Novel heterocycles as sPLA2-X inhibitors

Abstract

The present invention relates to compounds, pharmaceutically acceptable salts of compounds, and pharmaceutical compositions of compounds, or salts thereof, capable of inhibiting secretory phospholipase A2 (sPLA2-X) enzyme, wherein the compounds are compounds of Formula (I), wherein ring B, R6, Z1, Z2, Z3, and Z4 are described herein. The present invention also relates to the use of the compounds, salts, or compositions described herein in methods for inhibiting sPLA2-X enzyme in a sample. The present invention also relates to the use of the compounds, salts, or compositions in methods for treating or reducing the severity of sPLA2-X-mediated diseases in a subject. TIFF2025526401000363.tif11170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 392,092, filed July 25, 2022, and U.S. Provisional Patent Application No. 63 / 493,905, filed April 3, 2023, the disclosures of which are incorporated herein by reference in their entireties.

[0002] The present invention relates to compounds, pharmaceutically acceptable salts of compounds, and pharmaceutical compositions of compounds, or salts thereof, capable of inhibiting secretory phospholipase A2 group X (sPLA2-X) enzyme activity. The present invention also relates to the use of the compounds, salts, or compositions described herein in methods for inhibiting sPLA2-X enzyme activity in a sample. The present invention also relates to the use of the compounds, salts, or compositions in methods for treating or reducing the severity of sPLA2-X-mediated diseases in a subject. [Background technology]

[0003] Phospholipase A2 (PLA2) is a superfamily of key enzymes involved in numerous (patho)physiological and cellular processes (Balsinde et al., (1999) Annu. Rev. Pharmacol. Toxicol. 39:175-189 and Yuan and Tsai (1999) Biochim Biophys Acta 1441:215). Phospholipase A2 (PLA2) constitutes one of the largest families of lipolytic enzymes and is defined by its ability to catalyze the hydrolysis of ester bonds at the sn-2 position of glycerophospholipids, yielding free fatty acids and lysophospholipids from which secondary messengers can be generated. In vivo, the sn-2 position of phospholipids often contains polyunsaturated fatty acids, which can be metabolized to form various eicosanoids and related bioactive lipids. Lysophospholipids also play a variety of important roles in biological processes. The PLA2 superfamily currently consists of 16 groups and many subgroups that differ in primary sequence, structure, and catalytic mechanism. There are six main types or classes of PLA2s: secreted PLA2s (sPLA2s), cytosolic PLA2s (cPLA2s), CaPLA2s, and αPLA2s. 2+ These include independent PLA2 (iPLA2), lysosomal PLA2 (LPLA2), adipose PLA2 (AdPLA2), and lipoprotein-associated PLA2 (LpPLA2).

[0004] Various PLA2 types are involved in a wide variety of lipid signaling and inflammatory diseases, including rheumatoid arthritis, pulmonary inflammation, neurological disorders such as multiple sclerosis, cardiovascular diseases including atherosclerosis, and cancer.

[0005] Cancer remains one of the most deadly threats to human health. Worldwide, an estimated 19.3 million new cancer cases (18.1 million excluding non-melanoma skin cancer) and almost 10 million cancer deaths (9.9 million excluding non-melanoma skin cancer) occurred in 2020. These statistics are expected to increase further by 2025. Effective treatment strategies are needed.

[0006] Inhibition of PLA2 has found some practical uses in cancer treatment. For example, U.S. Patent Application Publication No. 2019 / 0142835 (the '835 publication) is directed to the treatment of cancer by administering an anticancer drug in combination with a PLA2 inhibitor. Cancer therapy also increases autophagy, although the mechanism involved is unclear. The '835 publication also found that the survival of cancer cells treated with anticancer drugs was critically dependent on phospholipase A2 (PLA2) to mobilize lysophospholipids and free fatty acids to maintain fatty acid oxidation and oxidative phosphorylation.

[0007] Despite existing cancer therapies and promising therapies in development, the high rates of relapsed and refractory disease among lymphoma and other cancer populations drives the ongoing need for novel approaches to effective cancer treatment for patients. [Brief explanation of the drawings]

[0008] [Figure 1] FIG. 11 is an affinity sensogram providing the kinetic and steady-state affinity (1:1 fitting) of compound 5 for sPLA2-X. Summary of the Invention

[0009] In one aspect, the present invention provides a compound of formula I [ka] or a pharmaceutically acceptable salt thereof, wherein: Z1 to Z4 are each independently selected from N and CH, and at least two of Z1 to Z4 are CH; Each R6 is independently CN, halo, NH2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl and -OC 1-6 haloalkyl; Ring B is selected from B1, B2, B3, B4, and B5. [ka] X' is O, S, Se, or NR9, and R9 is H, C 1-6 Alkyl, C 3-6 cyclyl, 3- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein each alkyl, cyclyl, heterocyclyl, or heteroaryl is independently and optionally selected from one or more R 10 is substituted with a substituent, X1 to X3 are each independently N or CH; A is —O—, —S—, —S(O2)—, or C(R2)R3; R1 is H or R7, R2 and R3 are each independently selected from hydrogen CN, OH, NH2, halo, and C 1-6 alkyl, or R and R together with the carbon atom to which they are attached form a 3- to 6-membered cyclyl or a 3- to 6-membered heterocyclyl, each alkyl, cyclyl, and heterocyclyl independently and optionally selected from one or more R 10 is substituted with a substituent, R4 and R5 are each independently hydrogen, CN, OH, NH2, halo, C 1-6 Alkyl and OC 1-6 alkyl, each alkyl independently and optionally selected from one or more R 10 Is substituted with a substituent, or R4 and R5 together with the carbon atom to which they are attached form oxo, a 3- to 6-membered cyclyl, or a 3- to 6-membered heterocyclyl, each cyclyl and heterocyclyl optionally containing one or more R 10 is substituted with a substituent, or R3 and R4 form a double bond or together with the carbon atom to which they are attached form a 3- to 6-membered cyclyl or a 3- to 6-membered heterocyclyl, each cyclyl and heterocyclyl optionally being joined by one or more R 10 is substituted with a substituent, Each R7 is independently R 10 and R8 and R 12 are each independently OH, OC1-6 Alkyl, O-phenyl, NH2, NH(C 1-6 alkyl), and N(C 1-6 alkyl)2, each alkyl and phenyl optionally and independently selected from 1 to 3 R 10 is substituted with a substituent, Ring E is a 5-6 membered fused cyclic moiety selected from cyclyl, heterocyclyl, and heteroaryl, each of which optionally and independently contains 1-3 R 10 is substituted with a substituent, L is a bond or C 1-6 Alkyl, C 3-6 a divalent moiety selected from cyclyl, and 3- to 6-membered heterocyclyl, each of which is optionally and independently selected from 1 to 3 R 11 is substituted with a substituent, Z is R 10 and Each R 10 is oxo, CN, OR 11 , N(R 11 )2, Halo, C(O)H, C(O)R 11 , C(O)OR 11 , C(O)N(R 11 )2, (C 1-6 alkyl)-C(O)R 11 , (C 1-6 alkyl)-C(O)OR 11 , (C 1-6 alkyl)-C(O)N(R 11 )2, N(R 11 )C(O)R 11 , N(R 11 )C(O)OR 11 , N(R 11 )C(O)NHR 11 , N(R 11 )-(CH2)-C(O)R 11 , N(R 11 )-(CH2)-C(O)OR 11 , N(R 11 )-(CH2)-C(O)NHR 11 , N(R 11 )SO2C 1-6 Alkyl, OSO2C 1-6 Alkyl, SO2C1-6 Alkyl, S(O)N(R 11 )2, C 1-6 alkyl, phenyl, 3- to 6-membered cyclyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl, each alkyl, phenyl, cyclyl, heterocyclyl, or heteroaryl being each independently and optionally selected from one or more R 11 is substituted with a substituent, Each R 11 are independently hydrogen, oxo, CN, OH, NH2, halo, OC 1-6 Alkyl, OC 1-6 Haloalkyl, C 1-6 Alkyl, and C 1-6 haloalkyl; n is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; provided that the compound of formula I is the following compound: [ka] A compound having R X is independently a single substituent selected from hydrogen, 4-methyl, 5-methyl, 6-methyl, 7-methyl, 6-fluoro, 6-chloro, 6-CN, 6-methoxy, 6-CF3, 6-OCF3, 6-OCF2H, 6-OCH2CF3, 6-CH2OH, 6-ethyl, and 6-cyclopropyl; or None of the compounds selected from the following: [ka]

[0010] In another aspect, the present invention includes a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0011] In another aspect, the invention includes a method of inhibiting the sPLA2-X enzyme, the method comprising contacting the enzyme with a compound described herein, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition.

[0012] In another aspect, the invention includes a method for treating or lessening the severity of a disease mediated by the sPLA2-X enzyme in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt, or pharmaceutical composition described herein. DETAILED DESCRIPTION OF THE INVENTION

[0013] Abbreviation In describing this invention, the chemical elements are identified according to the Periodic Table of the Elements. The abbreviations and symbols utilized herein are in accordance with common usage of such abbreviations and symbols by those skilled in the chemical arts. The following abbreviations are used herein: ACN Acetonitrile AcOEt ethyl acetate AcOH acetic acid APCI atmospheric pressure chemical ionization Boc tert-butyloxycarbonyl Br2 Bromine Cu(OAc)2Copper(II) acetate DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCM dichloromethane DIPEA Diisopropylethylamine DMAP 4-dimethylaminopyridine DMF Dimethylformamide DMSO-d6 Deuterated Dimethyl Sulfoxide DMSO dimethyl sulfoxide EtOH ethanol Et2NH diethylamine g grams Hep Heptane Hex h time H2O Water HPLC High Pressure Liquid Chromatography I2 Iodine i-PrOH isopropanol KI potassium iodide KHSO4 Potassium hydrogen sulfate K2CO3 Potassium Carbonate LDA Lithium diisopropylamide LiOH Lithium hydroxide M mole MeOH Methanol MαDG Methyl α-D-glucopyranoside MgSO4 Magnesium Sulfate min mg milligram mmol millimolar mol mole N2 nitrogen NaCl Sodium chloride NaH sodium hydride NaHCO3 Sodium Bicarbonate Na2SO4 Sodium Sulfate NaO t Bu Sodium tert-butoxide NaBH(OAc)3 Sodium triacetoxyborohydride NH4Cl Ammonium chloride NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance spectroscopy Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0) R f Retention Factor RT room temperature Rt retention time RuPhos 2-Dicyclohexylphosphino-2',6'-diisopropoxybiphenyl TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate TEA Triethylamine TFA trifluoroacetic acid THF tetrahydrofuran

[0014] definition For purposes of the present invention, chemical elements are identified according to the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75th Ed. In addition, general principles of organic chemistry are described in "Organic Chemistry," Thomas Sorrell, University Science Books, Sausalito: 1999, and "March's Advanced Organic Chemistry," 5th Ed., Ed.: Smith, M.B. and March, J., John Wiley & Sons, New York: 2001, the entire contents of which are incorporated herein by reference.

[0015] As used herein, an "alkyl" group refers to a saturated aliphatic hydrocarbon group containing 1 to 12 (e.g., 1 to 8, 1 to 6, or 1 to 4) carbon atoms. The alkyl group can be straight-chained or branched. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-heptyl, or 2-ethylhexyl. An alkyl group can have one or more substituents, such as halo, phospho, alicyclic [e.g., cycloalkyl or cycloalkenyl], heteroalicyclic [e.g., heterocycloalkyl or heterocycloalkenyl], aryl, heteroaryl, alkoxy, aroyl, heteroaroyl, acyl [e.g., (aliphatic)carbonyl, (alicyclic)carbonyl, or (heteroalicyclic)carbonyl], nitro, cyano, amido [e.g., (cycloalkylalkyl)carbonylamino, arylcarbonylamino, aralkylcarbonylamino, (heterocycloalkyl)carbonylamino, (heterocycloalkylalkyl)carbonylamino, heteroarylcarbonylamino, heteroaralkylcarbonylamino], or the like. and optionally substituted with an alkylaminocarbonyl, cycloalkylaminocarbonyl, heterocycloalkylaminocarbonyl, arylaminocarbonyl, or heteroarylaminocarbonyl, amino [e.g., aliphatic amino, alicyclic amino, or heteroalicyclic amino], sulfonyl [e.g., aliphatic -SO2-], sulfinyl, sulfanyl, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, carboxy, carbamoyl, alicyclicoxy, heterocycloaliphaticoxy, aryloxy, heteroaryloxy, aralkyloxy, heteroarylalkoxy, alkoxycarbonyl, alkylcarbonyloxy, or hydroxy.Without limitation, some examples of substituted alkyl include carboxyalkyl (e.g., HOOC-alkyl, alkoxycarbonylalkyl, and alkylcarbonyloxyalkyl), cyanoalkyl, hydroxyalkyl, alkoxyalkyl, acylalkyl, aralkyl, (alkoxyaryl)alkyl, (sulfonylamino)alkyl (e.g., (alkyl-SO2-amino)alkyl), aminoalkyl, amidoalkyl, (alicyclic)alkyl, or haloalkyl.

[0016] As used herein, an "aryl" group, used alone or as part of a larger moiety such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to monocyclic (e.g., phenyl), bicyclic (e.g., indenyl, naphthalenyl, tetrahydronaphthyl, tetrahydroindenyl), and tricyclic (e.g., fluorenyltetrahydrofluorenyl, or tetrahydroanthracenyl, anthracenyl) ring systems in which the monocyclic ring system is aromatic or at least one of the rings in the bicyclic or tricyclic ring system is aromatic. Bicyclic and tricyclic groups include benzo-fused 2- to 3-membered carbocyclic rings. For example, a benzo-fused group can be a ring system consisting of two or more C 4-8Aryl is optionally aliphatic [e.g., alkyl, alkenyl, or alkynyl], alicyclic, (alicyclic)aliphatic, heteroalicyclic, (heteroalicyclic)aliphatic, aryl, heteroaryl, alkoxy, (alicyclic)oxy, (heteroalicyclic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, oxo (on the non-aromatic carbocyclic ring of a benzo-fused bicyclic or tricyclic aryl), nitro, carboxy, amido, acyl [e.g., (aliphatic)carbonyl, (alicyclic)carbonyl], The aryl may be substituted with one or more substituents, including carbonyl, ((alicyclic)aliphatic)carbonyl, (araliphatic)carbonyl, (heteroalicyclic)carbonyl, ((heteroalicyclic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], sulfonyl [e.g., aliphatic -SO2- or amino-SO2-], sulfinyl [e.g., aliphatic -S(O)- or alicyclic -S(O)-], sulfanyl [e.g., aliphatic -S-], cyano, halo, hydroxy, mercapto, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, or carbamoyl. Alternatively, the aryl may be unsubstituted.

[0017] Non-limiting examples of substituted aryls include haloaryls [e.g., mono-, di(p,m-dihaloaryls, etc.), and (trihalo)aryls], (carboxy)aryls [e.g., (alkoxycarbonyl)aryls, ((aralkyl)carbonyloxy)aryls, and (alkoxycarbonyl)aryls]; (amido)aryls [e.g., (aminocarbonyl)aryls, (((alkylamino)alkyl)aminocarbonyl)aryls, (alkylcarbonyl)aminoaryls, (arylaminocarbonyl)aryls, and (((heteroaryl)amino)carbonyl)aryls], aminoaryls [e.g., ((alkylsulfonyl)amino)aryls or ((dialkyl)amino)aryls], (cyanoalkyl)aryls, (alkoxy)aryls, (sulfamoyl)aryls [e.g., (amino m-(heteroalicyclic)-o-(alkyl)aryl, (m-(heteroalicyclic)-m-alkoxy)aryl, (m-(heteroalicyclic)-o-(alkyl)aryl, (m-(heteroalicyclic)-m-alkoxy)aryl, (m-(heteroalicyclic)-o-(alkyl)aryl, (m-(heteroalicyclic)-m-alkoxy)aryl, (m-(heteroalicyclic)-m-cyanoaryl, (m-(heteroalicyclic)-o-(alkyl)aryl, (m-(heteroalicyclic)-m-alkoxy)aryl, (m-(heteroalicyclic)-m-cyanoaryl, (m-(heteroalicyclic)-o-(alkyl))aryl.

[0018] As used herein, a "cycloalkyl" group refers to a saturated carbocyclic monocyclic or bicyclic (fused or bridged) ring of 3 to 10 (e.g., 5 to 10) carbon atoms. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, cubyl, octahydro-indenyl, decahydro-naphthyl, bicyclo[3.2.1]octyl, bicyclo[2.2.2]octyl, bicyclo[3.3.1]nonyl, bicyclo[3.3.2]decyl, bicyclo[2.2.2]octyl, adamantyl, or ((aminocarbonyl)cycloalkyl)cycloalkyl.

[0019] Cycloalkyl groups are optionally selected from the group consisting of phospho, aliphatic [e.g., alkyl, alkenyl, or alkynyl], alicyclic, (alicyclic)aliphatic, heteroalicyclic, (heteroalicyclic)aliphatic, aryl, heteroaryl, alkoxy, (alicyclic)oxy, (heteroalicyclic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (alicyclic)carbonylamino, ((alicyclic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heteroalicyclic)carbonylamino, ((heteroalicyclic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, or can be substituted with one or more substituents such as (heteroaraliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (alicyclic)carbonyl, ((alicyclic)aliphatic)carbonyl, (araliphatic)carbonyl, (heteroalicyclic)carbonyl, ((heteroalicyclic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkyl-SO2- and aryl-SO2-], sulfinyl [e.g., alkyl-S(O)-], sulfanyl [e.g., alkyl-S-], sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, or carbamoyl.

[0020] As used herein, a "cyclyl" group includes all cycloalkyl moieties and further includes non-aromatic monocyclic or polycyclic carbocyclic rings having one or more degrees of unsaturation. Examples of cyclyl groups include, but are not limited to, cyclohexene, cyclohexa-1,3-diene, 4,5,6,7-tetrahydro-2H-indene, cyclohexa-1,4-diene, cyclopentene, cyclopentadiene, cyclobutene, and cyclopropane.

[0021] As used herein, a "heterocycloalkyl" group refers to a 3- to 10-membered monocyclic or bicyclic (fused or bridged) (e.g., 5- to 10-membered monocyclic or bicyclic) saturated ring structure in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or combinations thereof). Examples of heterocycloalkyl groups include piperidyl, piperazyl, tetrahydropyranyl, tetrahydrofuryl, 1,4-dioxolanyl, 1,4-dithianyl, 1,3-dioxolanyl, oxazolidyl, isoxazolidyl, morpholinyl, thiomorpholyl, octahydrobenzofuryl, octahydrochromenyl, octahydrothiochromenyl, octahydroindolyl, octahydropyrindinyl, decahydroquinolinyl, octahydrobenzo[b]thiopheneyl, 2-oxa-bicyclo[2.2.2]octyl, 1-aza-bicyclo[2.2.2]octyl, 3-aza-bicyclo[3.2.1]octyl, and 2,6-dioxa-tricyclo[3.3.1.0]nonyl. A monocyclic heterocycloalkyl group can be fused with a phenyl moiety to form structures such as tetrahydroisoquinoline, which are classified as heteroaryls.

[0022] Heterocycloalkyl groups are optionally selected from the group consisting of phospho, aliphatic [e.g., alkyl, alkenyl, or alkynyl], alicyclic, (alicyclic)aliphatic, heteroalicyclic, (heteroalicyclic)aliphatic, aryl, heteroaryl, alkoxy, (alicyclic)oxy, (heteroalicyclic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, amido [e.g., (aliphatic)carbonylamino, (alicyclic)carbonylamino, ((alicyclic)aliphatic)carbonylamino, (aryl)carbonylamino, (araliphatic)carbonylamino, (heteroalicyclic)carbonylamino, ((heteroalicyclic)aliphatic)carbonylamino, (heteroaryl)carbonylamino, or ( and (heteroaliphatic)carbonylamino], nitro, carboxy [e.g., HOOC-, alkoxycarbonyl, or alkylcarbonyloxy], acyl [e.g., (alicyclic)carbonyl, ((alicyclic)aliphatic)carbonyl, (araliphatic)carbonyl, (heteroalicyclic)carbonyl, ((heteroalicyclic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], nitro, cyano, halo, hydroxy, mercapto, sulfonyl [e.g., alkylsulfonyl or arylsulfonyl], sulfinyl [e.g., alkylsulfinyl], sulfanyl [e.g., alkylsulfanyl], sulfoxy, urea, thiourea, sulfamoyl, sulfamido, oxo, or carbamoyl.

[0023] As used herein, the term "heterocyclyl" includes all heterocycloalkyl moieties and further includes non-aromatic monocyclic or polycyclic heterocyclyls having one or more degrees of unsaturation. Examples of heterocyclyl groups include, but are not limited to, 3,4-dihydro-2H-pyran, 2H-pyran, dihydropyridine, 1,2,3,4-tetrahydropyridine, 4,5,6,7-tetrahydroisobenzofuran, 2,3-dihydro-1H-pyrrole, 1H-azirine, and 1,2-dihydroazeto.

[0024] As used herein, a "heteroaryl" group refers to a monocyclic, bicyclic, or tricyclic ring system having 4 to 15 ring atoms, in which one or more of the ring atoms is a heteroatom (e.g., N, O, S, or a combination thereof), and in which the monocyclic ring system is aromatic, or in which at least one of the rings in a bicyclic or tricyclic ring system is aromatic. Heteroaryl groups include benzo-fused ring systems having two to three rings. For example, benzo-fused groups include benzo (e.g., indolyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophen-yl, quinolinyl, or isoquinolinyl) fused to one or two 4-8 membered heterocycloaliphatic moieties. Some examples of heteroaryl are azetidinyl, pyridyl, 1H-indazolyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, tetrazolyl, benzofuryl, isoquinolinyl, benzthiazolyl, xanthene, thioxanthene, phenothiazine, dihydroindole, benzo[1,3]dioxole, benzo[b]furyl, benzo[b]thiophenyl, indazolyl, benzimidazolyl, benzthiazolyl, puryl, cinnolyl, quinolyl, quinazolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, isoquinolyl, 4H-quinolidyl, benzo-1,2,5-thiadiazolyl, or 1,8-naphthyridyl.

[0025] Monocyclic heteroaryls include, but are not limited to, furyl, thiophen-yl, 2H-pyrrolyl, pyrrolyl, oxazolyl, thazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,3,4-thiadiazolyl, 2H-pyranyl, 4-H-pranyl, pyridyl, pyridazyl, pyrimidyl, pyrazolyl, pyrazyl, or 1,3,5-triazyl. Monocyclic heteroaryls are numbered according to standard chemical nomenclature.

[0026] Bicyclic heteroaryls include, but are not limited to, indolyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furyl, benzo[b]thiophenyl, quinolinyl, isoquinolinyl, indolyl, isoindolyl, indolyl, benzo[b]furyl, bexo[b]thiophenyl, indazolyl, benzimidazyl, benzthiazolyl, purinyl, 4H-quinolizyl, quinolyl, isoquinolyl, cinnolyl, phthalazyl, quinazolyl, quinoxalyl, 1,8-naphthyridyl, or pteridyl. Bicyclic heteroaryls are numbered according to standard chemical nomenclature.

[0027] Heteroaryl is optionally selected from the group consisting of aliphatic [e.g., alkyl, alkenyl, or alkynyl], alicyclic, (alicyclic)aliphatic, heteroalicyclic, (heteroalicyclic)aliphatic, aryl, heteroaryl, alkoxy, (alicyclic)oxy, (heteroalicyclic)oxy, aryloxy, heteroaryloxy, (araliphatic)oxy, (heteroaraliphatic)oxy, aroyl, heteroaroyl, amino, oxo (on the non-aromatic carbocyclic or heterocyclic ring of a bicyclic or tricyclic heteroaryl), carboxy, amido, acyl [e.g., aliphatic carbonyl, (alicyclic )carbonyl, ((alicyclic)aliphatic)carbonyl, (araliphatic)carbonyl, (heteroalicyclic)carbonyl, ((heteroalicyclic)aliphatic)carbonyl, or (heteroaraliphatic)carbonyl], sulfonyl [e.g., aliphatic sulfonyl or aminosulfonyl], sulfinyl [e.g., aliphatic sulfinyl], sulfanyl [e.g., aliphatic sulfanyl], nitro, cyano, halo, hydroxy, mercapto, sulfoxy, urea, thiourea, sulfamoyl, sulfamido, or carbamoyl. Alternatively, heteroaryl can be unsubstituted.

[0028] Non-limiting examples of substituted heteroaryls include (halo)heteroaryls [e.g., mono- and di-(halo)heteroaryls], (carboxy)heteroaryls [e.g., (alkoxycarbonyl)heteroaryls], cyanoheteroaryls, aminoheteroaryls [e.g., ((alkylsulfonyl)amino)heteroaryls and ((dialkyl)amino)heteroaryls], (amido)heteroaryls [e.g., aminocarbonylheteroaryls, ((alkylcarbonyl)amino)heteroaryls, ((((alkyl)amino)alkyl)aminocarbonyl)heteroaryls, (((heteroaryl)amino)carbonyl)heteroaryls, ((heteroalicyclic)carbonyl)heteroaryls, and ((alkylcarbonyl)amino)heteroaryls], (cyanoalkyl)heteroaryls, (alkoxy)heteroaryls, (sulfamoyl)heteroaryls, and (aminocarbonyl)heteroaryls. Examples of heteroaryls include (aminosulfonyl)heteroaryls, (sulfonyl)heteroaryls [e.g., (alkylsulfonyl)heteroaryls], (hydroxyalkyl)heteroaryls, (alkoxyalkyl)heteroaryls, (hydroxy)heteroaryls, ((carboxy)alkyl)heteroaryls, (((dialkyl)amino)alkyl]heteroaryls, (heteroalicyclic)heteroaryls, (alicyclic)heteroaryls, (nitroalkyl)heteroaryls, (((alkylsulfonyl)amino)alkyl)heteroaryls, ((alkylsulfonyl)alkyl)heteroaryls, (cyanoalkyl)heteroaryls, (acyl)heteroaryls [e.g., (alkylcarbonyl)heteroaryls], (alkyl)heteroaryls, and (haloalkyl)heteroaryls [e.g., trihaloalkylheteroaryls].

[0029] As used herein, "cyclic moiety" and "cyclic group" refer to monocyclic, bicyclic, and tricyclic ring systems, including cycloaliphatic, heterocycloaliphatic, aryl, or heteroaryl, each of which is defined above.

[0030] As used herein, an "alkoxy" group refers to an alkyl-O- group, where "alkyl" is defined above.

[0031] As used herein, a "haloalkyl" group refers to an alkyl group that is substituted with one to three halogens. For example, the term haloalkyl includes the group -CF.

[0032] As used herein, "carbonyl" refers to --C(O)--.

[0033] As used herein, "carboxyl" refers to --C(O)OH.

[0034] As used herein, "oxo" refers to =O.

[0035] As used herein, the term "vicinal" generally refers to the arrangement of substituents on a group containing two or more carbon atoms, where the substituents are attached to adjacent carbon atoms.

[0036] As used herein, the term "geminal" generally refers to the arrangement of substituents on a group that includes two or more carbon atoms, where the substituents are attached to the same carbon atom.

[0037] The terms "terminally" and "internally" refer to the location of a group within a substituent. A group is terminal if it is at the end of a substituent that is not further attached to the rest of the chemical structure. Carboxyalkyl, i.e., R X O(O)C-alkyl is an example of a carboxy group used terminally. If the group is in the middle of a substituent in a chemical structure, the group is internal. Alkylcarboxy (e.g., alkyl-C(O)O- or alkyl-OC(O)-) and alkylcarboxyaryl (e.g., alkyl-C(O)O-aryl- or alkyl-O(CO)-aryl-) are examples of carboxy groups used internally.

[0038] The phrase "optionally substituted" is used interchangeably herein with the phrase "substituted or unsubstituted." As described herein, the compounds of the invention can be optionally substituted with one or more substituents, as generally indicated above or as exemplified by the particular classes, subclasses, and species of the invention. As described herein, the variable R 1 , X, L, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , and other variables contained in formulas (I), (II), and (II-A) described herein encompass specific groups such as alkyl and aryl. Unless otherwise specified, the variable R 1 , X, L, X 1 , X 2 , X 3 , X 4 , X 5 , X 6 Each of the specific groups of the other variables contained therein can be optionally substituted with one or more substituents described herein. Each substituent of the specific group can be further optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, alicyclic, heteroalicyclic, heteroaryl, haloalkyl, and alkyl. For example, an alkyl group can be substituted with alkylsulfanyl, which can be optionally substituted with one to three of halo, cyano, oxo, alkoxy, hydroxy, amino, nitro, aryl, haloalkyl, and alkyl. As an additional example, the cycloalkyl portion of (cycloalkyl)carbonylamino can be optionally substituted with one to three of halo, cyano, alkoxy, hydroxy, nitro, haloalkyl, and alkyl. When two alkoxy groups are bound to the same atom or adjacent atoms, the two alkoxy groups can form a ring together with the atoms to which they are bound.

[0039] As used herein, the term "substituted," whether preceded by the term "optionally" or not, refers to the replacement of a hydrogen atom in a given structure with the radical of a specified substituent. Specific substituents are described above in the definitions and below in the description of compounds and examples thereof. Unless otherwise indicated, an optionally substituted group may have a substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituents may be the same or different at all positions. A ring substituent, such as a heterocycloalkyl, may be attached to another ring, such as a cycloalkyl, to form a spiro-bicyclic ring system, e.g., both rings share one common atom. As one of ordinary skill in the art will recognize, combinations of substituents envisioned by this invention are those that result in the formation of stable or chemically feasible compounds.

[0040] As used herein, the phrase "stable or chemically feasible" refers to a compound that is substantially unchanged when subjected to conditions that allow for its production, detection, and preferably recovery, purification, and use for one or more purposes disclosed herein. In some embodiments, a stable compound or chemically feasible compound is a compound that is substantially unchanged when maintained at a temperature of 40° C. or less in the absence of moisture or other chemically reactive conditions for at least one week.

[0041] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure, such as the R and S configurations at each asymmetric center, (Z) and (E) double bond isomers, and (Z) and (E) conformational isomers. Accordingly, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the invention. Unless otherwise stated, all tautomeric forms of the compounds of the invention are within the scope of the invention. Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, the replacement of hydrogen by deuterium or tritium, or 13 C- or 14 Compounds having the present structure except for the replacement of a carbon by a C-enriched carbon are within the scope of this invention. Such compounds are useful, for example, as analytical tools or probes in biological assays, or as therapeutic agents.

[0042] It should be noted that the use of the descriptors "first," "second," "third," etc. is used to distinguish between separate elements (e.g., solvents, reaction steps, processes, reagents, etc.) and may or may not refer to the relative order or relative chronology of the elements described.

[0043] As used herein, the term "pharmaceutically acceptable salt" refers to any salt (e.g., obtained by reaction with an acid or base) of a compound of the present invention that is physiologically tolerated in a target patient (e.g., a mammal). Salts of the compounds of the present invention can be derived from inorganic or organic acids and bases. Examples of acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, toluene-p-sulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, ethanesulfonic acid, formic acid, benzoic acid, malonic acid, sulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, and the like. Other acids, such as oxalic acid, while not themselves pharmaceutically acceptable, can be used in the preparation of salts useful as intermediates in obtaining the compounds of the present invention and their pharmaceutically acceptable acid addition salts.

[0044] Examples of bases include alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and bases of formula NW4 + (W is C 1-4 Examples of suitable compounds include, but are not limited to, compounds in which the aryl group is alkyl.

[0045] Examples of salts include, but are not limited to, acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, flucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, chloride, bromide, iodide, 2-hydroxyethanesulfonate, lactate, maleate, mesylate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate. + , NH4 + , and NW4+ (W is C 1-4 Illustrative examples include anions of the compounds of the invention combined with suitable cations, such as alkyl groups. For therapeutic use, the salts of the compounds of the invention are contemplated as pharmaceutically acceptable. However, salts of non-pharmaceutically acceptable acids and bases may also be used, for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0046] The term "therapeutically effective amount," as used herein, refers to an amount of a therapeutic agent sufficient to result in the improvement of one or more symptoms of a disorder, or to prevent the progression of a disorder, or to cause regression of a disorder. For example, with respect to the treatment of cancer, in one embodiment, a therapeutically effective amount refers to an amount of a therapeutic agent that reduces the rate of tumor growth, reduces tumor mass, reduces the number of metastases, increases the time to tumor progression, or increases survival by at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, or at least 100%.

[0047] The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable vehicle" includes any of the standard pharmaceutical carriers, solvents, surfactants, or vehicles. Suitable pharmaceutically acceptable vehicles include aqueous and non-aqueous vehicles. Standard pharmaceutical carriers and their formulations are described in Remington's Pharmaceutical Sciences, Mack Publishing Co., Easton, PA, 19th ed. 1995.

[0048] As used herein, the term "prodrug" is intended to encompass therapeutically inactive compounds that are converted into therapeutically active agents of the present invention under physiological conditions. One method for creating a prodrug is to design a selected moiety that is hydrolyzed or cleaved under physiological conditions at a targeted in vivo site of action to reveal the desired molecule and produce its therapeutic effect. In certain embodiments, the prodrug is converted by the enzymatic activity of the subject. In some embodiments, the compounds of the present invention contain a carboxylic acid moiety that is converted into an alkyl, aryl, or heteroaryl ester or amide, and the ester or amide is cleaved under physiological conditions to release the base carboxylic acid compound.

[0049] The term "sPLA2-X" refers to an enzyme (also known as group X secreted phospholipase A2, phosphatidylcholine 2-acylhydrolase 10, PLA2G10, or GXPLA2) that is a calcium-dependent enzyme that hydrolyzes glycerophospholipids to produce free fatty acids and lysophospholipids. In various embodiments, exemplary human sPLA2-X enzymes inhibited by the compounds or pharmaceutically acceptable salts thereof described herein include human group X secreted phospholipase A2 having a preprotein sequence defined by NCBI Reference SEQ ID NO: NP_003552.1 (also UniProt / Swiss-Protein No. 015496). The mature sPLA2-X enzyme is amino acids 43-165 of the reference NP_003552.1 sPLA2-X amino acid sequence.

[0050] In an alternative embodiment, the present invention provides prodrugs of compounds of formula I.

[0051] Embodiments of the present invention In one aspect, the present invention provides a compound of formula I [ka] or a pharmaceutically acceptable salt thereof, wherein: Z1 to Z4 are each independently selected from N and CH, and at least two of Z1 to Z4 are CH; Each R6 is independently CN, halo, NH2, OH, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl and -OC 1-6 haloalkyl; Ring B is selected from B1, B2, B3, B4, and B5. [ka] X' is O, S, Se, or NR9, and R9 is H, C 1-6 Alkyl, C 3-6 cyclyl, 3- to 6-membered heterocyclyl, and 5- to 6-membered heteroaryl, wherein each alkyl, cyclyl, heterocyclyl, or heteroaryl is independently and optionally selected from one or more R 10 is substituted with a substituent, X1 to X3 are each independently N or CH; A is —O—, —S—, —S(O2)—, or C(R2)R3; R1 is H or R7, R2 and R3 are each independently selected from hydrogen CN, OH, NH2, halo, and C 1-6 alkyl, or R and R together with the carbon atom to which they are attached form a 3- to 6-membered cyclyl or a 3- to 6-membered heterocyclyl, each alkyl, cyclyl, and heterocyclyl independently and optionally selected from one or more R 10 is substituted with a substituent, R4 and R5 are each independently hydrogen, CN, OH, NH2, halo, C 1-6 Alkyl and OC 1-6 alkyl, each alkyl independently and optionally selected from one or more R 10 Is substituted with a substituent, or R4 and R5 together with the carbon atom to which they are attached form oxo, a 3- to 6-membered cyclyl, or a 3- to 6-membered heterocyclyl, each cyclyl and heterocyclyl optionally containing one or more R10 is substituted with a substituent, or R3 and R4 form a double bond or together with the carbon atom to which they are attached form a 3- to 6-membered cyclyl or a 3- to 6-membered heterocyclyl, each cyclyl and heterocyclyl optionally being joined by one or more R 10 is substituted with a substituent, Each R7 is independently R 10 and R8 and R 12 are each independently OH, OC 1-6 Alkyl, O-phenyl, NH2, NH(C 1-6 alkyl), and N(C 1-6 alkyl)2, each alkyl and phenyl optionally and independently selected from 1 to 3 R 10 is substituted with a substituent, Ring E is a 5-6 membered fused cyclic moiety selected from cyclyl, heterocyclyl, and heteroaryl, each of which optionally and independently contains 1-3 R 10 is substituted with a substituent, L is a bond or C 1-6 Alkyl, C 3-6 a divalent moiety selected from cyclyl, and 3- to 6-membered heterocyclyl, each of which is optionally and independently selected from 1 to 3 R 11 is substituted with a substituent, Z is R 10 and Each R 10 is oxo, CN, OR 11 , N(R 11 )2, Halo, C(O)H, C(O)R 11 , C(O)OR 11 , C(O)N(R 11 )2, (C 1-6 alkyl)-C(O)R 11 , (C 1-6 alkyl)-C(O)OR 11 , (C 1-6 alkyl)-C(O)N(R 11 )2, N(R 11 )C(O)R 11 , N(R 11 )C(O)OR11 , N(R 11 )C(O)NHR 11 , N(R 11 )-(CH2)-C(O)R 11 , N(R 11 )-(CH2)-C(O)OR 11 , N(R 11 )-(CH2)-C(O)NHR 11 , N(R 11 )SO2C 1-6 Alkyl, OSO2C 1-6 Alkyl, SO2C 1-6 Alkyl, S(O)N(R 11 )2, C 1-6 alkyl, phenyl, 3- to 6-membered cyclyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl, each alkyl, phenyl, cyclyl, heterocyclyl, or heteroaryl being each independently and optionally selected from one or more R 11 is substituted with a substituent, Each R 11 are independently hydrogen, oxo, CN, OH, NH2, halo, OC 1-6 Alkyl, OC 1-6 Haloalkyl, C 1-6 Alkyl, and C 1-6 haloalkyl; n is an integer selected from 0, 1, 2, and 3; m is an integer selected from 1, 2, 3, and 4; provided that the compound of formula I is the following compound: [ka] A compound having R X is independently a single substituent selected from hydrogen, 4-methyl, 5-methyl, 6-methyl, 7-methyl, 6-fluoro, 6-chloro, 6-CN, 6-methoxy, 6-CF3, 6-OCF3, 6-OCF2H, 6-OCH2CF3, 6-CH2OH, 6-ethyl, and 6-cyclopropyl; or None of the compounds selected from the following: [ka]

[0052] In one embodiment, at least three of Z1 to Z4 are CH.

[0053] In further embodiments, each of Z1-Z4 is CH.

[0054] In one embodiment, each R6 is independently halo, C 1-6 Alkyl, C 1-6 Haloalkyl, -OC 1-6 Alkyl and -OC 1-6 haloalkyl.

[0055] In another embodiment, each R6 is independently -OC 1-6 Alkyl and -OC 1-6 haloalkyl.

[0056] In further embodiments, each R6 is -OC 1-6 It is haloalkyl.

[0057] In one embodiment, m is an integer selected from 1, 2, and 3.

[0058] In another embodiment, m is an integer selected from 1 and 2.

[0059] In a further embodiment, m is 1.

[0060] In one embodiment, X' is O, S, Se, or NR9, and R9 is H, C 1-6 alkyl, and optionally one or more R 10 It is substituted with a substituent.

[0061] In another embodiment, X' is O.

[0062] In another embodiment, X' is S or Se.

[0063] In another embodiment, X' is NR9, where R9 is selected from H, methyl, ethyl, or isopropyl.

[0064] In one embodiment, two of X1-X3 are CH and one of X1-X3 is N.

[0065] In another embodiment, two of X1 and X2 are CH and X3 is N.

[0066] In a further embodiment, X1 to X3 are all CH.

[0067] In another embodiment, X' is NH.

[0068] In another embodiment, A is —O—, S(O) 2 , or —S—.

[0069] In another embodiment, A is C(R2)R3, and R2 and R3 are both hydrogen.

[0070] In one embodiment, A is C(R2)R3, and R2 and R3 are each independently CN, OH, NH2, halo, and C 1-6 alkyl, each alkyl independently and optionally selected from one or more R 10 It is substituted with a substituent.

[0071] In another embodiment, R2 and R3 are the same and are selected from halo and C 1-6 alkyl.

[0072] In further embodiments, R2 and R3 are both chloro, fluoro, methyl, or ethyl.

[0073] In still further embodiments, R2 and R3 are both fluoro or both methyl.

[0074] In one embodiment, R2 is hydrogen and R3 is NH2.

[0075] In one embodiment, A is C(R2)R3, where R2 and R3 together with the carbon atoms to which they are attached form a 3- to 6-membered cyclyl or a 3- to 6-membered heterocyclyl, and each cyclyl and heterocyclyl independently and optionally contains one or more R 10 It is substituted with a substituent.

[0076] In another embodiment, R and R, together with the carbon atoms to which they are attached, form one or more R 10 The substituents independently form a 3- to 6-membered cyclyl, optionally substituted.

[0077] In further embodiments, R2 and R3 together with the carbon atoms to which they are attached form a cyclopropyl or cyclobutyl ring.

[0078] In one embodiment, R1 is H.

[0079] In one embodiment, R4 and R5 are both hydrogen.

[0080] In another embodiment, R and R are each independently selected from hydrogen, CN, OH, NH, halo, and C 1-6 alkyl, each alkyl independently and optionally selected from one or more R 10 It is substituted with a substituent.

[0081] In further embodiments, R4 and R5 are the same and are selected from halo, NH2, and C 1-6 alkyl.

[0082] In still further embodiments, R4 and R5 are both chloro, fluoro, methyl, or ethyl.

[0083] In one embodiment, R4 and R5 are both fluoro or both methyl.

[0084] In one embodiment, one of R4 and R5 is hydrogen and the other of R4 and R5 is NH2.

[0085] In another embodiment, R4 and R5 together with the carbon atom to which they are attached form oxo, a 3- to 6-membered cyclyl, or a 3- to 6-membered heterocyclyl, each cyclyl and heterocyclyl optionally containing one or more R 10 It is substituted with a substituent.

[0086] In one embodiment, R and R together with the carbon atoms to which they are attached form a 3- to 6-membered cyclyl or a 3- to 6-membered heterocyclyl, each cyclyl and heterocyclyl optionally containing one or more R 10 It is substituted with a substituent.

[0087] In another embodiment, R4 and R5 together with the carbon atoms to which they are attached form a 3- to 6-membered cyclyl.

[0088] In a further embodiment, R4 and R5 together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl.

[0089] In one embodiment, A is C(R2)R3, and R3 and R4 form a double bond or, together with the carbon atom to which they are attached, form a 3- to 6-membered cyclyl or a 3- to 6-membered heterocyclyl, each cyclyl and heterocyclyl optionally containing one or more R 10 It is substituted with a substituent.

[0090] In one embodiment, R3 and R4 together with the carbon atoms to which they are attached form a 3- to 6-membered cyclyl or a 3- to 6-membered heterocyclyl, each cyclyl and heterocyclyl optionally containing one or more R 10 It is substituted with a substituent.

[0091] In another embodiment, R and R, together with the carbon atoms to which they are attached, optionally comprise one or more C 1-6 Forms a 3- to 6-membered cyclyl substituted with alkyl substituents.

[0092] In further embodiments, R3 and R4 together with the carbon atom to which they are attached form a cyclopropyl or cyclobutyl, optionally substituted with one or more methyl groups.

[0093] In one embodiment, Ring E is a 5-6 membered fused cyclic moiety selected from heterocyclyl and heteroaryl, each of which optionally and independently contains 1-3 R 10 It is substituted with a substituent.

[0094] In one embodiment, Ring E is a 5-membered fused cyclic moiety selected from heterocyclyl and heteroaryl, each of which is optionally and independently C(O)R 11 , C(O)OR 11 , C(O)N(R 11 )2, (C 1-6 alkyl)-C(O)R 11 , (C 1-6 alkyl)-C(O)OR 11 , and (C 1-6 alkyl)-C(O)N(R 11 )2, and R 11 is hydrogen or C 1-6 It is alkyl.

[0095] In a further embodiment, ring E is [ka] each of which is optionally and independently selected from C(O)OH and (C 1-6 and is substituted with 1 to 3 substituents selected from:-C(O)OH;-C(O)alkyl;-C(O)OH;

[0096] In one embodiment, L is a divalent moiety selected from methylene, ethylene, cyclopropylene, cyclobutylene, aziridine, and azetidine, each of which optionally and independently contains 1 to 3 R 11 It is substituted with a substituent.

[0097] In a further embodiment, L is methylene, [ka] is.

[0098] In one embodiment, Z is CN, OR 11 , N(R 11 )2, C(O)H, C(O)R 11 , C(O)OR 11 , C(O)N(R 11 )2, (C 1-6 alkyl)-C(O)R 11 , (C 1-6 alkyl)-C(O)OR 11 , (C 1-6 alkyl)-C(O)N(R 11 )2, N(R 11 )C(O)R 11 , N(R 11 )C(O)OR 11 , N(R 11 )C(O)NHR 11 , N(R 11 )-(CH2)-C(O)R 11 , N(R 11 )-(CH2)-C(O)OR 11 , N(R 11 )-(CH2)-C(O)NHR 11 , N(R 11 )SO2C 1-6 Alkyl, OSO2C 1-6 Alkyl, SO2C 1-6 Alkyl, and S(O)N(R 11 )2 and R 11 is hydrogen and C 1-6 alkyl.

[0099] In another embodiment, Z is OR 11 , N(R 11 )2, N(R 11 )C(O)R 11 , N(R 11 )C(O)OR 11 , N(R 11 )-(CH2)-C(O)OR 11 , and OSO2C 1-6 alkyl.

[0100] In further embodiments, Z is NHC(O)O-tert-butyl, NHCH2C(O)OH, NHC(O)CH3, NHC(O)CF3, NHS(O)2CH3, NH2, OS(O)2CH3, and OH.

[0101] In one embodiment, each R7 is independently selected from the group consisting of CN, OC 1-6 Alkyl, halo, and C 1-6 alkyl.

[0102] In another embodiment, each R7 is independently selected from halo and C 1-6 alkyl.

[0103] In one embodiment, n is 0 or 1.

[0104] In a further embodiment, n is 0.

[0105] In one embodiment, R8 is NH2, NHCH3, or OH.

[0106] In one embodiment, R 12 OH, OC 1-6 Alkyl, O-phenyl, NH2, NH(C 1-6 alkyl), and N(C 1-6 alkyl)2, each alkyl and phenyl optionally and independently selected from 1 to 3 R 10 It is substituted with a substituent.

[0107] In another embodiment, R 12 OH, OC 1-6 alkyl, and O-phenyl, each alkyl and phenyl optionally and independently selected from 1 to 3 R 10 It is substituted with a substituent.

[0108] In a further embodiment, R 12 OH, OC 1-6alkyl, and O-phenyl, each alkyl and phenyl optionally and independently selected from 1 to 3 R 10 It is substituted with a substituent.

[0109] In one embodiment, R 12 is O-Me, O-Et, O-Pr, Oi-Pr, O-tert-Bu, O-phenyl, or OH.

[0110] In one embodiment, R 12 is OCH3 or OH.

[0111] In one embodiment, the compound is of formula II: [ka] .

[0112] In one embodiment of this aspect, the chemical moiety: [ka] teeth, [ka] is selected from the group consisting of:

[0113] In one embodiment, the compound is a compound of formula IIIa: [ka] During the ceremony, A' is -O- or -S-; R1 is H or R7, R 4a and R 5a are each independently hydrogen, CN, OH, NH, halo, and C 1-6 alkyl, each alkyl independently and optionally selected from one or more R 10 Is substituted with a substituent, or R 4a and R 5atogether with the carbon atom to which they are attached form an oxo, a 3- to 6-membered cyclyl, or a 3- to 6-membered heterocyclyl, and each cyclyl and heterocyclyl may optionally be joined by one or more R 10 It is substituted with a substituent.

[0114] In one embodiment, A' is -O-.

[0115] In another embodiment, A' is -S- or -S(O)2-.

[0116] In another embodiment, R 4a and R 5a are each independently hydrogen and C 1-6 alkyl, each alkyl independently and optionally selected from one or more R 10 It is substituted with a substituent.

[0117] In a further embodiment, R 4a and R 5a are both hydrogen.

[0118] In one embodiment, R 4a and R 5a is selected from hydrogen, methyl, ethyl, propyl, isopropyl, and tert-butyl.

[0119] In a further embodiment, R 4a and R 5a are both methyl.

[0120] In one embodiment, R 4a and R 5a together with the carbon atom to which they are attached form an oxo, a 3- to 6-membered cyclyl, or a 3- to 6-membered heterocyclyl, and each cyclyl and heterocyclyl may optionally be joined by one or more R 10 It is substituted with a substituent.

[0121] In another embodiment, R 4a and R 5atogether with the carbon atoms to which they are attached form a 3- to 6-membered cyclyl or a 3- to 6-membered heterocyclyl, and each cyclyl and heterocyclyl optionally contains one or more R 10 It is substituted with a substituent.

[0122] In a further embodiment, R 4a and R 5a together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl.

[0123] In one embodiment, the chemical moiety: [ka] teeth, [ka] is selected from the group consisting of:

[0124] In another embodiment, the compound is of formula IIIb: [ka] During the ceremony, Ring E is a 5-6 membered fused cyclic moiety selected from cyclyl, heterocyclyl, and heteroaryl, each of which optionally and independently contains 1-3 R 10 is substituted with a substituent, Each R 10 CN, OR 11 , N(R 11 )2, Halo, C(O)H, C(O)R 11 , C(O)OR 11 , C(O)N(R 11 )2, (C 1-6 alkyl)-C(O)R 11 , (C 1-6 alkyl)-C(O)OR 11 , (C 1-6 alkyl)-C(O)N(R 11 )2, N(R 11 )C(O)R 11 , N(R 11 )C(O)OR 11, N(R 11 )C(O)NHR 11 , N(R 11 )-(CH2)-C(O)R 11 , N(R 11 )-(CH2)-C(O)OR 11 , N(R 11 )-(CH2)-C(O)NHR 11 , N(R 11 )SO2C 1-6 Alkyl, OSO2C 1-6 Alkyl, and SO2C 1-6 Alkyl, S(O)N(R 11 )2 is selected, Each R 11 are independently hydrogen, OH, NH2, OC 1-6 Alkyl, OC 1-6 Haloalkyl, C 1-6 Alkyl, and C 1-6 haloalkyl.

[0125] In one embodiment, Ring E is a 5-membered fused cyclic moiety selected from heterocyclyl and heteroaryl, each of which is optionally and independently C(O)R 11 , C(O)OR 11 , C(O)N(R 11 )2, (C 1-6 alkyl)-C(O)R 11 , (C 1-6 alkyl)-C(O)OR 11 , and (C 1-6 alkyl)-C(O)N(R 11 )2, and R 11 is hydrogen or C 1-6 It is alkyl.

[0126] In a further embodiment, ring E is [ka] each of which is optionally and independently selected from C(O)OH and (C 1-6 and is substituted with 1 to 3 substituents selected from:-C(O)OH;-C(O)alkyl;-C(O)OH;

[0127] In one embodiment, the chemical moiety: [ka] teeth, [ka] is selected from the group consisting of:

[0128] In one embodiment, the compound is of formula IIIc: [ka] During the ceremony, R 3c and R 4c forms a double bond, R 2c are hydrogen CN, OH, NH2, halo, and C 1-6 alkyl, each alkyl independently and optionally selected from one or more R 10 Is substituted with a substituent, or R1 and R 2c together with the atom to which they are attached form a phenyl, a 5- to 6-membered cyclyl, a 5- to 6-membered heterocyclyl, or a 5- to 6-membered heteroaryl, each optionally containing one or more R 10 is substituted with a substituent, R 5c are hydrogen, CN, OH, NH2, halo, and C 1-6 alkyl, each alkyl independently and optionally selected from one or more R 10 It is substituted with a substituent.

[0129] In one embodiment of this aspect, R 2c is selected from hydrogen, methyl, ethyl, and isopropyl.

[0130] In another embodiment, R 2c is methyl.

[0131] In a further embodiment, R 5cis hydrogen or methyl.

[0132] In one embodiment, the chemical moiety: [ka] teeth, [ka] is.

[0133] In another embodiment, the compound is of formula IIId: [ka] During the ceremony, R 4d and R 5d are each independently hydrogen, CN, OH, NH, halo, and C 1-6 alkyl, each alkyl independently and optionally selected from one or more R 10 is substituted with a substituent, R 4d and R 5d Aren't they both hydrogen? or R 4d and R 5d together with the carbon atom to which they are attached form an oxo, a 3- to 6-membered cyclyl, or a 3- to 6-membered heterocyclyl, and each cyclyl and heterocyclyl may optionally be one or more R 10 It is substituted with a substituent.

[0134] In one embodiment, R 4d and R 5d One of them is hydrogen and the other is NH2.

[0135] In another embodiment, R 4d and R 5d are each independently hydrogen, halo, and C 1-6 alkyl.

[0136] In a further embodiment, R 4d and R 5dare each independently selected from methyl, ethyl, and isopropyl.

[0137] In still further embodiments, R 4d and R 5d are both methyl.

[0138] In one embodiment, R 4d and R 5d together with the carbon atoms to which they are attached form a 3- to 6-membered cyclyl or a 3- to 6-membered heterocyclyl, and each cyclyl and heterocyclyl optionally contains one or more R 10 It is substituted with a substituent.

[0139] In another embodiment, R 4d and R 5d together with the carbon atom to which they are attached form a 3- to 6-membered cyclyl.

[0140] In a further embodiment, R 4d and R 5d together with the carbon atom to which they are attached form cyclopropyl or cyclobutyl.

[0141] In one embodiment, the chemical moiety: [ka] teeth, [ka] is.

[0142] In another embodiment, the compound is of formula IIIe: [ka] During the ceremony, R 2e and R 3e are each independently hydrogen CN, OH, NH, halo, and C 1-6 alkyl, or R 2e and R 3etogether with the carbon atoms to which they are attached form a 3- to 6-membered cyclyl or a 3- to 6-membered heterocyclyl, and each alkyl, cyclyl, and heterocyclyl independently and optionally contains one or more R 10 is substituted with a substituent, R 2e and R 3e are not both hydrogen.

[0143] In one embodiment of this aspect, R 2e and R 3e are each independently hydrogen, NH, halo, and C 1-6 alkyl.

[0144] In one embodiment, R 2e and R 3e are each independently selected from methyl, ethyl, and isopropyl.

[0145] In one embodiment, R 2e and R 3e are both methyl.

[0146] In a further embodiment, R 2e and R 3e are both halos.

[0147] In one embodiment, R 2e and R 3e together with the carbon atom to which they are attached form a 3- to 6-membered cyclyl or a 3- to 6-membered heterocyclyl.

[0148] In a further embodiment, R 2e and R 3e together with the carbon atom to which they are attached form a 3- to 6-membered cyclyl.

[0149] In another embodiment, the moiety [ka] teeth, [ka] is.

[0150] In another embodiment, the compound is a compound of formula IIIf-1 to IIIf-7: [ka] During the ceremony, R 2f are hydrogen CN, OH, NH2, halo, and C 1-6 alkyl, R 5f are hydrogen, CN, OH, NH2, halo, C 1-6 Alkyl and OC 1-6 alkyl, R 3f and R 4f together with the carbon atoms to which they are attached form a 3- to 6-membered cyclyl or a 3- to 6-membered heterocyclyl, and each cyclyl and heterocyclyl optionally contains one or more R 10 It is substituted with a substituent.

[0151] In one embodiment, R 3f and R 4f together with the carbon atoms to which they are attached, optionally one or more C 1-6 Forms a 3- to 6-membered cyclyl substituted with alkyl substituents.

[0152] In another embodiment, R 3f and R 4f together with the carbon atoms to which they are attached, optionally one or more C 1-6 It forms a cyclopropyl or cyclobutyl moiety substituted with alkyl substituents.

[0153] In another embodiment, the moiety [ka] teeth, [ka] is.

[0154] In one embodiment, the compound of formula I is a compound of formula IV: [ka] During the ceremony, X1, X2, X3, R1, R 10 , and R 12 is defined herein, X a is N or CH, Ring C is divalent and optionally contains one or more R 10 It is phenyl, 3- to 6-membered cyclyl, 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl, each of which is substituted by a substituent.

[0155] In one embodiment, the compound of formula IV is a compound of formula IVa: [ka]

[0156] In one embodiment, the compound of formula IV is a compound of formula IVb: [ka]

[0157] In one embodiment, the compound of formula IV is a compound of formula IVc. [ka]

[0158] In some embodiments of Formula IV, IVa, IVb, or IVc, each R 12 are independently OH, OC 1-6 Alkyl, NH2, NH(C 1-6 alkyl), and N(C 1-6 In another embodiment of Formula IV, IVa, IVb, or IVc, each R 12 is selected from OH or NH. In further embodiments of Formula IV, IVa, IVb, or IVc, each R 12is OH.

[0159] In some embodiments of Formulas IV and IVa, R is H or R 10 is.

[0160] In some embodiments of Formula IV, IVa, IVb, or IVc, each R 10 is oxo, CN, OR 11 , N(R 11 )2, Halo, C(O)H, C(O)R 11 , C(O)OR 11 , C(O)N(R 11 )2, (C 1-6 alkyl)-C(O)R 11 , (C 1-6 alkyl)-C(O)OR 11 , (C 1-6 alkyl)-C(O)N(R 11 )2, N(R 11 )C(O)R 11 , N(R 11 )C(O)OR 11 , N(R 11 )C(O)NHR 11 , N(R 11 )-(CH2)-C(O)R 11 , N(R 11 )-(CH2)-C(O)OR 11 , N(R 11 )-(CH2)-C(O)NHR 11 , N(R 11 )SO2C 1-6 Alkyl, OSO2C 1-6 Alkyl, SO2C 1-6 Alkyl, S(O)N(R 11 )2, C 1-6 alkyl, phenyl, 3- to 6-membered cyclyl, 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl; R 11 is defined herein.

[0161] In some embodiments of Formula IV, IVa, IVb, or IVc, each R 10 is oxo, CN, OR 11 , N(R 11)2, Halo, C(O)H, C(O)R 11 , C(O)OR 11 , C(O)N(R 11 )2, C 1-6 It is selected from alkyl, phenyl, 3- to 6-membered cyclyl, 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl.

[0162] In some embodiments of Formula IV, IVa, IVb, or IVc, each R 10 CN, OR 11 , N(R 11 )2, Halo, and C 1-6 alkyl.

[0163] In some embodiments of Formula IV, IVa, IVb, or IVc, each R 10 Halo and C 1-6 alkyl.

[0164] In some embodiments of Formula IV, IVa, IVb, or IVc, each ring C is divalent and optionally contains one or more R 10

[0023] In some embodiments of Formula IV, IVa, IVb, or IVc, each ring C is an optionally substituted 3- to 6-membered cyclyl, an optionally substituted 3- to 6-membered heterocyclyl, or a 5- or 6-membered heteroaryl. In other embodiments of Formula IV, IVa, IVb, or IVc, each ring C is an optionally substituted 3- to 6-membered cyclyl or an optionally substituted 3- to 6-membered heterocyclyl. In further embodiments of Formula IV, IVa, IVb, or IVc, each ring C is an optionally substituted 3- to 6-membered cyclyl. In still further embodiments of Formula IV, IVa, IVb, or IVc, each ring C is an optionally substituted cyclopropyl. In some embodiments of Formula IV, IVa, IVb, or IVc, ring C is unsubstituted.

[0165] In one embodiment, the compound of formula I is a compound of formula V: [ka] During the ceremony, X1, X2, X3, R1, and R 12 is defined herein, X a is N or CH.

[0166] In one embodiment, the compound of formula V is a compound of formula Va: [ka]

[0167] In one embodiment, the compound of formula V is a compound of formula Vb: [ka]

[0168] In one embodiment, the compound of formula V is a compound of formula Vc. [ka]

[0169] In some embodiments of Formula V, Va, Vb, or Vc, each R 12 are independently OH, OC 1-6 Alkyl, NH2, NH(C 1-6 alkyl), and N(C 1-6 In another embodiment of Formula V, Va, Vb, or Vc, each R 12 is selected from OH or NH. In further embodiments of Formula V, Va, Vb, or Vc, each R 12 is OH.

[0170] In some embodiments of Formulas V and Va, R is H or R 10 is.

[0171] In some embodiments of Formulas V and Va, each R 10 is oxo, CN, OR 11 , N(R 11 )2, Halo, C(O)H, C(O)R 11 , C(O)OR 11 , C(O)N(R 11 )2, (C 1-6alkyl)-C(O)R 11 , (C 1-6 alkyl)-C(O)OR 11 , (C 1-6 alkyl)-C(O)N(R 11 )2, N(R 11 )C(O)R 11 , N(R 11 )C(O)OR 11 , N(R 11 )C(O)NHR 11 , N(R 11 )-(CH2)-C(O)R 11 , N(R 11 )-(CH2)-C(O)OR 11 , N(R 11 )-(CH2)-C(O)NHR 11 , N(R 11 )SO2C 1-6 Alkyl, OSO2C 1-6 Alkyl, SO2C 1-6 Alkyl, S(O)N(R 11 )2, C 1-6 alkyl, phenyl, 3- to 6-membered cyclyl, 3- to 6-membered heterocyclyl, or 5- to 6-membered heteroaryl; R 11 is defined herein.

[0172] In some embodiments of Formulas V and Va, each R 10 is oxo, CN, OR 11 , N(R 11 )2, Halo, C(O)H, C(O)R 11 , C(O)OR 11 , C(O)N(R 11 )2, C 1-6 It is selected from alkyl, phenyl, 3- to 6-membered cyclyl, 3- to 6-membered heterocyclyl, or 5- or 6-membered heteroaryl.

[0173] In some embodiments of Formulas V and Va, each R 10 CN, OR 11 , N(R 11 )2, Halo, and C 1-6 alkyl.

[0174] In some embodiments of Formulas V and Va, each R 10 Halo and C 1-6 alkyl.

[0175] In another aspect, the present invention includes a process for producing compound 28a: [ka] The process comprises reacting a compound of formula X [ka] with a compound of formula XI [ka] in the presence of a copper catalyst, a solvent, and a base to provide compound 28a.

[0176] In one embodiment of this aspect, the copper catalyst is a copper I catalyst. In a further embodiment, the copper catalyst is a copper halide. In a still further embodiment, the copper catalyst is copper(I) iodide.

[0177] In another embodiment, the base is an organic base. In a further embodiment, the organic base is selected from trimethylamine, DBU, DIEA, and sodium hydride. In a further embodiment, the base is DBU.

[0178] In another embodiment, the solvent is selected from DMSO, dimethylacetamide, dimethylformamide, and THF, hi a further embodiment, the solvent is DMSO.

[0179] In another aspect, the process comprises reacting a compound of formula XII [ka] (R)-1-phenylethanylamine, [ka] under peptide coupling conditions, followed by recrystallization to produce a compound of formula XIII [ka] and hydrolyzing the compound of formula XIII with aqueous acid to provide a compound of formula XI.

[0180] In one embodiment of this aspect, the peptide coupling conditions comprise DMAP and EDC-HCl in an organic solvent. In a further embodiment, the organic solvent is selected from dichloromethane, chloroform, THF, DMF, ethyl acetate, hexane, heptane, or a combination thereof. In a further embodiment, the solvent is dichloromethane.

[0181] In another embodiment, the compound of formula III is recrystallized from a solvent selected from water, dichloromethane, chloroform, THF, DMF, ethyl acetate, hexane, heptane, or a combination thereof. In a further embodiment, the compound of formula III is recrystallized from a solvent mixture comprising heptane and ethyl acetate. In yet a further embodiment, the compound of formula XIII is recrystallized from a solvent mixture comprising about 70% heptane and about 30% ethyl acetate.

[0182] In one embodiment, the compound of Formula XIII is hydrolyzed by contacting the crystalline compound of Formula XIII with concentrated HCl. In a further embodiment, the mixture is stirred at an elevated temperature, for example, about 80° C.

[0183] In another aspect, the process comprises: Step 1) Compound of Formula XIV [ka] with triethylphosphonium acetate in the presence of LiCl, a solvent, and a base to provide a compound of formula XV; [ka] Step 2) contacting a compound of formula XV with trimethylsulfoxonium iodide in the presence of a base and a solvent to provide a compound of formula XVI; [ka] Step 3) hydrolyzing the compound of formula XVI to provide a compound of formula XII.

[0184] In one embodiment of this aspect, the base in step 1) is an organic base. In another embodiment, the base in step 1) is selected from triethylamine and DIEA. In a further embodiment, the base in step 1) is trimethylamine.

[0185] In one embodiment of this aspect, the solvent in step 1) is a polar aprotic solvent. In another embodiment, the solvent in step 1) is selected from THF, DMF, and DMSO. In a further embodiment, the solvent in step 1) is THF.

[0186] In one embodiment of this aspect, the base in step 2) is an alkoxide base. In another embodiment, the base in step 2) is selected from methoxide and tert-butoxide. In a further embodiment, the base in step 2) is potassium tert-butoxide.

[0187] In one embodiment of this aspect, the solvent in step 2) is a polar aprotic solvent. In another embodiment, the solvent in step 2) is selected from THF, DMF, and DMSO. In a further embodiment, the solvent in step 2) is DMSO.

[0188] In another embodiment, the compound of Formula XVI is hydrolyzed using aqueous hydroxide. In a further embodiment, the hydrolysis in step 3) is carried out in a solvent that is a mixture of DMSO and water. In yet a further embodiment, the hydrolysis in step 3) is carried out in a solvent that is a mixture of about 10% to about 20% DMSO.

[0189] In another aspect, the present invention also provides [ka] In a further aspect, the present invention provides a compound selected from the compound [ka] Includes:

[0190] In one embodiment, the compound is selected from the compounds listed in Table 1 below, or a pharmaceutically acceptable salt thereof. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10] [Table 11] [Table 12]

[0191] In one aspect, the present invention includes a pharmaceutical composition comprising a compound described herein, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0192] In another aspect, the invention includes a method of inhibiting the sPLA2-X enzyme, the method comprising contacting the enzyme with a compound described herein or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described herein.

[0193] In one embodiment of this aspect, the compound or a pharmaceutically acceptable salt thereof is a selective inhibitor of sPLA2-X over other sPLA2 enzymes.

[0194] In one embodiment, the 50% inhibition (IC) of the compound or a pharmaceutically acceptable salt thereof is 50 ) are at least 5-fold higher for other sPLA2 enzymes compared to sPLA2-X enzymes.

[0195] In another embodiment, the 50% inhibition (IC) of the compound or a pharmaceutically acceptable salt thereof is 50 ) are at least 10-fold higher for other sPLA2 enzymes compared to sPLA2-X enzymes.

[0196] In another embodiment, the 50% inhibition (IC) of the compound or a pharmaceutically acceptable salt thereof is 50 ) are at least 20-fold higher for other sPLA2 enzymes compared to sPLA2-X enzymes.

[0197] In another embodiment, the 50% inhibition (IC) of the compound or a pharmaceutically acceptable salt thereof is 50 ) are at least 50-fold higher for other sPLA2 enzymes compared to sPLA2-X enzymes.

[0198] In another embodiment, the 50% inhibition (IC) of the compound or a pharmaceutically acceptable salt thereof is 50 ) are at least 100-fold higher for other sPLA2 enzymes compared to sPLA2-X enzymes.

[0199] In another embodiment, the 50% inhibition (IC) of the compound or a pharmaceutically acceptable salt thereof is 50 ) is at least 500-fold higher for other sPLA2 enzymes compared to sPLA2-X enzymes.

[0200] In another embodiment, the 50% inhibition (IC) of the compound or a pharmaceutically acceptable salt thereof is 50 ) are at least 1000-fold higher for other sPLA2 enzymes compared to sPLA2-X enzymes.

[0201] In one embodiment, the other sPLA2 enzyme is selected from sPLA2-IIE, sPLA2-IIA, and sPLA2-V enzymes.

[0202] In one embodiment, the other sPLA2 enzyme is selected from sPLA2-IIA and sPLA2-V enzymes.

[0203] In another aspect, the invention includes a method of treating or lessening the severity of a disease mediated by the sPLA2-X enzyme in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound or pharmaceutically acceptable salt described herein, or a pharmaceutical composition described herein.

[0204] In one embodiment of this aspect, the disease is selected from cancer, atherosclerosis, or cardiovascular disease.

[0205] In another embodiment, the cancer is selected from multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), B-cell lymphoma, or non-small cell lung cancer.

[0206] In a further embodiment, the multiple myeloma (MM) and / or diffuse large B-cell lymphoma (DLBCL) is relapsed, refractory, or relapsing DLBCL and / or MM.

[0207] In another embodiment, the cancer is selected from B-cell lymphoma or non-small cell lung cancer.

[0208] Pharmaceutical Compositions The compounds described herein can be formulated into pharmaceutical compositions further comprising a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. In one embodiment, the present invention provides a pharmaceutical composition comprising the compound of the present invention described above and a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. In one embodiment, the present invention is a pharmaceutical composition comprising an effective amount of a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, diluent, adjuvant, or vehicle. Pharmaceutically acceptable carriers include, for example, pharmaceutical diluents, excipients, or carriers that are suitably selected for the intended form of administration and consistent with conventional pharmaceutical practice.

[0209] According to another embodiment, the present invention provides a composition comprising a compound of the present invention or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, adjuvant, or vehicle. The pharmaceutical composition of the present invention comprises a therapeutically effective amount of a compound of Formula I, where a "therapeutically effective amount" is an amount that is effective (a) to inhibit one or more secreted PLA2 enzyme subtypes, e.g., subtype-X, in a biological sample or in a patient, or (b) to treat and / or ameliorate a disease or disorder mediated by one or more secreted PLA2 enzyme subtypes, e.g., subtype-X.

[0210] The terms "patient" or "subject", used interchangeably herein, mean an animal, preferably a mammal, and most preferably a human.

[0211] It will also be understood that certain compounds of the present invention may be present for therapy in free form or, where appropriate, as a pharmaceutically acceptable derivative thereof (e.g., salt). In accordance with the present invention, a pharmaceutically acceptable derivative includes, but is not limited to, a pharmaceutically acceptable prodrug, salt, ester, salt of such an ester, or any other adduct or derivative that is capable of providing, directly or indirectly, a compound not described herein, or a metabolite or residue thereof, upon administration to a patient in need thereof.

[0212] As used herein, the term "pharmaceutically acceptable salt" refers to salts that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response, and the like.

[0213] Pharmaceutically acceptable salts are well known in the art.For example, S.M. Berge et al. describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, which is incorporated herein by reference.Pharmaceutically acceptable salts of the compounds of the present invention include those derived from suitable inorganic and organic acids and bases.Examples of pharmaceutically acceptable non-toxic acid addition salts include the salts of amino groups formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid, or organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid, or by using other methods used in the art, such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxyethanesulfonate, and lactobionate. Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium, and N-methyl-N ... + (C 1-4Examples of suitable pharmaceutically acceptable salts include ammonium, ammonium, ammonium phosphate ...

[0214] Pharmaceutically acceptable carrier can contain inactive ingredients that do not excessively inhibit the biological activity of compound.Pharmaceutically acceptable carrier must be biocompatible, for example, non-toxic, non-inflammatory, non-immunogenic, or lack other undesirable reactions or side effects when administered to subject.Standard pharmaceutical formulation techniques can be used.

[0215] Pharmaceutically acceptable carriers, adjuvants, or vehicles, as used herein, include any and all solvents, diluents, or other liquid vehicles, dispersing or suspending aids, surface active agents, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants, and the like, as appropriate for the particular dosage form desired. Remington's Pharmaceutical Sciences, Sixteenth Edition, E.W. Martin (Mack Publishing Co., Easton, Pa., 1980) discloses various carriers used in formulating pharmaceutically acceptable compositions and known techniques for their preparation. The use of any conventional carrier medium is contemplated within the scope of the present invention, except that such conventional carrier medium is incompatible with the compounds described herein, for example, by producing any undesired biological effects or otherwise interacting in a deleterious manner with any other component of the pharmaceutically acceptable composition. As used herein, the phrase "side effects" encompasses undesired and adverse effects of a therapy (e.g., a prophylactic or therapeutic agent). While side effects are always unwanted, unwanted effects are not necessarily harmful. Adverse effects from a therapy (e.g., a prophylactic or therapeutic agent) can be harmful, uncomfortable, or dangerous. Side effects include, but are not limited to, fever, chills, lethargy, gastrointestinal toxicity (including gastric and intestinal ulcers and erosions), nausea, vomiting, neurotoxicity, nephrotoxicity, renal toxicity (including conditions such as papillary necrosis and chronic interstitial nephritis), hepatotoxicity (including elevated serum liver enzyme levels), bone marrow toxicity (including leukopenia, bone marrow suppression, thrombocytopenia, and anemia), dry mouth, metallic taste, prolonged pregnancy, weakness, lethargy, pain (including muscle pain, bone pain, and headache), hair loss, asthenia, dizziness, extrapyramidal symptoms, inability to sit, cardiovascular problems, and sexual dysfunction.

[0216] Some examples of materials that can function as pharmaceutically acceptable carriers include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins (such as human serum albumin), buffer substances (such as twin80, phosphates, glycine, sorbic acid, or potassium sorbate), partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes (such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, sodium chloride, or zinc salts), colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, methylcellulose, hydroxypropylmethylcellulose, wool fat, sugars such as lactose, glucose, and sucrose; corn starch and potato starch. Starch such as cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; powdered tragacanth; malt; gelatin, talc; excipients such as cocoa butter and suppository wax; oils such as peanut oil, cottonseed oil; safflower oil, sesame oil, olive oil, corn oil, and soybean oil; glycols; propylene glycol or polyethylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffers such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol and phosphate buffer, and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweeteners, flavoring agents, and perfumes. Preservatives and antioxidants can also be present in the composition according to the judgment of the formulator.

[0217] The compositions of the present invention can be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally, or via an implanted reservoir. As used herein, the term "parenteral" includes subcutaneous, intravenous, intramuscular, intra-articular, intrasynovial, intrasternal, intrathecal, intraocular, intrahepatic, intralesional, and intracranial injection or infusion techniques. Preferably, the compositions are administered orally, intraperitoneally, or intravenously. Sterile injectable forms of the compositions of the present invention can be aqueous or oily suspensions. These suspensions can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be an injectable sterile solution, suspension, or emulsion in a non-toxic parenterally acceptable diluent or solvent, for example, as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be used are water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0218] For this purpose, any bland, fixed oil can be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful for preparing injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, especially their polyoxyethylated versions. These oil solutions or suspensions can also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween, Span, and other emulsifiers or bioavailability enhancers, commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms, can also be used for formulation purposes.

[0219] The pharmaceutically acceptable composition of the present invention can be orally administered in any orally acceptable dosage form, including but not limited to capsules, tablets, aqueous suspensions or solutions.For tablets for oral use, commonly used carriers include lactose and corn starch.Lubricants such as magnesium stearate are also typically added.For oral administration in capsule form, useful diluents include lactose and dry corn starch.When aqueous suspension is required for oral use, active ingredient is combined with emulsifying and suspending agent.If desired, certain sweeteners, flavors or coloring agents can also be added.

[0220] Alternatively, the pharmaceutically acceptable composition of the present invention can be administered in the form of suppositories for rectal or vaginal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature, thereby melting in the rectum or vaginal cavity to release the drug. Such materials include cocoa butter, polyethylene glycol, or suppository wax, which are solid at ambient temperature but liquid at body temperature, thereby melting in the rectum or vaginal cavity to release the active compound.

[0221] The pharmaceutically acceptable compositions of this invention may also be administered topically, particularly when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs.

[0222] Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation. Topical-transdermal patches may also be used.

[0223] For topical application, pharmaceutically acceptable compositions can be formulated into a suitable ointment containing the active ingredient suspended or dissolved in one or more carriers.Carriers for topical administration of the compounds of the present invention include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compounds, emulsifying wax, and water.Alternatively, pharmaceutically acceptable compositions can be formulated into a suitable lotion or cream containing the active ingredient suspended or dissolved in one or more pharmaceutically acceptable carriers.Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl ester wax, cetearyl alcohol, 2-octyldodecanol, benzyl alcohol, and water.

[0224] For ophthalmic use, the pharmaceutically acceptable composition may be formulated, for example, as a micronized suspension in isotonic, pH-adjusted, sterile saline or other aqueous solution, or preferably as a solution in isotonic, pH-adjusted, sterile saline or other aqueous solution, with or without a preservative such as benzylalkonium chloride. Alternatively, for ophthalmic use, the pharmaceutically acceptable composition may be formulated into an ointment such as petrolatum. The pharmaceutically acceptable composition of the present invention may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well known in the art of pharmaceutical formulation and may be prepared as a solution in saline, using benzyl alcohol or other suitable preservatives, absorption enhancers to enhance bioavailability, fluorocarbons, and / or other conventional solubilizers or dispersants.

[0225] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups, and elixirs.In addition to the active compound, liquid dosage forms can contain inert diluents commonly used in the art, such as water or other solvents, solubilizers and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethylformamide, oils (especially cottonseed oil, peanut oil, corn oil, germ oil, olive oil, castor oil, and sesame oil), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycol, and fatty acid esters of sorbitan, and mixtures thereof.In addition to inert diluents, oral compositions can also contain adjuvants such as wetting agents, emulsifiers, and suspending agents, sweeteners, flavoring agents, and flavoring agents.

[0226] Injectable preparations, for example, sterile injectable aqueous or oily suspensions, can be formulated according to known techniques using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be injectable sterile solutions, suspensions, or emulsions in non-toxic parenterally acceptable diluents or solvents, for example, as solutions in 1,3-butanediol. Among the acceptable vehicles and solvents that can be used are water, Ringer's solution, USP, and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as solvents or suspending media. For this purpose, any non-irritating fixed oil, including synthetic mono- or diglycerides, can be used. In addition, fatty acids such as oleic acid can be used in the preparation of injectables.

[0227] Injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other injectable sterile medium before use.

[0228] In order to prolong the effect of a compound of the present invention, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This can be accomplished by using a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends on its dissolution rate, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form can be achieved by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. The release rate of the compound can be controlled depending on the ratio of compound to polymer and the nature of the particular polymer used. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Injectable depot formulations can also be prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0229] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate, and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retardants such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) humectants such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0230] Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar and high molecular weight polyethylene glycols. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical formulation art. Solid dosage forms can optionally contain opacifying agents. These solid dosage forms can also be of a composition that releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type can also be used as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar and high molecular weight polyethylene glycols.

[0231] The active compound can also be in microencapsulated form with one or more excipients as described above. Solid dosage forms such as tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells, such as enteric coatings, controlled-release coatings, and other coatings well known in the pharmaceutical formulation art. In such solid dosage forms, the active compound can be mixed with at least one inert diluent, such as sucrose, lactose, or starch. Such dosage forms can also contain, as is common practice, additional substances other than inert diluents, such as tableting lubricants and other tableting aids, such as magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets, and pills, the dosage forms can also contain buffering agents. They can optionally contain opacifying agents and can be of a composition that releases the active ingredient only, or preferentially, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0232] Dosage forms for topical or transdermal administration of the compounds of the present invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, or patches. The active ingredient is mixed under sterile conditions with a pharmaceutically acceptable carrier and any necessary preservatives or buffers that may be required. Ophthalmic formulations, ear drops, and eye drops are also contemplated within the scope of the present invention. In addition, the present invention contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of the compound to the body. Such dosage forms can be prepared by dissolving or dispensing the compound in a suitable medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by providing a rate-controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0233] The compound of the present invention is preferably formulated into a unit dosage form for ease of administration and uniformity of dosage.As used herein, the phrase "unit dosage form" refers to a physically discrete unit of drug that is appropriate for the patient to be treated.However, it will be understood that the total daily use amount of the compounds and compositions of the present invention will be determined by the attending physician within the scope of sound medical judgment.The specific effective dose level for any specific patient or organism will depend on various factors, including the disorder being treated and the severity of the disorder; the activity of the specific compound used; the specific composition used; the patient's age, weight, general health, sex and diet; the administration time, administration route and excretion rate of the specific compound used; the duration of treatment; drugs used in combination or simultaneously with the specific compound used, and other factors well known in the medical field.

[0234] The amount of the compounds of the invention that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration, and other factors. Preferably, the compositions should be formulated so that a dosage of 0.01 to 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0235] Depending on the particular condition, or disease, to be treated or prevented, additional therapeutic agents, which are normally administered to treat or prevent that condition, may also be present in the compositions of this invention. As used herein, additional therapeutic agents that are normally administered to treat or prevent a particular disease or condition are known as "appropriate for the disease, or condition being treated."

[0236] Some embodiments of the present invention provide methods for administering an effective amount of a compound of the present invention, or a pharmaceutically acceptable salt thereof, and at least one additional therapeutic agent (including, but not limited to, chemotherapeutic anti-neoplastic agents, apoptosis inhibitors, antibacterial agents, antiviral agents, antifungal agents, and anti-inflammatory agents) and / or a therapeutic technique (e.g., surgical intervention and / or radiation therapy). In certain embodiments, the additional therapeutic agent is an anti-cancer agent.

[0237] Many suitable anti-cancer agents are contemplated for use in the methods of the present invention. Indeed, the present invention contemplates the administration of many anti-cancer agents, including, but not limited to, agents that induce apoptosis, polynucleotides (e.g., antisense agents, ribozymes, siRNAs), polypeptides (e.g., enzymes and antibodies), biomimetics, alkaloids, alkylating agents, antitumor antibiotics, antimetabolites, hormones, platinum compounds, monoclonal or polyclonal antibodies (e.g., antibodies conjugated to anti-cancer agents, toxins, defensins), toxins, radionuclides, biological response modifiers (e.g., interferons (e.g., IFN-α) and interleukins (e.g., IL-2)), adoptive immunotherapy agents, hematopoietic growth factors, tumor differentiation inducers (e.g., all-trans-retinoic acid), gene therapy reagents (e.g., antisense therapy reagents and nucleotides), tumor vaccines, angiogenesis inhibitors, proteosome inhibitors, NF-KB inhibitors, anti-CDK compounds, HDAC inhibitors, and the like. Many other examples of chemotherapeutic compounds and anti-cancer therapies suitable for co-administration with the disclosed compounds will be known to those of skill in the art.

[0238] In certain embodiments, the anti-cancer agent comprises an agent that induces or stimulates apoptosis. Agents that induce apoptosis include, but are not limited to, radiation (e.g., X-rays, gamma rays, ultraviolet light), tumor necrosis factor (TNF)-related factors (e.g., antibodies against TNF family receptor proteins, TNF family ligands, TRAIL, TRAIL-R1, or TRAIL-R2), kinase inhibitors (e.g., epidermal growth factor receptor (EGFR) kinase inhibitors, vascular growth factor receptor (VGFR) kinase inhibitors, fibroblast growth factor receptor (FGFR) kinase inhibitors, platelet-derived growth factor receptor (PDGFR) kinase inhibitors, and the like). and Bcr-Abl kinase inhibitors (e.g., Gleevec), antisense molecules, antibodies (e.g., Herceptin, Rituxan, Zevalin, and Avastin), antiestrogens (e.g., raloxene and tamoxifen), antiandrogens (e.g., flutamide, bicalutamide, finasteride, aminoglutethamide, ketoconazole, and corticosteroids), cyclooxygenase 2 (COX-2) inhibitors (e.g., celecoxib, anti-inflammatory drugs (e.g., butazolidine, Decadron, Deltasone, dexamethasone, dexamethasone intensol, Dexone, Hexadrol, hydroxychloroquine, methycorten, oradexon, orasone, oxyphenbutazone, pediaprex, phenylbutazone, phenylbutazone, phen ... antihistamines, anti-cancer drugs (e.g., irinotecan (CAMPTOSAR), CPT-11, fludarabine (FLUDARA), dacarbazine (DTIC), dexamethasone, mitoxantrone, MYLOTARG, VP-16, cisplatin, carboplatin, oxaliplatin, 5-FU, doxorubicin, gemcitabine, bortezomib,These include gefitinib, bevacizumab, taxotere, or taxol, cell signaling molecules, ceramides and cytokines, staurosporine, and the like.

[0239] In yet other embodiments, the compositions and methods of the present invention provide a compound of the present invention and at least one anti-hyperproliferative or anti-neoplastic agent selected from alkylating agents, antimetabolites, and natural products (e.g., herbs and other plant and / or animal derived compounds).

[0240] Alkylating agents suitable for use in the present compositions and methods include, but are not limited to, 1) nitrogen mustards (e.g., mechlorethamine, cyclophosphamide, ifosfamide, melphalan (L-sarcolysin), and chlorambucil), 2) ethyleneimines and methylmelamines (e.g., hexamethylmelamine and thiotepa), 3) alkylsulfonates (e.g., busulfan), 4) nitrosoureas (e.g., carmustine (BCNU), lomustine (CCNU); semustine (methyl-CCNU), and streptozotocin (streptozotocin)), and 5) triazenes (e.g., dacarbazine (DTIC, dimethyltriazenoimide-azolecarboxamide)).

[0241] In some embodiments, antimetabolites suitable for use in the compositions and methods of the present invention include, but are not limited to, 1) folic acid analogs (e.g., methotrexate (amethopterin)), 2) pyrimidine analogs (e.g., fluorouracil (5-fluorouracil, 5-FU), floxuridine (fluorodeoxyuridine, FudR), and cytarabine (cytosine arabinoside)), and 3) purine analogs (e.g., mercaptopurine (6-mercaptopurine, 6-MP), thioguanine (6-thioguanine, TG), and pentostatin (2'-deoxycoformycin)).

[0242] In still further embodiments, chemotherapeutic agents suitable for use in the compositions and methods of the present invention include: 1) vinca alkaloids (e.g., vinblastine (VLB), vincristine), 2) epipodophyllotoxins (e.g., etoposide and teniposide), 3) antibiotics (e.g., dactinomycin (actinomycin D), daunorubicin (daunomycin, rubidomycin), doxorubicin, bleomycin, plicamycin (mithramycin), and mitomycin (mitomycin C)), 4) enzymes (e.g., L-asparaginase), 5) biological response modifiers (e.g., interferon alpha), 6) platinum coordination complexes (e.g., cisplatin (cis-DDP) and carboplatin), 7) anthracenediones (e.g., mitoxantrone), 8) substituted ureas (e.g., hydroxyurea ), 9) methylhydrazine derivatives (e.g., procarbazine (N-methylhydrazine, MIH), 10) adrenocortical suppressants (e.g., mitotane ((o,p'-DDD) and aminoglutethimide), 11) corticosteroids (e.g., prednisone), 12) progestins (e.g., hydroxyprogesterone caproate, medroxyprogesterone acetate, and megestrol acetate), 13) estrogens (e.g., diethylstilbestrol and ethinyl estradiol), 14) antiestrogens (e.g., tamoxifen), 15) androgens (e.g., testosterone propionate and fluoxymesterone), 16) antiandrogens (e.g., flutamide), and 17) gonadotropin-releasing hormone analogs (e.g., leuprolide).

[0243] Any oncolytic agent routinely used in the context of cancer therapy finds use in the compositions and methods of the present invention. For example, the U.S. Food and Drug Administration maintains a formulary of oncolytic agents approved for use in the United States. The USFDA's international counterparts maintain similar formularies. Table 1 provides a list of exemplary antineoplastic agents approved for use in the United States. Those skilled in the art will understand that the required "product labeling" for all chemotherapeutic agents approved in the United States describes the approved indications, administration information, toxicity data, etc. for exemplary agents.

[0244] For example, chemotherapeutic agents or other antiproliferative agents can be combined with the compounds of the present invention to treat proliferative diseases and cancer. Examples of known chemotherapeutic agents include PI3K inhibitors (e.g., idelalisib and copanlisib), BCL-2 inhibitors (e.g., venetoclax), BTK inhibitors (e.g., ibrutinib and acalabrutinib), etoposide, CD20 antibodies (e.g., rituximab, ocrelizumab, obinutuzumab, ofatumumab, ibritumomab tiusetan, tositumomab, and ublituximab), aretuzumab, bendamustine, cladribine, doxorubicin, chlorambucil, prednisone, midostaurin, These include, but are not limited to, lenalidomide, pomalidomide, checkpoint inhibitors (e.g., ipilimumab, nivolumab, pembolizumab, atezolizumab, avelumab, durvalumab), engineered cell therapy (e.g., CAR-T therapy - Kymriah®, Yescarta®), Gleevec™, adriamycin, dexamethasone, vincristine, cyclophosphamide, fluorouracil, topotecan, taxol, interferon, and platinum derivatives.

[0245] Additionally, in some cases, radiation therapy is administered during the course of treatment in which a compound of the present invention (or a pharmaceutically acceptable salt thereof) is administered to a patient in need thereof.

[0246] Anti-cancer agents further include compounds that have been identified to have anti-cancer activity, including, but not limited to, 3-AP, 12-O-tetradecanoylphorbol-13-acetate, 17AAG, 852A, ABI-007, ABR-217620, ABT-751, ADI-PEG20, AE-941, AG-013736, AGRO100, alanosine, AMG706, antibody G250, antineoplaston, and AP2357. 3, apaziquone, APC8015, atiprimod, ATN-161, atrasenten, azacitidine, BB-10901, BCX-1777, bevacizumab, BG00001, bicalutamide, BMS247550, bortezomib, bryostatin-1, buserelin, calcitriol, CCI-779, CDB-2914, cefixime, cetaxel Cimab, CG0070, cilengitide, clofarabine, combretastatin A4 phosphate, CP-675,206, CP-724,714, CpG7909, curcumin, decitabine, DENSPM, doxercalciferol, E7070, E7389, ecteinascidin 743, efaproxiral, eflornithine, EKB-569, enzastaurin, erlotinib, exisulind, fenretinide, flavopiridol, fludarabine, flutamide, fotemustine, FR901228, G17DT, galiximab, gefitinib, genistein, glufosfamide, GTI-2040, histrelin, HKI-272, homoharringtonine, HSPPC-96, hu14.18-Interleukin-2 fusion protein, HuMax-CD4, iloprost, imiquimod, infliximab, interleukin-12, IPI-504, irofulven, ixabepilone, lapatinib, lenalidomide, lestaurtinib, leuprolide, LMB-9 immunotoxin, lonafarnib, luniliximab, mafosfamide, MB07133, MDX-010, MLN2704, monoclonal antibody 3F8, monoclonal antibody J591, motexafin, MS-275, MVA-MUC1-IL2, nilutamide, nitrocamptothecin, nolatrexed dihydrochloride, nolvadex, NS-9, O6-benzylguanine, oblimersen sodium, ONYX-015, oregovomab, OSI-774, panitumumab, paraplatin, PD-0325901, pemetrexed, PHY906, pioglitazone, pirfenidone, pixantrone, PS-341, PSC8 33, PXD101, pyrazoloacridine, R115777, RAD001, ranpirnase, rebeccamycin analog, rhu angiostatin protein, rhuMab2C4, rosiglitazone, rubitecan, S-1, S-8184, satraplatin, SB-, 15992, SGN-0010, SGN-40, sorafenib, SR31747A, ST1571, SU011248, suberoylanilide hydroxamic acid, suramin, talabos These include tat, talampanel, tariquidar, temsirolimus, TGFα-PE38 immunotoxin, thalidomide, thymalfasin, tipifarnib, tirapazamine, TLK286, trabectedin, trimetrexate glucuronate, TroVax, UCN-1, valproic acid, vinflunine, VNP40101M, volociximab, vorinostat, VX-680, ZD1839, ZD6474, zileuton, and zosuquidar trihydrochloride.

[0247] For a more detailed description of anti-cancer and other therapeutic agents, those skilled in the art can refer to any number of instruction manuals, including, but not limited to, the Physician's Desk Reference and Goodman and Gilman's "Pharmaceutical Basis of Therapeutics," 10th Edition, Eds. Hardman et al., 2002.

[0248] The amount of additional therapeutic agent present in the compositions of the invention will not exceed the amount that would normally be administered in a composition comprising that therapeutic agent as the only active agent. Preferably, the amount of additional therapeutic agent in the compositions of the present disclosure will range from about 50% to 100% of the amount that would normally be present in a composition comprising that agent as the only therapeutically active agent.

[0249] Treatment methods

[0250] The compounds of the present invention are inhibitors (eg, inhibitors) of the activity or function of secretory phospholipase A2-X (sPLA2-X) enzymes.

[0251] Accordingly, the present invention contemplates exposing a patient (e.g., a human) suffering from a condition characterized by aberrant sPLA2-X protein activity (e.g., cancer (e.g., B-cell lymphoma and non-small cell lung cancer) and atherosclerosis) to a therapeutically effective amount of an sPLA2-X inhibitor (e.g., inhibitor) of the present invention. Accordingly, the present invention contemplates exposing a patient (e.g., a human) suffering from a condition characterized by aberrant sPLA2-X protein activity (e.g., cancer (e.g., B-cell lymphoma and non-small cell lung cancer) and atherosclerosis) and in need of an sPLA2-X inhibitor to a therapeutically effective amount of an sPLA2-X inhibitor or combination of sPLA2-X inhibitors (e.g., inhibitors) of the present invention, wherein the sPLA2-X inhibitor is selected from the group consisting of Formulas I, II, IIIa, IIIb, IIIc, IIId, IIIe, IIIf-1, IIIf-2, IIIf-3, IIIf-4, IIIf-5, IIIf-6, IIIf-7, IIIf-8, IIIf-9, IIIf-10, IIIf-11, IIIf-12, IIIf-13, IIIf-14, IIIf-15, IIIf-16, IIIf-17, IIIf-18, IIIf-19, IIIf-20, IIIf-21, IIIf-22, IIIf-23, IIIf-24, IIIf-25, IIIf-26, IIIf-27, IIIf-28, IIIf-29, IIIf-30, IIIf-31, IIIf-32, IIIf-33, IIIf-34, IIIf-35, IIIf-36, IIIf-37, IIIf-38, IIIf-39, IIIf-40, IIIf-41, IIIf-42, The compound can be any of compounds selected from the group consisting of IIIf-7, IV, Iva, IVb, IVc, V, Va, Vb, and Vc, and / or those specifically listed in Table 1, or a pharmaceutically acceptable salt thereof, which are capable of inhibiting sPLA2-X protein activity in a therapeutically effective amount useful for treating diseases and / or disorders associated with abnormal sPLA2-X protein activity, such as cancer (e.g., B-cell lymphoma and non-small cell lung cancer) and atherosclerosis, among others exemplified below. The present invention contemplates that inhibitors of sPLA2-X, when administered as monotherapy or in a temporal relationship with additional agents, such as other cell death-inducing or cell cycle-disrupting therapeutic agents (e.g., cancer therapeutic agents or radiation therapy), will result in a greater proportion of cells (e.g., cancer cells) or supporting cells susceptible to execution of the apoptotic program compared to the corresponding proportion of cells in patients treated with the therapeutic agent or radiation therapy alone.

[0252] In some embodiments, the present disclosure provides a method for treating or reducing the severity of a disease mediated by sPLA2-X enzyme in a subject, the method comprising administering to the subject a therapeutically effective amount of a compound according to any one of Formulas IV, IVa, IVb, IVc, V, Va, Vb, or Vc, or a pharmaceutically acceptable salt thereof. As described herein, exemplary diseases mediated by or associated with abnormal sPLA2-X enzyme activity include, but are not limited to, cancer, atherosclerosis, and cardiovascular disease. In certain embodiments, the cancer comprises one or more of multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), B-cell lymphoma, or non-small cell lung cancer. In some exemplary embodiments, the multiple myeloma (MM) and / or diffuse large B-cell lymphoma (DLBCL) is relapsed, refractory, or relapsing DLBCL and / or MM. In further therapeutic methods contemplated herein, the sPLA2-X inhibitors (e.g., inhibitors) of the present invention can be used to treat cancer, which may include B-cell lymphoma or non-small cell lung cancer, in addition to other cancers exemplified herein.

[0253] In certain embodiments of the present invention, in which the condition being treated is cancer and is characterized by the presence of pathophysiological sPLA2-X protein activity, combination treatment of patients with therapeutically effective amounts of a compound of the present invention and a course of anticancer drugs results in greater anticancer responses and clinical benefits in such patients compared to those treated with the compound or anticancer drug / radiation alone. Because the doses of all approved anticancer drugs and radiation treatments are known, the present invention contemplates various combinations of the compound with these drugs. The administration of the combination therapy can be performed in any order, provided that the order of administration is contemplated with an appropriate risk / benefit ratio and, optionally, clinically tested in one or more clinical trials.

[0254] The present invention also provides a pharmaceutical composition comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, in a pharmaceutically acceptable carrier.

[0255] The present invention also provides kits comprising a compound of the present invention and instructions for administering the compound to a patient. The kits may optionally include other therapeutic agents, such as anti-cancer agents or apoptosis inhibitors.

[0256] Additionally, the present invention provides methods for inhibiting (e.g., inhibiting) sPLA2-X protein activity in cells by exposing such cells to one or more of the compounds of the present invention or their pharmaceutically acceptable salts thereof.

[0257] In some embodiments, the compositions and methods of the present invention are used to treat diseased cells, tissues, organs, or pathological and / or disease states in a patient (e.g., a mammalian patient, including, but not limited to, humans and veterinary animals). In this regard, a variety of diseases and conditions are amenable to treatment or prevention using the methods and compositions of the present invention. A non-limiting, exemplary list of these diseases and conditions includes colorectal cancer, non-small cell lung carcinoma, head or neck carcinoma, glioblastoma multiforme cancer, pancreatic cancer, breast cancer, prostate cancer, lymphoma, skin cancer, colon cancer, melanoma, malignant melanoma, ovarian cancer, brain cancer, primary brain carcinoma, head and neck cancer, glioma, glioblastoma, liver cancer, bladder cancer, non-small cell lung cancer, breast carcinoma, ovarian carcinoma, lung carcinoma, small cell lung carcinoma, Wilms' tumor, cervical carcinoma, testicular carcinoma, bladder carcinoma, pancreatic carcinoma, stomach carcinoma, colon carcinoma, prostate carcinoma, genitourinary carcinoma, thyroid carcinoma, esophageal carcinoma, myeloma, multiple myeloma, adrenal carcinoma, renal cell carcinoma, endometrial carcinoma, adrenocortical carcinoma, These include, but are not limited to, T-cell and B-cell mediated autoimmune diseases such as malignant pancreatic insulinoma, malignant carcinoid carcinoma, choriocarcinoma, mycosis fungoides, malignant hypercalcemia, cervical hyperplasia, leukemia, acute lymphocytic leukemia, chronic lymphocytic leukemia, acute myeloid leukemia, chronic myeloid leukemia, chronic granulocytic leukemia, acute granulocytic leukemia, hairy cell leukemia, lymphoma, neuroblastoma, rhabdomyosarcoma, Kaposi's sarcoma, polycythemia vera, essential thrombocytosis, Hodgkin's disease, non-Hodgkin's lymphoma, soft tissue sarcoma, osteosarcoma, primary macroglobulinemia, and retinoblastoma; inflammatory diseases; infectious diseases; hyperproliferative diseases; AIDS; degenerative diseases, vascular diseases, etc. In some embodiments, the cancer cells being treated are metastatic. In other embodiments, the cancer cells being treated are resistant to anti-cancer drugs.

[0258] In other embodiments, the disorder is any disorder having cells with aberrant sPLA2-X protein activity (eg, proliferative disorders and cardiovascular disorders).

[0259] The present invention provides a method for administering a compound of the present invention in conjunction with radiation therapy. The present invention is not limited by the type, amount, or delivery and administration system used to deliver a therapeutic dose of radiation to a patient. For example, a patient may receive photon radiation therapy, particle beam radiation therapy, other types of radiation therapy, and combinations thereof. In some embodiments, radiation is delivered to a patient using a linear accelerator. In yet other embodiments, radiation is delivered using a gamma knife.

[0260] The radiation source can be external or internal to the patient. External radiation therapy is the most common and involves directing a beam of high-energy radiation through the skin to the tumor site, for example, using a linear accelerator. While the radiation beam is localized to the tumor site, it is nearly impossible to avoid exposure to normal, healthy tissue. However, external radiation is usually well tolerated by animals. Internal radiation therapy involves placing a radiation-emitting source, such as beads, wires, pellets, capsules, or particles, inside the body at or near the tumor site, including the use of a delivery system that specifically targets cancer cells (e.g., using particles bound to cancer cell-binding ligands). Such placements can be removed after treatment or rendered inactive and left in the body. Types of internal radiation therapy include, but are not limited to, brachytherapy, interstitial radiation, intracavitary radiation, and radioimmunotherapy.

[0261] The patient may optionally receive radiosensitizers (e.g., metronidazole, misonidazole, intra-arterial Budr, intravenous iodooxyuridine (IudR), nitroimidazoles, 5-substituted-4-nitroimidazoles, 2H-isoindoledione, [[(2-bromoethyl)-amino]methyl]-nitro-1H-imidazole-1-ethanol, nitroaniline derivatives, DNA-affinity hypoxia-selective cytotoxins, halogenated DNA ligands, 1,2,4 benzotriazine oxide, 2-nitroimidazole derivatives, fluorine-containing nitroazole derivatives, benzamides, nicotinamide, acridine-intercalators). These drugs may be administered with other drugs, including but not limited to: 5-thiotrazol derivatives, 3-nitro-1,2,4-triazole, 4,5-nitroimidazole derivatives, hydroxylated texel purine, cisplatin, mitomycin, tirapazamine, nitrosoureas, mercaptopurine, methotrexate, fluorouracil, bleomycin, vincristine, carboplatin, epirubicin, doxorubicin, cyclophosphamide, vindesine, etoposide, paclitaxel, fever (hypersemia), etc.; and radioprotectors (e.g., cysteamine, aminoalkyl dihydrogen phosphorothioates, amifostine (WR2721), IL-1, IL-6, etc.). Radiosensitizers enhance tumor cell killing. Radioprotectors protect healthy tissue from the harmful effects of radiation.

[0262] Any type of radiation can be administered to a patient as long as the radiation dose is tolerated by the patient without unacceptable negative side effects. Suitable types of radiation therapy include, for example, ionizing (electromagnetic) radiation therapy (e.g., X-rays or gamma rays) or particle beam radiation therapy (e.g., high linear energy radiation). Ionizing radiation is defined as radiation containing particles or photons with sufficient energy to produce ionization, i.e., the gain or loss of electrons (e.g., as described in US Pat. No. 5,770,581, the entire contents of which are incorporated herein by reference). The effects of radiation can be at least partially controlled by the clinician. In one embodiment, the radiation dose is fractionated to maximize target cell exposure and reduce toxicity.

[0263] In one embodiment, the total dose of radiation administered to a patient is from about 0.01 Gray (Gy) to about 100 Gy. In another embodiment, from about 10 Gy to about 65 Gy (e.g., about 15 Gy, 20 Gy, 25 Gy, 30 Gy, 35 Gy, 40 Gy, 45 Gy, 50 Gy, 55 Gy, or 60 Gy) is administered over the course of treatment. In some embodiments, the complete dose of radiation can be administered over the course of one day, although the total dose is ideally fractionated and administered over several days. Desirably, radiation therapy is administered over the course of at least about 3 days, e.g., at least 5, 7, 10, 14, 17, 21, 25, 28, 32, 35, 38, 42, 46, 52, or 56 days (about 1 to 8 weeks). Thus, a daily dose of radiation would comprise approximately 1-5 Gy (e.g., about 1 Gy, 1.5 Gy, 1.8 Gy, 2 Gy, 2.5 Gy, 2.8 Gy, 3 Gy, 3.2 Gy, 3.5 Gy, 3.8 Gy, 4 Gy, 4.2 Gy, or 4.5 Gy), or 1-2 Gy (e.g., 1.5-2 Gy). The daily radiation dose should be sufficient to induce destruction of the targeted cells. If extended over a period of time, in one embodiment, radiation is not administered every day, thereby allowing the patient to rest and realize the benefits of the therapy. For example, radiation desirably is administered for 5 consecutive days and not administered for 2 days in each week of treatment, thereby allowing for 2 days of rest per week. However, radiation can be administered 1 day / week, 2 days / week, 3 days / week, 4 days / week, 5 days / week, 6 days / week, or all 7 days / week, depending on the patient's response and any potential side effects. Radiation therapy can be initiated at any time during the treatment period. In one embodiment, radiation is initiated during week 1 or week 2 and administered throughout the remainder of the treatment period. For example, radiation is administered during weeks 1-6 or weeks 2-6 of a treatment period that includes 6 weeks, e.g., to treat solid tumors. Alternatively, radiation is administered during weeks 1-5 or weeks 2-5 of a treatment period that includes 5 weeks. However, these exemplary radiation therapy administration schedules are not intended to limit the present invention.

[0264] Antibacterial therapeutic agents can also be used as therapeutic agents in the present invention. Any agent capable of killing, inhibiting, or otherwise attenuating the function of microorganisms, and any agent intended to have such activity, can be used. Antibacterial agents include, but are not limited to, natural and synthetic antibiotics, antibodies, inhibitory proteins (e.g., defensins), antisense nucleic acids, membrane-disrupting agents, and the like, used alone or in combination. In fact, any type of antibiotic can be used, including, but not limited to, antibacterial agents, antiviral agents, antifungal agents, and the like.

[0265] In some embodiments of the present invention, a compound of the present invention and one or more therapeutic or anti-cancer agents are administered to a patient under one or more of the following conditions: different cycles, different durations, different concentrations, and different routes of administration. In some embodiments, the compound is administered before the administration of the therapeutic or anti-cancer agent, for example, 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks before the administration of the therapeutic or anti-cancer agent. In some embodiments, the compound is administered after the therapeutic or anti-cancer agent, for example, 0.5, 1, 2, 3, 4, 5, 10, 12, or 18 hours, 1, 2, 3, 4, 5, or 6 days, or 1, 2, 3, or 4 weeks after the administration of the anti-cancer agent. In some embodiments, the compound and the therapeutic or anti-cancer agent are administered simultaneously but on different schedules, for example, the compound is administered daily while the therapeutic or anti-cancer agent is administered once a week, once every two weeks, once every three weeks, or once every four weeks. In other embodiments, the compound is administered weekly and the therapeutic or anti-cancer agent is administered once a day, once a week, once every two weeks, once every three weeks, or once every four weeks.

[0266] Compositions within the scope of the present invention contain a compound of the present invention or a pharmaceutically acceptable salt thereof in an amount effective to achieve its intended purpose. While individual needs vary, determining the optimal range of effective amounts of each component is within the skill of one of ordinary skill in the art. Typically, the compound may be orally administered to a mammal, e.g., a human, at a dose of 0.0025 to 100 mg / kg, or an equivalent amount of a pharmaceutically acceptable salt thereof, per day of body weight of the mammal being treated for a disorder responsive to the induction of apoptosis. In one embodiment, about 0.01 to about 25 mg / kg is orally administered to treat, ameliorate, or prevent such a disorder. For intramuscular injection, the dose is generally about half the oral dose. For example, a suitable intramuscular dose would be about 0.0025 to about 25 mg / kg, or about 0.01 to about 5 mg / kg.

[0267] A unit oral dose can contain about 0.01 to about 1,000 mg, e.g., about 0.1 to about 100 mg, of the compound. The unit dose can be administered one or more times daily as one or more tablets or capsules, each containing about 0.1 to about 1,000 mg, conveniently about 0.25 to 500 mg, of the compound or solvate thereof. In some embodiments, a unit, daily, or therapeutically effective dose can include doses of about 10 mg to about 1,000 mg, or about 20 mg to about 900 mg, or about 50 mg to about 800 mg, or about 60 mg to about 700 mg, or about 70 mg to about 600 mg, or about 80 mg to about 500 mg, or about 90 mg to about 400 mg, or about 100 mg to about 300 mg. A unit, daily, or therapeutically effective dose can include any integer or numerical range within these stated ranges described herein.

[0268] In topical formulations, the compound may be present at a concentration of about 0.01 to 100 mg per gram of carrier, hi one embodiment, the compound is present at a concentration of about 0.07 to 1.0 mg / ml, e.g., about 0.1 to 0.5 mg / ml, and in one embodiment, about 0.4 mg / ml.

[0269] In addition to administering the compounds as raw chemicals, the compounds of the present invention can be administered as part of a pharmaceutical preparation containing a suitable pharmaceutically acceptable carrier, including excipients and adjuvants that facilitate processing of the compound into a pharmaceutically usable preparation. Preparations, particularly those that can be administered orally or topically and are used as one type of administration, such as tablets, dragees, slow-release lozenges and capsules, mouth rinses and mouth washes, gels, liquid suspensions, hair rinses, hair gels, shampoos, and rectally administrable preparations, such as suppositories, and solutions suitable for administration by intravenous infusion, injection, topical, or oral administration, contain from about 0.01 to 99 percent, and in one embodiment, from about 0.25 to 75 percent, of the active compound together with the excipients.

[0270] The pharmaceutical compositions of the present invention can be administered to any patient who can experience the beneficial effects of the compounds of the present invention. Foremost among such patients are mammals, such as humans, although the present invention is not intended to be so limited. Other patients include veterinary patients (such as cattle, sheep, pigs, horses, dogs, cats, etc.).

[0271] The compounds and pharmaceutical compositions thereof can be administered by any means that achieve their intended purpose. For example, administration can be by parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, intracranial, intranasal, or topical routes. Alternatively, or concurrently, administration can be by oral route. The administered dosage will depend on the age, health, and weight of the recipient, the type of concurrent treatment, if any, the frequency of treatment, and the nature of the desired effect. Dosages can also be informed by clinical trials in which populations of subjects with and without the treatable diseases contemplated herein are administered varying amounts of the compositions of the present invention. The results of these clinical trials can also determine therapeutically effective doses and administration regimens.

[0272] Experimental Section Synthesis of Compounds of the Invention Synthesis method The general procedures used to synthesize the compounds are described in Reaction Schemes 1-X and illustrated in the following examples. The following examples are provided to enable a thorough understanding of the invention and are not intended to limit the scope of the invention, nor are they intended to represent all experiments that may be performed. The synthesized compounds were analyzed and characterized by the use of the following equipment: liquid chromatography-mass spectra (LC / MS) were obtained using an Agilent LC / MSD G1946D or an Agilent 1100 series LC / MSD Trap G1311A or G2435A. Quantitation was obtained using a Cary 50 Bio UV-visible spectrophotometer. 1H, 13C, and 19F nuclear magnetic resonance (NMR) spectra were obtained using a JEOL ECZ400S NMR spectrometer at 400, 100, and 376 MHz, respectively. High-performance liquid chromatography (HPLC) analytical separations were performed on an Agilent 1100 or Agilent 1200 HPLC analytical system, followed by an Agilent Technologies G1315B diode array detector set at or near UVmax@210nm. Preparative HPLC separations were performed on a Gilson preparative HPLC system or an Agilent 1100 preparative HPLC system, followed by an Agilent Technologies G1315B diode array detector set at or near UVmax@210nm. Analytical chiral HPLC separations were performed on an Agilent 1100 analytical system, followed by an Agilent Technologies G1315B diode array detector set at or near UVmax@210nm. Separations were achieved using Gemini 3μ or 5μ C18 50×2.5 mm or 250×4.6 mm solid-phase columns eluted with acetic acid-methanol-water gradients or ammonium acetate-acetonitrile-water gradients. Flash chromatography was performed using a CombiFlash NextGen 300+ using RediSep silica columns. All final compounds were purified by HPLC and 1Satisfactory purity (>95%) was obtained by H NMR spectroscopy. Thin-layer chromatography (TLC) analysis was performed on Uniplate 250μ silica gel plates (Analtech, Inc. catalog number 02521) and typically developed with 50% by volume concentrated sulfuric acid in water spray, iodine stain, or Hanessian stain, with UV / Vis visualization.

[0273] General synthetic scheme [ka] The compounds of the present invention can generally be synthesized according to the general synthetic scheme above, where X1, X2, X3, A, R1, R4, R5, R7, and n are defined herein, and PG is a protecting group. Referring to the scheme, 6-(trifluoromethoxy)-2-carboxyindole can be coupled with a reactant of formula G1 in the presence of an aryl bromide, a copper reagent such as Cu(OAc)2, methyl α-D-glucopyranoside, KI, DBU, and a solvent such as DMSO. The resulting carboxylic acid product of formula G2 can be converted to an amide of formula G3 under peptide coupling conditions such as TBTU, NH4Cl, and DIPEA in a solvent such as DMF. The compound of formula G3 can be converted to a carboxylic acid compound of formula G4 under hydrolysis conditions such as 1 M LiOH in MeOH.

[0274] Synthesis of the trifluoromethoxy core: Example 1: Preparation of tert-butyl 5-(trifluoromethoxy)benzofuran-2-carboxylate [ka] To a mixture of 2-hydroxy-5(trifluoromethoxy)benzaldehyde (1.03 g, 5.00 mmol) in DMSO (8 mL) was added cesium carbonate (5.05 g, 15.5 mmol) at room temperature under N2. The reaction mixture was heated to 100 °C and then treated with tert-butyl bromoacetate (1.02 g, 5.23 mmol) and stirred for 2 h. The reaction mixture was then partitioned between ethyl acetate (40 mL) and water (80 mL), and the phases were separated. The aqueous phase was once again partitioned with ethyl acetate (100 mL), and the phases were separated. The combined organic phases were washed sequentially with potassium carbonate (2 × 25 mL), 50% brine (2 × 25 mL), and brine (25 mL). The organic layer was then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to yield 1.16 g as a crude yellow oil. The product was obtained as 24 g RediSep Gold R f Purification by flash silica column chromatography using a flash silica cartridge on a Cole-Palmer digital gear pump system. The product was eluted after 400 mL of 1% ethyl acetate in heptane to give the title compound as a clear, colorless oil (1.04 g, 68%); 1 H-NMR(400MHz;CDCl3)δ 7.56(d,1H,J=8.9Hz),7.51(d,1H,J=0.9Hz),7.28(dd,1H,J=1.7,9.1Hz),7.25(s,1H),1.6-1.7(s,9H); 19 F-NMR(376MHz;CDCl3)δ-58.1(s,3F);MS(FIA MS-)m / z 245(M-tBu).

[0275] Example 2: Preparation of methyl 5-(trifluoromethoxy)benzo[b]thiophene-2-carboxylate [ka] To a mixture of 2-fluoro-5-(trifluoromethoxy)benzaldehyde (1.04 g, 5.00 mmol) in DMF (50 mL) was added potassium carbonate (1.38 g, 10.00 mmol), followed by methyl thioglycolate (583 mg, 5.49 mmol). The reaction mixture was heated to 60 °C under a N atmosphere and stirred overnight. The reaction mixture was then partitioned between HO (100 mL) and ethyl acetate (500 mL). The aqueous was re-extracted twice with ethyl acetate (200 mL). The combined organic phase was washed with 50% brine (3 × 100 mL) and brine (100 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 1.21 g of a crude yellow solid. The product was purified using a Cole-Palmer digital gear pump system and 24 g RediSep Gold R f Purification was carried out by flash silica column chromatography using a flash silica cartridge. The product was eluted with 20% DCM in heptane to give the title compound as a white crystalline solid (981 mg, 71%); 1 H-NMR(400MHz;CDCl3)δ 8.03(s,1H),7.86(d,1H,J=8.9Hz),7.71(s,1H),7.3-7.4(d,1H),3.95(s,3H); 19 F-NMR(CDCl3,376MHz)δ-57.8(s,3F);MS(FIA MS-)m / z 276.0(M-1);HPLC UV purity R t =9.901min,100%.

[0276] Example 3: Preparation of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 2-bromo-5-(trifluoromethoxy)aniline (63.0 g, 246 mmol) suspended in dimethylacetamide (540 mL) was added 2-oxopropanoic acid (65.0 g, 738 mmol), acetic acid (21.1 mL, 369 mmol), and magnesium sulfate (14.8 g, 123 mmol). Nitrogen was bubbled through the suspension with stirring for 20 minutes, then treated with potassium phosphate (67.9 g, 319.8 mmol), followed by bis(tri-t-butylphospine)palladium(0) (18.9 g, 36.9 mmol). Nitrogen was again bubbled through the solution for 20 minutes, and the reaction mixture was heated at 140 °C for 2 hours. The reaction mixture was cooled and passed through a pad of Celite. The filtrate was basified using 2 N sodium hydroxide (320 mL) and extracted with diethyl ether (2 × 250 mL). The aqueous phase was then acidified with 3N hydrochloric acid (250 mL) and extracted with ethyl acetate (1 × 2 L). The organic phase was washed with 50% brine (4 × 200 mL) and brine (2 × 200 mL), then dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give 74 g of crude material. The crude material was dissolved in a hot solution of dichloromethane (50 mL) and heptane (100 mL). The solution was then cooled to room temperature to precipitate, and the mixture was filtered through a medium frit filter. The filtrate was concentrated, and the precipitation procedure was repeated. To remove residual dimethylacetamide, the solid (51 g) was passed through a 2 kg column of 40-63 μm (230-400 mesh) silica gel. The product was eluted with 20% ethyl acetate in heptane to give the product as a white powder (30 g, 50%). 1 H-NMR(400MHz;CDCl3))δ 9.06(br s,1H),7.71(d,1H,J=8.7Hz),7.3-7.4(m,1H),7.31(s,1H),7.06(br d,1H,J=8.7Hz); 19 F-NMR(CDCl3,376MHz)δ-57.8(s,3F);MS(FIA-MS-)m / z 244.0(M-1).

[0277] Preparation of aryl bromides: Example 4: Preparation of ethyl 3-(3-bromophenyl)-2,2-dimethylpropanoate [ka] To an oven-dried flask containing ethyl isobutyrate (Alfa Aesar, 2.0 mL, 15 mmol) was added anhydrous THF (50 mL). The flask was cooled to -78 °C and placed under a N2 atmosphere. Lithium diisopropylamide solution (Aldrich, 2.0 M THF / heptane / ethylbenzene, 7.5 mL, 15 mmol) was then added portionwise to the cooled solution. After stirring at -78 °C for 30 minutes, 3-bromobenzyl bromide (CombiBlocks, 2.5 g, 10 mmol) was added dropwise as a solution in 3 mL of THF. The resulting mixture was stirred at -78 °C for 1 hour and then allowed to warm to room temperature. After 3 hours, the reaction was complete by TLC (10 / 90 EA / Hep). The crude reaction mixture was quenched by the slow addition of saturated ammonium chloride solution (25 mL). The phases were separated, and the organic phase was partitioned with HO (50 mL), followed by brine (50 mL). The organic layer was concentrated under reduced pressure to give the crude product as an orange oil (3.02 g). The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 120 g RediSep Gold Rf flash silica cartridge with 0-10% ethyl acetate in heptane gave the title compound as a colorless oil (1.70 g, 59% yield); Rf 0.70 (UV 254 nM) with 90:10 v / v heptane-ethyl acetate; 1 H-NMR(400MHz;CDCl3)δ 7.35(d,1H,J=7.5Hz),7.29(t,1H,J=1.6Hz),7.13(t,1H,J=7.7Hz),7.05(d,1H,J=7. 8Hz)4.13(q,2H,J=7.1Hz),2.82(s,2H),1.25(t,3H,J=7.1Hz),1.19(s,6H);MS(APCI +) m / z 285.0, 287.0 (M+1, Br isotope), HPLC UV purity Rt=10.737min, 99.79% purity.

[0278] Example 5: Preparation of methyl (E / Z)-3-(6-bromopyridin-2-yl)but-2-enoate [ka] To an oven-dried reaction flask charged with sodium hydride (Aldrich, 60% dispersion in mineral oil, 2.88 g, 72.0 mmol) was added anhydrous THF (90 mL). The reaction flask was cooled to 0 °C and placed under a N2 atmosphere. Trimethyl phosphonoacetate (CombiBlock, 13.11 g, 72.0 mmol) was then added dropwise as a solution in THF (30 mL). Stirred at 0 °C for 1 h, then 2-acetyl-6-bromopyridine (CombiBlock, 12.0 g, 60.0 mmol) was added dropwise as a solution in THF (25 mL). The mixture was stirred at 0 °C for 1 h and then overnight. The crude reaction mixture was then concentrated under reduced pressure to give a crude pink solid. The crude solid was partitioned between water (200 mL) and EA (250 mL). The organic layer was washed twice with water (200 mL) and then with brine (200 mL). The organic layer was dried over anhydrous MgSO, filtered, and concentrated under reduced pressure to give the title compound as a red oil (15.04 g, 97.9%); Rf 0.51 and 0.44 (E and Z isomers) in 75:25 v / v heptane-ethyl acetate (UV 254 nM); 1 H-NMR(400MHz;CDCl3)δ 7.5-7.6(m,2H),7.4-7.5(m,2H),7.23(d,1H,J=7.2Hz),6.76(d,1H,J=1.4Hz),6 .00(d,1H,J=1.4),3.76(s,2H),3.61(s,3H),2.56(s,2H),2.20(s,3H);MS(APCI + )m / z 256.0,258.0(M+1,Br isotope).

[0279] Example 6: Preparation of ethyl 2-((3-bromophenyl)thio)-2-methylpropanoate [ka] To a mixture of ethyl 2-bromo-2-methylpropanoate (0.516 g, 2.64 mmol) in DMF (10 mL) was added 3-bromobenzenethiol (0.500 g, 2.64 mmol) and cesium carbonate (1.72 g, 5.28 mmol). The reaction mixture was stirred overnight at 55 °C under N2. The reaction was partitioned between a saturated solution of ammonium chloride (200 mL) and ethyl acetate (200 mL). The phases were separated, and the organic phase was again partitioned with water, followed by brine. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude material was purified by flash silica column chromatography on a CombeFlash NextGen 300+ purification system. Elution of a 40 g RediSep Gold Rf flash silica cartridge with 5% ethyl acetate in heptane for 5 column volumes followed by a gradient to 10% ethyl acetate in heptane gave the title compound as a clear, colorless oil (0.621 g, 78%); Rf 0.37 (UV 254 nM and CAM stain) in 95:5 v / v heptane-ethyl acetate; 1 H-NMR(400MHz;CDCl3)δ 7.62(t,1H,J=1.7Hz),7.49(d,1H,J=8.2Hz),7.39(td,1H,J=1.2,7.7Hz),7.19(t ,1H,J=7.8Hz),4.11(q,2H,J=7.3Hz),1.48(s,6H),1.21(t,3H,J=7.1Hz);MS(APCI + )m / z 229.0,231.0(M+1,Br isotope).

[0280] Example 7: Preparation of ethyl 1-((3-bromophenyl)thio)cyclobutane-1-carboxylate [ka] To a mixture of ethyl 1-bromocyclobutane-1-carboxylate (0.547 g, 2.64 mmol) in DMF (10 mL) was added 3-bromobenzenethiol (0.500 g, 2.64 mmol) and cesium carbonate (1.72 g, 5.28 mmol). The reaction mixture was stirred overnight at 55 °C under N2. The reaction was partitioned between a saturated solution of ammonium chloride (200 mL) and ethyl acetate (200 mL). The phases were separated, and the organic phase was again partitioned with water, followed by brine. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude material was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution of a 40 g RediSep Gold Rf flash silica cartridge with 5% ethyl acetate in heptane for 5 column volumes followed by a gradient to 10% ethyl acetate in heptane gave the title compound as a clear, colorless oil (0.646 g, 78%); Rf 0.35 (UV 254 nM and CAM stain) in 95:5 v / v heptane-ethyl acetate; 1 H-NMR(400MHz;CDCl3)δ 7.52(t,1H,J=1.7Hz),7.38(d,1H,J=7.9Hz),7.3-7.3(m,1H),7.14(t,1H,J=8.5Hz),4.14(q,2 H,J=7.1Hz),2.6-2.7(m,2H),2.1-2.3(m,3H),1.8-2.0(m,1H),1.20(t,3H,J=7.1Hz);MS(APCI + )m / z 240.9,242.9(M+1,Br isotope).

[0281] Example 8: Preparation of ethyl 2-((3-bromophenyl)thio)-2,2-difluoroacetate [ka] To a mixture of ethyl 2-bromo-2,2-difluoroacetate (0.547 g, 2.64 mmol) in DMF (10 mL) was added 3-bromobenzenethiol (0.500 g, 2.64 mmol) and cesium carbonate (1.72 g, 5.28 mmol). The reaction mixture was stirred overnight at 55 °C under N2. The reaction was partitioned between a saturated solution of ammonium chloride (200 mL) and ethyl acetate (200 mL). The phases were separated, and the organic phase was again partitioned with water, followed by brine. The organic layer was separated, dried over magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product. The crude material was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution of a 40 g RediSep Gold Rf flash silica cartridge with 5 column volumes of 2% ethyl acetate in heptane followed by a gradient to 10% ethyl acetate in heptane gave the title compound as a clear, colorless oil (0.600 g, 73%); Rf 0.43 (UV 254 nM and CAM stain) in 95:5 v / v heptane-ethyl acetate; 1 H-NMR(400MHz;CDCl3)δ 7.77(t,1H,J=1.7Hz),7.6-7.6(m,1H),7.55(d,1H,J=7.8Hz),7.27(t,1H,J=8.9Hz),4.28(q,2H,J=7.3Hz),1.28(t,3H,J=7.1Hz); 19 F-NMR(376MHz;CDCl3)81.6;MS(APCI + )m / z 309.0,311.0(M-1,Br isotope).

[0282] Preparation of target compounds Example 9: Synthesis of 2-(5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 1) [ka] Step A: Preparation of 1-(3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-5-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (ChemShuttle, 0.400 g, 1.63 mmol), 5-bromo-2,3-dihydrobenzofuran-3-acetate (Accela, 0.442 g, 1.63 mmol), copper(II) acetate (CombiBlocks, 0.295 g, 1.63 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.316 g, 1.63 mmol), and potassium iodide (VWR, 0.541 g, 3.26 mmol) in DMSO (24 mL) was added DBU (Oakwood Chemicals, 0.73 mL, 4.89 mmol). The reaction mixture was stirred overnight at 115 °C under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (75 mL) and 1 M KHSO (50 mL). An emulsion formed and was broken up by the addition of 25 mL of brine. The phases were separated and the organic phase was partitioned with HO (75 mL) followed by brine (75 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 1.002 g of a crude red oil. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 40 g RediSep Gold Rf flash silica cartridge with 10 to 100% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a white solid (0.147 g, 21% yield); elution with 1:30:70 v / v acetic acid-ethyl acetate-hexane gave the title compound as a white solid (0.147 g, 21% yield). f 0.18 (UV254nM); 1H-NMR(400MHz;DMSO-d6)δ 12.7-13.0(bs,1H),7.87(d,1H,J=8.7Hz),7.42(s,1H),7.1-7.2(m,2H),6.90(d,2H,J=8.3Hz),4. 83(t,1H,J=9.2Hz),4.3-4.4(m,1H),3.8-4.0(m,1H),3.60(s,3H),2.9-3.0(m,2H)2.5-2.6(m,1H); 19 F-NMR (376MHz; DMSO-d6) δ-56.66; MS (APCI-) m / z 434 (M-1); HPLC UV purity Rt=9.275min, 97.93%.

[0283] Step B: Preparation of methyl 2-(5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)-2,3-dihydrobenzofuran-3-yl)acetate [ka] To a mixture of 1-(3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-5-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.30 g, 0.69 mmol) in DMF (1 mL) was added ammonium chloride (Chem-Impex, 0.11 g, 0.21 mmol). TBTU (Oakwood, 0.033 g, 0.104 mmol) was then added, followed by DIPEA (0.1 mL, 0.621 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (30 mL) and HO (30 mL). The phases were separated, and the organic phase was partitioned with 1 M KHSO (30 mL) followed by brine (30 mL). The organic layer was concentrated under reduced pressure to give the crude product as a colorless oil (0.026 g, 88%). The crude oil was carried forward without further purification. f 0.10 (UV 254 nM); MS (APCI + )m / z 435.0(M+1);HPLC UV purity Rt=8.452min,94.83%.

[0284] Step C: Preparation of 2-(5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 1) [ka] To a mixture of methyl 2-(5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)-2,3-dihydrobenzofuran-3-yl)acetate (0.026 mg, 0.06 mmol) in methanol (1.5 mL) was added 1 M lithium hydroxide (0.239 mL, 0.239 mmol). The reaction mixture was stirred at room temperature under a N atmosphere for 1.5 hours. The reaction mixture was then partitioned between ethyl acetate (10 mL) and 1 M HCl (10 mL). The phases were separated and the organic phase was partitioned with HO (5 mL) followed by brine (5 mL). The organic layer was concentrated under reduced pressure to give the crude product as a pink solid (0.025 g, 100%). The R was extracted with 1:80:20 v / v acetic acid-ethyl acetate-hexane. f 0.48(UV254nM; 1 H-NMR(400MHz;CDCl3)δ 12.34(br s,1H),7.91(br s,1H),7.78(d,1H,J=8.7Hz),7.32(br s,1H),7.10(br d,1H,J=9.6Hz),7.01(dd,1H,J=2.1,8.3Hz),6.88(s,1H).6.83(d,1H,J=8.5 Hz),3.7-3.9(m,1H),2.81(dd,1H,J=5.2,16.8Hz),2.5-2.7(m,1H);MS(APCI + ) m / z 421(M+1).HPLC UV purity, Rt=7.334min, 94.3%; melting point=222~223℃.

[0285] Example 10: Separation, Hydrolysis, and Isolation of (+) and (−) 2-(5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)-2,3-dihydrobenzofuran-3-yl)acetic Acid (Compounds 1a and 1b) [ka] Step A: Chiral separation of methyl 2-(5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)-2,3-dihydrobenzofuran-3-yl)acetate The enantiomers of methyl 2-(5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)-2,3-dihydrobenzofuran-3-yl)acetate (0.147 g) were separated by chiral HPLC on a Chiralpak IA column (250 mm × 20 mm, 5 μm particles) with UV detection at 292 nm using 90:10:0.1 heptane:IPA:TEA at a flow rate of 20 mL / min. Peak 1 eluted at 20.02 min, and peak 2 eluted at 25.04 min. Enantiomer 1 (peak 1) was concentrated under reduced pressure to give a white solid (56.1 mg, 38% recovery); R was purified with 1:30:70 v / v acetic acid-ethyl acetate-hexane. f 0.14 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 7.91(br s,1H),7.78(d,1H,J=8.7Hz),7.33(br s,1H),7.19(d,1H,J=1.4Hz),7.10(br d,1H,J=8.7Hz),7.01(dd,1H,J=2.1,8.3Hz),6.8-6.9(m,2H),4.77(t,1H,J=9.2Hz),4.30(dd,1H,J=7.1,8 .9Hz),3.8-3.9(m,1H),3.56(s,3H),3.04(q,1H,J=7.1Hz),2.87(dd,1H,J=5.5,16.7Hz),2.5-2.6(m,1H); 19 F-NMR (376 MHz; DMSO-d6) δ -56.71; MS (APCI+) m / z 435 (M+1); HPLC UV purity Rt = 8.497 min, 98.22%; chiral HPLC 98.9% area at 232 nM and 99.2% at 292 nM.

[0286] Enantiomer 2 (peak 2) was concentrated under reduced pressure to give a white solid (55.0 mg, 37% recovery); R was obtained with 1:30:70 v / v acetic acid-ethyl acetate-hexane. f 0.14 (UV254nM);1 H-NMR(400MHz;DMSO-d6)δ 7.91(br s,1H),7.78(d,1H,J=8.7Hz),7.33(br s,1H),7.19-7.21(m,2H),7.10(br d,1H,J=8.7Hz),7.01(dd,1H,J=2.1,8.5Hz),6.8-6.9(m,2H),4.77(t,1H,J=9.2Hz),4.30(dd,1H,J=7.1,8 .9Hz),3.8-3.9(m,1H),3.56(s,3H),3.04(q,1H,J=7.1Hz),2.87(dd,1H,J=5.5,16.7Hz),2.5-2.8(m,1H); 19 F-NMR (376 MHz; DMSO-d6) δ -56.71; MS (APCI+) m / z 435 (M+1); HPLC UV purity Rt = 8.499 min, 99.62%; chiral HPLC 98.9% area at 232 nM, 99% at 292 nM

[0287] Step B: Preparation of (+)-2-(5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 1a) and (−)-2-(5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 1b) To the individually separated enantiomers of methyl 2-(5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)-2,3-dihydrobenzofuran-3-yl)acetate (0.052 g, 0.12 mmol) in methanol (3.0 mL) was added 1 M lithium hydroxide (0.50 mL, 0.50 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (25 mL) and 1 M HCl (20 mL). The phases were separated and the organic phase was partitioned with HO (25 mL) followed by brine (25 mL). The organic layer was concentrated under reduced pressure to give the crude product as a white solid.

[0288] Enantiomer 1 (peak 1) was concentrated under reduced pressure to give a white solid (0.048 g, 95.8% yield); R was obtained with 1:30:70 v / v acetic acid-ethyl acetate-hexane. f 0.06 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.31(br s,1H),7.90(br s,1H),7.78(d,1H,J=8.7Hz),7.32(br s,1H),7.19-7.2(m,2H),7.10(br d,1H,J=8.7Hz),7.01(dd,1H,J=2.2,8.4Hz),6.88(s,1H),6.83(d,1H,J=8.3Hz),4.78(t,1H,J=9. 2Hz),4.27(dd,1H,J=7.8,8.8Hz),3.8-3.9(m,1H),2.80(dd,1H,J=5.3,16.7Hz),2.5-2.6(m,1H); 19 F-NMR(376MHz;DMSO-d6)δ-56.69;MS(APCI+)m / z 421(M+1),MS(APCI-)m / z 419(M-1);HPLC UV purity Rt=7.420min,98.05%;Melting point=236.7℃;Optical rotation [α] 25 D = +16.3(c = 1, 1.5 mL IPA, 1.0 mL CHCl3);

[0289] Enantiomer 2 (peak 2) was concentrated under reduced pressure to give a white solid (0.045 g, 87.9% yield); R was obtained by elution with 1:30:70 v / v acetic acid-ethyl acetate-hexane. f 0.06 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.33(br s,1H),7.90(br s,1H),7.78(d,1H,J=8.7Hz),7.32(br s,1H),7.19-7.2(m,2H),7.10(br d,1H,J=8.7Hz),7.01(dd,1H,J=2.2,8.4Hz),6.88(s,1H),6.83(d,1H,J=8.5Hz),4.78(t,1H,J=9. 2Hz),4.27(dd,1H,J=7.6,8.7Hz),3.8-3.9(m,1H),2.80(dd,1H,J=5.3,16.7Hz),2.5-2.6(m,1H);19 F-NMR(376MHz;DMSO-d6)δ-56.69;MS(APCI+)m / z 421(M+1),MS(APCI-)m / z 419(M-1);HPLC UV purity Rt=7.421min,99.44%,melting point=237.7℃;Optical rotation [α] 25 D = -10.9 (c = 1, 1.5 mL IPA, 0.5 mL CHCl3)

[0290] Example 11: Synthesis of 3-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)-2,2-dimethylpropanoic acid (Compound 3) Step A: Preparation of 1-(3-(3-ethoxy-2,2-dimethyl-3-oxopropyl)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (ChemShuttle, 0.200 g, 0.82 mmol), ethyl 3-(3-bromophenyl)-2,2-dimethylpropanoate (0.279 g, 0.98 mmol), copper(II) acetate (CombiBlocks, 0.148 g, 0.82 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.158 g, 0.82 mmol), and potassium iodide (VWR, 0.271 g, 1.63 mmol) in DMSO (5 mL) was added DBU (Oakwood Chemicals, 0.36 mL, 2.45 mmol). The reaction mixture was placed under a N atmosphere and heated in a microwave at 115 °C for 1 h. The reaction mixture was then partitioned between ethyl acetate (40 mL) and 1 M KHSO (40 mL). An emulsion formed and was broken up by the addition of 5 mL of brine. The phases were separated and the organic phase was partitioned with HO (50 mL) followed by brine (50 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 0.400 g of a crude brown oil. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 40 g RediSep Gold Rf flash silica cartridge with 10-20% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a colorless oil (0.181 g) in mixture with the starting material. The crude reaction mixture was used directly in the next step.

[0291] Step B: Preparation of ethyl 3-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)-2,2-dimethylpropanoate [ka] To a mixture of crude 1-(3-(3-ethoxy-2,2-dimethyl-3-oxopropyl)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.180 g, 0.43 mmol) in DMF (5 mL) was added solid ammonium chloride (Chem-Impex, 0.065 g, 1.21 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (Oakwood, 0.194 g, 0.61 mmol), followed by diisopropylethylamine (0.63 mL, 3.63 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (50 mL) and HO (50 mL). The phases were separated, and the organic phase was partitioned with 1 M KHSO (50 mL) followed by brine (50 mL). The organic layer was concentrated under reduced pressure to give the crude product as a colorless oil (0.163 g). The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 12 g RediSep Gold Rf flash silica cartridge with 10 to 30% ethyl acetate in hexane containing 1% acetic acid gave the title compound as a colorless oil (0.114 g, 96% yield); elution with 1:30:70 v / v acetic acid-ethyl acetate-hexane gave the title compound as a colorless oil (0.114 g, 96% yield). f 0.18 (UV 254 nM); MS (APCI+) m / z 449.2 (M+1), (APCI-) m / z 447.20 (M-1); HPLC UV purity Rt = 10.022 min, 42.5%. The product is a mixture of the desired product and an impurity: 6-(trifluoromethoxy)-1H-indole-2-carboxamide. The crude reaction mixture was used directly in the next step.

[0292] Step C: Preparation of 3-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)-2,2-dimethylpropanoic acid (compound 3) [ka] To a mixture of ethyl 3-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)-2,2-dimethylpropanoate (0.114 g, 0.25 mmol) in methanol (3 mL) was added 1 M lithium hydroxide (1.0 mL, 1.0 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (50 mL) and 1 M HCl (25 mL). The phases were separated and the organic phase was partitioned with HO (25 mL) followed by brine (25 mL). The organic layer was concentrated under reduced pressure to give the crude product as a colorless oil (0.120 g). The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 12 g RediSep Gold Rf flash silica cartridge with 10-50% ethyl acetate in hexane containing 1% acetic acid gave the title compound as a white solid (0.016 g); f 0.48 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.21(br s,1H),7.96(br s,1H),7.80(d,1H,J=8.7Hz),7.3-7.4(m,2H),7.24(s,1H),7.20(d,1H,J=7.8Hz),7.1-7.2(m,3H),6.89(s,1H),2.83(s,2H),1.06(s,6H); 19 F-NMR(376MHz;DMSO-d6)56.78;MS(APCI + )m / z 421(M+1),419(M-1).HPLC UV purity Rt=6.19min,98.37%;Melting point=88~89℃

[0293] Example 12: Synthesis of (E)-3-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)but-2-enoic acid (Compound 6) Step A: Preparation of (E)-1-(6-(4-methoxy-4-oxobut-2-en-2-yl)pyridin-2-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (ChemShuttle, 0.200 g, 0.82 mmol), methyl (E / Z)-3-(6-bromopyridin-2-yl)but-2-enoate (0.209 g, 0.82 mmol), copper(II) acetate (CombiBlocks, 0.148 g, 0.82 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.158 g, 0.82 mmol), and potassium iodide (VWR, 0.271 g, 1.63 mmol) in DMSO (5 mL) was added DBU (Oakwood Chemicals, 0.36 mL, 2.45 mmol). The reaction mixture was stirred overnight at 115 °C under a N atmosphere. The reaction mixture was partitioned between ethyl acetate (60 mL) and 1 M KHSO (50 mL). An emulsion formed and was broken up by the addition of 25 mL of brine. The phases were separated and the organic phase was partitioned with HO (60 mL) followed by brine (60 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 0.400 g of a crude brown oil. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 24 g RediSep Gold Rf flash silica cartridge with 10-50% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a white solid (0.061 g, 18% yield). The R was purified with 1:20:80 v / v acetic acid-ethyl acetate-hexane. f 0.09 (UV254nM); 1H-NMR(400MHz;CDCl3)δ 12.7-13.0(bs,1H),7.92(t,1H,J=8.7Hz),7.73(d,1H,J=8.7Hz),7.63(d,1H,J=7.8Hz),7.55(s, 1H),7.3-7.4(m,2H),7.0-7.2(m,1H),6.75(d,1H,J=1.1Hz),3.74(s,3H),2.62(d,3H,J=1.1Hz); 19 F-NMR (376MHz; DMSO-d6) δ check; MS (APCI+) m / z 421 (M+1), (APCI-) m / z 419 (M-1); HPLC UV purity Rt=9.396min, 99.09%.

[0294] Step B: Preparation of methyl (E)-3-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)but-2-enoate [ka] To a mixture of (E)-1-(6-(4-methoxy-4-oxobut-2-en-2-yl)pyridin-2-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.057 g, 0.14 mmol) in DMF (2 mL) was added solid ammonium chloride (Chem-Impex, 0.022 g, 0.41 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (Oakwood, 0.066 g, 0.20 mmol), followed by diisopropylethylamine (0.21 mL, 1.22 mmol). The reaction mixture was stirred at room temperature under a N atmosphere for 3 hours. The reaction mixture was then partitioned between ethyl acetate (25 mL) and HO (25 mL). The phases were separated and the organic phase was partitioned with 1 M KHSO4 (20 mL) followed by brine (30 mL). The organic layer was concentrated under reduced pressure to give the crude product as a yellow oil (0.056 g, 98% yield). R was extracted with 1:30:70 v / v acetic acid-ethyl acetate-hexane. f 0.07(UV254nM); 1H-NMR(400MHz;CDCl3)δ 8.18(br s,1H),8.02(t,1H,J=8.7Hz),7.8-7.9(m,2H),7.51(br s,1H),7.4-7.5(m,2H),7.25(s,1H),7.18(br d,1H,J=8.5Hz),6.77(d,1H,J=1.4Hz),3.66(s,3H),2.6-2.7(m,1H),2.53(d,3H,J=1.4Hz); 19 F-NMR(376MHz;DMSO-d6)δ-56.76:MS(APCI+)m / z 420.0(M+1);HPLC UV purity Rt=8.544min,88.1%.

[0295] Step C: Preparation of (E)-3-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)but-2-enoic acid (compound 6) [ka] To a mixture of (E)-1-(6-(4-methoxy-4-oxobut-2-en-2-yl)pyridin-2-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.056 g, 0.13 mmol) in methanol (3 mL) was added 1 M lithium hydroxide (0.5 mL, 0.5 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (25 mL) and 1 M HCl (10 mL). The phases were separated and the organic phase was partitioned with HO (25 mL) followed by brine (25 mL). The organic layer was concentrated under reduced pressure to give the crude product as a white solid (0.060 g). The crude solid was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution of a 4 g RediSep Gold Rf flash silica cartridge with 20-80% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a white solid (0.014 g, 26% yield); f 0.31 (UV254nM); 1H-NMR(400MHz;DMSO-d6)δ 12.45(br s,1H),8.21(br s,1H),8.05(t,1H,J=7.9Hz),7.87(d,1H,J=8.7Hz),7.80(d,1H,J=7.8Hz),7.54(br s,1H),7.48(s,1H),7.43(d,1H,J=7.8Hz),7.29(s,2H),7.21(br d,1H,J=8.5Hz),6.7-6.8(m,1H)2.53(d,3H,J=0.9Hz); 19 F-NMR(376MHz;DMSO-d6)56.78;MS(APCI + ) m / z 406 (M+1), 404 (M-1). HPLC UV purity Rt = 7.102 min, 99.00%; melting point = 232-234 °C. The product was confirmed to be (E) by NOE.

[0296] Example 13: Synthesis of 2-((3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)thio)-2-methylpropanoic acid (Compound 2) Step A: Preparation of 1-(3-((1-ethoxy-2-methyl-1-oxopropan-2-yl)thio)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (ChemShuttle, 0.200 g, 0.82 mmol), ethyl 2-((3-bromophenyl)thio)-2-methylpropanoate (0.248 g, 0.82 mmol), copper(II) acetate (CombiBlocks, 0.296 g, 1.64 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.158 g, 0.82 mmol), and potassium iodide (VWR, 0.272 g, 1.64 mmol) in DMSO (12 mL) was added DBU (Oakwood Chemicals, 0.36 mL, 2.45 mmol). The reaction mixture was stirred overnight at 115 °C under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (50 mL) and 1 M KHSO (50 mL). An emulsion formed and was broken up by the addition of 25 mL of brine. The phases were separated, and the organic phase was partitioned with HO (50 mL), followed by brine (50 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude red oil, 0.503 g. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. The title compound was obtained as a mixture with starting material by eluting a 24 g RediSep Gold Rf flash silica cartridge with 5-15% ethyl acetate in hexane containing 1% acetic acid. The mixture was collected as a white solid (0.082 g, 21% yield); the R was purified by elution with 1:30:70 v / v acetic acid-ethyl acetate-hexane. f 0.38 (UV 254 nM); MS (APCI-) m / z 466 (M-1). The isolated crude reaction mixture was used in the next step.

[0297] Step B: Preparation of ethyl 2-((3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)thio)-2-methylpropanoate [ka] To a mixture of ethyl 2-((3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)thio)-2-methylpropanoate (0.082 g, 0.17 mmol) in DMF (2 mL) was added solid ammonium chloride (Chem-Impex, 0.028 g, 0.53 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (Oakwood, 0.263 g, 0.84 mmol), followed by diisopropylethylamine (0.27 mL, 1.58 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (25 mL) and HO (25 mL). The phases were separated, and the organic phase was partitioned with 1 M KHSO (25 mL) followed by brine (25 mL). The organic layer was concentrated under reduced pressure to give the crude product as a colorless oil (0.073 g, 90.9% yield). The crude product was obtained as a mixture with known impurities. The crude product was used without further purification. R was extracted with 1:20:80 v / v acetic acid-ethyl acetate-hexane. f 0.11 (UV 254 nM); LCMS, 2 peaks, Rt = 7.55 min, m / z 467.10 (M+1);

[0298] Step C: Preparation of 2-((3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)thio)-2-methylpropanoic acid (compound 2) [ka] To a mixture of ethyl 2-((3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)thio)-2-methylpropanoate (0.073 g, 0.16 mmol) in methanol (3 mL) was added 1 M lithium hydroxide (0.63 mL, 0.63 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (25 mL) and 1 M HCl (10 mL). The phases were separated and the organic phase was partitioned with HO (25 mL) followed by brine (25 mL). The organic layer was concentrated under reduced pressure to give the crude product as a colorless oil (0.073 g). The crude product was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution of a 12 g RediSep Gold Rf flash silica cartridge with 10-80% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a white solid (0.036 g, 53% yield); f 0.09 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.66(br s,1H),8.02(br s,1H),7.82(d,1H,J=8.5Hz),7.4-7.5(m,2H),7.3-7.4(m,3H),7.29(s,1H),7.13(br d,1H,J=8.7Hz),6.93(br s,1H),1.38(s,6 H); 19 F-NMR(376MHz;DMSO-d6)56.74;MS(APCI + )m / z 439(M+1),437(M-1).HPLC UV purity Rt=8.376min,91.66%.

[0299] Example 14: Synthesis of 1-((3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)thio)cyclobutane-1-carboxylic acid (Compound 4) Step A: Preparation of 1-(3-((1-(ethoxycarbonyl)cyclobutyl)thio)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (ChemShuttle, 0.200 g, 0.82 mmol), ethyl 1-((3-bromophenyl)thio)cyclobutane-1-carboxylate (0.258 g, 0.82 mmol), copper(II) acetate (CombiBlocks, 0.296 g, 1.64 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.158 g, 0.82 mmol), and potassium iodide (VWR, 0.272 g, 1.64 mmol) in DMSO (12 mL) was added DBU (Oakwood Chemicals, 0.36 mL, 2.45 mmol). The reaction mixture was stirred overnight at 115 °C under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (50 mL) and 1 M KHSO (50 mL). An emulsion formed and was broken up by the addition of 25 mL of brine. The phases were separated and the organic phase was partitioned with HO (50 mL) followed by brine (50 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 0.475 g of a crude red oil. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. The title compound was obtained as a mixture with starting material by eluting a 24 g RediSep Gold Rf flash silica cartridge with 5-20% ethyl acetate in hexane containing 1% acetic acid. The mixture was collected as a white solid (0.135 g); the R was purified by elution with 1:30:70 v / v acetic acid-ethyl acetate-hexane. f 0.41 (UV 254 nM); MS (APCI-) m / z 478 (M-1). The isolated crude reaction mixture was used in the next step.

[0300] Step B: Preparation of ethyl 1-((3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)thio)cyclobutane-1-carboxylate [ka] To a mixture of 1-(3-((1-(ethoxycarbonyl)cyclobutyl)thio)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.125 g, 0.26 mmol) in DMF (3 mL) was added solid ammonium chloride (Chem-Impex, 0.042 g, 0.78 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (Oakwood, 0.125 g, 0.39 mmol), followed by diisopropylethylamine (0.41 mL, 2.34 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (25 mL) and HO (25 mL). The phases were separated, and the organic phase was partitioned with 1 M KHSO (25 mL) followed by brine (25 mL). The organic layer was concentrated under reduced pressure to give the crude product as a colorless oil (0.109 g, 87.9% yield). The crude product was obtained as a mixture with known impurities. The crude product was used without further purification. R was extracted with 1:20:80 v / v acetic acid-ethyl acetate-hexane. f 0.11 (UV 254 nM); LCMS, 2 peaks, Rt = 7.60 min, m / z 479.10 (M+1);

[0301] Step C: Preparation of 1-((3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)thio)cyclobutane-1-carboxylic acid (compound 4) [ka] To a mixture of ethyl 1-((3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)thio)cyclobutane-1-carboxylate (0.109 g, 0.23 mmol) in methanol (3 mL) was added 1 M lithium hydroxide (0.91 mL, 0.91 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (25 mL) and 1 M HCl (15 mL). The phases were separated and the organic phase was partitioned with HO (25 mL) followed by brine (25 mL). The organic layer was concentrated under reduced pressure to give the crude product as a colorless oil (0.100 g). The crude product was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution of a 12 g RediSep Gold Rf flash silica cartridge with 10-30% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a white solid (0.036 g, 33% yield); f 0.08 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.7-1.2.8(br s,1H),8.02(br s,1H),7.81(d,1H,J=8.7Hz),7.4-7.5(m,1H),7.3-7.4(m,1H),7.2-7.3(m,3H),7.13(br d,1H,J=8.3Hz),6.96(s,1H),2.5-2.7(m,5H),2.29(s,1H).2.1-2.2(m,3H); 19 F-NMR(376MHz;DMSO-d6)56.74;MS(APCI + )m / z 439(M+1),437(M-1).HPLC UV purity Rt=8.55min,84.81%.

[0302] Example 15: Synthesis of 3-(3-(2-carbamoyl-5-(trifluoromethoxy)benzo[b]thiophen-3-yl)phenyl)propanoic acid (Compound 5) [ka] Step A: Preparation of 3-(3-(3-methoxy-3-oxopropyl)phenyl)-5-(trifluoromethoxy)benzo[b]thiophene-2-carboxylic acid [ka] To a 24 mL septa-capped vial was added methyl 3-bromobenzenepropanoate (Combi-Blocks, 0.243 g, 1.0 mmol) and 5-(trifluoromethoxy)benzo[b]thiophene-2-carboxylic acid (0.262 g, 1.0 mmol) prepared by the method of Zhao, L. et al., Eur J Med Chem 2022, 228, 113987. Next, bis(dichloro(η 6 To the reaction mixture was added 10 mL of 1-p-cymene (ruthenium) (Strem, 0.025 g, 4 mol%), trimethylphosphonium tetrafluoroborate (Strem, 0.013 g, 8 mol%), K2CO3 (VWR, 0.152 g, 1.1 mmol), and NMP (5 mL). The mixture was degassed by bubbling nitrogen gas through it with stirring for 3 minutes and then heated to 105 °C overnight. The reaction mixture was then cooled to room temperature and then partitioned between ethyl acetate (30 mL) and 1 M KHSO4 (30 mL). The phases were separated, and the organic phase was partitioned with HO (75 mL) followed by brine (75 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude oil that was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution of a 40 g RediSep Gold Rf flash silica cartridge with 10 to 100% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as an amorphous solid (0.090 g, 21% yield); f 0.28 (UV254nM); 1H-NMR(400MHz;CD3OD)δ 8.05(d,1H,J=8.9Hz),7.4-7.5(m,2H),7.33(d,1H,J=7.8Hz),7.28(s,1H),7.2-7.3(m, 2H),3.64(s,3H),3.3-3.3(m,1H),3.01(t,2H,J=7.6Hz),2.70(t,2H,J=7.5Hz);MS(APCI + ) m / z 442.1(M+NH4 + ).

[0303] Step B: Preparation of methyl 3-(3-(2-carbamoyl-5-(trifluoromethoxy)benzo[b]thiophen-3-yl)phenyl)propanoate [ka] To a mixture of 3-(3-(3-methoxy-3-oxopropyl)phenyl)-5-(trifluoromethoxy)benzo[b]thiophene-2-carboxylic acid (0.090 g, 0.21 mmol) in DMF (1.5 mL) was added ammonium chloride (Chem-Impex, 0.034 g, 0.63 mmol). TBTU (Oakwood, 0.101 g, 0.31 mmol) was then added, followed by DIPEA (0.33 mL, 1.9 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then diluted with water (40 mL) and then extracted with 3 × 20 mL of ethyl acetate. The combined organic phases were dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give the crude product as a colorless oil. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution of a 12 g RediSep Gold Rf flash silica cartridge with 10 to 100% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a white semi-solid (0.076 g, 84% yield); f 0.47 (UV254nM); 1H-NMR(400MHz;CD3OD)δ 8.06(d,1H,J=8.9Hz),7.5-7.6(m,1H),7.4-7.5(m,2H),7.35(s,1H),7.31(d,1H,J=7. 6Hz),7.26(s,1H),3.63(s,3H),3.03(t,2H,J=7.3Hz),2.72(t,2H,J=7.3Hz) + ) m / z 424.0(M+1).

[0304] Step C: Preparation of methyl 3-(3-(2-carbamoyl-5-(trifluoromethoxy)benzo[b]thiophen-3-yl)phenyl)propanoate (Compound 5) [ka] To a mixture of methyl 3-(3-(2-carbamoyl-5-(trifluoromethoxy)benzo[b]thiophen-3-yl)phenyl)propanoate (0.071 g, 0.17 mmol) in MeOH (2 mL) was added dropwise a 1 M aqueous solution of LiOH (0.51 mL, 3 equiv.). The reaction mixture was stirred overnight at room temperature. The clear solution was then diluted with water (10 mL) and subjected to reduced pressure on a rotary evaporator to remove the MeOH. Additional water (10 mL) was added, and the solution was acidified with 1 N HCl to precipitate the product. The suspension was filtered, the solid washed with excess water, and then dried under high vacuum overnight to afford the title compound as a white solid (0.045 g, 65% yield); R was obtained by distilling off the solid with 1 / 40 / 60 acetic acid:ethyl acetate:heptane. f 0.27 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.17(br s,1H),8.25(d,1H,J=8.7Hz),7.75(br s,1H),7.4-7.6(m,2H),7.39(br MS(APCI +) m / z 409.1, 410.1 (M+1). HPLC UV purity, Rt = 7.98 min, 99.4%. Melting point 185.0-186.0 °C.

[0305] Example 16: Synthesis of 2-(5-(2-carbamoyl-5-(trifluoromethoxy)benzo[b]thiophen-3-yl)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 7). [ka] Step A: Preparation of 3-(3-(2-methoxy-2-oxoethyl)-2,3-dihydrobenzofuran-5-yl)-5-(trifluoromethoxy)benzo[b]thiophene-2-carboxylic acid [ka] To a 24 mL septa-capped vial was added methyl 5-bromo-2,3-dihydrobenzofuran-3-acetate (Accela, 0.298 g, 1.1 mmol) and 5-(trifluoromethoxy)benzo[b]thiophene-2-carboxylic acid (0.262 g, 1.0 mmol) prepared by the method of Zhao, L. et al., Eur J Med Chem 2022, 228, 113987. Next, bis(dichloro(η 6To the reaction mixture was added 10 mL of 1-p-cymene (ruthenium) (Strem, 0.025 g, 4 mol%), trimethylphosphonium tetrafluoroborate (Strem, 0.015 g, 8 mol%), K2CO3 (VWR, 0.153 g, 1.1 mmol), and NMP (5 mL). The mixture was degassed by bubbling nitrogen gas through it with stirring for 3 minutes and then heated to 105 °C overnight. The reaction mixture was then cooled to room temperature and then partitioned between ethyl acetate (30 mL) and 1 M KHSO4 (30 mL). The phases were separated, and the organic phase was partitioned with HO (75 mL), followed by brine (75 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude oil that was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution of a 40 g RediSep Gold Rf flash silica cartridge with 10 to 100% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as an amorphous solid (0.156 g, 34% yield); f 0.27 (UV254nM); 1 H-NMR(400MHz;CDCl3)δ 7.90(d,1H,J=8.9Hz),7.4-7.4(m,2H),7.2-7.2(m,2H),6.93(d,1H,J=8.0Hz),4.89(t,1H,J=9.2Hz),4.39(dd,1H ,J=6.3,9.3Hz),3.9-4.0(m,1H),3.71(s,3H),2.84(dd,1H,J=5.6,16.6Hz),2.69(dd,1H,J=9.1,16.6Hz);MS(APCI + ) m / z 435.0(M+1-H2O),(APCI - ) m / z 451.0(M-1).

[0306] Step B: Preparation of methyl 2-(5-(2-carbamoyl-5-(trifluoromethoxy)benzo[b]thiophen-3-yl)-2,3-dihydrobenzofuran-3-yl)acetate [ka] To a mixture of 3-(3-(3-methoxy-3-oxopropyl)phenyl)-5-(trifluoromethoxy)benzo[b]thiophene-2-carboxylic acid (0.090 g, 0.21 mmol) in DMF (2.0 mL) was added ammonium chloride (Chem-Impex, 0.052 g, 0.97 mmol). TBTU (Oakwood, 0.156 g, 0.49 mmol) was then added, followed by DIPEA (0.51 mL, 2.9 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then diluted with water (40 mL) and then extracted with 3 × 20 mL of ethyl acetate. The combined organic phases were dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give the crude product as a colorless oil. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution of a 12 g RediSep Gold Rf flash silica cartridge with 10 to 100% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a white semi-solid (0.119 g, 81% yield); f 0.26 (UV254nM); 1 H-NMR(400MHz;CD3OD)δ 7.88(d,1H,J=8.7Hz),7.32(d,1H,J=8.9Hz),7.2-7.2(m,3H),6.99(d,1H,J=8.7Hz),5.88(br s,1H),5.65(br s,1H),4.88(t,1H,J=9.2Hz),4.39(dd,1H,J=6.3,9.3Hz),3.9-4.0(m,1H),3. 69(s,3H),2.80(dd,1H,J=5.8,16.4Hz),2.67(dd,1H,J=8.6,16.4Hz);MS(APCI + ) m / z 452.0(M+1).

[0307] Step C: Preparation of 2-(5-(2-carbamoyl-5-(trifluoromethoxy)benzo[b]thiophen-3-yl)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 7) [ka] To a mixture of methyl 2-(5-(2-carbamoyl-5-(trifluoromethoxy)benzo[b]thiophen-3-yl)-2,3-dihydrobenzofuran-3-yl)acetate (0.114 g, 0.25 mmol) in MeOH (2 mL) was added dropwise a 1 M aqueous solution of LiOH (0.76 mL, 3 equiv). The reaction mixture was stirred overnight at room temperature. The reaction mixture was then partitioned between ethyl acetate (25 mL) and 1 M HCl (15 mL). The phases were separated and the organic phase was partitioned with HO (25 mL) followed by brine (25 mL). The organic layer was concentrated under reduced pressure to give the desired product as a white solid (0.104 g, 95% yield); Rf 0.10 (UV 254 nM) in 1 / 30 / 70 acetic acid:ethyl acetate:heptane; 1 H-NMR(400MHz;7DMSO-d6)δ 12.34(br s,1H),8.18(d,1H,J=8.9Hz),7.72(br s,1H),7.47(br d,1H,J=8.7Hz),7.33(s,1H),7.27(s,1H),7.18(dd,1H,J=1.6,8.9Hz),6.92(d,1H,J=8.3Hz),6.65(br s,1H),4.78(t,1H,J=9.2Hz),4.27(dd,1H,J=7.3,8.9Hz),3.8-3.9(m,1H),2.80(dd,1H,J=5.3,16.7Hz),2.55-2.62(m 1H); 19 F-NMR(376MHz;DMSO-d6)δ-56.79;MS(APCI + ) m / z 438.0(M+1),(APCI - ) m / z 436.0(M-1); HPLC UV purity, Rt=7.975min, 99.09%; melting point 235.4~235.7℃.

[0308] Example 17: Synthesis of ethyl 3-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)-2,2-dimethylpropanoate (Compound 8) [ka] Step A: Preparation of ethyl 3-(3-bromophenyl)-2,2-dimethylpropanoate [ka] To a solution of ethyl isobutyrate (805 μL, 5.98 mmol) in 20 mL of DMSO cooled to −78°C under a N atmosphere, 2 M LDA (3.0 mL, 5.98 mmol) was added dropwise. After stirring for 30 min, a solution of 1-bromo-3-(bromomethyl)benzene (996.5 mg, 3.97 mmol) in 3 mL of DMSO was added dropwise and stirred for 1 h. The reaction was then allowed to warm to room temperature and stirred for an additional 3 h. The reaction mixture was partitioned between 25 mL of ethyl acetate and 15 mL of saturated NH₄Cl. The organic layer was washed sequentially with HO (15 mL) and brine (15 mL) and then dried over anhydrous sodium sulfate. The crude reaction mixture was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through an 80 g RediSep Gold Rf flash silica cartridge with 0-10% ethyl acetate in hexane gave the title compound as a clear, colorless oil (0.7752 g, 68% yield); 1 H-NMR(400MHz;CDCl3-d)δ 7.40(t,1H,J=7.7Hz),7.29(d,1H,J=8.0Hz),7.04(d,1H,J=7.3Hz),4.14(q,2H,J=7.1Hz),3.00(s,2H),1.2-1.3(m,9H);MS(FIA MS+)m / z 287(M+1).

[0309] Step B: Preparation of 1-(6-(3-ethoxy-2,2-dimethyl-3-oxopropyl)pyridin-2-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To an oven-dried round-bottom flask flushed with N2, 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (196.3 mg, 0.80 mmol), copper(II) acetate (148.9 mg, 0.82 mmol), methyl-α-D-glucopyranoside (159.7 mg, 0.82 mmol), potassium iodide (272.8 mg, 1.64 mmol), followed by a 6 mL DMSO solution of ethyl 3-(3-bromophenyl)-2,2-dimethylpropanoate (281.9 mg, 0.98 mmol) were added. Finally, DBU (366 μL, 2.45 mmol) was added. The reaction mixture was stirred at 115 °C under a N2 atmosphere for 3 h. The reaction mixture was then partitioned between ethyl acetate (20 mL) and 1 M KHSO4 (15 mL). An emulsion formed and was broken down by the addition of 5 mL of brine. The phases were separated, and the organic phase was partitioned with HO (15 mL), followed by brine (15 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude oil. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 24 g RediSep Gold Rf flash silica cartridge with 5% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a white solid (108.5 mg, 12% yield); 1 H-NMR(400MHz;DMSO-d6)δ 13.04(br s,1H),7.8-7.9(m,2H),7.39(s,1H),7.32(d,1H,J=8.0Hz),7.26(d,1H,J=7.6Hz),7.16(br d,1H,J=8.7Hz),7.12(s,1H),3.99(d,1H,J=7.3Hz),3.8-3.9(m,1H),3.85(d,1H,J=7.1Hz),2.99(s,2H),1.95(s,1H),1.17(br d,1H,J=16.7Hz),1.13(s,6H),0.93(t,3H,J=7.1Hz),0.81(br s,1H);MS(APCI-)m / z 451(M+1);HPLC UV purity Rt=10.041min,98.29%.

[0310] Step C: Preparation of ethyl 3-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)-2,2-dimethylpropanoate [ka] To a solution of 1-(6-(3-ethoxy-2,2-dimethyl-3-oxopropyl)pyridin-2-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (39.6 mg, 0.08 mmol) in 2 mL of DMF was added solid ammonium chloride (14.3 mg, 0.26 mmol) and 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (42.5, 0.13 mmol), followed by diisopropylethylamine (0.138 mL, 0.79 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The residue was then partitioned between ethyl acetate (25 mL) and HO (20 mL). The phases were separated, and the organic phase was partitioned with 1 M KHSO (20 mL) followed by brine (20 mL). The organic layer was concentrated under reduced pressure to give the crude product as a golden oil (54.2 mg), which was subsequently used in the next reaction without further purification. 1 H-NMR (DMSO-d6,400MHz)δ 8.07(br s,1H),7.9-8.0(m,1H),7.84(t,1H,J=7.8Hz),7.80(d,1H,J=8.5Hz),7.68(br d,1H,J=8.3Hz),7.49(br t,1H,J=7.6Hz),7.3-7.4(m,2H),7.1-7.3(m,5H),3.90(q,2H,J=7.1Hz),3.0-3.0(m, 2H),2.85(s,2H),2.6-2.7(m,2H),1.14(s,6H),0.98(t,3H,J=7.1Hz);MS(APCI+)m / z 450(M+1).

[0311] Step D: Preparation of 3-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)-2,2-dimethylpropanoic acid (compound 8) [ka] To a solution of ethyl 3-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)-2,2-dimethylpropanoate (49.8 mg) in 3 mL of methanol was added 1 M lithium hydroxide (0.443 mL, 0.443 mmol). The reaction mixture was stirred at room temperature under a N atmosphere for 48 h. The reaction mixture was then partitioned between ethyl acetate (5 mL) and 1 M HCl (5 mL). The phases were separated and the organic phase was partitioned with HO (5 mL) followed by brine (5 mL). The organic layer was concentrated under reduced pressure to give the crude product. The crude mixture was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 4 g RediSep Gold Rf flash silica cartridge with 50-80% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a white film (13.2 mg, 29% yield); 1 H-NMR(DMSO-d6,400MHz)δ 12.1-12.4(m,1H),8.0-8.2(m,1H),7.8-7.9(m,2H),7.40(br s,1H),7.2-7.3(m,2H),7.19(d,1H,J=7.8Hz),2.96(s,2H),1.1-1.1(m,1H),1.12(s,5H); 19 F-NMR(376MHz;DMSO-d6)δ-56.76;MS(APCI + ) m / z 422(M+1).HPLC UV purity, Rt=7.372min, 85.77%.

[0312] Example 18: Synthesis of 2-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)-2,3-dihydrobenzofuran-3-yl)acetic acid (Compound 9) [ka] Step A: Preparation of 1-(3-(carboxymethyl)-2,3-dihydrobenzofuran-6-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (ChemShuttle, 0.245 g, 1.00 mmol), methyl 6-bromo-2,3-dihydrobenzofuran-3-acetate (Accela, 0.271 g, 1.00 mmol), copper(II) acetate (CombiBlocks, 0.182 g, 1.00 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.194 g, 1.00 mmol), and potassium iodide (VWR, 0.332 g, 2.00 mmol) in DMSO (15 mL) was added DBU (Oakwood Chemicals, 0.45 mL, 3.00 mmol). The reaction mixture was stirred overnight at 115 °C under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (50 mL) and 1 M KHSO (50 mL). An emulsion formed and was broken up by the addition of 25 mL of brine. The phases were separated and the organic phase was partitioned with HO (50 mL) followed by brine (50 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude red oil, 0.606 g. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 24 g RediSep Gold Rf flash silica cartridge with 10 to 100% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a white solid (0.119 g, 27% yield). The R was purified with 1:20:80 v / v acetic acid-ethyl acetate-hexane. f 0.12 (UV254nM); 1H-NMR(400MHz;DMSO-d6)δ 12.93(br s,1H),7.82(d,1H,J=8.7Hz),7.32-7.37(m,2H),7.1-7.2(br d,1H,J=8.7Hz),6.88(s,1H),6.79-6.84(m,2H),4.80(t,1H,J=9.2Hz),4.30(dd,1H,J=7.5,9. 1Hz),3.8-4.0(m,2H),3.63(s,3H),2.94(dd,1H,J=5.4,16.6Hz),2.73(dd,1H,J=8.9,16.7Hz); 19 F-NMR(376MHz;DMSO-d6)δ-56.67;MS(APCI-)m / z 434(M-1);HPLC UV purity Rt=9.508min,96.01%.

[0313] Step B: Preparation of methyl 2-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)-2,3-dihydrobenzofuran-3-yl)acetate [ka] To a mixture of 1-(3-(carboxymethyl)-2,3-dihydrobenzofuran-6-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.095 g, 0.218 mmol) in DMF (3 mL) was added ammonium chloride (Chem-Impex, 0.035 g, 0.65 mmol). TBTU (Oakwood, 0.105 g, 0.328 mmol) was then added, followed by DIPEA (0.35 mL, 1.96 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (25 mL) and HO (25 mL). The phases were separated, and the organic phase was partitioned with 1 M KHSO (25 mL) followed by brine (25 mL). The organic layer was concentrated under reduced pressure to give the crude product as a yellow solid (0.078 g, 84% yield). The crude solid was used in the next reaction without further purification. f 0.11 (UV254nM); 1H-NMR(400MHz;DMSO-d6)δ 7.95(br s,1H),7.78(d,1H,J=8.7Hz),7.32(br d,2H,J=8.0Hz),7.20(s,1H),7.11(d,1H,J=8.9Hz),6.94(s,1H),6.76(dd,1H,J=1.7,7.9Hz),6.70(d,1H,J=1.8Hz),4.79 (t,1H,J=9.2Hz),4.29(dd,1H,J=7.3,8.9Hz),3.8-3.9(m,1H),3.63(s,3H),2.93(dd,1H,J=5.4,16.6Hz)2.6-2.8(m,1H); 19 F-NMR(376MHz;DMSO-d6)δ-56.70;MS(APCI + )m / z 435.0(M+1),433(M-1);LC / MSRt=6.798min,100%.

[0314] Step C: Preparation of 2-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)-2,3-dihydrobenzofuran-3-yl)acetic acid (compound 9) [ka] To a mixture of methyl 2-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)-2,3-dihydrobenzofuran-3-yl)acetate (0.078 g, 0.18 mmol) in methanol (5 mL) was added 1 M lithium hydroxide (0.72 mL, 0.72 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (25 mL) and 1 M HCl (10 mL). The phases were separated and the organic phase was partitioned with water (20 mL) followed by brine (20 mL). The organic layer was concentrated under reduced pressure to give the crude product as a yellow solid (0.075 g, 98% yield). R was extracted with 1:50:50 v / v acetic acid-ethyl acetate-hexane. f 0.20 (UV 254 nM; 1H-NMR(400MHz;CDCl3)δ 12.39(br s,1H),7.95(br s,1H),7.78(d,1H,J=8.5Hz),7.34(d,2H,J=7.6Hz),7.2-7.3(m,1H),7.20(s,1H),7.1(m,1H),6.95(s,1H),6.76(dd,1H,J=1 .8,7.8Hz),6.69(d,1H,J=1.87Hz),4.79(t,1H,J=9.3Hz),4.2-4.3(m,1H),3.8-3.9(m,1H),2.8-2.9(m,1H),2.5-2.7(m,1H); 19 F-NMR(376MHz;DMSO-d6)δ-56.69;MS(APCI + ) m / z 421.0 (M+1), 419.0 (M-1); HPLC UV purity, Rt = 7.402 min, 96.0%; melting point = 180-181 °C.

[0315] Example 19: Synthesis of 1-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzyl)cyclobutane-1-carboxylic acid (Compound 10) [ka] Step A: Preparation of ethyl 1-(3-bromophenyl)cyclobutene-1-carboxylate [ka] To a solution of ethyl cyclobutanecarboxylate (830 □L, 6.00 mmol) in 20 mL of DMSO cooled to −78°C, 2 M LDA (3.0 mL, 6.00 mmol) was added dropwise under a N atmosphere. After stirring for 30 min, a solution of 1-bromo-3-(bromomethyl)benzene (0.997 g, 4.00 mmol) in 3 mL of DMSO was added dropwise and stirred for 1 h. The reaction was then allowed to warm to room temperature and stirred overnight. The reaction mixture was partitioned between 25 mL of ethyl acetate and 15 mL of saturated NH₄Cl. The organic layer was washed sequentially with water (15 mL) and brine (15 mL) and then dried over anhydrous sodium sulfate. The crude reaction mixture was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through an 80 g RediSep Gold Rf flash silica cartridge with 0-10% ethyl acetate in hexane gave the title compound as a clear, colorless oil (0.904 g, 76% yield); f 0.73(UV254nM);1H NMR(chloroform-d,400MHz)δ 7.32(d,1H,J=7.8Hz),7.3-7.3(m,1H),7.11(t,1H,J=7.8Hz),7.04(d,1H,J=7.6Hz),4.11(q,2H,J=7 MS(FIA MS+)m / z 297(M+1).

[0316] Step B: Preparation of 1-(3-((1-(ethoxycarbonyl)cyclobutyl)methyl)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (ChemShuttle, 0.245 g, 1.00 mmol), ethyl 1-(3-bromophenyl)cyclobutene-1-carboxylate (0.297 g, 1.00 mmol), copper(II) acetate (CombiBlocks, 0.182 g, 1.00 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.194 g, 1.00 mmol), and potassium iodide (VWR, 0.332 g, 2.00 mmol) in DMSO (15 mL) was added DBU (Oakwood Chemicals, 0.45 mL, 3.00 mmol). The reaction mixture was stirred overnight at 115 °C under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (50 mL) and 1 M KHSO (50 mL). An emulsion formed and was broken up by the addition of 25 mL of brine. The phases were separated and the organic phase was partitioned with HO (50 mL) followed by brine (50 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude red oil, 0.524 g. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 24 g RediSep Gold Rf flash silica cartridge with 10 to 100% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a white solid (0.250 g, a mixture of the desired product and starting material). The R was purified with 1:20:80 v / v acetic acid-ethyl acetate-hexane. f 0.29 (UV254nM); MS (APCI-)m / z 460.2 (M-1); HPLC UV purity Rt=11.002min, 87.8%.

[0317] Step C: Preparation of ethyl 1-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzyl)cyclobutane-1-carboxylate [ka] To a mixture of 1-(3-((1-(ethoxycarbonyl)cyclobutyl)methyl)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.250 g, 0.542 mmol) in DMF (3 mL) was added ammonium chloride (Chem-Impex, 0.087 g, 1.63 mmol). TBTU (Oakwood, 0.261 g, 0.812 mmol) was then added, followed by DIPEA (0.85 mL, 4.88 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (25 mL) and HO (25 mL). The phases were separated, and the organic phase was partitioned with 1 M KHSO (25 mL) followed by brine (25 mL). The organic layer was concentrated under reduced pressure to give the crude product as a yellow oil (0.195 g, product mixture). The crude solid was used in the next reaction without further purification. f 0.21 (UV 254 nM); MS (APCI + ) m / z 461.0 (M+1), 459 (M-1); LC / MS Rt = 7.608 min, multiple peaks).

[0318] Step D: Preparation of 1-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzyl)cyclobutane-1-carboxylic acid (compound 10) [ka] To a mixture of 1-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzyl)cyclobutane-1-carboxylate (0.195 g, 0.42 mmol) in methanol (5 mL) was added 1 M lithium hydroxide (1.70 mL, 1.70 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (25 mL) and 1 M HCl (10 mL). The phases were separated and the organic phase was partitioned with water (20 mL) followed by brine (20 mL). The organic layer was concentrated under reduced pressure to give the crude product as a yellow oil (0.195 g). The crude product was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 12 g RediSep Gold Rf flash silica cartridge with 10-100% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a yellow solid (0.032 g, 17% yield). f 0.37(UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.28(br s,1H),8.00(br s,1H),7.84(d,1H,J=8.7Hz),7.40-7.44(m,2H),7.28(s,1H),7.24(d,1H,J=7.6Hz),7.17(br d,2H,J=4.1Hz),7.14(s,1H),6.94(s,1H),),3.10(s,2H),2.2-2.4(m,2H),1.9-2.2(m,2H),1.7-1.9(m,2H); 19 F-NMR(376MHz;DMSO-d6)δ-56.76;MS(APCI + )m / z 433.0(M+1),431.0(M-1);HPLC UV purity, Rt=8.428min,98.9%;Melting point=178~179℃.

[0319] Example 20: Synthesis of 2-(1-(tert-butoxycarbonyl)-5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)indolin-3-yl)acetic acid (Compound 11) [ka] Step A: Preparation of 1-(1-(tert-butoxycarbonyl)-3-(2-methoxy-2-oxoethyl)indolin-5-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (ChemShuttle, 0.245 g, 1.00 mmol), tert-butyl 5-bromo-3-(2-methoxy-2-oxoethyl)-2,3-dihydro-1H-indole-1-carboxylate (Enamine, 0.269 g, 1.00 mmol), copper(II) acetate (CombiBlocks, 0.182 g, 1.00 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.194 g, 1.00 mmol), and potassium iodide (VWR, 0.332 g, 2.00 mmol) in DMSO (15 mL) was added DBU (Oakwood Chemicals, 0.45 mL, 3.00 mmol). The reaction mixture was heated to 150 °C under a N atmosphere for 1 h and then cooled to room temperature. The reaction mixture was then partitioned between ethyl acetate (50 mL) and water (50 mL x 2). The phases were separated, and the organic phase was partitioned with 1 M KOH (50 mL x 2), followed by brine (50 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude red oil, 0.710 g. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 24 g RediSep Gold Rf flash silica cartridge with 10-30% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as an orange solid (0.084 g, 21.2% yield). The R was purified with 1:30:70 v / v acetic acid-ethyl acetate-hexane. f 0.24(UV254nM); LC / MS Rt=6.316min, (APCI-)m / z 533.10(M-1).

[0320] Step B: Preparation of tert-butyl 5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)-3-(2-methoxy-2-oxoethyl)indoline-1-carboxylate [ka] To a mixture of 1-(1-(tert-butoxycarbonyl)-3-(2-methoxy-2-oxoethyl)indolin-5-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.084 g, 0.157 mmol) in DMF (5 mL) was added ammonium chloride (Chem-Impex, 0.025 g, 0.471 mmol). TBTU (Oakwood, 0.076 g, 0.235 mmol) was then added, followed by DIPEA (0.24 mL, 1.41 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (50 mL) and HO (25 mL). The phases were separated, and the organic phase was partitioned with 1 M KOH (50 mL) followed by brine (50 mL). The organic layer was concentrated under reduced pressure to give the crude product as an orange solid (0.076 g, 91% yield). The crude solid was used in the next reaction without further purification. f 0.14(UV254nM); LC / MS Rt=7.536min, (APCI-)m / z 532.10(M-1).

[0321] Step C: Preparation of 2-(1-(tert-butoxycarbonyl)-5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)indolin-3-yl)acetic acid [ka] To a mixture of tert-butyl 5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)-3-(2-methoxy-2-oxoethyl)indoline-1-carboxylate (0.102 g, 0.19 mmol) in methanol (5 mL) was added 1 M lithium hydroxide (1.00 mL, 1.00 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (15 mL) and 1 M HCl (10 mL). The phases were separated and the organic phase was partitioned with water (15 mL) followed by brine (15 mL). The organic layer was concentrated under reduced pressure to give the title product as a white solid (0.087 g). The crude product was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 12 g RediSep Gold Rf flash silica cartridge with 10-50% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as an orange solid (0.052 g, 52% yield). f 0.54 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.34(br s,1H),7.96(br s,1H),7.82(d,1H,J=8.5Hz),7.37(br s,1H),7.2-7.3(m,2H),7.1-7.2(m,2H),6.93(s,1H),4.22(m,1H),3.6-3.7(m,2H),2.7-2.9(m,1H),2.5-2.7(m,2H),1.53(br s,9H); 19 F-NMR (376MHz; DMSO-d6)δ-56.70; LC / MS Rt=5.848min, (APCI-)m / z 518.10(M-1); HPLC UV purity, Rt=8.919min, 98.2%.

[0322] Example 21: Synthesis of 2-(5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzofuran-3-yl)acetic acid (Compound 12) [ka] Step A: Preparation of 1-(3-(2-methoxy-2-oxoethyl)benzofuran-5-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (ChemShuttle, 0.245 g, 1.00 mmol), methyl 2-(5-bromo-1-benzofuran-3-yl)acetate (Accela, 0.269 g, 1.00 mmol), copper(II) acetate (CombiBlocks, 0.182 g, 1.00 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.194 g, 1.00 mmol), and potassium iodide (VWR, 0.332 g, 2.00 mmol) in DMSO (15 mL) was added DBU (Oakwood Chemicals, 0.45 mL, 3.00 mmol). The reaction mixture was heated to 115 °C under a N atmosphere for 10 h and then stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate (75 mL) and 1 M KHSO4 (50 mL). An emulsion formed and was broken up by the addition of 25 mL of brine. The phases were separated, and the organic phase was partitioned with HO (50 mL), followed by brine (50 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude red oil, 0.630 g. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 24 g RediSep Gold Rf flash silica cartridge with 10-30% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as an orange solid (0.068 g, 16% yield). The R was purified with 1:20:80 v / v acetic acid-ethyl acetate-hexane. f 0.09 (UV254nM); 1H-NMR(400MHz;DMSO-d6)δ 12.96(bs,1H),8.06(s,1H),7.91(d,1H,J=8.7Hz),7.83(br d,1H,J=8.9Hz),7.72(d,1H,J=8.7Hz),7.68(d,1H,J=2.1Hz),7.48(s,1H),7.32(dd,1H, J=2.2,8.6Hz),7.2-7.2(m,1H),6.91(s,1H),3.85(s,2H),3.6-3.7(m,1H),3.61(s,3H); 19 F-NMR (376MHz; DMSO-d6) δ-56.71; MS (APCI-) m / z 432 (M-1); HPLC UV purity Rt=10.972min, 94.58%.

[0323] Step B: Preparation of methyl 2-(5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzofuran-3-yl)acetate [ka] To a mixture of 1-(3-(2-methoxy-2-oxoethyl)benzofuran-5-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.065 g, 0.148 mmol) in DMF (3 mL) was added ammonium chloride (Chem-Impex, 0.024 g, 0.444 mmol). TBTU (Oakwood, 0.071 g, 0.222 mmol) was then added, followed by DIPEA (0.23 mL, 1.33 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (25 mL) and HO (25 mL). The phases were separated, and the organic phase was partitioned with 1 M KHSO (20 mL) followed by brine (20 mL). The organic layer was concentrated under reduced pressure to give the crude product as an orange solid (0.068 g, quantitative yield). The crude solid was used in the next reaction without further purification. f 0.09 (UV254nM); 1H-NMR(400MHz;DMSO-d6)δ 8.05(s,1H),8.02(br s,1H),7.86(d,1H,J=8.7Hz),7.70(d,1H,J=8.5Hz),7.62(d,1H,J=2.1Hz),7.39(br s,1H),7.32(s,1H),7.24(dd,1H,J=2.1,8.7Hz),7.20(d,1H,J=8.7Hz),6.95(s,1H),3.85(s,2H),3.62(s,3H); 19 F-NMR(376MHz;DMSO-d6)δ-56.74;MS(APCI+)m / z 433.1(M+1).

[0324] Step C: Preparation of 2-(5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzofuran-3-yl)acetic acid (compound 12) [ka] To a mixture of methyl 2-(5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzofuran-3-yl)acetate (0.064 g, 0.15 mmol) in methanol (3 mL) was added 1 M lithium hydroxide (0.60 mL, 0.60 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (15 mL) and 1 M HCl (10 mL). The phases were separated and the organic phase was partitioned with water (15 mL) followed by brine (15 mL). The organic layer was concentrated under reduced pressure to give the title product as an orange solid (0.049 g, 80% yield). R was dissolved in 1:50:50 v / v acetic acid-ethyl acetate-hexane. f 0.04(UV254nM); 1H-NMR(400MHz;DMSO-d6)δ 12.48(br s,1H),8.03(br s,2H),7.90(br d,1H,J=8.7Hz),7.85(d,1H,J=8.7Hz),7.69(d,1H,J=8.7Hz),7.61(d,1H,J=2.1Hz),7.37(br s,1H),7.32(s,1H),7.22(dd,1H,J=2.1,8.7Hz),7.1-7.2(m,1H),6.94(s,1H),3.73(s,2H); 19 F-NMR(376MHz;DMSO-d6)δ-56.71;MS(APCI + )m / z 419.0(M+1),417.0(M-1);HPLC UV purity, Rt=7.623min,93.8%;melting point=238℃.

[0325] Example 22: Synthesis of 3-(3-(2-carbamoylbenzo[b]thiophen-3-yl)phenyl)propanoic acid (Compound 13) [ka] Step A: Preparation of 3-(3-(3-methoxy-3-oxopropyl)phenyl)benzo[b]thiophene-2-carboxylic acid [ka] To a 24 mL septa-capped vial was added methyl 3-bromobenzenepropanoate (Combi-Blocks, 0.486 g, 2.0 mmol) and benzo[b]thiophene-2-carboxylic acid (VWR, 0.357 g, 2.0 mmol). Next, trimethylphosphonium tetrafluoroborate (Strem, 0.027 g, 8 mol%), KCO (VWR, 0.305 g, 2.2 mmol), and NMP (8 mL) were added. The mixture was degassed by bubbling nitrogen gas through it for 3 minutes while stirring, then bis(dichloro(η) 6(-p-cymene)ruthenium) (Strem, 0.049 g, 4 mol%) was added and the mixture was heated to 105 °C overnight. Subsequently, the reaction mixture was cooled to room temperature, then diluted with water and extracted with ethyl acetate (3 x 120 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude oil that was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 40 g RediSep Gold Rf flash silica cartridge with 10-60% ethyl acetate in heptane containing 1% acetic acid afforded the title compound as a white solid (0.171 g, 25% yield). R was purified by 1:30:70 v / v acetic acid-ethyl acetate-hexane. f 0.30 (UV254nM); 1 H-NMR(400MHz;CDCl3)δ 7.90(d,1H,J=8.0Hz),7.5-7.6(m,1H),7.3-7.4(m,2H),7.31(br d,1H,J=7.8Hz),7.3-7.3(m,1H),7.26(s,1H),3.68(s,2H),3.6-3.7(m,1H),3.04(t,2H,J=7.8Hz),2.70(t,2H,J=7.8Hz);FIA-MS(APCI negative scan) m / z 339.0(M-1); Melting point=134~135.5℃.

[0326] Step B: Preparation of methyl 3-(3-(2-carbamoylbenzo[b]thiophen-3-yl)phenyl)propanoate [ka] To a mixture of 3-(3-(3-methoxy-3-oxopropyl)phenyl)benzo[b]thiophene-2-carboxylic acid (0.166 g, 0.49 mmol) in DMF (2.0 mL) was added ammonium chloride (Chem-Impex, 0.078 g, 1.46 mmol). TBTU (Oakwood, 0.235 g, 0.73 mmol) was then added, followed by DIPEA (0.77 mL, 4.4 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then diluted with water (150 mL) and then extracted with 3 × 70 mL of ethyl acetate. The combined organic phases were dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give the crude product as a colorless oil. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 24 g RediSep Gold Rf flash silica cartridge with 10 to 100% ethyl acetate in heptane containing 1% acetic acid afforded the title compound as a white semi-solid (0.168 g, 99% yield). f 0.29 (UV254nM); 1 H-NMR(400MHz; CDCl3)δ 7.91(d,1H,J=8.3Hz),7.4-7.5(m,2H),7.3-7.4(m,5H),6.22(br s,1H),5.60(br s,1H),3.67(s,3H),3.06(t,2H,J=7.6Hz),2.71(t,2H,J=7.6Hz) + ) m / z 340.1.0(M+1).

[0327] Step C: Preparation of 3-(3-(2-carbamoylbenzo[b]thiophen-3-yl)phenyl)propanoic acid (compound 13) [ka] To a mixture of methyl 3-(3-(2-carbamoylbenzo[b]thiophen-3-yl)phenyl)propanoate (0.071 g, 0.17 mmol) in MeOH (2 mL) was added dropwise a 1 M aqueous solution of LiOH (0.51 mL, 3 equiv.). The reaction mixture was stirred overnight at room temperature. The clear solution was then diluted with water (10 mL) and subjected to reduced pressure on a rotary evaporator to remove the MeOH. Additional water (10 mL) was added, and the solution was acidified with 1 N HCl to precipitate the product. The suspension was filtered, and the solid was washed with excess water and then dried under high vacuum overnight to afford the title compound as a white solid (0.045 g, 65% yield). Rf 0.27 (UV 254 nM) in 1:40:60 v / v acetic acid-ethyl acetate-heptane; 1 H-NMR(400MHz;DMSO-d6)δ 12.18(br s,1H),8.06(d,1H,J=8.0Hz),7.66(br s,1H),7.4-7.5(m,5H),7.33(s,1H),7.28(br d,1H,J=7.6Hz),6.63(br s,1H),2.91(br t,2H,J=7.6Hz),2.60(br t,2H,J=7.6Hz);MS(APCI + )m / z 326.2,(M+1),m / z 324.0,(M-1);HPLC UV purity, Rt=6.77min,99.7%;Melting point=198.0~200.0℃.

[0328] Example 23: Synthesis of 3-(3-(2-(methylcarbamoyl)-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)propanoic acid (Compound 14) [ka] Step A: Preparation of 1-(3-(3-methoxy-3-oxopropyl)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (ChemShuttle, 0.245 g, 1.00 mmol), methyl 3-(3-bromophenyl)propanoate (CombiBlocks, 0.243 g, 1.00 mmol), copper(II) acetate (CombiBlocks, 0.182 g, 1.00 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.194 g, 1.00 mmol), and potassium iodide (VWR, 0.332 g, 2.00 mmol) in DMSO (15 mL) was added DBU (Oakwood Chemicals, 0.45 mL, 3.00 mmol). The reaction mixture was heated to 115 °C under a N atmosphere for 10 h and then stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate (75 mL) and 1 M KHSO4 (50 mL). An emulsion formed and was broken up by the addition of 25 mL of brine. The phases were separated, and the organic phase was partitioned with HO (75 mL), followed by brine (75 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude red oil, 0.530 g. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 12 g RediSep Gold Rf flash silica cartridge with 5-30% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a yellow oil (0.069 g, 17% yield). The R was purified with 1:30:70 v / v acetic acid-ethyl acetate-hexane. f 0.26 (UV254nM); MS (APCI-)m / z 460.2 (M-1); HPLC UV purity Rt=9.48min, 99.4%.

[0329] Step B: Preparation of methyl 3-(3-(2-(methylcarbamoyl)-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)propanoate [ka] To a mixture of 1-(3-(3-methoxy-3-oxopropyl)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.068 g, 0.167 mmol) in DCM (2 mL) was added TBTU (Oakwood, 0.064 g, 0.204 mmol), followed by DIPEA (0.07 mL, 0.40 mmol). The reaction mixture was stirred at room temperature under a N atmosphere for 15 minutes. Methylamine (2.0 M solution in THF, 0.2 mL, 0.4 mmol) was then added to the reaction mixture. After stirring at room temperature for 4 hours, the reaction was complete. The reaction mixture was then partitioned between DCM (15 mL) and saturated aqueous NaHCO (15 mL). The phases were separated, and the aqueous layer was back-extracted with DCM (10 mL). The separate layers and the combined organic layer were washed with brine (15 mL). The organic layer was concentrated under reduced pressure to give the crude product as a yellow oil (0.079 g, quantitative yield). The crude solid was used in the next reaction without further purification. R was extracted with 1:30:70 v / v acetic acid-ethyl acetate-hexane. f 0.14 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 8.54(m,1H),7.84(d,1H,J=8.5Hz),7.4-7.5(m,1H),7.32(d,1H,J=8.7Hz),7.2-7.2(m ,2H),7.1-7.2(m,2H),6.9-7.0(m,1H),3.57(s,3H),2.9-3.0(m,2H),2.9-3.0(m,5H); 19 F-NMR (376MHz; DMSO-d6) δ-56.76; MS (APCI+) m / z 421.0 (M+1); HPLC UV purity Rt=8.98min, 83.3%.

[0330] Step C: Preparation of 3-(3-(2-(methylcarbamoyl)-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)propanoic acid (compound 13) [ka] To a mixture of methyl 3-(3-(2-(methylcarbamoyl)-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)propanoate (0.074 g, 0.15 mmol) in methanol (2 mL) was added 1 M lithium hydroxide (0.70 mL, 0.70 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (15 mL) and 1 M HCl (10 mL). The phases were separated and the organic phase was partitioned with water (10 mL) followed by brine (10 mL). The organic layer was concentrated under reduced pressure to give the title product as a yellow solid (0.057 g, 80% yield). R was dissolved in 1:50:50 v / v acetic acid-ethyl acetate-hexane. f 0.19 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.16(s,1H),8.54(br d,1H,J=4.6Hz),7.84(d,1H,J=8.5Hz),7.43(t,1H,J=7.7Hz),7.32(d,1H,J=7.6Hz),7.2-7.2(m,2H),7.14(br t,2H,J=8.6Hz),6.98(s,1H),2.90(t,2H,J=7.6Hz),2.69(d,3H,J=4.6Hz),2.5-2.6(m,2H); 19 F-NMR(376MHz;DMSO-d6)δ-56.72;MS(APCI + )m / z 407.0(M+1),405.0(M-1);HPLC UV purity, Rt=7.71min,98.4%;Melting point=150~151℃.

[0331] Example 24: Synthesis of 3-(3-(2-(methylcarbamoyl)-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)propanoic acid (Compound 15) [ka] Step A: Preparation of trans-methyl-2-(3-bromophenyl)cyclopropane-1-carboxylate [ka] To a mixture of trans-2-(3-bromo-phenyl)-cyclopropanecarboxylic acid (J&W Pharmlab, 0.930 g, 3.86 mmol) in methanol (30 mL) was added acetyl chloride (Aldrich, 1.10 mL, 15.43 mmol) dropwise at 0° C. The reaction was allowed to warm to room temperature over 6 hours, and TLC showed the reaction was complete. The reaction mixture was then azeotroped under reduced pressure with toluene (2×100 mL) to give the desired product as a colorless oil (0.974 g, 98.9% yield). The R was purified with 1:30:70 v / v acetic acid-ethyl acetate-hexane. f 0.71 (UV254nM); 1 H-NMR(400MHz;CDCl3)δ 7.34(d,1H,J=7.6Hz),7.2-7.3(m,1H),7.15(t,1H,J=7.9Hz),7.04(d,1H,J=7.8Hz),3.73(s,3H),2.50(ddd,1H, MS(APCI+)m / z 257(M+1).

[0332] Step B: Preparation of 1-(3-(trans-2-(methoxycarbonyl)cyclopropyl)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (ChemShuttle, 0.245 g, 1.00 mmol), trans-methyl-2-(3-bromophenyl)cyclopropane-1-carboxylate (0.255 g, 1.00 mmol), copper(II) acetate (CombiBlocks, 0.182 g, 1.00 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.194 g, 1.00 mmol), and potassium iodide (VWR, 0.332 g, 2.00 mmol) in DMSO (15 mL) was added DBU (Oakwood Chemicals, 0.45 mL, 3.00 mmol). The reaction mixture was heated to 115 °C under a N atmosphere for 10 h and then stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate (75 mL) and 1 M KHSO4 (75 mL). An emulsion formed and was broken up by the addition of 25 mL of brine. The phases were separated, and the organic phase was partitioned with HO (75 mL), followed by brine (75 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude red oil, 0.537 g. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 12 g RediSep Gold Rf flash silica cartridge with 5-30% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a yellow solid (0.081 g, 19% yield). The R was purified with 1:30:70 v / v acetic acid-ethyl acetate-hexane. f 0.33 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.94(br s,1H),7.85(d,1H,J=8.5Hz),7.3-7.5(m,2H),7.28(d,1H,J=8.0Hz),7.2-7.2(m,2H),7.14(dd, 1H,J=0.9,8.7Hz),6.86(s,1H),3.60(s,3H),2.5-2.5(m,1H),1.9-2.0(m,1H),1.4-1.5(m,2H); 19F-NMR (376MHz; DMSO-d6) δ-56.68; MS (APCI-) m / z 418.0 (M-1); HPLC UV purity Rt=9.688min, 98.9%.

[0333] Step C: Preparation of methyl trans-2-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)cyclopropane-1-carboxylate [ka] To a mixture of 1-(3-(trans-2-(methoxycarbonyl)cyclopropyl)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.071 g, 0.171 mmol) in DMF (2 mL) was added ammonium chloride (Chem-Impex, 0.027 g, 0.513 mmol). TBTU (Oakwood, 0.082 g, 0.256 mmol) was then added, followed by DIPEA (0.27 mL, 1.54 mmol). The reaction mixture was stirred at room temperature under a N atmosphere for 4 h. The reaction mixture was then partitioned between ethyl acetate (25 mL) and HO (25 mL). The phases were separated, and the organic phase was partitioned with 1 M KHSO (20 mL) followed by brine (20 mL). The organic layer was concentrated under reduced pressure to give the crude product as an orange solid (0.041 g, 58% yield). The crude solid was used in the next reaction without further purification. f 0.12 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 7.97(br s,1H),7.80(d,1H,J=8.7Hz),7.3-7.4(m,2H),7.2-7.3(m,2H),7.13(br s,2H),7.11(br s,1H),6.90(s,1H),3.60(s,3H),2.5-2.6(m,1H),1.9-2.0(m,1H),1.4-1.5(m,2H); 19 F-NMR (376MHz; DMSO-d6) δ-56.70; MS (APCI+) m / z 419.0 (M+1); HPLC UV purity Rt=8.83min, 97.3%.

[0334] Step D: Preparation of trans-2-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)cyclopropane-1-carboxylic acid (compound 15) [ka] To a mixture of methyl trans-2-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)cyclopropane-1-carboxylate (0.041 g, 0.099 mmol) in methanol (2 mL) was added 1 M lithium hydroxide (0.40 mL, 0.40 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (10 mL) and 1 M HCl (10 mL). The phases were separated and the organic phase was partitioned with water (10 mL) followed by brine (10 mL). The organic layer was concentrated under reduced pressure to give the title product as a white solid (0.038 g, 96% yield). R was dissolved in 1:50:50 v / v acetic acid-ethyl acetate-hexane. f 0.20 (UV254nM), 1 H-NMR(400MHz;DMSO-d6)δ 12.35(s,1H),8.01(br s,1H),7.83(d,1H,J=8.7Hz),7.40-7.45(m,2H),7.28(s,1H),7.25(d,1H,J=7.8Hz),7.1-7.2(m,3H),6.9 4(s,1H),2.4-2.5(m,1H),1.8-1.9(m,1H),1.46(td,1H,J=4.7,9.2Hz),1.38(ddd,1H,J=4.4,6.4,8.3Hz); 19 F-NMR(376MHz;DMSO-d6)δ-56.71;MS(APCI - ) m / z 403.0 (M-1); HPLC UV purity, Rt = 7.53 min, 96.0%, chiral HPLC purity, Rt = 16.9 min, 45.1%, Rt = 20.6 min, 49.9%, melting point = 182-183 °C.

[0335] Example 25: Synthesis of trans-(+)- and trans-(-)-2-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 15a and Compound 15b) [ka] Step A: Chiral separation of methyl trans-2-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)cyclopropane-1-carboxylate Diastereomers of methyl trans-2-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)cyclopropane-1-carboxylate (0.132 g) were separated by chiral HPLC on an (R,R) Whelk-01 column (250 mm x 4.6 mm) using 75:25:0.1 heptane:IPA:TEA at a flow rate of 21.2 mL / min with UV detection at 290 nm. Peak 1 eluted at 30.95 min and peak 2 eluted at 36.28 min.

[0336] Diastereomer 1 (peak 1) was concentrated under reduced pressure to give a white solid (0.40 mg, 30% recovery); R was purified by 1:60:40 v / v acetic acid-ethyl acetate-hexane. f 0.43(UV254nM); MS(APCI+)m / z 419.0(M+1),(APCI-)m / z 417.0(M-1);HPLC UV purity Rt=8.825min, 100%.

[0337] Diastereomer 2 (peak 2) was concentrated under reduced pressure to give a white solid (64.7 mg, 49% recovery); R was purified by 1:60:40 v / v acetic acid-ethyl acetate-hexane. f 0.43(UV254nM);MS(APCI+)m / z 419.0(M+1),(APCI-)m / z 417.0(M-1);HPLC UV purity Rt=8.814min,99.64%.

[0338] Step B: Preparation of trans-(+) and trans-(-)-2-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)cyclopropane-1-carboxylic acid To the individually separated diastereomers of methyl trans-2-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)cyclopropane-1-carboxylate (Peak 1, 0.040 g, 0.095 mmol), (Peak 2, 0.065 g, 0.155 mmol) in methanol (3.0 mL) was added 1 M lithium hydroxide (0.75 mL, 0.75 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (10 mL) and 1 M HCl (10 mL). The phases were separated, and the organic phase was partitioned with HO (10 mL), followed by brine (10 mL). The organic layer was concentrated under reduced pressure to give the crude product as a white solid.

[0339] Diastereomer 1 (peak 1, 15a) was concentrated under reduced pressure to give a white solid (0.019 g, 52% yield). f 0.27(UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.35(s,1H),8.01(br s,1H),7.83(d,1H,J=8.7Hz),7.40-7.45(m,2H),7.28(s,1H),7.25(d,1H,J=8.0Hz),7.1-7.2(m,3H),6.9 4(s,1H),2.4-2.5(m,1H),1.8-1.9(m,1H),1.46(td,1H,J=4.7,9.2Hz),1.38(ddd,1H,J=4.4,6.4,8.3Hz); 19 F-NMR(376MHz;DMSO-d6)δ-56.70;MS(APCI+)m / z 405.0(M+1),MS(APCI-)m / z 403.0(M-1);HPLC UV purity Rt=7.537min,99.27%;Chiral HPLC purity Rt=18.63min,99.5%;Melting point=185~186℃;Optical rotation [α] 25 D= +76.8(c=0.5, 1.0mL IPA).

[0340] Diastereomer 2 (peak 2, 15b) was concentrated under reduced pressure to give a white solid (0.045 g, 72.5% yield). f 0.27 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.33(s,1H),8.01(br s,1H),7.83(d,1H,J=8.7Hz),7.40-7.45(m,2H),7.28(s,1H),7.25(d,1H,J=8.0Hz),7.1-7.2(m,3H),6.9 4(s,1H),2.4-2.5(m,1H),1.8-1.9(m,1H),1.46(td,1H,J=4.7,9.2Hz),1.38(ddd,1H,J=4.4,6.4,8.3Hz); 19 F-NMR(376MHz;DMSO-d6)δ-56.70;MS(APCI+)m / z 405.0(M+1),MS(APCI-)m / z 403.0(M-1);HPLC UV purity Rt=7.537min,97.2%;Chiral HPLC purity Rt=17.08min,96.4%;Melting point=181~182℃;Optical rotation [α] 25 D = -60.8 (c = 0.5 g, in 100 mL of MeOH).

[0341] Example 26: Synthesis of 5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzofuran-2-carboxylic acid (Compound 16) [ka] Step A: Preparation of 1-(2-(ethoxycarbonyl)benzofuran-5-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (ChemShuttle, 0.245 g, 1.00 mmol), ethyl 5-bromobenzofuran-2-carboxylate (CombiBlocks, 0.269 g, 1.00 mmol), copper(II) acetate (CombiBlocks, 0.182 g, 1.00 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.194 g, 1.00 mmol), and potassium iodide (VWR, 0.332 g, 2.00 mmol) in DMSO (15 mL) was added DBU (Oakwood Chemicals, 0.45 mL, 3.00 mmol). The reaction mixture was heated to 115 °C under a N atmosphere for 7 h and then stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate (50 mL) and 1 M KHSO (50 mL). An emulsion formed and was broken up by the addition of 25 mL of brine. The phases were separated and the organic phase was partitioned with HO (50 mL) followed by brine (50 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude red oil, 0.571 g. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 24 g RediSep Gold Rf flash silica cartridge with 5-30% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as an orange solid (0.048 g, 11% yield). The R was purified with 1:30:70 v / v acetic acid-ethyl acetate-hexane. f 0.33 (UV 254 nM); MS (APCI-) m / z 432 (M-1); the product was used in the next step without further characterization.

[0342] Step B: Preparation of ethyl 5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzofuran-2-carboxylate [ka] To a mixture of 1-(2-(ethoxycarbonyl)benzofuran-5-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.048 g, 0.110 mmol) in DMF (3 mL) was added ammonium chloride (Chem-Impex, 0.018 g, 0.33 mmol). TBTU (Oakwood, 0.053 g, 0.16 mmol) was then added, followed by DIPEA (0.17 mL, 0.99 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (25 mL) and HO (25 mL). The phases were separated, and the organic phase was partitioned with 1 M KHSO (15 mL) followed by brine (15 mL). The organic layer was concentrated under reduced pressure to give the crude product as a white solid (0.043 g, 91% yield). The crude solid was used in the next reaction without further purification. f 0.09 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 8.07(br s,1H),7.9-8.0(m,1H),7.87(dd,2H,J=4.2,8.6Hz),7.83(s,1H),7.79(d,1H,J=2.1Hz),7.46(dd,1H,J=2.3,8.7Hz),7.39(br s,1H),7.35(s,1H),7.17(d,1H,J=8.7Hz),6.95(s,1H),4.40(q,2H,J=7.1Hz),1.36(t,3H,J=7.1Hz); 19 F-NMR (376MHz; DMSO-d6) δ-56.71; MS (APCI+) m / z 433.2 (M+1), (APCI-) m / z 432.0 (M-1); HPLC UV purity, Rt=9.232min, 91.3%.

[0343] Step C: Preparation of 5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzofuran-2-carboxylic acid (compound 16) [ka] To a mixture of 5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzofuran-2-carboxylate (0.043 g, 0.09 mmol) in methanol (2 mL) was added 1 M lithium hydroxide (0.40 mL, 0.40 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (15 mL) and 1 M HCl (10 mL). The phases were separated and the organic phase was partitioned with water (10 mL) followed by brine (10 mL). The organic layer was concentrated under reduced pressure to give the crude product as a white solid (0.038 g, 95% yield). The R was extracted with 1:50:50 v / v acetic acid-ethyl acetate-hexane. f 0.12 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.09(s,1H),8.06(br s,1H),7.85(t,1H,J=8.5Hz),7.77(d,1H,J=2.1Hz),7.73(s,1H),7.4-7.5(m,2H),7.34(s,1H),7.17(dd,1H,J=2.2,8.7Hz),6.96(s,1H); 19 F-NMR(376MHz;DMSO-d6)δ-56.71;MS(APCI + )m / z 405.0(M+1),403.0(M-1);HPLC UV purity, Rt=7.39min,99.6%;Melting point=293~294℃.

[0344] Example 27: Synthesis of 3-(3-(2-carbamoyl-5-(trifluoromethoxy)benzofuran-3-yl)phenyl)propanoic acid (Compound 17) [ka] Step A: Preparation of 3-(3-(3-methoxy-3-oxopropyl)phenyl)-5-(trifluoromethoxy)benzofuran-2-carboxylic acid [ka] To a 24 mL septa-capped vial was added methyl 3-bromobenzenepropanoate (Combi-Blocks, 0.246 g, 1.0 mmol) and 5-(trifluoromethoxy)benzofuran-2-carboxylic acid (0.243 g, 1.0 mmol) (prepared by the method of Gensini, M. et al., ChemMedChem 2010, 5(1), 65-78). Then, bis(dichloro(η 6 To the reaction mixture was added (Strem, 0.025 g, 4 mol%), trimethylphosphonium tetrafluoroborate (Strem, 0.014 g, 8 mol%), K2CO3 (VWR, 0.152 g, 1.1 mmol), and NMP (5 mL). The mixture was degassed by bubbling nitrogen gas through it with stirring for 3 minutes and then heated to 110 °C overnight. The reaction mixture was then cooled to room temperature and diluted with water (140 mL). The mixture was extracted with ethyl acetate (3 × 100 mL), and the combined organics were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to give a crude oil that was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 24 g RediSep Gold Rf flash silica cartridge with 10–40% ethyl acetate in heptane containing 1% acetic acid afforded the title compound as an amorphous solid (0.167 g, 41% yield). 1:30:70 v / v acetic acid-ethyl acetate-hexane f 0.22 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ MS(APCI + )m / z 409.1(M+1),m / z 407.1,(M-1).

[0345] Step B: Preparation of methyl 3-(3-(2-carbamoyl-5-(trifluoromethoxy)benzofuran-3-yl)phenyl)propanoate [ka] To a mixture of 3-(3-(3-methoxy-3-oxopropyl)phenyl)-5-(trifluoromethoxy)benzofuran-2-carboxylic acid (0.160 g, 0.39 mmol) in DMF (2.0 mL) was added ammonium chloride (Chem-Impex, 0.063 g, 1.17 mmol). TBTU (Oakwood, 0.189 g, 0.59 mmol) was then added, followed by DIPEA (0.62 mL, 3.5 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then diluted with water (60 mL) and then extracted with 2×50 mL of ethyl acetate. The combined organic phases were dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give the crude product as a colorless oil. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 12 g RediSep Gold Rf flash silica cartridge with 10-30% ethyl acetate in heptane containing 1% acetic acid afforded the title compound as an off-white solid (0.122 g, 76% yield). f 0.29 (UV254nM); 1 H-NMR(400MHz; CDCl3)δ 7.59(d,1H,J=8.9Hz),7.46(d,3H,J=4.6Hz),7.42(s,1H),7.3-7.4(m,2H),6.34(br s,1H),5.74(br s,1H),3.68(s,3H),3.04(t,2H,J=7.7Hz),2.71(t,2H,J=7.7Hz);MS(APCI + )m / z 408.1.0(M+1),m / z 406.0,(M-1).

[0346] Step C: Preparation of 3-(3-(2-carbamoyl-5-(trifluoromethoxy)benzofuran-3-yl)phenyl)propanoic acid (compound 17) [ka] To a mixture of methyl 3-(3-(2-carbamoyl-5-(trifluoromethoxy)benzofuran-3-yl)phenyl)propanoate (0.113 g, 0.28 mmol) in MeOH (3 mL) was added dropwise a 1 M aqueous solution of LiOH (0.83 mL, 3 equiv). The reaction mixture was stirred overnight at room temperature. The clear solution was then diluted with water (10 mL) and subjected to reduced pressure on a rotary evaporator to remove the MeOH. Additional water (10 mL) was added and the solution was acidified with 1 N HCl to precipitate the product. The suspension was filtered, the solid was washed with excess water, and then dried under high vacuum overnight to afford the title compound as a white solid (0.096 g, 87% yield). R was dissolved in 1:40:60 v / v acetic acid-ethyl acetate-hexane. f 0.22 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.16(br s,1H),8.06(br s,1H),7.7-7.9(m,2H),7.5-7.6(m,2H),7.4-7.5(m,3H),7.31(br d,1H,J=7.1Hz),2.90(t,2H,J=7.6Hz),2.59(t,2H,J=7.7Hz); 19 F-NMR(376MHz;DMSO-d6)δ-57.02;MS(APCI + ) m / z 394.0 (M+1), 392.0 (M-1); HPLC UV purity, Rt = 7.55 min, 99.5%; melting point = 234.0-235.5 °C.

[0347] Example 28: Synthesis of 3-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)propanoic acid (Compound 18) [ka] Step A: Preparation of 1-(6-(3-methoxy-3-oxopropyl)pyridin-2-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (ChemShuttle, 0.368 g, 1.50 mmol), methyl 3-(6-bromopyridin-2-yl)propanoate (AstaTech, 0.366 g, 1.50 mmol), copper(II) acetate (CombiBlocks, 0.272 g, 1.50 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.291 g, 1.50 mmol), and potassium iodide (VWR, 0.498 g, 3.00 mmol) in DMSO (15 mL) was added DBU (Oakwood Chemicals, 0.67 mL, 4.50 mmol). The reaction mixture was heated to 115 °C under a N atmosphere for 3 h. The reaction mixture was then partitioned between ethyl acetate (75 mL) and 1 M KHSO (50 mL). An emulsion formed and was broken up by the addition of 25 mL of brine. The phases were separated and the organic phase was partitioned with HO (75 mL) followed by brine (75 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude red oil, 0.656 g. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 12 g RediSep Gold Rf flash silica cartridge with 5-30% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as an orange solid (0.059 g, 10% yield). The R was purified with 1:30:70 v / v acetic acid-ethyl acetate-hexane. f 0.15 (UV 254 nM); MS (APCI+) m / z 409.0 (M+1), (APCI-) m / z 407 (M-1), HPLC UV purity, Rt = 8.54 min, 93.6%. The product was used in the next step without further characterization.

[0348] Step B: Preparation of methyl 3-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)propanoate [ka] To a mixture of methyl 3-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)propanoate (0.059 g, 0.144 mmol) in DMF (3 mL) was added ammonium chloride (Chem-Impex, 0.023 g, 0.43 mmol). Next, TBTU (Oakwood, 0.070 g, 0.22 mmol) was added, followed by DIPEA (0.23 mL, 1.29 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (25 mL) and HO (25 mL). The phases were separated, and the organic phase was partitioned with 1 M KHSO (25 mL) followed by brine (25 mL). The organic layer was concentrated under reduced pressure to give the crude product as an orange solid (0.052 g, 90% yield). The crude solid was used in the next reaction without further purification. f 0.06(UV254nM); MS(APCI+)m / z 408.0(M+1),(APCI-)m / z 406.0(M-1), HPLC UV purity, Rt=7.698min, 86.1%.

[0349] Step C: Preparation of 3-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)propanoic acid (compound 18) [ka] To a mixture of methyl 3-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)propanoate (0.047 g, 0.12 mmol) in methanol (2 mL) was added 1 M lithium hydroxide (0.50 mL, 0.50 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (10 mL) and 1 M HCl (10 mL). The phases were separated and the organic phase was partitioned with water (10 mL) followed by brine (10 mL). The organic layer was concentrated under reduced pressure to give the crude product as a white solid (0.033 g, 74% yield). The crude product was triturated with EA / heptane (1:1, 10 mL) and filtered through a fritted funnel. The filtered white solid was isolated as the title product (0.013 g, 28% yield). 1:50:50 v / v acetic acid-ethyl acetate-hexane f 0.12 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.14(s,1H),8.15(br s,1H),7.88(t,1H,J=7.8Hz),7.84(d,1H,J=8.7Hz),7.49(br s,1H),7.46(s,1H),7.33(d,1H,J=7.6Hz),7.25(s,1H),7.18(d,2H,J=7.8Hz),3.03(t,2H,J=7.5Hz),2.70(t,2H,J=7.5Hz); 19 F-NMR(376MHz;DMSO-d6)δ-56.72;MS(APCI + ) m / z 394.0 (M+1), 392.0 (M-1); HPLC UV purity, Rt = 6.605 min, 96.6%; melting point = 210-211 °C.

[0350] Example 29: Synthesis of 1-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzyl)cyclopropane-1-carboxylic acid (Compound 19) [ka] Step A: Preparation of tert-butyl 1-(3-bromobenzyl)cyclopropane-1-carboxylate [ka] To a −78° C. solution of tert-butyl cyclopropanecarboxylate (Oakwood, 1.00 g, 7.03 mmol) in THF (10 mL) was added freshly prepared LDA (0.5 M solution in THF, 21 mL, 10.50 mmol) in portions over 15 minutes. The reaction mixture was stirred at −78° C. for 3 hours, after which 1-bromo-3-(bromomethyl)benzene (Combi-Blocks, 1.90 g, 7.66 mmol) was added. The reaction mixture was stirred overnight and then allowed to warm to room temperature. The reaction mixture was then partitioned between ethyl acetate (50 mL) and saturated ammonium chloride (75 mL). The phases were separated, and the ammonium chloride layer was back-extracted (2×) with additional ethyl acetate (50 mL). The combined organic layers were dried over MgSO4, filtered through a fritted funnel, and the filtrate was concentrated under reduced pressure to give the crude product as a yellow oil (2.05 g). The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 24 g RediSep Gold Rf flash silica cartridge with 5-30% ethyl acetate in hexane gave the title compound as a colorless oil (1.42 g, 67% yield). Elution with 1:30:70 v / v acetic acid-ethyl acetate-hexane gave the title compound as a colorless oil (1.42 g, 67% yield). f 0.75 (UV254nM); 1 H-NMR(400MHz;CDCl3)δ 7.43(br s,1H),7.33(d,1H,J=7.8Hz),7.1-7.2(m,2H),2.88(s,2H),1.36(s,9H),1.2-1.3(m,2H),0.7-0.8(m,2H);LC / MS,Rt=8.434min,MS(APCI-)m / z 254,256 (Mt-butyl, Br present).

[0351] Step B: Preparation of 1-(3-((1-(tert-butoxycarbonyl)cyclopropyl)methyl)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (ChemShuttle, 0.245 g, 1.00 mmol), tert-butyl 1-(3-bromobenzyl)cyclopropane-1-carboxylate (0.311 g, 1.00 mmol), copper(II) acetate (CombiBlocks, 0.182 g, 1.00 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.194 g, 1.00 mmol), and potassium iodide (VWR, 0.332 g, 2.00 mmol) in DMSO (15 mL) was added DBU (Oakwood Chemicals, 0.45 mL, 3.0 mmol). The reaction mixture was heated to 115 °C under a N atmosphere for 8 h and then stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate (75 mL) and 1 M KHSO4 (75 mL). An emulsion formed and was broken up by the addition of 25 mL of brine. The phases were separated and the organic phase was partitioned with HO (75 mL) followed by brine (75 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude red oil, 0.588 g. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 12 g RediSep Gold Rf flash silica cartridge with 5-30% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a white solid (0.279 g, product mixture). R was removed by 1:30:70 v / v acetic acid-ethyl acetate-hexane. f 0.31 (UV 254 nM); LC / MS Rt=6.3 min, MS (APCI-) m / z 474.0 (M-1). The product was used in the next step without further characterization or purification.

[0352] Step C: Preparation of tert-butyl 1-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzyl)cyclopropane-1-carboxylate [ka] To a mixture of 1-(3-((1-(tert-butoxycarbonyl)cyclopropyl)methyl)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.279 g, 0.586 mmol) in DMF (6 mL) was added ammonium chloride (Chem-Impex, 0.094 g, 1.76 mmol). TBTU (Oakwood, 0.283 g, 0.88 mmol) was then added, followed by DIPEA (0.91 mL, 5.27 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (30 mL) and HO (25 mL). The phases were separated, and the organic phase was partitioned with 1 M KHSO (25 mL) followed by brine (25 mL). The organic layer was concentrated under reduced pressure to give the crude product as a white solid (0.253 g, 96% yield). The crude solid was used in the next reaction without further purification. f 0.55 (UV 254 nM); LC / MS Rt=7.842 min, MS (APCI-) m / z 473.0 (M-1). The product was used in the next step without further characterization or purification.

[0353] Step D: Preparation of 1-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzyl)cyclopropane-1-carboxylic acid (compound 19) [ka] To a mixture of 1-(3-((1-(tert-butoxycarbonyl)cyclopropyl)methyl)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.253 g, 0.53 mmol) in methanol (10 mL) was added 1 M lithium hydroxide (2.20 mL, 2.20 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (25 mL) and 1 M HCl (15 mL). The phases were separated and the organic phase was partitioned with water (15 mL) followed by brine (15 mL). The organic layer was concentrated under reduced pressure to give the crude product as a colorless oil (0.244 g). The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution of a 24 g RediSep Gold Rf flash silica cartridge with 5-30% ethyl acetate in hexane containing 1% acetic acid afforded the desired compound as a mixture (0.053 g). The crude product was repurified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution of a 4 g RediSep Gold Rf flash silica cartridge with 5% ethyl acetate in hexane containing 1% acetic acid afforded the desired compound as a white solid (0.027 g, 12% yield). The R was purified with 1:50:50 v / v acetic acid-ethyl acetate-hexane. f 0.49 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.14(s,1H),8.15(br s,1H),7.88(t,1H,J=7.8Hz),7.84(d,1H,J=8.7Hz),7.49(br s,1H),7.46(s,1H),7.33(d,1H,J=7.6Hz),7.25(s,1H),7.18(d,2H,J=7.8Hz),3.03(t,2H,J=7.5Hz),2.70(t,2H,J=7.5Hz); 19 F-NMR(376MHz;DMSO-d6)δ-56.72;MS(APCI + ) m / z 394.0 (M+1), 392.0 (M-1); HPLC UV purity, Rt = 6.605 min, 96.6%; melting point = 141-142 °C.

[0354] Example 30: Synthesis of 5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzofuran-3-carboxylic acid (Compound 20) [ka] Step A: Preparation of 1-(3-(methoxycarbonyl)benzofuran-5-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (ChemShuttle, 0.245 g, 1.00 mmol), methyl 5-bromobenzofuran-3-carboxylate (0.255 g, 1.00 mmol), copper(II) acetate (CombiBlocks, 0.182 g, 1.00 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.194 g, 1.00 mmol), and potassium iodide (VWR, 0.332 g, 2.00 mmol) in DMSO (15 mL) was added DBU (Oakwood Chemicals, 0.45 mL, 3.0 mmol). The reaction mixture was heated to 115 °C under a N atmosphere for 8 h and then stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate (75 mL) and 1 M KHSO (75 mL). An emulsion formed and was broken up by the addition of 25 mL of brine. The phases were separated and the organic phase was partitioned with HO (75 mL) followed by brine (75 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude red oil, 0.633 g. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 12 g RediSep Gold Rf flash silica cartridge with 5-30% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a tan solid (0.041 g, 9.7% yield). The R was purified with 1:50:50 v / v acetic acid-ethyl acetate-hexane.f 0.56 (UV 254 nM); MS (APCI+) m / z 420.0 (M+1), (APCI-) m / z 419.0 (M-1), HPLC UV purity, Rt = 9.598 min, 96.8%. The product was used in the next step without further characterization or purification.

[0355] Step B: Preparation of methyl 5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzofuran-3-carboxylate [ka] To a mixture of 1-(3-(methoxycarbonyl)benzofuran-5-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.040 g, 0.095 mmol) in DMF (2 mL) was added ammonium chloride (Chem-Impex, 0.015 g, 0.143 mmol). TBTU (Oakwood, 0.046 g, 0.143 mmol) was then added, followed by DIPEA (0.15 mL, 0.855 mmol). The reaction mixture was stirred at room temperature under a N atmosphere for 4 h. The reaction mixture was then partitioned between ethyl acetate (15 mL) and HO (15 mL). The phases were separated, and the organic phase was partitioned with 1 M KHSO (10 mL) followed by brine (10 mL). The organic layer was concentrated under reduced pressure to give the crude product as a yellow film (0.36 g, 92% yield). The crude solid was used in the next reaction without further purification. f 0.34 (UV254nM): MS (APCI+) m / z 419.0 (M+1); HPLC UV purity, Rt=8.816min, 93.3%.

[0356] Step C: Preparation of 5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzofuran-3-carboxylic acid (compound 20) [ka] To a mixture of methyl 5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzofuran-3-carboxylate (0.036 g, 0.087 mmol) in methanol (2 mL) was added 1 M lithium hydroxide (0.35 mL, 0.35 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (15 mL) and 1 M HCl (10 mL). The phases were separated, and the organic phase was partitioned with water (10 mL) followed by brine (10 mL). The organic layer was concentrated under reduced pressure to give the crude product as a tan solid (0.030 g). TLC and LC / MS indicated the presence of starting material, so the crude material was redissolved in methanol (2 mL) and 1 M LiOH (1 mL) was added. The reaction mixture was heated to 45° C. for 5 h until the reaction showed complete conversion. The reaction mixture was then partitioned between ethyl acetate (25 mL) and 1 M HCl (15 mL). The phases were separated and the organic phase was partitioned with water (15 mL) followed by brine (15 mL). The organic layer was concentrated under reduced pressure to give the crude product as an orange solid (0.026 g). The product was triturated with (EA / Hep 40:60, 6 mL) and filtered through a fritted funnel to give the desired compound as a tan solid (0.016 g, 46% yield). 1:50:50 v / v acetic acid-ethyl acetate-hexanes was used to give the desired product as a tan solid (0.016 g, 46% yield). f 0.22 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 13.14(s,1H),8.82(s,1H),8.07(br s,1H),7.86(dd,1H,J=2.1Hz),7.40-7.45(m,2H),7.34(s,1H),7.18(d,1H,J=7.8Hz),6.93(s,1H); 19 F-NMR(376MHz;DMSO-d6)δ-56.74;MS(APCI + )m / z 405.0(M+1),403.0(M-1);HPLC UV purity, Rt=7.569min,96.5%;Melting point=277~278℃.

[0357] Example 31: Synthesis of 5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzofuran-3-carboxylic acid (Compound 21) [ka] Step A: Preparation of 1-(3-(3-methoxy-3-oxopropyl)phenyl)-1H-indole-2-carboxylic acid [ka] To a mixture of 1H-indole-2-carboxylic acid (Ambeed, 0.483 g, 3.00 mmol), methyl 3-(3-bromophenyl)propanoate (CombiBlocks, 0.729 g, 3.00 mmol), copper(II) acetate (CombiBlocks, 0.543 g, 3.00 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.582 g, 3.00 mmol), and potassium iodide (VWR, 0.996 g, 6.00 mmol) in DMSO (20 mL) was added DBU (Oakwood Chemicals, 1.34 mL, 9.0 mmol). The reaction mixture was heated to 115 °C under a N atmosphere for 8 h and then stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate (100 mL) and 1 M KHSO (50 mL). An emulsion formed and was broken up by the addition of 25 mL of brine. The phases were separated and the organic phase was partitioned with HO (50 mL) followed by brine (50 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude red oil, 1.15 g. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 24 g RediSep Gold Rf flash silica cartridge with 5-30% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a yellow oil (0.283 g, 29% yield). The R was purified with 1:30:70 v / v acetic acid-ethyl acetate-hexane. f0.30 (UV 254 nM); MS (APCI+) m / z 324.0 (M+1), (APCI-) m / z 322.0 (M-1), LC / MS, Rt = 5.401 min, (APCI+) m / z 324.0 (M+1). The product was used in the next step without further characterization or purification.

[0358] Step B: Preparation of methyl 3-(3-(2-carbamoyl-1H-indol-1-yl)phenyl)propanoate [ka] To a mixture of 1-(3-(3-methoxy-3-oxopropyl)phenyl)-1H-indole-2-carboxylic acid (0.265 g, 0.819 mmol) in DMF (6 mL) was added ammonium chloride (Chem-Impex, 0.131 g, 2.46 mmol). TBTU (Oakwood, 0.395 g, 1.23 mmol) was then added, followed by DIPEA (1.28 mL, 7.37 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (50 mL) and HO (50 mL). The phases were separated, and the organic phase was partitioned with 1 M KHSO (25 mL) followed by brine (25 mL). The organic layer was concentrated under reduced pressure to give the crude product as a yellow oil (0.49 g). The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 24 g RediSep Gold Rf flash silica cartridge with 5-30% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a yellow solid (0.069 g, 26% yield). Elution with 1:30:70 v / v acetic acid-ethyl acetate-hexane gave the title compound as a yellow solid (0.069 g, 26% yield). f 0.12 (UV 254 nM): MS (APCI+) m / z 323.2 (M+1); HPLC UV purity, Rt=7.428 min, 98.9%. The product was used in the next step without further characterization or purification.

[0359] Step C: Preparation of 5-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)benzofuran-3-carboxylic acid (compound 21) [ka] To a mixture of methyl 3-(3-(2-carbamoyl-1H-indol-1-yl)phenyl)propanoate (0.069 g, 0.217 mmol) in methanol (4 mL) was added 1 M lithium hydroxide (0.87 mL, 0.87 mmol). The reaction mixture was stirred overnight at room temperature under a N2 atmosphere. The reaction mixture was then partitioned between ethyl acetate (25 mL) and 1 M HCl (10 mL). The phases were separated and the organic phase was partitioned with water (25 mL) followed by brine (25 mL). The organic layer was concentrated under reduced pressure to give the title compound as a white solid (0.054 g, 82% yield). R was obtained by eluting with 1:10:90 v / v acetic acid-methanol-dichloromethane. f 0.71 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.15(s,1H),7.89(br s,1H),7.66(d,1H,J=7.8Hz),7.37(t,1H,J=7.7Hz),7.25(br MS(APCI + )m / z 309.0(M+1),307.0(M-1);HPLC UV purity, Rt=6.251min,99.7%;Melting point=221~222℃.

[0360] Example 32: Synthesis of 3-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)-3-methylbutanoic acid (Compound 22) [ka] Step A: Preparation of methyl 3-(3-bromophenyl)-3-methylbutanoate [ka] To an ice-bath (0 °C) reaction mixture of 3-(3-bromophenyl)-3-methylbutanoic acid (0.50 g, 1.94 mmol) in toluene (6 mL) and methanol (4 mL) was added TMS-diazomethane (2 M solution in ether, 1.45 mL, 2.91 mmol) dropwise. The reaction was stirred at 0 °C for 30 minutes and allowed to warm to room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to give the crude product as a yellow oil (0.550 g). The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 12 g RediSep Gold Rf flash silica cartridge with 5 to 100% ethyl acetate in heptane gave the title compound as a colorless oil (0.380 g, 72% yield). The R was removed by 25:75 v / v ethyl acetate-heptane. f 0.69 (UV254nM); 1 H-NMR(400MHz;CDCl3)δ 7.50(t,1H,J=1.8Hz),7.30-7.40(m,2H),7.1-7.2(m,1H),3.55(s,3H),2.62(s,2H),1.44(s,6H);MS(APCI+)m / z 271.0(M+1);HPLC UV purity Rt=9.620min,100%.

[0361] Step B: Preparation of 1-(3-(4-methoxy-2-methyl-4-oxobutan-2-yl)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (ChemShuttle, 0.339 g, 1.38 mmol), methyl 3-(3-bromophenyl)-3-methylbutanoate (0.375 g, 1.38 mmol), copper(II) acetate (CombiBlocks, 0.250 g, 1.38 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.268 g, 1.38 mmol), and potassium iodide (VWR, 0.458 g, 2.76 mmol) in DMSO (20 mL) was added DBU (Oakwood Chemicals, 0.61 mL, 4.14 mmol). The reaction mixture was heated to 115 °C under a N atmosphere for 8 h and then stirred at room temperature overnight. The reaction mixture was then partitioned between ethyl acetate (75 mL) and 1 M KHSO (50 mL). An emulsion formed and was broken up by the addition of 25 mL of brine. The phases were separated and the organic phase was partitioned with HO (50 mL) followed by brine (50 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude red oil, 0.724 g. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 24 g RediSep Gold Rf flash silica cartridge with 5 to 75% ethyl acetate in heptane containing 1% acetic acid afforded the title compound as a white solid (0.283 g). The resulting product contained two impurities and was used in the next reaction without further purification. The R was eluted with 1:30:70 v / v acetic acid-ethyl acetate-heptane. f 0.30 (UV254nM), MS (APCI+) m / z 436.2 (M+1), (APCI-) m / z 434.0 (M-1), HPLC UV purity, Rt=10.071min, 51.2%.

[0362] Step C: Preparation of methyl 3-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)-3-methylbutanoate [ka] To a mixture of 1-(3-(4-methoxy-2-methyl-4-oxobutan-2-yl)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.320 g, 0.735 mmol) in DMF (6 mL) was added ammonium chloride (Chem-Impex, 0.118 g, 2.21 mmol). TBTU (Oakwood, 0.354 g, 1.10 mmol) was then added, followed by DIPEA (1.15 mL, 6.62 mmol). The reaction mixture was stirred at room temperature under a N atmosphere for 3 h. The reaction mixture was then partitioned between ethyl acetate (50 mL) and HO (50 mL). The phases were separated, and the organic phase was partitioned with 1 M KHSO (25 mL) followed by brine (25 mL). The organic layer was concentrated under reduced pressure to give the crude product as a yellow oil (0.421 g). The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 24 g RediSep Gold Rf flash silica cartridge with 5-75% ethyl acetate in heptane containing 1% acetic acid afforded the title compound as a white solid (0.108 g, 34% yield). Elution with 1:30:70 v / v acetic acid-ethyl acetate-heptane gave the title compound as a white solid (0.108 g, 34% yield). f 0.17 (UV254nM): MS (APCI+) m / z 435.2 (M+1); HPLC UV purity, Rt=9.323min, 96.5%.

[0363] Step D: Preparation of 3-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)-3-methylbutanoic acid (compound 22) [ka] To a mixture of methyl 3-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)-3-methylbutanoate (0.108 g, 0.248 mmol) in methanol (4 mL) was added 1 M lithium hydroxide (1.00 mL, 1.00 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (25 mL) and 1 M HCl (10 mL). The phases were separated and the organic phase was partitioned with water (25 mL) followed by brine (25 mL). The organic layer was concentrated under reduced pressure to give the title compound as a white solid (0.054 g, 82% yield). R was obtained by eluting with 1:10:90 v / v acetic acid-methanol-dichloromethane. f 0.71 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 11.92(br s,1H),7.99(br s,1H),7.83(d,1H,J=8.7Hz),7.40-7.46(m,4H),7.27(s,1H),7.11-7.16(m,2H),7.08(br s,1H),2.62(s,2H),1.41(s,6H); 19 F-NMR(376MHz;DMSO-d6)δ-56.77;MS(APCI + )m / z 421.2(M+1),419.2(M-1);HPLC UV purity, Rt=8.166min,98.8%;Melting point=163~164℃.

[0364] Example 33: Synthesis of (R)-2-amino-3-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)propanoic acid TFA salt (Compound 23) [ka] Step A: Preparation of tert-butyl (R)-3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoate [ka] To a solution of (R)-3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (2.00 g, 5.80 mmol) in 20 mL of tBuOH at room temperature, DMAP (0.07 g, 0.58 mmol) and di-tert-butyl dicarbonate (1.65 g, 7.50 mmol) were added under a N atmosphere, and the reaction was stirred at room temperature for 14 h. The reaction mixture was evaporated to dryness and partitioned between 100 mL of ethyl acetate and 150 mL of water. The organic layer was washed sequentially with water (100 mL) and brine (100 mL), then dried over anhydrous sodium sulfate. The crude reaction mixture was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through an 80 g RediSep Gold Rf flash silica cartridge with 0-5% methanol in DCM gave the title compound as a clear, colorless oil (1.1 g, 47% yield). f 0.70 (UV254nM); 1 H NMR(400MHz,chloroform-d)δ 7.35(br d,J=7.57Hz,1H),7.25(d,J=1.38Hz,1H),7.05-7.19(m,2H),4.70-5.12(m,1H),4.31-4.59(m,1H),2.88-3.12(m,2H),1.41(br d,J=8.71Hz,18H);MS(FIA MS+)m / z 400(M+1).

[0365] Step B: Preparation of (R)-1-(3-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (ChemShuttle, 0.24 g, 0.98 mmol), tert-butyl (R)-3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoate (0.43 g, 1.00 mmol), copper(II) acetate (CombiBlocks, 0.18 g, 0.98 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.19 g, 0.98 mmol), and potassium iodide (VWR, 0.16 g, 0.98 mmol) in DMSO (10 mL) was added DBU (Oakwood Chemicals, 0.45 mL, 2.90 mmol). The reaction mixture was heated to 115 °C under a N atmosphere for 14 h and then stirred at room temperature for 1 h. The reaction mixture was then partitioned between ethyl acetate (75 mL) and 1 M KHSO4 (50 mL). An emulsion formed and was broken up by the addition of 25 mL of brine. The phases were separated, and the organic phase was partitioned with HO (75 mL), followed by brine (75 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 0.500 g of a crude gummy mass. The crude was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 24 g RediSep Gold Rf flash silica cartridge with 5-39% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as an off-white solid (0.18 g, 33% yield). The R was purified with 1:39:60 v / v acetic acid-ethyl acetate-hexane. f 0.32 (UV254nM); 1 H NMR(400MHz,chloroform-d)δ 8.03-8.86(m,1H),7.69(br d,1H,J=8.48Hz),7.48(s,1H),7.32-7.44(m,1H),7.20-7.31(m,2H),7.17(br MS(FIA-)m / z 565.0(M+1).

[0366] Step C: Preparation of tert-butyl (R)-2-((tert-butoxycarbonyl)amino)-3-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)propanoate [ka] To a mixture of (R)-1-(3-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.165 g, 0.29 mmol) in DMF (8 mL) was added ammonium chloride (Chem-Impex, 0.047 g, 0.88 mmol). Next, TBTU (Oakwood, 0.141 g, 0.43 mmol) was added, followed by DIPEA (0.34 mL, 2.61 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (50 mL) and HO (50 × 3 mL). The phases were separated, and the organic phase was partitioned with 1 M KHSO (50 mL) followed by brine (50 mL). The organic layer was concentrated under reduced pressure to give the crude product as an orange solid. The crude was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 12 g RediSep Gold Rf flash silica cartridge with 5-39% ethyl acetate in hexane containing 1% acetic acid gave the title compound as an off-white solid (0.14 g, 87% yield). Elution with 1:39:60 v / v acetic acid-ethyl acetate-hexane gave the title compound as an off-white solid (0.14 g, 87% yield). f 0.25 (UV254nM); 1H NMR(400MHz,chloroform-d)δ 7.71(d,1H,J=8.71Hz),7.43-7.55(m,1H),7.28-7.37(m,1H),7.30(br d,3H,J=11.00Hz),7.06-7.16(m,1H),6.93-7.04(m,1H),5.47-5.93(m,2H),5.01-5.31(m,1 MS(FIA-)m / z 564.0(M+1).

[0367] Step D: Preparation of (R)-2-amino-3-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)propanoic acid TFA salt [ka] To a mixture of tert-butyl (R)-2-((tert-butoxycarbonyl)amino)-3-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)propanoate (0.14 g, 0.248 mmol) in DCM (3 mL) was added trifluoroacetic acid (3.00 mL, 39.7 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was concentrated to dryness under reduced pressure, and then 10 mL of DCM was added and evaporated, and the process was repeated four times to give a crystalline material. This was washed with diethyl ether and dried to give the title compound as a white solid (0.080 g, 79% yield). R was dissolved in 1:40:60 v / v acetic acid-ethyl acetate-heptane. f 0.2 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 7.87-8.10(m,1H),7.78(d,1H,J=8.48Hz),7.29-7.47(m,3H),7.17-7.28(m,3 H),7.05-7.16(m,2H),3.48-3.62(m,2H),3.05-3.27(m,4H),2.92(br dd,1H,J=14.10,8.14Hz); 19F-NMR(376MHz;DMSO-d6)δ-59.43,-76.88;MS(FIA MS+)m / z 408(M+1);HPLC UV purity, Rt=5.88min,94.2%;Melting point=173~174℃.

[0368] Example 34: Synthesis of (S)-2-amino-3-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)propanoic acid TFA salt (Compound 24) [ka] Step A: Preparation of tert-butyl (S)-3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoate [ka] To a solution of (S)-3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoic acid (2.00 g, 5.80 mmol) in 20 mL of tBuOH at room temperature, DMAP (0.07 g, 0.58 mmol) and di-tert-butyl decarbonate (1.65 g, 7.50 mmol) were added under a N atmosphere, and the reaction was stirred at room temperature for 14 h. The reaction mixture was evaporated to dryness and partitioned between 100 mL of ethyl acetate and 150 mL of water. The organic layer was washed sequentially with water (100 mL) and brine (100 mL), then dried over anhydrous sodium sulfate. The crude reaction mixture was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through an 80 g RediSep Gold Rf flash silica cartridge with 0-5% methanol in DCM gave the title compound as a clear, colorless oil (1.1 g, 47% yield); f 0.70 (UV254nM); 1H NMR (400 MHz, chloroform-d) δ 7.27-7.40 (m, 2H), 7.05-7.19 (m, 2H), 4.70-5.14 (m, 1H), 4.28-4.63 (m, 1H), 2.80-3.25 (m, 2H), 1.41 (d, 18H, J = 8.94 Hz); MS (FIA MS+) m / z 400 (M+1).

[0369] Step B: Preparation of (S)-1-(3-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (ChemShuttle, 0.24 g, 0.98 mmol), tert-butyl (S)-3-(3-bromophenyl)-2-((tert-butoxycarbonyl)amino)propanoate (0.43 g, 1.00 mmol), copper(II) acetate (CombiBlocks, 0.18 g, 0.98 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.19 g, 0.98 mmol), and potassium iodide (VWR, 0.16 g, 0.98 mmol) in DMSO (10 mL) was added DBU (Oakwood Chemicals, 0.45 mL, 2.90 mmol). The reaction mixture was heated to 115 °C under a N atmosphere for 14 h and then stirred at room temperature for 1 h. The reaction mixture was then partitioned between ethyl acetate (75 mL) and 1 M KHSO4 (50 mL). An emulsion formed and was broken up by the addition of 25 mL of brine. The phases were separated, and the organic phase was partitioned with HO (75 mL), followed by brine (75 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude mass (0.500 g). The crude product was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 24 g RediSep Gold Rf flash silica cartridge with 5-39% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as an off-white solid (0.135 g, 24% yield). The R was purified with 1:39:60 v / v acetic acid-ethyl acetate-hexane. f 0.32 (UV254nM); 1 H NMR(400MHz,chloroform-d)δ 7.62-7.78(m,1H),7.37-7.55(m,2H),7.26-7.31(m,1H),7.15-7.23(m,1H),7.04-7.15(m,2H),6.91-7 .04(m,1H),4.92-5.39(m,1H),4.34-4.70(m,2H),2.82-3.33(m,2H),1.27-1.45(m,18H);MS(FIA-)m / z 565.0(M+1).

[0370] Step C: Preparation of tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)propanoate [ka] To a mixture of (S)-1-(3-(3-(tert-butoxy)-2-((tert-butoxycarbonyl)amino)-3-oxopropyl)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.125 g, 0.22 mmol) in DMF (8 mL) was added ammonium chloride (Chem-Impex, 0.036 g, 0.66 mmol). TBTU (Oakwood, 0.107 g, 0.33 mmol) was then added, followed by DIPEA (0.26 mL, 1.99 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (50 mL) and HO (50 × 3 mL). The phases were separated, and the organic phase was partitioned with 1 M KHSO (50 mL) followed by brine (50 mL). The organic layer was concentrated under reduced pressure to give the crude product as an orange solid. The crude was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 12 g RediSep Gold Rf flash silica cartridge with 5-39% ethyl acetate in hexane containing 1% acetic acid gave the title compound as an off-white solid (0.12 g, 96% yield). 1:39:60 v / v acetic acid-ethyl acetate-hexane gave the title compound as an off-white solid (0.12 g, 96% yield). f 0.25 (UV254nM); 1H NMR(400MHz,chloroform-d)δ 7.69(d,1H,J=8.71Hz),7.40-7.54(m,1H),7.25-7.35(m,4H),7.08(br d,1H,J=8.71Hz),6.96(br s,1H),5.64(br s,2H),5.16(br d,1H,J=7.34Hz),4.26-4.61(m,1H),3.21(br dd,1H,J=13.64,5.39Hz),2.98(br dd,1H,J=13.53,7.34Hz),1.40(s,9H),1.33(s,9H);MS(FIA MS+)m / z 564(M+1).

[0371] Step D: Preparation of (S)-2-amino-3-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)propanoic acid TFA salt (compound 24) [ka] To a mixture of tert-butyl (S)-2-((tert-butoxycarbonyl)amino)-3-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)propanoate (0.11 g, 0.195 mmol) in DCM (3 mL) was added trifluoroacetic acid (3.00 mL, 39.7 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was concentrated to dryness under reduced pressure, and then 10 mL of DCM was added and evaporated, and the process was repeated four times to give a crystalline material. This was washed with diethyl ether and dried to give the title compound as a white solid (0.050 g, 62% yield). The R was obtained by eluting with 1:40:60 v / v acetic acid-ethyl acetate-heptane. f 0.2 (UV254nM); 1H-NMR(400MHz;DMSO-d6)δ 7.90-8.05(m,1H),7.73-7.85(m,1H),7.39-7.47(m,1H),7.27-7.39(m,2H ),7.25(s,1H),7.23(s,1H),7.06-7.20(m,3H),3.61-3.86(m,2H),3.18(br dd,3H,J=14.21,4.81Hz),2.97(br dd,2H,J=14.21,8.02Hz); 19 F-NMR(376MHz;DMSO-d6)δ-59.43,-76.88;MS(FIA MS+)m / z 408(M+1);HPLC UV purity, Rt=5.88min,91.3%;Melting point=173~174℃.

[0372] Example 35: Synthesis of 3-(3-(2-carbamoylbenzofuran-3-yl)phenyl)propanoic acid (Compound 25) [ka] Step A Preparation of 3-(3-(3-methoxy-3-oxopropyl)phenyl)benzofuran-2-carboxylic acid [ka] To a 24 mL septa-capped vial was added methyl 3-bromobenzenepropanoate (Combi-Blocks, 0.547 g, 2.25 mmol) and benzofuran-2-carboxylic acid (Combi-Blocks, 0.243 g, 1.5 mmol). Next, rhodium diacetate (ArkPharm, 0.027 g, 4 mol%), K2CO3 (VWR, 0.311 g, 2.25 mmol), and DMF (6 mL) were added. The mixture was degassed by bubbling nitrogen gas through it with stirring for 3 minutes and then heated to 140 °C overnight. The reaction mixture was then cooled to room temperature and diluted with water (140 mL). The mixture was extracted with ethyl acetate (3 × 100 mL), and the combined organics were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give a crude oil that was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 24 g RediSep Gold Rf flash silica cartridge with 5-55% ethyl acetate:heptane containing 1% acetic acid gave the title compound as an amorphous solid (0.051 g, 10% yield). f 0.37(UV254nM); 1 H-NMR(400MHz;CD3OD)δ 7.63(d,1H,J=8.5Hz),7.57(d,1H,J=8.0Hz),7.53(dt,1H,J=0.9,7.8Hz),7.3- 7.5(m,5H),3.65(s,3H),3.01(t,2H,J=7.6Hz),2.70(t,2H,J=7.6Hz);MS(APCI + )m / z 325.0(M+1),m / z 323.2(M-1).

[0373] Step B: Preparation of methyl 3-(3-(2-carbamoylbenzofuran-3-yl)phenyl)propanoate [ka] To a mixture of 3-(3-(3-methoxy-3-oxopropyl)phenyl)benzofuran-2-carboxylic acid (0.048 g, 0.15 mmol) in DMF (1.0 mL) was added ammonium chloride (Chem-Impex, 0.024 g, 0.44 mmol). TBTU (Oakwood, 0.071 g, 0.22 mmol) was then added, followed by DIPEA (0.23 mL, 1.3 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then evaporated, and the residue was diluted with water (40 mL) and extracted with 3 × 20 mL of ethyl acetate. The combined organic phases were dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give the crude product as a colorless oil. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 24 g RediSep Gold Rf flash silica cartridge with 10 to 100% ethyl acetate in heptane containing 1% acetic acid afforded the title compound as a white semi-solid (0.032 g, 68% yield). f 0.25 (UV254nM); 1 H-NMR(400MHz;CD3OD)δ 7.60(dd,2H,J=8.1,18.5Hz),7.4-7.5(m,4H),7.3-7.4(m,2H),3.65(s,3H),3.00(t,2H,J=7.6Hz),2.70(t,2H,J=7.6Hz) + ) m / z 324.1(M+1).

[0374] Step C: Preparation of 3-(3-(2-carbamoylbenzofuran-3-yl)phenyl)propanoic acid (compound 25) [ka] To a mixture of methyl 3-(3-(2-carbamoylbenzofuran-3-yl)phenyl)propanoate (0.032 g, 0.10 mmol) in MeOH (2 mL) was added dropwise a 1 M aqueous solution of LiOH (0.3 mL, 3 equiv). The reaction mixture was stirred overnight at room temperature. The clear solution was then diluted with water (10 mL) and subjected to reduced pressure on a rotary evaporator to remove the MeOH. Additional water (10 mL) was added, and the solution was acidified with 1 N HCl to precipitate the product. The suspension was filtered, the solid was washed with excess water, and then dried under high vacuum overnight to afford the title compound as a white solid (0.020 g, 65% yield). The R was dissolved in 1:40:60 v / v acetic acid-ethyl acetate-heptane. f 0.13 (UV254nM); 1 H-NMR(400MHz;CD3OD)δ 7.61(dd,2H,J=8.1,11.3Hz),7.5-7.5(m,2H),7.4-7.5(m,2H),7.3-7.4(m,2H),3.00(t,2H,J=7.6Hz),2.67(t,2H,J=7.7Hz) + )m / z 310.1(M+1),308.1(M-1).HPLC UV purity, Rt=6.36min, 98.3%. Melting point 186.0~187.5℃ (dec.).

[0375] Example 36: Synthesis of tert-butyl ((6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)methyl)carbamate (Compound 26) and 1-(6-(aminomethyl)pyridin-2-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxamide TFA salt (Compound 27) [ka] Step A: Preparation of 1-(6-(((tert-butoxycarbonyl)amino)methyl)pyridin-2-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (ChemShuttle, 0.368 g, 1.50 mmol), tert-butyl ((6-bromopyridin-2-yl)methyl)carbamate (ChemScene, 0.386 g, 1.50 mmol), copper(II) acetate (CombiBlocks, 0.272 g, 1.50 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.291 g, 1.50 mmol), and potassium iodide (VWR, 0.498 g, 3.00 mmol) in DMSO (20 mL) was added DBU (Oakwood Chemicals, 0.67 mL, 4.50 mmol). The reaction mixture was heated to 115 °C under a N atmosphere for 4 h and then cooled to room temperature. The reaction mixture was then partitioned between ethyl acetate (75 mL) and 1 M KHSO4 (50 mL). An emulsion formed and was broken up by the addition of 25 mL of brine. The phases were separated, and the organic phase was partitioned with HO (50 mL), followed by brine (50 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude red oil, 1.02 g. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 24 g RediSep Gold Rf flash silica cartridge with 5 to 75% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a tan solid (0.087 g, 12% yield); elution with 1:30:70 v / v acetic acid-ethyl acetate-hexane yielded the title compound as a tan solid (0.087 g, 12% yield). f 0.14 (UV 254 nM); MS (APCI+) m / z 452.0 (M+1), (APCI-) m / z 450.0 (M-1); HPLC UV purity, Rt = 9.02 min, 83.8%. The product was used in the next step without further characterization.

[0376] Step B: Preparation of tert-butyl ((6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)methyl)carbamate (Compound 26) [ka] To a mixture of 1-(6-(((tert-butoxycarbonyl)amino)methyl)pyridin-2-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.083 g, 0.183 mmol) in DMF (2 mL) was added ammonium chloride (Chem-Impex, 0.029 g, 0.55 mmol). TBTU (Oakwood, 0.088 g, 0.275 mmol) was then added, followed by DIPEA (0.29 mL, 1.65 mmol). The reaction mixture was stirred at room temperature under a N atmosphere for 5 h. The residue was then partitioned between ethyl acetate (25 mL) and HO (20 mL). The phases were separated, and the organic phase was partitioned with 1 M KHSO (15 mL), followed by brine (15 mL). The organic layer was concentrated under reduced pressure to give the crude product as a yellow oil (0.081 g). The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 12 g RediSep Gold Rf flash silica cartridge with 10-70% ethyl acetate in heptane containing 1% acetic acid afforded the title compound as a white solid (0.058 g, 71% yield). Elution with 1:30:70 v / v acetic acid-ethyl acetate-heptane gave the title compound as a white solid (0.058 g, 71% yield). f 0.07(UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 8.16(br s,1H),8.07(br s,1H),7.94(t,1H,J=7.8Hz),7.84(d,1H,J=8.7Hz),7.45-7.51(m,2H),7.44(s ,1H),7.25-7.35(m,2H),7.17-7.21(m,2H),4.26(d,2H,J=6.0Hz),1.40(s,9H); 19 F-NMR(376MHz;DMSO-d6)δ-56.62;MS(APCI+)m / z 451.0(M+1),(APCI-)m / z 449.0(M-1);HPLC UV purity Rt=8.271min,99.0%.

[0377] Step C: Preparation of 1-(6-(aminomethyl)pyridin-2-yl)-6-(trifluoromethoxy)-1H-indole-2-carboxamide TFA salt (compound 27) [ka] To a mixture of tert-butyl ((6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)methyl)carbamate (0.058 g, 0.129 mmol) in DCM (2 mL) was added trifluoroacetic acid (Chem-Impex, 0.5 mL, 6.74 mmol). The reaction mixture was stirred at room temperature under a N atmosphere for 1 h. The reaction mixture was then concentrated under reduced pressure using co-evaporation with toluene (25 mL × 4) to give the crude product as a white solid (0.052 g, 88% yield). The R was extracted with 1:60:40 v / v acetic acid-ethyl acetate-heptane. f 0.05 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 8.32(br s,3H),8.20(br s,1H),8.04(t,1H,J=7.8Hz),7.86(d,1H,J=8.7Hz),7.55(d,1H,J=7.8Hz),7.45-7.50( m,2H),7.35(s,1H),7.32(d,1H,J=7.8Hz),7.21(d,1H,J=8.7Hz),4.31(d,2H,J=5.3Hz); 19 F-NMR(376MHz;DMSO-d6)δ-56.58,-73.45;MS(APCI+)m / z 351.0(M+1);HPLC UV purity, Rt=5.437min,99.5%;Melting point=187~188℃.

[0378] Example 37: Synthesis of trans-(rac)-3-(3-(2-(methylcarbamoyl)-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)propanoic acid (Compound 28) [ka] Step A: Preparation of (rac)-1-(3-(trans-2-(methoxycarbonyl)cyclopropyl)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (ChemShuttle, 0.726 g, 2.96 mmol), ethyl trans-2-(6-bromopyridin-2-yl)cyclopropane-1-carboxylate (prepared according to WO 2020 / 022470 A1, 0.800 g, 2.96 mmol), copper(II) acetate (CombiBlocks, 0.536 g, 2.96 mmol), methyl-α-D-glucopyranoside (CombiBlocks, 0.575 g, 2.96 mmol), and potassium iodide (VWR, 0.983 g, 5.92 mmol) in DMSO (40 mL) was added DBU (Oakwood Chemicals, 1.32 mL, 8.88 mmol). The reaction mixture was heated to 105 °C under a N atmosphere for 4 h and then cooled to room temperature. The reaction mixture was then partitioned between ethyl acetate (125 mL) and 1 M KHSO4 (60 mL). An emulsion formed and was broken up by the addition of 25 mL of brine. The phases were separated, and the organic phase was partitioned with HO (75 mL), followed by brine (75 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 1.82 g of a crude red oil. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 40 g RediSep Gold Rf flash silica cartridge with 5-40% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a yellow solid (0.272 g, 21% yield). The R was purified with 1:30:70 v / v acetic acid-ethyl acetate-hexane. f 0.20 (UV254nM); 1H-NMR(400MHz;DMSO-d6)δ 13.16(br s,1H),7.9-8.0(m,2H),7.58(d,1H J=7.3Hz),7.44(s,1H),7.39(d,1H,J=7.8Hz),7.28(s,1H),7.17-7.23(m,1H),4.09 (q,1H,J=7.1Hz),2.7-2.8(m,1H),2.0-2.1(m,1H),1.4-1.5(m,2H),1.2-1.3(m,3H); 19 F-NMR (376MHz; DMSO-d6) δ-56.74; MS (APCI+) m / z 435.0 (M+1), (APCI-) m / z 433.0 (M-1); HPLC UV purity Rt=9.719min, 85.3%.

[0379] Step B: Preparation of (rac)-ethyl trans-2-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)cyclopropane-1-carboxylate [ka] To a mixture of 1-(3-(trans-2-(methoxycarbonyl)cyclopropyl)phenyl)-6-(trifluoromethoxy)-1H-indole-2-carboxylic acid (0.261 g, 0.601 mmol) in DMF (5 mL) was added ammonium chloride (Chem-Impex, 0.096 g, 1.80 mmol). TBTU (Oakwood, 0.289 g, 0.901 mmol) was then added, followed by DIPEA (1.0 mL, 5.41 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (50 mL) and HO (50 mL). The phases were separated, and the organic phase was partitioned with 1 M KHSO (25 mL) followed by brine (25 mL). The organic layer was concentrated under reduced pressure to give the crude product as a colorless oil that solidified to a white solid (0.272 g). The crude solid was triturated with ethyl acetate and heptane (5 mL, 1:1 mixture) and filtered through a fritted funnel to give the title compound as a white solid (0.170 g, 65% yield).f 0.13 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 8.15(br s,1H),7.90(t,1H,J=7.7Hz),7.84(d,1H,J=8.7Hz),7.5-7.6(m,2H),7.38(s,1H),7.27(d,1H J=7.8Hz),7.23(s,1H),7.19(dd,1H,J=1.1,8.7Hz),4.06-4.13(m,2H),2.7- 2.8(m,1H),2.09-2.11(m,1H),1.50(t,2H,J=7.2Hz),1.19(t,3H,J=7.1Hz); 19 F-NMR(376MHz;DMSO-d6)δ-56.76;MS(APCI+)m / z 434.0(M+1),(APCI-)m / z 432.0(M-1);HPLC UV purity Rt=8.81min, 92.1%.

[0380] Step C: Preparation of trans-(rac)-2-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)cyclopropane-1-carboxylic acid (compound 28) [ka] To a mixture of ethyl trans-2-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)cyclopropane-1-carboxylate (0.055 g, 0.127 mmol) in methanol (2 mL) was added 1 M lithium hydroxide (0.51 mL, 0.51 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (15 mL) and 1 M HCl (10 mL). The phases were separated and the organic phase was partitioned with water (10 mL) followed by brine (10 mL). The organic layer was concentrated under reduced pressure to give the title product as a white solid (0.045 g, 89% yield). R was extracted with 1:60:40 v / v acetic acid-ethyl acetate-hexane. f 0.28(UV254nM), 1H-NMR(400MHz;DMSO-d6)δ 12.38(s,1H),8.14(br s,1H),7.89(t,1H,J=7.8Hz),7.84(d,1H,J=8.7Hz),7.52(br d,2H,J=7.3Hz),7.38(s,1H),7.2-7.3(m,1H),7.18-7.22(m,2H),2.6-2.8(m,1H),1.98-2.00(m,1H),1.46(t,2H,J=7.1Hz); 19 F-NMR(376MHz;DMSO-d6)δ-56.73;MS(APCI + ) m / z 406.0(M+1),(APCI - ) m / z 404.0 (M-1); HPLC UV purity, Rt = 7.18 min, 96.7%, chiral HPLC purity, Rt = 10.4 min, 45.0%, Rt = 15.1 min, 49.8%, melting point = 241-242 °C.

[0381] Example 38: Synthesis of trans-(-)- and trans-(+)-2-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)cyclopropane-1-carboxylic acid (Compound 28a and Compound 28b) [ka] Step A: Chiral separation of ethyl trans-2-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)cyclopropane-1-carboxylate The diastereomers of ethyl trans-2-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)cyclopropane-1-carboxylate (0.173 g) were separated by chiral HPLC on a (R,R) Whelk-01 column (250 mm x 4.6 mm) using 75:25:0.1 heptane:IPA:TEA at a flow rate of 1 mL / min with UV detection at 290 nm. Peak 1 eluted at 16.2 minutes, and peak 2 eluted at 23.1 minutes.

[0382] Diastereomer 1 (peak 1) was concentrated under reduced pressure to give a white solid (0.60 mg, 34% recovery); R was purified by 1:60:40 v / v acetic acid-ethyl acetate-hexane. f 0.40(UV254nM);MS(APCI+)m / z 434.0(M+1),(APCI-)m / z 432.0(M-1);HPLC UV purity Rt=8.794min,99.8%;Chiral HPLC purity Rt=14.11min,100%.

[0383] Diastereomer 2 (peak 2) was concentrated under reduced pressure to give a white solid (44.6 mg, 26% recovery); R was purified by 1:60:40 v / v acetic acid-ethyl acetate-hexane. f 0.40(UV254nM);MS(APCI+)m / z 434.0(M+1),(APCI-)m / z 432.0(M-1);HPLC UV purity Rt=8.796min,99.4%;Chiral HPLC purity Rt=20.87min,99.3%.

[0384] Step B: Preparation of trans-(-)- and trans-(+)-2-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)cyclopropane-1-carboxylic acid (Compound 28a and Compound 28b) To the individually separated diastereomers of methyl trans-2-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)cyclopropane-1-carboxylate (Peak 1, 0.051 g, 0.119 mmol), (Peak 2, 0.043 g, 0.100 mmol) in methanol (5.0 mL) was added 1 M lithium hydroxide (0.60 mL, 0.60 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (15 mL) and 1 M HCl (10 mL). The phases were separated, and the organic phase was partitioned with HO (10 mL), followed by brine (10 mL). The organic layer was concentrated under reduced pressure to give the crude product as a white solid.

[0385] Diastereomer 1 (peak 1, 28a) was concentrated under reduced pressure to give a white solid (0.014 g, 30% yield). f 0.22 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.36(s,1H),8.14(br s,1H),7.89(t,1H,J=7.8Hz),7.84(d,1H,J=8.5Hz),7.52(d,2H,J=7.3Hz),7.52(br s,2H),7.38(s,1H),7.26(d,1H,J=7.8Hz),7.22(s,1H),7.19(dd,1H,J=0. 9,8.7Hz),7.8Hz),2.6-2.7(m,1H),1.9-2.0(m,1H),1.45(t,2H,J=7.2Hz); 19 F-NMR(376MHz;DMSO-d6)δ-56.74;MS(APCI+)m / z 406.0(M+1),MS(APCI-)m / z 404.0(M-1);HPLC UV purity Rt=7.17min,98.0%;Chiral HPLC purity Rt=10.39min,97.1%;Optical rotation [α] 25 D =-207.6(c=0.5,100mL MeOH); Melting point=161.5~162.0℃.

[0386] Diastereomer 2 (peak 2, 28b) was concentrated under reduced pressure to give a white solid (0.014 g, 35% yield). f 0.21 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.36(s,1H),8.14(br s,1H),7.89(t,1H,J=7.8Hz),7.84(d,1H,J=8.5Hz),7.52(d,2H,J=7.3Hz),7.52(br s,2H),7.38(s,1H),7.26(dd,1H,J=0.7,8.0Hz),7.22(d,1H,J=0.7Hz),7.19( td,1H,J=1.0,9.7Hz),2.6-2.7(m,1H),1.9-2.0(m,1H),1.45(t,2H,J=7.2Hz); 19F-NMR(376MHz;DMSO-d6)δ-56.74;MS(APCI+)m / z 406.0(M+1),MS(APCI-)m / z 404.0(M-1);HPLC UV purity Rt=7.17min,99.8%;Chiral HPLC purity Rt=15.24min,99.1%;Optical rotation [α] 25 D =+217.6(c=0.5,100mL MeOH); Melting point=192~193℃.

[0387] Example 39: Alternative synthesis of trans(-)-2-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)cyclopropane-1-carboxylic acid (compound 28a) [ka] Step A: Preparation of trans-(-)-2-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)cyclopropane-1-carboxylic acid (compound 28a) [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxamide (0.244 g, 1.00 mmol), trans-(−)-2-(6-bromopyridin-2-yl)cyclopropane-1-carboxylic acid (0.266 g, 1.1 mmol), and copper(I) iodide (Strem, 0.190 g, 1.00 mmol) in DMSO (6 mL) was added DBU (Oakwood Chemicals, 0.3 mL, 2.00 mmol). The reaction mixture was heated to 110° C. under a N atmosphere for 2 hours and then cooled to room temperature. The reaction mixture was then partitioned between ethyl acetate (50 mL) and 1 M KHSO (30 mL). The precipitate that formed was collected by filtration on a fritted funnel and discarded. The filtrate was poured into a separatory funnel. The phases were separated and the organic phase was partitioned with HO (75 mL) followed by brine (75 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give 0.465 g of a crude brown oil. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 12 g RediSep Gold Rf flash silica cartridge with 10-70% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as an off-white solid (0.091 g, 22% yield). The R was purified with 1:60:40 v / v acetic acid-ethyl acetate-hexane. f 0.21 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.40(s,1H),8.14(br s,1H),7.89(t,1H,J=7.7Hz),7.84(d,1H,J=8.7Hz),7.52(br d,2H,J=7.6Hz),7.38(s,1H),7.2-7.3(m,1H),7.18-7.22(m,2H),2.6-2.8(m,1H),1.98-2.00(m,1H),1.46(t,2H,J=7.1Hz); 19 F-NMR(376MHz;DMSO-d6)δ-56.73;MS(APCI + ) m / z 406.0(M+1),(APCI -)m / z 404.0(M-1);HPLC UV purity, Rt=7.13min,99.5%;Chiral HPLC purity Rt=15.26min,91.5%;Optical rotation [α] 25 D = -260.0 (c = 0.25, 2.24 mL IPA); melting point = 161.5-162.0 °C.

[0388] Example 40: Synthesis of (1S,2S)-2-(6-bromopyridin-2-yl)cyclopropane-1-carboxylic acid (compound 28a) [ka] Step A: Preparation of ethyl (E)-3-(6-bromopyridin-2-yl)acrylate [ka] A clean, nitrogen-purged round-bottom flask equipped with a mechanical stirrer, temperature probe, nitrogen inlet / outlet, and addition funnel and connected to a circulator was charged with LiCl (6.24 g, 14.7 mmol, 1.1 equiv.) and THF (300 mL) and stirred until most of the solids dissolved. 6-Bromopyridine-2-carbaldehyde (25.0 g, 13.4 mmol, 1.0 equiv.) was added to the mixture, followed by triethylphosphonium acetate (33.17 g, 14.8 mmol, 1.1 equiv.). The homogeneous mixture was cooled to -20 °C. Triethylamine (14.98 g, 14.8 mmol, 1.1 equiv.) was added dropwise via the addition funnel at a rate such that the internal reaction temperature was below -10 °C. After complete addition, the reaction mixture was warmed to 0 °C and stirred overnight under nitrogen. After 18 hours, the reaction was quenched with 4% aqueous citric acid (0.4 L) to a pH of 3-4 and then warmed to 20°C. Ethyl acetate (0.2 L) was added, and the mixture was stirred for 10 minutes before the layers were separated. The upper organic phase was collected, and the lower aqueous phase was re-extracted with ethyl acetate (0.2 L). The combined organic fractions were washed with 14% aqueous sodium chloride (0.3 L). The organic solution was concentrated under reduced pressure to give a tan solid (41.5 g). The tan solid was suspended in EtOAc (40 mL). The suspension was heated to 35°C to dissolve. The heat was turned off, and heptane (200 mL) was added dropwise. A white solid precipitated, and the mixture was cooled to below 5°C using an ice / water bath and then stirred overnight. The solid was collected by filtration and washed with heptane (2 x 25 mL). The solid was dried under vacuum at 40° C. to give the product as a white solid (18.07 g, 54%). Purity by HPLC >99%. 1 H NMR(400MHz,CDCl3)δ 7.61-7.53(m,2H),7.44(d,J=7.9Hz,1H),7.35(d,J=7.5Hz,1H),6.95(d,J=15.6Hz,1H),4.26(q,J=7.1Hz,2H),1.33(t,J=7.1Hz,3H).

[0389] Step B: Preparation of trans-ethyl 2-(6-bromopyridin-2-yl)cyclopropane-1-carboxylate [ka] A clean, nitrogen-purged, 250 mL, three-necked round-bottom flask equipped with a magnetic stir bar, temperature probe, and nitrogen inlet / outlet was charged with trimethylsulfoxonium iodide (5.1 g, 23.4 mmol, 1.2 equiv.) followed by KOtBu (2.4 g, 21.5 mmol, 1.1 equiv.) and DMSO (50 mL) under nitrogen. The mixture was stirred at room temperature for 1 h to give a clear solution. A solution of ethyl (E)-3-(6-bromopyridin-2-yl)acrylate (5.0 g, 19.5 mmol, 1.0 equiv.) in DMSO (50 mL) was added quickly, maintaining the internal temperature below 30 °C. The reaction turned red and was stirred overnight at room temperature. After the reaction was deemed complete by TLC, the mixture was quenched with 1 N HCl (5 mL) to a pH of 4-5. The mixture was diluted with water (200 mL). The mixture was transferred to a separatory funnel using ethyl acetate (100 mL) for washing and transfer. The upper organic layer was collected, and then the aqueous layer was re-extracted with ethyl acetate (3 x 100 mL). The combined organic layers were dried over sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to give a yellow oil. The oil was purified on a pre-packed 40-g RediSep silica column on a Combiflash automated system using gradient elution (heptane / EtOAc (90:10) for 5 min, then heptane / EtOAc (80:20) for 5 min). The fractions (R f =0.33) were combined and concentrated under reduced pressure to give the product as a colorless oil (3.06 g, 11.4 mmol, 58%). 1 H NMR(400MHz,CDCl3)δ 7.39(t,J=7.7Hz,1H),7.25 9d,J=7.8Hz,1H),7.16(d,J=7.5Hz,1H),4.14(q,J=7.2Hz,2H),2.54-2.49(m,1H),2.30-2.21(m,1H),1.62-1.55(m,2H),1.26(t,J=7.2Hz,3H).

[0390] Step C: Preparation of trans-2-(6-bromopyridin-2-yl)cyclopropane-1-carboxylic acid [ka] A cleaned, nitrogen-purged 200 mL three-necked round-bottom flask equipped with a temperature probe, heating mantle, and magnetic stir bar was charged with trans-ethyl 2-(6-bromopyridin-2-yl)cyclopropane-1-carboxylate (17.12 g, 63.3 mmol, 1.0 equiv) and DMSO (20 mL). An aqueous solution of NaOH (1.0 N, 95 mL, 95 mmol, 1.5 equiv) was then added, and the mixture was stirred at 40° C. for 2 hours. After cooling to 23° C., the mixture was acidified to pH 2 with 1 N HCl. A white solid precipitated and was collected by filtration. The filter cake was washed with water (100 mL) and dried under vacuum to give the product as a white solid (14.48 g, 59.8 mmol, 95%). The product was used in the next step without further purification. 1 H NMR(400MHz,DMSO-d6)δ 12.41(br s,1H),7.61(t,J=7.7Hz,1H),7.46(d,J=7.6Hz,1H),7.41(d,J=7.8Hz,1H),2.58-2.50(m,1H),1.96-1.92(m,1H),1.45-1.34(m,2H). 13 C{ 1 H} NMR(101MHz,DMSO-d6)δ 173.3,160.7,141.1,139.7,125.7,121.8,25.7,24.3,17.0.

[0391] Step D: Preparation of (1S,2S)-2-(6-bromopyridin-2-yl)-N-((R)-1-phenylethyl)cyclopropane-1-carboxamide [ka] A cleaned, nitrogen-purged 200 mL three-neck round-bottom flask equipped with a magnetic stir bar was charged with trans-2-(6-bromopyridin-2-yl)cyclopropane-1-carboxylic acid (12.7 g, 52.4 mmol, 1.0 equiv.), (R)-1-phenylethylamine (8.48 mL, 65.8 mmol, 1.2 equiv.), DMAP (0.803 g, 6.58 mmol, 12 mol%), and dichloromethane (100 mL). The mixture was stirred at room temperature until all components dissolved, resulting in a clear solution. EDC·HCl (12.6 g, 65.8 mmol, 1.2 equiv.) was then added, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, and the residue was filtered through a plug of silica gel (30 g). The silica plug was washed with (70:30) heptane / EtOAc (500 mL). The filtrate was heated to reflux to obtain a clear solution and then cooled to room temperature overnight. The precipitated solid was collected by filtration and washed with (80:20) heptane / EtOAc (100 mL). The filter cake was dried under vacuum to give the product as a white solid (4.70 g, 13.6 mmol, 26%). 1 H NMR (400 MHz, CDCl3) δ 7.41-7.29 (m, 6H), 7.23 (d, J = 7.5 Hz, 1H), 7.18 (d, J = 7.5 Hz, 1H), 5.93 (br d, J = 7.5 Hz, 1H), 5.14 (p, J = 7.3 Hz, 1H), 2.55-2.46 (m, 1H), 2.09-2.05 (m, 1H), 1.63-1.59 (m, 1H), 1.52-1.44 (d overlaps with m, 4H). 13 C{ 1 H}(101MHz,CDCl3)δ 170.7,161.6,143.3,142.0,138.3,128.8,127.5,126.3,125.3,121.7,49.3,26.8,25.6,22.1,17.6.

[0392] Step E: Preparation of (1S,2S)-2-(6-bromopyridin-2-yl)cyclopropane-1-carboxylic acid [ka] A cleaned, nitrogen-purged 100 mL round-bottom flask equipped with a temperature probe, heating mantle, and magnetic stir bar was charged with (1S,2S)-2-(6-bromopyridin-2-yl)-N-((R)-1-phenylethyl)cyclopropane-1-carboxamide (4.70 g, 13.6 mmol) and concentrated HCl (15 mL). The mixture was heated to 80° C. and stirred for 5 h. The mixture was cooled to 0° C. in an ice / water bath and diluted with water (100 mL). The mixture was transferred to a separatory funnel with EtOAc (50 mL). The upper organic layer was collected, and the aqueous layer was re-extracted with EtOAc (4×20 mL). The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the product as a white solid (3.7 g, 13.6 mmol, >99%). 1 H NMR (400 MHz, DMSO-d6) δ 12.42 (br s, 1H), 7.64 (t, J = 7.7 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.43 (d, J = 7.8 Hz, 1H), 2.61-2.52 (m, 1H), 2.01-1.94 (m, 1H), 1.48-1.37 (m, 2H). HPLC analysis gave a 98:2 ratio (RegisWhelk01, hexane / hexane). i PrOH(70:30),1.2mL / min,t (-) =15.95min,t (+) =17.47min).

[0393] Example 41: Alternative synthesis of trans-(+)-2-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)cyclopropane-1-carboxylic acid (compound 28b) [ka] Step A: Preparation of trans-(+)-2-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)cyclopropane-1-carboxylic acid (compound 28b) [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxamide (0.244 g, 1.00 mmol), trans-(+)-2-(6-bromopyridin-2-yl)cyclopropane-1-carboxylic acid (0.266 g, 1.1 mmol), and copper(I) iodide (Strem, 0.190 g, 1.00 mmol) in DMSO (6 mL) was added DBU (Oakwood Chemicals, 0.3 mL, 2.00 mmol). The reaction mixture was heated to 110° C. under a N atmosphere for 6 hours and then cooled to room temperature. The reaction mixture was then partitioned between ethyl acetate (75 mL) and 1 M KHSO (50 mL). The precipitate that formed was collected by filtration on a fritted funnel and discarded. The filtrate was poured into a separatory funnel. The phases were separated, and the organic phase was partitioned with HO (75 mL), followed by brine (75 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude red oil, 0.565 g. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 12 g RediSep Gold Rf flash silica cartridge with 10 to 70% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a white solid (0.165 g, 40% yield); elution with 1:60:40 v / v acetic acid-ethyl acetate-hexane afforded the title compound as a white solid (0.165 g, 40% yield). f 0.21 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 12.35(s,1H),8.10(br s,1H),7.85(t,1H,J=7.8Hz),7.80(d,1H,J=8.7Hz),7.48(br d,2H,J=7.6Hz),7.34(s,1H),7.2-7.3(m,1H),7.18-7.22(m,2H),2.61-2.70(m,1H),1.93-2.00(m,1H),1.41(t,2H,J=7.1Hz); 19 F-NMR(376MHz;DMSO-d6)δ-56.73;MS(APCI + ) m / z 406.0(M+1),(APCI -)m / z 404.0(M-1);HPLC UV purity, Rt=7.13min,98.4%;Chiral HPLC purity Rt=15.27min,91.5%;Optical rotation [α] 25 D = +254.4 (c = 0.25, 2.24 mL IPA); melting point = 192-193 °C.

[0394] Example 42: Synthesis of cis-(rac)-2-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)cyclopropane-1-carboxylic acid (Compound 28c) [ka] Step A: Preparation of cis-(rac)-ethyl 2-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)cyclopropane-1-carboxylate [ka] To a mixture of 6-(trifluoromethoxy)-1H-indole-2-carboxamide (0.244 g, 1.00 mmol), cis-(rac)-2-(6-bromopyridin-2-yl)cyclopropane-1-carboxylic acid (0.297 g, 1.1 mmol), and copper(I) iodide (Strem, 0.190 g, 1.00 mmol) in DMSO (6 mL) was added DBU (Oakwood Chemicals, 0.3 mL, 2.00 mmol). The reaction mixture was heated to 110° C. under a N atmosphere for 5 hours and then cooled to room temperature. The reaction mixture was then partitioned between ethyl acetate (100 mL) and 1 M KHSO (50 mL). The precipitate that formed was collected by filtration on a fritted funnel and discarded. The filtrate was poured into a separatory funnel. The phases were separated, and the organic phase was partitioned with HO (2 x 50 mL), followed by brine (50 mL). The organic layer was separated, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give a crude red oil, 0.539 g. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 12 g RediSep Gold Rf flash silica cartridge with 10-50% ethyl acetate in hexane containing 1% acetic acid afforded the title compound as a tan solid (0.191 g, 44% yield). The R was purified with 1:60:40 v / v acetic acid-ethyl acetate-hexane. f 0.22 (UV254nM); 1 H-NMR(400MHz;DMSO-d6)δ 8.15(br s,1H),7.80-7.85(m,2H),7.38-7.51(m,2H),7.37(d,1H,J=7.6Hz),7.28(s,1H),7.17(dd,1H,J=1.0,8.6Hz),7.12(d,1H ,J=7.8Hz),3.72-3.85(m,2H),2.79-2.82(m,1H),1.79-1.82(m,1H),1.42(dt,1H,J=4.6,8.1Hz),0.87(t,3H,J=7.1Hz); 19 F-NMR(376MHz;DMSO-d6)δ-56.73;MS(APCI + ) m / z 434.0(M+1),(APCI -) m / z 432.0 (M-1); HPLC UV purity, Rt = 8.075 min, 97.6%; melting point = 110.5-111.0 °C.

[0395] Step B: Preparation of cis-(rac)-2-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)cyclopropane-1-carboxylic acid (compound 28C) [ka] To a mixture of cis-racemic-ethyl 2-(6-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)pyridin-2-yl)cyclopropane-1-carboxylate (0.156 g, 0.360 mmol) in methanol (5 mL) was added 1 M lithium hydroxide (1.80 mL, 1.80 mmol). The reaction mixture was stirred at room temperature for 2 h, and then HO (1 mL) and THF (2 mL) were added. The reaction mixture was then stirred overnight under a N atmosphere. The reaction mixture was then partitioned between ethyl acetate (30 mL) and 1 M HCl (10 mL). The phases were separated, and the organic phase was partitioned with water (15 mL) followed by brine (15 mL). The organic layer was concentrated under reduced pressure to give the desired compound as a white solid (0.135 g, 92.4%). R was extracted with 1:70:30 v / v acetic acid-ethyl acetate-heptane. f 0.11(UV254nM), 1 H-NMR(400MHz;DMSO-d6)δ 12.01(s,1H),8.16(br s,1H),7.80-7.90(m,2H),7.72(s,1H),7.50(br s,1H),7.35(d,1H,J=7.8Hz),7.26(s,1H),7.17(dd,1H,J=1.1,8.7Hz),7.08(d,1H,J=8.0Hz ),2.80(q,1H,J=8.4Hz),2,11-2.15(m,1H),1.79-1.82(m,1H),1.37(dt,1H,J=4.6,8.1Hz); 19 F-NMR(376MHz;DMSO-d6)δ-56.72;MS(APCI + ) m / z 406.0(M+1),(APCI- ) m / z 404.0 (M-1); HPLC UV purity, Rt = 6.585 min, 95.8%, chiral HPLC purity Rt = 12.1 min, 48.2%, 15.1 min, 50.3%, melting point = 219-220 °C.

[0396] Example 43: Synthesis of 3-(3-(2-carbamoyl-5-(trifluoromethoxy)benzo[b]selenophen-3-yl)phenyl)propanoic acid (Compound 29) [ka] Step A: Preparation of 2-(methylselanyl)-5-(trifluoromethoxy)benzaldehyde [ka] To a 200 mL round-bottom flask was added DL-dithiothreitol (Chem-Impex, 3.31 g, 15.9 mmol) and anhydrous DMF (35 mL). To this solution was added dimethyl diselenide (AK Scientific, 2.0 g, 10.6 mmol), and the solution was stirred at room temperature for 1 hour. Next, 2-fluoro-5-(trifluoromethoxy)benzaldehyde (Combi-Blocks, 3.31 g, 15.9 mmol) was added, followed by DBU (Oakwood Products, 6.05 g, 39.7 mmol), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into 2 L of cold water, precipitating a yellow solid, which was filtered and washed with water. The crude solid was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through an 80 g RediSep Gold Rf flash silica cartridge with 0-20% ethyl acetate in heptane gave the title compound as a pale yellow solid (2.69 g, 60% yield). f 0.53 (UV254nM), 1H-NMR (400 MHz; CDCl) δ 10.14 (s, 1H), 7.67 (d, 1H, J = 1.8 Hz), 7.50 (d, 1H, J = 8.7 Hz), 7.37 (dd, 1H, J = 1.9, 8.6 Hz), 2.33 (s, 3H). The target mass was not observed.

[0397] Step B: Preparation of ethyl 2-((2-formyl-4-(trifluoromethoxy)phenyl)selanyl)acetate [ka] To a 100 mL round-bottom flask was added 2-(methylselanyl)-5-(trifluoromethoxy)benzaldehyde (2.69 g, 9.50 mmol), followed by ethyl bromoacetate (Oakwood Products, 5.9 g, 35.3 mmol), and the mixture was heated with stirring at 150 °C for 2.5 h, at which point TLC (1:9, v / v ethyl acetate-heptane) indicated consumption of the starting material and the formation of a new, lower R spot. It was cooled to room temperature and used crude in the next step. 1 H-NMR(400MHz;CDCl3)δ 10.1-10.2(s,1H),7.84(d,1H,J=8.7Hz),7.71(d,1H,J=1.8Hz),7.41(dd,1H,J=1.9,8. 6Hz), 4.1-4.2(q,2H,J=7.1Hz),3.58(s,2H),1.24(t,3H,J=7.1Hz).Note: Also includes ethyl bromoacetate impurity.

[0398] Step C: Preparation of ethyl 5-(trifluoromethoxy)benzo[b]selenophene-2-carboxylate [ka] To a 100 mL round-bottom flask containing crude ethyl 2-((2-formyl-4-(trifluoromethoxy)phenyl)selanyl)acetate (3.37 g, 9.50 mmol, theoretical) was added acetonitrile (20 mL) and potassium carbonate (3.8 vg, 27.5 mmol). The mixture was stirred at reflux for 6 h, at which point TLC (1:9, ethyl acetate:heptane) indicated consumption of the starting material and the formation of a new, higher Rf spot. It was cooled to room temperature and filtered through a medium-frit sintered-glass funnel. The solvent was evaporated. The crude oil material was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through an 80 g RediSep Gold Rf flash silica cartridge with 1–30% ethyl acetate:heptane afforded the title compound as pale yellow crystals (2.74 g, 85% yield over two steps); elution with 1:9 v / v ethyl acetate-heptane afforded the title compound as pale yellow crystals (2.74 g, 85% yield over two steps). f 0.55 (UV254nM); 1 H-NMR(400MHz;CDCl3)δ MS(APCI) + ) m / z 324.1 (M+1). Target mass not observed. Melting point = 96.5-98.0 °C.

[0399] Step D: Preparation of 5-(trifluoromethoxy)benzo[b]selenophene-2-carboxylic acid (Intermediate X) [ka] To a 100 mL round-bottom flask were added ethyl 5-(trifluoromethoxy)benzo[b]selenophene-2-carboxylate (1.35 g, 4.0 mmol) and methanol (35 mL). Next, 1 M aqueous LiOH (12.0 mL, 3 equiv.) was added dropwise with stirring. The reaction mixture was stirred at room temperature for 4 hours, after which TLC (1:30:70 v / v acetic acid-ethyl acetate-heptane) indicated consumption of the starting material and the formation of a new, lower Rf spot. The solvent was removed by evaporation, followed by dilution of the residue with water (300 mL), and the solution was acidified with 1 N HCl to precipitate the product. The suspension was filtered, the solid washed with excess water, and then dried under high vacuum overnight to afford the title compound as a white solid (1.20 g, 99% yield). Rf 0.43 (UV 254 nM) in 1:30:70 v / v acetic acid-ethyl acetate-heptane; 1 H-NMR(400MHz;CDCl3)δ 8.40(s,1H),7.94(br d,1H,J=8.5Hz),7.79(br s,1H),7.3-7.3(br d,1H,J=8.5Hz); 19 F-NMR(376MHz;CDCl3)δ-57.90;MS(APCI + ) m / z 309.0 (M-1, Se isotope distribution), melting point = 179.5-180.2 °C.

[0400] Step E: Preparation of 3-(3-(3-methoxy-3-oxopropyl)phenyl)-5-(trifluoromethoxy)benzo[b]selenophene-2-carboxylic acid [ka] To a 24 mL septa-capped vial was added methyl 3-bromobenzenepropanoate (Combi-Blocks, 0.365 g, 1.5 mmol) and 5-(trifluoromethoxy)benzo[b]selenophene-2-carboxylic acid (0.463 g, 1.5 mmol). Then, bis(dichloro(η 6To the reaction mixture was added 100 mL of 1-(4-cymene)ruthenium) (Strem, 0.037 g, 4 mol%), trimethylphosphonium tetrafluoroborate (Strem, 0.020 g, 8 mol%), K2CO3 (VWR, 0.228 g, 1.65 mmol), and NMP (6 mL). The mixture was degassed by bubbling nitrogen gas through it with stirring for 3 minutes and then heated to 110 °C overnight. The reaction mixture was then cooled to room temperature and diluted with water (140 mL). The mixture was extracted with ethyl acetate (3 × 100 mL), and the combined organics were dried over Na2SO4, filtered, and the solvent was evaporated under reduced pressure to give a crude oil that was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 40 g RediSep Gold Rf flash silica cartridge with 10-30% ethyl acetate in heptane containing 1% acetic acid afforded the title compound as a viscous oil (0.127 g, 18% yield). f 0.24 (UV254nM); 1 H-NMR(400MHz;CDCl3)δ 7.93(d,1H,J=8.7Hz),7.4-7.5(m,1H),7.32(br d,2H,J=7.8Hz),7.2-7.2(m,2H),3.65(s,3H),3.02(t,2H,J=7.7Hz),2.68(t,2H,J=7.7Hz); 19 F-NMR(376MHz;CDCl3)δ-57.89;MS(APCI + ) m / z 471.0(M-1).

[0401] Step F: Preparation of methyl 3-(3-(2-carbamoyl-5-(trifluoromethoxy)benzo[b]selenophen-3-yl)phenyl)propanoate [ka] To a mixture of 3-(3-(3-methoxy-3-oxopropyl)phenyl)-5-(trifluoromethoxy)benzo[b]selenophene-2-carboxylic acid (0.120 g, 0.25 mmol) in DMF (1.5 mL) was added ammonium chloride (Chem-Impex, 0.041 g, 0.76 mmol). TBTU (Oakwood, 0.123 g, 0.38 mmol) was then added, followed by DIPEA (0.400 mL, 2.3 mmol). The reaction mixture was stirred overnight at room temperature under a N atmosphere. The reaction mixture was then diluted with water (40 mL) and then extracted with 3 × 20 mL of ethyl acetate. The combined organic phases were dried over NaSO, filtered, and the solvent was evaporated under reduced pressure to give the crude product as a colorless oil. The crude oil was purified by flash silica column chromatography on a CombiFlash NextGen 300+ purification system. Elution through a 12 g RediSep Gold Rf flash silica cartridge with 10-40% ethyl acetate in hexane containing 1% acetic acid gave the title compound as a clear oil (0.101 g, 86% yield). f 0.22 (UV254nM); 1 H-NMR(400MHz;CDCl3)δ 7.94(d,1H,J=8.7Hz),7.5-7.6(m,1H),7.41(d,1H,J=7.8Hz),7.3-7.3(m,3H),7.1-7.1(m,1H),5.91(br s,1H),5.44(br s,1H),3.66(s,3H),3.05(t,2H,J=7.5Hz),2.70(t,2H,J=7.5Hz); 19 F-NMR(376MHz;CDCl3)δ-57.89;MS(APCI + )m / z 472.0(M+1),m / z 470.0(M-1).

[0402] Step G: Preparation of 3-(3-(2-carbamoyl-5-(trifluoromethoxy)benzo[b]selenophen-3-yl)phenyl)propanoic acid (compound 29) [ka] To a mixture of methyl 3-(3-(2-carbamoyl-5-(trifluoromethoxy)benzo[b]selenophen-3-yl)phenyl)propanoate (0.100 g, 0.21 mmol) in MeOH (3 mL) was added dropwise a 1 M aqueous solution of LiOH (0.64 mL, 3 equiv.). The reaction mixture was stirred overnight at room temperature. The solvent was removed by evaporation, followed by dilution of the residue with water (30 mL), and acidification of the solution with 1 N HCl to precipitate the product. The suspension was filtered, the solid washed with excess water, and then dried under high vacuum overnight to afford the title compound as a white solid (0.081 g, 84% yield). Rf 0.15 (UV 254 nM) in 1:30:70 v / v acetic acid-ethyl acetate-heptane; 1 H-NMR(400MHz;CDCl3)δ 7.93(d,1H,J=8.7Hz),7.51(t,2H,J=7.6Hz),7.40(br d,1H,J=7.8Hz),7.3-7.3(m,2H),7.18(d,1H,J=7.6Hz),7.10(s,1H),5.63(br s,1H),3.04(br t,2H,J=6.4Hz),2.74(br t,2H,J=6.4Hz); 19 F-NMR(376MHz;CDCl3)δ-57.87;MS(APCI + )m / z 458.0(M+1),456.0(M-1).HPLC UV purity, Rt=8.14min,98.4%;Melting point=179.5~181.5℃.

[0403] Example 44: Synthesis of 2-(1-(3-(2-carbamoyl-6-(trifluoromethoxy)-1H-indol-1-yl)phenyl)cyclobutyl)acetic acid (Compound 30) [ka] Step A: Preparation of methyl 2-(1-(3-bromophenyl)cyclobutyl)acetate [ka] To an ice-bath (0°C) reaction mixture of 2-(1-(3-bromophenyl)cyclobutyl)acetic acid (Key Organics, 0.50 g, 1.96 mmol) in toluene (6 mL) and methanol (4 mL) was added TMS-diazomethane (2 M solution in ether, 1.5 mL, 2.94 mmol) dropwise. The reaction was stirred at 0°C for 45 minutes and then allowed to warm to room temperature for 2 h...

Claims

1. Compounds of formula IIIf-1, formula IIIf-2, formula IIIf-3, formula IIIf-4, formula IIIf-5, formula IIIf-6, or formula IIIf-7 【Chemistry 1】 or a pharmaceutically acceptable salt thereof During the ceremony X １ ~X ３ However, each is independently N or CH, R １ However, H or R ７ And, R ２ｆ However, hydrogen, CN, OH, NH ２ , Halo, and C １－６ Selected from alkyl groups, R ５ｆ is selected from hydrogen, CN, OH, NH ２ , halo, C １－６ alkyl, and OC １－６ alkyl, R ３ｆ and R ４ｆ However, together with the carbon atoms to which they are bonded, they form 3-6 membered cyclils or 3-6 membered heterocyclils, and each cyclil and heterocyclil optionally contains one or more R １０ Substituting with substituents, Each R 7 is independently R 10, Each R 10 is oxo, CN, OR 11, N(R 11) 2, halo, C(O)H, C(O)R 11, C(O)OR 11, C(O)N(R 11) 2, (C1-6 alkyl)-C(O)R 11, (C1-6 alkyl)-C(O)OR 11, (C1-6 alkyl)-C(O)N(R 11) 2, N(R 11)C(O)R 11, N(R 11)C(O)OR 11, N(R 11)C(O)NHR 11, N(R 11)-(CH 2)-C(O)R 11, N(R 11)-(CH 2) )-C(O)OR 11, N(R 11)-(CH 2)-C(O)NHR 11, N(R 11)SO 2 C 1-6 alkyl, OSO 2 C 1-6 alkyl, SO 2 C 1-6 alkyl, S(O) 2 N(R 11) 2, C 1-6 alkyl, phenyl, 3-6 membered cyclyl, 3-6 membered heterocyclyl, or 5 or 6 membered heteroaryl, and each alkyl, phenyl, cyclyl, heterocyclyl, or heteroaryl is independently and optionally substituted with one or more R 11 substituents. Each R11 is independently selected from hydrogen, oxo, CN, OH, NH2, halo, OC1-6 alkyl, OC1-6 haloalkyl, C1-6 alkyl, and C1-6 haloalkyl. Each R12 is independently selected from OH, OC1-6 alkyl, O-phenyl, NH2, NH(C1-6 alkyl), and N(C1-6 alkyl)2, and each alkyl and phenyl is optionally and independently substituted with 1 to 3 R10 substituents. n is an integer selected from 0, 1, 2, and 3. A compound, or a pharmaceutically acceptable salt thereof.

2. R ３ｆ and R ４ｆ However, together with the carbon atoms to which they bond, they form a 3- to 6-membered cycline, and optionally one or more C １－６ A compound according to claim 1 or a pharmaceutically acceptable salt thereof, substituted with an alkyl substituent.

3. R ３ｆ and R ４ｆ However, together with the carbon atoms to which they are bonded, they form a cyclopropyl or cyclobutyl moiety, and optionally one or more C １－６ A compound according to claim 2, or a pharmaceutically acceptable salt thereof, substituted with an alkyl substituent.

4. The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R1 is H.

5. The compound according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof, wherein each R7 is independently selected from CN, OC1-6 alkyl, halo, and C1-6 alkyl.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein each R7 is independently selected from halo and C1-6 alkyl.

7. The compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, wherein n is 0 or 1.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein n is 0.

9. portion 【Chemistry 2】 but, 【Transformation 3】 The compound according to any one of claims 1 to 8 or a pharmaceutically acceptable salt thereof.

10. The compound is selected from the following table: Table 1 Table 2 A compound according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

11. The compound is selected from the following table: Table 3 The compound according to claim 10 or a pharmaceutically acceptable salt thereof.

12. The compound is selected from the following table: Table 4 The compound according to claim 11 or a pharmaceutically acceptable salt thereof.

13. A compound selected from the following table Table 5 Or, a pharmaceutically acceptable salt thereof.

14. A pharmaceutical composition comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

15. An in vitro method for inhibiting the sPLA2-X enzyme, the method comprising contacting the enzyme with a pharmaceutical compound according to any one of claims 1 to 13, or a pharmaceutical composition according to claim 14, wherein the compound or a pharmaceutically acceptable salt thereof is a selective inhibitor of sPLA2-X more than other sPLA2 enzymes.

16. The in vitro method according to claim 15, wherein the other sPLA2 enzyme is selected from sPLA2-IIE, sPLA2-IIA, and sPLA2-V enzymes.

17. A pharmaceutical composition for use in the treatment of sPLA2-X enzyme-mediated diseases in a subject, comprising a compound according to any one of claims 1 to 13 or a pharmaceutically acceptable salt thereof.

18. The pharmaceutical composition according to claim 17, wherein the disease is selected from cancer, atherosclerosis, or cardiovascular disease.

19. The pharmaceutical composition according to claim 18, wherein the cancer is selected from multiple myeloma (MM), diffuse large B-cell lymphoma (DLBCL), B-cell lymphoma, or non-small cell lung cancer.

20. The method according to claim 19, wherein the multiple myeloma (MM) and / or diffuse large B-cell lymphoma (DLBCL) is relapsed, refractory, or recurrent DLBCL and / or MM.

21. The method according to claim 19, wherein the cancer is selected from B-cell lymphoma or non-small cell lung cancer.

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