)alkylene-(C3-C7)cycloalkyl, 3- to 7-memberedheterocyclyl, or -(C1-C6)alkylene-(3- to 7-membered heterocyclyl), wherein (C1-C6)alkyl, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, or (C3-C7)cycloalkyl of -(C1-C6)alkylene-(C3- C7)cycloalkyl is each substituted with 0, 1, 2, or 3 independently selected halogen.

[0063] In some embodiments, RP is, wherein RP1 and RP2 are each -OH.26 MOFO-358009544Attorney Docket No.: 183952036340

[0064] In some embodiments, RPis , wherein RP1is -OH and RP2is N-linked amino acid. In some embodiments, RPis, wherein RP1is -OH and RP2is N-linked amino acid ester.

[0065] In some embodiments, RPis , wherein RP1is -ORPaand RP2is N-linked amino acid ester. In some embodiments, RPais (C1-C6)alkyl, halo(C1-C6)alkyl, (C6-C10)aryl, or (C3-C6)cycloalkyl, wherein (C1-C6)alkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo and (C1-C6)alkoxy.

[0066] In some embodiments, RPis, wherein RP1and RP2are each independently N-linked amino acid.

[0067] In some embodiments, RPis, wherein RP1and RP2are each independently N-linked amino acid ester.

[0068] In some embodiments, RPis, wherein RP1is N-linked amino acid and RP2is Ring A, wherein Ring A issubstituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo, oxo, and -COOH.

[0069] In some embodiments, RPis, wherein RP1is N-linked amino acid ester and RP2is Ring A, wherein Ring A issubstituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo, oxo, and ester. 27MOFO-358009544Attorney Docket No.: 183952036340

[0070] In some embodiments, RPais phenyl. In some embodiments, RPais ethyl. In some embodiments, RPais -CH2CF3. In some embodiments, RPais, , ,, , cyclopropyl, cyclopentyl, or cyclohexyl. In some embodiments, RPacyclopropyl, cyclopentyl, or cyclohexyl.

[0071] In some embodiments,

[0072] In some embodiments, RP2is Ring A, wherein Ring A issubstituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo, oxo, and -C(O)ORPE. In some embodiments, each RPEis independently (C1-C6)alkyl, halo(C1- C6)alkyl, -(C1-C6)alkylene-(C1-C6)alkoxy, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, -(C1- C6)alkylene-(C6-C10)aryl, -(C1-C6)alkylene-(C1-C6)alkoxy, -(C1-C6)alkylene-(C3- C7)cycloalkyl, 3- to 7-membered heterocyclyl, or -(C1-C6)alkylene-(3- to 7-membered heterocyclyl), wherein (C1-C6)alkyl, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, or (C3- C7)cycloalkyl of -(C1-C6)alkylene-(C3-C7)cycloalkyl is each substituted with 0, 1, 2, or 3 independently selected halogen. In some embodiments, each RPEis independently ethyl,28MOFO-358009544Attorney Docket No.: 183952036340

[0074] In some embodiments, each N-linked amino acid is independently N-linked α- amino acid. In some embodiments, each N-linked amino acid ester is independently N-linked α-amino acid ester.

[0075] In some embodiments, each N-linked amino acid is independently - NRPaa1CRPaa2RPaa3C(O)OH. In some embodiments, each N-linked amino acid ester is independently -NRPaa1CRPaa2RPaa3C(O)ORPaa4.

[0076] In some embodiments, each RPaa1is independently H or (C1-C6)alkyl. In some embodiments, each RPaa2is independently H or (C1-C6)alkyl, and each RPaa3is independently H, (C1-C6)alkyl, -(C1-C6)alkylene-(C1-C6)alkoxy, or -(C1-C6)alkylene-(C6-C10)aryl; or RPaa2and RPaa3, together with the carbon atom to which they are attached form (C3-C6)cycloalkyl.

[0077] In some embodiments, RPaa1is H. In some embodiments, RPaa1is methyl.

[0078] In some embodiments, RPaa2is H. In some embodiments, RPaa2is methyl.

[0079] In some embodiments, RPaa3is methyl. In some embodiments, RPaa3is ethyl,

[0080] In some embodiments, RPaa2and RPaa3, together with the carbon atom to which they are attached form cyclopropyl.

[0081] In some embodiments, each RPaa4is independently (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylene-(C1-C6)alkoxy, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, -(C1- C6)alkylene-(C6-C10)aryl, -(C1-C6)alkylene-(C1-C6)alkoxy, -(C1-C6)alkylene-(C3- C7)cycloalkyl, 3- to 7-membered heterocyclyl, or -(C1-C6)alkylene-(3- to 7-membered 29MOFO-358009544Attorney Docket No.: 183952036340 heterocyclyl), wherein (C1-C6)alkyl, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, or (C3- C7)cycloalkyl of -(C1-C6)alkylene-(C3-C7)cycloalkyl is each substituted with 0, 1, 2, or 3 independently selected halogen. In some embodiments, each RPaa4is independently ethyl,

[0082] In some embodiments, provided herein are compounds of Table 1A, Table 1B, Table 1C, and pharmaceutically acceptable salts thereof. See Example 1.

[0083] In one aspect, provided herein is a parent drug. In some embodiments, a prodrug can be metabolized to produce the parent drug. In some embodiments, the prodrug can be metabolized to produce an intermediate metabolite. In some embodiments, the intermediate metabolite can be further metabolized to produce the parent drug. In some embodiments, the prodrug can be metabolized by enzymes such as carboxyesterase and / or phosphoramidase to produce the parent drug. In some embodiments, the prodrug is a ProTide prodrug analog (see, e.g., Mehellou, et al., J. Med. Chem. 61(6) 2211-2226 (2018). In some embodiments, the 30MOFO-358009544Attorney Docket No.: 183952036340 prodrug has an RPselected from those present in molecules described herein in the representative procedures for synthesis of phosphoryl groups of Example 1.

[0084] In some embodiments, the parent drug is the compound of Formula (I-A-1), (I-A- 2), (I-A-3), (I-A-4), (I-A-5), or (I-A-6), or a pharmaceutically acceptable salt thereof. In some embodiments, the parent drug is a compound of Formula (I), wherein RPis , or a pharmaceutically acceptable salt thereof. In some embodiments, the parent drug is a compound selected from the group consisting of the compounds of Table 1A, or a pharmaceutically acceptable salt thereof.

[0085] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a parent drug selected from the group consisting of:31MOFO-358009544Attorney Docket No.: 18395203634032MOFO-358009544Attorney Docket No.: 18395203634033MOFO-358009544Attorney Docket No.: 18395203634034MOFO-358009544Attorney Docket No.: 18395203634035MOFO-358009544Attorney Docket No.: 183952036340and pharmaceutically acceptable salts thereof.

[0086] In some embodiments, the prodrug is a compound of Formula (I), wherein RPis , wherein RP1and RP2are each independently -ORPa, or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments, the prodrug is the compound of Formula (I-C-1), (I-C-2), (I-C-3), (I-C-4), (I-C-5), or (I-C-6), or a pharmaceutically acceptable salt thereof. In some embodiments, the prodrug is a compound of Formula (I), wherein RPis, wherein RP1is -ORPaand RP2is N-linked amino acid ester, or a pharmaceutically acceptable salt thereof. In some embodiments, the intermediate metabolite of the prodrug is the compound of Formula (I-B-1), (I-B-2), (I-B-3), (I-B-4), (I-B-5), or (I-B-6), or a pharmaceutically acceptable salt thereof. In some embodiments, the intermediate metabolite of the prodrug is a compound of Formula (I), wherein RPis , wherein RP1is -OH and RP2is N-linked amino acid, or a pharmaceutically acceptable salt thereof. In some embodiments, the intermediate metabolite is a compound of formula (I), wherein RPis, wherein RP1issome embodiments, the intermediate metabolite is a compound of formula (I), wherein RPis, wherein RP1is -OH, and RP2is 36MOFO-358009544Attorney Docket No.: 183952036340. In some embodiments, the intermediate metabolite is a compound of formula (I), wherein RPis

[0088] In some embodiments, the prodrug is the compound of Formula (I-E-1), (I-E-2), (I-E-3), (I-E-4), (I-E-5), or (I-E-6), or a pharmaceutically acceptable salt thereof. In some embodiments, the prodrug is a compound of Formula (I), wherein RPis, wherein RP1and RP2are each independently N-linked amino acid ester, or a pharmaceutically acceptable salt thereof. In some embodiments, the intermediate metabolite of the prodrug is the compound of Formula (I-D-1), (I-D-2), (I-D-3), (I-D-4), (I-D-5), or (I-D-6), or a pharmaceutically acceptable salt thereof. In some embodiments, the intermediate metabolite of the prodrug is a compound of Formula (I), wherein RPis, wherein RP1and RP2are each independently N-linked amino acid, or a pharmaceutically acceptable salt thereof.

[0089] In some embodiments, the prodrug is the compound of Formula (I-G-1), (I-G-2), (I-G-3), (I-G-4), (I-G-5), or (I-G-6), or a pharmaceutically acceptable salt thereof, wherein Ring A is substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo, oxo, and ester. In some embodiments, the prodrug is a compound of Formula (I), wherein RPis, wherein RP1is N-linked amino acid ester and RP2is Ring A, wherein Ring A issubstituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo, oxo, and ester, or a pharmaceutically acceptable salt thereof. In some embodiments, the intermediate metabolite of the prodrug is the compound of Formula (I-F-1), (I-F-2), (I-F-3), (I-F-4), (I-F-5), or (I-F- 6), or a pharmaceutically acceptable salt thereof, wherein Ring A is substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo, oxo, and - COOH. In some embodiments, the intermediate metabolite of the prodrug is a compound of 37MOFO-358009544Attorney Docket No.: 183952036340 Formula (I), wherein RPis, wherein RP1is N-linked amino acid and RP2is Ring A, wherein Ring A issubstituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo, oxo, and -COOH, or a pharmaceutically acceptable salt thereof.

[0090] In some embodiments, the prodrug is a compound selected from the group consisting of the compounds of Table 1C, or a pharmaceutically acceptable salt thereof. In some embodiments, the intermediate metabolite is a compound selected from the group consisting of the compounds of Table 1B, or a pharmaceutically acceptable salt thereof.

[0091] In some embodiments, the intermediate metabolite is a compound of formula (I), wherein RPis, wherein RP1is -OH, and RP2is N-linked amino acid ester. In some embodiments, the intermediate metabolite is a compound of formula (I), wherein RPissome embodiments, the intermediate metabolite is a compound of formula (I), wherein RPis , wherein RP1issome embodiments, the intermediate metabolite is a compound of formula (I), wherein RPis. In some embodiments, the intermediate metabolite 38MOFO-358009544Attorney Docket No.: 183952036340 is a compound of formula (I), wherein RPis , wherein RP1is -OH, RP2iscompound of formula (I), wherein RPis

[0092] In some embodiments, the compound of Formula (I), or a pharmaceutically acceptable salt thereof, is a compound of Formula (I-J-1), (I-J-2), (I-J-3), (I-J-4), (I-J-5), or (I- J-6), or a pharmaceutically acceptable salt thereof:39MOFO-358009544Attorney Docket No.: 183952036340wherein RPaa2is H or (C1-C6)alkyl; and RPaa3is H, (C1-C6)alkyl, -(C1-C6)alkylene-(C1- C6)alkoxy, or -(C1-C6)alkylene-(C6-C10)aryl; or RPaa2and RPaa3, together with the carbon atom to which they are attached form (C3-C6)cycloalkyl; and RPaa4is (C1-C6)alkyl.

[0093] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is an intermediate metabolite selected from the group consisting of:40MOFO-358009544Attorney Docket No.: 18395203634041MOFO-358009544Attorney Docket No.: 183952036340and pharmaceutically acceptable salts thereof.

[0094] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is a prodrug selected from the group consisting of: 42MOFO-358009544Attorney Docket No.: 18395203634043MOFO-358009544Attorney Docket No.: 18395203634044MOFO-358009544Attorney Docket No.: 18395203634045MOFO-358009544Attorney Docket No.: 18395203634046MOFO-358009544Attorney Docket No.: 18395203634047MOFO-358009544Attorney Docket No.: 18395203634048MOFO-358009544Attorney Docket No.: 18395203634049MOFO-358009544Attorney Docket No.: 18395203634050MOFO-358009544Attorney Docket No.: 18395203634051MOFO-358009544Attorney Docket No.: 18395203634052MOFO-358009544Attorney Docket No.: 18395203634053MOFO-358009544Attorney Docket No.: 18395203634054MOFO-358009544Attorney Docket No.: 18395203634055MOFO-358009544Attorney Docket No.: 183952036340and pharmaceutically acceptable salts thereof.

[0095] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of parent drugs A3, A4, A5, A6, A7, A8, A11, A13, A14, A18, A19, A20, A21, A22, A23, A25, A30, A32, A33, A35, A36, A37, A38, A40, A42, A43, A44, A47, A48, A49, A50, A52, A53, A55, A57, A58, A59, A60, A61, and A65, and pharmaceutically acceptable salts thereof. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of compounds A3, A4, A5, A6, A7, A8, A11, A13, A14, A18, A19, A20, A21, A22, A23, A25, A30, A32, A33, A35, A36, A37, A38, A40, A42, A43, A44, A47, A48, A49, A50, A52, A53, A55, A57, A58, A59, A60, A61, and A65, prodrugs or intermediate metabolites thereof, and pharmaceutically acceptable salts of any of the foregoing.

[0096] In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of prodrugs C4, C5, C6, C7, C8, C10, C13, C17, C19, C23, C25, C53, C54, C61, C63, C64, C65, C66, C68, C70, C71, C73, C74, C75, C82, C83, C84, C89, C90, C91, C92, C93, C94, C96, C97, C96, C97, C102, C103, C015, C016, C017, C110, C111, C114, C116, C118, C121, C122, C123, C124, C125, C126, C127, C132, C133, C135, C136, C137, C140, C141, C143, C144, C148, C155, C156, C160, C162, 56MOFO-358009544Attorney Docket No.: 183952036340 C170, C173, C175, C176, C177, C180, C182, C185, C186, C188, C189, C194, C195, C197, C198, C205, C208, and C209, and pharmaceutically acceptable salts thereof.

[0097] Any variation or embodiment of R1a, R1b, R2, R3, R4, R4a, R4b, R5, RP, RP1, RP2, RPa, RPE, RPaa1, RPaa2, RPaa3, RPaa4, or Ring A provided herein can be combined with every other variation or embodiment of R1a, R1b, R2, R3, R4, R4a, R4b, R5, RP, RP1, RP2, RPa, RPE, RPaa1, RPaa2, RPaa3, RPaa4, or Ring A the same as if each and every combination had been individually and specifically described.

[0098] As used herein, when any variable occurs more than one time in a chemical formula, its definition on each occurrence is independent of its definition at every other occurrence. Methods of synthesis

[0099] Compounds of Formula (I), and those described herein may be prepared in various ways as generally described below and more specifically in the Examples hereinafter (such as the schemes provided in the Examples below). General synthetic routes to compounds of Formula (I), and some examples of starting materials used to synthesize compounds of Formula (I) are shown and described herein. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims.

[0100] Certain stereochemical centers have been left unspecified and certain substituents have been eliminated in the following schemes for the sake of clarity and are not intended to limit the teaching of the schemes in any way. Furthermore, individual isomers, enantiomers, and diastereomers may be separated or resolved by one of ordinary skill in the art at any convenient point in the synthesis of compounds of the invention, by methods such as selective crystallization techniques or chiral chromatography (See for example, J. Jacques, et al., "Enantiomers, Racemates, and Resolutions", John Wiley and Sons, Inc., 1981, and E.L. Eliel and S.H. Wilen,” Stereochemistry of Organic Compounds”, Wiley-Interscience, 1994). 57MOFO-358009544Attorney Docket No.: 183952036340

[0101] Compounds of Formula (I), (I-A-1), (I-A-2), (I-A-3), (I-A-4), (I-A-5), (I-A-6), (I- B-1), (I-B-2), (I-B-3), (I-B-4), (I-B-5), (I-B-6), (I-C-1), (I-C-2), (I-C-3), (I-C-4), (I-C-5), (I- C-6), (I-D-1), (I-D-2), (I-D-3), (I-D-4), (I-D-5), (I-D-6), (I-E-1), (I-E-2), (I-E-3), (I-E-4), (I- E-5), (I-E-6), (I-F-1), (I-F-2), (I-F-3), (I-F-4), (I-F-5), (I-F-6), (I-G-1), (I-G-2), (I-G-3), (I-G- 4), (I-G-5), (I-G-6), (I-H-1), (I-H-2), (I-H-3), (I-H-4), (I-H-5), (I-H-6), (I-J-1), (I-J-2), (I-J-3), (I-J-4), (I-J-5), or (I-J-6) can be prepared according to Scheme A, Scheme B, Scheme C, Scheme D, Scheme E, or Scheme F, wherein the R1a, R1b, R2, R3, R4, R4a, R4b, R5, RP, RPa, RPaa2, RPaa3, and RPaa4, are as defined for Formula (I) or any applicable variations thereof as detailed herein.

[0102] Methods for preparing compound (A) or a salt of thereof, are shown herein, as shown in Scheme A. The method of preparing compound (A) can be applied to prepare the starting material for Schemes B-F. Scheme A

[0103] In one aspect, provided herein is a method of preparing a compound of formulasalt thereof, comprising contacting a compound of 58MOFO-358009544Attorney Docket No.: 183952036340 formulasalt thereof, with a compound of formula (b),salt thereof, in the presence of a coupling reagent and an aliphatic amine. In some embodiments, the coupling reagent comprises O-(7-Azabenzotriazol-1-yl)- N,N,N’,N’-tetramethyluronium hexafluorophosphate (HATU). In some embodiments, the aliphatic amine comprises triethylamine. In some embodiments, the contacting of the compound of formula (d) or a salt thereof with a compound of formula (b) or a salt thereof is carried out at a temperature between about 20 °C and about 30 °C. In some embodiments, the contacting of the compound of formula (d) or a salt thereof with a compound of formula (b) or a salt thereof is carried out at a temperature between about 20 °C and about 25 °C. In some embodiments, the contacting of the compound of formula (d) or a salt thereof with a compound of formula (b) or a salt thereof is carried out at a temperature of about 25 °C. In some embodiments, the contacting of the compound of formula (d) or a salt thereof with a compound of formula (b) or a salt thereof is carried out for about one hour to five hours. In some embodiments, the contacting of the compound of formula (d) or a salt thereof with a compound of formula (b) or a salt thereof is carried out for about one hour to three hours. In some embodiments, the contacting of the compound of formula (d) or a salt thereof with a compound of formula (b) or a salt thereof is carried out for about two hours.

[0104] In some embodiments, the compound of Formula (d) or a salt thereof is prepared by contacting a compound of Formulasalt thereof, with a strong base in the presence of a polar aprotic solvent. In some embodiments, the strong base comprises a metal hydroxide. In some embodiments, the strong base comprises LiOH·H2O. In some embodiments, the polar aprotic solvent comprises tetrahydrofuran. In some embodiments, the contacting of the compound of Formula (c) or a salt thereof with a strong base in the presence of a polar aprotic solvent is carried out at a temperature between about 59MOFO-358009544Attorney Docket No.: 183952036340 10 °C and 30 °C. In some embodiments, the contacting of the compound of Formula (c) or a salt thereof with a strong base in the presence of a polar aprotic solvent is carried out at a temperature between about 15 °C and 25 °C. In some embodiments, the contacting of the compound of Formula (c) or a salt thereof with a strong base in the presence of a polar aprotic solvent is carried out at a temperature of about 20 °C. In some embodiments, the contacting of the compound of Formula (c) or a salt thereof with a strong base in the presence of a polar aprotic solvent is carried out for about one hour to five hours. In some embodiments, the contacting of the compound of Formula (c) or a salt thereof with a strong base in the presence of a polar aprotic solvent is carried out for about one hour to three hours. In some embodiments, the contacting of the compound of Formula (c) or a salt thereof with a strong base in the presence of a polar aprotic solvent is carried out for about two hours.

[0105] In one aspect, provided herein is a method of preparing a compound of formula thereof, comprising contacting a compound of Formula (a),salt thereof with a strong organic acid. In some embodiments, the strong organic acid comprises trifluoroacetic acid. In some embodiments, the contacting of the compound of Formula (a) or a salt thereof is carried out at a temperature between about 20 °C and about 30 °C. In some embodiments, the contacting of the compound of Formula (a) or a salt thereof is carried out at a temperature between about 20 °C and about 25 °C. In some embodiments, the contacting of the compound of Formula (a) or a salt thereof is carried out at a temperature of about 25 °C. In some embodiments, the contacting of the compound of Formula (a) or a salt thereof is carried out for about one hour to five hours. In some embodiments, the contacting of the compound of Formula (a) or a salt thereof is carried out for about one hour to three hours. In some embodiments, the contacting of the compound of Formula (a) or a salt thereof is carried out for about two hours.

[0106] Methods for preparing compound (D) or a salt of thereof, are shown herein, as shown in Scheme B. The method of preparing compound (D) can be applied to prepare the starting material for Schemes C-F. 60MOFO-358009544Attorney Docket No.: 183952036340 Scheme B.

[0107] In some embodiments, the compound of Formula (D) or a salt thereof is preparedby contacting a compound of Formulawith a strong organic acid and a polar aprotic solvent. In some embodiments, the strong organic acid comprises trifluoroacetic acid. In some embodiments, the polar aprotic solvent comprises dichloromethane. In some embodiments, the contacting of the compound of Formula (C) or a salt thereof is carried out at a temperature between about 20 °C and about 30 °C. In some embodiments, the contacting of the compound of Formula (C) or a salt thereof is carried out at a temperature between about 20 °C and about 25 °C. In some embodiments, the contacting of the compound of Formula (C) or a salt thereof is carried out at a temperature of about 25 °C. In some embodiments, the contacting of the compound of Formula (C) or a salt thereof is carried out for about 30 minutes to two hours. In some 61MOFO-358009544Attorney Docket No.: 183952036340 embodiments, the contacting of the compound of Formula (C) or a salt thereof is carried out for about one hour to two hours. In some embodiments, the contacting of the compound of Formula (C) or a salt thereof is carried out for about one hour.

[0108] In some embodiments, the compound of Formula (C) or a salt thereof is prepared by contacting a compound of Formulasalt thereof, with R2-C(O)H and one or more polar protic solvents. In some embodiments, the polar protic solvents comprise methanol or sodium borohydride, or both. In some embodiments, the contacting of the compound of Formula (B) or a salt thereof is carried out at a temperature between about 20 °C and about 30 °C. In some embodiments, the contacting of the compound of Formula (B) or a salt thereof is carried out at a temperature between about 20 °C and about 25 °C. In some embodiments, the contacting of the compound of Formula (B) or a salt thereof is carried out at a temperature of about 25 °C.

[0109] In some embodiments, the compound of Formula (B) or a salt thereof is preparedby contacting a compound of Formulasalt thereof,with R3-NH2. In some embodiments, the contacting of the compound of Formula (A) or a salt thereof with R3-NH2 is carried out in the presence of a catalyst, a polar protic solvent, and a mild reducing agent. In some embodiments, the catalyst is a metal halide. In some embodiments, the catalyst comprises zinc chloride. In some embodiments, the polar protic solvent comprises methanol. In some embodiments, the mild reducing agent comprises sodium cyanoborohydride. In some embodiments, the contacting of the compound of Formula (A) or a salt thereof with R3-NH2is carried out at a temperature between about 40 °C and about 60 °C. In some embodiments, the contacting of the compound of Formula (A) 62MOFO-358009544Attorney Docket No.: 183952036340 or a salt thereof with R3-NH2is carried out at a temperature between about 50 °C and about 60 °C. In some embodiments, the contacting of the compound of Formula (A) or a salt thereof with R3-NH2 is carried out at a temperature of about 55 °C. to 15 hours. In some embodiments, the contacting of the compound of Formula (A) or a salt thereof with R3-NH2is carried out for about 11 to 14 hours. In some embodiments, the contacting of the compound of Formula (A) or a salt thereof with R3-NH2 is carried out for about 12 hours.

[0110] Methods for preparing a parent compound, intermediate metabolite, or a prodrug, or a salt of any of the foregoing are shown herein, as shown in Scheme C. Scheme C.

[0111] In one aspect, provided herein is a method of preparing a compound of formulasalt thereof, comprising contacting a 63MOFO-358009544Attorney Docket No.: 183952036340compound of Formulasalt thereof with a compound ofFormulasalt thereof. PFP is perfluorophenyl. In some embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (E) or a salt thereof is carried out in the presence of a polar aprotic solvent and an aliphatic amine. In some embodiments, the polar aprotic solvent comprises dimethylformamide. In some embodiments, the aliphatic amine comprises triethylamine. In some embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (E) or a salt thereof is carried out at a temperature between about 20 °C and about 30 °C. In some embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (E) or a salt thereof is carried out at a temperature between about 20 °C and about 25 °C. In some embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (E) or a salt thereof is carried out at a temperature of about 25 °C. In some embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (E) or a salt thereof is carried out for about 30 minutes to two hours. In some embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (E) or a salt thereof is carried out for about one hour to two hours. In some embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (E) or a salt thereof is carried out for about one hour.

[0112] Methods for preparing a parent compound or a salt thereof are shown herein, as shown in Scheme D. 64MOFO-358009544Attorney Docket No.: 183952036340 Scheme D.

[0113] In one aspect, provided herein is a method of preparing a parent compound of formulasalt thereof, comprisingcontacting a compound of Formulasalt thereof with acompound of Formulasalt thereof. In some embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (F) or a salt thereof is carried out in the presence of a polar aprotic 65MOFO-358009544Attorney Docket No.: 183952036340 solvent and an aliphatic amine. In some embodiments, the polar aprotic solvent comprises dimethylformamide. In some embodiments, the aliphatic amine comprises triethylamine. In some embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (F) or a salt thereof is carried out at a temperature between about 20 °C and about 30 °C. In some embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (F) or a salt thereof is carried out at a temperature between about 20 °C and about 25 °C. In some embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (F) or a salt thereof is carried out at a temperature of about 25 °C. In some embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (F) or a salt thereof is carried out for about 30 minutes to two hours. In some embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (F) or a salt thereof is carried out for about one hour to two hours. In some embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (F) or a salt thereof is carried out for about one hour.

[0114] Methods for preparing a prodrug or intermediate metabolite or a salt thereof are shown herein, as shown in Scheme E. 66MOFO-358009544Attorney Docket No.: 183952036340 Scheme E.

[0115] In some embodiments, provided herein is a method of preparing a prodrug of the formulasalt thereof, comprising 67MOFO-358009544Attorney Docket No.: 183952036340embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (J) or a salt thereof is carried out in the presence of a polar aprotic solvent and an aliphatic amine. In some embodiments, the polar aprotic solvent comprises dimethylformamide. In some embodiments, the aliphatic amine comprises triethylamine. In some embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (J) or a salt thereof is carried out at a temperature between about 20 °C and about 30 °C. In some embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (J) or a salt thereof is carried out at a temperature between about 20 °C and about 25 °C. In some embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (J) or a salt thereof is carried out at a temperature of about 25 °C. In some embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (J) or a salt thereof is carried out for about 30 minutes to two hours. In some embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (J) or a salt thereof is carried out for about one hour to two hours. In some embodiments, the contacting of the compound of Formula (D) or a salt thereof with the compound of Formula (F) or a salt thereof is carried out for about one hour.

[0116] Methods for preparing an intermediate metabolite or a salt thereof are shown herein, as shown in Scheme F. 68MOFO-358009544Attorney Docket No.: 183952036340 Scheme F.

[0117] In some embodiments, provided herein is a method of preparing an intermediate metabolite of the formulasalt thereof, comprising contacting a compound of Formula (I-C-1),salt thereof, with a strong base in 69MOFO-358009544Attorney Docket No.: 183952036340 the presence of a polar aprotic solvent. In some embodiments, the strong base comprises a metal hydroxide. In some embodiments, the strong base comprises LiOH·H2O. In some embodiments, the polar aprotic solvent comprises tetrahydrofuran. In some embodiments, the contacting of the compound of Formula (I-C-1) or a salt thereof with a strong base in the presence of a polar aprotic solvent is carried out at a temperature between about 10 °C and 30 °C. In some embodiments, the contacting of the compound of Formula (I-C-1) or a salt thereof with a strong base in the presence of a polar aprotic solvent is carried out at a temperature between about 15 °C and 25 °C. In some embodiments, the contacting of the compound of Formula (I-C-1) or a salt thereof with a strong base in the presence of a polar aprotic solvent is carried out at a temperature of about 20 °C. In some embodiments, the contacting of the compound of Formula (I-C-1) or a salt thereof with a strong base in the presence of a polar aprotic solvent is carried out for about one hour to five hours. In some embodiments, the contacting of the compound of Formula (I-C-1) or a salt thereof with a strong base in the presence of a polar aprotic solvent is carried out for about one hour to three hours. In some embodiments, the contacting of the compound of Formula (I-C-1) or a salt thereof with a strong base in the presence of a polar aprotic solvent is carried out for about two hours. Uses, formulation, and administration

[0118] In one aspect, provided herein is a pharmaceutical composition comprising a compound of Formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, as an active ingredient. Such a pharmaceutical composition comprises a therapeutically effective amount of at least one compound of Formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. One or more pharmaceutically acceptable excipient is selected, in accordance with the pharmaceutical form and method of administration desired, from customary excipients. For examples of such excipients, see Remington’s Pharmaceutical Sciences (20th ed., Mack Publishing Co. 2000).

[0119] In certain aspects, a pharmaceutical composition described herein is formulated for administration to a patient in need of such composition. Pharmaceutical compositions described herein may be administered orally, topically, transdermally, by inhalation, nasally, or buccally, or parenterally. In some embodiments, the pharmaceutical composition is administered orally. Appropriate unit administration forms include oral forms such as tablets, 70MOFO-358009544Attorney Docket No.: 183952036340 soft or hard capsules, powders, granules, and oral solutions or suspensions; forms for inhalative administration such as an inhaler spray; and forms for topical administration, such as creams, gels, ointments, and lotions.

[0120] A specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, and the judgment of the treating physician and the severity of the particular disease being treated. The amount of a compound described herein in the composition will also depend upon the particular compound in the pharmaceutical composition.

[0121] In one aspect, provided herein are methods of treating a disease or condition in a subject in need thereof. In some embodiments, the method comprises administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to the subject in need thereof a therapeutically effective amount of a parent drug described herein. In some embodiments, the method comprises administering to the subject in need thereof a therapeutically effective amount of an intermediate metabolite described herein. In some embodiments, the method comprises administering to the subject in need thereof a therapeutically effective amount of a prodrug described herein. In some embodiments, the disease or condition is responsive to the modulation (e.g., inhibition) of STAT6.

[0122] In one aspect, provided is a method of administering a parent drug compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject, wherein the method comprises administering to the subject a prodrug, or a pharmaceutically acceptable salt thereof, of the parent drug compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the prodrug once administered to the subject is metabolized in the subject to the parent drug compound of Formula (I). In some embodiments, the prodrug once administered to the subject is first metabolized to an intermediate metabolite and subsequently to the parent drug compound of Formula (I). In some embodiments, the parent drug compound of Formula (I) is a compound selected from the groups consisting of the compounds in Table 1A, or a pharmaceutically acceptable salt thereof. In some embodiments, the prodrug is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, e.g., a compound selected from the group consisting of the compounds in Table 1C, or a 71MOFO-358009544Attorney Docket No.: 183952036340 pharmaceutically acceptable salt thereof. In some embodiments, the intermediate metabolite is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, e.g., a compound selected from the group consisting of the compounds in Table 1B, or a pharmaceutically acceptable salt thereof.

[0123] In one aspect, provided is a method of administering an intermediate metabolite compound of Formula (I), or a pharmaceutically acceptable salt thereof, to a subject, wherein the method comprises administering to the subject a prodrug, or a pharmaceutically acceptable salt thereof, of the intermediate metabolite compound of Formula (I), or a pharmaceutically acceptable salt thereof. In some embodiments, the prodrug once administered to a subject is metabolized in the subject to the intermediate metabolite of Formula (I). In some embodiments the intermediate metabolite compound of Formula (I) is a compound selected from the groups consisting of the compounds in Table 1B, or a pharmaceutically acceptable salt thereof. In some embodiments the prodrug is a compound of Formula (I), or a pharmaceutically acceptable salt thereof, e.g., a compound selected from the group consisting of the compounds in Table 1C, or a pharmaceutically acceptable salt thereof.

[0124] In some embodiments, a compound of Formula (I) is selective for inhibition of STAT6 vs. STAT1, STAT2, STAT3, STAT4, STAT5a, and / or STAT5b. In some embodiments, a compound of Formula (I) is at least about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1250, 1500, 1750, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 6000, 7000, 8000, 9000, or 10000 times selective for STAT6 vs. STAT1, STAT3, and / or STAT4. In some embodiments, a compound of Formula (I) is at least about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1250, 1500, 1750, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 6000, 7000, 8000, 9000, or 10000 times selective for STAT6 vs. STAT1, STAT2, STAT3, and / or STAT4. In some embodiments, a compound of Formula (I) is at least about 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1250, 1500, 1750, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 6000, 7000, 8000, 9000, or 10000 times selective for STAT6 vs. STAT1, STAT2, STAT3, STAT4, STAT5a, and / or STAT5b.

[0125] In some embodiments, a compound of Formula (I) inhibits IL-4 and / or IL-13 induced expression of thymus- and activation-regulated chemokine (TARC) (also known as, CC chemokine ligand 17 (CCL17)). In some embodiments, a compound of Formula (I) inhibits IL-4 and / or IL-13 induced expression of TARC in human peripheral blood 72MOFO-358009544Attorney Docket No.: 183952036340 mononuclear cells (PBMCs). In some embodiments, the IC50for inhibition of IL-4 and / or IL- 13 induced TARC expression (e.g., in human PBMCs) is less than or equal to about 500 nM, about 100 nM, about 50 nM, about 10 nM, about 5 nM, or about 1 nM.

[0126] In some embodiments, a compound of Formula (I) inhibits IL-4 induced expression of CD23 (also known as, Fc epsilon RII (FcεRII)). In some embodiments, a compound of Formula (I) inhibits IL-4 induced expression of CD23 in human PBMCs. In some embodiments, the IC50 for inhibition of IL-4 induced CD23 expression (e.g., in human PBMCs) is less than or equal to about 500 nM, about 100 nM, about 50 nM, about 10 nM, about 5 nM, or about 1 nM.

[0127] In some embodiments, a compound of Formula (I) inhibits T helper 2 (Th2) cell function. In some embodiments, the IC50for inhibition of Th2 cell function is less than or equal to about 500 nM, about 100 nM, about 50 nM, about 10 nM, about 5 nM, or about 1 nM. In some embodiments, inhibition of Th2 cell function is measured based on change in expression of IL-5. In some embodiments, a compound of Formula (I) inhibits T helper 2 (Th2) cell function selectively compared to inhibition of other T cell functions, for example, T cell activation, Th helper 1 (Th1) cell function, and / or T helper 17 (Th17) cell function. In some embodiments, the inhibition of Th2 cell function relative to inhibition of T cell activation is greater than or equal to about 30x, about 50x, about 100x, about 300x, about 500x, or about 1000x. In some embodiments, inhibition of T cell activation is measured based on change in expression of CD25. In some embodiments, the inhibition of Th2 cell function relative to inhibition of Th1 cell function is greater than or equal to about 30x, about 50x, about 100x, about 300x, about 500x, or about 1000x. In some embodiments, inhibition of Th1 cell function is measured based on change in expression of IFNγ. In some embodiments, the inhibition of Th2 cell function relative to inhibition of Th17 cell function is greater than or equal to about 30x, about 50x, about 100x, about 300x, about 500x, or about 1000x. In some embodiments, inhibition of Th1 cell function is measured based on change in expression of IL-17A. In some embodiments, a compound of Formula (I) inhibits T helper 2 (Th2) cell function selectively compared to modulation of hematologic homeostasis, for example inhibition of erythropoietin(EPO)-induced STAT5-driven transcription and / or thrombopoietin(TPO)-induced STAT5-driven transcription. In some embodiments, the inhibition of Th2 cell function relative to inhibition of EPO induced STAT5-driven transcription is greater than or equal to about 30x, about 50x, about 100x, about 300x, about 73MOFO-358009544Attorney Docket No.: 183952036340 500x, or about 1000x. In some embodiments, the inhibition of Th2 cell function relative to inhibition of TPO induced STAT5-driven transcription is greater than or equal to about 30x, about 50x, about 100x, about 300x, about 500x, or about 1000x.

[0128] In some embodiments, oral administration (e.g., P.O. in dogs) of a prodrug compound of Formula (I) provides durable bioavailability of the corresponding parent drug compound of Formula (I). In some embodiments, the oral administration (e.g., P.O. in dogs) of the prodrug compound of Formula (I) enables durable bioavailability of the parent drug in PBMCs. In some embodiments, the bioavailability is characterized by an effective concentration (e.g., in PBMCs) of the parent drug about 2 hours, about 6 hours, about 12 hours, or about 24 hours after dosing of the prodrug. In some embodiments, the bioavailability is characterized by an effective concentration (e.g., in PBMCs) of the parent drug averaged over about 6 hours, about 12 hours, or about 24 hours after dosing of the prodrug. In some embodiments the effective concentration (e.g., in PBMCs) is at least about 50 ng / mL, at least about 100 ng / mL, at least about 200 ng / mL, at least about 300 ng / mL, at least about 400 ng / mL, at least about 500 ng / mL, at least about 600 ng / mL, at least about 700 ng / mL, at least about 800 ng / mL, at least about 900 ng / mL, or at least about 1000 ng / mL. In some embodiments, the bioavailability is characterized by an area under the curve (AUC) of cellular concentration (e.g., ng / mL in PBMCs) over about 2 hours, about 6 hours, about 12 hours, or about 24 hours after dosing of the prodrug. In some embodiments, the AUC over 24 hours post-dosing is at least about 1200 ng*h / mL, at least about 2400 ng*h / mL, at least about 4800 ng*h / mL, at least about 7200 ng*h / mL, at least about 9600 ng*h / mL, at least about 12000 ng*h / mL, at least about 14400 ng*h / mL, at least about 16800 ng*h / mL, at least about 19200 ng*h / mL, or at least about 21600 ng*h / mL, at least about 24000 ng*h / mL.

[0129] In some embodiments, oral administration (e.g., P.O. in dogs) of a prodrug compound of Formula (I) the method enables durable and / or selective inhibition of pSTAT6. In some embodiments, the oral administration of a prodrug compound of Formula (I) enables therapeutically effective inhibition of pSTAT6. In some embodiments, therapeutically effective inhibition of pSTAT6 is characterized by the percentage of pSTAT6-positive cells (e.g., in whole blood, PBMCs, myeloid cells, lymphocytes) following oral administration compared to predose control. In some embodiments, the maximum percentage of pSTAT6- positive cells (e.g., in whole blood, PBMCs, myeloid cells, lymphocytes) compared to predose control following initial dose response is less than about 90%, is less than about 74MOFO-358009544Attorney Docket No.: 183952036340 80%, is less than about 70%, is less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, or less than about 10%. In some embodiments, a prodrug compound of Formula (I) inhibits pSTAT6 (e.g., depletes the percentage of pSTAT6-positive cells compared to predose control to less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, or less than about 10%) with dosing twice per day (e.g., P.O., BID in dogs). In some embodiments, a prodrug compound of Formula (I) inhibits pSTAT6 (e.g., depletes the percentage of pSTAT6-positive cells compared to predose control to less than about 90%, less than about 80%, less than about 70%, less than about 60%, less than about 50%, less than about 40%, less than about 30%, less than about 20%, or less than about 10%) with dosing once per day (e.g., P.O., QD in dogs).

[0130] In one aspect, provided herein is a method of treating a disease or condition responsive to the modulation (e.g., inhibition) of STAT6 in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof.

[0131] Also provided is the use of a compound of Formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament. Also provided is the use of a compound of Formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a disease or condition responsive to the modulation (e.g., inhibition) of STAT6. Also provided is a compound of Formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, for use as a drug. Also provided is a compound of Formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, for use in treating a disease or condition 75MOFO-358009544Attorney Docket No.: 183952036340 responsive to the modulation (e.g., inhibition) of STAT6. In some embodiments, the compound is selected from the group consisting of the parent drugs in Table 1A, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group consisting of the parent drugs in Table 1A, or a prodrug or intermediate metabolite thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is selected from the group consisting of the prodrugs in Table 1C, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of parent drugs A3, A4, A5, A6, A7, A8, A11, A13, A14, A18, A19, A20, A21, A22, A23, A25, A30, A32, A33, A35, A36, A37, A38, A40, A42, A43, A44, A47, A48, A49, A50, A52, A53, A55, A57, A58, A59, A60, A61, A65, and pharmaceutically acceptable salts thereof. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of compounds A3, A4, A5, A6, A7, A8, A11, A13, A14, A18, A19, A20, A21, A22, A23, A25, A30, A32, A33, A35, A36, A37, A38, A40, A42, A43, A44, A47, A48, A49, A50, A52, A53, A55, A57, A58, A59, A60, A61, and A65, prodrugs or intermediate metabolites thereof, and pharmaceutically acceptable salts of any of the foregoing. In some embodiments, the compound, or a pharmaceutically acceptable salt thereof, is selected from the group consisting of prodrugs C4, C5, C6, C7, C8, C10, C13, C17, C19, C23, C25, C53, C54, C61, C63, C64, C65, C66, C68, C70, C71, C73, C74, C75, C82, C83, C84, C89, C90, C91, C92, C93, C94, C96, C97, C96, C97, C102, C103, C015, C016, C017, C110, C111, C114, C116, C118, C121, C122, C123, C124, C125, C126, C127, C132, C133, C135, C136, C137, C140, C141, C143, C144, C148, C155, C156, C160, C162, C170, C173, C175, C176, C177, C180, C182, C185, C186, C188, C189, C194, C195, C197, C198, C205, C208, and C209, and pharmaceutically acceptable salts thereof.

[0132] In one aspect, the disease or condition responsive to the modulation (e.g., inhibition) of STAT6 is selected from the group consisting of an inflammatory disorder, autoimmune disorder, an allergic disorder, and a skin disorder. In some embodiments, the disease or condition is associated with T helper type 2 (Th2) inflammation. In some embodiments, the disease or condition is selected from the group consisting of atopic dermatitis, prurigo nodularis, asthma, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, and chronic obstructive pulmonary disease. 76MOFO-358009544Attorney Docket No.: 183952036340

[0133] In another aspect, provided herein is a method of modulating the activity of STAT6, comprising contacting a biological sample with or administering to a subject in need thereof a compound of Formula (I) or a prodrug thereof, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula (I) or a prodrug compound thereof, or a pharmaceutically acceptable salt thereof. In some embodiments, the method inhibits the activity of STAT6. In some embodiments, the method inhibits the activity of phospho-STAT6 (pSTAT6). In some embodiments, the method inhibits the activity of STAT6 and pSTAT6. In some embodiments, the method inhibits the phosphorylation of STAT6 to pSTAT6, for example by a JAK protein (e.g., JAK1). In some embodiments, the method inhibits the dimerization of pSTAT6. In some embodiments, the method inhibits the translocation of pSTAT6 into the nucleus. EXAMPLES

[0134] The presently disclosed subject matter will be better understood by reference to the following Examples, which are provided as exemplary of the invention, and not by way of limitation.

[0135] Abbreviations used in the Examples include the following: ACN, MeCN – acetonitrile AIBN – Azobisisobutyronitrile AcOH – acetic acid BSA – Bovine serum albumin CMPI – 2-chloro-1-methylpyridinium iodide CST – cell signaling technology DCM – dichloromethane DEA – diethanoloamine DFT – density functional theory DIEA – N,N-diisopropylethylamine DMAP – 4-Dimethylaminopyridine DME – dimethyl ether 77MOFO-358009544Attorney Docket No.: 183952036340 DMF – dimethylformamide DMSO – dimethyl sulfoxide DTT – Dithiothreitol EA, EtOAc – ethyl acetate EDCI – 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride EDTA – Ethylenediaminetetraacetic acid ESI – electrospray ionization FA – formic acid FBS – fetal bovine serum HATU – 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (Hexafluorophosphate Azabenzotriazole Tetramethyl Uronium) HEPES – 4-(2-Hydroxyethyl)piperazine-1-ethane-sulfonic acid HPLC – high-performance liquid chromatography IMDM – Iscove's Modified Dulbecco's Medium IPA – isopropyl alcohol LCMS – liquid chromatography-mass spectrometry LDA – Lithium diisopropylamide MeOH – methyl alcohol MS – mass spectrometry MSD – meso scale discovery NBS – N-Bromosuccinimide NMR – nuclear magnetic resonance__ PBS – phosphate buffered saline PE – phycoerythrin PK – pharmacokinetic PMBC – peripheral blood mononuclear cells qPCR – quantitative polymerase chain reaction 78MOFO-358009544Attorney Docket No.: 183952036340 RBC – red blood cell RT – retention time SFC – supercritical fluid chromatography SM – starting material TEA – triethylamine TFA – trifluoroacetic acid THF – tetrahydrofuran TLC – thin layer chromatography TMSBr – Bromotrimethylsilane TMSI – Trimethylsilyl iodide VCD – vibrational circular dichroism aq – aqueous eq – equivalents Hz – hertz MHz – megahertz h, hr – hour g – gram mg – milligram L – liter mL – milliliter uL – microliter m / z – mass-to-charge ratio mm – millimeter nm – nanometer um – micrometer min – minute mol – mole 79MOFO-358009544Attorney Docket No.: 183952036340 mmol – millimole umol – micromole M – molarity mM – millimolar N – normality Example 1: Preparation of compounds

[0136] The compounds of Formula (I) were prepared by adapting or following the procedures outlined in the following schemes and examples. For example, the representative procedures for the combination of cores, pyrrolidine groups, northern amines, and phosphoryl groups are not limited to the examples below and may be adapted to form other compounds of Formula(I) by utilizing the appropriate intermediates and / or starting materials (e.g., pyrrolidine groups, northern amines, and / or phosphoryl groups). In some embodiments, the compounds of Formula (I) or starting materials or intermediates thereto were prepared by adapting or following procedures described in WO 2023 / 133336, paragraphs

[0085] - [001573] (EXEMPLIFICATION: Preparation of Compounds,), WO 2023 / 164680 paragraphs

[0019] -

[0801] (EXEMPLIFICATION: Preparation of Compounds,), or WO 2023 / 192960, paragraphs

[0085] -

[0784] (EXEMPLIFICATION: Preparation of Compounds), each of which is incorporated herein by reference in its entirety.

[0137] Compound names were generated using the software built into ChemDraw. To the extent that there are discrepancies between the name of a compound and its depicted structure, the depicted chemical structure is to be taken as the appropriate compound.

[0138] Representative Procedures for Combination of Cores, Pyrrolidine Groups, Northern Amines, and Phosphoryl Groups:

[0139] The compounds of Formula (I) in Tables 1A, 1B, and 1C were prepared according to the general schemes and exemplary procedures for the combination of cores, pyrrolidine groups, northern amines, and phosphoryl groups with the appropriate starting materials, intermediates, and modifications. Preparation of tert-butyl ((3S,6S,10aR)-5,9-dioxo-3-((S)-6-phenyl-4- azaspiro[2.4]heptane-4-carbonyl)decahydropyrrolo[1,2-a]azocin-6-yl)carbamate (Int 1) 80MOFO-358009544Attorney Docket No.: 183952036340

[0140] Step A: (S)-6-phenyl-4-azaspiro[2.4]heptane

[0141] To a solution of tert-butyl (S)-6-phenyl-4-azaspiro[2.4]heptane-4-carboxylate (1, 20 g, 73.3 mmol, 1.0 eq.) in DCM (210 mL) was added trifluoroacetic acid (TFA) (70 mL), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture concentrated under reduced pressure to give crude (S)-6-phenyl-4- azaspiro[2.4]heptane (TFA salt) (2, 20 g, quant.) as a white solid, which was used in next Step directly without further purification. LCMS (ESI): m / z = 174 [M+H]+.

[0142] Step B: (3S,6S,10aR)-6-((tert-butoxycarbonyl)amino)-5,9- dioxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid

[0143] To a solution of methyl (3S,6S,10aR)-6-((tert-butoxycarbonyl)amino)-5,9- dioxodecahydropyrrolo[1,2-a]azocine-3-carboxylate (3, 30 g, 84.7 mmol, 1.0 eq.) in THF / H2O (300 mL / 60 mL) was added LiOH.H2O (10.4 g, 254 mmol, 3.0 eq. ), and the 81MOFO-358009544Attorney Docket No.: 183952036340 resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture was cooled down in an ice bath, then neutralized carefully with HCl (aq., 1 N) until the pH was adjusted to pH = 5-6. The resulting mixture was extracted with DCM (300 mL x 3), and the combined organic layers were washed with brine (100 mL x 2), dried over with anhydrous Na2SO4, then concentrated under reduced pressure to give crude (3S,6S,10aR)-6- ((tert-butoxycarbonyl)amino)-5,9-dioxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid (4, 26 g, quant.) as a white solid, which was used in next Step directly without further purification. LCMS (ESI): m / z = 341 [M+H]+.

[0144] Step C: tert-butyl ((3S,6S,10aR)-5,9-dioxo-3-((S)-6-phenyl-4- azaspiro[2.4]heptane-4-carbonyl)decahydropyrrolo[1,2-a]azocin-6-yl)carbamate

[0145] A solution of (3S,6S,10aR)-6-((tert-butoxycarbonyl)amino)-5,9- dioxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid (4, 26 g, 76.5 mmol, 1.0 eq.) and HATU (32 g, 84.2 mmol, 1.1 eq.) in DMF (500 mL) was stirred for 15 min, then TEA (38.6 g, 383 mmol, 5.0 eq.) and (S)-6-phenyl-4-azaspiro[2.4]heptane (TFA salt) (2, 13.3 g, 76.5 mmol, 1.0 eq.) were added, and the resulting mixture was stirred at room temperature for additional 2 hrs. After completion, the reaction was poured into H2O (1 L), and the suspension was filtered. The wet cake was slurried with H2O (1 L) and then filtered. The filter cake was washed with H2O (100 mL x 3). The wet cake was dried to afford tert-butyl ((3S,6S,10aR)-5,9-dioxo-3-((S)-6-phenyl-4-azaspiro[2.4]heptane-4- carbonyl)decahydropyrrolo[1,2-a]azocin-6-yl)carbamate (Int 1, 34 g, 68.6 mmol, 90%) as a white solid. LCMS (ESI): m / z = 496 [M+H]+. Preparation of tert-butyl ((3S,6S,9S,10aR)-9-morpholino-5-oxo-3-((S)-6-phenyl-4- azaspiro[2.4]heptane-4-carbonyl)decahydropyrrolo[1,2-a]azocin-6-yl)carbamate 82MOFO-358009544Attorney Docket No.: 183952036340

[0146] To a mixture of tert-butyl ((3S,6S,10aR)-5,9-dioxo-3-((S)-6-phenyl-4- azaspiro[2.4]heptane-4-carbonyl)decahydropyrrolo[1,2-a]azocin-6-yl)carbamate (Int 1, 3 g, 6.06 mmol, 1.0 eq.) and morpholine (2, 2.64 g, 30.3 mmol, 5 eq.) in MeOH (100 mL) was added ZnCl2 (8.12 g, 60.6 mmol, 10 eq.). The resulting mixture was stirred at 55 °C for 1 hr under N2, then NaBH3CN (1.27 g, 20.2 mmol, 10.0 eq.) was added to the reaction mixture in five portions (2 eq / hour) and the resulting mixture was stirred at 55 °C overnight under N2. After completion, the reaction mixture was concentrated under reduced pressure to remove MeOH (15 mL left). The residue was poured into H2O (150 mL) and then the suspension was filtered. The wet cake was dissolved in DCM (100 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The filtrate above was then extracted with DCM (50 mL x 3). The organic layers were combined and washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography using a 120 g C18 cartridge eluting with a gradient of 5-80 % MeCN in water (with 0.1% NH4OH) to afford the desired product as a white solid (3, 1.48 g, 2.61 mmol, 43% yield). LCMS (ESI): m / z = 567.2 [M+H]+. Preparation of (3S,6S,9S,10aR)-6-amino-9-((3,3-difluoropropyl)(methyl)amino)-3-((S)- 6-phenyl-4-azaspiro[2.4]heptane-4-carbonyl)octahydropyrrolo[1,2-a]azocin-5(1H)-one (5) 83MOFO-358009544Attorney Docket No.: 183952036340

[0147] Step A: tert-butyl ((3S,6S,10aR)-9-((3,3-difluoropropyl)amino)-5-oxo-3-((S)-6- phenyl-4-azaspiro[2.4]heptane-4-carbonyl)decahydropyrrolo[1,2-a]azocin-6-yl)carbamate

[0148] To a mixture of tert-butyl ((3S,6S,10aR)-5,9-dioxo-3-((S)-6-phenyl-4- azaspiro[2.4]heptane-4-carbonyl)decahydropyrrolo[1,2-a]azocin-6-yl)carbamate (Int 1, 1 g, 2.02 mmol, 1.0 eq.) and 3,3-difluoropropan-1-amine hydrochloride (2, 0.35 g, 3.64 mmol, 1.8 eq.) in MeOH (20 mL) was added ZnCl2 (1.35 g, 10.1 mmol, 5.0 eq.). The resulting mixture was stirred at 55 °C for 1 hr under N2, then NaBH3CN (1.27 g, 20.2 mmol, 10.0 eq.) was added to the reaction mixture in five portions and the resulting mixture was stirred at 55 °C 84MOFO-358009544Attorney Docket No.: 183952036340 overnight under N2. The reaction mixture was used in the next Step directly without further purification. LCMS (ESI): m / z = 575.4[M+H]+.

[0149] Step B: tert-butyl ((3S,6S,9S,10aR)-9-((3,3-difluoropropyl)(methyl)amino)-5-oxo- 3-((S)-6-phenyl-4-azaspiro[2.4]heptane-4-carbonyl)decahydropyrrolo[1,2-a]azocin-6- yl)carbamate

[0150] To a mixture of tert-butyl ((3S,6S,10aR)-9-((3,3-difluoropropyl)amino)-5-oxo-3- ((S)-6-phenyl-4-azaspiro[2.4]heptane-4-carbonyl)decahydropyrrolo[1,2-a]azocin-6- yl)carbamate (3, Step B above, crude.) were added CH2O (2 mL, 30 wt% in water) and NaBH3CN (0.26 g, 4.04 mmol, 2.0 eq.). The resulting mixture was stirred at 55 °C for 30 min under N2. After completion, the reaction mixture was concentrated under reduced pressure to remove MeOH. The residue was poured into H2O (50 mL) and then the suspension was filtered. The wet cake was dissolved in DCM (100 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The filtrate above was then extracted with DCM (20 mL x 3). The organic layers were combined and washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by reverse phase chromatography using a 120 g C18 cartridge eluting with a gradient of 5-80 % ACN in water (with 0.1% NH3H2O) to afford the desired product as a white solid (4, 700 mg, 12.0 mmol, 59% yield over 2 Steps) LCMS (ESI): m / z = 589.2 [M+H]+.

[0151] Step C: (3S,6S,9S,10aR)-6-amino-9-((3,3-difluoropropyl)(methyl)amino)-3-((S)-6- phenyl-4-azaspiro[2.4]heptane-4-carbonyl)octahydropyrrolo[1,2-a]azocin-5(1H)-one 85MOFO-358009544Attorney Docket No.: 183952036340

[0152] To a solution of tert-butyl ((3S,6S,9S,10aR)-9-((3,3- difluoropropyl)(methyl)amino)-5-oxo-3-((S)-6-phenyl-4-azaspiro[2.4]heptane-4- carbonyl)decahydropyrrolo[1,2-a]azocin-6-yl)carbamate (4, 600 mg, 1.02 mmol, 1.0 eq.) in DCM (10 mL) was added TFA (3 mL), and the resulting mixture was stirred at room temperature for 2 hrs. After completion, the reaction mixture concentrated under reduced pressure to give crude (3S,6S,9S,10aR)-6-amino-9-((3,3-difluoropropyl)(methyl)amino)-3- ((S)-6-phenyl-4-azaspiro[2.4]heptane-4-carbonyl)octahydropyrrolo[1,2-a]azocin-5(1H)-one (TFA salt) (5, 600 mg, quant.) as a white solid, which was used in next Step directly without further purification. LCMS (ESI): m / z = 489.4 [M+H]+. Preparation of propyl (((R)-(2-(((3S,6S,9S,10aR)-9-((3,3-difluoropropyl)(methyl)amino)- 5-oxo-3-((S)-6-phenyl-4-azaspiro[2.4]heptane-4-carbonyl)decahydropyrrolo[1,2- a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)fluoromethyl)(phenoxy)phosphoryl)-L- alaninate (prodrug C1), ((R)-(2-(((3S,6S,9S,10aR)-9-((3,3- difluoropropyl)(methyl)amino)-5-oxo-3-((R)-6-phenyl-4-azaspiro[2.4]heptane-4- carbonyl)decahydropyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5- yl)fluoromethyl)phosphonic acid (parent drug A20) 86MOFO-358009544Attorney Docket No.: 1839520363405-oxo-3-((S)-6-phenyl-4-azaspiro[2.4]heptane-4-carbonyl)decahydropyrrolo[1,2-a]azocin-6- yl)carbamoyl)benzo[b]thiophen-5-yl)fluoromethyl)(phenoxy)phosphoryl)-L-alaninate (Compound C1)

[0154] To a solution of (3S,6S,9S,10aR)-6-amino-9-((3,3- difluoropropyl)(methyl)amino)-3-((S)-6-phenyl-4-azaspiro[2.4]heptane-4- 87MOFO-358009544Attorney Docket No.: 183952036340 carbonyl)octahydropyrrolo[1,2-a]azocin-5(1H)-one (TFA salt) (5, 600 mg, 1.02mmol, 1.0 eq.) and TEA (515 mg, 5.1 mmol, 5.0 eq.) in DMF (5 mL) was added perfluorophenyl 5- ((1R)-fluoro((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (6, 650 mg, 1.02 mmol, 1.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for additional 2 hrs. After completion, the reaction mixture was poured into H2O (50 mL) and then the suspension was filtered. The wet cake was dissolved in DCM (100 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure.The mixture was dissolved in DMF (30 mL) and purified by reverse phase chromatography using a 120 g C18 cartridge eluting with a gradient of 5-80 % ACN in water (with 0.1% TFA) to afford the desired product (700 mg, TFA salt) as a white solid. The TFA salt was dissolved in DCM (50 mL) and washed with 5% NaHCO3 (aq.) (50 mL x 4); following by deionized water (50 mL x 4). The combined aqueous layers were was extracted with DCM (50 mL x 2), then the combined DCM layers concentrated under reduced pressure to give propyl (((R)-(2-(((3S,6S,9S,10aR)- 9-((3,3-difluoropropyl)(methyl)amino)-5-oxo-3-((S)-6-phenyl-4-azaspiro[2.4]heptane-4- carbonyl)decahydropyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5- yl)fluoromethyl)(phenoxy)phosphoryl)-L-alaninate (520 mg, 53.7% yield over 2 Steps) as a white solid.1H NMR (400 MHz, DMSO) δ 8.82 – 8.71 (m, 1H), 8.27 (s, 1H), 8.09 – 8.03 (m, 2H), 7.64 – 7.57 (m, 1H), 7.38 – 7.28 (m, 6H), 7.24 – 7.14 (m, 4H), 6.26 – 6.20 (m, 1H), 6.16 – 5.92 (m, 2H), 4.83 – 4.72 (m, 1H), 4.53 – 4.42 (m, 1H), 4.36 – 4.26 (m, 1H), 4.16 – 4.06 (m, 1H), 3.95 – 3.70 (m, 4H), 3.58 – 3.49 (m, 1H), 3.08 – 2.90 (m, 1H), 2.45 – 2.32 (m, 2H), 2.25 – 2.18 (m, 1H), 2.17 – 1.36 (m, 20H), 1.17 – 1.09 (m, 3H), 0.85 – 0.75 (m, 3H), 0.52 – 0.40 (m, 2H). LCMS (ESI): m / z = 950.8 [M+H]+.

[0155] Step E: ((R)-(2-(((3S,6S,9S,10a10aR)-9-((3,3-difluoropropyl)(methyl)amino)-5- oxo-3-((R)-6-phenyl-4-azaspiro[2.4]heptane-4-carbonyl)decahydropyrrolo[1,2-a]azocin-6- yl)carbamoyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid (Compound A20) 88MOFO-358009544Attorney Docket No.: 183952036340

[0156] To a solution of (3S,6S,9S,10aR)-6-amino-9-((3,3- difluoropropyl)(methyl)amino)-3-((S)-6-phenyl-4-azaspiro[2.4]heptane-4- carbonyl)octahydropyrrolo[1,2-a]azocin-5(1H)-one (TFA salt) (5, 60 mg, 0.1mmol, 1.0 eq.) and TEA (51 mg, 0.5 mmol, 5.0 eq.) in DMF (1 mL) was added (R)-(fluoro(2- ((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (7, 65 mg, 0.1 mmol, 1.0 eq.) at room temperature. The resulting mixture was stirred at room temperature for additional 2 hrs. After completion, the reaction mixture was purified by reverse phase chromatography using a 40 g C18 cartridge eluting with a gradient of 5-50 % ACN in water (with 0.1% TFA) to afford the desired product (75 mg, TFA salt) as a white solid. Then the TFA salt was dissolved in DMF (2 mL) and purified by reverse phase chromatography using a 40 g C18 cartridge eluting with a gradient of 5-50 % ACN in water (with 0.1% NH4HCO3) to give ((R)-(2-(((3S,6S,9S,10aR)-9-((3,3-difluoropropyl)(methyl)amino)-5-oxo-3-((R)-6- phenyl-4-azaspiro[2.4]heptane-4-carbonyl)decahydropyrrolo[1,2-a]azocin-6- yl)carbamoyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid (free base) (45 mg, 58.5% yield over 2 Steps) as a white solid.1H NMR (400 MHz, DMSO) δ 8.87 – 8.67 (m, 1H), 8.24 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.98 (s, 1H), 7.53 (d, J = 8.4 Hz, 1H), 7.38 – 7.29 (m, 4H), 7.26 – 7.19 (m, 1H), 6.40 – 6.03 (m, 1H), 5.91 – 5.75 (m, 1H), 4.81 (s, 1H), 4.60 – 4.50 (m, 2H), 4.17 – 4.09 (m, 1H), 3.85 – 3.70 (m, 2H), 3.57 – 3.51 (m, 1H), 3.35 – 3.19 (m, 2H), 2.80 – 2.69 (m, 3H), 2.49 – 2.42 (m, 1H), 2.39 – 1.70 (m, 14H), 1.56 (s, 1H), 0.59 – 0.42 (m, 2H). LCMS (ESI): m / z = 761.5 [M+H]+. Preparation of (((R)-(2-(((3S,6S,9S,10aR)-9-((3,3-difluoropropyl)(methyl)amino)-5-oxo- 3-((S)-6-phenyl-4-azaspiro[2.4]heptane-4-carbonyl)decahydropyrrolo[1,2-a]azocin-6- yl)carbamoyl)benzo[b]thiophen-5-yl)fluoromethyl)(hydroxy)phosphoryl)-L-alanine (intermediate metabolite, B6). 89MOFO-358009544Attorney Docket No.: 1839520363403-((S)-6-phenyl-4-azaspiro[2.4]heptane-4-carbonyl)decahydropyrrolo[1,2-a]azocin-6- yl)carbamoyl)benzo[b]thiophen-5-yl)fluoromethyl)(hydroxy)phosphoryl)-L-alanine (Compound B6)

[0158] To a solution of propyl (((R)-(2-(((3S,6S,9S,10aR)-9-((3,3- difluoropropyl)(methyl)amino)-5-oxo-3-((S)-6-phenyl-4-azaspiro[2.4]heptane-4- carbonyl)decahydropyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5- yl)fluoromethyl)(phenoxy)phosphoryl)-L-alaninate (200 mg, 0.21 mmol, 1.00 eq) in THF (3 mL) was added LiOH.H2O (2 M, 1 mL,10 eq) at 20 °C and stirred at 20 °C for 2 hrs. LCMS showed that SM was consumed and desired MS (0%-30% method) was detected. The mixture was concentrated to remove methanol. The water phase was purified by prep-HPLC (column: Waters Xbridge C18150*50mm* 10um; mobile phase: [water(NH4HCO3)-ACN]; gradient:10%-30% B over 10 min) and lyophilized to give (((R)-(2-(((3S,6S,9S,10aR)-9- ((3,3-difluoropropyl)(methyl)amino)-5-oxo-3-((S)-6-phenyl-4-azaspiro[2.4]heptane-4- carbonyl)decahydropyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5- yl)fluoromethyl)(hydroxy)phosphoryl)-L-alanine (110 mg, 132 μmol, 63 % yield,) as a white solid.1H NMR (400 MHz, DMSO) δ 8.70 (d, J = 7.4 Hz, 1H), 8.20 (s, 1H), 7.92 (d, J = 8.1 Hz, 2H), 7.54 (d, J = 8.5 Hz, 1H), 7.38 – 7.28 (m, 4H), 7.22 (t, J = 7.1 Hz, 1H), 6.10 (t, J = 57.2 Hz, 1H), 5.61 (dd, J = 45.7, 7.6 Hz, 1H), 4.81 – 4.69 (m, 1H), 4.49 (t, J = 8.3 Hz, 1H), 4.34 (s, 1H), 4.10 (t, J = 8.6 Hz, 1H), 3.74 (t, J = 9.8 Hz, 1H), 3.58 – 3.37 (m, 2H), 3.28 – 2.98 (m, 2H), 2.45 – 2.30 (m, 2H), 2.29 – 2.15 (m, 3H), 2.14 – 2.05 (m, 2H), 2.04 – 1.93 (m, 4H), 1.92 – 1.35 (m, 9H), 1.06 (d, J = 6.8 Hz, 3H), 0.53 – 0.41 (m, 2H). LCMS: m / z = 832.5 (M+H)+. 90MOFO-358009544Attorney Docket No.: 183952036340

[0159] Representative Procedures for Syntheses of Cores: Synthesis of (3S,6S,10aS)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydropyrrolo[1,2- a]azocine-3-carboxylic acid

[0160] Step 1: Preparation of methyl (2S)-5-allyl-1-((S)-2-((tert- butoxycarbonyl)amino)pent-4-enoyl)pyrrolidine-2-carboxylate

[0161] To a cooled (0 °C) solution of methyl (2S)-5-allylpyrrolidine-2-carboxylate hydrochloride (200 g, 972 mmol, 1.00 eq) and (S)-2-((tert-butoxycarbonyl)amino)pent-4- enoic acid (209 g, 972 mmol, 1.00 eq) in CH2Cl2 (1.60 L) was added Et3N (406 mL, 2.92 mol, 3.00 eq) and 2-chloro-1-methylpyridinium iodide (CMPI) (273 g, 1.07 mol, 1.10 eq). The solution was warmed to 25 °C and stirred for 1 h. The mixture was poured into water (5.0 L), extracted with CH2Cl2 (2.00 L x 3). The combined organic layers were washed with brine (2.0 L), dried over Na2SO4, filtered and concentrated under reduced pressure. Six individual batches of equal scale were performed in parallel and combined during work up. The resulting residue was purified by column chromatography (petroleum ether : EtOAc = 100:1 to 10:1) to give methyl (2S)-5-allyl-1-((S)-2-((tert-butoxycarbonyl)amino)pent-4- enoyl)pyrrolidine-2-carboxylate (1.18 kg, 3.22 mol, 55.2% yield) as yellow oil.1H NMR (400 MHz, CDCl3) δ 5.84 – 5.78 (m, 2H), 5.17 – 4.99 (m, 5H), 4.50 – 4.34 (m, 3H), 3.76 – 3.70 (m, 3H), 2.50 – 2.15 (m, 6H), 1.96 – 1.91 (m, 2H), 1.41 (s, 9H).

[0162] Step 2: Preparation of methyl (3S,6S,10aR,Z)-6-((tert-butoxycarbonyl)amino)-5- oxo-1,2,3,5,6,7,10,10a-octahydropyrrolo[1,2-a]azocine-3-carboxylate

[0163] To a solution of methyl (2S)-5-allyl-1-((S)-2-((tert-butoxycarbonyl)amino)pent-4- enoyl)pyrrolidine-2-carboxylate (200 g, 546 mmol, 1.00 eq) in CH2Cl2 (2.00 L) was added 1stgeneration Grubbs catalyst (44.9 g, 54.6 mmol, 0.10 eq) at 25 °C. The solution was 91MOFO-358009544Attorney Docket No.: 183952036340 subsequently heated to 50 °C and stirred for 36 h. Six individual batches of equal scale were performed in parallel and combined during work up. The combined reaction mixtures were concentrated to give a residue. The residue was purified by column chromatography (petroleum ether : EtOAc = 100:1 to 0:1) twice to give a crude product. The crude product was triturated with petroleum ether (2.00 L) for 12 h and filtered. The filter cake was dried under reduced pressure to give methyl (3S,6S,10aR,Z)-6-((tert-butoxycarbonyl)amino)-5- oxo-1,2,3,5,6,7,10,10a-octahydropyrrolo[1,2-a]azocine-3-carboxylate (510 g, 1.40 mol, 51.3% yield, 92.9% purity) as a solid. LCMS (ESI) m / z = 361.2 [M+Na]+;1H NMR (400 MHz, CDCl3) δ 5.82 – 5.80 (m, 1H), 5.73 – 5.71 (m, 1H), 5.58 –5.56 (m, 1H), 4.88 – 4.85 (m, 1H), 4.52 – 4.49 (m, 1H), 4.16 – 4.14 (m, 1H), 3.71 (s, 3H), 2.81 – 2.74 (m, 2H), 2.45 – 2.38 (m, 1H), 2.33 – 2.24 (m, 1H), 2.14 – 2.05 (m, 2H), 1.98 – 1.93 (m, 2H), 1.43 (s, 9H). Synthesis of (3S,6S,9R,10aR)-6-{[(tert-butoxy)carbonyl]amino}-9-hydroxy-5-oxo- decahydropyrrolo[1,2-a]azocine-3-carboxylic acid, (3S,6S,9S,10aR)-6-((tert- butoxycarbonyl)amino)-9-hydroxy-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid, (3S,6S,8S,10aR)-6-((tert-butoxycarbonyl)amino)-8-hydroxy-5- oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid, (3S,6S,8R,10aR)-6-((tert- butoxycarbonyl)amino)-8-hydroxy-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylic acid

[0164] Step 1: Preparation of methyl (3S,6S,10aR)-6-((tert-butoxycarbonyl)amino)-9- hydroxy-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylate and methyl (3S,6S,10aR)-6- ((tert-butoxycarbonyl)amino)-8-hydroxy-5-oxodecahydropyrrolo[1,2-a]azocine-3- carboxylate92MOFO-358009544Attorney Docket No.: 183952036340

[0165] Methyl (3S,6S,10aR)-6-((tert-butoxycarbonyl)amino)-9-hydroxy-5- oxodecahydropyrrolo[1,2-a]azocine-3-carboxylate and methyl (3S,6S,10aR)-6-((tert- butoxycarbonyl)amino)-8-hydroxy-5-oxodecahydropyrrolo[1,2-a]azocine-3-carboxylate were prepared starting from methyl (3S,6S,10aR,Z)-6-((tert-butoxycarbonyl)amino)-5-oxo- 1,2,3,5,6,7,10,10a-octahydropyrrolo[1,2-a]azocine-3-carboxylate and utilizing similar protocols established in Journal of Medicinal Chemistry (2010), 53(17), 6361-6367.

[0166] The mixture of alcohol diastereoisomers and regioisomers were separated by reverse phase chromatography [C18 cartridge eluting with a gradient of 5-40% MeOH in water (with 0.1% formic acid)] followed by chiral SFC separation [Lux i-Cellulose-521.2 x 250 mm 5 um column, column temp = 40°C, flow rate 75 mL / min, 20% MeOH, cycle time: 5 min]. A representative reaction starting from methyl (3S,6S,10aR,Z)-6-((tert- butoxycarbonyl)amino)-5-oxo-1,2,3,5,6,7,10,10a-octahydropyrrolo[1,2-a]azocine-3- carboxylate (4.3 g, 12.7 mmol) afforded the following products:

[0167] Peak 1: Methyl (3S,6S,9R,10aR)-6-{[(tert-butoxy)carbonyl]amino}-9-hydroxy-5- oxo-decahydropyrrolo[1,2-a]azocine-3-carboxylate (760 mg, 2.13 mmol, 16.8% yield) as a white solid. LCMS (ESI) m / z = 357.2 [M+H]+.

[0168] Peak 2: Methyl (3S,6S,9S,10aR)-6-{[(tert-butoxy)carbonyl]amino}-9-hydroxy-5- oxo-decahydropyrrolo[1,2-a]azocine-3-carboxylate (375 mg, 19% yield) as a clear thick oil. LCMS (ESI) m / z = 357.2 [M+H]+.

[0169] Peak 3: Methyl (3S,6S,8R,10aR)-6-{[(tert-butoxy)carbonyl]amino}-8-hydroxy-5- oxo-decahydropyrrolo[1,2-a]azocine-3-carboxylate (795 mg, 40% yield) as a white foam. LCMS (ESI) m / z = 357.2 [M+H]+.

[0170] Peak 4: Methyl (3S,6S,8S,10aR)-6-{[(tert-butoxy)carbonyl]amino}-8-hydroxy-5- oxo-decahydropyrrolo[1,2-a]azocine-3-carboxylate (600 mg, 30% yield) as a white solid. LCMS (ESI) m / z = 357.2 [M+H]+.

[0171] Step 2: Preparation of (3S,6S,9R,10aR)-6-{[(tert-Butoxy)carbonyl]amino}-9- hydroxy-5-oxo-decahydropyrrolo[1,2-a]azocine-3-carboxylic acid. 93MOFO-358009544Attorney Docket No.: 183952036340

[0172] To a solution of methyl (3S,6S,9R,10aR)-6-{[(tert-butoxy)carbonyl]amino}-9- hydroxy-5-oxo-decahydropyrrolo[1,2-a]azocine-3-carboxylate (Peak 1) (1.08 g, 3.03 mmol, 1 eq) in a mixture of THF (24 mL) and water (8 mL) was added LiOH▪H2O (380 mg, 9.08 mmol, 3.0 eq). The reaction mixture was stirred at room temperature for 2 hours. The reaction was subsequently concentrated under reduced pressure to remove tetrahydrofuran. The crude residue was purified by reverse phase chromatography [C18 cartridge eluting with a gradient of 5-60% Acetonitrile in water (with 0.1% formic acid)] to give (3S,6S,9R,10aR)- 6-{[(tert-butoxy)carbonyl]amino}-9-hydroxy-5-oxo-decahydropyrrolo[1,2-a]azocine-3- carboxylic acid (780 mg, 76% yield) as a white solid. LCMS (ESI) m / z = 343.2 [M+H]+.

[0173] The intermediates in the table below were prepared according to the general procedure described above starting from the appropriate starting materials.94MOFO-358009544Attorney Docket No.: 183952036340 Synthesis of methyl (3S,6S,10aR)-6-{[(tert-butoxy)carbonyl]amino}-5,9-dioxo- decahydropyrrolo[1,2-a]azocine-3-carboxylate and methyl (3S,6S,10aR)-6-{[(tert- butoxy)carbonyl]amino}-5,8-dioxo-decahydropyrrolo[1,2-a]azocine-3-carboxylate

[0174] Methyl (3S,6S,10aR)-6-{[(tert-butoxy)carbonyl]amino}-5,9-dioxo- decahydropyrrolo[1,2-a]azocine-3-carboxylate and methyl (3S,6S,10aR)-6-{[(tert- butoxy)carbonyl]amino}-5,8-dioxo-decahydropyrrolo[1,2-a]azocine-3-carboxylate were prepared using the protocol described in US 2009 / 0123480. The crude reaction mixture was purified by reverse phase chromatography using a [C18 cartridge eluting with a gradient of 5- 100 % acetonitrile in water (with 0.1% FA)] to give a mixture of ketone isomers (1.2 g) as a beige solid. The resultant ketone isomers were separated chiral SFC separation (Column Lux i-Cellulose-521.2 x 250 mm 5 um column, flow rate 75 mL / min, 15% MeOH) to give methyl (3S,6S,10aR)-6-{[(tert-butoxy)carbonyl]amino}-5,9-dioxo-decahydropyrrolo[1,2-a]azocine- 3-carboxylate (9) (424 mg, 35.6% yield) as a white solid and methyl (3S,6S,10aR)-6-{[(tert- butoxy)carbonyl]amino}-5,8-dioxo-decahydropyrrolo[1,2-a]azocine-3-carboxylate (433 mg, 36.3% yield) as a white solid.

[0175] Methyl (3S,6S,10aR)-6-{[(tert-butoxy)carbonyl]amino}-5,9-dioxo- decahydropyrrolo[1,2-a]azocine-3-carboxylate: LCMS (ESI) m / z = 299.1 [M+H]+;1H NMR: (400 MHz, CDCl3) δ 5.27 (d, J = 8.1 Hz, 1H), 4.59 (t, J = 8.7 Hz, 1H), 4.45 – 4.31 (m, 2H), 3.80 (s, 3H), 3.20 (td, J = 12.5, 4.9 Hz, 1H), 3.06 (t, J = 12.0 Hz, 1H), 2.47 – 2.15 (m, 5H), 2.13 – 2.00 (m, 1H), 1.87 (dd, J = 12.1, 7.0 Hz, 1H), 1.68 – 1.62 (m, 1H), 1.41 (s, 9H).

[0176] Methyl (3S,6S,10aR)-6-{[(tert-butoxy)carbonyl]amino}-5,8-dioxo- decahydropyrrolo[1,2-a]azocine-3-carboxylate: LCMS (ESI) m / z = 299.1 [M+H]+;1H NMR: (400 MHz, CDCl3) δ 5.56 (d, J = 7.6 Hz, 1H), 5.13 (ddd, J = 12.2, 7.6, 4.9 Hz, 1H), 4.51 (t, J = 8.8 Hz, 1H), 4.33 – 4.23 (m, 1H), 3.73 (s, 3H), 3.07 (dd, J = 13.8, 4.5 Hz, 1H), 2.96 (td, J = 11.9, 2.9 Hz, 1H), 2.65 – 2.50 (m, 2H), 2.36 – 1.91 (m, 4H), 1.90 – 1.76 (m, 2H), 1.45 (s, 9H).

[0177] Representative Procedures for Syntheses of Pyrrolidine Groups: 95MOFO-358009544Attorney Docket No.: 183952036340 Synthesis of (rel-trans)-6-phenyl-4-azaspiro[2.4]heptane-7-carbonitrile TFA salt

[0178] Step 1: 2-{1-[(2-oxo-2-phenylethyl)amino]cyclopropyl}acetonitrile

[0179] To a solution of 2-(1-aminocyclopropyl)acetonitrile hydrochloride (10.7 g, 81.0 mmol, 1 eq) in N,N-dimethylformamide (250 mL) were added 2-bromo-1-phenylethan-1-one (16.1 g, 81.0 mmol, 1 eq) followed by potassium phosphate tribasic (42.8 g, 202 mmol, 2.5 eq). The mixture was stirred at room temperature for 4 h. A yellowish mixture was observed over time. The reaction was quenched with the addition of 1 N HCl (600 mL, pH = 1) at room temperature. The aqueous solution was washed with EtOAc (2 x 500 mL) then basified with 1 N NaOH aqueous solution (until pH = 9, 600 mL) then extracted with EtOAc (2 x 600 mL). The combined organic extracts were washed with brine (2 x 300 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to give crude 2-{1-[(2-oxo- 2-phenylethyl)amino]cyclopropyl}acetonitrile (12.5 g, 72%) as a clear pale orange liquid. LCMS (ESI) m / z = 215.2 [M+H]+. 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 7.6 Hz, 2H), 7.66 (t, J = 7.1 Hz, 1H), 7.54 (t, J = 7.1 Hz, 2H), 4.25 (s, 2H), 2.79 (s, 2H), 0.76 - 0.70 (m, 2H), 0.61 - 0.56 (m, 1H).

[0180] Step 2: tert-butyl N-[1-(cyanomethyl)cyclopropyl]-N-(2-oxo-2- phenylethyl)carbamate

[0181] To a solution of 2-{1-[(2-oxo-2-phenylethyl)amino]cyclopropyl}acetonitrile (12.5 g, 58.3 mmol, 1 eq) in THF (150 mL) were added water (150 mL) and sodium bicarbonate (4.89 g, 58.3 mmol, 1.0 eq) followed by di-tert-butyl dicarbonate (25.3 g, 116 mmol, 2 eq). The reaction was stirred for 48 h at room temperature. The reaction was concentrated under reduced pressure (to remove THF) then diluted with EtOAc (250 mL) and water (50 mL). The phases were separated and the aqueous phase was back-extracted with EtOAc (2 x 250 mL). The combined organic layers were dried with sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified flash-chromatography on silica gel 96MOFO-358009544Attorney Docket No.: 183952036340 eluting with 1-25% EtOAc in heptane to give tert-butyl N-[1-(cyanomethyl)cyclopropyl]-N- (2-oxo-2-phenylethyl)carbamate (14.3 g, 78%) as a white solid. LCMS (ESI) m / z = 215.2 (M-Boc+2H), 259.2 (M-t-Bu+2H).1H NMR (400 MHz, DMSO-d6 at 80oC) δ 7.97 (d, J = 7.2 Hz, 2H), 7.67 (t, J = 7.1 Hz, 1H), 7.55 (t, J = 7.1 Hz, 2H), 4.73 (s, 2H), 2.87 (s, 2H), 1.54 - 1.24 (m, 9H), 1.04 - 0.99 (m, 2H), 0.94 - 0.90 (m, 2H).

[0182] Step 3: tert-butyl N-[1-(cyanomethyl)cyclopropyl]-N-(2-hydroxy-2- phenylethyl)carbamate

[0183] To a solution of tert-butyl N-[1-(cyanomethyl)cyclopropyl]-N-(2-oxo-2- phenylethyl)carbamate (14.33 g, 45.4 mmol, 1 eq) in methanol (260 mL) at 0oC was added sodium borohydride (1.71 g, 45.4 mmol, 1.0 eq) portion wise over 10 min. The reaction was stirred for 20 min at room temperature. The reaction was quenched with 1 N HCl (100 mL) and concentrated under reduced pressure (to remove MeOH). The crude residue was extracted with EtOAc (3 x 200 mL). The combined organic layers were over sodium sulfate, filtered and concentrated under reduced pressure to give tert-butyl N-[1- (cyanomethyl)cyclopropyl]-N-(2-hydroxy-2-phenylethyl)carbamate (14.7 g, 100%) as a clear pale pink oil. 1H NMR (400 MHz, DMSO-d6 at 80oC) δ 7.38 - 7.23 (m, 5H), 5.51 (br. s, 1H), 4.89 - 4.72 (m, 1H), 3.39 - 3.27 (m, 1H), 3.21 - 3.13 (m, 1H), 3.04 - 2.90 (m, 1H), 2.68 - 2.60 (m, 1H), 1.48 (s, 9H), 0.83 - 0.65 (m, 4H).

[0184] Step 4: tert-butyl (rel-trans)-7-cyano-6-phenyl-4-azaspiro[2.4]heptane-4- carboxylate

[0185] To a solution of tert-butyl N-[1-(cyanomethyl)cyclopropyl]-N-(2-hydroxy-2- phenylethyl)carbamate (12 g, 37.9 mmol, 1 eq) in THF (650 mL) at -15oC were added diethyl phosphorochloridate (5.74 mL, 39.7 mmol, 1.05 eq) followed by dropwise addition of 1 M LiHMDS in THF (94.7 mL, 94.7 mmol, 2.5 eq) over 30 min. The reaction was stirred at - 15oC for 30 min. The reaction was quenched with 1N HCl (200 mL) and concentrated under reduced pressure (to remove THF). The crude residue was purified flash-chromatography on silica gel eluting with 1-8% EtOAc in heptane to give rac-tert-butyl (rel-trans)-7-cyano-6- phenyl-4-azaspiro[2.4]heptane-4-carboxylate (3.7 g, 33%) as a clear oil. LCMS (ESI) m / z = 243.2 (M-t-Bu+2H)+.1H NMR (400 MHz, DMSO-d6) δ 7.59 - 7.21 (m, 5H), 4.01 (d, J = 10.5 Hz, 1H), 3.90 (dd, J = 10.5, 7.8 Hz, 1H), 3.69 (q, J = 10.2 Hz, 1H), 3.45 (t, J = 10.0 Hz, 1H), 97MOFO-358009544Attorney Docket No.: 183952036340 1.96 - 1.83 (m, 1H), 1.48 - 1.41 (m, 1H), 1.40 - 1.32 (m, 9H), 0.92 - 0.77 (m, 1H), 0.74 - 0.61 (m, 1H).

[0186] rac-tert-butyl (6R,7S)-7-cyano-6-phenyl-4-azaspiro[2.4]heptane-4-carboxylate was submitted to chiral SFC separation (SFC conditions: Column Lux Amylose 1, 30 x 250 mm 5 um column, 9.25 mg / inj, concentration 18.5 mg / mL, Column T = 40°C, Flow rate 100 mL / min, 10% MeOH, cycle time: 2 min) to give tert-butyl (6R,7S)-7-cyano-6-phenyl-4- azaspiro[2.4]heptane-4-carboxylate (1.57 g, 5.26 mmol, 42% recovery, 99.9% ee) as a white solid and tert-butyl (6S,7R)-7-cyano-6-phenyl-4-azaspiro[2.4]heptane-4-carboxylate (1.57 g, 0.70 mmol, 42% recovery, 99.9% ee) as a white solid.

[0187] The assignment of absolute stereochemical configuration was made by comparing experimental vibrational circular dichroism (VCD) spectra with theoretical VCD spectra obtained from DFT calculations.

[0188] Step 5: (rel-trans)-6-phenyl-4-azaspiro[2.4]heptane-7-carbonitrile TFA salt

[0189] To a solution of a tert-butyl (rel-trans)-7-cyano-6-phenyl-4-azaspiro[2.4]heptane- 4-carboxylate (32 mg, 0.1072 mmol, 1 eq) in methylene chloride (4 mL) was added TFA (1 mL). The reaction was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure to give crude (rel-trans)-6-phenyl-4-azaspiro[2.4]heptane-7- carbonitrile TFA salt (21.2 mg, 99%) as a thick oil. LCMS (ESI) m / z = 229.2 [M+H]+. Synthesis of racemic-(6S,7R)-6-(3-methoxyphenyl)-4-azaspiro[2.4]heptane-7- carbonitrile98MOFO-358009544Attorney Docket No.: 183952036340

[0190] Step 1: Preparation of 2-(1-((2-(3-methoxyphenyl)-2- oxoethyl)amino)cyclopropyl)acetonitrile

[0191] To a solution of 2-(1-aminocyclopropyl)acetonitrile hydrochloride (367 mg, 3.82 mmol, 1.0 eq) in DMF (10 mL ) were added 2-bromo-1-(3-methoxyphenyl)ethan-1-one (918 mg, 4.01 mmol, 1.05 eq) and NaHCO3(801 mg, 9.54 mmol, 2.5 eq). The mixture was stirred at room temperature for 20 h. The reaction was diluted with MeCN and filtered. The filtrate was concentrated under reduced pressure. The crude solution was purified by reverse phase chromatography on a C18cartridge eluting with 5-60% MeCN in basic water (10 mM NH4HCO3 (pH = 10) buffer). The pure fractions were concentrated under reduced pressure to give 2-(1-((2-(3-methoxyphenyl)-2-oxoethyl)amino)cyclopropyl)acetonitrile (522 mg, 55.9 %) as an orange oil. LCMS (ESI) m / z = 245.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.53 - 7.51 (m, 1H), 7.49 - 7.46 (m, 1H), 7.38 (t, J = 7.9 Hz, 1H), 7.16 - 7.10 (m, 1H), 4.25 (s, 2H), 3.86 (s, 3H), 2.58 (s, 2H), 0.89 - 0.84 (m, 2H), 0.74 - 0.70 (m, 2H).

[0192] The intermediates in the table below were prepared using the method described above in Step 1 for the preparation of 2-(1-((2-(3-methoxyphenyl)-2- oxoethyl)amino)cyclopropyl)acetonitrile utilizing the appropriate starting materials and modifications.

[0193] Step 2: Preparation of tert-butyl (1-(cyanomethyl)cyclopropyl)(2-(3- methoxyphenyl)-2-oxoethyl)carbamate

[0194] To a solution of 2-(1-((2-(3-methoxyphenyl)-2- oxoethyl)amino)cyclopropyl)acetonitrile (522 mg, 2.13 mmol, 1 eq) in THF (1 mL) were added water (1 mL) and NaHCO3 (178 mg, 2.13 mmol, 1.0 eq) followed by di-tert-butyl dicarbonate (929 mg, 4.26 mmol, 2 eq) at 0oC. The reaction was warmed up to room temperature and stirred for 48 h at room temperature. The reaction was diluted with MeCN and filtered. The filtrate was concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography on a C18cartridge eluting with 5-80% MeCN in water (with 0.1% formic acid) to give tert-butyl (1-(cyanomethyl)cyclopropyl)(2-(3- 99MOFO-358009544Attorney Docket No.: 183952036340 methoxyphenyl)-2-oxoethyl)carbamate (400 mg, 54.5%) as a sticky oil. LCMS (ESI) m / z = 245.2 [(M-Boc)+2H]+.

[0195] The intermediates in the table below were prepared using the method described above in Step 2 for the preparation of tert-butyl (1-(cyanomethyl)cyclopropyl)(2-(3- methoxyphenyl)-2-oxoethyl)carbamate utilizing the appropriate starting materials and modifications.

[0196] Step 3: Preparation of tert-butyl (1-(cyanomethyl)cyclopropyl)(2-hydroxy-2-(3- methoxyphenyl)ethyl)carbamate

[0197] To a solution of tert-butyl (1-(cyanomethyl)cyclopropyl)(2-(3-methoxyphenyl)-2- oxoethyl)carbamate (193 mg, 0.5603 mmol, 1 eq) in methanol (10 mL) at 0oC was added NaBH4 (21.1 mg, 0.5603 mmol, 1.0 eq). The reaction was stirred for 2 h at room temperature. The reaction was quenched with 1 N HCl (1 mL) and concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography on a C18 cartridge eluting with 5-60% MeCN in water (with 0.1% formic acid) to give tert-butyl (1- (cyanomethyl)cyclopropyl)(2-hydroxy-2-(3-methoxyphenyl)ethyl)carbamate (144 mg, 74.2%) as a thick clear oil.1H NMR (400 MHz, DMSO-d6) δ 7.26 (t, J = 7.8 Hz, 1H), 6.91 - 6.80 (m, 3H), 5.56 - 5.48 (m, 1H), 4.88 - 4.71 (m, 1H), 3.75 (s, 3H), 3.40 - 3.30 (m, 1H), 3.19 - 3.10 (m, 1H), 3.04 - 2.92 (m, 1H), 2.73 - 2.61 (m, 1H), 1.46 (s, 9H), 1.32 - 1.20 (m, 1H), 0.84 - 0.62 (m, 3H).

[0198] The intermediates in the table below were prepared using the method described above in Step 3 for the preparation of tert-butyl (1-(cyanomethyl)cyclopropyl)(2-hydroxy-2- (3-methoxyphenyl)ethyl)carbamate utilizing the appropriate starting materials and modifications.100MOFO-358009544Attorney Docket No.: 183952036340

[0199] Step 4: Preparation of racemic-tert-butyl (6S,7R)-7-cyano-6-(3-methoxyphenyl)- 4-azaspiro[2.4]heptane-4-carboxylate

[0200] To a solution of tert-butyl (1-(cyanomethyl)cyclopropyl)(2-hydroxy-2-(3- methoxyphenyl)ethyl)carbamate (115 mg, 0.3319 mmol, 1 eq) in THF (10 mL) at -15oC were added diethyl phosphorochloridate (50.3 µL, 0.3484 mmol, 1.05 eq) followed by dropwise addition of 1 M LiHMDS in THF (829 µL, 0.8297 mmol, 2.5 eq). The reaction was stirred at -15oC for 2 h. The reaction was quenched with 1 N HCl (1 mL) and concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography on a C18cartridge eluting with 5-70% MeCN in water (with 0.1% formic acid) to give racemic- tert-butyl (6S,7R)-7-cyano-6-(3-methoxyphenyl)-4-azaspiro[2.4]heptane-4-carboxylate (50.0 mg, 46.2%) as a white solid. LCMS (ESI) m / z = 273.2 [(M-t-Bu)+2H]+.1H NMR (400 MHz, C6D6) δ 7.03 - 6.98 (m, 1H), 6.66 - 6.61 (m, 2H), 6.53 - 6.49 (m, 1H), 3.72 - 3.62 (m, 1H), 3.29 (s, 3H), 3.25 - 3.18 (m, 1H), 3.04 - 2.96 (m, 1H), 2.71 (d, J = 10.5 Hz, 1H), 2.38 - 1.93 (m, 1H), 1.75 - 1.47 (m, 1H), 1.37 (s, 9H), 1.09 - 1.02 (m, 1H), 0.45 - 0.39 (m, 1H).

[0201] The intermediates in the table below were prepared using the method described above in Step 4 for the preparation of racemic-tert-butyl (6S,7R)-7-cyano-6-(3- methoxyphenyl)-4-azaspiro[2.4]heptane-4-carboxylate utilizing the appropriate starting materials and modifications.

[0202] Step 5: Preparation of racemic-(6S,7R)-6-(3-methoxyphenyl)-4- azaspiro[2.4]heptane-7-carbonitrile 101MOFO-358009544Attorney Docket No.: 183952036340

[0203] To a solution of a tert-butyl (6R,7S)-7-cyano-6-(3-methoxyphenyl)-4- azaspiro[2.4]heptane-4-carboxylate (44 mg, 0.1339 mmol, 1 eq) in methylene chloride (2 mL) was added TFA (0.5 mL). The reaction was stirred at room temperature for 2 h. The reaction was concentrated under reduced pressure to give crude racemic-(6S,7R)-6-(3- methoxyphenyl)-4-azaspiro[2.4]heptane-7-carbonitrile (30.5 mg, 99%, TFA salt) as a thick oil. LCMS (ESI) m / z = 229.2 [M+H]+.

[0204] The intermediates in the table below were prepared using the method described above in Step 5 for the preparation of racemic-(6S,7R)-6-(3-methoxyphenyl)-4- azaspiro[2.4]heptane-7-carbonitrile utilizing the appropriate starting materials and modifications.Synthesis of racemic-trans-6-(pyridin-3-yl)-4-azaspiro[2.4]heptane-7-carbonitrile 102MOFO-358009544Attorney Docket No.: 183952036340

[0205] Step 1: Preparation of 2-((2,4-dimethoxybenzyl)amino)-1-(pyridin-3-yl)ethan-1-ol

[0206] A solution of 2-amino-1-(pyridin-3-yl)ethan-1-ol dihydrochloride (1, 2.8 g, 13.2 mmol, 1 eq.) and 2,4-dimethoxybenzaldehyde (2.19 g, 13.2 mmol, 1 eq.) in MeOH (10 mL ) was stirred at 60 °C for 0.5 h, then NaBH4 (1.50 g, 39.5 mmol, 3 eq.) was added at 20 °C and the reaction mixture was stirred at 20 °C for 16 h under N2atmosphere. After completion, the reaction mixture was poured into ice-NH4Cl (100 mL), then extracted with EtOAc (50 mL x 3). The organic layers were combined and washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford 2-((2,4-dimethoxybenzyl)amino)- 1-(pyridin-3-yl)ethan-1-ol (2, 2.50 g, 8.67 mmol, 66%) as a yellow oil. LCMS (ESI): m / z = 289.2 [M+H]+.1H NMR (400 MHz, DMSO) δ 8.52 (d, J = 2.0 Hz, 1H), 8.44 (dd, J = 4.8, 1.6 Hz, 1H), 7.71 (dt, J = 7.8, 1.8 Hz, 1H), 7.33 (dd, J = 7.7, 4.9 Hz, 1H), 7.13 (d, J = 8.2 Hz, 1H), 6.52 (d, J = 2.3 Hz, 1H), 6.45 (dd, J = 8.2, 2.4 Hz, 1H), 5.46 (s, 1H), 4.70 (t, J = 6.0 Hz, 1H), 3.74 (d, J = 3.2 Hz, 6H), 3.64 (d, J = 4.7 Hz, 2H), 3.17 (d, J = 5.1 Hz, 1H), 2.70-2.62 (m, 2H).

[0207] Step 2: Preparation of 2-(1-((3,4-dimethylbenzyl)(2-hydroxy-2-(pyridin-3- yl)ethyl)amino)cyclopropyl)acetonitrile 103MOFO-358009544Attorney Docket No.: 183952036340

[0208] To a mixture of 2-((2,4-dimethoxybenzyl)amino)-1-(pyridin-3-yl)ethan-1-ol (2, 2.5g, 8.67 mmol, 1 eq.) in EtOH(5 mL) was added 2-cyclopropylideneacetonitrile in PE solution (1.36 g, 17.3 mmol, 2 eq.) and the resulting mixture was stirred at 20 °C for 1 h under N2atmosphere. After completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel to get 2-(1-((3,4-dimethylbenzyl)(2-hydroxy-2-(pyridin-3- yl)ethyl)amino)cyclopropyl)acetonitrile (3, 2.40 g, 6.53 mmol, 75%) as a pale-yellow oil. LCMS (ESI): m / z = 368.2 [M+H]+.1H NMR (400 MHz, DMSO) δ 8.40 (dd, J = 4.7, 1.6 Hz, 1H), 8.30 (d, J = 1.8 Hz, 1H), 7.54 (dt, J = 7.8, 1.8 Hz, 1H), 7.28 (dd, J = 7.8, 4.8 Hz, 1H), 7.18 (d, J = 8.3 Hz, 1H), 6.54 (d, J = 2.3 Hz, 1H), 6.47 (dd, J = 8.3, 2.4 Hz, 1H), 4.99 (d, J = 3.1 Hz, 1H), 4.28 (dd, J = 9.8, 6.6 Hz, 1H), 3.85-3.71 (m, 8H), 2.94-2.71 (m, 4H), 0.60-0.31 (m, 3H), 0.06 (s, 1H).

[0209] Step 3: Preparation of 2-(1-((2-chloro-2-(pyridin-3-yl)ethyl)(3,4- dimethylbenzyl)amino)cyclopropyl)acetonitrile

[0210] SOCl2 in DCM solution (3, 281 mg, 2.37 mmol, 1.2 eq.) was added to a solution 2-(1-((3,4-dimethylbenzyl)(2-hydroxy-2-(pyridin-3-yl)ethyl)amino)cyclopropyl)acetonitrile (3, 730 mg, 1.98 mmol, 1 eq.) in DCM (10 mL ) at 0 °C. The solution was stirred at room temperature for 0.5 h. After completion, the reaction mixture was quenched with NaHCO3(aq., sat.) (20 mL), then extracted with EtOAc (50 mL x 2). The organic layers were combined and washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 2-(1-((2-chloro-2-(pyridin-3-yl)ethyl)(3,4- dimethylbenzyl)amino)cyclopropyl)acetonitrile (4, 310 mg, 0.80 mmol, 41%) as an oil. LCMS (ESI): m / z = 386.2 [M+H]+.1H NMR (400 MHz, DMSO) δ 8.50 (dd, J = 4.8, 1.5 Hz, 1H), 8.31 (d, J = 1.9 Hz, 1H), 7.64-7.57 (m, 1H), 7.37 (dd, J = 7.9, 4.8 Hz, 1H), 7.13 (d, J = 8.3 Hz, 1H), 6.55 (d, J = 2.3 Hz, 1H), 6.49 (dd, J = 8.3, 2.4 Hz, 1H), 4.62 (t, J = 7.2 Hz, 1H), 3.81-3.72 (m, 8H), 3.36-3.23 (m, 2H), 2.91-2.75 (m, 2H), 0.61-0.38 (m, 3H), 0.06--0.04 (m, 1H).

[0211] Step 4: Preparation of racemic-trans-4-(3,4-dimethylbenzyl)-6-(pyridin-3-yl)-4- azaspiro[2.4]heptane-7-carbonitrile & racemic-cis-4-(3,4-dimethylbenzyl)-6-(pyridin-3-yl)- 4-azaspiro[2.4]heptane-7-carbonitrile 104MOFO-358009544Attorney Docket No.: 183952036340

[0212] To a solution of 2-(1-((2-chloro-2-(pyridin-3-yl)ethyl)(3,4- dimethylbenzyl)amino)cyclopropyl)acetonitrile (4, 310 mg, 0.80 mmol, 1 eq.) in THF (10 mL) was added LiHMDS (202 mg, 2.00 mmol, 2.5 eq.) dropwise at -10 °C and the solution was stirred at room temperature for 1 hr. After completion, the reaction mixture was quenched with NH4Cl (aq., sat.) (15 mL), then extracted with EtOAc (15 mL x 2). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford racemic-trans-4-(3,4-dimethylbenzyl)-6-(pyridin-3- yl)-4-azaspiro[2.4]heptane-7-carbonitrile (5A, 75 mg, 0.21 mmol, 27%) and cis-4-(3,4- dimethylbenzyl)-6-(pyridin-3-yl)-4-azaspiro[2.4]heptane-7-carbonitrile (5B, 55.0 mg, 0.16 mmol, 20%) as a yellow oil. LCMS (ESI): m / z = 350.2 [M+H]+.

[0213] Step 5: Preparation of racemic-trans-6-(pyridin-3-yl)-4-azaspiro[2.4]heptane-7- carbonitrile

[0214] A solution of racemic-trans-4-(3,4-dimethylbenzyl)-6-(pyridin-3-yl)-4- azaspiro[2.4]heptane-7-carbonitrile (5A, 100 mg, 0.29 mmol, 1 eq.) in TFA (5 mL ) was stirred at 20 °C overnight under N2. After completion, the reaction mixture was quenched with NaHCO3(aq., sat.) (20 mL), then extracted with EtOAc (20 mL x 2). The organic layers were combined and washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford racemic-trans-6-(pyridin-3-yl)-4- azaspiro[2.4]heptane-7-carbonitrile (6, 55.0 mg, quant.) as an oil for next Step without further purification. LCMS (ESI): m / z = 199.9 [M+H]+.

[0215] Rac- (6R,7S)-4-(2,4-dimethoxybenzyl)-6-(pyridin-3-yl)-4-azaspiro[2.4]heptane-7- carbonitrile (8 g) was separated by chiral SFC to afford (6S,7R)-4-(2,4-dimethoxybenzyl)-6- (pyridin-3-yl)-4-azaspiro[2.4]heptane-7-carbonitrile (Peak 1, 4.0 g, 50%) and (6R,7S)-4-(3,4- dimethoxybenzyl)-6-(pyridin-3-yl)-4-azaspiro[2.4]heptane-7-carbonitrile (Peak 2, 3.2 g, 40%) as a white solid. Absolute stereochemical configuration was assigned arbitrarily as drawn. 105MOFO-358009544Attorney Docket No.: 183952036340

[0216] Peak 1: Retention time: 1.946 min; >99% ee.

[0217] Peak 2: Retention time: 2.456 min; >99% ee.

[0218] Analytical method: Column: ChiralPak IG, 100×4.6mm I.D., 5um, Mobile phase: A for CO2and B for ethanol(0.05% DEA), Gradient: 8 min @B 30%, Flow rate: 2.5 mL / min, Back pressure: 100 bar, Column temperature: 35 °C.

[0219] SFC method: Instrument: Waters Thar 80 preparative SFC, Column: ChiralPak IG, 250×21.2 mm I.D., 5 µm, Mobile phase: A for CO2 and B for EtOH + 0.1%NH3H2O, Gradient: B 30%, Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 220 nm, Cycle-time: 5.2 min, Eluted time: 3 H.

[0220] The intermediates in the table below were prepared using the method described above in Step 5 for racemic-trans-6-(pyridin-3-yl)-4-azaspiro[2.4]heptane-7-carbonitrile utilizing the appropriate starting materials and modifications.Synthesis of tert-butyl (R)-6-(pyridin-3-yl)-4-azaspiro[2.4]heptane-4-carboxylate and tert-butyl (S)-6-(pyridin-3-yl)-4-azaspiro[2.4]heptane-4-carboxylate 106MOFO-358009544Attorney Docket No.: 183952036340

[0221] Step 1: Preparation of methyl 2-(pyridin-3-yl)acetate

[0222] To a solution of 3-methylpyridine (1, 30 g, 322 mmol, 1.0 eq.) in THF (600 mL) was added dropwise LDA (193 mL, 386 mmol, 2M, 1.2 eq.) at -65 °C under N2 atmosphere. The reaction solution was stirred at -65 °C for 1 h and dimethyl carbonate (57 g, 483mmol, 1.5 eq.) was added into the reaction mixture. After addition, the mixture was stirred at -65 °C for an additional 1 hr. After completion, the reaction mixture was quenched with saturated NH4Cl (aq.) solution (500 mL) at 0 °C, then extracted with EtOAc (500 mL x 2). The organic layers were combined and washed with brine (150 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford methyl 2-(pyridin-3-yl)acetate (2, 25.0 g, 165 mmol, 51%) as a yellow oil. LCMS (ESI): m / z = 152 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.60- 8.48 (m, 2H), 7.68-7.60 (m, 1H), 7.29-7.23 (m, 1H), 3.71 (s, 3H), 3.64 (s, 2H).

[0223] Step 2: Preparation of methyl 3-cyano-2-(pyridin-3-yl)propanoate

[0224] To a solution of LDA (99.0 mL, 198 mmol, 2M, 1.5 eq.) in THF (400 mL ) was added dropwise a solution of methyl 2-(pyridin-3-yl)acetate (2, 20 g, 132 mmol, 1.0 eq.) at - 65 °C under N2 atmosphere. The reaction solution was stirred at -65 °C for 1 h and 2- bromoacetonitrile ( 18.9 g, 158 mmol, 1.2 eq.) was added into the reaction mixture. After 107MOFO-358009544Attorney Docket No.: 183952036340 addition, the mixture was stirred at -65 °C for an additional 1 h. After completion, the reaction mixture was quenched with saturated ice-NH4Cl (aq.) solution (500 mL), then extracted with EtOAc (500 mL x 3). The organic layers were combined and washed with brine (500 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford methyl 3-cyano- 2-(2-methoxypyridin-4-yl)propanoate (3, 20.5 g, 107 mmol, 82%) as a yellow oil. LCMS (ESI): m / z = 191 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.62 (dd, J = 4.8, 1.5 Hz, 1H), 8.57 (d, J = 2.2 Hz, 1H), 7.69-7.61 (m, 1H), 7.34 (dd, J = 7.9, 4.8 Hz, 1H), 4.00 (t, J = 7.5 Hz, 1H), 3.75 (s, 3H), 3.07 (dd, J = 16.9, 7.1 Hz, 1H), 2.88 (dd, J = 16.9, 7.9 Hz, 1H).

[0225] Step 3: Preparation of 6-(pyridin-3-yl)-4-azaspiro[2.4]heptan-5-one

[0226] To a solution of methyl 3-cyano-2-(pyridin-3-yl)propanoate (3, 20.5 g, 107 mmol, 1.0 eq.) and Titanium tetraisopropanolate (36.8 g, 128 mmol, 1.2 eq.) in THF (400 mL ) was added dropwise EtMgBr (80 mL, 240 mmol, 3M, 2.25 eq.) at 0 °C. After addition, the reaction mixture was stirred at 0 °C for 1 hr. After completion, the reaction mixture was quenched by addition of HCl aqueous solution (140 mL, 2N) at 0 °C. The suspension was warmed to room temperature and filtered. The filtrate was poured into ice–water (500 mL) and extracted with EtOAc (200 mL x 2). The organic layers were combined, washed with brine (500 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 6-(pyridin-3-yl)- 4-azaspiro[2.4]heptan-5-one (4, 9.2 g, 48.8 mmol, 46%) as a yellow solid. LCMS (ESI): m / z = 189 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.59 (d, J = 2.1 Hz, 1H), 8.53 (dd, J = 4.8, 1.5 Hz, 1H), 7.74-7.65 (m, 1H), 7.29 (dd, J = 8.0, 4.9 Hz, 1H), 7.00 (s, 1H), 3.91 (t, J = 8.7 Hz, 1H), 2.53 (dd, J = 12.9, 9.3 Hz, 1H), 2.33 (dd, J = 12.9, 8.2 Hz, 1H), 1.00-0.68 (m, 4H).

[0227] Step 4: Preparation of 6-(pyridin-3-yl)-4-azaspiro[2.4]heptane

[0228] To a solution of 6-(pyridin-3-yl)-4-azaspiro[2.4]heptan-5-one (4, 3.0 g, 15.9 mmol, 1.0 eq.) and methanidylidyneoxidanium tris(triphenylphosphane) hydrogen rhodium (729 mg, 795 mmol, 0.05 eq.) in dioxane (60 mL) was added phenylsilane (10.32 g, 95.4 mmol, 6.0 eq.). The reaction solution was stirred at 100 °C for 12 h. After completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was triturated with 1N HCl ( 200 mL) at 25 °C for 0.5 h and then filtered. The filtrate was extracted with EtOAc (100 mL x 2). The organic layers were combined, dried over anhydrous 108MOFO-358009544Attorney Docket No.: 183952036340 Na2SO4and concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to afford 6-(pyridin-3-yl)-4-azaspiro[2.4]heptane (5, 2.2 g, 12.62 mmol, 79%) as a brown solid. LCMS (ESI): m / z = 175[M+H]+.1H NMR (400 MHz, CDCl3) δ 8.55-8.46 (m, 2H), 7.72-7.62 (m, 1H), 7.31-7.25 (m, 1H), 3.84-3.71 (m, 2H), 3.40-3.28 (m, 1H), 2.32-2.17 (m, 2H), 1.52-1.37 (m, 2H), 0.91-0.76 (m, 2H).

[0229] Step 5: Preparation of tert-butyl 6-(pyridin-3-yl)-4-azaspiro[2.4]heptane-4- carboxylate

[0230] To a solution of 6-(pyridin-3-yl)-4-azaspiro[2.4]heptane (5, 8 g, 45.9 mmol, 1 eq.) in THF / H2O (80 mL / 10 mL) were added NaHCO3 (7.7 g, 91.7 mmol, 2 eq.) and Boc2O (12 g, 55.1 mmol, 1.2 eq.). The solution was stirred at room temperature for 4 h. After completion, the reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (100 mL x 3). The organic layers were combined and washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl 6-(pyridin-3-yl)-4- azaspiro[2.4]heptane-4-carboxylate (6, 6.7 g, 24.5 mmol, 53%) as a white solid. LCMS (ESI): m / z = 275 [M+H]+.

[0231] Step 6: Preparation of tert-butyl (R)-6-(pyridin-3-yl)-4-azaspiro[2.4]heptane-4- carboxylate and tert-butyl (S)-6-(pyridin-3-yl)-4-azaspiro[2.4]heptane-4-carboxylate

[0232] tert-butyl 6-(pyridin-3-yl)-4-azaspiro[2.4]heptane-4-carboxylate (6, 6.7 g) was separated by chiral SFC to afford tert-butyl (R)-6-(pyridin-3-yl)-4-azaspiro[2.4]heptane-4- carboxylate (Peak 1, 3 g, 45%) and tert-butyl (S)-6-(pyridin-3-yl)-4-azaspiro[2.4]heptane-4- carboxylate (Peak 2, 3.1 g, 46%). LCMS (ESI): m / z = 275 [M+H]+. SFC method: Instrument: Waters Thar 80 preparative SFC Column: ChiralPak C-IG, 250×21.2 mm I.D., 5 µm Mobile phase: A for CO2and B for MEOH + 0.1%NH3H2O, Gradient: B 45 % Flow rate: 40 mL / min, Back pressure: 100 bar, Column temperature: 35 °C, Wavelength: 220 nm Cycle- time: 25 min Eluted time: 7H. The assignment of absolute stereochemical configuration was made by comparison of experimental vibrational circular dichroism (VCD) spectra with theoretical VCD spectra obtained from DFT calculations. Synthesis of (R)-6-phenyl-4-azaspiro[2.4]heptane and (S)-6-phenyl-4- azaspiro[2.4]heptane: 109MOFO-358009544Attorney Docket No.: 183952036340

[0233] Step 1: Preparation of methyl 3-cyano-2-phenylpropanoate

[0234] To a solution of LDA (5.95 mL, 47.8 mmol, 1.2 eq) in THF (80 mL) was added dropwise methyl 2-phenylacetate (6 g, 39.9 mmol, 1.0 eq) at -78 °C under N2 atmosphere. The reaction solution was stirred at -78 °C for 0.5 h and 2-bromoacetonitrile (5.25 g, 43.8 mmol, 1.1 eq) was introduced into the reaction. After addition, the mixture was stirred at -78 °C for 0.5 h. After completion, the reaction mixture was quenched with saturated ice-NH4Cl (aq.) solution (500 mL), then extracted with EtOAc (500 mL x 3). The organic layers were combined and washed with brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica 110MOFO-358009544Attorney Docket No.: 183952036340 gel to afford methyl 3-cyano-2-phenylpropanoate (6.20 g, 32.7 mmol, 82%) as a yellow oil. LCMS (ESI): m / z = 190 [M+H]+.

[0235] Step 2: Preparation of 6-phenyl-4-azaspiro[2.4]heptan-5-one

[0236] To a solution of methyl 3-cyano-2-phenylpropanoate (6.2 g, 32.7 mmol, 1 eq) in THF (50 mL ) was added dropwise Ti(Oi-Pr)4(10.2 g, 35.9 mmol, 1.1 eq) at -78 °C. The reaction solution was stirred at -78 °C for 10 min and EtMgBr (72 mL, 71.9 mmol, 2.2 eq) was added dropwise into the reaction mixture. The reaction was stirred at -78 °C for 10 min then warmed up to room temperature for 0.5 h. After completion, the reaction mixture was quenched with H2O (5 mL), followed by 10% aqueous HCl (50 mL) and EtOAc (500 mL). And 10 % aq. NaOH solution was added to the resulting clear mixture until the pH was adjusted pH = 8-9. The filtrate was extracted with EtOAc (200 mL x 2). The organic layers were combined, washed with brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 6-phenyl-4-azaspiro[2.4]heptan-5-one (9.2 g, 48.8 mmol, 46%) as a yellow solid. LCMS (ESI): m / z = 188.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.39-7.24 (m, 6H), 3.86 (dd, J = 9.4, 7.6 Hz, 1H), 2.51 (dd, J = 12.9, 9.4 Hz, 1H), 2.29 (dd, J = 12.9, 7.6 Hz, 1H), 0.85-0.88 (m, 1H), 0.87-0.81 (m, 1H), 0.76-0.64 (m, 2H).

[0237] Step 3: Preparation of 6-phenyl-4-azaspiro[2.4]heptane

[0238] To a solution of 6-phenyl-4-azaspiro[2.4]heptan-5-one (2.2 g, 11.7 mmol, 1 eq) in THF (100 mL) was added NaBH4(2.21 g, 58.5 mmol, 5 eq) at 0 °C, then Boron trifluoride etherate (8.30 g, 58.5 mmol, 5 eq) was added dropwise to the mixture. The mixture was stirred at room temperature for 5 h and then stirred at 50 °C overnight. After completion, the reaction mixture was quenched with NaHCO3 aqueous solution (20 mL) and extracted with EtOAc(20 mL x 2). The organic layers were combined, washed with brine (500 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by C18 column chromatography to afford 6-phenyl-4-azaspiro[2.4]heptane (1.50 g, 8.65 mmol, 74%) as an oil. LCMS (ESI): m / z = 174.3 [M+H]+.

[0239] Step 4: Preparation of tert-butyl 6-phenyl-4-azaspiro[2.4]heptane-4-carboxylate

[0240] To a solution of 6-phenyl-4-azaspiro[2.4]heptane (1.2 g, 6.92 mmol, 1 eq), DIEA (1.78 g, 13.8 mmol, 2 eq) and DMAP (84.5 mg, 692 µmol, 0.1 eq) in DCM (20 mL ) was 111MOFO-358009544Attorney Docket No.: 183952036340 added di-tert-butyl dicarbonate (301 mg, 1.38 mmol, 1.2 eq) at room temperature. The reaction solution was stirred at room temperature for 5 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to get tert-butyl 6-phenyl-4-azaspiro[2.4]heptane-4-carboxylate (1.50 g, 5.48 mmol, 79%) as a white solid. LCMS (ESI): m / z = 218.3 [(M-tBu)+H]+.1H NMR (400 MHz, CDCl3) δ 7.38-7.19 (m, 5H), 3.98 (s, 1H), 3.54-3.39 (m, 2H), 2.48-2.27 (m, 1H), 1.95 (dd, J = 12.2, 5.5 Hz, 1H), 1.52 (s, 2H), 1.43 (s, 9H), 0.55-0.42 (m, 2H)

[0241] Step 5: Preparation of tert-butyl (R)-6-phenyl-4-azaspiro[2.4]heptane-4- carboxylate and tert-butyl (S)-6-phenyl-4-azaspiro[2.4]heptane-4-carboxylate

[0242] Tert-butyl 6-phenyl-4-azaspiro[2.4]heptane-4-carboxylate (1.50 g, 5.48 mmol) was further separated by Chiral SFC to give: SFC Method: Instrument: SHIMADZU PREP SOLUTION SFC, Column: ChiralPak IH, 250×21.2mm I.D., 5µm, Mobile phase: A for CO2 and B for MeOH+0.1%NH3H2O, Gradient: B 10%, Flow rate: 10 mL / min, Back pressure: 100 bar, Column temperature: 35oC, Wavelength: 220 nm, Cycle-time: 4 min, Eluted time: 4 h. Absolute stereochemistry was arbitrarily assigned.

[0243] Peak 1: tert-butyl (R)-6-phenyl-4-azaspiro[2.4]heptane-4-carboxylate or tert-butyl (S)-6-phenyl-4-azaspiro[2.4]heptane-4-carboxylate (600 mg, 40%); Retention time: 3.287 min, 99% ee. LCMS (ESI): m / z = 218.3 [(M-tBu)+H]+.1H NMR (400 MHz, CDCl3) δ 7.35- 7.21 (m, 5H), 3.99 (s, 1H), 3.54-3.40 (m, 2H), 2.37 (dd, J = 13.9, 8.8 Hz, 1H), 1.96 (dd, J = 12.1, 5.5 Hz, 1H), 1.43 (s, 9H), 0.57-0.41 (m, 2H).

[0244] Peak 2: tert-butyl (S)-6-phenyl-4-azaspiro[2.4]heptane-4-carboxylate or tert-butyl (R)-6-phenyl-4-azaspiro[2.4]heptane-4-carboxylate (600 mg, 40%); Retention time: 3.582 min, 97% ee. LCMS (ESI): m / z = 218.3 [(M-tBu)+H]+.1H NMR (400 MHz, CDCl3) δ 7.37- 7.20 (m, 5H), 3.99 (s, 1H), 3.56-3.38 (m, 2H), 2.37 (dd, J = 13.8, 8.8 Hz, 1H), 1.96 (dd, J = 12.1, 5.5 Hz, 1H), 1.43 (s, 9H), 0.58-0.42 (m, 2H).

[0245] Analytical method: Column: (R,R)-Whelk-O1, 250×4.6mm I.D., 5um, Mobile phase: A for CO2and B for IPA (0.05%DEA), Gradient: 10 min @ B 20%, Flow rate: 2.0 mL / min, Back pressure: 100 bar, Column temperature: 35oC.

[0246] Step 6: Preparation of (R)-6-phenyl-4-azaspiro[2.4]heptane or (S)-6-phenyl-4- azaspiro[2.4]heptane 112MOFO-358009544Attorney Docket No.: 183952036340

[0247] To the solution of tert-butyl (R)-6-phenyl-4-azaspiro[2.4]heptane-4-carboxylate or tert-butyl (S)-6-phenyl-4-azaspiro[2.4]heptane-4-carboxylate (60 mg, 219 µmol, 1 eq, Peak 1) in DCM (2 mL ) was added TFA (1 mL ) at room temperature. The solution was stirred at room temperature. for 2 h. After completion, the reaction mixture was concentrated under reduced pressure to give (R)-6-phenyl-4-azaspiro[2.4]heptane or (S)-6-phenyl-4- azaspiro[2.4]heptane (70.0 mg, quant.) as an oil, which was used in next Step directly without further purification. LCMS (ESI): m / z = 174.2 [M+H]+.

[0248] Step 7: Preparation of (S)-6-phenyl-4-azaspiro[2.4]heptane or (R)-6-phenyl-4- azaspiro[2.4]heptane

[0249] To the solution of tert-butyl (6S)-6-phenyl-4-azaspiro[2.4]heptane-4-carboxylate or tert-butyl (R)-6-phenyl-4-azaspiro[2.4]heptane-4-carboxylate (60 mg, 219 µmol, 1 eq, Peak 2) in DCM (2 mL ) was added TFA (1 mL ) at room temperature. The solution was stirred at room temperature. for 2 h. After completion, the reaction mixture was concentrated under reduced pressure to give (S)-6-phenyl-4-azaspiro[2.4]heptane or (R)-6-phenyl-4- azaspiro[2.4]heptane (70.0 mg, quant.) as an oil, which was used in next Step directly without further purification. LCMS (ESI): m / z = 174.2 [M+H]+. Preparation of N,N-dimethyl-3-(4-azaspiro[2.4]heptan-6-yl)pyridin-4-amine 113MOFO-358009544Attorney Docket No.: 183952036340

[0250] Step A: 2-(4-chloropyridin-3-yl)acetonitrile

[0251] To a solution of t-BuOK (15.8 g, 141 mmol, 2 eq.) in DME (100 mL) was added TosMIC (16.5 g, 84.7 mmol, 1.2 eq.) at 25 °C. The reaction mixture was cooled to -60 °C. 4- chloronicotinaldehyde (10 g, 70.6 mmol, 1 eq.) in DME (100 mL) was added dropwise to the mixture at -60 °C. The reaction was stirred at -60 °C for 1 hr, then warmed up to 25 °C and stirred for 2 hrs under N2 atmosphere. MeOH (100 mL) was added to the mixture, and the reaction mixture was heated to 80 °C and stirred at 80 °C for 0.5 hrs under N2 atmosphere. After completion, the reaction mixture was quenched by adding H2O (200 mL), then extracted with EtOAc (100 mL x 3). The organic layers were combined and washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 2-(4- chloropyridin-3-yl)acetonitrile (4.2 g, 27.5 mmol, 39%) as a yellow solid. LC-MS (ESI) m / z = 153 [M+H]+.

[0252] Step B: 2-(4-chloropyridin-3-yl)acetic acid

[0253] 2-(4-chloropyridin-3-yl)acetonitrile (4.2 g, 27.5 mmol, 1.0 eq.) was added to a solution of sodium hydroxide (9 g, 225 mmol, 8.2 eq.) in H2O (51 mL ) at 25 °C. The 114MOFO-358009544Attorney Docket No.: 183952036340 reaction mixture was heated to 100 °C and stirred for 1 hr. After completion, the reaction mixture was cooled down in an ice bath, then acidified carefully with HCl (con.) until the pH was adjusted to pH =1. The resulting mixture was dissolved in MeOH (50 mL).The suspension was filtered through a pad of Celite, the filter cake was washed with MeOH (10 mL). The combined filtrates were concentrated under reduced pressure to give 2-(4- chloropyridin-3-yl)acetic acid (4.0 g, 23.3 mmol, 85%) as a brown solid. LC-MS (ESI) m / z = 172 [M+H]+.

[0254] Step C: methyl 2-(4-chloropyridin-3-yl)acetate

[0255] To a solution of 2-(4-chloropyridin-3-yl)acetic acid (4 g, 23.3 mmol, 1 eq.) in MeOH (50 mL ) was added dropwise thionyl chloride (13.7 g, 116 mmol, 5 eq.) at 25 °C. The reaction mixture was heated to 80 °C and stirred for 1 hr. After completion, the reaction mixture was concentrated under reduce pressure. The product was dissolved in water (100 mL), the aqueous phase was neutralized carefully with NaHCO3 (aq.) until the pH was adjusted to pH = 9. The resulting mixture was extracted with EtOAc (100 mL x 2), and the combined organic layers were washed with brine (100 mL), dried over with anhydrous Na2SO4, then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford methyl 2-(4-chloropyridin-3-yl)acetate (4.0 g, 21.5 mmol, 93%) as a yellow oil. LCMS (ESI): m / z = 186 [M+H]+.

[0256] Step D: methyl 2-(4-chloropyridin-3-yl)-3-cyanopropanoate

[0257] To a solution of methyl 2-(4-chloropyridin-3-yl)acetate (3 g, 16.1 mmol, 1 eq.) in dry THF (10 mL) was added LDA (9.7 mL, 19.3 mmol, 1.2 eq.) slowly at -65 °C under nitrogen. The mixture was stirred for additional 1 hr at -65oC, then 2-bromoacetonitrile (2.31 g, 19.3 mmol, 1.2 eq.) was added drop-wisely, after addition, the reaction mixture was stirred at -65 °C for 1 hr. After completion, the reaction mixture was quenched by adding sat. NH4Cl (100 mL), then extracted with EtOAc (100 mL x 2). The organic layers were combined and washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford methyl 2-(4-chloropyridin-3-yl)-3- cyanopropanoate (3.0 g, 13.3 mmol, 83%) as a yellow oil. LC-MS (ESI) m / z = 225 [M+H]+

[0258] Step E: 6-(4-chloropyridin-3-yl)-4-azaspiro[2.4]heptan-5-one 115MOFO-358009544Attorney Docket No.: 183952036340

[0259] To a solution of methyl 2-(4-chloropyridin-3-yl)-3-cyanopropanoate (1 g, 4.45 mmol, 1 eq.) and titanium isopropoxide (1.58 g, 5.56 mmol, 1.25 eq.) in THF (30 mL) was added dropwise EtMgBr (3.7 mL, 11.1 mmol, 2.5 eq.) at 25 °C for 2 hrs. The reaction mixture was stirred at 25 °C for 0.5 hrs under N2atmosphere. After completion, the reaction mixture was diluted with H2O (10 mL), then extracted with EtOAc (20 mL x 3). The organic layers were combined and washed with brine (150 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 6-(4-chloropyridin-3-yl)-4-azaspiro[2.4]heptan-5-one (500 mg, 2.25 mmol, 51%) as a yellow oil. LC-MS (ESI) m / z = 223 [M+H]+

[0260] Step F: 6-(4-chloropyridin-3-yl)-4-azaspiro[2.4]heptane hydrochloride

[0261] To a solution of 6-(4-chloropyridin-3-yl)-4-azaspiro[2.4]heptan-5-one (500 mg, 2.24 mmol, 1.0 eq.) in dioxane (10 mL ) were added lambda1-rhodium(1+) formyl radical tris(triphenylphosphine) hydride (103 mg, 112 µmol, 0.05 eq.) and phenylsilane (1.45 g, 13.4 mmol, 6 eq.) at 25 °C. The reaction mixture was heated to 100 °C and stirred for 12 hrs under N2 atmosphere. After completion, the reaction mixture was cooled to 25 °C and acidified carefully with HCl / dioxane (4 M) until the pH was adjusted to pH = 1. The resulting mixture was concentrated under reduce pressure. The residue was triturated with H2O (10 mL) and filtered. The filtrate was concentrate under reduce pressure to give 6-(4-chloropyridin-3-yl)- 4-azaspiro[2.4]heptane hydrochloride (200 mg, 815 µmol, 36%) as a yellow solid. LC-MS (ESI) m / z = 209 [M+H]+.

[0262] Step G: tert-butyl 6-(4-chloropyridin-3-yl)-4-azaspiro[2.4]heptane-4-carboxylate

[0263] To a solution of 6-(4-chloropyridin-3-yl)-4-azaspiro[2.4]heptane hydrochloride (200 mg, 958 µmol, 1 eq.) and sodium bicarbonate (402 mg, 4.79 mmol, 5 eq.) in a mixture of H2O (5 mL) and THF (5 mL) was added di-tert-butyl dicarbonate (312 mg, 1.43 mmol, 1.5 eq.) at 25 °C. The reaction mixture was stirred at 25 °C for 2 hrs. After completion, the reaction mixture was diluted with H2O (10 mL), then extracted with EtOAc (20 mL x 3). The organic layers were combined and washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford tert-butyl 6-(4- chloropyridin-3-yl)-4- azaspiro[2.4]heptane-4-carboxylate (200 mg, 647 µmol, 68%) as a yellow oil. LC-MS (ESI) m / z = 309 [M+H]+. 116MOFO-358009544Attorney Docket No.: 183952036340

[0264] Step H: tert-butyl 6-(4-(dimethylamino)pyridin-3-yl)-4-azaspiro[2.4]heptane-4- carboxylate

[0265] To a mixture of tert-butyl 6-(4- chloropyridin-3-yl)-4-azaspiro[2.4]heptane-4- carboxylate (100 mg, 0.32 mmol, 1 eq.), dimethylamine (0.64 mmol, 2.0 eq., 1 M in THF), and t-BuONa (61 mg, 0.64 mmol, 2.0 eq.) in THF(2 mL) were added Pd(OAc)2(5 mg, 32 µmol, 0.1 eq.) and Ruphos (30 mg, 64 µmol, 0.2 eq.). The suspension was degassed under vacuum and purged with N2 several times. The resulting mixture was stirred at 60 °C for 0.5 hrs. After completion, the mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give tert-butyl 6-(4- (dimethylamino)pyridin-3-yl)-4-azaspiro[2.4]heptane-4-carboxylate (70 mg, 0.22 mmol, 69%) as a yellow oil. LCMS (ESI): m / z = 318 [M+H]+.

[0266] Step I: N,N-dimethyl-3-(4-azaspiro[2.4]heptan-6-yl)pyridin-4-amine

[0267] A solution of tert-butyl 6-(4-(dimethylamino)pyridin-3-yl)-4- azaspiro[2.4]heptane-4-carboxylate (100 mg, 0.31 mmol, 1.0 eq.) in TFA (0.5 mL) was stirred at 40 °C for 6 hrs. After completion, the reaction mixture was concentrated under reduced pressure to afford N,N-dimethyl-3-(4-azaspiro[2.4]heptan-6-yl)pyridin-4-amine (100 mg, quant.) (TFA salt) as a brown solid, which was used without further purification. LCMS (ESI): m / z = 218 [M+H]+.

[0268] Representative Procedures for Syntheses of Phosphoryl Groups: Synthesis of 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0269] 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid was prepared according to the protocol described in WO 2020 / 205467 (e.g., paragraphs [0560- 0565], which are incorporated herein). Synthesis of (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid 117MOFO-358009544Attorney Docket No.: 183952036340

[0270] Step 1: Preparation of 4-nitrophenyl 5- ((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate

[0271] To a mixture of 5-[(diethoxyphosphoryl)difluoromethyl]-1-benzothiophene-2- carboxylic acid (10.0 g, 27.4 mmol), EDCI (7.85 g, 41.0 mmol) and DMAP (836 mg, 6.85 mmol) in CH2Cl2 (80 mL) was stirred at room temperature. After 15 min, 4-nitrophenol (4.75 g, 34.2 mmol) was added and the resulting yellow mixture was stirred at room temperature for 18 h. The reaction was quenched with water (30 mL) and the product was extracted with CH2Cl2(10 mL x 2). The combined organic extracts were washed with brine, dried with sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified by reverse phase chromatography [C18 cartridge eluting with a gradient of 5-100% acetonitrile in water] and the appropriate fractions were concentrated to give 4-nitrophenyl 5- ((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (7.80 g, 16.0 mmol, 59.0% yield) as a yellow solid. LCMS m / z = 486.2 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.32 – 8.37 (m, 3H), 8.22 (s, 1H), 8.01 (d, J = 9.1 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1 H), 7.51 – 7.45 (m, 2 H), 4.14 – 4.32 (m, 4H), 1.34 (t, J = 7.8 Hz, 6H).

[0272] Step 2: Preparation of (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen- 5-yl)methyl)phosphonic acid

[0273] To a cooled (0 °C) solution of 4-nitrophenyl 5- ((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (4.47 g, 9.20 mmol) in CH2Cl2(39 mL) was added N,O-bis(trimethylsilyl)trifluoroacetamide (12.1 mL, 46.0 mmol) and iodotrimethylsilane (5.23 mL, 36.8 mmol) as a solution in CH2Cl2 (10 mL). The reaction mixture was gradually allowed to warm to ambient temperatures. To the reaction mixture was added a mixture of 2:1 H2O / acetonitrile (with 0.1% TFA) (50 mL) and precipitation of product was observed. The volatiles were removed in vacuo and the crude residue was suspended in a mixture of acetonitrile / water solution (1:1 v / v, 100 mL). The 118MOFO-358009544Attorney Docket No.: 183952036340 suspension was filtered, the solids were washed with a 2:1 mixture acetonitrile / water solution, and the solid were dried under reduced pressure to afford [difluoro({2-[(4- nitrophenoxy)carbonyl]-1-benzothiophen-5-yl})methyl]phosphonic acid (6.5 g, 94%) as a beige solid. The filtrate was concentrated to 50% of solvent volume and the resulting suspension was filtered and washed with 1:2 acetonitrile / water solution. The solid was dried under reduced pressure to afford additional [difluoro({2-[(4-nitrophenoxy)carbonyl]-1- benzothiophen-5-yl})methyl]phosphonic acid (0.4 g) as a beige solid. Both products were lyophilized to give (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid (6.90 g, 16.0 mmol, 98.0% yield).1H NMR (400 MHz, DMSO- d6) δ 7.66 – 7.74 (m, 3H), 8.27 (d, J = 8.3 Hz, 1H), 8.30 (s, 1H), 8.36 – 8.41 (m, 2H), 8.66 (s, 1H).

[0274] The intermediates in the table below was prepared using a similar protocol outlined above for synthesis of [difluoro({2-[(4-nitrophenoxy)carbonyl]-1-benzothiophen-5- yl})methyl]phosphonic acid and utilizing the appropriate intermediate(s) as starting material(s).Synthesis of ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid 119MOFO-358009544Attorney Docket No.: 183952036340

[0275] Preparation of 5-methylbenzo[b]thiophene-2-carboxylic acid

[0276] 5-Methylbenzo[b]thiophene-2-carboxylic acid was prepared according to the procedure described in WO 2016 / 100184 (e.g., paragraphs

[0281] -

[0284] , which are incorporated by reference herein).

[0277] Step 1: Preparation of benzyl 5-methylbenzo[b]thiophene-2-carboxylate

[0278] To a solution of 5-methylbenzo[b]thiophene-2-carboxylic acid (21.2 g, 110.0 mmol, 1.0 eq) and K2CO3 (30.4 g, 220.0 mmol, 2.0 eq) in DMF (200 mL) was added benzyl bromide (20.6 g, 121.0 mmol, 1.1 eq). The mixture was stirred at room temperature for 14 h. The reaction mixture was poured into ice water (400 mL) and stirred for 5 min. The resulting solids were filtered, and the filter cake was washed with water (50 mL), dried in vacuum to give benzyl 5-methylbenzo[b]thiophene-2-carboxylate (30.1 g, 106.0 mmol, 97% yield) as a yellow solid.1H NMR (400 MHz, CDCl3) δ 8.01 (s, 1H), 7.71 (t, J = 12.2 Hz, 1H), 7.65 (s, 1H), 7.46 (d, J = 6.8 Hz, 2H), 7.42 – 7.35 (m, 3H), 7.29 – 7.26 (m, 1H), 5.38 (s, 2H), 2.47 (s, 3H).

[0279] Step 2: Preparation of benzyl 5-(bromomethyl)benzo[b]thiophene-2-carboxylate

[0280] To a solution of benzyl 5-methylbenzo[b]thiophene-2-carboxylate (15.0 g, 53.1 mmol, 1.0 eq) and NBS (10.3 g, 58.4 mmol, 1.1 eq) in CCl4 (30 mL) was added benzoyl peroxide (1.3 g, 5.31 mmol, 0.1 eq). The reaction flask was subjected to three cycles of evacuation and backfilling with N2(g). The mixture was stirred at 80oC for 16 h under constant atmosphere of N2 (g). The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 120MOFO-358009544Attorney Docket No.: 183952036340 benzyl 5-(bromomethyl)benzo[b]thiophene-2-carboxylate (6.80 g, 18.8 mmol, 36% yield) as a yellow solid.

[0281] Step 3: Preparation of benzyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene- 2-carboxylate

[0282] A solution of benzyl 5-(bromomethyl)benzo[b]thiophene-2-carboxylate (10.3 g, 28.5 mmol, 1.0 eq) dissolved in triethyl phosphite (30.0 g, 180.0 mmol, 6.3 eq) was stirred at 100 °C for 5 h. The reaction mixture was concentrated under reduced pressure directly, the residue was purified by flash column chromatography on silica gel to give benzyl 5- ((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (6.5 g, 15.5 mmol, 55% yield) as a colorless oil. LCMS (ESI) m / z = 419 [M+H]+;1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.80 (d, J = 8.3 Hz, 2H), 7.49 – 7.33 (m, 6H), 5.39 (s, 2H), 4.08 – 3.93 (m, 4H), 3.26 (d, J = 21.5 Hz, 2H), 1.24 (t, J = 7.1 Hz, 6H).

[0283] Step 4: Preparation of 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2- carboxylic acid

[0284] To a solution of benzyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2- carboxylate (5.6 g, 13.3 mmol, 1.0 eq) in dissolved in a mixture of THF (80 mL) and H2O (10 mL) was added LiOH (1.10 g, 26.6 mmol, 2.0 eq). The mixture was stirred at room temperature for 3 h and subsequently acidified with aqueous solution of 1 N HCl (adjusted to pH ~3-4). The product precipitated out of solution upon acidification. The resulting solids were filtered, the filter cake was washed with water (20 mL x 2), and the solids were dried under vacuum to give 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (3.9 g, 11.8 mmol, 88.9% yield) as a white solid. LCMS (ESI) m / z = 329 [M+H]+.

[0285] Step 5: Preparation of perfluorophenyl 5- ((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0286] To a cooled (0 °C) solution of 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene- 2-carboxylic acid (3.9 g, 11.8 mmol, 1.0 eq) in CH2Cl2 (50 mL) was added oxalyl chloride (2.2 g, 17.7 mmol, 1.5 eq) followed by addition of two drops of DMF. The mixture was stirred at 0 °C for 30 min, followed by evaporation of the reaction mixture to dryness. The resulting solids were dissolved in CH2Cl2 (50 mL), followed by addition of Et3N (3.6 g, 35.4 mmol, 3.0 eq) and pentafluorophenol (2.6 g, 14.1 mmol, 1.2 eq). The resulting mixture was 121MOFO-358009544Attorney Docket No.: 183952036340 stirred at room temperature for additional 2 h and subsequently, poured over H2O (30 mL). The bi-phasic solution was extracted with EtOAc (30 mL x 3). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure, the residue was purified by column chromatography on silica gel to give perfluorophenyl 5- ((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (4.7 g, 9.5 mmol, 81% yield) as a white solid. LCMS (ESI) m / z = 419 [M+H]+;1H NMR (400 MHz, CDCl3) δ 8.29 (s, 1H), 7.88 (d, J = 9.1 Hz, 2H), 7.51 (d, J = 8.4 Hz, 1H), 4.14 – 3.94 (m, 4H), 3.29 (d, J = 21.5 Hz, 2H), 1.26 (t, J = 7.0 Hz, 6H).

[0287] Step 6: Preparation of ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid

[0288] To a solution of perfluorophenyl 5- ((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (4.7 g, 9.5 mmol, 1.0 eq) in CH2Cl2 (60 mL) was added bromotrimethylsilane (12 mL). The mixture was stirred at room temperature for 14 h and subsequently concentrated under reduced pressure. The residue was purified by C18 column chromatography to give ((2- ((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (3.7 g, 8.4 mmol, 89% yield) as a white solid. LCMS (ESI) m / z = 439 [M+H]+. Synthesis of (R)- or (S)-5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2- carboxylic acid and (S)-5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2- carboxylic acid

[0289] Step 1: rac-benzyl 5-((diethoxyphosphoryl)(hydroxy)methyl)benzo[b]thiophene-2- carboxylate 122MOFO-358009544Attorney Docket No.: 183952036340

[0290] To a cooled (–78oC) solution of benzyl 5- ((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (2.4 g, 5.73 mmol, 1 eq) in THF (75 mL) and 2-(benzenesulfonyl)-3-phenyloxaziridine (2.97 g, 11.4 mmol, 2 eq) was added a 1 M solution of NaHMDS (11.4 mL, 11.4 mmol, 2 eq) in THF. A deep purple solution was observed upon addition of base that changed to orange after complete addition of the base. The mixture was stirred for an additional 10 min, followed by addition of aqueous saturated NH4Cl (50 mL). The mixture was warmed to ambient temperatures and EtOAc (75 mL) and water (25 mL) was added. After stirring for an additional 30 min, the phases were separated. The aqueous layer was extracted with EtOAc (125 mL x 2). The combined organic extracts were dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure. Another batch of equal scale was performed and combined for purification. The combined material (6.42 mmol, 12.15 mmol in total) was purified by flash chromatography (20% – 100% = EtOAc : heptane) to give rac-benzyl 5- ((diethoxyphosphoryl)(hydroxy)methyl)benzo[b]thiophene-2-carboxylate (3.69 g, 8.49 mmol, 70%) as a white sticky solid. LCMS (ESI) m / z = 869.4 [2M+H]+;1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 8.04 – 8.00 (m, 1H), 7.88 (d, J = 8.6 Hz, 1H), 7.61 (d, J = 8.6 Hz, 1H), 7.51 – 7.47 (m, 2H), 7.46 – 7.35 (m, 3H), 5.42 (s, 2H), 5.17 (dd, J = 10.4, 4.5 Hz, 1H), 4.18 – 3.95 (m, 4H), 3.10 – 2.99 (m, 1H), 1.33 – 1.20 (m, 6H).

[0291] Step 2: rac-benzyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2- carboxylate

[0292] To a cooled (–78oC) solution (under N2(g)) of rac-benzyl 5- ((diethoxyphosphoryl)(hydroxy)methyl)benzo[b]thiophene-2-carboxylate (cc) (1.56 g, 3.59 mmol, 1 eq) in CH2Cl2 (30 mL) was added (diethylamino)sulfur trifluoride (568 μL, 4.30 mmol, 1.2 eq). The reaction was stirred for 15 min, followed by addition of aqueous saturated NaHCO3 (50 mL). After warming to room temperature, the product was extracted with CH2Cl2 (50 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography on C18 cartridge (eluting with 5-80% acetonitrile in water) to give rac- benzyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (650 mg, 1.48 mmol, 41.6 %) as a thick clear oil. LCMS (ESI) m / z = 873.2 [2M+H]+;1H NMR (400 MHz, CDCl3) δ 8.12 (s, 1H), 8.02 – 7.99 (m, 1H), 7.92 (d, J = 8.7 Hz, 1H), 7.61 (d, J = 8.7 Hz, 1H), 123MOFO-358009544Attorney Docket No.: 183952036340 7.51 – 7.51 (m, 2H), 7.46 – 7.36 (m, 3H), 5.82 (dd, J = 44.4, 7.5 Hz, 1H), 5.42 (s, 2H), 4.21 – 4.02 (m, 4H), 1.34 – 1.26 (m, 6H).

[0293] Step 3: Preparation of benzyl (R)-5- ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate and benzyl (S)-5- ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate

[0294] rac-Benzyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2- carboxylate (650 mg, 1.48 mmol) was submitted to chiral SFC separation (Column: Lux i- Amylose 3, 21.2 x 250 mm 5 um column, 75 mL / min, 40% MeOH) to give benzyl (R)- or (S)-5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (304 mg, 0.70 mmol, 46.8% recovery, 99.9% ee) as a thick clear oil (Peak 1) and benzyl (R)- or (S)-5- ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (317 mg, 0.73 mmol, 49% recovery, 99.9% ee) as a thick clear oil (Peak 2). Note: Fastest eluting enantiomer by SFC was arbitrarily assigned as (R)-5-(fluoro(phosphono)methyl)benzo[b]thiophene-2- carboxylic acid and slowest eluting enantiomer by SFC as (S)-5- (fluoro(phosphono)methyl)benzo[b]thiophene-2-carboxylic acid. HPLC method for analysis of enantiomeric excess: Lux Cellulose-3150mm 45% H2O+0.05% TFA / 55% MeCN 1mL / min 8 min.

[0295] Step 4: Preparation of (R)- or (S)-5- ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0296] To a mixture of 10% Pd / C (60 mg, 50% wet) and benzyl (R)-5- ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (Peak 1) (60 mg, 0.1374 mmol, 1 eq) in THF (5 mL) was degassed with N2 (g) for 5 min. To the mixture was bubbled H2 (g) for 5 min then the reaction was allowed to stir at room temperature under H2 (g) (1 atm). The reaction mixture was stirred until consumption of starting material was detected by LCMS. The reaction mixture was subsequently sparged N2 (g) for 15 min and filtered over a pad of Celite®. The filter cake was washed with 2-MeTHF and the filtrate was concentrated to give (R)- or (S)-5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2- carboxylic acid (47.4 mg, 0.0137 mmol, 99%) as a thick clear oil. LCMS (ESI) m / z = 347.2 [M+H]+.

[0297] The intermediates in the table below was prepared using the procedure outlined above (in Step 4) starting from benzyl (S)- or (R)-5- 124MOFO-358009544Attorney Docket No.: 183952036340 ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (Peak 2) and using the appropriate reagents.Preparation of 5-(((((S)-1-isopropoxy-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acidcarboxylate

[0299] To a suspension of 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2- carboxylic acid (1.0 g, 3.0 mmol, 1.0 eq) and K2CO3 (839 mg, 6.1 mmol, 2.0 eq) in DMF (20 mL) was added 3-bromoprop-1-ene (440 mg, 3.6 mmol, 1.2 eq). The mixture was stirred at room temperature for 14 h and poured over water (30 mL). The mixture was extracted with EtOAc (25 mL x 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure, the residue was purified by column chromatography to give allyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (0.980 g, 2.7 mmol, 88% yield) as a light-yellow solid. LCMS (ESI) m / z = 369 [M+H]+;1H NMR (400 MHz, CDCl3) δ 8.04 (s, 1H), 7.84 – 7.77 (m, 2H), 7.45 – 7.37 (m, 1H), 6.18 – 5.94 (m, 1H), 5.49 – 5.39 (m, 1H), 5.36 – 5.28 (m, 1H), 4.87 – 4.83 (m, 2H), 4.08 – 3.97 (m, 4H), 3.27 (d, J = 21.4 Hz, 2H), 1.25 (t, J = 7.1 Hz, 6H). 125MOFO-358009544Attorney Docket No.: 183952036340

[0300] Step 2: Preparation of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid

[0301] To a solution of allyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2- carboxylate (980 mg, 2.7 mmol, 1.0 eq) in CH2Cl2(15 mL) was added bromotrimethylsilane (3 mL). The mixture was stirred at room temperature for 14 h and subsequently concentrated under reduced pressure. The resulting residue was triturated with H2O (5 mL) and the resulting precipitates were filtered. The filter cake was washed with H2O (5 mL x 2) and dried under reduced pressure to give ((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid (0.710 g, 2.3 mmol, 86% yield) as a white solid. LCMS (ESI) m / z = 313 [M+H]+;1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.92 – 7.83 (m, 1H), 7.50 – 7.38 (m, 1H), 6.12 – 5.98 (m, 1H), 5.46 – 5.38 (m, 1H), 5.32 – 5.27 (m, 1H), 4.85 – 4.80 (m, 2H), 3.08 (d, J = 21.2 Hz, 2H).

[0302] Step 3: Preparation of allyl 5-(((((S)-1-isopropoxy-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0303] To a cooled (0 °C) solution (under a constant stream of N2(g)) of ((2- ((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (2.80 g, 8.96 mmol, 1 eq) and catalytic DMF (1 drop) in dry CH2Cl2(50 mL) was added oxalyl chloride (3.40 g, 26.8 mmol, 3 eq). After effervescence of gas ceased, the mixture was warmed at 40°C. After 2 h, the mixture was cooled to room temperature and concentrated in vacuo to give yellow solids. The solids were subsequently diluted CH2Cl2(50 mL) and cooled to 0 °C. To the cooled solution was added phenol (0.843 g, 8.96 mmol, 1 eq) and Et3N (4.53 g, 44.8 mmol, 5 eq). After complete addition, the mixture was warmed to room temperature and stirred for 1 h, followed by introduction of propan-2-yl (2S)-2-aminopropanoate (1.75 g, 13.4 mmol, 1.5 eq) to the mixture. After stirring for an additional 2 h, the mixture was concentrated to dryness. The residue was purified by C18 column (elution 50% – 80% acetonitrile in water) to give allyl 5-(((((S)-1-isopropoxy-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (2.23 g, 4.44 mmol, 49.6% yield) as white solids. LCMS (ESI) m / z = 502.0 [M+H]+;1H NMR (400 MHz, CDCl3) δ 8.05 (d, J = 6.9 Hz, 1H), 7.91 – 7.80 (m, 2H), 7.53 – 7.43 (m, 1H), 7.29 (d, J = 8.1 Hz, 2H), 7.18 – 7.09 (m, 3H), 6.05 (ddd, J = 16.1, 10.9, 5.6 Hz, 1H), 5.48 – 5.40 (m, 1H), 5.32 (dd, J = 10.4, 1.2 Hz, 1H), 4.98 – 4.87 (m, 1H), 4.85 (d, J = 5.7 Hz, 2H), 4.04 – 3.85 (m, 1H), 3.44 (dd, J = 20.7, 14.1 Hz, 2H), 3.12 (t, J = 10.9 Hz, 1H), 1.21 – 1.10 (m, 9H). 126MOFO-358009544Attorney Docket No.: 183952036340

[0304] Step 4: Preparation of 5-(((((S)-1-isopropoxy-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0305] A solution of allyl 5-(((((S)-1-isopropoxy-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (90 mg, 0.1794 mmol, 1 eq), pyrrolidine (12.7 mg, 179 µmol, 1 eq), Pd(PPh3)4(10.3 mg, 8.97 µmol, 0.05 eq) in CH2Cl2 (5 mL ) was stirred under N2 (g). After 2 h, the reaction was concentrated in vacuo. The residue was purified by C18 column (elution 30% – 70% acetonitrile in water) to yield 5- (((((S)-1-isopropoxy-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (64.0 mg, 0.1386 mmol, 77.4% yield) as white solids. LCMS (ESI) m / z = 462.1 [M+H]+.

[0306] The intermediates in the table below were prepared using the described above for synthesis of 5-(((((S)-1-isopropoxy-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid and utilizing the appropriate utilizing the appropriate starting materials and modifications.127MOFO-358009544Attorney Docket No.: 183952036340Synthesis of 5-(((((S)-1-(benzyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0307] Step 1: Preparation of allyl 5-(((((S)-1-(benzyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate

[0308] To a solution of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid (300 mg, 861 µmol, 1 eq) in DCM (5 mL) at 0oC were added 2 drops of DMF (cat.) followed by dropwise addition of oxalyl chloride (220 µL, 2.58 mmol, 3 eq). The reaction was warmed up to room temperature and stirred for 16 h. The reaction mixture was concentrated under reduced pressure and dried completely under high vacuum for 30 min. to give a yellow solid. The yellow solid was diluted in DCM (5 mL) and cooled to 0°C. A solution of phenol (89.1 mg, 947 µmol, 1.1 eq) and triethylamine (599 µL, 4.30 mmol, 5 eq) in DCM (1 mL, dried on Na2SO4) was slowly added to the yellow solution. The reaction mixture was stirred at 0°C for 2 min. and then warmed up to room temperature and stirred for 2 h. A solution of L-alanine benzyl ester p-toluenesulfonate salt (453 mg, 1.29 mmol, 1.5 eq) in DCM (1 mL, dried on Na2SO4) was slowly added to the yellow solution. The reaction mixture was stirred at room temperature for 18 h. The solvent 128MOFO-358009544Attorney Docket No.: 183952036340 was removed in vacuo. The crude product was purified by reverse phase chromatography on a 50 g C18 cartridge eluting with a gradient of 5-100% acetonitrile in water. The pure fractions were combined and concentrated under reduced pressure to give allyl 5-(((((S)-1- (benzyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (196 mg, 38.8%) as a yellow oil. LCMS (ESI) m / z = 586.2.

[0309] The intermediates in the table below were prepared using the method described above in Step 1 for the preparation of allyl 5-(((((S)-1-(benzyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate and utilizing the appropriate starting materials and modifications.

[0310] Step 2: Preparation of 5-(((((S)-1-(benzyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0311] To a stirred solution of allyl 5-(((((S)-1-(benzyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (196 mg, 334 µmol, 1 eq) in THF (5 mL) were added morpholine (143 µL, 1.67 mmol, 5 eq) 129MOFO-358009544Attorney Docket No.: 183952036340 and Pd(PPh3)4(38.5 mg, 33.4 µmol, 0.10 eq) under nitrogen. The reaction mixture was stirred 1 h at room temperature. The reaction mixture was directly purified by reverse phase chromatography on a 50 g C18 cartridge eluting with a gradient of 5-100% acetonitrile in water (with 0.1% formic acid). The pure fractions were concentrated under reduced pressure to give 5-(((((S)-1-(benzyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (164 mg, 90.1%) as a light brown solid.1H NMR (400 MHz, CDCl3) δ 8.22 - 8.09 (m, 1H), 7.88 - 7.76 (m, 2H), 7.66 - 7.59 (m, 1H), 7.43 - 7.29 (m, 7.6H), 7.26 - 7.15 (m, 2.4H), 5.24 (s, 1H), 5.13 (s, 1H), 4.83 - 4.67 (m, 0.5H), 4.62 - 4.44 (m, 0.5H), 4.39 - 4.14 (m, 1H), 1.50 - 1.35 (m, 3H).

[0312] The intermediates in the table below were prepared using the method described above in Step 2 for the preparation of 5-(((((S)-1-(benzyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid and utilizing the appropriate starting materials and modifications.Synthesis of 5-(((((S)-1-butoxy-1-oxopropan-2-yl)amino)(naphthalen-1- yloxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid 130MOFO-358009544Attorney Docket No.: 183952036340

[0313] Step 1: Preparation of butyl ((benzyloxy)carbonyl)-L-alaninate

[0314] To a solution of ((benzyloxy)carbonyl)-L-alanine (5 g, 22 mmol, 1 eq) in DMF (50 mL) was added 1-chlorobutane (2.1 g, 22 mmol, 1 eq) and dipotassium carbonate (6.2 g, 45 mmol, 2 eq), the mixture was stirred at 60oC for 1 h to give yellow solution. The mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL × 2), the combined organic layers were washed with saturated brine (200 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give butyl ((benzyloxy)carbonyl)-L-alaninate (3.6 g, 13 mmol, 57.8% yield) as a yellow oil. LCMS (ESI) m / z = 280.0

[0315] Step 2: Preparation of butyl L-alaninate

[0316] To a solution of butyl ((benzyloxy)carbonyl)-L-alaninate (3 g, 11 mmol, 1 eq) in THF (30 mL) was added Pd / C (3 g, 10%) under N2, the mixture was stirred at 25oC for 2 h under H2(15 Psi). The reaction mixture was filtered and the filter was concentrated to give butyl L-alaninate (1.7 g, crude) as a yellow oil. LCMS (ESI) m / z = 146.1 [M+H]+.

[0317] Step 3: Preparation of allyl 5- ((dichlorophosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate

[0318] To a solution of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid (0.2 g, 0.57 mmol, 1 eq) in DCM (5 mL) was added 131MOFO-358009544Attorney Docket No.: 183952036340 dimethylformamide (0.42 mg, 5.7 µmol, 0.01 eq), the mixture was stirred at 0oC for 5 min, then a solution of oxalyl chloride (0.22 g, 1.7 mmol, 3 eq) in DCM (5 mL) was added to the mixture, the mixture was stirred at 40oC for 15 min to give yellow solution. The reaction mixture was concentrated under reduced pressure to give allyl 5- ((dichlorophosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (0.2 g, crude) as a yellow oil. LCMS (ESI) m / z = 377.0 [M+H]+.

[0319] Step 4: Preparation of allyl 5-(((((S)-1-butoxy-1-oxopropan-2- yl)amino)(naphthalen-1-yloxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate

[0320] To a solution of allyl 5-((dichlorophosphoryl)difluoromethyl)benzo[b]thiophene- 2-carboxylate (0.2 g, 0.52 mmol, 1 eq) in DCM (10 mL) was added naphthalen-1-ol (60 mg, 0.42 mmol, 0.8 eq), the mixture was stirred at 0oC for 5 min, then a solution of N,N- diisopropylethylamine (0.2 g, 1.6 mmol, 3.0 eq) in DCM (10 mL) was added to the mixture, then a solution of butyl L-alaninate (75 mg, 0.52 mmol, 1 eq) in DCM (10 mL) was added to the mixture, the mixture was stirred at 0oC for 30 min to give yellow solution. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give allyl 5-(((((S)-1-butoxy-1-oxopropan-2- yl)amino)(naphthalen-1-yloxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (0.15 g, 0.24 mmol, 46.4% yield) as a yellow oil. LCMS (ESI) m / z = 602.1 [M+H]+.

[0321] Step 5: Preparation of 5-(((((S)-1-butoxy-1-oxopropan-2-yl)amino)(naphthalen-1- yloxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0322] To a solution of allyl 5-(((((S)-1-butoxy-1-oxopropan-2-yl)amino)(naphthalen-1- yloxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (0.14 g, 0.23 mmol, 1 eq) in DCM (1.0 mL) was added Pd(PPh3)4 (27 mg, 23 µmol, 0.1 eq), the mixture was stirred at 0oC for 5 min, then pyrrolidine (17 mg, 0.23 mmol, 1 eq) was added to the mixture, the mixture was stirred at 25oC for 5 min to give yellow solution. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (TFA) to give 5-(((((S)-1-butoxy-1-oxopropan-2-yl)amino)(naphthalen-1- yloxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (97 mg, 0.17 mmol, 74.6% yield) as a yellow oil. LCMS (ESI) m / z = 562.1 [M+H]+. Synthesis of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid and ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid: 132MOFO-358009544Attorney Docket No.: 183952036340

[0323] Ethyl 5-methylbenzo[b]thiophene-2-carboxylate was prepared according to the procedure described in WO 2016 / 100184 (e.g., paragraphs

[0281] -

[0284] , which are incorporated by reference herein).

[0324] Step 1: Preparation of ethyl 5-(bromomethyl)benzo[b]thiophene-2-carboxylate

[0325] To a solution of ethyl 5-methylbenzo[b]thiophene-2-carboxylate (1, 7.3 kg, 33.1 mol, 1.0 eq.) in CHCl3(58 L) stirred at 20oC was added AIBN (544 g, 3.31 mol, 0.10 eq.) and NBS (6.19 kg, 34.8 mol, 1.05 eq.). The mixture was heated from 30oC to 50oC over 4 h and was then heated to 60oC and stirred for 12 hours. After completion, the reaction mixture was cooled to 10oC and 15% Na2SO3 (20 L) was added. The organic layers were washed with H2O (20 L * 2), dried over Na2SO4, and concentrated under reduced pressure at 45oC to afford ethyl 5-(bromomethyl)benzo[b]thiophene-2-carboxylate (2, 9.50 kg, 23.5 mol, 70.9% yield, 74.0% purity) as a yellow solid. LCMS (ESI): m / z = 298.9 [M+H]+.1H NMR (400 MHz, CDCl3) δ 133MOFO-358009544Attorney Docket No.: 183952036340 8.034 (s, 1H), 7.89 – 7.84 (m, 2H), 7.50 (d, J = 9.6 Hz, 1H), 4.64 (s, 2H), 4.45 - 4.40 (m, 2H), 1.45 – 1.41 (m, 3H).

[0326] Step 2: Preparation of ethyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2- carboxylate

[0327] To a solution of ethyl 5-(bromomethyl)benzo[b]thiophene-2-carboxylate (2, 9.50 kg, 31.8 mol, 1.0 eq.) in DMF (28.5 L) stirred at 20oC was added triethyl phosphite (5.8 kg, 34.9 mol, 1.1 equiv). The mixture was heated to 100 °C and stirred for 5 h. After completion, the reaction mixture was cooled to 15oC, poured into H2O (50.0 L), and extracted with EtOAc (20 L *2). The combined organics were washed with H2O (20 L * 2) and brine (10 L), dried over Na2SO4, and concentrated under reduced pressure at 45oC to give a residue. Crude residue was purified by silica gel chromatography (Petroleum ether / Ethyl acetate = 100 / 1 to 1 / 1, Petroleum ether / Ethyl acetate = 0 / 1) to afford ethyl 5- ((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (3, 5.24 kg, 14 mol, 44.4% yield) as yellow solid. LCMS (ESI): m / z = 356.9 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.02 (s, 1H), 7.82 – 7.80 (m, 2H), 7.41 (d, J = 2.0 Hz, 1H), 4.44 – 4.41 (m, 2H), 4.05 - 4.01 (m, 4H), 3.27 (d, J = 21.6 Hz, 2H), 1.46 – 1.42 (m, 3H), 1.27 – 1.23 (m, 6H).

[0328] Step 3: Preparation of ethyl 5- ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate

[0329] Three batches were carried out in parallel.

[0330] To a solution of ethyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2- carboxylate (3, 250 g, 702 mmol, 1.00 eq) and N-(benzenesulfonyl)-N- fluorobenzenesulfonamide (221 g, 702 mmol, 1.00 eq) in THF (2.50 L) was added dropwise LiHMDS (1 M, 702 mL, 1.00 eq) at -70 °C under N2. The mixture was stirred at -70 °C for 3 h. Following completion, the reaction mixture was poured into saturated NH4Cl aqueous solution (5.00 L) slowly at 0 °C and the mixture was stirred at 0 °C for 0.5 hr. Then three batches were combined to workup. The mixture was extracted with ethyl acetate (5.00 L * 3). The organic layers were combined, washed with brine (5.00 L), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 - 3 / 1, Rf = 0.30, petroleum ether / ethyl acetate = 1 / 1) to give ethyl 5- ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (4, 357 g, 928 mmol, 134MOFO-358009544Attorney Docket No.: 183952036340 44.1% yield) as yellow oil. LCMS (ESI): m / z = 375.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.07 (s, 1H), 8.00 (s, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.8 Hz, 1H), 5.88 - 5.75 (m, 1H), 4.45 - 4.40 (m, 2H), 4.15 - 4.05 (m, 4H), 1.45 - 1.41 (m 3H), 1.31 - 1.28 (m, 6H).

[0331] Step 4: Preparation of 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2- carboxylic acid

[0332] To a solution of ethyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2- carboxylate (4, 252 g, 673 mmol, 1.00 eq) in MeOH (1.80 L) was added H2O (760 mL) and LiOH•H2O (56.5 g, 1.35 mol, 2.00 eq) at 10 - 20 °C under N2. The mixture was stirred at 10 - 20 °C for 1 hr. TLC (petroleum ether / ethyl acetate = 1 / 1) showed that compound 4 was consumed (Rf = 0.30) and desired spot (Rf = 0.10) was formed. The reaction mixture was quenched by H2O (2.50 L) and then adjusted pH to 3 - 4 with HCl (aq.1M). The mixture was extracted with dichloromethane (2.50 L * 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure to give 5- ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid (5, 222 g, 626 mmol, 93.0% yield) as a white solid.

[0333] Step 5: Preparation of allyl 5- ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate

[0334] Two batches were carried out in parallel.

[0335] To a solution of 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2- carboxylic acid (5, 178 g, 514 mmol, 1.00 eq) in DMF (1.78 L) was added K2CO3(142 g, 1.03 mol, 2.00 eq) and allyl bromide (68.4 g, 565 mmol, 1.10 eq) at 10 - 20 °C. The mixture was stirred at 10 - 20 °C for 12 h. TLC (petroleum ether / ethyl acetate = 0 / 1) showed that compound 5 was consumed (Rf = 0.60) and a new spot (Rf = 0.70) was formed. The reaction mixture was diluted with H2O (6.00 L), extracted with ethyl acetate (2.00 L * 3). The organic layers were combined. The mixture was washed with brine (2.00 L) and NH4Cl (2.00 L), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give allyl 5- ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (6, 388 g, 985 mmol, 95.8% yield) as yellow oil.

[0336] Step 6: Preparation of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid 135MOFO-358009544Attorney Docket No.: 183952036340

[0337] To a solution of allyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2- carboxylate (3, 50 g, 136 mmol, 1.0 eq.) in DCM (5 L) was added TMSBr (411 g, 2.71 mol, 20.0 eq.) dropwise at 0oC. After addition, the reaction mixture was allowed to warm to room temperature and stirred for an additional 12 h. The reaction progress was monitored by LCMS. After completion, the reaction mixture was concentrated under reduced pressure and water was added. The resulting mixture was filtered and the filter cake was washed with water (2 L), then dried in vacuum to afford ((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid (40.3 g, 129 mmol, 95%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.20 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.87 (s, 1H), 7.43 (d, J = 8.4 Hz, 1H), 6.10-5.98 (m, 1H), 5.46-5.37 (m, 1H), 5.33-5.24 (m, 1H), 4.86-4.77 (m, 2H), 3.08 (d, J = 21.2 Hz, 2H). LCMS (ESI) m / z = 313.1 [M+H]+.

[0338] Step 7: Preparation of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)fluoromethyl)phosphonic acid

[0339] To a solution of allyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2- carboxylate (6, 5.2 g, 13.5 mmol, 1.0 eq.) in DCM (500 mL) was added TMSBr (41.1 g, 270 mmol, 20.0 eq.) dropwise at 0oC. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for an additional 12 h. The reaction progress was monitored by LCMS. After completion, the reaction mixture was concentrated under reduced pressure and water was added. The resulting mixture was filtered and the filter cake was washed with water (200 mL), then dried in vacuum to afford ((2- ((allyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid (3.1 g, 9.37 mmol, 69%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.32 (s, 1H), 8.14-8.05 (m, 2H), 7.59 (d, J = 8.4 Hz, 1H), 6.12-5.99 (m, 1H), 5.84 (dd, J = 44.3, 8.2 Hz, 1H), 5.49-5.40 (m, 1H), 5.35-5.27 (m, 1H), 4.88-4.81 (m, 2H). LCMS (ESI): m / z = 329.1 [M-H]-. Chiral separation of allyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2- carboxylate

[0340] Rac-allyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (617 g, 1.62 mol, 1.00 eq) was purified by SFC to give allyl (S)-5- ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (Peak 1) and allyl (R)- 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (Peak 2). 136MOFO-358009544Attorney Docket No.: 183952036340

[0341] Preparative SFC method: Instrument: Waters 350 Preparative SFC. Column: REGIS (S,S) WHELK-O1, 250×50 mm I.D., 10 µm. Mobile phase: A for CO2 and B for MEOH (Neu). Gradient: B 30 %. Flow rate: 220 g / min. Back pressure: 100 bar. Column temperature: 35 °C. Wavelength: 220 nm. Cycle-time: 3.3 min.

[0342] Analytical SFC method: Column: Kromasil (S,S) WHELK-O1, 50×4.6 mm I.D., 3.5 µm. Mobile phase: A for CO2 and B for MEOH (0.05% DEA). Gradient: B 5 to 40 % Flow rate: 3 mL / min. Back pressure: 100 bar. Column temperature: 35 °C. Wavelength: 220 nm.

[0343] allyl (S)-5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (Peak 1, 267 g, 685 mmol, 39.7% yield, >99 %ee, RT= 1.36 min) was obtained as yellow oil. LCMS (ESI): m / z = 387.1 [M+H]+.

[0344] allyl (R)-5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (Peak 2, 270 g, 676 mmol, 39.2% yield, >99 %ee, RT= 1.55 min) was obtained as yellow oil. LCMS (ESI): m / z = 387.1 [M+H]+.

[0345] Assignment of absolute stereochemical configuration was made by comparison of experimental vibrational circular dichroism (VCD) spectra with theoretical VCD spectra obtained from DFT calculations.

[0346] The intermediates in the table below were prepared using the method described above in Step 7 for the preparation of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)fluoromethyl)phosphonic acid and utilizing the appropriate starting materials and modifications.137MOFO-358009544Attorney Docket No.: 183952036340 Synthesis of 5-(((2,6-dimethylphenoxy)(((S)-1-oxo-1-propoxypropan-2- yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0347] Step 1: Preparation of allyl 5-(((2,6-dimethylphenoxy)(((S)-1-oxo-1- propoxypropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0348] To a suspension of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid (0.150 g, 480 µmol, 1 eq) and 1 drop of DMF (cat.) in DCM (4 mL) at 0 °C was added oxalyl chloride (122 µL, 1.44 mmol, 3 eq) and the mixture was stirred for 2 days at room temperature. The reaction was concentrated under reduced pressure and then dried under high vacuum for 20 min. The crude residue was diluted in toluene (5 mL). A solution of 2,6-dimethylphenol (58.6 mg, 480 µmol, 1 eq) and triethylamine (333 µL, 2.40 mmol, 5 eq) in toluene (2 mL, dried with sodium sulfate) was added to the mixture and stirred at 90 °C for 3 h. Propyl (2S)-2-aminopropanoate hydrochloride (80.4 mg, 480 µmol, 1 eq) was added at once at 90 °C and the reaction was stirred at 90°C for 2 h. The reaction was cooled down to room temperature and quenched with 2 drops of water and toluene was removed under reduced pressure. The product was purified by reverse phase chromatography on a 100 g C18cartridge eluting with a gradient of 5-100% acetonitrile in water (with 0.1% formic acid) to afford allyl 5-(((2,6-dimethylphenoxy)(((S)-1-oxo-1- propoxypropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (50.0 mg, 19.6%) as a pale yellow oil. LCMS (ESI) m / z = 530.4 [M+H]+.

[0349] The intermediates in the table below were prepared using the method described above in Step 1 for the preparation of allyl 5-(((2,6-dimethylphenoxy)(((S)-1-oxo-1- 138MOFO-358009544Attorney Docket No.: 183952036340 propoxypropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate and utilizing the appropriate starting materials and modifications.139MOFO-358009544Attorney Docket No.: 183952036340140MOFO-358009544Attorney Docket No.: 183952036340141MOFO-358009544Attorney Docket No.: 183952036340142MOFO-358009544Attorney Docket No.: 183952036340

[0350] Step 2: Preparation of 5-(((2,6-dimethylphenoxy)(((S)-1-oxo-1-propoxypropan-2- yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0351] To a stirred solution of allyl 5-(((2,6-dimethylphenoxy)(((S)-1-oxo-1- propoxypropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (50 mg, 94.4 µmol, 1 eq) in THF (4 mL) were added morpholine (40.6 µL, 472 µmol, 5 eq) and Pd(PPh3)4 (3.27 mg, 2.83 µmol, 0.03 eq) under nitrogen. The reaction mixture was stirred at room temperature 1 h. The solvent was removed under reduced pressure and the product was directly purified by reverse phase chromatography on a 100 g C18cartridge eluting with a gradient of 5-80% acetonitrile in water (with 0.1% formic acid) to afford 5-(((2,6- dimethylphenoxy)(((S)-1-oxo-1-propoxypropan-2- yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (36.0 mg, 77.9%) as a pale yellow solid.1H NMR (400 MHz, CDCl3) δ 7.93 - 7.84 (m, 1H), 7.83 - 7.71 (m, 2H), 7.48 - 7.36 (m, 1H), 7.08 - 6.93 (m, 3H), 4.17 - 3.98 (m, 3H), 3.59 - 3.42 (m, 2H), 2.37 (s, 3H), 2.30 (s, 3H), 1.65 - 1.57 (m, 2H), 1.27 - 1.22 (m, 3H), 1.15 - 1.11 (m, 1H), 0.94 - 0.88 (m, 3H). 143MOFO-358009544Attorney Docket No.: 183952036340

[0352] The intermediates in the table below were prepared using the method described above in Step 2 for the preparation of 5-(((2,6-dimethylphenoxy)(((S)-1-oxo-1- propoxypropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid and utilizing the appropriate starting materials and modifications.144MOFO-358009544Attorney Docket No.: 183952036340145MOFO-358009544Attorney Docket No.: 183952036340146MOFO-358009544Attorney Docket No.: 183952036340147MOFO-358009544Attorney Docket No.: 183952036340 Synthesis of 5-((morpholino(((S)-1-oxo-1-propoxypropan-2- yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0353] Step 1: Synthesis of allyl 5-((chloro(((S)-1-oxo-1-propoxypropan-2- yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0354] Oxalyl chloride (10 mL) was added dropwise to the solution of ((2- ((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (1 g, 3.20 mmol, 1.0 eq.) in dry DCM (20 mL) and DMF (1 drop) at 20oC. The reaction mixture was stirred at 25 °C for an additional 1 hr. The reaction was monitored by pipetting out a small amount of crude sample and quenching it with MeOH to ensure bis-Cl phosphoryl chloride had been formed completely (bis-methoxy phosphonate was observed by LCMS). After completion, the excess oxalyl chloride and solvent were removed under reduced pressure to afford allyl 5- ((dichlorophosphoryl)methyl)benzo[b]thiophene-2-carboxylate (960 mg, 2.74 mmol, 86%). allyl 5-((dichlorophosphoryl)methyl)benzo[b]thiophene-2-carboxylate (100 mg, 251 µmol, 1.0 eq.) was re-dissolved in anhydrous DCM (2 mL), then added to a mixture of propyl L- alaninate (36 mg, 276 µmol, 1.1 eq.) and triethylamine (101 mg, 1.00 mmol, 4.0 eq.) in anhydrous DCM (2 mL) at 0oC. The reaction was allowed to warm to 25 °C, and stirred for an additional 15 min. The reaction progress was monitored by LCMS, and after completion, the reaction mixture was used in next Step directly without further purification.

[0355] Step 2: Synthesis of allyl 5-((morpholino(((S)-1-oxo-1-propoxypropan-2- yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate 148MOFO-358009544Attorney Docket No.: 183952036340

[0356] Allyl 5-((chloro(((S)-1-oxo-1-propoxypropan-2- yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (200 mg, 450 µmol, 1.0 eq.) as a solution in DCM (5 mL) was added to a solution of morpholine (196 mg, 2.25 mmol, 5 eq.) and triethylamine (TEA) (273 mg, 2.7 mmol, 6 eq.) in DCM (1 mL). The mixture was stirred at 25 °C for 15 min, at which time LCMS showed formation of product. The mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give allyl 5-((morpholino(((S)-1-oxo-1-propoxypropan-2- yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (82 mg, 0.17 mmol, 38%) as a white solid. LCMS (ESI): m / z = 495 [M+H]+.

[0357] The intermediates in the table below were prepared using the method described above in Step 2 for the preparation of allyl 5-((morpholino(((S)-1-oxo-1-propoxypropan-2- yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate and utilizing the appropriate starting materials and modifications.149MOFO-358009544Attorney Docket No.: 183952036340

[0358] Step 3: Synthesis of 5-((morpholino(((S)-1-oxo-1-propoxypropan-2- yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0359] To a solution of allyl 5-((morpholino(((S)-1-oxo-1-propoxypropan-2- yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (82 mg, 0.17 mmol, 1.0 eq) in DCM (3 mL) were added Pd(PPh3)4(20 mg, 17 µmol, 0.1 eq.) and pyrrolidine (12 mg, 0.17 mmol, 1.0 eq.). The mixture was purged and degassed with N2 (three times), then stirred at 25 °C for 0.5 h. After completion, the mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give 5-((morpholino(((S)- 1-oxo-1-propoxypropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (50 mg, 0.11 mmol, 65%) as a white solid. LCMS (ESI): m / z = 455 [M+H]+.

[0360] The intermediates in the table below were prepared using the method described above in Step 3 for the preparation of 5-((morpholino(((S)-1-oxo-1-propoxypropan-2- yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid and utilizing the appropriate starting materials and modifications.150MOFO-358009544Attorney Docket No.: 183952036340Synthesis of 5-(((((S)-4-methoxy-1-oxo-1-propoxybutan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0361] Step 1: Preparation of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)(2- oxopyrrolidin-1-yl)phosphinic acid

[0362] Oxalyl chloride (10 mL) was added dropwise to the solution of ((2- ((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (300 mg, 960 µmol, 1 eq.) in dry DCM (20 mL) and DMF (0.1 mL) at 0oC. The reaction mixture was stirred at 40 °C for an additional 1 hr. The reaction was monitored by pipetting out a small amount of crude sample and quenching it with MeOH to ensure bis-Cl phosphoryl chloride had been formed completely (bis-methoxy phosphonate was observed by LCMS). After completion, the excess oxalyl chloride and solvent were removed under reduced pressure to afford allyl 5- ((dichlorophosphoryl)methyl)benzo[b]thiophene-2-carboxylate (300 mg). The residue (300 mg, 859 µmol, 1 eq.) was re-dissolved in anhydrous DCM (5 mL), then added to a mixture of pyrrolidin-2-one (218 mg, 2.57 mmol, 3 eq.) and TEA (259 mg, 2.57 mmol, 3 eq.) in anhydrous DCM (10 mL) at 0oC. The reaction was allowed to warm to 25 °C and stirred for 151MOFO-358009544Attorney Docket No.: 183952036340 an additional 2 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give ((2- ((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)(2-oxopyrrolidin-1-yl)phosphinic acid (100 mg, 263 µmol, 31%) as a colorless oil. LCMS (ESI): m / z = 380 [M+H]+.

[0363] Step 2: Preparation of allyl 5-(((((S)-1-oxo-1-propoxypropan-2-yl)amino)(2- oxopyrrolidin-1-yl)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0364] Oxalyl chloride (201 mg, 1.59 mmol, 5 eq.) was added dropwise to the solution of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)(2-oxopyrrolidin-1-yl)phosphinic acid (100 mg, 320 µmol, 1 eq.) in dry DCM (5 mL) and DMF (0.1 mL) at 0oC. The reaction mixture was stirred at 40 °C for an additional 1 hr. The reaction was monitored by pipetting out a small amount of crude sample and quenching it with MeOH to ensure mono-Cl phosphoryl chloride had been formed completely (mono-methoxy phosphonate was observed by LCMS). After completion, the excess oxalyl chloride and solvent were removed under reduced pressure to afford allyl 5-((chloro(2-oxopyrrolidin-1- yl)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (100 mg). The residue (100 mg, 251 µmol, 1 eq.) was re-dissolved in anhydrous DCM (10 mL), then added to a mixture of propyl L-alaninate (65.8 mg, 502 µmol, 2 eq.) and TEA (101 mg, 1.00 mmol, 4 eq.) in anhydrous DCM (10 mL) at 0oC. The reaction was allowed to warm to 25 °C and stirred for an additional 2 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give allyl 5- (((((S)-1-oxo-1-propoxypropan-2-yl)amino)(2-oxopyrrolidin-1- yl)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (23.0 mg, 46.6 µmol, 19%) as a colorless oil. LCMS (ESI): m / z = 493 [M+H]+.

[0365] Step 3: Preparation of 5-(((((S)-1-oxo-1-propoxypropan-2-yl)amino)(2- oxopyrrolidin-1-yl)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0366] To a solution of allyl 5-(((((S)-1-oxo-1-propoxypropan-2-yl)amino)(2- oxopyrrolidin-1-yl)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (22 mg, 44.6 µmol, 1 eq) in DCM (2 mL) were added Pd(PPh3)4 (5 mg, 4.46 µmol, 0.1 eq.) and pyrrolidine (3 mg, 44.6 µmol, 1.0 eq.). The mixture was purged and degassed with N2 (three times), then stirred at 25 °C for 0.5 h. After completion, the mixture was quenched with HCl aqueous solution (1 N) and extracted with DCM (10 mL x 3). The organic layers were combined and 152MOFO-358009544Attorney Docket No.: 183952036340 washed with brine (15 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give 5- (((((S)-4-methoxy-1-oxo-1-propoxybutan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (13.0 mg, 28.7 µmol, 65%) as a colorless oil. LCMS (ESI): m / z = 453 [M+H]+. Synthesis of 5-((bis((S)-2-(propoxycarbonyl)pyrrolidin-1- yl)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0367] Step 1: Preparation of propyl L-prolinate

[0368] To a solution of (2S)-pyrrolidine-2-carboxylic acid (2.00 g, 17.3 mmol, 1 eq) in propan-1-ol (13.0 mL, 266 mmol) at -78 °C was added dropwise thionyl chloride (3.76 mL, 51.9 mmol, 3 eq). The mixture was allowed to warm to room temperature and then heated at 80 °C overnight. The reaction mixture was concentrated under reduced pressure and the crude propyl L-prolinate (2.62 g, 16.6 mmol, 96.6%) was isolated as an orange sticky oil that was used directly in the next Step. LCMS (ESI): m / z = 158.1 [M+H]+.

[0369] Step 2: Preparation of dipropyl (((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphoryl)(S)-di-L-prolinate 153MOFO-358009544Attorney Docket No.: 183952036340

[0370] To a solution of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid (300 mg, 0.9606 mmol, 1 eq) in DCM (10 mL) at 0 °C were added 2 drops of DMF (cat) and oxalyl chloride (246 µL, 2.88 mmol, 3 eq). The solution was stirred at 0 °C and was allowed to warm slowly to room temperature overnight. The reaction was concentrated under reduced pressure and then dried under high vacuum during 30 min. The crude residue was diluted in DCM (10 mL, dried with Na2SO4) and cooled down to 0 °C. A solution of propyl L-prolinate (603 mg, 3.84 mmol, 4 eq) and triethylamine (668 µL, 4.80 mmol, 5 eq) in DCM (3 mL, dried with Na2SO4) was added and the mixture was stirred at room temperature for 3 d. The reaction was concentrated under reduced pressure and the crude residue was purified by reverse phase chromatography on a 150 g C18 cartridge eluting with 5-100% MeCN in water (with 0.1% formic acid) to give propyl dipropyl (((2- ((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphoryl)(S)-di-L-prolinate (274 mg, 48.3%) as an orange oil. LCMS (ESI): m / z = 591.2 [M+H]+.

[0371] The intermediates in the table below were prepared using the method described above in Step 2 for the preparation of dipropyl (((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphoryl)(S)-di-L-prolinate and utilizing the appropriate starting materials and modifications.

[0372] Step 3: Preparation of 5-((bis((S)-2-(propoxycarbonyl)pyrrolidin-1- yl)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0373] To a solution of propyl dipropyl (((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphoryl)(S)-di-L-prolinate (274 mg, 0.4638 mmol, 1 eq) in THF (30 mL) were added morpholine (199 µL, 2.31 mmol, 5 eq) and Pd(PPh3)4(53.5 mg, 0.04638 mmol, 0.10 eq). The reaction mixture was stirred at room temperature for 2 h and THF was removed under reduced pressure. The crude residue was purified by reverse phase chromatography on a 100 g C18 cartridge eluting with 5-100% MeCN in water (with 0.1% formic acid) to give 5- 154MOFO-358009544Attorney Docket No.: 183952036340 ((bis((S)-2-(propoxycarbonyl)pyrrolidin-1-yl)phosphoryl)methyl)benzo[b]thiophene-2- carboxylic acid (203 mg, 79.6%) as a white solid. LCMS (ESI): m / z = 551.2 [M+H]+.

[0374] The intermediates in the table below were prepared using the method described above in Step 2 for the preparation of 5-((bis((S)-2-(propoxycarbonyl)pyrrolidin-1- yl)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid and utilizing the appropriate starting materials and modifications.Synthesis of 5-(((((S)-1-isopropoxy-3-methoxy-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid:

[0375] Step 1: Preparation of allyl 5-(((((S)-1-isopropoxy-3-methoxy-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0376] To a solution of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid (49.3 mg, 158 µmol, 1 eq.), propan-2-yl (2S)-2-amino3- 155MOFO-358009544Attorney Docket No.: 183952036340 methoxypropanoate hydrochloride (31.2 mg, 158 µmol, 1 eq.) and phenol (19.3 mg, 206 µmol, 1.3 eq.) in pyridine (3 mL ) were added N,N-diisopropylethylamine (162 mg, 1.26 mmol, 8 eq.), 2,2-dipyridyl-disulfide (140 mg, 635 µmol, 4 eq.) and triphenylphosphine (166 mg, 635 µmol, 4 eq.) at 25 °C. The mixture was heated to 60 °C and stirred at 60 °C for 48 h under N2atmosphere. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to afford allyl 5-(((((S)-1-isopropoxy-3-methoxy-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (35.0 mg, 65.8 µmol, 42%) as a yellow solid. LCMS (ESI): m / z = 532 [M+H]+.

[0377] The intermediates in the table below were prepared using the method described above in Step 1 for the preparation of allyl 5-(((((S)-1-isopropoxy-3-methoxy-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate and utilizing the appropriate starting materials and modifications.

[0378] Step 2: Preparation of 5-(((((S)-1-isopropoxy-3-methoxy-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid 156MOFO-358009544Attorney Docket No.: 183952036340

[0379] To a solution of allyl 5-(((((S)-1-isopropoxy-3-methoxy-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (2, 150 mg, 282 µmol, 1 eq) in DCM (5 mL) were added Pd(PPh3)4 (65.1 mg, 56.4 µmol, 0.2 eq.) and pyrrolidine (20.0 mg, 282 µmol, 1.0 eq.). The mixture was purged and degassed with N2(three times), then stirred at 25 °C for 1 hr. After completion, the mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give 5-(((((S)-1-isopropoxy-3-methoxy-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (120 mg, 244 µmol, 87%) as a yellow solid. LCMS (ESI): m / z = 492.1 [M+H]+.

[0380] The intermediates in the table below were prepared using the method described above in Step 2 for the preparation of 5-(((((S)-1-isopropoxy-3-methoxy-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid and utilizing the appropriate starting materials and modifications.Synthesis of 5-(1-fluoro-1-((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)ethyl)benzo[b]thiophene-2-carboxylic acid 157MOFO-358009544Attorney Docket No.: 183952036340

[0381] Step 1: Preparation of allyl 5-(1-(diethoxyphosphoryl)-1- fluoroethyl)benzo[b]thiophene-2-carboxylate

[0382] To a solution of allyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2- carboxylate (2.66 g, 6.88 mmol, 1 eq) in THF (50 mL) at -78oC were added 1 M LiHMDS in THF (6.88 mL, 6.88 mmol, 1 eq) and methyl iodide (850 µL, 13.7 mmol, 2 eq) dropwise. The mixture was stirred at -78oC for 5 min. The reaction was quenched with a saturated aqueous solution of ammonium chloride (30 mL), warmed up to room temperature and the product was extracted with EtOAc (2 x 100 mL). The combined organic extracts were dried with sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by reverse phase chromatography on a 150 g C18cartridge eluting with a gradient of 5-80% acetonitrile in water (with 0.1% formic acid). The fractions were combined and concentrated under reduced pressure to give allyl 5-(1-(diethoxyphosphoryl)-1- fluoroethyl)benzo[b]thiophene-2-carboxylate (1.44 g, 52.3%) as a brown oil. LCMS (ESI) m / z = 401.2

[0383] Step 2: Preparation of (1-(2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)-1- fluoroethyl)phosphonic acid

[0384] To a solution of allyl 5-(1-(diethoxyphosphoryl)-1-fluoroethyl)benzo[b]thiophene- 2-carboxylate (1.44 g, 3.59 mmol, 1 eq) in DCM (30 mL) at 0°C were added N,O- 158MOFO-358009544Attorney Docket No.: 183952036340 bis(trimethylsilyl)trifluoroacetamide (4.74 mL, 17.9 mmol) followed by slow addition of trimethylsilyl iodide (1.52 mL, 10.7 mmol, 3 eq) in DCM (2 mL). The solution was stirred at 0°C for 1 h. The reaction was quenched with the addition of a 2:1 solution of water and acetonitrile (with 0.1% TFA) (2 mL). The solvent was removed under reduced pressure. The crude residue was purified by reverse phase chromatography on a 150 g C18cartridge eluting with a gradient of 5-60% acetonitrile in water (with 0.1% formic acid). The combined fractions were concentrated and freeze-dried to give (1-(2- ((allyloxy)carbonyl)benzo[b]thiophen-5-yl)-1-fluoroethyl)phosphonic acid (887 mg, 72.1%) as a pale-yellow solid.1H NMR (400 MHz, DMSO-d6) 11.84 - 11.05 (m, 2H), 8.34 - 8.28 (m, 1H), 8.12 - 8.02 (m, 2H), 7.66 - 7.56 (m, 1H), 6.12 - 5.98 (m, 1H), 5.49 - 5.39 (m, 1H), 5.35 - 5.27 (m, 1H), 4.89 - 4.81 (m, 2H), 1.96 - 1.78 (m, 3H).

[0385] Step 3: Preparation of allyl 5-(1-fluoro-1-((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)ethyl)benzo[b]thiophene-2-carboxylate

[0386] To a suspension of (1-(2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)-1- fluoroethyl)phosphonic acid (160 mg, 464 µmol, 1 eq) and 1 drop of DMF (cat) in DCM (30 mL) at 0°C was added oxalyl chloride (118 µL, 1.39 mmol, 3 eq) and the reaction was stirred for 20 h. The reaction was concentrated under reduced pressure and then dried under high vacuum during 10 min. The crude residue was diluted in 1,2-dichloroethane (3 mL) and a solution of phenol (43.6 mg, 464 µmol, 1 eq) and triethylamine (322 µL, 2.32 mmol, 5 eq) in 1,2-dichloroethane (3 mL, dried with Na2SO4) was added to the mixture which was stirred at 45°C for 3 h. Propyl (2S)-2-aminopropanoate hydrochloride (77.7 mg, 464 µmol, 1 eq) in dichloromethane (10 mL, dried with Na2SO4) was added directly to the solution and stirred at room temperature overnight. The reaction mixture was quenched with water and the dichloromethane was removed in vacuo. The product was purified by reverse phase chromatography on a 50 g C18 cartridge eluting with a gradient of 5-100% acetonitrile in water (with 0.1% formic acid) to afford allyl 5-(1-fluoro-1-((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)ethyl)benzo[b]thiophene-2-carboxylate (30.0 mg, 12%).1H NMR (400 MHz, CDCl3) δ 8.12 - 8.02 (m, 2H), 7.93 - 7.82 (m, 1H), 7.72 - 7.64 (m, 1H), 7.38 - 7.28 (m, 1H), 7.25 - 7.13 (m, 2H), 7.09 - 7.00 (m, 1H), 7.00 - 6.92 (m, 1H), 6.13 - 5.98 (m, 1H), 5.45 (br d, J = 17.1 Hz, 1H), 5.33 (br d, J = 10.5 Hz, 1H), 4.86 (br d, J = 4.9 Hz, 2H), 4.25 - 4.11 (m, 0.5H), 4.10 - 4.00 (m, 1H), 3.95 - 3.76 (m, 1H), 3.68 - 3.48 (m, 1.25H), 3.45 - 3.36 (m, 0.25H), 2.44 - 2.74 (m, 1H), 2.17 - 2.01 (m, 3H), 1.70 - 1.59 (m, 1H), 1.56 - 159MOFO-358009544Attorney Docket No.: 183952036340 1.46 (m, 0.5H), 1.45 - 1.33 (m, 0.5H), 1.32 - 1.23 (m, 1.5H), 1.13 - 1.05 (m, 0.5H), 0.97 - 0.89 (m, 1.5H), 0.87 - 0.80 (m, 0.5H), 0.80 - 0.72 (m, 1H).

[0387] Step 4: Preparation of 5-(1-fluoro-1-((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)ethyl)benzo[b]thiophene-2-carboxylic acid

[0388] To a stirred solution of allyl 5-(1-fluoro-1-((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)ethyl)benzo[b]thiophene-2-carboxylate (30 mg, 56.2 µmol, 1 eq) in THF (3 mL) were added morpholine (24.1 µL, 281 µmol, 5 eq) and Pd(PPh3)4(3.24 mg, 2.81 µmol, 0.05 eq) under nitrogen. The reaction mixture was stirred at room temperature for 1 h. The reaction was concentrated and the crude was directly purified by reverse phase chromatography on a 50 g C18 cartridge eluting with a gradient of 5-100% acetonitrile in water (with 0.1% formic acid) to afford 5-(1-fluoro-1-((((S)-1-oxo-1- propoxypropan-2-yl)amino)(phenoxy)phosphoryl)ethyl)benzo[b]thiophene-2-carboxylic acid (30.0 mg, 108%) as a beige solid. LCMS (ESI) m / z = 494.2 [M+H]+. Synthesis of perfluorophenyl 5-(((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate160MOFO-358009544Attorney Docket No.: 183952036340

[0389] Step 1: Preparation of allyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2- carboxylate

[0390] To a solution of 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (25 g, 76 mmol,1eq) in DMF (250 mL) was added Na2CO3(20 g, 190 mmol, 2.5 eq) and 3-bromoprop-1-ene (23 g, 190 mmol, 2.5 eq), the mixture was stirred at 25 °C for 12 h. The mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL × 3). The combined organic layers were washed with brine (500 mL × 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give allyl 5- ((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (25 g, 68 mmol, 89% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.79 - 7.67 (m, 2H), 7.39 - 7.28 (m, 1H), 6.05 - 5.88 (m, 1H), 5.43 - 5.33 (m, 1H), 5.29 - 5.20 (m, 1H), 4.83 - 4.73 (m, 2H), 4.00 - 3.88 (m, 4H), 3.29 - 3.11 (m, 2H), 1.18 (d, J = 6.4 Hz, 6H).

[0391] Step 2: Preparation of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid

[0392] To a solution of allyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2- carboxylate (25 g, 68 mmol, 1 eq) in DCM (250 mL) was added TMSI (54 g, 272 mmol, 4 eq) in a dropwise manner at 0 °C, the mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a yellow oil. The oil was purified by reversed phase (TFA) to lyophilized to give ((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid (13 g, 42 mmol, 61% yield) as a white solid. LCMS (ESI) m / z = 313.2 [M+H]+.

[0393] Step 3: Preparation of allyl 5-((dichlorophosphoryl)methyl)benzo[b]thiophene-2- carboxylate

[0394] To a solution of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid (2.0 g, 6.4 mmol, 1 eq) in DCM (30 mL) was added DMF (0.09 mL) and was cooled to 0 °C, then oxalic dichloride (2.4 g, 19.2 mmol, 3 eq) was dropwise, after that the reaction was warmed to 40 °C and was stirred 1 h to give a yellow clean solution. The reaction mixture was concentrated under reduced pressure to give allyl 5 ((dichlorophosphoryl)methyl)benzo[b]thiophene-2-carboxylate (2.0 g, crude) as a brassy yellow solid. LCMS (ESI) m / z = 341.2 [M+H]+. 161MOFO-358009544Attorney Docket No.: 183952036340

[0395] Step 4: Preparation of allyl 5-(((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0396] To a solution of allyl 5-((dichlorophosphoryl)methyl)benzo[b]thiophene-2- carboxylate (2.0 g, crude, 1 eq) in DCM (40 mL) was cooled to 0 °C and was added a solution of phenol (0.43 g, 4.58 mmol, 1 eq) in DCM (8 mL), then ethylbis(propan-2- yl)amine (2.2 g, 17 mmol, 3 eq) in DCM (50 mL) was dropwise over 0.5 h. Then propyl L- alaninate hydrochloride (1.44 g, 1.58 mmol, 1.5 eq) in DCM (8 mL) was added, the mixture was stirred at 0 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give allyl 5-(((((S)- 1-oxo-1-propoxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2- carboxylate (1.4 g, 2.8 mmol, 43.8% yield) as a yellow oil. LCMS (ESI) m / z = 502.2 [M+H]+.

[0397] Step 5: Preparation of 5-(((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0398] To a solution of allyl 5-(((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (1.4 g, 2.8 mmol) in DCM (20 mL) was added Pd(PPh3)4(0.3 g, 0.3 mmol, 0.1 eq) and pyrrolidine (0.4 g, 5.6 mmol, 2 eq). Then the reaction was stirred at 25 °C for 15 min to give a yellow clean solution. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (TFA) to freeze-drying to give 5-(((((S)-1-oxo-1- propoxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (1.1 g, 2.4 mmol, 85.9% yield) as a yellow oil. LCMS (ESI) m / z = 461.9 [M+H]+.1H NMR (400 MHz, CDCl3) δ 7.91 – 7.86 (m, 1H), 7.84 – 7.76 (m, 2H), 7.45 – 7.38 (m, 1H), 7.38 – 7.31 (m, 2H), 7.27 – 7.15 (m, 3H), 4.28 – 3.95 (m, 3H), 3.56 – 3.42 (m, 2H), 1.64 (td, J = 7.2, 14.0 Hz, 2H), 1.33 – 1.18 (m, 3H), 0.93 (dt, J = 4.8, 7.2 Hz, 3H).

[0399] Step 6: Preparation of perfluorophenyl 5-(((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0400] To a solution of 5-(((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (19 g, 41 mmol, 1 eq) and pyridine (11 g, 0.14 mol, 3.5 eq) in DMF (100 mL) was cooled to 0 °C, then the solution of perfluorophenyl 2,2,2-trifluoroacetate (57 g, 0.21 mol, 5 eq) was dropwise added 162MOFO-358009544Attorney Docket No.: 183952036340 to the mixture at 0 °C. Then the mixture was stirred at 0 °C for 1 h to give a yellow solution. The mixture was diluted with water (500 mL) and extracted with EtOAc (500 mL × 3), the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give perfluorophenyl 5-(((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (17 g, 27 mmol, 65% yield) was obtained as a yellow oil. LCMS (ESI) m / z = 628.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.33 - 8.23 (m, 1H), 8.03 - 7.85 (m, 2H), 7.60-7.53 (m, 1H), 7.28 (s, 2H), 7.20 - 7.05 (m, 3H), 4.08 - 3.87 (m, 3H), 3.55 - 3.42 (m, 2H), 1.63-1.52 (m, 2H), 1.19-1.15 (m, 3H), 0.95 - 0.83 (m, 3H). Synthesis of perfluorophenyl 5-((S)-fluoro((R)-(((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate163MOFO-358009544Attorney Docket No.: 183952036340

[0401] Step 1: Preparation of (S)-((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)fluoromethyl)phosphonic acid

[0402] To a solution of allyl (S)-5- ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (20 g, 52 mmol, 1 eq) in methylene chloride (500 mL) was added trimethylsilyl iodide (21 g, 0.10 mol, 2 eq). The mixture was stirred at 0 °C for 1 hour to give a brown solution. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction residue was purified by prep-HPLC (TFA) to lyophilized to give (S)-((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)fluoromethyl)phosphonic acid (12 g, 36 mmol, 70% yield) as a brown solid. LCMS (ESI) m / z = 330.9

[0403] Step 2: Preparation of allyl (S)-5- ((dichlorophosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate

[0404] To a solution of (S)-((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)fluoromethyl)phosphonic acid (11 g, 33 mmol, 1 eq) in methylene chloride (200 mL) was added dimethylformamide (0.24 g, 3.3 mmol, 0.1 eq) at 0 °C under N2 atmosphere, then oxalyl chloride (13 g, 0.10 mol, 3 eq) was added dropwise and stirred at 0 °C for 30 minutes 164MOFO-358009544Attorney Docket No.: 183952036340 and warmed to 40 °C for 1 hour to give a brown solution. The reaction mixture was concentrated under reduced pressure to give allyl (S)-5- ((dichlorophosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (11 g crude) as a yellow solid. LCMS (ESI) m / z = 358.9.

[0405] Step 3: Preparation of allyl 5-((1S)-fluoro((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0406] To a solution of (S)-5-((dichlorophosphoryl)fluoromethyl)benzo[b]thiophene-2- carboxylate (11 g, 30 mmol, 1 eq) in methylene chloride (150 mL) was added phenol (2.2 g, 24 mmol, 0.8 eq) in methylene chloride (20 mL) in 10 minutes at 0 °C, then the solution of N,N-diisopropylethylamine (12 g, 90 mmol, 3 eq) in methylene chloride (200 mL) was dropwise over 1.5 hours and the mixture was stirred at 25 °C for 5 minutes to give a yellow clean solution then the solution of propyl (2S)-2-aminopropanoate (3.9 g, 30 mmol, 1 eq) in methylene chloride (20 mL) was added, the mixture was stirred at 25 °C for 1 hour to give a yellow clean solution. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give allyl 5-((1S)- fluoro((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (7.4 g, 14.2 mmol, 47% yield) as a yellow solid. LCMS (ESI) m / z = 520.2

[0407] Step 4: Preparation of 5-((1S)-fluoro((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0408] To a solution of allyl 5-((1S)-fluoro((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (3.5 g, 6.7 mmol, 1 eq) in methylene chloride (40 mL) at 0 °C under N2 atmosphere, then pyrrolidine (0.38 g, 5.4 mmol, 0.8 eq) and Pd(PPh3)4(0.7 g, 0.67 mmol, 0.11 eq) was added dropwise and stirred at 0 °C for 10 minutes and warmed to 25 °C for 10 minutes to give a brown solution. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction residue was purified by prep-HPLC (TFA) to lyophilized to give 5-((1S)-fluoro((((S)-1-oxo-1- propoxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (2.8 g, 5.9 mmol, 87% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 11.2 Hz, 2H), 7.97 (d, J = 8.4 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 7.38 - 7.30 (m, 2H), 7.19 (d, 165MOFO-358009544Attorney Docket No.: 183952036340 J = 7.6 Hz, 3H), 6.20 - 5.99 (m, 1H), 4.05 - 3.77 (m, 3H), 1.68 - 1.42 (m, 2H), 1.22 (d, J = 7.2 Hz, 3H), 0.89 - 0.85 (m, 3H)

[0409] Step 5: Preparation of perfluorophenyl 5-((S)-fluoro((R)-(((S)-1-oxo-1- propoxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate and perfluorophenyl 5-((S)-fluoro((S)-(((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0410] To a solution of 5-((1S)-fluoro((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (3.0 g, 6.3 mmol, 1 eq) in pyridine (15 mL) at 0 °C under N2 atmosphere, then 2,3,4,5,6- pentafluorophenyl 2,2,2-trifluoroacetate (5.2 g, 19 mmol, 3 eq) was added dropwise and stirred at 0 °C for 10 minutes and warmed to 25 °C for 1 hour to give a brown solution. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography in 3:1 Petroleum ether / ethyl acetate to give the separated Phos isomers. The analogous (R)-F isomer was made in a similar manner. Analytical data for all 4 isomers are listed in the table below. SFC conditions used in the peak assignments are as follows: Chiralpak AS-350x4.6mm I.D., 3um. Mobile phase: Phase A for CO2, and Phase B for EtOH (0.05%DEA); Gradient elution: B in A from 5% to 40%. Flow rate: 3mL / min; Detector: PDA;Column Temp: 35C;Back Pressure: 100Bar.166MOFO-358009544Attorney Docket No.: 183952036340167MOFO-358009544Attorney Docket No.: 183952036340

[0411] The intermediates in the table below were prepared using the synthetic procedure described above Synthesis of perfluorophenyl 5-((S)-fluoro((R)-(((S)-1-oxo-1-propoxypropan- 2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate and utilizing the appropriate starting materials and modifications. 168MOFO-358009544Attorney Docket No.: 183952036340

[0412] The intermediates in the table below were prepared using the synthetic procedure described above for allyl 5-((1S)-fluoro((((S)-1-oxo-1-propoxypropan-2- 169MOFO-358009544Attorney Docket No.: 183952036340 yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate and utilizing the appropriate starting materials and modifications.

[0413] The chiral intermediates in the table below were obtained by chiral SFC separation of the corresponding P-isomer mixtures, which were prepared using the synthetic procedure described above for allyl 5-((1S)-fluoro((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate and utilizing the appropriate starting materials and modifications. Absolute stereochemical configuration at phosphorus is arbitrarily assigned as drawn.170MOFO-358009544Attorney Docket No.: 183952036340

[0414] The intermediates in the table below were prepared using the synthetic procedure described above for 5-((1S)-fluoro((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid and utilizing the appropriate starting materials and modifications.

[0415] The intermediates in the table below were prepared using the protocol described above for synthesis of 5-(((((S)-1-isopropoxy-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid and utilizing the appropriate starting materials and modifications.171MOFO-358009544Attorney Docket No.: 183952036340Synthesis of perfluorophenyl 5-((R)-fluoro((S)-(((S)-1-(neopentyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate and perfluorophenyl 5-((R)-fluoro((R)-(((S)-1-(neopentyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate 172MOFO-358009544Attorney Docket No.: 183952036340

[0416] Step 1: Preparation of allyl (R)-5- ((dichlorophosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate

[0417] To a solution of (R)-((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)fluoromethyl)phosphonic acid (2.0 g, 6.1 mmol, 1.0 eq) in DCM (30 mL) was added 3 drops of DMF (0.03 mL) cooled to 0 °C, then the reaction was added oxalyl chloride (2.3 g, 18.1 mmol, 3 eq) slowly, after that the reaction was warmed to 45 °C and stirred 20 min to give a yellow clean solution. The reaction mixture was concentrated under reduced pressure to give allyl (R)-5-((dichlorophosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (2.0 g, crude) as a yellow oil and was used into the next Step without further purification. LCMS (ESI) m / z=358.9 [M+H]+.

[0418] Step 2: Preparation of allyl 5-((1R)-fluoro((((S)-1-(neopentyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate 173MOFO-358009544Attorney Docket No.: 183952036340

[0419] To a solution of allyl (R)-5- ((dichlorophosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (2.0 g, 5.4 mmol, 1.0 eq) in DCM (40 mL) was cooled to 0 °C and was added a solution of phenol (0.5 g, 5.4 mmol, 1.0 eq) in DCM (10 mL), then the mixture was added N,N-diisopropylethylamine (2.1 g, 16 mmol, 3.0 eq) in DCM (40 mL) dropwise. The reaction was stirred at 0 °C for 10 min and was added 2,2-dimethylpropyl (2S)-2-aminopropanoate (0.9 g, 5.4 mmol, 1.0 eq) in DCM (20 mL). Then the reaction was warmed to 25 °C and stirred for 1 h to give a light- yellow clean solution. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel to get allyl 5-((1R)-fluoro((((S)-1-(neopentyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (1.7 g, 3.1 mmol, 57% yield) was obtained as a yellow oil. LCMS (ESI) m / z=548.2.1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 8.07 - 7.99 (m, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.68 - 7.59 (m, 1H), 7.41 - 7.25 (m, 3H), 7.23 - 7.06 (m, 3H), 6.12 - 5.90 (m, 2H), 5.48 - 5.44 (m, 1H), 5.39 - 5.30 (m, 1H), 4.87 (d, J = 5.6 Hz, 2H), 4.22 - 4.07 (m, 2H), 3.90 - 3.83 (m, 1H), 3.74 - 3.63 (m, 2H), 1.38 - 1.30 (m, 3H), 0.92 (s, 9H).

[0420] Step 3: Preparation of 5-((1R)-fluoro((((S)-1-(neopentyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0421] To a solution of allyl 5-((1R)-fluoro((((S)-1-(neopentyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (1.7 g, 3.1 mmol, 1.0 eq) in DCM (20 mL) was added pyrrolidine (0.4 g, 6.2 mmol, 2.0 eq) and Pd(PPh3)4(0.4 g, 0.3 mmol, 0.1 eq). Then the reaction stirred for 15 min to give a yellow clean solution. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (TFA) to lyophilized to give 5-((1R)-fluoro((((S)-1- (neopentyloxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2- carboxylic acid (1.3 g, 2.6 mmol, 83% yield) as a white solid. LCMS (ESI) m / z=508.2

[0422] Step 4: Preparation of perfluorophenyl 5-((R)-fluoro((S)-(((S)-1-(neopentyloxy)-1- oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate and perfluorophenyl 5-((R)-fluoro((R)-(((S)-1-(neopentyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate 174MOFO-358009544Attorney Docket No.: 183952036340

[0423] To a solution of 5-((1R)-fluoro((((S)-1-(neopentyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (1.2 g, 2.4 mmol, 1.0 eq) in pyridine (100 mL) was added 2,3,4,5,6-pentafluorophenyl 2,2,2- trifluoroacetate (0.66 g, 2.4 mmol, 1.0 eq) at 0 °C, the mixture was stirred at 25 °C for 10 min to give a yellow clean solution. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash column chromatography on silica gel to give perfluorophenyl 5-((R)-fluoro((S)-(((S)-1-(neopentyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate or perfluorophenyl 5-((R)-fluoro((R)-(((S)-1-(neopentyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (0.4 g, 0.59 mmol, 25% yield, Rt = 1.883 min, Peak 2) as a yellow oil and perfluorophenyl 5-((R)-fluoro((R)- (((S)-1-(neopentyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate or perfluorophenyl 5-((R)-fluoro((S)-(((S)-1-(neopentyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (0.50 g, 0.74 mmol, 32% yield, Rt = 1.442 min, Peak 1) as a yellow oil.

[0424] Peak 2: perfluorophenyl 5-((R)-fluoro((S)-(((S)-1-(neopentyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate: LCMS (ESI) m / z = 674.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 8.09 (s, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.68 (d, J = 8.4 Hz, 1H), 7.40 - 7.35 (m, 2H), 7.32 - 7.27 (m, 2H), 7.24 - 7.19 (m, 1H), 6.07 - 5.89 (m, 1H), 4.16 - 4.05 (m, 1H), 3.88 - 3.76 (m, 2H), 3.72 - 3.64 (m, 1H), 1.15 (d, J = 7.2 Hz, 3H), 0.91 (s, 9H)

[0425] Peak 1: perfluorophenyl 5-((R)-fluoro((R)-(((S)-1-(neopentyloxy)-1-oxopropan- 2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate or perfluorophenyl 5-((R)-fluoro((S)-(((S)-1-(neopentyloxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate: LCMS (ESI) m / z=674.0 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.34 (s, 1H), 8.12 (s, 1H), 7.96 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 7.29 (s, 1H), 7.25 (s, 1H), 7.16 - 7.05 (m, 3H), 6.13 - 5.96 (m, 1H), 4.22 - 4.10 (m, 1H), 3.89 – 3.83 (m, 1H), 3.73 - 3.66 (m, 1H), 3.62 - 3.54 (m, 1H), 1.33 (d, J = 7.2 Hz, 3H), 0.92 (s, 9H). Synthesis of 5-(difluoro((((S)-1-isopropoxy-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid 175MOFO-358009544Attorney Docket No.: 183952036340

[0426] Step 1: Preparation of allyl 5- ((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate

[0427] To a solution of 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2- carboxylic acid (5 g, 14 mmol, 1 eq) in dimethyl sulfoxide (40 mL) was added disodium carbonate (4.3 g, 41 mmol, 3 eq) and 3-bromoprop-1-ene (1.7 g, 14 mmol, 1 eq), the mixture was stirred at 25oC for 12 h to give a white suspension. The mixture was diluted with water (200 mL) and extracted with EtOAc (200 mL × 2), the combined organic layers were washed with saturated brine (200 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give allyl 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (4.6 g, 11.3 mmol, 83% yield) as a white oil.1H NMR (400 MHz, CDCl3) δ 8.17 - 8.13 (m, 2H), 7.96 (d, J = 8.8 Hz, 1H), 7.70 (d, J = 8.4 Hz, 1H), 6.13 - 5.99 (m, 1H), 5.50 - 5.42 (m, 1H), 5.37 - 5.32 (m, 1H), 4.87 (d, J = 5.6 Hz, 2H), 4.27 - 4.12 (m, 4H), 1.33 (t, J = 7.2 Hz, 6H).

[0428] Step 2: Preparation of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid

[0429] To a solution of allyl 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene- 2-carboxylate (4.6 g, 11.3 mmol, 1 eq) in DCM (40 mL) was added iodotrimethylsilane (9.0 176MOFO-358009544Attorney Docket No.: 183952036340 g, 45 mmol, 4 eq) at 0 ºC, the mixture was stirred at 0 ºC for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (TFA) to give ((2-((allyloxy) carbonyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid (2.3 g, 6.6 mmol, 58% yield) as a white solid. LCMS (ESI) m / z = 348.7

[0430] Step 3: Preparation of allyl 5- ((dichlorophosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate

[0431] To a solution of ((2-((allyloxy) carbonyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid (1 g, 2.9 mmol, 1 eq) in DCM (3 mL) was added DMF (21 mg, 0.29 mmol, 0.1 eq), oxalic dichloride (1.2 g, 28 mmol, 3 eq) was dropwise at 0 ºC, the mixture was stirred at 40 ºC for 1 h to give a yellow solution. The reaction mixture was concentrated under reduced pressure to give allyl 5- ((dichlorophosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (1 g, crude) as a yellow solid. LCMS (ESI) m / z = 376.6.

[0432] Step 4: Preparation of allyl 5-(((((S)-1-butoxy-1-oxopropan-2- yl)amino)(naphthalen-1-yloxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate

[0433] To a solution of prop-2-en-1-yl 5-[(dichlorophosphoryl)difluoromethyl]-1- benzothiophene-2-carboxylate (0.2 g, 0.52 mmol, 1 eq) in methylene chloride (10 mL) was added naphthalen-1-ol (60 mg, 0.42 mmol, 0.8 eq), the mixture was stirred at 0oC for 5 min, then a solution of N,N-diisopropylethylamine (0.2 g, 1.6 mmol, 3.0 eq) in methylene chloride (10 mL) was added to the mixture, then a solution of butyl (2S)-2-aminopropanoate (75 mg, 0.52 mmol, 1 eq) in methylene chloride (10 mL) was added to the mixture, the mixture was stirred at 0oC for 30 min to give yellow solution. The reaction mixture was concentrated under reduced pressure to give a residue.

[0434] The residue was purified by column chromatography to give prop-2-en-1-yl 5- [({[(2S)-1-butoxy-1-oxopropan-2-yl]amino}(naphthalen-1- yloxy)phosphoryl)difluoromethyl]-1-benzothiophene-2-carboxylate (0.15 g, 0.24 mmol, 46.4% yield) as a yellow oil. LCMS (ESI) m / z = 602.1

[0435] Step 5: Preparation of 5-(((((S)-1-butoxy-1-oxopropan-2-yl)amino)(naphthalen-1- yloxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid 177MOFO-358009544Attorney Docket No.: 183952036340

[0436] To a solution of prop-2-en-1-yl 5-[({[(2S)-1-butoxy-1-oxopropan-2- yl]amino}(naphthalen-1-yloxy)phosphoryl)difluoromethyl]-1-benzothiophene-2-carboxylate (0.14 g, 0.23 mmol, 1 eq) in methylene chloride (1.0 mL) was added Pd(PPh3)4 (27 mg, 23 µmol, 0.1 eq), the mixture was stirred at 0oC for 5 min, then pyrrolidine (17 mg, 0.23 mmol, 1 eq) was added to the mixture, the mixture was stirred at 25oC for 5 min to give yellow solution. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (TFA) to give 5-[({[(2S)-1-butoxy-1-oxopropan- 2-yl]amino}(naphthalen-1-yloxy)phosphoryl)difluoromethyl]-1-benzothiophene-2-carboxylic acid (97 mg, 0.17 mmol, 74.6% yield) as a yellow oil. LCMS (ESI) m / z = 562.1. Synthesis of 5-(((((S)-1-butoxy-1-oxopropan-2- yl)(methyl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0437] Step 1: Preparation of allyl 5-((dichlorophosphoryl)methyl)benzo[b]thiophene-2- carboxylate

[0438] To a solution of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid (0.1 g, 0.32 mmol, 1 eq) in DCM (2 mL) was added DMF (2.3 mg, 32 µmol, 0.1 eq). The mixture was stirred at 0 ºC for 5 min, then a solution of oxalyl chloride (0.12 g, 0.96 mmol, 3 eq) in DCM (2 mL) was added to the mixture, the mixture was stirred at 40 ºC for 1 h to give yellow solution. The reaction mixture was concentrated under reduced pressure to give allyl 5-((dichlorophosphoryl)methyl)benzo[b]thiophene-2- carboxylate (0.100 g, crude) as a yellow oil. LCMS (ESI) m / z =341.0 (MeOH quench) 178MOFO-358009544Attorney Docket No.: 183952036340

[0439] Step 2: Preparation of allyl 5-(((((S)-1-butoxy-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0440] To a solution of allyl 5-((dichlorophosphoryl)methyl)benzo[b]thiophene-2- carboxylate (0.10 g, 0.29 mmol, 1 eq) in DCM (2 mL) was added phenol (22 mg, 0.23 mmol, 0.8 eq) at 0 ºC for 30 min, then a solution of DIEA (0.1 g, 0.86 mmol, 3.0 eq) in DCM (2 mL) was added to the mixture at 0 ºC for 15 min, then a solution of butyl L-alaninate (42 mg, 0.29 mmol, 1 eq) in DCM (2 mL) was added to the mixture at 0 ºC for 15 min to give yellow solution. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give allyl 5-(((((S)-1-butoxy-1- oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (80 mg, 0.15 mmol, 80% yield, ) as a yellow oil. LCMS (ESI) m / z =516.2 [M+H]+.

[0441] Step 3: Preparation of allyl 5-(((((S)-1-butoxy-1-oxopropan-2- yl)(methyl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0442] To a solution of allyl 5-(((((S)-1-butoxy-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (0.2 g, 0.39 mmol, 1 eq) in THF (5 mL) was added LDA (83 mg, 0.77 mmol, 2 eq) and methyl iodide (0.55 g, 3.9 mmol, 10 eq), the mixture was stirred at -70 oC for 15 min to give yellow solution. The reaction mixture was added water (0.5 mL) and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give allyl 5-(((((S)-1-butoxy- 1-oxopropan-2-yl)(methyl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2- carboxylate (60 mg, 0.11 mmol, 28% yield) as a yellow oil. LCMS (ESI) m / z =530.2 [M+H]+.

[0443] Step 4: Preparation of 5-(((((S)-1-butoxy-1-oxopropan-2- yl)(methyl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0444] To a solution of allyl 5-(((((S)-1-butoxy-1-oxopropan-2- yl)(methyl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (60 mg, 0.11 mmol, 1 eq) in DCM (2 mL) was added pyrrolidine (6.4 mg, 90 µmol, 0.8 eq) and Pd(PPh3)4 (1.3 mg, 1.1 µmol, 0.01 eq), the mixture was stirred at 25 oC for 5 min to give yellow solution. The reaction mixture was added water and concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (TFA) then lyophilized to give 5-(((((S)-1-butoxy-1-oxopropan-2- 179MOFO-358009544Attorney Docket No.: 183952036340 yl)(methyl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (49 mg, 99 µmol, 88% yield) as a yellow oil. LCMS (ESI) m / z =490.1 [M+H]+. Synthesis of perfluorophenyl 5-(fluoro((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0445] Step 1: Preparation of ethyl 5- ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate

[0446] To a solution of ethyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2- carboxylate (58 g, 0.16 mol, 1 eq) in THF (600 mL) was added lithium bis(trimethylsilyl)azanide (170 mL, 0.17 mol, 1.1 eq, 1.0 M in THF) at -70 °C, then N- (benzenesulfonyl)-N-fluorobenzenesulfonamide (54 g, 0.17 mol, 1.1 eq) was added at -70 °C, then stirred at -70 °C for 0.5 h. The reaction mixture was quenched by water (500 mL) at -70 °C, then extracted with EtOAc (500 mL × 2), the combined organic layers were washed with saturated brine (400 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give ethyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (26 g, 67 mmol, 43% yield) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.92 (s, 1H), 180MOFO-358009544Attorney Docket No.: 183952036340 7.83 (d, J = 8.4 Hz, 1H), 7.51 (d, J = 8.4 Hz, 1H), 5.84 - 5.63 (m, 1H), 4.39 - 4.29 (m, 2H), 4.09 - 3.96 (m, 4H), 1.35 (t, J = 7.1 Hz, 3H), 1.23 - 1.19 (m, 6H).

[0447] Step 2: Preparation of 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene- 2-carboxylic acid

[0448] To a solution of ethyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2- carboxylate (15 g, 40 mmol, 1 eq) in THF (40 mL) was dropwise added LiOH▪H2O (1.8 g, 44 mmol, 1.1 eq) in H2O (40 mL) at 0 °C and stirred at 25 °C for 1 h to give a yellow solution. The reaction mixture was extracted with EtOAc (80 mL), then the aqueous phase was used 1M HCl to adjust the pH = 4~3 extracted with EtOAc (100 mL × 2), the combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give 5- ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid (11 g, crude) as a white solid. LCMS (ESI) m / z = 346.8 [M+H]+.

[0449] Step 3: Preparation of allyl 5- ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate

[0450] To a solution of 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2- carboxylic acid (11 g, 32 mmol, 1 eq) in DMF (120 mL) was added sodium carbonate (6.7 g, 63 mmol, 2 eq) and stirred at 25 °C for 30 min, then 3-bromoprop-1-ene (7.7 g, 63 mmol, 2 eq) was added in it and stirred at 25 °C for 5 h to give a white suspension. The reaction mixture was diluted with water (300 mL) and extracted with EtOAc (400 mL × 3), the combined organic layers were washed with saturated brine (500 mL × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give allyl 5- ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (10 g, 26 mmol, 82% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 8.05 - 7.98 (m, 1H), 7.91 (d, J = 8.4 Hz, 1H), 7.59 (d, J = 8.4 Hz, 1H), 6.13 - 5.97 (m, 1H), 5.91 - 5.71 (m, 1H), 5.52 - 5.40 (m, 1H), 5.33 (dd, J = 1.2, 10.4 Hz, 1H), 4.86 (dd, J = 1.2, 5.6 Hz, 2H), 4.19 - 4.03 (m, 4H), 1.33 - 1.24 (m, 6H).

[0451] Step 4: Preparation of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)fluoromethyl)phosphonic acid 181MOFO-358009544Attorney Docket No.: 183952036340

[0452] To a solution of allyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2- carboxylate (9 g, 23 mmol, 1 eq) and (E)-(trimethylsilyl 2,2,2-trifluoro-N- (trimethylsilyl)ethanimidate) (18 g, 70 mmol, 3 eq) in DCM (100 mL) was added iodotrimethylsilane (16 g, 93 mmol, 4 eq) at 0 °C and stirred at 0 °C for 1 h to give a brown solution. The reaction mixture was concentrated under reduced pressure to give a residue. The crude was purified by reverse phase chromatography (TFA) then lyophilization to give ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid (6.0 g, 18 mmol, 78% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.31 (s, 1H), 8.14 - 8.05 (m, 2H), 7.59 (d, J = 8.4 Hz, 1H), 6.13 - 5.98 (m, 1H), 5.90 - 5.76 (m, 1H), 5.44 (dd, J = 1.6, 17.2 Hz, 1H), 5.31 (dd, J = 1.6, 10.4 Hz, 1H), 4.86 - 4.83 (m, 2H).

[0453] Step 5: Preparation of allyl 5- ((dichlorophosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate

[0454] To a solution of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)fluoromethyl)phosphonic acid (2 g, 6.0 mmol, 1 eq) and DMF (88 mg, 1.2 mmol, 0.2 eq) in DCM (20 mL) was added oxalic dichloride (2.7 g, 21 mmol, 3.5 eq) at 0 °C and stirred at 40 °C for 0.5 h to give a yellow solution. The reaction mixture was concentrated under reduced pressure to give allyl 5-((dichlorophosphoryl)fluoromethyl)benzo[b]thiophene-2- carboxylate (2.2 g, crude) as a yellow solid. LCMS (ESI) m / z = 717.1 (MeOH quench)

[0455] Step 6: Preparation of allyl 5-(fluoro((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0456] To a solution of allyl 5-((dichlorophosphoryl)fluoromethyl)benzo[b]thiophene-2- carboxylate (2.2 g, 6.0 mmol, 1 eq) in DCM (20 mL), the solution was under N2 and cooled to 0 °C, then phenol (0.56 g, 6.0 mmol, 1 eq) in DCM (10 mL) was added in it, ethylbis(propan-2-yl)amine (3.1 g, 24 mmol, 4 eq) in DCM (60 mL) was dropwise added in it and stirred at 0 °C for 5 min, 3,3,3-trifluoropropyl (2S)-2-aminopropanoate (0.91 g, 6.0 mmol, 1 eq) in DCM (20 mL) was added in it and stirred at 0 °C for 10 min to give a yellow solution. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give allyl 5-(fluoro((((S)-1-oxo-1- propoxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (1.1 g, 1.9 mmol, 33% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.11 - 8.07 (m, 1H), 8.05 - 7.99 (m, 1H), 7.93 - 7.86 (m, 1H), 7.67 - 7.58 (m, 1H), 7.40 - 7.32 (m, 1H), 7.27 - 182MOFO-358009544Attorney Docket No.: 183952036340 7.17 (m, 2H), 7.15 - 7.05 (m, 2H), 6.10 - 5.89 (m, 2H), 5.50 - 5.42 (m, 1H), 5.34 (dd, J = 1.2, 10.4 Hz, 1H), 4.87 (d, J = 5.6 Hz, 2H), 4.22 - 4.08 (m, 1H), 4.00 - 3.76 (m, 1H), 3.69 - 3.51 (m, 1H), 1.67 - 1.59 (m, 2H), 1.33 - 1.26 (m, 3H), 0.96 - 0.89 (m, 3H).

[0457] Step 7: Preparation of 5-(fluoro((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0458] To a solution of allyl 5-(fluoro((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (1 g, 1.9 mmol, 1 eq) and pyrrolidine (82 mg, 1.2 mmol, 0.6 eq) in DCM (10 mL) was added Pd(PPh3)4(0.22 g, 0.19 mmol, 0.1 eq) and stirred at 25 °C for 1 h to give a yellow solution. The reaction mixture was concentrated under reduced pressure to give a residue. The crude was purified by reverse phase chromatography (TFA) then lyophilized to give 5-(fluoro((((S)-1-oxo-1- propoxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (0.70 g, 1.5 mmol, 76% yield) as a white solid.1H NMR (400 MHz, CDCl3) δ 8.15 - 7.91 (m, 1H), 7.90 - 7.79 (m, 2H), 7.70 - 7.51 (m, 1H), 7.46 - 7.29 (m, 3H), 7.25 - 7.15 (m, 2H), 6.15 - 5.98 (m, 1H), 4.24 - 4.05 (m, 3H), 1.79 - 1.58 (m, 2H), 1.41 - 1.22 (m, 3H), 0.96 (dd, J = 12.4, 19.6 Hz, 3H).

[0459] Step 8: Preparation of perfluorophenyl 5-(fluoro((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0460] To a solution of 5-(fluoro((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (0.70 g, 1.5 mmol, 1 eq) and pyridine (0.57 g, 7.2 mmol, 5 eq) in DMF (10 mL) was added 2,3,4,5,6- pentafluorophenyl 2,2,2-trifluoroacetate (2.0 g, 7.2 mmol, 5 eq) and stirred at 25 °C for 0.5 h to give a yellow solution. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 2), the combined organic layers were washed with saturated brine (40 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give perfluorophenyl 5- (fluoro((((S)-1-oxo-1-propoxypropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (0.80 g, 1.2 mmol, 86% yield) as a white solid. LCMS (ESI) m / z = 646.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.38 - 8.30 (m, 1H), 8.15 - 8.07 (m, 1H), 8.02 - 7.91 (m, 1H), 7.78 - 7.63 (m, 1H), 7.43 - 7.34 (m, 1H), 7.31 - 7.28 (m, 1H), 7.25 - 7.17 (m, 1H), 7.16 - 7.06 (m, 2H), 6.13 - 5.89 (m, 183MOFO-358009544Attorney Docket No.: 183952036340 1H), 4.11 - 4.01 (m, 2H), 3.70 - 3.51 (m, 1H), 1.72 - 1.59 (m, 3H), 1.32 (d, J = 7.2 Hz, 2H), 0.99 - 0.87 (m, 3H). Synthesis of ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid

[0461] Step 1: Preparation of ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid

[0462] To a solution of 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (2 g, 6.1 mmol, 1 eq) in dimethylformamide (100 mL) was added pyridine (1.9 g, 24 mmol, 4 eq), the mixture was stirred at 0oC for 5 min, then 2,3,4,5,6-pentafluorophenyl 2,2,2-trifluoroacetate (6.8 g, 24 mmol, 4 eq) was added to the mixture, the mixture was stirred at 25oC for 15 min to give yellow solution. The mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL × 2), the combined organic layers were washed with saturated brine (40 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give perfluorophenyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (1.4 g, 2.9 mmol, 47% yield) as a yellow oil. LCMS (ESI) m / z =495.0

[0463] Step 2: Preparation of ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid

[0464] To a solution of perfluorophenyl 5- ((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (1.4 g, 2.8 mmol, 1 eq) in DCM (10 mL) was added trimethylsilyl iodide (2.3 g, 11 mmol, 4 eq), the mixture was stirred at 0oC for 15 min to give yellow solution. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by reversed phase (TFA) to give ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (0.9 g, 2.1 184MOFO-358009544Attorney Docket No.: 183952036340 mmol, 74% yield) as a white solid. LCMS (ESI) m / z = 438.9 [M+H]+.1H NMR (400 MHz, CD3OD) δ 8.41 (s, 1H), 8.01 - 7.94 (m, 2H), 7.60 - 7.55 (m, 1H), 3.32 - 3.32 (m, 1H), 3.26 (s, 1H). Synthesis of (fluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid

[0465] Step 1: Preparation of perfluorophenyl 5- ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate

[0466] To a solution of 5-[(diethoxyphosphoryl)(fluoro)methyl]-1-benzothiophene-2- carboxylic acid (5 g, 14.40 mmol, 1 eq) in piperidine (6.13 g, 72 mmol, 5 eq) was added 2,3,4,5,6-pentafluorophenyl 2,2,2-trifluoroacetate (12 g, 43.20 mmol, 3 eq), the mixture was stirred at 0 ℃ for 30 min to give a brown clean solution. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (200 mL) and extracted with EtOAc (500 mL × 2), the combined organic layers were washed with saturated brine (500 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give perfluorophenyl 5- ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (6.50 g, 11.70 mmol, 81.40%) as a yellow oil. LCMS (ESI) m / z = 513.1 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.35 (s, 1H), 8.08 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.67 (d, J = 8.4 Hz, 1H), 5.93 - 5.77 (m, 1H), 4.22 - 4.17 (m, 1H), 4.16 - 4.13 (m, 1H), 4.13 - 4.11 (m, 1H), 4.10 - 4.06 (m, 1H), 1.34 - 1.31 (m, 3H), 1.30 - 1.27 (m, 3H).

[0467] Step 2: Preparation of (fluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen- 5-yl)methyl)phosphonic acid 185MOFO-358009544Attorney Docket No.: 183952036340

[0468] To a solution of perfluorophenyl 5- ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (6 g,12 mmol, 1 eq) in DCM (60 mL) was dropwise TMSI (9.3 g,47 mmol,4 eq) at 0 C, the mixture was stirred at 0 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a yellow oil. The oil was purified by reversed phase (TFA) to lyophilized to give (fluoro(2- ((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (3.0 g, 6.6 mmol, 56% yield) as a white solid. LCMS (ESI) m / z = 457.2 [M+H]+.1H NMR (400 MHz, CD3OD) δ 8.48 (s, 1H), 8.17 (s, 1H), 8.07 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 5.97 - 5.78 (m, 1H). Synthesis of 5-((1S)-fluoro(phenoxy((S)-2-(propoxycarbonyl)pyrrolidin-1- yl)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0469] Step 1: Preparation of propyl L-prolinate hydrochloride

[0470] Thionyl chloride (2.01 mL, 27.8 mmol, 3 eq) was added dropwise to a solution of (tert-butoxycarbonyl)-L-proline (2.00 g, 9.29 mmol, 1 eq) in propan-1-ol (20 mL, 332 µmol, eq) at 0°C. The mixture was allowed to warm to ambient temperature and then heated at 80 °C overnight. The reaction mixture was concentrated under reduced pressure to give crude propyl L-prolinate hydrochloride (1.85 g, 103%) as a brown oil.1H NMR (400 MHz, DMSO- 186MOFO-358009544Attorney Docket No.: 183952036340 d6) δ 4.36 - 4.33 (m, 1H), 4.18 - 4.07 (m, 2H), 3.26 - 3.14 (m, 2H), 2.32 - 2.22 (m, 1H), 2.01 - 1.85 (m, 3H), 1.66 - 1.59 (m, 2H), 0.92 - 0.89 (m, 3H).

[0471] The intermediates in the table below were prepared using the method described above in Step 1 for the preparation of propyl L-prolinate hydrochloride and utilizing the appropriate starting materials and modifications.

[0472] Step 2: Preparation of propyl (((S)-(2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)fluoromethyl)(phenoxy)phosphoryl)-L-prolinate

[0473] To a solution of (S)-((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)fluoromethyl)phosphonic acid (500 mg, 1.51 mmol, 1 eq) and DMF (2 drops) in DCM (15 mL) was added dropwise oxalyl chloride (1.02 mL, 12.0 mmol, 8 eq). The reaction mixture was stirred 2 h at room temperature under N2. The reaction mixture was concentrated under reduced pressure and dried completely under high vacuum for 30 min. to give a yellow solid. The yellow solid was diluted in DCM (15 mL, dried on Na2SO4) and cooled down to 0oC. A solution of phenol (134 mg, 1.43 mmol, 0.95 eq) and triethylamine (1.26 mL, 9.06 mmol, 6.0 eq) in DCM (5 mL, dried on Na2SO4) was slowly added onto the solution. The reaction mixture was stirred at 0oC for 2 min. and then warmed up to room temperature and stirred for 18 h. A solution of propyl L-prolinate hydrochloride (584 mg, 3.02 mmol, 2 eq) in DCM (5 mL, dried on Na2SO4) was slowly added onto the orange solution. The reaction mixture was stirred at room temperature for 4 h. Water (1 mL) was added. The solvent was removed under reduced pressure. The crude residue was purified by reverse phase chromatography on a 150 g C18cartridge eluting with 5-100% MeCN in water. The pure fractions were then concentrated under reduced pressure to give propyl (((S)-(2- ((allyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)(phenoxy)phosphoryl)-L-prolinate (320 mg, 38.8%) as a yellow oil. LCMS (ESI): m / z = 546.2 [M+H]+.1H NMR (400 MHz, CDCl3) δ 8.17 - 8.04 (m, 2H), 7.94 - 7.86 (m, 1H), 7.79 - 7.62 (m, 1H), 7.34 - 7.28 (m, 2H), 187MOFO-358009544Attorney Docket No.: 183952036340 7.24 - 7.20 (m, 1H), 7.19 - 7.03 (m, 2H), 6.10 - 6.00 (m, 1H), 5.49 - 5.31 (m, 2H), 4.89 - 4.84 (m, 2H), 4.57 - 4.22 (m, 1H), 4.15 - 3.96 (m, 2H), 3.66 - 3.21 (m, 1H), 3.13 - 2.67 (m, 1H), 2.18 - 2.04 (m, 1H), 1.97 - 1.86 (m, 1H), 1.83 - 1.46 (m, 5H), 1.00 - 0.86 (m, 3H).

[0474] The intermediates in the table below were prepared using the method described above in Step 2 for the preparation of propyl (((S)-(2-((allyloxy)carbonyl)benzo[b]thiophen- 5-yl)fluoromethyl)(phenoxy)phosphoryl)-L-prolinate and utilizing the appropriate starting materials and modifications.

[0475] Step 3: Preparation of 5-((1S)-fluoro(phenoxy((S)-2-(propoxycarbonyl)pyrrolidin- 1-yl)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0476] To a solution of propyl (((S)-(2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)fluoromethyl)(phenoxy)phosphoryl)-L-prolinate (320 mg, 586 µmol, 1 eq) in THF (6 mL) were added morpholine (251 µL, 2.92 mmol, 5 eq) and Pd(PPh3)4(13.5 mg, 11.7 µmol, 0.02 eq). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated to a volume of 2 mL under N2. The crude product was purified by reverse phase chromatography on a 100 g C18cartridge eluting with 5-80% MeCN in water (with 0.1% formic acid). The combined fractions were concentrated under reduced pressure and then freeze dried to give 5-((1S)-fluoro(phenoxy((S)-2-(propoxycarbonyl)pyrrolidin-1- yl)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (172 mg) as a white solid which was re-purified by reverse phase chromatography on a 275 g C18 cartridge eluting with 5-80% MeCN in water (with 0.1% formic acid). The combined fractions were concentrated under reduced pressure and then freeze dried to give 5-((1S)-fluoro(phenoxy((S)-2- (propoxycarbonyl)pyrrolidin-1-yl)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (75.0 mg, 25.3%) as a white solid. LCMS (ESI): m / z = 506.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) δ 13.58 (br. s., 1H), 8.21 - 8.10 (m, 2H), 7.73 - 7.63 (m, 1H), 7.41 - 7.31 (m, 3H), 188MOFO-358009544Attorney Docket No.: 183952036340 7.30 - 7.16 (m, 2H), 7.12 - 7.08 (m, 1H), 6.86 - 6.28 (m, 1H), 4.43 - 3.41 (m, 4H), 3.19 - 2.82 (m, 1H), 2.10 - 1.61 (m, 4H), 1.57 - 1.45 (m, 2H), 0.92 - 0.72 (m, 3H).

[0477] The intermediates in the table below were prepared using the method described above in Step 3 for the preparation of 5-((1S)-fluoro(phenoxy((S)-2- (propoxycarbonyl)pyrrolidin-1-yl)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid and utilizing the appropriate starting materials and modifications.Synthesis of 5-((1R)-fluoro((((S)-1-(2-methoxy-2-methylpropoxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0478] Step 1: Preparation of 2-methoxy-2-methylpropyl ((benzyloxy)carbonyl)-L- alaninate 189MOFO-358009544Attorney Docket No.: 183952036340

[0479] To a solution of ((benzyloxy)carbonyl)-L-alanine (1.64 g, 7.34 mmol, 1 eq.) and 2-methoxy-2-methylpropan-1-ol (916 mg, 8.80 mmol, 1.2 eq.) in ACN (20 ml) were added EDCI (1.68 g, 8.80 mmol, 1.2 eq.) and DMAP (1.07 g, 8.80 mmol, 1.2 eq.). The mixture was stirred at 25 °C for 16 h. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 2-methoxy- 2-methylpropyl ((benzyloxy)carbonyl)-L-alaninate (2, 1.63 g, 5.27 mmol, 72%) as a colorless oil. LCMS (ESI): m / z = 310 [M+H]+.

[0480] The intermediates in the table below were prepared using the method described above in Step 1 for the preparation of 2-methoxy-2-methylpropyl ((benzyloxy)carbonyl)-L- alaninate and utilizing the appropriate starting materials and modifications.190MOFO-358009544Attorney Docket No.: 183952036340

[0481] Step 2: Preparation of 2-methoxy-2-methylpropyl L-alaninate

[0482] To a solution of 2-methoxy-2-methylpropyl ((benzyloxy)carbonyl)-L-alaninate (1.5 g, 4.84 mmol, 1.0 eq.) in EtOAc (15 ml ) was added Pd / C (150 mg) under nitrogen. The suspension was degassed under vacuum and purged with H2several times. The resulting mixture was stirred at room temperature for 14 h. After completion, the suspension was filtered through a pad of Celite®, the filter cake was washed with MeOH (20 mL). The combined filtrates were concentrated to dryness to give 2-methoxy-2-methylpropyl L- alaninate (640 mg, 3.65 mmol, 75%) as a colorless oil. LCMS (ESI): m / z = 176 [M+H]+.

[0483] The intermediates in the table below were prepared using the method described above in Step 2 for the preparation of 2-methoxy-2-methylpropyl ((benzyloxy)carbonyl)-L- alaninate and utilizing the appropriate starting materials and modifications.191MOFO-358009544Attorney Docket No.: 183952036340

[0484] Step 3: Preparation of allyl 5-((1R)-fluoro((((S)-1-(2-methoxy-2-methylpropoxy)- 1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0485] Oxalyl chloride (576 mg, 4.54 mmol, 5 eq.) was added dropwise to the solution of (R)-((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid (300 mg, 0.91 mmol, 1 eq.) in dry DCM (10 mL) and DMF (1 drop) at 25oC. The reaction mixture was stirred at 40 °C for an additional 0.5 hr. The reaction was monitored by pipetting out a small amount of crude sample and quenching it with MeOH to ensure bis-Cl phosphoryl chloride had been formed completely (bis-methoxy phosphonate was observed by LCMS). After completion, the excess oxalyl chloride and solvent were removed under reduced pressure. The residue was re-dissolved in anhydrous DCM (10 mL), then added to a mixture of phenol (88.8 mg, 0.94mmol, 1.05 eq.) and TEA (908 mg, 8.98 mmol, 10.0 eq.) in anhydrous DCM (5 mL) at 0oC. The reaction was stirred for 0.5 h. Then 2-methoxy-2-methylpropyl L- alaninate (313 mg, 1.79 mmol, 2 eq.) was added at 0 °C and the resulting mixture was stirred at 20 °C for 1 h under N2. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give allyl 5-((1R)-fluoro((((S)-1-(2-methoxy-2-methylpropoxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (45.0 mg, 80 µmol, 9%) as a yellow solid. LCMS (ESI): m / z = 564.0 [M+H]+.

[0486] The intermediates in the table below were prepared using the method described above in Step 3 for the preparation of allyl 5-((1R)-fluoro((((S)-1-(2-methoxy-2- methylpropoxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene- 2-carboxylate and utilizing the appropriate starting materials and modifications.192MOFO-358009544Attorney Docket No.: 183952036340

[0487] Step 4: Preparation of 5-((1R)-fluoro((((S)-1-(2-methoxy-2-methylpropoxy)-1- oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0488] To a solution of allyl 5-((1R)-fluoro((((S)-1-(2-methoxy-2-methylpropoxy)-1- oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (45.0 mg, 80 µmol, 1.0 eq) in DCM (6 mL) were added Pd(PPh3)4 (5 mg, 8 µmol, 0.1 eq.) and pyrrolidine (6 mg, 80 µmol, 1.0 eq.). The mixture was purged and degassed with N2(three times), then stirred at 25 °C for 1 hr. After completion, the mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give 5-((1R)-fluoro((((S)-1-(2-methoxy-2-methylpropoxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (40 mg, 76 µmol, 95%) as a colorless oil. LCMS (ESI): m / z = 524 [M+H]+.

[0489] The intermediates in the table below were prepared using the method described above in Step 4 for the preparation of 5-((1R)-fluoro((((S)-1-(2-methoxy-2-methylpropoxy)- 193MOFO-358009544Attorney Docket No.: 183952036340 1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid and194MOFO-358009544Attorney Docket No.: 183952036340 Synthesis of 5-((1R)-fluoro((((S)-1-((1-methyl-1H-tetrazol-5-yl)methoxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0490] Step 1: Preparation of (1-methyl-1H-tetrazol-5-yl)methyl (tert-butoxycarbonyl)-L- alaninate

[0491] To a solution of (tert-butoxycarbonyl)-L-alanine (1 g, 5.28 mmol, 1 eq.) and (1- methyl-1H-1,2,3,4-tetrazol-5-yl)methanol (903 mg, 7.92 mmol, 1.5 eq.) in DCM (15 ml) were added T3P (50%) (5.02 g, 15.8 mmol, 3 eq.), DMAP (32.2 mg, 264 µmol, 0.05 eq.) and 4-methylmorpholine (1.59 g, 15.8 mmol, 3 eq.). The mixture was stirred at room temperature for 2 h. After completion, the reaction mixture was diluted with H2O (10 mL) and extracted with DCM (10 mL x 3). The organic layers were combined and washed with brine (10 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford (1-methyl-1H-tetrazol-5- yl)methyl (tert-butoxycarbonyl)-L-alaninate (900 mg, 3.15 mmol, 60%) as a colorless oil. LCMS (ESI): m / z = 286 [M+H]+.

[0492] The intermediates in the table below were prepared using the method described above in Step 1 for the preparation of (1-methyl-1H-tetrazol-5-yl)methyl (tert- butoxycarbonyl)-L-alaninate and utilizing the appropriate starting materials and modifications. 195MOFO-358009544Attorney Docket No.: 183952036340196MOFO-358009544Attorney Docket No.: 183952036340

[0493] Step 2: Preparation of (1-methyl-1H-tetrazol-5-yl)methyl L-alaninate

[0494] A solution of (1-methyl-1H-tetrazol-5-yl)methyl (tert-butoxycarbonyl)-L- alaninate (600 mg, 2.10 mmol, 1 eq) in HCl / EA (10 mL) was stirred at room temperature for 1 hr. After completion, the reaction mixture was concentrated under reduced pressure to give crude (1-methyl-1H-tetrazol-5-yl)methyl L-alaninate (390 mg, quant.)(HCl salt) as a white solid, which was used in next Step directly without further purification. LCMS (ESI): m / z = 186 [M+H]+.

[0495] The intermediates in the table below were prepared using the method described above in Step 2 for the preparation of (1-methyl-1H-tetrazol-5-yl)methyl L-alaninate and utilizing the appropriate starting materials and modifications.197MOFO-358009544Attorney Docket No.: 183952036340198MOFO-358009544Attorney Docket No.: 183952036340

[0496] Step 3: Preparation of allyl 5-((1R)-fluoro((((S)-1-((1-methyl-1H-tetrazol-5- yl)methoxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2- carboxylate

[0497] Oxalyl chloride (1.05 g, 8.35 mmol, 5 eq.) was added dropwise to a solution of (R)-((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid (550 mg, 1.67 mmol, 1 eq.) in dry DCM (10 mL) and DMF (1 drop) at 25oC. The reaction mixture was stirred at 40 °C for an additional 0.5 hr. The reaction was monitored by pipetting out a small amount of crude sample and quenching it with MeOH to ensure bis-Cl phosphoryl chloride had been formed completely (bis-methoxy phosphonate was observed by LCMS). After completion, the excess oxalyl chloride and solvent were removed under reduced pressure. The residue was re-dissolved in anhydrous DCM (10 mL), then added to a mixture of phenol (146 mg, 1.56 mmol, 1.05 eq.) and TEA (752 mg, 7.45 mmol, 5 eq.) in anhydrous DCM (5 mL) at 0oC. The reaction was stirred for 0.5 h. Then (1-methyl-1H-tetrazol-5-yl)methyl L- alaninate (3, 551 mg, 2.98 mmol, 2 eq.) was added at 0 °C and the resulting mixture was stirred at 20 °C for 1 h under N2. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give allyl 5-((1R)-fluoro((((S)-1-((1-methyl-1H-tetrazol-5-yl)methoxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (90.0 mg, 156 µmol, 11%) as a yellow oil. LCMS (ESI): m / z = 574 [M+H]+.

[0498] The intermediates in the table below were prepared using the method described above in Step 3 for the preparation of allyl 5-((1R)-fluoro((((S)-1-((1-methyl-1H-tetrazol-5- yl)methoxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2- carboxylate and utilizing the appropriate starting materials and modifications.199MOFO-358009544Attorney Docket No.: 183952036340200MOFO-358009544Attorney Docket No.: 183952036340201MOFO-358009544Attorney Docket No.: 183952036340

[0499] Step 4: Preparation of 5-((1R)-fluoro((((S)-1-((1-methyl-1H-tetrazol-5- yl)methoxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2- carboxylic acid

[0500] To a solution of allyl 5-((1R)-fluoro((((S)-1-((1-methyl-1H-tetrazol-5- yl)methoxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2- carboxylate (90 mg, 156 µmol, 1 eq.) in DCM (5 mL) were added Pd(PPh3)4(9.0 mg, 7.8 µmol, 0.05 eq.) and pyrrolidine (11.0 mg, 156 µmol, 1.0 eq.). The mixture was purged and degassed with N2 (three times), then stirred at 25 °C for 1 hr. After completion, the mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give 5-((1R)-fluoro((((S)-1-((1-methyl-1H-tetrazol-5-yl)methoxy)-1- oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (50.0 mg, 93.7 µmol, 60%) as a yellow oil. LCMS (ESI): m / z = 534 [M+H]+. 202MOFO-358009544Attorney Docket No.: 183952036340

[0501] The intermediates in the table below were prepared using the method described above in Step 4 for the preparation of 5-((1R)-fluoro((((S)-1-((1-methyl-1H-tetrazol-5- yl)methoxy)-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2- carboxylic acid and utilizing the appropriate starting materials and modifications.203MOFO-358009544Attorney Docket No.: 183952036340204MOFO-358009544Attorney Docket No.: 183952036340Synthesis of 5-((1R)-fluoro((3-(2-methoxyethoxy)phenoxy)(((S)-1-oxo-1-propoxypropan- 2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid 205MOFO-358009544Attorney Docket No.: 183952036340

[0502] Step 1: Preparation of 3-(2-methoxyethoxy)phenol

[0503] To a solution of 3-hydroxyphenyl acetate (5 g, 32.9 mmol, 1.0 eq.) and K2CO3 (13.6 g, 98.7 mmol, 3.0 eq.) in DMF (100 ml) was added 2-methoxyethyl 4- methylbenzenesulfonate (11.4 g, 49.4 mmol, 1.5 eq.). The mixture was stirred at 80 °C for 4 h. After completion, the reaction was cooled to room temperature and 20% NaOH (aq.) was added into the reaction mixture. The resulting mixture was stirred for 0.5 h and then quenched with HCl (1 N, aq.), diluted with H2O (100 mL) and extracted with DCM (100 mL x 3). The organic layers were combined and washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 3-(2-methoxyethoxy)phenol (4 g, 23.8 mmol, 72%) as a colorless oil. LCMS (ESI): m / z = 169 [M+H]+.

[0504] Step 2: Preparation of allyl 5-((1R)-fluoro(hydroxy(3-(2- methoxyethoxy)phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0505] Oxalyl chloride (3.82 g, 30.3 mmol, 5 eq.) was added dropwise to a solution of (R)-((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid (3, 2 g, 6.06 mmol, 1 eq.) in dry DCM (30 mL) and DMF (1 drop) at 25oC. The reaction mixture was stirred at 40 °C for an additional 0.5 h. The reaction was monitored by pipetting out a small amount of crude sample and quenching it with MeOH to ensure bis-Cl phosphoryl chloride 206MOFO-358009544Attorney Docket No.: 183952036340 had been formed completely (bis-methoxy phosphonate was observed by LCMS). After completion, the excess oxalyl chloride and solvent were removed under reduced pressure. The residue was re-dissolved in anhydrous DCM (20 mL), then added to a mixture of 3-(2- methoxyethoxy)phenol (1.07 g, 6.36 mmol, 1.05 eq.) and TEA (6.12 g, 60.6 mmol, 10.0 eq.) in anhydrous DCM (10 mL) at 0oC. The reaction was stirred for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give allyl 5-((1R)-fluoro(hydroxy(3-(2- methoxyethoxy)phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (2.00 g, 4.17 mmol, 69%) as a yellow solid. LCMS (ESI): m / z = 481 [M+H]+.

[0506] Step 3: Preparation of allyl 5-((1R)-fluoro((3-(2-methoxyethoxy)phenoxy)(((S)-1- oxo-1-propoxypropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0507] Oxalyl chloride (2.63 g, 20.85 mmol, 5 eq.) was added dropwise to the solution of allyl 5-((1R)-fluoro(hydroxy(3-(2- methoxyethoxy)phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (2 g, 4.17 mmol, 1 eq.) in dry DCM (10 mL) and DMF (1 drop) at 25oC. The reaction mixture was stirred at 40 °C for an additional 0.5 h. The reaction was monitored by pipetting out a small amount of crude sample and quenching it with MeOH to ensure mono-Cl phosphoryl chloride had been formed completely (mono-methoxy phosphonate was observed by LCMS). After completion, the excess oxalyl chloride and solvent were removed under reduced pressure. The residue was re-dissolved in anhydrous DCM (20 mL), then added to a mixture of propyl L-alaninate ( 1.09 g, 8.34 mmol, 2.0 eq.) and TEA (4.21 g, 41.7 mmol, 10.0 eq.) in anhydrous DCM (20 mL) at 0oC. The reaction was stirred for 0.5 h. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give allyl 5-((1R)-fluoro((3-(2-methoxyethoxy)phenoxy)(((S)-1- oxo-1-propoxypropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (1.8 g, 3.04 mmol, 73%) as a yellow solid. LCMS (ESI): m / z = 594 [M+H]+.

[0508] Step 4: 5-((1R)-fluoro((3-(2-methoxyethoxy)phenoxy)(((S)-1-oxo-1- propoxypropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0509] To a solution of allyl 5-((1R)-fluoro((3-(2-methoxyethoxy)phenoxy)(((S)-1-oxo- 1-propoxypropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (900 mg, 1.52 mmol, 1.0 eq) in DCM (6 mL) were added Pd(PPh3)4(175 mg, 152 µmol, 0.1 eq.) and 207MOFO-358009544Attorney Docket No.: 183952036340 pyrrolidine (109 mg, 1.52 mmol, 1.0 eq.). The mixture was purged and degassed with N2three times, then stirred at 25 °C for 1 hr. After completion, the mixture was concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give 5-((1R)-fluoro((3-(2-methoxyethoxy)phenoxy)(((S)-1-oxo-1-propoxypropan-2- yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (370 mg, 0.67 mmol, 44%) as a white solid. LCMS (ESI): m / z = 554 [M+H]+. Synthesis of perfluorophenyl 5-(fluoro((((S)-1-oxo-1-(3,3,3-trifluoropropoxy)propan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0510] Step 1: Preparation of (S)-3,3,3-trifluoropropyl 2-((tert- butoxycarbonyl)amino)propanoate

[0511] To a solution of (S)-2-((tert-butoxycarbonyl)amino)propanoic acid (5 g, 26.4 mmol, 1 eq) in dimethylformamide (50 mL) was added 3-chloro-1,1,1-trifluoropropane (10 g, 79 mmol, 3 eq ) and K2CO3(7.3 g, 53 mmol, 2 eq). The mixture was stirred at 60 °C for 16 h to give a white suspension. The mixture was diluted with water (250 mL) and extracted with 208MOFO-358009544Attorney Docket No.: 183952036340 EtOAc (1 L × 3), the combined organic layers were washed with saturated brine (1 L × 3), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give a (S)-3,3,3-trifluoropropyl 2- ((tert-butoxycarbonyl)amino)propanoate (4.5 g, 15 mmol, 20% yield) as an off-white solid. LCMS (ESI) m / z =286.1 [M+H]+.

[0512] Step 2: Preparation of (S)-3,3,3-trifluoropropyl 2-aminopropanoate

[0513] The (S)-3,3,3-trifluoropropyl 2-((tert-butoxycarbonyl)amino)propanoate (2 g, 7.0 mmol, 1 eq) was dissolved in DCM (20 mL) and HCL / dioxane (20 mL), the reaction solution was stirred at 25 °C for 1 h. The reaction mixture was concentrated under reduced pressure to give a (S)-3,3,3-trifluoropropyl 2-aminopropanoate (1.1 g, crude) as an off-white solid.1H NMR (400 MHz, CD3OD) δ 4.59 - 4.40 (m, 2H), 4.15 (q, J = 7.2 Hz, 1H), 2.75 - 2.61 (m, 2H), 1.56 (d, J = 7.2 Hz, 3H).

[0514] Step 3: Preparation of allyl 5- ((dichlorophosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate

[0515] To a solution of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)fluoromethyl)phosphonic acid (0.90 g, 2.7 mmol, 1 eq) in DCM (9 mL) was added N,N- dimethylformamide (20 mg, 0.27 mmol, 0.1 eq) at 25 °C, then cooled to 0 °C, then oxalic dichloride (1.2 g, 9.5 mmol, 3.5 eq) was added at 0 °C, then stirred at 40 °C for 0.5 h. The reaction mixture was concentrated under reduced pressure to give 5- ((dichlorophosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (1.0 g, crude) as a yellow oil. LCMS (ESI) m / z =368.0 [M+H]+.

[0516] Step 4: Preparation of allyl 5-(fluoro((((S)-1-oxo-1-(3,3,3- trifluoropropoxy)propan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2- carboxylate

[0517] To a solution of allyl 5-((dichlorophosphoryl)fluoromethyl)benzo[b]thiophene-2- carboxylate (1.0 g, 2.7 mmol, 1eq) in DCM (4 mL), the solution was under N2 and cooled to 0 °C, then phenol (0.20 g, 2.2 mmol, 0.8 eq) in DCM (4 mL) was added in it, ethylbis(propan-2-yl)amine (1.4 g, 11 mmol, 4 eq) in DCM (20 mL) was dropwise added in it and stirred at 0 °C for 5 min, (S)-3,3,3-trifluoropropyl 2-aminopropanoate (0.60 g, 3.3 mmol, 1.2 eq) in DCM (4 mL) was added in it and stirred at 0 °C for 10 min to give a yellow 209MOFO-358009544Attorney Docket No.: 183952036340 solution. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give a product 5-(fluoro((((S)- 1-oxo-1-(3,3,3-trifluoropropoxy)propan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (0.70 g, 1.2 mmol, 44% yield) as a white solid. LCMS (ESI) m / z = 574.1

[0518] Step 5: Preparation of 5-(fluoro((((S)-1-oxo-1-(3,3,3-trifluoropropoxy)propan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0519] To a solution of 5-(fluoro((((S)-1-oxo-1-(3,3,3-trifluoropropoxy)propan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (0.58 g, 1.0 mmol, 1 eq) and Pd(PPh3)4 (0.17 g, 0.15 mmol, 1.5 eq) in DCM (5 mL) was added pyrrolidine (50 mg, 0.71 mmol, 0.7 eq) at 0 °C. The mixture was stirred at 25°C for 0.5 h to give a yellow suspension. The reaction mixture was filtrated. The filtered and concentrated under reduced pressure to give a residue. The residue was purified by reverse phase (TFA) to lyophilized to give 5-(fluoro((((S)-1-oxo-1-(3,3,3-trifluoropropoxy)propan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (0.38 g, 0.71 mmol, 70% yield) as a yellow solid. LCMS (ESI) m / z = 534.1 [M+H]+.

[0520] Step 6: Preparation of perfluorophenyl 5-(fluoro((((S)-1-oxo-1-(3,3,3- trifluoropropoxy)propan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2- carboxylate

[0521] To a solution of 5-(fluoro((((S)-1-oxo-1-(3,3,3-trifluoropropoxy)propan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (0.40 g, 0.75 mmol, 1 eq) in dimethylformamide (4 mL) was added pyridine (0.18 g, 2.2 mmol, 3 eq), then perfluorophenyl 2,2,2-trifluoroacetate (1.0 g, 3.7 mmol, 5 eq) was added in the mixture at 0 °C to give a yellow solution. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL × 2), the combined organic layers were washed with saturated brine (20 mL × 2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give a product perfluorophenyl 5- (fluoro((((S)-1-oxo-1-(3,3,3-trifluoropropoxy)propan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (0.45 mg, 0.64 mmol, 86% yield) as a white solid. LCMS (ESI) m / z = 700.0 [M+H]+. 210MOFO-358009544Attorney Docket No.: 183952036340 Syntheses of perfluorophenyl 5- ((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate

[0522] To a solution of 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2- carboxylic acid (1, 3.64 g, 9.99 mmol, 1 eq.) in DMF (30 mL) were added pyridine (1.60 mL, 19.9 mmol, 2 eq.) and 2,3,4,5,6-pentafluorophenyl 2,2,2-trifluoroacetate (2.55 mL, 14.9 mmol, 1.5 eq.) under N2with stirring. The resulting mixture was stirred at room temperature for 1 hr. After completion, the reaction mixture was poured into H2O (20 mL), then extracted with EtOAc (50 mL x 3). The organic layers were combined and washed with brine (50 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford perfluorophenyl 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (2, 5.20 g, quant.) as a white solid. LCMS (ESI) m / z = 531.0 [M+H]+. Preparation of 5-(((benzylamino)(((S)-1-isopropoxy-1-oxopropan-2- yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0523] Step A: allyl 5-(((benzylamino)(((S)-1-isopropoxy-1-oxopropan-2- yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0524] Oxalyl chloride (814.4 mg, 6.4 mmol, 10 eq.) was added dropwise to the solution of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (200 mg, 0.64 211MOFO-358009544Attorney Docket No.: 183952036340 mmol, 1.0 eq.) in dry DCM (6 mL) and DMF (1 drop) at 0oC. The reaction was allowed to warm to 40oC, then stirred for additional 1~2 hrs. The reaction was monitored by pipetting out a small amount of crude sample and quenching it with MeOH to ensure bis-Cl phosphoryl chloride allyl 5-((dichlorophosphoryl)methyl)benzo[b]thiophene-2-carboxylate had been formed completely (bis-methoxy phosphonate was observed by LCMS). After completion, the excess of oxalyl chloride and solvent were removed under reduced pressure, and the residue was re-dissolved in anhydrous DCM (5 mL). To the solution was then added BnNH2 (64.8 mg, 0.64 mmol, 1.0 eq.) in anhydrous DCM (2 mL) and Et3N (194.32 mg, 1.92 mmol, 3.0 eq.) at -40oC. The reaction was monitored by pipetting out a small amount of crude sample and quenching it with MeOH to ensure the most of the product was allyl 5- (((benzylamino)chlorophosphoryl)methyl)benzo[b]thiophene-2-carboxylate (mono-methoxy phosphonate was observed by LCMS). To the solution was then added isopropyl L-alaninate (107.2 mg, 0.64 mmol, 1.0 eq.) in anhydrous DCM (2 mL) at -40oC. The reaction was allowed to warm to room temperature and stirred for additional 2 hrs. After completion, the reaction was quenched by adding H2O (10 mL), and extracted with DCM (10 mL x 3). The organic layers were combined and washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford allyl 5-(((benzylamino)(((S)-1-isopropoxy-1- oxopropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (100 mg, 194.33 µmol, 30%). LCMS (ESI): m / z = 515.2 [M+H]+.

[0525] Step B: 5-(((benzylamino)(((S)-1-isopropoxy-1-oxopropan-2- yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0526] A solution of allyl 5-(((benzylamino)(((S)-1-isopropoxy-1-oxopropan-2- yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (100 mg, 194 µmol, 1 eq.), Pd(PPh3)4 (22.47 mg, 19.4 µmol, 0.1 eq.) and pyrrolidine (13.8 mg, 194 µmol, 1 eq.) in DCM (3 mL) was stirred at room temperature for 1 hr. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford 5-(((benzylamino)(((S)-1-isopropoxy-1-oxopropan-2- yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (70 mg, 147.5 µmol, 76%). LCMS (ESI): m / z = 475.1 [M+H]+. Synthesis of 5-((bis(((S)-1-isopropoxy-1-oxopropan-2- yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid 212MOFO-358009544Attorney Docket No.: 183952036340((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphoryl)bis(azanediyl))(2S,2'S)- dipropionate

[0528] To a solution of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphonic acid (300 mg, 960 µmol, 1.0 eq.) in dry DCM (10 mL) and DMF (cat.) at 0 °C was added oxalyl chloride (609 mg, 4.80 mmol, 5.0 eq.) dropwise. The reaction mixture was allowed to warm to 40 °C, then stirred for additional 1~2 h. The reaction was monitored by pipetting out a small amount of crude sample and quenching it with MeOH to ensure bis-Cl phosphoryl chloride had been formed completely (bis-methoxy phosphonate was observed by LCMS). After completion, the excess of oxalyl chloride and solvent were removed under reduced pressure, and the residue was re-dissolved in anhydrous DCM (5 mL). This solution was then added to a mixture of isopropyl L-alaninate (502 mg, 3.83 mmol, 4.0 eq.) and N,N-diisopropylethylamine (620 mg, 4.80 mmol, 5.0 eq.) in anhydrous DCM (10 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred for additional 18 h. The progress was monitored by LCMS. After completion, the reaction was quenched by adding H2O (10 mL) and extracted with DCM (10 mL x 3). The organic layers were combined and washed with brine (20 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford diisopropyl 2,2'-((((2- ((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphoryl)bis(azanediyl))(2S,2'S)- dipropionate (70.0 mg, 129 µmol, 14% yield). LCMS (ESI): m / z = 539.2 [M+H]+. 213MOFO-358009544Attorney Docket No.: 183952036340

[0529] Step 2: Preparation of 5-((bis(((S)-1-isopropoxy-1-oxopropan-2- yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0530] To a solution of diisopropyl 2,2'-((((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)methyl)phosphoryl)bis(azanediyl))(2S,2'S)-dipropionate (70 mg, 129 µmol, 1.0 eq.) in DCM (1 mL) was added pyrrolidine (9.17 mg, 129 µmol, 1.0 eq.) and Pd(PPh3)4(14.9 mg, 12.9 µmol, 0.1 eq.) under N2, and the resulting mixture was stirred at room temperature for 2 h. After completion, the reaction mixture was cooled down in an ice-bath, then neutralized carefully with HCl (aq. 1M) until the pH was adjusted to pH = 4-6. The resulting mixture was extracted with DCM (10 mL x 3), and the combined organic layers were washed with brine (10 mL x 2), dried over anhydrous Na2SO4, then concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give 5-((bis(((S)-1- isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (70.0 mg, 140 µmol, 108%, 60% purity) as a colorless oil. LCMS (ESI): m / z = 499.2 [M+H]+. Synthesis of 5-(difluoro(((2-isopropoxy-2- oxoethyl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0531] Step 1: Preparation of benzyl 5-(difluoro(((2-isopropoxy-2- oxoethyl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0532] To a solution of ((2-((benzyloxy)carbonyl)benzo[b]thiophen-5- yl)difluoromethyl)phosphonic acid (300 mg, 753 µmol, 1 eq) in methylene chloride (8 mL) at 0oC was added 2 drops of DMF (cat.) followed by dropwise addition of oxalyl chloride (192 µL, 2.25 mmol, 3 eq). The reaction was warmed up to room temperature and stirred for 2 h. The reaction was not soluble at first but became a clear solution upon adding oxalyl chloride 214MOFO-358009544Attorney Docket No.: 183952036340 and warming up to room temperature. The reaction was concentrated under reduced pressure. Then, the latter was diluted in methylene chloride (8 mL) and the solution was cooled down to -78oC. A solution of phenol (56.6 mg, 602 µmol, 0.8 eq) and triethylamine (155 µL, 1.12 mmol, 1.5 eq) in DCM (1 mL) was slowly added on the yellow solution over 5 min. The reaction mixture was stirred at -78oC for 15 min., then warmed up to room temperature and stirred for 2 h. The reaction mixture was cooled down to -78oC. A solution of propan-2-yl 2- aminoacetate (88.2 mg, 753 µmol, 1 eq) and triethylamine (155 µL, 1.12 mmol, 1.5 eq) in DCM (1 mL) was slowly added on the yellow solution over 5 min. The reaction mixture was stirred at -78oC for 15 min., then warmed up to room temperature and stirred for 18 h. Water (2-3 drops) was added and the reaction was concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography on a 50 g C18cartridge eluting with 5- 100% MeCN in water (with 0.1% formic acid) to give benzyl 5-(difluoro(((2-isopropoxy-2- oxoethyl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (90.0 mg, 156 µmol, 20.8% yield) as a yellow oil. LCMS: m / z = 574.2 [M+H]+.

[0533] Step 2: Preparation of 5-(difluoro(((2-isopropoxy-2- oxoethyl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0534] To a solution of benzyl 5-(difluoro(((2-isopropoxy-2- oxoethyl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (90 mg, 156 µmol, 1 eq) in anhydrous tetrahydrofuran (10 mL) under nitrogen was added 10% palladium on carbon (50% wet) (166 mg, 78.0 µmol, 0.5 eq). Hydrogen was bubbled for 5 min. and the reaction mixture was stirred at room temperature for 18 h under hydrogen (1 atm). Nitrogen was bubbled int the mixture and it was then filtered over Celite (rinsing with 2-MeTHF) and concentrated under reduced pressure. The isolated product 5-(difluoro(((2-isopropoxy-2- oxoethyl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid was used without further purification. LCMS: m / z = 484.2 [M+H]+.

[0535] The intermediates in the table below were prepared according to the procedure described for the synthesis of 5-(difluoro(((2-isopropoxy-2- oxoethyl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid utilizing the appropriate starting materials.215MOFO-358009544Attorney Docket No.: 183952036340Synthesis of perfluorophenyl 5-((1R)-(ethoxy((2-methyl-1-oxo-1-propoxypropan-2- yl)amino)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate

[0536] Step A: propyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate 216MOFO-358009544Attorney Docket No.: 183952036340

[0537] To a solution of 2-((tert-butoxycarbonyl)amino)-2-methylpropanoic acid (1, 2.0 g, 9.8 mmol, 1.0 eq.), EDCI (2.8 g, 14.7 mmol, 1.5 eq.) and DMAP (1.79 g, 14.7 mmol, 1.5 eq.) in DCM (30 mL) was added propan-1-ol (588 mg, 9.8 mmol, 1.0 eq.). The reaction mixture was stirred at 25°C for 12 hrs. After completion, the mixture was diluted with water (30 mL) and extracted with DCM (30 mL × 3), the organic layers were washed with saturated brine (30 mL × 2), dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography on C18 (20%-80% ACN in H2O) to afford propyl 2-((tert-butoxycarbonyl)amino)-2-methylpropanoate (2, 2.2 g, 9.0 mmol, 92%) as a colorless oil. LCMS (ESI): m / z = 246 [M+H]+.

[0538] Step B: propyl 2-amino-2-methylpropanoate hydrochloride

[0539] A solution of propyl 2-((tert-butoxycarbonyl) amino)-2-methylpropanoate (2, 2.2 g, 9.0 mmol, 1.0 eq.) in 4M HCl / dioxane (20 mL) was stirred at 25°C for 2 hrs. After completion, the reaction mixture was concentrated under reduced pressure to give propyl 2- amino-2-methylpropanoate hydrochloride (3, 1.63 g, 9.0 mmol, crude) as a white solid, which was used in the next step directly without further purification. LCMS (ESI): m / z = 146 [M+H]+.

[0540] Step C: (R)-((2-((allyloxy)carbonyl)benzo[b]thiophen-5- yl)fluoromethyl)phosphonic acid 217MOFO-358009544Attorney Docket No.: 183952036340

[0541] To a solution of methyl allyl (R)-5- ((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (4, 50 g, 130 mmol, 1.0 eq.) in DCM (500 mL) was added TMSBr (100 ml, 766 mol, 5.9 eq.). The resulting mixture was stirred at 25°C for 16 hrs. After completion, the mixture was concentrated under reduced pressure. The residue was purified by flash chromatography on C18 to give (R)-((2- ((allyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid (5, 35 g, 106 mmol, 81%) as a white solid. LCMS (ESI): m / z = 331 [M+H]+.

[0542] Step D: allyl 5-((1R)-(ethoxy((2-methyl-1-oxo-1-propoxypropan-2- yl)amino)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate

[0543] To a solution of allyl 5-((1R)-(ethoxy((2-methyl-1-oxo-1-propoxypropan-2- yl)amino)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (5, 5 g, 15.2 mmol, 1.0 eq.) in DCM (60 mL) were added oxalyl chloride (9.6 g, 75.6 mmol, 5.0 eq.) and DMF (0.1 mL) at 25°C. The reaction mixture was stirred at 25°C for 2 hrs under N2 atmosphere. The reaction solvent was removed under reduce pressure, the residue was dissolved in DCM (60 mL), triethylamine (7.73 g, 76.5 mmol, 5 eq.) was added to the above mixture at 0°C, then a solution of propyl 2-amino-2-methylpropanoate hydrochloride (6, 3.04 g, 16.7 mmol, 1.1 eq.) in DCM (10 mL) was added to the above mixture dropwise at 0°C. EtOH (6.7 g, 76.5 mmol, 5.0 eq.) was added dropwise after the reaction was stirred at 0°C for 30 min under N2218MOFO-358009544Attorney Docket No.: 183952036340 atmosphere. The reaction mixture was stirred at 25°C for 16 hrs under N2atmosphere. After completion, the reaction mixture was poured into water (100 mL) and extracted with DCM (100 mL x 2), the combined organic layers were washed with brine (100 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure. The residue was purified by flash chromatography on C18 to give allyl 5-((1R)-(ethoxy((2-methyl-1-oxo-1- propoxypropan-2-yl)amino)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (7, 3.0 g, 6.18 mmol, 40%) as a yellow solid. LCMS (ESI): m / z = 486 [M+H]+.

[0544] Step E: 5-((1R)-(ethoxy((2-methyl-1-oxo-1-propoxypropan-2- yl)amino)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0545] To a solution of allyl 5-((1R)-(ethoxy((2-methyl-1-oxo-1-propoxypropan-2- yl)amino)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (7, 3.0 g, 6.18 mmol, 1.0 eq.) and pyrrolidine (439 mg, 6.18 mmol, 1.0 eq.) in DCM (30 mL) was added, Pd(PPh3)4(358 mg, 0.31 mmol, 0.05 eq.).The resulting mixture was stirred at 25°C for 0.5 hrs under N2 atmosphere. After completion, the mixture was adjusted to pH = 5 with 1N HCl. The reaction mixture was poured into water (30 mL) and extracted with DCM (30 mL x 2), the combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to afford 5-((1R)-fluoro((((S)-1-((1s,3R)-3- fluorocyclobutoxy)-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (8, 3.0 g, crude) as a yellow solid, which was used in the next step directly without further purification. LCMS (ESI): m / z = 446 [M+H]+.

[0546] Step F: perfluorophenyl 5-((1R)-(ethoxy((2-methyl-1-oxo-1-propoxypropan-2- yl)amino)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate 219MOFO-358009544Attorney Docket No.: 183952036340

[0547] To a solution of 5-((1S)-fluoro((((S)-1-isobutoxy-1-oxopropan-2- yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (...

Claims

1. Attorney Docket No.: 183952036340 CLAIMS What is claimed is:

1. A compound of Formula (I), or a pharmaceutically acceptable salt thereof, wherein: R1aand R1bare each independently H or halogen; R2is H, (C1-C6)alkyl, or (C3-C6)cycloalkyl; R3is (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, 3- to 7-membered heterocyclyl, -(C1-C6)alkylene-(C3-C6)cycloalkyl, or -(C1-C6)alkylene-(3- to 7- membered heterocyclyl), wherein (C1-C6)alkyl, (C3-C6)cycloalkyl, (C3- C6)cycloalkyl of -(C1-C6)alkylene-(C3-C6)cycloalkyl, or (3- to 7-membered heterocyclyl) of -(C1-C6)alkylene-(3- to 7-membered heterocyclyl) is each substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, cyano, halogen, halo(C1- C6)alkyl, and halo(C1-C6)alkoxy, or R2and R3together with the nitrogen atom to which they are attached form 5- to 7- membered heterocyclyl substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of (C1-C6)alkyl, (C1-C6)alkoxy, cyano, halogen, halo(C1-C6)alkyl, and halo(C1-C6)alkoxy; R4is H, (C6-C10)aryl, or 5- to 10-membered heteroaryl, wherein (C6-C10)aryl or 5- to 10-membered heteroaryl is each substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halogen, cyano, (C1-C6)alkyl, (C1-C6)alkoxy, halo(C1-C6)alkyl, halo(C1-C6)alkoxy, and -NR4aR4b, wherein: each R4aand R4bis independently H or (C1-C6)alkyl; R5is H, cyano, or (C1-C6)alkoxy; and RPis phosphonic acid, phosphonate, phosphonamidate, or phosphondiamidate. 558MOFO-358009544 Attorney Docket No.: 183952036340 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1ais F.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1bis H.

4. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1ais F and R1bis H.

5. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R1aand R1bare each F.

6. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R2is methyl or ethyl.

7. The compound of any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R3is (C1-C6)alkyl, halo(C1-C6)alkyl, (C3-C6)cycloalkyl, 3- to 7- membered heterocyclyl, or -(C1-C6)alkylene-(3- to 7-membered heterocyclyl).

8. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R3is halo(C1-C6) alkyl.

9. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R3is (C3-C6)cycloalkyl substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halogen, cyano, halo(C1-C6)alkyl, and halo(C1- C6)alkoxy.

10. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R3is 3-to 7-membered heterocyclyl.

11. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R3is -(C1-C6)alkylene-[3-to 7-membered heterocyclyl substituted with 0 or 1 (C1-C6)alkyl].

12. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R3is (C1-C6)alkyl substituted with 0, 1, 2, 3, 4, or 5 substituents each independently selected from the group consisting of halo, (C1-C6)alkoxy, and halo(C1-C6)alkoxy.

13. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein R3is , , , , , , 559MOFO-358009544 Attorney Docket No.: 183952036340 14. The compound of claim 7, or a pharmaceutically acceptable salt thereof, wherein 15. The compound of any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof, wherein R2and R3together with the nitrogen atom to which they are attached form 6-membered heterocyclyl.

16. The compound of claim 15, or a pharmaceutically acceptable salt thereof, wherein of Formula 17. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable salt thereof, wherein R4is H. 560MOFO-358009544 Attorney Docket No.: 18395203634018. The compound of any one of claims 1 to 16, or a pharmaceutically acceptable saltthereof, wherein R4 is (C6-C10)aryl or 5- to 10-membered heteroaryl.

19. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R4is phenyl substituted with 0, 1, 2, or 3 halogen.

20. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein R4 21. The compound of claim 19, or a pharmaceutically acceptable salt thereof, wherein R4 22. The compound of claim 18, or a pharmaceutically acceptable salt thereof, wherein R4is pyridinyl substituted with 0 or 1 -NR4aR4b.

23. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein R4 24. The compound of claim 22, or a pharmaceutically acceptable salt thereof, wherein R4 25. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable saltthereof, wherein R5is H.

26. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable saltthereof, wherein R5is cyano.

27. The compound of any one of claims 1 to 24, or a pharmaceutically acceptable saltthereof, wherein R5is methoxy.

28. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein RPis , wherein RP1and RP2are each independently -OH, - ORPa, N-linked amino acid, N-linked amino acid ester, or , wherein 561 MOFO-358009544 Attorney Docket No.: 183952036340 is substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo, oxo, COOH, and -C(O)ORPE, wherein:each RPais independently (C1-C6)alkyl, halo(C1-C6)alkyl, (C6-C10)aryl, or (C3- C6)cycloalkyl, wherein (C1-C6)alkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo and (C1-C6)alkoxy; and each RPEis independently (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylene-(C1- C6)alkoxy, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, -(C1-C6)alkylene-(C6- C10)aryl, -(C1-C6)alkylene-(C1-C6)alkoxy, -(C1-C6)alkylene-(C3-C7)cycloalkyl, 3- to7-membered heterocyclyl, or -(C1-C6)alkylene-(3- to 7-membered heterocyclyl),wherein (C1-C6)alkyl, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, or (C3- C7)cycloalkyl of -(C1-C6)alkylene-(C3-C7)cycloalkyl is each substituted with 0, 1, 2, or 3 independently selected halogen.

29. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable saltthereof, wherein RPis , wherein RP1and RP2are each independently -OH, - wherein is substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo, oxo, COOH, and -C(O)ORPE, wherein: each RPais independently (C1-C6)alkyl, halo(C1-C6)alkyl, (C6-C10)aryl, or (C3- C6)cycloalkyl, wherein (C1-C6)alkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo and (C1-C6)alkoxy; each RPEis independently (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylene-(C1- C6)alkoxy, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, -(C1-C6)alkylene-(C6- C10)aryl, -(C1-C6)alkylene-(C1-C6)alkoxy, -(C1-C6)alkylene-(C3-C7)cycloalkyl, 3- to7-membered heterocyclyl, or -(C1-C6)alkylene-(3- to 7-membered heterocyclyl),wherein (C1-C6)alkyl, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, or (C3- C7)cycloalkyl of -(C1-C6)alkylene-(C3-C7)cycloalkyl is each substituted with 0, 1, 2, or 3 independently selected halogen; each RPaa1is independently H or (C1-C6)alkyl; 562 MOFO-358009544 Attorney Docket No.: 183952036340 each RPaa2is independently H or (C1-C6)alkyl, and each RPaa3is independently H, (C1- C6)alkyl, -(C1-C6)alkylene-(C1-C6)alkoxy, or -(C1-C6)alkylene-(C6-C10)aryl; or RPaa2and RPaa3, together with the carbon atom to which they are attached form (C3-C6)cycloalkyl; and each RPaa4is independently (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylene-(C1- C6)alkoxy, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, -(C1-C6)alkylene-(C6- C10)aryl, -(C1-C6)alkylene-(C1-C6)alkoxy, -(C1-C6)alkylene-(C3-C7)cycloalkyl, 3- to 7-membered heterocyclyl, or -(C1-C6)alkylene-(3- to 7-membered heterocyclyl), wherein (C1-C6)alkyl, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, or (C3- C7)cycloalkyl of -(C1-C6)alkylene-(C3-C7)cycloalkyl is each substituted with 0, 1, 2, or 3 independently selected halogen.

30. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein RPis , wherein RP1and RP2are each -OH.

31. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein RPis , wherein RP1is -OH and RP2is N-linked amino acid.

32. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein RPis , wherein RP1is -ORPaand RP2is N-linked amino acid ester, wherein RPais (C1-C6)alkyl, halo(C1-C6)alkyl, (C6-C10)aryl, or (C3- C6)cycloalkyl, wherein (C1-C6)alkyl is substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo and (C1-C6)alkoxy.

33. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein RPis , wherein RP1and RP2are each independently N- linked amino acid.

34. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, wherein RPis , wherein RP1and RP2are each independently N- linked amino acid ester. 563MOFO-358009544 Attorney Docket No.: 18395203634035. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable saltthereof, wherein RP is , wherein RP1 is N-linked amino acid and RP2 is substituted with 0, 1, 2, or 3 substituents each independently selected from the group consisting of halo, oxo, and -COOH.

36. The compound of any one of claims 1 to 27, or a pharmaceutically acceptable saltthereof, wherein RPis , wherein RP1is N-linked amino acid ester and RP2is substituted with 0, 1, 2, or 3 substituents eachindependently selected from the group consisting of halo, oxo, and ester.

37. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein RPais phenyl.

38. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein RPais ethyl.

39. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein RPais -CH2CF3.

40. The compound of claim 32, or a pharmaceutically acceptable salt thereof, wherein RPa cyclopropyl, cyclopentyl, or cyclohexyl.

41. The compound of claim 35, or a pharmaceutically acceptable salt thereof, wherein RP2 42. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein RP2is , wherein substituted with 0, 1, 2, or 3 substituents eachindependently selected from the group consisting of halo, oxo, and -C(O)ORPE,wherein each RPEis independently (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylene- (C1-C6)alkoxy, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, -(C1-C6)alkylene-(C6- C10)aryl, -(C1-C6)alkylene-(C1-C6)alkoxy, -(C1-C6)alkylene-(C3-C7)cycloalkyl, 3- to564 MOFO-358009544 Attorney Docket No.: 183952036340 7-membered heterocyclyl, or -(C1-C6)alkylene-(3- to 7-membered heterocyclyl), wherein (C1-C6)alkyl, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, or (C3-C7)cycloalkyl of -(C1-C6)alkylene-(C3-C7)cycloalkyl is each substituted with 0, 1, 2, or 3 independently selected halogen.

43. The compound of claim 42, or a pharmaceutically acceptable salt thereof, wherein 44. The compound of claim 43, or a pharmaceutically acceptable salt thereof, wherein each 45. The compound of claim 36, or a pharmaceutically acceptable salt thereof, wherein RP2 46. The compound of any one of claims 31, 33, 35, and 41, or a pharmaceutically acceptable salt thereof, wherein each N-linked amino acid is independently N-linked α-amino acid.

47. The compound of claim 46, or a pharmaceutically acceptable salt thereof, wherein each N-linked amino acid is independently -NRPaa1CRPaa2RPaa3C(O)OH, wherein: each RPaa1is independently H or (C1-C6)alkyl; and each RPaa2is independently H or (C1-C6)alkyl, and each RPaa3is independently H, (C1- C6)alkyl, -(C1-C6)alkylene-(C1-C6)alkoxy, or -(C1-C6)alkylene-(C6-C10)aryl; or RPaa2and RPaa3, together with the carbon atom to which they are attached form (C3-C6)cycloalkyl. 565MOFO-358009544 Attorney Docket No.: 183952036340 48. The compound of any one of claims 32, 34, 36, 37 to 40, and 42 to 45, or a pharmaceutically acceptable salt thereof, wherein each N-linked amino acid ester is independently N-linked α-amino acid ester.

49. The compound of claim 48, or a pharmaceutically acceptable salt thereof, wherein each N-linked amino acid ester is independently -NRPaa1CRPaa2RPaa3C(O)ORPaa4, wherein: each RPaa1is independently H or (C1-C6)alkyl; each RPaa2is independently H or (C1-C6)alkyl, and each RPaa3is independently H, (C1- C6)alkyl, -(C1-C6)alkylene-(C1-C6)alkoxy, or -(C1-C6)alkylene-(C6-C10)aryl; or RPaa2and RPaa3, together with the carbon atom to which they are attached form (C3-C6)cycloalkyl; and each RPaa4is independently (C1-C6)alkyl, halo(C1-C6)alkyl, -(C1-C6)alkylene-(C1- C6)alkoxy, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, -(C1-C6)alkylene-(C6- C10)aryl, -(C1-C6)alkylene-(C1-C6)alkoxy, -(C1-C6)alkylene-(C3-C7)cycloalkyl, 3- to 7-membered heterocyclyl, or -(C1-C6)alkylene-(3- to 7-membered heterocyclyl), wherein (C1-C6)alkyl, (C3-C6)cycloalkyl, (C5-C8)spirocycloalkyl, or (C3-C7)cycloalkyl of -(C1-C6)alkylene-(C3-C7)cycloalkyl is each substituted with 0, 1, 2, or 3 independently selected halogen.

50. The compound of claim 49, or a pharmaceutically acceptable salt thereof, wherein 51. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein 566MOFO-358009544 Attorney Docket No.: 183952036340 52. The compound of claim 50, or a pharmaceutically acceptable salt thereof, wherein 53. The compound of Claim 50, or a pharmaceutically acceptable salt thereof, wherein 54. The compound of any one of claims 47 and 49 to 53, or a pharmaceutically acceptable salt thereof, wherein RPaa1is H.

55. The compound of any one of claims 47 and 49 to 53, or a pharmaceutically acceptable salt thereof, wherein RPaa1is methyl.

56. The compound of any one of claims 47 and 49 to 55, or a pharmaceutically acceptable salt thereof, wherein RPaa2is H.

57. The compound of any one of claims 47 and 49 to 55, or a pharmaceutically acceptable salt thereof, wherein RPaa2is methyl.

58. The compound of any one of claims 47 and 49 to 57, or a pharmaceutically acceptable salt thereof, wherein RPaa3is methyl.

59. The compound of any one of claims 47 and 49 to 57, or a pharmaceutically acceptable salt thereof, wherein RPaa3is ethyl, , , or -CH2OCH3.

60. The compound of any one of claims 47 and 49 to 57, or a pharmaceutically acceptable salt thereof, wherein 61. The compound of any one of claims 47 and 49 to 53 or a pharmaceutically acceptable salt thereof, wherein RPaa2and RPaa3, together with the carbon atom to which they are attached form cyclopropyl.

62. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from the group consisting of the compounds of Table 1A, Table 1B, and Table 1C. 567MOFO-358009544 Attorney Docket No.: 183952036340 63. A pharmaceutical composition comprising the compound of any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

64. A medicament comprising a compound of any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 63.

65. A method of treating a disease or condition responsive to the modulation (e.g., inhibition) of STAT6 in a subject in need thereof, the method comprising administering to the subject in need thereof a therapeutically effective amount of the compound of any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 63.

66. A compound of any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 63, for use as a drug.

67. A compound of any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 63, for use in the treatment of a disease or condition responsive to the modulation (e.g., inhibition) of STAT6 in a subject.

68. Use of a compound of any one of claims 1 to 62, or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of claim 63, for use in the preparation of a medicament.

69. The use of claim 67, wherein the medicament is intended for the treatment of a disease or condition responsive to the modulation (e.g., inhibition) of STAT6 in a subject.

70. The method of claim 65, the compound for use of claim 67, or the use of claim 69, wherein the disease or condition is selected from the group consisting of an inflammatory disorder, autoimmune disorder, an allergic disorder, and a skin disorder.

71. The method of claim 65, the compound for use of claim 67, or the use of claim 69, wherein the disease or condition is selected from the group consisting of atopic dermatitis, prurigo nodularis, asthma, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, and chronic obstructive pulmonary disease. 568MOFO-358009544

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