6-Oxodecahydropyrrolo[1,2-a][1,5]diazocine and 6-Oxodecahydro-4H-pyrrolo[2,1-d][1,5]thiazocine Derivatives as STAT3 and STAT6 Modulators for Treating Cancer and Inflammatory Conditions

Abstract

For example, compounds of formula (I): The compounds of formula I and their pharma- ceutically acceptable salts are provided, as well as compositions thereof.Preferred compounds are 6-oxodecahydropyrrolo[1,2-a][1,5]diazocine and 6-oxodecahydro-4H-pyrrolo[2,1-d][1,5]thiazocine derivatives.In one embodiment, the disclosed compounds of formula I and their pharma-ceutically acceptable salts inhibit STAT3 and / or STAT6 and are useful in various therapeutic applications, such as, for example, in the treatment of cancer and inflammatory conditions.

Description

[Technical field]

[0001] Related Applications This application claims the benefit of priority to U.S. Provisional Application No. 63 / 313,916, filed February 25, 2022, and U.S. Provisional Application No. 63 / 337,428, filed May 2, 2022, the entire contents of which are incorporated herein by reference. [Background technology]

[0002] background The signal transducer and activator of transcription (STAT) family of proteins consists of transcription factors that play essential roles in regulating 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 interest because it is strongly implicated in tumor growth promotion and immune evasion, and it is the only STAT family member whose genetic deletion results in embryonic lethality. Indeed, abnormally elevated STAT3 activity has been speculated in more than 70% of human cancers. Activated STAT3 mediates key gene expression changes and molecular events that dysregulate cell growth and apoptosis, promotes angiogenesis, invasion, metastasis, and the development of resistance to apoptosis, and suppresses host tumor immune surveillance, making constitutively active STAT3 a key mediator of carcinogenesis and tumor progression.

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

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

[0006] summary Modulators of STAT3 and / or STAT6 are provided herein. Such modulators have the structure I: [ka] and pharma- ceutically acceptable salts, and compositions thereof, wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , X, q, t and p are as described herein.

[0007] In one embodiment, the disclosed compounds of Formula I and pharma- ceutically acceptable salts thereof inhibit STAT3 and / or STAT6 and are useful in a variety of therapeutic applications, such as, for example, in the treatment of cancer and inflammatory conditions.

[0008] Also included are pharmaceutical compositions comprising the present compounds and pharma- ceutically acceptable salts of the disclosed compounds of Formula I, as well as methods for their preparation.

[0009] Also included are methods of treating conditions that respond to modulation of STAT3 and / or STAT6 using the disclosed compounds, pharma- ceutically acceptable salts, and compositions thereof. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Detailed Description 1. General description of the compound In a second embodiment, a compound of structural formula I: [ka] is provided herein (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; X is S, SO 2 , -S(=O)=NH and NR 8 is selected from R 1 -CR 1a R 2a P(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][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 ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][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 , -CR1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T aryl substituted with cyano, (C 1 ~C 4 ) optionally further substituted with one or two groups independently selected from alkoxy and halo);-(C 1 ~C 4 )Alkyl(aryl)(-(C 1 ~C 4 The aryl portion of the 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 ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ], -[P(O)[NH(AA)C(O)ORT][NH(AA)C(O)ORT] or -P(O)[OR 1b ][NH(AA)C(O)OR T ]); and -(C 2 ~C 4 )Alkenyl(aryl)(-(C 2 ~C 4 The aryl portion of 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], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ]), R 1a and R 2a is hydrogen, cyano, (C 1 ~C 4 ) Alkyl, Hydroxy (C 1 ~C 4 ) alkyl and fluoro; or R 1a and R 2a together with the carbon to which they are attached to form an oxo, R 1b and R 2b is 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 heterocyclyl], [(C 1 ~C 4 )alkyl]-OC(O)-[5-7 membered heterocyclyl], -[(C 1 ~C 4 ) alkyl]-OC(O)-[(C1 ~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 ) 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 aryl, wherein the 5- to 6-membered heteroaryl and aryl are each independently selected from halo, cyano, and (C 1 ~C 4 )alkyl, each of which is optionally and independently substituted with 1 to 2 groups selected from [(C 1 ~C 4 )alkyl]-OC(O)O-[5-7 membered heterocyclyl] and [(C 1 ~C 4 )alkyl]-OC(O)-[5- to 7-membered heterocyclyl], where valence permits, the 5- to 7-membered heterocyclyl is C(O)OR h each optionally and independently substituted with 1 to 2 groups selected from R 2 is 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 is hydrogen, halo, (C 1 ~C 4 ) alkyl, halo(C 1 ~C 4 ) Alkyl, Hydroxy (C 1 ~C 4 ) alkyl, -(C 1 ~C 4 ) alkylphenyl, (C 1 ~C 4 )Alkoxy, halo(C 1 ~C 4 )alkoxy, -(C 1 ~C4 )Alkyl(C 1 ~C 4 ) Alkoxy, hydroxyl, cyano, -NR a R b , phenyl, (C 3 ~C 6 )cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl, wherein the phenyl, (C 3 ~C 6 Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl are, where valences permit, R S each optionally substituted with 1 to 3 groups selected from R 5 and R 6 is hydrogen, phenyl and (C 1 ~C 4 ) alkyl, R 7 is (C 1 ~C 4 ) alkyl, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, 1 ~C 4 ) Alkyl, when valence permits, R Y and wherein the phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are optionally substituted, where valences permit, with 1 to 3 groups selected from R Z each optionally substituted with 1 to 3 groups selected from 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, when valences permit, is R Q and optionally substituted with 1 to 3 groups selected from R 8 is hydrogen, (C 1 ~C4 ) alkyl, halo(C 1 ~C 4 ) alkyl, (C 3 ~C 6 )cycloalkyl, 5-7 membered heterocyclyl, -(C 1 ~C 4 )[5-7 membered heterocyclyl], 5-10 membered heteroaryl, -(C 1 ~C 4 )[5-10 membered heteroaryl], phenyl, -(C 1 ~C 4 ) alkylphenyl, -C(O)R Ha , -C(O)OR Ha , -C(O)NR Ha R Hb , -C(O)OR Ha , -SOR Ha R Hb and -SO 2 R Ha The (C 3 ~C 6 ) cycloalkyl, 5-7 membered heterocyclyl, 5-10 membered heteroaryl, phenyl, (C 1 ~C 4 ) phenyl on alkylphenyl, -(C 1 ~C 4 )[5- to 7-membered heterocyclyl] and -(C 1 ~C 4 ) [5-6 membered heteroaryl] The 5-6 membered heteroaryl on the above is R U each optionally substituted with 1 to 3 groups selected from R Ha is (C 1 ~C 10 ) alkyl, (C 2 ~C 10 ) alkenyl, (C 2 ~C 10 ) selected from alkynyl, phenyl, 5-10 membered monocyclic or bicyclic heteroaryl and 4-10 membered monocyclic or bicyclic heterocyclyl, 1 ~C 10 ) alkyl, (C 2 ~C 10) alkenyl, (C 2 ~C 10 ) Alkynyl is, when valence permits, R O wherein said 5-10 membered monocyclic or bicyclic heteroaryl and said 4-10 membered monocyclic or bicyclic heterocyclyl are each optionally substituted, where valences permit, with one or two groups selected from halo, (C 1 ~C 4 ) alkyl, halo(C 1 ~C 4 ) alkyl, (C 1 ~C 4 )Alkoxy, halo(C 1 ~C 4 ) alkoxy, oxo, cyano and 4-6 membered heterocyclyl (C 1 ~C 4 each optionally substituted with 1 to 3 groups selected from R O Halo, (C 1 ~C 4 ) Alkoxy, OH, Phenyl, NH 2 , -NH(C 1 ~C 10 ) alkyl, -N[(C 1 ~C 10 ) alkyl], (C 3~6 cycloalkyl), 4-10 membered monocyclic or fused bicyclic heterocyclyl, and 5-10 membered monocyclic or bicyclic heteroaryl, wherein said 5-10 membered monocyclic or bicyclic heteroaryl and said 4-10 membered monocyclic or bicyclic heterocyclyl are selected from halo, (C 1 ~C 4 ) alkyl, halo(C 1 ~C 4 ) alkyl, (C 1 ~C 4 )Alkoxy, halo(C 1 ~C 4 ) each optionally substituted with 1 to 3 groups selected from alkoxy, oxo, and cyano; R Hb is hydrogen or (C 1 ~C4 ) alkyl, AA is a residue of a natural or unnatural alpha or beta amino acid; R T and R Ty is (C 1 ~C 4 ) alkyl, benzyl and phenyl, wherein said phenyl is selected from halo, (C 1 ~C 4 ) alkyl and halo(C 1 ~C 4 ) alkyl, R Q and R U Halo, (C 2 ~C 4 ) alkenyl, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 )Alkoxy, halo(C 1 ~C 4 ) alkoxy, cyano, phenyl, hydroxyl, 4-9 membered monocyclic or bicyclic heterocyclyl, 5-10 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 (C 2 ~C 4) alkenyl and (C 1 ~C 4 ) Alkyl, when valence permits, R M each optionally and independently substituted with 1 to 3 groups selected from the group consisting of phenyl, 5-10 membered monocyclic or bicyclic heteroaryl, (C 3 ~C 6 Cycloalkyl and 4-9 membered monocyclic or bicyclic heterocyclyl are, where valences permit, R F each optionally and independently substituted with 1 to 3 groups selected from R Y Halo, (C 1 ~C 4 )Alkoxy, halo(C 1 ~C 4 )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) 2 R f , -S(O)NR e R f , -S(O)=NH(C 1 ~C 4 ) alkyl, -S(O) 2 NR 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 selected from R X each optionally substituted with 1 to 3 groups selected from R M and R J Halo, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 )Alkoxy, halo(C 1 ~C 4)Alkoxy, 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)=NH(C 1 ~C 4 ) alkyl, -S(O) 2 NR 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 independently selected from R X each optionally substituted with 1 to 3 groups selected from R F , R S , R X and R Z is halo, cyano, (C 1 ~C 4 ) alkyl, (C 3 ~C 6 Cycloalkyl), halo(C 1 ~C 4 ) alkyl, -(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 ) alkylheteroaryl, (C 2 ~C 4 ) alkenyl, halo(C 2 ~C 4 ) alkenyl, (C 2 ~C4 ) alkynyl, halo(C 2 ~C 4 ) alkynyl, (C 1 ~C 4 )Alkoxy, halo(C 1 ~C 4 ) Alkoxy, -OR e , oxo, imino, phenyl, 4-6 membered heterocyclyl, -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 , -C(O)OR e , -NR c C(O)R e , -(C 1 ~C 4 Alkyl)C(O)R g , -C(O)R g , -(C 1 ~C 4 Alkyl)C(O)NR c R d , -C(O)NR c R d , -NO 2 and -NR a R b are independently selected from (C 1 ~C 4 )alkyl is optionally substituted by cyano, and includes the phenyl, the 4- to 6-membered heterocyclyl and -(C 1 ~C 4 ) alkylphenyl, where valences permit, may be halo, cyano, oxo, (C 1 ~C 10 ) alkyl, (C 2 ~C 10 ) alkenyl, (C 2 ~C 10 ) alkynyl, halo(C 1 ~C 10 ) alkyl, (C 1 ~C 10) alkoxy and halo(C 1 ~C 10 ) alkoxy, each of which is optionally and independently substituted with 1 to 3 groups selected from the group consisting of (C 1 ~C 10 ) alkyl, (C 2 ~C 10 ) alkenyl and (C 2 ~C 10 ) alkynyl is optionally substituted, where valences permit, by 5-10 membered monocyclic or bicyclic heteroaryl or 4-10 membered monocyclic or bicyclic heterocyclyl, respectively, and said 5-10 membered monocyclic and bicyclic heteroaryl or 4-10 membered monocyclic or bicyclic heterocyclyl, respectively, is optionally substituted by oxo or 5-7 membered heterocyclyl (optionally substituted by 1-2 oxo); R a , R b , R c , R d , R e , R f , R g and R h is hydrogen, if valence allows, (C 1 ~C 4 ) alkyl, (C 2 ~C 4 ) alkynyl, -(C 1 ~C 4 ) alkylphenyl, phenyl, (C 3 ~C 6 ) cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl, 1 ~C 4 ) Alkyl, when valence permits, R J and the phenyl, (C 3 ~C 6 )Cycloalkyl, 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are, where valences permit, halo, cyano, (C 1 ~C 4 ) alkyl, halo(C 1 ~C4 ) alkyl, (C 1 ~C 4 )Alkoxy, halo(C 1 ~C 4 ) each independently optionally substituted with 1 to 3 groups selected from alkoxy, hydroxyl, phenyl, and benzyl). 2.Definition

[0011] A hyphen (-), when used in conjunction with a chemical group that may have multiple points of attachment, represents the point of attachment of that group to the variable being defined. For example, -NR c C(O)R e means that the point of attachment of this group is on 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 monovalent saturated straight-chain or branched 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 a linking oxygen atom, represented by -O-alkyl. For example, "(C 1 ~C 4 )Alkoxy" includes methoxy, ethoxy, proproxy and butoxy.

[0016] "Haloalkoxy" is, for example, -OCHF 2 Or -OCF 3 and the like, which are attached to another moiety through an oxygen atom.

[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 5-12 membered aromatic radical containing 1-4 heteroatoms selected from N, O and S. In some cases, the nitrogen atom in a heteroaryl may be quaternized. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group" or "heteroaromatic". A heteroaryl group may be monocyclic or bicyclic. Monocyclic heteroaryls include, for example, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, 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, benzothiazolyl, benzothiopheneyl, 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 (where valence allows).

[0020] Unless otherwise specified, the term "heterocyclyl" refers to a 4-12 membered saturated or partially unsaturated heterocyclic ring containing 1-4 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 may be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure. A heterocyclyl group may be monocyclic or bicyclic (e.g., bridged, fused, or spiro bicyclic rings). Examples of saturated or partially unsaturated monocyclic 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, unsaturated heterocyclic radicals fused to another unsaturated heterocyclic radical, a cycloalkyl, an aryl, or a heteroaryl ring, such as, for example, benzodioxolyl, dihydrobenzodioxinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, 5-oxa-2,6-diazaspiro[3.4]oct-6-enyl, 6-thia-2,7-diazaspiro[3.4]octanyl, 2,6-diazaspiro[3.3]heptanyl, spiro[indoline-3,3'-pyrrolidine]-yl, thiochromanyl, etc. It is understood that, when specified, optional substituents on a heterocyclyl group may be present at any substitutable position, including, for example, the position at which the heterocyclyl is attached (where valence allows).

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

[0022] The term "fused" refers to two rings which share two adjacent ring atoms with each other.

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

[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," used alone or as part of a larger moiety, refers to a saturated cycloaliphatic 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 will be understood that optional substituents on a cycloalkyl or alicyclic group can 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 remaining after formation of a bond between a reactive group in another compound (e.g., an amino group) and a carboxylic acid 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 the reactive group in the compound. The amino group only has 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, a "residue of an alpha amino acid" is an NH 2A "residue of a beta amino acid" can be structurally illustrated as -CR'RC(O)-, -NHCR'RC(O)OH or -NHCR'RC(O)-, and a "residue of a beta amino acid" can be represented by NH 2 CR'RCH 2 -C(O)-, -NHCR'RCH 2 -C(O)OH or -NHCR'RCH 2 -C(O)-, where R' is H or C 1 ~C 6 alkyl, R is H, or halo, (C 1 ~C 3 ) Alkoxy, OH, NH 2 , -NH(C 1 ~C 4 alkyl), -N[(C 1 ~C 4 alkyl)] 2 , SH, S(C 1 ~C 4 alkyl), imino, COOH, -COO(C 1 ~C 4 alkyl), -CO(C 1 ~C 4 alkyl), -CONH(C 1 ~C 4 C optionally substituted with 1 to 3 groups selected from alkyl, phenyl, phenyl, and 5 to 10 membered heteroaryl 1 ~C 6 alkyl, 1 ~C 6 The alkyl may be optionally interrupted by sulfur or nitrogen heteroatoms, and the phenyl may be optionally substituted with OH, cyano, (C 1 ~C 4 Alkyl) and halo(C 1 ~C 4 or R together with a nitrogen atom from an alpha or beta amino acid residue forms a 4-6 membered heterocyclyl. For natural alpha amino acids (i.e., naturally occurring amino acids), R' is H and R is hydrogen, methyl, isopropyl, -CH 2 CH(CH 3 )2 , -(CH 2 ) 2 SCH 3 , -CH(CH 3 )(CH 2 CH 3 ), C.H. 2 OH, -CH(OH)(CH 3 ), C.H. 2 SH, -CH 2 C(O)NH 2 , -(CH 2 ) 2 C(O)NH 2 , benzyl, p-hydroxybenzyl, -CH 2 (indolyl), -(CH 2 ) 4 NH 2 , -(CH 2 ) 3 NHC(=NH 2 )NH 2 , -CH 2 (imidazolyl), -(CH 2 )COOH and -(CH 2 ) 2 COOH, or R together with the nitrogen atom of an alpha or beta amino acid residue forms a pyrrolidinyl ring.

[0027] Unnatural amino acids are known in the art and include, for example, alpha-alkyl amino acids (e.g., alpha-methyl), alpha-alkylalkoxy amino acids (e.g., alpha-CH 2 OCH 3 ), N-methylamino acids, homoamino acids, etc.

[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 racemic forms and mixtures thereof. "Geometric isomer" refers to isomers that differ in the orientation of substituents in relationship to a carbon-carbon double bond, a cycloalkyl ring, or a bridged bicyclic system. The atoms (other than H) on each side of a carbon-carbon double bond can be in the E (substituents are on opposite sides of the carbon-carbon double bond) or Z (substituents are oriented on the same side) configuration. "Cis" refers to substituents oriented on the same side of the ring, while "trans" refers to substituents oriented on opposite sides of the ring.

[0029] In a compound having one or more chiral centers, where the stereochemical configuration at the chiral center is depicted by its chemical name (e.g., where the configuration is depicted in the chemical name by "R" or "S") or structure (e.g., where the configuration is depicted by a "wedge" bond), the enrichment of the depicted configuration relative to the opposite configuration is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. "Enrichment of the depicted configuration relative to the opposite configuration" is a mole percentage and is determined by dividing the number of compounds having the depicted stereochemical configuration at the chiral center(s) in the mixture by the total number of compounds having the same or opposite stereochemical configuration.

[0030] When geometric isomers are depicted by name or structure, the enrichment of the indicated isomer relative to the opposite isomer is greater than 50%, 60%, 70%, 80%, 90%, 99% or 99.9%. "Enrichment of the indicated isomer relative to the opposite isomer" is a mole percentage and is determined by dividing the number of compounds having the indicated geometric configuration in a mixture by the total number of compounds having the same or opposite geometric configuration.

[0031] When a disclosed compound is named or illustrated by a structure without indicating stereochemistry, it is understood that the name or structure encompasses one of the possible stereoisomers or geometric isomers (but not 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 in the compound name by the term "rel-" and by using a flat bond in place of a wedge. For example, the structure: [ka] ((2-(((5S,8S,10aR)-8-((rel-trans)-3-cyano-4-phenylpyrrolidine-1-carbonyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid has the substituents around the pyrrolidine ring in trans and is a mixture of both diastereomers. [ka] is meant to encompass.

[0033] The terms "subject" and "patient" may be used interchangeably and refer to a mammal in need of treatment, such as companion animals (e.g., dogs, cats, etc.), farm animals (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 reduction 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 described herein, or one or more symptoms thereof. In some embodiments, treatment may be administered after one or more symptoms have developed (i.e., therapeutic treatment). In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or exposure to a particular organism or other susceptibility factor) (i.e., prophylactic treatment). Treatment may also be continued after symptoms have resolved, e.g., to delay their recurrence.

[0036] The term "pharmaceutical acceptable carrier" refers to a non-toxic carrier, adjuvant or vehicle that does not destroy the pharmacological activity of the compound and is formulated with the compound.The pharmaceutical acceptable carrier, adjuvant or vehicle that can be used in the compositions described herein includes, but is not limited to, ion exchanger, alumina, aluminum stearate, lecithin, serum protein (such as human serum albumin), buffer substance (such as phosphate, glycine, sorbic acid, potassium sorbate), partial glyceride mixture of vegetable saturated fatty acid, water, salt or electrolyte (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate), polyvinylpyrrolidone, cellulose-based substance, polyethylene glycol, sodium carboxymethylcellulose, polyacrylate, wax, polyethylene-polyoxypropylene-block polymer, polyethylene glycol and wool fat.

[0037] For pharmaceutical use, the salts of the compounds described herein refer to non-toxic "pharmaceutical acceptable salts". Pharmaceutically acceptable salt forms include pharmaceutical acceptable acid / anionic or basic / cationic salts. Suitable pharmaceutical acceptable acid addition salts of the compounds described herein include, for example, salts of inorganic acids (such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, and sulfuric acid) and organic acids (such as 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 pharmaceutical acceptable salts with a pharmaceutical acceptable base(s). Suitable pharmaceutical acceptable base salts include, for example, ammonium salts, alkali metal salts (such as sodium salts and potassium salts), and alkaline earth metal salts (such as magnesium salts and calcium salts). Compounds having a quaternary ammonium group also contain counterions such as chloride, bromide, iodide, acetate, and perchlorate. Other examples of such salts include hydrochlorides, hydrobromides, sulfates, methanesulfonates, nitrates, benzoates, and salts with amino acids, such as glutamic acid.

[0038] The term "effective amount" or "therapeutically effective amount" refers to an amount of a compound described herein that is sufficient, under the conditions of administration, to achieve the desired therapeutic effect (such as treatment of the conditions recited herein), e.g., a dosage of between 0.01 to 100 mg per kg of body weight per day. 3.Compound

[0039] In a first embodiment, a compound of structural formula I: [ka] or a pharma- ceutically acceptable salt thereof is provided, wherein the variables are as defined above.

[0040] In a second embodiment, R in a compound of formula I or a pharma- ceutically acceptable salt thereof is 1 -CR 1a R 2a P(O)OR 1bOR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][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 ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][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 ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T aryl substituted with -(C 1 ~C 4 )Alkyl(aryl)(-(C 1 ~C 4 The aryl portion of the alkyl(aryl) is -CR 1a R 2aP(O)OR 1b OR 2b , -CR 1a R 2a P(O)[OR 1b ][NH(AA)C(O)OR T ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ]); and -(C 2 ~C 4 )Alkenyl(aryl)(-(C 2 ~C 4 The aryl portion of 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 ], -P(O)OR 1b OR 2b , -[P(O)[NHR Ty ][NH(AA)C(O)OR T ] or -P(O)[OR 1b ][NH(AA)C(O)OR T ]), R 8 is hydrogen, (C 1 ~C 4 ) alkyl, halo(C 1 ~C 4 ) alkyl, (C 3 ~C 6 )cycloalkyl, 5-7 membered heterocyclyl, -(C 1 ~C 4 )[5-7 membered heterocyclyl], 5-6 membered heteroaryl, -(C 1 ~C 4 )[5-6 membered heteroaryl], phenyl, -(C 1 ~C 4 ) alkylphenyl, -C(O)R Ha, -C(O)OR Ha , -C(O)NR Ha R Hb , -C(O)OR Ha , -SOR Ha R Hb and -SO 2 R Ha The above (C 3 ~C 6 ) cycloalkyl, 5-7 membered heterocyclyl, 5-6 membered heteroaryl, phenyl, (C 1 ~C 4 ) phenyl on alkylphenyl, -(C 1 ~C 4 )[5- to 7-membered heterocyclyl] and -(C 1 ~C 4 ) [5-6 membered heteroaryl] The 5-6 membered heteroaryl on the above is R U each optionally substituted with 1 to 3 groups selected from R Ha is (C 1 ~C 10 ) alkyl, (C 2 ~C 10 ) alkenyl, (C 2 ~C 10 ) selected from alkynyl, phenyl, 5-10 membered monocyclic or bicyclic heteroaryl and 4-10 membered monocyclic or bicyclic heterocyclyl, 1 ~C 10 ) alkyl, (C 2 ~C 10 ) alkenyl, (C 2 ~C 10 ) Alkynyl is, when valence permits, R O wherein said 5-10 membered monocyclic or bicyclic heteroaryl and said 4-10 membered monocyclic or bicyclic heterocyclyl are each optionally substituted, where valences permit, with one or two groups selected from halo, (C 1 ~C 4 ) alkyl, halo(C 1 ~C 4 ) alkyl, (C 1 ~C 4)Alkoxy, halo(C 1 ~C 4 ) each optionally substituted with 1 to 3 groups selected from alkoxy, oxo, and cyano; R O Halo, (C 1 ~C 4 ) Alkoxy, OH, Phenyl, NH 2 , -NH(C 1 ~C 10 ) alkyl, -N[(C 1 ~C 10 )alkyl], 4-10 membered monocyclic or fused bicyclic heterocyclyl and 5-10 membered monocyclic or bicyclic heteroaryl, wherein said 5-10 membered monocyclic or bicyclic heteroaryl and said 4-10 membered monocyclic or bicyclic heterocyclyl are selected from halo, (C 1 ~C 4 ) alkyl, halo(C 1 ~C 4 ) alkyl, (C 1 ~C 4 )Alkoxy, halo(C 1 ~C 4 ) each optionally substituted with 1 to 3 groups selected from alkoxy, oxo, and cyano, and the remaining variables are as described above for Formula I.

[0041] In a third embodiment, the compound of formula I has structural formula II: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as described above with respect to Formula I or the second embodiment.

[0042] In a fourth embodiment, in a compound of Formula I or II, or a pharma- ceutically acceptable salt thereof, p is 1, and the remaining variables are as described above for Formula I or the second embodiment.

[0043] In a fifth embodiment, in a compound of formula I or II, or a pharma- ceutically acceptable salt thereof, R 2 is hydrogen, and the remaining variables are as described above with respect to Formula I, or any one of the second or fourth embodiments.

[0044] In a sixth embodiment, in a compound of formula I or II, or a pharma- ceutically acceptable salt thereof, R 3 is hydrogen, and the remaining variables are as described above with respect to Formula I, or any one of the second, fourth or fifth embodiments.

[0045] In a seventh embodiment, in a compound of formula I or II, or a pharma- ceutically acceptable salt thereof, R 4 is hydrogen, and the remaining variables are as described above for Formula I or any one of the second and fourth through sixth embodiments.

[0046] In an eighth embodiment, in a compound of formula I or II, or a pharma- ceutically acceptable salt thereof, q is 0, t is 2, and the remaining variables are as described above for Formula I or any one of the second and fourth through seventh embodiments. Alternatively, as part of the eighth embodiment, in a compound of formula I or II, or a pharma- ceutically acceptable salt thereof, q is 1, t is 1, and the remaining variables are as described above for Formula I or any one of the second and fourth through seventh embodiments. In another alternative, as part of the eighth embodiment, in a compound of formula I or II, or a pharma- ceutically acceptable salt thereof, q is 0, t is 1, and the remaining variables are as described above for Formula I or any one of the second and fourth through seventh embodiments.

[0047] In a ninth embodiment, the compound of formula I has structural formula III, IV, V, VI, VII or VIII: [ka] or a pharma- ceutically acceptable salt thereof, wherein the variables are as described above with respect to Formula I or the second embodiment.

[0048] In a tenth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R 5 is hydrogen, and the remaining variables are as described above for Formula I or any one of the second and fourth through eighth embodiments.

[0049] In an eleventh embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R 1 is selected from 8-10 membered fused bicyclic heteroaryl and aryl, each of which is -CR 1a R 2a P(O)OR 1b OR 2b and the remaining variables are as described above with respect to Formula I, or any one of the second, fourth through eighth, and tenth embodiments. Alternatively, as part of the eleventh embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R 1 is selected from benzothiophenyl, indolyl, naphthalenyl, thienopyridinyl, benzothiazoyl, quinolinyl, isoquinolinyl, 4,5,6,7-tetrahydropyrrolopyridinyl, and 5,6,7,8-tetrahydroimidazopyrazinyl, each of which is represented by -CR 1a R 2a P(O)OR 1b OR 2b and the remaining variables are as described above with respect to Formula I, or any one of the second, fourth through eighth, and tenth embodiments. In another alternative, as part of the eleventh embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R 1 teeth, [ka] and the remaining variables are as described above with respect to Formula I, or any one of the second, fourth through eighth, and tenth embodiments. In another alternative, as part of the eleventh embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R 1 teeth [ka] and the remainder of the variables are as described above with respect to Formula I or any one of the second, fourth through eighth and tenth embodiments.

[0050] In a twelfth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R 1a is hydrogen and R 2a is fluoro or R 1a is fluoro and R 2a is fluoro, and the remaining variables are as described above with respect to Formula I, or any one of the second, fourth through eighth, tenth, and eleventh embodiments. Alternatively, as part of the twelfth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R 1a is fluoro and R 2a is fluoro, and the remaining variables are as described above with respect to Formula I or any one of the second, fourth through eighth, tenth and eleventh embodiments.

[0051] In a thirteenth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R 1b and R 2b is hydrogen, (C 1 ~C 4 ) alkyl, -[(C 1 ~C4 ) alkyl]-OC(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)-[halo(C 1 ~C 4 ) alkyl], -[(C 1 ~C 4 )alkyl]-OC(O)NR 2c R 2d ], [(C 1 ~C 4 )alkyl]-OC(O)O-[5- to 7-membered heterocyclyl] and phenyl, 1 ~C 4 )alkyl]-OC(O)O-[5-7 membered heterocyclyl] is C(O)OR 2c is replaced as necessary by (C 1 ~C 4 ) alkyl group may have one or two (C 1 ~C 4 ) alkyl, and the remaining variables are as described above with respect to Formula I or any one of the second, fourth through eighth, and tenth through twelfth embodiments. Alternatively, as part of the thirteenth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R 1b and R 2b are respectively, -[(C 1 ~C 4 ) alkyl]-OC(O)-[(C 1 ~C 4) alkyl], and the remaining variables are as described above with respect to Formula I or any one of the second, fourth through eighth, and tenth through twelfth embodiments. In another alternative, as part of the thirteenth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R 1b and R 2b are each hydrogen, and the remaining variables are as described above for Formula I or any one of the second, fourth through eighth, and tenth through twelfth embodiments.

[0052] In a fourteenth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII or VIII, or a pharma- ceutically acceptable salt thereof, -CR 1a R 2a P(O)OR 1b OR 2b teeth, [ka] [ka] [ka] and the remaining variables are as described above with respect to Formula I or any one of the second, fourth through eighth, and tenth through thirteenth embodiments. Alternatively, as part of the fourteenth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, -CR 1a R 2a P(O)OR 1b OR 2b teeth [ka] and the remaining variables are as described above for Formula I or any one of the second, fourth through eighth and tenth through thirteenth embodiments.

[0053] In a fifteenth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R 7 is (C 1 ~C 4 ) alkyl, phenyl, 4- to 6-membered monocyclic heterocyclyl, 9- or 10-membered fused bicyclic heterocyclyl, 5- or 6-membered monocyclic heteroaryl, and 9- or 10-membered fused bicyclic heteroaryl, 1 ~C 4 ) Alkyl, when valence permits, R Y wherein the phenyl, 5- or 6-membered monocyclic heterocyclyl, 9- or 10-membered fused bicyclic heterocyclyl, 5- or 6-membered monocyclic heteroaryl, and 9- or 10-membered fused bicyclic heteroaryl are optionally substituted, where valences permit, with 1 to 3 groups selected from R Z and the remaining variables are as described above for Formula I, or any one of the second, fourth through eighth, and tenth through fourteenth embodiments. Alternatively, as part of the fifteenth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R 7 is (C 1 ~C 4 ) alkyl, phenyl, pyridinyl, pyrimidinyl, naphthyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, chromanyl, pyrazoyl, indazolyl, benzisoxazolyl, imidazo[1,2-a]pyridinyl, pyrrolidinyl, cyclopentyl, cyclohexyl, azetidinyl, piperidinyl, and dihydropyridinyl; 1 ~C 4 ) Alkyl, when valence permits, R Yand wherein, where valences permit, phenyl, pyridinyl, pyrimidinyl, naphthyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, chromanyl, pyrazoyl, indazolyl, benzisoxazolyl, imidazo[1,2-a]pyridinyl, pyrrolidinyl, cyclopentyl, cyclohexyl, azetidinyl, piperidinyl, and dihydropyridinyl are optionally substituted with 1 to 3 groups selected from R Z and the remaining variables are as described above for Formula I, or any one of the second, fourth through eighth, and tenth through fourteenth embodiments.

[0054] In a sixteenth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R Y is cyano, (C 1 ~C 4 ) alkyl, -NR a R b and hydroxyl, with the remaining variables being as described above for Formula I or any one of the second, fourth through eighth and tenth through fifteenth embodiments.

[0055] In a seventeenth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R Z is halo, cyano, (C 1 ~C 4 ) alkyl, halo(C 1 ~C 4 ) Alkyl, Hydroxy (C 1 ~C 4 ) alkyl, -(C 1 ~C 4 ) alkylphenyl, -(C 1 ~C 4 ) alkylheteroaryl, (C 1 ~C 4 )Alkoxy, halo(C 1 ~C 4 ) Alkoxy, -OR e, oxo, phenyl, 4-6 membered heterocyclyl, -S(O) 2 R f , -(C 1 ~C 4 Alkyl)C(O)R g , -C(O)R g , -(C 1 ~C 4 Alkyl)C(O)NR c R d , -C(O)NR c R d , -NO 2 and -NR a R b is selected from (C 1 ~C 4 ) alkyl is optionally substituted with cyano, said phenyl and said 4-6 membered heterocyclyl are each optionally and independently substituted, where valences permit, with one to three groups selected from cyano and oxo, and the remaining variables are as described above with respect to Formula I or any one of the second, fourth through eighth, and tenth through sixteenth embodiments. Alternatively, as part of the seventeenth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII or VIII, or a pharma- ceutically acceptable salt thereof, R Z is halo, cyano, (C 1 ~C 4 ) alkyl, halo(C 1 ~C 4 ) Alkyl, Hydroxy (C 1 ~C 4 ) alkyl, -(C 1 ~C 4 ) alkylphenyl, -(C 1 ~C 4 ) alkylheteroaryl, (C 1 ~C 4 )Alkoxy, halo(C 1 ~C 4 ) Alkoxy, -OR e , oxo, -S(O) 2 R f , -(C 1 ~C 4 Alkyl)C(O)R g , -C(O)R g, -(C 1 ~C 4 Alkyl)C(O)NR c R d , -C(O)NR c R d , -NO 2 , -NR a R b , phenyl and dihydropyridinyl; 1 ~C 4 ) alkyl is optionally substituted with cyano, said phenyl and said dihydropyridinyl are each optionally and independently substituted, where valences allow, with one to three groups selected from cyano and oxo, and the remaining variables are as described above for Formula I or any one of the second, fourth through eighth, and tenth through sixteenth embodiments.

[0056] In an eighteenth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R 6 and R 7 together with the nitrogen atom to which they are attached form a 4- to 6-membered monocyclic heterocyclyl, a 7- to 13-membered spiro bicyclic heterocyclyl, or a 9- to 10-membered fused bicyclic heterocyclyl, each of which, when valences permit, is selected from R Q and the remaining variables are as described above with respect to Formula I, or any one of the second, fourth through eighth, and tenth through seventeenth embodiments. Alternatively, as part of the eighteenth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R 6 and R 7together with the nitrogen atom to which they are attached, represent azetidinyl, spiro[indoline-3,3'-pyrrolidinyl], pyrrolidinyl, 3,4-dihydrobenzoxazinyl, 1,2,3,4-tetrahydroquinolinyl, octahydrothiopyranopyrroyl, octahydro-1H-thieno[3',4':3,4]cyclobuta[1,2-c]pyrroyl, 2,6-diazabicyclo[3.2.0]heptanyl, piperazinyl, R aryl, morpholinyl, 1,4,5,6-tetrahydropyrrolopyrazoyl, 4-azaspiro[2.4]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 7-oxa-4-azaspiro[2.5]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 4,6-diazaspiro[2.4]heptanyl, 5-oxa-2,6-diazaspiro[3.4]oct-6-enyl or piperidinyl, each of which, when valences permit, is selected from R Q and the remaining variables are as described above with respect to Formula I, or any one of the second, fourth through eighth, and tenth through seventeenth embodiments. In another alternative, as part of the eighteenth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R 6 and R 7 together with the nitrogen atom to which they are attached form pyrrolidinyl or azetidinyl, each of which, when valences permit, is selected from R Q and the remaining variables are as described above for Formula I, or any one of the second, fourth through eighth, and tenth through seventeenth embodiments.

[0057] In a nineteenth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R Q Halo, (C 1 ~C 4 ) alkyl, halo(C 1 ~C4 ) alkyl, cyano, phenyl, 4-9 membered monocyclic or bicyclic heterocyclyl, 5-10 membered monocyclic or bicyclic heteroaryl, (C 3 ~C 6 ) Cycloalkyl, oxo, -OR e , -C(O)R g , -C(O)NR c R d , -C(O)OR e , -NR c C(O)R e The (C 1 ~C 4 ) Alkyl, when valence permits, R M each optionally and independently substituted with 1 to 3 groups selected from the group consisting of phenyl, 4- to 6-membered heterocyclyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, and (C 3 ~C 6 ) Cycloalkyl, when valence permits, R F and the remaining variables are as described above for Formula I, or any one of the second, fourth through eighth, and tenth through eighteenth embodiments. Alternatively, as part of the nineteenth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R Q is cyano, (C 1 ~C 4 ) alkyl, halo(C 1 ~C 4 )Alkyl, oxo, -C(O)R g , -OR e , -C(O)OR e , -C(O)NR c R d , -NR c C(O)R e , cyclobutyl, cyclopropyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, dihydropyridinyl, pyrazoyl, piperidinyl, tetrahydroimidazopyridinyl and isothiazolidinyl, 1 ~C 4) Alkyl, when valence permits, R M wherein cyclobutyl, cyclopropyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, dihydropyridinyl, pyrazoyl, piperidinyl, tetrahydroimidazopyridinyl, and isothiazolidinyl are optionally and independently substituted, where valences permit, with one to three groups selected from R F and the remaining variables are as described above for Formula I, or any one of the second, fourth through eighth, and tenth through eighteenth embodiments.

[0058] In a twentieth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R M is selected from phenyl and 5-6 membered monocyclic heteroaryl, wherein the phenyl, 5-6 membered monocyclic heteroaryl and phenyl are, where valences permit, R X and the remaining variables are as described above for Formula I, or any one of the second, fourth through eighth, and tenth through nineteenth embodiments. Alternatively, as part of the twentieth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R M is selected from phenyl and pyridinyl, said phenyl and pyridinyl being, where valences permit, R X and the remaining variables are as described above for Formula I or any one of the second, fourth through eighth and tenth through nineteenth embodiments.

[0059] In a twenty-first embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R X is halo and (C 1 ~C 4) alkoxy, and the remaining variables are as described above for Formula I or any one of the second, fourth through eighth, and tenth through twentieth embodiments.

[0060] In a twenty-second embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R F is halo, cyano, (C 1 ~C 4 ) alkoxy, oxo and -NR c C(O)R e and the remaining variables are as described above for Formula I or any one of the second, fourth through eighth and tenth through twenty-first embodiments.

[0061] In a twenty-third embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R c and R d is hydrogen and (C 1 ~C 4 ) alkyl, 1 ~C 4 ) Alkyl, when valence permits, R J and the remaining variables are as described above for Formula I, or any one of the second, fourth through eighth, and tenth through twenty-second embodiments.

[0062] In a twenty-fourth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R e is hydrogen, phenyl, 5- to 6-membered heteroaryl and (C 1 ~C 4 ) alkyl, 1 ~C 4 ) Alkyl, when valence permits, R Jand the remaining variables are as described above for Formula I, or any one of the second, fourth through eighth, and tenth through twenty-third embodiments.

[0063] In a twenty-fifth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R J is independently selected from phenyl and 5- to 6-membered heteroaryl, wherein the 5- to 6-membered heteroaryl is selected from (C 3 ~C 6 ) cycloalkyl, and the remaining variables are as described above with respect to Formula I, or any one of the second, fourth through eighth, and tenth through twenty-fourth embodiments. Alternatively, as part of the twenty-fifth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R J is phenyl, and the remaining variables are as described above for Formula I or any one of the second, fourth through eighth, and tenth through twenty-fourth embodiments.

[0064] In a twenty-sixth embodiment, in a compound of structural formula I, II, III, IV, V, VI, VII, or VIII, or a pharma- ceutically acceptable salt thereof, R g is selected from piperidinyl, morpholinyl, and piperizinyl, and the remaining variables are as described above for Formula I or any one of the second, fourth through eighth, and tenth through twenty-fifth embodiments.

[0065] In a twenty-seventh embodiment, in a compound of structural formula I, II, III, VI, or VIII, or a pharma- ceutically acceptable salt thereof, R 8 is hydrogen, -C(O)R Ha , -C(O)OR Ha , (C 1 ~C 4 ) Alkyl, -SO 2 R Ha , -C(O)NRHa R Hb , Haro (C 1 ~C 4 ) alkyl, phenyl, -(C 1 ~C 4 )[4-10 membered monocyclic or bicyclic heterocyclyl], -(C 1 ~C 4 )[5-10 membered monocyclic or bicyclic heteroaryl], -(C 3 ~C 6 )cycloalkyl or 4-10 membered monocyclic or bicyclic heterocyclyl; 1 ~C 4 ) The phenyl on the alkylphenyl is -(C 1~3 alkoxy) and 5-6 membered heteroaryl (-(C 1 ~C 4 ) alkyl; and 1 ~C 4 ) alkyl is optionally substituted with 1 to 3 phenyl; R Ha is (C 1 ~C 4 ) alkyl, -(C 1 ~C 4 )[5-6 membered heteroaryl], -(C 1 ~C 4 )[phenyl], -(C 1 ~C 4 )[(C 3 ~C 6 )cycloalkyl], phenyl, 4-10 membered monocyclic or bicyclic heterocyclyl, where phenyl and 4-10 membered monocyclic or bicyclic heterocyclyl are selected from the group consisting of halo, (C 1 ~C 4 ) alkyl, (C 1 ~C 4 ) alkoxy and 4-6 membered monocyclic heterocyclyl (C 1 ~C 4 each optionally substituted with 1 to 3 groups independently selected from R Hbis H, and the remaining variables are as described above with respect to Formula I, or any one of the second, fourth through eighth, and tenth through twenty-sixth embodiments. Alternatively, as part of the twenty-seventh embodiment, in a compound of structural formula I, II, III, VI, or VIII, or a pharma- ceutically acceptable salt thereof, R 8 -H, -CH 2 CH 3 , -CH 2 CH(CH 3 ) 2 , -CH 2 CF 2 , -CH 2 CF 3 , cyclobutyl, -CH 2 -Quinuclidinyl, -CH 2 -Imidazo[1,5-a]pyridinyl, -CH 2 -pyrimidinyl, -CH 2 -Phenyl, phenyl, pyrimidinyl, pyridinyl, isoquinolinyl, -C(O)R Ha , -C(O)OR Ha , -SO 2 R Ha , -C(O)NR Ha R Hb or R 8 has the following structure: [ka] Represented by;R Ha is methyl, ethyl, propyl, isopropyl, -CH 2 -Quinolinyl, -CH 2 -phenyl, -CH 2 CH 2 -phenyl, -CH(CH 3 )-phenyl, -CH(CH 3 )CH 2 -phenyl, -CH 2 CH(CH 3 )-phenyl, -CH 2 CH 2 -pyrimidinyl, -CH 2 C(CH 3 ) 2-cyclohexyl, quinolinyl, indazoyl, benzisoxazolyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, 5,6,7,8-tetrahydroimidazo[1,5-a]pyridinyl, 4,5,6,7-tetrahydrobenzo[d]isoxazolyl or 6,7-dihydro-4H-pyrano[3,4-d]isoxazolyl and the quinolinyl, indazoyl, benzisoxazolyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, 5,6,7,8-tetrahydroimidazo[1,5-a]pyridinyl, 4,5,6,7-tetrahydrobenzo[d]isoxazolyl, and 6,7-dihydro-4H-pyrano[3,4-d]isoxazolyl are selected from the group consisting of -Cl, -CH 3 , -CH 2 CH 3 , -OCH 3 or N-methylpiperazinyl, and the remaining variables are as described above for Formula I, or any one of the second, fourth through eighth, and tenth through twenty-sixth embodiments.

[0066] Compounds having Formula I are further disclosed in the Exemplifications and are included in the present disclosure, including their pharma- ceutically acceptable salts and neutral forms. 4. Use, Formulation and Administration

[0067] 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, pharma- ceutically acceptable salts, and pharmaceutical compositions described herein inhibit STAT3 and / or STAT6 activity.

[0068] In some aspects, the compounds and pharmaceutical compositions described herein are useful in conditions that respond to modulation of STAT3 and / or STAT6. Accordingly, provided herein is a method of treating a condition in a subject that responds to modulation (e.g., inhibition) of STAT3 and / or STAT6, comprising administering to a subject in need thereof a therapeutically effective amount of a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or a pharma- ceutically acceptable salt thereof.

[0069] Similarly, there is provided the use of a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or a pharma- ceutically acceptable salt thereof, for the manufacture of a medicament for treating a condition responsive to modulation (e.g., inhibition) of STAT3 and / or STAT6. Similarly, there is provided a compound described herein, or a pharma- ceutically acceptable salt thereof, or a pharmaceutical composition comprising a disclosed compound or a pharma- ceutically acceptable salt thereof, for use in treating a condition responsive to modulation (e.g., inhibition) of STAT3 and / or STAT6.

[0070] In one embodiment, conditions responsive to modulation (e.g., inhibition) of STAT3 and / or STAT6 include, but are not limited to, cancer, neurodegenative disorders, viral diseases, autoimmune diseases, inflammatory disorders, genetic disorders, hormone-related diseases, metabolic disorders, conditions associated with organ transplantation, immunodeficiency disorders, destructive bone disorders, proliferative disorders, infectious diseases, conditions associated with cell death, thrombin-induced platelet aggregation, liver diseases, pathological immune conditions involving T cell activation, cardiovascular disorders or CNS disorders.

[0071] In another embodiment, conditions responsive to modulation (e.g., inhibition) of STAT3 and / or STAT6 include, but are not limited to, 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 diseases (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., Thromho., Vase. Bio. 2009, 29:525), psoriasis (see, e.g., Andres et al., Exp. Derm. 2013, 22(5):323), allergic disorders (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., J. Gastroenterol. 2013, 14(33):5110), and the like. al., Arierio. Thrombo., Vasc. Bio. 2011, 31:980), acute and chronic gout and gouty arthritis, neuropathies (see, e.g., Campbell, Brain Res. Rev. 2005, 48(2): 166), metabolic syndrome, immune deficiency disorders such as AIDS and HIV (see, e.g., O'Shea et al., N.Engl. J.Med. 2013, 368:161), destructive bone disorders (see, e.g., Jatiani et al., Genes & Can. 2011, 1(10):979), osteoarthritis, proliferative disorders, 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 disorders.

[0072] Proliferative disorders include, but are not limited to, benign or malignant tumors, solid tumors, liquid tumors, cancer of the brain, kidney, liver, adrenal gland, bladder, breast, stomach, gastric tumor, ovary, colon, rectum, prostate, pancreas, lung, vagina, cervix, testis, genitourinary tract, esophagus, larynx, skin, bone or thyroid, sarcoma, glioblastoma, neuroblastoma, multiple myeloma, gastrointestinal cancer, especially colon cancer or colorectal adenoma, tumors of the head and neck, epidermal hyperproliferation, psoriasis, prostatic hyperplasia, neoplasia of epithelial character), adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, large cell carcinoma, non-small cell lung cancer, lymphoma, Hodgkin and non-Hodgkin, breast adenocarcinoma, follicular adenocarcinoma, anaplastic carcinoma, papillary carcinoma, seminoma, melanoma, IL-I driven disorders, MyD88 driven disorders, asymptomatic multiple myeloma smoldering or hematological malignancies (including leukemia, diffuse large B cell lymphoma (DLBCL), ABC DLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma, primary effusion lymphoma, Burkitt lymphoma / leukemia, acute lymphocytic leukemia, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, Waldenstrom's macroglobulinemia (WM), splenic marginal zone lymphoma, multiple myeloma, plasmacytoma, intravascular large B cell lymphoma).

[0073] In some embodiments, the cancer to be 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 tumor (MPNST), and pancreatic cancer. In other embodiments, the cancer to be 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 tumor (MPNST), pancreatic cancer, non-small cell lung cancer (NSCLC), including EGFR-mutated NSCLC, urothelial cancer, liver cancer, cholangiocarcinoma, renal cancer, colon cancer, esophageal cancer, gastric cancer, gastrointestinal stromal tumor, and hematological malignancies include lymphoma, leukemia, myeloma, myeloproliferative neoplasm, and myelodysplastic syndrome. 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, cancer of the head and neck, thyroid cancer, glioblastoma, Kaposi's sarcoma, Castleman's disease, uterine leiomyosarcoma, melanoma, etc.), hematological cancers (e.g., lymphoma, leukemia (such as acute lymphoblastic 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 CTCL include Sezary syndrome and mycosis fungoides.

[0074] The compounds, salts and compositions described herein are also useful for treating inflammatory or obstructive airway diseases, for example, by reducing tissue damage, airway inflammation, bronchial hyperresponsiveness, remodeling or disease progression.Inflammatory or obstructive airway diseases include asthma of any type or origin, 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 after bacterial infection.Treatment of asthma should also be understood to include treatment of subjects, for example, under 4 or 5 years old, who show wheezing symptoms and are diagnosed or can be diagnosed as "wheezing infants", which is established in the patient classification of serious medical concern, and is now often identified as early or early stage asthma patients.

[0075] The compounds, salts and compositions described herein are also useful for treating heteroautoimmune diseases, including, but not limited to, graft versus host disease, transplants, blood transfusions, anaphylaxis, allergies (e.g., allergies to plant pollen, latex, drugs, foods, insect venom, animal hair, animal dander, house dust mites or cockroach calyces), hypersensitivity type I, allergic conjunctivitis, allergic rhinitis and atopic dermatitis.

[0076] The compounds, salts and compositions described herein are also useful for treating 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, airway or lung disease (COPD, COAD or COLD) (including chronic bronchitis or associated dyspnea), emphysema, and exacerbations of airway hyperresponsiveness secondary to other medications, particularly other inhaled medications. The compounds, salts and compositions described herein are also useful for treating bronchitis, including, but not limited to, acute bronchitis, arachidonic bronchitis, catarrhal bronchitis, croup bronchitis, chronic bronchitis or tuberculous bronchitis. The compounds, salts and compositions described herein are also useful for the treatment of pneumoconiosis (an inflammation of the lungs, whether chronic or acute, induced by repeated inhalation of dust, often accompanied by airway obstruction) of any type or origin, including, for example, aluminosis, anthracosis, asbestosis, lithiasis, trichiasis, hemosiderosis, silicosis, tobaccoosis and byssinosis.

[0077] 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.

[0078] The compounds, salts and compositions described herein may also be used to treat other diseases or conditions, such as diseases or conditions that have an inflammatory component, e.g., diseases and conditions of the eye, such as ocular allergies, conjunctivitis, keratoconjunctivitis sicca, and vernal conjunctivitis, diseases affecting the nose, including allergic rhinitis, and inflammatory diseases in which an autoimmune response is involved or that have an autoimmune component or etiology, including autoimmune hematological disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia, and idiopathic thrombocytopenia), systemic lupus erythematosus, rheumatoid arthritis, polychondritis, scleroderma, Wegener's disease, and the like. Bacteriofibroma, dermatomyositis, chronic active hepatitis, myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmune inflammatory bowel disease (e.g. ulcerative colitis and Crohn's disease), irritable bowel syndrome, celiac disease, periodontitis, hyaline membrane disease, renal 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 keratoconjunctivitis, psoriatic arthritis, systemic juvenile idiopathic keratoconjunctivitis, psoriatic arthritis, idiopathic keratoconjunctiv ... Arthritis, cryopyrin-associated periodic syndromes, nephritis, vasculitis, diverticulitis, interstitial cystitis, glomerulonephritis (e.g., with and without nephrotic syndrome, including 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 wasting, catabolic disorders, obesity, fetal growth retardation, hypercholesterolemia, heart disease, chronic heart failure, mesothelioma, anhidrotic ectodermal hypoplasia, Behcet's disease, incontinentia pigmenti, Paget's disease, pancreatitis, hereditary periodic fever syndromes, asthma (allergic and non-allergic, mild, moderate, severe bronchitis and exercise-induced), acute lung injury, acute respiratory distress syndrome, eosinophilia, hypersensitivity, anaphylaxis, sinusitis, ocular allergies, silica-induced disease, COPD (reduction of damage, airway inflammation, bronchial hyperresponsiveness, remodeling or disease progression), pulmonary disease, cystic fibrosis, acid-induced lung injury, pulmonary hypertension, polyneuropathy, cataracts, muscle inflammation 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, connective tissue inflammation, gastritis, gastroenteritis, Henoch-Schönlein purpura, hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy, interstitial lung disease, laryngitis, mastitis, meningitis, myelitis It is also useful in the treatment of myocarditis, myositis, nephritis, ovariitis, orchitis, osteitis, otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis, pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis, prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis, stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis, uveitis, vaginitis, vasculitis or vulvitis.

[0079] In some embodiments, cardiovascular diseases that may be treated by 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, occlusive peripheral arterial disease, pulmonary embolism, and deep vein thrombosis.

[0080] In some embodiments, neurodegenerative diseases that may be treated by 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 traumatic injury, glutamate neurotoxicity, hypoxia, epilepsy, treatment of diabetes, metabolic syndrome, obesity, organ transplantation, and graft-versus-host disease.

[0081] In certain aspects, the pharmaceutical compositions described herein are formulated for administration to a patient in need of such compositions. The pharmaceutical compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, orally, vaginally or via an implanted reservoir. The term "parenterally" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, 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 oleaginous suspensions. These suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents.

[0082] In some aspects, the pharmaceutical composition is administered orally.

[0083] The specific dosage and treatment regimen for any particular patient will depend on a variety of factors, including the activity of the specific compound used, age, body weight, general health, sex, diet, administration time, excretion rate, combination drug, as well as the judgment of the treating physician and the severity of the specific disease being treated. The amount of the compound described herein in the composition will also depend on the specific compound in the pharmaceutical composition. EXAMPLES

[0084] Preparation of compounds The compounds claimed herein were prepared according to the procedure outlined in the following scheme. The names of the compounds were generated using the software integrated in ChemDraw. To the extent that there is a difference between the name of the compound and its depicted structure, the depicted chemical structure should be considered as the appropriate compound.

[0085] Core synthesis

[0086] Synthesis of methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,4]diazocine-8-carboxylate [ka]

[0087] Step 1: Preparation of methyl (2S,5R)-1-((S)-4-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)butanoyl)-5-vinylpyrrolidine-2-carboxylate

[0088] A solution of (2S,5R)-methyl 5-vinylpyrrolidine-2-carboxylate hydrochloride (12.1 g, 63.1 mmol, 1.00 equiv.) in DCM (302 mL) was diluted with BOPCl (16.1 g, 63.1 mmol, 1.00 equiv.), NaHCO 3 (21.2 g, 252 mmol, 9.81 mL, 4.00 equiv.) and (S)-4-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)butanoic acid (20.0 g, 56.8 mmol, 0.90 equiv.) were added. The reaction mixture was heated to 40° C. The reaction mixture was stirred for 2 h and then concentrated under reduced pressure. The residue was purified by column chromatography (gradient elution, petroleum ether / EtOAc=1 / 0 to 0 / 1) to give methyl (2S,5R)-1-((S)-4-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)butanoyl)-5-vinylpyrrolidine-2-carboxylate (18.3 g, crude) as a light yellow gel. 1 H NMR (400 MHz, CDCl 3) δ 7.43 - 7.28 (m, 5H), 5.99 - 5.83 (m, 1H), 5.43 (br d, J = 17.0 Hz, 1H), 5.24 - 5.12 (m, 2H), 5.12 - 5.03 (m, 2H), 4.77 - 4.61 (m, 1H), 4.58 - 4.43 (m, 2H), 3.76 - 3.69 (m, 3H), 3.56 - 3.41 (m, 1H), 3.01 (tdd, J = 6.0, 9.4, 14.2 Hz, 1H), 2.27 - 2.13 (m, 2H), 2.02 - 1.91 (m, 2H), 1.88 - 1.80 (m, 1H), 1.68 - 1.55 (m, 2H), 1.42 (s, 9H).

[0089] Step 2: Preparation of methyl (2S,5R)-1-((S)-4-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)butanoyl)-5-formylpyrrolidine-2-carboxylate

[0090] Ozone (5 psi) was bubbled through a cooled (-40 °C) solution of methyl (2S,5R)-1-((S)-4-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)butanoyl)-5-vinylpyrrolidine-2-carboxylate (18.3 g, 37.4 mmol, 1.00 equiv) in DCM (183 mL). After 1 h, the reaction mixture was purged with N 2 (g) to remove excess ozone, then Et 3N (14.1 mL, 101 mmol, 2.71 equiv) was added. The reaction mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was concentrated in vacuo and the resulting residue was purified by column chromatography (gradient elution, petroleum ether / EtOAc = 0 / 1 to 1 / 0) to give methyl (2S,5R)-1-((S)-4-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)butanoyl)-5-formylpyrrolidine-2-carboxylate (13.7 g, 18.6 mmol, 49.7% yield for two steps, 66.6% purity) as a light yellow syrup. LCMS (ESI) m / z = 492.2 [M+H] +

[0091] Step 3: Preparation of methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,4]diazocine-8-carboxylate

[0092] To a solution of methyl (2S,5R)-1-((S)-4-(((benzyloxy)carbonyl)amino)-2-((tert-butoxycarbonyl)amino)butanoyl)-5-formylpyrrolidine-2-carboxylate (13.7 g, 18.6 mmol, 66.6% purity, 1.00 equiv.) in i-PrOH (137 mL) was added N 2 (g) Pd / C (6.30 g, 10.0% purity) was added. The suspension was subjected to evacuation and H 2 (g) (50 Psi) was applied for three cycles. The mixture was heated to 40°C. After 12 hours, the mixture was purged with N 2(g) was purged. The suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by preparative HPLC (column: Kromasil Eternity XT 250×80 mm×10 um; mobile phase: [water (ammonium hydroxide v / v)-acetonitrile]; B%: 10%-40%, 20 min) and lyophilized to give methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,4]diazocine-8-carboxylate (3.39 g, 9.38 mmol, 50.5% yield, 94.4% purity) as a white solid. LCMS (ESI) m / z=342.1 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 5.51 (br d, J = 8.0 Hz, 1H), 4.80 - 4.72 (m, 1H), 4.53 (t, J = 8.6 Hz, 1H), 4.30 - 4.21 (m, 1H), 3.76 (s, 3H), 3.16 - 3.08 (m, 1H), 2.99 - 2.84 (m, 3H), 2.34 - 2.28 (m, 1H), 2.20 - 2.16 (m, 2H), 2.06 - 1.89 (m, 2H), 1.77 - 1.59 (m, 2H), 1.42 (s, 9H).

[0093] Synthesis of (5R,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxooctahydro-4H-pyrrolo[2,1-d][1,5]thiazocine-8-carboxylic acid [ka]

[0094] Step 1: Preparation of (S)-tert-butyl 1-benzyl-5-oxopyrrolidine-2-carboxylate

[0095] To a cooled (0° C.) suspension of NaH (32.4 g, 810 mmol, 60% purity, 1.20 equiv.) in THF (250 mL) was added dropwise a solution of (S)-tert-butyl 5-oxopyrrolidine-2-carboxylate (125 g, 675 mmol, 1.00 equiv.) in THF (1.00 L). The mixture was warmed to 25° C. and stirred for 1 h. The mixture was then subsequently cooled to 0° C. and then benzyl bromide (88.2 mL, 742 mmol, 1.10 equiv.) was added dropwise. After the addition of benzyl bromide was complete, the reaction mixture was warmed to 25° C. and stirred for 2 h. Four batches of the same scale were performed and then combined for workup. The reaction mixture was washed with cold saturated aqueous NH 4 The biphasic mixture was extracted with EtOAc (500 mL×3) and the organic phases were combined. The combined organic layers were washed with brine (800 mL) and added Na 2 SO 4 The crude product was purified by column chromatography (gradient elution: petroleum ether / EtOAc = 1 / 0 to 50 / 1) and concentrated under reduced pressure to give (S)-tert-butyl 1-benzyl-5-oxopyrrolidine-2-carboxylate (397 g, 1.41 mol, 52.1% yield, 98.0% purity) as a yellow solid. LCMS (ESI) m / z = 275.9 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.34 - 7.28 (m, 3H), 7.23 - 7.21 (m, 2H), 5.06 (d, J = 14.8 Hz, 1H), 3.96 (d, J = 14.8 Hz, 1H), 3.85 - 3.82 (m, 1H), 2.56 - 2.44 (m, 1H), 2.43 - 2.41 (m, 1H), 2.24 - 2.19 (m, 1H), 2.06 - 2.04 (m, 1H), 1.44 (s, 9H).

[0096] Step 2: Preparation of (S)-tert-butyl 1-benzyl-5-thioxopyrrolidine-2-carboxylate

[0097] To a solution of (S)-tert-butyl 1-benzyl-5-oxopyrrolidine-2-carboxylate (179 g, 648 mmol, 1.00 equiv) in DCM (1.79 L) at 25 °C was added Lawesson's reagent (131 g, 324 mmol, 0.50 equiv). Two batches of the same scale were performed and subsequently combined for workup. After stirring for 4 h, the reaction mixture was filtered and the filtrate was concentrated under reduced pressure to give the crude product. The crude product was purified by column chromatography (gradient elution: petroleum ether / EtOAc = 1 / 0 to 50 / 1) to give (S)-tert-butyl 1-benzyl-5-thioxopyrrolidine-2-carboxylate (324 g, 1.11 mol, 85.5% yield, 99.7% purity) as a yellow solid. LCMS (ESI) m / z = 292.1 [M + H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 - 7.30 (m, 5H), 5.81 (d, J = 14.4 Hz, 1H), 4.28 (d, J = 14.8 Hz, 1H), 4.17 - 4.14 (m, 1H), 3.16 - 3.09 (m, 2H), 2.27 - 2.23 (m, 1H), 2.22 - 2.10 (m, 1H), 1.45 (s, 9H).

[0098] Step 3: Preparation of tert-butyl (S,Z)-1-benzyl-5-(2-methoxy-2-oxoethylidene)pyrrolidine-2-carboxylate

[0099] A solution of (S)-tert-butyl 1-benzyl-5-thioxopyrrolidine-2-carboxylate (58.0 g, 199 mmol, 1.00 equiv) and methyl bromoacetate (37.7 g, 247 mmol, 23.3 mL, 1.24 equiv) in acetonitrile (160 mL) was stirred at 25° C. After stirring for 40 h, the reaction mixture was diluted with dichloromethane (1.20 L) and cooled to 0° C. After an additional 10 min, PPh 3 (78.3 g, 298 mmol, 1.50 equiv.) and Et3 N (83.1 mL, 597 mmol, 3.00 equiv.) was added stepwise. The reaction mixture was allowed to warm to ambient temperature and stirred for 16 h. Six batches were run on the same scale and then combined for workup. The mixture was diluted with aqueous 1N NaH 2 PO 4 (2.00 L). The biphasic mixture was extracted with dichloromethane (800 mL×3). The combined organic layers were washed with brine (800 mL) and 2 SO 4 The residue was purified by column chromatography (gradient elution: petroleum ether / EtOAc = 80 / 1 to 15 / 1) to give tert-butyl (S,Z)-1-benzyl-5-(2-methoxy-2-oxoethylidene)pyrrolidine-2-carboxylate (255 g, 706 mmol, 59.2% yield, 91.8% purity) as a yellow oil. LCMS (ESI) m / z = 332.1 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.35 - 7.29 (m, 3H), 7.20 - 7.18 (m, 2H), 4.76 (s, 1H), 4.54 (d, J = 15.6 Hz, 1H), 4.20 (d, J = 15.6 Hz, 1H), 3.98 - 3.95 (m, 1H), 3.75 (s, 3H), 3.62 - 3.40 (m, 1H), 3.11 - 3.09 (m, 1H), 2.25 - 2.20 (m, 1H), 2.10 - 2.05 (m, 1H), 1.44 (s, 9H).

[0100] Step 4: Preparation of tert-butyl (2S,5R)-1-benzyl-5-(2-methoxy-2-oxoethyl)pyrrolidine-2-carboxylate

[0101] To a suspension of tert-butyl (S,Z)-1-benzyl-5-(2-methoxy-2-oxoethylidene)pyrrolidine-2-carboxylate (125 g, 377 mmol, 1.00 equiv) in EtOAc (1.25 L) was added N2 (g) 10% Pd / C (125 g) was added. The suspension was then evacuated and heated under H 2 (g) (50 psi) purging cycle was performed three times. 2 (g) (50 psi) at 25 °C. After stirring for 12 h, the mixture was evacuated and N 2 The mixture was subjected to three cycles of purging with (g) and filtering through a pad of Celite®. The filtrate was transferred to a separate container and purged with N 2 (g) Pt / C (125 g, 5% purity) was added to the suspension. 2 The reaction mixture was heated to 60° C. and purged with H 2 (50 Psi) for 16 h. Two batches were performed on the same scale and then combined for workup. The combined reaction mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography (gradient elution: petroleum ether / EtOAc = 80 / 1 to 30 / 1) to give tert-butyl (2S,5R)-1-benzyl-5-(2-methoxy-2-oxoethyl)pyrrolidine-2-carboxylate (119 g, 358 mmol, 47.5% yield, 100% purity) as a yellow oil. LCMS (ESI) m / z = 334.1 [M + H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.33 - 7.30 (m, 4H), 7.24 - 7.22 (m, 1H), 3.89 - 3.78 (m, 2H), 3.63 (s, 3H), 3.29 - 3.25 (m, 2H), 2.60 - 2.55 (m, 1H), 2.37 - 2.31 (m, 1H), 2.05 - 2.00 (m, 2H), 1.99 - 1.88 (m, 1H), 1.68 - 1.66 (m, 1H), 1.45 (s, 9H).

[0102] Step 5: Preparation of tert-butyl (2S,5R)-1-benzyl-5-(2-hydroxyethyl)pyrrolidine-2-carboxylate

[0103] To a cooled (0° C.) solution of tert-butyl (2S,5R)-1-benzyl-5-(2-methoxy-2-oxoethyl)pyrrolidine-2-carboxylate (58.5 g, 175 mmol, 1.00 equiv.) in THF (585 mL), 2 (g) Lower, LiBH 4 (2.00M, 175 mL, 2.00 equiv.) was added. The reaction mixture was warmed to 25° C. and stirred for 16 h. Two batches of the same scale were run and then combined for workup. The combined reaction mixture was diluted with aqueous 1N K 2 CO 3 (1.20 L) and extracted with EtOAc (800 mL×3). The combined organic layers were washed with brine (1.00 L) and diluted with Na 2 SO 4 The mixture was dried by filtration, filtered and concentrated to give a residue. The residue was purified by column chromatography (gradient elution: petroleum ether / EtOAc = 80 / 1 to 10 / 1) to give tert-butyl (2S,5R)-1-benzyl-5-(2-hydroxyethyl)pyrrolidine-2-carboxylate (60.0 g, 196 mmol) as a yellow oil. LCMS (ESI) m / z = 306.1 [M + H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 7.33 - 7.28 (m, 4H), 7.26 - 7.24 (m, 1H), 4.09 - 4.00 (m, 2H), 3.76 - 3.73 (m, 1H), 3.58 - 3.55 (m, 1H), 3.30 - 3.28 (m, 1H), 3.27 - 3.21 (m, 1H), 2.08 - 2.04 (m, 2H), 1.91 - 1.87 (m, 3H), 1.55 - 1.54 (m, 1H), 1.50 (s, 9H).

[0104] Step 6: Preparation of tert-butyl (2S,5R)-1-benzyl-5-(2-((methylsulfonyl)oxy)ethyl)pyrrolidine-2-carboxylate

[0105] To a cooled (-10 °C) solution of tert-butyl (2S,5R)-1-benzyl-5-(2-hydroxyethyl)pyrrolidine-2-carboxylate (29.5 g, 96.6 mmol, 1.00 equiv) in DCM (295 mL) was added methanesulfonyl chloride (11.7 mL, 151 mmol, 1.57 equiv), DMAP (590 mg, 4.83 mmol, 0.05 equiv) and Et 3 N (40.3 mL, 290 mmol, 3.00 equiv) was added. The mixture was warmed to 25° C. and stirred for 1 h. Two batches on the same scale were run and then combined for workup. The reaction mixture was combined and diluted with dichloromethane (800 mL). The resulting mixture was washed with 0.5 N HCl (1.00 L) and saturated aqueous NaHCO 3 (1.00 L) and brine (1.00 L) to remove Na 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure afforded tert-butyl (2S,5R)-1-benzyl-5-(2-((methylsulfonyl)oxy)ethyl)pyrrolidine-2-carboxylate (72.0 g, crude) as a yellow oil. LCMS (ESI) m / z=384.1 [M+H] +

[0106] Step 7: Preparation of S-(2-((2R,5S)-1-benzyl-5-(tert-butoxycarbonyl)pyrrolidin-2-yl)ethyl)-N-(tert-butoxycarbonyl)-L-cysteine

[0107] To a cooled (0 °C) solution of tert-butyl (2S,5R)-1-benzyl-5-(2-((methylsulfonyl)oxy)ethyl)pyrrolidine-2-carboxylate (20.8 g, 93.9 mmol, 1.00 equiv) in DMF (360 mL), was added N 2(g) NaH (7.51 g, 187 mmol, 60% purity, 2.00 equiv.) was added in small portions. The mixture was stirred at 0° C. for 1 h, then a solution of (tert-butoxycarbonyl)-L-cysteine ​​(36.0 g, 93.9 mmol, 1.00 equiv.) in DMF (360 mL) was added. The mixture was warmed to 25° C. and stirred for 1 h. Two batches of the same scale were performed and then combined for workup. The reaction mixtures were combined and the pH of the mixture was adjusted (to pH approx. 2) with aqueous 1N HCl. The acidic mixture was extracted with EtOAc (2.00 L×2). The combined organic layers were washed with brine (2.00 L) and Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by column chromatography (gradient elution; petroleum ether / EtOAc=20 / 1 to 0 / 1) to give S-(2-((2R,5S)-1-benzyl-5-(tert-butoxycarbonyl)pyrrolidin-2-yl)ethyl)-N-(tert-butoxycarbonyl)-L-cysteine ​​(92.0 g, crude) as a yellow oil. LCMS (ESI) m / z=509.2 [M+H] +

[0108] Step 8: Preparation of N-(tert-butoxycarbonyl)-S-(2-((2R,5S)-5-(tert-butoxycarbonyl)pyrrolidin-2-yl)ethyl)-L-cysteine

[0109] To a solution of S-(2-((2R,5S)-1-benzyl-5-(tert-butoxycarbonyl)pyrrolidin-2-yl)ethyl)-N-(tert-butoxycarbonyl)-L-cysteine ​​(46.0 g, 90.4 mmol, 1.00 equiv) in MeOH (460 mL), 2 (g) Raney-Ni (46.0 g) was added. The suspension was then evacuated and heated under H 2 The mixture was subjected to three cycles of purging with H 2 (g) (50 Psi) at 60° C. After stirring for 16 h, the mixture was agitated with N 2 (g) was purged and filtered. The filtrate was transferred to a reaction vessel and N2 (g) Raney-Ni (92.0 g) was added to the filtrate. The suspension was then subjected to evacuation and H 2 The mixture was heated to 80° C. and purged with H 2 (g) (50 Psi) for 40 h at 80° C. LCMS analysis showed approximately 54.0% S-(2-((2R,5S)-1-benzyl-5-(tert-butoxycarbonyl)pyrrolidin-2-yl)ethyl)-N-(tert-butoxycarbonyl)-L-cysteine ​​(Rt=0.582 min) remaining with the desired MS (Rt=0.487 min). The mixture was filtered and purified with N 2 (g) Raney-Ni (46.0 g) was added to the filtrate. The suspension was degassed under vacuum and H 2 The mixture was heated to 80° C. and purged with H 2 Stirred at 80° C. under (50 Psi) for 40 h. LCMS analysis showed 39.0% S-(2-((2R,5S)-1-benzyl-5-(tert-butoxycarbonyl)pyrrolidin-2-yl)ethyl)-N-(tert-butoxycarbonyl)-L-cysteine ​​(Rt=0.584 min) remaining with the desired MS (Rt=0.492 min). Two batches were run on the same scale and then combined for workup. The reaction mixture was filtered and the combined filtrate was concentrated to give a residue that gave N-(tert-butoxycarbonyl)-S-(2-((2R,5S)-5-(tert-butoxycarbonyl)pyrrolidin-2-yl)ethyl)-L-cysteine ​​(59.0 g, crude) as a yellow solid. LCMS(ESI)m / z=419.2[M+H] + .

[0110] Step 9: Preparation of tert-butyl (5R,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxooctahydro-4H-pyrrolo[2,1-d][1,5]thiazocine-8-carboxylate

[0111] To a cooled (0° C.) solution of N-(tert-butoxycarbonyl)-S-(2-((2R,5S)-5-(tert-butoxycarbonyl)pyrrolidin-2-yl)ethyl)-L-cysteine ​​(14.5 g, 34.6 mmol, 1.00 equiv.) in DCM (1.50 L) was added PyBOP (54.1 g, 104 mmol, 3.00 equiv.) and DIPEA (24.9 g, 192 mmol, 33.5 mL, 5.55 equiv.). The mixture was then warmed to 25° C. and stirred for 3 h. Four batches of the same scale were performed and then combined for workup. The reaction mixture was poured into aqueous 0.5 N HCl (4.50 L) and extracted with dichloromethane (2.00 L×2). The combined organic layers were washed with saturated NaHCO 3 The combined organic layers were washed with brine (1.00 L) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by column chromatography (gradient elution: petroleum ether / EtOAc=1 / 0 to 20 / 1) and concentrated under reduced pressure to give tert-butyl (5R,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxooctahydro-4H-pyrrolo[2,1-d][1,5]thiazocine-8-carboxylate (12.6 g, 31.1 mmol, 22.4% yield, 98.8% purity) as a white solid. LCMS (ESI) m / z=401.1 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 5.98 - 5.96 (m, 1H), 4.69 - 4.68 (m, 1H), 4.66 - 4.58 (m, 1H), 4.40 - 4.35 (m, 1H), 2.94 - 2.90 (m, 2H), 2.76 - 2.74 (m, 2H), 2.73 - 2.74 (m, 1H), 1.99 - 1.96 (m, 3H), 1.71 - 1.67 (m, 2H), 1.48 - 1.42 (m, 18H).

[0112] Step 10: Preparation of (5R,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxooctahydro-4H-pyrrolo[2,1-d][1,5]thiazocine-8-carboxylic acid

[0113] To a cooled (0° C.) solution of tert-butyl (5R,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxooctahydro-4H-pyrrolo[2,1-d][1,5]thiazocine-8-carboxylate (6.30 g, 15.7 mmol, 1.00 equiv) in DCM (64.0 mL) was added triisopropylsilane (323 uL, 1.57 mmol, 0.10 equiv), followed by a solution of TFA (143 mL, 1.93 mol, 123 equiv) in DCM (64.0 mL). The reaction mixture was stirred for 1 h and then concentrated to give an oil. The resulting amino acid (oil) was diluted with acetonitrile (176 mL) and H 2 2H 2 O (8.80 mL) and then diluted with Et 3 N (17.7 mL, 127 mmol, 8.10 equiv.) and Boc 2 2H2O (10.3 g, 47.2 mmol, 10.8 mL, 3.00 equiv.) was added. The mixture was warmed to 25° C. for 2 h. Two batches on the same scale were run and then combined for workup. The reaction mixtures were combined and concentrated under reduced pressure. The resulting residue was purified by H 2 The aqueous layer was adjusted to pH ∼2 with aqueous 1N HCl and extracted with EtOAc (50.0 mL×3). The combined organic layers were washed with brine (40.0 mL×2) and diluted with 1H2O (80.0 mL) and extracted with EtOAc (60.0 mL×2). The aqueous layer was adjusted to pH ∼2 with aqueous 1N HCl and extracted with EtOAc (50.0 mL×3). The combined organic layers were washed with brine (40.0 mL×2) and diluted with Na 2 SO 4 The residue was dried over H, filtered and concentrated under reduced pressure to give a residue. 2Dilution with 20H2O (20.0 mL) and acetonitrile (6.00 mL) and lyophilization afforded (5R,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxooctahydro-4H-pyrrolo[2,1-d][1,5]thiazocine-8-carboxylic acid (5.50 g, 15.4 mmol, 48.9% yield, 96.4% purity) as a white solid. LCMS (ESI) m / z=367.1 [M+Na] + ; 1 H NMR (400 MHz, CDCl 3 ) δ 6.10 (brs, 1H), 5.87 - 5.85 (m, 1H), 4.73 - 4.70 (m, 2H), 4.68 - 4.58 (m, 1H), 2.98 - 2.94 (m, 2H), 2.89 - 2.74 (m, 1H), 2.72 - 2.71(m, 1H), 2.54 - 2.38(m, 2H), 2.05 - 2.02 (m, 1H), 1.89 - 1.86 (m, 2H), 1.75 - 1.48 (m, 1H), 1.44 (s, 9H).

[0114] (5S,8S,10aR)-3-acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid: [ka]

[0115] It is commercially available: CAS2497590-06-2

[0116] Synthesis of the linker

[0117] Steps for the synthesis of the linker:

[0118] The following intermediates in Table 1 were prepared according to the protocols described in WO2020 / 205467. [Table 1]

[0119] Synthesis of (E)-3-(4-((diethoxyphosphoryl)difluoromethyl)phenyl)acrylic acid [ka]

[0120] (E)-3-(4-((diethoxyphosphoryl)difluoromethyl)phenyl)acrylic acid was prepared according to the protocol described in US2004 / 0225146.

[0121] Representative Procedure for the Preparation of Activated Ester Phosphonic Acids

[0122] Synthesis of (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid [ka]

[0123] Step 1: Preparation of 4-nitrophenyl 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate

[0124] CH 2 Cl 2 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 10 mL of ethyl acetate 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 separated into CH 2 Cl 2(10 mL x 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-d 6 ) 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).

[0125] Step 2: Preparation of (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid

[0126] 4-Nitrophenyl 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (4.47 g, 9.20 mmol) in cooled (0 °C) CH 2 Cl 2 (39 mL) solution was dissolved in CH 2 Cl 2 (10 mL) of water was added as a solution. The reaction mixture was allowed to warm slowly to ambient temperature. The reaction mixture was diluted with 2:1 H 2A mixture of O / acetonitrile (containing 0.1% TFA) (50 mL) was added 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 and the solid was washed with a 2:1 mixture of acetonitrile / water solution and the solid was dried under reduced pressure to give [difluoro({2-[(4-nitrophenoxy)carbonyl]-1-benzothiophen-5-yl})methyl]phosphonic acid (6.5 g, 94%) as a beige solid. The filtrate was concentrated to 50% of the solvent volume and the resulting suspension was filtered and washed with 1:2 acetonitrile / water solution. The solid was dried under reduced pressure to give additional [difluoro({2-[(4-nitrophenoxy)carbonyl]-1-benzothiophen-5-yl})methyl]phosphonic acid (0.4 g) as a beige solid. Both products were lyophilized to give (difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (6.90 g, 16.0 mmol, 98.0% yield). 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0127] The following intermediates in Table 2 were prepared using a protocol similar to that outlined above for the synthesis of [difluoro({2-[(4-nitrophenoxy)carbonyl]-1-benzothiophen-5-yl})methyl]phosphonic acid, utilizing the appropriate previous intermediate as the starting material. [Table 2]

[0128] Synthesis of ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid [ka]

[0129] Preparation of 5-methylbenzo[b]thiophene-2-carboxylic acid

[0130] 5-Methylbenzo[b]thiophene-2-carboxylic acid was prepared according to the procedure described in WO2016 / 100184(A1).

[0131] Step 1: Preparation of benzyl 5-methylbenzo[b]thiophene-2-carboxylate

[0132] 5-Methylbenzo[b]thiophene-2-carboxylic acid (21.2 g, 110.0 mmol, 1.0 equiv.) and K 2 CO 3 To a solution of (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 h. The reaction mixture was poured into ice water (400 mL) and stirred for 5 min. The resulting solid was filtered, the filter cake was washed with water (50 mL), and dried in vacuum to give benzyl 5-methylbenzo[b]thiophene-2-carboxylate (30.1 g, 106.0 mmol, 97% yield) as a yellow solid. 1 H NMR (400 MHz, CDCl 3 ) 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).

[0133] Step 2: Preparation of benzyl 5-(bromomethyl)benzo[b]thiophene-2-carboxylate

[0134] 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 CCl 4 To the (30 mL) solution was added benzoyl peroxide (1.3 g, 5.31 mmol, 0.1 equiv.). The reaction flask was evacuated and N 2 The mixture was subjected to three cycles of back-filling with (g). 2 The mixture was stirred at 80° C. under a constant atmosphere of (g) 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.

[0135] Step 3: Preparation of benzyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0136] 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, CDCl 3 ) 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).

[0137] Step 4: Preparation of 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0138] THF (80 mL) and H 2 To a solution of benzyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (5.6 g, 13.3 mmol, 1.0 equiv.) in a mixture of 2,4-dichlorophenyl ether (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 (pH adjusted to about 3-4) with an aqueous solution of 1N HCl. Upon acidification, the product precipitated out of solution. The resulting solid was filtered, the filter cake was washed with water (20 mL x 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] + .

[0139] Step 5: Preparation of perfluorophenyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0140] 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (3.9 g, 11.8 mmol, 1.0 equiv.) in cooled (0 °C) CH 2 Cl 2 (50 mL) solution was added oxalyl chloride (2.2 g, 17.7 mmol, 1.5 equiv.) followed by 2 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 extracted with CH 2 Cl 2 (50 mL) and then 3 N (3.6 g, 35.4 mmol, 3.0 equiv.) and pentafluorophenol (2.6 g, 14.1 mmol, 1.2 equiv.) were added. The resulting mixture was stirred at room temperature for an additional 2 h, followed by H 2The biphasic solution was extracted with EtOAc (30 mL x 3). The combined organic layers were washed with MgSO 4 After drying at 40° C., filtration and concentration under reduced pressure, the residue was purified by column chromatography on silica gel to give perfluorophenyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (4.7 g, 9.5 mmol, 81% yield) as a white solid. LCMS (ESI) m / z=419 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) 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).

[0141] Step 6: Preparation of ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid

[0142] CH of perfluorophenyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (4.7 g, 9.5 mmol, 1.0 equiv.) 2 Cl 2 To the (60 mL) solution 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 C18 column chromatography to give ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (3.7 g, 8.4 mmol, 89% yield) as a white solid. LCMS (ESI) m / z=439 [M+H] + .

[0143] 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]

[0144] Step 1: benzyl rac-5-((diethoxyphosphoryl)(hydroxy)methyl)benzo[b]thiophene-2-carboxylate

[0145] 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 THF 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 the addition of the base was complete. The mixture was stirred for an additional 10 min and then washed with aqueous saturated NH 4 Cl (50 mL) was added. 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 x 2). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. Additional batches on the same scale were performed 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 benzyl rac-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, CDCl 3) 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).

[0146] Step 2: benzyl rac-5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate

[0147] rac-5-((diethoxyphosphoryl)(hydroxy)methyl)benzyl benzo[b]thiophene-2-carboxylate (cc) (1.56 g, 3.59 mmol, 1 equiv.) in cooled (−78 °C) CH 2 Cl 2 (30mL) solution (N 2 (g) below) was added (diethylamino)sulfur trifluoride (568 μL, 4.30 mmol, 1.2 equiv). The reaction was stirred for 15 min and then washed with saturated aqueous NaHCO 3 (50 mL) was added. After warming to room temperature, the product was 2 Cl 2 (50 mL x 3). The combined organic layers were dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude residue was purified by reverse phase chromatography on a C18 cartridge (eluted with 5-80% acetonitrile in water) to give benzyl rac-5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (650 mg, 1.48 mmol, 41.6%) as a viscous, clear oil. LCMS (ESI) m / z=873.2 [2M+H] + ; 1 H NMR (400 MHz, CDCl 3) 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).

[0148] Step 3: Preparation of (R)-benzyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate and (S)-benzyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate

[0149] Benzyl rac-5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (650 mg, 1.48 mmol) was subjected to chiral SFC separation (column: Lux i-Amylose3, 21.2 × 250 mm 5um column, 75mL / min, 40% MeOH) gave (R)- or (S)-benzyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (304mg, 0.70mmol, 46.8% recovery, 99.9%ee) as a viscous clear oil (peak 1) and (R)- or (S)-benzyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (317mg, 0.73mmol, 49% recovery, 99.9%ee) as a viscous clear oil (peak 2). NOTE: The enantiomer eluting fastest by SFC was arbitrarily assigned as (R)-5-(fluoro(phosphono)methyl)benzo[b]thiophene-2-carboxylic acid, and the enantiomer eluting slowest by SFC was arbitrarily assigned as (S)-5-(fluoro(phosphono)methyl)benzo[b]thiophene-2-carboxylic acid.

[0150] HPLC method for analyzing enantiomeric excess: Lux Cellulose-3 150mm 45%H 2 O+0.05% TFA / 55% MeCN 1 mL / min for 8 min.

[0151] Step 4: Preparation of (R)- or (S)-5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0152] A mixture of 10% Pd / C (60 mg, 50% wet) and (R)-benzyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (peak 1) (60 mg, 0.1374 mmol, 1 equiv.) in THF (5 mL) was diluted with N 2 (g) for 5 minutes. 2 (g) was vented for 5 min and then the reaction was diluted with H 2 (g) (1 atm) at room temperature. The reaction mixture was stirred until the consumption of the starting material was detected by LCMS. The reaction mixture was then added with N 2 (g) was sprayed 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] + .

[0153] The following intermediates in Table 3 were prepared using the procedure outlined above (in step 4) starting from (S)- or (R)-benzyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (peak 2) using the appropriate reagents. [Table 3]

[0154] Representative methods for the synthesis of activated linkers

[0155] Method 1: Stepwise acid chloride approach for the synthesis of mixed linkers

[0156] Representative Procedure for the Synthesis of 4-Nitrophenyl 5-(((2-(butyrylthio)ethoxy)(pyridin-3-yloxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate [ka]

[0157] Step 1: Preparation of 4-nitrophenyl 5-(difluoro(hydroxy(pyridin-3-yloxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0158] (Difluoro(2-((4-nitrophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (100 mg, 0.2329 mmol, 1 equiv.) was dissolved in cold (0 °C) heterogeneous CH 2 Cl 2 To the (4 mL) solution was added catalyst DMF (2 drops) followed by 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. The yellow solid was purified by HPLC using HCl as a distillation buffer. 2 Cl 2 (4 mL) and cooled to -78 °C. Pyridin-3-ol (22.0 mg, 232 μmol, 1 equiv.) and triethylamine (64.7 μL, 465 μmol, 2 equiv.) in CH 2 Cl 2(1 mL) solution [sonicated for 1 min to dissolve] was added slowly. The homogeneous reaction mixture was stirred at -78°C for 2 min, then warmed to ambient temperature and stirred overnight. After 24 h the reaction mixture became heterogeneous and the reaction was concentrated under reduced pressure. The crude product, 4-5-(nitrophenyl 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] + .

[0159] Step 2: Preparation of 4-nitrophenyl 5-(((2-(butyrylthio)ethoxy)(pyridin-3-yloxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate

[0160] 5-(difluoro(hydroxy(pyridin-3-yloxy)phosphoryl)methyl)benzo[b]thiophene-2-nitrophenyl carboxylate (117 mg, 0.2329 mmol, 1 equiv.) in cooled (0 °C) CH 2 Cl 2 To the (5 mL) solution 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 purified by HPLC using HCl. 2 Cl 2 (5 mL) and cooled to -78 °C. The cooled solution was added with CH 2 Cl 2 (1mL) [Anhydrous Na 2 SO 4A solution of 1-[(2-hydroxyethyl)sulfanyl]butan-1-one (103 mg, 698 μmol, 3 equiv.) diluted in hexane (previously dried by passing through a 300 sieve) was slowly added followed by triethylamine (134 μL, 967 μmol, 2 equiv.). After stirring for 2 min, the resulting mixture was allowed to warm to ambient temperature and stirred overnight. To the mixture was added Celite® 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] + ; 1 H NMR: (400 MHz, DMSO-d 6 ) 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).

[0161] The following intermediates in Table 4 were prepared using a similar protocol described above for the synthesis of 4-nitrophenyl 5-(((2-(butyrylthio)ethoxy)(pyridin-3-yloxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate utilizing the appropriate previous intermediate as the starting material. [Table 4-1] [Table 4-2]

[0162] Method 2: One-pot acid chloride method for the synthesis of activated linkers

[0163] Representative Procedure for the Synthesis of Perfluorophenyl 5-((bis(4-((3-methylbutanoyl)thio)butoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate [ka]

[0164] Dry CH 2 Cl 2 To a cooled (0° C.) solution of 3 (200 mg, 0.42 mmol, 1.0 equiv.) in DMF (15 mL) and catalyst DMF (3.2 μL, 42.1 μmol, 0.1 equiv.) was added dropwise oxalyl chloride (266 mg, 2.10 mmol, 5.0 equiv.). 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 purified by elution with anhydrous CH 2 Cl 2 (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 N,N-diisopropylethylamine (217 mg, 1.68 mmol, 4.0 equiv) in anhydrous CH 2 Cl 2 (10 mL) solution was added. The reaction mixture was allowed to warm to room temperature and stirred for an additional 18 h. 2 The reaction was quenched by adding O (10 mL) and CH 2 Cl 2 (3×10 mL). The combined organic layers were washed with brine (20 mL) and anhydrous Na 2 SO 4The 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] + .

[0165] The following intermediates in Table 5 were prepared using a similar protocol described above for the synthesis of perfluorophenyl 5-((bis(4-((3-methylbutanoyl)thio)butoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate utilizing the appropriate previous intermediate as the starting material. [Table 5]

[0166] Method 3: One-pot silver salt method for the synthesis of activated linkers

[0167] Representative Procedure for the Synthesis of Perfluorophenyl 5-((bis(((isopropoxycarbonyl)oxy)methoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate [ka]

[0168] Step 1: Preparation of ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonate silver(I)

[0169] Deionized H 2 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 2O (4 mL) and THF (2 mL) was added Amberlite IR120® resin (Na +The resulting mixture was stirred at room temperature for 1 h, and then the suspension was filtered. The filtrate was diluted with AgNO 3 (463 mg, 2.73 mmol, 4.0 equiv.) of deionized H 2 A solution of 2 mL of HO was added and the resulting mixture was stirred at room temperature for an additional 1 h. The formation of a white precipitate was observed and the solid was collected by filtration. The filter cake was then diluted with cold H 2 After washing with O (3 × 2 mL) and drying the solid under reduced pressure, silver ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonate (I) was obtained as a dry powder. This silver salt was used without further purification.

[0170] Step 2: Preparation of perfluorophenyl 5-((bis(((isopropoxycarbonyl)oxy)methoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0171] Silver ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonate (I) was suspended in anhydrous toluene (10 mL) and added dropwise to iodomethyl 2-methylpropanoate (500 mg, 2.05 mmol, 3.0 equiv). After addition, the resulting mixture was stirred at room temperature for an additional 12 h. The reaction progress was monitored by LCMS, and upon completion, the unreacted silver salt was collected by filtration. The filtrate solution was concentrated in vacuo and the resulting residue was purified by reverse phase chromatography [C18 column gradient elution water / acetonitrile=90% to 1%] to give 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, CDCl 3) 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).

[0172] The following intermediates in Table 6 were prepared using a similar protocol described above for the synthesis of perfluorophenyl 5-((bis(4-((3-methylbutanoyl)thio)butoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate utilizing the appropriate previous intermediate as the starting material. [Table 6-1] [Table 6-2] [Table 6-3]

[0173] (R)- or (S)-5-((bis((pivaloyloxy)methoxy)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid [ka]

[0174] Step 1: Preparation of (R)- or (S)-((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid

[0175] (R)- or (S)-benzyl 5-((diethoxyphosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylate (peak 1) (205 mg, 0.4697 mmol) in cooled (0 °C) CH 2 Cl 2(8.0 mL) solution was diluted with BSTFA (746 μL, 2.81 mmol) followed by trimethylsilyl iodide (1.87 mL, 1.87 mmol) in 1.0 M CH 2 Cl 2 solution was added. 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 give (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-d 6 ) 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).

[0176] Step 2: Preparation of (R)- or (S)-((2-((benzyloxy)carbonyl)benzo[b]thiophen-5-yl)fluoromethyl)phosphonic acid

[0177] [The following reaction was carried out in a foil covered vessel 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 a solution of aqueous 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 dark yellow powder was suspended in toluene (10 mL) and iodomethyl 2,2-dimethylpropanoate (191 μL, 1.28 mmol, 3 equiv.) was added. The reaction mixture was stirred for 20 h and then 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 give (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, CDCl 3 ) 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).

[0178] Step 3: Preparation of (R)- or (S)-5-((bis((pivaloyloxy)methoxy)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid

[0179] 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) was added N 2 (g) 10% Pd / C (50% wet, 120 mg, 0.1127 mmol, 0.56 equiv.) was added to the suspension. 2 (g) was aerated for 5 min. The reaction mixture was then cooled to 100° C. 2 The reaction mixture was stirred at room temperature under (g) (1 atm). After stirring for 22 h, the reaction mixture was 2 (g) was purged 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.

[0180] The following intermediates in Table 7 were prepared using a similar protocol described above for the synthesis of (R)- or (S)-5-((bis((pivaloyloxy)methoxy)phosphoryl)fluoromethyl)benzo[b]thiophene-2-carboxylic acid, utilizing the appropriate previous intermediate as the starting material. The absolute configuration of the starting material (R)- or (S)-((2-((benzyloxy)carbonyl)benzo[b]thiophene-5-yl)fluoromethyl)phosphonic acid was not determined, but the elution peak ("Peak 1" or "Peak 2") of the starting material utilized is indicated in the table. [Table 7]

[0181] Method 4: Stepwise silver salt method for the synthesis of mixed linkers

[0182] Representative Procedure for Perfluorophenyl 5-(((2-(butyrylthio)ethoxy)(2-(pivaloylthio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate [ka]

[0183] Step 1: Preparation of perfluorophenyl 5-(difluoro(hydroxy(2-(pivaloylthio)ethoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate silver(I) (Difluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonate was prepared starting from (difluoro(2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid using the method described in Method 3, step 1 for the synthesis of ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonate silver(I).

[0184] To a suspension of ((2-((perfluorophenoxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonate silver(I) (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.) dropwise. After complete addition of the alcohol, the resulting mixture was stirred for an additional 12 h at room temperature. 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] - .

[0185] Step 2: Preparation of perfluorophenyl 5-(((2-(butyrylthio)ethoxy)(2-(pivaloylthio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate

[0186] Perfluorophenyl 5-(((2-(butyrylthio)ethoxy)(2-(pivaloylthio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate was synthesized using a similar protocol outlined above. Perfluorophenyl 5-(difluoro(hydroxy(2-(pivaloylthio)ethoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (190 mg, 307 μmol, 1.0 equiv.), AgNO 3 Starting with S-(2-iodoethyl)butanethioate (207 mg, 1.22 mmol, 4.0 equiv.) and S-(2-iodoethyl)butanethioate (94.9 mg, 368 μmol, 1.2 equiv.), perfluorophenyl 5-(((2-(butyrylthio)ethoxy)(2-(pivaloylthio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate (55.0 mg, 73.4 μmol, 24%) was produced as a white solid. LCMS (ESI) m / z=749 [M+H] + .

[0187] The following intermediates in Table 8 were prepared using a similar protocol described above for the synthesis of perfluorophenyl 5-(((2-(butyrylthio)ethoxy)(2-(pivaloylthio)ethoxy)phosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylate utilizing the appropriate previous intermediate as the starting material. [Table 8]

[0188] Preparation of 5-(((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid [ka]

[0189] Step 1: Preparation of allyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0190] 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid (1.0 g, 3.0 mmol, 1.0 equiv.) and K 2 CO 3 To a suspension of (839 mg, 6.1 mmol, 2.0 equiv.) 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 washed with Na 2 SO 4 After drying at 40° C., filtration and concentration under reduced pressure, the residue was purified by column chromatography to give allyl 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (0.980 g, 2.7 mmol, 88% yield) as a light yellow solid. LCMS (ESI) m / z=369 [M+H] + ; 1 H NMR (400 MHz, CDCl 3 ) 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).

[0191] Step 2: Preparation of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid

[0192] CH of 5-((diethoxyphosphoryl)methyl)benzo[b]thiophene-2-carboxylate (980 mg, 2.7 mmol, 1.0 equiv.) 2 Cl 2 (15 mL) solution was added bromotrimethylsilane (3 mL). The mixture was stirred at room temperature for 14 hours and then concentrated under reduced pressure. The resulting residue was 2 The mixture was triturated with 200 mL of H2O (5 mL) and the resulting precipitate was filtered. The filter cake was diluted with H2O and the precipitate was collected by filtration. 2 Washing with O (5 mL x 2) and drying under reduced pressure gave ((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-d 6 ) 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).

[0193] Step 3: Preparation of allyl 5-(((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0194] Dissolve ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (2.80 g, 8.96 mmol, 1 equiv.) and DMF catalyst (1 drop) in cooled (0 °C) and dry CH 2 Cl 2 (50mL) solution (N 2(g)) was added oxalyl chloride (3.40 g, 26.8 mmol, 3 equiv.). After gas bubbling 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 purified by HCl. 2 Cl 2 (50 mL) and cooled to 0° C. To this cooled solution was added phenol (0.843 g, 8.96 mmol, 1 equiv) and Et 3 N (4.53 g, 44.8 mmol, 5 equiv.) was added. After the addition was complete, the mixture was warmed to room temperature and stirred for 1 h, and then propan-2-yl(2S)-2-aminopropanoate (1.75 g, 13.4 mmol, 1.5 equiv.) was introduced into the mixture. After stirring for an additional 2 h, the mixture was concentrated to dryness.

[0195] The residue was purified by C18 column (eluted with 50%-80% acetonitrile in water) to give allyl 5-(((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate (2.23 g, 4.44 mmol, 49.6% yield) as a white solid. LCMS (ESI) m / z=502.0 [M+H] + ; 1 H NMR (400 MHz, CDCl 3) 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).

[0196] Step 4: Preparation of 5-(((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0197] 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 3 ) 4 (10.3 mg, 8.97 μmol, 0.05 equiv.) 2 Cl 2 (5 mL) solution, 2 The mixture was stirred under reduced pressure (g). After 2 h, the reaction was concentrated in vacuo. The residue was purified by C18 column (eluted with 30%-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] + .

[0198] The following intermediates in Table 9 were prepared using the appropriate starting materials and modifications described above for the synthesis of 5-(((((S)-1-isopropoxy-1-oxopropan-2-yl)amino)(phenoxy)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid. [Table 9]

[0199] Synthetic scheme: Preparation of 5-[1-(diethoxyphosphoryl)-2-hydroxyethyl]-1-benzothiophene-2-carboxylic acid [ka]

[0200] Step 1: Benzyl 5-[1-(diethoxyphosphoryl)-2-hydroxyethyl]-1-benzothiophene-2-carboxylate

[0201] 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 a solution of sodium bis(trimethylsilylamide) (1 M in THF) (1.43 mL, 1.43 mmol, 3.0 equiv.) dropwise. The reaction was stirred at −78° C. for 5 min, then 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 h. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (10 mL) at −78° C., then the ice bath was removed. The product was extracted with ethyl acetate (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 viscous, colorless oil. LCMS: m / z=449.2 (M+H). + ; 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0202] Step 2: 5-[1-(diethoxyphosphoryl)-2-hydroxyethyl]-1-benzothiophene-2-carboxylic acid

[0203] A mixture of 10% palladium on carbon (50% wet) (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 min. Hydrogen was bubbled in for 5 min, then the reaction was stirred under hydrogen (1 atm) at room temperature for 20 h. 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 of C1H2O, eluted with 5-80% MeCN in water (containing 0.1% formic acid). 18Purification by reverse phase chromatography on a cartridge, followed by concentration under reduced pressure and lyophilization afforded 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-d 6 ) 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).

[0204] Synthetic scheme: 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]

[0205] Step 1: benzyl rac-5-[1-(diethoxyphosphoryl)ethyl]-1-benzothiophene-2-carboxylate and benzyl 5-[2-(diethoxyphosphoryl)propan-2-yl]-1-benzothiophene-2-carboxylate

[0206] 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. was added a solution of sodium bis(trimethylsilylamide) (1 M in THF) (1.43 mL, 1.43 mmol, 3 equiv.) 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 solution (10 mL). The product was extracted with ethyl acetate (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). 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. rac-5-[1-(diethoxyphosphoryl)ethyl]-1-benzothiophene-2-carboxylate LCMS: m / z=433.0 (M+H). + . 1 H NMR (400 MHz, DMSO-d 6) 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).

[0207] Benzyl 5-[2-(diethoxyphosphoryl)propan-2-yl]-1-benzothiophene-2-carboxylate: LCMS: m / z=447.0 (M+H) + . 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0208] Step 2: rac-5-[1-(diethoxyphosphoryl)ethyl]-1-benzothiophene-2-carboxylic acid

[0209] A mixture of 10% palladium on carbon (50% wet) (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 min. Hydrogen was bubbled in for 5 min, then 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 50 g of C4H4Cl, eluting with a gradient of 5-80% MeCN in water (containing 0.1% formic acid). 18 Purification by reverse phase chromatography on a cartridge afforded 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). + .

[0210] Step 3: 5-[2-(diethoxyphosphoryl)propan-2-yl]-1-benzothiophene-2-carboxylic acid

[0211] 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 min. Hydrogen was bubbled in for 5 min, then 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 in tetrahydrofuran (2 mL). 10% palladium on carbon (50% wet) (20 mg, 0.009396 mmol, 0.13 equiv) was added under nitrogen bubble, then hydrogen was bubbled in for 5 min. The reaction was stirred under hydrogen (1 atm) at room temperature overnight. The reaction was filtered through a syringe filter and eluted with MeOH. The filtrate was concentrated under reduced pressure. The crude residue was diluted in tetrahydrofuran (2 mL) then 10% palladium on carbon (50% wet) (20 mg, 0.009396 mmol, 0.13 equiv) was added with a nitrogen sparge and then hydrogen was sparged for 5 min. The reaction was stirred under hydrogen (1 atm) at room temperature for 40 h. 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). + .

[0212] Synthetic scheme: Preparation of benzyl 5-{[bis({[(2-methoxyethoxy)carbonyl]oxy}methoxy)phosphoryl]difluoromethyl}-1-benzothiophene-2-carboxylate [ka]

[0213] Step 1: Chloromethyl 2-methoxyethyl carbonate

[0214] 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 and the reaction was then stirred at 0° C. for 15 min and then at room temperature for 16 h. 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%) as a clear liquid: 1 H NMR (400 MHz, CDCl 3 ) 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).

[0215] Step 2: Benzyl 5-{[bis({[(2-methoxyethoxy)carbonyl]oxy}methoxy)phosphoryl]difluoromethyl}-1-benzothiophene-2-carboxylate

[0216] To a stirred solution of ({2-[(benzyloxy)carbonyl]-1-benzothiophen-5-yl}difluoromethyl)phosphonic acid (300 mg, 0.7531 mmol, 1 equiv.) in water (15 mL) was added dropwise sodium hydroxide (59.9 mg, 1.50 mmol, 2 equiv.) in water (2 mL). When the mixture reached pH .about.8, silver nitrate (382 mg, 2.25 mmol, 3 equiv.) was added in one portion. After 2 h at room temperature, the grey suspension was cooled to 0° C. The precipitate was collected by filtration, washed with water, taken up in MeCN, dried under reduced pressure, and then dried under high vacuum for 2 h. The solid was suspended in dry 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 to 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 give benzyl 5-{[bis({[(2-methoxyethoxy)carbonyl]oxy}methoxy)phosphoryl]difluoromethyl}-1-benzothiophene-2-carboxylate (290 mg, 0.4377 mmol, 58.2%) as a clear oil. LCMS: m / z=663.2 (M+H). + . 1 H NMR (400 MHz, CDCl 3 ) 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).

[0217] Step 3: Benzyl 5-{[bis({[(2-methoxyethoxy)carbonyl]oxy}methoxy)phosphoryl]difluoromethyl}-1-benzothiophene-2-carboxylate

[0218] To a mixture of benzyl 5-{[bis({[(2-methoxyethoxy)carbonyl]oxy}methoxy)phosphoryl]difluoromethyl}-1-benzothiophene-2-carboxylate (145 mg, 0.2188 mmol, 1 equiv.) in anhydrous tetrahydrofuran (15 mL) was added 10% palladium on carbon (50% wet) (145 mg, 0.1353 mmol, equiv.). Hydrogen was bubbled through the suspension for 2 min, then the reaction mixture was stirred under hydrogen (1 atm) for 20 h. Nitrogen was bubbled through and the reaction was filtered through Celite, rinsed with 2-MeTHF, then concentrated under reduced pressure to give crude benzyl 5-{[bis({[(2-methoxyethoxy)carbonyl]oxy}methoxy)phosphoryl]difluoromethyl}-1-benzothiophene-2-carboxylate (144 mg, 0.2188 mmol, 99%) as a grey solid. LCMS: m / z=573.2 (M+H) + .

[0219] Synthetic scheme: Preparation of 5-{cyano[ethoxy(hydroxy)phosphoryl]methyl}-1-benzothiophene-2-carboxylic acid

[0220] Step 1: 5-[cyano(diethoxyphosphoryl)methyl]-1-benzothiophene-2-carboxylate

[0221] 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 room temperature for 10 min, then 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 (eluted with DCM) and the filtrate was concentrated under reduced pressure. The crude residue was purified by elution with 50 g of C4H4Cl2 with 5-80% MeCN in water. 18 Purification was performed by reverse phase chromatography on a cartridge. The combined fractions were concentrated to give ethyl 5-[cyano(diethoxyphosphoryl)methyl]-1-benzothiophene-2-carboxylate (50.0 mg, 131 μmol, 21.8%) as an orange solid. LCMS: m / z=382.2 (M+H). + . 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0222] Step 2: 5-{cyano[ethoxy(hydroxy)phosphoryl]methyl}-1-benzothiophene-2-carboxylic acid

[0223] To a solution of ethyl 5-[cyano(diethoxyphosphoryl)methyl]-1-benzothiophene-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 h. Additional hydrochloric acid (1.5 mL, 3N) was added and the reaction mixture was stirred at 70° C. for an additional 22 h. Hydrochloric acid (1.5 mL, 3N) was added and the reaction mixture was stirred at 80° C. for an additional 20 h. The reaction mixture was concentrated under reduced pressure. The crude product was purified by elution with a gradient of MeCN in water (5% in 3 CV, then from 5 to 100% in 18 CV) from 50 g of C. 18 Direct purification by reverse phase chromatography using a cartridge afforded 5-{cyano[ethoxy(hydroxy)phosphoryl]methyl}-1-benzothiophene-2-carboxylic acid (52.0 mg, 159 μmol, 76.5%) as a white solid. 1 H NMR (400 MHz, DMSO-d 6 ) 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 (quin, J = 7.3 Hz, 2H), 1.22 - 1.13 (m, 3H).

[0224] Synthetic scheme: Preparation of rac-5-[1-(diethoxyphosphoryl)-1-fluoroethyl]-1-benzothiophene-2-carboxylic acid [ka]

[0225] Step 1: benzyl rac-5-[(diethoxyphosphoryl)(hydroxy)methyl]-1-benzothiophene-2-carboxylate

[0226] 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., then 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 Upon addition of the base, a dark purple solution was observed which quickly turned orange. The mixture was stirred at -78 °C for 10 min. The reaction mixture was diluted with saturated NH 4 The mixture was quenched with aqueous Cl (50 mL) and then 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 then the aqueous layer was 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 crude 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 benzyl rac-5-[(diethoxyphosphoryl)(hydroxy)methyl]-1-benzothiophene-2-carboxylate (3.69 g, 8.49 mmol, 70%) as a white sticky solid. LCMS: m / z=869.4 (2M+H). + . 1 H NMR (400 MHz, CDCl 3) 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).

[0227] Step 2: benzyl rac-5-[(diethoxyphosphoryl)(fluoro)methyl]-1-benzothiophene-2-carboxylate

[0228] To a solution of benzyl rac-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 min. The reaction was quenched by adding 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 eluted with 5-80% MeCN in water to give 275 g of C. 18 Purification by reverse phase chromatography on a cartridge afforded benzyl rac-5-[(diethoxyphosphoryl)(fluoro)methyl]-1-benzothiophene-2-carboxylate (650 mg, 1.48 mmol, 41.6%) as a viscous, clear oil. LCMS: m / z=873.2 (2M+H). + . 1 H NMR (400 MHz, CDCl 3) 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).

[0229] Step 3: benzyl rac-5-[1-(diethoxyphosphoryl)-1-fluoroethyl]-1-benzothiophene-2-carboxylate

[0230] 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. The crude material was purified by elution with 50 g of C4H4Cl2 with 5–80% MeCN in water (containing 0.1% formic acid). 18 The mixture was purified by reverse phase chromatography on a cartridge. The fractions were combined, concentrated under reduced pressure, and then lyophilized to give benzyl rac-5-[1-(diethoxyphosphoryl)-1-fluoroethyl]-1-benzothiophene-2-carboxylate (67.0 mg, 0.1487 mmol, 65.0%) as a yellow oil. LCMS: m / z=451.2 (M+H). + . 1 H NMR (400 MHz, CDCl 3) 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).

[0231] Step 4: rac-5-[1-(diethoxyphosphoryl)-1-fluoroethyl]-1-benzothiophene-2-carboxylic acid

[0232] A mixture of 10% palladium on carbon (50% wet) (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 min. Hydrogen was bubbled in for 5 min, then the reaction was stirred under hydrogen (1 atm) at room temperature for 20 h. 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%) as a clear oil. LCMS: m / z=361.2 (M+H). + .

[0233] Synthetic scheme: Preparation of rac-7-[(diethoxyphosphoryl)(fluoro)methyl]naphthalene-2-carboxylic acid [ka]

[0234] Step 1: 7-Bromonaphthalene-2-carboxylic acid

[0235] 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 at −78° C. for 15 min, then the reaction mixture was agitated with CO 2 The ice bath was removed and CO 2 The reaction was stirred under air for 1 h. The reaction was quenched by the addition of 1N HCl (50 mL, pH=2), and then the product was extracted with EtOAc (3×75 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), 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%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) 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).

[0236] Step 2: tert-Butyl 7-bromonaphthalene-2-carboxylate

[0237] To a stirred suspension of 7-bromonaphthalene-2-carboxylic acid (1 g, 3.98 mmol, 1 equiv) in toluene (9 mL) was added N,N-dimethylformamide dibutyl acetal (3.80 mL, 15.9 mmol, 4 equiv) over 15 min at 90° C. The reaction was stirred at 90° C. for 2 h, then 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 min. 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%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) 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).

[0238] Step 3: tert-Butyl 7-methylnaphthalene-2-carboxylate

[0239] 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 to 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 give tert-butyl 7-methylnaphthalene-2-carboxylate (808 mg, 3.33 mmol, 92.4%) as a white crystalline solid. 1 H NMR (400 MHz, CDCl 3 ) 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).

[0240] Step 4: tert-Butyl 7-(bromomethyl)naphthalene-2-carboxylate

[0241] To a solution of tert-butyl 7-methylnaphthalene-2-carboxylate (808 mg, 3.33 mmol) in anhydrous carbon tetrachloride (25 mL) was added N-bromosuccinimide (621 mg, 3.49 mmol) and benzoyl peroxide (32.2 mg, 133 μmol) under nitrogen atmosphere. The reaction mixture was heated to reflux and stirred at this temperature for 20 h. The precipitate was filtered off and washed with carbon tetrachloride (10 mL), then the filtrate was adsorbed onto silica gel and concentrated under reduced pressure. The 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%) as a white solid that contained residual starting material (approximately 25%). 1 H NMR (400 MHz, CDCl 3 ) 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).

[0242] Step 5: tert-Butyl 7-[(diethoxyphosphoryl)methyl]naphthalene-2-carboxylate 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 in solution at 110 °C). The reaction was cooled to room temperature and purified with 50 g of C using a gradient of 5-80% MeCN in water. 18 Direct purification by reverse phase chromatography on a cartridge afforded tert-butyl 7-[(diethoxyphosphoryl)methyl]naphthalene-2-carboxylate (580 mg, 1.53 mmol, 68.4%) as a viscous yellow oil. LCMS: m / z=379.3 (M+H). + . 1H NMR (400 MHz, CDCl 3 ) 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).

[0243] Step 6: tert-butyl rac-7-[(diethoxyphosphoryl)(hydroxy)methyl]naphthalene-2-carboxylate

[0244] 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 a solution of sodium bis(trimethylsilylamide) (1 M in THF) (792 μL, 792 μmol, 1.5 equiv.) dropwise. The mixture was stirred for 2 min, then 2-(benzenesulfonyl)-3-phenyloxaziridine (274 mg, 1.05 mmol, 2.0 equiv.) was added in small portions. The dark red solution was stirred at −78° C. for 20 min. The reaction mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) at −78° C., then the ice bath was removed. EtOAc (25 mL) and water (25 mL) were added and the mixture was stirred for 30 min. The phases were separated and the aqueous layer was then back-extracted with EtOAc (2 x 25 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash-chromatography on a 24 g silica gel cartridge, eluting with 20-100% EtOAc in heptane to give tert-butyl rac-7-[(diethoxyphosphoryl)(hydroxy)methyl]naphthalene-2-carboxylate (140 mg, 0.3549 mmol, 67.3%) as a white sticky solid. LCMS: m / z=394.6 (M+H). + . 1 H NMR (400 MHz, CDCl 3) 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).

[0245] Step 7: tert-butyl rac-7-[(diethoxyphosphoryl)(fluoro)methyl]naphthalene-2-carboxylate

[0246] 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 was added a solution of (diethylamino)sulfur trifluoride (56.1 μL, 425 μmol, 1.2 equiv) dropwise. The reaction was stirred at −78° C. for 20 min. The reaction was quenched by adding 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 50 g of C4H4Cl2 with a gradient of 5–80% MeCN in water. 18 Purification by reverse phase chromatography on a cartridge afforded tert-butyl rac-7-[(diethoxyphosphoryl)(fluoro)methyl]naphthalene-2-carboxylate (80.0 mg, 0.2018 mmol, 57.1%) as a clear oil. LCMS: m / z=397.4 (M+H). + . 1 H NMR (400 MHz, CDCl 3) 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).

[0247] Step 8: rac-7-[(diethoxyphosphoryl)(fluoro)methyl]naphthalene-2-carboxylic acid

[0248] To a solution of tert-butyl rac-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 h. 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, 1 equiv) as a clear oil. LCMS: m / z=341.2 (M+H). + .

[0249] Synthetic scheme: Preparation of 5-{[bis({[(2S)-2-(methoxycarbonyl)pyrrolidine-1-carbonyloxy]methoxy})phosphoryl]difluoromethyl}-1-benzothiophene-2-carboxylic acid [ka]

[0250] Step 1: 2-Methyl(2S)-pyrrolidine-1,2-dicarboxylate 1-chloromethyl

[0251] To a solution of (2S)-methylpyrrolidine-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) was added chloroacetyl chloride (777 mg, 6.03 mmol) at 0° C. under nitrogen atmosphere. The reaction mixture was stirred for 0.5 h and then washed successively with 1N 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 ethyl acetate in heptane (0-50%). 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%). 1 H NMR: (400 MHz, CDCl 3 ) 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).

[0252] Step 2: 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

[0253] 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 room temperature 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 dry toluene (10 mL) and (2S)-pyrrolidine-1,2-dicarboxylate 1-chloromethyl 2-methyl (582 mg, 2.63 mmol, 3.5 equiv.) was added. The mixture was stirred at room temperature for 18 h. The crude material was directly purified by normal phase chromatography using a 12 g silica gel cartridge eluted with a gradient of ethyl acetate in heptane (0 to 100% over 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%) as a white solid. 1 H NMR: (400 MHz, CDCl 3 ) 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).

[0254] Step 3: 5-{[bis({[(2S)-2-(methoxycarbonyl)pyrrolidine-1-carbonyloxy]methoxy})phosphoryl]difluoromethyl}-1-benzothiophene-2-carboxylic acid

[0255] 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% wet loading) (62.1 mg, 58.5 μmol, 0.5 equiv.). Hydrogen was bubbled through the suspension for 2 min, then the reaction mixture was stirred under 1 atm (balloon) of hydrogen for 16 h. 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%) as a colorless oil. 1 H NMR: (400 MHz, CDCl 3 ) 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).

[0256] Preparation of 5-(((benzylamino)(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid: [ka]

[0257] Step A: Allyl 5-(((benzylamino)(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylate

[0258] To a solution of ((2-((allyloxy)carbonyl)benzo[b]thiophen-5-yl)methyl)phosphonic acid (200 mg, 0.64 mmol, 1.0 equiv) in dry DCM (6 mL) and DMF (1 drop) at 0 °C was added oxalyl chloride (814.4 mg, 6.4 mmol, 10 equiv) dropwise. The reaction was warmed to 40 °C and then stirred for an additional 1-2 h. The reaction was monitored by pipetting a small crude sample and quenching it with MeOH to ensure complete formation of the bis-Cl phosphoryl chloride, 5-((dichlorophosphoryl)methyl)benzo[b]thiophene-2-carboxylate allyl (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 treated with BnNH in anhydrous DCM (2 mL) at -40 °C. 2 (64.8 mg, 0.64 mmol, 1.0 equiv.) and Et 3 N (194.32 mg, 1.92 mmol, 3.0 equiv) was added. The reaction was monitored by pipetting a small crude sample and quenching it 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 L-alanine isopropyl (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. Upon completion, H 2The reaction was quenched by adding O (10 mL) and extracted with DCM (10 mL x 3). The organic layers were combined, washed with brine (20 mL) and diluted with anhydrous Na 2 SO 4 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%). LCMS (ESI): m / z=515.2 [M+H] + .

[0259] Step B: 5-(((benzylamino)(((S)-1-isopropoxy-1-oxopropan-2-yl)amino)phosphoryl)methyl)benzo[b]thiophene-2-carboxylic acid

[0260] 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(PPh 3 ) 4 A solution of (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. After 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%). LCMS (ESI): m / z=475.1 [M+H] + .

[0261] Synthetic scheme: Preparation of 4-nitrophenyl 5-[(di{[(propoxycarbonyl)oxy]methoxy}phosphoryl)difluoromethyl]-1-benzothiophene-2-carboxylate [ka]

[0262] Step 1: Chloromethylpropyl carbonate

[0263] 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 and the reaction mixture was then stirred at 0° C. for 15 min and then at room temperature for 3 h. The white suspension was filtered and rinsed with diethyl ether (20 mL). The filtrate was washed with 1N HCl (20 mL) and water (2×15 mL), then dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give chloromethylpropyl carbonate (1.26 g, 8.25 mmol, 50.1%) as a clear oil: 1 H NMR (400 MHz, CDCl 3 ) δ 5.74 (s, 2H), 4.25 - 4.17 (m, 2H), 1.74 (sxt, J = 7.1 Hz, 2H), 1.02 - 0.94 (m, 3H).

[0264] Step 2: 4-Nitrophenyl 5-[(di{[(propoxycarbonyl)oxy]methoxy}phosphoryl)difluoromethyl]-1-benzothiophene-2-carboxylate

[0265] To a stirred suspension of [difluoro({2-[(4-nitrophenoxy)carbonyl]-1-benzothiophen-5-yl})methyl]phosphonic acid (200 mg, 465 μmol, 1 equiv.) in water (4 mL) was added H 2Sodium hydroxide (37.1 mg, 930 μmol, 2 equiv) in 20 (1 mL) was added dropwise. When the mixture reached pH ∼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 dry toluene (10 mL) and chloromethylpropyl carbonate (282 mg, 1.85 mmol, 4 equiv) was added. The mixture was stirred at room temperature for 18 h. The crude material was directly purified by normal phase chromatography using a 24 g silica gel cartridge eluted with a gradient of EtOAc in heptane (0 to 60% in 18 CV) to give 4-nitrophenyl 5-[(di{[(propoxycarbonyl)oxy]methoxy}phosphoryl)difluoromethyl]-1-benzothiophene-2-carboxylate (10 mg, 15.1 μmol, 3.25%) as a white semi-solid: LCMS: m / z=662.2 (M+H). + . 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0266] Synthesis scheme: 4-nitrophenyl 5-({bis[({[(1-methoxy-2-methylpropan-2-yl)oxy]carbonyl}oxy)methoxy]phosphoryl}difluoromethyl)-1-benzothiophene-2-carboxylate [ka]

[0267] Step 1: Chloromethyl 1-methoxy-2-methylpropan-2-yl carbonate

[0268] 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 and the reaction mixture was then stirred at 0° C. for 15 min and then at room temperature for 3 h. The white suspension was filtered and rinsed with diethyl ether (20 mL). The filtrate was washed with 1N 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%) as a clear oil. 1 H NMR (400 MHz, CDCl 3 ) δ 7.20 - 7.17 (m, 2H), 5.04 - 5.00 (m, 2H), 4.90 (s, 3H), 3.03 - 2.99 (m, 6H).

[0269] Step 2: 4-Nitrophenyl 5-[(di{[(propoxycarbonyl)oxy]methoxy}phosphoryl)difluoromethyl]-1-benzothiophene-2-carboxylate

[0270] To a stirred suspension of [difluoro({2-[(4-nitrophenoxy)carbonyl]-1-benzothiophen-5-yl})methyl]phosphonic acid (200 mg, 465 μmol, 1 equiv.) in water (5 mL) was added H 2Sodium hydroxide (37.1 mg, 930 μmol, 2 equiv) in 20 (1 mL) was added dropwise. When the mixture reached pH ∼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 dry 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 eluted with a gradient of EtOAc in heptane (0 to 60% in 18 CV) to give 4-nitrophenyl 5-({bis[({[(1-methoxy-2-methylpropan-2-yl)oxy]carbonyl}oxy)methoxy]phosphoryl}difluoromethyl)-1-benzothiophene-2-carboxylate (51.0 mg, 68.0 μmol, 14.6%) as a white semi-solid: 1 H NMR (400 MHz, CDCl 3 ) 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).

[0271] Synthetic scheme: Preparation of 4-nitrophenyl 5-[(di{[(dipropylcarbamoyl)oxy]methoxy}phosphoryl)difluoromethyl]-1-benzothiophene-2-carboxylate [ka]

[0272] Step 1: N,N-Dipropylcarbamate

[0273] To a solution of chloroacetyl chloride (2.06 mL, 23.2 mmol, 1 equiv.) in hexane (30 mL) was added dipropylamine (5.85 g, 57.9 mmol, 2.5 equiv.) under nitrogen at 0° C. and stirred at the same temperature for 30 min. The reaction mixture was then diluted with ethyl acetate (50 mL). The phases were separated and the organic layer was washed successively with 1N 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 a 80 g silica gel cartridge eluted with a gradient of 0-10% ethyl acetate in heptane. The combined pure fractions were dried under reduced pressure to give chloromethyl N,N-dipropylcarbamate (2.89 g, 14.9 mmol, 64.3%) as a colorless oil. LCMS: m / z=194.2 (M+H) + . 1 H NMR (400 MHz, CDCl 3 ) δ 5.75 (s, 2H), 3.21 - 3.11 (m, 4H), 1.59 - 1.47 (m, 4H), 0.87 - 0.82 (m, 6H).

[0274] Step 2: 4-Nitrophenyl 5-[(di{[(dipropylcarbamoyl)oxy]methoxy}phosphoryl)difluoromethyl]-1-benzothiophene-2-carboxylate

[0275] H 2 To a stirred suspension of [difluoro({2-[(4-nitrophenoxy)carbonyl]-1-benzothiophen-5-yl})methyl]phosphonic acid (200 mg, 465 μmol, 1 equiv.) in HO (5 mL) was added H 2Sodium hydroxide (37.1 mg, 930 μmol, 2 equiv) in 20 (1 mL) was added dropwise. When the mixture reached pH ∼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 dry toluene (10 mL) and chloromethyl N,N-dipropylcarbamate (313 mg, 1.62 mmol, 3.5 equiv) was added. The mixture was stirred at room temperature for 18 h. The crude material 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-[(di{[(dipropylcarbamoyl)oxy]methoxy}phosphoryl)difluoromethyl]-1-benzothiophene-2-carboxylate (110 mg, 147 μmol, 31.8%) as a clear oil: 1 H NMR (400 MHz, DMSO-d 6 ) 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).

[0276] Synthesis scheme: 4-nitrophenyl 5-{[bis({1-[(propoxycarbonyl)oxy]ethoxy})phosphoryl]difluoromethyl}-1-benzothiophene-2-carboxylate [ka]

[0277] Step 1: 1-Chloroethyl propyl carbonate

[0278] 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 and the reaction mixture was then stirred at 0° C. for 15 min and then at room temperature for 3 h. The white suspension was filtered and rinsed with diethyl ether (20 mL). The filtrate was washed with 1N 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%) as a clear oil. 1 H NMR (400 MHz, CDCl 3 ) 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).

[0279] Step 2: 4-Nitrophenyl 5-{[bis({1-[(propoxycarbonyl)oxy]ethoxy})phosphoryl]difluoromethyl}-1-benzothiophene-2-carboxylate

[0280] H 2 To a stirred suspension of [difluoro({2-[(4-nitrophenoxy)carbonyl]-1-benzothiophen-5-yl})methyl]phosphonic acid (200 mg, 465 μmol, 1 equiv.) in HO (4 mL) was added H 2Sodium hydroxide (37.1 mg, 930 μmol, 2 equiv) in 20 (1 mL) was added 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 dry toluene (10 mL) and 1-chloroethylpropyl carbonate (269 mg, 1.62 mmol, 3.5 equiv) was added. The mixture was stirred at room temperature for 18 h. The crude material 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({1-[(propoxycarbonyl)oxy]ethoxy})phosphoryl]difluoromethyl}-1-benzothiophene-2-carboxylate (113 mg, 163 μmol, 35.3%) as a clear oil. LCMS: m / z=712.2 (M+Na). + .

[0281] Preparation of (E)-3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)-2-methylacrylic acid [ka]

[0282] Step A: tert-Butyl 2-(diethoxyphosphoryl)propanoate

[0283] A mixture of tert-butyl 2-bromopropanoate (3 g, 14.3 mmol, 1 equiv.) and ethane-2-ylium-1-yl diethyl phosphite (2.82 g, 17.1 mmol, 1.2 equiv.) was stirred at 110° C. for 16 h. 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%) as a white solid. LCMS (ESI): m / z=267 [M+H] + .

[0284] Step B: (E)-tert-butyl 3-(3-iodophenyl)-2-methylacrylate

[0285] 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) under nitrogen at −78° C. 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 and after addition, the reaction mixture was allowed to warm to room temperature and stirred for 14 h. Upon completion, the reaction mixture was diluted with H 2 The mixture was quenched by the addition of O (20 mL) and then extracted with EtOAc (15 mL×3). The combined organic layers were washed with brine (15 mL) and anhydrous Na 2 SO 4 The residue was purified by flash column chromatography on silica gel to give (E)-tert-butyl 3-(3-iodophenyl)-2-methylacrylate (739.6 mg, 2.15 mmol, 50%) as a white solid. LC-MS (ESI) m / z=345 [M+H] + .

[0286] Step C: (E)-tert-butyl 3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)-2-methylacrylate

[0287] A solution of diethyl(bromodifluoromethyl)phosphonate (1.08 g, 4.06 mmol, 2 equiv.), zinc (265 mg, 4.06 mmol, 2 equiv.) in DMAc (7 mL) was stirred at 60° C. for 1 h under 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. (E)-tert-butyl 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 (E)-tert-butyl 3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)-2-methylacrylate (180 mg, 445 μmol, 22%) as a yellow oil. LCMS (ESI): m / z=405 [M+H] + .

[0288] Step D: (E)-3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)-2-methylacrylic acid

[0289] A solution of (E)-tert-butyl 3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)-2-methylacrylic acid (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] + .

[0290] Preparation of (E)-3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)but-2-enoic acid [ka]

[0291] Step A: tert-Butyl (E)-3-(3-iodophenyl)but-2-enoate

[0292] To tert-butyl 2-(diethoxyphosphoryl)acetate (1.02 g, 4.06 mmol, 1 equiv) in THF (20 mL) at -78°C was added n-BuLi (1.72 mL, 4.06 mmol, 1.0 equiv) 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 addition, the reaction mixture was allowed to warm to room temperature and stirred for 18 h. Upon completion, the reaction mixture was diluted with H 2 The mixture was quenched by the addition of O (20 mL) and then extracted with EtOAc (20 mL x 3). The organic layers were combined, washed with brine (15 mL) and diluted with anhydrous Na 2 SO 4 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%) as an oil. 1 H NMR (400 MHz, CDCl 3 ) 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).

[0293] Step B: tert-Butyl (E)-3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)but-2-enoate

[0294] To a stirred suspension of Zn (301 mg, 4.64 mmol, 2 equiv.) in dry 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 nitrogen atmosphere. The reaction mixture was stirred at 45° C. for 2 h, then CuBr (665 mg, 4.64 mmol, 2 equiv.) was added and the resulting mixture was stirred at room temperature for 45 min. To this reaction mixture was added a suspension of tert-butyl (E)-3-(3-iodophenyl)but-2-enoate (800 mg, 2.32 mmol, 1 equiv.) in DMAc (3 mL). The mixture was stirred at 45° C. for 24 h under 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 anhydrous Na 2 SO 4 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%) as an oil. 1 H NMR (400 MHz, CDCl 3 ) 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).

[0295] Step C: (E)-3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)but-2-enoic acid

[0296] 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) at room temperature was added TFA (6.13 g, 53.8 mmol, 62.2 equiv) and the resulting mixture was stirred at room temperature for 18 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (E)-3-(3-((diethoxyphosphoryl)difluoromethyl)phenyl)but-2-enoic acid (250 mg, 0.72 mmol, 83%) as an oil which was used in the next step without further purification. LC-MS (ESI) m / z=347.2 [MH] -

[0297] Preparation of perfluorophenyl 5-((ethoxy(hydroxy)phosphoryl)difluoromethyl)-6-fluorobenzo[b]thiophene-2-carboxylate [ka]

[0298] Step A: Methyl 4-amino-2-chloro-5-iodobenzoate

[0299] Methyl 4-amino-2-chlorobenzoate (5.0 g, 26.9 mmol, 1 equiv.) and CaCO in MeOH (54 mL) 3 To a suspension of (5.4 g, 53.8 mmol, 2.0 equiv) at room temperature was added a solution of ICl (4.8 g, 29.5 mmol, 1.1 equiv) in DCM (25 mL). The reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure to give a residue. The residue was triturated from petroleum ether:ethyl acetate=3:1 (30 mL) to give methyl 4-amino-2-chloro-5-iodobenzoate (6.1 g, 19.5 mmol, 73%) as a yellow solid. LCMS (ESI) m / z=312 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6) δ 8.10 (s, 1H), 6.80 (s, 1H), 6.24 (s, 2H), 3.75 (s, 3H).

[0300] Step B: (4-amino-2-chloro-5-iodophenyl)methanol

[0301] To a solution of methyl 4-amino-2-chloro-5-iodobenzoate (6.1 g, 19.5 mmol, 1 equiv.) in DCM (120 mL) and THF (30 mL) under nitrogen at −78° C., DIBAL-H (48.7 mL, 48.7 mmol, 2.5 equiv.) was added slowly over 30 min. After addition, the reaction mixture was stirred at room temperature for 30 min. After completion, the reaction mixture was quenched with saturated sodium potassium tartrate solution (100 mL) at 0° C. and stirred at room temperature for 2 h. The mixture was extracted with DCM (200 mL). The organic phase was washed with brine (50 mL) and anhydrous Na 2 SO 4 The mixture was dried over 1000 ml of ethyl acetate, filtered and concentrated under reduced pressure to give (4-amino-2-chloro-5-iodophenyl)methanol (5.0 g, 17.6 mmol, 91%) as a yellow solid. LCMS (ESI) m / z=284 [M+H] + .

[0302] Step C: 4-Amino-2-chloro-5-iodobenzaldehyde

[0303] (4-amino-2-chloro-5-iodophenyl)methanol (4.0 g, 14.1 mmol, 1 equiv.) in CHCl 3 (50 mL) solution at room temperature 2 (7.4 g, 84.6 mmol, 6.0 equiv) was added. After addition, the mixture was stirred at 60° C. for 5 h. Upon completion, the reaction mixture was cooled to room temperature and filtered. The filtrate was concentrated under reduced pressure to give 4-amino-2-chloro-5-iodobenzaldehyde (3.80 g, 13.5 mmol, 96%) as a yellow solid. LCMS: m / z=282 [M+H] + .

[0304] Step D: Ethyl 6-amino-5-iodobenzo[b]thiophene-2-carboxylate

[0305] 4-Amino-2-chloro-5-iodobenzaldehyde (900 mg, 3.19 mmol, 1 equiv.) and K 2 CO 3 To a solution of (881 mg, 6.38 mmol, 2.0 equiv) in DMA (10 mL) was added ethyl 2-sulfanylacetate (420 mg, 3.50 mmol, 1.1 equiv) at room temperature. After addition, the reaction mixture was stirred at 60° C. for 16 h. The reaction mixture was cooled to room temperature and poured into water (50 mL). The mixture was extracted with EtOAc (50 mL×3). The combined organic phase was washed with brine (50 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel to give ethyl 6-amino-5-iodo-1-benzothiophene-2-carboxylate (5, 410 mg, 1.18 mmol, 37%) as a yellow solid. LCMS (ESI): m / z=348 [M+H] + .

[0306] Step E: 6-fluoro-5-iodobenzo[b]thiophene-2-carboxylate ethyl

[0307] A solution of ethyl 6-amino-5-iodo-1-benzothiophene-2-carboxylate (410 mg, 1.18 mmol, 1 equiv.) in THF (4 mL) was added to 48% HBF at 0°C. 4 (2.4 g, 12.9 mmol, 11.0 equiv.) was then added. 2A solution of (73 mg, 1.06 mmol, 0.9 equiv) in water (4 mL) was added dropwise and the resulting yellow suspension was stirred at 0° C. for 1 h. The solid was collected by vacuum filtration and dried to give 400 mg of the diazonium salt. The diazobenzene tetrafluoroborate salt was heated to 160° C. under nitrogen for 3 h. The residual material was purified by flash column chromatography on silica gel to give ethyl 6-fluoro-5-iodobenzo[b]thiophene-2-carboxylate (210 mg, 599 μmol, 51%) as a yellow oil. 1 H NMR (400 MHz, CDCl 3 ) δ 8.26 (d, J = 5.8 Hz, 1H), 7.93 (s, 1H), 7.55 (d, J = 7.6 Hz, 1H), 4.41 (q, J = 7.1 Hz, 2H), 1.41 (t, J = 7.1 Hz, 3H).

[0308] Step F: Ethyl 5-((diethoxyphosphoryl)difluoromethyl)-6-fluorobenzo[b]thiophene-2-carboxylate

[0309] A mixture of diethyl(bromodifluoromethyl)phosphonate (317 mg, 1.19 mmol, 2.0 equiv.) and activated Zn powder (67 mg, 1.19 mmol, 2.0 equiv.) in DMA (4 mL) was stirred at 60° C. for 1 h. Then CuBr (170 mg, 1.19 mmol, 2.0 equiv.) was added. The mixture was stirred at 50° C. for 1 h. A solution of ethyl 6-fluoro-5-iodobenzo[b]thiophene-2-carboxylate (210 mg, 599 μmol, 1 equiv.) in DMA (2 mL) was added. After addition, the reaction mixture was stirred overnight at 60° C. under nitrogen. The reaction mixture was cooled to room temperature and filtered. The filtrate was diluted with water (10 mL) and extracted with EtOAc (20 mL×3). The combined organic phase was washed with brine (20 mL) and diluted with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel to give ethyl 5-[(diethoxyphosphoryl)difluoromethyl]-6-fluoro-1-benzothiophene-2-carboxylate (94.0 mg, 229 μmol, 38%) as a yellow oil. LCMS (ESI): m / z=411 [M+H] + .

[0310] Step G: 5-((ethoxy(hydroxy)phosphoryl)difluoromethyl)-6-fluorobenzo[b]thiophene-2-carboxylic acid

[0311] THF (2 mL) and H 2 A solution of 5-[(diethoxyphosphoryl)difluoromethyl]-6-fluoro-1-benzothiophene-2-carboxylate (7, 94 mg, 229 μmol, 1 equiv.) in a mixture of 2,4-dichloro-1,2,3-tetrafluoroethane (DMSO) (0.5 mL) was added to a solution of 1,2,3-tetrafluoroethane (DMSO) (0.5 mL) in 0.5 mL of LiOH. 2 2H2O (48 mg, 1.14 mmol, 5.0 equiv.) was added. After addition, the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was carefully neutralized with 5N aqueous HCl until the pH was adjusted to pH=3. The mixture was extracted with EtOAc (10 mL×2). The organic phase was washed with brine (10 mL) to remove Na 2 SO 4 Drying at 40° C., filtration, and concentration under reduced pressure afforded 5-{[ethoxy(hydroxy)phosphoryl]difluoromethyl}-6-fluoro-1-benzothiophene-2-carboxylic acid (50.0 mg, 141 μmol, 62%) as a yellow solid. LCMS (ESI): m / z=355 [M+H] + .

[0312] Step H: Perfluorophenyl 5-((ethoxy(hydroxy)phosphoryl)difluoromethyl)-6-fluorobenzo[b]thiophene-2-carboxylate

[0313] To a solution of 5-{[ethoxy(hydroxy)phosphoryl]difluoromethyl}-6-fluoro-1-benzothiophene-2-carboxylic acid (50 mg, 141 μmol, 1 equiv.), pentafluorophenol (26 mg, 141 μmol, 1 equiv.) and DMAP (2 mg, 14.1 μmol, 0.1 equiv.) in THF (10 mL) was added DCC (41 mg, 197 μmol, 1.4 equiv.) at 0° C. After addition, the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was diluted with water (10 mL) and extracted with EtOAc (10 mL×3). The organic phase was washed with brine (10 mL) and diluted with anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered and concentrated under reduced pressure to give a residue which was purified by flash column chromatography on silica gel to give perfluorophenyl 5-((ethoxy(hydroxy)phosphoryl)difluoromethyl)-6-fluorobenzo[b]thiophene-2-carboxylate (60.0 mg, 115 μmol, 82%) as a white solid. LCMS (ESI): m / z=520 [M+H] + .

[0314] Bis-SATE and mono-SATE of diFs naphthyl PFP ester:

[0315] Preparation of 7-((bis(2-(butyrylthio)ethoxy)phosphoryl)difluoromethyl)-2-perfluorophenyl naphthoate and 7-(((2-(butyrylthio)ethoxy)(hydroxy)phosphoryl)difluoromethyl)-2-perfluorophenyl naphthoate: [ka]

[0316] Step A: 7-((bis(2-(butyrylthio)ethoxy)phosphoryl)difluoromethyl)-2-perfluorophenyl naphthoate and 7-(((2-(butyrylthio)ethoxy)(hydroxy)phosphoryl)difluoromethyl)-2-perfluorophenyl naphthoate [ka]

[0317] 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) at 25° C. was added oxalyl chloride (266 mg, 2.13 mmol, 1.0 equiv.) dropwise followed by DMF (155 mg, 2.13 mmol, 1.0 equiv.). The reaction mixture was warmed to 40° C. and then stirred at reflux for an additional 1.2 h. The reaction was monitored by pipetting a small crude sample and quenching it with MeOH to ensure complete formation of 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 progress of the reaction was monitored by LCMS and upon completion, H 2 The reaction was quenched by the addition of O (10 mL) and concentrated under reduced pressure. The residue was purified by C18 column chromatography to give 7-((bis(2-(butyrylthio)ethoxy)phosphoryl)difluoromethyl)-2-perfluorophenyl naphthoate (2A, 680 mg, 1.13 mmol, 58%) as a white solid and 7-(((2-(butyrylthio)ethoxy)(hydroxy)phosphoryl)difluoromethyl)-2-perfluorophenyl naphthoate (2B, 65.0 mg, 89.2 μmol) as a white solid. 2A: LCMS (ESI): m / z=729 [M+H] + 2B: LCMS (ESI): m / z = 599 [M + H] + .

[0318] Step B: 7-(((2-(butyrylthio)ethoxy)(((isopropoxycarbonyl)oxy)methoxy)phosphoryl)difluoromethyl)-2-naphthoic acid perfluorophenyl [ka]

[0319] Deionized H 2 To a solution of perfluorophenyl 7-(((2-(butyrylthio)ethoxy)(hydroxy)phosphoryl)difluoromethyl)-2-naphthoate (300 mg, 501 μmol, 1 equiv.) in a mixture of 2O (8 mL) and THF (2 mL) was added Amberlite IR120® resin (Na + Form (233 mg, 751 μmol, 1.5 equiv.) was added. The resulting mixture was stirred at room temperature for 1 h, and then the excess resin was removed by filtration. The resulting solution was then washed with deionized H 2 AgNO in O (2 mL) 3 (127 mg, 751 μmol, 1.5 equiv.) was added. After the addition, the resulting mixture was stirred for an additional hour at room temperature. During this period, silver salts formed as a white precipitate, which was collected by filtration. The filter cake was washed with cold H 2 O (2 mL × 3) and the silver salt was further dried under reduced pressure to give a dry powder, which was pure enough for the next step without further purification.

[0320] 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 addition, the resulting mixture was stirred for an additional 12 h at 40° C. The reaction progress was monitored by LCMS and 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 give 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] + .

[0321] Preparation of 5-((diethoxyphosphoryl)difluoromethyl)thieno[2,3-b]pyridine-2-carboxylic acid: [ka]

[0322] Step 1: Ethyl 5-bromothieno[2,3-b]pyridine-2-carboxylate.

[0323] To a solution of 5-bromo-2-fluoropyridine-3-carbaldehyde (10 g, 49 mmol, 1 equiv.) in dimethylformamide (70 mL) was added potassium carbonate (27 g, 0.2 mol, 4 equiv.) and ethyl 2-sulfanylacetate (6.5 g, 54 mmol, 1.1 equiv.). The mixture was stirred at 60° C. for 16 h. The reaction was diluted with water (200 mL), extracted with ethyl acetate (200 mL×2), and the combined organic layers were washed with saturated brine (200 mL×2) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give ethyl 5-bromothieno[2,3-b]pyridine-2-carboxylate (13 g, 96% yield) as a yellow solid. LCMS: m / z (M+H) + =287.9

[0324] Step 2: Ethyl 5-iodothieno[2,3-b]pyridine-2-carboxylate.

[0325] A solution of ethyl 5-bromothieno[2,3-b]pyridine-2-carboxylate (13 g, 45 mmol, 1 equiv.) and sodium iodide (14 g, 91 mmol, 2 equiv.) in dioxane (90 mL) was 1 ,N 2 -Dimethylethane-1,2-diamine (0.4 g, 4.5 mmol, 0.1 equiv.) and CuI (0.4 g, 2.3 mmol, 0.05 equiv.) were added and the mixture was then subjected to N 2 The mixture was stirred under microwave conditions at 100° C. for 5 h under reduced pressure. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give ethyl 5-iodothieno[2,3-b]pyridine-2-carboxylate (13 g, 89% yield) as a yellow solid. LCMS: m / z (M+H) + =333.8.

[0326] Step 3: 5-Iodothieno[2,3-b]pyridine-2-carboxylic acid.

[0327] Ethyl 5-iodothieno[2,3-b]pyridine-2-carboxylate (12 g, 36 mmol, 1 equiv.) 2 To a solution of 1:1:1 O:THF:MeOH (90 mL) was added lithium hydroxide (2.6 g, 0.1 mol, 3 equiv). The mixture was stirred at 25° C. for 4 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was then diluted with water (50 mL) and extracted with ethyl acetate (50 mL). The aqueous phase was adjusted to PH=5-6 using FA (1M) and extracted with ethyl acetate (50 mL×2) to give Na 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure gave crude 5-iodothieno[2,3-b]pyridine-2-carboxylic acid (8 g, crude) as a yellow oil. LCMS: m / z (M+H) + =305.9.

[0328] Step 4: Benzyl 5-iodothieno[2,3-b]pyridine-2-carboxylate.

[0329] To a solution of 5-iodothieno[2,3-b]pyridine-2-carboxylic acid (8 g, 26 mmol, 1 equiv.) in DMF (50 mL) was added potassium carbonate (7.2 g, 52 mmol, 2 equiv.) and (bromomethyl)benzene (4.9 g, 29 mmol, 1.1 equiv.). The mixture was stirred at 25° C. for 16 h. The reaction mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×2), and the combined organic layers were washed with saturated brine (100 mL×2) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give benzyl 5-iodothieno[2,3-b]pyridine-2-carboxylate (4.4 g, 43% yield) as a yellow solid. LCMS: m / z (M+H) + =396.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 9.03 - 8.63 (m, 1H), 8.12 (s, 1H), 7.62 - 7.08 (m, 6H), 5.55 - 5.02 (m, 2H).

[0330] Step 5: Benzyl 5-((diethoxyphosphoryl)difluoromethyl)thieno[2,3-b]pyridine-2-carboxylate.

[0331] To a suspension of zinc (0.4 g, 5.7 mmol, 2 equiv.) in degassed anhydrous THF (10 mL), chlorotrimethylsilane (0.1 g, 1.2 mmol, 0.4 equiv.) was added and the suspension was heated to 50 °C for 1.5 h with vigorous stirring. A solution of diethyl (bromodifluoromethyl)phosphonate (1.6 g, 6.1 mmol, 2 equiv.) in THF (15 mL) was added dropwise (maintaining the temperature between 50-55 °C). The reaction mixture was stirred at 50 °C for 2 h, lambda 1-copper(1+) bromide (0.4 g, 3.0 mmol, 1.0 equiv.) and dimethylacetamide (6.7 mL, 73 mmol, 24 equiv.) were added and the mixture was stirred at room temperature for 30 min. To this reaction mixture was slowly added a solution of benzyl 5-iodothieno[2,3-b]pyridine-2-carboxylate (1.2 g, 3.0 mmol, 1 equiv.) in N,N-dimethylacetamide (10 mL), then heated to 50° C. for 12 h. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL×2), and the combined organic layers were washed with saturated brine (50 mL×2) and added with Na 2 SO 4 The residue was purified by reverse phase chromatography (column: 120 g of Flash® Coulmn Welch Ultimate XB_C18 20-40 μm; 120A, mobile phase: H 2 Purification by 0+ACN; gradient B%: 10-65%, 15 min; 65% for 3 min) and lyophilization afforded benzyl 5-((diethoxyphosphoryl)difluoromethyl)thieno[2,3-b]pyridine-2-carboxylate (0.6 g, 42% yield) as a yellow oil. LCMS: m / z (M+H) + =456.3. 1 H NMR (400 MHz, methanol-d 4 ) δ 8.84 (s, 1H), 8.59 (s, 1H), 8.24 (s, 1H), 7.57 - 7.31 (m, 5H), 5.43 (s, 2H), 4.38 - 4.16 (m, 4H), 1.33 (t, J = 7.2 Hz, 6H)

[0332] Step 6: 5-((diethoxyphosphoryl)difluoromethyl)thieno[2,3-b]pyridine-2-carboxylic acid.

[0333] To a solution of benzyl 5-((diethoxyphosphoryl)difluoromethyl)thieno[2,3-b]pyridine-2-carboxylate (0.3 g, 0.7 mmol, 1 equiv.) in methanol (1.5 mL) and tetrahydrofuran (1.5 mL), N 2 Dry Pd / C (30 mg) was added under reduced pressure. 2 The mixture was stirred at 25° C. under (15 psi) for 4 h. The reaction mixture was filtered and the filtrate was concentrated to give crude 5-((diethoxyphosphoryl)difluoromethyl)thieno[2,3-b]pyridine-2-carboxylic acid (0.2 g, crude) as a yellow oil. LCMS: m / z (M+H)+=365.9.

[0334] Preparation of 6-(difluoro(phosphono)methyl)-2-naphthoic acid: [ka]

[0335] Step 1: Methyl 6-iodo-2-naphthoate.

[0336] A solution of methyl 6-bromonaphthalene-2-carboxylate (5.0 g, 19 mmol, 1 equiv.) and sodium iodide (5.6 g, 38 mmol, 2 equiv.) in dioxane (50 mL) was 1 ,N 2 -Dimethylethane-1,2-diamine (0.17 g, 1.9 mmol, 0.1 equiv.) and CuI (0.18 g, 0.94 mmol, 0.05 equiv.) were added and the mixture was then subjected to N 2 The mixture was stirred at 100° C. for 5 h under microwave conditions under 100° C. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2), and the combined organic layer was washed with saturated brine (50 mL×2) and added Na 2 SO 4The residue was purified by RP-flash (column: 330 g flash column, Welch Ultimate XB_C18 20-40 μm; 120A; mobile phase: 5-80%, 35 min; 80% for 10 min) and lyophilized to give methyl 6-iodo-2-naphthoate (4.2 g, 70% yield) as a white solid. LCMS: m / z (M+H) + =313.0

[0337] Step 2: Methyl 6-((diethoxyphosphoryl)difluoromethyl)-2-naphthoate.

[0338] To a solution of diethyl(bromodifluoromethyl)phosphonate (5.4 g, 20 mmol, 3.5 equiv.) in DMF (50 mL), cadmium (2.3 g, 21 mmol, 3.6 equiv.) was added and the mixture was cooled to 37° C. 2 The mixture was stirred at 25° C. for 8 hours under reduced pressure to obtain solution A. To a solution of methyl 6-iodo-2-naphthoate (1.8 g, 5.8 mmol, 1 equivalent) in dimethylformamide (20 mL) was added CuCl (1.1 g, 11 mmol, 2.0 equivalents), and the mixture was diluted with N 2 The mixture was stirred at 25° C. for 2 hours under reduced pressure to obtain solution B. Next, solution A was filtered, and the filtrate was added to solution B. This mixture was then heated under N 2 The mixture was stirred at 25° C. for 16 hours under reduced pressure. The reaction mixture was filtered, and the filtrate was quenched with water (100 mL) and extracted with 240 mL of ethyl acetate (80 mL×3). The combined organic layer was washed with 240 mL of brine (80 mL×3) and diluted with Na 2 SO 4 The residue was purified by RP-Flash (Column: 330 g flash column, Welch Ultimate XB_C18 20-40 μm; 120A; Mobile phase: 5-60%, 30 min; 60% for 5 min) to give methyl 6-((diethoxyphosphoryl)difluoromethyl)-2-naphthoate (1.0 g, 47% yield) as a white solid. LCMS: m / z (M+1) + =373.0

[0339] Step 3: 6-((Ethoxy(hydroxy)phosphoryl)difluoromethyl)-2-naphthoic acid.

[0340] To a solution of methyl 6-((diethoxyphosphoryl)difluoromethyl)-2-naphthoate (0.35 g, 0.94 mmol, 1 equiv.) in tetrahydrofuran (3 mL) and water (1 mL) was added lithium hydroxide(1+) monohydrate (79 mg, 1.9 mmol, 2 equiv.), and the mixture was then stirred at 25° C. for 2 h.

[0341] The reaction mixture was concentrated under reduced pressure to give 6-((ethoxy(hydroxy)phosphoryl)difluoromethyl)-2-naphthoic acid (0.29 g, crude) as a white solid. LCMS: m / z (M+H) + =331.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.38 (s, 1H), 8.05 - 8.00 (m, 2H), 7.91 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.4 Hz, 1H), 7.64 (d, J = 8.8 Hz, 1H), 3.80-3.76 (m, 2H), 1.07 (t, J = 7.2Hz, 3H)

[0342] Step 4: 6-(Difluoro(phosphono)methyl)-2-naphthoic acid.

[0343] To a solution of 6-((ethoxy(hydroxy)phosphoryl)difluoromethyl)-2-naphthoic acid (0.10 g, 0.30 mmol, 1 equiv) in methylene chloride (1 mL) was added BSTFA (0.46 g, 1.8 mmol, 6 equiv) at 0° C., then the mixture was stirred at 0° C. for 10 min, then TMSI (0.24 g, 1.2 mmol, 4 equiv) in methylene chloride (1 mL) was added at 0° C. and stirred at 0° C. for 20 min. The reaction was concentrated under reduced pressure to provide a residue. The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150 x 25 x 10 um; mobile phase: [water (0.225% FA)-ACN]; B%: 10%-40%, 11 min) to give 6-(difluoro(phosphono)methyl)-2-naphthoic acid (20 mg, 25% yield) as a yellow oil. LCMS: m / z (M+H) + =302.9

[0344] Preparation of 6-(dimethoxyphosphoryl)-2-naphthoic acid [ka]

[0345] Step 1: Methyl 6-(dimethoxyphosphoryl)-2-naphthoate.

[0346] To a solution of methyl 6-bromonaphthalene-2-carboxylate (5.0 g, 19 mmol, 1 equiv.) in dioxane (50 mL), 2 Bottom, K 3 PO 4 (8.0g, 38mmol, 2eq), NiCl 2 (dppp) (1.0 g, 1.9 mmol, 0.1 equiv) was added, followed by dropwise addition of a solution of dimethylphosphonate (4.1 g, 38 mmol, 2 equiv) in dioxane (50 mL). The reaction mixture was stirred at 100° C. for 12 h. The reaction mixture was diluted with water (200 mL), extracted with ethyl acetate (200 mL×2), and the combined organic layers were washed with saturated brine (200 mL×2) and diluted with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography to give methyl 6-(dimethoxyphosphoryl)-2-naphthoate (1.5 g, 27% yield) as a white solid. LCMS: m / z (M+H) + =295.3. 1 H NMR (400 MHz, CD 3 OD) δ 8.66 (s, 1H), 8.45 (d, J = 15.6 Hz, 1H), 8.19 - 8.08 (m, 3H), 7.81 (m, 1H), 3.98 (s, 3H), 3.85 - 3.76 (m, 6H)

[0347] Step 2: 6-(Dimethoxyphosphoryl)-2-naphthoic acid

[0348] To a solution of methyl 6-(dimethoxyphosphoryl)-2-naphthoate (0.50 g, 1.7 mmol, 1 equiv.) in methanol (13 mL), tetrahydrofuran (13 mL) and water (13 mL) was added lithium hydroxide (1+) monohydrate (0.14 g, 3.4 mmol, 2 equiv.). The mixture was stirred at 25° C. for 2 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2), which was adjusted to pH=4-6 by the addition of HCl (1 M). The solution was then extracted with ethyl acetate (50 mL×2) to give Na 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure gave crude 6-(dimethoxyphosphoryl)-2-naphthoic acid (0.30 g, crude) as a white solid.

[0349] Preparation of 7-(dimethoxyphosphoryl)-2-naphthoic acid [ka]

[0350] Step 1: 7-Bromo-2-naphthoic acid.

[0351] A solution of 2,7-dibromonaphthalene (20 g, 69 mmol, 1 equiv.) in tetrahydrofuran (200 mL) was cooled to −76° C., and n-BuLi (4.5 g, 70 mmol, 1 equiv.) was added dropwise. The reaction mixture was then cooled to −76° C. with CO. 2 After 15 min, the cold bath was removed and CO 2 The reaction was allowed to warm to room temperature while continuing to ventilate, and the reaction mixture was stirred at room temperature for 1.5 hours. The reaction mixture was diluted with saturated NH 4 The mixture was quenched with Cl (200 mL), extracted with ethyl acetate (200 mL x 2), and the combined organic layers were washed with saturated brine (200 mL x 2) and Na 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure gave 7-bromo-2-naphthoic acid (14 g, crude) as a yellow solid. LCMS: m / z (MH) - =250.0. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.60 (d, J = 0.8 Hz, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.07 - 8.01 (m, 2H), 8.01 - 7.95 (m, 1H), 7.77 (dd, J = 2.2, 8.7 Hz, 1H)

[0352] Step 2: Methyl 7-bromo-2-naphthoate.

[0353] 7-Bromo-2-naphthoic acid (4.3 g, 17 mmol, 1 equiv.) in methanol (40 mL) and H 2 SO 4 (8 mL) was stirred at 70° C. for 12 h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2), and the combined organic layers were washed with saturated brine (50 mL×2) and added Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography to give methyl 7-bromo-2-naphthoate (3.6 g, 84% yield) as a yellow solid.1 H NMR (400 MHz, methanol-d 4 ) δ 8.58 - 8.53 (m, 1H), 8.22 (d, J = 2.0 Hz, 1H), 8.08 - 8.03 (m, 1H), 7.95 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.73 - 7.67 (m, 1H), 3.97 (s, 3H)

[0354] Step 3: Methyl 7-(dimethoxyphosphoryl)-2-naphthoate.

[0355] To a solution of methyl 7-bromo-2-naphthoate (3.3 g, 12 mmol, 1 equiv.) in dioxane (30 mL) was added potassium phosphate tribasic (5.3 g, 24 mmol, 2 equiv.) and dimethylphosphonate (2.7 g, 25 mmol, 2 equiv.), followed by NiCl 2 (dppp) (0.67 g, 1.2 mmol, 0.1 equiv.) 2 The mixture was stirred at 100° C. for 12 hours. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL×2), and the combined organic layer was washed with saturated brine (100 mL×2) and added with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which was purified by column chromatography to give methyl 7-(dimethoxyphosphoryl)-2-naphthoate (0.60 g, 16% yield) as a white solid. LCMS: m / z (M+H) + =295.1

[0356] Step 4: 7-(Dimethoxyphosphoryl)-2-naphthoic acid.

[0357] To a solution of methyl 7-(dimethoxyphosphoryl)-2-naphthoate (0.6 g, 2.0 mmol, 1 equiv.) in water (2 mL), tetrahydrofuran (2 mL), and methanol (2 mL), lithium hydroxide hydrate (85 mg, 2.0 mmol, 1 equiv.) was added and the mixture was stirred at 25° C. for 3 h. The reaction mixture was concentrated under reduced pressure to remove THF and methanol to give a suspension. The suspension was purified by preparative HPLC (column: Phenomenex Luna C18 150×25 mm×10 um, mobile phase: water (0.225% FA)-ACN; B%: 13%-43%, 11.5 min) and lyophilized to give 7-(dimethoxyphosphoryl)-2-naphthoic acid (0.45 g, 79% yield) as a white solid. 1 H NMR (400 MHz, methanol-d 4 ) δ 8.77 (s, 1H), 8.55 (d, J = 15.6 Hz, 1H), 8.27 - 8.18 (m, 1H), 8.16 - 8.10 (m, 1H), 8.09 - 8.04 (m, 1H), 7.93 - 7.82 (m, 1H), 3.85 (d, J = 11.2 Hz, 6H)

[0358] Preparation of ((2-(((5S,8S,10aR)-3-acetyl-8-(methyl(phenyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)benzo[d]thiazol-5-yl)difluoromethyl)phosphonic acid [ka]

[0359] Step 1: 5-Iodobenzo[d]thiazole.

[0360] To a solution of benzo[d]thiazol-5-amine (10 g, 67 mmol, 1 equiv.) in acetonitrile (50 mL) was added HCl (7.3 g, 200 mmol, 3 equiv.) at 0° C., followed by sodium nitrite (5.5 g, 80 mmol, 1.2 equiv.) in water (50 mL). The solution was stirred at 0° C. for 30 min. Then, potassium iodide (17 g, 0.1 mol, 1.5 equiv.) in water (50 mL) was added at 0° C. The reaction mixture was stirred at 0° C. for 1 h to give a black suspension. The reaction mixture was poured into water (100 mL). The aqueous phase was extracted with ethyl acetate (200 mL×2). The combined organic phase was washed with brine (200 mL×2) and anhydrous Na 2 SO 4 The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel, petroleum ether / ethyl acetate = 100 / 1, 5 / 1) to give 5-iodobenzo[d]thiazole (9.0 g, 34 mmol, 52% yield) as a yellow solid. LCMS: m / z (M+H) + =243.9

[0361] Step 2: Ethyl 5-iodobenzo[d]thiazole-2-carboxylate.

[0362] Next, a solution of 5-iodobenzo[d]thiazole (1 g, 3.8 mmol, 1 equiv.) and ethyl cyanoformate (0.76 g, 7.7 mmol, 2 equiv.) in THF (15 mL) at −78 °C was added with N 2 Lithium bis(trimethylsilyl)azanide (1.6 g, 9.6 mmol, 2.5 equiv.) was added at −78° C. under reduced pressure, and the reaction mixture was stirred at −78° C. for 1 h to give a yellow solution. The reaction solution was poured into water (45 mL). The aqueous phase was extracted with ethyl acetate (45 mL×2). The combined organic phase was washed with brine (45 mL×2) and diluted with anhydrous Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated in vacuo to give a residue. The residue was purified by silica gel chromatography (column height: 250 mm, diameter: 100 mm, 100-200 mesh silica gel) to give ethyl 5-iodobenzo[d]thiazole-2-carboxylate (1 g, 3.0 mmol, 79% yield) as a yellow oil. LCMS: m / z (M-28+H) + =305.8. 1 H NMR (400 MHz, chloroform-d) δ 8.97 (s, 1H), 8.52 (d, J = 0.8 Hz, 1H), 7.73 (d, J = 2.0 Hz, 1H), 4.57 (d, J = 7.2 Hz, 2H), 1.50 (t, J = 7.2 Hz, 3H).

[0363] Step 3: Ethyl 5-((diethoxyphosphoryl)difluoromethyl)benzo[d]thiazole-2-carboxylate.

[0364] A suspension of zinc (0.22 g, 3.4 mmol, 2.5 equiv) in THF (5 mL) was added to 2 Chlorotrimethylsilane (59 mg, 0.54 mmol, 0.4 equiv) was added under reduced pressure and the reaction mixture was then stirred at 55° C. for 1.5 h. The contents were cooled to 30° C. and a solution of diethyl(bromodifluoromethyl)phosphonate (0.72 g, 2.7 mmol, 2 equiv) in THF (5 mL) was added dropwise (maintaining the temperature between 50-55° C.). The reaction mixture was stirred at 30° C. for 2 h (the cloudy suspension went into solution) and then copper bromide (1 mL) in DMA (2 mL) was added. + ) (0.19 g, 1.4 mmol, 1.0 equiv) was added and the mixture was stirred at 20° C. for 10 min. A solution of ethyl 5-iodobenzo[d]thiazole-2-carboxylate (0.45 g, 1.4 mmol, 1 equiv) in DMA (2 mL) was added and the reaction mixture was stirred at 55° C. for 16 h to give a green suspension. The reaction solution was poured into ice water (w / w=1 / 1) (35 mL). The aqueous phase was extracted with ethyl acetate (35 mL×2). The combined organic phase was washed with brine (35 mL×2) and diluted with anhydrous Na 2 SO 4The mixture was dried at 4° C., filtered and concentrated in vacuo to give a residue which was purified by silica gel chromatography to give ethyl 5-((diethoxyphosphoryl)difluoromethyl)benzo[d]thiazole-2-carboxylate (0.1 g, 0.25 mmol, 19% yield) as a yellow solid. LCMS: m / z (M+H) + =394.4. 1 H NMR (400 MHz, chloroform-d) δ 8.49 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.8 Hz, 1H), 4.58 (q, J = 7.2 Hz, 2H), 4.30 - 4.19 (m, 4H), 1.51 (t, J = 7.2 Hz, 3H), 1.34 (t, J = 7.2 Hz, 6H).

[0365] Preparation of ((2-(((5S,8S,10aR)-3-acetyl-8-(cinnolin-6-yl(methyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)quinolin-7-yl)difluoromethyl)phosphonic acid [ka]

[0366] Step 1: Benzyl 7-bromoquinoline-2-carboxylate.

[0367] To a solution of 7-bromoquinoline-2-carboxylic acid (2.0 g, 7.9 mmol, 1 equiv.) in dimethylformamide (10 mL) was added (bromomethyl)benzene (1.3 g, 7.9 mmol, 1 equiv.) and potassium carbonate (2.2 g, 16 mmol, 2 equiv.). The mixture was stirred at 25° C. for 16 h to give a white suspension. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (30 mL×2), and the combined organic layers were washed with saturated brine (30 mL×2) and diluted with Na 2 SO 4The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (40 g SepaFlash® silica flash column, eluent of a gradient of 0-25% petroleum ether / ethyl acetate at 50 mL / min) to give benzyl 7-bromoquinoline-2-carboxylate (2.1 g, 77% yield) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 8.44 (s, 1H), 8.25 - 8.04 (m, 2H), 7.68 - 7.62 (m, 2H), 7.54 - 7.41 (m, 2H), 7.37 - 7.24 (m, 3H), 5.45 (s, 2H).

[0368] Step 2: Benzyl 7-iodoquinoline-2-carboxylate.

[0369] To a solution of benzyl 7-bromoquinoline-2-carboxylate (2.0 g, 5.8 mmol, 1 equiv.) and sodium iodide (1.7 g, 12 mmol, 2 equiv.) in dioxane (10 mL) was added methyl[2-(methylamino)ethyl]amine (51.4 mg, 584 μmol, 0.1 equiv.) and lambda 1-copper(1+) iodide (56 mg, 0.29 mmol, 0.05 equiv.). The mixture was heated in a microwave reactor with N 2 The mixture was stirred at 150° C. for 5 hours under reduced pressure to give a black suspension. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (40 g SepaFlash® silica flash column, eluent of a gradient of 0-25% petroleum ether / ethyl acetate at 12 mL / min), collected and concentrated in vacuo to give benzyl 7-iodoquinoline-2-carboxylate (1.3 g, 57% yield) as a white solid. LCMS: m / z (M+H) + =390.0. 1H NMR (400 MHz, chloroform-d) δ 8.20 - 8.15 (m, 1H), 8.13 - 8.08 (m, 1H), 7.85-7.82(M, 1H), 7.54 - 7.41 (m, 3H), 7.37 - 7.27 (m, 4H), 5.45 (s, 2H).

[0370] Step 3: Benzyl 7-((diethoxyphosphoryl)difluoromethyl)quinoline-2-carboxylate.

[0371] To a suspension of zinc (0.44 g, 6.7 mmol, 2 equiv.) in degassed anhydrous tetrahydrofuran (30 mL) was added chlorotrimethylsilane (0.14 mg, 1.3 mmol, 0.4 equiv.) and the suspension was heated to 60 °C for 1.5 h with vigorous stirring. The contents were cooled to 30 °C and a solution of diethyl (bromodifluoromethyl)phosphonate (1.1 g, 4.0 mmol, 1.2 equiv.) in tetrahydrofuran (10 mL) was added dropwise (maintaining the temperature between 50-55 °C). The reaction mixture was stirred at 30 °C for 2 h (the cloudy suspension went into solution) and copper bromide (1 + ) (479 mg, 3.34 mmol, 1.0 equiv) and dimethylacetamide (7.0 g, 80 mmol, 24 equiv) were added and the mixture was stirred at room temperature for 10 min. A solution of benzyl 7-iodoquinoline-2-carboxylate (1.3 g, 3.4 mmol, 1 equiv) in tetrahydrofuran (10 mL) was slowly added to the reaction mixture, which was heated to 50° C. for 12 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2), and the combined organic layers were washed with saturated brine (50 mL×2) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which was purified by RP-flash (TFA system) and lyophilized to give benzyl 7-((diethoxyphosphoryl)difluoromethyl)quinoline-2-carboxylate (0.3 g, 19% yield) as a yellow oil. LCMS: m / z (M+H) + =450.1. 1H NMR (400 MHz, chloroform-d) δ 8.59 (s, 1H), 8.43 - 8.33 (m, 1H), 8.32 - 8.22 (m, 1H), 8.04 - 7.97 (m, 1H), 7.96 - 7.89 (m, 1H), 7.61 - 7.53 (m, 2H), 7.47 - 7.33 (m, 3H), 5.57 (s, 2H), 4.39 - 4.15 (m, 4H), 1.35 (t, J = 7.2, 6H).

[0372] Step 4: Benzyl 7-iodoquinoline-2-carboxylate.

[0373] To a solution of benzyl 7-((diethoxyphosphoryl)difluoromethyl)quinoline-2-carboxylate (0.32 mg, 0.71 mmol, 1 equiv.) in methanol (3 mL), wet Pd / C (0.1 g, 2.9 mmol) was added and degassed with H 2 The mixture was purged with H 2 Stirring at (15 psi) for 3 h at 25° C. gave a black suspension. The reaction mixture was filtered and the filtrate was concentrated to give benzyl 7-((diethoxyphosphoryl)difluoromethyl)quinoline-2-carboxylate (0.25 g, crude). LCMS: m / z (M+H) + =360.1.

[0374] Step 5: 4-Nitrophenyl 7-((diethoxyphosphoryl)difluoromethyl)quinoline-2-carboxylate.

[0375] To a solution of benzyl 7-((diethoxyphosphoryl)difluoromethyl)quinoline-2-carboxylate (50 mg, 0.14 mmol, 1 equiv) in methylene chloride (1 mL) was added 4-dimethylaminopyridine (25 mg, 0.21 mmol, 1.5 equiv), 4-nitrophenol (25 mg, 0.18 mmol, 1.3 equiv) and dicyclohexylcarbodiimide (43 mg, 0.21 μmol, 1.5 equiv). The mixture was stirred at 25° C. for 1 h to give a yellow suspension. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (4 g SepaFlash® silica flash column, eluting with a gradient of 0-60% petroleum ether / ethyl acetate at 30 mL / min) to give 4-nitrophenyl 7-((diethoxyphosphoryl)difluoromethyl)quinoline-2-carboxylate (30 mg, 45% yield). LCMS: m / z (M+H) + =481.1. 1 H NMR (400 MHz, chloroform-d) δ 8.65 (s, 1H), 8.49 - 8.45 (m, 1H), 8.42 - 8.36 (m, 2H), 8.16 - 8.11 (m, 1H), 8.08 - 8.03 (m, 1H), 8.00 - 7.94 (m, 1H), 7.59 - 7.47 (m, 1H), 6.97 - 6.84 (m, 1H), 4.40 - 4.05 (m, 4H), 1.42 - 1.31 (m, 6H).

[0376] Step 6: (Difluoro(2-((4-nitrophenoxy)carbonyl)quinolin-7-yl)methyl)phosphonic acid.

[0377] To a solution of 4-nitrophenyl 7-((diethoxyphosphoryl)difluoromethyl)quinoline-2-carboxylate (30 mg, 62 μmol, 1 equiv.) in methylene chloride (1 mL) was added trimethylsilyl (1E)-2,2,2-trifluoro-N-trimethylsilylethaneimidate (96 mg, 0.37 mmol, 6 equiv.) and trimethylsilyl iodide (50 mg, 0.25 mmol, 4 equiv.). The mixture was stirred at 0° C. for 2 h to give a yellow solution. The reaction mixture was concentrated under reduced pressure to give crude (difluoro(2-((4-nitrophenoxy)carbonyl)quinolin-7-yl)methyl)phosphonic acid (30 mg, crude). LCMS: m / z (M+H) + =425.1

[0378] Preparation of ((6-(((5S,8S,10aR)-3-acetyl-8-(cinnolin-6-yl(methyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)isoquinolin-3-yl)difluoromethyl)phosphonic acid [ka]

[0379] Step 1: 3-Chloroisoquinoline-6-carboxylic acid.

[0380] THF (45 mL) and H 2 To a solution of 6-bromo-3-chloroisoquinoline (5.0 g, 21 mmol, 1 equiv.) in O (5 mL) was added iron (2 +) bis((cyclopenta-2,4-diyn-1-yl)diphenylphosphane)palladium dichloride (1.5 g, 2.1 mmol, 0.1 equiv.) and triethylamine (4.2 g, 41 mmol, 2 equiv.) were added. The mixture was stirred at 70° C. under CO (50 psi) for 16 h to give a black solution. The reaction mixture was quenched with water (50 mL) and extracted with 150 mL of ethyl acetate (50 mL×3), and then the combined aqueous layers were collected. The combined aqueous layers were adjusted to pH=3-4 with 20 mL of 1N formic acid and then extracted with 150 mL of ethyl acetate (50 mL×3). The combined organic layers were washed with 450 mL of saturated brine (150 mL×3) and diluted with Na 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure gave 3-chloroisoquinoline-6-carboxylic acid (3.5 g, 76% yield) as a white solid. LCMS: m / z (M+H) + =208.1. 1 H NMR (400 MHz, DMSO-d 6 ) δ 13.94 - 13.02 (m, 1H), 9.33 (s, 1H), 8.64 (s, 1H), 8.33 - 8.22 (m, 2H), 8.13 (dd, J = 1.6, 8.4 Hz, 1H).

[0381] Step 2: Benzyl 3-chloroisoquinoline-6-carboxylate.

[0382] To a solution of 3-chloroisoquinoline-6-carboxylic acid (3.5 g, 17 mmol, 1 equiv.) and (bromomethyl)benzene (4.3 g, 25 mmol, 1.5 equiv.) in DMF (40 mL) was added dipotassium carbonate (4.6 g, 34 mmol, 2 equiv.). The mixture was stirred at 25° C. for 2 h to give a grey solution. The reaction mixture was quenched with 50 mL of water and extracted with 150 mL of ethyl acetate (50 mL×3). The combined organic layers were washed with brine (50 mL×3) and diluted with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (40 g SepaFlash® silica flash column, eluent of a gradient of 0-100% ethyl acetate / petroleum ether at 40 mL / min) to give benzyl 3-chloroisoquinoline-6-carboxylate (3.6 g, 71% yield) as a white solid. LCMS: m / z (M+H) + =297.9. 1 H NMR (400 MHz, chloroform-d) δ 9.17 (s, 1H), 8.55 (s, 1H), 8.23 ​​(d, J = 8.4 Hz, 1H), 8.06 (d, J = 8.8 Hz, 1H), 7.85 (s, 1H), 7.59 - 7.35 (m, 5H), 5.47 (s, 2H).

[0383] Step 3: Benzyl 3-iodoisoquinoline-6-carboxylate.

[0384] A solution of benzyl 3-chloroisoquinoline-6-carboxylate (1.0 g, 3.4 mmol, 1 equiv.) and sodium iodide (1.0 g, 6.7 mmol, 2 equiv.) in dioxane (10 mL) was added to copper iodide (1 + ) (32 mg, 0.17 mmol, 0.05 equiv.) and methyl[2-(methylamino)ethyl]amine (30 mg, 0.34 mmol, 0.1 equiv.) were added, and the mixture was then heated in a microwave reactor under N 2 The mixture was stirred at 150° C. for 8 hours under reduced pressure to give a grey suspension. The reaction mixture was filtered, and the filtrate was quenched with 20 mL of water and extracted with 60 mL of ethyl acetate (20 mL×3). The combined organic layer was washed with 60 mL of brine (20 mL×3) and diluted with Na 2 SO 4The residue was purified by flash silica gel chromatography (40 g SepaFlash® silica flash column, eluent of 0-100% ethyl acetate / petroleum ether gradient at 40 mL / min) to afford benzyl 3-iodoisoquinoline-6-carboxylate (0.80 g, 22% yield) as a white solid. LCMS: m / z (M+H) + =389.9

[0385] Step 4: Benzyl 3-((diethoxyphosphoryl)difluoromethyl)isoquinoline-6-carboxylate

[0386] To a solution of zinc (0.27 g, 4.1 mmol, 2 equiv.) in THF (8 mL) was added chlorotrimethylsilane (0.11 g, 1.0 mmol, 0.5 equiv.), followed by N 2 The mixture was stirred at 55° C. for 1.5 h under reduced pressure. Then, a solution of diethyl(bromodifluoromethyl)phosphonate (1.1 g, 4.1 mmol, 2 equiv.) in THF (8 mL) was added and N 2 The mixture was stirred at 55°C for 2 hours under reduced pressure. + ) (0.59 g, 4.1 mmol, 2 eq.) and DMA (4 mL) were added and stirred at 55° C. for 10 min. Next, a solution of benzyl 3-iodoisoquinoline-6-carboxylate (0.8 g, 2.1 mmol, 1 eq.) in DMA (4 mL) was added and N 2 The reaction mixture was stirred at 55° C. for 16 h under reduced pressure to give a bright yellow solution. The reaction mixture was filtered and the filtrate was 2 The mixture was quenched with 20 mL of O and extracted with 60 mL of ethyl acetate (20 mL x 3). The combined organic layers were washed with 60 mL of brine (20 mL x 3) and diluted with Na 2 SO 4 The residue was purified by preparative HPLC (column: Phenomenex Luna C18 150×25×10 um; mobile phase: [water (10 mM NH 4 HCO 3)-ACN; B%: 50%-75%, 18 min). The solution was lyophilized to give benzyl 3-((diethoxyphosphoryl)difluoromethyl)isoquinoline-6-carboxylate (0.30 g, 32% yield) as a yellow solid. LCMS: m / z (M+H) + =450.0. 1 H NMR (400 MHz, chloroform-d) δ 9.33 (s, 1H), 8.63 (s, 1H), 8.26 (dd, J = 1.2, 8.8 Hz, 1H), 8.14 (s, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.46 - 7.40 (m, 2H), 7.39 - 7.25 (m, 3H), 5.38 (s, 2H), 4.38 - 4.10 (m, 4H), 1.31 (t, J = 7.2 Hz, 6H).

[0387] Step 5: 3-((diethoxyphosphoryl)difluoromethyl)isoquinoline-6-carboxylic acid.

[0388] To a solution of benzyl 3-((diethoxyphosphoryl)difluoromethyl)isoquinoline-6-carboxylate (0.27 g, 0.60 mmol, 1 equiv.) in MeOH (5 mL) was added wet Pd / C (0.15 g). This mixture was heated at 37° C. for 1 hour at 4° C. for 2 hours at 4° C. for 1 hour at 4° C. 2 The mixture was stirred at 25° C. under (15 psi) for 3 hours. The reaction mixture was filtered and concentrated under reduced pressure to give crude 3-((diethoxyphosphoryl)difluoromethyl)isoquinoline-6-carboxylic acid (0.2 g, crude). LCMS: m / z (M+H) + =359.9

[0389] Preparation of ((7-(((5S,8S,10aR)-3-acetyl-8-(cinnolin-6-yl(methyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)quinolin-2-yl)difluoromethyl)phosphonic acid [ka]

[0390] Step 1: Benzyl 2-chloroquinoline-7-carboxylate

[0391] To a solution of ethyl 2-chloroquinoline-7-carboxylate (0.50 g, 2.1 mmol, 1 equiv.) in benzyl alcohol (5 mL), tripotassium phosphate (45 mg, 0.21 mmol, 0.1 equiv.) and potassium carbonate (0.30 g, 2.1 mmol, 1 equiv.) were added, and the mixture was then stirred at 25° C. for 12 h. The residue was diluted with water (20 mL), extracted with ethyl acetate (40 mL×2), and the combined organic layer was washed with saturated brine (20 mL×2) and diluted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100:0 to 90:10) to give benzyl 2-chloroquinoline-7-carboxylate (0.39 g, 62% yield) as a white solid. 1 H NMR (400 MHz, chloroform-d) δ 8.80 (s, 1H), 8.24 - 8.12 (m, 2H), 7.89 (d, J = 8.4 Hz, 1H), 7.52 - 7.47 (m, 3H), 7.46 - 7.35 (m, 3H)

[0392] Step 2: Benzyl 2-iodoquinoline-7-carboxylate

[0393] A solution of benzyl 2-chloroquinoline-7-carboxylate (0.3 g, 0.87 mmol, 1 equiv.) and sodium iodide (0.26 g, 1.7 mmol, 2 equiv.) in dioxane (38 mL) was added with copper iodide (1 + ) (8.3 mg, 44 μmol, 0.05 equiv) was added and the mixture was then stirred at 150° C. for 5 h under microwave as a grey suspension. The reaction mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by column chromatography (SiO 2, petroleum ether / ethyl acetate=10:1 to 3:1) to give benzyl 2-iodoquinoline-7-carboxylate (0.1 g, 29% yield) as a white solid. LCMS: m / z (M+H) + =389.9

[0394] Step 3: Benzyl 2-((diethoxyphosphoryl)difluoromethyl)quinoline-7-carboxylate

[0395] A suspension of zinc (47 mg, 0.72 mmol, 2 equiv.) in tetrahydrofuran (2 mL) was 2 Chlorotrimethylsilane (16 mg, 0.14 mmol, 0.4 equiv) was added, the reaction mixture was then stirred at 55° C. for 1.5 h, and then a solution of diethyl(bromodifluoromethyl)phosphonate (0.19 g, 0.72 mmol, 2 equiv) in tetrahydrofuran (2 mL) was added dropwise (maintaining the temperature between 50-55° C.). The reaction mixture was stirred at 55° C. for 2 h (the cloudy suspension became a solution) and then copper bromide (1 mL) in dimethylacetamide (2 mL) was added dropwise. + ) (51 mg, 0.36 mmol, 1 equiv) was added and the mixture was stirred at 55° C. for 10 min. A solution of 2-iodoquinoline-7-benzyl carboxylate (0.1 g, 0.36 mmol, 1 equiv) in dimethylacetamide (2 mL) was added and the reaction mixture was stirred at 55° C. for 16 h to give a green suspension. The reaction mixture was concentrated under reduced pressure to remove THF. The mixture was purified by preparative HPLC (column: Phenomenex Luna C18 150×25 mm×10 um, mobile phase: water (0.225% FA)-ACN; B%: 54%-84%, 10 min) and lyophilized to give 2-((diethoxyphosphoryl)difluoromethyl)quinoline-7-benzyl carboxylate (40 mg, 30% yield) as a yellow oil. 1H NMR (400 MHz, chloroform-d) δ 8.95 (s, 1H), 8.36 (d, J = 8.4 Hz, 1H), 8.31 - 8.22 (m, 1H), 7.95 (d, J = 8.8 Hz, 1H), 7.53 - 7.49 (m, 2H), 7.46 - 7.35 (m, 4H), 5.46 (s, 2H), 4.40 - 4.31 (m, 4H), 1.39 (t, J = 7.2 Hz, 6H)

[0396] Step 4: 2-((diethoxyphosphoryl)difluoromethyl)quinoline-7-carboxylic acid

[0397] To a solution of benzyl 2-((diethoxyphosphoryl)difluoromethyl)quinoline-7-carboxylate (40 mg, 89 μmol, 1 equiv.) in methanol (1 mL) and tetrahydrofuran (1 mL), N 2 Wet Pd / C (40 mg) was added and the mixture was heated under H 2 The mixture was stirred at 25° C. under (15 psi) for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to give 2-((diethoxyphosphoryl)difluoromethyl)quinoline-7-carboxylic acid (15 mg, crude) as a yellow oil. LCMS: m / z (M+H) + =360.1

[0398] Building Block Synthesis

[0399] Synthesis of 6-phenyl-4-azaspiro[2.4]heptane [ka]

[0400] Step 1: Preparation of methyl 3-cyano-2-phenylpropanoate

[0401] To a cooled (-78 °C) solution of methyl 2-phenylacetate (5.0 g, 33.3 mmol, 1.0 equiv) in dry 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 aged at -78 °C for an additional 1 h. The mixture was diluted with saturated aqueous NH 4 Cl (5 mL) was added and the mixture was allowed to warm to room temperature. The mixture was extracted with EtOAc (20 mL×3). The combined organic layers were washed with brine (150 mL) and anhydrous Na 2 SO 4 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%) as a white solid. LCMS (ESI) m / z=190.1 [M+H] + .

[0402] Step 2: Preparation of 6-phenyl-4-azaspiro[2.4]heptan-5-one

[0403] Methyl 3-cyano-2-phenylpropanoate (5.0 g, 26.5 mmol, 1.0 equiv.) and Ti(OiPr) 4 To a cooled (0° C.) solution of (9.0 g, 31.7 mmol, 1.2 equiv.) in dry THF (100 mL) was slowly added a 3 M solution of EtMgBr (20 mL, 59.6 mmol, 2.25 equiv.) while maintaining the 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 adding aqueous 2N 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) and extracted with anhydrous Na 2 SO 4The 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] + ; 1 H NMR (400 MHz, CDCl 3 ) 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).

[0404] Step 3: Preparation of 6-phenyl-4-azaspiro[2.4]heptane

[0405] 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 dry THF (50 mL) was added NaBH 4 (2.1 g, 56.0 mmol, 5.0 equiv.) was added to the mixture. 3 Et 2 2H2O (6.7 mL, 56.0 mmol, 5.0 equiv) was added dropwise. The reaction mixture was heated at 60° C. for 16 h. The mixture was cooled to ambient temperature and aqueous 2N HCl (30 mL) was slowly introduced. The acidic mixture was extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (20 mL) and anhydrous Na 2 SO 4 The residue was purified by Biotage® C18 column to give 6-phenyl-4-azaspiro[2.4]heptane (1.5 g, 8.7 mmol, 78%) as a colorless oil. LCMS (ESI) m / z=174 [M+H] + ; 1 H NMR (400 MHz, CDCl 3) 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).

[0406] Synthesis of pyrrolidine building blocks:

[0407] Synthesis of rel-(trans)-4-cyclohexylpyrrolidine-3-carbonitrile [ka]

[0408] Step 1: Preparation of (E)-3-cyclohexylacrylonitrile

[0409] To a solution of cyclohexanecarbaldehyde (500 mg, 4.45 mmol, 1.0 equiv) in THF (15 mL) at room temperature was added t-BuOK (998 mg, 8.90 mmol, 2.0 equiv) and diethyl(cyanomethyl)phosphonate (788 mg, 4.45 mmol, 1.0 equiv). The solution was stirred at room temperature for 1 h. Upon completion, the reaction mixture was diluted with H 2 The mixture was quenched by the addition of 2H2O (10 mL) and then extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL) and anhydrous Na 2 SO 4 The mixture was dried over 100 ml of ethyl acetate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give (E)-3-cyclohexylacrylonitrile (300 mg, 2.21 mmol, 50% yield) as a colorless oil. LC-MS (ESI) m / z=136 [M+H] + .

[0410] Step 2: Preparation of rel-(trans)-1-benzyl-4-cyclohexylpyrrolidine-3-carbonitrile

[0411] (E)-3-Cyclohexylacrylonitrile (300 mg, 2.21 mmol, 1.0 equiv.) 2 Cl 2 To the (5 mL) solution 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 CH 2 Cl 2 (10 mL) and dilute with saturated aqueous NaHCO 3 (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] + .

[0412] Step 3: Preparation of rel-(trans)-4-cyclohexylpyrrolidine-3-carbonitrile

[0413] To a solution of (trans)-1-benzyl-4-cyclohexylpyrrolidine-3-carbonitrile (700 mg) in dry 1,2-dichloroethane (15 mL) was added 1-chloroethyl chloroformate (3.71 g, 26.0 mmol, 10.0 equiv). The resulting mixture was stirred at 70° C. for 12 h, then concentrated under reduced pressure, and the crude product was dissolved in MeOH (5 mL) and stirred at 70° C. for 1 h. 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 give 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] + .

[0414] The following intermediates in Table 10 were prepared following the representative procedure (Steps 1 to 3) described for rel-(trans)-4-cyclohexylpyrrolidine-3-carbonitrile using the appropriate starting materials and modifications. The compounds were prepared as racemates with trans stereochemical configuration relative to the C3 and C4 stereocenters in the pyrrolidine ring. [Table 10]

[0415] 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 according to the method described above for the synthesis of rel-(trans)-4-cyclohexylpyrrolidine-3-carbonitrile. The racemic mixture of the trans-isomers was purified under SFC conditions and the absolute stereochemistry was arbitrarily assigned as shown. [ka]

[0416] Preparative separation method:

[0417] Equipment: Waters Thar 80 preparative SFC; Column: ChiralPak C-IG, 100 x 4.6mm ID, 5μm; Mobile phase: A:CO 2 and 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.

[0418] The following intermediates in Table 11 were prepared following the procedure described for rel-(trans)-4-cyclohexylpyrrolidine-3-carbonitrile using the appropriate starting materials and modifications. [Table 11]

[0419] Synthesis of 2-methyl-2-(4-(methylamino)phenyl)propanenitrile [ka]

[0420] 2-(4-aminophenyl)-2-methylpropanenitrile (360 mg, 2.24 mmol, 1 equiv.), PPh 3 A solution of 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (587 mg, 2.24 mmol, 1 equiv), 4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (508 mg, 2.24 mmol, 1 equiv) and MeOH (71.6 mg, 2.24 mmol, 1.0 equiv) in DCM (10 mL) was stirred at room temperature under nitrogen for 1 h. Upon completion, the reaction was filtered and concentrated to give a residue which was purified by flash column chromatography on silica gel to give 2-methyl-2-(4-(methylamino)phenyl)propanenitrile (90.0 mg, 516 μmol, 23%) as a white solid. LCMS (ESI): m / z=175.3 [M+H] + .

[0421] The following intermediates in Table 12 were prepared following the procedure described for 2-methyl-2-(4-(methylamino)phenyl)propanenitrile using the appropriate starting materials and modifications. [Table 12]

[0422] Synthesis of 2-methyl-2-(4-(methylamino)phenyl)propan-1-ol [ka]

[0423] A solution of 2-(4-aminophenyl)-2-methylpropan-1-ol (230 mg, 1.39 mmol, 1 equiv), formaldehyde (112 mg, 1.39 mmol, 1 equiv), sodium cyanoborohydride (87.3 mg, 1.39 mmol, 1 equiv) in MeOH (20 mL) was stirred overnight at room temperature under nitrogen. Upon completion, the reaction was filtered and concentrated. The residue was purified by C18 column to give 2-methyl-2-[4-(methylamino)phenyl]propan-1-ol (60.0 mg, 334 μmol, 24%) as a white solid. LCMS (ESI): m / z=180.2 [M+H] + .

[0424] The following intermediates in Table 13 were prepared following the procedure described for 2-methyl-2-(4-(methylamino)phenyl)propan-1-ol using the appropriate starting materials and modifications. [Table 13]

[0425] Synthesis of intermediate: (rel-trans)-5-phenylpiperidine-3-carbonitrile [ka]

[0426] Step A: Methyl 5-phenylnicotinate

[0427] Methyl 5-bromonicotinate (2.0 g, 9.25 mmol, 1 equiv.) and Pd(PPh 3 ) 4 A stirred solution of (320 mg, 277 μmol, 0.03 equiv.) was added under nitrogen to H 2 Na in O (10 mL) 2 CO 3(1.96 g, 18.5 mmol, 2.0 equiv) in water and a solution of phenylboronic acid (1.34 g, 11.0 mmol, 1.2 equiv) in MeOH (5 mL) were added. The stirred mixture was stirred at 80° C. for 4 h. The reaction mixture was cooled to room temperature and extracted with EtOAc (60 mL). The solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel to give methyl 5-phenylnicotinate (1.30 g, 6.09 mmol, 61%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 9.19 (d, J = 1.9 Hz, 1H), 9.01 (d, J = 2.3 Hz, 1H), 8.49 (t, J = 2.1 Hz, 1H), 7.68-7.57 (m, 2H), 7.56-7.35 (m, 3H), 3.99 (s, 3H).

[0428] Step B: Methyl 5-phenylpiperidine-3-carboxylate

[0429] Methyl 5-phenylnicotinate (1.0 g, 4.68 mmol, 1 equiv.) and H 2 SO 4 (0.05 mL) in MeOH (10 mL) 2 (100 mg, 10%) was added. The suspension was degassed under vacuum and H 2 The mixture was purged with H 2 The mixture was stirred at room temperature under a balloon for 16 hours. The reaction mixture was filtered through celite. The filtrate was concentrated under reduced pressure to give methyl 5-phenylpiperidine-3-carboxylate (1 g, 4.56 mmol, 98%) as a white solid. LCMS (ESI) m / z=220 [M+H] + .

[0430] Step C: (rel-trans)-5-phenylpiperidine-1,3-dicarboxylate 1-(tert-butyl) 3-methyl

[0431] To a solution of methyl 5-phenylpiperidine-3-carboxylate (1.0 g, 4.56 mmol, 1 equiv.) in THF (10 mL) at room temperature was added TEA (1.37 g, 13.6 mmol, 3.0 equiv.) and di-tert-butyl dicarbonate (1.49 g, 6.84 mmol, 1.5 equiv.). After addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the resulting residue was purified by flash chromatography on silica gel (cis and trans isomers were separable) to give 1-(tert-butyl)3-methyl (rel-trans)-5-phenylpiperidine-1,3-dicarboxylate (800 mg, 2.50 mmol, 55%) as a colorless oil. LCMS (ESI) m / z=320 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.34-7.23 (m, 5H), 4.46-3.96 (m, 2H), 3.72 (s, 3H), 3.29-2.89 (m, 3H), 2.81-2.64 (m, 1H), 2.44-2.24 (m, 1H), 1.98-1.83 (m, 1H), 1.45 (s, 9H).

[0432] Step D: (rel-trans)-1-(tert-butoxycarbonyl)-5-phenylpiperidine-3-carboxylic acid

[0433] THF (4 mL), H 2 A solution of 1-(tert-butyl)3-methyl (rel-trans)-5-phenylpiperidine-1,3-dicarboxylate (120 mg, 375 μmol, 1 equiv.) in a mixture of 2H2O (1 mL) and MeOH (1 mL) was added to the solution of 1-(tert-butyl)3-methyl (rel-trans)-5-phenylpiperidine-1,3-dicarboxylate (120 mg, 375 μmol, 1 equiv.) in a mixture of 2H2O (1 mL) and MeOH (1 mL) at room temperature with LiOH-H 2 2H2O (78.4 mg, 1.87 mmol, 5.0 equiv.) was added. After the addition, the reaction mixture was stirred at room temperature overnight. The reaction mixture was cooled to 0° C. and acidified to pH=3 with 2.0 M aqueous HCl. The mixture was extracted with EtOAc (30 mL). The organic phase was washed with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give (rel-trans)-1-(tert-butoxycarbonyl)-5-phenylpiperidine-3-carboxylic acid (110 mg, 360 μmol, 96.4%) as a colorless oil. LCMS (ESI): m / z=304 [MH] - .

[0434] Step E: (rel-trans)-3-carbamoyl-5-phenylpiperidine-1-carboxylate tert-butyl

[0435] A solution of (rel-trans)-1-(tert-butoxycarbonyl)-5-phenylpiperidine-3-carboxylic acid (110 mg, 360 μmol, 1 equiv.) and CDI (64 mg, 396 μmol, 1.1 equiv.) in EtOAc (4 mL) was stirred at room temperature for 2 h. Then, NH 3 .H 2 0 (1 mL) was added. The reaction mixture was stirred at 45° C. for 2 h. The reaction mixture was cooled to room temperature and extracted with EtOAc (15 mL). The mixture was washed with water (5 mL). The organic phase was concentrated under reduced pressure to give a residue. The residue was purified by C18 column to give tert-butyl (rel-trans)-3-carbamoyl-5-phenylpiperidine-1-carboxylate (80 mg, 262 μmol, 73%) as a white solid. LCMS (ESI): m / z=305.2 [M+H] + .

[0436] Step F: (rel-trans)-3-cyano-5-phenylpiperidine-1-carboxylate tert-butyl

[0437] To a solution of tert-butyl (rel-trans)-3-carbamoyl-5-phenylpiperidine-1-carboxylate (80 mg, 262 μmol, 1 eq.) in DCM (2 mL) was added TEA (66 mg, 655 μmol, 2.5 eq.) at room temperature. The mixture was cooled to 0° C. and TFAA (71 mg, 340 μmol, 1.3 eq.) was added dropwise. After addition, the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was diluted with DCM (15 mL). The mixture was washed with water (5 mL). The organic phase was concentrated under reduced pressure to give a residue. The residue was purified by C18 column to give tert-butyl (rel-trans)-3-cyano-5-phenylpiperidine-1-carboxylate (57 mg, 199 μmol, 76%) as a white solid. LCMS (ESI): m / z=309 [M+Na] + .

[0438] Step G: (rel-trans)-5-phenylpiperidine-3-carbonitrile

[0439] A solution of tert-butyl (rel-trans)-3-cyano-5-phenylpiperidine-1-carboxylate (57 mg, 199 μmol, 1 equiv.) in 4.0 M HCl / dioxane (2 mL) was stirred at room temperature for 1 h. The reaction mixture was concentrated under reduced pressure to give (rel-trans)-5-phenylpiperidine-3-carbonitrile (35 mg, 187 μmol, 95%) as a white solid, which was used in the next step without purification. LCMS (ESI): m / z=187 [M+H] + .

[0440] Preparation of (3S,5R)-5-benzylpyrrolidine-3-carbonitrile [ka]

[0441] Step A: (S)-2-(benzylamino)-3-phenylpropan-1-ol

[0442] LiAlH in THF (30 mL)4 (421 mg, 11.1 mmol, 3 equiv.) was added dropwise to benzoyl-L-phenylalanine (1 g, 3.71 mmol, 1 equiv.) at room temperature, and the resulting mixture was stirred at 70° C. for 18 hours. Upon completion, the reaction was 2 SO 4 -10H 2 The mixture was quenched with O, filtered, and the filter cake was washed with DCM (50 mL). The filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel to give (S)-2-(benzylamino)-3-phenylpropan-1-ol (700 mg, 2.90 mmol, 78%) as a white solid. LCMS (ESI): m / z=242.2 [M+H] + .

[0443] Step B: (S)-3-(benzyl(1-hydroxy-3-phenylpropan-2-yl)amino)propanenitrile

[0444] To (S)-2-(benzylamino)-3-phenylpropan-1-ol (650 mg, 2.69 mmol, 1 eq.) and prop-2-enenitrile (9.97 g, 188 mmol, 70 eq.) in 1,4-dioxane (15 mL) was added AcOH (322 mg, 5.38 mmol, 2 eq.) at room temperature, and the solution was then stirred at 80° C. for 48 h. After completion, the solvent was removed under reduced pressure and the residue was purified by flash column chromatography on silica gel to give (S)-3-(benzyl(1-hydroxy-3-phenylpropan-2-yl)amino)propanenitrile (560 mg, 1.90 mmol, 71%) as a white solid. LCMS (ESI): m / z=295.2 [M+H] + .

[0445] Step C: (S)-3-(benzyl(1-chloro-3-phenylpropan-2-yl)amino)propanenitrile

[0446] (S)-3-(benzyl(1-hydroxy-3-phenylpropan-2-yl)amino)propanenitrile (550 mg, 1.86 mmol, 1 equiv.) in DCM (10 mL) was treated with SOCl at room temperature. 2 (553 mg, 4.65 mmol, 2.5 equiv) was added and the solution was then stirred at 70° C. for 0.5 h. Upon completion, the reaction was cooled to room temperature and added NaHCO 3 (aqueous) (2 mL) and extracted with EtOAc (10 mL x 2). The combined organic layers were washed with brine and 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure gave crude (S)-3-(benzyl(1-chloro-3-phenylpropan-2-yl)amino)propanenitrile (550 mg, 1.75 mmol, 95%) as an oil. LCMS (ESI): m / z=313.2 [M+H] + .

[0447] Step D: (3R,5S)-1,5-Dibenzylpyrrolidine-3-carbonitrile

[0448] To (S)-3-(benzyl(1-chloro-3-phenylpropan-2-yl)amino)propanenitrile (550 mg, 1.75 mmol, 1 equiv.) in THF (20 mL) was added NaHMDS (3 mL, 1.2 equiv.) at room temperature under nitrogen, and the solution was then stirred at room temperature for 0.5 h. Upon completion, the reaction was quenched with NH 4 The mixture was quenched with Cl(aq) (0.5 mL) and extracted with EtOAc (5 mL×2). The combined organic layers were washed with brine to remove Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give (3S,5R)-1,5-dibenzylpyrrolidine-3-carbonitrile (150 mg, 0.54 mmol, 31%) as an oil and (3R,5R)-1,5-dibenzylpyrrolidine-3-carbonitrile (250 mg, 0.90 mmol, 52%). LCMS (ESI): m / z=277.2 [M+H] + .

[0449] Step E: (3R,5S)-5-benzylpyrrolidine-3-carbonitrile

[0450] To a solution of (3S,5R)-1,5-dibenzylpyrrolidine-3-carbonitrile (150 mg, 0.5427 mmol, 1 equiv) in DCE (10 mL) at room temperature was added 1-chloroethyl chloroformate (387 mg, 2.71 mmol, 5 equiv) and then stirred at 80° C. for 18 h. The solution was concentrated and then the residue was dissolved in MeOH (10 mL) and the solution was stirred at 70° C. for 2 h. After completion, the solution was concentrated and then the residue was purified by flash column chromatography on silica gel to give (3S,5R)-5-benzylpyrrolidine-3-carbonitrile (50.0 mg, 0.27 mmol, 50%). LCMS (ESI): m / z=187.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.34-7.16 (m, 5H), 3.35-3.24 (m, 2H), 3.19-3.10 (m, 1H), 2.96-2.72 (m, 3H), 2.32-2.20 (m, 1H), 1.79-1.63 (m, 1H).

[0451] Step E (cis): (3R,5R)-5-benzylpyrrolidine-3-carbonitrile

[0452] To a solution of (3R,5R)-1,5-dibenzylpyrrolidine-3-carbonitrile (200 mg, 0.72 mmol, 1 equiv) in DCM (10 mL) was added 1-chloroethyl chloroformate (516 mg, 3.61 mmol, 5 equiv) at room temperature, and the solution was then stirred at 80° C. for 18 h. After completion, the solution was concentrated, and the residue was then dissolved in MeOH (10 mL) and the solution was stirred at 70° C. for 2 h. The solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography on silica gel to give (3R,5R)-5-benzylpyrrolidine-3-carbonitrile (30.0 mg, 0.16 mmol, 22%). LCMS (ESI): m / z=187.2 [M+H] + . 1 H NMR (400 MHz, CDCl 3 ) δ 7.34-7.16 (m, 5H), 3.56-3.43 (m, 1H), 3.42-3.30 (m, 1H), 3.11-3.01 (m, 1H), 2.99-2.88 (m, 1H), 2.76 (d, J = 6.7 Hz, 2H), 2.22-2.10 (m, 1H), 1.85-1.73 (m, 1H).

[0453] Preparation of (rel-trans)-4-phenylpiperidine-3-carbonitrile [ka]

[0454] Step A: (rel-trans)-3-carbamoyl-4-phenylpiperidine-1-carboxylate tert-butyl

[0455] A solution of (rel-trans)-1-(tert-butoxycarbonyl)-4-phenylpiperidine-3-carboxylic acid (400 mg, 1.30 mmol, 1 equiv.) and CDI (231 mg, 1.43 mmol, 1.1 equiv.) in EtOAc (5 mL) was stirred at room temperature for 2 h. Then, NH 3 -H 22 mL of H2O was added. The reaction mixture was stirred at 45° C. for 2 h. After completion, the reaction mixture was cooled to room temperature and then diluted with H 2 The mixture was diluted with 200 mL of EtOAc (5 mL) and extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (10 mL) and diluted with anhydrous Na 2 SO 4 The residue was purified by C18 column to give tert-butyl (rel-trans)-3-carbamoyl-4-phenylpiperidine-1-carboxylate (390 mg, 1.28 mmol, 99%) as a white solid. LCMS (ESI) m / z=305 [M+H] + .

[0456] Step B: (rel-trans)-3-cyano-4-phenylpiperidine-1-carboxylate tert-butyl

[0457] To a solution of tert-butyl (rel-trans)-3-carbamoyl-4-phenylpiperidine-1-carboxylate (390 mg, 1.28 mmol, 1 equiv) in DCM (5 mL) at room temperature was added TEA (323 mg, 3.20 mmol, 2.5 equiv). The mixture was cooled to 0° C. and TFAA (348 mg, 1.66 mmol, 1.3 equiv) was added dropwise. After addition, the reaction mixture was stirred at room temperature for 16 h. After completion, the reaction mixture was diluted with H 2 The organic layers were combined, washed with brine (10 mL) and diluted with anhydrous NaCl. 2 SO 4 The mixture was dried by HPLC and concentrated under reduced pressure. The residue was purified by C18 column to give tert-butyl (rel-trans)-3-cyano-4-phenylpiperidine-1-carboxylate (160 mg, 558 μmol, 44%) as a white solid. LCMS (ESI) m / z=309 [M+Na].

[0458] Step C: (rel-trans)-4-Phenylpiperidine-3-carbonitrile hydrochloride

[0459] A solution of (rel-trans)-3-cyano-4-phenylpiperidine-1-carboxylate (80 mg, 279 μmol, 1 eq) in 4.0 M HCl / dioxane (2 mL) was stirred at room temperature for 1 h. After completion, the reaction mixture was concentrated under reduced pressure to give (rel-trans)-4-phenylpiperidine-3-carbonitrile hydrochloride (52 mg, 279 μmol, 100%) as a white solid, which was used directly in the next step without purification. LCMS: m / z=187 [M+H] + .

[0460] Preparation of (rel-trans)-3-(difluoromethyl)-4-phenylpyrrolidine [ka]

[0461] Step A: (rel-trans)-3-formyl-4-phenylpyrrolidine-1-carboxylate tert-butyl

[0462] To a solution of tert-butyl (rel-trans)-3-cyano-4-phenylpyrrolidine-1-carboxylate (500 mg, 1.83 mmol, 1 equiv.) in THF (10 mL), 2 A solution of DIBAL-H (3.66 mL, 3.66 mmol, 2 equiv) was added via syringe over 10 min at −78 °C under reduced pressure. The mixture was then stirred at −78 °C for 1 h. After completion, once the reaction mixture was at −60 to −20 °C, NH 4 A solution of 1 mL of aqueous Cl (1 mL) was added dropwise. The residue was partitioned between EtOAc (20 mL) and 1N aqueous HCl (10 mL). The separated organic layer was washed with brine (10 mL) and sodium chloride. 2 SO 4The crude product was purified by flash column chromatography on silica gel to give tert-butyl (rel-trans)-3-formyl-4-phenylpyrrolidine-1-carboxylate (300 mg, 1.08 mmol, 60%) as a colorless oil. LCMS (ESI): m / z=221.2 [M+H-56] + .

[0463] Step B: (rel-trans)-3-(difluoromethyl)-4-phenylpyrrolidine-1-carboxylate tert-butyl

[0464] To a solution of tert-butyl (rel-trans)-3-formyl-4-phenylpyrrolidine-1-carboxylate (100 mg, 363 μmol, 1 equiv.) in dry DCM (2 mL) at 0° C., DAST (117 mg, 726 μmol, 2 equiv.) was added in portions, and the mixture was stirred at room temperature for 14 h. The reaction was then quenched with MeOH (2.0 mL) and extracted with dichloromethane (10 mL×3). The combined organic layers were washed with brine (10 mL×2) and purified with anhydrous NaCl. 2 SO 4 The residue was purified by column chromatography on silica gel to give tert-butyl (rel-trans)-3-(difluoromethyl)-4-phenylpyrrolidine-1-carboxylate (100 mg, 336 μmol, 93%) as a colorless oil.

[0465] Step C: (rel-trans)-3-(difluoromethyl)-4-phenylpyrrolidine

[0466] To a solution of tert-butyl (rel-trans)-3-(difluoromethyl)-4-phenylpyrrolidine-1-carboxylate (110 mg, 369 μmol, 1 equiv.) in DCM (2 mL) was added TFA (419 mg, 3.68 mmol, 10 equiv.). The reaction mixture was stirred at room temperature for 1 h. Upon completion, the reaction was cooled in an ice bath and then diluted with NaHCO until the pH was adjusted to pH=8-9. 3The resulting mixture was extracted with DCM (10 mL×3), and the combined organic layers were washed with brine (10 mL×2) and diluted with anhydrous Na 2 SO 4 Drying at 40° C. and then concentration under reduced pressure gave crude (rel-trans)-3-(difluoromethyl)-4-phenylpyrrolidine (73 mg, 369 μmol, quantitative) as a white solid, which was used directly in the next step without further purification. LCMS (ESI): m / z=198.2 [M+H] + .

[0467] Synthesis of 2-(4-amino-[1,1'-biphenyl]-3-yl)acetonitrile [ka]

[0468] Step 1: 2-(2-amino-4-bromophenyl)acetonitrile

[0469] To a solution of 2-(2-aminophenyl)acetonitrile (2.0 g, 15 mmol, 1 equiv.) in dimethylformamide (20 mL) was added N-bromosuccinimide (3.0 g, 17 mmol, 1.1 equiv.). The mixture was stirred at 25° C. for 12 h. The mixture was diluted with water (200 mL) and extracted with ethyl acetate (200 mL×2), and the combined organic layers were washed with saturated brine (200 mL×2) and diluted with Na 2 SO 4 Drying at 40° C., filtration and concentration under reduced pressure gave 2-(2-amino-4-bromophenyl)acetonitrile (3.2 g, crude) as a white solid. LCMS: m / z (M+H)+=210.9.

[0470] Step 2: 2-(4-amino-[1,1'-biphenyl]-3-yl)acetonitrile

[0471] To a solution of 2-(2-amino-4-bromophenyl)acetonitrile (1 g, 4.7 mmol, 1 equiv.) in water (2 mL) and dioxane (8 mL) was added tetrakis(triphenylphosphine)palladium (0.27 g, 0.24 mmol, 0.05 equiv.), potassium carbonate (1.9 g, 14 mmol, 3 equiv.) and phenylboronic acid (0.65 g, 5.2 mmol, 1.1 equiv.). The mixture was degassed and diluted with N 2 The mixture was purged with 3× with 500 ml of ethyl acetate and then stirred at 85° C. for 12 h. The reaction mixture was filtered and the filtrate was concentrated to give a residue. The residue was extracted with water (100 mL) and ethyl acetate (100 mL×2). The combined organic layers were washed with saturated brine (100 mL×2) and diluted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1:0 to 2:1) to give 2-(4-amino-[1,1'-biphenyl]-3-yl)acetonitrile (0.50 g, crude) as a white solid. LCMS: m / z(M+1)=209.0.

[0472] Synthesis of 2-(4-amino-[1,1'-biphenyl]-3-yl)acetamide [ka]

[0473] Step 1: 2-(5-bromo-2-nitrophenyl)acetyl chloride

[0474] 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.

[0475] Step 2: 2-(5-bromo-2-nitrophenyl)acetamide

[0476] Tetrahydrofuran (3 mL) and NH 3 .H 2 A solution of 2-(5-bromo-2-nitrophenyl)acetyl chloride (0.30 g, 1.1 mmol, 1 equiv) in 0 (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.

[0477] Step 3: 2-(4-nitro-[1,1'-biphenyl]-3-yl)acetamide

[0478] 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 ethyl acetate (20 mL×2), the combined organic layers were washed with saturated brine (20 mL×2) and concentrated to 100° C. with 100% NaCl. 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which 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+23)+=279.0. 1 H NMR (400 MHz, CD 3 OD) 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)

[0479] Step 4: 2-(4-amino-[1,1'-biphenyl]-3-yl)acetamide

[0480] 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 h. 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. 1 H NMR (400 MHz, DMSO) 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).

[0481] Synthesis of 3-(thiazol-2-ylmethyl)-[1,1'-biphenyl]-4-amine [ka]

[0482] Step 1: 4-Nitro-[1,1'-biphenyl]-3-carbaldehyde

[0483] To a solution of 5-bromo-2-nitrobenzaldehyde (5 g, 22 mmol, 1 equiv.) in dioxane (30 mL) and water (10 mL), 2Phenylboronic acid (5.3 g, 43 mmol, 2 equiv.) and potassium carbonate (12 g, 87 mmol, 4 equiv.), tetrakis(triphenylphosphine)palladium (1.2 g, 1.1 mmol, 0.05 equiv.) were added under reduced pressure. The reaction was stirred at 90° C. for 16 h to give a black solution. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL×2), and the combined organic layers were washed with saturated brine (50 mL×2) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give 4-nitro-[1,1′-biphenyl]-3-carbaldehyde (3.5 g, 71% yield) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 10.52 (s, 1H), 8.22 (d, J = 8.4 Hz, 1H), 8.14 (d, J = 2.0 Hz, 1H), 7.94 (d, J = 6.4 Hz, 1H), 7.69 - 7.63 (m, 2H), 7.56 - 7.46 (m, 3H).

[0484] Step 2: (4-nitro-[1,1'-biphenyl]-3-yl)(thiazol-2-yl)methanol

[0485] To a solution of 2-bromo-1,3-thiazole (2.2 g, 13 mmol, 1 equiv.) in tetrahydrofuran (30 mL) was added dropwise monobutyl lithium hydride (6.3 mL, 16 mmol, 1.2 equiv.) at -60°C and stirred at -60°C for 30 min. Then, a solution of 4-nitro-[1,1'-biphenyl]-3-carbaldehyde (3 g, 13 mmol, 1 equiv.) in THF (10 mL) was added dropwise at -60°C. The reaction mixture was warmed to 25°C and stirred for 2 h to give a black solution. The reaction mixture was quenched with saturated ammonium chloride (80 mL). The mixture was diluted with water (150 mL) and extracted with ethyl acetate (150 mL x 2), and the combined organic layers were washed with saturated brine (150 mL x 2) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered, and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give (4-nitro-[1,1′-biphenyl]-3-yl)(thiazol-2-yl)methanol (1.9 g, 46% yield) as a yellow solid. 1 H NMR (400 MHz, chloroform-d) δ 8.17 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 1.6 Hz, 1H), 7.79 - 7.67 (m, 2H), 7.67 - 7.57 (m, 2H), 7.53 - 7.42 (m, 3H), 7.35 (d, J = 3.2 Hz, 1H), 6.76 (s, 1H)

[0486] Step 3: 3-(thiazol-2-ylmethyl)-[1,1'-biphenyl]-4-amine

[0487] A solution of (4-nitro-[1,1'-biphenyl]-3-yl)(thiazol-2-yl)methanol (0.1 g, 0.3 mmol, 1 equiv.) in methanol (1 mL) and tetrahydrofuran (1 mL) was added to H 2Under reduced pressure, HCl (0.5 mL, 1 M) and Pd / C (0.1 g) were added. The mixture was stirred at 60° C. for 6 h at 50 Psi. The reaction mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by flash silica gel chromatography to give 3-(thiazol-2-ylmethyl)-[1,1′-biphenyl]-4-amine (70 mg, 82% yield) as a red oil. LCMS: (ES+) m / z (M+H)+=266.9 1 H NMR (400 MHz, chloroform-d) δ 7.60 (d, J = 3.2 Hz, 1H), 7.47 (dd, J = 1.2, 8.4 Hz, 2H), 7.36 - 7.26 (m, 4H), 7.22 - 7.17 (m, 1H), 7.12 (d, J = 3.2 Hz, 1H), 6.69 (d, J = 8.0 Hz, 1H), 4.24 (s, 2H).

[0488] Synthesis of 6-phenyl-1,2,3,4-tetrahydroquinoline-4-carboxamide [ka]

[0489] Step 1: 6-Phenylquinoline-4-carboxylic acid

[0490] To a solution of 6-bromoquinoline-4-carboxylic acid (0.50 g, 2.0 mmol), phenylboronic acid (0.29 g, 2.4 mmol), palladium(2+) bis(triphenylphosphine) dichloride (0.14 g, 0.20 mmol) in dioxane (6 mL) and water (2 mL) was added potassium carbonate (0.55 g, 4.0 mmol). The reaction mixture was then stirred at 100° C. for 3 h to give a black suspension. The reaction mixture was filtered, the filtrate was collected and poured into water (20 mL), adjusted to pH=12 with NaOH (2 M), washed with EtOAc (30 mL×2), and then the aqueous phase was adjusted to pH=5 with HCl (1 M) to give a white suspension. The suspension was extracted with ethyl acetate (30 mL×2). The combined organic phase was washed with saturated brine (30 mL) and anhydrous Na 2 SO 4 The mixture was dried by filtration, then the filtrate was concentrated in vacuo to give 6-phenylquinoline-4-carboxylic acid (0.6 g, crude) as a white solid. LCMS: m / z (M+H)+=251.0.

[0491] Step 2: Ethyl 5-iodobenzo[d]thiazole-2-carboxylate

[0492] N 2 6-Phenylquinoline-4-carboxylic acid (1.2 g, 4.8 mmol) was dissolved in AcOH (5 mL) and MeOH (10 mL) and then cooled to 37° C. 2 Pd / C (0.15 g, dried) was added at 15° C. under reduced pressure, and the reaction mixture was then diluted with H 2 (15 psi) at 15° C. for 16 hours to give a black suspension. The reaction mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by silica gel chromatography to give 6-phenyl-1,2,3,4-tetrahydroquinoline-4-carboxylic acid (0.45 g, 37% yield) as a white solid. LCMS: m / z (M+H)+=254.0

[0493] Step 3: 6-Phenyl-1,2,3,4-tetrahydroquinoline-4-carboxamide

[0494] To 6-phenyl-1,2,3,4-tetrahydroquinoline-4-carboxylic acid (0.3 g, 1.2 mmol) dissolved in DCM (5 mL) was added carbonyldiimidazole (0.21 g, 1.3 mmol) at 0 °C for 30 min, followed by addition of NH 3 (15 psi, balloon) was added, and then the reaction mixture was stirred at 15° C. for 4 h to give a yellow solution. The mixture was poured into water (35 mL) and the aqueous phase was extracted with ethyl acetate (35 mL×3). The combined organic phase was washed with brine (35 mL×2) and anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo to give a residue which was purified by silica gel chromatography to give 6-phenyl-1,2,3,4-tetrahydroquinoline-4-carboxamide (0.15 g, 50% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 7.55 - 7.50 (m, 2H), 7.44 - 7.34 (m, 3H), 7.34 - 7.28 (m, 2H), 6.64 (d, J = 8.4 Hz, 1H), 5.82 - 5.38 (m, 2H), 3.81 - 3.69 (m, 1H), 3.44 - 3.28 (m, 2H), 2.52 (qd, J = 3.2, 13.2 Hz, 1H), 2.11 - 2.00 (m, 1H).

[0495] Synthesis of 2-(4-amino-[1,1'-biphenyl]-3-yl)-N-methylacetamide [ka]

[0496] Step 1: 2-(5-bromo-2-nitrophenyl)-N-methylacetamide

[0497] To a solution of 2-(5-bromo-2-nitrophenyl)acetic acid (0.10 g, 0.38 mmol, 1 equiv.) in methylene chloride (1 mL), O-(7-azabenzotriazol-1-yl)-N,N,N,N-tetramethyluronium hexafluorophosphate (0.062 g, 0.38 mmol, 1 equiv.) and N,N-diisopropylethylamine (0.13 g, 1.5 mmol, 3 equiv.) were added and the mixture was stirred at 25° C. for 15 min. Then, to the mixture was added methanamine (0.014 g, 0.46 mmol, 1.2 equiv.). The mixture was stirred at 25° C. for 12 h. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=1:0 to 0:1) and concentrated in vacuo to give 2-(5-bromo-2-nitrophenyl)-N-methylacetamide (0.10 g, 96.1% yield) as a white solid. LCMS: m / z (M+H) + =272.8. 1 H NMR (400 MHz, methanol-d 4 ) δ7.98 (d, J = 9.2 Hz, 1H), 7.73 - 7.63 (m, 2H), 3.91 (s, 2H), 2.73 (s, 3H).

[0498] Step 2: N-methyl-2-(4-nitro-[1,1'-biphenyl]-3-yl)acetamide

[0499] A solution of 2-(5-bromo-2-nitrophenyl)-N-methylacetamide (0.10 g, 0.37 mmol, 1 equiv.) in dioxane (1 mL) and water (0.2 mL) was treated with sodium carbonate (0.12 g, 1.1 mmol, 3 equiv.), phenylboronic acid (0.054 g, 0.44 mmol, 1.2 equiv.) and iron (2 +)Bis(cyclopenta-2,4-diyn-1-yldiphenyllambda-4-phosphane)palladium dichloride (0.013 g, 0.018 mmol, 0.05 equiv.) was added and the mixture was stirred at 100° C. for 12 hours. The reaction mixture was filtered to obtain a filtrate. The filtrate was diluted with water (20 mL) and extracted with ethyl acetate (20 mL×2), and the combined organic layer was washed with saturated brine (20 mL×2) and diluted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=10:1 to 0:1) to give N-methyl-2-(4-nitro-[1,1'-biphenyl]-3-yl)acetamide (0.10 g, 91.0% yield) as a white solid. LCMS: m / z (M+H) + =271.0

[0500] Step 3: 2-(4-amino-[1,1'-biphenyl]-3-yl)-N-methylacetamide

[0501] To a solution of N-methyl-2-(4-nitro-[1,1'-biphenyl]-3-yl)acetamide (0.10 g, 0.37 mmol, 1 equiv) in ethyl alcohol (0.8 mL) and water (0.2 mL) was added ammonium chloride (0.059 g, 1.1 mmol, 3 equiv) and iron (0.21 g, 3.7 mmol, 10 equiv). The mixture was stirred at 25° C. for 4 h. The reaction mixture was filtered and the filtrate was concentrated to give 2-(4-amino-[1,1'-biphenyl]-3-yl)-N-methylacetamide (0.10 g, crude) as a white solid. LCMS: m / z (M+H) + =241.2.

[0502] Synthesis of (rel-trans)-2-phenylazetidine-3-carbonitrile [ka]

[0503] Step 1: (E)-N-benzylidene-1-(4-methoxyphenyl)methanamine

[0504] To a solution of benzaldehyde (5.0 g, 36 mmol, 1.5 equiv.) and 1-(4-methoxyphenyl)methanamine (9.7 g, 71 mmol, 1.5 equiv.) in DCM (15 mL) was added magnesium sulfate (4.4 g, 36 mmol, 1.5 equiv.) at 15° C., and the reaction mixture was then stirred at 15° C. for 16 h to give a white suspension. The mixture was poured into water (50 mL). The aqueous phase was extracted with ethyl acetate (50 mL×2). The combined organic phase was washed with brine (50 mL×2) and diluted with anhydrous Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated in vacuo to give a residue which was purified by silica gel chromatography to give (E)-N-benzylidene-1-(4-methoxyphenyl)methanamine (5.6 g, 82% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 8.27 (s, 1H), 7.71 - 7.63 (m, 2H), 7.46 - 7.28 (m, 3H), 7.16 (d, J = 8.8 Hz, 2H), 6.83 - 6.75 (m, 2H), 4.67 (s, 2H), 3.69 (s, 3H).

[0505] Step 2: (rel-trans)-3-chloro-1-(4-methoxybenzyl)-4-phenylazetidin-2-one

[0506] To a solution of (E)-N-benzylidene-1-(4-methoxyphenyl)methanamine (5.6 g, 25 mmol, 1 equiv.) and lutidine (6.7 g, 62 mmol, 2.5 equiv.) in toluene (30 mL) was added 2-chloroacetyl chloride (4.2 g, 37 mmol, 1.5 equiv.) at 15° C., and the reaction mixture was then stirred at 80° C. for 16 h to give a yellow solution. The mixture was diluted with water (100 mL), extracted with ethyl acetate (100 mL×2), and the combined organic layer was washed with saturated brine (100 mL×2) and diluted with Na 2 SO4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which was purified by silica gel chromatography to give (rel-trans)-3-chloro-1-(4-methoxybenzyl)-4-phenylazetidin-2-one (4.5 g, 60% yield) as a yellow oil. LCMS: m / z (M+H)+=302.1. 1 H NMR (400 MHz, chloroform-d) δ 7.50 - 7.39 (m, 3H), 7.27 (s, 2H), 7.11 (s, 2H), 6.89 - 6.82 (m, 2H), 4.89 - 4.81 (m, 1H), 4.57 (d, J = 0.8 Hz, 1H), 4.38 (d, J = 1.2 Hz, 1H), 3.83 (s, 3H), 3.80 (d, J = 15.2 Hz, 1H).

[0507] Step 3: (rel-trans)-3-chloro-1-(4-methoxybenzyl)-2-phenylazetidine

[0508] To a solution of aluminum chloride (5.9 g, 4.9 mmol, 3 equiv.) in THF (45 mL) was added lithium aluminum(3+) tetrahydride(1+) (1.7 g, 4.9 mmol, 3 equiv.) at 0° C., then the reaction mixture was stirred at 0° C. for 10 min and at 70° C. for 30 min. (rel-trans)-3-chloro-1-(4-methoxybenzyl)-4-phenylazetidin-2-one (4.5 g, 1.7 mmol, 1 equiv.) in THF (45 mL) was slowly added, and the reaction was stirred at 70° C. for 4 h to give a white suspension. 5 mL of water was added to the reaction at 0° C. and stirred for 30 min, then the reaction mixture was filtered, and the filtrate was collected and concentrated in vacuo to give a yellow solid. The residue was purified by silica gel chromatography to give (rel-trans)-3-chloro-1-(4-methoxybenzyl)-2-phenylazetidine (2.5 g, 59% yield) as an off-yellow oil. LCMS: m / z (M+H)+ = 288.1.

[0509] Step 4: (rel-trans)-1-(4-methoxybenzyl)-2-phenylazetidine-3-carbonitrile

[0510] To a solution of (rel-trans)-3-chloro-1-(4-methoxybenzyl)-2-phenylazetidine (1.5 g, 5.2 mmol, 1 equiv.) in dimethylsulfoxide (20 mL) was added potassium cyanide (0.67 g, 10 mmol, 2 equiv.) and the mixture was stirred at 100° C. for 4 h to give a brown solution. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL×2), and the combined organic layers were washed with saturated brine (100 mL×2) and diluted with Na 2 SO 4 The residue was dried over 1000 ml, filtered and concentrated under reduced pressure to give a residue. The aqueous phase was adjusted to pH=14 with 1N NaOH, then NaOCl(aq) (200 mL) was added, left for 48 hours, awaited expert approval and then discarded. The residue was purified by column chromatography (SiO 2 , petroleum ether / ethyl acetate=100:1 to 90:10) to give (rel-trans)-1-(4-methoxybenzyl)-2-phenylazetidine-3-carbonitrile (0.65 g, 45% yield) as a yellow oil. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.49 - 7.44 (m, 2H), 7.41 - 7.30 (m, 3H), 7.20 - 7.15 (m, 2H), 6.86 - 6.81 (m, 2H), 4.31 (d, J = 8.4 Hz, 1H), 3.71 (s, 3H), 3.66 (d, J = 12.8 Hz, 1H), 3.49 - 3.42 (m, 2H), 3.40 - 3.34 (m, 1H), 3.10 - 3.04 (m, 1H).

[0511] Step 5: (rel-trans)-2-phenylazetidine-3-carbonitrile

[0512] To a solution of (rel-trans)-1-(4-methoxybenzyl)-2-phenylazetidine-3-carbonitrile (0.1 g, 0.36 mmol, 1 equiv.) in acetonitrile (3 mL) and water (3 mL), cerium(4+) bis(nitrate)diaminetetranitrate (1.2 g, 2.2 mmol, 6 equiv.) was added to give a red solution, and the mixture was stirred at 60° C. for 12 h to give a yellow solution. The mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL×2), and the combined organic layers were washed with saturated brine (50 mL×2) and diluted with Na 2 SO 4 The residue was purified by column chromatography (SiO 2 , DCM:MeOH=100:1 to 10:1, UV=220 nm) to give (rel-trans)-2-phenylazetidine-3-carbonitrile (80 mg, crude) as a yellow oil. LCMS: m / z (M+H) + =159.6.

[0513] Synthesis of (3R,5R)-5-phenylpyrrolidine-3-carbonitrile and (3R,5S)-5-phenylpyrrolidine-3-carbonitrile [ka]

[0514] Step 1: (4R)-tert-butyl 4-cyano-2-phenylpyrrolidine-1-carboxylate

[0515] In an oven-dried 40 mL vial equipped with a magnetic stir bar, add iodobenzene (0.20 g, 0.98 mmol, 1 equiv.), (3R,4R)-1-[(tert-butoxy)carbonyl]-4-cyanopyrrolidine-3-carboxylic acid (0.31 g, 1.3 mmol, 1.3 equiv.), Ir[dF(Me)ppy] in DMA (10 mL). 2 (dtbpy)(PF 6 )(8.0 mg, 0.01 equivalent), NiCl 2.dtbbpy (12 mg, 0.05 equiv.) and cesium carbonate (0.48 g, 1.5 mmol, 1.5 equiv.) were charged. The vial was placed under nitrogen and sealed. The reaction was stirred and irradiated with a 10 W blue LED lamp (3 cm away) and the reaction temperature was maintained at 25° C. for 12 h with cooling water. The mixture was purified by preparative HPLC (column: Phenomenex Luna C18 150×25 mm×10 um, mobile phase: water (0.1% TFA)-ACN; B%: 38%-68%, 11.5 min) and lyophilized to give (4R)-tert-butyl 4-cyano-2-phenylpyrrolidine-1-carboxylate (0.15 g, 55% yield) as a yellow oil. 1 H NMR (400 MHz, chloroform-d) δ 7.30 - 7.23 (m, 2H), 7.22 - 7.13 (m, 2H), 7.06 (d, J = 7.2 Hz, 1H), 5.14 - 4.60 (m, 1H), 3.90 - 3.80 (m, 1H), 3.15 - 3.01 (m, 1H), 2.80 - 2.69 (m, 1H), 2.65 - 2.48 (m, 1H), 2.21 - 2.13 (m, 1H), 1.57 - 0.93 (m, 9H).

[0516] Step 2: SFC separation of tert-butyl (2R,4R)-4-cyano-2-phenylpyrrolidine-1-carboxylate and tert-butyl (2S,4R)-4-cyano-2-phenylpyrrolidine-1-carboxylate

[0517] SFC showed that (4R)-tert-butyl 4-cyano-2-phenylpyrrolidine-1-carboxylate had two peaks (rt = 0.848 min, 1.136 min). The residue was purified by SFC (column: REGIS(S,S)WHELK-O1 (250 mm x 25 mm, 10 um), mobile phase: 0.1% NH 3 H 2Purification with O MeOH; B%: 15%-15%) and concentration under reduced pressure gave tert-butyl (2R,4R)-4-cyano-2-phenylpyrrolidine-1-carboxylate (40 mg, 27% yield, rt=0.848 min) as a white solid and tert-butyl (2S,4R)-4-cyano-2-phenylpyrrolidine-1-carboxylate (80 mg, 54% yield, rt=1.136 min) as a white solid. (2R,4R)-tert-butyl 4-cyano-2-phenylpyrrolidine-1-carboxylate: 1 H NMR (400 MHz, chloroform-d) δ 7.38 - 7.31 (m, 2H), 7.30 - 7.19 (m, 3H), 4.85 - 4.52 (m, 1H), 4.20 (s, 1H), 3.78 - 3.69 (m, 1H), 3.17 - 3.03 (m, 1H), 2.87 - 2.76 (m, 1H), 2.28 - 2.11 (m, 1H), 1.51 - 1.01 (m, 9H)(2S,4R)-tert-butyl 4-cyano-2-phenylpyrrolidine-1-carboxylate: 1 H NMR (400 MHz, chloroform-d) δ 7.30 - 7.22 (m, 2H), 7.22 - 7.15 (m, 1H), 7.06 (d, J = 7.2 Hz, 2H), 5.18 - 4.84 (m, 1H), 3.91 - 3.64 (m, 2H), 3.08 (m, 1H), 2.56 (m, 1H), 2.24 - 2.07 (m, 1H), 1.43 - 1.03 (m, 9H).

[0518] Step 3: (3R,5R)-5-phenylpyrrolidine-3-carbonitrile and (3R,5S)-5-phenylpyrrolidine-3-carbonitrile

[0519] To a solution of (4R)-tert-butyl 4-cyano-2-phenylpyrrolidine-1-carboxylate (1 eq) in methylene chloride (0.1 mL) was added trifluoroacetic acid (0.3 mL) and the mixture was stirred at 25° C. for 1 h to give a yellow solution. The reaction mixture was concentrated under reduced pressure to give (3R,5R)-5-phenylpyrrolidine-3-carbonitrile (40 mg, crude) and (3R,5S)-5-phenylpyrrolidine-3-carbonitrile (80 mg, crude) as a yellow oil. (3R,5R)-5-phenylpyrrolidine-3-carbonitrile: LCMS: m / z (M+H)+=173.0 (3R,5S)-5-phenylpyrrolidine-3-carbonitrile: LCMS: m / z (M+H)+=173.0

[0520] Synthesis of (rel-trans)-2-phenylpyrrolidine-3-carbonitrile [ka]

[0521] Step 1: Ethyl 2-(cyclohexa-1,5-dien-1-yl)-1H-pyrrole-3-carboxylate

[0522] To a solution of ethyl 2-cyano-4,4-diethoxybutanoate (8.0 g, 35 mmol, 1.0 equiv.) in acetic acid (12 mL) and water (12 mL) was added phenylboronic acid (5.1 g, 42 mmol, 1.2 equiv.), bipyridyl (0.27 g, 1.7 mmol, 0.05 equiv.) and the mixture was added with N 2 The mixture was then purged with N 2 Palladium(2+) acetate (0.29 g, 1.7 mmol, 0.05 equiv.) was added under atmospheric pressure and stirred at 80° C. for 16 h to give a black cloudy solution. The reaction was diluted with water (500 mL) and extracted with ethyl acetate (500 mL×2), and the combined organic layers were washed with saturated brine (500 mL×2) and diluted with Na 2 SO 4The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography (80 g SepaFlash® silica flash column, eluent of a gradient of 0-10% ethyl acetate / petroleum ether at 80 mL / min) to give ethyl 2-(cyclohexa-1,5-dien-1-yl)-1H-pyrrole-3-carboxylate (3.00 g, 40% yield) as a white solid. LCMS: m / z (M+H) + =215.9. 1H NMR (400 MHz, chloroform-d) δ 8.54 (s, 1H), 7.66 - 7.55 (m, 2H), 7.45 - 7.32 (m, 3H), 6.75 (d, J = 2.4 Hz, 2H), 4.21 (q, J = 7.2 Hz, 2H), 1.26 (t, J =7.2 Hz, 3H).

[0523] Step 2: 1-tert-butyl-3-ethyl 2-phenyl-1H-pyrrole-1,3-dicarboxylate

[0524] To a solution of ethyl 2-(cyclohexa-1,5-dien-1-yl)-1H-pyrrole-3-carboxylate (3.0 g, 14 mmol, 1.0 equiv.) in DCM (30 mL) was added di-tert-butyl dicarbonate (9.1 g, 42 mmol, 3.0 equiv.), 4-dimethylaminopyridine (0.17 g, 1.4 mmol, 0.1 equiv.) and triethylamine (2.1 g, 21 mmol, 1.5 equiv.) and the mixture was stirred at 25° C. for 1 h to give a clear black solution. The reaction was diluted with water (200 mL) and extracted with ethyl acetate (200 mL×2), the combined organic layers were washed with saturated brine (200 mL×2) and diluted with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give 1-tert-butyl 3-ethyl 2-phenyl-1H-pyrrole-1,3-dicarboxylate (3.5 g, 80% yield) as a light yellow oil. LCMS: m / z (M+H) + =316.0. 1H NMR (400 MHz, chloroform-d) δ 7.32 - 7.27 (m, 3H), 7.25 (dd, J = 1.2, 3.6 Hz, 1H), 7.23 - 7.17 (m, 2H), 6.60 (dd, J = 1.2, 3.6 Hz, 1H), 4.00 (q, J = 7.2 Hz, 2H), 1.16 (s, 9H), 1.00 (t, J = 7.2 Hz, 3H).

[0525] Step 3: 1-tert-butyl-3-ethyl 2-phenylpyrrolidine-1,3-dicarboxylate

[0526] To a solution of tert-butyl 3-ethyl 2-phenyl-1H-pyrrole-1,3-dicarboxylate (3.5 g, 11 mmol, 1.0 equiv.) in EtOH (30 mL) was added platinum dioxide (7.5 g, 33 mmol, 3.0 equiv.). The mixture was heated at 40° C. for 1 hour at 37° C. for 2 hours at 37° C. for 1 hour at 37° C. 2 The mixture was stirred at 25° C. for 3 hours under reduced pressure to give a colorless solution. The reaction mixture was filtered and the filtrate was concentrated to give 1-tert-butyl 3-ethyl 2-phenylpyrrolidine-1,3-dicarboxylate (1.8 g, crude) as a white solid. LCMS: m / z (M-Boc+H) + =219.9. 1 H NMR (400 MHz, chloroform-d) δ = 7.26 - 7.19 (m, 3H), 7.16 - 7.09 (m, 2H), 5.27 - 4.99 (m, 1H), 3.95 - 3.73 (m, 3H), 3.57 - 3.37 (m, 2H), 2.56 - 2.35 (m,1H), 2.13 - 2.01 (m, 1H), 1.57 (s, 9H), 1.17 (s, 3H).

[0527] Step 4: 1-(tert-butoxycarbonyl)-2-phenylpyrrolidine-3-carboxylic acid

[0528] To a solution of 1-tert-butyl 3-ethyl 2-phenylpyrrolidine-1,3-dicarboxylate (1.8 g, 5.6 mmol, 1.0 equiv.) in THF (6.0 mL), water (6.0 mL), and MeOH (6.0 mL) was added lithium hydroxide(1+) monohydrate (0.47 g, 11 mmol, 2.0 equiv.) and the mixture was stirred at 25° C. for 1 h to give a clear yellow solution. The reaction mixture was filtered and the filtrate was concentrated to give a residue. The residue was purified by preparative HPLC (basic conditions; (column: Welch Xtimate C18 150×25 mm×5 um, mobile phase: water (NH 3 H 2 Purification by HPLC (O)-ACN; B%:B%:5% to 35%, 8 min) and lyophilization afforded 1-(tert-butoxycarbonyl)-2-phenylpyrrolidine-3-carboxylic acid (0.8 g, 2.7 mmol, 49% yield) as a white solid. LCMS: m / z (MH) - =290.1

[0529] Step 5: tert-Butyl 3-carbamoyl-2-phenylpyrrolidine-1-carboxylate

[0530] To a solution of 1-(tert-butoxycarbonyl)-2-phenylpyrrolidine-3-carboxylic acid (0.8 g, 2.7 mmol, 1.0 equiv.) in THF (10 mL) was added carbonyldiimidazole (1.3 g, 8.2 mmol, 3 equiv.). The mixture was stirred at 25° C. for 30 min to give a clear, colorless solution. NH 3 H 2 HO (3.0 mL) was added and the reaction mixture was stirred for 10 min to give a clear, colorless solution. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography (12 g SepaFlash® silica flash column, eluent of 0-10% DCM:MeOH at 22 mL / min) to give tert-butyl 3-carbamoyl-2-phenylpyrrolidine-1-carboxylate (0.8 g, 2.1 mmol, 75% yield) as a white solid. LCMS: m / z (M-Boc+H) + =191.1.1 H NMR (400 MHz, chloroform-d) δ 7.32 - 7.11 (m, 5H), 5.70 (s, 1H), 5.43 (s, 1H), 4.87 (s, 1H), 3.88 (s, 1H), 3.63 - 3.52 (m, 1H), 2.78 (d, J= 6.8 Hz, 1H), 2.26 - 2.07 (m, 2H), 1.45 - 1.05 (m, 9H).

[0531] Step 6: (rel-trans)-3-cyano-2-phenylpyrrolidine-1-carboxylate tert-butyl

[0532] To a solution of tert-butyl 3-carbamoyl-2-phenylpyrrolidine-1-carboxylate (0.6 g, 2.1 mmol, 1.0 equiv) in DCM (6.0 mL) was added trimethylamine (0.5 g, 5.2 mmol, 2.5 equiv), the mixture was cooled to 0° C., and trifluoroacetic anhydride (0.5 g, 2.6 mmol, 1.3 equiv) was added. The reaction was warmed to 25° C. and stirred for 1 h to give a colorless solution. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by preparative HPLC (FA conditions; (column: Phenomenex Luna C18 100 x 30 mm x 5 um, mobile phase: water (FA)-ACN; B%: 42% to 72%, 8 min) and lyophilized to give tert-butyl (2S,3S)-3-cyano-2-phenylpyrrolidine-1-carboxylate (0.2 g, 0.73 mmol, 36% yield) as a white solid. The rel-trans stereochemistry was assigned by 2D NMR. LCMS: m / z (Mt-bu+H) + = 217.1. 1H NMR (400 MHz, chloroform-d) δ 7.40 - 7.28 (m, 3H), 7.20 (d, J = 7.2 Hz, 2H), 5.02 (s, 1H), 3.87 (s, 1H), 3.76 - 3.68 (m, 1H), 3.05 - 2.93 (m, 1H), 2.36 - 2.16 (m, 2H), 1.49 - 1.13 (m, 9H).

[0533] Step 7: (rel-trans)-2-phenylpyrrolidine-3-carbonitrile

[0534] (rel-trans)-tert-Butyl 3-cyano-2-phenylpyrrolidine-1-carboxylate (50 mg, 0.18 mmol, 1.0 equiv) was dissolved in a solution of DCM (1.0 mL) and TFA (0.5 mL). The reaction was stirred at 25° C. for 0.5 h to give a colorless solution. The reaction mixture was concentrated under reduced pressure to give (2S,3S)-2-phenylpyrrolidine-3-carbonitrile (50 mg, crude) as a light yellow oil which was used in the next step without further purification.

[0535] Synthesis of (5S,8S,10aR)-3-acetyl-5-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid [ka]

[0536] Step 1: (5S,8S,10aR)-Benzyl 3-acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate

[0537] A solution of (5S,8S,10aR)-3-acetyl-5-{[(tert-butoxy)carbonyl]amino}-6-oxo-decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (1.0 g, 2.7 mmol, 1.0 equiv.) in dimethylformamide (10 mL) was 2 CO 3(0.56 g, 4.1 mmol, 1.5 equiv) was added followed by (bromomethyl)benzene (0.5 g, 3.0 mmol, 1.1 equiv) at 0° C. The mixture was stirred at 25° C. for 2 h. The reaction was diluted with water (100 mL), extracted with ethyl acetate (100 mL×2), and the combined organic layers were washed with saturated brine (100 mL×2) and added with Na 2 SO 4 The mixture was dried at 40° C., filtered and concentrated under reduced pressure to give a residue which was purified by flash silica gel chromatography to give benzyl (5S,8S,10aR)-benzyl 3-acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (0.5 g, 40% yield) as a white solid. LCMS: m / z (M+H) + =460.1.

[0538] Step 2: (5S,8S,10aR)-3-acetyl-5-amino-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate benzyl

[0539] A mixture of (5S,8S,10aR)-3-acetyl-5-amino-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate benzyl (0.5 g, 1.1 mmol, 1.0 equiv) in methylene chloride (2.5 mL) and HCl / dioxane (2.5 mL) was stirred at 25° C. for 2 h. The reaction mixture was concentrated under reduced pressure to give (5S,8S,10aR)-3-acetyl-5-amino-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate benzyl (0.5 g, crude) as a white solid. LCMS: m / z (M+H) + =360.3.

[0540] Step 3: (5S,8S,10aR)-Benzyl 3-acetyl-5-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate

[0541] To a solution of 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (0.34 g, 0.93 mmol, 1.0 equiv.) in dimethylformamide (1.0 mL) was added N,N-diisopropylethylamine (0.48 g, 3.7 mmol, 4.0 equiv.) and HATU (0.53 g, 1.39 mmol, 1.5 equiv.). The mixture was stirred at 25° C. for 10 min. Then, a solution of (5S,8S,10aR)-3-acetyl-5-amino-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate benzyl (0.4 g, 1.1 mmol, 1.2 equiv.) in dimethylformamide (1.0 mL) and N,N-diisopropylethylamine (0.48 g, 3.7 mmol, 4.0 equiv.) was added. The reaction mixture was stirred at 25° C. for 1 h. The reaction was diluted with water (50 mL) and extracted with ethyl acetate (50 mL×2), and the combined organic layers were washed with saturated brine (40 mL×2) and added Na 2 SO 4 The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by flash silica gel chromatography to give (5S,8S,10aR)-benzyl 3-acetyl-5-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (0.3 g, 46% yield) as a yellow solid. LCMS: m / z (M+H) + =706.4.

[0542] Step 4: (5S,8S,10aR)-3-acetyl-5-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid

[0543] A solution of (5S,8S,10aR)-benzyl 3-acetyl-5-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (0.4 g, 0.56 mmol, 1.0 equiv.) in methanol (20 mL) was degassed with N 2 To this mixture was carefully added Pd / C (0.4 g) and the system was then purged with H 2 The mixture was placed under atmosphere and stirred at 25° C. for 2 hours. The reaction mixture was filtered and the filtrate was concentrated to give (5S,8S,10aR)-3-acetyl-5-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (0.3 g, crude) as an off-white oil, which was used in the next step without further purification.

[0544] Representative protocols:

[0545] Representative Procedure for General Scheme 1: Synthesis of 1 [ka]

[0546] Step A: tert-Butyl ((5S,8S,10aR)-3-acetyl-6-oxo-8-(6-phenyl-4-azaspiro[2.4]heptane-4-carbonyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0547] A mixture of 6-phenyl-4-azaspiro[2.4]heptane (168 mg, 0.97 mmol, 1.2 equiv), (5S,8S,10aR)-3-acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (300 mg, 0.812 mmol, 1.0 equiv), HATU (463 mg, 1.218 mmol, 1.5 equiv) and N,N-diisopropylethylamine (246.8 mg, 2.43 mmol, 3.0 equiv) in DCM (10 mL) was stirred at room temperature for 3 h in a sealed tube. After completion, H 2 The reaction mixture was quenched by adding O (5 mL), extracted with EtOAc (5 mL x 3), and the combined organic layers were washed with brine (5 mL x 2) and anhydrous Na 2 SO 4 The mixture was dried at 40° C. and concentrated under reduced pressure. The residue was purified by C18 column to give tert-butyl ((5S,8S,10aR)-3-acetyl-6-oxo-8-(6-phenyl-4-azaspiro[2.4]heptane-4-carbonyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (80 mg, 152.5 μmol, 19%) as a white solid. LCMS (ESI): m / z=525.4 [M+H] + .

[0548] Step B: (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

[0549] A solution of tert-butyl ((5S,8S,10aR)-3-acetyl-6-oxo-8-(6-phenyl-4-azaspiro[2.4]heptane-4-carbonyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (80 mg, 152.5 μmol, 1 equiv.) in DCM (3 mL) and TFA (2 mL) was stirred at room temperature for 1 h. Upon completion, the reaction was cooled in an ice bath and then diluted with NaHCO until the pH was adjusted to pH=8-9. 3The resulting mixture was extracted with DCM (10 mL×3), and the combined organic layers were washed with brine (10 mL×2) and diluted with anhydrous Na 2 SO 4 Drying at 40° C. and then concentration under reduced pressure afforded crude tert-butyl ((5S,8S,10aR)-3-acetyl-6-oxo-8-(6-phenyl-4-azaspiro[2.4]heptane-4-carbonyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (60 mg, 141.3 μmol) as a white solid, which was used directly in the next step without further purification. LCMS (ESI): m / z=425.3 [M+H] + .

[0550] Step C: S,S'-((((7-(((5S,8S,10aR)-3-acetyl-6-oxo-8-(6-phenyl-4-azaspiro[2.4]heptane-4-carbonyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl))bis(3-methylbutanethioate)

[0551] To 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 (30 mg, 70.7 μmol, 1 equiv.) and DIEA (27.4 mg, 212 μmol, 3 equiv.) in DMF (3 mL) was added perfluorophenyl 7-((bis(2-((3-methylbutanoyl)thio)ethoxy)phosphoryl)difluoromethyl)-2-naphthoate (53.5 mg, 70.7 μmol, 1 equiv.). The resulting mixture was stirred at room temperature for 2 h and then diluted with H 2 The reaction was quenched by adding 2H2O (10 mL) and extracted with DCM (10 mL x 3). The combined organic layers were washed with brine (20 mL x 2) and anhydrous Na 2 SO 4The mixture was dried at 40° C. and then concentrated under reduced pressure. The residue was purified by C18 column to give S,S'-((((7-(((5S,8S,10aR)-3-acetyl-6-oxo-8-(6-phenyl-4-azaspiro[2.4]heptane-4-carbonyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)naphthalen-2-yl)difluoromethyl)phosphoryl)bis(oxy))bis(ethane-2,1-diyl))bis(3-methylbutanethioate) (15.4 mg, 15.4 μmol, 22%) as a white solid. 1 H NMR (400 MHz, CDCl 3 ) δ 8.51-8.45 (m, 1H), 8.29-8.19 (m, 1H), 8.04-7.89 (m, 4H), 7.83-7.76 (m, 1H), 7.43-7.34 (m, 3H), 7.34-7.30 (m, 2H), 4.95-4.80 (m, 1H), 4.66-4.45 (m, 1H), 4.33-4.16 (m, 7H), 4.07-3.86 (m, 1H), 3.72-56 (m, 1H), 3.41-3.24 (m, 2H), 3.22-3.13 (m, 4H), 2.55-2.49 (m, 3H), 2.47-2.41 (m, 5H), 2.40-2.22 (m, 3H), 2.21-2.18 (m, 1H), 2.18-2.12 (m, 2H), 2.09-2.01 (m, 2H), 1.96-1.79 (m, 3H), 1.67 (s, 1H), 0.96 (d, J = 6.6 Hz, 12H), 0.83-0.39 (m, 2H).LCMS(ESI):m / z=997.4[M+H] + .

[0552] Representative Procedure for General Scheme 2: Synthesis of 2 [ka]

[0553] Step A: Allyl (5S,8S,10aR)-3-acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate

[0554] (5S,8S,10aR)-3-acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (3 g, 8.12 mmol, 1 equiv.) and K 2 CO 3 To a solution of (2.25 g, 16.2 mmol, 2 equiv.) in DMF (2 mL) was added 3-bromoprop-1-ene (1.17 g, 9.74 mmol, 1.2 equiv.). The reaction mixture was stirred at 20° C. for 16 h. After completion, the reaction mixture was poured into water (10 mL) and then extracted with EtOAc (20 mL×2). The combined organic layers were washed with brine (150 mL) and anhydrous Na 2 SO 4 The residue was purified by C18 column to give allyl (5S,8S,10aR)-3-acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (2.10 g, 5.12 mmol, 63%) as a white solid. LCMS (ESI): m / z=410.2 [M+H] + .

[0555] Step B: Allyl (5S,8S,10aR)-3-acetyl-5-amino-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate

[0556] A solution of allyl (5S,8S,10aR)-3-acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (2.1 g, 5.12 mmol, 1 equiv.) in HCl / EtOAc (15 mL) was stirred at room temperature for 3 h. After completion, the reaction mixture was concentrated under reduced pressure to give allyl (5S,8S,10aR)-3-acetyl-5-amino-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (HCl salt) (1.30 g, 4.20 mmol, 82%) as a white solid, which was used directly in the next step without further purification. LCMS (ESI): m / z=310.1 [M+H] + .

[0557] Step C: Allyl (5S,8S,10aR)-3-acetyl-5-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate

[0558] To a solution of allyl (5S,8S,10aR)-3-acetyl-5-amino-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (1.3 g, 4.20 mmol, 1 equiv.), 5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxylic acid (1.68 g, 4.62 mmol, 1.1 equiv.) and TEA (1.27 g, 12.6 mmol, 3 equiv.) in DCM (20 mL) was added EDCI (885 mg, 4.62 mmol, 1.1 equiv.) and HOBt (574 mg, 4.62 mmol, 1.1 equiv.) and the resulting mixture was stirred at room temperature under nitrogen overnight. Upon completion, the reaction was filtered and concentrated to give a residue which was purified by C18 column to give allyl (5S,8S,10aR)-3-acetyl-5-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (1.80 g, 2.74 mmol, 65%) as a white solid. LCMS (ESI): m / z=656.2 [M+H] + .

[0559] Step D: (5S,8S,10aR)-3-acetyl-5-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid

[0560] Allyl (5S,8S,10aR)-3-acetyl-5-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (1.8 g, 2.74 mmol, 1 equiv.), Pd(PPh 3 ) 4A solution of (158 mg, 137 μmol, 0.05 equiv) and pyrrolidine (194 mg, 2.74 mmol, 1 equiv) in DCM (20 mL) was stirred overnight at room temperature under nitrogen. The reaction was filtered and concentrated to give a residue which was purified by C18 column to give (5S,8S,10aR)-3-acetyl-5-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (1.28 g, 2.07 mmol, 76%) as a white solid. LCMS (ESI): m / z=616.1 [M+H] + .

[0561] Step E: Diethyl ((2-(((5S,8S,10aR)-3-acetyl-8-((4-(2-cyanopropan-2-yl)phenyl)(methyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonate

[0562] A solution of (5S,8S,10aR)-3-acetyl-5-(5-((diethoxyphosphoryl)difluoromethyl)benzo[b]thiophene-2-carboxamido)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (60 mg, 97.4 μmol, 1 equiv.), 2-chloro-1-methylpyridin-1-ium iodide (29.6 mg, 116 μmol, 1.2 equiv.), 2-methyl-2-(4-(methylamino)phenyl)propanenitrile (18.6 mg, 107 μmol, 1.1 equiv.) and TEA (29.5 mg, 292 μmol, 3 equiv.) in DCM (2 mL) was stirred at 35° C. for 30 h. Upon completion, the reaction was filtered and concentrated to give a residue which was purified by flash column chromatography on silica gel to give diethyl ((2-(((5S,8S,10aR)-3-acetyl-8-((4-(2-cyanopropan-2-yl)phenyl)(methyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonate (25.0 mg, 32.3 μmol, 33%) as a white solid. LCMS (ESI): m / z=772 [M+H] + .

[0563] Step F: ((2-(((5S,8S,10aR)-3-acetyl-8-((4-(2-cyanopropan-2-yl)phenyl)(methyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid

[0564] To a solution of diethyl ((2-(((5S,8S,10aR)-3-acetyl-8-((4-(2-cyanopropan-2-yl)phenyl)(methyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonate (23 mg, 29.7 μmol, 1 equiv) in DCM (2 mL) was added TMSBr (226 mg, 1.48 mmol, 50 equiv) and the resulting mixture was stirred at 35° C. for 30 h. Upon completion, the reaction was filtered and concentrated to give a residue which was purified by C18 column to give ((2-(((5S,8S,10aR)-3-acetyl-8-((4-(2-cyanopropan-2-yl)phenyl)(methyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)benzo[b]thiophen-5-yl)difluoromethyl)phosphonic acid (20.0 mg, 27.9 μmol, 94%) as a white solid. 1 H NMR (400 MHz, CD 3 OD) δ 8.06-7.85 (m, 3H), 7.70-7.62 (m, 1H), 7.53-7.33 (m, 4H), 5.20-5.10 (m, 1H), 4.42-3.66 (m, 6H), 3.25-3.15 (m, 3H), 2.34-2.21 (m, 3H), 2.12-1.76 (m, 6H), 1.65-1.49 (m, 6H).LCMS(ESI):m / z=716.1[M+H] + .

[0565] Representative Procedure for General Scheme 3: Synthesis of 3 [ka]

[0566] Step A: 3-benzyl 8-methyl(5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxylate

[0567] Methyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylate (1 g, 2.92 mmol, 1 equiv.) and NaHCO in a mixture of THF (10 mL) and water (2 mL). 3 To a solution of (1.21 g, 14.5 mmol, 5 equiv) was added benzyl chloroformate (996 mg, 5.84 mmol, 2 equiv) at room temperature. After addition, the reaction mixture was stirred at room temperature for 3 h. After completion, the reaction mixture was poured into water and then extracted with EtOAc (100 mL×3). The combined organic layer was washed with brine (50 mL) and diluted with anhydrous Na 2 SO 4 Drying by HPLC and concentration under reduced pressure gave crude 3-benzyl 8-methyl(5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxylate (1.10 g, 2.31 mmol, 80%) as a yellow oil. LCMS (ESI): m / z=476.2 [M+H] + .

[0568] Step B: (5S,8S,10aR)-3-((benzyloxy)carbonyl)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid

[0569] To a solution of 3-benzyl 8-methyl(5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3,8(4H)-dicarboxylate (1.3 g, 2.73 mmol, 1 equiv.) in a mixture of MeOH (5 mL) and water (1.5 mL) was added lithium hydroxide (544 mg, 13.6 mmol, 5 equiv.) and the resulting mixture was stirred at room temperature for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by hexane distillation with Et 2Trituration from 0 (30 mL) gave (5S,8S,10aR)-3-((benzyloxy)carbonyl)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (1.15 g, 2.49 mmol, 92%) as a white solid. LCMS (ESI): m / z=462.2 [M+H] + .

[0570] Step C: Benzyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-8-(methyl(phenyl)carbamoyl)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3(4H)-carboxylate

[0571] A solution of (5S,8S,10aR)-3-((benzyloxy)carbonyl)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocine-8-carboxylic acid (400 mg, 866 μmol, 1 equiv.), TEA (262 mg, 2.59 mmol, 3 equiv.) and N-methylaniline (185 mg, 1.73 mmol, 2 equiv.) in DCE (15 mL) was added at room temperature. 3 P (550 mg, 1.73 mmol, 2 equiv.) was added and the resulting mixture was heated at 90° C. for 20 h. After completion, the reaction mixture was poured into water (50 mL) and then extracted with EtOAc (100 mL×3). The combined organic layers were washed with brine (50 mL) and anhydrous Na 2 SO 4 The residue was purified by C18 column to give benzyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-8-(methyl(phenyl)carbamoyl)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3(4H)-carboxylate (400 mg, 726 μmol, 84%) as a white solid. LC-MS (ESI) m / z=551.2 [M+H] + .

[0572] Step D: tert-Butyl ((5S,8S,10aR)-8-(methyl(phenyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0573] To a solution of benzyl (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-8-(methyl(phenyl)carbamoyl)-6-oxooctahydropyrrolo[1,2-a][1,5]diazocine-3(4H)-carboxylate (540 mg, 980 μmol, 1 equiv.) in THF (20 mL) was added Pd / C (100 mg) under nitrogen. The suspension was degassed under vacuum and purified with H 2 The 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 THF (20 mL). The combined filtrate was concentrated to dryness to give tert-butyl ((5S,8S,10aR)-8-(methyl(phenyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (400 mg, 960 μmol, 98%) as a white solid. LCMS (ESI): m / z=417 [M+H] + .

[0574] Step E: tert-Butyl ((5S,8S,10aR)-8-(methyl(phenyl)carbamoyl)-6-oxo-3-(2-phenylacetyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate

[0575] To a solution of tert-butyl ((5S,8S,10aR)-8-(methyl(phenyl)carbamoyl)-6-oxodecahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (80 mg, 192 μmol, 1 equiv.) and TEA (58.2 mg, 576 μmol, 3 equiv.) in DCM (3 mL) at 20° C., 2-phenylacetyl chloride (44.5 mg, 288 μmol, 1.5 equiv.) was added and the resulting mixture was stirred at 20° C. for 1 h. After completion, the reaction mixture was poured into water (10 mL) and then extracted with DCM (20 mL×3). The combined organic layer was washed with brine (20 mL) and diluted with anhydrous NaCl. 2 SO 4 Drying by hexanes and concentration under reduced pressure afforded crude tert-butyl ((5S,8S,10aR)-8-(methyl(phenyl)carbamoyl)-6-oxo-3-(2-phenylacetyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (90.0 mg, 168 μmol, 88%) as a yellow solid, which was used directly in the next step without further purification. LC-MS (ESI) m / z=573 [M+K] + .

[0576] Step F: (5S,8S,10aR)-5-amino-N-methyl-6-oxo-N-phenyl-3-(2-phenylacetyl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide

[0577] A solution of tert-butyl ((5S,8S,10aR)-8-(methyl(phenyl)carbamoyl)-6-oxo-3-(2-phenylacetyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamate (90 mg, 168 μmol, 1 equiv.) in HCl / dioxane (2 mL, 4 M) was stirred at 20° C. for 1 h. After completion, the reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by C18 column to give (5S,8S,10aR)-5-amino-N-methyl-6-oxo-N-phenyl-3-(2-phenylacetyl)decahydropyrrolo[1,2-a][1,5]diazocin-8-carboxamide (70.0 mg, 161 μmol, 96%) as a white solid. LC-MS(ESI)m / z=435.2[M+H] + .

[0578] Step G: Diethyl (difluoro(2-(((5S,8S,10aR)-8-(methyl(phenyl)carbamoyl)-6-oxo-3-(2-phenylacetyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)-1H-indol-5-yl)methyl)phosphonate

[0579] To a solution of (5S,8S,10aR)-5-amino-N-methyl-6-oxo-N-phenyl-3-(2-phenylacetyl)decahydropyrrolo[1,2-a][1,5]diazocine-8-carboxamide (69.8 mg, 161 μmol, 1 equiv.), TEA (81.3 mg, 805 μmol, 5 equiv.) and HATU (91.8 mg, 241 μmol, 1.5 equiv.) in DMF (1 mL) was added 8 (61.4 mg, 177.1 μmol, 1.1 equiv.), and the resulting mixture was then stirred at 20° C. for 16 h. After completion, the reaction mixture was diluted with water (10 mL) and then extracted with EtOAc (20 mL×3). The combined organic layer was washed with brine (20 mL) and diluted with anhydrous NaCl. 2 SO 4The residue was purified by C18 column to give diethyl (difluoro(2-(((5S,8S,10aR)-8-(methyl(phenyl)carbamoyl)-6-oxo-3-(2-phenylacetyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)-1H-indol-5-yl)methyl)phosphonate (120 mg, 157 μmol, 69%) as a white solid. LC-MS(ESI)m / z=764.1[M+H] + .

[0580] Step H: (Difluoro(2-(((5S,8S,10aR)-8-(methyl(phenyl)carbamoyl)-6-oxo-3-(2-phenylacetyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)-1H-indol-5-yl)methyl)phosphonic acid

[0581] To a solution of diethyl (difluoro(2-(((5S,8S,10aR)-8-(methyl(phenyl)carbamoyl)-6-oxo-3-(2-phenylacetyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)-1H-indol-5-yl)methyl)phosphonate (90 mg, 0.12 mmol, 1.0 equiv) in DCM (1 mL) at room temperature was added TMSBr (179 mg, 1.17 mmol, 10 equiv). After addition, the reaction mixture was stirred at room temperature overnight. After completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by RP-prep HPLC to give (difluoro(2-(((5S,8S,10aR)-8-(methyl(phenyl)carbamoyl)-6-oxo-3-(2-phenylacetyl)decahydropyrrolo[1,2-a][1,5]diazocin-5-yl)carbamoyl)-1H-indol-5-yl)methyl)phosphonic acid (3) (50.0 mg, 70.6 μmol, 60%) as a yellow solid. LCMS (ESI): m / z=708.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d 6) δ 12.37-11.72 (m, 1H), 8.89-8.29 (m, 1H), 7.98-7.82 (m, 1H), 7.57-7.13 (m, 13H), 5.09-4.91 (m, 1H), 4.32-4.20 (m, 2H), 4.08-4.00 (m, 1H), 3.96-3.89 (m, 2H), 3.81- 3.75 (m, 1H), 3.42 -3.31 (m, 2H), 3.20 (s, 3H), 2.20-1.53 ​​(m, 6H).

[0582] Representative Procedure for General Scheme 4: Synthesis of 4 [ka]

[0583] Step A: Methyl (5S,8S,10aR)-2-acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,4]diazocine-8-carboxylate

[0584] To a solution of (5S,8S,10aR)-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,4]diazocine-8-carboxylate (400 mg, 1.17 mmol, 1 equiv.) and DIEA (453 mg, 3.51 mmol, 3 equiv.) in DMF (6 mL) was added acetyl acetate (178 mg, 1.75 mmol, 1.5 equiv.) and the resulting mixture was stirred at room temperature for 2 h. Upon completion, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to give methyl (5S,8S,10aR)-2-acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,4]diazocine-8-carboxylate (320 mg, 834 μmol, 71%) as a white solid. LCMS(ESI):m / z=384[M+H] + .

[0585] Step B: (5S,8S,10aR)-2-Acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,4]diazocine-8-carboxylic acid

[0586] To a solution of (5S,8S,10aR)-2-acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,4]diazocine-8-carboxylate (200 mg, 521 μmol, 1 equiv.) in MeOH (8 mL) and water (2 mL) was added LiOH (37.3 mg, 1.56 mmol, 3 equiv.) and the resulting mixture was stirred at room temperature for 12 h. Upon completion, the reaction mixture was concentrated under reduced pressure to give (5S,8S,10aR)-2-acetyl-5-((tert-butoxycarbonyl)amino)-6-oxodecahydropyrrolo[1,2-a][1,4]diazocine-8-carboxylic acid (192 mg, 519 μmol...

Claims

1. Compounds Having Structural Formula I: 【Chemistry 105】 or a pharma- ceutically 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; X is S, SO ２ , -S(=O)=NH and NR ８ is selected from R １ 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 ], -P(O)OR １ｂ OR ２ｂ , -[P(O)[NHR Ｔｙ ][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 ], -P(O)OR １ｂ OR ２ｂ , -[P(O)[NHR Ｔｙ ][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 ], -P(O)OR １ｂ OR ２ｂ , -[P(O)[NHR Ｔｙ ][NH(AA)C(O)OR Ｔ ] or -P(O)[OR １ｂ ][NH(AA)C(O)OR Ｔ aryl substituted with cyano, (C １ ~C ４ ) optionally further substituted with one or two groups independently selected from alkoxy and halo); １ ~C ４ ) alkyl (aryl) (-(C １ ~C ４ The aryl portion of the 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 ], -P(O)OR １ｂ OR ２ｂ , -[P(O)[NHR Ｔｙ ][NH(AA)C(O)OR Ｔ ], -[P(O)[NH(AA)C(O)ORT][NH(AA)C(O)ORT] or -P(O)[OR １ｂ ][NH(AA)C(O)OR Ｔ substituted by -(C ２ ~C ４ ) alkenyl (aryl) (-(C ２ ~C ４ The aryl portion of the 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 ], -P(O)OR １ｂ OR ２ｂ , -[P(O)[NHR Ｔｙ ][NH(AA)C(O)OR Ｔ ] or -P(O)[OR １ｂ ][NH(AA)C(O)OR Ｔ [0046] wherein R １ａ and R ２ａ is hydrogen, cyano, (C １ ~C ４ ) alkyl, hydroxy (C １ ~C ４ ) alkyl and fluoro; or R １ａ and R ２ａ together with the carbon to which they are attached to form an oxo, R １ｂ and R ２ｂ is 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- to 7-membered heterocyclyl], [(C １ ~C ４ ) alkyl]-OC(O)-[5- to 7-membered 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 ) 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 aryl, wherein the 5- to 6-membered heteroaryl and aryl are each independently selected from halo, cyano and (C １ ~C ４ ) alkyl, each of which is optionally and independently substituted with 1 to 2 groups selected from [(C １ ~C ４ )alkyl]-OC(O)O-[5- to 7-membered heterocyclyl] and [(C １ ~C ４ ) alkyl]-OC(O)-[5- to 7-membered heterocyclyl], where valence permits, C(O)OR ｈ each optionally and independently substituted with 1 to 2 groups selected from R ２ is 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 is hydrogen, halo, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, hydroxy (C １ ~C ４ ) alkyl, -(C １ ~C ４ ) alkylphenyl, (C １ ~C ４ ) alkoxy, halo (C １ ~C ４ ) alkoxy, -(C １ ~C ４ ) alkyl(C １ ~C ４ ) Alkoxy, hydroxyl, cyano, -NR ａ R ｂ , phenyl, (C ３ ~C ６ ) cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl; ３ ~C ６ Cycloalkyl, 5- to 6-membered heteroaryl, and 4- to 6-membered heterocyclyl are, when valences permit, R Ｓ each optionally substituted with 1 to 3 groups selected from R ５ and R ６ is hydrogen, phenyl and (C １ ~C ４ ) alkyl; R ７ (C １ ~C ４ ) alkyl, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, １ ~C ４ ) Alkyl is, when valence permits, R Ｙ wherein the phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are optionally substituted, where valences permit, with 1 to 3 groups selected from R Ｚ each optionally substituted with 1 to 3 groups selected from 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, when valences permit, is selected from R Ｑ and optionally substituted with 1 to 3 groups selected from R ８ is hydrogen, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, (C ３ ~C ６ ) cycloalkyl, 5- to 7-membered heterocyclyl, -(C １ ~C ４ ) [5- to 7-membered heterocyclyl], 5- to 10-membered heteroaryl, -(C １ ~C ４ ) [5- to 10-membered heteroaryl], phenyl, -(C １ ~C ４ ) alkylphenyl, —C(O)R Ｈａ , -C(O)OR Ｈａ , -C(O)NR Ｈａ R Ｈｂ , -C(O)OR Ｈａ , -SOR Ｈａ R Ｈｂ and -SO ２ R Ｈａ and (C ３ ~C ６ ) cycloalkyl, 5-7 membered heterocyclyl, 5-10 membered heteroaryl, phenyl, (C １ ~C ４ ) the phenyl on the alkylphenyl, -(C １ ~C ４ ) [5- to 7-membered heterocyclyl], and -(C １ ~C ４ ) [5-6 membered heteroaryl] The 5-6 membered heteroaryl on the above may be, if valence permits, R Ｕ each optionally substituted with 1 to 3 groups selected from R Ｈａ (C １ ~C １０ ) alkyl, (C ２ ~C １０ ) alkenyl, (C ２ ~C １０ ) selected from alkynyl, phenyl, 5-10 membered monocyclic or bicyclic heteroaryl and 4-10 membered monocyclic or bicyclic heterocyclyl, １ ~C １０ ) alkyl, (C ２ ~C １０ ) alkenyl, (C ２ ~C １０ ) Alkynyl is, when valence permits, R Ｏ wherein said 5-10 membered monocyclic or bicyclic heteroaryl and said 4-10 membered monocyclic or bicyclic heterocyclyl are each optionally substituted, where valences permit, with one or two groups selected from halo, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, halo (C １ ~C ４ ) alkoxy, oxo, cyano and 4-6 membered heterocyclyl (C １ ~C ４ each optionally substituted with 1 to 3 groups selected from R Ｏ Halo, (C １ ~C ４ ) Alkoxy, OH, phenyl, NH ２ , -NH(C １ ~C １０ ) alkyl, -N[(C １ ~C １０ ) alkyl], (C ３～６ cycloalkyl), 4-10 membered monocyclic or fused bicyclic heterocyclyl and 5-10 membered monocyclic or bicyclic heteroaryl, wherein said 5-10 membered monocyclic or bicyclic heteroaryl and said 4-10 membered monocyclic or bicyclic heterocyclyl are selected from halo, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, halo (C １ ~C ４ ) each optionally substituted with 1 to 3 groups selected from alkoxy, oxo, and cyano; R Ｈｂ is hydrogen or (C １ ~C ４ ) alkyl; AA is a residue of a natural or unnatural alpha or beta amino acid, R Ｔ and R Ｔｙ (C １ ~C ４ ) alkyl, benzyl and phenyl, wherein said phenyl is selected from halo, (C １ ~C ４ ) alkyl and halo(C １ ~C ４ ) alkyl, R Ｑ and R Ｕ Halo, (C ２ ~C ４ ) alkenyl, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, halo (C １ ~C ４ ) alkoxy, cyano, phenyl, hydroxyl, 4-9 membered monocyclic or bicyclic heterocyclyl, 5-10 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 N.R. ｅ R ｆ are each independently selected from the group consisting of ２ ~C ４ ) alkenyl and (C １ ~C ４ ) Alkyl is, when valence permits, R Ｍ each optionally and independently substituted with 1 to 3 groups selected from the group consisting of phenyl, 5-10 membered monocyclic or bicyclic heteroaryl, (C ３ ~C ６ Cycloalkyl and 4-9 membered monocyclic or bicyclic heterocyclyl are, when valences permit, R Ｆ each optionally and independently substituted with 1 to 3 groups selected from R Ｙ Halo, (C １ ~C ４ ) alkoxy, halo (C １ ~C ４ ) 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) ２ R ｆ , -S(O)NR ｅ R ｆ , -S(O)=NH(C １ ~C ４ ) alkyl, -S(O) ２ N.R. ｅ R ｆ , hydroxyl, phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are, where valences permit, selected from R Ｘ each optionally substituted with 1 to 3 groups selected from R Ｍ and R Ｊ Halo, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, halo (C １ ~C ４ ) alkoxy, 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)=NH(C １ ~C ４ ) alkyl, -S(O) ２ N.R. ｅ R ｆ , hydroxyl, phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl, wherein said phenyl, 4- to 6-membered heterocyclyl, and 5- to 10-membered monocyclic or bicyclic heteroaryl are each independently selected from R Ｘ each optionally substituted with 1 to 3 groups selected from R Ｆ , R Ｓ , R Ｘ and R Ｚ is halo, cyano, (C １ ~C ４ ) alkyl, (C ３ ~C ６ cycloalkyl), halo (C １ ~C ４ ) alkyl, -(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 ) alkylheteroaryl, (C ２ ~C ４ ) alkenyl, halo(C ２ ~C ４ ) alkenyl, (C ２ ~C ４ ) alkynyl, halo(C ２ ~C ４ ) alkynyl, (C １ ~C ４ ) alkoxy, halo (C １ ~C ４ ) alkoxy, -OR ｅ , oxo, imino, phenyl, 4- to 6-membered heterocyclyl, -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 N.R. 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 １ ~C ４ alkyl)C(O)NR ｃ R ｄ , -C(O)NR ｃ R ｄ , -NO ２ and -NR ａ R ｂ are each independently selected from the group consisting of １ ~C ４ )alkyl is optionally substituted by cyano, and includes the phenyl, the 4- to 6-membered heterocyclyl and -(C １ ~C ４ ) alkylphenyl, where valences permit, may be halo, cyano, oxo, (C １ ~C １０ ) alkyl, (C ２ ~C １０ ) alkenyl, (C ２ ~C １０ ) alkynyl, halo(C １ ~C １０ ) alkyl, (C １ ~C １０ ) alkoxy and halo(C １ ~C １０ ) alkoxy, each of which is optionally and independently substituted with 1 to 3 groups selected from (C １ ~C １０ ) alkyl, (C ２ ~C １０ ) alkenyl and (C ２ ~C １０ ) alkynyl is optionally substituted, where valences permit, 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); R ａ , R ｂ , R ｃ , R ｄ , R ｅ , R ｆ , R ｇ and R ｈ is hydrogen, (C １ ~C ４ ) alkyl, (C ２ ~C ４ ) alkynyl, -(C １ ~C ４ ) alkylphenyl, phenyl, (C ３ ~C ６ ) cycloalkyl, 4- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl, １ ~C ４ ) Alkyl is, when valence permits, R Ｊ and optionally substituted with 1 to 3 groups selected from the phenyl, (C ３ ~C ６ )Cycloalkyl, 4- to 6-membered heterocyclyl and 5- to 6-membered heteroaryl are, where valences permit, halo, cyano, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, halo (C １ ~C ４ ) each independently optionally substituted with 1 to 3 groups selected from alkoxy, hydroxyl, phenyl, and benzyl.

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 ], -P(O)OR １ｂ OR ２ｂ , -[P(O)[NHR Ｔｙ ][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 ], -P(O)OR １ｂ OR ２ｂ , -[P(O)[NHR Ｔｙ ][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 ], -P(O)OR １ｂ OR ２ｂ , -[P(O)[NHR Ｔｙ ][NH(AA)C(O)OR Ｔ ] or -P(O)[OR １ｂ ][NH(AA)C(O)OR Ｔ aryl substituted with -(C １ ~C ４ ) alkyl (aryl) (-(C １ ~C ４ The aryl portion of the 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 ], -P(O)OR １ｂ OR ２ｂ , -[P(O)[NHR Ｔｙ ][NH(AA)C(O)OR Ｔ ] or -P(O)[OR １ｂ ][NH(AA)C(O)OR Ｔ substituted by -(C ２ ~C ４ ) alkenyl (aryl) (-(C ２ ~C ４ The aryl portion of the 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 ], -P(O)OR １ｂ OR ２ｂ , -[P(O)[NHR Ｔｙ ][NH(AA)C(O)OR Ｔ ] or -P(O)[OR １ｂ ][NH(AA)C(O)OR Ｔ [0046] wherein R ８ is hydrogen, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, (C ３ ~C ６ ) cycloalkyl, 5- to 7-membered heterocyclyl, -(C １ ~C ４ ) [5- to 7-membered heterocyclyl], 5- to 6-membered heteroaryl, -(C １ ~C ４ ) [5-6 membered heteroaryl], phenyl, -(C １ ~C ４ ) alkylphenyl, —C(O)R Ｈａ , -C(O)OR Ｈａ , -C(O)NR Ｈａ R Ｈｂ , -C(O)OR Ｈａ , -SOR Ｈａ R Ｈｂ and -SO ２ R Ｈａ and (C ３ ~C ６ ) cycloalkyl, 5- to 7-membered heterocyclyl, 5- to 6-membered heteroaryl, phenyl, (C １ ~C ４ ) the phenyl on the alkylphenyl, -(C １ ~C ４ ) [5- to 7-membered heterocyclyl], and -(C １ ~C ４ ) [5- to 6-membered heteroaryl], where valence permits, R Ｕ each optionally substituted with 1 to 3 groups selected from R Ｈａ However, (C １ ~C １０ ) alkyl, (C ２ ~C １０ ) alkenyl, (C ２ ~C １０ ) selected from alkynyl, phenyl, 5-10 membered monocyclic or bicyclic heteroaryl and 4-10 membered monocyclic or bicyclic heterocyclyl, １ ~C １０ ) alkyl, (C ２ ~C １０ ) alkenyl, (C ２ ~C １０ ) alkynyl, if valence permits, is R Ｏ wherein said 5-10 membered monocyclic or bicyclic heteroaryl and said 4-10 membered monocyclic or bicyclic heterocyclyl are each optionally substituted, where valences permit, with one or two groups selected from halo, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, halo (C １ ~C ４ ) each optionally substituted with 1 to 3 groups selected from alkoxy, oxo, and cyano; R Ｏ But, Halo, (C １ ~C ４ ) Alkoxy, OH, phenyl, NH ２ , -NH(C １ ~C １０ ) alkyl, -N[(C １ ~C １０ )alkyl], 4-10 membered monocyclic or fused bicyclic heterocyclyl and 5-10 membered monocyclic or bicyclic heteroaryl, wherein said 5-10 membered monocyclic or bicyclic heteroaryl and said 4-10 membered monocyclic or bicyclic heterocyclyl are, where valences permit, selected from halo, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy, halo (C １ ~C ４ ) each optionally substituted with 1 to 3 groups selected from alkoxy, oxo, and cyano; 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

3. The compound has the structural formula II: 【Chemistry 106】 3. The compound of claim 1 or 2, which is a compound of the formula: or a pharma- ceutically acceptable salt thereof.

4. 4. The compound according to claim 1, wherein p is 1, or a pharma- ceutically acceptable salt thereof.

5. R ２ 5. The compound according to claim 1, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

6. R ３ 6. The compound according to any one of claims 1 to 5, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

7. R ４ 7. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein: is hydrogen.

8. 8. The compound according to any one of claims 1 to 7, wherein q is 1 and t is 1, or a pharma- ceutically acceptable salt thereof.

9. 8. The compound according to any one of claims 1 to 7, wherein q is 0 and t is 2, or a pharma- ceutically acceptable salt thereof.

10. The compound has structural formula III, IV, V, VI, VII or VIII: 【Chemistry 107】 8. The compound of claim 1 , which is a compound of the formula:

11. R ５ 11. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

12. R １ is selected from 8-10 membered fused bicyclic heteroaryl and aryl, each of which is -CR １ａ R ２ａ P(O)OR １ｂ OR ２ｂ 12. The compound of claim 1 , wherein the compound is substituted with:

13. R １ is selected from benzothiophenyl, indolyl, naphthalenyl, thienopyridinyl, benzothiazoyl, quinolinyl, isoquinolinyl, 4,5,6,7-tetrahydropyrrolopyridinyl, and 5,6,7,8-tetrahydroimidazopyrazinyl, each of which is -CR １ａ R ２ａ P(O)OR １ｂ OR ２ｂ 13. The compound of claim 1 , wherein the compound is substituted with:

14. R １ but, 【Chemistry 108】 14. The compound of any one of claims 1 to 13, selected from: or a pharma- ceutically acceptable salt thereof.

15. R １ but, 【Chemistry 109】 15. The compound of claim 1, wherein:

16. R １ａ is hydrogen, R ２ａ is fluoro or R １ａ is fluoro, R ２ａ 16. The compound of any one of claims 1 to 15, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

17. R １ａ and R ２ａ 17. The compound of any one of claims 1 to 16, or a pharma- ceutically acceptable salt thereof, wherein is fluoro.

18. R １ｂ and R ２ｂ is hydrogen, (C １ ~C ４ ) alkyl, -[(C １ ~C ４ ) alkyl]-OC(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)-[halo(C １ ~C ４ ) alkyl], -[(C １ ~C ４ ) alkyl]-OC(O)NR ２ｃ R ２ｄ ], [(C １ ~C ４ )alkyl]-OC(O)O-[5- to 7-membered heterocyclyl] and phenyl; １ ~C ４ ) alkyl]-OC(O)O-[5- to 7-membered heterocyclyl], wherein the 5- to 7-membered heterocyclyl is C(O)OR ２ｃ and optionally substituted by the above (C １ ~C ４ ) alkyl group is one or two (C １ ~C ４ 20. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, optionally substituted with alkyl.

19. R １ｂ and R ２ｂ are respectively -[(C １ ~C ４ ) alkyl]-OC(O)-[(C １ ~C ４ 20. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein: R is 0, R is 1, R is 2, and R is 3.

20. R １ｂ and R ２ｂ 19. The compound of any one of claims 1 to 18, or a pharma- ceutically acceptable salt thereof, wherein is hydrogen.

21. -CR １ａ R ２ａ P(O)OR １ｂ OR ２ｂ が、 【Chemistry 110】 【Chemistry 111】 【Chemistry 112】 20. The compound of any one of claims 1 to 15 and 18, or a pharma- ceutically acceptable salt thereof, selected from:

22. -CR １ａ R ２ａ P(O)OR １ｂ OR ２ｂ が、 【Chemistry 113】 22. The compound of any one of claims 1 to 15, 18 and 21, wherein:

23. R ７ However, (C １ ~C ４ ) alkyl, phenyl, 4- to 6-membered monocyclic heterocyclyl, 9- or 10-membered fused bicyclic heterocyclyl, 5- or 6-membered monocyclic heteroaryl, and 9- or 10-membered fused bicyclic heteroaryl, １ ~C ４ ) alkyl, if valence permits, R Ｙ wherein said phenyl, 5- or 6-membered monocyclic heterocyclyl, 9- or 10-membered fused bicyclic heterocyclyl, 5- or 6-membered monocyclic heteroaryl, and 9- or 10-membered fused bicyclic heteroaryl are optionally substituted, where valences permit, with 1 to 3 groups selected from R Ｚ 23. The compound of any one of claims 1 to 22, or a pharma- ceutically acceptable salt thereof, each optionally substituted with 1 to 3 groups selected from:

24. R ７ However, (C １ ~C ４ ) alkyl, phenyl, pyridinyl, pyrimidinyl, naphthyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, chromanyl, pyrazoyl, indazolyl, benzisoxazolyl, imidazo[1,2-a]pyridinyl, pyrrolidinyl, cyclopentyl, cyclohexyl, azetidinyl, piperidinyl and dihydropyridinyl; １ ~C ４ ) alkyl, if valence permits, R Ｙ and wherein, where valences permit, said phenyl, pyridinyl, pyrimidinyl, naphthyl, cinnolinyl, quinoxalinyl, quinazolinyl, quinolinyl, isoquinolinyl, chromanyl, pyrazoyl, indazolyl, benzisoxazolyl, imidazo[1,2-a]pyridinyl, pyrrolidinyl, cyclopentyl, cyclohexyl, azetidinyl, piperidinyl, and dihydropyridinyl are optionally substituted with one to three groups selected from R Ｚ 24. The compound of any one of claims 1 to 23, or a pharma- ceutically acceptable salt thereof, each optionally substituted with 1 to 3 groups selected from:

25. R Ｙ But cyano, (C １ ~C ４ ) alkyl, -NR ａ R ｂ 25. The compound of any one of claims 1 to 24, or a pharma- ceutically acceptable salt thereof, wherein said compound is selected from:

26. R Ｚ But halo, cyano, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, hydroxy (C １ ~C ４ ) alkyl, -(C １ ~C ４ ) alkylphenyl, -(C １ ~C ４ ) alkylheteroaryl, (C １ ~C ４ ) alkoxy, halo (C １ ~C ４ ) alkoxy, -OR ｅ , oxo, phenyl, 4-6 membered heterocyclyl, -S(O) ２ R ｆ , -(C １ ~C ４ alkyl)C(O)R ｇ , -C(O)R ｇ , -(C １ ~C ４ alkyl)C(O)NR ｃ R ｄ , -C(O)NR ｃ R ｄ , -NO ２ and -NR ａ R ｂ and (C １ ~C ４ 26. The compound of any one of claims 1 to 25, or a pharma- ceutically acceptable salt thereof, wherein said alkyl is optionally substituted with cyano, and said phenyl and said 4-6 membered heterocyclyl are each optionally and independently substituted, where valences permit, with one to three groups selected from cyano and oxo.

27. R Ｚ But halo, cyano, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, hydroxy (C １ ~C ４ ) alkyl, -(C １ ~C ４ ) alkylphenyl, -(C １ ~C ４ ) alkylheteroaryl, (C １ ~C ４ ) alkoxy, halo (C １ ~C ４ ) alkoxy, -OR ｅ , oxo, -S(O) ２ R ｆ , -(C １ ~C ４ alkyl)C(O)R ｇ , -C(O)R ｇ , -(C １ ~C ４ alkyl)C(O)NR ｃ R ｄ , -C(O)NR ｃ R ｄ , -NO ２ , -NR ａ R ｂ , phenyl and dihydropyridinyl, １ ~C ４ 27. The compound of any one of claims 1 to 26, or a pharma- ceutically acceptable salt thereof, wherein said alkyl is optionally substituted with cyano, and said phenyl and said dihydropyridinyl are each optionally and independently substituted, where valences permit, with one to three groups selected from cyano and oxo.

28. R ６ and R ７ together with the nitrogen atom to which they are attached form a 4- to 6-membered monocyclic heterocyclyl, a 7- to 13-membered spiro bicyclic heterocyclyl, or a 9- to 10-membered fused bicyclic heterocyclyl, each of which, when valences permit, is selected from R Ｑ 23. The compound of any one of claims 1 to 22, or a pharma- ceutically acceptable salt thereof, optionally substituted with 1 to 3 groups selected from:

29. R ６ and R ７ together with the nitrogen atom to which they are attached, represent azetidinyl, spiro[indoline-3,3'-pyrrolidinyl], pyrrolidinyl, 3,4-dihydrobenzoxazinyl, 1,2,3,4-tetrahydroquinolinyl, octahydrothiopyranopyroyl, octahydro-1H-thieno[3',4':3,4]cyclobuta[1,2-c]pyrroyl, 2,6-diazabicyclo[3.2.0]heptanyl, piperazinyl, morpholinyl, 1,4,5 , 6-tetrahydropyrrolopyrazoyl, 4-azaspiro[2.4]heptanyl, 2-oxa-5-azabicyclo[2.2.1]heptanyl, 7-oxa-4-azaspiro[2.5]octanyl, 8-oxa-3-azabicyclo[3.2.1]octanyl, 4,6-diazaspiro[2.4]heptanyl, 5-oxa-2,6-diazaspiro[3.4]oct-6-enyl or piperidinyl, each of which, when valences permit, is selected from R Ｑ 29. The compound of any one of claims 1 to 22 and 28, or a pharma- ceutically acceptable salt thereof, optionally substituted with one to three groups selected from:

30. R ６ and R ７ together with the nitrogen atom to which they are attached form azetidinyl, spiro[indoline-3,3'-pyrrolidinyl], pyrrolidinyl, 3,4-dihydrobenzoxazinyl, 1,2,3,4-tetrahydroquinolinyl, octahydrothiopyranopyroyl, octahydro-1H-thieno[3',4':3,4]cyclobuta[1,2-c]pyrroyl, 2,6-diazabicyclo[3.2.0]heptanyl, piperazinyl, 1,4,5,6-tetrahydropyrrolopyrazoyl, 5-oxa-2,6-diazaspiro[3.4]oct-6-enyl, or piperidinyl, each of which, when valences permit, is selected from R Ｑ 29. The compound of any one of claims 1 to 22 and 28, or a pharma- ceutically acceptable salt thereof, optionally substituted with one to three groups selected from:

31. R ６ and R ７ together with the nitrogen atom to which they are attached form pyrrolidinyl or azetidinyl, each of which, when valences permit, is R Ｑ 31. The compound according to any one of claims 1 to 22, 28, 29 and 30, or a pharma- ceutically acceptable salt thereof, optionally substituted with one to three groups selected from:

32. R Ｑ But, Halo, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, -S(O) ２ R ｆ , cyano, phenyl, 4- to 9-membered monocyclic or bicyclic heterocyclyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, (C ３ ~C ６ ) cycloalkyl, oxo, -OR ｅ , -C(O)R ｇ , -C(O)NR ｃ R ｄ , -C(O)OR ｅ , -NR ｃ C(O)R ｅ and (C １ ~C ４ ) alkyl, if valence permits, R Ｍ each optionally and independently substituted with 1 to 3 groups selected from: phenyl, 4- to 6-membered heterocyclyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, and (C ３ ~C ６ ) Cycloalkyl, if valence permits, is R Ｆ or a pharma- ceutically acceptable salt thereof.

32. The compound of any one of claims 1 to 31, or a pharma- ceutically acceptable salt thereof, each optionally and independently substituted with 1 to 3 groups selected from:

33. R Ｑ But, Halo, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, cyano, phenyl, 4-9 membered monocyclic or bicyclic heterocyclyl, 5-10 membered monocyclic or bicyclic heteroaryl, (C ３ ~C ６ ) cycloalkyl, oxo, -OR ｅ , -C(O)R ｇ , -C(O)NR ｃ R ｄ , -C(O)OR ｅ , -NR ｃ C(O)R ｅ and (C １ ~C ４ ) alkyl, if valence permits, R Ｍ each optionally and independently substituted with 1 to 3 groups selected from: phenyl, 4- to 6-membered heterocyclyl, 5- to 10-membered monocyclic or bicyclic heteroaryl, and (C ３ ~C ６ ) Cycloalkyl, if valence permits, is R Ｆ or a pharma- ceutically acceptable salt thereof.

32. The compound of any one of claims 1 to 31, or a pharma- ceutically acceptable salt thereof, each optionally and independently substituted with 1 to 3 groups selected from:

34. R Ｑ But cyano, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, -S(O) ２ R ｆ , oxo, -C(O)R ｇ , -OR ｅ , -C(O)OR ｅ , -C(O)NR ｃ R ｄ , -NR ｃ C(O)R ｅ , cyclobutyl, cyclopropyl, cyclohexyl, phenyl, benzisothiazoyl, pyridinyl, pyrimidinyl, dihydropyridinyl, pyrazoyl, piperidinyl, tetrahydroimidazopyridinyl and isothiazolidinyl, １ ~C ４ ) alkyl, if valence permits, R Ｍ wherein cyclobutyl, cyclopropyl, cyclohexyl, phenyl, benzisothiazoyl, pyridinyl, pyrimidinyl, dihydropyridinyl, pyrazoyl, piperidinyl, tetrahydroimidazopyridinyl, and isothiazolidinyl are optionally and independently substituted with one to three groups selected from R Ｆ or a pharma- ceutically acceptable salt thereof.

34. The compound of any one of claims 1 to 33, or a pharma- ceutically acceptable salt thereof, each optionally and independently substituted with 1 to 3 groups selected from:

35. R Ｑ But cyano, (C １ ~C ４ ) alkyl, halo (C １ ~C ４ ) alkyl, oxo, -C(O)R ｇ , -OR ｅ , -C(O)OR ｅ , -C(O)NR ｃ R ｄ , -NR ｃ C(O)R ｅ , cyclobutyl, cyclopropyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, dihydropyridinyl, pyrazoyl, piperidinyl, tetrahydroimidazopyridinyl and isothiazolidinyl, １ ~C ４ ) alkyl, if valence permits, R Ｍ wherein cyclobutyl, cyclopropyl, cyclohexyl, phenyl, pyridinyl, pyrimidinyl, dihydropyridinyl, pyrazoyl, piperidinyl, tetrahydroimidazopyridinyl, and isothiazolidinyl are optionally and independently substituted, where valences permit, with one to three groups selected from R Ｆ or a pharma- ceutically acceptable salt thereof.

34. The compound of any one of claims 1 to 33, or a pharma- ceutically acceptable salt thereof, each optionally and independently substituted with 1 to 3 groups selected from:

36. R Ｍ is selected from phenyl and 5-6 membered monocyclic heteroaryl, said phenyl and 5-6 membered monocyclic heteroaryl and phenyl being, where valences permit, R Ｘ 36. The compound of any one of claims 1 to 35, or a pharma- ceutically acceptable salt thereof, each optionally substituted with 1 to 3 groups selected from:

37. R Ｍ is selected from phenyl and pyridinyl, said phenyl and pyridinyl being, when valences permit, R Ｘ 37. The compound of any one of claims 1 to 36, or a pharma- ceutically acceptable salt thereof, each optionally substituted with 1 to 3 groups selected from:

38. R Ｘ Halo and (C １ ~C ４ 38. The compound of any one of claims 1 to 37, or a pharma- ceutically acceptable salt thereof, wherein said compound is selected from:

39. R Ｆ But halo, cyano, (C １ ~C ４ ) Alkoxy, oxo and -NR ｃ C(O)R ｅ 39. The compound of any one of claims 1 to 38, selected from: or a pharma- ceutically acceptable salt thereof.

40. R ｃ and R ｄ is, if valence permits, hydrogen and (C １ ~C ４ ) alkyl, １ ~C ４ ) alkyl, if valence permits, R Ｊ 40. The compound of any one of claims 1 to 39, or a pharma- ceutically acceptable salt thereof, optionally substituted with 1 to 3 groups selected from:

41. R ｅ is hydrogen, phenyl, 5- to 6-membered heteroaryl and (C １ ~C ４ ) alkyl, １ ~C ４ ) alkyl, if valence permits, R Ｊ 41. The compound of any one of claims 1 to 40, or a pharma- ceutically acceptable salt thereof, optionally substituted with one to three groups selected from:

42. R Ｊ is independently selected from phenyl and 5- to 6-membered heteroaryl, said 5- to 6-membered heteroaryl being selected from (C ３ ~C ６ 42. The compound of any one of claims 1 to 41, or a pharma- ceutically acceptable salt thereof, optionally substituted with cycloalkyl.

43. R Ｊ 43. The compound of any one of claims 1 to 42, or a pharma- ceutically acceptable salt thereof, wherein is phenyl.

44. R ｇ 44. The compound of any one of claims 1 to 43, or a pharma- ceutically acceptable salt thereof, wherein is selected from piperidinyl, morpholinyl, and piperazinyl.

45. X is NR ８ 45. The compound of any one of claims 1 to 9 or 11 to 44, which is: or a pharma- ceutically acceptable salt thereof.

46. R ８ is hydrogen, -C(O)R Ｈａ , -C(O)OR Ｈａ , (C １ ~C ４ ) alkyl, -SO ２ R Ｈａ , -C(O)NR Ｈａ R Ｈｂ , Haro (C １ ~C ４ ) alkyl, phenyl, -(C １ ~C ４ ) [4- to 10-membered monocyclic or bicyclic heterocyclyl], -(C １ ~C ４ ) [5-10 membered monocyclic or bicyclic heteroaryl], -(C ３ ~C ６ )cycloalkyl or 4-10 membered monocyclic or bicyclic heterocyclyl, １ ~C ４ ) alkylphenyl, wherein the phenyl is -(C １～３ alkoxy) and 5-6 membered heteroaryl (-(C １ ~C ４ ) alkyl; and １ ~C ４ ) alkyl is optionally substituted with 1 to 3 phenyl; R Ｈａ However, (C １ ~C ４ ) alkyl, -(C １ ~C ４ ) [5-6 membered heteroaryl], -(C １ ~C ４ ) [phenyl], -(C １ ~C ４ ) [(C ３ ~C ６ )cycloalkyl], phenyl, 4-10 membered monocyclic or bicyclic heterocyclyl, wherein the phenyl and 4-10 membered monocyclic or bicyclic heterocyclyl are halo, (C １ ~C ４ ) alkyl, (C １ ~C ４ ) alkoxy and 4-6 membered monocyclic heterocyclyl (C １ ~C ４ each optionally substituted with 1 to 3 groups independently selected from R Ｈｂ is H, 46. ​​A compound according to any one of claims 1 to 45.

47. R ８ is -H, -CH ２ CH ３ , -CH ２ CH (CH ３ ) ２ , -CH ２ CF ２ , -CH ２ CF ３ , cyclobutyl, -CH ２ -Quinuclidinyl, -CH ２ -imidazo[1,5-a]pyridinyl, -CH ２ -pyrimidinyl, -CH ２ -phenyl, phenyl, pyrimidinyl, pyridinyl, isoquinolinyl, -C(O)R Ｈａ , -C(O)OR Ｈａ , -SO ２ R Ｈａ Or -C(O)NR Ｈａ R Ｈｂ or R ８ has the following structure: 【Chemistry 114】 is represented by R Ｈａ is methyl, ethyl, propyl, isopropyl, -CH ２ -quinolinyl, -CH ２ -phenyl, -CH ２ CH ２ -phenyl, -CH(CH ３ )-phenyl, -CH(CH ３ ) CH ２ -phenyl, -CH ２ CH (CH ３ )-phenyl, -CH ２ CH ２ -pyrimidinyl, -CH ２ C (CH ３ ) ２ -cyclohexyl, quinolinyl, indazoyl, benzisoxazolyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, 5,6,7,8-tetrahydroimidazo[1,5-a]pyridinyl, 4,5,6,7-tetrahydrobenzo[d]isoxazolyl or 6,7-dihydro-4H-pyrano[3,4-d]isoxazolyl, and said quinolinyl, indazoyl, benzisoxazolyl, imidazo[1,5-a]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, 5,6,7,8-tetrahydroimidazo[1,5-a]pyridinyl, 4,5,6,7-tetrahydrobenzo[d]isoxazolyl, 6,7-dihydro-4H-pyrano[3,4-d]isoxazolyl is selected from the group consisting of -Cl, -CH ３ , -CH ２ CH ３ , -OCH ３ or N-methylpiperazinyl, each optionally substituted with 1 to 3 groups independently selected from 47. The compound of claim 46.

48. 2. The compound of claim 1, or a pharma- ceutically acceptable salt thereof, wherein the compound is selected from any one of compounds 1 to 441.

49. 49. A pharma- ceutically acceptable composition comprising a compound according to any one of claims 1 to 48, or a pharma- ceutically acceptable salt thereof, and a pharma- ceutically acceptable carrier.

50. A method of treating a condition responsive to modulation of STAT3 or STAT6 in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any one of claims 1 to 48 or a pharma- ceutically acceptable salt thereof, or a pharma- ceutically acceptable composition of claim 49.

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