STAT Modulators and Uses Thereof

Abstract

Compounds of formula (I) and pharma- ceutically acceptable salts and compositions thereof are provided that are useful for treating a variety of conditions associated with STAT3 and / or STAT6. [Formula 1] JPEG2025514628000506.jpg3435

Description

[Technical Field]

[0001] This application claims priority to U.S. Provisional Application No. 63 / 325,908, filed March 31, 2022, and U.S. Provisional Application No. 63 / 337,388, filed May 2, 2022, the entire contents of each of which are incorporated herein by reference. [Background technology]

[0002] The signal transducer and activator of transcription (STAT) family of proteins consists of transcription factors that play important roles in the regulation of cellular 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.

[0003] STAT3 has attracted particular attention because it is strongly associated with promoting tumor growth and immune evasion, and is the only STAT family member whose genetic deletion results in embryonic lethality. In fact, abnormally elevated STAT3 activity is estimated to occur in more than 70% of human cancers. Activated STAT3 mediates critical gene expression changes and molecular events that dysregulate cell proliferation and apoptosis, promote the progression of angiogenesis, invasion, metastasis, and apoptosis resistance, and suppress host tumor immunosurveillance, making constitutively active STAT3 a critical mediator of carcinogenesis and tumor progression.

[0004] Another STAT protein that has recently attracted attention is STAT6. Recent studies have shown that STAT6 signaling is important for IL-4 and IL-13-induced epithelial-mesenchymal transition (EMT) and aggressiveness of colorectal cancer cells (CRC). STAT6 is involved in several aspects of inflammatory diseases and other related conditions.

[0005] Given their role in regulating cellular processes, modulating the activity of one or more STAT proteins, particularly STAT3 and / or STAT6, represents a highly important area of ​​research for the treatment of cancer, inflammatory conditions, and other therapeutic needs. Summary of the Invention

[0006] Modulators of STAT3 and / or STAT6 are provided herein. Such modulators have the formula I: [ka] and pharmaceutically acceptable salts and compositions thereof, 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , q, t, and p are as described herein.

[0007] In one aspect, the disclosed compounds of Formula I, and pharmaceutically acceptable salts thereof, inhibit STAT3 and / or STAT6 and are useful in a variety of therapeutic applications, such as treating cancer and inflammatory conditions.

[0008] Also included are pharmaceutical compositions comprising compounds and pharmaceutically acceptable salts of the disclosed compounds of Formula I, and methods for their preparation.

[0009] Also included are methods of treating conditions responsive to modulation of STAT3 and / or STAT6 using the disclosed compounds, pharmaceutically acceptable salts, and compositions thereof. DETAILED DESCRIPTION OF THE INVENTION

[0010] 1. Overview of the compound In a first embodiment, compounds of structural formula I: [ka] or a pharmaceutically acceptable salt thereof, q is 0 or 1 and t is 0, 1, or 2, provided that at least one of q or t is 1; p is 1 or 2, R 1 But, -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -CR 1a R 2a P(O)[NHR Ty ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ], -CR 1a R 2a P(O)[NH(AA)C(O)OR T ]][NH(AA)C(O)OR T ], or -P(O)[OR 1b ][NH(AA)C(O)OR T 8-10 membered fused bicyclic heteroaryl substituted with -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -CR 1a R 2a P(O)[NHR Ty ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ], -CR 1a R 2aP(O)[NH(AA)C(O)OR T ]][NH(AA)C(O)OR T ], or -P(O)[OR 1b ][NH(AA)C(O)OR T 8-10 membered fused bicyclic heterocyclyl substituted by -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -CR 1a R 2a P(O)[NHR Ty ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ], -CR 1a R 2a P(O)[NH(AA)C(O)OR T ]][NH(AA)C(O)OR T ], or -P(O)[OR 1b ][NH(AA)C(O)OR T aryl substituted with -(C1-C4) alkyl(aryl), wherein the aryl moiety of -(C1-C4) alkyl(aryl) is -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -CR 1a R 2a P(O)[NHR Ty ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ], or -CR 1a R2a P(O)[NH(AA)C(O)OR T ]][NH(AA)C(O)OR T ], -P(O)[OR 1b ][NH(AA)C(O)OR T and -(C2-C4)alkenyl(aryl), wherein the aryl moiety of -(C2-C4)alkenyl(aryl) is -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -CR 1a R 2a P(O)[NHR Ty ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ], -CR 1a R 2a P(O)[NH(AA)C(O)OR T ]][NH(AA)C(O)OR T ], or -P(O)[OR 1b ][NH(AA)C(O)OR T -(C2-C4)alkenyl(aryl) substituted with R 1a and R 2a are each independently selected from hydrogen, cyano, (C1-C4)alkyl, hydroxy(C1-C4)alkyl, and fluoro, or R 1a and R 2a form an oxo group together with the carbon to which they are attached, R 1b and R 2bare each independently hydrogen, (C1-C4) alkyl, halo(C1-C4) alkyl, -[(C1-C4) alkyl]-OC(O)-[(C1-C4) alkyl], -[(C1-C4) alkyl]-C(O)O-[(C1-C4) alkyl], -[(C1-C4) alkyl]-O-[(C1-C 20 ) alkyl], -[(C1-C4) alkyl]-OC(O)-[halo(C1-C4) alkyl], [(C1-C4) alkyl]-OC(O)O-[5- to 7-membered heterocyclyl], [(C1-C4) alkyl]-OC(O)-[5- to 7-membered heterocyclyl], -[(C1-C4) alkyl]-OC(O)-[(C1-C4) alkyl]-OH, -[(C1-C4) alkyl]-OC(O)-[(C1-C4) alkyl]-O-[(C1-C4) alkyl], -[(C1-C4) alkyl]-OC (O)O-[(C1-C4) alkyl], -[(C1-C4) alkyl]-OC(O)O-[halo(C1-C4) alkyl], -[(C1-C4) alkyl]-OC(O)O-[(C1-C4) alkyl]-OH, -[(C1-C4) alkyl]-OC(O)O-[(C1-C4) alkyl]-O-[(C1-C4) alkyl], -[(C1-C4) alkylphenyl]-C(O)O-[(C1-C4) alkyl], -[(C1-C4) alkyl]-OC(O)-[NH(AA)C(O)OR T], -[(C1~C4)alkyl]-SC(O)-[(C1~C4)alkyl], -[(C1~C4)alkyl]-SC(O)-[halo(C1~C4)alkyl], -[(C1~C4)alkyl]-SC(O)-[(C1~C4)alkyl]-OH, -[(C1~C4)alkyl]-SC(O)-[(C1~C4)alkyl]-O-[(C1~C4)alkyl], -[(C1~C4)alkyl]-OC(O)NH(C1~C4)alkyl], -[(C1~C4)alkyl]-OC(O)N[(C4 )alkyl]2, and aryl, wherein the 5- to 6-membered heteroaryl and aryl are each optionally and independently substituted, as valence allows, by 1 to 2 groups selected from halo, cyano, and (C1-C4)alkyl, and the 5- to 7-membered heterocyclyl of [(C1-C4)alkyl]-OC(O)O-[5- to 7-membered heterocyclyl] and [(C1-C4)alkyl]-OC(O)-[5- to 7-membered heterocyclyl] is each optionally and independently substituted, as valence allows, by C(O)OR h and is substituted with 1 to 2 groups selected from R 2 is selected from hydrogen, halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, cyano, and hydroxyl; R 3 and R 4 are each independently selected from hydrogen, halo, and (C1-C4) alkyl; R 5 and R 6 are each independently selected from hydrogen, phenyl, and (C1-C4) alkyl; R 7 is selected from (C1-C4) alkyl, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, and said (C1-C4) alkyl, when valence permits, is selected from R Yand wherein the phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each, as valence permits, optionally substituted with 1 to 3 groups selected from R Z or R 6 and R 7 together with the nitrogen atom to which they are attached form a 4- to 14-membered monocyclic or bicyclic heterocyclyl or a 5- to 12-membered monocyclic or bicyclic heteroaryl, each of which, valence permitting, is R Q and optionally substituted with 1 to 3 groups selected from R 8 is hydrogen or (C1-C4) alkyl, AA is a residue of an α or β natural or unnatural amino acid; R T and R Ty are each independently selected from (C1-C4)alkyl, (C1-C4)alkyl-C(O)O(C1-C4)alkyl, benzyl, and phenyl, wherein said phenyl is optionally substituted with one or two groups selected from halo, (C1-C4)alkyl, and halo(C1-C4)alkyl; R Q is halo, (C2-C4)alkenyl, (C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, phenyl, hydroxyl, 4-9 membered monocyclic or bicyclic heterocyclyl, 5-10 membered monocyclic or bicyclic heteroaryl, (C3-C6)cycloalkyl, oxo, imino, -OR e , -C(O)R g , -C(O)OR e , -NR c C(O)R e , -C(O)NR c R d , -NR a R b , -S(O)R e R f , -S(O)2R f , -S(O)=NH(C1-C4)alkyl, -S(O)NRe R f , and -S(O)NR e R f wherein said (C2-C4)alkenyl and (C1-C4)alkyl are each optionally and independently selected, valence permitting, from R M and wherein said phenyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, (C-C)cycloalkyl, and 4- to 9-membered monocyclic or bicyclic heterocyclyl are each optionally and independently, as valence permits, R F and is substituted with 1 to 3 groups selected from R Y halo, (C1-C4)alkoxy, halo(C1-C4)alkoxy, cyano, -C(O)R g , -C(O)OR e , -NHC(O)R e , -NR a R b , -S(O)R e R f , -S(O)2R f , -S(O)NR e R f , -S(O)=NH(C1-C4)alkyl, -S(O)2NR e R f , hydroxyl, phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein the phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each, as far as valence permits, selected from R X and optionally substituted with 1 to 3 groups selected from R M and R J each independently represents halo, (C1-C4) alkyl, (C1-C4) alkoxy, halo(C1-C4) alkoxy, cyano, or -C(O)R g , -C(O)OR e , -NHC(O)R e , -C(O)NR c R d , -NR a R b , -S(O)R e Rf , -S(O)2R f , -S(O)NR e R f , -S(O)=NR e (C1-C4) alkyl, -S(O)2NR e R f , hydroxyl, phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein the phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each, as far as valence permits, selected from R X and optionally substituted with 1 to 3 groups selected from R F , R X , and R Z each independently represents halo, cyano, (C1-C4) alkyl, cyano(C1-C4) alkyl, C3-C6 cycloalkyl, halo(C1-C4) alkyl, -(C1-C4) alkylC(O)NR c R d , -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkylphenyl, -(C1-C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -OR e , oxo, imino, phenyl, 4- to 6-membered heterocyclyl, 5- to 6-membered monocyclic heteroaryl, -S(O)R e R f , -S(O)2R f , -S(O)=NH(C1-C4)alkyl, -S(O)NR e R f , -S(O)NR e R f , -C(O)OR e , -NR c C(O)R e , -(C1-C4 alkyl)C(O)R g , -C(O)R g , -C(O)NR c R d , NO2, and -NRa R b wherein the phenyl of the phenyl, the 4- to 6-membered heterocyclyl, and the -(C1-C4) alkylphenyl are each optionally and independently selected, as far as valence allows, from halo, cyano, oxo, (C1-C 10 ) Alkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, halo(C1-C 10 ) alkyl, (C1-C 10 )alkoxy, -(C1-C4)alkyl(C1-C4)alkoxy, and halo(C1-C 10 ) alkoxy, and the (C1-C 10 ) Alkyl, (C2-C 10 ) alkenyl, and (C2-C 10 ) alkynyl is optionally substituted, where valence allows, by 5-10 membered monocyclic or bicyclic heteroaryl, or 4-10 membered monocyclic or bicyclic heterocyclyl, each of which is optionally substituted by oxo or 5-7 membered heterocyclyl optionally substituted by 1-2 oxo; and R a , R b , R c , R d , R e , R f , R g , and R h are each independently selected, as valences permit, from hydrogen, (C1-C4) alkyl, (C2-C4) alkynyl, -(C1-C4) alkylphenyl, phenyl, (C3-C6) cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl, and the (C1-C4) alkyl, as valences permit, is selected from R Jwherein said phenyl, (C3-C6)cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl are each independently optionally substituted, as valence allows, with 1 to 3 groups selected from halo, cyano, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, hydroxyl, phenyl, and benzyl, or a pharmaceutically acceptable salt thereof.

[0011] 2.Definition When used in connection with describing a chemical group that may have multiple points of attachment, the hyphen (-) designates the point of attachment of that group to the defined variable. For example, -NR c C(O)R e means that the point of attachment of this group is at the nitrogen atom.

[0012] 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," means a saturated, straight-chain or branched, monovalent hydrocarbon radical.

[0014] The term "haloalkyl" includes mono-, poly-, and perhaloalkyl groups, where the halogens are independently selected from fluorine, chlorine, bromine, and iodine.

[0015] "Alkoxy" refers to an alkyl radical attached through an oxygen linking atom, represented by -O-alkyl. For example, "(C1-C4)alkoxy" includes methoxy, ethoxy, propoxy, and butoxy.

[0016] A "haloalkoxy" is a haloalkyl group that is attached to another moiety through an oxygen atom, for example, -OCHF2 or -OCF3.

[0017] The term "oxo" refers to the group =O.

[0018] The term "imino" refers to the group =NH.

[0019] Unless otherwise specified, the term "heteroaryl" refers to a 5- to 12-membered aromatic radical containing 1 to 4 heteroatoms selected from N, O, and S. In some examples, the nitrogen atom in a heteroaryl may be quaternized. The term "heteroaryl" may be used interchangeably with "heteroaryl ring," "heteroaryl group," or "heteroaromatic." Heteroaryl groups may be monocyclic or bicyclic. Monocyclic heteroaryls include, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridalizinyl, pyrimidinyl, pyrazinyl, and the like. Bicyclic heteroaryls include groups in which a monocyclic heteroaryl ring is fused to one or more aryl or heteroaryl rings. Non-limiting examples include indolyl, benzoxazolyl, benzoxodiazolyl, indazolyl, benzimidazolyl, benzthiazolyl, benzothiophenyl, quinolinyl, quinazolinyl, quinoxalinyl, pyrrolopyridinyl, pyrrolopyrimidinyl, pyrrolopyridinyl, thienopyridinyl, thienopyrimidinyl, indolizinyl, purinyl, cinnolinyl, naphthyridinyl, and pteridinyl. When specified, it is understood that optional substituents on a heteroaryl group may be present at any substitutable position, including, for example, the position at which the heteroaryl is attached (valency permitting).

[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 can be monocyclic or bicyclic (e.g., bridged, fused, or spiro bicyclic rings). Examples of monocyclic saturated or partially unsaturated heterocyclic radicals include, but are not limited to, azetidinyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydropyranyl, pyrrolidinyl, pyrrolidonyl, piperidinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, morpholinyl, dihydrofuranyl, dihydropyranyl, dihydropyridinyl, tetrahydropyridinyl, dihydropyrimidinyl, tetrahydropyrimidinyl, dihydrooxadizolyl, and dihydroisoxazolyl. Bicyclic heterocyclyl groups include, for example, Includes unsaturated heterocyclic radicals, cycloalkyl, aryl, or heteroaryl rings fused to another unsaturated heterocyclic radical, 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'-pyrrolidin]-yl, thiochromanyl, etc. When specified, it is understood that optional substituents on a heterocyclyl group may be present at any substitutable position, including, for example, the position at which the heterocyclyl is attached (valence allowing).

[0021] The term "spiro" refers to two rings that share one ring atom (eg, carbon).

[0022] The term "fused" refers to two rings that share two adjacent ring atoms.

[0023] The term "bridged" refers to two rings which share three adjacent ring atoms.

[0024] The term "aryl" refers to an aromatic carbocyclic monocyclic or two fused ring system containing 6 to 10 carbon atoms. Examples include phenyl, indanyl, tetrahydronaphthalene, and naphthyl. In one embodiment, aryl is phenyl or naphthyl.

[0025] The term "cycloalkyl," when used alone or as part of a larger moiety, refers to a saturated, aliphatic, cyclic, monocyclic or bicyclic ring system, as described herein, having 3 to 10 carbon ring atoms unless otherwise specified. Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptenyl, and cyclooctyl. When specified, it is understood that optional substituents on the cycloalkyl or alicyclic group may be present at any substitutable position, including, for example, the position at which the cycloalkyl group is attached.

[0026] A "residue of an amino acid" is the moiety that remains after the formation of a bond between a reactive group (e.g., an amino group) in another compound and a carboxylic acid in the amino acid, after the formation of a bond between a reactive group (e.g., a carboxylic acid) in another compound and an amino group in the amino acid, or both. As a result of the bond(s) formation, the carboxylic acid in the amino acid no longer has an OH group but instead has a bond between the carbonyl group and a reactive group in the compound, or the amino group has only one hydrogen atom but instead has a bond between a reactive group in another compound and the nitrogen of the amino group, or both. For example, an "α-amino acid residue" can be structurally represented as NH2CR'RC(O)-, -NHCR'RC(O)OH, or -NHCR'RC(O)-, and a "β-amino acid residue" can be structurally represented as NH2CR'RCH2-C(O)-, -NHCR'RCH2-C(O)OH, or -NHCR'RCH2-C(O)-, where R' is H or C1-C6 alkyl, and R is H or halo, (C1-C3)alkoxy, OH, NH2, -NH(C1-C4 alkyl), -N[(C1-C4 alkyl)]2, SH, S(C1-C4 alkyl), imino, COOH, -COO(C1 -C4 alkyl), -CO(C1-C4 alkyl), -CONH(C1-C4 alkyl), C1-C6 alkyl optionally substituted with 1-3 groups selected from phenyl, phenyl, and 5-10 membered heteroaryl, wherein the C1-C6 alkyl may also be optionally interrupted by sulfur or nitrogen heteroatoms, and the phenyl is optionally substituted with 1-3 groups selected from OH, cyano, (C1-C4 alkyl), and halo(C1-C4 alkyl), or R together with the nitrogen atom of the α or β amino acid residue forms a 4-6 membered heterocyclyl.For naturally occurring α-amino acids (i.e., amino acids found in nature), R' is H and R is selected from hydrogen, methyl, isopropyl, -CHCH(CH), -(CH)SCH, -CH(CH)(CHCH), CHOH, -CH(OH)(CH), CHSH, -CHC(O)NH, -(CH)C(O)NH, benzyl, p-hydroxybenzyl, -CH(indolyl), -(CH)NH, -(CH)NHC(=NH)NH, -CH(imidazolyl), -(CH)COOH, and -(CH)COOH, or R together with the nitrogen atom of the α or β amino acid residue form a pyrrolidinyl ring.

[0027] Unnatural amino acids are known in the art and include, for example, α-alkyl amino acids (eg, α-methyl), α-alkylalkoxy amino acids (eg, α-CH 2 OCH 3 ), N-methyl amino acids, homo-amino acids, and the like.

[0028] Compounds with 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. "Geometric isomers" refer to isomers that differ in the orientation of substituents in relationship to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic ring system. The atoms (other than H) on each side of a carbon-carbon double bond may be in the E (substituents on opposite sides of the carbon-carbon double bond) or Z (substituents oriented on the same side) configuration. "Cis" refers to substituents oriented on the same side of the ring, while "trans" refers to substituents oriented on opposite sides of the ring.

[0029] When the stereoisomeric configuration at a chiral center in a compound having one or more chiral centers is represented by its chemical name (e.g., the configuration is indicated by "R" or "S" in the chemical name) or structure (e.g., the configuration is indicated by a "wedge" bond), the enrichment of the represented configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99%, or 99.9%. The "enrichment of the represented configuration relative to the opposite configuration" is a mole percent determined by dividing the number of compounds having the represented stereoisomeric configuration at the chiral center by the total number of all compounds having the same or opposite stereoisomeric configuration in the mixture.

[0030] When geometric isomers are represented 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%. The "enrichment of the indicated isomer relative to the opposite isomer" is a mole percent and is determined by dividing the number of compounds having the indicated geometric isomer configuration by the total number of all compounds having the same or opposite geometric isomer configuration in the mixture.

[0031] When a disclosed compound is named or represented by a structure without indicating stereochemistry, it is understood that the name or structure encompasses one of the possible stereoisomers or geometric isomers without the others, or a mixture of the stereoisomers or geometric isomers encompassed.

[0032] In certain instances, compounds were isolated and tested as a 1:1 mixture of diastereomers. In such cases, the relative stereochemistry is indicated by the term "rel-" and by using a flat bond instead of a wedge. For example, [ka] The substituents on the pyrrolidine ring are trans, and both diastereomers [ka] The term "aromatic" is intended to encompass mixtures of aromatic and non-aromatic compounds.

[0033] The terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as pets (e.g., dogs, cats, etc.), livestock (e.g., cows, pigs, horses, sheep, goats, etc.), and laboratory animals (e.g., rats, mice, guinea pigs, etc.). Typically, the subject is a human in need of treatment.

[0034] The terms "inhibit," "inhibition," or "inhibiting" include a decrease in the baseline activity of a biological activity or process.

[0035] As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progression of a disease or disorder, as described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have arisen, i.e., curative treatment. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual (e.g., given history of symptoms and / or exposure to a particular organism or other susceptibility factor) prior to the onset of symptoms, i.e., prophylactic treatment. Treatment may also be continued after symptoms have disappeared, e.g., to delay their recurrence.

[0036] The term "pharmaceutically acceptable carrier" refers to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants, or vehicles that can be used in the compositions described herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol, and wool fat.

[0037] When used in medicine, the salts of the compounds described herein refer to non-toxic "pharmaceutically acceptable salts." Pharmaceutically acceptable salt forms include pharmaceutically acceptable acidic / anionic or basic / cationic salts. Suitable pharmaceutically acceptable acid addition salts of the compounds described herein include, for example, salts of inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid) and organic acids (e.g., acetic acid, benzenesulfonic acid, benzoic acid, methanesulfonic acid, and p-toluenesulfonic acid). Compounds of the present teachings having an acidic group, such as a carboxylic acid, can form pharmaceutically acceptable salts with pharmaceutically acceptable base(s). Suitable pharmaceutically acceptable base salts include, for example, ammonium salts, alkali metal salts (e.g., sodium salts and potassium salts), and alkaline earth metal salts (e.g., magnesium salts and calcium salts). Compounds with a quaternary ammonium group also include a counteranion, such as chloride, bromide, iodide, acetate, perchlorate, etc. Other examples of such salts include hydrochloride, hydrobromide, sulfate, methanesulfonate, nitrate, benzoate, and salts with amino acids, such as glutamic acid.

[0038] The terms "effective amount" or "therapeutically effective amount" refer to an amount of a compound described herein sufficient to achieve the desired therapeutic effect (e.g., treatment of a condition listed herein) under the conditions of administration, e.g., a dosage of between 0.01 and 100 mg / kg body weight / day.

[0039] 3.Compound In a first embodiment, the compound of formula I: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as described above. Alternatively, as part of the first embodiment, R F , R X , and R Z are each independently halo, cyano, (C1-C4)alkyl, cyano(C1-C4)alkyl, (C3-C6)cycloalkyl, halo(C1-C4)alkyl, or -(C1-C4)alkylC(O)NR c R d , -(C1-C4)alkyl(C1-C4)alkoxy, hydroxy(C1-C4)alkyl, -(C1-C4)alkylphenyl, -(C1-C4)alkylheteroaryl, (C2-C4)alkenyl, halo(C2-C4)alkenyl, (C2-C4)alkynyl, halo(C2-C4)alkynyl, (C1-C4)alkoxy, halo(C1-C4)alkoxy, -OR e , oxo, imino, phenyl, 4- to 6-membered heterocyclyl, 5- to 6-membered monocyclic heteroaryl, -S(O)R e R f , -S(O)2R f , -S(O)=NH(C1-C4)alkyl, -S(O)NR e R f , -S(O)NR e R f , -C(O)OR e , -NR c C(O)R e , -(C1-C4 alkyl)C(O)R g , -C(O)R g , -C(O)NR c Rd , NO2, and -NR a R b wherein the phenyl in the phenyl, the 4- to 6-membered heterocyclyl, and the -(C1-C4) alkylphenyl are each optionally and independently selected, as far as valence allows, from halo, cyano, oxo, (C1-C 10 ) Alkyl, (C2-C 10 ) alkenyl, (C2-C 10 ) alkynyl, halo(C1-C 10 ) alkyl, (C1-C 10 ) alkoxy, and halo(C1-C 10 ) alkoxy, and the (C1-C 10 ) Alkyl, (C2-C 10 ) alkenyl, and (C2-C 10 ) alkynyl is optionally substituted, where valence allows, by 5-10 membered monocyclic or bicyclic heteroaryl, or 4-10 membered monocyclic or bicyclic heterocyclyl, wherein each of said 5-10 membered monocyclic and bicyclic heteroaryl, or 4-10 membered monocyclic or bicyclic heterocyclyl is optionally substituted by oxo, or 5-7 membered heterocyclyl optionally substituted by 1-2 oxo, and the remaining variables are as described above.

[0040] In a second embodiment, the compound of formula I has formula II: [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0041] In a third embodiment, q in the compound of Formula I or II, or a pharmaceutically acceptable salt thereof, is q, and the remaining variables are as described above for Formula I.

[0042] In a fourth embodiment, R in a compound of Formula I or II, or a pharmaceutically acceptable salt thereof,2 is hydrogen, and the remaining variables are as described above for Formula I, or the third embodiment.

[0043] In a fifth embodiment, the compound of formula I is represented by formula III or IV [ka] or a pharmaceutically acceptable salt thereof, wherein the variables are as described above for Formula I.

[0044] In a sixth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, 5 is hydrogen, and the remaining variables are as described in Formula I, or any one of the third or fourth embodiments.

[0045] In a seventh embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, 3 and R 4 are each independently selected from hydrogen and halo, and the remaining variables are as described in Formula I, or any one of the third, fourth, or sixth embodiments. Alternatively, as part of the seventh embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, 3 and R 4 are each hydrogen, and the remaining variables are as described in Formula I, or any one of the third, fourth, or sixth embodiments. Alternatively, as part of the seventh embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, 3 and R 4 are each fluoro, and the remaining variables are as described in Formula I, or any one of the third, fourth, or sixth embodiments.

[0046] In an eighth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, 1is selected from 8-10 membered fused bicyclic heteroaryl and aryl, each of which is -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[NHR Ty ][NH(AA)C(O)OR T ], -CR 1a R 2a P(O)[NH(AA)C(O)OR T ]][NH(AA)C(O)OR T ], or -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T and the remaining variables are as described in Formula I, or any one of the third, fourth, sixth, or seventh embodiments. Alternatively, as part of the eighth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is 1 is selected from benzothiophenyl and naphthalenyl, each of which is -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[NHR Ty ][NH(AA)C(O)OR T ], -CR 1a R 2a P(O)[NH(AA)C(O)OR T ]][NH(AA)C(O)OR T ], or -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T and the remaining variables are as described in Formula I, or any one of the third, fourth, sixth, or seventh embodiments. Alternatively, as part of the eighth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is 1 teeth, [ka] and the remaining variables are as described in Formula I, or any one of the third, fourth, sixth, or seventh embodiments. Alternatively, as part of the eighth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is selected from: 1 teeth, [ka] and the remaining variables are as described in Formula I, or any one of the third, fourth, sixth, or seventh embodiments. Alternatively, as part of the eighth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is selected from: 1 teeth, [ka] and the remaining variables are as described in Formula I, or any one of the third, fourth, sixth, or seventh embodiments.

[0047] In a ninth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, 1a and R 2a are each independently selected from hydrogen and fluoro, and the remaining variables are as described in Formula I, or any one of the third, fourth, and sixth through eighth embodiments. Alternatively, as part of the ninth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is 1a and R 2a are each hydrogen, and the remaining variables are as described in Formula I, or any one of the third, fourth, and sixth through eighth embodiments. Alternatively, as part of the ninth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, can be 1a is hydrogen and R 2ais fluoro, and the remaining variables are as described in Formula I, or any one of the third, fourth, and sixth through eighth embodiments. Alternatively, as part of the ninth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, 1a and R 2a are each fluoro, and the remaining variables are as described in Formula I, or any one of the third, fourth, and sixth through eighth embodiments.

[0048] In a tenth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, 1b and R 2b are each independently hydrogen, (C1-C4) alkyl, halo(C1-C4) alkyl, -[(C1-C4) alkyl]-OC(O)-[(C1-C4) alkyl], -[(C1-C4) alkyl]-C(O)O-[(C1-C4) alkyl], -[(C1-C4) alkylphenyl]-C(O)O-[(C1-C4) alkyl], -[(C1-C4) alkyl]-OC(O)-[NH(AA)C(O)OR T ], —[(C1-C4)alkyl]-OC(O)—[(C1-C4)alkyl]-OH, —[(C1-C4)alkyl]-OC(O)O-[5-7 membered heterocyclyl], —[(C1-C4)alkyl]-OC(O)O—[(C1-C4)alkyl]-O—[(C1-C4)alkyl], —[(C1-C4)alkyl]-OC(O)O—[(C1-C4)alkyl], —[(C1-C4)alkyl]-SC(O)—[(C1-C4)alkyl], —[(C1-C4)alkyl]-SC(O)—[(C1-C4)alkyl]-OH, and phenyl, with the remaining variables being as described in Formula I, or any one of the third, fourth, and sixth through ninth embodiments. Alternatively, as part of the tenth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, 1b and R 2bare each independently selected from hydrogen, [(C1-C4) alkyl]-OC(O)-[(C1-C4) alkyl], —[(C1-C4) alkyl]-OC(O)O-[(C1-C4) alkyl]-O-[(C1-C4) alkyl], —[(C1-C4) alkyl]-OC(O)O-[(C1-C4) alkyl], and —[(C1-C4) alkyl]-SC(O)-[(C1-C4) alkyl], and the remaining variables are as described in Formula I, or any one of the third, fourth, and sixth through ninth embodiments. Alternatively, as part of the tenth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, can be 1b and R 2b are each -[(C1-C4)alkyl]-OC(O)-[(C1-C4)alkyl], and the remaining variables are as described in Formula I, or any one of the third, fourth, and sixth through ninth embodiments. Alternatively, as part of the tenth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, 1b and R 2b are each hydrogen, and the remaining variables are as described in Formula I, or any one of the third, fourth, and sixth through ninth embodiments.

[0049] In a tenth embodiment, -CR in a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof. 1a R 2a P(O)OR 1b OR 2b teeth, [ka] [ka] [ka] and the remaining variables are as described in Formula I, or any one of the third, fourth, and sixth through eighth embodiments. Alternatively, as part of the tenth embodiment, -CR in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is selected from: 1a R 2a P(O)OR 1b OR 2b teeth, [ka] and the remaining variables are as described in Formula I, or any one of the third, fourth, and sixth through eighth embodiments.

[0050] In an eleventh embodiment, -(AA)C(O)OR in a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof. T is -C(R')(R)C(O)R T or -C(R')(R)CH2C(O)R T wherein R' is hydrogen, R is selected from hydrogen, methyl, -CHCH(CH), benzyl, and -CHCH-phenyl, and the remaining variables are as described in Formula I, or any one of the third, fourth, and sixth through eighth embodiments.

[0051] In a twelfth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, T is selected from (C1-C4) alkyl, (C1-C4) alkyl-C(O)O—C1-4 alkyl, and benzyl, and the remaining variables are as described in Formula I, or any one of the third, fourth, and sixth to eighth, and eleventh embodiments.

[0052] In a thirteenth embodiment, -CR in a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof. 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ]teeth, [ka] [ka] and the remaining variables are as described in Formula I, or any one of the third, fourth, sixth to eighth, eleventh, and twelfth embodiments. In another thirteenth embodiment, -CR in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is selected from: 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ]teeth, [ka] [ka] and the remaining variables are as described in Formula I, or any one of the third, fourth, sixth to eighth, eleventh, and twelfth embodiments.

[0053] In a fourteenth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, 6 is hydrogen, and the remaining variables are as described in Formula I, or any one of the third through thirteenth embodiments.

[0054] In a fifteenth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, 7 is selected from (C1-C4) alkyl, phenyl, and 4- to 6-membered monocyclic heterocyclyl, and the (C1-C4) alkyl is, as far as valence allows, R Y and wherein the phenyl and 4- to 6-membered monocyclic heterocyclyl are each optionally substituted with 1 to 3 groups selected from R Zand the remaining variables are as described in Formula I, or any one of the third through fourteenth embodiments. Alternatively, as part of the fifteenth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is 7 is selected from (C1-C4) alkyl, phenyl, pyrrolidinyl, and azetidinyl, and the (C1-C4) alkyl is, where valence permits, R Y wherein the phenyl, pyrrolidinyl, and azetidinyl are each optionally substituted, as valence permits, with 1 to 3 groups selected from R Z and the remaining variables are as described in Formula I, or any one of the third through fourteenth embodiments.

[0055] In a sixteenth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, Z is halo, -(C1-C4) alkylC(O)NR c R d , hydroxyl, phenyl, 4- to 6-membered heterocyclyl, 5- to 6-membered monocyclic heteroaryl, -C(O)NR c R d , and -C(O)R g wherein said phenyl is optionally substituted, where valence allows, with 1 to 3 groups selected from halo, (C1-C4)alkyl, halo(C1-C4)alkyl, (C1-C4)alkoxy, and halo(C1-C4)alkoxy, and the remaining variables are as described in Formula I, or any one of the third through fifteenth embodiments. Alternatively, as part of the sixteenth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is Z is halo, -(C1-C4) alkylC(O)NR c R d , hydroxyl, phenyl, tetrahydropyran, tetrahydrofuran, oxetanyl, pyridinyl, pyrazolyl, pyridazinyl, -C(O)NR c R d, and -C(O)R g and the remaining variables are as described in Formula I, or any one of the third through fifteenth embodiments. Alternatively, as part of the sixteenth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is selected from: Z is halo, -(C1-C4) alkylC(O)NR c R d , hydroxyl, phenyl, tetrahydropyran, tetrahydrofuran, oxetanyl, pyridinyl, pyrimidinyl, imidazoyl, triazoyl, pyrazolyl, pyridazinyl, -C(O)NR c R d , and -C(O)R g wherein the pyridinyl, imidazoyl, and triazoyl are optionally substituted with one or two groups selected from halo and methyl, and the remaining variables are as described in Formula I, or any one of the third through fifteenth embodiments.

[0056] In a seventeenth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, Y is selected from hydroxyl and 5-10 membered monocyclic or bicyclic heteroaryl, and the 5-10 membered monocyclic or bicyclic ring is, as far as valence permits, R X and the remaining variables are as described in Formula I, or any one of the third through sixteenth embodiments. Alternatively, as part of the seventeenth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is Y is selected from hydroxyl, pyridinyl, and pyrrolopyridinyl, and the remaining variables are as described in Formula I, or any one of the third through sixteenth embodiments.

[0057] In an eighteenth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, c and R dare each hydrogen, and the remaining variables are as described in Formula I, or any one of the third through seventeenth embodiments.

[0058] In a nineteenth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, g is -(C1-C4)alkyl, and the remaining variables are as described in Formula I, or any one of the third through eighteenth embodiments.

[0059] In a twentieth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, 6 and R 7 together with the nitrogen atom to which they are attached form a 4- to 14-membered monocyclic or bicyclic heterocyclyl or a 5- to 12-membered monocyclic or bicyclic heteroaryl, each of which, valence permitting, is R Q and the remaining variables are as described in Formula I, or any one of the third through nineteenth embodiments. Alternatively, as part of the twentieth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is 6 and R 7 together with the nitrogen atom to which they are attached, form azetidinyl, 2,5-diazaspiro[3.4]octanyl, pyrrolidinyl, 2,6-diazaspiro[3.3]heptanyl, piperazinyl, spiro[indoline-3,3'-pyrrolidin]yl, 6',7'-dihydrospiro[azetidin-3,5'-pyrrolo[1,2-a]imidazol]yl, each of which, as valence permits, R Q and the remaining variables are as described in Formula I, or any one of the third through nineteenth embodiments. Alternatively, as part of the twentieth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is 6 and R 7together with the nitrogen atom to which they are attached, include azetidinyl, 2,5-diazaspiro[3.4]octanyl, pyrrolidinyl, 2,6-diazaspiro[3.3]heptanyl, 2,6-diazabicyclo[3.2.0]heptanyl, piperazinyl, spiro[indoline-3,3'-pyrrolidin]yl, 6',7'-dihydrospiro[azetidin-3,5'-pyrrolo[1,2-a]imidazol]yl, 3,4-dihydro-2H-benzo[b] [1,4]oxazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine, 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1-azaspiro[3.5]nonanyl, 4-azaspiro[2.4]heptanyl, each of which, as far as valence permits, is substituted by R Q and the remaining variables are as described in Formula I, or any one of the third through nineteenth embodiments.

[0060] In a twenty-first embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, Q is halo, (C1-C4) alkyl, (C1-C4) alkoxy, cyano, phenyl, hydroxyl, 4- to 6-membered heterocyclyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, oxo, and -C(O)R g and the (C1-C4) alkyl is selected from R M wherein the phenyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, and 4- to 6-membered heterocyclyl are each optionally and independently, as valence permits, R F and the remaining variables are as described in Formula I, or any one of the third through thirteenth and twentieth embodiments. Alternatively, as part of the twenty-first embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is Q is halo, (C1-C4) alkyl, -ORe , cyano, phenyl, hydroxyl, 4- to 6-membered heterocyclyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, oxo, and -C(O)R g and the (C1-C4) alkyl is selected from R M wherein the phenyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, and 4- to 6-membered heterocyclyl are each optionally and independently, as valence permits, R F and R e is (C1-C4) alkyl or 5-6 membered heteroaryl, and the remaining variables are as described in Formula I, or any one of the third through thirteenth and twentieth embodiments. Alternatively, as part of the twenty-first embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, Q is halo, (C1-C4) alkyl, (C1-C4) alkoxy, cyano, phenyl, hydroxyl, morpholinyl, tetrahydropyranyl, thiomorpholinyl, piperidinyl, oxatanyl, pyrazolyl, pyridinyl, tetrazolyl, imidazolyl, pyrazinyl, oxadiazolyl, triazolyl, pyrimidinyl, benzimidazolyl, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, oxo, and -C(O)R g and the (C1-C4) alkyl is selected from R M wherein said morpholinyl, tetrahydropyranyl, thiomorpholinyl, piperidinyl, oxatanyl, pyrazolyl, pyridinyl, tetrazolyl, imidazolyl, pyrazinyl, oxadiazolyl, triazolyl, pyrimidinyl, benzimidazolyl, and 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl are each optionally and independently, as valence permits, R Fand the remaining variables are as described in Formula I, or any one of the third through thirteenth and twentieth embodiments. Alternatively, as part of the twenty-first embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is Q is halo, (C1-C4) alkyl, -OR e , cyano, phenyl, hydroxyl, morpholinyl, tetrahydropyranyl, thiomorpholinyl, piperidinyl, oxatanyl, pyrazolyl, pyridinyl, tetrazolyl, imidazolyl, pyrazinyl, isoxazoyl, oxazoyl, oxadiazolyl, triazolyl, pyrimidinyl, benzimidazolyl, 1H-pyrrolo[3,2-c]pyridine, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, oxo, and -C(O)R g and the (C1-C4) alkyl is selected from R M wherein said morpholinyl, tetrahydropyranyl, thiomorpholinyl, piperidinyl, oxatanyl, pyrazolyl, pyridinyl, tetrazolyl, imidazolyl, pyrazinyl, isoxazoyl, oxazoyl, oxadiazolyl, triazolyl, pyrimidinyl, benzimidazolyl, 1H-pyrrolo[3,2-c]pyridine, and 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl are each optionally and independently, as valence permits, R F and R e is (C1-C4) alkyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazole, and R e is optionally substituted with (C1-C4) alkyl, and the remaining variables are as described in Formula I, or any one of the third through thirteenth and twentieth embodiments.

[0061] In a twenty-second embodiment, R in a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, gis selected, as valence permits, from (C1-C4) alkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl, and the (C1-C4) alkyl, as valence permits, from R J wherein said 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are each independently, where valence allows, optionally substituted with 1-3 groups selected from (C1-C4) alkyl, (C1-C4) alkoxy, benzyl, and hydroxyl, and the remaining variables are as described in Formula I, or any one of the third to twenty-first embodiments.

[0062] In a twenty-third embodiment, R in a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, J is phenyl, and the remaining variables are as described in Formula I, or any one of the third through twenty-second embodiments.

[0063] In a twenty-fourth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, g is selected, as valences permit, from (C1-C4) alkyl, morpholinyl, azetidinyl, tetrahydropyranyl, oxatanyl, pyrrolidinyl, and pyrazolyl, and the (C1-C4) alkyl is, as valences permit, selected from R J wherein said morpholinyl, azetidinyl, tetrahydropyranyl, oxatanyl, pyrrolidinyl, and pyrazolyl are each independently optionally substituted, where valence allows, with 1 to 3 groups selected from (C1-C4) alkyl, (C1-C4) alkoxy, benzyl, and hydroxyl, and the remaining variables are as described in Formula I, or any one of the third through twenty-third embodiments.

[0064] In a twenty-fifth embodiment, R in a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, Fis selected from cyano, (C1-C4) alkyl, hydroxyl, and oxo, and the remaining variables are as described in Formula I, or any one of the third through twenty-fourth embodiments. Alternatively, as part of the twenty-fifth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, F is selected from halo, cyano, (C1-C4)alkyl, (C1-C4)haloalkyl, (C1-C4)alkoxy, hydroxyl, —N[(C1-C4)alkyl]2, morpholinyl, piperazinyl, azetidinyl, pyrrolidinyl, and oxo, wherein said piperazinyl, pyrrolidinyl, and azetidinyl are each optionally substituted with one or two groups selected from cyano, halo, (C1-C4)alkyl, (C1-C4)alkoxy, and (C1-C4)alkyl(C1-C4)alkoxy, and the remaining variables are as described in Formula I, or any one of the third through twenty-fourth embodiments.

[0065] In a twenty-sixth embodiment, R in a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, M is halo, (C1-C4)alkoxy, -S(O)2R f and —S(O)═NH(C1-C4)alkyl, the remaining variables being as described in Formula I, or any one of the third through twenty-fifth embodiments. Alternatively, as part of the twenty-sixth embodiment, R in a compound of Formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, is M is halo, hydroxy, (C1-C4)alkoxy, -S(O)2R f , —S(O)═NH(C1-C4)alkyl, pyridinyl, pyrazoyl, and phenyl optionally substituted with 1 or 2 halo, the remaining variables being as described in Formula I, or any one of the third through twenty-fifth embodiments.

[0066] In a twenty-seventh embodiment, R in a compound of formula I, II, III, or IV, or a pharmaceutically acceptable salt thereof, fis (C1-C4) alkyl, said (C1-C4) alkyl being optionally substituted, where valence allows, with 1 to 3 halo, and the remaining variables are as described in Formula I, or any one of the third through twenty-sixth embodiments.

[0067] Compounds having Formula I are further disclosed in the Examples and are included in this disclosure, including their pharmaceutically acceptable salts and neutral forms.

[0068] 4. Uses, Formulation and Administration The compounds and compositions described herein are generally useful for modulating the activity of STAT proteins, particularly STAT3 and / or STAT6. In some embodiments, the compounds, pharmaceutically acceptable salts, and pharmaceutical compositions described herein inhibit the activity of STAT3 and / or STAT6.

[0069] In some embodiments, the compounds and pharmaceutical compositions described herein are beneficial in conditions responsive to modulation of STAT3 and / or STAT6. Accordingly, provided herein are methods of treating a condition responsive to modulation (e.g., inhibition) of STAT3 and / or STAT6 in a subject, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or a pharmaceutically acceptable salt thereof.

[0070] Also provided is the use of a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or a pharmaceutically acceptable salt thereof, for the manufacture of a medicament for treating a condition responsive to modulation (e.g., inhibition) of STAT3 and / or STAT6. Also provided is a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or a pharmaceutically acceptable salt thereof, for use in treating a condition responsive to modulation (e.g., inhibition) of STAT3 and / or STAT6.

[0071] In one aspect, conditions responsive to modulation (e.g., inhibition) of STAT3 and / or STAT6 include, but are not limited to, cancer, neurodegenerative diseases, viral diseases, autoimmune diseases, inflammatory diseases, genetic diseases, hormone-related diseases, metabolic disorders, conditions associated with organ transplantation, immunodeficiency diseases, destructive bone diseases, proliferative diseases, infectious diseases, conditions associated with cell death, pathological immune conditions including thrombin-induced platelet aggregation, liver diseases, T-cell activation, cardiovascular diseases, or CNS diseases.

[0072] In another aspect, the condition responsive to modulation (e.g., inhibition) of STAT3 and / or STAT6 is cancer (see, e.g., Turkson & Jove, Oncogene 2000, 19:6613-6626), diabetes (see, e.g., Gurzov et al., FEBS 2016, 283:3002), cardiovascular disease (see, e.g., Grote et al., Vasc. Pharmacol. 2005, 43:2005), viral disease (see, e.g., Gao et al., J. Hepatol. 2012, 57(2):430), autoimmune diseases such as lupus (see, e.g., Goropevsek et al., Clin. Rev. Alleg. & Immun. 2017, 52(2):164), and rheumatoid arthritis (see, e.g., Walker & Smith, J. Rheumat. 2005, 32(9):1650), autoinflammatory syndromes (see, e.g., Rauch et al., Jak-Stat. 2013,2(l):e23820), atherosclerosis (see, e.g., Ortiz-Munoz et al., Arterio., Thrombo., Vasc. Bio. 2009,29:525), psoriasis (see, e.g., Andres et al., Exp. Derm. 2013,22(5):323), allergic diseases (see, e.g., Oh et al., Eur. Respir. Rev. 2019,19(115):46), inflammatory bowel disease (see, e.g., Sugimoto, World J Gastroenterol. 2008,14(33):5110), inflammation (see, e.g., Tamiya et al., Arierio. Thrombo., Vasc. Bio. 2011,31:980), acute and chronic gout and gouty arthritis, neurological disorders (see, e.g., Campbell, Brain Res. Rev. 2005, 48(2):166), metabolic syndrome, immunodeficiency diseases such as AIDS and HIV (see, e.g., O'Shea et al., N. Engl. J. Med. 2013, 368:161), destructive bone diseases (see, e.g., Jatiani et al., Genes & Can. 2011, 1(10):979), osteoarthritis, proliferative diseases, Waldenstrom's macroglobulinemia (see, e.g., Hodge et al., Blood 2014, 123(7):1055), infectious diseases, conditions associated with cell death, pathological immune conditions involving T-cell activation, and CNS diseases.

[0073] Proliferative disorders include benign or malignant tumors, solid tumors, liquid tumors, carcinomas of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumors, ovaries, colon, rectum, prostate, pancreas, lung, vagina, cervix, testes, genitourinary tract, esophagus, larynx, skin, bone, or thyroid, non-carcinomas, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, especially colon cancer or colorectal adenoma, cancer of the head and neck, epidermal hyperproliferation, psoriasis, benign prostatic hyperplasia, neoplasia Neoplasia of epithelial origin, adenoma, adenocarcinoma, keratoacanthoma, squamous cell carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin's lymphoma and non-Hodgkin's lymphoma, breast cancer, follicular adenocarcinoma, undifferentiated carcinoma, papillary carcinoma, seminoma, melanoma, IL-I-induced disease, MyD88-induced disease, smoldering late-onset multiple myeloma, or hematological malignancies (leukemia, diffuse large B-cell lymphoma (DLBCL), ABC These include, but are not limited to, DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt's lymphoma / leukemia, acute lymphocytic leukemia, B-cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, and intravascular large B-cell lymphoma.

[0074] In some embodiments, the cancer being treated is selected from glioma, breast cancer, prostate cancer, squamous cell carcinoma of the head and neck, cutaneous melanoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), and pancreatic cancer. In other embodiments, the cancer being treated is selected from glioma, breast cancer, prostate cancer, squamous cell carcinoma of the head and neck, cutaneous melanoma, ovarian cancer, malignant peripheral nerve sheath tumors (MPNST), pancreatic cancer, non-small cell lung cancer (NSCLC), including EGFR-mutant NSCLC, urothelial cancer, liver cancer, cholangiocarcinoma, renal cancer, colon cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumors, and hematological malignancies, including lymphoma, leukemia, myeloma, myeloproliferative neoplasms, and myelodysplastic syndromes. In other embodiments, the cancer is selected from solid tumors (e.g., prostate cancer, renal cancer, liver cancer, pancreatic cancer, gastric cancer, breast cancer, lung cancer, head and neck cancer, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, uterine leiomyosarcoma, melanoma, etc.), blood cancers (e.g., lymphoma, leukemia, such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), or multiple myeloma), and skin cancers, such as cutaneous T-cell lymphoma (CTCL) and cutaneous B-cell lymphoma. Examples of CTCLs include Sézary syndrome and mycosis fungoides.

[0075] The compounds, salts, and compositions described herein are also useful in the treatment of inflammatory or obstructive airway diseases, for example, resulting in a reduction in cell damage, airway inflammation, bronchial hyperresponsiveness, remodeling, or disease progression. Inflammatory or obstructive airway diseases include asthma of all types and origins, including both intrinsic (non-allergic) and extrinsic (allergic) asthma, mild asthma, moderate asthma, severe asthma, bronchitis asthma, exercise-induced asthma, occupational asthma, and asthma induced by bacterial infection. Treatment of asthma is also understood to include the comprehensive treatment of subjects, e.g., under the age of 4 or 5, who exhibit wheezing symptoms and have been or can be diagnosed as "wheezing infants," an established patient category of major medical concern now often identified as having onset or early asthma.

[0076] The compounds, salts, and compositions described herein are also useful in the treatment of heteroimmune diseases, including, but not limited to, graft-versus-host disease, transplants, blood transfusions, anaphylaxis, allergies (e.g., allergies to pollen, rubber products, drugs, foods, insect venom, animal hair, animal dander, house dust mites, or cockroach cups), Type I hypersensitivity, allergic conjunctivitis, allergic rhinitis, and atopic dermatitis.

[0077] The compounds, salts, and compositions described herein are also useful in the treatment of other inflammatory or obstructive airway diseases and conditions to which the present invention is applicable, including acute lung injury (ALI), adult / acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease, airway or lung diseases including chronic bronchitis or associated dyspnea (COPD, COAD, or COLD), emphysema, and exacerbations of airway hyperresponsiveness resulting from other medications, particularly other inhaled medications. The compounds, salts, and compositions described herein are also useful in the treatment of bronchitis, including, but not limited to, acute, arachidic, catarrhal, croupus, chronic, or phthinoid bronchitis. The compounds, salts, and compositions described herein are also useful in the treatment of pneumoconiosis (an inflammatory, generally occupational, lung disease caused by repeated inhalation of dust, either chronic or acute, often accompanied by airway obstruction) of all types and origins, including, for example, aluminum lung disease, anthraxosis, asbestosis, silicosis, lash loss, siderosis, silicosis, tobacco poisoning, and byssinosis.

[0078] The compounds, salts, and compositions described herein are also useful in the treatment of inflammatory or allergic conditions of the skin, such as psoriasis, contact dermatitis, atopic dermatitis, alopecia areata, erythema multiforme, dermatitis herpetiformis, scleroderma, vitiligo, hypersensitivity vasculitis, urticaria, bullous pemphigoid, lupus erythematosus, systemic lupus erythematosus, pemphigus vulgaris, pemphigus foliaceus, paraneoplastic pemphigus, epidermolysis bullosa acquisita, acne vulgaris, and other inflammatory or allergic conditions of the skin.

[0079] The compounds, salts, and compositions described herein may also be used in the treatment of other diseases or conditions, e.g., diseases or conditions having an inflammatory component, such as diseases and conditions of the eye, e.g., ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal keratoconjunctivitis, diseases affecting the nose, including allergic rhinitis, and autoimmune blood diseases (e.g., hemolytic anemia, aplastic anemia, pure red cell anemia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's granulomatosis, dermatomyositis, chronic active hepatitis, myasthenia gravis, Stevens-Johnson disease. syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g., ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, kidney disease, glomerular disease, alcoholic liver disease, multiple sclerosis, endocrine ophthalmopathy, Graves' disease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis, multiple sclerosis, primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren's syndrome, keratoconjunctivitis sicca and vernal conjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, systemic juvenile idiopathic arthritis, cryopyrin-associated periodic syndrome, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis ( Nephrotic syndrome (with or without, including, for example, idiopathic nephrotic syndrome or minimal change nephropathy), chronic granulomatous disease, endometriosis, leptospirosis, kidney disease, glaucoma, retinal disease, aging, headache, pain, complex regional pain syndrome, cardiac hypertrophy, muscle atrophy, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal dysplasia, Behçet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and non-allergic, mild, moderate, severe, bronchitis, exercise-induced), acute lung injury, acute respiratory distress Distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, eye allergies, silica-induced disease, COPD (damage, airway inflammation, bronchial hyperresponsiveness, remodeling or reduction in disease progression), lung disease, cystic fibrosis, acid-induced lung disease, pulmonary hypertension, polyneuropathy, cataracts, myositis associated with systemic sclerosis, inclusion body myositis, myasthenia gravis, thyroiditis, Addison's disease, lichen planus, type 1 or type 2 diabetes, appendicitis, atopic dermatitis, asthma, allergies, blepharitis, bronchiolitis, bronchitis, bursitis, cervicitis, cholangitis, cholecystitis, chronic graft rejection, colitis, conjunctivitis,Crohn's disease, cystitis, dacryoadenitis, dermatitis, dermatomyositis, encephalitis, encephalomyelitis, endocarditis, endometritis, enteritis, enterocolitis, epicondylitis, epididymitis, fasciitis, fibrositis, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis abscess, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis, myocarditis, myositis, nephritis, oophoritis, orchitis, osteitis, otitis, pancreatitis The compounds are useful in the treatment of inflammatory diseases involving an autoimmune response or having an autoimmune component or etiology, including parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonia, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis, or vulvitis.

[0080] In some embodiments, cardiovascular diseases that can be treated according to the present methods include, but are not limited to, restenosis, cardiac hypertrophy, atherosclerosis, myocardial infarction, ischemic stroke, congestive heart failure, angina pectoris, reocclusion after angioplasty, restenosis after angioplasty, reocclusion after aortocoronary bypass, restenosis after aortocoronary bypass, stroke, transient ischemia, peripheral arterial occlusive disease, pulmonary embolism, and deep vein thrombosis.

[0081] In some embodiments, neurodegenerative diseases that can be treated according to the present methods include, but are not limited to, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemia, and neurodegenerative diseases caused by trauma, glutamate neurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolic syndrome, obesity, organ transplantation, and graft-versus-host disease.

[0082] In certain aspects, the pharmaceutical compositions described herein are formulated for administration to a patient in need of such a composition. The pharmaceutical compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. The term "parenteral," as used herein, includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional, and intracranial injection or infusion techniques. In some embodiments, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the pharmaceutical compositions described herein may be aqueous or oily suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.

[0083] In some embodiments, the pharmaceutical composition is administered orally.

[0084] The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, excretion rate, 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 on the particular compound in the pharmaceutical composition. [Example]

[0085] Preparation of compounds The compounds claimed herein were prepared according to the following procedure, summarized in the scheme below. Compound names were generated using software integrated into ChemDraw. To the extent that there is an inconsistency between a compound name and its depicted structure, the depicted chemical structure is considered the appropriate compound.

[0086] Core Synthesis

[0087] Synthesis of (3S,6S,7aS,8aR,9aR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylic acid and (3S,6S,7aR,8aS,9aR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylic acid [ka]

[0088] Step 1: Preparation of methyl (2S)-5-allyl-1-((S)-2-((tert-butoxycarbonyl)amino)pent-4-enoyl)pyrrolidine-2-carboxylate

[0089] To a cooled (0 °C) solution of methyl (2S)-5-allylpyrrolidine-2-carboxylate hydrochloride (200 g, 972 mmol, 1.00 equiv.) and (S)-2-((tert-butoxycarbonyl)amino)pent-4-enoic acid (209 g, 972 mmol, 1.00 equiv.) in CHCl (1.60 L) was added EtN (406 mL, 2.92 mol, 3.00 equiv.) and 2-chloro-1-methylpyridinium iodide (CMPI) (273 g, 1.07 mol, 1.10 equiv.). The solution was warmed to 25 °C and stirred for 1 h. The mixture was poured into water (5.0 L) and extracted with CHCl (2.00 L × 3). The combined organic layers were washed with brine (2.0 L), dried over Na2SO4, filtered, and concentrated under reduced pressure. Six batches of the same scale were run in parallel and combined during workup. 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 a 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).

[0090] 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

[0091] 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 equiv.) in CHCl (2.00 L) at 25 °C, Grubbs' first generation catalyst (44.9 g, 54.6 mmol, 0.10 equiv.) was added. The solution was then heated to 50 °C and stirred for 36 h. Six batches of the same scale were run in parallel and combined during workup. The combined reaction mixture was concentrated to give a residue. The residue was purified twice by column chromatography (petroleum ether: EtOAc = 100:1 to 0:1) to give the 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).

[0092] Step 3: Preparation of methyl (3S,6S,7aS,8aR,9aR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylate and methyl (3S,6S,7aR,8aS,9aR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylate

[0093] To a cooled (0 °C) solution of 1-methyl-1-nitrosourea (50.0 g, 485 mmol, 1.00 equiv.) in EtO (1.50 L) was slowly added dropwise a solution of KOH (144 g, 2.57 mol, 5.30 equiv.) in HO (150 mL). The mixture was stirred at 0 °C for 30 min, at which point the organic layer turned yellow, indicating completion of the reaction. The aqueous layer of the reaction mixture was separated, and the yellow EtO layer was used in the next step without further manipulation. [Diazomethane (20.0 g, 475 mmol, 98.0% yield) in EtO (1.50 L) was obtained.]

[0094] A solution of approximately 85% diazomethane (20.0 g, 476 mmol, 16.1 equiv.) in EtO (1.50 L) was carefully transferred to a solution 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 (10.0 g, 29.5 mmol, 1.00 equiv.) in THF (320 mL) at 0 °C. To the resulting mixture was slowly added a solution of approximately 50% Pd(OAc) (1.99 g, 8.87 mmol, 0.30 equiv.) in THF (60.0 mL). The reaction mixture was stirred at 0°C for 2 minutes, followed by the sequential addition of the remaining ethereal diazomethane solution and the palladium solution. The reaction was stirred at 0°C for 20 minutes, then the ice-water bath was removed and the reaction was allowed to warm to 20°C. After stirring for 60 minutes, the solvent was removed by a stream of nitrogen. The resulting dry reaction mixture was diluted with EtOAc and filtered through Celite. The residue (total: 37.0 g) was purified using a Phenomenex Luna C18 250 x 80 mm x 10 μm column; mobile phase: [water (0.225% FA)-ACN]; B%: 45% to 70%, 21 minutes. The appropriate peak corresponding to the product was collected. Each sample was adjusted to pH 8 with saturated aqueous NaHCO3 and concentrated. Each aqueous layer was extracted with EtOAc (2 x 1.00 L), washed with brine (1.00 L), dried over Na2SO4, filtered, and concentrated to give methyl (3S,6S,7aS,8aR,9aR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylate (12.13 g, 33.5 mm ol, 31.5% yield, 97.3% purity) as a white solid, and methyl (3S,6S,7aR,8aS,9aR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylate (9.12 g, 25.5 mmol, 24.0% yield, 98.6% purity) as a white solid.Additionally, 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 (7.60 g, 99.0% purity) was recovered as a yellow oil: methyl (3S,6S,7aS,8aR,9aR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylate: LCMS (ESI) m / z = 353.0 [M+H]. + ; 1 H NMR (400 MHz, DMSO-d6) δ 6.81 (d, J = 7.6 Hz, 0.8H), 6.50 (d, J = 3.6 Hz, 0.2H), 4.44 - 4.27 (m, 2H), 4.08 - 3.99 (m, 1H), 3.58 (s, 3H), 2.19 - 2.07 (m, 4H), 1.88 - 1.86 (m, 2H), 1.73 - 1.59 (m, 2H), 1.35 - 1.31 (m, 9H), 1.08 - 1.05 (m, 1H), 0.73 - 0.71 (m, 2H), 0.02 - 0.03 (m, 1H).

[0095] 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: LCMS (ESI) m / z = 353.0 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 6.75 (d, J = 7.6 Hz, 0.9H), 6.22 (d, J = 2.0 Hz, 0.1H), 4.33 - 4.25 (m, 2H), 4.14 - 4.12 (m, 1H), 3.60 (s, 3H), 2.20 - 2.10 (m, 1H), 2.08 - 2.03 (m, 3H), 1.85 - 1.84 (m, 1H), 1.74 - 1.57 (m, 2H), 1.38 (s, 9H), 1.34 - 1.14 (m, 3H), 0.75 - 0.73 (m, 1H), 0.03 - 0.01 (m, 1H).

[0096] Step 4: Preparation of 3S,6S,7aS,8aR,9aR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylic acid

[0097] To a solution of methyl (3S,6S,7aS,8aR,9aR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylate (2.00 g, 5.67 mmol, 1 equiv.) in a mixture of MeOH (1.0 mL), THF (1.0 mL), and water (1.0 mL) was added LiOH·HO (270 mg, 11.3 mmol, 2 equiv.). After stirring at ambient temperature for 2 h, the reaction mixture turned cloudy white. The reaction mixture was carefully concentrated under reduced pressure to give a residue. This residue was diluted with water (50 mL) and extracted with EtOAc (2 × 50 mL). The aqueous phase was acidified to pH 4–5 with 1 N aqueous HCl. The resulting acidic phase was extracted with EtOAc (2 x 50 mL), and the combined organic layers were concentrated under reduced pressure to give a residue. The product, (3S,6S,7aS,8aR,9aR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylic acid (2.00 g), was isolated as a yellow oil and used without further purification or manipulation. LCMS (ESI) m / z = 339.0 [M+H]+ .

[0098] The intermediates shown in Table 1 were synthesized using the appropriate starting materials and reagents under the conditions described above for the preparation of (3S,6S,7aS,8aR,9aR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylic acid. [Table 1]

[0099] Synthesis of methyl (3S,6S,9aR)-6-((tert-butoxycarbonyl)amino)-5-oxo-2,3,5,6,7,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate and methyl (3S,6S,9aR)-6-((tert-butoxycarbonyl)amino)-8-methyl-5-oxo-2,3,5,6,7,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate [ka]

[0100] Step 1: Preparation of methyl (S)-2-((tert-butoxycarbonyl)amino)-5-oxo-7-(trimethylsilyl)hept-6-ynoate

[0101] To a cooled (0 °C) solution of isopropylmagnesium chloride (2.0 M, 9.04 L, 1.10 equiv.) and THF (4.00 L) was added ethynyltrimethylsilane (1.86 kg, 18.9 mol, 2.62 L, 1.15 equiv.). The reaction mixture was stirred for 1 h, followed by the slow addition of a solution of 1-(tert-butyl) 2-methyl(S)-5-oxopyrrolidine-1,2-dicarboxylate (4.00 kg, 16.4 mol, 1.00 equiv.) in THF (8.0 L) over 1.5 h. After stirring for an additional 30 min, the reaction mixture was transferred to a stirred, cooled (0 °C) biphasic mixture of iPAc (5.00 L) and 20% aqueous NH4Cl (16.0 L). The biphasic mixture was separated, and the aqueous layer was extracted with iPAc (8.00 L). The combined organic layers were washed with 20% aqueous NH4Cl (8.00 L), brine (8.00 L), dried over Na2SO4, filtered, and concentrated under reduced pressure to give methyl (S)-2-((tert-butoxycarbonyl)amino)-5-oxo-7-(trimethylsilyl)hept-6-ynoate (5.50 kg) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 5.11 - 5.09 (m, 1H), 4.32 - 4.30 (m, 1H), 3.77 - 3.72 (m, 3H), 2.72 - 2.64 (m, 2H), 2.04 - 2.01 (m, 1H), 1.73 - 1.71 (m, 1H), 1.41 (s, 9H), 0.24 (s, 9H).

[0102] Step 2: Preparation of 1-(tert-butyl) 2-methyl (2S,5R)-5-((trimethylsilyl)ethynyl)pyrrolidine-1,2-dicarboxylate

[0103] To a suspension of NaBH(OAc)3 (4.03 kg, 19.0 mol, 1.30 equiv.) in iPAc (5.00 L) was added a solution of methyl (S)-2-((tert-butoxycarbonyl)amino)-5-oxo-7-(trimethylsilyl)hept-6-ynoate in iPAc (20.0 L). The batch was cooled to (-10 °C), followed by the slow addition of TFA (7.18 kg, 62.9 mol, 4.66 L, 4.30 equiv.) over 1.5 h. The mixture was warmed to 10 °C and stirred for an additional 2 h. The reaction mixture was transferred to a cooled (0 °C) solution of 25% aqueous K2HPO4 (40.0 L). The pH of the suspension was adjusted to pH 6-7 with saturated aqueous NaHCO3. The biphasic mixture was separated, and the aqueous layer was extracted with iPAc (8.00 L). The combined organic layers were washed with 25% KHPO solution (8.00 L), brine (5.00 L), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 30 / 1 to 3 / 1) to give 1-(tert-butyl) 2-methyl(2S,5R)-5-((trimethylsilyl)ethynyl)pyrrolidine-1,2-dicarboxylate (2.27 kg, 6.97 mol, 42.4% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 4.49 - 4.32 (m, 1H), 4.16 (s, 1H), 3.63 (s, 3H), 2.16 (s, 2H), 1.95 - 1.88 (m, 2H), 1.40 - 1.32 (m, 9H), 0.13 (s, 9H).

[0104] Step 3: Preparation of 1-(tert-butyl) 2-methyl (2S,5R)-5-ethynylpyrrolidine-1,2-dicarboxylate

[0105] To a cooled (0 °C) solution of 1-(tert-butyl) 2-methyl(2S,5R)-5-((trimethylsilyl)ethynyl)pyrrolidine-1,2-dicarboxylate (500 g, 1.54 mol, 1.00 equiv.) in THF (2.00 L) was added a 1.0 M solution of TBAF (1.84 L, 1.20 equiv.), followed by stirring for 1 h. Four batches of the same scale were run in parallel, and the reaction mixtures were combined and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 0 / 1) to give 1-(tert-butyl) 2-methyl(2S,5R)-5-ethynylpyrrolidine-1,2-dicarboxylate (920 g, 2.95 mol, 48.0% yield, 81.2% purity) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 4.62 - 4.50 (m, 1H), 4.30 - 4.20 (m, 1H), 3.74 - 3.70 (m, 3H), 2.31 - 2.14 (m, 5H), 1.47 - 1.40 (m, 9H).

[0106] Step 4: Preparation of 1-(tert-butyl) 2-methyl (2S,5R)-5-vinylpyrrolidine-1,2-dicarboxylate

[0107] To a suspension of 1-(tert-butyl) 2-methyl(2S,5R)-5-ethynylpyrrolidine-1,2-dicarboxylate (150 g, 592 mmol, 1.00 equiv.) in EtOAc (1.50 L) was added Lindlar's catalyst (7.50 g, 1.82 mmol, 5.0% wt.) and quinoline (163 g, 1.27 mol, 150 mL, 2.14 equiv.) under N2(g). The suspension was degassed under vacuum and purged with H2(g) (3x). The mixture was stirred under H2(g) (50 psi) for 1 h. Six batches of the same scale were run in parallel and filtered, and the filtrates were combined during workup. The mixture was filtered, and the filtrate was washed with 1 N aqueous HCl (9.00 L), separated, and concentrated. The combined residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 0 to 0 / 1) to give 1-(tert-butyl) 2-methyl (2S,5R)-5-vinylpyrrolidine-1,2-dicarboxylate (745 g, 2.23 mol, 62.8% yield, 76.5% purity) as a yellow oil. 1 H NMR (400 MHz, DMSO-d6) δ 5.84 - 5.76 (m, 1H), 5.34 - 5.27 (m, 1H), 5.06 - 5.04 (m, 1H), 4.29 - 4.17 (m, 2H), 3.65 - 3.62 (m, 3H), 2.16 - 2.14 (m, 2H), 1.79 - 1.78 (m, 1H), 1.69 - 1.65 (m, 1H), 1.34 - 1.32 (m, 9H).

[0108] Step 5: Preparation of methyl (2S,5R)-5-vinylpyrrolidine-2-carboxylate

[0109] To a solution of 1-(tert-butyl) 2-methyl(2S,5R)-5-vinylpyrrolidine-1,2-dicarboxylate (245 g, 959 mmol, 1.00 equiv) in EtOAc (1.25 L) was added a solution of a 4.0 M solution of HCl in EtOAc (959 mL, 4.00 equiv). Three batches of the same scale were run in parallel and the mixture was stirred at 25° C. for 2 h. The reaction mixture was combined and concentrated under reduced pressure to give the product, methyl (2S,5R)-5-vinylpyrrolidine-2-carboxylate (520 g, HCl) as an off-white solid. 1 H NMR (400 MHz, DMSO-d6) δ 6.03 - 5.95 (m, 1H), 5.44 - 5.33 (m, 2H), 4.49 - 4.45 (m, 1H), 4.11 - 4.05 (m, 1H), 3.76 (s, 3H), 2.31 - 2.28 (m, 1H), 2.16 - 2.10 (m, 1H), 1.81 - 1.76 (m, 1H).

[0110] Step 6: Preparation of methyl (2S,5R)-1-((S)-2-((tert-butoxycarbonyl)amino)pent-4-enoyl)-5-vinylpyrrolidine-2-carboxylate

[0111] To a solution of (S)-2-((tert-butoxycarbonyl)amino)pent-4-enoic acid (35.9 g, 167 mmol, 1.00 equiv) in CHCl (320 mL) was added methyl (2S,5R)-5-vinylpyrrolidine-2-carboxylate (32.0 g, 167 mmol, 1.00 equiv, HCl) and EtN (69.7 mL, 0.501 mol, 3.00 equiv). The mixture was cooled to 0 °C, and CMPI (98.8 g, 387 mmol, 1.10 equiv) was added. The reaction mixture was then warmed to 25 °C and stirred for 3 h. The reaction mixture was poured into water (500 mL) and extracted with CHCl (200 mL × 3). The combined organic layers were washed with saturated aqueous NH4Cl (300 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (petroleum ether / EtOAc = 50 / 1 to 5 / 1) to give methyl (2S,5R)-1-((S)-2-((tert-butoxycarbonyl)amino)pent-4-enoyl)-5-vinylpyrrolidine-2-carboxylate (47.0 g) as a yellow oil. LCMS (ESI) m / z = 367.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 6.03 - 5.94 (m, 1H), 5.77 - 5.66 (m, 1H), 5.52 (d, J = 16.8 Hz, 1H), 5.22 (d, J = 10.4 Hz, 1H), 5.12 - 5.00 (m, 4H), 4.81 (br d, J = 6.4 Hz, 1H), 4.53 - 4.44 (m, 2H), 3.73 (s, 3H), 2.45 - 2.38 (m, 1H), 2.32 - 2.27 (m, 1H), 2.22 - 2.15 (m, 2H), 2.02 - 1.83 (m, 3H), 1.41 (s, 9H).

[0112] The intermediates shown in Table 2 were synthesized using methyl (2S,5R)-5-vinylpyrrolidine-2-carboxylate, the appropriate N-protected amino acid, CMPI, triethylamine, and CHCl under the reaction conditions described above. The intermediate(s) were purified using standard methods. [Table 2]

[0113] Step 7: Preparation of methyl (3S,6S,9aR)-6-((tert-butoxycarbonyl)amino)-5-oxo-2,3,5,6,7,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate

[0114] To a solution of methyl (2S,5R)-1-((S)-2-((tert-butoxycarbonyl)amino)pent-4-enoyl)-5-vinylpyrrolidine-2-carboxylate (21.0 g, 59.6 mmol, 1.00 equiv) in CHCl (2.10 L) was added Grubbs' catalyst 1 (4.90 g, 5.96 mmol, 0.10 equiv). The mixture was heated to 50 °C and stirred for 12 h. Two batches of the same scale were run in parallel. The reaction mixtures were then combined and concentrated to give a residue. The residue was purified by column chromatography (petroleum ether / EtOAc = 10 / 1 to 1 / 1) to give methyl (3S,6S,9aR)-6-((tert-butoxycarbonyl)amino)-5-oxo-2,3,5,6,7,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate (35.0 g, 94.8 mmol, 56.6% yield, 87.9% purity) as a gray solid. LCMS (ESI) m / z = 225.0 [(M-Boc)+H] + ; 1 H NMR (400 MHz, CDCl3) δ 5.78 - 5.71 (m, 2H), 5.55 (d, J = 11.6 Hz, 1H), 4.75 - 4.63 (m, 3H), 3.72 (s, 3H), 2.64 - 2.58 (m, 1H), 2.38 - 2.29 (m, 2H), 2.11 - 2.05 (m, 2H), 1.93 - 1.85 (m, 1H), 1.44 (s, 9H).

[0115] The intermediates shown in Table 3 were synthesized using the appropriate starting materials and reagents under the conditions described above for the preparation of methyl (3S,6S,9aR)-6-((tert-butoxycarbonyl)amino)-5-oxo-2,3,5,6,7,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate. [Table 3]

[0116] Synthesis of (3S,6S,7aS,8aS,8bR)-6-((tert-butoxycarbonyl)amino)-7a-methyl-5-oxodecahydrocyclopropa[c]pyrrolo[1,2-a]azepine-3-carboxylic acid and (3S,6S,7aR,8aR,8bR)-6-((tert-butoxycarbonyl)amino)-7a-methyl-5-oxodecahydrocyclopropa[c]pyrrolo[1,2-a]azepine-3-carboxylic acid [ka]

[0117] Step 1: Preparation of methyl (3S,6S,7aS,8aS,8bR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydrocyclopropa[c]pyrrolo[1,2-a]azepine-3-carboxylate and methyl (3S,6S,7aR,8aR,8bR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydrocyclopropa[c]pyrrolo[1,2-a]azepine-3-carboxylate

[0118] To a stirred, cooled (-40 °C) solution of 0.5 M diazomethane (1.29 g, 30.8 mmol, 10 equiv) in MTBE (40 mL) was added a solution of methyl (3S,6S,9aR)-6-((tert-butoxycarbonyl)amino)-5-oxo-2,3,5,6,7,9a-hexahydro-1H-pyrrolo[1,2-a]azepine-3-carboxylate (1.00 g, 3.08 mmol, 1 equiv) in DCM. To this cooled mixture was added Pd(OAc) (6.91 mg, 30.8 μmol, 0.01 equiv) in DCM. The mixture was then warmed to -10 °C, and N(g) gas effervescence was observed. The reaction mixture was aged at this temperature for 2 h or until N(g) evolution ceased. The reaction mixture was warmed to room temperature and filtered. The filtrate was concentrated to give the crude product as a mixture of diastereomers. The resulting mixture was purified by HPLC, and the mixture was separated to give methyl (3S,6S,7aS,8aS,8bR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydrocyclopropa[c]pyrrolo[1,2-a]azepine-3-carboxylate (100 mg, 295 μmol, 9.61%) and methyl (3S,6S,7aR,8aR,8bR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydrocyclopropa[c]pyrrolo[1,2-a]azepine-3-carboxylate (110 mg, 325 μmol, 10.5%).

[0119] Methyl (3S,6S,7aS,8aS,8bR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydrocyclopropa[c]pyrrolo[1,2-a]azepine-3-carboxylate: LCMS (ESI) m / z = 239.0 [(M-Boc)+H] + .

[0120] Methyl (3S,6S,7aR,8aR,8bR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydrocyclopropa[c]pyrrolo[1,2-a]azepine-3-carboxylate: LCMS (ESI) m / z = 239.0 [(M-Boc)+H] + .

[0121] Step 2: Preparation of (3S,6S,7aS,8aS,8bR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydrocyclopropa[c]pyrrolo[1,2-a]azepine-3-carboxylic acid and (3S,6S,7aR,8aR,8bR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydrocyclopropa[c]pyrrolo[1,2-a]azepine-3-carboxylic acid

[0122] For the synthesis of (3S,6S,7aS,8aR,9aR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylic acid and / or (3S,6S,7aR,8aS,9aR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylic acid, the intermediates shown in Table 4 were synthesized using the appropriate starting materials and LiOH·HO under the hydrolysis conditions described in Step 4. [Table 4]

[0123] Synthesis of (3S,6S,7aS,8aR,9aR)-6-((tert-butoxycarbonyl)amino)-8,8-difluoro-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylic acid [ka]

[0124] Step 1: Preparation of methyl (3S,6S,10aR,Z)-6-amino-5-oxo-1,2,3,5,6,7,10,10a-octahydropyrrolo[1,2-a]azocine-3-carboxylate

[0125] To a solution 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 (1.0 g, 2.95 mmol, 1 equiv.) in dichloromethane (15 mL) was added trifluoroacetic acid (4.0 mL, 52 mmol, 17 equiv.). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated to dryness and directly purified by reverse-phase chromatography using a gradient of 5 to 100% MeCN in basic water (10 mM NH4HCO3, pH = 10) to give methyl (3S,6S,10aR,Z)-6-amino-5-oxo-1,2,3,5,6,7,10,10a-octahydropyrrolo[1,2-a]azocine-3-carboxylate (588 mg, 2.46 mmol, 83% yield) as a white solid. 1 H NMR (400 MHz, CD3OD) δ 5.78 - 5.64 (m, 2 H), 4.45 - 4.41 (m, 1 H), 4.25 - 4.17 (m, 1 H), 4.11 (dd, 1 H, J = 9.7, 6.0 Hz), 3.66 (s, 3 H), 2.81 - 2.67 (m, 2 H), 2.41 - 2.33 (m, 1 H), 2.22 - 2.05 (m, 3 H), 1.97 - 1.86 (m, 2 H).

[0126] Step 2: Preparation of methyl (3S,6S,10aR,Z)-6-(1,3-dioxoisoindolin-2-yl)-5-oxo-1,2,3,5,6,7,10,10a-octahydropyrrolo[1,2-a]azocine-3-carboxylate

[0127] A solution of methyl (3S,6S,10aR,Z)-6-amino-5-oxo-1,2,3,5,6,7,10,10a-octahydropyrrolo[1,2-a]azocine-3-carboxylate (500 mg, 2.09 mmol, 1 equiv) and phthalic anhydride (318 mg, 2.15 mmol, 1.03 equiv) in toluene (20 mL) was heated at reflux for 24 h. The solvent was then evaporated and the product was directly purified by reverse-phase chromatography using a gradient of 5–100% MeCN in water to give methyl (3S,6S,10aR,Z)-6-(1,3-dioxoisoindolin-2-yl)-5-oxo-1,2,3,5,6,7,10,10a-octahydropyrrolo[1,2-a]azocine-3-carboxylate (659 mg, 1.78 mmol, 85% yield) as an off-white solid. 1 H NMR (400 MHz, CDCl3) δ 7.86 - 7.80 (m, 2 H), 7.72 - 7.66 (m, 2 H), 6.18 - 6.09 (m, 1 H), 5.88 - 5.81 (m, 1 H), 5.31 (dd, J = 7.9, 4.5 Hz, 1 H), 4.46 - 4.38 (m, 2 H), 3.70 (s, 3 H), 3.13 - 3.03 (m, 1 H), 2.96 - 2.88 (m, 1 H), 2.63 - 2.54 (m, 1 H), 2.49 - 2.40 (m, 1 H), 2.32 - 2.23 (m, 1H), 2.22 - 2.12 (m, 1 H), 2.05 - 1.94 (m, 1 H), 1.92 - 1.84 (m, 1 H).

[0128] Step 3: Preparation of methyl (3S,6S,7aS,8aR,9aR)-6-(1,3-dioxoisoindolin-2-yl)-8,8-difluoro-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylate

[0129] A round-bottom flask equipped with a magnetic stirrer and a water condenser was charged with methyl (3S,6S,10aR,Z)-6-(1,3-dioxoisoindolin-2-yl)-5-oxo-1,2,3,5,6,7,10,10a-octahydropyrrolo[1,2-a]azocine-3-carboxylate (150 mg, 0.407 mmol, 1 equiv.), sodium fluoride (5.12 mg, 0.122 mmol, 0.3 equiv.), and anhydrous toluene (2 mL). The mixture was heated to reflux for 30 min, after which a solution of trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (159 μL, 0.814 mmol, 2 equiv.) in toluene (2 mL) was added via syringe over 1 h. The clear solution turned pale orange. The reaction was allowed to stir at reflux for 1.5 hours, then additional trimethylsilyl 2,2-difluoro-2-(fluorosulfonyl)acetate (159 μL, 0.814 mmol, 2 equiv) in toluene (2 mL) was added via syringe pump over 40 minutes, and the reaction was allowed to stir at reflux for 1 hour. The reaction mixture was cooled to room temperature, diluted with saturated aqueous sodium bicarbonate and EtOAc, and stirred for 10 minutes. The layers were separated. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated to dryness to give a crude orange foam (238 mg, 140%). Purification by reverse-phase chromatography eluting with 5–100% MeCN in water (containing 0.1% formic acid) gave methyl (3S,6S,7aS,8aR,9aR)-6-(1,3-dioxoisoindolin-2-yl)-8,8-difluoro-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylate (48 mg, 0.114 mmol, 28% yield). 1 H NMR (400 MHz, CDCl3) δ 7.86 - 7.81 (m, 2 H), 7.74 - 7.68 (m, 2 H), 5.25 - 5.20 (m, 1 H), 4.40 (t, J = 8.1 Hz, 1 H), 4.28 - 4.20 (m, 1 H), 3.72 (s, 3 H), 2.74 - 2.61 (m, 2 H), 2.38 - 1.80 (m, 8 H).

[0130] Step 4: Preparation of (3S,6S,7aS,8aR,9aR)-6-((tert-butoxycarbonyl)amino)-8,8-difluoro-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylic acid

[0131] To a solution of methyl (3S,6S,7aS,8aR,9aR)-6-(1,3-dioxoisoindolin-2-yl)-8,8-difluoro-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylate (145 mg, 0.346 mmol, 1 equiv.) in water (2 mL) and tetrahydrofuran (6 mL) was added lithium hydroxide monohydrate (43.2 mg, 1.03 mmol, 3 equiv.). The reaction was stirred at 20 °C for 1 h. The volatiles were removed in vacuo. The aqueous residue was diluted with 3 M aqueous hydrochloric acid (5 mL), and the solution was heated at 100 °C for 20 h. The reaction mixture was concentrated to dryness. The residue was diluted with 1 M aqueous NaOH (6 mL), and di-tert-butyl dicarbonate (377 mg, 1.73 mmol, 5 equiv.) was added. The reaction was stirred at 20° C. for 20 hours. Additional di-tert-butyl dicarbonate (800 mg) was added and the reaction was stirred at 20° C. for 16 hours. The volatiles were removed in vacuo. The resulting aqueous solution was acidified to pH 2 using 6N aqueous HCl, and the product was extracted with EtOAc (2×15 mL). The combined organic layers were washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by reverse-phase chromatography using a gradient of 5 to 100% MeCN in water (containing 0.1% formic acid) to give (3S,6S,7aS,8aR,9aR)-6-((tert-butoxycarbonyl)amino)-8,8-difluoro-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylic acid (84.0 mg, 0.224 mmol, 65%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 5.40 - 5.33 (m, 1 H), 4.72 (d, J = 7.4 Hz, 1 H), 4.64 (q, J = 8.5 Hz, 1 H), 4.28 - 4.18 (m, 1 H), 2.43 - 2.26 (m, 2 H), 2.25 - 2.16 (m, 1 H), 2.11 - 1.90 (m, 5 H), 1.74 - 1.63 (m, 2 H), 1.43 (s, 9 H). Linker synthesis

[0132] The following intermediates in Table 5 were prepared according to the protocols described in WO2020205467: [Table 5]

[0133] Representative Procedure for the Preparation of Activated Ester Phosphonic Acids

[0134] Synthesis of (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid [ka]

[0135] Step 1: Preparation of 4-nitrophenyl 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate

[0136] A mixture of 5-[(diethoxyphosphoryl)difluoromethyl]-1-benzothiophene-2-carboxylic acid (L1) (10.0 g, 27.4 mmol), EDCI (7.85 g, 41.0 mmol), and DMAP (836 mg, 6.85 mmol) in CHCl (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 CHCl (10 mL × 2). The combined organic extracts were washed with brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (C18 cartridge eluted 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] + ; 1 H 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).

[0137] Step 2: Preparation of (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid

[0138] To a cooled (0 °C) solution of 4-nitrophenyl 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (4.47 g, 9.20 mmol) in CHCl (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 CHCl (10 mL). The reaction mixture was allowed to warm gradually to ambient temperature. To this reaction mixture was added a mixture of 2:1 HO / acetonitrile (containing 0.1% TFA) (50 mL), and precipitation of the 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 suspension was filtered, the solid washed with a 2:1 mixture of acetonitrile / water solution, and the solid dried under reduced pressure to give (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (6.5 g, 94%) as a beige solid. The filtrate was concentrated to 50% of the solvent volume, and the resulting suspension was filtered and washed with a 1:2 acetonitrile / water solution. The solid was dried under reduced pressure to give additional (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-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). 1 H 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).

[0139] Using a protocol similar to that outlined above for the synthesis of (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid and utilizing the appropriate higher intermediate(s) as the starting material(s), the following intermediates in Table 6 were prepared.

[0140] [Table 6]

[0141] Synthesis of ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid [ka]

[0142] Preparation of 5-methylbenzo[b]thiophene-2-carboxylic acid

[0143] 5-Methylbenzo[b]thiophene-2-carboxylic acid was prepared according to the procedure described in WO2016100184 A1.

[0144] Step 1: Preparation of benzyl 5-methylbenzo[b]thiophene-2-carboxylate

[0145] To a solution of 5-methylbenzo[b]thiophene-2-carboxylic acid (21.2 g, 110.0 mmol, 1.0 equiv.) and KCO (30.4 g, 220.0 mmol, 2.0 equiv.) in DMF (200 mL) was added benzyl bromide (20.6 g, 121.0 mmol, 1.1 equiv.). The mixture was stirred at room temperature for 14 hours. The reaction mixture was poured into ice water (400 mL) and stirred for 5 minutes. The resulting solid was filtered, and the filter cake was washed with water (50 mL) and dried in vacuo 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).

[0146] Step 2: Preparation of benzyl 5-(bromomethyl)benzo[b]thiophene-2-carboxylate

[0147] To a solution of benzyl 5-methylbenzo[b]thiophene-2-carboxylate (15.0 g, 53.1 mmol, 1.0 equiv.) and NBS (10.3 g, 58.4 mmol, 1.1 equiv.) in CCl4 (30 mL) was added benzoyl peroxide (1.3 g, 5.31 mmol, 0.1 equiv.). The reaction flask was cycled through three cycles of evacuation and refilling with N2(g). The mixture was stirred at 80 °C under a constant N2(g) atmosphere for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give benzyl 5-(bromomethyl)benzo[b]thiophene-2-carboxylate (6.80 g, 18.8 mmol, 36% yield) as a yellow solid.

[0148] Step 3: Preparation of benzyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0149] A solution of benzyl 5-(bromomethyl)benzo[b]thiophene-2-carboxylate (10.3 g, 28.5 mmol, 1.0 equiv) in triethyl phosphite (30.0 g, 180.0 mmol, 6.3 equiv) was stirred at 100° C. for 5 h. The reaction mixture was directly concentrated under reduced pressure, and 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] + ; 1 H 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).

[0150] Step 4: Preparation of 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0151] To a solution of benzyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (5.6 g, 13.3 mmol, 1.0 equiv.) dissolved in a mixture of THF (80 mL) and HO (10 mL) was added LiOH (1.10 g, 26.6 mmol, 2.0 equiv.). The mixture was stirred at room temperature for 3 h and then acidified with an aqueous solution of 1 N HCl (adjusted to pH 3-4). Upon acidification, the product precipitated in the solution. The resulting solid was filtered, the filter cake was washed with water (20 mL × 2), and the solid was 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] + .

[0152] Step 5: Preparation of perfluorophenyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0153] To a cooled (0 °C) solution of 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (3.9 g, 11.8 mmol, 1.0 equiv.) in CHCl (50 mL) was added oxalyl chloride (2.2 g, 17.7 mmol, 1.5 equiv.), followed by two drops of DMF. The mixture was stirred at 0 °C for 30 min, and then the reaction mixture was evaporated to dryness. The resulting solid was dissolved in CHCl (50 mL), followed by the addition of EtN (3.6 g, 35.4 mmol, 3.0 equiv.) and pentafluorophenol (2.6 g, 14.1 mmol, 1.2 equiv.). The resulting mixture was stirred at room temperature for an additional 2 h and then poured into HO (30 mL). The biphasic solution was extracted with EtOAc (30 mL × 3). The combined organic layers were dried over MgSO, filtered, concentrated under reduced pressure, and 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] + ; 1 H 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).

[0154] Step 6: Preparation of ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid

[0155] To a solution of perfluorophenyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (4.7 g, 9.5 mmol, 1.0 equiv.) in CHCl (60 mL) was added bromotrimethylsilane (12 mL). The mixture was stirred at room temperature for 14 h and then concentrated under reduced pressure. The residue was purified by C 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] + .

[0156] 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 [ka]

[0157] Step 1: rac-Benzyl 5-((diethoxyphosphoryl)(hydroxy)methyl)benzo[b]thiophene-2-carboxylate

[0158] To a cooled (−78 °C) solution of benzyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (2.4 g, 5.73 mmol, 1 equiv.) and 2-(benzenesulfonyl)-3-phenyloxaziridine (2.97 g, 11.4 mmol, 2 equiv.) in THF (75 mL) was added a 1 M solution of NaHMDS (11.4 mL, 11.4 mmol, 2 equiv.). Upon addition of the base, a dark purple solution was observed, which turned orange after complete addition of the base. The mixture was stirred for an additional 10 min, followed by the addition of saturated aqueous NH4Cl (50 mL). The mixture was warmed to ambient temperature, and EtOAc (75 mL) and water (25 mL) were added. After stirring for an additional 30 min, the phases were separated. The aqueous layer was extracted with EtOAc (125 mL × 2). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Separate batches on an equal scale were run and combined for purification. The combined material (6.42 mmol, 12.15 mmol total) was purified by flash chromatography (20% to 100% EtOAc:heptane) to afford 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] + ; 1 H 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).

[0159] Step 2: rac-Benzyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate

[0160] To a cooled (-78 °C) solution (under N(g)) of rac-benzyl 5-((diethoxyphosphoryl)(hydroxy)methyl)benzo[b]thiophene-2-carboxylate (cc) (1.56 g, 3.59 mmol, 1 equiv.) in CHCl (30 mL) was added (diethylamino)sulfur trifluoride (568 μL, 4.30 mmol, 1.2 equiv.). The reaction was stirred for 15 min, followed by the addition of saturated aqueous NaHCO (50 mL). After warming to room temperature, the product was extracted with CHCl (50 mL × 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 a 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] + ; 1 H 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), 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).

[0161] 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

[0162] Chiral SFC separation of rac-benzyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (650 mg, 1.48 mmol) (column: Lux i-Amylose 3, 21.2 × 250 mm 5 μm column, 75 mL / min, 40% MeOH) afforded 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).

[0163] NOTE: The fastest eluting enantiomer by SFC was arbitrarily assigned as (R)-5-(fluoro(phosphono)methyl)benzo[b]thiophene-2-carboxylic acid, and the slowest eluting enantiomer by SFC was arbitrarily assigned as (S)-5-(fluoro(phosphono)methyl)benzo[b]thiophene-2-carboxylic acid.

[0164] HPLC method for enantiomeric excess analysis: Lux Cellulose-3 150 mm 45% H2O + 0.05% TFA / 55% MeCN 1 mL / min 8 min.

[0165] Step 4: Preparation of (R)- or (S)-5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0166] A mixture of 10% Pd / C (60 mg, 50% aqueous) and benzyl (R)-5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (peak 1) (60 mg, 0.1374 mmol, 1 equiv.) in THF (5 mL) was degassed with N2(g) for 5 min. H2(g) was bubbled through the mixture for 5 min, after which the reaction was stirred at room temperature under H2(g) (1 atm). The reaction mixture was stirred until consumption of the starting material was detected by LCMS. The reaction mixture was then sparged with N2(g) for 15 min and filtered through 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] + .

[0167] Using the procedure outlined above (Step 4) starting from benzyl (S)- or (R)-5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (peak 2) and using the appropriate reagents, the following intermediates in Table 7 were prepared: [Table 7]

[0168] Representative methods for the synthesis of activated linkers

[0169] Method 1: Stepwise acid chloride method for the synthesis of mixed linkers

[0170] Representative procedure for the synthesis of 4-nitrophenyl 5-(((2-(butyrylthio)ethoxy)(pyridin-3-yloxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate [ka]

[0171] Step 1: Preparation of 4-nitrophenyl 5-(difluoro(hydroxy(pyridin-3-yloxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0172] To a cooled (0 °C) heterogeneous solution of (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (100 mg, 0.2329 mmol, 1 equiv.) in CHCl (4 mL) was added catalytic DMF (2 drops), followed by the dropwise addition of oxalyl chloride (198 μL, 2.32 mmol, 10 equiv.). The homogeneous reaction mixture was allowed to warm to room temperature and stirred for 2 h. The reaction was concentrated in vacuo and further dried under high vacuum for 30 min to give a yellow solid. This yellow solid was diluted with CHCl (4 mL) and cooled to −78 °C. A solution of pyridin-3-ol (22.0 mg, 232 μmol, 1 equiv.) and triethylamine (64.7 μL, 465 μmol, 2 equiv.) in CHCl (1 mL) [sonicated for 1 min to solubilize] was slowly added. The homogeneous reaction mixture was stirred at -78°C for 2 minutes, then warmed to ambient temperature and stirred overnight. After 24 hours, the reaction mixture became heterogeneous and was concentrated under reduced pressure. The crude product, 4-nitrophenyl 5-(difluoro(hydroxy(pyridin-3-yloxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate, was used directly in the next step without further purification or manipulation. LCMS m / z = 507.2 [M+H] + .

[0173] Step 2: Preparation of 4-nitrophenyl 5-(((2-(butyrylthio)ethoxy)(pyridin-3-yloxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate

[0174] To a cooled (0 °C) solution of nitrophenyl 5-(difluoro(hydroxy(pyridin-3-yloxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (117 mg, 0.2329 mmol, 1 equiv.) in CHCl (5 mL) was added 2 drops of DMF, followed by the dropwise addition of oxalyl chloride (198 μL, 2.32 mmol, 10 equiv.). The reaction was allowed to warm to room temperature and stirred for 1.5 h. LCMS analysis indicated partial conversion to the desired activated intermediate. Additional oxalyl chloride (198 μL, 2.32 mmol, 10 equiv.) was introduced to the reaction mixture, and the mixture was stirred for an additional 1 h. The reaction was concentrated in vacuo and further dried under high vacuum for 30 min to give a yellow solid. The yellow solid was diluted with CHCl (5 mL) and cooled to −78 °C. To this cooled solution was slowly added a solution of 1-[(2-hydroxyethyl)sulfanyl]butan-1-one (103 mg, 698 μmol, 3 equiv.) diluted in CHCl (1 mL) [pre-dried over anhydrous NaSO], followed by triethylamine (134 μL, 967 μmol, 2 equiv.). After stirring for 2 min, the resulting mixture was warmed to ambient temperature and stirred overnight. Celite® was added to the mixture, and the mixture was carefully concentrated in vacuo. The crude residue was purified by flash chromatography (gradient elution: 0–60% EtOAc in heptane) to afford 4-nitrophenyl 5-(((2-(butyrylthio)ethoxy)(pyridin-3-yloxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (22.0 mg, 0.03455 mmol, 14.9% yield) as a clear oil. LCMS m / z = 637.2 [M+H] + ; 1H NMR: (400 MHz, DMSO-d6) δ 8.50 - 8.44 (m, 2H), 8.33 - 8.38 (m, 3H), 8.25 (s, 1H), 8.04 (d, J = 8.0 Hz, 1H), 7.79 (d, J = 8.6 Hz, 1H), 7.57 - 7.53 (m, 1 H), 7.50 - 7.45 (m, 2H), 7.31 - 7.26 (m, 1H), 4.37 - 4.24 (m, 2 H), 3.20 - 3.08 (m, 2H), 2.52 (t, J = 7.6 Hz, 2H), 1.67 (sextet, J = 7.3 Hz, 2H), 0.94 (t, J = 7.6 Hz, 3H).

[0175] Using a protocol similar to that described above for the synthesis of 4-nitrophenyl 5-(((2-(butyrylthio)ethoxy)(pyridin-3-yloxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate and utilizing the appropriate higher intermediate(s) as the starting material(s), the following intermediates in Table 8 were prepared. [Table 8-1] [Table 8-2] [Table 8-3]

[0176] Method 2: One-pot acid chloride method for the synthesis of activated linkers

[0177] Representative procedure for the synthesis of perfluorophenyl 5-((bis(4-((3-methylbutanoyl)thio)butoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate [ka]

[0178] To a cooled (0 °C) solution of 3 (200 mg, 0.42 mmol, 1.0 equiv) in anhydrous CHCl (15 mL) and catalytic DMF (3.2 μL, 42.1 μmol, 0.1 equiv) was added oxalyl chloride (266 mg, 2.10 mmol, 5.0 equiv) in a dropwise manner. The reaction mixture was warmed to 40 °C. After stirring for 2 h, the reaction mixture was concentrated in vacuo and dried (to remove excess oxalyl chloride). The resulting solid was redissolved in anhydrous CHCl (5 mL) and cooled to 0 °C. To this cooled solution was added S-(4-hydroxybutyl) 3-methylbutanethioate (239 mg, 1.26 mmol, 3.0 equiv), DMAP (5.14 mg, 42.1 μmol, 0.1 equiv), and a solution of N,N-diisopropylethylamine (217 mg, 1.68 mmol, 4.0 equiv) in anhydrous CHCl (10 mL). The reaction mixture was allowed to warm to room temperature and stirred for an additional 18 h. The reaction was quenched by the addition of HO (10 mL) and extracted with CHCl (3 × 10 mL). The organic layers were combined, washed with brine (20 mL), dried over anhydrous NaSO, and concentrated in vacuo. The residue was purified by flash column chromatography to give perfluorophenyl 5-((bis(4-((3-methylbutanoyl)thio)butoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (15.0 mg, 18.3 μmol, 4.4% yield). LCMS (ESI) m / z = 819 [M+H] + .

[0179] Using a protocol similar to that described above for the synthesis of perfluorophenyl 5-((bis(4-((3-methylbutanoyl)thio)butoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate and utilizing the appropriate higher intermediate(s) as the starting material(s), the following intermediates in Table 9 were prepared. [Table 9]

[0180] Method 3: One-pot silver salt method for the synthesis of activated linkers

[0181] Representative procedure for the synthesis of perfluorophenyl 5-((bis(((isopropoxycarbonyl)oxy)methoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate [ka]

[0182] Step 1: Preparation of silver(I) ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonate

[0183] To a solution of ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (300 mg, 684 μmol, 1.0 equiv.) in a mixture of deionized HO (4 mL) and THF (2 mL) was added Amberlite IR120® resin (Na + To the resulting solution was added AgNO (463 mg, 2.73 mmol, 4.0 equiv.) (1.5 g). The resulting mixture was stirred at room temperature for 1 hour, after which the suspension was filtered. To the filtrate was added a solution of AgNO (463 mg, 2.73 mmol, 4.0 equiv.) in deionized HO (2 mL), and the resulting mixture was stirred at room temperature for an additional 1 hour. The formation of a white precipitate was observed, and the solid was collected by filtration. The filter cake was then washed with cold HO (3 × 2 mL), and the solid was dried under reduced pressure to give silver(I) ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonate as a dry powder. This silver salt was used without further purification.

[0184] Step 2: Preparation of perfluorophenyl 5-((bis(((isopropoxycarbonyl)oxy)methoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0185] To a suspension of silver(I) (2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonate in anhydrous toluene (10 mL), iodomethyl 2-methylpropanoate (500 mg, 2.05 mmol, 3.0 equiv.) was added dropwise. After the addition, the resulting mixture was stirred at room temperature for an additional 12 h. The reaction progress was monitored by LCMS. Upon completion, the unreacted silver salt was collected by filtration. The filtrate was concentrated in vacuo, and the resulting residue was purified by reverse-phase chromatography [C18 column, gradient elution, water / acetonitrile = 90% to 1%] to afford perfluorophenyl 5-((bis(((isopropoxycarbonyl)oxy)methoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (165 mg, 246 μmol, 36% yield) as a white solid. LCMS (ESI) m / z = 671 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.96-7.80 (m, 2H), 7.48 (d, J = 8.5 Hz, 1H), 5.70-5.53 (m, 4H), 4.90 (dt, J = 12.6, 6.2 Hz, 2H), 3.42 (d, J = 22.2 Hz, 2H), 1.31 (d, J = 6.2 Hz, 12H).

[0186] Using a protocol similar to that described above for the synthesis of perfluorophenyl 5-((bis(4-((3-methylbutanoyl)thio)butoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate and utilizing the appropriate higher intermediate(s) as the starting material(s), the following intermediates in Table 10 were prepared. [Table 10-1] [Table 10-2] [Table 10-3]

[0187] (R)- or (S)-5-((bis((pivaloyloxy)methoxy)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid [ka]

[0188] Step 1: Preparation of (R)- or (S)-((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid

[0189] To a cooled (0 °C) solution of benzyl (R)- or (S)-5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (peak 1) (205 mg, 0.4697 mmol) in CHCl (8.0 mL) was added BSTFA (746 μL, 2.81 mmol), followed by a 1.0 M solution of trimethylsilyl iodide (1.87 mL, 1.87 mmol) in CHCl. ​​After stirring for 1 h, a mixture of acetonitrile (0.66 mL), water (0.33 mL), and 0.1% TFA was added. The solvent was removed under reduced pressure at 0 °C. The crude residue was purified by reverse-phase chromatography (C18 cartridge eluted with 5-40% acetonitrile in water) to afford (R)- or (S)-((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid (163 mg, 0.4285 mmol) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.11 - 8.06 (m, 2H), 7.58 (d, J = 8.6 Hz, 1H), 7.51 - 7.47 (m, 2H), 7.45 - 7.33 (m, 3H), 5.84 (dd, J = 44.6, 8.3 Hz, 1H), 5.40 (s, 2H).

[0190] Step 2: Preparation of (R)- or (S)-((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid

[0191] [The following reaction was carried out in a foil-wrapped container in the absence of ambient light]: To a suspension of (R)- or (S)-((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid (163 mg, 0.4285 mmol, 1 equiv.) in water (5 mL) was added an aqueous solution of sodium hydroxide (34.2 mg, 857 μmol, 2 equiv.) in water (2 mL). To this yellow solution was added silver(I) nitrate (181 mg, 1.07 mmol, 2.5 equiv.), and the resulting off-white suspension was stirred at room temperature for 1.5 h. The suspension was cooled to 0° C., filtered, and dried under high vacuum. The solid was resuspended in acetonitrile, concentrated under reduced pressure, and further dried under high vacuum (3 h). The resulting deep yellow powder was suspended in toluene (10 mL) and iodomethyl 2,2-dimethylpropanoate (191 μL, 1.28 mmol, 3 equiv.) was added. After stirring for 20 h, the reaction mixture was stirred at room temperature for 20 h. The reaction mixture was filtered and rinsed with toluene. The filtrate was concentrated under reduced pressure. The crude residue was purified (C18 cartridge eluted with 5–100% acetonitrile in water) to afford (R)- or (S)-((((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (122 mg, 0.2004 mmol, 46.9%) as a clear oil. 1 H NMR (400 MHz, CDCl3) δ 8.11 (s, 1 H), 8.01 - 7.99 (m, 1 H), 7.92 (d, J = 8.3 Hz, 1H), 7.59 (d, J = 8.3 Hz, 1H), 7.52 - 7.47 (m, 2 H), 7.46 - 7.36 (m, 3H), 8.87 (dd, J = 44.3, 7.5 Hz, 1H), 5.72 - 5.62 (m, 4H), 5.43 (s, 2H), 1.21 (s, 18H).

[0192] Step 3: Preparation of (R)- or (S)-5-((bis((pivaloyloxy)methoxy)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0193] To a solution of (R)-((((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphoryl)bis(oxy))bis(methylene)bis(2,2-dimethylpropanoate) (122 mg, 0.200 mmol, 1 equiv) in THF (10 mL) under N2(g) was added 10% Pd / C (50% aqueous, 120 mg, 0.1127 mmol, 0.56 equiv). H2(g) was bubbled through the suspension for 5 minutes. The reaction mixture was stirred under H2(g) (1 atm) at room temperature. After stirring for 22 hours, the reaction mixture was purged with N2(g) and filtered through Celite®. The filter pad was washed with THF and concentrated under reduced pressure to give (R)-5-((bis((pivaloyloxy)methoxy)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid (0.200 mmol, 99.9%) as a thick, clear oil. LC-MS (ESI) m / z [M+H] + = 519.1.

[0194] Using a protocol similar to that described above for the synthesis of (R)- or (S)-5-((bis((pivaloyloxy)methoxy)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid and utilizing the appropriate higher intermediate(s) as the starting material(s), the following intermediates in Table 11 were prepared. The absolute configuration of the starting (R)- or (S)-((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid was not determined. [Table 11]

[0195] Method 4: Stepwise silver salt method for the synthesis of mixed linkers

[0196] Representative procedure for perfluorophenyl 5-(((2-(butyrylthio)ethoxy)(2-(pivaloylthio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate [ka]

[0197] Step 1: Preparation of perfluorophenyl 5-(difluoro(hydroxy(2-(pivaloylthio)ethoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0198] Starting from (difluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid and using the method described in step 1, Method 3 for the synthesis of silver(I)((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonate, silver(I)(difluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonate was synthesized.

[0199] To a suspension of silver(I) ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonate (647 mg, 940 μmol, 1.0 equiv.) in anhydrous toluene (10 mL) was added S-(2-iodoethyl) 2,2-dimethylpropanethioate (310 mg, 1.14 mmol, 1.2 equiv.) in a dropwise manner. After complete addition of the alcohol, the resulting mixture was stirred at room temperature for an additional 12 h. The heterogeneous mixture was filtered, and the filtrate was concentrated in vacuo. The resulting residue was purified by reverse-phase chromatography to give perfluorophenyl 5-(difluoro(hydroxy(2-(pivaloylthio)ethoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (240 mg, 388 μmol, 41% yield). LCMS (ESI) m / z = 617 [MH] - .

[0200] Step 2: Preparation of perfluorophenyl 5-(((2-(butyrylthio)ethoxy)(2-(pivaloylthio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate

[0201] Perfluorophenyl 5-(((2-(butyrylthio)ethoxy)(2-(pivaloylthio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate was synthesized using a similar protocol as outlined above. Starting with perfluorophenyl 5-(difluoro(hydroxy(2-(pivaloylthio)ethoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (190 mg, 307 μmol, 1.0 equiv.), AgNO (207 mg, 1.22 mmol, 4.0 equiv.), and S-(2-iodoethyl)butanethioate (94.9 mg, 368 μmol, 1.2 equiv.) afforded perfluorophenyl 5-(((2-(butyrylthio)ethoxy)(2-(pivaloylthio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (55.0 mg, 73.4 μmol, 24%) as a white solid. LCMS (ESI) m / z = 749 [M+H] + .

[0202] Using a protocol similar to that described above for the synthesis of perfluorophenyl 5-(((2-(butyrylthio)ethoxy)(2-(pivaloylthio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate and utilizing the appropriate higher intermediate(s) as the starting material(s), the following intermediates in Table 12 were prepared. [Table 12]

[0203] Preparation of 5-(((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid [ka]

[0204] Step 1: Preparation of allyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0205] To a suspension of 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (1.0 g, 3.0 mmol, 1.0 equiv.) and K2CO3 (839 mg, 6.1 mmol, 2.0 equiv.) in DMF (20 mL) was added 3-bromoprop-1-ene (440 mg, 3.6 mmol, 1.2 equiv.). The mixture was stirred at room temperature for 14 h and poured into water (30 mL). The mixture was extracted with EtOAc (25 mL × 3). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure, and 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 pale yellow solid. LCMS (ESI) m / z = 369 [M+H] + ; 1 H 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).

[0206] Step 2: Preparation of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid

[0207] To a solution of allyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (980 mg, 2.7 mmol, 1.0 equiv) in CHCl (15 mL) was added bromotrimethylsilane (3 mL). The mixture was stirred at room temperature for 14 h and then concentrated under reduced pressure. The resulting residue was triturated with HO (5 mL), and the resulting precipitate was filtered. The filter cake was washed with HO (5 mL × 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] + ; 1 H 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).

[0208] Step 3: Preparation of allyl 5-(((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0209] To a cooled (0 °C) solution (under a steady stream of N (g)) of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (2.80 g, 8.96 mmol, 1 equiv.) and catalytic DMF (1 drop) in anhydrous CHCl (50 mL) was added oxalyl chloride (3.40 g, 26.8 mmol, 3 equiv.). After gas effervescence ceased, the mixture was warmed to 40 °C. After 2 h, the mixture was cooled to room temperature and concentrated in vacuo to give a yellow solid. The solid was then diluted with CHCl (50 mL) and cooled to 0 °C. To this cooled solution was added phenol (0.843 g, 8.96 mmol, 1 equiv.) and EtN (4.53 g, 44.8 mmol, 5 equiv.). After complete addition, the mixture was warmed to room temperature and stirred for 1 hour, after which propan-2-yl(2S)-2-aminopropanoate (1.75 g, 13.4 mmol, 1.5 equiv.) was introduced to the mixture. After stirring for an additional 2 hours, the mixture was concentrated to dryness. The residue was purified on a C18 column (eluted with 50% to 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 a white solid. 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).

[0210] Step 4: Preparation of 5-(((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0211] 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 equiv), pyrrolidine (12.7 mg, 179 μmol, 1 equiv), Pd(PPh) (10.3 mg, 8.97 μmol, 0.05 equiv) in CHCl (5 mL) was stirred under N (g). After 2 h, the reaction was concentrated in vacuo. The residue was purified by C18 column (eluted with 30% to 70% acetonitrile in water) to give 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 a white solid. LCMS (ESI) m / z = 462.1 [M+H] + .

[0212] Using the above for the 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, the following intermediates in Table 13 were prepared. [Table 13]

[0213] Synthesis scheme:

[0214] Synthesis of 5-[1-(diethoxyphosphoryl)-2-hydroxyethyl]-1-benzothiophene-2-carboxylic acid [ka]

[0215] Step 1: Preparation of benzyl 5-[1-(diethoxyphosphoryl)-2-hydroxyethyl]-1-benzothiophene-2-carboxylate

[0216] To a solution of benzyl 5-[(diethoxyphosphoryl)methyl]-1-benzothiophene-2-carboxylate (200 mg, 0.4779 mmol, 1 equiv.) in tetrahydrofuran (10 mL) at −78° C. was added dropwise a solution of sodium bis(trimethylsilylamide) (1 M in THF) (1.43 mL, 1.43 mmol, 3.0 equiv.). The reaction was stirred for 5 minutes at −78° C., after which 1H-benzotriazole-1-methanol (142 mg, 0.955 mmol, 2 equiv.) was added in one portion. The reaction was stirred at −78° C. for 2 hours. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL) at −78° C., after which the ice bath was removed. The product was extracted with EtOAc (3×30 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was eluted with a gradient of 5-80% MeCN in water (containing 0.1% formic acid). 18Purification by reverse phase chromatography on a cartridge gave benzyl 5-[1-(diethoxyphosphoryl)-2-hydroxyethyl]-1-benzothiophene-2-carboxylate (24 mg, 0.05351 mmol, 11.2%) as a clear thick oil. LCMS: m / z = 449.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.27 (s, 1 H), 8.02 (d, J = 8.5 Hz, 1 H), 7.99 (s, 1 H), 5.40 (s, 2 H), 4.87 (t, J = 5.5 Hz, 1 H), 4.07- 3.94 (m, 3 H), 3.93- 3.71 (m, 3 H), 3.52 - 3.41 (m, 1 H), 1.21 (t, J = 7.3 Hz, 3 H), 1.03 (t, J = 7.3 Hz, 3 H).

[0217] Step 2: Preparation of 5-[1-(diethoxyphosphoryl)-2-hydroxyethyl]-1-benzothiophene-2-carboxylic acid

[0218] A mixture of 10% palladium on carbon (50% aqueous) (80 mg, 0.03758 mmol, 0.163 equiv) and benzyl 5-[1-(diethoxyphosphoryl)-2-hydroxyethyl]-1-benzothiophene-2-carboxylate (38 mg, 0.08473 mmol, 1 equiv) in tetrahydrofuran (8 mL) was degassed with nitrogen for 5 minutes. Hydrogen was bubbled through for 5 minutes, after which the reaction was stirred under hydrogen (1 atm) at room temperature for 20 hours. The reaction was filtered through Celite and eluted with MeOH. The filtrate was concentrated under reduced pressure. The crude residue was purified by elution with 50 g C in water (containing 0.1% formic acid) with 5-80% MeCN. 18Purification by reverse phase chromatography on a cartridge followed by concentration under reduced pressure and lyophilization gave 5-[1-(diethoxyphosphoryl)-2-hydroxyethyl]-1-benzothiophene-2-carboxylic acid (8.00 mg, 0.02232 mmol, 26.4%) as a white solid. LCMS: m / z = 359.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.02 - 7.92 (m, 2 H), 7.90 (s, 1 H), 7.48 - 7.42 (m, 1 H), 4.92 - 4.79 (m, 1 H), 4.08 - 3.69 (m, 6 H), 3.52 - 3.39 (m, 1 H), 1.21 (t, J = 7.2 Hz, 3 H), 1.03 (t, J = 7.3 Hz, 3 H).

[0219] Synthesis of 5-(1-(diethoxyphosphoryl)ethyl)benzo[b]thiophene-2-carboxylic acid and 5-(2-(diethoxyphosphoryl)propan-2-yl)benzo[b]thiophene-2-carboxylic acid [ka]

[0220] Step 1: Preparation of rac-benzyl 5-[1-(diethoxyphosphoryl)ethyl]-1-benzothiophene-2-carboxylate and benzyl 5-[2-(diethoxyphosphoryl)propan-2-yl]-1-benzothiophene-2-carboxylate

[0221] To a solution of benzyl 5-[(diethoxyphosphoryl)methyl]-1-benzothiophene-2-carboxylate (200 mg, 0.4779 mmol, 1 equiv.) and methyl iodide (88.5 μL, 1.43 mmol, 3 equiv.) in tetrahydrofuran (5 mL) at −78° C., a solution of sodium bis(trimethylsilylamide) (1 M in THF) (1.43 mL, 1.43 mmol, 3 equiv.) was added dropwise. The mixture was stirred at −78° C. for 2 h. The ice bath was removed, and the reaction was stirred at room temperature for 1 h. The reaction mixture was quenched with saturated aqueous ammonium chloride (10 mL). The product was extracted with EtOAc (3×30 mL). The combined extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by elution with a gradient of 5–80% MeCN in water (containing 0.1% formic acid). 50 g C 18 Purification by reverse-phase chromatography on a cartridge gave benzyl rac-5-[1-(diethoxyphosphoryl)ethyl]-1-benzothiophene-2-carboxylate (89.0 mg, 0.1993 mmol, 41.9%) as a clear oil and benzyl 5-[2-(diethoxyphosphoryl)propan-2-yl]-1-benzothiophene-2-carboxylate (22.0 mg, 0.5087 mmol, 10.6%) as a clear oil.

[0222] rac-Benzyl 5-[1-(diethoxyphosphoryl)ethyl]-1-benzothiophene-2-carboxylate LCMS: m / z = 433.0 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.08 (s, 1 H), 7.88 - 7.85 (m, 1 H), 7.83 (d, J = 8.7 Hz, 1 H), 7.52 - 7.47 (m, 3 H), 7.45- 7.36 (m, 3 H), 5.42 (s, 2 H), 4.12 - 4.02 (m, 2 H), 4.00 - 3.91 (m, 1 H), 3.89 - 3.78 (m, 1 H), 3.38 - 3.25 (m, 1 H), 1.66 (dt, J = 18.3, 7.6 Hz, 3 H), 1.30 (t, J = 7.3 Hz, 3 H), 1.16 (t, J = 7.3 Hz, 3 H).

[0223] Benzyl 5-[2-(diethoxyphosphoryl)propan-2-yl]-1-benzothiophene-2-carboxylate: LCMS: m / z = 447.0 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 8.01 (s, 1 H), 7.93 - 7.90 (m, 1 J), 7.74 (d, J = 8.6 Hz, 1 H), 7.69 - 7.63 (m, 1 H), 7.39 (d, J = 8.6 Hz, 1 H), 7.36 - 7.25 (m, 3 H), 5.32 (s, 2 H), 3.92 - 3.73 (m, 4 H), 1.61 (d, J = 16.8 Hz, 6 H), 1.11 (t, J = 7.2 Hz, 6 H).

[0224] Step 2: Preparation of rac-5-[1-(diethoxyphosphoryl)ethyl]-1-benzothiophene-2-carboxylic acid

[0225] A mixture of 10% Pd / C (50% aqueous) (80 mg, 0.03758 mmol, 0.163 equiv) and benzyl 5-[1-(diethoxyphosphoryl)ethyl]-1-benzothiophene-2-carboxylate (100 mg, 0.2312 mmol, 1 equiv) in tetrahydrofuran (8 mL) was degassed with nitrogen for 5 minutes. Hydrogen was bubbled through for 5 minutes, after which the reaction was stirred under hydrogen (1 atm) at room temperature. The reaction was filtered through Celite and eluted with THF. The filtrate was concentrated under reduced pressure. The crude residue was purified by elution with a gradient of 5 to 80% MeCN in water (containing 0.1% formic acid) to give 50 g C. 18 Purification by reverse phase chromatography on a cartridge gave rac-5-[1-(diethoxyphosphoryl)ethyl]-1-benzothiophene-2-carboxylic acid (51 mg, 0.1489 mmol, 65%) as a white solid. LCMS: m / z = 343.0 [M+H] + .

[0226] Step 3: Preparation of 5-[2-(diethoxyphosphoryl)propan-2-yl]-1-benzothiophene-2-carboxylic acid

[0227] A mixture of 10% palladium on carbon (50% wet) (5 mg, 0.002349 mmol, equiv.) and 5-[2-(diethoxyphosphoryl)propan-2-yl]-1-benzothiophene-2-carboxylate (33 mg, 0.07390 mmol, 1 equiv.) in tetrahydrofuran (2 mL) was degassed with nitrogen for 5 minutes. Hydrogen was bubbled through for 5 minutes, after which the reaction was stirred under hydrogen (1 atm) at room temperature. The reaction was filtered through a syringe filter and eluted with MeOH. The filtrate was concentrated under reduced pressure. The crude residue was diluted with tetrahydrofuran (2 mL). 10% palladium on carbon (50% wet) (20 mg, 0.009396 mmol, 0.13 equiv.) was added under nitrogen bubbling, after which hydrogen was bubbled through for 5 minutes. The reaction was stirred at room temperature overnight under hydrogen (1 atm). The reaction was filtered through a syringe filter and eluted with MeOH. The filtrate was concentrated under reduced pressure. The crude residue was diluted with tetrahydrofuran (2 mL), then 10% palladium on carbon (50% aqueous) (20 mg, 0.009396 mmol, 0.13 equiv) was added under nitrogen bubbling, followed by hydrogen bubbling for 5 minutes. The reaction was stirred under hydrogen (1 atm) at room temperature for 40 hours. The reaction was filtered through a syringe filter and eluted with MeOH. The filtrate was concentrated under reduced pressure to give crude 5-[2-(diethoxyphosphoryl)propan-2-yl]-1-benzothiophene-2-carboxylic acid (26.3 mg, 0.0738 mmol, 99%) as a clear oil. LCMS: m / z = 357.2 [M+H] + .

[0228] Synthesis of 5-((bis((((2-methoxyethoxy)carbonyl)oxy)methoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid [ka]

[0229] Step 1: Preparation of chloromethyl 2-methoxyethyl carbonate

[0230] A solution of 2-methoxyethan-1-ol (1 g, 13.1 mmol, 1 equiv.) and chloroacetyl chloride (1.68 g, 13.1 mmol, 1 equiv.) in diethyl ether (30 mL) was cooled to 0° C. under nitrogen. Pyridine (1.04 mL, 13.1 mmol, 1.0 equiv.) was added dropwise, after which the reaction was stirred at 0° C. for 15 minutes, followed by room temperature for 16 hours. The white suspension was filtered and rinsed with diethyl ether (30 mL). The filtrate was washed with 1N HCl (20 mL) and water (2×20 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give chloromethyl 2-methoxyethyl carbonate (1.63 g, 9.66 mmol, 74.0% yield) as a clear liquid. 1 H NMR (400 MHz, CDCl3) δ 5.76 (s, 2 H), 4.42 - 4.37 (m, 2 H), 3.68 - 3.64 (m, 2 H), 3.42 (s, 3 H).

[0231] Step 2: Preparation of benzyl 5-((bis((((2-methoxyethoxy)carbonyl)oxy)methoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate

[0232] To a stirred solution of ((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid (300 mg, 0.7531 mmol, 1 equiv.) in water (15 mL) was added sodium hydroxide (59.9 mg, 1.50 mmol, 2 equiv.) in water (2 mL) dropwise. When the mixture reached a pH of approximately 8, silver nitrate (382 mg, 2.25 mmol, 3 equiv.) was added in one portion. After 2 h at room temperature, the gray suspension was cooled to 0° C. The precipitate was collected by filtration, washed with water, taken up in MeCN, and dried under reduced pressure, then under high vacuum for 2 h. The solid was suspended in anhydrous toluene (10 mL), and chloromethyl 2-methoxyethyl carbonate (379 mg, 2.25 mmol, 3 equiv.) was added. The mixture was stirred at room temperature for 18 h and then heated at 50° C. for 5 days. The mixture was adsorbed onto silica gel and concentrated under reduced pressure. The crude residue was purified by flash chromatography on a 24 g silica gel cartridge eluting with 0-90% EtOAc in heptane to afford benzyl 5-((bis((((2-methoxyethoxy)carbonyl)oxy)methoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (290 mg, 0.4377 mmol, 58.2% yield) as a clear oil. LCMS: m / z = 663.2 [M+H] + . 1 H NMR (400 MHz, CDCl3) δ 8.17 (s, 1 H), 8.16 - 8.14 (m, 1 H), 7.98 (d, J = 8.4 Hz, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 7.51 - 7.48 (m, 2 H), 7.46 - 7.36 (m, 3 H), 5.75 (dd, J = 12.0, 5.5, Hz, 2 H), 5.69 (dd, J = 12.0, 5.5 Hz, 2 H), 5.43 (s, 2 H), 4.36 - 4.31 (m, 4 H), 3.64 - 3.60 (m, 4 H), 3.39 (s, 6 H).

[0233] Step 3: Preparation of 5-((bis((((2-methoxyethoxy)carbonyl)oxy)methoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0234] To a mixture of benzyl 5-((bis((((2-methoxyethoxy)carbonyl)oxy)methoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (145 mg, 0.2188 mmol, 1 equiv.) in anhydrous tetrahydrofuran (15 mL) was added 10% palladium on carbon (50% aqueous) (145 mg, 0.1353 mmol, equiv.). Hydrogen was bubbled through the suspension for 2 minutes, after which the reaction mixture was stirred under hydrogen (1 atm) for 20 hours. Nitrogen was bubbled through, and the reaction was filtered through Celite, rinsed with 2-MeTHF, and then concentrated under reduced pressure to give crude 5-((bis((((2-methoxyethoxy)carbonyl)oxy)methoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (144 mg, 0.2188 mmol, 99% yield) as a gray solid. LCMS: m / z = 573.2 [M+H] + .

[0235] Following the procedure described for the synthesis of 5-((bis((((2-methoxyethoxy)carbonyl)oxy)methoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid, utilizing the appropriate starting materials, the following linkers in Table 14 were prepared. [Table 14]

[0236] Synthesis of 5-((bis(4-ethoxy-4-oxobutoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid [ka]

[0237] Step 1: Preparation of diethyl 4,4'-((((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoryl)bis(oxy))dibutyrate

[0238] To a stirred solution of ((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid (300 mg, 0.7531 mmol, 1 equiv)) in HO (15 mL) was added sodium hydroxide (59.9 mg, 1.50 mmol) in HO (2 mL) dropwise. When the mixture reached a pH of approximately 8, silver nitrate (382 mg, 2.25 mmol) was added. After 2 h at room temperature, the gray suspension was cooled to 0 °C. The precipitate was collected by filtration, washed with water, taken up in MeCN, concentrated under reduced pressure, and then dried under high vacuum. The solid was suspended in anhydrous toluene (10 mL), and ethyl 4-bromobutanoate (438 mg, 2.25 mmol, 3 equiv) was added. The mixture was stirred at 50 °C for 18 h. The mixture was adsorbed onto silica gel and concentrated under reduced pressure. The crude residue was purified by flash chromatography on a 24 g silica gel cartridge eluting with 0-90% EtOAc in heptane to give diethyl 4,4'-((((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoryl)bis(oxy))dibutyrate (320 mg, 0.5106 mmol, 67.9% yield) as a clear oil. 1 H NMR (400 MHz, CDCl3) δ 8.18 - 8.13 (m, 2 H), 7.97 (d, J = 8.6 Hz, 1 H), 7.70 (d, J = 8.5 Hz, 1 H), 7.53 - 7.35 (m, 5 H). 5.43 (s, 2 H), 4.28 - 4.09 (m, 8 H), 2.44 - 2.36 (m, 4 H), 2.04 - 1.92 (m, 4 H), 1.32 - 1.22 (m, 6 H).

[0239] Step 2: Preparation of 5-((bis(4-ethoxy-4-oxobutoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0240] To a mixture of diethyl 4,4'-((((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphoryl)bis(oxy))dibutyrate (100 mg, 0.1595 mmol, 1 equiv.) in anhydrous tetrahydrofuran (10 mL) was added 10% palladium on carbon (50% aqueous) (100 mg, 0.04698 mmol, 0.3 equiv.). Hydrogen was bubbled through the suspension for 2 minutes, after which the reaction mixture was stirred under 1 atm of hydrogen for 16 hours. Nitrogen was bubbled through the reaction mixture, then filtered through Celite (rinsing with 2-MeTHF) and concentrated under reduced pressure to give 5-((bis(4-ethoxy-4-oxobutoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (85.3 mg, 0.1595 mmol, 100% yield) as a clear oil. LCMS: m / z = 559.2 [M+Na] + .

[0241] Synthesis of 5-(cyano(ethoxy(hydroxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid [ka]

[0242] Step 1: Preparation of ethyl 5-(cyano(diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0243] To a solution of diethyl(cyanomethyl)phosphonate (127 mg, 722 μmol, 1.2 equiv.) in anhydrous 1,2-dimethoxyethane (5 mL) under nitrogen was added sodium hydride (60% in mineral oil) (50.3 mg, 1.26 mmol, 2.1 equiv.). The reaction was stirred at rt for 10 min, after which tetrakis(triphenylphosphine)palladium (34.7 mg, 30.1 μmol, 0.05 equiv.) and ethyl 5-iodo-1-benzothiophene-2-carboxylate (200 mg, 602 μmol, 1 equiv.) were added. The reaction mixture was stirred at 85°C for 16 h. The reaction mixture was filtered through Celite (eluting with DCM), and the filtrate was concentrated under reduced pressure. The crude residue was dissolved in 50 g CHCl3 in water, eluting with 5-80% MeCN. 18 Purification was carried out by reverse phase chromatography on a cartridge. The combined fractions were concentrated to give ethyl 5-(cyano(diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (50.0 mg, 131 μmol, 21.8% yield) as an orange solid. LCMS: m / z = 382.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.33 (s, 1H), 8.18 - 8.06 (m, 2H), 7.54 (d, J = 8.6 Hz, 1H), 5.67 - 5.56 (m, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.11 - 3.97 (m, 4H), 1.34 (t, J = 7.1 Hz, 3H), 1.20 (dt, J = 9.8, 7.1 Hz, 6H).

[0244] Step 2: Preparation of 5-(cyano(ethoxy(hydroxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0245] To a solution of ethyl 5-(cyano(diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (80 mg, 209 μmol, 1 equiv.) in acetonitrile (4 mL) was added hydrochloric acid (6 mL, 3N). The reaction mixture was stirred at 70° C. for 7 hours. Additional hydrochloric acid (1.5 mL, 3N) was added, and the reaction mixture was stirred at 70° C. for an additional 22 hours. Hydrochloric acid (1.5 mL, 3N) was added, and the reaction mixture was stirred at 80° C. for an additional 20 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by eluting 50 g C with a gradient of MeCN in water (5% for 3 CV, then 5-100% for 18 CV). 18 Direct purification by reverse phase chromatography using a cartridge gave 5-(cyano(ethoxy(hydroxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (52.0 mg, 159 μmol, 76.5% yield) as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ 8.19 (s, 1H), 8.12 - 7.98 (m, 2H), 7.52 (d, J = 8.6 Hz, 1H), 5.23 - 5.12 (m, 1H), 3.97 (quintet, J = 7.3 Hz, 2H), 1.22 - 1.13 (m, 3H).

[0246] Synthesis of rac-5-[1-(diethoxyphosphoryl)-1-fluoroethyl]-1-benzothiophene-2-carboxylic acid [ka]

[0247] Step 1: Preparation of rac-benzyl 5-[(diethoxyphosphoryl)(hydroxy)methyl]-1-benzothiophene-2-carboxylate

[0248] A solution of benzyl 5-[(diethoxyphosphoryl)methyl]-1-benzothiophene-2-carboxylate (2.4 g, 5.73 mmol, 1 equiv.) in tetrahydrofuran (75 mL) was cooled to −78° C., after which 2-(benzenesulfonyl)-3-phenyloxaziridine (2.97 g, 11.4 mmol, 2 equiv.) was added, followed by the dropwise addition of a solution of sodium bis(trimethylsilylamide) (1.0 M in THF) (11.4 mL, 11.4 mmol, 2 equiv.) (internal THF). o =-75°C to -69°C). Upon addition of the base, a dark purple solution was observed, which rapidly turned orange. The mixture was stirred at -78°C for 10 min. The reaction mixture was quenched with saturated aqueous NH4Cl (50 mL) at -78°C, after which the dry ice bath was removed. EtOAc (75 mL) and water (25 mL) were added, and the mixture was stirred for 30 min (until the internal temperature reached 15°C). The phases were separated, and the aqueous layer was then back-extracted with EtOAc (125 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, adsorbed onto silica gel, and concentrated under reduced pressure. The material was combined with another batch (6.42 mmol, 12.15 mmol total) and purified by flash chromatography on a 330 g silica gel cartridge eluting with 20-100% EtOAc in heptane to give rac-benzyl 5-[(diethoxyphosphoryl)(hydroxy)methyl]-1-benzothiophene-2-carboxylate (3.69 g, 8.49 mmol, 70% yield) as a white sticky solid. LCMS: m / z = 869.4 (2M+H). + ; 1 H 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).

[0249] Step 2: Preparation of rac-benzyl 5-[(diethoxyphosphoryl)(fluoro)methyl]-1-benzothiophene-2-carboxylate

[0250] To a solution of rac-benzyl 5-[(diethoxyphosphoryl)(hydroxy)methyl]-1-benzothiophene-2-carboxylate (1.56 g, 3.59 mmol, 1 equiv.) in methylene chloride (30 mL) at -78 °C under nitrogen was added (diethylamino)sulfur trifluoride (568 μL, 4.30 mmol, 1.2 equiv.). The reaction was stirred at -78 °C for 15 minutes. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (50 mL), and the product was extracted with DCM (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by elution with 5–80% MeCN in water to give 275 g C. 18 Purification by reverse-phase chromatography on a cartridge gave rac-benzyl 5-[(diethoxyphosphoryl)(fluoro)methyl]-1-benzothiophene-2-carboxylate (650 mg, 1.48 mmol, 41.6% yield) as a thick, clear oil. LCMS: m / z = 873.2 (2M+H). + ; 1 H 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), 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).

[0251] Step 3: Preparation of rac-benzyl 5-[1-(diethoxyphosphoryl)-1-fluoroethyl]-1-benzothiophene-2-carboxylate

[0252] To a solution of benzyl 5-[(diethoxyphosphoryl)(fluoro)methyl]-1-benzothiophene-2-carboxylate (100 mg, 0.2291 mmol, 1 equiv.) and methyl iodide (42.7 μL, 687 μmol, 3 equiv.) in tetrahydrofuran (4 mL) at −78 °C, a solution of sodium bis(trimethylsilylamide) (1 M in THF) (458 μL, 458 μmol, 2 equiv.) was added dropwise. The mixture was stirred at −78 °C for 5 min. The reaction was quenched with 1 M HCl (10 mL), warmed to room temperature, and extracted with DCM (2 × 25 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This crude material was purified by eluting with 5–80% MeCN in water (containing 0.1% formic acid) to give 50 g C. 18 Purification was carried out by reverse-phase chromatography on a cartridge. The fractions were combined, concentrated under reduced pressure, and then lyophilized to give rac-benzyl 5-[1-(diethoxyphosphoryl)-1-fluoroethyl]-1-benzothiophene-2-carboxylate (67.0 mg, 0.1487 mmol, 65.0% yield) as a yellowish oil. LCMS: m / z = 451.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.13 (s, 1 H), 8.05 - 8.02 (m, 1 H), 7.90 (d, J = 8.7 Hz, 1 H), 7.65 (d, J = 8.7 Hz, 1 H), 7.52 - 7.47 (m, 2 H), 7.46 - 7.36 (m, 3 H), 5.42 (s, 2 H), 4.27 - 4.16 (m, 2 H), 4.05 - 3.94 (m, 1 H), 3.90 - 3.79 (m, 1 H), 2.03 (dd, J = 25.0, 14.0 Hz, 3 H), 1.37 (t, J = 7.1 Hz, 3 H), 1.17 (t, J = 7.1 Hz, 3 H).

[0253] Step 4: Preparation of rac-5-[1-(diethoxyphosphoryl)-1-fluoroethyl]-1-benzothiophene-2-carboxylic acid

[0254] A mixture of 10% palladium on carbon (50% aqueous) (99 mg, 0.04651 mmol, 0.21 equiv) and benzyl 5-[1-(diethoxyphosphoryl)-1-fluoroethyl]-1-benzothiophene-2-carboxylate (99 mg, 0.2197 mmol, 1 equiv) in tetrahydrofuran (6 mL) was degassed with nitrogen for 5 minutes. Hydrogen was bubbled through for 5 minutes, after which the reaction was stirred under hydrogen (1 atm) at room temperature for 20 hours. The reaction was filtered through a syringe filter and rinsed with THF. The filtrate was concentrated under reduced pressure to give crude rac-5-[1-(diethoxyphosphoryl)-1-fluoroethyl]-1-benzothiophene-2-carboxylic acid (78.9 mg, 0.2197 mmol, 100% yield) as a clear oil. LCMS: m / z = 361.2 [M+H] + .

[0255] Synthesis of rac-7-[(diethoxyphosphoryl)(fluoro)methyl]naphthalene-2-carboxylic acid [ka]

[0256] Step 1: Preparation of 7-bromonaphthalene-2-carboxylic acid

[0257] A solution of 2,7-dibromonaphthalene (2 g, 6.99 mmol, 1 equiv.) in tetrahydrofuran (24 mL) was cooled to −78° C. under nitrogen. A solution of n-butyllithium (1.6 M in hexanes) (4.58 mL, 7.33 mmol, 1.05 equiv.) was added dropwise. The reaction was stirred for 15 minutes at −78° C., after which CO was bubbled through the reaction mixture. The ice bath was removed, and the reaction was stirred for 1 hour under CO bubbling. The reaction was quenched by the addition of 1 N HCl (50 mL, pH=2), after which the product was extracted with EtOAc (3×75 mL). The combined organic layers were washed with water (50 mL), brine (50 mL), and then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was triturated in heptane and the resulting solid was filtered and dried to give 7-bromonaphthalene-2-carboxylic acid (1.27 g, 5.05 mmol, 72.5% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 13.21 (s, 1 H), 8.61 (s, 1 H), 8.44 (s, 1 H), 8.08 - 7.96 (m, 3 H), 7.81 - 7.76 (m, 1 H).

[0258] Step 2: Preparation of tert-butyl 7-bromonaphthalene-2-carboxylate

[0259] To a stirred suspension of 7-bromonaphthalene-2-carboxylic acid (1.00 g, 3.98 mmol, 1 equiv) in toluene (9 mL) at 90° C. was added N,N-dimethylformamide dibutyl acetal (3.80 mL, 15.9 mmol, 4 equiv) over 15 minutes. The reaction was stirred at 90° C. for 2 hours, after which an additional amount of N,N-dimethylformamide dibutyl acetal (0.9 mL, 3.38 mmol, 1 equiv) was added dropwise and the reaction was stirred at 90° C. for 30 minutes. The reaction was cooled to room temperature and stirred overnight. The reaction was adsorbed onto silica gel and concentrated under reduced pressure. The crude residue was purified by flash chromatography on a 40 g silica gel cartridge eluting with a gradient of 0 to 10% EtOAc in heptane to give tert-butyl 7-bromonaphthalene-2-carboxylate (1.11 g, 3.61 mmol, 90.9% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.46 (s, 1 H), 8.14 (s, 1 H), 8.06 (dd, J = 8.6, 1.6 Hz, 1 H), 7.86 (d, J = 8.6 Hz, 1 H), 7.77 (d, J = 8.6, Hz, 1 H), 7.66 (dd, J = 8.6, 1.6 Hz, 1 H), 1.67 (s, 9 H).

[0260] Step 3: Preparation of tert-butyl 7-methylnaphthalene-2-carboxylate

[0261] A mixture of tert-butyl 7-bromonaphthalene-2-carboxylate (1.11 g, 3.61 mmol, 1 equiv.), trimethylboroxine (906 mg, 7.22 mmol, 2 equiv.), tetrakis(triphenylphosphine)palladium (834 mg, 722 μmol, 0.2 equiv.), and potassium carbonate (1.99 g, 14.4 mmol, 4 equiv.) in 1,4-dioxane (20 mL) was degassed for 5 min, then sealed and heated at 110 °C for 20 h. The reaction was diluted with EtOAc (20 mL) and adsorbed onto silica gel. The crude residue was purified by flash chromatography, eluting with 0–10% EtOAc in heptane, to afford tert-butyl 7-methylnaphthalene-2-carboxylate (808 mg, 3.33 mmol, 92.4% yield) as a white crystalline solid. 1 H NMR (400 MHz, CDCl3) δ 8.45 (s, 1 H), 7.95 (d, J = 8.7, Hz, 1 H), 7.80 (d, J = 8.5, Hz, 1 H), 7.77 (d, J = 8.5 Hz, 1 H), 7.71 (s, 1 H), 7.40 (d, J = 8.7 Hz, 1 H), 2.53 (s, 3 H), 1.65 (s, 9 H).

[0262] Step 4: Preparation of tert-butyl 7-(bromomethyl)naphthalene-2-carboxylate

[0263] To a solution of tert-butyl 7-methylnaphthalene-2-carboxylate (808 mg, 3.33 mmol) in anhydrous carbon tetrachloride (25 mL) under a nitrogen atmosphere was added N-bromosuccinimide (621 mg, 3.49 mmol) and benzoyl peroxide (32.2 mg, 133 μmol). The reaction mixture was heated to reflux and stirred at this temperature for 20 h. The precipitate was filtered and washed with carbon tetrachloride (10 mL), after which the filtrate was adsorbed onto silica gel and concentrated under reduced pressure. This crude material was purified by flash chromatography on an 80 g silica gel cartridge eluting with 0–10% EtOAc in heptane to give tert-butyl 7-(bromomethyl)naphthalene-2-carboxylate (720 mg, 2.24 mmol, 67.9% yield) as a white solid, which contained residual starting material (approximately 25%). 1 H NMR (400 MHz, CDCl3) δ 8.50 (s, 1 H), 8.04 (dd, J = 8.6, 1.6 Hz, 1 H), 7.93 (s, 1 H), 7.85 (t, J = 8.8 Hz, 2 H), 7.60 (dd, J = 8.6, 1.6 Hz, 1 H), 4.67 (s, 2 H), 1.64 (s, 9 H).

[0264] Step 5: Preparation of tert-butyl 7-[(diethoxyphosphoryl)methyl]naphthalene-2-carboxylate

[0265] tert-Butyl 7-(bromomethyl)naphthalene-2-carboxylate (720 mg, 2.24 mmol) was suspended in triethyl phosphite (2 mL, 11.6 mmol) and the reaction mixture was heated at reflux for 1.5 h (once solution was achieved at 110 °C). The reaction was cooled to room temperature and purified by elution with 50 g CHCl using a gradient of 5-80% MeCN in water. 18 Direct purification via reverse phase chromatography on a cartridge gave tert-butyl 7-[(diethoxyphosphoryl)methyl]naphthalene-2-carboxylate (580 mg, 1.53 mmol, 68.4% yield) as a thick, yellowish oil. LCMS: m / z = 379.3 [M+H] +; 1 H NMR (400 MHz, CDCl3) δ 8.52 (s, 1 H), 8.08 - 8.00 (m, 1 H), 7.89 - 7.83 (m, 3 H), 7.58 - 7.54 (m, 1 H), 4.11 - 3.97 (m, 4 H), 3.36 (d, J = 21.6 Hz, 2 H), 1.67 (s, 9 H), 1.26 (t, J = 7.0 Hz, 6 H).

[0266] Step 6: Preparation of rac-tert-butyl 7-[(diethoxyphosphoryl)(hydroxy)methyl]naphthalene-2-carboxylate

[0267] To a solution of tert-butyl 7-[(diethoxyphosphoryl)methyl]naphthalene-2-carboxylate (200 mg, 0.5285 mmol, 1 equiv.) in tetrahydrofuran (5 mL) at −78° C. was added dropwise a solution of sodium bis(trimethylsilylamide) (1 M in THF) (792 μL, 792 μmol, 1.5 equiv.). The mixture was stirred for 2 minutes, after which 2-(benzenesulfonyl)-3-phenyloxaziridine (274 mg, 1.05 mmol, 2.0 equiv.) was added in one portion. The dark red solution was stirred at −78° C. for 20 minutes. The reaction mixture was quenched with saturated aqueous ammonium chloride (50 mL) at −78° C., after which the ice bath was removed. EtOAc (25 mL) and water (25 mL) were added, and the mixture was stirred for 30 minutes. The phases were separated, and then the aqueous layer was back-extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. This material was purified by flash chromatography on a 24 g silica gel cartridge, eluting with 20-100% EtOAc in heptane, to afford rac-tert-butyl 7-[(diethoxyphosphoryl)(hydroxy)methyl]naphthalene-2-carboxylate (140 mg, 0.3549 mmol, 67.3% yield) as a white sticky solid. LCMS: m / z = 394.6 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ 8.57 (s, 1 H), 8.08 (s, 1 H), 8.05 (d, J = 8.6, Hz, 1 H), 7.90 (d, J = 8.3 Hz, 1 H), 7.87 (d, J = 8.3 Hz, 1 H), 7.72 (d, J = 8.3 Hz, 1 H), 5.24 (dd, J = 11.1, 4.7 Hz, 1 H), 4.18 - 3.99 (m, 4 H), 3.31 (dd, J = 11.1, 4.7 Hz, 1 H), 1.66 (s, 9 H), 1.32 - 1.22 (m, 6 H).

[0268] Step 7: Preparation of rac-tert-butyl 7-[(diethoxyphosphoryl)(fluoro)methyl]naphthalene-2-carboxylate

[0269] To a solution of tert-butyl 7-[(diethoxyphosphoryl)(hydroxy)methyl]naphthalene-2-carboxylate (140 mg, 0.3549 mmol, 1 equiv.) in methylene chloride (5 mL) at -78 °C under nitrogen, a solution of (diethylamino)sulfur trifluoride (56.1 μL, 425 μmol, 1.2 equiv.) was added dropwise. The reaction was stirred at -78 °C for 20 min. The reaction was quenched by the addition of saturated aqueous sodium bicarbonate (50 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by elution with a gradient of 5–80% MeCN in water to give 50 g C 18 Purification by reverse-phase chromatography on a cartridge gave rac-tert-butyl 7-[(diethoxyphosphoryl)(fluoro)methyl]naphthalene-2-carboxylate (80.0 mg, 0.2018 mmol, 57.1% yield) as a clear oil. LCMS: m / z = 397.4 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1 H), 8.11 - 8.04 (m, 2 H), 7.94 (d, J = 8.3, Hz, 1 H), 7.90 (d, J = 8.3 Hz, 1 H), 7.72 (d, J = 8.6, 1 H), 5.90 (dd, J = 44.6, 8.1 Hz, 1 H), 4.24 - 4.02 (m, 4 H), 1.35 - 1.25 (m, 6 H).

[0270] Step 8: Preparation of rac-7-[(diethoxyphosphoryl)(fluoro)methyl]naphthalene-2-carboxylic acid

[0271] To a solution of rac-tert-butyl 7-[(diethoxyphosphoryl)(fluoro)methyl]naphthalene-2-carboxylate (80 mg, 0.2018 mmol) in methylene chloride (4 mL) was added trifluoroacetic acid (1 mL). The resulting yellow solution was stirred at room temperature for 2.5 hours. The reaction was concentrated under reduced pressure to give crude rac-7-[(diethoxyphosphoryl)(fluoro)methyl]naphthalene-2-carboxylic acid (68.3 mg, 0.2018 mmol) as a clear oil. LCMS: m / z = 341.2 [M+H] + .

[0272] Synthesis of 5-{[bis({[(2S)-2-(methoxycarbonyl)pyrrolidine-1-carbonyloxy]methoxy})phosphoryl]difluoromethyl}-1-benzothiophene-2-carboxylic acid [ka]

[0273] Step 1: Preparation of 1-chloromethyl 2-methyl(2S)-pyrrolidine-1,2-dicarboxylate

[0274] To a solution of methyl (2S)-pyrrolidine-2-carboxylate hydrochloride (1.00 g, 6.03 mmol) and N,N-diisopropylethylamine (818 mg, 6.33 mmol, 1.05 equiv.) in dichloromethane (15 mL) at 0 °C under a nitrogen atmosphere was added chloroacetyl chloride (777 mg, 6.03 mmol). After stirring for 0.5 h, the reaction mixture was washed successively with 1 N aqueous hydrochloric acid (50 mL), water (50 mL), and brine. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The product was purified by flash chromatography using a 25 g silica gel cartridge eluted with a gradient of 0 to 50% EtOAc in heptane. The combined fractions were concentrated under reduced pressure to give 1-chloromethyl 2-methyl(2S)-pyrrolidine-1,2-dicarboxylate (701 mg, 3.16 mmol, 52.7% yield). 1 H NMR (400 MHz, CDCl3) δ 5.88 (d, J = 6.0 Hz, 0.5H), 5.76 - 5.70 (m, 1H), 5.65 (d, J = 6.2 Hz, 0.5H), 4.39 (ddd, J = 18.8, 8.5, 3.6 Hz, 1H), 3.74 (d, J = 3.4 Hz, 3H), 3.68 - 3.45 (m, 2H), 2.32 - 2.16 (m, 1H), 2.10 - 1.87 (m, 3H).

[0275] Step 2: Preparation of 1-{[({2-[(benzyloxy)carbonyl]-1-benzothiophen-5-yl}difluoromethyl)({[(2S)-2-(methoxycarbonyl)pyrrolidine-1-carbonyloxy]methoxy})phosphoryl]oxy}methyl 2-methyl(2S)-pyrrolidine-1,2-dicarboxylate

[0276] To a stirred solution of ({2-[(benzyloxy)carbonyl]-1-benzothiophen-5-yl}difluoromethyl)phosphonic acid (300 mg, 753 μmol, 1 equiv.) in water (15 mL) was added dropwise sodium hydroxide (59.9 mg, 1.50 mmol) in water (2 mL), followed by silver nitrate (382 mg, 2.25 mmol). After 2 h at rt, the suspension was cooled to 0° C. The precipitate was collected by filtration, washed with water, coevaporated with toluene (2×), and dried under high vacuum. The powder was suspended in anhydrous toluene (10 mL), and 1-chloromethyl 2-methyl(2S)-pyrrolidine-1,2-dicarboxylate (582 mg, 2.63 mmol, 3.5 equiv.) was added. The mixture was stirred at room temperature for 18 h. The crude product was directly purified by normal phase chromatography using a 12 g silica gel cartridge eluted with a gradient of EtOAc in heptane (0 to 100% in 18 CV) to give 1-{[({2-[(benzyloxy)carbonyl]-1-benzothiophen-5-yl}difluoromethyl)({[(2S)-2-(methoxycarbonyl)pyrrolidine-1-carbonyloxy]methoxy})phosphoryl]oxy}methyl 2-methyl(2S)-pyrrolidine-1,2-dicarboxylate (90.0 mg, 117 μmol, 15.5% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 8.20 - 8.12 (m, 2H), 7.97 - 7.91 (m, 1H), 7.69 - 7.64 (m, 1H), 7.48 - 7.33 (m, 5H), 5.79 - 5.66 (m, 2H), 5.66 - 5.52 (m, 2H), 5.41 - 5.38 (m, 2H), 4.40 - 4.31 (m, 2H), 3.75 - 3.65 (m, 6H), 3.63 - 3.40 (m, 4H), 2.25 - 2.11 (m, 2H), 2.04 - 1.81 (m, 6H).

[0277] Step 3: Preparation of 5-{[bis({[(2S)-2-(methoxycarbonyl)pyrrolidine-1-carbonyloxy]methoxy})phosphoryl]difluoromethyl}-1-benzothiophene-2-carboxylic acid

[0278] To a mixture of 1-{[({2-[(benzyloxy)carbonyl]-1-benzothiophen-5-yl}difluoromethyl)({[(2S)-2-(methoxycarbonyl)pyrrolidine-1-carbonyloxy]methoxy})phosphoryl]oxy}methyl 2-methyl(2S)-pyrrolidine-1,2-dicarboxylate (90 mg, 117 μmol, 1 equiv.) in anhydrous tetrahydrofuran (10 mL) was added palladium on carbon (10% loading, 50% aqueous) (62.1 mg, 58.5 μmol, 0.5 equiv.). Hydrogen was bubbled through the suspension for 2 minutes, after which the reaction mixture was stirred under 1 atm (balloon) of hydrogen for 16 hours. The reaction mixture was filtered through Celite and rinsed with Me-THF. The filtrate was concentrated in vacuo to give crude 5-{[bis({[(2S)-2-(methoxycarbonyl)pyrrolidine-1-carbonyloxy]methoxy})phosphoryl]difluoromethyl}-1-benzothiophene-2-carboxylic acid (95.0 mg, 140 μmol, 119% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3) δ 8.18 - 8.13 (m, 1H), 8.13 - 8.07 (m, 1H), 7.97 - 7.92 (m, 1H), 7.69 - 7.63 (m, 1H), 5.82 - 5.58 (m, 4H), 4.43 - 4.34 (m, 2H), 3.77 - 3.67 (m, 6H), 3.64 - 3.42 (m, 4H), 2.27 - 2.15 (m, 2H), 2.09 - 1.82 (m, 6H).

[0279] The following linkers in Table 15 were prepared according to the procedure described for the synthesis of 5-{[bis({[(2S)-2-(methoxycarbonyl)pyrrolidine-1-carbonyloxy]methoxy})phosphoryl]difluoromethyl}-1-benzothiophene-2-carboxylic acid utilizing the appropriate starting materials. [Table 15]

[0280] Synthesis of 5-(((benzylamino)(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid: [ka]

[0281] Step 1: Preparation of allyl 5-(((benzylamino)(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0282] To a solution of (2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (200 mg, 0.64 mmol, 1.0 equiv.) in anhydrous DCM (6 mL) and DMF (1 drop) at 0 °C, oxalyl chloride (814.4 mg, 6.4 mmol, 10 equiv.) was added dropwise. The reaction was warmed to 40 °C and then stirred for an additional 1–2 h. The reaction was monitored by pipetting out a small crude sample and quenching with MeOH to confirm complete formation of bis-phosphoryl chloride allylic 5-((dichlorophosphoryl)methyl)benzo[b]thiophene-2-carboxylate (bis-methoxyphosphonate was observed by LCMS). Upon completion, excess oxalyl chloride and solvent were removed under reduced pressure, and the residue was redissolved in anhydrous DCM (5 mL). To this solution was then added BnNH (64.8 mg, 0.64 mmol, 1.0 equiv) and EtN (194.32 mg, 1.92 mmol, 3.0 equiv) in anhydrous DCM (2 mL) at −40 °C. The reaction was monitored by pipetting out a small crude sample and quenching with MeOH, which confirmed that the majority of the product was allyl 5-(((benzylamino)chlorophosphoryl)methyl)benzo[b]thiophene-2-carboxylate (mono-methoxyphosphonate was observed by LCMS). To this solution was then added isopropyl L-alaninate (107.2 mg, 0.64 mmol, 1.0 equiv) in anhydrous DCM (2 mL) at −40 °C. The reaction was allowed to warm to room temperature and stirred for an additional 2 h. After completion, the reaction was quenched by adding HO (10 mL) and extracted with DCM (10 mL × 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give allyl 5-(((benzylamino)(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (100 mg, 194.33 μmol, 30% yield). LCMS (ESI): m / z = 515.2 [M+H] + .

[0283] Step 2: Preparation of 5-(((benzylamino)(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0284] 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 equiv.), Pd(PPh3)4 (22.47 mg, 19.4 μmol, 0.1 equiv.), and pyrrolidine (13.8 mg, 194 μmol, 1 equiv.) in DCM (3 mL) was stirred at room temperature for 1 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 5-(((benzylamino)(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (70 mg, 147.5 μmol, 76% yield). LCMS (ESI): m / z = 475.1 [M+H] + .

[0285] Synthesis of 4-nitrophenyl 5-((bis(((propoxycarbonyl)oxy)methoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate [ka]

[0286] Step 1: Preparation of chloromethyl propyl carbonate

[0287] A solution of propan-1-ol (1.24 mL, 16.5 mmol, 1 equiv) and chloroacetyl chloride (1.46 mL, 16.5 mmol, 1 equiv) in diethyl ether (50 mL) was cooled to 0° C. under nitrogen. Pyridine (1.32 mL, 16.5 mmol, 1.0 equiv) was added dropwise, after which the reaction mixture was stirred at 0° C. for 15 minutes, followed by room temperature for 3 hours. The white suspension was filtered and rinsed with diethyl ether (20 mL). The filtrate was washed with 1 N HCl (20 mL) and water (2×15 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give chloromethyl propyl carbonate (1.26 g, 8.25 mmol, 50.1% yield) as a clear oil. 1 H NMR (400 MHz, CDCl3) δ 5.74 (s, 2H), 4.25 - 4.17 (m, 2H), 1.74 (sextet, J = 7.1 Hz, 2H), 1.02 - 0.94 (m, 3H).

[0288] Step 2: Preparation of 4-nitrophenyl 5-((bis(((((1-methoxy-2-methylpropan-2-yl)oxy)carbonyl)oxy)methoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate

[0289] To a stirred suspension of (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (200 mg, 465 μmol, 1 equiv.) in water (4 mL) was added dropwise sodium hydroxide (37.1 mg, 930 μmol, 2 equiv.) in HO (1 mL). When the mixture reached a pH of approximately 8, the product began to precipitate, and silver nitrate (236 mg, 1.39 mmol, 3 equiv.) was added in one portion. After 2 h at 0 °C, the yellow precipitate was collected by filtration, washed with water, and dried under vacuum. The powder was suspended in anhydrous toluene (10 mL), and chloromethyl propyl carbonate (282 mg, 1.85 mmol, 4 equiv.) was added. The mixture was stirred at room temperature for 18 h. The crude product was directly purified by normal phase chromatography using a 24 g silica gel cartridge eluting with a gradient of EtOAc in heptane (0-60% in 18 CV) to give 4-nitrophenyl 5-((bis(((((1-methoxy-2-methylpropan-2-yl)oxy)carbonyl)oxy)methoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (10 mg, 15.1 μmol, 3.25% yield) as a white semi-solid: LCMS: m / z = 662.2 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) δ 8.64 (s, 1H), 8.43 - 8.27 (m, 4H), 7.72 - 7.65 (m, 3H), 5.75 - 5.65 (m, 4H), 4.12 - 4.02 (m, 4H), 1.67 - 1.55 (m, 4H), 0.90 - 0.84 (m, 6H).

[0290] Synthesis of 4-nitrophenyl 5-((bis(((((1-methoxy-2-methylpropan-2-yl)oxy)carbonyl)oxy)methoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate [ka]

[0291] Step 1: Preparation of chloromethyl 1-methoxy-2-methylpropan-2-yl carbonate

[0292] A solution of 1-methoxy-2-methylpropan-2-ol (2 g, 19.2 mmol, 1 equiv.) and chloroacetyl chloride (1.7 mL, 19.2 mmol, 1 equiv.) in diethyl ether (60 mL) was cooled to 0° C. under nitrogen. Pyridine (1.53 mL, 19.2 mmol, 1.0 equiv.) was added dropwise, after which the reaction mixture was stirred at 0° C. for 15 minutes, followed by room temperature for 3 hours. The white suspension was filtered and rinsed with diethyl ether (20 mL). The filtrate was washed with 1 N HCl (30 mL) and water (2×30 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give chloromethyl 1-methoxy-2-methylpropan-2-yl carbonate (860 mg, 4.37 mmol, 22.8% yield) as a clear oil. 1 H NMR (400 MHz, CDCl3) δ 7.20 - 7.17 (m, 2H), 5.04 - 5.00 (m, 2H), 4.90 (s, 3H), 3.03 - 2.99 (m, 6H).

[0293] Step 2: Preparation of 4-nitrophenyl 5-((bis(((((1-methoxy-2-methylpropan-2-yl)oxy)carbonyl)oxy)methoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate

[0294] To a stirred suspension of (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (200 mg, 465 μmol, 1 equiv.) in water (5 mL) was added dropwise sodium hydroxide (37.1 mg, 930 μmol, 2 equiv.) in HO (1 mL). When the mixture reached a pH of approximately 8, the product began to precipitate, and silver nitrate (236 mg, 1.39 mmol, 3 equiv.) was added in one portion. After 2 h at 0 °C, the white precipitate was collected by filtration, washed with water, and dried under vacuum. The powder was suspended in anhydrous toluene (10 mL), and chloromethyl 1-methoxy-2-methylpropan-2-yl carbonate (318 mg, 1.62 mmol, 3.5 equiv.) was added. The mixture was stirred at 50 °C for 18 h. The crude mixture was directly purified by normal phase chromatography using a 24 g silica gel cartridge eluting with a gradient of EtOAc in heptane (0 to 60% in 18 CV) to afford 4-nitrophenyl 5-((bis(((((1-methoxy-2-methylpropan-2-yl)oxy)carbonyl)oxy)methoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (51.0 mg, 68.0 μmol, 14.6% yield) as a white semi-solid. 1 H NMR (400 MHz, CDCl3) δ 8.38 - 8.33 (m, 3H), 8.24 (s, 1H), 8.03 (d, J = 8.8 Hz, 1H), 7.76 (d, J = 8.8 Hz, 1H), 7.51 - 7.47 (m, 2H), 5.74 - 5.62 (m, 4H), 3.53 - 3.50 (m, 4H), 3.41 - 3.38 (m, 6H), 1.51 (s, 12H).

[0295] Synthesis of 4-nitrophenyl 5-((bis(((dipropylcarbamoyl)oxy)methoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate [ka]

[0296] Step 1: Preparation of chloromethyl dipropyl carbamate

[0297] To a solution of chloroacetyl chloride (2.06 mL, 23.2 mmol, 1 equiv.) in hexane (30 mL) at 0 °C under nitrogen, dipropylamine (5.85 g, 57.9 mmol, 2.5 equiv.) was added and stirred at the same temperature for 30 min. The reaction mixture was then diluted with EtOAc (50 mL). The phases were separated, and the organic layer was washed successively with 1 N hydrochloric acid (50 mL), water, and brine. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The product was purified by flash chromatography using an 80 g silica gel cartridge eluted with a gradient of 0 to 10% EtOAc in heptane. The pure combined fractions were dried under reduced pressure to give chloromethyl dipropylcarbamate (2.89 g, 14.9 mmol, 64.3% yield) as a colorless oil. LCMS: m / z = 194.2 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 5.75 (s, 2H), 3.21 - 3.11 (m, 4H), 1.59 - 1.47 (m, 4H), 0.87 - 0.82 (m, 6H).

[0298] Step 2: Preparation of 4-nitrophenyl 5-((bis(((dipropylcarbamoyl)oxy)methoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate

[0299] To a stirred suspension of (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (200 mg, 465 μmol, 1 equiv.) in HO (5 mL) was added dropwise sodium hydroxide (37.1 mg, 930 μmol, 2 equiv.) in HO (1 mL). When the mixture reached a pH of approximately 8, the product began to precipitate, and silver nitrate (236 mg, 1.39 mmol, 3 equiv.) was added in one portion. After 2 h at 0 °C, the yellow precipitate was collected by filtration, washed with water, and dried under vacuum. The powder was suspended in anhydrous toluene (10 mL), and chloromethyl dipropyl carbamate (313 mg, 1.62 mmol, 3.5 equiv.) was added. The mixture was stirred at room temperature for 18 h. The crude product was directly purified by normal phase chromatography using a 12 g silica gel cartridge eluted with a gradient of EtOAc in heptane (0 to 60% in 18 CV) to give 4-nitrophenyl 5-((bis(((dipropylcarbamoyl)oxy)methoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (110 mg, 147 μmol, 31.8% yield) as a clear oil. 1 H NMR (400 MHz, DMSO-d6) δ 8.65 - 8.56 (m, 1H), 8.41 - 8.21 (m, 4H), 7.76 - 7.59 (m, 3H), 5.77 - 5.60 (m, 4H), 3.17 - 2.99 (m, 8H), 1.53 - 1.38 (m, 8H), 0.85 - 0.75 (m, 12H).

[0300] Synthesis of 4-nitrophenyl 5-((bis(1-((propoxycarbonyl)oxy)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate [ka]

[0301] Step 1: Preparation of 1-chloroethyl propyl carbonate

[0302] A solution of propan-1-ol (2 g, 33.2 mmol, 1 equiv.) and 1-chloroethyl chloroformate (4.74 g, 33.2 mmol, 1 equiv.) in diethyl ether (100 mL) was cooled to 0° C. under nitrogen. Pyridine (2.66 mL, 33.2 mmol, 1.0 equiv.) was added dropwise, after which the reaction mixture was stirred at 0° C. for 15 minutes, followed by room temperature for 3 hours. The white suspension was filtered and rinsed with diethyl ether (20 mL). The filtrate was washed with 1 N HCl (20 mL) and water (2×15 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1-chloroethyl propyl carbonate (4.62 g, 27.7 mmol, 83.5% yield) as a clear oil. 1 H NMR (400 MHz, CDCl3) δ 6.44 (q, J = 5.8 Hz, 1H), 4.24 - 4.10 (m, 2H), 1.84 (d, J = 5.9 Hz, 3H), 1.78 - 1.66 (m, 2H), 1.01 - 0.94 (m, 3H).

[0303] Step 2: Preparation of 4-nitrophenyl 5-((bis(1-((propoxycarbonyl)oxy)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate

[0304] To a stirred suspension of (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (200 mg, 465 μmol, 1 equiv.) in HO (4 mL) was added sodium hydroxide (37.1 mg, 930 μmol, 2 equiv.) in HO (1 mL) dropwise. When the mixture became clear (pH ∼8), silver nitrate (236 mg, 1.39 mmol, 2 equiv.) was added in one portion. After 2 h at 0 °C, the yellow precipitate was collected by filtration and dried under vacuum. The powder was suspended in anhydrous toluene (10 mL), and 1-chloroethyl propyl carbonate (269 mg, 1.62 mmol, 3.5 equiv.) was added. The mixture was stirred at room temperature for 18 h. The crude product was directly purified by normal phase chromatography using a 12 g silica gel cartridge eluting with a gradient of EtOAc in heptane (0-60% in 18 CV) to give 4-nitrophenyl 5-((bis(1-((propoxycarbonyl)oxy)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (113 mg, 163 μmol, 35.3% yield) as a clear oil. LCMS: m / z = 712.2 (M+Na). + .

[0305] Synthesis of (E)-3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)-2-methylacrylic acid [ka]

[0306] Step 1: Preparation of tert-butyl 2-(diethoxyphosphoryl)propanoate

[0307] A mixture of tert-butyl 2-bromopropanoate (3 g, 14.3 mmol, 1 equiv.) and ethan-2-ylium-1-yldiethylphosphite (2.82 g, 17.1 mmol, 1.2 equiv.) was stirred at 110° C. for 16 hours. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give tert-butyl 2-(diethoxyphosphoryl)propanoate (3.0 g, 11.3 mmol, 79% yield) as a white solid. LCMS (ESI): m / z = 267 [M+H] + .

[0308] Step 2: Preparation of tert-butyl (E)-3-(3-iodophenyl)-2-methylacrylate

[0309] To a solution of tert-butyl 2-(diethoxyphosphoryl)propanoate (1.14 g, 4.30 mmol, 1 equiv.) in THF (10 mL) was added n-BuLi (1.72 mL, 4.30 mmol, 1.0 equiv.) at −78° C. under nitrogen, and the resulting mixture was stirred at this temperature for 0.5 h. Then, a solution of 3-iodobenzaldehyde (1.0 g, 4.30 mmol, 1 equiv.) in THF (5 mL) was added. After the addition, the reaction mixture was warmed to room temperature and stirred for 14 h. Upon completion, the reaction mixture was quenched by adding HO (20 mL) and then extracted with EtOAc (15 mL × 3). The organic layers were combined, washed with brine (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give tert-butyl (E)-3-(3-iodophenyl)-2-methylacrylate (739.6 mg, 2.15 mmol, 50% yield) as a white solid. LC-MS (ESI) m / z = 345 [M+H] + .

[0310] Step 3: Preparation of tert-butyl (E)-3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)-2-methylacrylate

[0311] A solution of diethyl(bromodifluoromethyl)phosphonate (1.08 g, 4.06 mmol, 2 equiv.) and zinc (265 mg, 4.06 mmol, 2 equiv.) in DMAc (7 mL) was stirred at 60° C. for 1 h under a nitrogen atmosphere. CuBr (582 mg, 4.06 mmol, 2 equiv.) was then added and the mixture was stirred at 60° C. for an additional 1 h. tert-Butyl (E)-3-(3-iodophenyl)-2-methylacrylate (700 mg, 2.03 mmol, 1 equiv.) was added and the mixture was stirred at 60° C. for an additional 12 h. Upon completion, the suspension was filtered through a pad of Celite® and the filtrate was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give tert-butyl (E)-3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)-2-methylacrylate (180 mg, 445 μmol, 22% yield) as a yellow oil. LCMS (ESI): m / z = 405 [M+H] + .

[0312] Step 4: Preparation of (E)-3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)-2-methylacrylic acid

[0313] A solution of tert-butyl (E)-3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)-2-methylacrylate (180 mg, 445 μmol, 1 equiv.) in a mixture of DCM (8 mL) and TFA (4 mL) was stirred at room temperature for 1 h. After completion, the reaction mixture was concentrated under reduced pressure to give (E)-3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)-2-methylacrylic acid (154 mg, quantitative) as a white solid, which was used directly in the next step without further purification. LCMS (ESI): m / z = 349 [M+H] + .

[0314] Synthesis of (E)-3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)but-2-enoic acid [ka]

[0315] Step 1: Preparation of tert-butyl (E)-3-(3-iodophenyl)but-2-enoate

[0316] To tert-butyl 2-(diethoxyphosphoryl)acetate (1.02 g, 4.06 mmol, 1 equiv.) in THF (20 mL) was added n-BuLi (1.72 mL, 4.06 mmol, 1.0 equiv.) at −78° C., and the mixture was stirred at −78° C. for 0.5 h. Then, a solution of 1-(3-iodophenyl)ethan-1-one (1 g, 4.06 mmol, 1 equiv.) in THF (5 mL) was added dropwise to the reaction. After the addition, the reaction mixture was allowed to warm to room temperature and stirred for 18 h. Upon completion, the reaction mixture was quenched by adding HO (20 mL) and then extracted with EtOAc (20 mL × 3). The organic layers were combined, washed with brine (15 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give tert-butyl (E)-3-(3-iodophenyl)but-2-enoate (800 mg, 2.32 mmol, 58% yield) as an oil. 1 H NMR (400 MHz, CDCl3) δ 7.79 (t, J = 1.6 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.40 (d, J = 7.9 Hz, 1H), 7.09 (t, J = 7.9 Hz, 1H), 6.01 (d, J = 1.2 Hz, 1H), 2.49 (d, J = 1.2 Hz, 3H), 1.52 (s, 9H).

[0317] Step 2: Preparation of tert-butyl (E)-3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)but-2-enoate

[0318] To a stirred suspension of Zn (301 mg, 4.64 mmol, 2 equiv.) in anhydrous DMAc (2 mL) was slowly added a solution of diethyl (bromodifluoromethyl)phosphonate (1.23 g, 4.64 mmol, 2 equiv.) in DMAc (2 mL) under a nitrogen atmosphere. The reaction mixture was stirred at 45 °C for 2 h, after which CuBr (665 mg, 4.64 mmol, 2 equiv.) was added, and the resulting mixture was stirred at room temperature for 45 min. A suspension of tert-butyl (E)-3-(3-iodophenyl)but-2-enoate (800 mg, 2.32 mmol, 1 equiv.) in DMAc (3 mL) was added to the reaction mixture. The mixture was stirred at 45 °C for 24 h under a nitrogen atmosphere. The reaction mixture was then partitioned between water and ether. The mixture was passed through Celite and extracted with ether. The organic extract was washed with brine and dried over anhydrous Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography on silica to give tert-butyl (E)-3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)but-2-enoate (350 mg, 0.87 mmol, 37% yield) as an oil. 1 H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 13.2 Hz, 1H), 7.63-7.54 (m, 2H), 7.45 (t, J = 7.7 Hz, 1H), 6.07 (d, J = 1.2 Hz, 1H), 4.27-4.11 (m, 4H), 2.54 (d, J = 1.0 Hz, 3H), 1.52 (s, 9H), 1.32 (t, J = 7.1 Hz, 6H).

[0319] Step 3: Preparation of (E)-3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)but-2-enoic acid

[0320] To a solution of tert-butyl (E)-3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)but-2-enoate (350 mg, 0.87 mmol, 1 equiv.) in DCM (4 mL) was added TFA (6.13 g, 53.8 mmol, 62.2 equiv.) at room temperature, and the resulting mixture was stirred at room temperature for 18 h. Upon completion, the reaction mixture was concentrated under reduced pressure to afford (E)-3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)but-2-enoic acid (250 mg, 0.72 mmol, 83% yield) as an oil, which was used in the next step without further purification. LC-MS (ESI) m / z = 347.2 [M−H] - .

[0321]

[0322] Synthesis of perfluorophenyl 7-((bis(2-(butyrylthio)ethoxy)phosphoryl)difluoromethyl)-2-naphthoate and perfluorophenyl 7-(((2-(butyrylthio)ethoxy)(hydroxy)phosphoryl)difluoromethyl)-2-naphthoate [ka]

[0323] To a solution of (difluoro(7-((perfluorophenoxy)carbonyl)naphthalen-2-yl)methyl)phosphonic acid (1 g, 2.10 mmol, 1 equiv.) in dry DCM (18 mL) was added oxalyl chloride (266 mg, 2.13 mmol, 1.0 equiv.) dropwise, followed by DMF (155 mg, 2.13 mmol, 1.0 equiv.) at 25° C. The reaction mixture was warmed to 40° C. and then stirred under reflux for an additional 1.2 h. The reaction was monitored by pipetting out a small crude sample and quenching with MeOH to confirm complete formation of the bis-Cl phosphoryl chloride (bis-methoxyphosphonate was observed by LCMS). Upon completion, excess oxalyl chloride and solvent were removed under reduced pressure. The residue was redissolved in anhydrous DCM (14 mL) and then added to a mixture of S-(2-hydroxyethyl)butanethioate (641 mg, 4.33 mmol, 2.2 equiv.) and triethylamine (198 mg, 1.97 mmol, 1.0 equiv.) in anhydrous DCM (15 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred for an additional 12 h. The reaction progress was monitored by LCMS, and upon completion, the reaction was quenched by adding HO (10 mL) and concentrated under reduced pressure. The residue was purified by C18 column chromatography to give two products: perfluorophenyl 7-((bis(2-(butyrylthio)ethoxy)phosphoryl)difluoromethyl)-2-naphthoate (680 mg, 1.13 mmol, 58% yield) as a white solid; LCMS (ESI): m / z = 729 [M+H]. + , and perfluorophenyl 7-(((2-(butyrylthio)ethoxy)(hydroxy)phosphoryl)difluoromethyl)-2-naphthoate (65.0 mg, 89.2 μmol) as a white solid. LCMS (ESI): m / z = 599 [M+H] + .

[0324] Synthesis of perfluorophenyl 7-(((2-(butyrylthio)ethoxy)(hydroxy)phosphoryl)difluoromethyl)-2-naphthoate [ka]

[0325] To a solution of perfluorophenyl 7-(((2-(butyrylthio)ethoxy)(hydroxy)phosphoryl)difluoromethyl)-2-naphthoate (300 mg, 501 μmol, 1 equiv.) in a mixture of deionized HO (8 mL) and THF (2 mL) was added Amberlite IR120® resin (Na + To the resulting solution was added AgNO (233 mg, 751 μmol, 1.5 equiv.). The resulting mixture was stirred at room temperature for 1 h, after which the excess resin was removed by filtration. AgNO (127 mg, 751 μmol, 1.5 equiv.) in deionized HO (2 mL) was then added to the resulting solution. After the addition, the resulting mixture was stirred at room temperature for an additional 1 h. During this period, the silver salt formed as a white precipitate, which was collected by filtration. The filter cake was washed with cold HO (2 mL × 3), and the silver salt was further dried under reduced pressure to give a dry powder that was sufficiently pure for the next step without further purification.

[0326] The isolated mono-Ag salt was suspended in ACN (8 mL) and iodomethyl isopropyl carbonate (244 mg, 1.00 mmol, 2 equiv.) was added dropwise. After the addition, the resulting mixture was stirred at 40° C. for an additional 12 h. The reaction progress was monitored by LCMS. Upon completion, the unreacted silver salt was collected by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by preparative TLC to afford perfluorophenyl 7-(((2-(butyrylthio)ethoxy)(((isopropoxycarbonyl)oxy)methoxy)phosphoryl)difluoromethyl)-2-naphthoate (30 mg, 41.9 μmol, 8%) as a colorless oil. LCMS (ESI) m / z = 737 [M+Na] + .

[0327] Synthesis of 5-((bis(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid [ka]

[0328] Step 1: Preparation of diisopropyl 2,2'-((((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphoryl)bis(azanediyl)) (2S,2'S)-dipropionate

[0329] To a solution of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (300 mg, 960 μmol, 1.0 equiv.) in anhydrous DCM (10 mL) and DMF (catalytic amount) was added oxalyl chloride (609 mg, 4.80 mmol, 5.0 equiv.) dropwise at 0°C. The reaction mixture was warmed to 40°C and then stirred for an additional 1-2 h. The reaction was monitored by pipetting out a small crude sample and quenching with MeOH to confirm complete formation of the bis-Cl phosphoryl chloride (bis-methoxyphosphonate was observed by LCMS). Upon completion, excess oxalyl chloride and solvent were removed under reduced pressure, and the residue was redissolved in anhydrous DCM (5 mL). This solution was then added to a mixture of isopropyl L-alaninate (502 mg, 3.83 mmol, 4.0 equiv) and N,N-diisopropylethylamine (620 mg, 4.80 mmol, 5.0 equiv) in anhydrous DCM (10 mL) at 0 °C. The reaction was allowed to warm to room temperature and stirred for an additional 18 h. The progress was monitored by LCMS. Upon completion, the reaction was quenched by adding HO (10 mL) and extracted with DCM (10 mL × 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give 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] + .

[0330] Step 2: Preparation of 5-((bis(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0331] 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 equiv.) in DCM (1 mL), pyrrolidine (9.17 mg, 129 μmol, 1.0 equiv.) and Pd(PPh3)4 (14.9 mg, 12.9 μmol, 0.1 equiv.) were added under N2, and the resulting mixture was stirred at room temperature for 2 h. After completion, the reaction mixture was cooled in an ice bath and then carefully neutralized with HCl (1 M aqueous solution) until the pH was adjusted to pH = 4-6. The resulting mixture was extracted with DCM (10 mL × 3), and the combined organic layers were washed with brine (10 mL × 2), dried over anhydrous Na2SO4, and 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] + .

[0332] Synthesis of 5-(difluoro(((2-isopropoxy-2-oxoethyl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid [ka]

[0333] Step 1: Preparation of benzyl 5-(difluoro(((2-isopropoxy-2-oxoethyl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0334] To a solution of ((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid (300 mg, 753 μmol, 1 equiv.) in methylene chloride (8 mL) at 0° C. was added two drops (catalytic amount) of DMF, followed by the dropwise addition of oxalyl chloride (192 μL, 2.25 mmol, 3 equiv.). The reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was initially insoluble, but upon addition of oxalyl chloride and warming to room temperature, a clear solution developed. The reaction was concentrated under reduced pressure. The latter was then diluted with methylene chloride (8 mL), and the solution was cooled to −78° C. A solution of phenol (56.6 mg, 602 μmol, 0.8 equiv.) and triethylamine (155 μL, 1.12 mmol, 1.5 equiv.) in DCM (1 mL) was added slowly to the yellow solution over 5 min. The reaction mixture was stirred at -78°C for 15 minutes, then warmed to room temperature and stirred for 2 hours. The reaction mixture was cooled to -78°C. A solution of propan-2-yl 2-aminoacetate (88.2 mg, 753 μmol, 1 equiv) and triethylamine (155 μL, 1.12 mmol, 1.5 equiv) in DCM (1 mL) was added slowly to the yellow solution over 5 minutes. The reaction mixture was stirred at -78°C for 15 minutes, then warmed to room temperature and stirred for 18 hours. Water (2-3 drops) was added, and the reaction was concentrated under reduced pressure. The crude residue was purified by elution with 50 g C in water (containing 0.1% formic acid) with 5-100% MeCN. 18 Purification by reverse phase chromatography on a cartridge gave 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] + .

[0335] Step 2: Preparation of 5-(difluoro(((2-isopropoxy-2-oxoethyl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0336] 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 equiv.) in anhydrous tetrahydrofuran (10 mL) under nitrogen was added 10% palladium on carbon (50% aqueous) (166 mg, 78.0 μmol, 0.5 equiv.). Hydrogen was bubbled through for 5 minutes, and the reaction mixture was stirred at room temperature for 18 hours under hydrogen (1 atm). Nitrogen was bubbled through the mixture, which was then filtered through 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] + .

[0337] Following 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, the following linkers in Table 16 were prepared. [Table 16]

[0338] Synthesis of 4-nitrophenyl 5-(difluoro((2-isopropoxy-2-oxoethoxy)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate [ka]

[0339] Step 1: Preparation of 4-nitrophenyl 5-(difluoro(hydroxy(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0340] To a solution of (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (1 g, 2.32 mmol, 1 equiv.) in methylene chloride (6 mL) at 0 °C, 2 drops of DMF (catalytic amount) were added, followed by the dropwise addition of oxalyl chloride (1.18 mL, 13.9 mmol, 6 equiv.). The reaction was allowed to warm to room temperature and stirred for 2 h. The reaction was initially insoluble (a white solid floated on the surface) but became a clear solution after addition of oxalyl chloride and warming to room temperature. The reaction was concentrated under reduced pressure and dried under full high vacuum for 30 min to give a yellow solid. The latter was then diluted with methylene chloride (10 mL) and cooled to -78 °C. A solution of phenol (218 mg, 2.32 mmol, 1 equiv.) and triethylamine (646 μL, 4.64 mmol, 2 equiv.) in DCM (1 mL) (anhydrous over NaSO) was added slowly to the yellow solution over 5 min. The reaction mixture was stirred at -78 °C for 15 min, then warmed to room temperature and stirred for 2 h. Water (1 mL) was added, and the reaction mixture was concentrated under reduced pressure. The crude residue was purified by elution with a gradient of 5 to 100% MeCN in water (containing 0.1% formic acid) to give 50 g C 18 Purification by reverse phase chromatography on a cartridge gave 4-nitrophenyl 5-(difluoro(hydroxy(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (848 mg, 1.67 mmol, 72.4%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6) δ 9.04 (br. s., 1H), 8.63 (s, 1H), 8.37 (d, J = 9.0 Hz, 2H), 8.29 (s, 1H), 8.19 (d, J = 8.8 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.71 (d, J = 9.0 Hz, 2H), 7.27 - 7.18 (m, 2H), 7.10 (d, J = 8.3 Hz, 2H), 7.02 - 6.95 (m, 1H).

[0341] Step 2: Preparation of 4-nitrophenyl 5-(difluoro((2-isopropoxy-2-oxoethoxy)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0342] To a solution of 4-nitrophenyl 5-(difluoro(hydroxy(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (100 mg, 197 μmol, 1 equiv.) in methylene chloride (5 mL) at 0 °C, 2 drops of DMF (catalytic amount) were added, followed by the dropwise addition of oxalyl chloride (168 μL, 1.97 mmol, 10 equiv.). The reaction was allowed to warm to room temperature and stirred for 18 h. The reaction mixture was concentrated under reduced pressure and dried under full high vacuum. The latter was then diluted with methylene chloride (5 mL) and cooled to 0 °C. A solution of propan-2-yl 2-hydroxyacetate (30.2 mg, 256 μmol, 1.3 equiv.) and triethylamine (82.3 μL, 591 μmol, 3 equiv.) in DCM (1 mL) (anhydrous over Na2SO4) was slowly added to the orange solution. The reaction mixture was stirred at 0°C for 5 minutes, then warmed to room temperature and stirred for 5 hours. The reaction mixture was concentrated under reduced pressure. The crude residue was purified by reverse-phase chromatography on a 50 g C18 cartridge, eluting with 5-100% MeCN in basic water (10 mM NH4HCO3, pH = 10) to afford 4-nitrophenyl 5-(difluoro((2-isopropoxy-2-oxoethoxy)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (65.0 mg, 107 μmol, 54.6%) as a yellow oil. LCMS: m / z = 606.2 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.46 (s, 1H), 8.41 - 8.35 (m, 3H), 7.83 (d, J = 8.3 Hz, 1H), 7.72 - 7.67 (m, 2H), 7.44 - 7.38 (m, 2H), 7.28 - 7.20 (m, 3H), 5.02 - 4.94 (m, 1H), 4.91 - 4.73 (m, 2H), 1.18 (dd, J = 6.4, 2.4 Hz, 6H).

[0343] Following the procedure described for 4-nitrophenyl 5-(difluoro((2-isopropoxy-2-oxoethoxy)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate, utilizing the appropriate starting materials, the following linkers in Table 17 were prepared: [Table 17]

[0344] Synthesis of 5-(((((S)-1-(benzyloxy)-1-oxopropan-2-yl)amino)(2-((3-methylbutanoyl)thio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid [ka]

[0345] Step 1: Preparation of allyl 5-(((((S)-1-(benzyloxy)-1-oxopropan-2-yl)amino)(2-((3-methylbutanoyl)thio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate

[0346] To a solution of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid (200 mg, 0.5742 mmol, 1 equiv) in methylene chloride (10 mL) at 0° C. was added 3 drops of DMF, followed by the dropwise addition of oxalyl chloride (147 μL, 1.72 mmol, 3 equiv). The reaction was allowed to warm to room temperature and stirred for 3 hours. The reaction was concentrated under reduced pressure and dried under high vacuum for 30 minutes to give an off-white solid. The crude solid was diluted with methylene chloride (10 mL) and cooled to 0° C. A solution of 1-[(2-hydroxyethyl)sulfanyl]-3-methylbutan-1-one (93.1 mg, 574 μmol, 1 equiv) in DCM (2 mL) (anhydrous over NaSO) was added dropwise, followed by the slow addition of triethylamine (299 μL, 2.87 mmol, 5 equiv) in DCM (2 mL) (anhydrous over NaSO) to the yellow solution over 1 minute. The reaction mixture was stirred at 0° C. for 1 minute, then warmed to room temperature and stirred for 1 hour. The reaction was cooled to 0° C., then benzyl (2R)-2-aminopropanoate 4-methylbenzene-1-sulfonate (302 mg, 861 μmol, 1.5 equiv) was added in one portion. The reaction was allowed to warm to room temperature and stirred for 20 hours. The reaction was concentrated under reduced pressure and then diluted with DMSO / MeCN / water (3 mL). This crude residue was eluted with 5-100% MeCN in water. 18 Purification by reverse-phase chromatography on a cartridge afforded allyl 5-(((((S)-1-(benzyloxy)-1-oxopropan-2-yl)amino)(2-((3-methylbutanoyl)thio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (180 mg, 0.2753 mmol, 48.0% yield) as a thick brownish oil. 1H NMR (400 MHz, CDCl3) δ 8.16 - 8.12 (m, 1 H), 7.94 (d, J = 8.5 Hz, 0.5 H), 7.78 (d, J = 8.5 Hz, 0.5 H), 7.70 - 7.64 (m, 1 H), 7.43 - 7.31 (m, 6 H), 6.12 - 6.01 (m, 1 H), 5.47 (d, J = 16.8 Hz, 1 H), 5.35 (d, J = 10.4 Hz, 1 H), 5.25 - 5.11 (m, 2 H), 4.90 - 4.86 (m, 2 H), 4.24 - 4.00 (m, 2 H), 3.82 - 3.69 (m, 1 H), 3.24 - 2.92 (m, 2 H), 2.45 - 2.40 (m, 2 H), 2.18 - 2.10 (m, 1 H), 1.44 (dd, J = 16.0, 7.1 Hz, 3 H), 0.98 - 0.94 (m, 6 H).

[0347] Step 2: Preparation of 5-(((((S)-1-(benzyloxy)-1-oxopropan-2-yl)amino)(2-((3-methylbutanoyl)thio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0348] To a stirred solution of allyl 5-(((((S)-1-(benzyloxy)-1-oxopropan-2-yl)amino)(2-((3-methylbutanoyl)thio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (60 mg, 0.09178 mmol, 1 equiv.) in tetrahydrofuran (3 mL) was added morpholine (39.5 μL, 458 μmol, 5 equiv.) and tetrakis(triphenylphosphine)palladium (10.5 mg, 9.17 μmol, 0.10 equiv.) under nitrogen. The reaction mixture was stirred at room temperature for 1.5 hours. The reaction was loaded directly onto a column. The product was purified by elution with 50 g C elution with 5-80% MeCN in water (containing 0.1% formic acid). 18Purification by reverse phase chromatography on a cartridge followed by lyophilization afforded 5-(((((S)-1-(benzyloxy)-1-oxopropan-2-yl)amino)(2-((3-methylbutanoyl)thio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (40.0 mg, 0.06518 mmol, 71.1% yield) as an off-white sticky solid. LCMS: m / z = 611.9 [M+H] + ; 1 H NMR (400 MHz, CDCl3) δ 8.10 (d, J = 16.8 Hz, 1 H), 7.86 - 7.78 (m, 2 H), 7.61 - 7.54 (m, 1 H), 7.45 - 7.35 (m, 5 H), 5.25 (d, J = 13.0 Hz, 2 H), 4.60 - 4.45 (m, 1 H), 4.40 - 4.14 (m, 3 H), 3.36 - 3.14 (m, 2 H), 2.48 (t, J = 7.1 Hz, 3 H), 2.25 - 2.13 (m, 1 H), 1.58 - 1.51 (m, 3 H), 1.02 - 0.96 (m, 6 H).

[0349] Building Block Synthesis

[0350] Synthesis of 6-phenyl-4-azaspiro[2.4]heptane [ka]

[0351] Step 1: Preparation of methyl 3-cyano-2-phenylpropanoate

[0352] To a cooled (-78 °C) solution of methyl 2-phenylacetate (5.0 g, 33.3 mmol, 1.0 equiv.) in anhydrous THF (50 mL) was slowly added a solution of 2 M LDA (20 mL, 40.0 mmol, 1.2 equiv.) in THF. After 1 h, 2-bromoacetonitrile (4.2 g, 35.0 mmol, 1.1 equiv.) was slowly added dropwise, and the reaction was further allowed to stand at -78 °C for an additional 1 h. To this mixture was added saturated aqueous NH4Cl (5 mL), and the mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc (20 mL × 3). The organic layers were combined, 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 give methyl 3-cyano-2-phenylpropanoate (5.0 g, 26.5 mmol, 79% yield) as a white solid. LCMS (ESI) m / z = 190.1 [M+H] + .

[0353] Step 2: Preparation of 6-phenyl-4-azaspiro[2.4]heptan-5-one

[0354] To a cooled (0 °C) solution of methyl 3-cyano-2-phenylpropanoate (5.0 g, 26.5 mmol, 1.0 equiv.) and Ti(OiPr) (9.0 g, 31.7 mmol, 1.2 equiv.) in anhydrous THF (100 mL) was slowly added a 3 M solution of EtMgBr (20 mL, 59.6 mmol, 2.25 equiv.) while maintaining an internal temperature between -5 °C and 0 °C. After complete addition of EtMgBr, the mixture was stirred at 0 °C for an additional 1 h. The reaction mixture was quenched by the addition of 2 N aqueous HCl (60 mL). The resulting acidic solution was extracted with EtOAc (50 mL × 3). The combined organic layers were washed with brine (20 mL × 2), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography to give 6-phenyl-4-azaspiro[2.4]heptan-5-one (2.1 g, 11.2 mmol, 42% yield) as a white solid. LCMS (ESI) m / z = 188 [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).

[0355] Step 3: Preparation of 6-phenyl-4-azaspiro[2.4]heptane

[0356] To a cooled (10 °C) solution of 6-phenyl-4-azaspiro[2.4]heptan-5-one (2.1 g, 11.2 mmol, 1.0 equiv.) in anhydrous THF (50 mL) was added NaBH (2.1 g, 56.0 mmol, 5.0 equiv.) in portions. To this mixture was added BF·EtO (6.7 mL, 56.0 mmol, 5.0 equiv.) dropwise. The reaction mixture was heated at 60 °C for 16 h. The mixture was cooled to ambient temperature, and 2 N aqueous HCl (30 mL) was slowly introduced. The acidic mixture was extracted with EtOAc (30 mL × 3). The organic layers were combined, washed with brine (20 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by Biotage® C18 column to give 6-phenyl-4-azaspiro[2.4]heptane (1.5 g, 8.7 mmol, 78% yield) as a colorless oil. LCMS (ESI) m / z = 174 [M+H] + ; 1 H NMR (400 MHz, CDCl3) 8.59 (s, 1H), δ 7.38-7.27 (m, 5H), 3.85-3.57 (m, 2H), 3.40-3.17 (m, 1H), 2.43-2.09 (m, 2H), 1.46-1.18 (m, 2H), 0.98-0.66 (m, 2H).

[0357] Pyrrolidine Building Block Synthesis:

[0358] Synthesis of rel-(trans)-4-cyclohexylpyrrolidine-3-carbonitrile [ka]

[0359] Step 1: Preparation of (E)-3-cyclohexylacrylonitrile

[0360] To a solution of cyclohexanecarbaldehyde (500 mg, 4.45 mmol, 1.0 equiv) in THF (15 mL) was added t-BuOK (998 mg, 8.90 mmol, 2.0 equiv) and diethyl(cyanomethyl)phosphonate (788 mg, 4.45 mmol, 1.0 equiv) at room temperature. The solution was stirred at room temperature for 1 h. Upon completion, the reaction mixture was quenched by adding HO (10 mL) and then extracted with EtOAc (10 mL × 3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous NaSO, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford (E)-3-cyclohexylacrylonitrile (300 mg, 2.21 mmol, 50% yield) as a colorless oil. LC-MS (ESI) m / z = 136 [M+H] + .

[0361] Step 2: Preparation of rel-(trans)-1-benzyl-4-cyclohexylpyrrolidine-3-carbonitrile

[0362] To a solution of (E)-3-cyclohexylacrylonitrile (300 mg, 2.21 mmol, 1.0 equiv.) in CHCl (5 mL) was added N-benzyl-1-methoxy-N-((trimethylsilyl)methyl)methanamine (524 mg, 2.21 mmol, 1.0 equiv.) and TFA (25.1 mg, 221 μmol, 0.1 equiv.). The reaction mixture was stirred at room temperature for 12 h. Upon completion, the reaction mixture was diluted with CHCl (10 mL), washed with saturated aqueous NaHCO (5 mL), and the organic layer was separated and concentrated under reduced pressure to give crude rel-(trans)-1-benzyl-4-cyclohexylpyrrolidine-3-carbonitrile (700 mg) as a colorless oil. LC-MS (ESI) m / z = 269 [M+H] + .

[0363] Step 3: Preparation of rel-(trans)-4-cyclohexylpyrrolidine-3-carbonitrile

[0364] To a solution of (trans)-1-benzyl-4-cyclohexylpyrrolidine-3-carbonitrile (700 mg) in dry 1,2-dichloroethane (15 mL) was added 1-chloroethyl carbonochloridate (3.71 g, 26.0 mmol, 10.0 equiv.). The resulting mixture was stirred at 70° C. for 12 hours, then concentrated under reduced pressure. The crude product was dissolved in MeOH (5 mL) and stirred at 70° C. for 1 hour. Upon completion, the reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford rel-(trans)-4-cyclohexylpyrrolidine-3-carbonitrile (211 mg, 1.18 mmol, 46% yield) as a colorless oil. LC-MS (ESI) m / z = 179 [M+H] + .

[0365] Following the representative procedure (Steps 1 to 3) described for rel-(trans)-4-cyclohexylpyrrolidine-3-carbonitrile, utilizing the appropriate starting materials and modifications, the following intermediates in Table 18 were prepared. The compounds were prepared as racemates with trans stereochemical configurations about the C3 and C4 stereocenters in the pyrrolidine ring. [Table 18]

[0366] Following the procedure described above for the synthesis of rel-(trans)-4-cyclohexylpyrrolidine-3-carbonitrile, tert-butyl rel-(trans)-3-cyano-4-phenylpyrrolidine-1-carboxylate and tert-butyl (trans)-3-cyano-4-(2-oxo-1,2-dihydropyridin-4-yl)pyrrolidine-1-carboxylate were prepared. The racemic mixture of trans isomers was purified under SFC conditions, and its absolute stereochemistry was arbitrarily assigned as depicted. [ka]

[0367] Preparative separation method:

[0368] Instrument: Waters Thar 80 Preparative SFC; Column: ChiralPak C-IG, 100 × 4.6 mm ID, 5 μm; Mobile phase: A CO2, B methanol (0.05% diethylamine); Gradient: 10% to 40% B in 8 min; Flow rate: 2.5 mL / min; Back pressure: 100 bar; Column temperature: 40 °C; Wavelength: 210 nm; Cycle time: 2 min

[0369] Following the procedure described for rel-(trans)-4-cyclohexylpyrrolidine-3-carbonitrile, utilizing the appropriate starting materials and modifications, the following intermediates in Table 19 were prepared. [Table 19]

[0370] Synthesis of 2-(4-amino-[1,1'-biphenyl]-3-yl)acetamide [ka]

[0371] Step 1: Preparation of 2-(5-bromo-2-nitrophenyl)acetyl chloride

[0372] A solution of 2-(5-bromo-2-nitrophenyl)acetic acid (0.30 g, 1.2 mmol, 1 equiv) in thionyl chloride (2 mL) was stirred for 1 h at 80° C. The reaction mixture was concentrated under reduced pressure to give 2-(5-bromo-2-nitrophenyl)acetyl chloride (0.30 g, crude) as a white solid.

[0373] Step 2: Preparation of 2-(5-bromo-2-nitrophenyl)acetamide

[0374] A solution of 2-(5-bromo-2-nitrophenyl)acetyl chloride (0.30 g, 1.1 mmol, 1 equiv) in tetrahydrofuran (3 mL) and NH3·H2O (4 mL) was stirred at 25 °C for 30 min. The reaction mixture was concentrated under reduced pressure to give 2-(5-bromo-2-nitrophenyl)acetamide (0.30 g, crude) as a white solid. LCMS: m / z [M+H] + = 258.9.

[0375] Step 3: Preparation of 2-(4-nitro-[1,1'-biphenyl]-3-yl)acetamide

[0376] To a solution of 2-(5-bromo-2-nitrophenyl)acetamide (0.10 g, 0.39 mmol, 1 equiv.) in dioxane (1 mL) and water (0.2 mL) was added sodium carbonate (0.12 g, 1.2 mmol, 3 equiv.), phenylboronic acid (52 mg, 0.42 mmol, 1.1 equiv.), iron(2+)bis(cyclopenta-2,4-diyn-1-yldiphenyl-lambda-4-phosphane)palladium dichloride (14 mg, 0.019 mmol, 0.05 equiv.), and the mixture was stirred at 100° C. for 12 h. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL × 2), and the combined organic layers were washed with saturated brine (20 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 2-(4-nitro-[1,1'-biphenyl]-3-yl)acetamide (60 mg, 60% yield) as a white solid. LCMS: m / z (M+Na) + = 279.0. 1 H NMR (400 MHz, CD3OD) δ 8.17 (d, J = 8.4 Hz, 1H), 7.79 - 7.69 (m, 4H), 7.52 - 7.40 (m, 3H), 4.06 (s, 2H)

[0377] Step 4: Preparation of 2-(4-amino-[1,1'-biphenyl]-3-yl)acetamide

[0378] To a solution of 2-(4-nitro-[1,1'-biphenyl]-3-yl)acetamide (60 mg, 0.23 mmol, 1 equiv.) in ethyl alcohol (0.8 mL) and water (0.2 mL) was added ammonium chloride (0.038 g, 0.70 mmol, 3 equiv.) and iron (0.13 g, 2.4 mmol, 10 equiv.). The mixture was stirred at 25° C. for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated to give 2-(4-amino-[1,1'-biphenyl]-3-yl)acetamide (0.043 g, crude) as a white solid. LCMS: m / z [M+H] + = 227.0. 1H NMR (400 MHz, DMSO-d6) δ 7.53 (d, J = 7.6 Hz, 3H), 7.41 - 7.35 (m, 3H), 7.30 - 7.20 (m, 2H), 6.98 (s, 1H), 6.73 (d, J = 8.4 Hz, 1H), 5.26 (s, 2H), 3.32 (s, 2H).

[0379] Synthesis of 1-((3S,4R)-3-amino-4-fluoropyrrolidin-1-yl)ethan-1-one [ka]

[0380] Step 1: Preparation of tert-butyl (3S,4R)-3-(((benzyloxy)carbonyl)amino)-4-fluoropyrrolidine-1-carboxylate

[0381] To a solution of tert-butyl (3S,4R)-3-amino-4-fluoropyrrolidine-1-carboxylate (250 mg, 1.22 mmol, 1.0 equiv.) and sodium bicarbonate (512 mg, 6.10 mmol, 5.0 equiv.) in THF (10 mL) and water (2 mL) was added benzyl carbonochloridate (416 mg, 2.44 mmol, 2.0 equiv.) at room temperature. After the addition, the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was poured into water (10 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure to give tert-butyl (3S,4R)-3-(((benzyloxy)carbonyl)amino)-4-fluoropyrrolidine-1-carboxylate (2, 400 mg, 1.18 mmol, 97%) as a yellow oil, which was used directly in the next step without further purification. LCMS (ESI): m / z = 361.1 [M+Na] + .

[0382] Step 2: Preparation of benzyl ((3S,4R)-4-fluoropyrrolidin-3-yl)carbamate

[0383] A solution of tert-butyl (3S,4R)-3-(((benzyloxy)carbonyl)amino)-4-fluoropyrrolidine-1-carboxylate (200 mg, 0.59 mmol, 1.0 equiv) in DCM (1 mL) and TFA (0.5 mL) was stirred at 25° C. overnight under N. After completion, the reaction mixture was concentrated under reduced pressure to give crude benzyl ((3S,4R)-4-fluoropyrrolidin-3-yl)carbamate (140 mg, quantitative) as a white solid, which was used directly in the next step without further purification. LCMS (ESI): m / z = 239.3 [M+H] + .

[0384] Step 3: Preparation of benzyl ((3S,4R)-1-acetyl-4-fluoropyrrolidin-3-yl)carbamate

[0385] To a solution of benzyl ((3S,4R)-4-fluoropyrrolidin-3-yl)carbamate (140 mg, 0.59 mmol, 1.0 equiv) and TEA (179 mg, 1.77 mmol, 3.0 equiv) in anhydrous DCM (6 mL) was added acetyl chloride (46.0 mg, 0.59 mmol, 1.0 equiv) at 0 °C. After the addition, the resulting mixture was warmed to 20 °C and stirred under N for 2 h. Upon completion, the reaction mixture was poured into water (10 mL) and extracted with DCM (10 mL × 3). The organic layers were combined, washed with brine (10 mL), dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give benzyl ((3S,4R)-1-acetyl-4-fluoropyrrolidin-3-yl)carbamate (611 mg, 1.29 mmol, 62%) as a white solid. LCMS (ESI): m / z = 281.1 [M+H] + .

[0386] Step 4: Preparation of 1-((3S,4R)-3-amino-4-fluoropyrrolidin-1-yl)ethan-1-one

[0387] To a solution of benzyl ((3S,4R)-1-acetyl-4-fluoropyrrolidin-3-yl)carbamate (250 mg, 1.22 mmol, 1.0 equiv) in EtOH (10 mL) was added Pd / C (50 mg) under nitrogen. The suspension was degassed under vacuum and purged with H2 several times. The resulting mixture was stirred at room temperature overnight. Upon completion, the suspension was filtered through a pad of Celite® and the filter cake was washed with EtOH (20 mL). The combined filtrates were concentrated to dryness to afford 1-((3S,4R)-3-amino-4-fluoropyrrolidin-1-yl)ethan-1-one (375 mg, 2.10 mmol, 87%) as a colorless oil. LCMS (ESI): m / z = 147.1 [M+H] + .

[0388] Synthesis of (R)-azetidin-3-yl(2-methylmorpholino)methanone [ka]

[0389] Step 1: Preparation of tert-butyl (R)-3-(2-methylmorpholine-4-carbonyl)azetidine-1-carboxylate

[0390] To a solution of 1-[(tert-butoxy)carbonyl]azetidine-3-carboxylic acid (1, 100 mg, 496 μmol, 1.0 equiv.), HATU (226 mg, 595 μmol, 1.2 equiv.), and triethylamine (100 mg, 992 μmol, 2.0 equiv.) in DMF (2 mL) was added (2R)-2-methylmorpholine (55.1 mg, 545 μmol, 1.1 equiv.), and the resulting mixture was stirred at 20° C. overnight under N2. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give tert-butyl (R)-3-(2-methylmorpholine-4-carbonyl)azetidine-1-carboxylate (2, 140 mg, 492 μmol, 99%) as a white solid. LCMS (ESI): m / z = 229.2 [(M-56)+H] + .

[0391] Step 2: Preparation of (R)-azetidin-3-yl(2-methylmorpholino)methanone

[0392] A solution of tert-butyl (R)-3-(2-methylmorpholino-4-carbonyl)azetidine-1-carboxylate (2, 50 mg, 175 μmol, 1.0 equiv.) in DCM (6 mL) and TFA (2 mL) was stirred overnight at 25° C. under N. After completion, the reaction mixture was concentrated to give crude (R)-azetidin-3-yl(2-methylmorpholino)methanone (3, 40.0 mg, quantitative) as a white solid, which was used directly in the next step without further purification. LCMS (ESI): m / z = 185.3 [M+H] + .

[0393] According to the above scheme, the following building blocks were prepared:

[0394] Following the procedure described for (R)-azetidin-3-yl(2-methylmorpholino)methanone, utilizing the appropriate starting materials and modifications, the following intermediates in Table 20 were prepared. [Table 20]

[0395] Synthesis of (R)-morpholino(pyrrolidin-3-yl)methanone [ka]

[0396] Step 1: Preparation of benzyl (R)-3-(morpholine-4-carbonyl)pyrrolidine-1-carboxylate

[0397] To a solution of (R)-1-((benzyloxy)carbonyl)pyrrolidine-3-carboxylic acid (0.15 g, 0.60 mmol) and HATU (0.34 g, 0.90 mmol) in DMF (1 mL) was added morpholine (58 mg, 0.66 mmol) and DIEA (0.23 g, 1.8 mmol) and stirred at 15 °C for 1 h to give a brown solution. The solution was quenched with water (10 mL) and extracted with EtOAc (10 mL × 2). The combined organic layers were washed with saturated brine (10 mL × 3), dried over NaSO, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography to give benzyl (R)-3-(morpholine-4-carbonyl)pyrrolidine-1-carboxylate (0.10 g, 52% yield) as a brown oil. 1 H NMR (400 MHz, CDCl3) δ 7.41 - 7.28 (m, 5H), 5.14 (s, 2H), 3.68 (d, J = 4.4 Hz, 9H), 3.53 - 3.40 (m, 3H), 3.24 - 3.16 (m, 1H), 2.34 - 2.13 (m, 1H), 1.49 - 1.42 (m, 1H).

[0398] Step 2: Preparation of (R)-morpholino(pyrrolidin-3-yl)methanone

[0399] To a solution of benzyl (R)-3-(morpholine-4-carbonyl)pyrrolidine-1-carboxylate (0.10 g, 0.31 mmol) in MeOH (5 mL) was added aqueous Pd / C (0.10 g) and stirred under H (15 psi) at 15 °C for 2 h to give a black suspension. The reaction mixture was filtered and concentrated in vacuo to give (R)-morpholino(pyrrolidin-3-yl)methanone (60 mg, crude) as a colorless oil. LCMS: (ESI) m / z [M+H] + = 185.3

[0400] Following the procedure described for (R)-morpholino(pyrrolidin-3-yl)methanone, utilizing the appropriate starting materials and modifications, the following intermediates in Table 21 were prepared. [Table 21]

[0401] Synthesis of (S)-1-(tetrahydrofuran-3-yl)azetidin-3-amine [ka]

[0402] Step 1: Preparation of (R)-tetrahydrofuran-3-yl methanesulfonate

[0403] To a solution of (R)-tetrahydrofuran-3-ol (2.0 g, 23 mmol, 1.0 equiv) and TEA (6.9 g, 69 mmol, 3.0 equiv) in DCM (20 mL) at 0 °C, methanesulfonyl chloride (3.4 g, 29 mmol, 1.3 equiv) was added dropwise, and the mixture was stirred at 25 °C for 2 h to give a yellow mixture. The mixture was quenched with HO (50 mL) and extracted with DCM (50 mL × 2), and the combined organic layers were dried over NaSO, filtered, and concentrated to give (R)-tetrahydrofuran-3-yl methanesulfonate (3.5 g, crude) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 5.28 - 5.20 (m, 1H), 3.99 - 3.75 (m, 4H), 2.97 (s, 3H), 2.23 - 2.11 (m, 2H)

[0404] Step 2: Preparation of tert-butyl (S)-(1-(tetrahydrofuran-3-yl)azetidin-3-yl)carbamate

[0405] To a solution of (R)-tetrahydrofuran-3-yl methanesulfonate (1.5 g, 9.0 mmol, 1.0 equiv.) and tert-butyl azetidin-3-ylcarbamate (4.7 g, 27 mmol, 3.0 equiv.) in MeCN (15 mL) was added KCO (5.6 g, 41 mmol, 4.5 equiv.), and the mixture was stirred at 80° C. for 12 hours to give a pale yellow suspension. The mixture was filtered and concentrated to give a residue. The residue was purified by column chromatography to give tert-butyl (S)-(1-(tetrahydrofuran-3-yl)azetidin-3-yl)carbamate (0.6 g, crude) as a yellow oil. LCMS: (ESI) m / z [M+H] + = 243.0

[0406] Step 3: Preparation of (S)-1-(tetrahydrofuran-3-yl)azetidin-3-amine

[0407] A solution of tert-butyl (S)-(1-(tetrahydrofuran-3-yl)azetidin-3-yl)carbamate (0.10 mg, 0.41 mmol, 1 equiv) in DCM (1.5 mL) and TFA (0.50 mL) was stirred at 25° C. for 2 h to give a pink solution. The reaction mixture was concentrated under reduced pressure to give (S)-1-(tetrahydrofuran-3-yl)azetidin-3-amine (0.10 mg, crude) as a yellow oil. LCMS: (ESI) m / z [M+H] + = 143.3

[0408] Following the procedure described for (S)-1-(tetrahydrofuran-3-yl)azetidin-3-amine, utilizing the appropriate starting materials and modifications, the following intermediates in Table 22 were prepared. [Table 22]

[0409] Synthesis of (3S,4R)-4-fluoro-1-(pyridin-3-yl)pyrrolidin-3-amine [ka]

[0410] Step 1: Preparation of tert-butyl ((3S,4R)-4-fluoro-1-(pyridin-3-yl)pyrrolidin-3-yl)carbamate

[0411] To a solution of tert-butyl ((3S,4R)-4-fluoropyrrolidin-3-yl)carbamate (0.1 g, 0.49 mmol, 1.0 equiv) in dioxane (2.5 mL) was added 3-bromopyridine (93 mg, 0.59 mmol, 1.2 equiv), Xantphos (25 mg, 44 μmol, 0.1 equiv), and cesium carbonate (0.25 g, 0.78 mmol, 1.6 equiv). The reaction was degassed and purged with N three times, after which Pd(dba) (0.13 g, 14 μmol, 0.3 equiv) was added. The resulting reaction mixture was stirred at 100 °C for 72 h to give a black suspension. The reaction mixture was filtered, and the filtrate was concentrated to give a residue. The residue was diluted with water (50 mL) and extracted with EtOAc (50 mL x 2), and the combined organic layers were washed with saturated brine (50 mL x 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 tert-butyl ((3S,4R)-4-fluoro-1-(pyridin-3-yl)pyrrolidin-3-yl)carbamate (0.1 g, 73% yield) as a yellow oil. LCMS: (ESI) m / z [M+H] + =282.1

[0412] Step 2: Preparation of (3S,4R)-4-fluoro-1-(pyridin-3-yl)pyrrolidin-3-amine

[0413] A solution of tert-butyl ((3S,4R)-4-fluoro-1-(pyridin-3-yl)pyrrolidin-3-yl)carbamate (0.1 g, 0.36 mmol, 1.0 equiv) in DCM (0.3 mL) and trifluoroacetic acid (0.1 mL) was stirred at 20° C. for 1 h to give a yellow solution. The reaction mixture was concentrated under reduced pressure to give (3S,4R)-4-fluoro-1-(pyridin-3-yl)pyrrolidin-3-amine (0.1 g, crude) as a yellow oil. LCMS: (ESI) m / z [M+H] + =182.1

[0414] Following the procedure described for (3S,4R)-4-fluoro-1-(pyridin-3-yl)pyrrolidin-3-amine, utilizing the appropriate starting materials and modifications, the following intermediates in Table 23 were prepared. [Table 23]

[0415] Preparation of 1-((3S,4S)-3-amino-4-fluoropyrrolidin-1-yl)ethan-1-one [ka]

[0416] Step 1: Preparation of tert-butyl ((3S,4S)-1-acetyl-4-fluoropyrrolidin-3-yl)carbamate

[0417] To a solution of tert-butyl ((3S,4S)-4-fluoropyrrolidin-3-yl)carbamate (0.1 g, 0.49 mmol, 1 equiv) in DCM (0.5 mL) was added TEA (0.1 g, 0.98 mmol, 2 equiv) and the mixture was stirred at 0° C. for 5 min, then a solution of AcO (0.05 g, 0.49 mmol, 1 equiv) in DCM (0.5 mL) was added and the mixture was stirred at 25° C. for 30 min. The reaction mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL×2), and the combined organic layers were washed with saturated brine (50 mL×2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, petroleum ether / EtOAc = 10:1 to 3:1) to give tert-butyl ((3S,4S)-1-acetyl-4-fluoropyrrolidin-3-yl)carbamate (60 mg, 49% yield) as a yellow oil. LCMS: (ESI) m / z [M+H] + = 247.1

[0418] Step 2: Preparation of 1-((3S,4S)-3-amino-4-fluoropyrrolidin-1-yl)ethanone

[0419] A solution of tert-butyl ((3S,4S)-1-acetyl-4-fluoropyrrolidin-3-yl)carbamate (60 mg, 0.24 mmol, 1 equiv) in TFA (0.3 mL) and DCM (0.9 mL) was stirred at 25° C. for 30 min to give a yellow solution. The reaction mixture was concentrated under reduced pressure to give 1-((3S,4S)-3-amino-4-fluoropyrrolidin-1-yl)ethanone (60 mg, crude) as a yellow oil. LCMS: (ESI) m / z [M+H] + = 147.2

[0420] Following the procedure described for 1-((3S,4S)-3-amino-4-fluoropyrrolidin-1-yl)ethan-1-one, utilizing the appropriate starting materials and modifications, the following intermediates in Table 24 were prepared. [Table 24]

[0421] Synthesis of 2-phenyl-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one [ka]

[0422] Step 1: Preparation of tert-butyl 6-(2-phenylacetyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0423] To a solution of 2-phenylacetic acid (0.20 g, 1.5 mmol, 1 equiv) in DMF (1 mL) was added HATU (0.83 g, 2.2 mmol, 1.5 equiv) and DIEA (0.38 g, 3.0 mmol, 2 equiv), followed by a solution of tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (0.35 g, 1.8 mmol, 1.2 equiv) and DIEA (0.57 g, 4.5 mmol, 3 equiv) in DMF (1 mL), and the mixture was stirred at 25 °C for 2 h to give a yellow solution. The mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL × 2), and the combined organic layers were washed with saturated brine (10 mL × 2), dried over Na SO , filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO, DCM:MeOH=100:1 to 10:1) to give tert-butyl 6-(2-phenylacetyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.100 g, 23% yield) as a yellow oil. LCMS: (ESI) m / z [M+H] + = 317.0

[0424] Step 2: Preparation of 2-phenyl-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone

[0425] To a solution of tert-butyl 6-(2-phenylacetyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (0.1 g, 0.32 mmol, 1 equiv.) in DCM (3 mL) and TFA (1 mL) was added the mixture, which was stirred for 2 h at 25° C. to give a yellow solution. The reaction mixture was concentrated under reduced pressure to give 2-phenyl-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethanone (0.100 g, crude) as a yellow oil: (3-methylazetidin-3-yl)(piperidin-1-yl)methanone: 1 H NMR (400 MHz, CDCl3) δ 4.07 - 3.96 (m, 2H), 3.67 (s, 2H), 3.24 - 3.13 (m, 2H), 3.09 (s, 2H), 2.99 (s, 2H), 2.91 (s, 2H), 1.74 (s, 3H).

[0426] Following the procedure described for 2-phenyl-1-(2,6-diazaspiro[3.3]heptan-2-yl)ethan-1-one, utilizing the appropriate starting materials and modifications, the following intermediates in Table 25 were prepared. [Table 25]

[0427] Synthesis of 4-(3-fluoroazetidin-3-yl)benzonitrile [ka]

[0428] Step 1: Preparation of tert-butyl 3-(4-cyanophenyl)-3-fluoroazetidine-1-carboxylate

[0429] To a solution of tert-butyl 3-(4-bromophenyl)-3-fluoroazetidine-1-carboxylate (0.50 g, 1.5 mmol, 1.0 equiv) in DMF (10 mL) was added KFe(CN) (0.16 g, 0.38 mmol, 0.25 equiv), sodium carbonate (0.16 mg, 1.51 mmol, 1.0 equiv), and Pd(dppf)Cl (55 mg, 75.5 μmol, 0.05 equiv), and the mixture was stirred at 25 °C for 12 h to give a black mixture. The reaction mixture was filtered, and the filtrate was diluted with water (50 mL) and extracted with EtOAc (50 mL × 2). The combined organic layers were washed with saturated brine (50 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give tert-butyl 3-(4-cyanophenyl)-3-fluoroazetidine-1-carboxylate (0.35 g, 83% yield) as a white solid. LCMS: (ESI) m / z [M+H] + = 277.0

[0430] Step 2: Preparation of 4-(3-fluoroazetidin-3-yl)benzonitrile

[0431] A solution of tert-butyl 3-(4-cyanophenyl)-3-fluoroazetidine-1-carboxylate (0.25 mg, 0.90 mmol, 1.0 equiv) in DCM (1.5 mL) and TFA (0.50 mL) was stirred at 25° C. for 30 min to give a yellow solution. The reaction mixture was concentrated under reduced pressure to give 4-(3-fluoroazetidin-3-yl)benzonitrile (0.16 g, crude) as a yellow oil. LCMS: (ESI) m / z [M+H] + = 177.3

[0432] Synthesis of 2-(4-amino-[1,1'-biphenyl]-3-yl)propanamide [ka]

[0433] Step 1: Preparation of 2-(5-bromo-2-nitrophenyl)acetyl chloride

[0434] A solution of 2-(5-bromo-2-nitrophenyl)acetic acid (1.0 g, 3.8 mmol, 1 equiv) in SOCl was stirred at 80° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give 2-(5-bromo-2-nitrophenyl)acetyl chloride (1 g, crude) as a yellow oil. LCMS: (ESI) m / z (M+MeOH) + = 273.9.

[0435] Step 2: Preparation of 2-(5-bromo-2-nitrophenyl)acetamide

[0436] To a solution of 2-(5-bromo-2-nitrophenyl)acetyl chloride (1.0 g, 3.6 mmol, 1 equiv.) in THF (20 mL) at 0 °C, NH3·H2O (0.63 g, 17 mmol, 5 equiv.) was added dropwise, and the reaction mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 2-(5-bromo-2-nitrophenyl)acetamide (0.8 g, 86% yield) as a white solid. LCMS: (ESI) m / z [M+H] + = 258.9.

[0437] Step 3: Preparation of 2-(4-nitro-[1,1'-biphenyl]-3-yl)acetamide

[0438] To a solution of 2-(5-bromo-2-nitrophenyl)acetamide (0.8 g, 3.1 mmol, 1 equiv.) in dioxane (10 mL) and HO (1 mL) was added NaCO (0.65 g, 6.2 mmol, 2 equiv.) and phenylboronic acid (0.45 g, 3.7 mmol, 1.2 equiv.), followed by Pd(dppf)Cl (0.22 g, 0.31 mmol, 0.1 equiv.) under N, and the mixture was stirred at 100 °C for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 2-(4-nitro-[1,1'-biphenyl]-3-yl)acetamide (0.5 g, 63% yield) as a white solid. LCMS: (ESI) m / z [M+H] + = 257.0. Step 4: Preparation of 2-(4-nitro-[1,1'-biphenyl]-3-yl)propenamide

[0439] To a solution of 2-(4-nitro-[1,1'-biphenyl]-3-yl)acetamide (50 mg, 0.19 mmol, 1 equiv.) in dimethylformamide (10 mL) was added cesium carbonate (0.13 g, 0.38 mmol, 2 equiv.) and methyl iodide (41 mg, 0.29 mmol, 1.5 equiv.), and the mixture was stirred at 80° C. under microwave irradiation for 2 hours. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by column chromatography to give 2-(4-nitro-[1,1'-biphenyl]-3-yl)propanamide (34 mg, 64% yield) as a white solid. LCMS: (ESI) m / z [M+H] + = 271.2.

[0440] Step 5: Preparation of 2-(4-amino-[1,1'-biphenyl]-3-yl)propanamide

[0441] To a solution of 2-(4-nitro-[1,1'-biphenyl]-3-yl)propanamide (30 mg, 0.11 mmol, 1 equiv.) in ethyl alcohol (0.4 mL) and water (0.1 mL) was added ammonium chloride (18 mg, 0.33 mmol, 3 equiv.) and iron (61 mg, 1.1 mmol, 10 equiv.). The mixture was stirred at 25°C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated to give 2-(4-amino-[1,1'-biphenyl]-3-yl)propanamide (30 mg, crude) as a white solid. LCMS: (ESI) m / z [M+H] + = 241.1

[0442] Synthesis of (R)-azetidin-3-yl(3-methoxypyrrolidin-1-yl)methanone [ka]

[0443] Step 1: Preparation of benzyl (R)-3-(3-hydroxypyrrolidine-1-carbonyl)azetidine-1-carboxylate

[0444] To a solution of 1-((benzyloxy)carbonyl)azetidine-3-carboxylic acid (0.5 g, 2.1 mmol, 1 equiv) in DMF (5 mL) was added HATU (1.2 g, 3.2 mmol, 1.5 equiv), DIEA (0.82 g, 6.3 mmol, 3 equiv), and (R)-pyrrolidin-3-ol (0.18 g, 2.1 mmol, 1 equiv), and the mixture was stirred at 25° C. for 2 h to give a yellow solution. The mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL×2), and the combined organic layers were washed with saturated brine (20 mL×2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give benzyl (R)-3-(3-hydroxypyrrolidine-1-carbonyl)azetidine-1-carboxylate (0.55 g, 85% yield) as a yellow oil. 1H NMR (400 MHz, CDCl3) δ 7.44 - 7.30 (m, 5H), 5.16 - 5.02 (m, 2H), 4.59 - 4.49 (m, 1H), 4.37 - 4.06 (m, 5H), 3.74 - 3.16 (m, 6H).

[0445] Step 2: Preparation of benzyl (R)-3-(3-methoxypyrrolidine-1-carbonyl)azetidine-1-carboxylate

[0446] To a solution of benzyl (R)-3-(3-hydroxypyrrolidine-1-carbonyl)azetidine-1-carboxylate (50 mg, 0.16 mmol, 1 equiv.) in THF (1 mL) was added NaH (13 mg, 0.33 mmol, 2 equiv.) at 0° C. and stirred for 10 minutes under N2, followed by the addition of methyl iodide (47 mg, 0.33 mmol, 2 equiv.). The mixture was stirred at 25° C. for 2 hours to give a white suspension. The reaction mixture was quenched with HO (1 mL) and then concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give benzyl (R)-3-(3-methoxypyrrolidine-1-carbonyl)azetidine-1-carboxylate (22 mg, 42% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 7.44 - 7.30 (m, 5H), 5.11 (s, 2H), 4.17-8.15 (m, 2H), 4.07 - 3.92 (m, 1H), 3.79 - 3.38 (m, 6H), 3.34 (d, J = 3.2 Hz, 3H), 2.22 - 1.79 (m, 2H), 1.77 - 1.41 (m, 1H).

[0447] Step 3: Preparation of (R)-azetidin-3-yl(3-methoxypyrrolidin-1-yl)methanone

[0448] To a solution of benzyl (R)-3-(3-methoxypyrrolidine-1-carbonyl)azetidine-1-carboxylate (50 mg, 0.16 mmol, 1 equiv) in MeOH (2.5 mL) was added Pd / C (10 mg) under N. The mixture was stirred at 25 °C for 16 h under H (15 psi) to give a black suspension. The reaction mixture was filtered, and the filtrate was concentrated to give (R)-azetidin-3-yl(3-methoxypyrrolidin-1-yl)methanone (40 mg, crude) as a yellow oil.

[0449] Synthesis of (R)-1-(1H-pyrazol-4-yl)pyrrolidin-3-amine [ka]

[0450] Step 1: Preparation of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole

[0451] A solution of 4-bromo-1H-pyrazole (2.0 g, 14 mmol, 1 equiv) in THF (30 mL) was cooled to 0 °C, then sodium hydride (1.1 g, 27 mmol, 1.5 equiv) was added at 0 °C under N. The mixture was stirred at 0 °C for 30 min, then SEMCl (3.4 g, 20 mmol, 1.5 equiv) was added dropwise at 0 °C. The mixture was stirred at 25 °C for 12 h under N to give a yellow solution. The reaction mixture was quenched with HO (20 mL) at 0 °C, then diluted with water (50 mL) and extracted with EtOAc (50 mL × 2), and the combined organic layers were washed with saturated brine (50 mL × 2), dried over NaSO, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO 2 , petroleum ether / EtOAc=1:0 to 95:5) to give 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (1.2 g, 31% yield) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 7.93 (s, 1H), 7.54 (s, 1H), 5.40 (s, 2H), 3.62–3.50 (m, 2H), 0.91–0.83 (m, 2H), 0.05–0.09 (m, 9H).

[0452] Step 2: Preparation of (R)-tert-butyl (1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrrolidin-3-yl)carbamate

[0453] A solution of 4-bromo-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazole (0.50 g, 1.8 mmol, 1 equiv.), tert-butyl (R)-pyrrolidin-3-ylcarbamate (0.67 g, 3.6 mmol, 2 equiv.), and potassium tert-butoxide (0.40 g, 3.6 mmol, 2 equiv.) in ortho-xylene (10 mL) was degassed and purged with N three times, and then Pd(dba) (0.16 g, 0.18 mmol, 0.1 equiv.) and t-BuDavephos (0.12 g, 0.36 mmol, 0.2 equiv.) were added to the mixture. The mixture was stirred at 90 °C for 12 h, resulting in a black 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 (50 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 1:0 to 6:1) to give (R)-tert-butyl (1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrrolidin-3-yl)carbamate (60 mg, 8.7% yield) as a white solid. 1H NMR (400 MHz, methanol-d4) δ 7.26 - 7.13 (m, 2H), 5.38 - 5.25 (m, 2H), 4.24 - 4.14 (m, 1H), 3.57 - 3.48 (m, 2H), 3.21 (m, 1H), 3.05 (m, 1H), 2.93 - 2.89 (m, 1H), 2.33 - 2.22 (m, 1H), 1.90 - 1.79 (m, 1H), 1.48 - 1.41 (m, 9H), 1.36 - 1.27 (m, 1H), 0.92 - 0.82 (m, 2H), 0.03 -0.06 (m, 9H).

[0454] Step 3: Preparation of (R)-1-(1H-pyrazol-4-yl)pyrrolidin-3-amine

[0455] A solution of (R)-tert-butyl (1-(1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazol-4-yl)pyrrolidin-3-yl)carbamate (30 mg, 78 μmol, 1 equiv) in DCM (2 mL) and TFA (2 mL) was stirred at 25° C. for 1 h. The reaction mixture was concentrated under reduced pressure to give (R)-1-(1H-pyrazol-4-yl)pyrrolidin-3-amine (30 mg, crude) as a yellow oil. LCMS: (ESI) m / z [M+H] + = 153.0

[0456] Synthesis of (R)-3-aminopyrrolidine-1-carboxamide [ka]

[0457] Step 1: Preparation of tert-butyl (R)-(1-carbamoylpyrrolidin-3-yl)carbamate

[0458] To a solution of tert-butyl (R)-pyrrolidin-3-ylcarbamate (1.0 g, 5.4 mmol, 1.0 equiv.) in 1,4-dioxane (20 mL) was added urea (1.3 g, 16 mmol, 3.0 equiv.), and the mixture was stirred at 140° C. for 12 hours to give a yellow solution. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was washed with DCM and filtered. The filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography to give tert-butyl (R)-(1-carbamoylpyrrolidin-3-yl)carbamate (0.800 g, 66% yield) as a white solid. 1 H NMR (400 MHz, CDCl3) δ 5.06 - 4.06 (m, 4H), 3.62 (dd, J = 6.0, 10.4 Hz, 1H), 3.48 (s, 2H), 3.25 (dd, J = 3.6, 10.0 Hz, 1H), 2.28 - 2.08 (m,1H), 1.90 (dd, J = 6.4, 12.0 Hz, 1H), 1.45 (s, 9H)

[0459] Step 2: Preparation of (R)-3-aminopyrrolidine-1-carboxamide

[0460] A solution of tert-butyl (R)-(1-carbamoylpyrrolidin-3-yl)carbamate (0.8 g, 3.5 mmol, 1 equiv) in DCM (10 mL) and trifluoroacetic acid (3 mL) was stirred at 20° C. for 1 h to give a white solution. The reaction mixture was concentrated under reduced pressure to give (R)-3-aminopyrrolidine-1-carboxamide (1 g, crude) as a yellow oil. LCMS: (ESI) m / z [M+H] + = 130.1.

[0461] Synthesis of 1-(pyridin-2-yl)azetidin-3-amine [ka]

[0462] Step 1: Preparation of tert-butyl (1-(pyridin-2-yl)azetidin-3-yl)carbamate

[0463] To a solution of 2-bromopyridine (0.50 g, 3.2 mmol, 1 equiv.) and tert-butyl azetidin-3-ylcarbamate (0.54 g, 3.2 mmol, 1 equiv.) in DMF (5 mL) was added K2CO3 (1.3 g, 9.5 mmol, 3 equiv.). The mixture was stirred at 80 °C for 16 h to give an off-white suspension. The reaction mixture was quenched with water (30 mL) and extracted with 90 mL of EtOAc (30 mL × 3). The combined organic layers were washed with saturated brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: YMC Triart C18 250 × 50 mm × 7 μm; mobile phase: [water (FA)-ACN]; B%: 7% to 37%, 10 min), followed by lyophilization to give tert-butyl (1-(pyridin-2-yl)azetidin-3-yl)carbamate (0.12 g, 15% yield) as a white solid. LCMS: (ESI) m / z [M+H] + = 250.1

[0464] Step 2: Preparation of 1-(pyridin-2-yl)azetidin-3-amine

[0465] A solution of tert-butyl (1-(pyridin-2-yl)azetidin-3-yl)carbamate (0.10 g, 0.40 mmol, 1 equiv) in DCM (0.9 mL) and TFA (0.3 mL) was stirred at 25° C. for 1 h to give a pale yellow solution. The reaction mixture was concentrated under reduced pressure to give 1-(pyridin-2-yl)azetidin-3-amine (0.10 g, crude) as a yellow oil. LCMS: (ESI) m / z [M+H] + = 150.2

[0466] SFC method: [ka]

[0467] After chiral SFC separation (column designation: Cellulose 4, 15% methanol (0.1% DEA), flow rate: 4 mL / min, injection volume: 14 μL, outlet pressure: 100 bar), (3R,4'R)-2-oxospiro[indoline-3,3'-pyrrolidine]-4'-carbonitrile (fastest eluting enantiomer) and (3S,4'S)-2-oxospiro[indoline-3,3'-pyrrolidine]-4'-carbonitrile (slowest eluting enantiomer) were isolated. The relative stereochemistry of the oxospiro[indoline-3,3'-pyrrolidine] system is as depicted, but the absolute stereochemistry is unknown.

[0468] Representative Procedures for General Schemes

[0469] Representative Procedure: General Scheme 1 (Phosphonate Acids):

[0470] Synthesis of (difluoro(2-(((3S,6S,7aS,8aR,9aR)-3-(3-((R)-2-methylmorpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (Example 1) [ka]

[0471] Step 1: Preparation of tert-butyl ((3S,6S,7aS,8aR,9aR)-3-(3-((R)-2-methylmorpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamate

[0472] To a solution of (3S,6S,7aS,8aR,9aR)-6-((tert-butoxycarbonyl)amino)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylic acid (50 mg, 147 μmol, 1.0 equiv.), HATU (66.8 mg, 176 μmol, 1.2 equiv.), and triethylamine (44.6 mg, 441 μmol, 3.0 equiv.) in DMF (2 mL) was added (R)-azetidin-3-yl(2-methylmorpholino)methanone (29.6 mg, 161 μmol, 1.1 equiv.), and the resulting mixture was stirred at 20 °C overnight under N. Upon completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give tert-butyl ((3S,6S,7aS,8aR,9aR)-3-(3-((R)-2-methylmorpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamate (70.0 mg, 138 μmol, 94%) as a white solid. LCMS (ESI): m / z = 505.4 [M+H] + .

[0473] Step 2: Preparation of (5S,8S,10aR)-3-acetyl-5-amino-8-(6-phenyl-4-azaspiro[2.4]heptane-4-carbonyl)octahydropyrrolo[1,2-a][1,5]diazocin-6(1H)-one

[0474] A solution of tert-butyl ((3S,6S,7aS,8aR,9aR)-3-(3-((R)-2-methylmorpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamate (80 mg, 158 μmol, 1.0 equiv) in DCM (6 mL) and TFA (2 mL) was stirred at 25 °C overnight under N. After completion, the reaction mixture was concentrated to give crude (5S,8S,10aR)-3-acetyl-5-amino-8-(6-phenyl-4-azaspiro[2.4]heptane-4-carbonyl)octahydropyrrolo[1,2-a][1,5]diazocin-6(1H)-one (63.0 mg, quantitative) as a white solid, which was used directly in the next step without further purification. LCMS (ESI): m / z = 405.4 [M+H] + .

[0475] Step 3: Preparation of (difluoro(2-(((3S,6S,7aS,8aR,9aR)-3-(3-((R)-2-methylmorpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid

[0476] A solution of (5S,8S,10aR)-3-acetyl-5-amino-8-(6-phenyl-4-azaspiro[2.4]heptane-4-carbonyl)octahydropyrrolo[1,2-a][1,5]diazocin-6(1H)-one (7, 60 mg, 148 μmol, 1.0 equiv.), triethylamine (44.8 mg, 443 μmol, 3.0 equiv.), DMAP (9.03 mg, 74.0 μmol, 0.5 equiv.), and (difluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (83.9 mg, 177 μmol, 1.2 equiv.) in DMF (2 mL) was stirred at 30 °C overnight under N. After completion, the reaction mixture was filtered and concentrated under reduced pressure. The residue was purified by Biotage® C18 column chromatography to give (difluoro(2-(((3S,6S,7aS,8aR,9aR)-3-(3-((R)-2-methylmorpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (80.0 mg, 115 μmol, 78%) as a white solid. LCMS (ESI): m / z = 695.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 9.00-8.84 (m, 1H), 8.34 (s, 1H), 8.13 (d, J = 8.5 Hz, 1H), 8.08 (s, 1H), 7.58 (d, J = 8.6 Hz, 1H), 5.00-4.86 (m, 1H), 4.68-4.46 (m, 1H), 4.40-4.25 (m, 2H), 4.22-4.09 (m, 2H), 4.05-3.85 (m, 2H), 3.81-3.63 (m, 2H), 3.48-3.27 (m, 3H), 3.11-2.98 (m, 1H), 2.78-2.62 (m, 1H), 2.39-2.28 (m, 1H), 2.18-1.96 (m, 4H), 1.91-1.75 (m, 2H), 1.70-1.55 (m, 1H), 1.42-1.27 (m, 1H), 1.12-1.01 (m, 3H), 0.84-0.66 (m, 2H), 0.03-0.04 (m, 1H).

[0477] Representative Procedure: General Scheme 2: (Phosphonate Ester or Amide)

[0478] Synthesis of isopropyl ((difluoro(2-(((3S,6S,7aS,8aR,9aR)-3-(3-(morpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)(phenoxy)phosphoryl)glycinate (Example 2) [ka]

[0479] To a solution of (3S,6S,7aS,8aR,9aR)-6-amino-3-(3-(morpholine-4-carbonyl)azetidine-1-carbonyl)decahydro-5H-cyclopropa[d]pyrrolo[1,2-a]azocin-5-one (50 mg, 99.1 μmol, 1 equiv.), DIPEA (99.2 mg, 768 μmol, 7.75 equiv.), and 5-(difluoro(((2-isopropoxy-2-oxoethyl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (73.9 mg, 153 μmol, 1.54 equiv.) in DMF (3 mL) was added HATU (63.1 mg, 166 μmol, 1.67 equiv.). The reaction was stirred at room temperature for 1 h. The reaction mixture was directly purified by reverse phase chromatography on a 50 g C18 cartridge eluting with 5-100% MeCN in water to give isopropyl ((difluoro(2-(((3S,6S,7aS,8aR,9aR)-3-(3-(morpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)(phenoxy)phosphoryl)glycinate (88.2 mg, 103 μmol, 104%) as a white solid. LCMS: (ESI) m / z = 856.1 [M+H] + ; 1H NMR (400 MHz, CD3OD) δ 8.23 ​​- 8.12 (m, 2H), 8.07 - 7.98 (m, 1H), 7.75 - 7.69 (m, 1H), 7.36 - 7.29 (m, 2H), 7.23 - 7.15 (m, 3H), 5.07 - 4.92 (m, 2H), 4.73 - 4.70 (m, 1H), 4.54 - 4.37 (m, 2H), 4.33 - 4.16 (m, 2H), 4.11 - 4.02 (m, 1H), 3.82 - 3.71 (m, 1H), 3.71 - 3.44 (m, 8H), 3.38 - 3.34 (m, 1H), 3.30 - 3.20 (m, 1H), 2.50 - 2.38 (m, 1H), 2.35 - 2.06 (m, 4H), 2.04 - 1.92 (m, 2H), 1.78 - 1.67 (m, 1H), 1.45 - 1.36 (m, 1H), 1.20 - 1.16 (m, 6H), 0.98 - 0.89 (m, 1H), 0.88 - 0.79 (m, 1H), 0.10 - 0.02 (m, 1H).

[0480] Representative Procedure: General Scheme 3 (Phosphonate Acids):

[0481] Synthesis of ((2-(((3S,6S,7aS,8aR,9aR)-3-([1,1′-biphenyl]-4-ylcarbamoyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid (Example 3) [ka]

[0482] Step 1: Preparation of methyl (3S,6S,7aR,8aS,9aR)-6-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylate

[0483] To a solution of 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (29 mg, 0.79 mmol, 1 equiv.) in DMF (1 mL) was added HATU (45 mg, 1.2 mmol, 1.5 equiv.), followed by a solution of methyl (3S,6S,7aR,8aS,9aR)-6-amino-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylate (20 mg, 0.79 mmol, 1.2 equiv.) and DIEA (41 mg, 3.2 mmol, 4 equiv.) in DMF (1 mL), and the mixture was stirred at 25° C. for 1 h. The reaction mixture was quenched with water (10 mL) and extracted with EtOAc (10 mL × 3). The combined organic layers were washed with saturated brine (10 mL × 3), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, petroleum ether / EtOAc = 1:1 to 15:85) to give methyl (3S,6S,7aR,8aS,9aR)-6-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylate (15 mg, 41% yield) as a yellow solid. LCMS: m / z [M+H] + = 599.4.

[0484] Step 2: Preparation of (3S,6S,7aR,8aS,9aR)-6-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylic acid

[0485] To a solution of methyl (3S,6S,7aR,8aS,9aR)-6-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylate (15 mg, 0.25 mmol, 1 equiv) in ACN (0.9 mL) and 2 N HCl (0.3 mL) was added this mixture and stirred at 70° C. for 5 h. The reaction mixture was filtered, and the filter residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 × 25 mm × 10 μm, mobile phase: water (0.1% TFA)-ACN; B%: 28% to 58%, 10 min), followed by lyophilization to give (3S,6S,7aR,8aS,9aR)-6-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylic acid (4 mg, 43% yield) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 8.11 (s, 1H), 7.95 (m, 2H), 7.85 (d, J = 5.6 Hz, 1H), 7.66 (d, J = 8.4 Hz, 1H), 4.96 (d, J = 5.2 Hz, 1H), 4.56 - 4.45 (m, 1H), 4.32 - 4.10 (m, 5H), 2.39 - 2.27 (m, 2H), 2.24 - 2.12 (m, 2H), 2.10 - 2.00 (m, 1H), 1.99 - 1.88 (m, 1H), 1.82 - 1.72 (m, 1H), 1.72 - 1.64 (m, 2H), 1.37 - 1.29 (m, 6H), 1.27 - 1.18 (m, 1H), 0.87 - 0.75 (m, 1H), 0.10 (d, J = 4.8 Hz, 1H).

[0486] Step 3: Preparation of diethyl ((2-(((3S,6S,7aR,8aS,9aR)-3-([1,1'-biphenyl]-4-ylcarbamoyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonate

[0487] To a solution of (3S,6S,7aR,8aS,9aR)-6-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylic acid (4 mg, 6.8 μmol, 1 equiv.) in DMF (0.3 mL) was added HATU (3.8 mg, 10 μmol, 1.5 equiv.), followed by a solution of [1,1′-biphenyl]-4-amine (1.4 mg, 8.2 μmol, 1.2 equiv.) in DMF (0.3 mL) and DIEA (4.0 mg, 0.33 mmol, 4 equiv.), and the mixture was stirred at 25° C. for 1 h. This mixture was directly purified by column chromatography (SiO, petroleum ether / EtOAc = 10:1 to 3:1) to give diethyl ((2-(((3S,6S,7aR,8aS,9aR)-3-([1,1'-biphenyl]-4-ylcarbamoyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonate (12 mg, crude) as a yellow oil. LCMS: m / z [M+H] + =736.2

[0488] Step 4: Preparation of ((2-(((3S,6S,7aR,8aS,9aR)-3-([1,1'-biphenyl]-4-ylcarbamoyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid

[0489] To a solution of diethyl ((2-(((3S,6S,7aR,8aS,9aR)-3-([1,1'-biphenyl]-4-ylcarbamoyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonate (12 mg, 0.16 mmol, 1 equiv) in DCM (0.5 mL) was added BSTFA (25 mg, 0.96 mmol, 6 equiv), and TMSI (13 mg, 0.64 mmol, 4 equiv) in DCM (0.5 ml) was added dropwise at 0° C., and the mixture was stirred at 0° C. for 15 minutes. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 x 25 mm x 10 μm, mobile phase: water (0.1% TFA)-ACN; B%: 40% to 70%, 10 min), followed by lyophilization to give ((2-(((3S,6S,7aR,8aS,9aR)-3-([1,1'-biphenyl]-4-ylcarbamoyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid (1.22 mg, 9.45% yield) as a white solid. LCMS: (ESI) m / z [M+H] + = 680; 1H NMR (400 MHz, CD3OD) δ 8.18 - 8.08 (m, 2H), 7.98 (d, J = 8.4 Hz, 1H), 7.69 (d, J = 8.4 Hz, 1H), 7.66 - 7.61 (m, 2H), 7.61 - 7.54 (m, 4H), 7.41 (t, J = 7.6 Hz, 2H), 7.33 - 7.26 (m, 1H), 5.00 (d, J = 4.4 Hz, 1H), 4.55 (t, J = 8.4 Hz, 1H), 4.37 (t, J = 7.6 Hz, 1H), 2.42 - 2.31 (m, 2H), 2.27 - 2.14 (m, 2H), 2.12 - 2.04 (m, 1H), 2.03 - 1.96 (m, 2H), 1.89 - 1.76 (m, 1H), 1.54 - 1.41 (m, 1H), 1.38 - 1.23 (m, 3H), 0.92 - 0.84 (m, 1H), 0.29 - 0.22 (m, 1H)

[0490] Specific analogue synthesis

[0491] Synthesis of (((difluoro(2-(((3S,6S,7aS,8aR,9aR)-3-(3-(morpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphoryl)bis(oxy))bis(methylene)dipentanoate (Example 4) [ka]

[0492] Step 1: Preparation of chloromethyl butyrate

[0493] To a solution of pentanoic acid (1, 1 g, 9.79 mmol, 1.0 equiv.), tetrabutylammonium hydrogen sulfate (332 mg, 979 μmol, 0.1 equiv.), and chloromethyl sulfuric acid (1.76 g, 10.7 mmol, 1.1 equiv.) in DCM (10 mL) at 0 °C, a solution of NaHCO (1.63 g, 19.5 mmol, 2.0 equiv.) in water (10 mL) was added dropwise. The reaction was then warmed to room temperature and stirred overnight under N. Upon completion, the reaction mixture was extracted with dichloromethane (20 mL × 3). The organic layers were combined, dried over anhydrous NaSO, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to give chloromethyl butyrate (1.40 g, 9.29 mmol, 95% yield) as a clear oil. 1 H NMR (400 MHz, CDCl3) δ 5.71 (s, 2H), 2.39 (t, J = 7.5 Hz, 2H), 1.69-1.60 (m, 2H), 1.41-1.33 (m, 2H), 0.93 (t, J = 7.4 Hz, 3H).

[0494] Step 2: Preparation of iodomethyl pentanoate

[0495] A solution of chloromethyl butyrate (400 mg, 2.65 mmol, 1.0 equiv) and NaI (794 mg, 5.30 mmol, 2.0 equiv) in MeCN (10 mL) was stirred at 40 °C overnight under N. After completion, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel to afford iodomethyl pentanoate (3, 100 mg, 413 μmol, 16%) as a yellow oil. 1 H NMR (400 MHz, CDCl3) δ 5.91 (s, 2H), 2.34 (t, J = 7.5 Hz, 2H), 1.68-1.58 (m, 2H), 1.41-1.31 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H).

[0496] Step 3: Preparation of (((difluoro(2-(((3S,6S,7aS,8aR,9aR)-3-(3-(morpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphoryl)bis(oxy))bis(methylene)dipentanoate

[0497] A solution of NaOH (7.03 mg, 176 μmol, 2.0 equiv.) in water (2 mL) was added dropwise to a stirred suspension of (difluoro(2-(((3S,6S,7aS,8aR,9aR)-3-(3-(morpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (60 mg, 88.1 μmol, 1.0 equiv.) in HO (6 mL). When the mixture became clear (pH ∼9), AgNO (32.7 mg, 193 μmol, 2.2 equiv.) was added. After stirring at 0 °C for 2 h, the gray precipitate was collected by filtration and dried under vacuum. This powder was suspended in anhydrous toluene (1 mL), and iodomethyl pentanoate (3, 63.9 g, 264 μmol, 3.0 equiv.) was added. The mixture was stirred at room temperature for 24 hours. After filtration, the solvent was removed in vacuo. The crude residue was directly purified by flash chromatography on silica gel to give (((difluoro(2-(((3S,6S,7aS,8aR,9aR)-3-(3-(morpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphoryl)bis(oxy))bis(methylene)dipentanoate (ST-214-2, 2.00 mg, 2.20 μmol, 3% yield) as a white solid. LCMS (ESI): m / z = 909.3 [M+H] + ; 1H NMR (400 MHz, DMSO-d6) δ 8.99 (dd, J = 22.8, 7.5 Hz, 1H), 8.39-8.00 (m, 3H), 7.55 (d, J = 8.6 Hz, 1H), 5.86-5.36 (m, 4H), 4.99-4.89 (m, 1H), 4.68-4.50 (m, 1H), 4.37-4.24 (m, 2H), 4.20-4.11 (m, 1H), 4.05-3.85 (m, 2H), 3.75-3.64 (m, 1H), 3.56-3.50 (m, 4H), 3.48-3.44 (m, 2H), 3.28-3.23 (m, 2H), 2.34-2.24 (m, 4H), 2.17-1.94 (m, 4H), 1.90-1.75 (m, 2H), 1.68-1.57 (m, 1H), 1.54-1.40 (m, 4H), 1.36-1.19 (m, 6H), 0.89-0.67 (m, 8H), 0.01--0.02 (m, 1H).

[0498] Isopropyl ((R)-((2-(((3S,6S,7aS,8aR,9aR)-3-(3-(morpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)(phenoxy)phosphoryl)-L-alaninate and isopropyl Preparation of ((S)-((2-(((3S,6S,7aS,8aR,9aR)-3-(3-(morpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)(phenoxy)phosphoryl)-L-alaninate (Examples 5 and 6) [ka]

[0499] Preparative separation method: Instrument: Waters Thar 80 Preparative SFC; Column: ChiralPak IB, 250 x 21.2 mm ID, 5 μm; Mobile phase: A is CO2, B is MeOH + 0.1% NH3H2O; Gradient: B 35%; Flow rate: 40 mL / min; Back pressure: 100 bar; Column temperature: 35 °C, Wavelength: 220 nm, Cycle time: 4 min

[0500] Isopropyl (((2-(((3S,6S,7aS,8aR,9aR)-3-(3-(morpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)(phenoxy)phosphoryl)-L-alaninate (60 mg, 71.9 μmol, 1.0 equiv) was purified by preparative SFC to give:

[0501] Peak 1: isopropyl ((R)-((2-(((3S,6S,7aS,8aR,9aR)-3-(3-(morpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)(phenoxy)phosphoryl)-L-alaninate as a white solid ,8aR,9aR)-3-(3-(morpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)(phenoxy)phosphoryl)-L-alaninate (20.0 mg, 24.0 μmol, 99.9% ee, 33% yield), Peak 1 data (Example 5), P-chirality arbitrarily assigned LCMS (ESI): m / z = 834.4 [M+H] + ; 1H NMR (400 MHz, CDCl3) δ 7.89-7.73 (m, 3H), 7.49-7.42 (m, 1H), 7.37-7.27 (m, 3H), 7.16-7.08 (m, 3H), 5.10-5.01 (m, 1H), 4.99-4.73 (m, 2H), 4.58-4.50 (m, 1H), 4.48-4.39 (m, 1H), 4.35-4.26 (m, 1H), 4.22-4.05 (m, 2H), 4.00-3.91 (m, 1H), 3.74-3.53 (m, 7H), 3.45 (d, J = 20.8 Hz, 2H), 3.33-3.23 (m, 2H), 3.18-3.08 (m, 1H), 2.37-2.24 (m, 3H), 2.16-1.97 (m, 4H), 1.67-1.61 (m, 1H), 1.50-1.38 (m, 1H), 1.21-1.16 (m, 6H), 1.12 (d, J = 7.1 Hz, 3H), 1.01-0.91 (m, 1H), 0.86-0.77 (m, 1H), 0.06-0.00 (m, 1H) and Peak 2: isopropyl ((S)-((2-(((3S,6S,7aS,8aR,9aR)-3-(3-(morpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)(phenoxy)phosphoryl)-L-alaninate or isopropyl as a white solid ((R)-((2-(((3S,6S,7aS,8aR,9aR)-3-(3-(morpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)(phenoxy)phosphoryl)-L-alaninate (30.0 mg, 36.0 μmol, 99.7% ee, 50% yield). LCMS (ESI): m / z = 834.4 [M+H] + Peak 2 data (Example 6), P-chirality arbitrarily assigned: 1H NMR (400 MHz, CDCl3) δ 7.86-7.69 (m, 3H), 7.55-7.33 (m, 2H), 7.32-7.27 (m, 2H), 7.19-7.06 (m, 3H), 5.11-5.00 (m, 1H), 4.95-4.72 (m, 2H), 4.58-4.48 (m, 1H), 4.46-4.37 (m, 1H), 4.35-4.26 (m, 1H), 4.22-4.05 (m, 2H), 3.98-3.87 (m, 1H), 3.74-3.51 (m, 7H), 3.46-3.20 (m, 5H), 2.37-2.23 (m, 3H), 2.15-1.96 (m, 4H), 1.72-1.62 (m, 1H), 1.50-1.39 (m, 1H), 1.21-1.08 (m, 9H), 1.00-0.89 (m, 1H), 0.86-0.76 (m, 1H), 0.04-0.00 (m, 1H).

[0502] Synthesis of (difluoro(2-(((3S,6S,7aS,8aR,9aR)-5-oxo-3-(4-((R)-tetrahydrofuran-3-carbonyl)piperazine-1-carbonyl)decahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (Example 7) [ka]

[0503] Step 1: Preparation of tert-butyl 4-((3S,6S,7aS,8aR,9aR)-6-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carbonyl)piperazine-1-carboxylate

[0504] To a solution of (3S,6S,7aS,8aR,9aR)-6-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylic acid (0.4 g, 0.68 mmol, 1.0 equiv.) in DCM (1 mL) was added tert-butyl piperazine-1-carboxylate (0.13 g, 0.68 mmol, 1.0 equiv.), T3P (0.46 g, 1.0 mmol, 1.5 equiv., 50% purity), and DIEA (0.13 g, 1.0 mmol, 1.5 equiv.). The mixture was stirred at 20° C. for 16 h to give a yellow cloudy solution. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give tert-butyl 4-((3S,6S,7aS,8aR,9aR)-6-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carbonyl)piperazine-1-carboxylate (0.43 g, 83% yield) as a white solid. LCMS: (ESI) m / z [M-Boc] + = 653.2

[0505] Step 2: Preparation of diethyl (difluoro(2-(((3S,6S,7aS,8aR,9aR)-5-oxo-3-(piperazine-1-carbonyl)decahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphonate

[0506] To a solution of tert-butyl 4-((3S,6S,7aS,8aR,9aR)-6-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carbonyl)piperazine-1-carboxylate (0.43 g, 0.56 mmol, 1.0 equiv) in DCM (3.0 mL) was added TFA (1.0 mL). The resulting mixture was stirred at 25° C. for 1 h to give a yellow solution. The reaction mixture was concentrated under reduced pressure to give diethyl (difluoro(2-(((3S,6S,7aS,8aR,9aR)-5-oxo-3-(piperazine-1-carbonyl)decahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphonate (0.43 g, crude) as a yellow oil.

[0507] Step 3: Preparation of diethyl (difluoro(2-(((3S,6S,7aS,8aR,9aR)-5-oxo-3-(4-((R)-tetrahydrofuran-3-carbonyl)piperazine-1-carbonyl)decahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphonate

[0508] To a solution of diethyl (difluoro(2-(((3S,6S,7aS,8aR,9aR)-5-oxo-3-(piperazine-1-carbonyl)decahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphonate (50 mg, 77 μmol, 1.0 equiv) in DMF (1.0 mL) was added DIEA (30 mg, 0.23 mmol, 3.0 equiv) and the reaction was stirred at 20° C. for 30 min to give a colorless solution. To a separate solution of (3R)-oxolane-3-carboxylic acid (8.9 mg, 77 μmol, 1.0 equiv) in DMF (1.0 mL) was added DIEA (30 mg, 0.23 mmol, 3.0 equiv) and HATU (43 mg, 0.1 mmol, 1.5 equiv) and stirred at 20° C. for 30 min to give a black solution. The two mixtures were combined and stirred at 20° C. for 1 h to give a solution. The mixture was quenched with water (10 mL), extracted with EtOAc (10 mL x 2), and the combined organic layers were washed with saturated brine (10 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to give diethyl (difluoro(2-(((3S,6S,7aS,8aR,9aR)-5-oxo-3-(4-((R)-tetrahydrofuran-3-carbonyl)piperazine-1-carbonyl)decahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphonate (50 mg, crude) as a yellow oil. LCMS: (ESI) m / z [M+H] + = 751.3

[0509] Step 4: Preparation of (difluoro(2-(((3S,6S,7aS,8aR,9aR)-5-oxo-3-(4-((R)-tetrahydrofuran-3-carbonyl)piperazine-1-carbonyl)decahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid

[0510] To a solution of diethyl (difluoro(2-(((3S,6S,7aS,8aR,9aR)-5-oxo-3-(4-((R)-tetrahydrofuran-3-carbonyl)piperazine-1-carbonyl)decahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphonate (50 mg, 0.07 mmol, 1.0 equiv) in DCM (1.0 mL) was added BSTFA (0.1 g, 0.4 mmol, 6.0 equiv) at 0° C., followed by the dropwise addition of trimethylsilyl iodide (54 mg, 0.27 mmol, 4.0 equiv) and stirring at 0° C. for 0.5 h to give a yellow mixture. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (neutral; (Column: Waters Xbridge 150 × 25 mm 10 μm, Mobile phase: water (10 mM NH4HCO3)-ACN; B%: 5% to 35%, 10 min) followed by lyophilization to give (difluoro(2-(((3S,6S,7aS,8aR,9aR)-5-oxo-3-(4-((R)-tetrahydrofuran-3-carbonyl)piperazine-1-carbonyl)decahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (1.2 mg, 2.6% yield) as a white solid. LCMS: (ESI) m / z [M+H] + = 695.2; 1H NMR (400 MHz, CD3OD) δ 8.17 (s, 1H), 8.11 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.4 Hz, 1H), 5.09 - 5.01 (m, 1H), 5.00 - 4.95 (m, 1H), 4.31 (d, J = 6.4 Hz, 1H), 3.95 (s, 1H), 3.91 - 3.65 (m, 8H), 3.64 - 3.51 (m, 2H), 3.50 - 3.40 (m, 2H), 2.53 - 2.42 (m, 1H), 2.33 (dd, J = 2.0, 14.4 Hz, 1H), 2.19 (s, 5H),2.05 - 1.87 (m, 2H), 1.85 - 1.68 (m, 1H), 1.45 (s, 1H), 1.02 (d, J = 8.8 Hz, 1H), 0.91 - 0.79 (m, 1H), 0.08 (d, J = 5.2Hz, 1H)

[0511] 2. Following the procedure described above for (difluoro(2-(((3S,6S,7aS,8aR,9aR)-5-oxo-3-(4-((R)-tetrahydrofuran-3-carbonyl)piperazine-1-carbonyl)decahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid, appropriate starting Materials were used to prepare (difluoro(2-(((3S,6S,7aS,8aR,9aR)-5-oxo-3-(4-((S)-tetrahydrofuran-3-carbonyl)piperazine-1-carbonyl)decahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (Example 8): [ka]

[0512] (difluoro(2-(((3S,6S,7aS,8aR,9aR)-5-oxo-3-(4-((S)-tetrahydrofuran-3-carbonyl)piperazine-1-carbonyl)decahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid: 1 H NMR (400 MHz, CD3OD) δ 8.27 - 8.07 (m, 2H), 7.93 (d, J = 8.4 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 5.13 - 4.94 (m, 2H), 4.36 - 4.19 (m, 1H), 4.04 - 3.38 (m, 13H), 2.56 - 2.42 (m, 1H), 2.38 - 2.29 (m, 1H), 2.24 - 1.88 (m, 7H), 1.78-1.75 (m, 1H), 1.51 - 1.36 (m, 1H), 1.08 - 0.97 (m, 1H), 1.11-0.87 (m, 1H), 0.12-0.08 (m, 1H).

[0513] Synthesis of ((2-(((3S,6S,7aS,8aR,9aR)-3-(((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)carbamoyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid (Example 9) [ka]

[0514] Step 1: Preparation of tert-butyl (3S,4S)-3-((3S,6S,7aS,8aR,9aR)-6-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxamido)-4-hydroxypyrrolidine-1-carboxylate

[0515] To a solution of (3S,6S,7aS,8aR,9aR)-6-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxylic acid (0.1 g, 0.17 mmol, 1 equiv.) in DCM (5 mL) was added CMPI (44 mg, 0.34 mmol, 2 equiv.) and TEA (52 mg, 0.51 mmol, 3 equiv.), and the mixture was stirred at 20 °C for 1 h to give a yellow solution. The solution was quenched with water (10 mL) and extracted with EtOAc (10 mL × 2), and the combined organic layers were washed with saturated brine (10 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 tert-butyl (3S,4S)-3-((3S,6S,7aS,8aR,9aR)-6-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxamido)-4-hydroxypyrrolidine-1-carboxylate (90 mg, 79% yield) as a yellow solid. LCMS: (ESI) m / z [M+H] + = 769.2

[0516] Step 2: Preparation of diethyl (difluoro(2-(((3S,6S,7aS,8aR,9aR)-3-(((3S,4S)-4-hydroxypyrrolidin-3-yl)carbamoyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphonate

[0517] A solution of tert-butyl (3S,4S)-3-((3S,6S,7aS,8aR,9aR)-6-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocine-3-carboxamido)-4-hydroxypyrrolidine-1-carboxylate (90 mg, 0.12 mmol, 1 equiv) in DCM (3 mL) and TFA (0.6 mL) was stirred at 20° C. for 1 h to give a yellow solution. The mixture was concentrated in vacuo to give diethyl (difluoro(2-(((3S,6S,7aS,8aR,9aR)-3-(((3S,4S)-4-hydroxypyrrolidin-3-yl)carbamoyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphonate (90 mg, crude) as a brown oil. LCMS: (ESI) m / z [M+H] + = 669.2

[0518] Step 3: Preparation of diethyl ((2-(((3S,6S,7aS,8aR,9aR)-3-(((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)carbamoyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonate

[0519] A solution of diethyl (difluoro(2-(((3S,6S,7aS,8aR,9aR)-3-(((3S,4S)-4-hydroxypyrrolidin-3-yl)carbamoyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphonate (90 mg, 0.12 mmol, 1 equiv) in DCM (5 mL) and triethylamine (24 mg, 0.24 mmol, 2 equiv) was stirred at 20° C. for 10 min, then AcO (15 mg, 0.14 mmol, 1.2 equiv) was added dropwise at 0° C. and the mixture was stirred at 20° C. for 2 h to give a yellow solution. The mixture was concentrated in vacuo to give a yellow solid. The solid was purified by flash silica gel chromatography to give diethyl ((2-(((3S,6S,7aS,8aR,9aR)-3-(((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)carbamoyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonate (47 mg, 55% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl3) δ 8.10 (s, 1H), 7.98 - 7.89 (m, 2H), 7.71 (d, J = 3.2 Hz, 1H), 7.63 (d, J = 8.4 Hz, 1H), 5.18 - 5.06 (m, 1H), 4.72 - 4.57 (m, 1H), 4.32 - 4.14 (m, 6H), 3.81 (d, J = 5.6 Hz, 1H), 3.72 (q, J = 7.2 Hz, 3H), 3.08 - 3.06 (m, 1H), 3.14 (dd, J = 4.4, 7.2 Hz, 1H), 2.41 - 2.18 (m, 4H), 2.09 - 2.05 (m, 2H), 1.95 (s, 3H), 1.61 (dd, J = 3.6, 7.6 Hz, 1H), 1.34 - 1.30 (m, 6H), 0.86 - 0.71 (m, 2H), 0.07 (dd, J = 4.0, 7.6 Hz, 1H)

[0520] Step 4: Preparation of ((2-(((3S,6S,7aS,8aR,9aR)-3-(((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)carbamoyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid

[0521] To a solution of diethyl ((2-(((3S,6S,7aS,8aR,9aR)-3-(((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)carbamoyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonate (47 mg, 86 μmol, 1 equiv) in DCM (3 mL) at 0° C., BSTFA (89 mg, 0.34 mmol, 4 equiv) and trimethylsilyl iodide (69 mg, 0.34 mmol, 4 equiv) were added dropwise, and the reaction mixture was stirred at 0° C. for 1 h to give a yellow suspension. The mixture was concentrated in vacuo to give a brown solid. The solid was purified by preparative HPLC (column: Phenomenex Luna C18 100 × 30 mm × 5 μm, conditions: water (10 mM NH4HCO3)-ACN, flow rate (ml / min): 25 min), followed by lyophilization to give ((2-(((3S,6S,7aS,8aR,9aR)-3-(((3S,4S)-1-acetyl-4-hydroxypyrrolidin-3-yl)carbamoyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid (11 mg, 20% yield) as a yellow solid. LCMS: (ESI) m / z [M+H] + = 655.1; 1H NMR (400 MHz, CD3OD) δ 8.19 (s, 1H), 8.13 (s, 1H), 7.93 (d, J = 8.4 Hz, 1H), 7.74 (d, J = 8.4 Hz, 1H), 5.03 (t, J = 9.2 Hz, 1H), 4.61 - 4.50 (m,1H), 4.31 - 4.25 (m, 1H), 4.19 - 4.05 (m, 2H), 3.89 - 3.53 (m, 2H), 3.49 - 3.36 (m, 2H), 2.54 - 2.40 (m, 1H), 2.34 - 2.25 (m, 1H), 2.23 - 2.09 (m, 3H), 2.05 (d, J =10.4 Hz, 4H), 2.01 - 1.92 (m, 1H), 1.81 - 1.62 (m, 1H), 1.25 - 0.99 (m, 1H), 0.93 - 0.81 (m, 2H), 0.10 (dd, J = 3.2, 5.4 Hz, 1H)

[0522] Phosphonate Acid Data Table

[0523] Prepared according to general scheme 1: phosphonate acids

[0524] Following the representative procedure described above for the synthesis of (difluoro(2-(((3S,6S,7aS,8aR,9aR)-3-(3-((R)-2-methylmorpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (Example 1), utilizing the appropriate starting materials and modifications, the following compounds in Table 26 were prepared.

[0525] [Table 26-1] [Table 26-2]

Table 26-3

Table 26-4

Table 26-5

Table 26-6

Table 26-7

Table 26-8

Table 26-9

Table 26-10

Table 26-11

Table 26-12

Table 26-13

Table 26-14

Table 26-15

Table 26-16

Table 26-17

Table 26-18

Table 26-19

Table 26-20

Table 26-21

Table 26-22

Table 26-23

Table 26-24

Table 26-25

Table 26-26

Table 26-27

Table 26-28

Table 26-29

Table 26-30

Table 26-31

Table 26-32

Table 26-33

Table 26-34

Table 26-35

Table 26-36

Table 26-37

Table 26-38

Table 26-39

Table 26-40

Table 26-41

Table 26-42

Table 26-43

Table 26-44

[0526] Prepared according to general scheme 2: phosphonate acids

[0527] Following the representative procedure described above for the synthesis of ((2-(((3S,6S,7aS,8aR,9aR)-3-([1,1′-biphenyl]-4-ylcarbamoyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid (Example 3), utilizing the appropriate starting materials and modifications, the following compounds in Table 27 were prepared. [Table 27-1] [Table 27-2] [Table 27-3]

Table 27-4

Table 27-5

Table 27-6

Table 27-7

Table 27-8

Table 27-9

Table 27-10

Table 27-11

Table 27-12

Table 27-13

Table 27-14

Table 27-15

Table 27-16

Table 27-17

[0528] Phosphonate Esters and Amides Data Table:

[0529] General Scheme 1: Phosphonate Ester or Amide

[0530] Following the representative procedure described above for the synthesis of isopropyl ((difluoro(2-(((3S,6S,7aS,8aR,9aR)-3-(3-(morpholine-4-carbonyl)azetidine-1-carbonyl)-5-oxodecahydro-1H-cyclopropa[d]pyrrolo[1,2-a]azocin-6-yl)carbamoyl)benzo[b]thiophen-5-yl)methyl)(phenoxy)phosphoryl)glycinate (Example 2), utilizing the appropriate starting materials and modifications, the following compounds in Table 28 were prepared. [Table 28-1] [Table 28-2] [Table 28-3] [Table 28-4] [Table 28-5] [Table 28-6]

Table 28-7

Table 28-8

Table 28-9

Table 28-10

Table 28-11

Table 28-12

Table 28-13

Table 28-14

Table 28-15

Table 28-16

Table 28-17

Table 28-18

Table 28-19

Table 28-20

Table 28-21

Table 28-22

Table 28-23

Table 28-24

Table 28-25

Table 28-26

Table 28-27

Table 28-28

Table 28-29

Table 28-30

Table 28-31

Table 28-32

Table 28-33

Table 28-34

Table 28-35

Table 28-36

Table 28-37

Table 28-38

Table 28-39

Table 28-40

Table 28-41

Table 28-42

Table 28-43

Table 28-44

Table 28-45

Table 28-46

Table 28-47

Table 28-48

Table 28-49

Table 28-50

Table 28-51

Table 28-52

Table 28-53

Table 28-54

Table 28-55

Table 28-56

Table 28-57

Table 28-58

Table 28-59

Table 28-60

Table 28-61

Table 28-62

Table 28-63

Table 28-64

Table 28-65

Table 28-66

Table 28-67

Table 28-68

Table 28-69

Table 28-70

Table 28-71

Table 28-72

Table 28-73

Table 28-74

[0531] Step 1: (3S,6S,10aR)-6-((tert-butoxycarbonyl)amino)-9-methyl-5-oxo-1,2,3,5,6,7,8,10a-octahydropyrrolo[1,2-a]azocine-3-carboxylic acid [ka]

[0532] To a solution of (3S,6S,10aR)-methyl 6-((tert-butoxycarbonyl)amino)-9-methyl-5-oxo-1,2,3,5,6,7,8,10a-octahydropyrrolo[1,2-a]azocine-3-carboxylate (1.5 g, 4.25 mmol, 1 equiv.) in tetrahydrofuran (6 mL) and water (2 mL) was added lithium hydroxide monohydrate (356 mg, 8.50 mmol, 2.0 equiv.). The reaction was stirred at room temperature for 16 h. The reaction was then partially concentrated under reduced pressure to remove THF. The reaction was diluted with water (20 mL) and EtOAc (50 mL). The phases were separated, and the aqueous phase was acidified to pH = 1-2 with 1N aqueous HCl. The product was then extracted with DCM (3 x 50 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure to give (3S,6S,10aR)-6-((tert-butoxycarbonyl)amino)-9-methyl-5-oxo-1,2,3,5,6,7,8,10a-octahydropyrrolo[1,2-a]azocine-3-carboxylic acid (1.43 g, 100%) as a white solid. LCMS (ESI) m / z = 339.2 (M+H) + .

[0533] Step 2: (3S,6S,8aR,9aR,9bR)-9,9-dibromo-6-((tert-butoxycarbonyl)amino)-8a-methyl-5-oxodecahydro-1H-cyclopropa[c]pyrrolo[1,2-a]azocine-3-carboxylic acid and (3S,6S,8aS,9aS,9bR)-9,9-dibromo-6-((tert-butoxycarbonyl)amino)-8a-methyl-5-oxodecahydro-1H-cyclopropa[c]pyrrolo[1,2-a]azocine-3-carboxylic acid [ka]

[0534] To a solution of (3S,6S,10aR)-6-((tert-butoxycarbonyl)amino)-9-methyl-5-oxo-1,2,3,5,6,7,8,10a-octahydropyrrolo[1,2-a]azocine-3-carboxylic acid (1.45 g, 4.28 mmol, 1 equiv.) in methylene chloride (15 mL) was added bromoform (5.22 mL, 59.9 mmol, 14 equiv.) and benzyltriethylammonium chloride (309 mg, 1.36 mmol, 0.32 equiv.) under a nitrogen atmosphere. A solution of sodium hydroxide (3.76 g, 94.1 mmol, 22 equiv.) in water (7.52 mL) was added. The reaction was heated at reflux for 72 h. The reaction was then concentrated under reduced pressure to remove DCM, water, and most of the excess bromoform. The resulting dark brown residue was dissolved in water (50 mL) and acidified to pH 1-2 with 3N aqueous HCl. The aqueous layer was extracted with DCM (3 x 50 mL), and the combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. This crude residue was purified by elution with 5-60% MeCN in water (containing 0.1% formic acid) to give 275 g C 18 Purification was performed by reverse-phase chromatography on a cartridge. The first eluted product, (3S,6S,8aS,9aS,9bR)-9,9-dibromo-6-((tert-butoxycarbonyl)amino)-8a-methyl-5-oxodecahydro-1H-cyclopropa[c]pyrrolo[1,2-a]azocine-3-carboxylic acid (479 mg, 21.9%), was isolated as a white solid. LCMS (ESI) m / z = 408.9 (M-Boc+H). + ; 1 H NMR (400 MHz, CDCl3) δ 5.87 (d, J = 6.8 Hz, 1H), 4.54 (t, J = 8.8 Hz, 1H), 4.30 - 4.22 (m, 1H), 3.96 - 3.88 (m, 1H), 2.52 - 1.96 (m, 8H), 1.69 (d, J = 10.8 Hz, 1H), 1.44 (s, 9H), 1.36 (s, 3H).

[0535] The second eluting product, (3S,6S,8aR,9aR,9bR)-9,9-dibromo-6-((tert-butoxycarbonyl)amino)-8a-methyl-5-oxodecahydro-1H-cyclopropa[c]pyrrolo[1,2-a]azocine-3-carboxylic acid (191 mg, 8.8%), was isolated as a white solid. LCMS (ESI) m / z = 408.9 (M-Boc+H). + ; 1 H NMR (400 MHz, CDCl3) δ 5.91 (s, 1H), 5.36 (d, J = 8.8 Hz, 1H), 4.78 - 4.70 (m, 1H), 4.66 (t, J = 7.6 Hz, 1H), 3.39 - 3.28 (m, 2H), 2.89 (dt, J = 13.9, 7.2 Hz, 2H), 2.48 - 2.38 (m, 1H), 2.34 - 2.24 (m, 1H), 2.05 - 1.95 (m, 1H), 1.87 (s, 3H), 1.84 - 1.75 (m, 1H), 1.61 - 1.52 (m, 1H), 1.44 (s, 9H).

[0536] Step 3: (3S,6S,8aR,9aS,9bR)-6-((tert-butoxycarbonyl)amino)-8a-methyl-5-oxodecahydro-1H-cyclopropa[c]pyrrolo[1,2-a]azocine-3-carboxylic acid [ka]

[0537] In a tube, (3S,6S,8aS,9aS,9bR)-9,9-dibromo-6-((tert-butoxycarbonyl)amino)-8a-methyl-5-oxodecahydro-1H-cyclopropa[c]pyrrolo[1,2-a]azocine-3-carboxylic acid (600 mg, 1.17 mmol, 1 equiv.) was dissolved in 2-propanol (10 mL) under a nitrogen atmosphere. Potassium hydroxide (393 mg, 7.02 mmol, 6 equiv.) and 10% palladium on carbon (50% aqueous) (400 mg, 188 μmol, 0.16 equiv.) were then added. The tube was charged with hydrogen (40 psi) and sealed. The reaction mixture was heated at 70° C. for 20 h. The reaction mixture was then cooled to room temperature, diluted with MeOH, and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The crude residue was eluted with 5-60% MeCN in water (containing 0.1% formic acid). 18 Purification by reverse phase chromatography on a cartridge gave, after lyophilization, (3S,6S,8aR,9aS,9bR)-6-((tert-butoxycarbonyl)amino)-8a-methyl-5-oxodecahydro-1H-cyclopropa[c]pyrrolo[1,2-a]azocine-3-carboxylic acid (120 mg, 29.1%) as a white solid. LCMS (ESI) m / z = 353.2 (M+H). + ; 1 H NMR (400 MHz, CDCl3) δ 5.87 (d, J = 6.8 Hz, 1H), 4.56 (t, J = 8.6 Hz, 1H), 4.24 (t, J = 7.9 Hz, 1H), 3.63 (dd, J = 11.0, 6.4 Hz, 1H), 2.68 - 2.51 (m, 1H), 2.38 - 2.20 (m, 2H), 2.14 - 1.87 (m, 4H), 1.53 (dd, J = 15.3, 10.6 Hz, 1H), 1.44 (s, 9H), 1.04 - 0.93 (m, 4H), 0.54 (dd, J = 8.6, 4.9 Hz, 1H), 0.33 (t, J = 5.0 Hz, 1H). [ka]

[0538] (3S,6S,8aS,9aR,9bR)-6-((tert-butoxycarbonyl)amino)-8a-methyl-5-oxodecahydro-1H-cyclopropa[c]pyrrolo[1,2-a]azocine-3-carboxylic acid was synthesized under the same conditions as above. LCMS (ESI) m / z = 353.2 (M+H) + . [(2-{[(1R,3S,5R,7S,10S)-3-methyl-8-oxo-10-[3-(pyridin-3-yl)azetidine-1-carbonyl]-9-azatricyclo[7.3.0.0 3 , 5 Synthesis of ]dodecan-7-yl]carbamoyl}-1-benzothiophen-5-yl)methyl]phosphonic acid [ka]

[0539] Step 1: (3S,6S,10aR)-6-{[(tert-butoxy)carbonyl]amino}-9-methyl-5-oxo-1H,2H,3H,5H,6H,7H,10H,10aH-pyrrolo[1,2-a]azocine-3-carboxylic acid [ka]

[0540] To a solution of methyl (3S,6S,10aR)-6-{[(tert-butoxy)carbonyl]amino}-9-methyl-5-oxo-1H,2H,3H,5H,6H,7H,10H,10aH-pyrrolo[1,2-a]azocine-3-carboxylate (3.5 g, 9.93 mmol, 1 equiv.) in tetrahydrofuran (24 mL) and water (8 mL) was added lithium hydroxide monohydrate (1.04 g, 24.8 mmol, 2.5 equiv.). The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was partially concentrated under reduced pressure (to remove THF). The crude mixture was diluted with water (40 mL) and EtOAc (60 mL). The phases were separated, and the aqueous phase was acidified with 1 N HCl (pH = 1-2), after which the product was extracted with DCM (3 × 60 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by eluting 150 g C in water (containing 0.1% formic acid) with 5-60% MeCN. 18 Purification by reverse-phase chromatography on a cartridge gave (3S,6S,10aR)-6-{[(tert-butoxy)carbonyl]amino}-9-methyl-5-oxo-1H,2H,3H,5H,6H,7H,10H,10aH-pyrrolo[1,2-a]azocine-3-carboxylic acid (2.85 g, 84.8%) as a white solid. LCMS (ESI): m / z = 339.1 (M+H) + ; 1 H NMR (400 MHz, DMSO-d6) δ 12.32 (br. s., 1H), 6.75 (d, J = 7.3 Hz, 1H), 5.48 - 5.39 (m, 1H), 4.47 (q, J = 7.4 Hz, 1H), 4.19 (d, J = 7.1 Hz, 2H), 2.77 - 2.52 (m, 2H), 2.26 - 2.03 (m, 4H), 1.83 (br. s., 2H), 1.74 (s, 3H), 1.36 (s, 9H).

[0541] Step 2: (1R,7S,10S)-4,4-Dibromo-7-{[(tert-butoxy)carbonyl]amino}-3-methyl-8-oxo-9-azatricyclo[7.3.0.0 3,5]dodecane-10-carboxylic acid [ka]

[0542] To a solution of (3S,6S,10aR)-6-{[(tert-butoxy)carbonyl]amino}-9-methyl-5-oxo-1H,2H,3H,5H,6H,7H,10H,10aH-pyrrolo[1,2-a]azocine-3-carboxylic acid (1.5 g, 4.43 mmol, 1 equiv.) in methylene chloride (50 mL) was added tribromomethane (3.84 mL, 44.3 mmol, 10 equiv.) and benzyltriethylammonium chloride (201 mg, 886 μmol, 0.2 equiv.) under a nitrogen atmosphere. A solution of sodium hydroxide (3.89 g, 97.4 mmol, 22 equiv.) in water (7.8 mL) was added. The reaction mixture was heated at 40 °C for 24 h. The reaction mixture was concentrated under reduced pressure to remove DCM, water, and most of the bromoform. The dark brown residue was dissolved in water (30 mL) and slowly acidified with 3N aqueous HCl to pH = 2 under stirring. The acidic aqueous layer was washed with DCM (3 x 30 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude residue was purified by elution with 5-60% MeCN (containing 0.1% formic acid in water) to give 150 g of C 18 Purification by reverse phase chromatography on a cartridge gave (1R,7S,10S)-4,4-dibromo-7-{[(tert-butoxy)carbonyl]amino}-3-methyl-8-oxo-9-azatricyclo[7.3.0.0 3 ,5]dodecane-10-carboxylic acid (1.42 g, 62.8%) was obtained as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ 12.45 (br. s., 1H), 6.70 (d, J = 6.8 Hz, 1H), 4.55 - 4.03 (m, 3H), 2.43 - 2.08 (m, 4H), 2.06 - 1.97 (m, 1H), 1.96 - 1.67 (m, 4H), 1.55 - 1.50 (m, 1H), 1.48 - 1.44 (m, 1H), 1.42 - 1.24 (m, 10H).

[0543] Step 3: (1R,7S,10S)-4,4-Dibromo-7-{[(tert-butoxy)carbonyl]amino}-3-methyl-8-oxo-9-azatricyclo[7.3.0.0 3 ,5]dodecane-10-carboxylic acid [ka]

[0544] In a pressure vessel, (1R,7S,10S)-4,4-dibromo-7-{[(tert-butoxy)carbonyl]amino}-3-methyl-8-oxo-9-azatricyclo[7.3.0.0 3 ,5]Dodecane-10-carboxylic acid (1.4 g, 2.74 mmol, 1 equiv.) was dissolved in 2-propanol (40 mL), followed by the addition of potassium hydroxide (920 mg, 16.4 mmol, 6 equiv.) and 10% palladium on carbon (50% wet) (1.44 g, 0.68 mmol, 0.25 equiv.) under a nitrogen atmosphere. The reaction mixture was heated at 70 °C under 40 psi of hydrogen for 21 hours. The reaction mixture was cooled to room temperature, diluted with MeOH, and filtered through a pad of Celite. The filtrate was concentrated under reduced pressure. The crude carboxylate was diluted with a minimal amount of water. The crude product was purified by elution with 50 g C in water (containing 0.1% formic acid) with 5-60% MeCN. 18The product was purified by reverse-phase chromatography on a cartridge. The tube containing the pure product was concentrated under reduced pressure to give the desired product (460 mg) as a white solid (a mixture of two isomers). This product was subjected to chiral SFC separation (SFC conditions: column Lux amylose-1 21.2 × 250 mm 5 μm column, 10 mg / injection, concentration 1.67 mg / mL, column T = 40 °C, flow rate 25 mL / min, 10% MeOH, cycle time: 4.6 min) to give (1R,3S,5R,7S,10S)-7-{[(tert-butoxy)carbonyl]amino}-3-methyl-8-oxo-9-azatricyclo[7.3.0.0]. 3 ,5]dodecane-10-carboxylic acid (180 mg, 18.6%, fastest eluting isomer) was obtained as a white solid. LCMS (ESI): m / z = 353.2 (M+H) + . 1 H NMR (400 MHz, benzene-d6) δ 6.30 - 6.18 (m, 1H), 4.52 - 4.32 (m, 2H), 3.60 - 3.47 (m, 1H), 2.25 - 2.20 (m, 1H), 1.77 - 1.72 (m, 1H), 1.66 - 1.53 (m, 3H), 1.46 (s, 9H), 1.42 - 1.25 (m, 4H), 1.17 - 1.06 (m, 1H), 0.81 (s, 3H), 0.33 - 0.30 (m, 1H), 0.04 - -0.10 (m, 1H).(1R,3R,5S,7S,10S)-7-{[(tert-butoxy)carbonyl]amino}-3-methyl-8-oxo-9-azatricyclo[7.3.0.0 3 ,5]Dodecane-10-carboxylic acid (256 mg, 26.5%, slowest eluting isomer) was also isolated as a white solid. LCMS (ESI): m / z = 353.2 (M+H) + ; 1H NMR (400 MHz, benzene-d6) δ 5.33 - 5.31 (m, 1H), 4.52 - 4.46 (m, 1H), 4.11 - 4.09 (m, 1H), 3.30 - 3.26 (m, 1H), 2.34 - 2.31 (m, 1H), 2.02 - 1.86 (m, 1H), 1.62 - 1.45 (m, 3H), 1.44 (s, 9H), 1.36 - 1.09 (m, 2H), 1.12 - 0.90 (m, 2H), 0.75 (s, 3H), 0.46 - 0.32 (m, 1H), 0.17 - 0.14 (m, 1H), -0.42 (t, J = 4.4 Hz, 1H). Linker synthesis: 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: [ka]

[0545] Ethyl 5-methylbenzo[b]thiophene-2-carboxylate was prepared according to the procedure described in WO2016 / 100184.

[0546] Step 1: Ethyl 5-(bromomethyl)benzo[b]thiophene-2-carboxylate

[0547] To a solution of ethyl 5-methylbenzo[b]thiophene-2-carboxylate (1, 7.3 kg, 33.1 mol, 1.0 equiv.) in CHCl (58 L) stirred at 20 °C, AIBN (544 g, 3.31 mol, 0.10 equiv.) and NBS (6.19 kg, 34.8 mol, 1.05 equiv.) were added. The mixture was heated from 30 °C to 50 °C for 4 h, then heated to 60 °C and stirred for 12 h. Upon completion, the reaction mixture was cooled to 10 °C and 15% NaSO (20 L) was added. The organic layer was washed with HO (20 L × 2), dried over NaSO, and concentrated under reduced pressure at 45 °C to give 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] + ; 1 H NMR (400 MHz, CDCl3) δ 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).

[0548] Step 2: Ethyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0549] To a solution of ethyl 5-(bromomethyl)benzo[b]thiophene-2-carboxylate (2, 9.50 kg, 31.8 mol, 1.0 equiv.) in DMF (28.5 L) stirred at 20 °C 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. Upon completion, the reaction mixture was cooled to 15 °C, poured into HO (50.0 L), and extracted with EtOAc (20 L × 2). The combined organics were washed with HO (20 L × 2) and brine (10 L), dried over NaSO, and concentrated under reduced pressure at 45 °C to give a residue. The crude residue was purified by silica gel chromatography (petroleum ether / ethyl acetate = 100 / 1 to 1 / 1, petroleum ether / ethyl acetate = 0 / 1) to give ethyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (3, 5.24 kg, 14 mol, 44.4% yield) as a yellow solid. LCMS (ESI): m / z = 356.9 [M+H] + . 1 H 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).

[0550] Step 3: Ethyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate

[0551] Three batches were run in parallel.

[0552] To a solution of ethyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (3, 250 g, 702 mmol, 1.00 equiv.) and N-(benzenesulfonyl)-N-fluorobenzenesulfonamide (221 g, 702 mmol, 1.00 equiv.) in THF (2.50 L) was added LiHMDS (1 M, 702 mL, 1.00 equiv.) dropwise at −70° C. under N2. The mixture was stirred at −70° C. for 3 h. After completion, the reaction mixture was slowly poured into saturated aqueous NH4Cl (5.00 L) at 0° C., and the mixture was stirred at 0° C. for 0.5 h. The three batches were then combined for 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 Na2SO4, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, petroleum ether / ethyl acetate = 1 / 0 to 3 / 1, R f =0.30, petroleum ether / ethyl acetate=1 / 1) to give ethyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (4, 357 g, 928 mmol, 44.1% yield) as a yellow oil. LCMS (ESI): m / z = 375.0 [M+H] + . 1 H 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).

[0553] Step 4: 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0554] To a solution of ethyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (4, 252 g, 673 mmol, 1.00 equiv.) in MeOH (1.80 L) was added HO (760 mL) and LiOH·HO (56.5 g, 1.35 mol, 2.00 equiv.) at 10-20 °C under N. The mixture was stirred at 10-20 °C for 1 h. TLC (petroleum ether / ethyl acetate = 1 / 1) showed that compound 4 was consumed (R f =0.30), the desired spot (R f =0.10) was formed. The reaction mixture was quenched with HO (2.50 L), and then the pH was adjusted to 3-4 with HCl (1 M aqueous solution). This mixture was extracted with dichloromethane (2.50 L × 3). The combined organic layers were dried over anhydrous NaSO 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.

[0555] Step 5: Allyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate

[0556] Two batches were run in parallel.

[0557] To a solution of 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid (5, 178 g, 514 mmol, 1.00 equiv.) in DMF (1.78 L) was added K2CO3 (142 g, 1.03 mol, 2.00 equiv.) and allyl bromide (68.4 g, 565 mmol, 1.10 equiv.) 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 (R f =0.60), new spots (R f=0.70) was formed. The reaction mixture was diluted with HO (6.00 L) and extracted with ethyl acetate (2.00 L × 3). The organic layers were combined. This 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 a yellow oil.

[0558] Step 6: ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid

[0559] To a solution of allyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (7, 50 g, 136 mmol, 1.0 equiv) in DCM (5 L) at 0 °C was added TMSBr (411 g, 2.71 mol, 20.0 equiv) dropwise. After the addition, the reaction mixture was warmed to room temperature and stirred for an additional 12 h. The reaction progress was monitored by LCMS. Upon 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) and then dried in vacuo to afford ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (40.3 g, 129 mmol, 95%) as a yellow solid. 1 H 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] + .

[0560] Step 7: ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid

[0561] To a solution of allyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (9, 5.2 g, 13.5 mmol, 1.0 equiv) in DCM (500 mL) at 0° C. was added TMSBr (41.1 g, 270 mmol, 20.0 equiv) dropwise. After the addition, the reaction mixture was warmed to room temperature and stirred for an additional 12 h. The reaction progress was monitored by LCMS. Upon 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) and then dried in vacuo to afford ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid (3.1 g, 9.37 mmol, 69%) as a yellow solid. 1 H 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 [MH] - . Chiral separation of allyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate

[0562] Rac-allyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (617 g, 1.62 mol, 1.00 equiv.) 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).

[0563] Preparative SFC method: Instrument: Waters 350 Preparative SFC. Column: REGIS(S,S)WHELK-O1, 250 x 50 mm ID, 10 μm. Mobile phase: A CO2, B 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.

[0564] Analytical SFC method: Column: Kromasil (S,S) WHELK-O1, 50 x 4.6 mm ID, 3.5 μm. Mobile phase: A is CO2, B is MEOH (0.05% DEA). Gradient: B 5-40%, Flow rate: 3 mL / min. Back pressure: 100 bar. Column temperature: 35 °C. Wavelength: 220 nm.

[0565] 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 a yellow oil. LCMS (ESI): m / z = 387.1 [M+H] + .

[0566] 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 a yellow oil. LCMS (ESI): m / z = 387.1 [M+H] + .

[0567] The assignment of absolute stereochemical configurations was made by comparing the experimental vibrational circular dichroism (VCD) spectra with the theoretical VCD spectra obtained from DFT calculations.

[0568] Using the method described above in Step 7 for the preparation of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid, utilizing the appropriate starting materials and modifications, the following intermediates in Table 29 were prepared. [Table 29] Synthesis of perfluorophenyl 5-((S)-fluoro((R)-(((S)-1-oxo-1-propoxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate [ka]

[0569] Step 1: Preparation of (S)-((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid

[0570] To a solution of allyl (S)-5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (20 g, 52 mmol, 1 equiv.) in methylene chloride (500 mL) was added trimethylsilyl iodide (21 g, 0.10 mol, 2 equiv.). 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 preparative HPLC (TFA) and 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

[0571] Step 2: Preparation of allyl (S)-5-((dichlorophosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate

[0572] To a solution of (S)-((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid (11 g, 33 mmol, 1 equiv.) in methylene chloride (200 mL) was added dimethylformamide (0.24 g, 3.3 mmol, 0.1 equiv.) at 0 °C under a N atmosphere, followed by the dropwise addition of oxalyl chloride (13 g, 0.10 mol, 3 equiv.), stirring at 0 °C for 30 min and warming to 40 °C for 1 h 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.

[0573] Step 3: Preparation of allyl 5-((1S)-fluoro((((S)-1-oxo-1-propoxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0574] To a solution of (S)-5-((dichlorophosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (11 g, 30 mmol, 1 equiv.) in methylene chloride (150 mL) was added phenol (2.2 g, 24 mmol, 0.8 equiv.) in methylene chloride (20 mL) over 10 minutes at 0° C., followed by the dropwise addition of a solution of N,N-diisopropylethylamine (12 g, 90 mmol, 3 equiv.) in methylene chloride (200 mL) over 1.5 hours. The mixture was stirred at 25° C. for 5 minutes to give a yellow solution, to which was added a solution of propyl(2S)-2-aminopropanoate (3.9 g, 30 mmol, 1 equiv.) in methylene chloride (20 mL), and the mixture was stirred at 25° C. for 1 hour to give a clear yellow 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

[0575] Step 4: Preparation of 5-((1S)-fluoro((((S)-1-oxo-1-propoxypropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0576] 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 equiv.) in methylene chloride (40 mL) at 0° C. under a N atmosphere, pyrrolidine (0.38 g, 5.4 mmol, 0.8 equiv.) and palladium;triphenylphosphane (0.7 g, 0.67 mmol, 0.11 equiv.) were added dropwise, 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 preparative HPLC (TFA) and 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. 1 H 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, 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)

[0577] 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

[0578] 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 equiv.) in pyridine (15 mL) at 0 °C under a N atmosphere was added 2,3,4,5,6-pentafluorophenyl 2,2,2-trifluoroacetate (5.2 g, 19 mmol, 3 equiv.) dropwise, 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. This residue was purified by flash silica gel chromatography with 3:1 petroleum ...

Claims

1. Formula I: 【Chemistry 1】 A compound thereof, or a pharmaceutically acceptable salt thereof, q is 0 or 1, and t is 0, 1, or 2, provided that at least one of q or t is 1. p is 1 or 2, R １ However, they are selected from 8-10 membered ring-condensed bicyclic heteroaryls, 8-10 membered ring-condensed bicyclic heterocyclyls, C6-C10 aryls, -(C1-C4) alkyl(C6-C10 aryls), and -(C2-C4) alkenyl(C6-C10 aryls), Here, the C6-C10 aryls in the heteroaryl, heterocyclyl, C6-C10 aryl, or -(C1-C4) alkyl(C6-C10 aryl) and -(C2-C4) alkenyl(C6-C10 aryl) are each independently, -CR １ａ R ２ａ P(O)OR １ｂ OR ２ｂ 、 -CR １ａ R ２ａ P(O)[OR １ｂ ][NH(AA)C(O)OR Ｔ ]、 -CR １ａ R ２ａ [O[[ER Ｔｙ ][E(AA)C(O)OR Ｔ ]、 -P(O)OR １ｂ OR ２ｂ 、 -[P(O)[NHR Ｔｙ ][E(AA)C(O)OR Ｔ ]、 -CR １ａ R ２ａ P(O)[NH(AA)C(O)OR Ｔ [NH(AA)C(O)OR Ｔ , or -P(O)[OR １ｂ ][NH(AA)C(O)OR Ｔ ] It has been replaced by, R １ａ and R ２ａ However, each is independent of hydrogen, cyano, (C １ ~C ４ ) alkyl, hydroxy (C １ ~C ４ ) Selected from alkyl and fluoro, or R １ａ and R ２ａ However, they form an oxo with the carbon atoms to which they bond, R １ｂ and R ２ｂ However, each independently, hydrogen, (C １ ~C ４ ) alkyl, halo(C １ ~C ４ ) alkyl, -[(C １ ~C ４ )alkyl]-OC(O)-[(C １ ~C ４ ) alkyl], -[(C １ ~C ４ )alkyl]-C(O)O-[(C １ ~C ４ ) alkyl], -[(C １ ~C ４ )alkyl]-O-[(C １ ~C ２０ ) alkyl], -[(C １ ~C ４ )alkyl]-OC(O)-[halo(C １ ~C ４ ) alkyl], [(C １ ~C ４ )alkyl]-OC(O)O-[5-7 membered ring heterocyclyl],[(C １ ~C ４ )alkyl]-OC(O)-[5-7 membered ring heterocyclyl],-[(C １ ~C ４ )alkyl]-OC(O)-[(C １ ~C ４ ) alkyl]-OH,-[(C １ ~C ４ )alkyl]-OC(O)-[(C １ ~C ４ )alkyl]-O-[(C １ ~C ４ ) alkyl], -[(C １ ~C ４ )alkyl]-OC(O)O-[(C １ ~C ４ ) alkyl], -[(C １ ~C ４ )alkyl]-OC(O)O-[halo(C １ ~C ４ ) alkyl], -[(C １ ~C ４ )alkyl]-OC(O)O-[(C １ ~C ４ )alkyl] - OH, - [(C １ ~C ４ )alkyl] - OC(O)O - [(C １ ~C ４ )alkyl] - O - [(C １ ~C ４ )alkyl], - [(C １ ~C ４ )alkylphenyl] - C(O)O - [(C １ ~C ４ )alkyl], - [(C １ ~C ４ )alkyl] - OC(O) - [NH(AA)C(O)OR Ｔ , - [(C １ ~C ４ )alkyl] - SC(O) - [(C １ ~C ４ )alkyl], - [(C １ ~C ４ )alkyl] - SC(O) - [halo(C １ ~C ４ )alkyl], - [(C １ ~C ４ )alkyl] - SC(O) - [(C １ ~C ４ )alkyl] - OH, - [(C １ ~C ４ )alkyl] - SC(O) - [(C １ ~C ４ )alkyl] - O - [(C １ ~C ４ )alkyl], - [(C １ ~C ４ )alkyl] - OC(O)NH(C １ ~C ４ )alkyl], - [(C １ ~C ４ )alkyl] - OC(O)N[(C １ ~C ４ )alkyl] ２ 、and selected from C6 - C10 aryl, The aforementioned 5-6 membered heteroaryl ring and aryl ring are each optionally and independently composed of 1 or 2 halo, cyano, or (C) １ ~C ４ ) Substituted with alkyl, [(C １ ~C ４ )alkyl]-OC(O)O-[5-7 membered ring heterocyclyl] and [(C １ ~C ４ The 5-7 membered ring heterocyclyl of )alkyl-OC(O)-[5-7 membered ring heterocyclyl] is each optionally and independently substituted with 1 or 2 C(O)OR h, R ２ However, hydrogen, halo, (C １ ~C ４ ) alkyl, halo(C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkoxy, Halo (C １ ~C ４ ) Alkoxy, hydroxy (C １ ~C ４ ) Selected from alkyl, cyano, and hydroxyl, R ３ and R ４ However, each independently produces hydrogen, halo, and (C) １ ~C ４ ) Selected from alkyl groups, R ５ and R ６ However, each independently, hydrogen, phenyl, and (C １ ~C ４ ) Selected from alkyl groups, R ７ However, (C １ ~C ４ ) Selected from alkyl, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, where, Said (C １ ~C ４ The alkyl group is optionally substituted with 1 to 3 R Y groups. The phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclil, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each optionally and independently substituted with 1 to 3 R Z groups, or R ６ and R ７ However, together with the nitrogen atom to which they are bonded, they form a 4- to 14-membered monocyclic or bicyclic heterocyclil, or a 5- to 12-membered monocyclic or bicyclic heteroaryl, each of which is independently and arbitrarily substituted by 1 to 3 R Q atoms. R ８ However, hydrogen or (C １ ~C ４ ) is alkyl, AA is a residue of an α or β natural or unnatural amino acid, R Ｔ and R Ｔｙ However, each is independent of the others, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkyl-C(O)O(C １ ~C ４ ) Selected from alkyl, benzyl, and phenyl, where the phenyl is one or two halo, (C １ ~C ４ ) alkyl, or halo(C １ ~C ４ ) optionally substituted with alkyl groups, R Ｑ However, each is independent of, Haro, (C ２ ~C ４ ) Alkenil, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkoxy, Halo (C １ ~C ４ ) Alkoxy, cyano, phenyl, hydroxyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, (C ３ ~C ６ ) Cycloalkyl, oxo, imino, -OR ｅ , -C(O)R ｇ , -C(O)OR ｅ , -NR ｃ C(O)R ｅ , -C(O)NR ｃ R ｄ , -NR ａ R ｂ , -S(O)R ｅ R ｆ , -S(O) ２ R ｆ , -S(O)=NH(C １ ~C ４ ) Alkyl, -S(O)NR ｅ R ｆ , and -S(O) ２ NR ｅ R ｆ Selected from, here, Said (C ２ ~C ４ ) Alkenyl and (C １ ~C ４ Each alkyl group is optionally and independently substituted with 1 to 3 R M groups. The aforementioned phenyl, 5-10 membered monocyclic or bicyclic heteroaryl, (C ３ ~C ６ ) Cycloalkyl groups and 4- to 9-membered monocyclic or bicyclic heterocyclines are each optionally and independently substituted with 1 to 3 R F groups. R Ｙ However, each is independent of the others, Haro, (C １ ~C ４ ) Alkoxy, Halo (C １ ~C ４ ) Alkyl, cyano, -C(O)R ｇ , -C(O)OR ｅ ,-NHC(O)R ｅ , -NR ａ R ｂ , -S(O)R ｅ R ｆ , -S(O) ２ R ｆ , -S(O)NR ｅ R ｆ , -S(O)=NH(C １ ~C ４ ) alkyl, -S(O) ２ NR ｅ R ｆ Selected from hydroxyl, phenyl, 4-6 membered heterocyclil, and 5-10 membered monocyclic or bicyclic heteroaryl, where each of the phenyl, 4-6 membered heterocyclil, and 5-10 membered monocyclic or bicyclic heteroaryl is independently and optionally substituted with 1-3 R X groups. R Ｍ and R Ｊ However, each is independent of the others, Haro, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkoxy, Halo (C １ ~C ４ ) Alkyl, cyano, -C(O)R ｇ , -C(O)OR ｅ ,-NHC(O)R ｅ , -C(O)NR ｃ R ｄ , -NR ａ R ｂ , -S(O)R ｅ R ｆ , -S(O) ２ R ｆ , -S(O)NR ｅ R ｆ -S(O) = NR ｅ (C １ ~C ４ ) alkyl, -S(O) ２ NR ｅ R ｆ Selected from hydroxyl, phenyl, 4-6 membered heterocyclil, and 5-10 membered monocyclic or bicyclic heteroaryl, where each of the phenyl, 4-6 membered heterocyclil, and 5-10 membered monocyclic or bicyclic heteroaryl is independently and optionally substituted with 1-3 R X groups. R Ｆ , R Ｘ , and R Ｚ However, each is independent of the others: Halo, Cyano, (C １ ~C ４ ) alkyl, cyano(C １ ~C ４ ) alkyl, (C ３ ~C ６ ) Cycloalkyl, Halo(C １ ~C ４ ) alkyl, -(C １ ~C ４ ) Alkyl C(O)NR ｃ R ｄ , - (C １ ~C ４ ) Alkyl (C １ ~C ４ ) Alkoxy, hydroxy (C １ ~C ４ ) alkyl, -(C １ ~C ４ ) alkylphenyl, -(C １ ~C ４ ) alkyl heteroaryl, (C ２ ~C ４ ) Alkenil, Halo (C ２ ~C ４ ) Alkenil, (C ２ ~C ４ ) Alkinil, Halo (C ２ ~C ４ ) Alkinyl, (C １ ~C ４ ) Alkoxy, Halo (C １ ~C ４ ) Alkyl, -OR ｅ , oxo, imino, phenyl, 4- to 6-membered heterocyclyl, 5 or 6-membered monocyclic heteroaryl, -S(O)R ｅ R ｆ , -S(O) ２ R ｆ , -S(O)=NH(C １ ~C ４ ) Alkyl, -S(O)NR ｅ R ｆ , -S(O) ２ NR ｅ R ｆ , -C(O)OR ｅ , -NR ｃ C(O)R ｅ , - (C １ ~C ４ Alkyl)C(O)R ｇ , -C(O)R ｇ , -C(O)NR ｃ R ｄ NO ２ , and -NR ａ R ｂ Selected from, here, The phenyl, the 4-6 membered heterocyclyl ring, and -(C １ ~C ４ ) The phenyl in the alkylphenyl is optionally and independently composed of 1 to 3 halo, cyano, oxo, (C １ ~C １０ ) alkyl, (C ２ ~C １０ ) Alkenil, (C ２ ~C １０ ) Alkinil, Halo (C １ ~C １０ ) alkyl, (C １ ~C １０ ) Alkoxy, -(C １ ~C ４ ) Alkyl (C １ ~C ４ ) Alkoxy, or halo(C １ ~C １０ ) It is substituted with an alkoxy, and furthermore, Said (C １ ~C １０ ) alkyl, (C ２ ~C １０ ) alkenyl, and (C ２ ~C １０ ) Alkinyl, each, Oxo, or a 5- to 7-membered ring heterocyclyl optionally substituted with one or two oxos, or a 5- to 10-membered ring monocyclic or bicyclic heteroaryl, or 4-10 membered monocyclic or bicyclic heterocyclines that are optionally substituted with oxo or 5-7 membered heterocyclines optionally substituted with one or two oxo. It is replaced independently by choice, R ａ , R ｂ , R ｃ , R ｄ , R ｅ , R ｆ , R ｇ , and R ｈ However, each independently, hydrogen, (C １ ~C ４ ) alkyl, (C ２ ~C ４ ) Alkinyl, -(C １ ~C ４ ) alkylphenyl, phenyl, (C ３ ~C ６ ) Selected from cycloalkyl, 4-6 membered heterocyclyl, and 5-6 membered heteroaryl, Said (C １ ~C ４ ) The alkyl group is optionally substituted with 1 to 3 R J groups. The aforementioned phenyl, (C ３ ~C ６ ) Cycloalkyl, 4-6 membered heterocyclyl, and 5 or 6 membered heteroaryl each contain 1-3 halo, cyano, (C １ ~C ４ ) alkyl, halo(C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkoxy, Halo (C １ ~C ４ A compound, or a pharmaceutically acceptable salt thereof, which is optionally and independently substituted with an alkoxy, hydroxyl, phenyl, or benzyl group.

2. R Ｆ , R Ｘ , and R Ｚ However, each is independent of the others: Halo, Cyano, (C １ ~C ４ ) alkyl, cyano(C １ ~C ４ ) alkyl, (C ３ ~C ６ ) Cycloalkyl, Halo(C １ ~C ４ ) alkyl, -(C １ ~C ４ ) Alkyl C(O)NR ｃ R ｄ , - (C １ ~C ４ ) Alkyl (C １ ~C ４ ) Alkoxy, hydroxy (C １ ~C ４ ) alkyl, -(C １ ~C ４ ) alkylphenyl, -(C １ ~C ４ ) alkyl heteroaryl, (C ２ ~C ４ ) Alkenil, Halo (C ２ ~C ４ ) Alkenil, (C ２ ~C ４ ) Alkinil, Halo (C ２ ~C ４ ) Alkinyl, (C １ ~C ４ ) Alkoxy, Halo (C １ ~C ４ ) Alkyl, -OR ｅ , oxo, imino, phenyl, 4-6 membered heterocyclyl, 5-6 membered monocyclic heteroaryl, -S(O)R ｅ R ｆ , -S(O) ２ R ｆ , -S(O)=NH(C １ ~C ４ ) Alkyl, -S(O)NR ｅ R ｆ , -S(O) ２ NR ｅ R ｆ , -C(O)OR ｅ , -NR ｃ C(O)R ｅ , - (C １ ~C ４ Alkyl)C(O)R ｇ , -C(O)R ｇ , -C(O)NR ｃ R ｄ NO ２ , and -NR ａ R ｂ Selected from, here, The phenyl, the 4-6 membered heterocyclyl ring, and -(C １ ~C ４ ) The phenyl in the alkylphenyl is optionally and independently composed of 1 to 3 halo, cyano, oxo, (C １ ~C １０ ) alkyl, (C ２ ~C １０ ) Alkenil, (C ２ ~C １０ ) Alkinil, Halo (C １ ~C １０ ) alkyl, (C １ ~C １０ ) Alkoxy, or halo(C １ ~C １０ ) It is substituted with alkoxy, and furthermore, Said (C １ ~C １０ ) alkyl, (C ２ ~C １０ ) alkenyl, and (C ２ ~C １０ ) Alkinyl, each, Oxo, or a 5- to 7-membered ring heterocyclyl optionally substituted with one or two oxos, or a 5- to 10-membered ring monocyclic or bicyclic heteroaryl, or 4-10 membered monocyclic or bicyclic heterocyclines that are optionally substituted with oxo or 5-7 membered heterocyclines optionally substituted with one or two oxo. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is optionally and independently substituted by [the specified agent].

3. The compound having the structure of formula II, III, or IV: 【Chemistry 2】 、 【change】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein q is 1, t is 1, and p is 1.

5. R ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

6. R ５ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

7. R ３ and R ４ However, each is independently selected from hydrogen and halo, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

8. R ３ and R ４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each of the atoms is hydrogen or fluoro.

9. R １ However, they are selected from benzothiophenyl and naphthalenyl, and each of them is -CR １ａ R ２ａ P(O)OR １ｂ OR ２ｂ 、 -CR １ａ R ２ａ [O[[ER Ｔｙ ][E(AA)C(O)OR Ｔ ]、 -CR １ａ R ２ａ P(O)[NH(AA)C(O)OR Ｔ [NH(AA)C(O)OR Ｔ , or -CR １ａ R ２ａ P(O)[OR １ｂ ][NH(AA)C(O)OR Ｔ ] The compound according to claim 1, or a pharmaceutically acceptable salt thereof, which is independently substituted by.

10. R １ but, 【Chemistry 4】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from the above.

11. R １ but, 【Transformation 6】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

12. R １ａ and R ２ａ However, each is independently selected from hydrogen and fluoro, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

13. R １ａ is hydrogen, R ２ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R1a is fluoro, or R2a is fluoro and R2a is hydrogen.

14. R １ａ and R ２ａ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each of the elements is fluoro.

15. R １ｂ and R ２ｂ However, each independently, hydrogen, (C １ ~C ４ ) alkyl, halo(C １ ~C ４ ) alkyl, -[(C １ ~C ４ )alkyl]-OC(O)-[(C １ ~C ４ ) alkyl], -[(C １ ~C ４ )alkyl]-C(O)O-[(C １ ~C ４ ) alkyl], -[(C １ ~C ４ )alkylphenyl]-C(O)O-[(C １ ~C ４ ) alkyl], -[(C １ ~C ４ )alkyl]-OC(O)-[NH(AA)C(O)OR Ｔ ], -[(C １ ~C ４ )alkyl]-OC(O)-[(C １ ~C ４ ) alkyl]-OH,-[(C １ ~C ４ )alkyl]-OC(O)O-[5-7 membered ring heterocyclyl],-[(C １ ~C ４ )alkyl]-OC(O)O-[(C １ ~C ４ )alkyl]-O-[(C １ ~C ４ ) alkyl], -[(C １ ~C ４ )alkyl]-OC(O)O-[(C １ ~C ４ ) alkyl], -[(C １ ~C ４ )alkyl]-SC(O)-[(C １ ~C ４ ) alkyl], -[(C １ ~C ４ )alkyl]-SC(O)-[(C １ ~C ４ A compound according to claim 1, selected from alkyl-OH and phenyl, or a pharmaceutically acceptable salt thereof.

16. R １ｂ and R ２ｂ Each of these is hydrogen or -[(C １ ~C ４ )alkyl]-OC(O)-[(C １ ~C ４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl.

17. -CR １ａ R ２ａ P(O)OR １ｂ OR ２ｂ However, each of them, 【Chemistry 7-1】 【Chemistry 7-2】 【Transformation 7-3】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, independently selected from the above.

18. -CR １ａ R ２ａ P(O)OR １ｂ OR ２ｂ が、 【Transformation 8】 The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

19. -(AA)C(O)OR Ｔ However, each is independent of the other, -C(R')(R)C(O)R Ｔ or -C(R')(R)CH ２ C(O)R Ｔ And, R' is hydrogen or methyl, R is hydrogen, methyl, ethyl, -CH ２ CH (CH ３ ) ２ ien-CH ２ OCH ３ , benzyl, and -CH ２ CH ２ - Selected from phenyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

20. R Ｔ However, each of them, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkyl-C(O)O-C １ ~ ４ A compound according to claim 1, independently selected from alkyl and benzyl, or a pharmaceutically acceptable salt thereof.

21. -CR １ａ R ２ａ P(O)[OR １ｂ ][NH(AA)C(O)OR Ｔ ] each 【Chemistry 9-1】 【Chemistry 9-2】 A compound according to claim 1, or a pharmaceutically acceptable salt thereof, independently selected from the above.

22. R ６ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is hydrogen.

23. R ７ However, (C １ ~C ４ ) Selected from alkyl, phenyl, pyrrolidinyl, and azetidinyl, Said (C １ ~C ４ The alkyl group is optionally substituted with 1 to 3 R Y groups. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the phenyl, pyrrolidinyl, and azetidinyl are each optionally and independently substituted with 1 to 3 R and Z groups.

24. R Ｚ However, respectively, Halo, -(C １ ~C ４ ) Alkyl C(O)NR ｃ R ｄ hydroxyl, phenyl, 4-6 membered heterocyclyl, 5 or 6 membered monocyclic heteroaryl, -C(O)NR ｃ R ｄ , and -C(O)R ｇ Independently selected from, the phenyl contains 1 to 3 halo, (C １ ~C ４ ) alkyl, halo(C １ ~C ４ ) alkyl, (C １ ~C ４ ) Alkoxy, or halo(C １ ~C ４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted with an alkoxy.

25. R Ｚ However, respectively, Halo, -(C １ ~C ４ ) Alkyl C(O)NR ｃ R ｄ Hydroxyl, phenyl, tetrahydropyran, tetrahydrofuran, oxetanyl, pyridinyl, pyrazolyl, pyridadinyl, -C(O)NR ｃ R ｄ , and -C(O)R ｇ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, independently selected from the above.

26. R Ｙ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, each independently selected from hydroxyl, pyridinyl, and pyrrolopyridinyl.

27. R ｃ and R ｄ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each of the atoms is hydrogen.

28. R ｇ Each of them is independent, -(C １ ~C ４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is alkyl.

29. R ６ and R ７ However, along with the nitrogen atom to which they are bound, azetidinyl, 2,5-diazaspiro[3.4]octanyl, pyrrolidinyl, 2,6-diazaspiro[3.3]heptanyl, 2,6-diazabicyclo[3.2.0]heptanyl, piperazinyl, spiro[indoline-3,3'-pyrroridine]yl, 6',7'-dihydrospiro[azetidine-3,5'-pyrrolo[1,2-a]imidazole]yl, 3,4-dihydro-2H-benzo[b The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each of these compounds forms ][1,4]oxazinyl, 3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazine, 2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine, 2,3,4,5-tetrahydrobenzo[b][1,4]oxazepinyl, 1,2,3,4-tetrahydroquinoxalinyl, 1-azaspiro[3.5]nonanyl, or 4-azaspiro[2.4]heptanyl, each of which is optionally and independently substituted with 1 to 3 R Qs.

30. R Ｑ However, each of them is Halo, (C １ ~C ４ ) alkyl, -OR ｅ cyano, phenyl, hydroxyl, 4-6 membered heterocyclyl, 5-10 membered monocyclic or bicyclic heteroaryl, oxo, and -C(O)R ｇ Selected independently from, Said (C １ ~C ４ ) The alkyl group is optionally substituted with 1 to 3 R M groups. The phenyl, 5-10 membered monocyclic or bicyclic heteroaryl, and 4-6 membered heterocyclil are each optionally and independently substituted with 1-3 R F groups. R ｅ However, (C １ ~C ４ The compound according to claim 1, which is alkyl or a five- or six-membered ring heteroaryl, or a pharmaceutically acceptable salt thereof.

31. R Ｑ However, each of them is Halo, (C １ ~C ４ ) alkyl, -OR ｅ cyano, phenyl, hydroxyl, morpholinyl, tetrahydropyranyl, thiomorpholinyl, piperidinyl, oxetanyl, pyrazolyl, pyridinyl, tetrazolyl, imidazolyl, pyrazinyl, isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, pyrimidinyl, benzimidazolyl, 1H-pyrrolo[3,2-c]pyridine, 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl, oxo, and -C(O)R ｇ Selected independently from, Said (C １ ~C ４ ) The alkyl group is optionally substituted with 1 to 3 R M groups. The aforementioned morpholinyl, tetrahydropyranil, thiomorpholinyl, piperidinil, oxetanil, pyrazolyl, pyridinil, tetrazolyl, imidazolyl, pyrazinil, isoxazolyl, oxazolyl, oxadiazolyl, triazolyl, pyrimidinil, benzimidazolyl, 1H-pyrrolo[3,2-c]pyridine, and 2,4,5,6-tetrahydrocyclopenta[c]pyrazolyl are each optionally and independently substituted with 1 to 3 R F groups. R ｅ However, (C １ ~C ４ ) Alkyl, pyridinyl, pyrazinyl, pyrimidinyl, pyrazole, R ｅ Pyrazoyl represented by (C １ ~C ４ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, optionally substituted with an alkyl group.

32. R ｇ However, each of them, (C １ ~C ４ ) Independently selected from alkyl, morpholinyl, azetidinyl, tetrahydropyranil, oxetanyl, pyrrolidinyl, and pyrazolyl, Said (C １ ~C ４ ) The alkyl group is optionally substituted with 1 to 3 R J groups. The morpholinil, azetidinil, tetrahydropyranil, oxetanil, pyrrolidinil, and pyrazolyl each contain 1 to 3 (C) １ ~C ４ ) alkyl, (C １ ~C ４ ) optionally and independently substituted with alkoxy, benzyl, or hydroxyl, The compound according to claim 1, or a pharmaceutically acceptable salt thereof.

33. R Ｊ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each is independently phenyl.

34. R Ｆ However, each is independent of cyano, (C １ ~C ４ ) A compound according to claim 1, selected from alkyl, hydroxyl, and oxo, or a pharmaceutically acceptable salt thereof.

35. R Ｍ However, each is independent of halo, hydroxy, and (C) １ ~C ４ ) Alkoxy, -S(O) ２ R ｆ , -S(O)=NH(C １ ~C ４ A compound according to claim 1, or a pharmaceutically acceptable salt thereof, selected from alkyl, pyridinyl, pyrazoyl, and phenyl optionally substituted with one or two halos.

36. R ｆ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein each of the alkyl groups is independently and optionally substituted with one to three halos (C1 to C4).

37. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound is selected from any one of compound 1 to compound 435.

38. A pharmaceutically acceptable composition comprising a compound according to any one of claims 1 to 37, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

39. A pharmaceutically acceptable composition according to claim 38 for treating a condition in which the subject responds to the regulation of STAT3 or STAT6.

40. A pharmaceutically acceptable composition according to claim 38 for treating a disease or disorder in a subject.

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