Flavone derivatives for the treatment and prophylaxis of Hepatitis B Vims disease

The present invention relates to organic compounds useful for therapy and/or prophylaxis of HBV infection in a mammal, and in particular to cccDNA (covalently closed circular DNA) inhibitors useful for treating HBV infection.

FIELD OF THE INVENTION

The present invention relates to flavone derivatives having pharmaceutical activity, their manufacture, pharmaceutical compositions containing them and their potential use as medicaments.

The present invention relates to compounds of formula (I)

wherein R ¹ to R ⁶ , Gi, G ₂ , Ai to A ₄ and m are as described below, or pharmaceutically acceptable salts thereof.

Hepatitis B virus (HBV) infection is one of the most prevalent viral infections and is a leading cause of chronic hepatitis. It is estimated that worldwide, around 2 billion people have evidence of past or present infection with HBV. Over 250 million individuals are currently chronically infected with HBV and are therefore at high risk to develop liver fibrosis, cirrhosis and hepatocellular carcinoma (HCC). There are data to indicate -800,000 deaths per year are directly linked to HBV infection ( Lozano, R. et al., Lancet (2012), 380 (9859), 2095-2128; Goldstein, S.T. et al., Int J Epidemiol (2005), 34 (6), 1329-1339).

Many countries in the world administer hepatitis B vaccine starting at birth or in early childhood, which has greatly reduced the incidence and prevalence of hepatitis B in most endemic regions over the past few decades. However the vaccine has no impact on people who were infected before the widely use of the vaccine in developing end-stage liver disease or HCC (Chen, D.S., J Hepatol (2009), 50 (4), 805-816). Vaccination at birth of infants bom to HBV positive mothers is usually not sufficient for protecting vertical transmission and combination with hepatitis B immune globulin is needed (Li, X.M. et al., World J Gastroenterol (2003), 9 (7), 1501-1503).

Currently FDA-approved treatments for chronic hepatitis B include two type 1 interferons (IFN) which are IFNalfa-2b and pegylated IFN alfa-2a and six nucleos(t)ide analogues (NAs) which are lamivudine (3TC), tenofovir disoproxil fumarate (TDF), adefovir (ADV), telbivudine (LdT), entecavir (ETV), and vemlidy (tenofovir alafenamide (TAF)). IFN treatment is finite, but it is known to have severe side effects, and only a small percentage of patients showed a sustained viro logical response, measured as loss of hepatitis B surface antigen (HBsAg). NAs are inhibitors of the HBV reverse transcriptase, profoundly reduce the viral load in vast majority of treated patients, and lead to improvement of liver function and reduced incidence of liver failure and hepatocellular carcinoma. However, the treatment of NAs is infinite (Ahmed, M. et al., Dmg Discov Today (2015), 20 (5), 548-561; Zoulim, F. and Locamini, S., Gastroenterology (2009), 137 (5), 1593-1608 el59l-l592).

HBV chronic infection is caused by persistence of covalently closed circular (ccc)DNA, which exists as an episomal form in hepatocyte nuclei. cccDNA serves as the template for viral RNA transcription and subsequent viral DNA generation. Only a few copies of cccDNA per liver cell can establish or re-initiate viral replication. Therefore, a complete cure of chronic hepatitis B will require elimination of cccDNA or permanently silencing of cccDNA. However, cccDNA is intrinsically very stable and currently available therapeutics could not eliminate cccDNA or permanently silence cccDNA (Nassal, M., Gut (2015), 64 (12), 1972-1984; Gish, R.G. et al., Antiviral Res (2015), 121, 47-58; Levrero, M. et al., J Hepatol (2009), 51 (3), 581-592.). The current SoC could not eliminate the cccDNA which are already present in the infected cells. There is an urgent need to discover and develop new anti-HBV reagents to eliminate or permanently silence cccDNA, the source of chronicity (Ahmed, M. et al., Drug Discov Today (2015), 20 (5), 548-561; Nassal, M., Gut (2015), 64 (12), 1972-1984).

SUMMARY OF THE INVENTION

Objects of the present invention are novel compounds of formula (I), their manufacture, medicaments based on a compound in accordance with the invention and their production as well as the use of compounds of formula (I) as cccDNA inhibitors and for the treatment or prophylaxis of HBV infection. The compounds of formula (I) show superior anti-HBV activity. In addition, the compounds of formula (I) also show good PK profiles and good liver micro some stability.

The present invention relates to a compound of formula (I)

wherein

R ¹ is selected from halogen and haloCi_6alkyl;

R ² is selected from H, halogen, Ci_6alkyl, Ci_6alkoxy, C _3-7 cycloalkyl and haloCi_6alkyl;

R ³ is selected from H, halogen and Ci_6alkoxy;

R ⁴ is selected from H, hydroxy and haloCi_6alkyl;

R ⁵ is selected from H, halogen, Ci_6alkyl, Ci_6alkoxy and hydroxy;

R ⁶ is selected from carboxy, Ci_ ₆ alkoxycarbonyl, carboxyCi_ ₆ alkoxycarbonyl, carboxyC ₃ _ 7cycloalkylaminocarbonyl, carboxyheterocyclylcarbonyl, C _{3- 7} cycloalkylsulfonylaminocarbonyl, hydroxyCi- ₆ alkylaminocarbonyl, Ci_

6alkylsulfonylheterocyclylcarbonyl, heterocyclylcarbonyl, hydroxyheterocyclylcarbonyl, (hydroxy) ₂ heterocyclylcarbonyl, C _h alky lsulfonylaminocarbonylheterocyclylcarbonyl, Ci- 6alkylsulfonylaminocarbonyl, cyano, (Ci_ ₆ alkyl) ₂ aminosulfonyl, aminocarbonyl, aminosulfonyl, C _3-7 cycloalkylaminocarbonylcarbonyl and C _3-7 cycloalkylaminocarbonyl;

Ai is selected from N and CR ⁷ ; wherein R ⁷ is selected from H, halogen and haloCi_6alkyl;

A ₂ is selected from N and CR ⁸ ; wherein R ⁸ is selected from H, halogen, hydroxy, Ci_6alkyl,

Ci_6alkoxy, C _3-7 cycloalkyl, haloCi_6alkyl, haloCi_6alkoxy, haloCi_6alkylCi_6alkoxy, Ci_ 6alkylsulfanyl, Ci_6alkylsulfonyl, C _3-7 cycloalkylCi_ ₆ alkoxy and heterocyclyl; wherein heterocyclyl is unsubstituted or substituted one or two or three times independently by oxo;

A ₃ is selected from N and CR ⁹ ; wherein R ⁹ is selected from H, amino, halogen, hydroxy, Ci_ 6alkyl, Ci- ₆ alkoxy, haloCi- ₆ alkyl, haloCi- ₆ alkoxy, haloCi- ₆ alkylCi- ₆ alkoxy and C _{3- 7} cycloalky 1C _{1 -6} alkoxy ; or R ⁸ and R ⁹ , together with the atoms to which they are attached, form a heterocyclyl ring; wherein heterocyclyl ring is unsubstituted or substituted by one or two or three or four substituents independently selected from halogen, Ci_ ₆ alkyl and oxo;

A ₄ is selected from N and CR ¹⁰ ; wherein R ¹⁰ is selected from H and halogen;

Gi is selected from Ci- ₆ alkyl, C3-7cycloalkyl, C3-7cycloalkylCi-6alkyl, phenylCi- ₆ alkyl, Ci_ 6alkylC3-7cycloalkylCi-6alkyl and heterocyclyl; wherein Ci- ₆ alkyl, C3-7cycloalkyl, C3- 7cycloalkylCi-6alkyl, phenylCi- ₆ alkyl, Ci-6alkylC3-7cycloalkylCi-6alkyl and heterocyclyl are unsubstituted or substituted by one or two or three substituents independently selected from hydroxy, amino, C3_7cycloalkylsulfonylamino, Ci_ ₆ alkylphenylsulfonylamino, phenylsulfonyl, C3_7cycloalkylsulfonyl, Ci_ ₆ alkoxyphenylsulfonyl, phenylcarbonyl, phenylcarbonylamino, Ci_ ₆ alkylcarbonylamino, C _h alky laminosulfonylamino,

aminocarbonyamino, (Ci_6alkoxy)2phenylaminosulfonylamino, Ci_

6alkoxycarbonylcarbonylamino, (Ci_6alkyl)2aminosulfonylamino, Ci_

6alkylaminocarbonylamino, Ci_6alkylaminosulfonyl, aminosulfonylamino, C3- 7cycloalkylaminosulfonylamino and phenylCi _ ₆ alkylaminosulfonylamino ;

G2 is selected from Ci- ₆ alkyl, C3-7cycloalkyl and phenyl;

m is selected from 0 and 1 ;

or a pharmaceutically acceptable salt thereof.

DETAILED DESCRIPTION OF THE INVENTION

DEFINITIONS

As used herein, the term“Ci_ ₆ alkyl” alone or in combination signifies a saturated, linear- or branched chain alkyl group containing 1 to 6, particularly 1 to 4 carbon atoms, for example methyl, ethyl, propyl, isopropyl, 1 -butyl, 2 -butyl, ZerZ-butyl, neopentyl, hexyl, isohexyl and the like. Particular“Ci_ ₆ alkyl” groups are methyl, ethyl, propyl, isopropyl and tert- butyl. More particularly,“Ci_ ₆ alkyl” groups are methyl, ethyl and propyl.

The term“Ci_ ₆ alkoxy” alone or in combination signifies a group Ci_ ₆ alkyl-0-, wherein the “Ci_ ₆ alkyl” is as defined above; for example methoxy, ethoxy, propoxy, /.vopropoxy, //-hutoxy, /.vobutoxy, 2-butoxy, ZerZ-butoxy, pentoxy, hexyloxy and the like. Particular“Ci_ ₆ alkoxy” groups are methoxy, ethoxy and propoxy. More particularly,“Ci_ ₆ alkoxy” group is methoxy.

The term“halogen” and“halo” are used interchangeably herein and denote fluoro, chloro, bromo, or iodo. The term“haloCi_6alkyl” denotes an alkyl group wherein at least one of the hydrogen atoms of the alkyl group is replaced by same or different halogen atoms, particularly fluoro atoms. Examples of haloCi_6alkyl include monochloro-, difluoro-or trifluoro -methyl, -ethyl or - propyl, for example difluoromethyl and trifluoromethyl.

The term“haloCi-6alkoxy” denotes a Ci-6alkoxy group wherein at least one of the hydrogen atoms of the Ci-6alkoxy group is replaced by same or different halogen atoms, particularly fluoro atoms. Examples of haloCi-6alkoxy include mono fluoro-, difluoro- or trifluoro-methoxy, -ethoxy or -propoxy, for example difluoromethoxy and trifluoromethoxy.

The term‘ ^cycloalkyl” denotes to a saturated carbon ring containing from 3 to 7 carbon atoms, particularly from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Particular“C3_7cycloalkyl” group is cyclopropyl, cyclobutyl or cyclopentyl.

The term“C3_7cycloalkoxy” denotes a group C3_7cycloalkyl-0-, wherein the“C3- 7cycloalkyl” is as defined above; for example cyclopropoxy, cyclobutoxy, cyclopentoxy.

Particular“C3_7cycloalkoxy” group is cyclobutoxy.

"heterocyclyl" refers to any mono-, hi-, tricyclic or spiro, saturated or unsaturated, aromatic (heteroaryl) or non-aromatic (e.g., heterocycloalkyl), ring system, having 3 to 20 ring atoms, where the ring atoms are carbon, and at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. If any ring atom of a cyclic system is a heteroatom, that system is a heterocyclyl, regardless of the point of attachment of the cyclic system to the rest of the molecule. In one example, heterocyclyl includes 3-11 ring atoms ("members") and includes monocycles, bicycles, tricycles and spiro ring systems, wherein the ring atoms are carbon, where at least one atom in the ring or ring system is a heteroatom selected from nitrogen, sulfur or oxygen. In one example, heterocyclyl includes 3- to 7-membered monocycles having 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclyl includes 4-, 5- or 6-membered monocycles having 1, 2, 3 or 4 heteroatoms selected from nitrogen, sulfur or oxygen. In one example, heterocyclyl includes 8- to 12- membered bicycles having 1, 2, 3, 4, 5 or 6 heteroatoms selected from nitrogen, sulfur or oxygen. In another example, heterocyclyl includes 9- or lO-membered bicycles having 1, 2, 3, 4, 5 or 6 heteroatoms selected from nitrogen, sulfur or oxygen. Examplary heterocyclyls are pyrrolidinyl, morpholinyl, thiazolyl, oxazolidinyl, l,3-dioxole, 2,3-dihydrofuran, 2,3-dihydro- l,4-dioxine or 2,3-dihydro- lH-pyrrole. Heterocyclyl may be optionally substituted by halogen, OH, SH, cyano, NH ₂ , NHCH ₃ , N(CH ₃ ) ₂ , N0 ₂ , N ₃ , C(0)CH ₃ , COOH, C0 ₂ CH ₃ , Ci_ ₆ alkyl, Ci_ r,alkoxy, oxo, haloCi_ ₆ alkyl, phenyl or heterocyclyl.

The term“cyano” as used herein means a substituent having a carbon atom joined to a nitrogen atom by a triple bond.

The term "oxo" means an =0 group and may be attached to a carbon atom or a sulfur atom.

The term“enantiomer” denotes two stereoisomers of a compound which are non- superimposable mirror images of one another.

The term“diastereomer” denotes a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g. melting points, boiling points, spectral properties, and reactivities.

The term“PG” denotes a protecting group, which is introduced into a molecule by chemical modification of a functional group to obtain chemo selectivity in a subsequent chemical reaction. Typical protecting groups are Boc, Cbz and Bn.

The compounds according to the present invention may exist in the form of their pharmaceutically acceptable salts. The term“pharmaceutically acceptable salt” refers to conventional acid-addition salts or base-addition salts that retain the biological effectiveness and properties of the compounds of formula (I) and are formed from suitable non-toxic organic or inorganic acids or organic or inorganic bases. Acid-addition salts include for example those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid and nitric acid, and those derived from organic acids such as -tolucnesul Ionic acid, salicylic acid, methanesulfonic acid, oxalic acid, succinic acid, citric acid, malic acid, lactic acid, fumaric acid, and the like. Base-addition salts include those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethyl ammonium hydroxide. The chemical modification of a pharmaceutical compound into a salt is a technique well known to pharmaceutical chemists in order to obtain improved physical and chemical stability, hygroscopicity, flowability and solubility of compounds. It is for example described in Bastin R.J., et al, Organic Process Research & Development 2000, 4, 427-435. Particular are the sodium salts of the compounds of formula (I).

Compounds of the general formula (I) which contain one or several chiral centers can either be present as racemates, diastereomeric mixtures, or optically active single isomers. The racemates can be separated according to known methods into the enantiomers. Particularly, diastereomeric salts which can be separated by crystallization are formed from the racemic mixtures by reaction with an optically active acid such as e.g. D- or L-tartaric acid, mandelic acid, malic acid, lactic acid or camphorsulfonic acid. cccDNA INHIBITORS

The present invention provides (i) a compound having the general formula (I):

wherein

R ¹ is selected from halogen and haloCi-6alkyl;

R ² is selected from H, halogen, Ci-6alkyl, Ci-6alkoxy, C _3-7 cycloalkyl and haloCi-6alkyl;

R ³ is selected from H, halogen and Ci-6alkoxy;

R ⁴ is selected from H, hydroxy and haloCi-6alkyl;

R ⁵ is selected from H, halogen, Ci_6alkyl, Ci_6alkoxy and hydroxy;

R ⁶ is selected from carboxy, Ci_ ₆ alkoxycarbonyl, carboxyCi_ ₆ alkoxycarbonyl, carboxyC ₃ _ 7cycloalkylaminocarbonyl, carboxyheterocyclylcarbonyl, C _{3- 7} cycloalkylsulfonylaminocarbonyl, hydroxyCi_ ₆ alkylaminocarbonyl, Ci_

6alkylsulfonylheterocyclylcarbonyl, heterocyclylcarbonyl, hydroxyheterocyclylcarbonyl, (hydroxy) ₂ heterocyclylcarbonyl, Ci_ ₆ alkylsulfonylaminocarbonylheterocyclylcarbonyl, Ci_ 6alkylsulfonylaminocarbonyl, cyano, (Ci_ ₆ alkyl) ₂ aminosulfonyl, aminocarbonyl, aminosulfonyl, C _3-7 cycloalkylaminocarbonylcarbonyl and C _3-7 cycloalkylaminocarbonyl;

Ai is selected from N and CR ⁷ ; wherein R ⁷ is selected from H, halogen and haloCi-6alkyl;

A ₂ is selected from N and CR ⁸ ; wherein R ⁸ is selected from H, halogen, hydroxy, C _h alky 1,

Ci-6alkoxy, C _3-7 cycloalkyl, haloCi-6alkyl, haloCi-6alkoxy, haloCi-6alkylCi-6alkoxy, Ci_ 6alkylsulfanyl, Ci-6alkylsulfonyl, C _3-7 cycloalkylCi- ₆ alkoxy and heterocyclyl; wherein heterocyclyl is unsubstituted or substituted one or two or three times independently by oxo; A ₃ is selected from N and CR ⁹ ; wherein R ⁹ is selected from H, amino, halogen, hydroxy, Ci_ 6alkyl, Ci_ ₆ alkoxy, haloCi_ ₆ alkyl, haloCi_ ₆ alkoxy, haloCi_ ₆ alkylCi_ ₆ alkoxy and C ₃ _ 7cycloalky 1C i _ ₆ alkoxy ;

or R ⁸ and R ⁹ , together with the atoms to which they are attached, form a heterocyclyl ring; wherein heterocyclyl ring is unsubstituted or substituted by one or two or three or four substituents independently selected from halogen, Ci- ₆ alkyl and oxo;

A ₄ is selected from N and CR ¹⁰ ; wherein R ¹⁰ is selected from H and halogen;

Gi is selected from Ci_6alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkylCi_ ₆ alkyl, phenylCi_6alkyl, Ci_ 6a]kylC _3-7 cycloalkylCi_ ₆ alkyl and heterocyclyl; wherein Ci_6alkyl, C _3-7 cycloalkyl, C ₃ _ 7cycloalkylCi_ ₆ alkyl, phenylCi_6alkyl, Ci- ₆ a]kylC _3-7 cycloalkylCi_ ₆ alkyl and heterocyclyl are unsubstituted or substituted by one or two or three substituents independently selected from hydroxy, amino, C _3-7 cycloalkylsulfonylamino, Ci_6alkylphenylsulfonylamino, phenylsulfonyl, C _3-7 cycloalkylsulfonyl, Ci_6alkoxyphenylsulfonyl, phenylcarbonyl, phenylcarbonylamino, Ci_6alkylcarbonylamino, C _h alky laminosulfonylamino, aminocarbonyamino, (Ci- ₆ alkoxy) ₂ phenylaminosulfonylamino, Ci- 6alkoxycarbonylcarbonylamino, (Ci- ₆ alkyl) ₂ aminosulfonylamino, Ci- 6alkylaminocarbonylamino, Ci-6alkylaminosulfonyl, aminosulfonylamino, C _{3- 7} cycloalkylaminosulfonylamino and phenylCi _6alkylaminosulfonylamino ;

G ₂ is selected from Ci_6alkyl, C _3-7 cycloalkyl and phenyl;

m is selected from 0 and 1 ;

or a pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is (ii) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from halogen and haloCi-6alkyl;

R ² is selected from H, halogen, Ci_6alkyl, Ci_6alkoxy, C _3-7 cycloalkyl and haloCi_6alkyl;

R ³ is selected from H, halogen and Ci_6alkoxy;

R ⁴ is selected from H, hydroxy and haloCi_6alkyl;

R ⁵ is selected from H, halogen, Ci_6alkyl, Ci_6alkoxy and hydroxy;

R ⁶ is selected from carboxy, Ci_6alkoxycarbonyl, carboxyCi_6alkoxycarbonyl, carboxyC ₃ _ 7cycloalkylaminocarbonyl, carboxypyrrolidinylcarbonyl, C ₃ _

7cycloalkylsulfonylaminocarbonyl, hydroxyCi_6alkylaminocarbonyl, Ci_

6alkylsulfonylpyrrolidinylcarbonyl, morpholinylcarbonyl, hydroxypyrrolidinylcarbonyl, (hydroxy) ₂ pyrrolidinylcarbonyl, C _h alky lsulfonylaminocarbonylpyrrolidinylcarbonyl, Ci- ₆ alkylsulfonylaminocarbonyl, cyano, (Ci_ ₆ alkyl) ₂ aminosulfonyl, aminocarbonyl, aminosulfonyl, C _3-7 cycloalkylaminocarbonylcarbonyl and C _3-7 cycloalkylaminocarbonyl;

Ai is selected from N and CR ⁷ ; wherein R ⁷ is selected from H, halogen and haloCi_ ₆ alkyl;

A ₂ is selected from N and CR ⁸ ; wherein R ⁸ is selected from H, halogen, hydroxy, C _h alky 1,

Ci-6alkoxy, C _3-7 cycloalkyl, haloCi-6alkyl, haloCi-6alkoxy, haloCi-6alkylCi-6alkoxy, Ci_ 6alkylsulfanyl, Ci-6alkylsulfonyl, C _3-7 cycloalkylCi- ₆ alkoxy, thiazolyl, morpholinyl, pyrrolidinyl and oxazolidinyl; wherein pyrrolidinyl and oxazolidinyl are unsubstituted or substituted by one or two or three substituents independently selected from oxo;

A ₃ is selected from N and CR ⁹ ; wherein R ⁹ is selected from H, amino, halogen, hydroxy, Ci_ 6alkyl, Ci_ ₆ alkoxy, haloCi_ ₆ alkyl, haloCi_ ₆ alkoxy, haloCi_ ₆ alkylCi_ ₆ alkoxy and C _{3- 7} cycloalky 1C ₁ _ ₆ alkoxy ;

or R ⁸ and R ⁹ , together with the atoms to which they are attached, form a 5- or 6-membered heterocyclyl ring; wherein 5- or 6-membered heterocyclyl ring is unsubstituted or substituted by one or two or three or four substituents independently selected from halogen, Ci- ₆ alkyl and oxo;

A ₄ is selected from N and CR ¹⁰ ; wherein R ¹⁰ is selected from H and halogen;

Gi is selected from Ci-6alkyl, C _3-7 cycloalkyl, C _3-7 cycloalkylCi- ₆ alkyl, phenylCi-6alkyl, Ci_ 6alkylC _3-7 cycloalkylCi _-6 alkyl and pyrrolidinyl; wherein Ci-6alkyl, C _3-7 cycloalkyl, C _{3- 7} cycloalkylCi_ ₆ alkyl, phenylCi_6alkyl, Ci- ₆ a]kylC _3-7 cycloalkylCi_ ₆ alkyl and pyrrolidinyl are unsubstituted or substituted by one or two or three substituents independently selected from hydroxy, amino, C _3-7 cycloalkylsulfonylamino, Ci_6alkylphenylsulfonylamino, phenylsulfonyl, C _3-7 cycloalkylsulfonyl, Ci_6alkoxyphenylsulfonyl, phenylcarbonyl, phenylcarbonylamino, C _h alky lcarbonylamino, C _h alky laminosulfonylamino,

aminocarbonyamino, (Ci_ ₆ alkoxy) ₂ phenylaminosulfonylamino, Ci_

6alkoxycarbonylcarbonylamino, (Ci- ₆ alkyl) ₂ aminosulfonylamino, Ci- 6alkylaminocarbonylamino, Ci- ₆ alkylaminosulfonyl, aminosulfonylamino, C _{3- 7} cycloalkylaminosulfonylamino and phenylCi _6alkylaminosulfonylamino ;

G ₂ is selected from Ci- ₆ alkyl, C _3-7 cycloalkyl and phenyl;

m is selected from 0 and 1.

A further embodiment of the present invention is (iii) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from F, Cl, Br and CF ₃ ;

R ² is selected from H, F, Cl, Br, methyl, methoxy, CF ₃ and cyclopropyl; R ³ is selected from H, F and methoxy;

R ⁴ is selected from H, hydroxy and CF ₃ ;

R ⁵ is selected from H, hydroxy, methyl and methoxy;

R ⁶ is selected from carboxy, methoxycarbonyl, carboxyisopropoxycarbonyl,

carboxycyclobutylaminocarbonyl, carboxypyrrolidinylcarbonyl,

cyclopropylsulfonylaminocarbonyl, hydroxyethylaminocarbonyl,

methylsulfonylpyrrolidinylcarbonyl, hydroxypyrrolidinylcarbonyl,

(hydroxy)2pyrrolidinylcarbonyl, morpholinylcarbonyl,

methylsulfonylaminocarbonylpyrrolidinylcarbonyl, methylsulfonylaminocarbonyl, cyano, (methyl)2aminosulfonyl, aminocarbonyl, aminosulfonyl,

cyclopropylaminocarbonylcarbonyl and cyclopropylaminocarbonyl;

Ai is selected from N and CR ⁷ ; wherein R ⁷ is selected from H, F, Cl, Br and CF ₃ ;

A2 is selected from N and CR ⁸ ; wherein R ⁸ is selected from H, F, Cl, Br, CF ₃ hydroxy, methyl, ethyl, isopropyl, methoxy, ethoxy, propoxy, cyclopropyl, trifluoro methoxy,

difluoromethoxy, trifluoro methylmethoxy, methylsulfonyl, methylsulfanyl,

cyclopropylmethoxy, thiazolyl, morpholinyl, pyrrolidinyl and oxazolidinyl; wherein pyrrolidinyl and oxazolidinyl are unsubstituted or substituted one or two or three times independently by oxo;

A ₃ is selected from N and CR ⁹ ; wherein R ⁹ is selected from H, amino, hydroxy, F, Cl, Br, CF ₃ , methyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoromethylmethoxy, difluoromethyl and cyclopropylmethoxy;

or R ⁸ and R ⁹ , together with the atoms to which they are attached, form a 5- or 6-membered heterocyclyl ring; wherein 5- or 6-membered heterocyclyl ring is unsubstituted or substituted by one or two or three or four substituents independently selected from F, methyl and oxo;

A4 is selected from N and CR ¹⁰ ; wherein R ¹⁰ is selected from Fl and F;

Gi is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl, hexyl, isohexyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylmethyl, phenylmethyl,

methylcyclopropylmethyl and pyrrolidinyl; wherein methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl, hexyl, isohexyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclobutylmethyl, phenylmethyl, methylcyclopropylmethyl and pyrrolidinyl are unsubstituted or substituted by one or two or three substituents independently selected from hydroxy, amino, cyclopropylsulfonylamino, methylphenylsulfonylamino, phenylsulfonyl, cyclopropylsulfonyl, methoxyphenylsulfonyl, phenylcarbonyl, phenylcarbonylamino, methylcarbonylamino, ethylaminosulfonylamino, aminocarbonylamino,

(methoxy) ₂ phenylcarbamoylamino , ethyoxycarbonylcarbonylamino ,

dimethylaminosulfonylamino, ethylaminocarbonylamino, ethylaminosulfonyl, aminosulfonylamino, methylaminosulfonylamino, isoprop ylaminosulfonylamino, cyclopropylaminosulfonylamino and phenylmethylaminosulfony lamino ;

G ₂ is selected from methyl, isopropyl, cyclobutyl, cyclopentyl and phenyl;

m is selected from 0 and 1.

A further embodiment of the present invention is (iv) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein

R ¹ is halogen;

R ² is selected from H, halogen, Ci- ₆ alkoxy and C _3-7 cycloalkyl;

R ³ is selected from H, halogen and Ci_ ₆ alkoxy;

R ⁴ is selected from H and hydroxy;

R ⁵ is selected from H, Ci_ ₆ alkyl, Ci_ ₆ alkoxy and hydroxy;

R ⁶ is selected from carboxy, Ci_ ₆ alkoxycarbonyl, carboxyCi_ ₆ alkoxycarbonyl, carboxyC ₃ _ 7cycloalkylaminocarbonyl, carboxypyrrolidinylcarbonyl, C _{3- 7} cycloalkylsulfonylaminocarbonyl, hydroxyCi_ ₆ alkylaminocarbonyl, Ci_

6alkylsulfonylpyrrolidinylcarbonyl, morpholinylcarbonyl, hydroxypyrrolidinylcarbonyl, (hydroxy) ₂ pyrrolidinylcarbonyl, Ci_ ₆ alkylsulfonylaminocarbonylpyrrolidinylcarbonyl, (Ci_ 6alkyl) ₂ aminosulfonyl and aminosulfonyl;

Ai is CR ⁷ ; wherein R ⁷ is selected from H and halogen;

A ₂ is CR ⁸ ; wherein R ⁸ is selected from H, hydroxy, halogen, Ci- ₆ alkyl, Ci- ₆ alkoxy, haloCi- 6alkyl, haloCi- ₆ alkoxy and haloCi- ₆ alkylCi- ₆ alkoxy;

A ₃ is selected from N and CR ⁹ ; wherein R ⁹ is selected from H, halogen, hydroxy, C _h alky 1, Ci_ ₆ alkoxy and haloCi_ ₆ alkoxy;

or R ⁸ and R ⁹ , together with the atoms to which they are attached, form a 5- or 6- membered heterocyclyl ring;

A ₄ is selected from N and CR ¹⁰ ; wherein R ¹⁰ is selected from H and halogen;

Gi is selected from Ci_ ₆ alkyl and Ci- ₆ alkylC _3-7 cycloalkylCi_ ₆ alkyl; wherein Ci_ ₆ alkyl is

unsubstituted or substituted by one or two or three substituents independently selected from hydroxy, amino, C _3-7 cycloalkylsulfonylamino, Ci- ₆ alkylphenylsulfonylamino and Ci_ 6alkylaminosulfony lamino ; m is 0.

A further embodiment of the present invention is (v) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from F, Cl and Br;

R ² is selected from H, F, Cl, Br, methoxy and CF ₃ ;

R ³ is selected from H, F and methoxy;

R ⁴ is selected from Fl and hydroxy;

R ⁵ is selected from Fl and hydroxy;

R ⁶ is carboxy, methoxycarbonyl, carboxyisopropoxycarbonyl,

carboxycyclobutylaminocarbonyl, carboxypyrrolidinylcarbonyl,

cyclopropylsulfonylaminocarbonyl, hydroxyethylaminocarbonyl,

methylsulfonylpyrrolidinylcarbonyl, hydroxypyrrolidinylcarbonyl,

(hydroxy)2pyrrolidinylcarbonyl, morpholinylcarbonyl,

methylsulfonylaminocarbonylpyrrolidinylcarbonyl, (methyl^aminosulfonyl or

aminosulfonyl;

Ai is CR ⁷ ; wherein R ⁷ is selected from H, F, Cl and Br;

A ₂ is CR ⁸ ; wherein R ⁸ is selected from H, F, Cl, Br, CF ₃ hydroxy, methyl, methoxy,

trifluoromethoxy and trifluoromethylmethoxy;

A ₃ is CR ⁹ ; wherein R ⁹ is selected from H, hydroxy, F, Cl, Br, methyl, methoxy and

trifluoromethoxy ;

or R ⁸ and R ⁹ , together with the atoms to which they are attached, form a 5- or 6- membered heterocyclyl ring;

A4 is selected from N and CR ¹⁰ ; wherein R ¹⁰ is selected from Fl and F;

Gi is selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, neopentyl, hexyl, isohexyl and methylcyclopropylmethyl; wherein ethyl is unsubstituted or substituted by one or two or three substituents independently selected from hydroxy, amino,

cyclopropylsulfonylamino, methylphenylsulfonylamino and ethylaminosulfonylamino; m is 0.

A further embodiment of the present invention is (vi) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein R ¹ is halogen.

A further embodiment of the present invention is (vii) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from Cl and Br. A further embodiment of the present invention is (viii) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt, or enantiomer, or diastereomer thereof, wherein R ⁶ is selected from carboxy and Ci_ ₆ alkoxycarbonyl.

A further embodiment of the present invention is (ix) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein R ⁶ is selected from carboxy and methoxycarbonyl.

A further embodiment of the present invention is (x) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein A ₂ is CR ⁸ ; wherein R ⁸ is selected from halogen, Ci_ ₆ alkoxy, haloCi_ ₆ alkyl and haloCi_ ₆ alkoxy.

A further embodiment of the present invention is (xi) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein A ₂ is CR ⁸ ; wherein R ⁸ is selected from Cl, Br, CIC methoxy and trifluoromethoxy.

A further embodiment of the present invention is (xii) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein A ₃ is CR ⁹ ; wherein R ⁹ is selected from H, Ci_ ₆ alkyl and Ci_ ₆ alkoxy.

A further embodiment of the present invention is (xiii) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein A ₃ is CR ⁹ ; wherein R ⁹ is selected from H, methyl and methoxy.

A further embodiment of the present invention is (xiv) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein Gi is Ci_ ₆ alkyl; wherein Ci_ ₆ alkyl is unsubstituted or substituted by one substituent independently selected from C ₃ _7cycloalkylsulfonylamino and Ci_ ₆ alkylaminosulfonylamino.

A further embodiment of the present invention is (xv) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein Gi is ethyl; wherein ethyl is unsubstituted or substituted by one substituent independently selected from

cyclopropylsulfonylamino and ethylaminosulfonylamino.

A further embodiment of the present invention is (xvi) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein

R ¹ is halogen;

R ² is H;

R ³ is H; R ⁴ is H;

R ⁵ is H;

R ⁶ is selected from carboxy and Ci_6alkoxycarbonyl;

Ai is CH;

A ₂ is CR ⁸ ; wherein R ⁸ is selected from halogen, Ci-6alkoxy, haloCi-6alkyl and haloCi-6alkoxy;

A ₃ is CR ⁹ ; wherein R ⁹ is selected from H, methyl and methoxy;

A4 is CH;

Gi is Ci_6alkyl; wherein Ci_6alkyl is unsubstituted or substituted by one substituent

independently selected from C3_7cycloalkylsulfonylamino and Ci_

6alkylaminosulfonylamino ;

m is 0.

A further embodiment of the present invention is (xvii) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from Cl and Br;

R ² is H;

R ³ is H;

R ⁴ is H;

R ⁵ is H;

R ⁶ is selected from carboxy and methoxycarbonyl;

Ai is CH;

A ₂ is CR ⁸ ; wherein R ⁸ is selected from Cl, Br, Cf\ methoxy and trifluoro methoxy;

A3 is CR ⁹ ; wherein R ⁹ is selected from H, methyl and methoxy;

A4 is CH;

Gi is ethyl; wherein ethyl is unsubstituted or substituted by one substituent independently selected from cyclopropylsulfonylamino and ethylaminosulfonylamino;

m is 0.

In another embodiment (xviii) of the present invention, particular compounds of the present invention are selected from:

3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]propanoic acid;

methyl 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]propanoate; 3-[2-(8-chloro-6-fluoro-4-oxo-chromen-2-yl)-5-(trifluorometh yl)phenoxy]propanoic acid; 3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]propanoic acid;

3-[5-chloro-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-phenoxy ]propanoic acid; 3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-phenoxy] propanoic acid;

3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-phenoxy ]propanoic acid;

3-[5-chloro-2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-phenox y]propanoic acid;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethoxy)pheno xy]propanoic acid;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dimethoxy-phenoxy]pro panoic acid;

3-[[6-(8-chloro-4-oxo-chromen-2-yl)-l,3-benzodioxol-5-yl]oxy ]propanoic acid;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methoxy-4-methyl-phenox y]propanoic acid;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methyl-phenoxy]propanoi c acid;

3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-(trifluorometho xy)phenoxy]propanoic acid;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-5-methyl-phenox y]propanoic acid;

3-[4-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluorometho xy)phenoxy]propanoic acid;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-5-(trifluorometh oxy)phenoxy]propanoic acid;

3-[2-bromo-6-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-phenoxy] propanoic acid;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methyl-4-(trifluorometh oxy)phenoxy]propanoic acid;

3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-3-fluoro-phenoxy] propanoic acid;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-3-fluoro-5-methyl-phenoxy ]propanoic acid;

3-[2-(8-bromo-4-oxo-chromen-2-yl)-5-(trifluoromethoxy)phenox y]propanoic acid;

3-[2-(7-bromo-8-chloro-4-oxo-chromen-2-yl)-5-(trifluorometho xy)phenoxy]propanoic acid;

3-[2-(8-bromo-4-oxo-chromen-2-yl)-5-methyl-phenoxy]propanoic acid;

3-[2-(8-bromo-4-oxo-chromen-2-yl)-5-chloro-4-methyl-phenoxy] propanoic acid;

3-[[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-3-pyridyl]oxy]pr opanoic acid;

3-[2-(8-chloro-7-fluoro-4-oxo-chromen-2-yl)-5-(trifluorometh yl)phenoxy]propanoic acid; 3-[2-(8-chloro-7-methoxy-4-oxo-chromen-2-yl)-5-(trifluoromet hyl)phenoxy]propanoic acid;

3-[2-(8-chloro-6-methoxy-4-oxo-chromen-2-yl)-5-(trifluoromet hyl)phenoxy]propanoic acid;

3-[2-(8-chloro-3-methyl-4-oxo-chromen-2-yl)-5-(trifluorometh yl)phenoxy]propanoic acid; methyl 3-[5-chloro-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-phenoxy ]propanoate; 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoroniethyl)pheno xy]butanoic acid;

3-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phe noxy]butanoyloxy]butanoic acid;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-5-(2,2,2- trifluoroethoxy)phenoxy]propanoic acid ;

3-[2-[8-chloro-4-oxo-7-(trifluoromethyl)chromen-2-yl]-5- (trifluoromethoxy)phenoxy]propanoic acid ;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-5-(trifluoromet hyl)phenoxy]propanoic acid;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-5-(trifluorometh yl)phenoxy]propanoic acid; 3-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-5-(trifluoromet hyl)phenoxy]propanoic acid;

3-[2-(8-chloro-3-hydroxy-4-oxo-chromen-2-yl)-5-(trifluoromet hyl)phenoxy]propanoic acid;

3-[2-(8-chloro-3-methoxy-4-oxo-chromen-2-yl)-5-(trifluoromet hyl)phenoxy]propanoic acid;

2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethoxy)pheno xy]acetic acid;

2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methyl-phenoxy]acetic acid;

2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dimethoxy-phenoxy]ace tic acid;

2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]acetic acid;

4-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]butanoic acid;

4-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethoxy)pheno xy]butanoic acid;

4-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-phenoxy] butanoic acid;

4-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]butanoic acid;

4-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dimethoxy-phenoxy]but anoic acid

4-[5-chloro-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-phenoxy ]butanoic acid

4-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-phenoxy ]butanoic acid

4-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methyl-phenoxy]butanoic acid

4-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methoxy-4-methyl-phenox y]butanoic acid;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethoxy)pheno xy]-2, 2-dimethyl- propanoic acid;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]-2, 2-dimethyl-propanoic acid; 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methyl-phenoxy]-2, 2-dimethyl-propanoic acid;

3-[5-chloro-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-phen oxy]-2, 2- dimethyl-propanoic acid;

5-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]pentanoic acid;

7-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]heptanoic acid;

2-[l-[[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dimethoxy- phenoxy ] methyl] cyclopropyl] acetic ac id ;

2-[l-[[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl- phenoxy ] methyl] cyclopropyl] acetic ac id ;

2-[l-[[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]methyl ]cyclopropyl]acetic acid;

2- [5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy] -2-methyl-propanoic acid;

5-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethoxy)pheno xy]-2, 2-dimethyl- pentanoic acid;

2- [5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-phenoxy] acetic acid;

3-[[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]acetyl]amino]cyclobutanecarboxylic acid;

(2R)-l-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]pr opanoyl]pyrrolidine-2- carboxylic acid;

(2S)-l-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]pr opanoyl]pyrrolidine-2- carboxylic acid;

(2R)-l-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methyl-phenoxy] acetyl]pyrrolidine-2- carboxylic acid;

(2S)-l-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methyl-phenoxy] acetyl]pyrrolidine-2- carboxylic acid;

(2R)-l-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl- phenoxy]acetyl]pyrrolidine-2-carboxylic acid;

(2S)-l-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl- phenoxy]acetyl]pyrrolidine-2-carboxylic acid;

(2R)-l-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]acetyl]pyrrolidine-2-carboxylic acid;

(2S)-l-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]acetyl]pyrrolidine-2-carboxylic acid; (3S)-l-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy] acetyl]pyrrolidine-3 -carboxylic acid ;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]-N-cyclopropylsulfonyl- propanamide;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dimethoxy-phenoxy]-N- cyclopropylsulfonyl- propanamide;

2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]-N-(2- hydroxy ethyl) acetamide ;

8-chloro-2-[2-[2-(3-methylsulfonylpyrrolidin-l-yl)-2-oxo-eth oxy]-4- (trifluoromethy l)phenyl] chromen- 4-one ;

2-[4-bromo-2-[2-[(3S)-3-hydroxypyrrolidin-l-yl]-2-oxo-ethoxy ]-5-methyl-phenyl]-8- chloro-chromen-4-one;

2-[4-bromo-2-[2-[(3R)-3-hydroxypyrrolidin-l-yl]-2-oxo-ethoxy ]-5-methyl-phenyl]-8- chloro-chromen-4-one;

2-[4-bromo-5-methyl-2-[2-oxo-2-[rac-(3S,4R)-3,4-dihydroxypyr rolidin-l- yl]ethoxy]phenyl]-8-chloro-chromen-4-one;

2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dimethoxy-phenoxy]-N- cyclopropylsulfonyl- acetamide;

8-chloro-2-[2-(2-morpholino-2-oxo-ethoxy)-4-(trifluoromethyl )phenyl]chromen-4-one;

(2S)-l-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methyl-pheno xy]acetyl]-N-methylsulfonyl- pyrrolidine-2-carboxamide;

(2R)-l-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methyl-phenoxy] acetyl]-N-methylsulfonyl- pyrrolidine-2-carboxamide;

(2S)-2-amino-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoro methyl)phenoxy]propanoic acid;

(2S)-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)p henoxy]-2- (cyclopropylsulfonylamino)propanoic acid;

(2S)-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)p henoxy]-2-(p- tolylsulfonylamino)propanoic acid;

methyl (2S)-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)p henoxy]-2- (ethylsulfamoylamino)propanoate;

(2S)-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)p henoxy]-2- (ethylsulfamoylamino)propanoic acid ; 4-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-5-(trifluoronie thyl)phenoxy]butanoic acid; 3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-N,N-dimet hyl-propane-l- sulfonamide;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]propane-l -sulfonamide; and

3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]-2-hydroxy-propanoic acid;

or a pharmaceutically acceptable salt thereof.

In another embodiment (xix) of the present invention, particular compounds of the present invention are selected from:

3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]propanoic acid;

methyl 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]propanoate; 3-[5-chloro-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-phenoxy ]propanoic acid;

3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-phenoxy] propanoic acid;

3-[5-chloro-2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-phenox y]propanoic acid;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethoxy)pheno xy]propanoic acid;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methoxy-4-methyl-phenox y]propanoic acid;

3-[2-(8-bromo-4-oxo-chromen-2-yl)-5-chloro-4-methyl-phenoxy] propanoic acid;

(2S)-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)p henoxy]-2- (cyclopropylsulfonylamino)propanoic acid; and

(2S)-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)p henoxy]-2- (ethylsulfamoylamino)propanoic acid ;

or a pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is (xx) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein

R ¹ is halogen;

R ² is H;

R ³ is H;

R ⁴ is selected from H and hydroxy;

R ⁵ is H;

R ⁶ is selected from carboxy, C3_7cycloalkylsulfonylaminocarbonyl and Ci_

6alkylsulfonylaminocarbonyl;

Ai is CH; A ₂ is CR ⁸ ; wherein R ⁸ is selected from H, halogen, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, C _3-7 cycloalkyl, haloCi_ ₆ alkyl and haloCi_ ₆ alkoxy;

A ₃ is CR ⁹ ; wherein R ⁹ is selected from H, halogen, Ci_ ₆ alkyl, Ci_ ₆ alkoxy and haloCi_ ₆ alkyl; or R ⁸ and R ⁹ , together with the atoms to which they are attached, form a 5-membered heterocyclyl ring;

A ₄ is CH;

Gi is selected from C _3-7 cycloalkyl, C _3-7 cycloalkylCi- ₆ alkyl, phenylCi- ₆ alkyl and pyrrolidinyl; wherein pyrrolidinyl is unsubstituted or substituted by one or two or three substituents independently selected from phenylsulfonyl, C _3-7 cycloalkylsulfonyl, Ci_

6alkoxyphenylsulfonyl and phenylcarbonyl;

m is 0.

A further embodiment of the present invention is (xxi) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from F, Cl and Br;

R ² is H;

R ³ is H;

R ⁴ is selected from Fl and hydroxy;

R ⁵ is H;

R ⁶ is selected from carboxy, cyclopropylsulfonylaminocarbonyl,

methylsulfonylaminocarbonyl and cyano;

Ai is CH;

A ₂ is CR ⁸ ; wherein R ⁸ is selected from H, F, Cl, Br, CF _3. methyl, ethyl, isopropyl, methoxy, ethoxy, cyclopropyl and trifluoromethoxy;

A ₃ is CR ⁹ ; wherein R ⁹ is selected from H, F, Cl, Br, methyl, methoxy and trifluoro methyl; or R ⁸ and R ⁹ , together with the atoms to which they are attached, form a 5-membered heterocyclyl ring;

A ₄ is CH;

Gi is selected from phenylmethyl, cyclobutyl, cyclohexyl, cyclobutylmethyl, cyclopentyl and pyrrolidinyl; wherein pyrrolidinyl is unsubstituted or substituted by one or two or three substituents independently selected from phenylsulfonyl, cyclopropylsulfonyl, methoxyphenylsulfonyl and phenylcarbonyl;

m is 0. A further embodiment of the present invention is (xxii) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein R ¹ is halogen.

A further embodiment of the present invention is (xxiii) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from Cl and Br.

A further embodiment of the present invention is (xxiv) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein R ⁶ is selected from carboxy and C _3- 7cycloalkylsulfonylaminocarbonyl.

A further embodiment of the present invention is (xxv) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein R ⁶ is selected from carboxy and cyclopropylsulfonylaminocarbonyl.

A further embodiment of the present invention is (xxvi) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt, or enantiomer, or

diastereomer thereof, wherein A ₂ is CR ⁸ ; wherein R ⁸ is selected from halogen and haloCi_ ₆ alkyl.

A further embodiment of the present invention is (xxvii) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein A ₂ is CR ⁸ ; wherein R ⁸ is selected from Cl and CIA

A further embodiment of the present invention is (xxviii) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein A ₃ is CR ⁹ ; wherein R ⁹ is selected from H and C _h alky 1.

A further embodiment of the present invention is (xxix) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein A ₃ is CR ⁹ ; wherein R ⁹ is selected from H and methyl.

A further embodiment of the present invention is (xxx) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein wherein Gi is selected from C ₃ _7cycloalkyl and pyrrolidinyl; wherein pyrrolidinyl is substituted one time by phenylsulfonyl.

A further embodiment of the present invention is (xxxi) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein Gi is cyclobutyl or pyrrolidinyl; wherein pyrrolidinyl is substituted one time by phenylsulfonyl. A further embodiment of the present invention is (xxxii) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein

R ¹ is halogen;

R ² is H;

R ³ is H;

R ⁴ is H;

R ⁵ is H;

R ⁶ is selected from carboxy and C3_7cycloalkylsulfonylaminocarbonyl;

Ai is CH;

A ₂ is CR ⁸ ; wherein R ⁸ is selected from halogen and haloCi_6alkyl;

A ₃ is CR ⁹ ; wherein R ⁹ is selected from H and Ci_6alkyl;

A4 is CH;

Gi is selected from C3_7cycloalkyl and pyrrolidinyl; wherein pyrrolidinyl is substituted one time by phenylsulfonyl.

m is 0.

A further embodiment of the present invention is (xxxiii) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from Cl and Br;

R ² is H;

R ³ is H;

R ⁴ is H;

R ⁵ is H;

R ⁶ is selected from carboxy and cyclopropylsulfonylaminocarbonyl;

Ai is CH;

A ₂ is CR ⁸ ; wherein R ⁸ is selected from F, Cl, Br and CF ₃ ;

A3 is CR ⁹ ; wherein R ⁹ is selected from H and methyl;

A4 is CH;

Gi is selected from cyclobutyl and pyrrolidinyl; wherein pyrrolidinyl is substituted one time by phenylsulfonyl;

m is 0.

In another embodiment (xxxiv) of the present invention, particular compounds of the present invention are selected from:

3-[[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]methyl]be nzoic acid; 3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]cyclobutan ecarboxylic acid;

s-3-[2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]cyclobutanecarbo xylic acid;

fra¾s-3-[2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]cyclobutane carboxylic acid;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]cyclobutanecarboxylic acid;

3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-phenoxy ]cyclobutanecarboxylic acid;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethoxy)pheno xy]cyclobutanecarboxylic acid;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dimethoxy-phenoxy]cyc lobutanecarboxylic acid; 3-[4-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethoxy)phenoxy]cyclobutanecarboxylic acid;

3-[2-bromo-6-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-phenoxy] cyclobutanecarboxylic acid;

4-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]cyclohexan ecarboxylic acid;

s-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methoxy-phenoxy]cyclo butanecarboxylic acid; //Y///v-3-[2-(8-chloro-4-oxo-chronicn-2-yl)-5-nicthoxy-phcno xy]cyclobutanccarboxylic acid;

r/ ^' v-3-|5-chloro-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl - phcnoxy ]cyclobutanccarboxylic acid;

fra¾s-3-[5-chloro-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl- phcnoxy ]cyclobutanccarboxylic acid;

s-3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl- phcnoxy ]cyclobutanccarboxylic acid;

fra¾s-3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl- phcnoxy ]cyclobutanccarboxylic acid;

fra¾s-3-[4-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-5-methoxy- phcnoxy ]cyclobutanccarboxylic acid;

s-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethoxy)phenoxy]cyclobutanecarboxylic acid;

s-3-[2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-phenoxy]cyclob utanecarboxylic acid //U///L-3- 12-(8-chloro-4-oxo-chromen-2-yl)-5-methoxy-4- methyl- phc no x y ] cy c lo bu tanccarbo x y 1 i c acid; s-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methyl-phenoxy]cyclob utanecarboxylic acid; //Y// -3-|2-(8-chloro-4-oxo-chromen-2-yl)-5-methyl-phenoxy]cyclobu tanecarboxylic acid; s-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-ethyl-phenoxy]cyclobu tanecarboxylic acid; fra¾s-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-ethyl-phenoxy]cy clobutanecarboxylic acid; r/v-3-[2-(8-chloro-4-oxo-chronicn-2-yl)-5-isopropyl-phcnoxy] cyclobutanccarboxylic acid; //Y// -3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-isopropyl-phenoxy]cycl obutanecarboxylic acid;

//Y///v-3-[2-(8-chloro-4-oxo-chronicn-2-yl)-4-nicthoxy-phcno xy]cyclobutanccarboxylic acid;

//Y///v-3-[2-(8-bronio-4-oxo-chronicn-2-yl)phcnoxy ]cyclobutanccarboxylic acid;

r/v-3-[2-(8-bronio-4-oxo-chronicn-2-yl)phcnoxy]cyclobutancca rboxylic acid;

fra¾s-3-[[6-(8-chloro-4-oxo-chromen-2-yl)-2,3-dihydrobenzof uran-5- yl]oxy]cyclobutanecarboxylic acid;

//Y///v-3-[5-bronio-2-(8-chloro-4-oxo-chronicn-2-yl)-4- (trifluoromethyl)phenoxy]cyclobutanecarboxylic acid;

r/x-3- 1 |5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy ] methyl ]cyclobutanecarboxylic acid;

//Y///v-3-[ [5-bronio-2-(8-chloro-4-oxo-chronicn-2- yl)phenoxy]methyl]cyclobutanecarboxylic acid;

r/ ^' v-3-[ [ 2-(8-chloro-4-oxo-chronicn-2-y bphcnoxy] methyl ]cyclobutanccarboxy lie acid; fra¾s-3-[[2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]methyl]cyc lobutanecarboxylic acid; Y /.S-3- 112-(8-ch loro-4-oxo-chro mcn-2-y l)-4- nicthox y- phenoxy]methyl]cyclobutanecarboxylic acid;

//Y//i.s-3- 112-(8-ch loro-4-oxo-chro mcn-2-y 1 )-4- methoxy- phenoxy]methyl]cyclobutanecarboxylic acid;

/x-3-[5-bromo-2-(8-chloro-4-oxo-chromcn-2-yl)phcnoxy]cyclopc ntanccarboxylic acid; fra¾s-3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]cyc lopentanecarboxylic acid; fra¾s-3-[[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-3-pyridyl ]oxy]cyclobutanecarboxylic acid;

s-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-cyclopropyl-phenoxy]c yclobutanecarboxylic acid;

fra¾s-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-cyclopropyl-phen oxy]cyclobutanecarboxylic acid; s-3-[5-bromo-2-(8-chloro-5-hydroxy-4-oxo-chromen-2- yl)phenoxy]cyclobutanecarboxylic acid;

s-3-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-5-methyl- phcnoxy ]cyclobutanccarboxylic acid;

//Y// '-3- 12-(8-chloro-54iydroxy-4-oxo-chromen-2-yl)-5- methyl- phcnoxy ]cyclobutanccarboxylic acid;

fra¾s-3-[5-bromo-2-(8-chloro-5-hydroxy-4-oxo-chromen-2- yl)phenoxy]cyclobutanecarboxylic acid;

s-3-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]cyclobutanecarboxylic acid;

//Y// -3-| 2-(8-chloro-5-hydroxy-4-oxo-chromcn-2-yl)-5- (trifluoromethyl)phenoxy]cyclobutanecarboxylic acid;

s-3-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-5-ethoxy- phcnoxy ]cyclobutanccarboxylic acid;

fra¾s-3-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-5-ethoxy - phcnoxy ]cyclobutanccarboxylic acid;

s-3-[5-bromo-2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-4-met hyl- phc no x y ] cy c lo bu tanccarbo x y 1 ic acid;

fra¾s-3-[5-bromo-2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)- 4-methyl- phcnoxy ]cyclobutanccarboxylic acid;

3-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-4,5-dimethoxy- phcnoxy ]cyclobutanccarboxylic acid;

s-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phen oxy]-N- cyclopropylsulfonyl-cyclobutanecarboxamide;

//U///L-3-[ 2-(8-chloro-4-oxo-chronicn-2-yl )-5-(tri liuoro methyl )phcnoxy]-N- cyclopropylsulfonyl-cyclobutanecarboxamide;

s-3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-N-methy lsulfonyl- cyclobutanecarboxamide ;

fra¾s-3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-N- methylsulfonyl- cyclobutanecarboxamide ;

r/x-3-|2-(8-chloro-4-oxo-chromcn-2-yl)-5-(tnfluoromcthoxy)ph cnoxy]-N-mcthylsulfonyl- cyclobutanecarboxamide ; frans-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethoxy )phenoxy]-N- methylsulfonyl-cyclobutanecarboxamide;

s-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phen oxy]-N-methylsulfonyl- cyclobutanecarboxamide ;

irans-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl) phenoxy]-N-methylsulfonyl- cyclobutanecarboxamide ;

s-3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-phenox y]-N-methylsulfonyl- cyclobutanecarboxamide ;

//Y// -3-| 5-bromo-2-(8-chlora-4-oxo-chromen-2-yl)-4-methyl-phenoxy]-N- methylsulfonyl- cyclobutanecarboxamide;

s-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methoxy-4-methyl-phen oxy]-N-methylsulfonyl- cyclobutanecarboxamide ;

frans-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methoxy-4-methyl- phenoxy]-N- methylsulfonyl-cyclobutanecarboxamide;

s-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methyl-phenoxy]-N-met hylsulfonyl- cyclobutanecarboxamide ;

//Y// -3-| 2-(8-chloro-4-oxo-chromen-2-yl)-5-methyl-phenoxy]-N-methylsu lfonyl- cyclobutanecarboxamide ;

s-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methyl-phenoxy]-N-cyc lopropylsulfonyl- cyclobutanecarboxamide ;

frans-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methyl-phenoxy]-N -cyclopropylsulfonyl- cyclobutanecarboxamide ;

r/x-3-|5-bromo-2-(8-chloro-4-oxo-chromcn-2-yl)-4-mcthoxy-phc noxy ]-N-mcthylsulfonyl- cyclobutanecarboxamide ;

//Y///v-3-[5-bromo-2-(8-chloro-4-oxo-chromcn-2-yl)-4-mcthoxy -phcnoxy]-N- methylsulfonyl-cyclobutanecarboxamide;

r/v-3-[5-bromo-2-(8-chloro-4-oxo-chromcn-2-yl)-4-mcthoxy-phc noxy ]-N- cyclopropylsulfonyl-cyclobutanecarboxamide;

r/v-3-[4-bromo-2-(8-chloro-4-oxo-chromcn-2-yl)-5-mcthoxy-phc noxy l-N-mcthylsuH ^' onyl- cyclobutanecarboxamide ;

//Y// -3-[4-bromo-2-(8-chloro-4-oxo-chromcn-2-yl)-5-mcthoxy-phcnox y]-N- methylsulfonyl-cyclobutanecarboxamide; s-3-[4-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-5-methoxy-pheno xy]-N- cyclopropylsulfonyl-cyclobutanecarboxamide;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dimethoxy-phenoxy]-N- methylsulfonyl- cyclobutanecarboxamide ;

3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]cyclobutanecarbonitrile;

(25.45)-4-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy ]pyrrolidine-2-carboxylic acid;

(2S,4R)-l-(benzenesulfonyl)-4-[2-(8-chloro-4-oxo-chromen-2-y l)-5- (trifluoromethyl)phenoxy]pyrrolidine-2-carboxylic acid;

(2S,4R)-4-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethy l)phenoxy]-l- cyclopropylsulfonyl-pyrrolidine-2-carboxylic acid;

(25.45)-4-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethy l)phenoxy]-l- cyclopropylsulfonyl-pyrrolidine-2-carboxylic acid;

(25.45)-4-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethy l)phenoxy]-l-(3- methoxyphenyl)sulfonyl-pyrrolidine-2-carboxylic acid;

(25.45)-l-(benzenesulfonyl)-4-[2-(8-chloro-4-oxo-chromen-2-y l)-5- (trifluoromethyl)phenoxy]pyrrolidine-2-carboxylic acid;

(25.45)-l-(benzenesulfonyl)-4-[2-(8-chloro-4-oxo-chromen-2-y l)-4,5-dimethoxy- phenoxy]pyrrolidine-2-carboxylic acid;

(25.45)-l-(benzenesulfonyl)-4-[5-bromo-2-(8-chloro-4-oxo-chr omen-2- yl)phenoxy]pyrrolidine-2-carboxylic acid;

(25.45)-4-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-l -cyclopropylsulfonyl- pyrrolidine-2-carboxylic acid;

(25.45)-l-(benzenesulfonyl)-4-[5-chloro-2-(8-chloro-4-oxo-ch romen-2-yl)-4-methyl- phenoxy]pyrrolidine-2-carboxylic acid;

(25.45)-l-(benzenesulfonyl)-4-[2-(8-chloro-4-oxo-chromen-2-y l)-5- (trifluoromethoxy)phenoxy]pyrrolidine-2-carboxylic acid;

(25.45)-l-benzoyl-4-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl) phenoxy]pyrrolidine-2- carboxylic acid;

(2R,4S)-l-(benzenesulfonyl)-4-[2-(8-chloro-4-oxo-chromen-2-y l)-5- (trifluoromethyl)phenoxy]pyrrolidine-2-carboxylic acid; and

(2R,4R)-l-(benzenesulfonyl)-4-[2-(8-chloro-4-oxo-chromen-2-y l)-5- (trifluoromethyl)phenoxy]pyrrolidine-2-carboxylic acid; or a pharmaceutically acceptable salt thereof.

In another embodiment (xxxv) of the present invention, particular compounds of the present invention are selected from:

3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]cyclobutanecarboxylic acid;

frans-3-[5-chloro-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl- phcnoxy lcyclobutanccarboxylic acid;

//U///L-3-[ 2-(8-chloro-4-oxo-chro mcn-2-yl)-5-(trinuoro methyl )phcnoxy]-N- cyclopropylsulfonyl-cyclobutanecarboxamide;

(2S,4R)-l-(benzenesulfonyl)-4-[2-(8-chloro-4-oxo-chromen-2-y l)-5- (trifluoromethyl)phenoxy]pyrrolidine-2-carboxylic acid; and

(2R,4S)-l-(benzenesulfonyl)-4-[2-(8-chloro-4-oxo-chromen-2-y l)-5- (trifluoromethyl)phenoxy]pyrrolidine-2-carboxylic acid;

or a pharmaceutically acceptable salt thereof.

A further embodiment of the present invention is (xxxvi) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from halogen and haloCi- ₆ alkyl;

R ² is selected from H, halogen, Ci- ₆ alkyl, C3- ₇ cycloalkyl and haloCi- ₆ alkyl;

R ³ is selected from H and halogen;

R ⁴ is selected from H, hydroxy and haloCi_ ₆ alkyl;

R ⁵ is selected from H and Ci_ ₆ alkoxy;

R ⁶ is selected from carboxy, Ci_ ₆ alkoxycarbonyl, carboxypyrrolidinylcarbonyl, C ₃ _

7cycloalkylsulfonylaminocarbonyl, hydroxypyrrolidinylcarbonyl, Ci_

6alkylsulfonylaminocarbonyl and aminocarbonyl;

Ai is CR ⁷ ; wherein R ⁷ is selected from H and halogen;

A ₂ is selected from N and CR ⁸ ; wherein R ⁸ is selected from H, halogen, hydroxy, C _h alky 1,

Ci- ₆ alkoxy, C3- ₇ cycloalkyl, haloCi- ₆ alkyl, haloCi- ₆ alkoxy, Ci- ₆ alkylsulfanyl, Ci- 6alkylsulfonyl, C3- ₇ cycloalkylCi-6alkoxy, thiazolyl, morpholinyl, pyrrolidinyl and oxazolidinyl; wherein pyrrolidinyl and oxazolidinyl are unsubstituted or substituted one or two or three times independently by oxo;

A ₃ is CR ⁹ ; wherein R ⁹ is selected from H, amino, halogen, hydroxy, Ci_ ₆ alkyl, Ci_ ₆ alkoxy, haloCi_ ₆ alkyl, haloCi_ ₆ alkoxy, haloCi_ ₆ alkylCi_ ₆ alkoxy and C3_ ₇ cycloalkylCi_6alkoxy; or R ⁸ and R ⁹ , together with the atoms to which they are attached, form a 5- or 6-membered heterocyclyl ring; wherein 5- or 6-membered heterocyclyl ring is unsubstituted or substituted by one or two or three or four substituents independently selected from halogen, Ci-6alkyl and oxo;

A4 is selected from N and CR ¹⁰ ; wherein R ¹⁰ is selected from H and halogen;

Gi is Ci-6alkyl; wherein Ci-6alkyl is unsubstituted or substituted one or two or three times by hydroxy;

( T ₂ is selected from Ci_6alkyl, C _3- 7cycloalkyl and phenyl;

m is 1.

A further embodiment of the present invention is (xxxvi) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from F, Cl, Br and CF ₃ ;

R ² is selected from H, F, Cl, Br, methyl, CF ₃ and cyclopropyl;

R ³ is selected from Fl and F;

R ⁴ is selected from H, hydroxy and CF ₃ ;

R ⁵ is selected from Fl and methoxy;

R ⁶ is selected from carboxy, methoxycarbonyl, carboxypyrrolidinylcarbonyl,

cyclopropylsulfonylaminocarbonyl, hydroxypyrrolidinylcarbonyl,

methylsulfonylaminocarbonyl and aminocarbonyl;

Ai is CR ⁷ ; wherein R ⁷ is selected from H, F, Cl and Br;

A ₂ is selected from N and CR ⁸ ; wherein R ⁸ is selected from H, F, Cl, Br, CF ₃ hydroxy, methyl, methoxy, ethoxy, propoxy, cyclopropyl, trifluoromethoxy, difluoromethoxy,

trifluoromethylmethoxy, methylsulfonyl, methylsulfanyl, cyclopropylmethoxy, thiazolyl, morpholinyl, pyrrolidinyl and oxazolidinyl; wherein pyrrolidinyl and oxazolidinyl are unsubstituted or substituted one or two or three times independently by oxo;

A ₃ is CR ⁹ ; wherein R ⁹ is selected from H, amino, hydroxy, F, Cl, Br, CF3, methyl, methoxy, ethoxy, difluoromethoxy, trifluoromethoxy, trifluoromethylmethoxy, difluoromethyl and cyclopropylmethoxy;

or R ⁸ and R ⁹ , together with the atoms to which they are attached, form a 5- or 6-membered heterocyclyl ring; wherein 5- or 6-membered heterocyclyl ring is unsubstituted or substituted by one or two or three or four substituents independently selected from F, methyl and oxo;

A4 is selected from N and CR ¹⁰ ; wherein R ¹⁰ is selected from Fl and F; Gi is selected from ethyl, propyl, butyl and neopentyl; wherein propyl is unsubstituted or substituted one or two or three times by hydroxy;

( T ₂ is selected from methyl, isopropyl, cyclobutyl, cyclopentyl and phenyl;

m is 1.

A further embodiment of the present invention is (xxxvii) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein R ¹ is halogen.

A further embodiment of the present invention is (xxxviii) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein R ¹ is selected from Cl and Br.

A further embodiment of the present invention is (xxxix) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein R ⁶ is carboxy.

A further embodiment of the present invention is (xl) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein A ₂ is CR ⁸ ; wherein R ⁸ is selected from halogen, Ci_ ₆ alkyl, Ci_ ₆ alkoxy and haloCi_ ₆ alkyl.

A further embodiment of the present invention is (xli) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein A ₂ is CR ⁸ ; wherein R ⁸ is selected from Cl, CF3, methyl and methoxy.

A further embodiment of the present invention is (xlii) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein A ₃ is CR ⁹ ; wherein R ⁹ is selected from H, Ci- ₆ alkyl and Ci- ₆ alkoxy.

A further embodiment of the present invention is (xliii) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein A ₃ is CR ⁹ ; wherein R ⁹ is selected from H, methyl and methoxy.

A further embodiment of the present invention is (xliv) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein Gi is Ci_ ealkyl.

A further embodiment of the present invention is (xlv) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein Gi is selected from ethyl and propyl. A further embodiment of the present invention is (xlvi) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein G ₂ is selected from Ci_6alkyl and C3_7cycloalkyl.

A further embodiment of the present invention is (xlvii) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein G ₂ is selected from methyl and cyclobutyl.

A further embodiment of the present invention is (il) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein

R ¹ is halogen;

R ² is H;

R ³ is H;

R ⁴ is H;

R ⁵ is H;

R ⁶ is carboxy;

Ai is CH;

A ₂ is CR ⁸ ; wherein R ⁸ is selected from halogen, Ci-6alkyl, Ci-6alkoxy and haloCi-6alkyl;

A ₃ is CR ⁹ ; wherein R ⁹ is selected from H, Ci-6alkyl and Ci-6alkoxy;

A4 is CH;

Gi is Ci_6alkyl.

G ₂ is selected from Ci_6alkyl and C3_7cycloalkyl.

m is 1.

A further embodiment of the present invention is (1) a compound of formula (I) according to embodiment (i) or a pharmaceutically acceptable salt thereof, wherein

R ¹ is selected from Cl and Br;

R ² is H;

R ³ is H;

R ⁴ is H;

R ⁵ is H;

R ⁶ is carboxy;

Ai is CH;

A ₂ is CR ⁸ ; wherein R ⁸ is selected from Cl, CF3, methyl and methoxy;

A3 is CR ⁹ ; wherein R ⁹ is selected from H, methyl and methoxy;

A4 is CH; Gi is selected from ethyl and propyl;

( T ₂ is selected from methyl and cyclobutyl;

m is 1.

In another embodiment (li) of the present invention, particular compounds of the present invention are selected from:

2-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phe noxy]propoxy]acetic acid;

2-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methyl-phenoxy]pr opoxy]acetic acid;

methyl 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylate;

s-3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;

//Y// -3-|2-|5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;

3-[2-[5-chloro-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy ]cyclobutanecarboxylic acid;

2-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phe noxy]ethoxy]acetic acid; 2-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy] acetic acid;

2-[3-[5-chloro-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]propox y]acetic acid;

2-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]propoxy ]acetic acid;

2-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-pheno xy]propoxy]acetic acid; 2-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dimethoxy-phenoxy] propoxy]acetic acid; 2-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-phen oxy]propoxy]acetic acid; 2-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethoxy)ph enoxy]propoxy]acetic acid; 2-[3-[[6-(8-chloro-4-oxo-chromen-2-yl)-l,3-benzodioxol-5-yl] oxy]propoxy]acetic acid; 2-[3-[5-chloro-2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-phe noxy]propoxy]acetic acid; 2-[3-[2-(8-bromo-4-oxo-chromen-2-yl)-5-methyl-phenoxy]propox y]acetic acid;

2-[3-[2-(8-bromo-4-oxo-chromen-2-yl)-5-chloro-4-methyl-pheno xy]propoxy]acetic acid; 2-[3-[5-chloro-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-phen oxy]propoxy]acetic acid; 2-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-phen oxy]ethoxy]acetic acid; 2-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-pheno xy]ethoxy]acetic acid; 2-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dimethoxy-phenoxy] ethoxy]acetic acid;

2-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethoxy)ph enoxy]ethoxy]acetic acid; 2-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phe noxy]butoxy]acetic acid; -3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobu tanecarboxylic acid; //Y///v-3-[2-[2-(8-chloro-4-oxo-chronicn-2-yl)phcnoxy]cthoxy ]cyclobutanccarboxylic acid; s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]ethoxy]cyclobutanecarboxylic acid ;

fra¾s-3-[2-[[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-3- pyridyl]oxy]ethoxy]cyclobutanecarboxylic acid;

r/x-3-|2-|5-bromo-2-(8-chloro-6-fluoro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[2-(8-chloro-7-methyl-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;

fra¾s-3-[2-[2-(8-chloro-7-methyl-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;

r/x-3-|2-|5-bromo-2-(8-chloro-7-fluoro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;

fra¾s-3-[2-[5-bromo-2-(8-chloro-7-fluoro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl- phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[4-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-5-fluoro- phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-fluoro- phenoxy]ethoxy]cyclobutanecarboxylic acid;

//Y// -3-| 2-| 2-(8-chloro-4-oxo-chromen-2-yl)-4-fluoro- phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-fluoro- phenoxy]ethoxy]cyclobutanecarboxylic acid;

fra¾s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-fluoro- phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-ethoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

fra¾s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-ethoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid; s-3-[2-[2-(8-chloro-6-fluoro-4-oxo-chromen-2-yl)phenoxy]etho xy]cyclobutanecarboxylic acid;

//Y// -3-| 2-| 2-(8-chlora-6-fluoro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-6-fluoro- phenoxy]ethoxy]cyclobutanecarboxylic acid;

fra¾s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-6-fluoro- phenoxy]ethoxy]cyclobutanecarboxylic acid;

r/x-3-|2-|2-(8-chloro-4-oxo-chromen-2-yl)-5-methyl- phenoxy]ethoxy]cyclobutanecarboxylic acid;

fra¾s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methyl- phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

//Y// -3-| 2-| 2-(8-chloro-4-oxo-chromen-2-yl)-5-methoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[4-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-5-methoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

fra¾s-3-[2-[4-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-5-metho xy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methoxy-4-methyl- phenoxy]ethoxy]cyclobutanecarboxylic acid;

//U///L-3-[ 2- [2-(8-chloro-4-oxo-chronicn-2-yl)-5-nicthoxy-4- methyl- phenoxy]ethoxy]cyclobutanecarboxylic acid;

r/x-3-|2-|5-bromo-2-(8-chloro-4-oxo-chromcn-2-yl)-4- (trifluoromethyl)phenoxy]ethoxy]cyclobutanecarboxylic acid ;

fra¾s-3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4- (trifluoromethyl)phenoxy]ethoxy]cyclobutanecarboxylic acid;

r/ ^' v-3-[2-[ [6-(8-chloro-4-oxo-chronicn-2-yl)- 1 ,3-bcnzodioxol-5- yl]oxy]ethoxy]cyclobutanecarboxylic acid ;

//U///L-3-[2-[ [6-(8-chloro-4-oxo-chronicn-2-yl)- 1 ,3-bcnzodioxol-5- yl]oxy]ethoxy]cyclobutanecarboxylic acid ; s-3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-fluoro- phenoxy]ethoxy]cyclobutanecarboxylic acid;

fra¾s-3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-fluor o- phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[2-(8-chloro-6-fluoro-4-oxo-chromen-2-yl)-5-fluoro- phenoxy]ethoxy]cyclobutanecarboxylic acid;

iraw5-3-[2-[2-(8-chloro-6-fluoro-4-oxo-chromen-2-yl)-5-fluor o- phenoxy]ethoxy]cyclobutanecarboxylic acid;

r/v-3-[2-[2-(8-bronio-4-oxo-chronicn-2-yl)phcnoxy]cthoxy]cyc lobutanccarboxylic acid; //Y///v-3-[2-[2-(8-bronio-4-oxo-chronicn-2-yl)phcnoxy]cthoxy ]cyclobutanccarboxylic acid; r/x-3-|2-|2-|4-oxo-8-(tnfluoromethyl)chromen-2- yl]phenoxy]ethoxy]cyclobutanecarboxylic acid;

iraw5-3-[2-[2-[4-oxo-8-(trifluoromethyl)chromen-2- yl]phenoxy]ethoxy]cyclobutanecarboxylic acid;

r/ ^' v-3-[ 2- [5-bronio-2-[8-chloro-4-oxo-7-(trinuoro methyl )chronicn-2- yl]phenoxy]ethoxy]cyclobutanecarboxylic acid;

trans-3- [2- [5-bromo-2- [8-chloro-4-oxo-7-(trifluoromethyl)chromen-2- yl]phenoxy]ethoxy]cyclobutanecarboxylic acid;

r/ ^' v-3-[ 2- [5-bronio-2-[8-chloro-4-oxo-5-(trinuoro methyl )chronicn-2- yl]phenoxy]ethoxy]cyclobutanecarboxylic acid;

/rc//i.s-3- 12- 15-hromo-2- 18-ch loro-4-oxo-5-( tri fluoro methyl )chromcn-2- yl]phenoxy]ethoxy]cyclobutanecarboxylic acid;

3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-phenoxy]ethox y]cyclobutanecarboxylic acid;

/rc//i.s-3- 12- 12-(8-ch loro-4-oxo-chromcn-2- yl )-4- mcthyl- phenoxy]ethoxy]cyclobutanecarboxylic acid;

7 /.S-3- 12- 12-(8-ch loro-4-oxo-chro mcn-2-yl )-4-cthoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

//Ύ7/7L-3- 12- 12-(8-ch loro-4-oxo-chromcn-2- yl )-4-cthoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

7 /.S-3- 12- 12-(8-ch loro-4-oxo-chro mcn-2-yl )-5- (trifluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylic acid; //Y// -3-[ 2-[4-bromo-2-(8-chloro-6-fluoro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[2-(8-chloro-7-fluoro-4-oxo-chromen-2-yl)phenoxy]etho xy]cyclobutanecarboxylic acid;

s-3-[2-[5-chloro-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl- phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]propoxy]cyclobutanecarboxylic acid;

//Y// -3-| 3-| 5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]propoxy]cyclobutanecarboxylic acid;

c¾5-3-[2-[5-bromo-4-chloro-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[2-(8-chloro-7-cyclopropyl-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;

r/x-3-|2-|2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

3-[2-[[4-(8-chloro-4-oxo-chromen-2-yl)-3-pyridyl]oxy]ethoxy] cyclobutanecarboxylic acid 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(2-oxooxazolidin-3- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;

methyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(2-oxooxazolidin-3- yl)phenoxy]ethoxy]cyclobutanecarboxylate;

r/v-3-[2-[2-(8-chloro-4-oxo-chronicn-2-yl)-5-(2-oxopyrrolidi n- 1 - yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;

//Y// -3-| 2-| 2-(8-chloro-4-oxo-chromcn-2-yl)-5-(2-oxopyrrolidin- 1 - yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;

c¾5-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methylsulfanyl- phenoxy]ethoxy]cyclobutanecarboxylic acid;

iraw5-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methylsulfanyl - phenoxy]ethoxy]cyclobutanecarboxylic acid;

trans- methyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methylsulfonyl- phenoxy]ethoxy]cyclobutanecarboxylate;

r/v-3-[2-[2-(8-chloro-4-oxo-chromcn-2-yl)-5-thiazol-2-yl- phenoxy]ethoxy]cyclobutanecarboxylic acid; //Y// -3-| 2-| 2-(8-chloiO-4-oxo-chromen-2-yl)-5-thiazol-2-yl- phenoxy]ethoxy]cyclobutanecarboxylic acid;

fra¾s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-morpholino- phenoxy]ethoxy]cyclobutanecarboxylic acid;

r/v-3-[2-[2-(8-chloro-4-oxo-chronicn-2-yl)-5-pyrrolidin- 1 - yl- phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-cyclopropyl- phenoxy]ethoxy]cyclobutanecarboxylic acid;

//Y// -3-| 2-| 2-(8-chloro-4-oxo-chromen-2-yl)-5-cyclopropyl- phenoxy]ethoxy]cyclobutanecarboxylic acid;

3-[2-[2-bromo-6-(8-chloro-6-fluoro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-3-fluoro- phenoxy]ethoxy]cyclobutanecarboxylic acid;

r/v-3-[2-[2-(8-chloro-4-oxo-chronicn-2-yl)-4,5-dinicthoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

3-[2- [[7-(8-chloro-4-oxo-chromen-2-yl)-2, 3-dihydro- 1, 4-benzodioxin-6- yl]oxy]ethoxy]cyclobutanecarboxylic acid ;

c¾5-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-(difluoromethyl )-5-methyl- phenoxy]ethoxy]cyclobutanecarboxylic acid;

c¾5-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-hydroxy-4-metho xy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

r/x-3-|2-|2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-5-propox y- phenoxy]ethoxy]cyclobutanecarboxylic acid;

c¾5-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-ethoxy-4-methox y- phenoxy]ethoxy]cyclobutanecarboxylic acid;

c¾5-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(cyclopropylmet hoxy)-4-methoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

c¾5-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-5-(2,2, 2- trifluoroethoxy)phenoxy]ethoxy]cyclobutanecarboxylic acid; -3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(dinuoromethoxy)-4- methoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-(cyclopropylmethox y)-5-methoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

r/x-3-|2-|2-(8-chloro-4-oxo-chromen-2-yl)-44iydroxy-5-methox y- phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-ethoxy-5-methoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methoxy-4-(2,2,2- trifluoroethoxy)phenoxy]ethoxy]cyclobutanecarboxylic acid;

r/x-3-|2-|2-(8-chloro-4-oxo-chromen-2-yl)-4-(difluoromethoxy )-5-methoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5- bis(difluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylic acid;

r/v-3-[2-[2-(8-chloro-4-oxo-chronicn-2-yl)-4,5-dicthoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methoxy-4- (trifluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylic acid;

c¾5-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-hydroxy-4- (trifluoromethoxy)phenoxy] ethoxy] cyclobutanecarboxylic acid ;

r/.s-3- 12- 16-(8-ch loro-4-oxo-chro mcn-2-yl )-2-o xo-i ndo lin-5- yl]oxyethoxy]cyclobutanecarboxylic acid;

r/.s-3- 12- 16-(8-ch loro-4-oxo-chro mcn-2-yl )-3 ,3 -d i nicthy 1-2-oxo- indo lin-5- yl]oxyethoxy]cyclobutanecarboxylic acid;

s-3-[2-[6-(8-chloro-4-oxo-chromen-2-yl)-l,3,3-trimethyl-2-ox o-indolin-5- yl]oxyethoxy]cyclobutanecarboxylic acid;

r/x-3-|2-|2-|8-chloro-4-oxo-5-(tnfluoromcthyl)chromcn-2- yl]phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[2-[8-chloro-4-oxo-5-(trifluoromethyl)chromen-2-yl]-5 -ethoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

r/.s-3- 12- 12- 18-ch loro-4-oxo-5-( Lri fluoro methyl )chromcn-2-yl ]-4, 5-di nicthoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid; 3-[2-[2-[8-chloro-4-oxo-7-(trifluoromethyl)chromen-2-yl]-5-e thoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-4,5-dimeth oxy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]ethoxy]cyclobutanecarboxylic acid;

2-[3-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propoxy]acetic acid;

s-3-[2-[5-bromo-2-(8-chloro-3-methoxy-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid;

s-3-[2-[[6-(8-chloro-4-oxo-chromen-2-yl)-2,2-difluoro-l,3-be nzodioxol-5- yl]oxy]ethoxy]cyclobutanecarboxylic acid ;

3-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propoxy]cyclobutanecarboxylic acid;

3-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propoxy]cyclopentanecarboxylic acid;

3-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]propoxy ]cyclopentanecarboxylic acid;

3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy] cyclopentanecarboxylic acid;

4-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy] benzoic acid;

3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy] benzoic acid;

2- [3- [2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenoxy] propoxy] -2-methyl- propanoic acid;

s-3-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-2, 2-dimethyl- propoxyjcyclobutanecarboxylic acid;

//U///L -3- [ 3- [5-bromo-2-(8-chloro-4-oxo-chromcn-2-yl)phcnoxy]-2,2-di methyl- propoxyjcyclobutanecarboxylic acid;

(3R)-l-[2-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy] ethoxy] acetyl]pyrrolidine-3 -carboxylic acid ;

(3S)-l-[2-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy] ethoxy] acetyl]pyrrolidine-3 -carboxylic acid ;

2-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-2-hydr oxy-propoxy]acetic acid; 2-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-2-hydr oxy-propoxy]acetamide;

2-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl) phenoxy]-2-hydroxy- propoxy] acetic acid;

2-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy] -N-cyclopropylsulfonyl- acetamide;

2-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phe noxy]propoxy]-N- cyclopropylsulfonyl-acetamide;

2-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phe noxy]ethoxy]-N- cyclopropylsulfonyl-acetamide;

s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dimethoxy-phenox y]ethoxy]-N- cyclopropylsulfonyl-cyclobutanecarboxamide;

2-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phe noxy]ethoxy]-N- methy lsulfo ny 1- acetamide ;

.v-3- 12- |2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoro methyl )phenoxy|ethoxy|-N- methylsulfonyl-cyclobutanecarboxamide;

s-3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethox y]-N-methylsulfonyl- cyclobutanecarboxamide ;

frans-3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]e thoxy]-N-methylsulfonyl- cyclobutanecarboxamide ;

3-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phe noxy]propoxy]-N- methylsulfonyl-cyclopentanecarboxamide;

r/v-3-[2-[2-(8-chloro-4-oxo-chromcn-2-yl)-4,5-dimcthoxy-phcn oxy]cthoxy ]-N- methylsulfonyl-cyclobutanecarboxamide; and

2- [4-bromo-2- [2- [2-(3-hydroxypyrrolidin- 1 -yl)-2-oxo-ethoxy]ethoxy]phenyl]-8-chloro- chromen-4-one;

or a pharmaceutically acceptable salt thereof.

In another embodiment (lii) of the present invention, particular compounds of the present invention are selected from:

2-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phe noxy]propoxy]acetic acid;

2-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methyl-phenoxy]pr opoxy]acetic acid;

2-[3-[5-chloro-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]propox y]acetic acid;

2-[3-[2-(8-bromo-4-oxo-chromen-2-yl)-5-methyl-phenoxy]propox y]acetic acid; 2-[3-[5-chloro-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-phen oxy]propoxy]acetic acid; and

s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dimethoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid;

or a pharmaceutically acceptable salt thereof.

SYNTHESIS

The compounds of the present invention can be prepared by any conventional means. Suitable processes for synthesizing these compounds as well as their starting materials are provided in the schemes below and in the subsequent examples. All substituents, in particular, R ¹ to R ⁶ , Gi, G ₂ , A ¹ to A ⁴ and m are defined above unless otherwise indicated. Furthermore, and unless explicitly otherwise stated, all reactions, reaction conditions, abbreviations and symbols have the meanings well known to a person of ordinary skill in the art.

Scheme 1

Wherein Q is halogen, OTs or OMs; R ¹¹ is C3-7cycloalkylamino or hydroxyCi- ₆ alkylamino; R ¹² is Ci_ ₆ alkyl; R ¹³ is selected from Ci_ ₆ alkyl and C3_7cycloalkyl.

Condensation of ketone IV with aldehyde V in the presence of a base, such as KOH, in a suitable solvent, such as ethanol, affords a,b-unsaturated carbonyl intermediate VI. Cyclization of a,b-unsaturated carbonyl intermediate VI in the presence of a suitable Lewis acid, such as L, KI or Nal, in a suitable solvent, such as DMSO, affords flavone derivative VII. Demethylation of flavone derivative VII with a suitable Lewis acid, such as BBr3, in a suitable solvent, such as dichloromethane, affords compound of formula VIII. Substitution of compound of formula VIII with compound of formula IX in the presence of a suitable base, such as K2CO3, in a suitable solvent, such as DMF, affords compound of formula I. Treatment of compound of formula VIII with oxetan-2-one in the presence of a suitable base, such as t-BuOK, in a suitable solvent, such as DMF, affords propanoic acid derivative 1-1. Condensation of propanoic acid derivative 1-1 with compound of formula X-l in the presence of a suitable condensation reagent, such as F1ATU, with a suitable base, such as TEA, in a suitable solvent, such as DCM, affords amide derivative 1-2. Esterification of propanoic acid derivative 1-1 with compound of formula X-2 in the presence of a suitable acid, such as F1C1, affords ester derivative 1-3. Substitution of ester derivative 1-3 with compound of formula X-3 in the presence of a suitable acid, such as T1CI4, in a suitable solvent, such as DCM, affords compound of formula 1-4.

Scheme 2

The compound of formula VIII can also be prepared according to the Scheme 2.

Formylation of compound of formula XI with formaldehyde in the presence of a suitable base, such as TEA, with a suitable Lewis acid, such as MgCL, in a suitable solvent, such as ACN, affords aldehyde derivative XII. Protection hydroxy group of aldehyde derivative XII with bromo(methoxy)methane in the presence of a suitable base, such as NaFl, in a suitable solvent, such as TF1F, affords compounds of formula XIII. Condensation of compound of formula XIII with substituted ketone IV in the presence of a base, such as KOF1, in a suitable solvent, such as ethanol, affords a,b-unsaturated carbonyl intermediate XIV. Cyclization of intermediate XIV in the presence of a suitable Lewis acid, such as I ₂ , KI or Nal, in a suitable solvent, such as DMSO, affords compound of formula VIII.

Scheme 3

The flavone derivative VII can also be prepared according to the Scheme 3. Treatment of substituted ketone IV with substituted acyl chloride XV in the presence of a base, such as TEA, in a suitable solvent, such as DCM, affords ester derivative XVI. Treatment ester derivative XVI with a suitable base, such as KOH, in a suitable solvent, such as pyridine, affords intermediate XVII. Cyclization of intermediate XVII in the presence of a suitable acid such as H2SO4, in a suitable solvent, such as acetic acid, affords flavone derivative VII.

Scheme 4

Wherein Q is halogen, OTs or OMs.

Substitution of aldehyde derivative XII with compound of formula IX or oxetan-2-one in the presence of a suitable base, such as K ₂ CO ₃ or NaH, in a suitable solvent, such as DMF, affords compound of formula XVIII. Condensation of compound of formula XVIII with ketone IV in the presence of a base, such as KOH, in a suitable solvent, such as ethanol, affords a,b- unsaturated carbonyl intermediate XIX. Cyclization of a,b-unsaturated carbonyl intermediate XIX in the presence of a suitable Lewis acid, such as I ₂ , KI or Nal, in a suitable solvent, such as DMSO, affords compound of formula I.

Scheme 5

Protection hydroxy group of compound of formula XX with bromo(methoxy)methane in the presence of a suitable base, such as NaH, in a suitable solvent, such as THF, affords compound of formula XXI. Condensation of compound of formula XXI with compound of formula XVIII in the presence of a base, such as KOH, in a suitable solvent, such as ethanol, affords a,b-unsaturated carbonyl intermediate XXII. Cyclization of a,b-unsaturated carbonyl intermediate XXII in the presence of a suitable Lewis acid, such as I ₂ , KI or Nal, in a suitable solvent, such as DMSO, affords compound of formula 1 5

Scheme 6

Wherein Q is halogen, OTs or OMs; L is halogen; T is H, B(OH) ₂ or R ¹⁴ -S(0)-; R ¹⁴ is C _3- 7cycloalkyl, Ci_ ₆ alkylsulfanyl, morpholinyl, pyrrolidinyl, oxazolidinyl, haloCi_ ₆ alkyl, thiazolyl; wherein pyrrolidinyl and oxazolidinyl are unsubstituted or substituted one time by oxo.

Condensation of ketone IV with aldehyde V-l in the presence of a base, such as KOH, in a suitable solvent, such as ethanol, affords a,b-unsaturated carbonyl intermediate VI- 1. Cyclization of a,b-unsaturated carbonyl intermediate VI- 1 in the presence of a suitable Lewis acid, such as L, KI or Nal, in a suitable solvent, such as DMSO, affords flavone derivative VII- 1. Demethylation of flavone derivative VII- 1 with a suitable Lewis acid, such as BBr ₃ , in a suitable solvent, such as dichloromethane, affords compound of formula VIII- 1. Substitution of compound of formula VIII- 1 with compound of formula IX in the presence of a suitable base, such as K ₂ C0 ₃ , in a suitable solvent, such as DMF, affords compound of formula XXIII. Treatment of compound of formula XXIII with compound of formula X-4 in the presence of a suitable catalyst, such as Cul or Pd(OAc) ₂ , in a suitable solvent, such as DMF, affords compound of formula 1-6.

Scheme 7

Wherein Q is halogen, OTs or OMs; R ¹² is Ci_6alkyl; R ¹⁵ is selected from C3_7cycloalkylamino, C3-7cycloalkylsulfonylamino, Ci-6alkylsulfonylamino and Ci-6alkylamino.

Substitution of compound of formula VIII with compound of formula IX-1 in the presence of a suitable base, such as K2CO3, in a suitable solvent, such as DMF, affords compound of formula XXIV. Hydrolysis of compound of formula XXIV in the presence of a suitable base, such as LiOH, in a suitable solvent, such as THF and water, affords compound of formula 1-7. Condensation of compound of formula 1-7 with compound of formula X-5 in the presence of a suitable condensation reagent, such as HATU, with a suitable base, such as TEA, in a suitable solvent, such as DCM, affords amide derivative 1-8.

Scheme 8

Wherein Q is halogen, OTs or OMs; R ¹⁶ is C _h alky! or haloCi_ ₆ alkyl.

Protection the hydroxy group of 2,4-dihydroxy-5-methoxy-benzaldehyde with 1- (bromomethyl)-4-methoxy-benzene in the presence of a suitable base, such as NaFlCCL, in a suitable solvent, such as DMF, affords 2-hydroxy-5-methoxy-4-[(4- methoxyphenyl)methoxy]benzaldehyde. Substitution of 2-hydroxy-5-methoxy-4-[(4- methoxyphenyl)methoxy]benzaldehyde with compound of formula IX in the presence of a suitable base, such as K ₂ CO ₃ , in a suitable solvent, such as DMF, affords compound of formula XXV. Condensation of compound of formula XXV with ketone IV in the presence of a base, such as KOF1, in a suitable solvent, such as ethanol, affords a,b-unsaturated carbonyl intermediate XXVI. Cyclization of intermediate XXVI in the presence of a suitable Lewis acid, such as L, KI or Nal, in a suitable solvent, such as DMSO, affords compound of formula 1 9 Alkylation of compound of formula 1-9 with compound of formula X-6 in the presence of a suitable base, such as K ₂ CO ₃ , in a suitable solvent, such as DMF, affords compound of formula 1 10

Wherein Q is halogen, OTs or OMs; PG is Boc; R ¹⁷ is C3_7cycloalkylsulfonyl, Ci_ ₆ alkylsulfonyl, phenylsulfonyl or phenylcarbonyl;

Substitution of compound of formula VIII with compound of formula XXVII in the presence of a suitable base, such as K2CO ₃ , in a suitable solvent, such as DMF, affords compound of formula XXVIII. Deprotection of compound of formula XXVIII with a suitable acid, such as TFA, in a suitable solvent, such as DCM, affords compound of formula XXIX. Flydrolysis of compound of formula XXIX with a suitable base, such as LiOFl, in a suitable solvent, such as TF1F and water, affords compound of formula 1-11 Treatment of compound of formula 1-11 with compound of formula X-7 in the presence of a suitable base, such as LiOFl, in a suitable solvent such as TF1F, affords compound of formula 1-12.

Wherein Q is halogen, OTs, OTf or OMs; PG is Boc; R ¹⁸ is C3_7cycloalkylsulfonyl, Ci_ ₆ alkylsulfonyl, phenylsulfonyl or Ci_ ₆ alkylaminosulfonyl; n=l or 2

Condensation of compound of formula VIII with compound of formula XXX, affords compound of formula XXXI. Deprotection of compound of formula XXXI with a suitable acid, such as TFA, in a suitable solvent, such as DCM, affords compound of formula XXXII.

Hydrolysis of compound of formula XXXII with a suitable base, such as LiOH, in a suitable solvent, such as THF and water, affords compound of formula 1-13. Treatment of compound of formula 1-13 with compound of formula X-8 in the presence of a suitable base, such as LiOH, in a suitable solvent such as THF, affords compound of formula 1-15. Treatment of compound of formula XXXII with compound of formula X-8 in the presence of a suitable base, such as TEA, in a suitable solvent such as DCM, affords compound of formula 1-14. Hydrolysis of compound of formula 1-14 with a suitable base, such as trimethylstannanol, in a suitable solvent, such as DCE, affords compound of formula 1 15

This invention also relates to a process for the preparation of a compound of formula (I) comprising any one of the following steps:

(a) substitution of a compound of formula (VIII),

(VIII),

with a compound of formula (IX),

(IX), in the presence of a base;

(b) treatment of a compound of formula (VIII), with oxetan-2-one in the presence of a base; (c) condensation of propanoic acid derivative (1-1),

(1-1),

with a compound of formula (X-l),

1 1

-

H'

(X-l), in the presence of a condensation reagent with a base;

(d) esterification of propanoic acid derivative (1-1), with a compound of formula (X-2),

,12

R ¹

HO

(X-2), in the presence of an acid;

(e) substitution of ester derivative (1-3),

(1-3), with a compound of formula (X-3), the presence of an acid;

(f) cyclization of a,b-unsaturated carbonyl intermediate (XIX),

(XIX), in the presence of a suitable Lewis acid;

(g) cyclization of a,b-unsaturated carbonyl intermediate (XXII),

(XXII), in the presence of a suitable Lewis acid;

(h) treatment of compound of formula (XXIII),

(XXIII), with a compound of formula (X-4),

(X-4), in the presence of a catalyst;

(i) hydrolysis of compound of formula (XXIV),

(xxiv), in the presence of a base;

(j) condensation of compound of formula (1-7),

(1-7),

with a compound of formula (X-5),

5

H'

(X-5), in the presence of a condensation reagent, with a base;

(k) cyclization of intermediate (XXVI),

(xxvi), in the presence of a suitable Lewis acid;

(1) alkylation of compound of formula (1-9),

with a compound of formula (X-6), the presence of a base;

(m) hydrolysis of compound of formula (XXIX),

(XXIX),

in the presence of a base;

(n) hydrolysis of compound of formula (I- 11),

(1-11),

with a compound of formula (X-7),

7

,R

cr (X-7), in the presence of a base;

(o) hydrolysis of compound of formula (XXXII),

(XXXII),

in the presence of a base;

(p) treatment of compound of formula (1-13),

(1-13),

with a compound of formula (X-8),

(X-8), in the presence of a base;

(q) treatment of compound of formula (XXXII), with a compound of formula (X-8) in the presence of a base;

(r) hydrolysis of compound of formula (1-14),

with a compound of formula (X-8) in the presence of a base;

wherein R ¹ to R ¹⁰ , Gi, G ₂ , A ¹ to A ⁴ and m are defined as any one of claims 1 to 66; Q is halogen, OTs or OMs; L is halogen; T is H, B(OH) ₂ or R ¹⁴ -S(0)-; R ¹¹ is C3_7cycloalkylamino or hydroxyCi- ₆ alkylamino; R ¹² is Ci- ₆ alkyl; R ¹³ is Ci- ₆ alkyl or C3-7cycloalkyl; R ¹⁴ is C3-7cycloalkyl, Ci_ ₆ alkylsulfanyl, morpholinyl, pyrrolidinyl, oxazolidinyl, haloCi_ ₆ alkyl, thiazolyl; wherein pyrrolidinyl and oxazolidinyl are unsubstituted or substituted one time by oxo; R ¹⁵ is selected from C3_7cycloalkylamino, C3_7cycloalkylsulfonylamino, Ci_ ₆ alkylsulfonylamino and Ci_ ₆ alkylamino; R ¹⁶ is Ci_ ₆ alkyl or haloCi_ ₆ alkyl; PG is Boc; R ¹⁷ is C3_7cycloalkylsulfonyl, Ci_ ₆ alkylsulfonyl, phenylsulfonyl, phenylcarbonyl; R is C3-7cycloalkylsulfonyl, Ci- ₆ alkylsulfonyl, phenylsulfonyl or Ci_ ₆ alkylaminosulfonyl; n=l or 2;

the base in step (a) can be for example K2CO ₃ ;

the base in step (b) can be for example t-BuOK;

the condensation reagent in step (c) can be for example HATU; the base in step (c) can be for example TEA;

the acid in step (d) can be for example HC1;

the acid in step (e) can be for example TiCl ₄ ;

the Lewis acid in step (f) can be for example I ₂ , KI or Nal;

the Lewis acid in step (g) can be for example I ₂ , KI or Nal;

the catalyst in step (h) can be for example Cul or Pd(OAc) ₂ ;

the base in step (i) can be for example LiOH;

the condensation reagent in step (j) can be for example HATU; the base in step (j) can be for example TEA;

the Lewis acid in step (k) can be for example I ₂ , KI or Nal;

the base in step (1) can be for example K ₂ C(T;

the base in step (m) can be for example LiOH;

the base in step (n) can be for example LiOH;

the base in step (o) can be for example LiOH;

the base in step (p) can be for example LiOH; the base in step (q) can be for example TEA;

the base in step (r) can be for example trimethylstannanol.

A compound of formula (I) when manufactured according to the above process is also an object of the invention.

PHARMACEUTICAL COMPOSITIONS AND ADMINISTRATION

The invention also relates to a compound of formula (I) for use as therapeutically active substance. Another embodiment provides pharmaceutical compositions or medicaments containing the compounds of the invention and a therapeutically inert carrier, diluent or excipient, as well as methods of using the compounds of the invention to prepare such compositions and medicaments. In one example, compounds of formula (I) may be formulated by mixing at ambient temperature at the appropriate pH, and at the desired degree of purity, with physiologically acceptable carriers, i.e., carriers that are non-toxic to recipients at the dosages and concentrations employed into a galenical administration form. The pH of the formulation depends mainly on the particular use and the concentration of compound, but preferably ranges anywhere from about 3 to about 8. In one example, a compound of formula (I) is formulated in an acetate buffer, at pH 5. In another embodiment, the compounds of formula (I) are sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation or as an aqueous solution.

Compositions are formulated, dosed, and administered in a fashion consistent with good medical practice. Factors for consideration in this context include the particular disorder being treated, the particular mammal being treated, the clinical condition of the individual patient, the cause of the disorder, the site of delivery of the agent, the method of administration, the scheduling of administration, and other factors known to medical practitioners. The“effective amount” of the compound to be administered will be governed by such considerations, and is the minimum amount necessary to inhibit cccDNA in HBV patients, consequently lead to the reduction of HBsAg and HBeAg (HBV e antigen) in serum. For example, such amount may be below the amount that is toxic to normal cells, or the mammal as a whole.

In one example, the pharmaceutically effective amount of the compound of the invention administered parenterally per dose will be in the range of about 0.1 to 100 mg/kg, alternatively about 0.1 to 50 mg/kg of patient body weight per day, with the typical initial range of compound used being 0.3 to 15 mg/kg/day. In another embodiment, oral unit dosage forms, such as tablets and capsules, preferably contain from about 25 to about 1000 mg of the compound of the invention.

The compounds of the invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal and epidural and intranasal, and, if desired for local treatment, intralesional administration. Parenteral infusions include intramuscular, intravenous, intraarterial, intraperitoneal, or subcutaneous administration.

The compounds of the present invention may be administered in any convenient administrative form, e.g., tablets, powders, capsules, solutions, dispersions, suspensions, symps, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components conventional in pharmaceutical preparations, e.g., diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents.

A typical formulation is prepared by mixing a compound of the present invention and a carrier or excipient. Suitable carriers and excipients are well known to those skilled in the art and are described in detail in, e.g., Ansel, Howard C., et al., Ansel’s Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C. Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulations may also include one or more buffers, stabilizing agents, surfactants, wetting agents, lubricating agents, emulsifiers, suspending agents, preservatives, antioxidants, opaquing agents, glidants, processing aids, colorants, sweeteners, perfuming agents, flavoring agents, diluents and other known additives to provide an elegant presentation of the drug (i.e., a compound of the present invention or pharmaceutical composition thereof) or aid in the manufacturing of the pharmaceutical product (i.e., medicament).

An example of a suitable oral dosage form is a tablet containing about 25 to 500 mg of the compound of the invention compounded with about 90 to 30 mg anhydrous lactose, about 5 to 40 mg sodium croscarmellose, about 5 to 30 mg polyvinylpyrrolidone (PVP) K30, and about 1 to 10 mg magnesium stearate. The powdered ingredients are first mixed together and then mixed with a solution of the PVP. The resulting composition can be dried, granulated, mixed with the magnesium stearate and compressed to tablet form using conventional equipment. An example of an aerosol formulation can be prepared by dissolving the compound, for example 5 to 400 mg, of the invention in a suitable buffer solution, e.g. a phosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride, if desired. The solution may be filtered, e.g., using a 0.2 micron filter, to remove impurities and contaminants.

An embodiment, therefore, includes a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof.

In a further embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or excipient.

Another embodiment includes a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt thereof for use in the treatment of HBV infection.

INDICATIONS AND METHODS OF TREATMENT

The compounds of the invention can inhibit cccDNA and have anti-HBV activity. Accordingly, the compounds of the invention are useful for the treatment or prophylaxis of HBV infection.

The invention relates to the use of a compound of formula (I) for the inhibition of cccDNA.

The invention also relates to the use of a compound of formula (I) for the inhibition of HBeAg.

The invention further relates to the use of a compound of formula (I) for the inhibition of HBsAg.

The invention relates to the use of a compound of formula (I) for the inhibition of HBV

DNA.

The invention relates to the use of a compound of formula (I) for the treatment or prophylaxis of HBV infection.

The use of a compound of formula (I) for the preparation of medicaments useful in the treatment or prophylaxis diseases that are related to HBV infection is an object of the invention.

The invention relates in particular to the use of a compound of formula (I) for the preparation of a medicament for the treatment or prophylaxis of HBV infection. Another embodiment includes a method for the treatment or prophylaxis of E1BV infection, which method comprises administering an effective amount of a compound of Formula (I), or pharmaceutically acceptable salts thereof.

BRIEF DESCRIPTION OF THE FIGURED

Figure 1: the result of BIO-Example 3 in cccDNA Southern Blot assay, it indicates that C003-A dose-dependently reduced cccDNA level in FlepDESl9 cells.

EXAMPLES

The invention will be more fully understood by reference to the following examples. They should not, however, be construed as limiting the scope of the invention.

Abbreviations used herein are as follows:

ACN : acetonitrile

BBr ₃ : boron tribromide

DMAP: 4-dimethylaminopyridine

DMF: iV,iV-dimethylformamide

IC50: the molar concentration of an inhibitor, which produces 50% of the maximum possible response for that inhibitor.

EBS: fetal bovine serum

EECE: hydrogen peroxide

E1PLC: high performance liquid chromatography

MS (ESI): mass spectroscopy (electron spray ionization)

Ms: methylsulfonyl

obsd. : observed

PE: petroleum ether

EtOAc: ethyl acetate

AcOEl _; acetic acid

DIBAL: diisobutylaluminium hydride

TE1F: tetrahydrofuran

LiElMDS: lithium bis(trimethylsilyl)amide

LiAlEL* : lithium aluminium hydride TFA: trifluoro acetic acid

Mn() ₂ : manganese dioxide

DIPEA : N,N-Diisopropylethylamine

E1ATU : 1- [Bis(dimethylamino)methylene] -1H-1 ,2,3-triazolo [4,5-b]pyridinium 3 -oxid hexafluorophosphate

DIAD: Diisopropyl azodicarboxylate

DABCO: l,4-Diazabicyclo[2.2.2]octane

m-CPBA: 3-Chlorobenzene-l-carboperoxoic acid

DAST: Diethylaminosulfur trifluoride

RuPhos Pd G2: Chloro(2-dicyclohexylphosphino-2\ 6’-diisopropoxy-l,l’-biphenyl)[2-(2’- amino- 1 , 1’-biphenyl)]palladium(II)

Ts: -tolylsulfonyl

d: chemical shift

GENERAL EXPERIMENTAL CONDITIONS

Intermediates and final compounds were purified by flash chromatography using one of the following instruments: i) Biotage SP1 system and the Quad 12/25 Cartridge module, ii) column chromatography on silica gel combi- flash chromatography instmment. Silica gel Brand and pore size: i) KP-SIL 60 A, particle size: 40-60 pm; ii) CAS registry NO: Silica Gel: 63231-67-4, particle size: 47-60 micron silica gel; iii) ZCX from Qingdao Elaiyang Chemical Co., Ltd, pore: 200-300 or 300-400.

Intermediates and final compounds were purified by preparative E1PLC on reversed phase column using X Bridge™ Perp Cis (5 pm, OBD™ 30 x 100 mm) column or SunFire™ Perp Cis (5 pm, OBD™ 30 x 100 mm) column.

LC/MS spectra were obtained using a Waters UPLC-SQD Mass. Standard LC/MS conditions were as follows (running time 3 minutes):

Acidic condition: A: 0.1% formic acid and 1% acetonitrile in I LO; B: 0.1% formic acid in acetonitrile;

Basic condition: A: 0.05% NEfl-ELO in 11 ₂ 0; B: acetonitrile. Mass spectra (MS): generally only ions which indicate the parent mass are reported, and unless otherwise stated the mass ion quoted is the positive mass ion (M+H) ⁺ .

NMR Spectra were obtained using Bruker Avance 400MHz.

All reactions involving air-sensitive reagents were performed under an argon atmosphere. Reagents were used as received from commercial suppliers without further purification unless otherwise noted.

PREPARATIVE EXAMPLES

Intermediate 1: 8-chloro-2-[2-hydroxy-4-(trifluoromethyl)phenyl]chromen-4-on e

Step 1: Preparation of (Z7)-l-(3-chloro-2-hydroxy-phenyl)-3-[2-methoxy-4- (trifluoromethyl)phenyl]prop-2-en-l-one

Int-la

A mixture of l-(3-chloro-2-hydroxy-phenyl)ethanone (CAS #: 3226-34-4, Cat.#: BD11027, from Bide Pharmatech, 2.5 g, 14.7 mmol), 2-methoxy-4-(trifluoromethyl)benzaldehyde (CAS #: 132927-09-4, Cat.#: H26797, from Alfa Aesar, 2 g, 14.7 mmol) and KOH (1.64 g, 29.3 mmol) in EtOH (25 mL) was stirred at l00°C for 3 hours. After the reaction was completed, the mixture was then adjusted to pH~4 by addition of 2N HC1 and the resulting suspension was filtered. The solid was collected and dried in vacuo to give the cmde (77)- 1 -(3-chloro-2-hydroxy-phcnyl)-3-[2- methoxy-4-(trifluoromethyl)phenyl]prop-2-en-l-one (3.3 g, 78%) as a yellow solid, which was used in the next step directly without further purification. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:357.2.

Step 2: Preparation of 8-chloro-2-[2-methoxy-4-(trifluoromethyl)phenyl]chromen-4-on e

Int-lb

To a solution of (E)- 1 -(3-chloro-2-hydroxy-phenyl)-3-|2-methoxy-4- (trifluoromethyl)phenyl]prop-2-en-l-one (5.3 g, 18.4 mmol) in DMSO (60 mL) was added I ₂ (466 mg, 1.84 mmol) and then the mixture was stirred at 140 °C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature, quenched with saturated NaHSCL solution (10 mL). The mixture was diluted with water (100 mL) and the resulting suspension was filtered. The solid was collected and dried in vacuo to give the 8-chloro-2-[2-methoxy-4- (trifluoromethyl)phenyl]chromen-4-one (5 g, 95% yield) as a yellow solid, which was used in the next step directly without further purification. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 355.1.

Step 3: Preparation of 8-chloro-2-[2-hydroxy-4-(trifluoromethyl)phenyl]chromen-4-on e

To a solution of 8-chloro-2-[2-methoxy-4-(trifluoromethyl)phenyl]chromen-4-on e (5 g, 14.0 mmol) in dichloromethane (40 mL) was added BBr ₃ (1 M solution in dichloromethane, 69.8 mL, 69.8 mmol) at room temperature. The mixture was stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated in vacuo and the residue was suspended in saturated NLLCl solution (30 mL). The solid was collected by filtration and dried in vacuo to give the crude 8-chloro-2-[2-hydroxy-4-(trifluoromethyl)phenyl]chromen-4-on e (4. lg, 85.9%yield) as a yellow solid, which was used in the next step directly without further purification. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 341.2.

Intermediate 2: 8-chloro-2-(2-hydroxy-4-methyl-phenyl)chromen-4-one

Int-2 was prepared in analogy to the procedure described for the preparation of compound Int-1 by using 2-methoxy-4-methyl-benzaldehyde as the starting material instead of 2-methoxy- 4-(trifluoromethyl)benzaldehyde in Step 1. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 287.1.

Intermediate 3: 8-chloro-2-(2-hydroxyphenyl)chromen-4-one

Int-3 was prepared in analogy to the procedure described for the preparation of compound Int-1 by using 2-hydroxybenzaldehyde as the starting material instead of 2-methoxy-4- (trifluoromethyl)benzaldehyde in Step 1. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 273.2.

Intermediate 4: 2-(4-bromo-2-hydroxy-phenyl)-8-chloro-chromen-4-one

Int-4 was prepared in analogy to the procedure described for the preparation of compound

Int-1 by using 4-bromo-2-hydroxy-benzaldehyde as the starting material instead of 2-methoxy- 4-(trifluoromethyl)benzaldehyde in Step 1. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:35l.2.

Intermediate 5: 8-chloro-2-(4-chloro-2-hydroxy-5-methyl-phenyl)chromen-4-one

Int-5 Step 1: Preparation of 4-chloro-2-hydroxy-5-methyl-benzaldehyde

Int-5a

To a solution of 3-chloro-4-methyl-phenol (10.0 g, 70.1 mmol) in ACN (200 mL) were added formaldehyde (8.42 g, 280.54 mmol), TEA (39.1 mL, 280.5 mmol) and magnesium chloride (27.0 mL, 210.4 mmol) and the mixture was stirred at 80 °C for 16 hours. After the reaction was completed, the reaction was quenched with 1M E1C1 (500 mL) and extracted with EtOAc (150 mL) three times. The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo to give the crude 4-chloro-2-hydroxy-5-methyl-benzaldehyde (11.3 g, 66.24 mmol, 94.45% yield) as brown oil, which was used in the next step directly without further purification.

Step 2: Preparation of 4-chloro-2-(methoxymethoxy)-5-methyl-benzaldehyde

Int-5b

To a solution of 4-chloro-2-hydroxy-5-methyl-benzaldehyde (9.6 g, 56.28 mmol, in THF (100 mL) cooled at 0 °C was added sodium hydride (3.38 g, 84.41 mmol) in portions. After addition, the mixture was stirred at 0 °C for 30 minutes and then to the resulting mixture was added bromomethyl methyl ether (10.55 g, 84.41 mmol) dropwise. The reaction mixture was stirred at 0 °C for another 2 hours. After the reaction was complete, the mixture was poured into ice-water (200 ml) slowly and extracted with EtOAc (80 mL) three times. The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo to give the crude 4- chloro-2-(methoxymethoxy)-5-methyl-benzaldehyde (12 g 99.34% yield) as a white solid, which was used in the next step directly without further purification. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 215.1. Step 3: Preparation of (£')-l-(3-chloro-2-hydroxy-phenyl)-3-[4-chloro-2-(methoxyme thoxy)- 5-methyl-phenyl]prop-2-en-l-one

Int-5c

To a solution of 4-chloro-2-(methoxymethoxy)-5-methyl-benzaldehyde (6.0 g, 27.95 mmol), l-(3-chloro-2-hydroxy-phenyl)ethanone (4.77 g, 27.95 mmol) in EtOH (300 mL) was added KOH (15.68 g, 279.52 mmol) and the mixture was then stirred at 35 °C for 16 hours. After the reaction was completed, the mixture was poured into 0.5 M HC1 (200 mL) and the resulting suspension was then filtered. The solid was collected and then dried under vacuum to give the crude (77)- 1 -(3-chloro-2-hydroxy-phcnyl)-3-[4-chloro-2-(mcthoxymcthoxy)- 5- methyl- phenyl]prop-2-en-l-one (10 g, 27.23 mmol, 97.42% yield) as a yellow solid, which was used in the next step directly without further purification. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 367.0.

Step 4: Preparation of 8-chloro-2-[4-chloro-2-(methoxymethoxy)-5-methyl- phenyl]chromen-4-one

Int-5d

To a solution of (E)- 1 -(3-chloro-2-hydroxy-phenyl)-3-|4-chloro-2-(methoxymethoxy)- 5- methyl-phenyl]prop-2-en-l-one (10.0 g, 27.23 mmol, 1 eq) in DMSO (250 mL) was added iodine (345.58 mg, 1.36 mmol, 0.050 eq) and the mixture was then stirred at 140 °C under N ₂ for 2 hours. After the reaction was complete, the mixture was poured into ice-water and the resulting suspension was filtered. The solid was washed with water and then collected to give the cmde 8- chloro-2-[4-chloro-2-(methoxymethoxy)-5-methyl-phenyl]chrome n-4-one (8.7 g, 23.82 mmol, 87.48% yield) as a yellow solid, which was used in the next step directly without further purification. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 365.0.

Step 5: Preparation of 8-chloro-2-(4-chloro-2-hydroxy-5-methyl-phenyl)chromen-4-one

Int-5

To a solution of 8-chloro-2-[4-chloro-2-(methoxymethoxy)-5-methyl-phenyl]chro men-4- one (3.4 g, 9.31 mmol, 1 eq) in dichloro methane (10 mL) was added trifluoro acetic acid (10.0 mL, 129.8 mmol, 13.94 eq). The reaction mixture was then stirred at room temperature for 16 hours. After the reaction was completed, The reaction mixture was concentrated in vacuo to give the crude 8-chloro-2-(4-chloro-2-hydroxy-5-methyl-phenyl)chromen-4-one (2.7 g, 8.41 mmol, 90.31% yield) as a brown solid, which was used in the next step directly. MS obsd. (ESI ⁺ )

[(M+H) ⁺ ]: 320.9.

Intermediate 6: 2-(4-bromo-2-hydroxy-5-methyl-phenyl)-8-chloro-chromen-4-one

Int-6

Step 1: Preparation of 4-bromo-2-hydroxy-5-methyl-benzaldehyde

Int-6a

Int-6a was prepared in analogy to the procedure described for the preparation of compound Int-5a by using 3 -bromo- 4- methyl-phenol as the starting material instead of 3-chloro- 4- methyl-phenol in Step 1.

Step 2: Preparation of 2-(4-bromo-2-hydroxy-5-methyl-phenyl)-8-chloro-chromen-4-one

Int-6

Int-6 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 4-bromo-2-hydroxy-5-methyl-benzaldehyde as the starting material instead of 4- chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 341.0.

Intermediate 7: 2-(4-bromo-2-hydroxy-5-methoxy-phenyl)-8-chloro-chromen-4-on e

Int-7

Int-7 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 4-bromo-2-hydroxy-5-methoxy-benzaldehyde (CAS #: 63272-66-2, Cat.#:

SY025557, from Accela ChemBio Inc.) as the starting material instead of 4-chloro-2-hydroxy-5- methyl-benzaldehyde in Step 2. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 381.1.

Intermediate 8: 8-chloro-2-(4-chloro-2-hydroxy-5-methoxy-phenyl)chromen-4-on e

Step 1: Preparation of 4-chloro-2-hydroxy-5-methoxy-benzaldehyde

Int-8a Int-8a was prepared in analogy to the procedure described for the preparation of compound Int-5a by using 3-chloro-4-methoxy-phenol as the starting material instead of 3- chloro-4-methyl-phenol in Step 1.

Step 2: Preparation of 8-chloro-2-(4-chloro-2-hydroxy-5-methoxy-phenyl)chromen-4-on e

Int-8

Int-8 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 4-chloro-2-hydroxy-5-methoxy-benzaldehyde as the starting material instead of 4-chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 337.2.

Intermediate 9: 8-chloro-2-[2-hydroxy-4-(trifluoromethoxy)phenyl]chromen-4-o ne

Int-9

Int-9 was prepared in analogy to the procedure described for the preparation of compound Int-1 by using 2-methoxy-4-(trifluoromethoxy)benzaldehyde (CAS #: 886500-13-6, Cat.#: BD188719, from Bepharm) as the starting material instead of 2-methoxy-4-

(trifluoromethyl)benzaldehyde in Step 1. MS obsd. (ESI ⁺ ) [(M+H) ¹ ]: 357.1.

Intermediate 10: 8-chloro-2-(2-hydroxy-4,5-dimethoxy-phenyl)chromen-4-one

Int-10

Int-10 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 2-hydroxy-4,5-dimethoxy-benzaldehyde (CAS #: 14382-91-3, Cat.#: SY025559, from Accela ChemBio Inc.) as the starting material instead of 4-chloro-2-hydroxy-5- methyl-benzaldehyde in Step 2. MS obsd. (ESI ⁺ ) [(M+H) ¹ ]: 333.2.

Intermediate 11: 8-chloro-2-(6-hydroxy-l,3-benzodioxol-5-yl)chromen-4-one

Int-11

Int-11 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using l,3-benzodioxol-5-ol (CAS #: 533-31-3, Cat.#: SY015819, from Accela ChemBio Inc.) as the starting material instead of 3 -chloro -4-methyl-phenol in Step 1. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 317.3.

Intermediate 12: 8-chloro-2-(2-hydroxy-4-methoxy-5-methyl-phenyl)chromen-4-on e

Int-12

Step 1: Preparation of 2-hydroxy-4-methoxy-5-methyl-benzaldehyde

Int-12a

Int-12a was prepared in analogy to the procedure described for the preparation of compound Int-5a by using 3-methoxy-4-methyl-phenol as the starting material instead of 3- chloro-4-methyl-phenol in Step 1.

Step 2: Preparation of 8-chloro-2-(2-hydroxy-4-methoxy-5-methyl-phenyl)chromen-4-on e

Int-12

Int-12 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 2-hydroxy-4-methoxy-5-methyl-benzaldehyde (Int-12a) as the starting material instead of 4-chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 317.1.

Intermediate 13: 8-chloro-2-(2-hydroxy-4-methoxy-phenyl)chromen-4-one

Int-13

Int-13 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 2-hydroxy-4-methoxy-benzaldehyde (CAS #: 673-22-3, Cat.#:

SY012912, from Accela ChemBio Inc.) as the starting material instead of 4-chloro-2-hydroxy-5- methyl-benzaldehyde in Step 2. MS obsd. (ESI ⁺ ) [(M+H) ¹ ]: 302.9.

Intermediate 14: 2-[4-bromo-2-hydroxy-5-(trifluoromethoxy)phenyl]-8-chloro-ch romen-4- one

Int-14

Step 1: Preparation of 2-bromo-4-methoxy-l-(trifluoromethoxy)benzene

Int-14a

To a solution of 3-bromo-4-(trifluoromethoxy)phenol (CAS #: 886496-88-4, Cat.#:

SY024383, from Accela ChemBio Inc., 2000.0 mg, 7.9 mmol) and K ₂ CO ₃ (2151.0 mg, 15.8 mmol) in acetone (50 mL) were added iodomethane (2.2 g, 15.6 mmol) and the mixture was stirred at room temperature for 18 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent with PE:EtOAc = 10:1 to 3:1) to give 2-bromo-4-methoxy- l-(trifluoromethoxy)benzene (1800 mg, yield 85.3%) as a yellow solid. MS obsd. (ESI ⁺ )

[(M+Na)] ⁺ : 294.0.

Step 2: Preparation of 4-bromo-2-methoxy-5-(trifluoromethoxy)benzaldehyde

Int-14b

To a solution of 2-bromo-4-methoxy-l-(trifluoromethoxy)benzene (2000 mg, 7.4 mmol) in DCM (20 mL) cooled at 78 °C was added T1CI ₄ (1680 mg, 8.86 mmol) and the mixture was stirred at -78 °C for 30 minutes. To the resulting solution was added l,l-dichlorodimethyl ether (1866 mg, 16.3 mmol). The reaction was then warmed to room temperature and stirred at room temperature for 2 hours. After the reaction was completed, the reaction was quenched by NH ₄ CI solution (30 mL) and extracted with DCM (20mL) three times. The combined organic layer was dried over MgSC> ₄ and concentrated in vacuo. The residue was purified by column

chromatography on silica gel (eluent with PE:EtOAc 100:1 to 3:1) to give 4-bromo-2-methoxy- 5-(trifluoromethoxy)benzaldehyde (500 mg, 22.7% yield) as a white solid. ¹ 11 NMR ( CDCk , 400MHz): d ppm 10.30 (s, 1H), 7.69 (d, J= 1.3 Hz, 1H), 7.22 (s, 1H), 3.90 (s, 3H). Step 3: Preparation of 2-[4-bromo-2-hydroxy-5-(trifhioromethoxy)phenyl]-8-chloro- chromen-4-one

Int-14

Int-14 was prepared in analogy to the procedure described for the preparation of compound Int-1 by using 4-bromo-2-methoxy-5-(trifluoromethoxy)benzaldehyde as the starting material instead of 2-methoxy-4-(trifluoromethyl)benzaldehyde in Step 1. MS obsd. (ESI ⁺ ) [(M+H)] ⁺ : 436.0.

Intermediate 15: 8-chloro-2-(2-hydroxy-5-methoxy-4-methyl-phenyl)chromen-4-on e

Int-15

Step 1: Preparation of 2-hydroxy-5-methoxy-4-methyl-benzaldehyde

Int-15a

Int-15a was prepared in analogy to the procedure described for the preparation of compound Int-5a by using 4- methoxy- 3 -methyl-phenol as the starting material instead of 3- chloro-4-methyl-phenol in Step 1.

Step 2: Preparation of 8-chloro-2-(2-hydroxy-5-methoxy-4-methyl-phenyl)chromen-4-on e

Int-15

Int-15 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 2-hydroxy-5-methoxy-4-methyl-benzaldehyde (Int-15a) as the starting material instead of 4-chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2. MS obsd. (ESI ⁺ ) [(M+H)] ⁺ : 317.2.

Intermediate 16: 2-[5-bromo-2-hydroxy-4-(trifluoromethoxy)phenyl]-8-chloro-ch romen-4- one

Int-16

Step 1: Preparation of 5-bromo-2-hydroxy-4-(trifluoromethoxy)benzaldehyde

Int-16a

Int-16a was prepared in analogy to the procedure described for the preparation of compound Int-5a by using 4-bromo-3-(trifluoromethoxy)phenol (CAS #: 886499-93-0, Cat.#: BD217660, from Bide Pharmtach) as the starting material instead of 3-chloro-4-methyl-phenol in Step 1.

Step 2: Preparation of 5-bromo-2-(methoxymethoxy)-4-(trifluoromethoxy)benzaldehyde

Int-16b

Int-16b was prepared in analogy to the procedure described for the preparation of compound Int-5b by using 5-bromo-2-hydroxy-4-(trifluoromethoxy)benzaldehyde as the starting material instead of 4-chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2.

Step 3: Preparation of 2-[5-bromo-2-hydroxy-4-(trifluoromethoxy)phenyl]-8-chloro- chromen-4-one

Int-16

Int-16 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 5-bromo-2-(methoxymethoxy)-4-(trifluoromethoxy)benzaldehyde as the starting material instead of 4-chloro-2-(methoxymethoxy)-5-methyl-benzaldehyde in Step 3. MS obsd. (ESI ⁺ ) [(M+H)] ⁺ : 435.1.

Intermediate 17 : 8-chloro-2-[2-hydroxy-5-methyl-4-(trifluoromethoxy)phenyl]ch romen-4- one

Int-17

Step 1: Preparation of 2-(methoxymethoxy)-5-methyl-4-(trifluoromethoxy)benzaldehyde

Int-17a

To a solution of 5-bromo-2-(methoxymethoxy)-4-(trifluoromethoxy)benzaldehyde (Int- 16b, 500 mg, 1.52 mmol), trimethylboroxine (381 mg, 3.02 mmol), K CO (630 mg, 4.56 mmol) in dioxane (10 mL) under N was added Pd(dppf) Cl (111.1 mg, 0.1 mmol) and the mixture was then stirred at 110 °C under N? for 1 hour. After the reaction was completed, the mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent with PE/EtOAc= 100:1 to 2:1) to give 2-(methoxymethoxy)- 5-methyl-4-(trifluoromethoxy)benzaldehyde (310 mg, 77.2% yield) as an off-white solid.

Step 2: Preparation of 8-chloro-2-[2-hydroxy-5-methyl-4- (trifluoromethoxy)phenyl]chromen-4-one

Int-17

Int-17 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 2-(methoxymethoxy)-5-methyl-4-(trifluoromethoxy)benzaldehyde as the starting material instead of 4-chloro-2-(methoxymethoxy)-5-methyl-benzaldehyde in Step 3. MS obsd. (ESI ⁺ ) [(M+H)] ⁺ : 371.2.

Intermediate 18: 2-(3-bromo-2-hydroxy-5-methyl-phenyl)-8-chloro-chromen-4-one

Int-18

Step 1: Preparation of 3-bromo-2-hydroxy-5-methyl-benzaldehyde

Int-18a

Int-18a was prepared in analogy to the procedure described for the preparation of compound Int-5a by using 2-bromo-4-methyl-phenol as the starting material instead of 3-chloro- 4- methyl-phenol in Step 1.

Step 2: Preparation of 2-(3-bromo-2-hydroxy-5-methyl-phenyl)-8-chloro-chromen-4-one

Int-18

Int-18 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 3-bromo-2-hydroxy-5-methyl-benzaldehyde as the starting material instead of 4-chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2. MS obsd. (ESI ⁺ ) [(M+H)] ⁺ : 365.1.

Intermediate 19: 8-chloro-2-[2-hydroxy-4-methyl-5-(trifluoromethoxy)phenyl]ch romen-4- one

Int-19

Step 1: Preparation of 4-bromo-2-hydroxy-5-(trifluoromethoxy)benzaldehyde

Int-19a

To a solution of 4-bromo-2-methoxy-5-(trifluoromethoxy)benzaldehyde (Int-14b, 2 g, 4.7 mmol) in DCM (30 mL) cooled at -78 °C under N ₂ atmosphere was added BBn (3.35 g, 13.6 mmol). After completion of addition, the solution was stirred at -78 °C for additional 30 minutes. After the reaction was completed, the solution was poured into ice-water (50 mL) and the resulting suspension was extracted with EtOAc (100 mL) three times. The combined organic layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluent with PE:DCM = 1:1) to give the 4-bromo-2-hydroxy-5- (trifluoromethoxy)benzaldehyde (1.7 g, 75.8%) as a brown solid. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 285.0.

Step 2: Preparation of 4-bromo-2-(methoxymethoxy)-5-(trifluoromethoxy)benzaldehyde

Int-19b

Int-19b was prepared in analogy to the procedure described for the preparation of compound Int-5b by using 4-bromo-2-hydroxy-5-(trifluoromethoxy)benzaldehyde as the starting material instead of 4-chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2.

Step 3: Preparation of 2-(methoxymethoxy)-4-methyl-5-(trifluoromethoxy)benzaldehyde

Int-19c Int-19c was prepared in analogy to the procedure described for the preparation of compound Int-17a by using 4-bromo-2-(methoxymethoxy)-5-(trifluoromethoxy)benzaldehyde as the starting material instead of 5-bromo-2-(methoxymethoxy)-4- (trifluoromethoxy)benzaldehyde in Step 1.

Step 4: Preparation of8-chloro-2-[2-hydroxy-4-methyl-5- (trifluoromethoxy)phenyl]chromen-4-one

Int-19

Int-19 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 2-(methoxymethoxy)-4-methyl-5-(trifluoromethoxy)benzaldehyde as the starting material instead of 4-chloro-2-(methoxymethoxy)-5-methyl-benzaldehyde in Step 3. MS obsd. (ESI ⁺ ) [(M+H)] ⁺ : 371.1.

Intermediate 20: 2-(4-bromo-2-fluoro-6-hydroxy-phenyl)-8-chloro-chromen-4-one

Int-20

Step 1: Preparation of 2-(4-bromo-2-fluoro-6-methoxy-phenyl)-8-chloro-chromen-4-one

Int-20a

Int-20a was prepared in analogy to the procedure described for the preparation of compound Int-lb by using 4-bromo-2-fluoro-6-methoxybenzaldehyde (CAS #: 856767-09-4, Cat.#: BD259901, from Bide Pharmatech) as the starting material instead of 2-methoxy-4- (trifluoromethyl)benzaldehyde in Step 1.

Step 2: Preparation of 2-(4-bromo-2-fluoro-6-hydroxy-phenyl)-8-chloro-chromen-4-one

Int-20

Int-20 was prepared in analogy to the procedure described for the preparation of compound Int-1 by using 2-(4-bromo-2-fluoro-6-methoxy-phenyl)-8-chloro-chromen-4-one as the starting material instead of 8-chloro-2-[2-methoxy-4-(trifluoromethyl)phenyl]chromen-4-on e in Step 3. MS obsd. (ESI ⁺ ) [(M+H)] ⁺ : 369.2.

Intermediate 21: 8-chloro-2-(2-fluoro-6-hydroxy-4-methyl-phenyl)chromen-4-one

Int-21

Step 1: Preparation of 8-chloro-2-(2-fluoro-6-methoxy-4-methyl-phenyl)chromen-4-one

Int-21a

To a solution of 2-(4-bromo-2-fluoro-6-methoxy-phenyl)-8-chloro-chromen-4-one (Int- 22a, 300.0 mg, 0.8 mmol), trimethylboroxine (196.4 mg, 1.56 mmol), K ₂ CO ₃ (324.3 mg, 2.35 mmol) in dioxane (10 mL) under N ₂ was added Pd(dppf) ₂ Cl ₂ (57.8 mg, 0.08mmol) and the mixture was then stirred at 110 °C under N ₂ for 1 hour. After the reaction was completed, the mixture was cooled to room temperature and concentrated in vacuo, the residue was purified by column chromatography on silica gel (eluent with PE/EtOAc= 100:1 to 2:1) to give 8-chloro-2- (2-fluoro-6-methoxy-4-methyl-phenyl)chromen-4-one (150 mg, 57.2% yield) as an off-white solid. Step 2: Preparation of 8-chloro-2-(2-fluoro-6-hydroxy-4-methyl-phenyl)chromen-4-one

Int-21

Int-21was prepared in analogy to the procedure described for the preparation of compound Int-1 by using 8-chloro-2-(2-fluoro-6-methoxy-4-methyl-phenyl)chromen-4-one as the starting material instead of 8-chloro-2-[2-methoxy-4-(trifluoromethyl)phenyl]chromen-4-on e in Step 3. MS obsd. (ESI ⁺ ) [(M+H)] ⁺ : 305.0.

Intermediate 22: 8-bromo-2-[2-hydroxy-4-(trifluoromethoxy)phenyl]chromen-4-on e

Int-22

Int-22 was prepared in analogy to the procedure described for the preparation of compound Int-1 by using l-(3-bromo-2-hydroxy-phenyl)ethanone (CAS #: 1836-05-1, Cat.#: BD50461, from Bide Pharmatech) and 2-methoxy-4-(trifluoromethoxy)benzaldehyde as the starting materials instead of l-(3-chloro-2-hydroxy-phenyl)ethanone and 2-methoxy-4- (trifluoromethyl)benzaldehyde in Step 1. MS obsd. (ESI ⁺ ) [(M+H)] ⁺ : 401.2.

Intermediate 23: 7-bromo-8-chloro-2-[2-hydroxy-4-(trifluoromethoxy)phenyl]chr omen-4- one

Int-23

Step 1: Preparation of (3-bromo-2-chloro-phenyl) acetate

Int-23a

To a mixture of 3-bromo-2-chloro-phenol (10.0 g, 68.24 mmol) and TEA (7.6 g, 75.06 mmol) in dichloro methane (150 mL) was added acetyl chloride (5.36 g, 68.24 mmol) at 0 °C and the mixture was then stirred at room temperature for 16 hours. After the reaction was completed, the mixture was poured into water (30mL) and extracted with dichloromethane (50mL) three times. The combined organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was then purified by column chromatography on silica gel (elution with PE: EtOAc=50: 1-20:1) to give (3-bromo-2-chloro-phenyl) acetate (10.0 g, 75%) as colorless oil. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 247.9.

Step 2: Preparation of l-(4-bromo-3-chloro-2-hydroxy-phenyl)ethanone

Int-23b

A mixture of (3-bromo-2-chloro-phenyl) acetate (10.0 g, 53.03 mmol) and A1CT (7.07 g, 53.03 mmol) was stirred at 150 °C for 5 hours. After the reaction was completed, the mixture was poured into water (lOOmL) and extracted with EtOAc (250mL) twice. The combined organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was then purified by column chromatography on silica gel (elution with PE:

EtOAc=50: 1-20:1) to give l-(4-bromo-3-chloro-2-hydroxy-phenyl)ethanone (3.0 g, 30.0%) as a white solid. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 247.9.

Step 3: Preparation of 7-bromo-8-chloro-2-[2-hydroxy-4- (trifluoromethoxy)phenyl]chromen-4-one

Int-23

Int-23 was prepared in analogy to the procedure described for the preparation of compound Int-1 by using l-(4-bromo-3-chloro-2-hydroxy-phenyl)ethanone and 2-methoxy-4- (trifluoromethoxy)benzaldehyde as the starting materials instead of l-(3-chloro-2-hydroxy- phenyl)ethanone and 2-methoxy-4-(trifluoromethyl)benzaldehyde in Step 1. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 435.1.

Intermediate 24: 8-bromo-2-(2-hydroxy-4-methyl-phenyl)chromen-4-one

Int-24

Int-24 was prepared in analogy to the procedure described for the preparation of compound Int-1 by using l-(3-bromo-2-hydroxy-phenyl)ethanone and 2-methoxy-4-methyl- benzaldehyde as the starting materials instead of l-(3-chloro-2-hydroxy-phenyl)ethanone and 2- methoxy-4-(trifluoromethyl)benzaldehyde in Step 1. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 331.1.

Intermediate 25: 8-bromo-2-(4-chloro-2-hydroxy-5-methyl-phenyl)chromen-4-one

Int-25

Int-25 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using l-(3-bromo-2-hydroxy-phenyl)ethanone as the starting material instead of l-(3-chloro-2-hydroxy-phenyl)ethanone in Step 3. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 365.0.

Intermediate 26: 2-(5-bromo-3-hydroxy-2-pyridyl)-8-chloro-chromen-4-one

Int-26

Step 1: Preparation of 5-bromo-3-methoxy-pyridine-2-carboxylic acid

Int-26a

To a solution of 5-bromo-3-methoxy-pyridine-2-carbonitrile (CAS #: 36057-46-2, Cat.#: SY162901, from Accela ChemBio Inc, 3.2 g, 15.02 mmol) in THF (80 mL) was added 5N NaOH solution (15 mL, 75 mmol) and the mixture was stirred at 110 °C for 6 hours. The mixture was then cooled to room temperature and adjusted to pH~3 by addition of 6N HC1. The resulting mixture was diluted with EtOAc (150 mL), washed with water (30 mL) twice, brine (30 mL), dried over MgS0 ₄ and concentrated in vacuo to give 5-bromo-3-methoxy-pyridine-2-carboxylic acid (2.5 g, 71.73% yield) as a white solid, ' l l NMR (400 MHz, (TXT) d ppm: 13.27 (br s, 1H), 8.29 (d, J = 1.7 Hz, 1H), 7.92 (d, J = 1.7 Hz, 1H), 3.88 (s, 3H). MS obsd. (ESI ⁺ )[(M+H) ⁺ j: 232.0. Step 2: Preparation of 5-bromo-3-methoxy-pyridine-2-carbonyl chloride

Int-26b

To a solution of 5-bromo-3-methoxy-pyridine-2-carboxylic acid (1.5 g, 6.46 mmol) in DCM (60 mL) was added oxalyl chloride (4.1 g, 32.32 mmol, 5 eq) at 0 °C and the mixture was stirred at room temperature for 2 hours. The resulting mixture was concentrated in vacuo to give 5-bromo-3-methoxy-pyridine-2-carbonyl chloride (1.61 g, 99.43% yield) as dark brown oil, which was used in the next step directly without further purification. Step 3: Preparation of (2-acetyl-6-chloro-phenyl) 5-bromo-3-methoxy-pyridine-2- carboxylate

Int-26c

To a solution of l-(3-chloro-2-hydroxy-phenyl)ethanone (1.1 g, 6.47 mmol) and TEA (4.51 mL, 32.34 mmol) in DCM (40 mL) was added 5-bromo-3-methoxy-pyridine-2-carbonyl chloride solution (1.62 g, 6.47 mmol, dissolved in DCM (15 mL)) at 0 °C. The mixture was stirred at room temperature for 2 hours. The mixture was then concentrated in vacuo and the residue was redissolved in EtOAc (150 mL). The resulting solution was washed with water (30 mL) twice, brine (50 mL), dried over Na ₂ S0 ₄ and concentrated in vauco. The residue was then purified by column chromatography (eluted with PE/EtOAc = 100:1 to 2:1) to give (2-acetyl-6- chloro-phenyl) 5-bromo-3-methoxy-pyridine-2-carboxylate (1.0 g, 40.2% yield) as a red solid. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 383.9.

Step 4: Preparation of 2-(5-bromo-3-methoxy-2-pyridyl)-8-chloro-chromen-4-one

Int-26d

To a solution of (2-acetyl-6-chloro-phenyl) 5-bromo-3-methoxy-pyridine-2-carboxylate (1.0 g, 2.6 mmol) in pyridine (15 mL) was added KOH (218.8 mg, 3.9 mmol) and the mixture was stirred at 50°C for 30 minutes. The mixture was poured into 4N HC1 (50 mL) and the mixture was adjusted to pH~9 by addition of saturated Na ₂ CC>3 solution. The mixture was extracted with CHCh (50 mL) four times. The combined organic layer was washed with H ₂ 0 (100 mL), brine, dried over MgS0 ₄ , filtered and the filtrate was concentrated in vacuo. The residue was dissolved in AcOH (20 mL) and to the resulting solution was added H ₂ S0 ₄ (0.26 g, 2.6 mmol). The mixture was stirred at 100 °C for 2 hours and the mixture was concentrated in vacuo. The residue was diluted with water (30 mL) and adjusted to pH~9 by addition of saturated Na ₂ CC>3. The resulting mixture was extracted with CHCI3 (50 mL) four times. The combined organic layer was washed with H ₂ 0 (100 mL), brine, dried over MgS0 ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent with PE/EtOAc = 3:1) to give 2-(5-bromo-3-methoxy-2-pyridyl)-8-chloro- chromen-4-one (420 mg, 44.06% yield,) as a red solid. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 366.0.

Step 5: Preparation of 2-(5-bromo-3-hydroxy-2-pyridyl)-8-chloro-chromen-4-one

Int-26

To a solution of 2-(5-bromo-3-methoxy-2-pyridyl)-8-chloro-chromen-4-one (200.0 mg, 0.550 mmol) in chloroform (20 mL) was added BBr ₃ (25.0 mL) at 0 °C and the mixture was stirred at 50 °C for 48 hours. Then to the resulting solution was added MeOH (10 mL) and the mixture was concentrated in vacuo. The residue was triturated with solvent (eluted with

PE:EtOAc = 20:1, 15 mL) and the mixture was then filtered to give 2-(5-bromo-3-hydroxy-2- pyridyl)-8-chloro-chromen-4-one (150 mg, 77.98% yield) as a brown solid. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 351.9.

Intermediate 27 : 2-[4-bromo-2-hydroxy-5-(trifluoromethyl)phenyl]-8-chloro-chr omen-4- one

Int-27

Step 1: Preparation of methyl 4-amino-5-iodo-2-methoxy-benzoate

Int-27a To a solution of methyl 4-amino-2-methoxybenzoate (CAS #: 27492-84-8, Cat.#:

SY007291, from Accela ChemBio Inc, 20.0 g, 110.38 mmol) in l,4-dioxane (80 mL) and pyridine (80 mL) was added iodine (56.0 g, 220.76 mmol) at room temperature. The resulting mixture was heated at 50 °C for 3 hours. After the reaction was completed, the mixture was cooled to room temperature and quenched by 2M Na ₂ S0 ₃ solution (200 mL). The resulting solution was extracted with EtOAc (50 mL) three times. The combined organic layer was washed with water, brine, dried over Na ₂ S0 ₄ and then concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with PE:EtOAc = 2/1) to give methyl 4- amino-5-iodo-2-methoxy-benzoate (21.0 g, 68.38 mmol, 57.62% yield, purity 93.78%) as a light yellow solid. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 308.0.

Step 2: Preparation of methyl 4-bromo-5-iodo-2-methoxy-benzoate

Int-27b

To a mixture of methyl 4-amino-5-iodo-2-methoxy-benzoate (2 g, 6.51 mmol) and copper (I) bromide (1.3 g, 9.12 mmol) in ACN (15 mL) cooled in an ice-water bath were added isoamyl nitrite (839.27 mg, 7.16 mmol). Then the mixture was stirred at 70 °C for 1 hour. After the reaction was completed, the reaction mixture was poured into water (40 mL) and the resulting suspension was extracted with EtOAc (30 mL) three times. The combined organic phase was washed with brine (20 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with PE/EtOAc = 10/1) to give methyl 4-bromo-5-iodo-2-methoxy-benzoate (1.5 g, 4.04 mmol, 57.74% yield, purity 83.31%) as a light yellow solid.

Step 3: Preparation of methyl 4-bromo-2-methoxy-5-(trifhioromethyl)benzoate

Int-27c To a solution of methyl 4-bromo-5-iodo-2-methoxy-benzoate (1.82 g, 4.91 mmol) in DMF (20 mL) were added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (1.88 g, 9.81 mmol) and iodocopper (1.86 g, 9.81 mmol) under N ₂ atmosphere . The mixture was then stirred at 85 °C for 6 hours. The reaction mixture was then filtered and the filtrate was diluted with water (lOOmL). The resulting suspension was extracted with EtOAc (80 mL) three times. The combined organic layer was washed by brine, dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with PE : EtOAc = 4:1) to give methyl 4-bromo-2-methoxy-5-(trifluoromethyl)benzoate (1.20 mg, 3.83 mmol, 68.75 % yield) as a light yellow solid. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 313.0.

Step 4: Preparation of [4-bromo-2-methoxy-5-(trifluoromethyl)phenyl]methanol

Int-27d

To a solution of methyl 4-bromo-2-methoxy-5-(trifluoromethyl)benzoate (1500.0 mg, 4.79 mmol) in TE1F (20 mL) was added DIBAL (2 mol/L in TE1F, 12 mL, 24 mmol) dropwise at -78 °C and the reaction was stirred at -78 °C for extra 2 hours after addition. After the reaction was completed, the reaction was quenched with NELCl solution (4 mL) and the resulting solution was stirred at room temperature for 10 minutes. The mixture was then diluted with water (40 mL) and extracted with EtOAc (50 mL) three times. The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo to give [4-bromo-2-methoxy-5- (trifluoromethyl)phenyl]methanol (1100 mg, 72.49% yield) as a light yellow solid.

Step 5: Preparation of 4-bromo-2-methoxy-5-(trifluoromethyl)benzaldehyde

Int-27e

To a solution of [4-bromo-2-methoxy-5-(trifluoromethyl)phenyl]methanol (120.0 mg, 0.420 mmol) in DCM (5 mL) cooled in an ice-water bath was added Dess-Martin periodinane (214.26 mg, 0.510 mmol) and the resulting mixture was stirred at room temperature for another 0.5 hour. After the reaction was completed, the reaction mixture was quenched with water (20mL) and then extracted with DCM (20 mL) three times, the combined organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give 4-bromo-2- methoxy-5-(trifluoromethyl)benzaldehyde (86 mg, 64.24% yield) as a light yellow solid.MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 283.0.

Step 6: Preparation of 2-[4-bromo-2-hydroxy-5-(trifluoromethyl)phenyl]-8-chloro- chromen-4-one

Int-27

Int-27 was prepared in analogy to the procedure described for the preparation of compound Int-1 by using 4-bromo-2-hydroxy-benzaldehyde as the starting material instead of 2- methoxy-4-(trifluoromethyl)benzaldehyde in Step 1. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 419.2.

Intermediate 28: 8-bromo-2-(2-hydroxyphenyl)chromen-4-one

Int-28

Int-28 was prepared in analogy to the procedure described for the preparation of compound Int-1 by using l-(3-bromo-2-hydroxy-phenyl)ethanone and 2-methoxybenzaldehyde as the starting materials instead of l-(3-chloro-2-hydroxy-phenyl)ethanone and 2-methoxy-4- (trifluoromethyl)benzaldehyde in Step 1. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 317.1.

Intermediate 29: 8-chloro-2-(4-ethyl-2-hydroxy-phenyl)chromen-4-one

Int-29 Int-29 was prepared in analogy to the procedure described for the preparation of compound Int-1 by using 4-ethyl-2-methoxy-benzaldehyde as the starting materials instead of 2- methoxy-4-(trifluoromethyl)benzaldehyde in Step 1. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 301.2.

Intermediate 30: 8-chloro-2-(2-hydroxy-4-isopropyl-phenyl)chromen-4-one

Int-30

Int-30 was prepared in analogy to the procedure described for the preparation of compound Int-1 by using 4-isopropyl-2-methoxy-benzaldehyde as the starting materials instead of 2-methoxy-4-(trifluoromethyl)benzaldehyde in Step 1. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 315.1. Intermediate 31: 8-chloro-2-(2-hydroxy-5-methyl-phenyl)chromen-4-one

Int-31

Int-31 was prepared in analogy to the procedure described for the preparation of compound Int-1 by using 2-methoxy-5-methyl-benzaldehyde as the starting materials instead of 2-methoxy-4-(trifluoromethyl)benzaldehyde in Step 1. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 287.1.

Intermediate 32: 8-chloro-2-(2-hydroxy-5-methoxy-phenyl)chromen-4-one

Int-32

Int-32 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 2-hydroxy-5-methoxy-benzaldehyde as the starting material instead of 4-chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 303.0. Intermediate 33: 8-chloro-2-(5-hydroxy-2,3-dihydrobenzofuran-6-yl)chromen-4-o ne

Int-33

Step 1: Preparation of 5-hydroxy-2,3-dihydrobenzofuran-6-carbaldehyde

Int-33a

Int-33a was prepared in analogy to the procedure described for the preparation of compound Int-5a by using 2,3-dihydrobenzofuran-5-ol as the starting material instead of 3- chloro-4-methyl-phenol in Step 1.

Step 2: Preparation of 8-chloro-2-(5-hydroxy-2,3-dihydrobenzofuran-6-yl)chromen-4-o ne

Int-33

Int-33 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 5-hydroxy-2,3-dihydrobenzofuran-6-carbaldehyde as the starting material instead of 4-chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2. MS obsd.

(ESI ⁺ )[(M+H) ⁺ ]: 314.9.

Intermediate 34: 2-(5-bromo-2-hydroxy-4-methoxy-phenyl)-8-chloro-chromen-4-on e

Int-34

Int-34 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 5-bromo-2-hydroxy-4-methoxybenzaldehyde as the starting material instead of 4-chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 381.1.

Intermediate 35: 8-chloro-2-(4-chloro-2-hydroxy-phenyl)chromen-4-one

Int-35

Int-35 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 4-chloro-2-hydroxy-benzaldehyde as the starting material instead of 4- chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 307.1.

Intermediate 36: 2-(5-bromo-2-hydroxy-phenyl)-8-chloro-chromen-4-one

Int-36

Int-36 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 5-bromo-2-hydroxy-benzaldehyde as the starting material instead of 4- chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 351.0.

Intermediate 37 : 2-(4-bromo-2-hydroxy-phenyl)-8-chloro-6-fluoro-chromen-4-one

Int-37

Step 1: Preparation of l-(3-chloro-5-fluoro-2-hydroxy-phenyl)ethanone Cl

Int-37a

Compound Int-37a was prepared in analogy to the procedure described for the preparation of compound Int-23b by using 2-chloro-4-fluoro-phenol as the starting materials instead of 3- bromo-2-chloro-phenol in Step 1.

Step 2: Preparation of 2-(4-bromo-2-hydroxy-phenyl)-8-chloro-6-fluoro-chromen-4-one

Int-37

Int-37 was prepared in analogy to the procedure described for the preparation of compound Int-1 by using l-(3-chloro-5-fluoro-2-hydroxy-phenyl)ethanone and 4-bromo-2- methoxy-benzaldehyde as the starting materials instead of l-(3-chloro-2-hydroxy- phenyl)ethanone and 2-methoxy-4-(trifluoromethyl)benzaldehyde in Step 1. MS obsd.

(ESI ⁺ )[(M+H) ⁺ ]: 369.1.

Intermediate 38: 8-chloro-2-(2-hydroxyphenyl)-7-methyl-chromen-4-one

Int-38

Step 1: Preparation of l-(3-chloro-2-hydroxy-4-methyl-phenyl)ethanone

Int-38a To a solution of l-(4-bromo-3-chloro-2-hydroxy-phenyl)ethanone (2.4 g, 9.62 mmol), trimethylboroxine (1449.06 mg, 11.54 mmol), potassium carbonate (3323.72 mg, 24.05 mmol) in l,4-dioxane (30 mL) and water (2 mL) was added Pd(dppf) ₂ Cl2 (791.39 mg, 0.960 mmol) under N ₂ atmosphere. The mixture was stirred at H0 °C for 5 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent with PE:EtOAc = 20: 1 to 3:1) to give l-(3-chloro-2-hydroxy-4-methyl- phenyl)ethanone (l.3g, 69.5% yield) as an off-white solid.MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 185.1. Step 2: Preparation of 8-chloro-2-(2-hydroxyphenyl)-7-methyl-chromen-4-one

Int-38

Int-38 was prepared in analogy to the procedure described for the preparation of compound Int-1 by using l-(3-chloro-2-hydroxy-4-methyl-phenyl)ethanone and 2-methoxybenzaldehyde as the starting materials instead of l-(3-chloro-2-hydroxy-phenyl)ethanone and 2-methoxy-4- (trifluoromethyl)benzaldehyde in Step 1. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 287.2. Intermediate 39: 2-(4-bromo-2-hydroxy-phenyl)-8-chloro-7-fluoro-chromen-4-one

Int-39

Step 1: Preparation of l-(3-chloro-4-fluoro-2-hydroxy-phenyl)ethanone

Int-39a Compound Int-39a was prepared in analogy to the procedure described for the preparation of compound Int-23b by using 2-chloro-3-fluoro-phenol as the starting materials instead of 3- bromo-2-chloro-phenol in Step 1.

Step 2: Preparation of 2-(4-bromo-2-hydroxy-phenyl)-8-chloro-7-fluoro-chromen-4-one

Int-39

Int-39 was prepared in analogy to the procedure described for the preparation of compound Int-1 by using l-(3-chloro-4-fluoro-2-hydroxy-phenyl)ethanone and 4-bromo-2- methoxy-benzaldehyde as the starting materials instead of l-(3-chloro-2-hydroxy- phenyl)ethanone and 2-methoxy-4-(trifluoromethyl)benzaldehyde in Step 1. MS obsd.

(ESI ⁺ )[(M+H) ⁺ ]: 369.2.

Intermediate 40: 2-(5-bromo-4-fluoro-2-hydroxy-phenyl)-8-chloro-chromen-4-one

Int-40

Int-40 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 5-bromo-4-fluoro-2-hydroxybenzaldehyde as the starting material instead of 4-chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 369.2.

Intermediate 41: 8-chloro-2-(5-fluoro-2-hydroxy-phenyl)chromen-4-one

Int-41

Int-41 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 5-fluoro-2-hydroxy-benzaldehyde as the starting material instead of 4- chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 291.1.

Intermediate 42: 8-chloro-2-(4-fluoro-2-hydroxy-phenyl)chromen-4-one

Int-42

Int-42 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 4-fluoro-2-hydroxy-benzaldehyde as the starting material instead of 4- chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 291.1.

Intermediate 43: 8-chloro-2-(4-ethoxy-2-hydroxy-phenyl)chromen-4-one

Int-43

Int-43 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 4-ethoxy-2-hydroxy-benzaldehyde as the starting material instead of 4- chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 317.2.

Intermediate 44: 8-chloro-6-fluoro-2-(2-hydroxyphenyl)chromen-4-one

Int-44

Int-44was prepared in analogy to the procedure described for the preparation of compound Int-1 by using l-(3-chloro-5-fluoro-2-hydroxy-phenyl)ethanone and 2-methoxybenzaldehyde as the starting materials instead of l-(3-chloro-2-hydroxy-phenyl)ethanone and 2-methoxy-4- (trifluoromethyl)benzaldehyde in Step 1. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 291.2.

Intermediate 45: 8-chloro-2-(3-fluoro-2-hydroxy-phenyl)chromen-4-one

Int-45

Int-45 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 3-fluoro-2-hydroxy-benzaldehyde as the starting material instead of 4- chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 291.1.

Intermediate 46: 2-(4-bromo-5-fluoro-2-hydroxy-phenyl)-8-chloro-chromen-4-one

Int-46

Int-46 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 4-bromo-5-fluoro-2-hydroxy-benzaldehyde as the starting material instead of 4-chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 369.2.

Intermediate 47 : 8-chloro-6-fluoro-2-(4-fluoro-2-hydroxy-phenyl)chromen-4-one

Int-47

Int-47 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 4-fluoro-2-hydroxy-benzaldehyde as the starting material instead of 4- chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2 and using l-(3-chloro-5-fluoro-2-hydroxy- phenyl)ethanone as the starting materials instead of l-(3-chloro-2-hydroxy-phenyl)ethanone in Step 3. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 309.1.

Intermediate 48: 2-(2-hydroxyphenyl)-8-(trifluoromethyl)chromen-4-one

Int-48

Step 1: Preparation of l-[2-fluoro-3-(trifluoromethyl)phenyl]-3-(2- methoxyphenyl)propane-l,3-dione

Int-48a

To a solution of 2-fluoro-3-(trifluoromethyl)benzoic acid (208 mg, 999 mihoΐ) in DCM (15 ml) was added oxalyl chloride (254 mg, 175 mΐ, 2 mmol) and the mixture was then stirred at room temperature for 3 hours. The mixture was then concentrated in vacuo to give the crude 2- fluoro-3-(trifluoromethyl)benzoyl chloride, which was then dissolved in THF (2 mL).

To a solution of l-(2-methoxyphenyl)ethan-l-one (225 mg, 1.5 mmol) in THF (15 ml) cooled at 0°C was added LiHMDS (3 ml, 3 mmol) and the mixture was stirred at room temperature for 30 minutes. Then to the resulting solution was added 2-fluoro-3- (trifluoromethyl)benzoyl chloride solution prepared above. The mixture was then stirred at room temperature. The mixture was concentrated in vacuo to give the crude l-[2-fluoro-3- (trifluoromethyl)phenyl]-3-(2-methoxyphenyl)propane-l,3-dion e (340 mg, 100% yield), which was used in the next step directly without further purification. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 341.1.

Step 2: Preparation of 2-(2-methoxyphenyl)-8-(trifluoromethyl)chromen-4-one

Int-48b

To a solution of l-[2-fluoro-3-(trifluoromethyl)phenyl]-3-(2-methoxyphenyl)pr opane-l,3- dione (340 mg, 999 pmol) in DMF (3 mL) was added K ₂ CO ₃ (414 mg, 3 mmol) and the mixture was then stirred at l00°C under microwave condition for 30minutes. The mixture was then quenched with 4N HC1 (4 mL) and water (20 mL), the resulting mixture was extracted with EtOAc (30 mL) three times. The combined organic layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel to give 2-(2-methoxyphenyl)-8- (trifluoromethyl)chromen-4-one (270 mg, 84.4% yield ) as a yellow solid. MS obsd.

(ESI ⁺ )[(M+H) ⁺ ]: 321.2.

Step 3: Preparation of 2-(2-hydroxyphenyl)-8-(trifluoromethyl)chromen-4-one

Int-48

Int-48 was prepared in analogy to the procedure described for the preparation of compound Int-1 by using 2-(2-methoxyphenyl)-8-(trifluoromethyl)chromen-4-one as the starting material instead of 8-chloro-2-[2-methoxy-4-(trifluoromethyl)phenyl]chromen-4-on e in Step 3. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 307.1.

Intermediate 49: 2-(4-bromo-2-hydroxy-phenyl)-8-chloro-7-(trifluoromethyl)chr omen-4- one

Int-49 Step 1: preparation of l-[4-bromo-3-chloro-2-[(4- methoxyphenyl)methoxy]phenyl]ethanone

Int-49a

To a solution of l-(4-bromo-3-chloro-2-hydroxy-phenyl)ethanone (1800.0 mg, 7.21 mmol) in DMF (15 mL) were added potassium carbonate (2.16 mL, 18.04 mmol) and 4- methoxybenzylchloride (0.98 mL, 7.21 mmol) at room temperature. The mixture was stirred at

80 °C for 2 hours. The mixture was the quenched with water (50 mL) and extracted with EtOAc

(150 mL) three times. The combined organic layer was washed with brine (80 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent with PE:EtOAc 100:1 to 10:1) to give l-[4-bromo-3-chloro-2-[(4- methoxyphenyl)methoxy]phenyl]ethanone (1800 mg, 67.5% yield) as a light yellow solid. MS obsd. (ESI ⁺ ) [(M+Na) ⁺ ]: 391.0.

Step 2: preparation of l-[3-chloro-2-[(4-methoxyphenyl)methoxy]-4- (trifluoromethyl)phenyl]ethanone

Int-49b

To a solution of l-[4-bromo-3-chloro-2-[(4-methoxyphenyl)methoxy]phenyl]ethan one (1500.0 mg, 4.06 mmol) in DMF (8 mL) were added Cul (3864.23 mg, 20.29 mmol) and methyl 2,2-difluoro-2-fluorosulfinyl-acetate (3573.27 mg, 20.29 mmol) at room temperature. The mixture was stirred at H0 °C for 18 hours. The mixture was then quenched with water (100 mL) and extracted with EtOAc (130 mL) three times. The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent with PE:EtOAc = 100:1 to 15 :l) to give l-[3-chloro-2-[(4- methoxyphenyl)methoxy]-4-(trifluoromethyl)phenyl]ethanone (700 mg, 1.95 mmol) as a light yellow solid.

Step 3: preparation of l-[3-chloro-2-hydroxy-4-(trifluoromethyl)phenyl]ethanone

Int-49c

A solution of l-[3-chloro-2-[(4-methoxyphenyl)methoxy]-4- (trifluoromethyl)phenyl]ethanone (700.0 mg, 1.95 mmol) in trifluoro acetic acid (2.8 mL, 36.34 mmol) was stirred at 120 °C for 1.5 hours. The mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluent with PE:EtOAc = 100:1 to 4 :1) to give l-[3-chloro-2-hydroxy-4-(trifluoromethyl)phenyl]ethanone (360 mg, 75.78 % yield) as colorless liquid. MS obsd. (EST)[(M-H) ]: 236.9.

Step 4: preparation of 2-(4-bromo-2-hydroxy-phenyl)-8-chloro-7- (trifluoromethyl)chromen-4-one

Int-49

Int-49 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 4-bromo-2-hydroxy-benzaldehyde as the starting material instead of 4- chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2 and using l-[3-chloro-2-hydroxy-4- (trifluoromethyl)phenyl]ethanone as the starting materials instead of l-(3-chloro-2-hydroxy- phenyl)ethanone in Step 3. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 419.1.

Intermediate 50: 2-(4-bromo-2-hydroxy-phenyl)-8-chloro-5-(trifluoromethyl)chr omen-4- one

Int-50

Step 1: preparation of l-(6-bromo-3-chloro-2-hydroxy-phenyl)ethanone

Int-50a

Compound Int-50a was prepared in analogy to the procedure described for the preparation of compound Int-23b by using 5-bromo-2-chloro-phenol as the starting materials instead of 3- bromo-2-chloro-phenol in Step 1.

Step 2: preparation of l-[3-chloro-2-hydroxy-6-(trifluoromethyl)phenyl]ethanone

Int-50b

Compound Int-50b was prepared in analogy to the procedure described for the preparation of compound Int-49c by using l-(6-bromo-3-chloro-2-hydroxy-phenyl)ethanone as the starting materials instead of l-(4-bromo-3-chloro-2-hydroxy-phenyl)ethanone in Step 1.

Step 3: preparation of 2-(4-bromo-2-hydroxy-phenyl)-8-chloro-5- (trifluoromethyl)chromen-4-one

Int-50

Int-50 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 4-bromo-2-hydroxy-benzaldehyde as the starting material instead of 4- chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2 and using l-[3-chloro-2-hydroxy-6- (trifluoromethyl)phenyl]ethanone as the starting materials instead of l-(3-chloro-2-hydroxy- phenyl)ethanone in Step 3. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 419.0.

Intermediate 51:8-chloro-2-(5-ethoxy-2-hydroxy-phenyl)chromen-4-one

Int-51

Int-51 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 5-ethoxy-2-hydroxy-benzaldehyde as the starting material instead of 4- chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 317.2.

Intermediate 52: 2-(5-bromo-2-hydroxy-phenyl)-8-chloro-6-fluoro-chromen-4-one

Int-52

Int-52 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 5-bromo-2-hydroxy-benzaldehyde as the starting material instead of 4- chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2 and using l-(3-chloro-5-fluoro-2-hydroxy- phenyl)ethanone as the starting materials instead of l-(3-chloro-2-hydroxy-phenyl)ethanone in Step 3. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 369.1.

Intermediate 53: 2-(5-bromo-2-hydroxy-phenyl)-8-chloro-7-fluoro-chromen-4-one

Int-53

Int-53 was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 5-bromo-2-hydroxy-benzaldehyde as the starting material instead of 4- chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2 and using l-(3-chloro-4-fluoro-2-hydroxy- phenyl)ethanone as the starting materials instead of l-(3-chloro-2-hydroxy-phenyl)ethanone in Step 3. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 369.1.

Intermediate 54: 2-(4-bromo-5-chloro-2-hydroxy-phenyl)-8-chloro-chromen-4-one

Int-54

Step 1 : preparation of methyl 4-amino-5-chloro-2-methoxy-benzoate

Int-54a

To a solution of 4-amino-5-chloro-2-methoxybenzoic acid (2.0 g, 9.92 mmol) in methanol (50 mL) was added SOCT (23.6 g, 198.4 mmol) dropwise and the resulting solution was stirred at 60 °C for 16 hours. The mixture was then concentrated in vacuo to give the crude methyl 4- amino-5-chloro-2-methoxy-benzoate (3.5 g, 98.17% yield) as a yellow solid, which was used in the next step directly without further purification. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 216.1.

Step 2: preparation of methyl 4-bromo-5-chloro-2-methoxy-benzoate

Int-54b

To a solution of methyl 4-amino-5-chloro-2-methoxy-benzoate (3.3 g, 15.3 mmol) in hydrobromic acid (74.29 g, 918.24 mmol) cooled at 0 °C was added a solution of sodium nitrite (1.16 g, 16.83 mmol) in water (20 mL) slowly. After addition, the solution was stirred at 0 °C for 1 hour. To the resulting solution was added CuBr (3.07 g, 21.43 mmol) and the mixture was stirred at 25 °C for 2 hours. The mixture was then diluted with water (100 mL) and extracted with EtOAc (100 mL) twice. The combined organic phase was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluted with PE:EtOAc = 4:1) to give methyl 4-bromo-5-chloro-2-methoxy-benzoate (1.8 g, 37.87% yield) as a yellow solid.

Step 3: preparation of (4-bromo-5-chloro-2-methoxy-phenyl)methanol

Int-54c

To a solution of methyl 4-bromo-5-chloro-2-methoxy-benzoate (1.0 g, 3.58 mmol) in THF (20 mL) cooled at -78 °C was added LiAlEL* (271.89 mg, 7.16 mmol) and the mixture was stirred at -78 °C for 2 hours. After the reaction was completed, to the resulting mixture was added water (0.5 mL), 10 % NaOH aqueous solution (0.5 mL) and water (1.5 mL) in sequence. The resulting mixture was filtered and the filtrate was concentrated in vacuo to give (4-bromo-5-chloro-2- methoxy-phenyl)methanol (1.5 g, 100 % yield) as a yellow solid, which was used in the next step directly without further purification.

Step 4: preparation of 4-bromo-5-chloro-2-methoxy-benzaldehyde

Int-54d

To a solution of (4-bromo-5-chloro-2-methoxy-phenyl)methanol (1.5 g, 5.96 mmol) in DCM (30 mL) was added MnCL (5.19 g, 59.64 mmol, 10 eq) and the mixture was stirred at 25 °C for 16 hours. The mixture was then filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent with PE:DCM = 1: 1) to give 4-bromo-5-chloro-2-methoxy-benzaldehyde (625 mg, 37.8 % yield,) as a white solid. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 249.0.

Step 5: preparation of 2-(4-bromo-5-chloro-2-hydroxy-phenyl)-8-chloro-chromen-4-one

Int-54

Int-54 was prepared in analogy to the procedure described for the preparation of compound Int-1 by using 4-bromo-5-chloro-2-methoxy-benzaldehyde as the starting material instead of 2-methoxy-4-(trifluoromethyl)benzaldehyde in Step 1. MS obsd. (ESI ⁺ )

[(M+H) ⁺ ]:385.l.

Intermediate 55: 8-chloro-7-cyclopropyl-2-(2-hydroxyphenyl)chromen-4-one

Int-55

Step 1 : Preparation of l-(3-chloro-4-cyclopropyl-2-hydroxy-phenyl)ethanone

Int-55a

To a solution of l-(4-bromo-3-chloro-2-hydroxy-phenyl)ethanone (1000.0 mg, 4.01 mmol), CS2CO3 (2611.89 mg, 8.02 mmol), potassium cyclopropyltrifluoroborate (2372.52 mg, 16.03 mmol) in l,4-dioxane (30 mL) and water (2 mL) was added Pd(dppf)2Cl2 (2932.78 mg, 4.01 mmol) under N2 atmosphere. The mixture was stirred at 110 °C for 5 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with PE:EtOAc = 20:1 to 3:1) to give l-(3-chloro-4- cyclopropyl-2-hydroxy-phenyl)ethanone (560 mg, 66.32% yield). MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 211.1.

Step 2: Preparation of 8-chloro-7-cyclopropyl-2-(2-hydroxyphenyl)chromen-4-one

Int-55

Int-55 was prepared in analogy to the procedure described for the preparation of compound Int-1 by using l-(3-chloro-4-cyclopropyl-2-hydroxy-phenyl)ethanone and 2- methoxybenzaldehyde as the starting materials instead of l-(3-chloro-2-hydroxy- phenyl)ethanone and 2-methoxy-4-(trifluoromethyl)benzaldehyde in Step 1. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:3l3.2.

Intermediate Al: l-(3-chloro-2-hydroxy-4-methoxy-phenyl)ethanone

Int-Al

Compound Int-Al was prepared in analogy to the procedure described for the preparation of compound Int-23b by using 2-chloro-3-methoxy-phenol as the starting materials instead of 3- bromo-2-chloro-phenol in Step 1.

Intermediate A2: l-(3-chloro-2-hydroxy-5-methoxy-phenyl)ethanone

Int-A2

Compound Int-A2 was prepared in analogy to the procedure described for the preparation of compound Int-23b by using 2-chloro-4-methoxy-phenol as the starting materials instead of 3- bromo-2-chloro-phenol in Step 1.

Intermediate Tl: methyl 3-[2-(p-tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate

Int-Tl

Step 1: Preparation of 2-benzyloxyethoxy(trimethyl)silane

Int-Tla

To a solution of 2-benzyloxyethanol (20.0 g, 131.4 mmol) and TEA (20.0 g, 197.1 mmol) in dichloro methane (200 mL) cooled at 0 °C was added trimethylsilyl chloride (17.1 g, 157.7 mmol) and the mixture was then stirred at 25 °C for 16 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluted with PE:EtOAc=50:l to 10:1) to give the 2- benzyloxyethoxy(trimethyl)silane (25.0 g, 84.9%) as a colorless oil.

Step 2: Preparation of methyl 3-(2-benzyloxyethoxy)cyclobutanecarboxylate

Int-Tlb

To a solution of 2-benzyloxyethoxy(trimethyl)silane (25.0 g, 111.4 mmol) and methyl 3- oxocyclobutanecarboxylate (CAS #: 4934-99-0, Cat.#: PB01390, from PharmaBlock (Nan./ing) R&D Co. Ltd, 15.0 g, 117.0 mmol) in dichloro methane (200 mL) was added trimethylsilyl trifluoromethanesulfonate (12.4 g, 55.7 mmol) dropwise at -78 °C. After addition, the mixture was stirred at -78 °C for additional 1 hour, then to the resulting mixture was added triethylsilane (14.25 g, 122.57 mmol). After addition, the resulting mixture was warmed to room temperature and stirred for additional 1 hour. After the reaction was completed, the mixture was washed with saturated NH ₄ CI solution, brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elution with

PE/EtOAc=100: 1-50:1) to give methyl 3-(2-benzyloxyethoxy)cyclobutanecarboxylate (28 g, 95.1%) as a colorless oil. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 265.1. Step 3: Preparation of methyl 3-(2-hydroxyethoxy)cyclobutanecarboxylate

Int-Tlc

To a solution of methyl 3-(2-benzyloxyethoxy)cyclobutanecarboxylate (28.0 g, 105.9 mmol) in MeOH (300.0 mL) was added Pd(OH) ₂ (wet) (1.48 g, 10.6 mmol) at room temperature and the mixture was then hydrogenated under 1 L atmosphere at room temperature overnight. After the reaction was completed, the reaction was filtered through silica gel pad and the filtrate was concentrated in vacuo to give 18 g crude methyl 3-(2- hydroxyethoxy)cyclobutanecarboxylate (18 g, 97.6%) as a colorless oil.

Step 4: Preparation of methyl 3-[2-(p-tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate

Int-Tl

To a solution of methyl 3-(2-hydroxyethoxy)cyclobutanecarboxylate (5 g, 28.7 mmol) and DMAP (5.26 g, 43.1 mmol) in dichloromethane (80 mL) was added 4-methylbenzene-l-sulfonyl chloride (6.02 g, 31.6 mmol) at room temperature and the mixture was then stirred at room temperature overnight. After the reaction was completed, the mixture was washed with 1N HC1 (25 mL), water (l5mL), saturated NaHCCL solution, brine and concentrated in vacuo to give the crude methyl 3-[2-(p-tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate (8.1 g, 85.6%) as a colorless oil, which was used in next step directly without further purification. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 329.2.

Intermediate T2: methyl 3-[3-(p-tolylsulfonyloxy)propoxy]cyclobutanecarboxylate

Int-T2 Int-T2 was prepared in analogy to the procedure described for the preparation of compound Int-Tl by using 3-benzyloxypropan-l-ol as the starting material instead of 2- benzyloxyethanol in Step 1. MS obsd. (ESI ⁺ ) [(M+H) ¹ ]: 343.1.

Intermediate T3: tert- butyl 2-[3-(p-tolylsulfonyloxy)propoxy]acetate

Int-T3

Step 1: Preparation of tert-butyl 2-(3-(benzyloxy)propoxy)acetate

Int-T3a

To a mixture of NaOH (10M, 300.0 ml .), ferf-butyl 2-bromoacetate (23.5 g, 120.3 mmol) and tetrabutylammonium iodide (8.8 g, 24.06 mmol) in DCM (300 mL) was added 3- benzyloxypropan-l-ol (12.99 mL, 120.32 mmol) at 30 °C and the mixture was stirred at 30 °C for 72 hours. After the reaction was completed, the organic phase was separated out and the aquatic phase was extracted with DCM (150 mL) twice. The combined organic layer was washed with brine, dried over MgS0 ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent with PE: EtOAc = 3:1) to give ferf-butyl 2-(3- (benzyloxy)propoxy)acetate (21.3g, 63.3% yield) as a colorless liquid. MS obsd. (ESI ⁺ )

[(M+Na) ⁺ ]: 303.2.

Step 2: Preparation of tert-butyl 2-[3-(p-tolylsulfonyloxy)propoxy]acetate

Int-T3

Int-T3 was prepared in analogy to the procedure described for the preparation of compound Int-Tl by using ferf-butyl 2-(3-(benzyloxy)propoxy)acetate as the starting material instead of methyl 3-(2-benzyloxyethoxy)cyclobutanecarboxylate in Step 3. MS obsd. (ESI ⁺ ) [(M+H) ¹ ]: 345.0.

Intermediate T4: methyl 2-[2-(p-tolylsulfonyloxy)ethoxy]acetate

Int-T4

Int-T4 was prepared in analogy to the procedure described for the preparation of compound Int-T3 by using 2-benzyloxyethanol and methyl 2-bromoacetate as the starting material instead of 3-benzyloxypropan-l-ol and tert- butyl bromoacetate in Step 1. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 289.1.

Intermediate T5: methyl 3-[2-(p-tolylsulfonyloxy)ethoxy]cyclopentanecarboxylate

Int-T5

Int-T5 was prepared in analogy to the procedure described for the preparation of compound Int-Tl by using methyl 3-oxocyclobutanecarboxylate as the starting material instead of methyl 3-oxocyclopentanecarboxylate in Step 2. MS obsd. (ESI ⁺ ) [(M+H) ¹ ]: 343.0.

Intermediate T6: methyl 3-[3-(p-tolylsulfonyloxy)propoxy]cyclopentanecarboxylate

Int-T6

Int-T6 was prepared in analogy to the procedure described for the preparation of compound Int-Tl by using 3-benzyloxypropan-l-ol as the starting material instead of 2- benzyloxy ethanol in Step 1 and using methyl 3-oxocyclobutanecarboxylate as the starting material instead of methyl 3-oxocyclopentanecarboxylate in Step 2. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 357.1.

Intermediate T7: methyl 2,2-dimethyl-3-(p-tolylsulfonyloxy)propanoate

Int-T7

Int-T7 was prepared in analogy to the procedure described for the preparation of compound Int-Tl by using methyl 3-hydroxy-2,2-dimethyl-propanoate as the starting material instead of methyl 3-(2-hydroxyethoxy)cyclobutanecarboxylate in Step 4. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 287.1.

Intermediate T8: methyl 3-(p-tolylsulfonyloxymethyl)cyclobutanecarboxylate

Int-T8

Int-T8 was prepared in analogy to the procedure described for the preparation of compound Int-Tl by using methyl 3-(hydroxymethyl)cyclobutanecarboxylate as the starting material instead of methyl 3-(2-hydroxyethoxy)cyclobutanecarboxylate in Step 4. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 299.2.

Intermediate T9: methyl 3-(p-tolylsulfonyloxy)cyclopentanecarboxylate

Int-T9

Int-T9 was prepared in analogy to the procedure described for the preparation of compound Int-Tl by using methyl 3-hydroxycyclopentanecarboxylate as the starting material instead of methyl 3-(2-hydroxyethoxy)cyclobutanecarboxylate in Step 4. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 299.2.

Intermediate T10: methyl 4-(p-tolylsulfonyloxy)cyclohexanecarboxylate

Int-TIO Int-TIO was prepared in analogy to the procedure described for the preparation of compound Int-Tl by using methyl 4-hydroxycyclohexanecarboxylate as the starting material instead of methyl 3-(2-hydroxyethoxy)cyclobutanecarboxylate in Step 4. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 313.1.

Intermediate Til: cis-tert- butyl 3-[2-(p-tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate

Int-Tl 1

Step 1: preparation of cis-tert-buty\ 3-(2-benzyloxyethoxy)cyclobutanecarboxylate

Int-Tl la

To a solution of trifluoromethanesulfonic anhydride (27.8 g, 98.56 mmol) and 2,6-lutidine (11.48 mL, 98.56 mmol) in DCM (100 mL) cooled at -30°C was added 2-(benzyloxy)ethanol (10.0 g, 65.71 mmol) and the reaction mixture was stirred at -30 °C for 1 hour. The reaction mixture was washed with brine (30ml) twice and the organic layer was concentrated in vacuo to give the crude 2-(benzyloxy)ethyl trifluoromethanesulfonate (18.7 g) as yellow oil.

To a solution of cis-tert- butyl 3-hydroxycyclobutanecarboxylate (CAS #: 939768-64-6, Cat.#: B253665, from BePharm Ltd., 11.3g, 65.71 mmol) in THF (150 mL) cooled at 0 °C was added NaH (3942.44 mg, 98.56 mmol) and the mixture was stirred at room temperature for 1 hour. To the resulting solution was added 2-(benzyloxy)ethyl trifluoromethanesulfonate (18.7 g, previously prepared) and the mixture was stirred at room temperature for 2 hours. The reaction was then quenched with ice water (100 mL) and the resulting reaction was extracted with EtOAc (200 mL) twice. The combined organic layer was dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent with PE:EtOAc 100:1 to 2:1) to give cis-tert- butyl 3-(2-benzyloxyethoxy)cyclobutanecarboxylate (10.0 g, 49.67% yield) as a yellow oil. 1H NMR (CDCfs, 400MHz): d ppm 1.44 (s, 9H), 2.17 (m, 2H), 2.54 - 2.42

(m, 3H), 3.55 - 3.50 (m, 2H), 3.62 - 3.57 (m, 2H), 3.99 - 3.83 (m, 1H), 4.57 (s, 2H), 7.30 - 7.27 (m, 1H), 7.34 (d, J= 4.3 Hz, 4H). MS obsd. (ESI ⁺ ) [(M+Na) ⁺ ]: 329.1. Step 2: preparation of cis-tert-buty\ 3-[2-(p-tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate

Int-Tll

Int-Tll was prepared in analogy to the procedure described for the preparation of compound Int-Tl by using cis-tert- butyl 3-(2-benzyloxyethoxy)cyclobutanecarboxylate as the starting material instead of methyl 3-(2-benzyloxyethoxy)cyclobutanecarboxylate in Step 3. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 371.2.

Intermediate Prol: Ol-tert-butyl 02-methyl (2/?,4S)-4-(p-tolylsulfonyloxy)pyrrolidine-l,2- dicarboxylate

Int-Prol

Int-Prol is commercially available from TCI Shanghai, CAS #: 88043-21-4, Cat.#: B5247.

Intermediate Pro2: Ol-tert-butyl 02-methyl (2.S,4.S)-4-(p-tolylsulfonyloxy)pyrrolidine- l,2- dicarboxylate

Int-Pro2

Int-Pro2 was prepared in analogy to the procedure described for the preparation of compound Int-Tl by using Ol-ferf-butyl 02-methyl (2.S',4.S')-4-hydroxypyrrolidinc- 1 ,2- dicarboxylate (CAS #: 102195-79-9, Cat.#: PB02365, from PharmaBlock (Nanjing) R&D Co. Ltd) as the starting material instead of methyl 3-(2-hydroxyethoxy)cyclobutanecarboxylate in Step 4. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 400.1. Intermediate Pro3: Ol-tert-butyl 02-methyl (2R,4R)-4-(p-tolylsulfonyloxy)pyrrolidine- l,2- dicarboxylate

Int-Pro3

Int-Pro3 was prepared in analogy to the procedure described for the preparation of compound Int-Tl by using Ol-ferf-butyl 02-methyl (2R,4R)-4-hydroxypyrrolidine-l,2- dicarboxylate (CAS #: 114676-69-6, Cat.#: PB06230, from PharmaBlock (Nanjing) R&D Co. Ltd) as the starting material instead of methyl 3-(2-hydroxyethoxy)cyclobutanecarboxylate in Step 4. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 400.1.

Intermediate Pro4: Ol-tert-butyl 02-methyl (2.S,4/i)-4-(p-tolylsulfonyloxy)pyrrolidine- l,2- dicarboxylate

Int-Pro4

Int-Pro4 was prepared in analogy to the procedure described for the preparation of compound Int-Tl by using Ol-ferf-butyl 02-methyl (2.S',4/^)-4-hydroxypyrrolidinc- 1 ,2- dicarboxylate (CAS #: 74844-91-0, Cat.#: PB02363, from PharmaBlock (Nanjing) R&D Co. Ltd) as the starting material instead of methyl 3-(2-hydroxyethoxy)cyclobutanecarboxylate in Step 4. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 400.1.

Example A001: 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]propanoic acid

A001

Step 1: preparation of 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoic acid

To a solution of 8-chloro-2-[2-hydroxy-4-(trifluoromethyl)phenyl]chromen-4-on e (Int-1, 0.37 g, 1.09 mmol, as the“CORE” in Table 1) in DMF (8 mL) was added NaH (26.1 mg, 1.09 mmol) and the mixture was stirred at 60 °C for 10 minutes. Then to the resulting suspension was added oxetan-2-one (115 mg, 100 mΐ, 1.6 mmol) dropwise and the reaction mixture was stirred at 60 °C for 4 hours. After the reaction was completed, the reaction was adjusted to pH~4 by addition of 4N HC1 and extracted with EtOAc (30 mL) three times. The combined organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by Prep-HPLC to give 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoic acid (61 mg, 12.9 % yield) as a yellow solid. ¹ 11 NMR (DMSO-ife, 400MHz): d ppm 12.35-12.55 (m, 1H), 8.15 (d, 7=7.9 Hz, 1H), 7.99-8.06 (m, 2H), 7.57-7.63 (m, 2H), 7.52 (t, 7=7.9 Hz, 1H), 7.04-7.10 (m, 1H), 4.47 (t, 7=5.8 Hz, 2H), 2.81 (t, 7=5.8 Hz, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ j: 413.1.

Example A002: methyl 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoate

A002

To a solution of 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoic acid (9.0 g, 21.81 mmol, crude prepared above) in methanol (90 mL) was added thionyl chloride (4.75 mL, 65.42 mmol). Then the mixture was stirred at 40

°C for 2 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was diluted with water (40 mL). The resulting suspension was extracted with EtOAc (50 mL) three times. The combined organic layer was washed with brine (50 mL), dried with MgS0 ₄ and concentrated in vacuo. The residue was then purified by column chromatography on silica gel (eluted with PE:EtOAc = 2:1) to give methyl 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-

(trifluoromethyl)phenoxy]propanoate (5.3 g, 56.95% yield) as a yellow solid. ¹ 11 NMR (DMSO- d ₆ , 400MHz): d ppm 8.15 (d, 7=8.1 Hz, 1H), 7.99-8.05 (m, 2H), 7.57-7.64 (m, 2H), 7.52 (t, 7=7.9 Hz, 1H), 6.96-7.01 (m, 1H), 4.50 (t, 7=5.7 Hz, 2H), 3.62 (s, 3H), 2.89 (s, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 427.0.

Example A003: 3-[2-(8-chloro-6-fluoro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoic acid

A003

Step 1: Preparation of 3-[2-formyl-5-(trifluoromethyl)phenoxy]propanoic acid

A003a

To a solution of NaOH (315 mg, 7.9 mmol) in water (10 mL) was added 3-bromopropionic acid (1.27 g, 7.9 mmol) and the mixture was stirred at r.t. for 30 minutes. The resulting mixture was added into a mixture of 2-hydroxy-4-(trifluoromethyl)benzaldehyde (l500mg, 7.9 mmol, as the“SM1” in Table 2) and NaOH (315 mg, 7.9 mmol)in water (10 mL) at l00°C dropwise and the mixture was stirred at l00°C for another 30 minutes. After the reaction was completed, the mixture was diluted with water (30 mL) and adjusted to pH~2 by addition of 1N hydrochloric acid. The resulting solution was extracted with EtOAc (30 mL) three times. The combined organic layer was washed with brine (30 mL) twice, dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent with PE: EtOAc = 3:1) to give 3-[2-formyl-5-(trifluoromethyl)phenoxy]propanoic acid (600 mg, yield 29%) as a white solid. MS obsd. (ESI ⁺ ) [(M+H) ⁺ j: 263.1.

Step 2: Preparation of 3-[2-[(£')-3-(3-chloro-5-fluoro-2-hydroxy-phenyl)-3-oxo-pro p-l- enyl]-5-(trifluoromethyl)phenoxy]propanoic acid

A003b

To a solution of 3-[2-formyl-5-(trifluoromethyl)phenoxy]propanoic acid (230.0 mg, 0.870 mmol) and l-(3-chloro-5-fluoro-2-hydroxy-phenyl)ethanone (165.0 mg, 0.85mmol, as the “SM2” in Table 2) in ethanol (10 mL) was added KOH (492.0 mg, 8.7 mmol). The mixture was stirred at 35°C for 16 hours. After the reaction was completed, the reaction mixture was diluted with water (50 mL) and acidified to pH~l.O by addition of 1N HC1. The resulting suspension was filtered. The solid was collected and dried in vacuo to give the crude 3- [ 2- [ ( T')-3-( 3-chloro- 5-fluoro-2-hydroxy-phenyl)-3-oxo-prop-l-enyl]-5-(trifluorome thyl)phenoxy]propanoic acid (200.0 mg, 52.6% yield) as a yellow solid, which was used in the next step directly. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:433.0.

Step 3: Preparation of 3-[2-(8-chloro-6-fluoro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoic acid

A003

To a solution of 3-[2-[(£ ^' )-3-(3-chloro-5-fluoro-2-hydroxy-phenyl)-3-oxo-prop-l- enyl]-5- (trifluoromethyl)phenoxy]propanoic acid (150.0 mg, 0.34 mmol) in DMSO (3 mL) was added iodine (4 mg, 0.05 mmol). Then the mixture was stirred at 140 °C for 3 hours. After the reaction was completed, the mixture was poured into water (50 mL). The resulting suspension was filtred and the filtered cake was washed with water (50 mL) twice. The filtered cake was then collected, triturated with EtOAc (20 mL) and the resulting suspension was then filtered to give 3-[2-(8- chloro-6-fluoro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)pheno xy]propanoic acid (30.2 mg, 19.2% yield) as a yellow solid. NMR (DMSO-tfe, 400MHz): d ppm 12.28-12.58 (m, 1H),

8.08-8.19 (m, 2H), 7.71-7.79 (m, 1H), 7.54-7.63 (m, 2H), 7.00-7.10 (m, 1H), 4.46 (t, J = 5.9 Hz, 2H), 2.80 (t, J = 5.7 Hz, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:43l.O.

The following Example A004 to Example A026 were prepared in analogy to the procedure described for the preparation of Example A001, replacing 8-chloro-2-[2-hydroxy-4-

(trifluoromethyl)phenyl]chromen-4-one (Int-1) with“CORE” by the reagent indicated in Table

1.

Table 1: Compounds synthesis and characterization

The following Example A031 to Example A040 were prepared in analogy to the procedure described for the preparation of Example A003, replacing 2-hydroxy-4- (trifluoromethyl)benzaldehyde with“SMI” in step 1, and replacing l-(3-chloro-5-fluoro-2- hydroxy-phenyl)ethanone with“SM2” in step2. The“SMI” and“SM2” are the reagents indicated in Table 2.

Table 2: Compounds synthesis and characterization

phenoxy]propanoate

A038

Example A038 was prepared in analogy to the procedure described for the preparation of

Example A002 by using 3-[5-chloro-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl- phcnoxy Ipropanoic acid (Example A005) as the starting material instead of 3-[2-(8-chloro-4- oxo-chromen-2-yl)-5-(trifluoromethyl)phenoxy]propanoic acid (Example A001). ¹ 11 NMR (DMSO-ife, 400MHz): d ppm. 7.93-8.08 (m, 2H), 7.79-7.91 (m, 1H), 7.45-7.58 (m, 1H), 7.30- 7.45 (m, 1H), 6.83-6.97 (m, 1H), 4.39 (m, 2H), 3.63 (s, 3H), 2.87 (m, 2H), 2.35 (s, 3H). MS obsd.

(ESI ⁺ ) [(M+H) ⁺ ]:407.0.

Example A039: 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]butanoic acid and Example A040: 3-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]butanoyloxy]butanoic acid

A039 and A040

To a solution of 8-chloro-2-[2-hydroxy-4-(trifluoromethyl)phenyl]chromen-4-on e (Int-1, 0.37 g, 1.09 mmol) in DMF (8 mL) was added NaH (26.1 mg, 1.09 mmol) and the mixture was stirred at 60 °C for 10 minutes. Then to the resulting suspension was dropwise added 4- methyloxetan-2-one (115 mg, 100 mΐ, 1.6 mmol) dropwise and the reaction mixture was stirred at 60 °C for 4 hours. After the reaction was completed, the reaction was adjusted to pH~4 by addition of 4N HC1 and extracted with EtOAc (30 mL) three times. The combined organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by Prep-HPLC to give 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]butanoic acid (l5.8mg, 2.4 % yield) and 3-[3-[2-(8-chloro-4-oxo- chromen-2-yl)-5-(trifluoromethyl)phenoxy]butanoyloxy]butanoi c acid (5.5 mg, 0.7% yield) as yellow solid.

Example A039: 1H NMR (DMSO-tfe, 400MHz): d ppm. 8.06-8.15 (m, 1H), 7.99-8.05 (m, 2H), 7.54-7.68 (m, 3H), 7.03 (s, 1H), 5.17 (q, 1H, 7=6.2 Hz), 2.71 (d, 2H, 7=6.2 Hz), 1.38 (d, 3H, 7=6.1 Hz). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:427.4.

Example A040: 1H NMR (DMSO-tfe, 400MHz): d ppm 8.12 (d, 7 = 7.7 Hz, 1H), 8.02 (dq,

7 = 7.9, 1.3 Hz, 2H), 7.61-7.65 (m, 1H), 7.56 (d, 7 = 8.2 Hz, 1H), 7.52 (t, 7 = 7.9 Hz, 1H), 7.00 (s,

1H), 5.19 (br d, 7 = 6.1 Hz, 1H), 5.04 (d, 7 = 6.4 Hz, 1H), 2.75 (d, 7 = 6.4 Hz, 2H), 2.43 (d, 7 =

6.6 Hz, 2H), 1.38 (d, 7 = 6.1 Hz, 3H), 1.05 (d, 7 = 6.4 Hz, 3H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:5l3.4.

Example A041: [2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-5-(2,2,2- trifluoroethoxy)phenoxy]propanoic acid

Step 1: Preparation of 2,4-dihydroxy- 5-methoxy-benzaldehyde

A041a Compound A041a was prepared in analogy to the procedure described for the preparation of compound Int-5a by using 4-methoxybenzene-l,3-diol as the starting material instead of 3- chloro-4-methyl-phenol in Step 1.

Step 2: Preparation of 2-hydroxy-5-methoxy-4-(2,2,2-trifluoroethoxy)benzaldehyde

A041b

To a solution of 2,4-dihydroxy-5-methoxy-benzaldehyde (1300.0 mg, 7.73 mmol) in DMF (15 mL) was added Sodium bicarbonate (779.4 mg, 9.28 mmol) and 2,2,2-trifluoroethyl trifluoromethanesulfonate (0.92 mL, 7.73 mmol) and the mixture was stirred at 85 °C for 24 hours. After the reaction was completed, the reaction mixture was quenched with water (100 mL) and the resulting mixture was extracted with EtOAc (50 mL) three times. The combined organic layer was washed with brine (50 mL) twice, dried over MgS04 and then concentrated in vacuo. The residue was then purified by column chromatography on silica gel (eluent with PE : EtOAc = 5: 1) to give 2-hydroxy-5-methoxy-4-(2,2,2-trifluoroethoxy)benzaldehyde (880 mg, 45.5% yield) as a light yellow solid. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:25l.O.

Step 3: Preparation of 3-[2-fomiyl-4-methoxy-5-(2,2,2-trifluoroethoxy)phenoxy]propa noic acid

A041c

To a solution of 2-hydroxy-5-methoxy-4-(2,2,2-trifluoroethoxy)benzaldehyde (800.0 mg, 3.2 mmol) in DMF (10 mL) was added sodium hydride (84.42 mg, 3.52 mmol) and the mixture was stirred at 25 °C for 30 minutes. Then to the resulting solution was added beta-propiolactone (230.44 mg, 3.2 mmol) and the mixture was stirred at 25 °C for 16 hours. After the reaction was completed, the reaction was quenched with water (100 mL) and the resulting mixture was adjusted to pEl~2 with 1N hydrochloric acid. The resulting solution was then extracted with EtOAc (50 mL) three times. The combined organic layer was washed with brine (50 mL) twice, dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by Prep-HPLC to give 3- [2-formyl-4-methoxy-5-(2,2,2-trifluoroethoxy)phenoxy]propano ic acid (270 mg, 26.2% yield) as a white solid. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 323.1.

Step 4: Preparation of 3-[2-[(£')-3-(3-chloro-2-hydroxy-phenyl)-3-oxo-prop-l-enyl] -4- methoxy-5-(2,2,2-trifluoroethoxy)phenoxy]propanoic acid

A041d

To a solution of 3-[2-formyl-4-methoxy-5-(2,2,2-trifluoroethoxy)phenoxy]propa noic acid (270.0 mg, 0.840 mmol) and l-(3-chloro-2-hydroxy-phenyl)ethanone (142.94 mg, 0.840 mmol) in ethanol (10 mL) was added KOH (470.11 mg, 8.38 mmol) and the mixture was stirred at 35°C for 16 hours. After the reaction was completed, the reaction mixture was diluted with water (50 mL) and acidified to pH 1.0 by addition of IN HC1. The resulting suspension was filtered and solid was washed with water. The cake was collected and dried in vacuo to give the crude 3-[2- |(/7)-3-(3-chloro-2-hydroxy-phenyl)-3-oxo-prop- 1 -enyl ]-4-mcthoxy-5-(2,2,2- trifluoroethoxy)phenoxy]propanoic acid (280 mg, 70.38% yield) as an orange solid, which was used in the next step directly. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:475.1.

Step 5: Preparation of 3-[2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-5-(2,2,2- trifluoroethoxy)phenoxy]propanoic acid

A041

To a solution of 3-|2-|(/7)-3-(3-chloro-2-hydroxy-phenyl)-3-oxo-prop- 1 -enyl]-4-methoxy- 5-(2,2,2-trifluoroethoxy)phenoxy]propanoic acid (230.0 mg, 0.480 mmol) in DMSO (3 mL) was added iodine (8.61 mg, 0.030 mmol). Then the mixture was stirred at 140 °C for 3 hours. After the reaction was completed, the mixture was poured into water (50 mL) and the resulting suspension was filtrate, the filtered cake was washed with water (50 mL) twice. The filtered cake was then collected, triturated with EtOAc (20 mL) and the resulting suspension was then filtered to give 3-[2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-5-(2,2,2- trifluoroethoxy)phenoxy]propanoic acid (116.4 mg, 50.82% yield) as a yellow solid. ¹ 11 NMR (DMSO-ife, 400MHz): d ppm 12.38-12.53 (m, 1H), 7.92-8.04 (m, 2H), 7.58-7.70 (m, 1H), 7.40- 7.53 (m, 1H), 7.06 (s, 2H), 4.88-5.03 (m, 2H), 4.38 (t, J = 5.8 Hz, 2H), 3.74-3.93 (m, 3H), 2.74- 2.88 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:473.0.

Example A042: 3-[2-[8-chloro-4-oxo-7-(trifhioromethyl)chromen-2-yl]-5- (trifluoromethoxy)phenoxy]propanoic acid

Step 1: Preparation of methyl 3-[2-(7-bromo-8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethoxy)phenoxy]propanoate

A042a

To a solution of 3-[2-(7-bromo-8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethoxy)phenoxy]propanoic acid (Example A023, 600 mg, 1.18 mmol) in methanol (8 mL) was added SOCT (1.64 g, 1 mL, 13.8 mmol) at room temperature and the resulting mixture was stirred at 25 °C for 4 hours. After the reaction was completed, the reaction was adjusted to pH~4 by addition of 4N HC1 and then extracted with EtOAc (50 mL) three times. The combined organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by Prep-HPLC to give methyl 3-[2-(7-bromo-8-chloro-4-oxo-chromen- 2-yl)-5-(trifluoromethoxy)phenoxy]propanoate (100 mg, 16.2 % yield) as a white foam . MS obsd. (ESI ⁺ ) [(M+H) ⁺ j: 521.1.

Step 2: Preparation of methyl 3-[2-[8-chloro-4-oxo-7-(trifhioromethyl)chromen-2-yl]-5- (trifhioromethoxy)phenoxy]propanoate

A042b

To a solution of methyl 3-[2-(7-bromo-8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethoxy)phenoxy]propanoate (100 mg, 192 pmol) and copper (I) iodide (110 mg, 575 pmol) in DMF (2 mL) was added methyl 2,2-difluoro-2-(fluorosulfonyl)acetate (368 mg, 246 pL, 1.92 mmol) at room temperature and the resulting mixture was stirred at 105 °C for 4 hours.

After the reaction was completed, the reaction was adjusted to pH~4 by addition of 4N HC1 and then extracted with EtOAc (50 mL) three times. The combined organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent with PE : EtOAc = 10:1 to 3:1) to give methyl 3-[2- [8-chloro-4-oxo-7-(trifluoromethyl)chromen-2-yl]-5-(trifluor omethoxy)phenoxy]propanoate (40 mg, 40.9 % yield) as a white foam. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:5ll.l.

Step 3: Preparation of 3-[2-[8-chloro-4-oxo-7-(trifluoromethyl)chromen-2-yl]-5- (trifluoromethoxy)phenoxy]propanoic acid

To a solution of methyl 3-(2-(8-chloro-4-oxo-7-(trifluoromethyl)-4H-chromen-2-yl)-5- (trifluoromethoxy)phenoxy)propanoate (50 mg, 97.9 pmol) in the mixed solvent of THF (5 mL) and water (5 mL) was added 3.0 M HC1 (261 pL, 783 pmol) at room temperature and the mixture was then stirred at 60 °C for 2 hours. After the reaction was completed, the mixture was extracted with EtOAc (10 mL) three times. The combined organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by Prep- HPLC to give 3-[2-[8-chloro-4-oxo-7-(trifluoromethyl)chromen-2-yl]-5- (trifluoromethoxy)phenoxy]propanoic acid (7 mg, 113.7 % yield) as a white foam. ¹ 11 NMR (DMSO-ife, 400MHz): d ppm 8.09-8.20 (m, 2H), 7.83-7.98 (m, 1H), 7.31-7.41 (m, 1H), 7.22- 7.30 (m, 1H), 7.10 (s, 1H), 4.34-4.45 (m, 2H), 2.74-2.85 (m, 2H). MS obsd. (ESI ⁺ )

[(M+H) ⁺ ]:497.l. Example A043: 3-[2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-5- (trifluoromethyl)phenoxy]propanoic acid

A043

Example A043 was prepared in analogy to the procedure described for the preparation of example A042 by using 3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy- phcnoxy Ipropanoic acid (Example A007) as the starting material instead of 3-[2-(7-bromo-8- chloro-4-oxo-chromen-2-yl)-5-(trifluoromethoxy)phenoxy]propa noic acid (Example A023) in step 1. 1H NMR (DMSO-rfe, 400MHz): d ppm 7.99-8.05 (m, 3H), 7.74-7.82 (m, 1H), 7.46-7.57 (m, 2H), 7.06-7.12 (m, 1H), 4.33-4.43 (m, 2H), 3.95 (s, 3H), 2.70-2.80 (m, 2H). MS obsd. (ESI ⁺ )

[(M+H) ⁺ ]:443.l.

Example A044: 3-[2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl-5- (trifluoromethyl)phenoxy]propanoic acid

A044

Example A044 was prepared in analogy to the procedure described for the preparation of example A042 by using 3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methyl- phenoxy Ipropanoic acid (Example A006) as the starting material instead of 3-[2-(7-bromo-8- chloro-4-oxo-chromen-2-yl)-5-(trifluoromethoxy)phenoxy]propa noic acid (Example A023) in Step 1. 1H NMR (DMSO-tfe, 400MHz): d ppm7.98-8.08 (m, 2H), 7.90-7.98 (m, 1H), 7.47-7.55 (m, 2H), 7.04 (s, 1H), 4.37-4.47 (m, 2H), 2.74-2.84 (m, 2H), 2.48 (s, 3H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:427.l.

Example A045: 3-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoic acid

A045

Step 1: Preparation of l-(3-chloro-2,6-dihydroxy-phenyl)ethanone

A045a

A mixture of l-(2,6-dihydroxyphenyl)ethan-l-one (5.0 g, 32.9 mmol), l-chloropyrrolidine- 2,5-dione (5.27 g, 39.4 mmol) in acetic acid (25 mL) was stirred at 50 °C for 2 hours. After the reaction was completed, the mixture was concentrated in vacuo, the residue was triturated with EtOAc (15 mL) and the suspension was then filtered. The filtrate was concentrated in vacuo, the residue was purified by column chromatography on silica gel (eluent with PE: EtOAc= 100:1 to 3: 1) to give l-(3-chloro-2,6-dihydroxy-phenyl)ethanone (5.0 g, 81.5% yield) as a yellow solid. Step 2: Preparation of l-[3-chloro-2,6-bis(methoxymethoxy)phenyl]ethanone

A045b

To a solution of l-(3-chloro-2,6-dihydroxy-phenyl)ethanone (500.0 mg, 2.68 mmol) in

THF (10 mL) cooled at 0°C was added sodium hydride (321.56 mg, 8.04 mmol) and the mixture was stirred at 0°C for 20 minutes Then to the resulting solution was added bromomethyl methyl ether (0.66 mL, 8.04 mmol) and the mixture stirred at room temperature for another 30 minutes. After the reaction was completed, the reaction was quenched with water (20 mL) and extracted with EtOAc (50 mL) twice. The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with PE:EtOAc = 100:1 to 10 :l) to give l-[3-chloro-2,6- bis(methoxymethoxy)phenyl]ethanone (400 mg, 53.4% yield) as an off-white solid.

Step 3: Preparation of 3-[2-[(£')-3-[3-chloro-2,6-bis(methoxymethoxy)phenyl]-3-oxo -prop- l-enyl]-5-(trifluoromethyl)phenoxy]propanoic acid

A045c

To a solution of l-[3-chloro-2,6-bis(methoxymethoxy)phenyl]ethanone (83.1 mg, 0.3mmol) and 3-[2-formyl-5-(trifluoromethyl)phenoxy]propanoic acid (80 mg, 0.3 mmol) in ethanol (5 mL) was added KOH (171 mg, 3.05 mmol) and the mixture was then stirred at 40 °C for 16 hours. After the reaction was completed, the mixture was diluted with water (20 mL) and adjusted to pH~6 by addition of 1N HC1. The resulting mixture was extracted with EtOAc (20 mL) three times. The combined organic layer was washed with brine (20 mL) twice, dried over Na ₂ S0 ₄ and concentrated in vacuo to give 3- 12- 1 (/T)-3- 13 -chloro- 2,6-h is( mcthoxymcthoxy)phcnyl ]-3-oxo- prop-l-enyl]-5-(trifluoromethyl)phenoxy]propanoic acid (150 mg, 97.4% yield) as an orange oil. Step 4: Preparation of 3-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoic acid

To a solution of 3-[2-[(/7)-3-[3-chloro-2,6-his( mcthoxymcthoxy)phcnyl]-3-oxo-prop- 1 - enyl]-5-(trifluoromethyl)phenoxy]propanoic acid (150 mg, 0.29 mmol) in DMSO (8 ml) was added I ₂ (5.1 mg, 0.02 mmol) and the mixture was stirred at 140 °C for 2 hours. After the reaction was completed, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL) three times. The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by Prep-HPLC to give 3-[2-(8-chloro-5- hydroxy-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenoxy]propa noic acid (39.3 mg, 37.1 % yield) as a yellow solid. 1H NMR (DMSO-ife, 400MHz): d ppm. 12.53 (s, 1H), 8.11-8.19 (m, 1H), 7.83-7.91 (m, 1H), 7.58-7.65 (m, 2H), 7.14 (s, 1H), 6.89 (d, J = 8.8 Hz, 1H), 4.48 (t, J = 5.8 Hz, 2H), 2.81 (t, J = 5.8 Hz, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:429.0.

Example A046: 3-[2-(8-chloro-3-hydroxy-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoic acid

A046

Step 1: Preparation of 3-[2-[(£')-3-(3-chloro-2-hydroxy-phenyl)-3-oxo-prop-l-enyl] -5- (trifluoromethyl)phenoxy]propanoic acid

A046a

Compound A046a was prepared in analogy to the procedure described for the preparation of example A003b by using l-(3-chloro-2-hydroxy-phenyl)ethanone as the starting material instead of l-(3-chloro-5-fluoro-2-hydroxy-phenyl)ethanone in step 2.

Step 2: Preparation of 3-[2-(8-chloro-3-hydroxy-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoic acid

To a solution of 3-|2-|(/7)-3-(3-chloro-2-hydroxy-phenyl)-3-oxo-prop- 1 -cnyl]-5- (trifluoromethyl)phenoxy]propanoic acid (100 mg, 240 pmol) in dioxane (3 mL) was added diethylamine (52.3 mg, 0.7 mmol) and I OC WO.S mL, 30%) at room temperature and the reaction was then stirred at room temperature for 2hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was purified by Prep-HPLC to give 3-[2-(8-chloro-3- hydroxy-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenoxy]propa noic acid (70 mg, 22.5 % yield) as a white solid. 1H NMR (DMSO-ife, 400MHz): d ppm 12.21-12.31 (m, 1H), 8.09 (dd, 7 = 8.0, 1.5 Hz, 1H), 8.01 (dd, 7 = 7.8, 1.5 Hz, 1H), 7.79 (d, 7 = 7.6 Hz, 1H), 7.58-7.61 (m, 1H), 7.48- 7.55 (m, 2H), 4.39 (t, 7 = 6.1 Hz, 2H), 2.62 (t, 7 = 6.1 Hz, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 429.1. Example A047: 3-[2-(8-chloro-3-methoxy-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoic acid

A047

Step 1: Preparation of methyl 3-[2-(8-chloro-3-methoxy-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoate

A047a

To a solution of 3-[2-(8-chloro-3-hydroxy-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoic acid (Example A046, 70.0 mg, 0.16 mmol) and cesium carbonate (150 mg, 0.49 mmol) in DMF (5 mL) was added iodomethane (75 mg, 0.48 mmol) and the mixture was stirred at 40 °C for 2 hours. After the reaction was completed, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (20 mL) three times. The combined organic layer was washed with brine (20 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent with PE: EtOAc = 3:1) to give methyl 3-[2-(8-chloro-3-methoxy-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoate (50 mg, 57.4% yield) as a yellow oil. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:457.1. Step 2: Preparation of 3-[2-(8-chloro-3-methoxy-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoic acid

A047

A mixture of methyl 3-[2-(8-chloro-3-methoxy-4-oxo-chromen-2-yl)-5-

(trifluoromethyl)phenoxy]propanoate (50 mg, 57.4% yield) in hydrochloric acid (36%~38%) was stirred at 100 °C for 2 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was purified by Prep-HPLC to give 3-[2-(8-chloro-3- methoxy-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenoxy]propa noic acid (21.6 mg, 45.7% yield) as a white solid. NMR (DMSO-ife, 400MHz): d ppm 12.24-12.32 (m, 1H), 8.07-8.12 (m, 1H), 8.01 (dd, 7 = 7.8, 1.5 Hz, 1H), 7.76-7.81 (m, 1H), 7.58-7.61 (m, 1H), 7.51 (s, 2H), 4.39 (t, J = 6.1 Hz, 2H), 3.75 (s, 3H), 2.62 (t, J = 6.1 Hz, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:443.l. Example A048: 2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethoxy)pheno xy]acetic acid

A048

Step 1: Preparation of methyl 2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethoxy)phenoxy]acetate

A048 To a solution of 8-chloro-2-[2-hydroxy-4-(trifluoromethoxy)phenyl]chromen-4-o ne (Int-9, 1.2 g, 3.36 mmol, as the“CORE” in Table 3) and methyl 2-bromoacetate (772 mg, 5.05 mmol, as the“SM3” in Table 3) in DMF (10 mL) was added K ₂ C0 ₃ (1.39 g, 10.1 mmol) and the mixture was stirred at 50 °C overnight. After the reaction was completed, the reaction mixture was diluted with water (20 mL) and adjusted to PH~4 by addition of 4N HC1. The resulting suspension was extracted with EtOAc (30 ml) three times. The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with PE : EtOAc = 100: 1 to 3 : 1) to give methyl 2- [2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethoxy)phenoxy ]acetate (1.0 g, 69.3 % yield) as a yellow solid.MS obsd. (ESI ⁺ ) [(M+H) ⁺ j: 429.1.

Step 2: Preparation of 2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethoxy)phenoxy]acetic acid

A048

To a mixture solution of methyl 2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethoxy)phenoxy]acetate (1.0 g, 2.33 mmol) in THF (5 ml) and water (5 ml) was added LiOH (335 mg, 14 mmol) and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was adjusted to pH~4 by addition of 4N HC1 and then extracted with EtOAc (50 mL) three times. The combined organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by Prep-HPLC to give 2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethoxy)pheno xy]acetic acid (700 mg, 72.4 % yield) as a white foam. 1H NMR (DMSO-ife, 400MHz): d ppm 8.08-8.18 (m, 1H), 7.96-8.05 (m, 2H), 7.46-7.57 (m, 1H), 7.31-7.37 (m, 1H), 7.21-7.31 (m, 2H), 5.07 (s, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:4l5.l.

The following Example A049 to Example A072 were prepared in analogy to the procedure described for the preparation of Example A048, replacing 8-chloro-2-[2-hydroxy-4- (trifluoromethoxy)phenyl]chromen-4-one (Int-9) with“CORE”, and replacing methyl 2- bromoacetate with“SM3” in stepl. The“CORE” and“SM3” are the reagent indicated in Table

3.

Table 3. Compounds synthesis and characterization

Example A074: 3-[[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]acetyl]amino]cyclobutanecarboxylic acid

A074

Step 1: Preparation of methyl 3-[[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]acetyl]amino]cyclobutanecarboxylate

A074a

To a solution of 2- [2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenoxy] acetic acid (Example A051, 200.0 mg, 0.5 mmol), methyl 3-aminocyclobutanecarboxylate (77.8 mg, 0.60 mmol ) and DIPEA (0.25 mL, 1.42 mmol) in DMF (5 mL) was added HATU (269.26 mg, 0.710 mmol) and the reaction mixture was stirred at room temperature for 2 hours. After reaction was completed, the reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL) three times. The combined organic layer was washed with brine (40 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent with PE:EtOAc = 1:1) to afford methyl 3-[[2-[2-(8-chloro-4-oxo-chromen-2- yl)-5-(trifluoromethyl)phenoxy]acetyl]amino]cyclobutanecarbo xylate ( 150 mg, 58.1% yield) as a light yellow oil. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 510.0.

Step 2: Preparation of 3-[[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]acetyl]amino]cyclobutanecarboxylic acid

A074

To a solution of methyl 3-[[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]acetyl]amino]cyclobutanecarboxylate ( 150.0 mg, 0.29 mmol) in a mixed solvent of THF (8 mL) and water (2mL) was added lithium hydroxide (44 mg, 2.0 mmol) and the mixture was stirred at 25 °C for 2 hours. After the reaction was completed, the mixture was adjusted to pH~3 by addition of HC1 (1 M). The resulting suspension was then filtered and the solid was collected to give 3-[[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]acetyl]amino]cyclobutanecarboxylic acid (114.7 mg, 58.09% yield) as a white solid. (DMSO-ife, 400MHz): d ppm 11.99-12.28 (br s, 1H), 8.44-8.52 (m, 1H), 8.16 (d, / = 7.9 Hz, 1H), 8.03 (d, / = 7.9 Hz, 2H), 7.61 (dd, / = 8.1, 0.7 Hz, 1H), 7.52 (t, / = 7.9 Hz, 1H), 7.39-7.44 (m, 1H), 7.27 (s, 1H), 4.77-4.88 (m, 2H), 4.11-4.26 (m, 1H), 2.66-2.80 (m, 1H), 2.33-2.42 (m, 2H), 1.99-2.11 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ j: 496.0.

Example A075: (2/?)-l-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]propanoyl]pyrrolidine-2-carboxylic acid

A075

Step 1: Preparation of tert-butyl (2/?)-l-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]propanoyl]pyrrolidine-2-carboxylate

A075a

To a solution of 3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]propanoic acid (Example A004, 200.0 mg, 0.470 mmol, as the“EX” in Table 4 ), ferf-butyl (2R)-pyrrolidine-2- carboxylate (121.26 mg, 0.710 mmol, as the“AMINE” in Table 4) and DIPEA (0.25 mL, 1.42 mmol) in DMF (5 mL) was added HATU (269.26 mg, 0.710 mmol) and the reaction mixture was stirred at room temperature for 2 hours. After reaction was completed, the reaction was quenched with water (30 mL) and extracted with EtOAc (30 mL) three times. The combined organic layer was washed with brine (40 mb), dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with PE: EtOAc = 1:1) to afford tert- butyl (2R)-l-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]pr opanoyl]pyrrolidine-2- carboxylate (200 mg, 73.44% yield) as a light yellow oil. MS obsd. (ESI ⁺ ) [(M+H) ¹ ]: 576.0.

Step 2: Preparation of (2/?)-l-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]propanoyl]pyrrolidine-2-carboxylic acid

A075

To a solution of ferf-butyl (2R)~ 1 -|3-|5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]propanoyl]pyrrolidine-2-carboxylate (200.0 mg, 0.350 mmol) in DCM (2 mL) was added TFA (2.0 mL, 25.96 mmol) and the mixture was then stirred at room temperature for 4 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was purified by Prep-HPLC to give ( 2R)~ 1 -| 3-| 5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]propanoyl]pyrrolidine-2-carboxylic acid (85.1 mg, 46.97% yield) as a white solid. ppm 12.38 (s, 1H), 7.99-8.01 (m, 2H), 7.88 (d, / = 8.5 Hz, 1H), 7.46- 7.54 (m, 2H), 7.43 (d, J = 8.4 Hz, 1H), 6.98 (d, / = 8.7 Hz, 1H), 4.37-4.49 (m, 2H), 4.26 (dd, 7 = 8.9, 3.3 Hz, 1H), 3.50-3.61 (m, 2H), 3.39-3.46 (m, 1H), 2.87-2.92 (m, 1H), 2.74 (dt, 7 = 7.4, 4.5 Hz, 1H), 2.09-2.15 (m, 1H), 1.81-1.92 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 520.0.

The following Example A076to Example A083 were prepared in analogy to the procedure described for the preparation of Example A075, replacing 3-[5-bromo-2-(8-chloro-4-oxo- chromen-2-yl)phenoxy]propanoic acid (Example A004) with“EX”, ferf-butyl (2R)-pyrrolidine- 2-carboxylate“AMINE” in stepl. The“EX” and“AMINE” are the reagents indicated in Table 4.

Table 4: Compounds synthesis and characterization

Example A084: 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]-b cyclopropylsulfonyl-propanamide

A084

To a solution of methyl 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoate (Example A002, 1450.0 mg, 3.4 mmol) and

cyclopropanesulfonamide (617.48 mg, 5.1 mmol) in l,2-dichloroethane (100 mL) cooled at 0 °C was added titanium tetrachloride (1611.15 mg, 8.49 mmol). After addition, the mixture was stirred at 110 °C for 16 hours. After the reaction was completed, the reaction was quenched by pour into ice water (50 mL) and the resulting solution was extracted with EtOAc (50 mL) three times. The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was then purified by column chromatography on silica gel (PE:EtOAc = 2: 1) to give the crude 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]-N- cyclopropylsulfonyl-propanamide, which was further purified by Prep-HPLC to afford 3-[2-(8- chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenoxy]- N-cyclopropylsulfonyl-propanamide as a white solid. NMR (DMSO-ife, 400MHz): d ppm 11.87 (s, 1H), 8.16 (d, 7 = 7.9 Hz, 1H), 8.02 (td, J = 7.6, 1.5 Hz, 2H), 7.56-7.64 (m, 2H), 7.46-7.55 (m, 1H), 7.03 (s, 1H), 4.46-4.55 (m,

2H), 2.93-2.99 (m, 1H), 2.86-2.93 (m, 2H), 0.90-1.10 (m, 4H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:5l6.l. Example A085: 3-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dimethoxy-phenoxy]-N- cyclopropylsulfonyl-propanamide

Stepl: preparation of methyl 3-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dimethoxy- phenoxy]propanoate

A085a

Example A038 was prepared in analogy to the procedure described for the preparation of Example A002 by using 3-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dimethoxy-phenoxy]pro panoic acid (Example A010) as the starting material instead of 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoic acid (Example A001).

Stepl: preparation of 3-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dimethoxy-phenoxy]-N- cyclopropylsulfonyl-propanamide

Example A085 was prepared in analogy to the procedure described for the preparation of example A084 by using methyl 3-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dimethoxy- phe no x y ] pro pano ate as the starting material instead of methyl 3-[2-(8-chloro-4-oxo-chromen-2- yl)-5-(trifluoromethyl)phenoxy]propanoate. ¹ H NMR (DMSO-ife, 400MHz): d ppm 11.81-11.96 (br s, 1H), 7.96-8.04 (m, 2H), 7.60 (s, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.03 (s, 1H), 6.91 (s, 1H), 4.43 (t, J = 5.7 Hz, 2H), 3.90-3.98 (m, 3H), 3.73-3.86 (m, 3H), 2.94-3.02 (m, 1H), 2.79-2.95 (m, 2H), 0.92-1.10 (m, 4H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:508.0.

Example A086: 2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]-N-(2- hydroxyethyl)acetamide

A086

To a solution of 2- [2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenoxy] acetic acid (Example A051, 93.0 mg, 0.230 mmol, as the“EX” in Table 5), 2-hydroxyethylamine (0.03 mL, 0.470 mmol, as the“AMINE” in Table 5), DIPEA (0.12 mL, 0.700 mmol) in DMF (8 mL) was added HATU(l33.0 mg, 0.350 mmol) and the mixture was stirred at room temperature for 18 hours. After the reaction was completed, the reaction was diluted with water (20 mL) and extracted with EtOAc (30 mL) three times. The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by Prep-HPLC to give 2- [2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenoxy] -N-(2-hydroxyethyl)acetamide (59 mg, 0.130 mmol, 56.11% yield) as a white solid. ¹ H NMR (DMSO-tfe, 400MHz): d ppm 8.11-8.20 (m, 2H), 7.99-8.05 (m, 2H), 7.61 (dd, J = 8.1, 1.0 Hz, 1H), 7.52 (s, 1H), 7.44-7.47 (m, 1H), 7.26-7.29 (m, 1H), 4.84-4.90 (m, 2H), 4.60-4.73 (m, 1H), 3.42 (s, 2H), 3.15-3.21 (m, 2H). MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 442.0.

The following Example A087 to A083 were prepared in analogy to the procedure described for the preparation of Example A086, replacing 2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy] acetic acid (Example A051) with“EX”, 2-hydroxyethylamine with “AMINE” in by the reagent indicated in Table 5.

Table 5: Compounds synthesis and characterization

Example A095: (2S)-2-amino-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoic acid

Step 1 : Preparation of methyl (25)-2-amino-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoate

A095a

To a solution of 8-chloro-2-[2-hydroxy-4-(trifluoromethyl)phenyl]chromen-4-on e (Int-1, 1000 mg, 2.94 mmol), methyl trityl-L-serinate (1.27 g, 3.52 mmol) and triphenylphosphine (1.92 g, 7.34 mmol) in THF (10 ml) was added DIAD (1.19 g, 1.14 ml, 5.87 mmol) and the mixture was then stirred at room temperature overnight. The mixture was then diluted with water (30 mL) - Isanti extracted with EtOAc (30 mL) three times. The combined organic layer was washed with 1 N HC1 (20 mL), brine (20 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo.

The residue was dissolved in DCM (20 mL) and to the resulting solution was added TFA (3 mL). The mixture was then stirred at room temperature for 2hours. The mixture was then concentrated in vacuo and the residue was triturated with EtOAc (30 mL). The suspension was then filtered and the solid was collected to give methyl (2.V)-2-amino-3-|2-(8-chloro-4-oxo- chromen-2-yl)-5-(trifluoromethyl)phenoxy]propanoate (1.1 g, 80% yield) as a white solid. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 442.1.

Step 2: Preparation of (2S)-2-amino-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoic acid

To a solution of methyl (2.S')-2-amino-3-[2-(8-chloro-4-oxo-chromcn-2-yl)-5- (trifluoromethyl)phenoxy]propanoate (500 mg, 1.13 mmol) in the mixed solvent of THF (10 ml) and water (1 ml) was added LiOH (27.1 mg, 1.13 mmol). The mixture was then stirred at room temperature for 2 hours. The reaction was then quenched by addition of AcOH (1 mL) and the resulting suspension was filtered. The solid was collected and suspended in a mixed solvent of EtOAc (10 mL) and water (10 mL). The suspension was then filtered. The solid was collected and dried in vacuo to give (2.S')-2-amino-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propanoic acid (200 mg, 39.2% yield) as a white solid. ¹ 11 NMR

(DMSO-ife, 400MHz): d ppm 7.98 (m, 4H), 7.67 (s, 1H), 7.48-7.62 (m, 2H), 7.08 (s, 1H), 4.61- 4.69 (m, 1H), 4.41-4.49 (m, 1H), 3.69 (m, 1H), 3.44 (s, 3H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 428.3. Example A096: (2.S)-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl) phenoxy]-2- (cyclopropylsulfonylamino)propanoic acid

To a solution of (2.S')-2-aniino-3-[2-(8-chloro-4-oxo-chronicn-2-yl)-5- (trifluoromethyl)phenoxy]propanoic acid (40 mg, 93.5 pmol) and TEA (284 mg, 2.81 mmol) in the DCM (10 mL) was added cyclopropanesulfonyl chloride (263 mg, 1.87 mmol) and the mixture was then stirred at room temperature overnight. The mixture was then adjusted to pH~5.0 by addition of AcOH. The resulting mixture was washed with water (10 mL), brine, dreid over MgS0 ₄ and then concentrated in vacuo. The residue was then purified by Prep-HPLC to give (2.S')-3-[ 2-(8-chlora-4-oxo-chromcn-2-yl)-5-(trinuoro methyl )phcnoxy] -2- (cyclopropylsulfonylamino)propanoic acid (11 mg, 21.7% yield) as a white solid. ¹ 11 NMR (DMSO-ife, 400MHz): d ppm 8.11-8.16 (m, 1H), 7.99-8.07 (m, 2H), 7.72-7.85 (m, 1H), 7.57- 7.67 (m, 2H), 7.48-7.55 (m, 1H), 7.05-7.13 (m, 1H), 4.45-4.57 (m, 2H), 4.30-4.41 (m, 1H), 2.58- 2.62 (m, 1H), 0.71-0.96 (m, 4H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ j: 532.1.

Example A097: (2,S)-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl) phenoxy]-2-(p- tolylsulfonylamino)propanoic acid

A097

Example A097 was prepared in analogy to the procedure described for the preparation of example A096 by using 4-methylbenzenesulfonyl chloride as the starting material instead of clopropanesulfonyl chloride. NMR (l)MSO- _< %. 400MHz): d ppm 8.09 (d, J = 8.3 Hz, 1H), 8.03 (d, 7 = 7.8 Hz, 2H), 7.54-7.63 (m, 3H), 7.48-7.54 (m, 1H), 7.44-7.48 (m, 1H), 7.15-7.19 (m, 2H), 7.01-7.06 (m, 1H), 4.39-4.47 (m, 1H), 4.29-4.38 (m, 1H), 4.03-4.12 (m, 1H), 2.21-2.27 (s, 3H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:583.3. Example A098: methyl (2S)-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]-2-(ethylsulfamoylamino)propanoate

A098

To a solution of methyl (2.S')-2-aniino-3-[2-(8-chloro-4-oxo-chronicn-2-yl)-5-

(trifluoromethyl)phenoxy]propanoate (200 mg, 0.45 mmol) and TEA (202 mg, 2 2mol) in DCM (10 mL) was added ethylsulfamoyl chloride (143 mg, lmmol) and the mixture was then stirred at room temperature for 2 hours. The mixture was then diluted with EtOAc (50 mL) and the resulting solution was washed with water (15 mL), brine (15 mL), dried over Na ₂ S04. The organic layer was then concentrated in vacuo and the residue was purified by column

chromatography on silica gel (eluent with PE:EtOAc 10:1 to 3: 1) to give methyl (2S)-3-[2-(8- chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenoxy]-2-(et hylsulfamoylamino)propanoate (120 mg, 45.9 % yield) as a white solid. 1H NMR (DMSO-ife, 400MHz): d ppm 8.13 (d, 7 = 7.8 Hz, 1H), 8.03 (d, 7 = 7.8 Hz, 2H), 7.71-7.76 (m, 1H), 7.59-7.65 (m, 2H), 7.52 (t, 7 = 7.9 Hz, 1H), 7.00 (s, 1H), 6.95 (t, 7 = 5.7 Hz, 1H), 4.51-4.56 (m, 1H), 4.43-4.49 (m, 1H), 4.25-4.32 (m, 1H), 3.64 (s, 3H), 2.77-2.86 (m, 2H), 0.97 (t, 7 = 7.2 Hz, 3H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:549.l. Example A099: (2S)-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)p henoxy]-2- (ethylsulfamoylamino)propanoic acid

A099 To a solution of methyl (2S)-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]-2-(ethylsulfamoylamino)propanoate (160 mg, 291 pmol) in DCE (15 mL) was added trimethylstannanol (158 mg, 874 pmol) and the mixture was then stirred at 90 °C for 10 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was dissolved with 4 N HC1 (20 mL). The mixture was then extracted with EtOAc (20 mL) three times. The combined organic layer was concentrated in vacuo and the residue was purified by Prep-HPLC to give (2S)-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]-2-(ethylsulfamoylamino)propanoic acid (43.5 mg, 26.5% yield) as a white solid. 1H NMR (DMSO-rfc, 400MHz): d ppm 8.13 (d, J = 7.9 Hz, 1H), 8.02 (d, J = 7.8 Hz, 2H), 7.58-7.65 (m, 2H), 7.51 (t, / = 7.9 Hz, 1H), 7.24 (d, / = 7.0 Hz, 1H), 7.09 (s, 1H), 6.90 (t, J = 5.6 Hz, 1H), 4.45-4.56 (m, 2H), 4.11-4.17 (m, 1H), 2.76-2.87 (m, 2H), 0.95 (t, / = 7.3 Hz, 3H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:535.0.

Example B001: 3-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy] cyclobutanecarboxylic acid

B001

Step 1: Preparation of methyl 3-methylsulfonyloxycyclobutanecarboxylate

BOOla

To a solution of methyl 3-hydroxycyclobutanecarboxylate (1 g, 7.68 mmol, as the“SM4” in Table 6) and TEA (1.17 g, 1.61 mL, 11.5 mmol) in dichloromethane (10 mL) was added methanesulfonyl chloride (1.14 g, 778 pL, 9.99 mmol) at 0°C and the mixture was then stirred at room temperature overnight. The mixture was then diluted with dichloromethane (50 mb), the resulting solution was then washed with water (20 mL) twice, saturated NaHCCL (20 mL) twice, brine (20 mL), dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the crude methyl 3-methylsulfonyloxycyclobutanecarboxylate (1.6 g, 100%) as a colorless oil. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 209.2.

Step 2: Preparation of methyl 3-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]cyclobutanecarboxylate

BOOlb

To a mixture of 2-(4-bromo-2-hydroxy-phenyl)-8-chloro-chromen-4-one (Int-4, 100 mg, 284 mihoΐ, as the“CORE” in Table 6), methyl 3-methylsulfonyloxycyclobutanecarboxylate (592 mg, 2.84 mmol) in DMF (5 ml) was added K ₂ CO ₃ (393 mg, 2.84 mmol) and the mixture was stirred at l20°C for l2hours. After the reaction was completed, the mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL) three times. The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo to give the crude methyl 3-[5- bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]cyclobutanecarb oxylate, which was used in the next step directly without further purification.

Step 3: Preparation of 3-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy] cyclobutanecarboxylic acid

A solution of methyl 3-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy] eye lobutanecarboxy late (crude prepared above) in the mixed solvent of THF(lOmL) and LiOH solution (2N, 2mL) was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was adjusted to pH~4 by addition of 2 N HC1. The resulting mixture was concentrated in vacuo and the residue was purified by Prep-HPLC to give 3-[5-bromo-2-(8- chloro-4-oxo-chromen-2-yl)phenoxy]cyclobutanecarboxylic acid (30 mg, 22%yield over 2 steps) ¹ H NMR (DMSO-rfc, 400MHz): d ppm 8.01 (d, 7=7.83 Hz, 2H), 7.88 (s, 1H), 7.51 (t, 7=7.70 Hz,

1H), 7.43 (d, 7=8.56 Hz, 1H), 7.20 (s, 1H), 7.04-7.09 (m, 1H), 4.87-5.15 (m, 1H), 3.07-3.12 (m,

1H), 2.68-2.76 (m, 2H), 2.43-2.47 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:449.l.

Example B002-A and Example B002-B

C¾-3-[2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]cyclobutane carboxylic acid and trans- 3-[2- (8-chloro-4-oxo-chromen-2-yl)phenoxy]cyclobutanecarboxylic acid

B002-A, B002-B

Step 1: Preparation of methyl 3-[2-(8-chloro-4-oxo-chromen-2

yl)phenoxy] cyclobutanecarboxylate

B002a

To a mixture of 8-chloro-2-(2-hydroxyphenyl)chromen-4-one (Int-3, 100 mg, 367 mihoΐ), methyl 3-methylsulfonyloxycyclobutanecarboxylate (305 mg, 1.47 mmol) in DMF (5 ml) was added CS ₂ CO ₃ (478 mg, 1.47 mmol) and the mixture was stirred at l20°C for 12 hours. After the reaction was completed, the mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL) three times. The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo to give the crude methyl 3-[2-(8-chloro-4-oxo-chromen-2- yl)phenoxy] cyclobutanecarboxylate, which was used in the next directly without further purification.

Step 2: Preparation of C7s-3-[2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]cyclobutanecarboxylic acid and iraras-3-[2-(8-chloro-4-oxo-chromen-2- yl)phenoxy] cyclobutanecarboxylic acid

B002-A,B002-B

A solution of methyl 3-[2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]cyclobutanecarboxy late (crude prepared above) in the mixed solvent of THF (lOmL) and LiOH solution (2N, 2mL) was stirred at room temperature for 2 hours. After the reaction was completed, the reaction was adjusted to pH~4 by addition of 2 N HC1, the resulting mixture was concentrated in vacuo to give the crude -[2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]cyclobutanecarboxyl ic acid. The crude was further purified by Prep-HPLC to give two diastereomers of r/.v-3- 12-(8-chloro-4-oxo- chromen-2-yl)phenoxy]cyclobutanecarboxylic acid (Example B002-A, 9 mg, % yield) and irans- 3-[2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]cyclobutanecarboxy lic acid (Example B002-B,56 mg, % yield).

Example ppm 8.01 (qd, 7=1.52, 7.92 Hz, 2H), 7.97 (dd, 7=1.71, 7.83 Hz, 1H), 7.57 (ddd, 7=1.71, 7.34, 8.56 Hz, 1H), 7.50 (t, 7=7.83 Hz, 1H), 7.17-7.23 (m, 1H), 7.08-7.13 (m, 1H), 7.07 (s, 1H), 4.79-4.91 (m, 1H), 2.80 (d, 7=4.65 Hz, 3H), 2.27 (d, 7=7.09 Hz, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ j: 371.0.

Example B002-B: 1H NMR (DMSO-tfe, 400MHz): d ppm 12.33-12.41 (m, 1H), 8.01 (d, 7=7.83 Hz, 2H), 7.97 (dd, 7=1.71, 7.83 Hz, 1H), 7.53-7.61 (m, 1H), 7.50 (t, 7=7.95 Hz, 1H),

7.16-7.23 (m, 1H), 7.10 (s, 1H), 7.03 (d, 7=8.31 Hz, 1H), 5.02 (s, 1H), 3.10-3.20 (m, 1H), 2.69- 2.79 (m, 2H), 2.37-2.47 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ j: 371.1.

The following Example B003 to Example B010 were prepared in analogy to the procedure described for the preparation of Example B001, replacing methyl 3- hydroxycyclobutanecarboxylate with“SM4” in stepl, and replacing 2-(4-bromo-2-hydroxy- phenyl)-8-chloro-chromen-4-one (Int-4) with“CORE” in step 2.“SM4” and“CORE” are the reagents indicated in Table 6.

Table 6. Compounds synthesis and characterization

The following compounds B011 to B029 were prepared in analogy to the procedure described for the preparation of example B002-A and B002-B, replacing methyl 3- methylsulfonyloxycyclobutanecarboxylate with“SM4” in stepl, 8-chloro-2-(2- hydroxyphenyl)chromen-4-one with“CORE” in step 1. The“CORE” and“SM4” are the reagent indicated in Table 6.

Table 6. Compounds synthesis and characterization

Example B035-A and Example B035-B: s-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- cyclopropyl-phenoxy]cyclobutanecarboxylic acid and traras-3-[2-(8-chloro-4-oxo-chromen- 2-yl)-5-cyclopropyl-phenoxy]cyclobutanecarboxylic acid

B035-A, B035-B

Step 1: Preparation of methyl 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-cyclopropyl- phenoxy]cyclobutanecarboxylate

B035a

To a mixture of methyl 3-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]cyclobutanecarboxylate (Example BOOlb, 800.0 mg, 1.73 mmol), potassium cyclopropyltrifluoroborate (1021.19 mg, 6.9 mmol), 2-dicyclohexylphosphino-2',6'- dimethoxybiphenyl (70.83 mg, 0.170 mmol) in the mixed solvent of toluene (10 mL) and water (1 mL) was added Pd(OAc) ₂ (387.33 mg, 1.73 mmol) under N ₂ atmosphere and the reaction was stirred at 90 °C for 3 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was purified by column chromatography on solica gel (eluent with PE:EtOAc = 100:1 to 2:1) to give methyl 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-cyclopropyl- phcnoxy ]cyclohutanccarhoxylatc (430 mg, 57.8 % yield) as a yellow solid. MS obsd.

(ESI ⁺ )[(M+H) ⁺ ]: 425.1.

Step 2: Preparation of 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-cyclopropyl- phenoxy]cyclobutanecarboxylic acid

s-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-cyclopropyl-phenoxy]c yclobutanecarboxylic acid and trans-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-cyclopropyl- phenoxy]cyclobutanecarboxylic acid

B035-A, B035-B

Example B035-A and B035-B was prepared in analogy to the procedure described for the preparation of example B002-A and B002-B by using methyl 3-[2-(8-chloro-4-oxo-chromen-2- yl)-5-cyclopropyl-phenoxy]cyclobutanecarboxylate as the starting material instead of methyl 3- [2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]cyclobutanecarboxyla te in step 2.

Example B035-A: ' l l NMR (DMSO-ife, 400MHz): drrih 7.94-8.04 (m, 2H), 7.82-7.90 (m, 1H), 7.42-7.57 (m, 1H), 7.03-7.11 (m, 1H), 6.83-6.92 (m, 1H), 6.72-6.79 (m, 1H), 4.79-4.96 (m,

1H), 2.73-2.87 (m, 3H), 2.20-2.36 (m, 2H), 1.97-2.10 (m, 1H), 0.99-1.15 (m, 2H), 0.76-0.89 (m,

2H). MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 411.0.

Example B035-B: NMR (DMSO-ife, 400MHz): d ppm 7.95-8.03 (m, 2H), 7.80-7.92 (m, 1H), 7.43-7.55 (m, 1H), 7.04-7.15 (m, 1H), 6.77-6.88 (m, 1H), 6.65-6.75 (m, 1H), 4.98-5.13 (m,

1H), 3.04-3.21 (m, 1H), 2.69-2.82 (m, 2H), 2.34-2.46 (m, 2H), 2.01-2.11 (m, 1H), 1.00-1.13 (m,

2H), 0.71-0.85 (m, 2H). MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 411.0.

Example B036-A and Example B036-B: C¾-3-[5-bromo-2-(8-chloro-5-hydroxy-4-oxo- chromen-2-yl)phenoxy]cyclobutanecarboxylic acid and iraras-3-[5-bromo-2-(8-chloro-5- hydroxy-4-oxo-chromen-2-yl)phenoxy]cyclobutanecarboxylic acid

B036-A,B036-B

Step 1: Preparation of methyl 3-(5-bromo-2-formyl-phenoxy)cyclobutanecarboxylate

B036a

To a mixture of 4-bromo-2-hydroxy-benzaldehyde (500 mg, 2.5 mmol), methyl 3- methylsulfonyloxycyclobutanecarboxylate (750 mg, 4.2 mmol) in DMF (10 ml) was added K CO ( 690 mg, 5.0 mmol) and the mixture was stirred at l20°C for 2 hours. After the reaction was completed, the mixture was diluted with water (15 mL) and extracted with EtOAc (30 mL) three times. The combined organic layer was washed with brine, dried over Na S0 and concentrated in vacuo to give the crude methyl 3-(5-bromo-2-formyl- phenoxy)cyclobutanecarboxylate (657 mg, 82.1% yield), which was used in the next directly without further purification. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:3l2.9.

Step 2: Preparation of 3-[5-bromo-2-[(£')-3-[3-chloro-2,6-bis(methoxymethoxy)pheny l]-3- oxo-prop-l-enyl]phenoxy]cyclobutanecarboxylic acid

B036b

To a solution of l-[3-chloro-2,6-bis(methoxymethoxy)phenyl]ethanone (83.1 mg, 0.3mmol) and methyl 3-(5-bromo-2-formyl-phenoxy)cyclobutanecarboxylate (80 mg, 0.3 mmol) in ethanol (5 mL) was added KOH (171 mg, 3.05 mmol) and the mixture was then stirred at 40 °C for 16 hours. After the reaction was completed, the mixture was diluted with water (20 mL) and adjusted to PH~6 by addition of 1N HC1. The resulting mixture was extracted with EtOAc (20 mL) three times, the combined organic layer was washed with brine (20 mL) twice, dried over Na ₂ S0 ₄ and concentrated in vacuo to give 3-[ 5-hromo-2-[(/7)-3-[ 3-chloro-2,6- bis(methoxymethoxy)phenyl]-3-oxo-prop-l-enyl]phenoxy]cyclobu tanecarboxylic acid (150 mg, 97.4% yield) as an orange oil. MS obsd. (ESf) [(M+H) ⁺ ]:555.l.

Step 3: Preparation of C¾-3-[5-bromo-2-(8-chloro-5-hydroxy-4-oxo-chromen-2- yl)phenoxy]cyclobutanecarboxylic acid and Zraras-3-[5-bromo-2-(8-chloro-5-hydroxy-4-oxo- chromen-2-yl)phenoxy]cyclobutanecarboxylic acid

B036-A,B036-B

To a solution of 3-[5-bromo-2-[(E)-3-[3-chloro-2,6-bis(methoxymethoxy)phenyl] -3-oxo- prop-l-enyl]phenoxy]cyclobutanecarboxylic acid (150 mg, 0.29 mmol) in DMSO (8 ml) was added L (5.1 mg, 0.02 mmol) and the mixture was stirred 140 °C at for 2hours. After the reaction was completed, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL) three times. The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by Prep-HPLC to give two diastereomers of cis- 3-[5-bromo-2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)phenoxy] cyclobutanecarboxylic acid (Example B036-A, 9 mg, % yield) and Zrans-3-[5-bromo-2-(8-chloro-5-hydroxy-4-oxo-chromen- 2-yl)phenoxy]cyclobutanecarboxylic acid (Example B036-B,56 mg, % yield).

Example B036-A: 1H NMR (DMSO-zfe, 400MHz): d ppm 12.58 (s, 1H), 12.23-12.39 (br, 1H), 7.87 (dd, 7 = 16.1, 8.7 Hz, 2H), 7.44 (dd, 7 = 8.5, 1.8 Hz, 1H), 7.31 (d, 7 = 1.7 Hz, 1H),

7.11 (s, 1H), 6.87 (d, 7 = 8.9 Hz, 1H), 4.88-5.00 (m, 1H), 2.75-2.83 (m, 3H), 2.21-2.29 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:465.l.

Example B036-B: 1H NMR (DMSO-tfe, 400MHz): d ppm 12.58 (s, 1H), 7.88 (s, 2H), 7.41-7.47 (m, 1H), 7.14 (s, 1H), 6.96 (s, 1H), 6.88 (d, 7 = 8.8 Hz, 1H), 5.07-5.12 (m, 1H), 3.11- 3.18 (m, 2H), 2.72-2.77 (m, 2H), 2.39-2.442 (m, 1H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:465.l.

Example B037-A and Example B037-B: Cis-3-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-5-methyl- phenoxy]cyclobutanecarboxylic acid and 7’rans-3-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2- yl)-5-methyl-phenoxy]cyclobutanecarboxylic acid

B037-A,B037-B

Example B037-A and B037-B were prepared in analogy to the procedure described for the preparation of example B036-A and B036-B by using 2-hydroxy-4-methyl-benzaldehyde as the starting material instead of 4-bromo-2-hydroxy-benzaldehyde in step 1.

Example B037-A: 1H NMR (DMSO-ife, 400MHz): d ppm 12.57 (s, 1H), 12.36 (s, 1H), 7.76-7.92 (m, 2H), 7.07-7.15 (m, 1H), 6.95-7.02 (m, 1H), 6.79-6.93 (m, 2H), 4.76-4.88 (m, 1H),

2.74-2.91 (m, 3H), 2.35 (s, 3H), 2.18-2.33 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:40l.0.

Example B037-B: 1H NMR (DMSO-ife, 400MHz): d ppm 12.61 (s, 1H), 12.36 (s, 1H), 7.76-7.92 (m, 2H), 7.11-7.16 (m, 1H), 6.96-7.04 (m, 1H), 6.80-6.89 (m, 2H), 4.95-5.06 (m, 1H), 3.06-3.20 (m, 1H), 2.69-2.84 (m, 2H), 2.39-2.45 (m, 5H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:40l.0. Example B038-A and Example B038-B: C7s-3-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)- 5-(trifbioromethyl)phenoxy]cyclobutanecarboxylic acid and 7 Y»/s-3-[2-(8-chloro-5- hydroxy-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenoxy]cyclo butanecarboxylic acid

B038-A,B038-B

Example B038-A and B038-B were prepared in analogy to the procedure described for the preparation of example B036-A and B036-B by using 2-hydroxy-4- (trifluoromethyl)benzaldehyde as the starting material instead of 4-bromo-2-hydroxy- benzaldehyde in step 1. Example B038-A: 1H NMR (DMSO- , 400MHz): d ppm 12.58 (s, 1H), 12.36 (s, 1H), 8.08-8.17 (m, 1H), 7.83-7.91 (m, 1H), 7.53-7.62 (m, 1H), 7.30-7.38 (m, 1H), 7.12-7.19 (m, 1H), 6.83-6.93 (m, 1H), 4.96-5.09 (m, 1H), 2.70-2.88 (m, 3H), 2.19-2.37 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:455.0.

Example B038-B: 1H NMR (DMSO-ife, 400MHz): d ppm 12.51 (s, 1H), 8.05-8.18 (m, 1H), 7.75-7.90 (m, 1H), 7.49-7.61 (m, 1H), 7.13-7.29 (m, 2H), 6.79-6.92 (m, 1H), 5.11-5.24 (m, 1H), 3.06-3.18 (m, 1H), 2.65-2.82 (m, 2H), 2.33-2.46 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:455. l.

Example B039-A and Example B039-B: Cis-3-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)- 5-ethoxy-phenoxy]cyclobutanecarboxylic acid and 7’rans-3-[2-(8-chloro-5-hydroxy-4-oxo- chromen-2-yl)-5-ethoxy-phenoxy]cyclobutanecarboxylic acid

B039-A,B039-B

Example B039-A and B039-B were prepared in analogy to the procedure described for the preparation of example B036-A and B036-B by using 4-ethoxy-2-hydroxy-benzaldehyde as the starting material instead of 4-bromo-2-hydroxy-benzaldehyde in step 1.

Example B039-A: 1H NMR (DMSO-ife, 400MHz): d ppm 12.69 (s, 1H), 12.17-12.50 (br s, 1H), 7.92-8.02 (m, 1H), 7.73-7.85 (m, 1H), 7.04-7.16 (m, 1H), 6.73-6.89 (m, 2H), 6.47-6.60 (m, 1H), 4.83-4.94 (m, 1H), 4.04-4.21 (m, 2H), 2.73-2.89 (m, 3H), 2.19-2.39 (m, 2H), 1.29-1.42 (m, 3H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:43l.l.

Example B039-B: NMR (DMSO-ife, 400MHz): d ppm 12.79 (s, 1H), 7.92-8.02 (m, 1H), 7.73-7.87 (m, 1H), 7.07-7.18 (m, 1H), 6.71-6.91 (m, 2H), 6.32-6.47 (m, 1H), 4.96-5.10 (m, 1H), 4.08-4.22 (m, 2H), 3.07-3.21 (m, 1H), 2.69-2.82 (m, 2H), 2.36-2.45 (m, 2H), 1.29-1.40 (m, 3H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:43l.l.

Example B040-A and Example B040-B: s-3-[5-bromo-2-(8-chloro-5-hydroxy-4-oxo- chromen-2-yl)-4-methyl-phenoxy]cyclobutanecarboxylic acid and traras-3-[5-bromo-2-(8- chloro-5-hydroxy-4-oxo-chromen-2-yl)-4-methyl-phenoxy]cyclob utanecarboxylic acid

B040-A,B040-B

Example B040-A and B040-B were prepared in analogy to the procedure described for the preparation of example B036-A and B036-B by using 4-bromo-2-hydroxy-5-methyl- benzaldehyde as the starting material instead of 4-bromo-2-hydroxy-benzaldehyde in step 1.

Example B040-A: 1H NMR (DMSO- , 400MHz): d ppm 12.64 (s, 1H), 12.34 (s, 1H),

7.78-7.90 (m, 2H), 7.27-7.34 (m, 1H), 7.04-7.11 (m, 1H), 6.78-6.92 (m, 1H), 4.81-4.95 (m, 1H), 2.65-2.86 (m, 3H), 2.36 (s, 3H), 2.17-2.30 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:479.0.

Example B040-B: 1H NMR (DMSO-ife, 400MHz): d ppm 12.52 (s, 1H), 12.38 (s, 1H),

7.79-7.89 (m, 2H), 7.17-7.23 (m, 1H), 7.06-7.13 (m, 1H), 6.75-6.92 (m, 1H), 4.95-5.11 (m, 1H), 3.07-3.19 (m, 1H), 2.66-2.79 (m, 2H), 2.38-2.45 (m, 2H), 2.35 (s, 3H). MS obsd. (ESI ⁺ )

[(M+H) ⁺ ]:479.0.

Example B041 4-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]butanoic acid

Example B041 was prepared in analogy to the procedure described for the preparation of example B036-A and B036-B by using 2-hydroxy-4-(trifluoromethyl)benzaldehyde and methyl 4-bromobutanoate as the starting material and methyl 3- methylsulfonyloxycyclobutanecarboxylate instead of 4-bromo-2-hydroxy-benzaldehyde in step 1.

Example B041: 1H NMR (DMSO-ife, 400MHz): d ppm 12.63 (s, 1H), 8.09-8.17 (m, 1H), 7.82-7.89 (m, 1H), 7.54-7.63 (m, 2H), 7.11-7.18 (m, 1H), 6.82-6.96 (m, 1H), 4.21-4.36 (m, 2H), 2.38-2.45 (m, 2H), 1.99-2.08 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:443.l. Example B042 3-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-4,5-dimethoxy- phenoxy]cyclobutanecarboxylic acid

B042

Example B042 were prepared in analogy to the procedure described for the preparation of example B036-A and B036-B by using 2-hydroxy-4,5-dimethoxy-benzaldehyde as the starting material instead of 4-bromo-2-hydroxy-benzaldehyde in step 1. After purified by Prep-HPLC in step 3, the cis-and trans- two diastereomers were afforded as a mixture.

Example B042 : ^l U NMR (DMSO-ifc, 400MHz): d ppm 13.51 (s, 1H), 12.11-12.37 (br, 1H), 7.84 (d, J = 9.0 Hz, 1H), 7.52 (s, 1H), 7.31 (d, 7 = 9.0 Hz, 1H), 7.06-7.16 (m, 1H), 6.62-

6.69 (m, 1H), 4.82-4.96 (m, 1H), 3.90 (s, 3H), 3.80-3.86 (m, 3H), 2.75-2.86 (m, 3H), 2.21-2.29

(m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:447.0.

Example B043-A and B043-B:

C7s-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)ph enoxy]-N- cyclopropylsulfonyl-cyclobutanecarboxamide and iraras-3-[2-(8-chloro-4-oxo-chromen-2- yl)-5-(trifluoromethyl)phenoxy]-N-cyclopropylsulfonyl-cyclob utanecarboxamide

B043-A, B043-B

Step 1: Preparation of methyl 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifhioromethyl)phenoxy]cyclobutanecarboxylate

B043a

To a solution of 8-chloro-2-[2-hydroxy-4-(trifluoromethyl)phenyl]chromen-4-on e (Int-1, 470.0 mg, 1.38 mmol, as the“CORE” in Table 7 ), methyl 3-(p- tolylsulfonyloxy)cyclobutanecarboxylate (615 mg, 4.1 mmol) in DMF (5 mL) was added

CS ₂ CO ₃ (2.25 g, 6.9 mmol) and the reaction mixture was stirred at 100 °C for 16 hours. After the reaction was completed, the mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL) three times. The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo to give the crude methyl 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]cyclobutanecarboxylate (600 mg, 96.0 % yield) as a brown solid, which was used in the next step directly. MS obsd. (ESI ⁺ ) [(M+Na) ⁺ ]: 475.0.

Step 2: Preparation of 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]cyclobutanecarboxylic acid

B043b

To a solution of methyl 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]cyclobutanecarboxylate (600 mg, 1.2 mmol) in THF (8 mL) and water (8 mL) was added LiOH (408 mg, 9.3mmol). The reaction mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water (15 mL) and extracted with EtOAc (20 mL) three times. The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo to give the crude product of 3- [2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenoxy] cyclobutanecarboxylic acid (570 mg, 98.8% yield), which was used in the next step directly without further purification. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 439.0.

Step 3: Preparation of B043-A and B043-B:

C¾-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)ph enoxy]-N- cyclopropylsulfonyl-cyclobutanecarboxamide and trans- 3- [2-(8-chloro-4-oxo-chromen-2- yl)-5-(trifluoromethyl)phenoxy]-N-cyclopropylsulfonyl-cyclob utanecarboxamide

B043-A, B043-B

To a solution of 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]cyclobutanecarboxylic acid (0.33 g, 752 pmol) and DIPEA (292 mg, 2.26 mmol) in DMF (10 mL) was added HATU (429 mg, 1.13 mmol) and the mixture was stirred at room temperature for 30 minutes. Then to the resulting solution was added solution of cyclopropanesulfonamide (364 mg, 3.01 mmol, as the“AMINE” in Table 7) and DMAP (368 mg, 3.01 mmol) in DMF (5 mL). The reaction was then stirred at room temperature overnight. After the reaction was completed, the reaction mixture was quenched with water (30 mL) and extracted with DCM (30 mL) three times. The combined organic layer was washed with brine, dried over MgS0 ₄ and concentrated in vacuo to give the crude 3-[2-(8-chloro-4-oxo-chromen-2- yl)-5-(trifluoromethyl)phenoxy]-N-cyclopropylsulfonyl-cyclob utanecarboxamide. The cmde was further purified by Prep-HPLC to give s-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]-N-cyclopropylsulfonyl-cyclobutanec arboxamide(Example B043-A) and Zrans-3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl) phenoxy]-N- cyclopropylsulfonyl-cyclobutanecarboxamide (Example B043-B). The configuration of Example B043-A and Example B043-B were further confirmed by NOESY.

Example B043-A: 1H NMR (DMSO-zfe, 400MHz): d ppm 11.86 (s, 1H), 8.10-8.19 (m,

1H), 7.95-8.08 (m, 2H), 7.48-7.63 (m, 2H), 7.30-7.41 (m, 1H), 7.00-7.14 (m, 1H), 4.98-5.14 (m, 1H), 2.87-3.01 (m, 2H), 2.72-2.83 (m, 2H), 2.21-2.36 (m, 2H), 0.99-1.14 (m, 4H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:542.l . Example B043-B: 1H NMR (DMSO-ife, 400MHz): d ppm 11.82 (s, 1H), 8.11-8.18 (m, 1H), 7.95-8.09 (m, 2H), 7.48-7.66 (m, 2H), 7.18-7.27 (m, 1H), 7.08-7.17 (m, 1H), 5.06-5.22 (m, 1H), 3.97-4.10 (m, 1H), 2.90-3.04 (m, 1H), 2.68-2.80 (m, 2H), 2.37-2.47 (m, 2H), 1.06-1.12 (m, 4H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:542.l .

(NOESY correlation observed) (no NOESY correlation observed)

Example B044-A and B044-B: s-3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-N- methylsulfonyl-cyclobutanecarboxamide and irans-3-[5-bromo-2-(8-chloro-4-oxo-chromen- 2-yl)phenoxy]-N-methylsulfonyl-cyclobutanecarboxamide

To a solution of 3-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]cyclobutanecarboxylic acid (Example B001, 250 mg, 556 pmol) and DIPEA (719 mg, 971 mΐ, 5.56 mmol) in DCM (5 ml) were added HATU (423 mg, 1.11 mmol) and methanesulfonamide (106 mg, 1.11 mmol) and the mixture was stirred at room temperature for 12 hours. After the reaction was completed, the reaction was concentrated in vacuo and the residue was purified by Prep-HPLC to give s-3-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]-N-methylsulfonyl-cyclobutanecarboxamide (Example B044-A, 4 mg, 1.4% yield) and frans-3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-N-m ethylsulfonyl- cyclobutanecarboxamide (Example B044-B, 12 mg, 4.1% yield).

Example B044-A: 1H NMR (DMSO-ife, 400MHz): d ppm 11.78 (s, 1H), 7.97-8.04 (m, 2H), 7.84-7.92 (m, 1H), 7.47-7.54 (m, 1H), 7.40-7.47 (m, 1H), 7.26-7.34 (m, 1H), 7.02-7.08 (m, 1H), 4.89-5.03 (m, 1H), 3.17 (s, 3H), 2.70-2.94 (m, 3H), 2.23-2.35 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:526.l .

Example B044-B: 1H NMR (DMSO-ife, 400MHz): d ppm 11.81 (s, 1H), 7.97-8.06 (m, 2H), 7.84-7.93 (m, 1H), 7.48-7.56 (m, 1H), 7.38-7.46 (m, 1H), 7.19-7.21 (m, 1H), 7.07-7.12 (m, 1H), 4.98-5.10 (m, 1H), 3.31 (s, 3H), 3.22-3.27 (m, 1H), 2.71-2.79 (m, 2H), 2.35-2.45 (m, 2H).

MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:526.l .

The following Example B047 to Example B035 were prepared in analogy to the procedure described for the preparation of Example B043-A, B043-B, replacing 8-chloro-2-[2-hydroxy-4- (trifluoromethyl)phenyl]chromen-4-one(Int-l) with“CORE” in step 1,

cyclopropanesulfonamide with“AMINE” in step 3. The“CORE” and“AMINE” are the reagents indicated in Table 7.

Table 7: Compounds synthesis and characterization

Example B070: 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]cyclobutanecarbonitrile

Step 1: Preparation of (3-cyanocyclobutyl) 4-methylbenzenesulfonate

B070a

To a solution of 3-hydroxycyclobutane-l-carbonitrile (500 mg, 5.15 mmol),DMAP (1.01 g, 8.24 mmol) in DCM (25 mL) was added 4-methylbenzenesulfonyl chloride (1.18 g, 6.2 mmol) and the mixture was then stirred at room temperature overnight. After the reaction was completed, the mixture was concentrated in vacuo and the residue was partitioned between EtOAc (30 mL) and water (20 mL). The organic layer was separated out and washed by brine, dried over Na ₂ S0 ₄ , then concentrated in vacuo to give the crude (3-cyanocyclobutyl) 4- methylbenzenesulfonate (0.517 g, 40 % yield) as a colorless oil, which was used in the next step directly without further purification.

Step 2: Preparation of 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]cyclobutanecarbonitrile

A mixture of 8-chloro-2-[2-hydroxy-4-(trifluoromethyl)phenyl]chromen-4-on e (Int-1, 117 mg, 342 mihoΐ), 3-cyanocyclobutyl 4-methylbenzenesulfonate (86 mg, 342 mhioΐ) and K2CO ₃ (236 mg, 1.71 mmol) in DMF(5 mL) was stirred at 70 °C overnight. After the reaction was completed, the mixture was diluted with water (15 mL) and extracted with EtOAc (30 mL) three times. The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by Prep-HPLC to give 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]cyclobutanecarbonitrile (31 mg, 21.4% yield) as a white solid. ¹ 11 NMR (DMSO-ife, 400MHz): d ppm 8.09-8.17 (m, 1H), 7.97-8.07 (m, 2H), 7.47-7.62 (m, 2H), 7.35-7.44 (m, 1H), 7.04-7.11 (m, 1H), 5.28-5.45 (m, 1H), 3.44-3.55 (m, 1H), 2.85-2.97 (m, 2H), 2.55-2.68 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 419.1.

Example B071: 3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-N,N-dimet hyl- propane- 1 -sulfonamide

To a suspension of 2-(4-bromo-2-hydroxy-phenyl)-8-chloro-chromen-4-one (Int-4, 150 mg, 427 mitioΐ) and 3 -chloro-N,N-dimethylpropane-l -sulfonamide (111 mg, 597 mitioΐ) in DMF (5 mL) was added K2CO ₃ (354 mg, 2.56 mmol) and the mixture was then stirred at 40°C for 4 hours. The mixture was then purified by Prep-ElPLC to give 3-[5-bromo-2-(8-chloro-4-oxo- chromen-2-yl)phenoxy]-N,N-dimethyl-propane-l-sulfonamide (112 mg, 51.4% yield) as a white solid. NMR (DMSO-tfc, 400MHz): d ppm 8.01 (dd, J = 7.9, 1.3 Hz, 2H), 7.85 (d, J = 8.3 Hz, 1H), 7.43-7.52 (m, 3H), 6.98 (s, 1H), 4.31 (t, J = 6.1 Hz, 2H), 3.13-3.22 (m, 2H), 2.74 (s, 6H), 2.13-2.23 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 500.2. Example B072: 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]propane-l- sulfonamide

B072

Stepl: preparation of 3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-N-tert-bu tyl- propane- 1 -sulfonamide

B072a

To a suspension of 2-(4-bromo-2-hydroxy-phenyl)-8-chloro-chromen-4-one (Int-4, 150 mg, 440 pmol) and N-(/ /7-butyl)-3-chloropropane- 1 -sulfonamide (132 mg, 616 pmol) in DMF (5 mL)was added K ₂ CO ₃ (365 mg, 2.64 mmol). The mixture was then stirred at 40°C for 4 hours. After the reaction was completed, the mixture was poured into water (20 mL) and extracted with EtOAc (30 mL) three times. The combined organic layer was concentrated in vacuo to give the crude 3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-N-ferf-bu tyl-propane-l- sulfonamide (200 mg, 87.7 % yield) as a white solid, which was used in the next step directly without further purification. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 518.3.

Step 2: preparation of 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propane-l-sulfonamide

B072

To a suspension of 3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-N-ferf-bu tyl- propane-l -sulfonamide (30 mg, 57.9 pmol) in AcOH (4 mL) was added concentrated HC1 (1 mL) and the mixture was stirred at HO °C for 4 hours. The mixture was then diluted with water (15 mL) and extracted with EtOAc (20 mL) three times. The combined organic layer was concentrated in vacuo and the residue was purified by Prep-HPLC to give 3-[2-(8-chloro-4-oxo- chromen-2-yl)-5-(trifluoromethyl)phenoxy]propane-l-sulfonami de (15 mg, 55.0% yield) as a white solid. 1H NMR (DMSO-rfe, 400MHz): d ppm 8.14 (s, 1H), 8.01-8.06 (m, 2H), 7.49-7.62 (m, 3H), 7.07 (s, 1H), 6.88 (s, 2H), 4.40 (t, J = 6.5 Hz, 2H), 3.09-3.17 (m, 2H), 2.17-2.26 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 462.3.

Example B073: 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]-2- hydroxy-propanoic acid

Step 1: Preparation of methyl 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]-2-hydroxy-propanoate

B073a

To a suspension of 8-chloro-2-[2-hydroxy-4-(trifluoromethyl)phenyl]chromen-4-on e (Int- 1, 100 mg, 294 pmol) and methyl oxirane-2-carboxylate (300 mg, 2.94 mmol) in DMSO (5 mL)was added K ₂ CO ₃ (243 mg, 1.76 mmol) and the mixture was then stirred at 80 °C for 40 hours. The mixture was then poured into water (20 mL) and extracted with EtOAc (20 mL) three times. The combined organic layer was concentrated in vacuo to give the crude methyl 3-[2-(8- chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenoxy]-2-hyd roxy-propanoate (50 mg, 25% purity), which was used in the next step directly without further purification. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 443.1

Step 2: Preparation of 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]-2- hydroxy-propanoic acid

B073

To a solution of methyl 3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenox y]- 2-hydroxy-propanoate (20 mg, 45.2 pmol) in a mixed solvent of THF (6 mL), MeOH (3mL) and water (1 mL) was added LiOH (54.1 mg, 2.26 mmol) and the mixture was stirred at room temperature for 4 hours. The mixture was then adjusted to PH-6.0 by addition of AcOH and the resulting mixture was concentrated in vacuo. The residue was purified by Prep-HPLC to give 3- [2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenoxy] -2-hydroxy-propanoic acid (7.1 mg, 34.8% yield) as an off-white solid. ¹ H NMR (l )MSO- _< %, 400MHz): d ppm 12.80-12.99 (m, 1H), 8.16 (s, 1H), 8.02 (dd, J = 7.8, 2.3 Hz, 2H), 7.65 (s, 2H), 7.49-7.58 (m, 1H), 7.22 (s, 1H),

5.69-5.78 (m, 1H), 4.41-4.55 (m, 3H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ j: 429.1.

Example B075: (2,S,4,S)-4-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy] pyrrolidine- 2-carboxylic acid

B075

Step 1: Preparation of Ol-tert-butyl 02-methyl (2S,4S)-4-[5-bromo-2-(8-chloro-4-oxo- chromen-2-yl)phenoxy]pyrrolidine-l,2-dicarboxylate

B075a A mixture of 2-(4-bromo-2-hydroxy-phenyl)-8-chloro-chromen-4-one (Int-4, 100 mg, 284 mihoΐ), Ol-ferf-butyl 02-methyl ( 2 /^,4.V) -4 - ( p- to ly 1 su 11 ^' o ny lo x y ) p yrro 1 id i nc- 1 ,2-dicarboxylatc (114 mg, 284 mhioΐ) and K ₂ CO ₃ (197 mg, 1.42 mmol) in DMF (15 mL) was stirred at 50 °C overnight. The mixture was then poured into water (50mL) and extracted with EtOAc (50 mL) three times. The combined organic layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel (elueted with PE:EtOAc = 100:1 to 3:1) to give 01 -tert- butyl 02-methyl (25',45')-4-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy] pyrrolidine- 1,2- dicarboxylate (150 mg, 91.1% yield) as a yellow solid. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 578.1.

Step 2: Preparation of methyl (2.S,4.S)-4-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]pyrrolidine-2-carboxylate

B075b

To a solution of Ol-ferf-butyl 02-methyl (2.S',4.S')-4-[5-bromo-2-(8-chloro-4-oxo-chromcn- 2-yl)phenoxy]pyrrolidine-l,2-dicarboxylate (1.3g, 2.25 mmol) in DCM (30 mL) was added TFA (1.28 g, 865 mΐ, 1 1.2 mmol) and the mixture was then stirred at room temperature overnight.

After the reaction was completed, the mixture was concentrated in vacuo to give the crude methyl (2.S',4.S')-4-[5-bromo-2-(8-chloro-4-oxo-chromcn-2-yl)phcnox y]pyrrolidinc-2-carboxylatc (1.08 g, 100% yield) as a white solid, which was used in the next step directly without further purification. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 578.1.

Step 3: preparation of (2.S,4.S)-4-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]pyrrolidine-2-carboxylic acid

B075 To a solution of methyl (2.S',4.S')-4-| 5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]pyrrolidine-2-carboxylate (150 mg, 313 pmol) in the mixed solvent of THF (20 ml) and MeOH (10 ml) was added LiOH (30 mg, 1.25 mmol) and the mixture was then stirred at room temperature for 4 hours. The mixture was then quenched by addition of AcOH (0.5 mL) and the resulting mixture was concentrated in vacuo. The residue was purified by Prep-HPLC to give (2.S',4.S')-4-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenox y]pyrrolidine-2-carboxylic acid (45 mg, 29.4%) yield as white solid. 1H NMR (DMSO-tfe, 400MHz): d ppm 8.00 (d, J = 7.8 Hz, 2H), 7.83 (d, J = 8.3 Hz, 1H), 7.43-7.55 (m, 3H), 6.95 (s, 1H), 5.34 (br s, 1H), 4.37-4.40 (m, 1H), 3.62-3.69 (m, 1H), 3.51-3.56 (m, 1H), 2.60-2.84 (m, 2H), 2.37-2.66 (m, 1H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 464.0.

Example B076: (2S,4R)-l-(benzenesulfonyl)-4-[2-(8-chloro-4-oxo-chromen-2-y l)-5- (trifluoromethyl)phenoxy]pyrrolidine-2-carboxylic acid

Step 1: Preparation of Ol-terZ-butyl 02-methyl (2S,4R)-4-[2-(8-chloro-4-oxo-chromen-2- yl)-5-(trifluoromethyl)phenoxy]pyrrolidine-l,2-dicarboxylate

B076a

A mixture of 8-chloro-2-[2-hydroxy-4-(trifluoromethyl)phenyl]chromen-4-on e (Int-1, 323 mg, 948 pmol, as the“CORE” in Table 8 ), l-(ZerZ-butyl) 2-methyl (2.S',4.S')-4-

((methylsulfonyl)oxy)pyrrolidine-l,2-dicarboxylate (460 mg, 1.42 mmol, as the“SM5” in Table 8 ) and K ₂ CO ₃ (524 mg, 3.79 mmol) in DMF (10 mL) was stirred at 80 °C overnight. After the reaction was completed, the mixture was diluted with water (30 mL) and extracted with EtOAc (30 mL) three times. The combined organic layer was concentrated in vacuo and the residue was purified by column chromatography on silica gel to give Ol-ferf-butyl 02-methyl (2S,4R)-4-[2- (8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenoxy]pyr rolidine-l,2-dicarboxylate (400 mg, 74.3 % yield) as a light yellow solid.

Step 2: Preparation of methyl (2S,4R)-4-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]pyrrolidine-2-carboxylate

B076b

To a solution of Ol-ferf-butyl 02-methyl (2S,4R)-4-[2-(8-chloro-4-oxo-chromen-2-yl)-5-

(trifluoromethyl)phenoxy]pyrrolidine-l,2-dicarboxylate (400 mg, 704 pmol) in DCM (10 mL) was added TLA (402 mg, 3.52 mmol) and the mixture was then stirred at room temperature overnight. The mixture was then concentrated in vacuo to give the crude methyl (2S,4R)-4-[2-(8- chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenoxy]pyrrol idine-2-carboxylate (320 mg, 97.1% yield) as a white solid, which was used in the next step directly without further purification. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 468.9.

Step 3: Preparation of (2S,4R)-l-(benzenesulfonyl)-4-[2-(8-chloro-4-oxo-chromen-2-y l)-5- (trifhioromethyl)phenoxy]pyrrolidine-2-carboxylic acid

To a solution of methyl (2S,4R)-4-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]pyrrolidine-2-carboxylate (120 mg, 250 pmol) in the mixed solvent of THF (10 ml) and Water (1 ml) was added LiOH (20.5 mg, 855 mihoΐ) and the mixture was then stirred at room temperature for 2 hours. After complete conversion of methyl (2S,4R)-4-[2-(8- chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenoxy]pyrrol idine-2-carboxylate to the (2S,4R)-4-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethy l)phenoxy]pyrrolidine-2- carboxylic acid, to the resulting solution was added benzenesulfonyl chloride (195 mg, 1.1 mmol, as the“SM6” in Table 8) and the mixture was then stirred at room temperature for 30 minutes. The mixture was diluted with water (15 mL) and adjusted to pH 3.0 by addition of 2 N HC1. The resulting suspension was then extracted with EtOAc (30 mL) twice. The combined organic layer (60 mL) was washed with brine, dried over Na ₂ S0 ₄ , concentrated in vacuo and the residue was purified by Prep-HPLC to give (2S,4R)-l-(benzenesulfonyl)-4-[2-(8-chloro-4-oxo-chromen-2- yl)-5-(trifluoromethyl)phenoxy]pyrrolidine-2-carboxylic acid (87 mg, 65.1% yield) as a white solid. 1H NMR (DMSO-ifc, 400MHz): d ppm 8.02-8.09 (m, 3H), 7.51-7.61 (m, 4H), 7.45 (s, 1H), 7.07-7.17 (m, 3H), 6.65 (s, 1H), 5.35 (br s, 1H), 4.16 (dd, 7 = 9.5, 7.2 Hz, 1H), 3.85 (dd, 7 =

12.7, 3.4 Hz, 1H), 3.60 (br d, 7 = 12.1 Hz, 1H), 2.61 (br dd, 7 = 13.9, 7.2 Hz, 1H), 2.35 (ddd, 7 = 13.9, 9.6, 4.5 Hz, lH).MS obsd. (ESI ⁺ ) [(M+H) ⁺ j: 594.4.

The following Example B077 to Example B088 were prepared in analogy to the procedure described for the preparation of Example B076, replacing 8-chloro-2-[2-hydroxy-4- (trifluoromethyl)phenyl]chromen-4-one with“CORE”, 1 -(7 e /7-butyl) 2-methyl (2.S',4.S')-4- ((methylsulfonyl)oxy)pyrrolidine-l,2-dicarboxylate with“SM5” in stepl and benzenesulfonyl chloride with“SM6” in step 3. The“CORE”,“SM5” and“SM6” are the reagents indicated in Table 8.

Table 8. Compounds synthesis and characterization

Example C001: 2-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propoxy]acetic acid

Step 1: Preparation of tert-butyl 2-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propoxy]acetate

COOla

To a mixture of 8-chloro-2-[2-hydroxy-4-(trifluoromethyl)phenyl]chromen-4-on e (Int-1, 500.0 mg, 1.47 mmol, as the“CORE” in Table 9), K CO (608.5 mg, 4.4 mmol) in DMF (10 mL) was added ferf-butyl 2-[2-(p-tolylsulfonyloxy)ethoxy]acetate (Int-T3, 533.4 mg, 1.61 mmol, as the“Tail” in Table 9 ) and the mixture was stirred at 80 °C for 4 hours. After the reaction was completed, the mixture was diluted with water (15 mL) and extracted with EtOAc (15 mL) three times. The combined organic layer was washed with brine, dried over Na S0 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (elueted with PE: EtOAc = 3:1 to 1:1) to give ferf-butyl 2-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propoxy]acetate (632 mg, 83.9% yield) as a colorless oil. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 513.1.

Step 2: Preparation of 2-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propoxy]acetic acid

To a mixture of ferf-butyl 2-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propoxy]acetate (2000.0 mg, 3.9 mmol) in DCM (50 mL) was added TFA(5.0 mL, 64.9 mmol) and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was concentrated in vacuo. The residue was triturated with EtOAc(30 mL) and then filtered, the solid was collected and dried in vacuo to give 2-[3-[2-(8- chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phenoxy]propox y]acetic acid (1580 mg, 88.7 % yield) as a white solid. 1H NMR (DMSO-ife, 400MHz): d ppm 8.21-8.27 (m, 1H), 8.08-8.15 (m, 1H), 7.87-7.99 (m, 1H), 7.45-7.58 (m, 3H), 7.29-7.36 (m, 1H), 4.36-4.48 (m, 2H), 4.01-4.10 (m, 2H), 3.73-3.83 (m, 2H), 2.16-2.30 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 457.1.

Example C002: 2-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methyl-phenoxy]propo xy]acetic acid

Example C002 was prepared in analogy to the procedure described for the preparation of Example C001 by using 8-chloro-2-(2-hydroxy-4-methyl-phenyl)chromen-4-one (Int-2) as the starting materials instead of 8-chloro-2-[2-hydroxy-4-(trifluoromethyl)phenyl]chromen-4-on e (Int-1) in Step ppm 12.42 (s, 1H), 7.96-8.03 (m, 2H), 7.83- 7.93 (m, 1H), 7.44-7.53 (m, 1H), 7.10-7.16 (m, 1H), 7.07-7.10 (m, 1H), 6.99-7.04 (m, 1H), 4.19- 4.29 (m, 2H), 3.97-4.04 (m, 2H), 3.60-3.70 (m, 2H), 2.43 (s, 3H), 2.01-2.10 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 403.1.

Example C003-A and Example C003-B: C7s-3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid and tram— 3-[2-[5-bromo-2-(8-chloro-4-oxo- chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid

Step 1: preparation of methyl 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylate

C003a

To a mixture of 2-(4-bromo-2-hydroxy-phenyl)-8-chloro-chromen-4-one (Int-4, 300.0 mg, 0.850 mmol) and methyl 3-[2-(p-tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate ( Int-Tl,

336.24 mg, 1.02 mmol) in DMF (5 mL) was added K ₂ CO ₃ (176.89 mg, 1.28 mmol) at 25 °C and the mixture was then stirred at 80 °C for 16 hours. After the reaction was completed, the mixture was poured into water (50 mL) and extracted with EtOAc (100 mL) twice. The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with PE: EtOAc = 3:1 to 1:1) to give methyl 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylate (300 mg, 69.4% yield) as a yellow solid. ¹ 11 NMR (DMSO-ife, 400MHz): d ppm 7.95-8.02 (m, 2H), 7.90 (s, 1H), 7.85-7.94 (m, 1H), 7.46-7.53 (m, 2H), 7.37-7.43 (m, 1H), 7.31 (s, 1H), 4.27-4.35 (m, 2H), 4.20 (t, J = 6.8 Hz, 0.6H), 3.96 (t, J = 7.0 Hz, 0.4H), 3.66-3.73 (m, 2H), 3.53-3.61 (m, 3H), 3.02-3.11 (m, 0.6 H), 2.60-2.67 (m, 0.4 H), 2.36-2.42 (m, 2H), 2.17-2.29 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 509.3.

Step 2: preparation of C¾-3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid and tram— 3-[2-[5-bromo-2-(8-chloro-4-oxo- chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid

To a mixture of methyl 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylate (300.0 mg, 0.590 mmol) in THF (3 mL) and water (1 mL) was added I.iOI I*H ₂ 0 (74.37 mg, 1.77 mmol) at 25 °C and the mixture was then stirred at 25 °C for 3 hours. After the reaction was completed, the mixture was poured into water (30 mL) and adjusted to pH ~5 by addition of HC1 (4 N). The resulting solution was then extracted with EtOAc (50 mL) twice. The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo to give the crude 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid. The crude was purified by Prep-HPLC to give two sets of diastereomers of the 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid with cis- and trans- configuration, one of which is characterized as Example C003-A (25 mg, 8.3 %) and the other is Example C003-B (48 mg, 16.0 %).

Example C003-A: NMR (DMSO-ifc, 400MHz): d ppm 12.10 (br s, 1H), 7.98 (br d, J = 7.7 Hz, 2H), 7.90 (br d, J = 8.4 Hz, 1H), 7.35-7.57 (m, 3H), 7.13-7.27 (m, 1H), 4.23-4.40 (m, 2H), 3.86-4.01 (m, 1H), 3.68-3.72 (m, 2H), 2.30-2.47 (m, 3H), 1.94-2.06 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:495.0 . ExampleC003-B : 1H NMR (DMSO-ifc, 400MHz): d ppm 11.28-12.64 (m, 1H), 7.72-8.19 (m, 3H), 7.14-7.67 (m, 4H), 4.07-4.39 (m, 3H), 3.51-3.56 (m, 2H), 2.83-3.08 (m, 1H), 2.40 (br s, 2H), 2.24 (br s, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:495.0.

Example C004: 3-[2-[5-chloro-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid

C004

Step 1: Preparation of methyl 3-[2-[5-chloro-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylate

C004a

To a solution of 8-chloro-2-(4-chloro-2-hydroxy-phenyl)chromen-4-one(Int-35, 200.0 mg, 0.650 mmol) and K CO (180.0 mg, 1.3 mmol) in DMF (5 mL) was added methyl 3-[2-(p- tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate (213.84 mg, 0.650 mmol) and the reaction mixture was stirred at 80 °C for 16 hours. The reaction mixture was then poured into water (30 mL) and extracted with EtOAc (30 mL) twice. The combined organic layer was washed with brine, dried over Na S0 and concentrated in vacuo to give the crude methyl 3-[2-[5-chloro-2- (8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobutanecarbo xylate (210 mg, 55.68% yield) as a yellow solid, which was used in the next step directly without further purification.

Step 2: Preparation of 3-[2-[5-chloro-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid

C004 To a solution of methyl 3-[2-[5-chloro-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylate (210.0 mg, 0.450 mmol) in DMF (5 mL) was added sodium hydroxide (54.4 mg, 1.36 mmol) at 20 °C and the reaction mixture was stirred at 20 °C for 3 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was purified by Prep-HPLC to give the product 3-[2-[5-chloro-2-(8-chloro-4-oxo- chromen-2-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid (20.4 mg, 9.85% yield) as a yellow solid. 1H NMR (DMSO-ife, 400MHz): d ppm 7.91-8.02 (m, 3H), 7.46 (t, 7 = 7.9 Hz, 1H), 7.19- 7.38 (m, 3H), 4.27-4.34 (m, 2H), 4.15-4.22 (m, 1H), 3.662-3.72 (m, 2H), 2.86-2.95 (m, 1H), 2.35-2.41 (m, 2H), 2.10-2.24 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 449.6.

Example C005: 2-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]ethoxy]acetic acid

Step 1: Preparation of methyl 2-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]ethoxy]acetate

C005a

Compound C005a was prepared in analogy to the procedure described for the preparation of compound C003a by using 8-chloro-2-[2-hydroxy-4-(trifluoromethyl)phenyl]chromen-4-on e (Int-1) and methyl 2-[2-(p-tolylsulfonyloxy)ethoxy]acetate (Int-T4) as the starting materials instead of 2-(4-bromo-2-hydroxy-phenyl)-8-chloro-chromen-4-one (Int-4) and methyl 3-[2-(p- tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate (Int-Tl) in Step 1.

Step 2: Preparation of 2-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]ethoxy]acetic acid

To a solution of methyl 2-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy] ethoxy] acetate (400 mg, 876 mihoΐ) in the THF(20 mL)/water (5 mL) was added LiOH (220 mg, 5.25 mmol). The reaction was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was purified by Prep-HPLC to give 2-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy] ethoxy] acetic acid (128.4, 31.8% yield) as a white solid. ¹ 11 NMR (DMSO-ife, 400MHz): d ppm 8.11-8.20 (m, 1H), 7.96-8.05 (m, 2H), 7.48-7.64 (m, 3H), 7.21- 7.28 (m, 1H), 4.40-4.48 (m, 2H), 4.13 (s, 2H), 3.83-3.97 (m, 2H). (ESI ⁺ ) [(M+H) ⁺ ]: 443.1.

Example C006: 2-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy] acetic acid

Step 1: Preparation of methyl 2-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]acetate

C006a

Compound C006a was prepared in analogy to the procedure described for the preparation of compound C003a by using methyl 2-[2-(p-tolylsulfonyloxy)ethoxy]acetate (Int-T4) as the starting materials instead of methyl 3-[2-(p-tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate

(Int-Tl) in Step 1. Step 2: Preparation of 2-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]acetic acid

To a solution of methyl 2-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy] ethoxy] acetate (400 mg, 855 mihoΐ) in a mixed solvent of MeOH (10 ml) and THF (10 ml) was added LiOH (20.5 mg, 855 mihoΐ) and the mixture was stirred at room temperature for 4 hours. After the reaction was completed, the mixture was adjusted to pH ~ 5.0 by addition of concentrated HC1. The resulting solution was concentrated in vacuo and the residue was triturated with EtOH (15 mL). The suspension was then filtered, the solid was collected and dried in vacuo to give 2-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy] acetic acid (220 mg, 50.5% yield) as a yellow solid, ' l l NMR (DMSO- , 400MHz): d ppm 8.00 (dd, .1 = 7.9, 2.1 Hz, 2H), 7.92 (d, J = 8.6 Hz, 1H), 7.47-7.57 (m, 2H), 7.43 (dd, J = 8.5, 1.8 Hz, 1H), 7.23 (s, 1H), 4.31-4.37 (m, 2H), 3.82-3.89 (m, 2H), 3.68-3.73 (m, 2H). (ESI ⁺ ) [(M+H) ⁺ ]: 453.0.

The following Example C009 to Example C019 were prepared in analogy to the procedure described for the preparation of Example C001. By replacing ferf-butyl 2-[2-(p- tolylsulfonyloxy)ethoxy] acetate with“Tail”, 8-chloro-2-[2-hydroxy-4-

(trifluoromethyl)phenyl]chromen-4-one with“CORE” in step 1. The Tail” and“CORE” are the reagents indicated in Table 9.

Table 9. Compounds synthesis and characterization

The following compounds C020 to C058 were preparec in analogy to the procedure described for the preparation of example C005. By replacing methyl 2-[2-(p- tolylsulfonyloxy)ethoxy] acetate with“Tail”, 8-chloro-2-[2-hydroxy-4- (trifluoromethyl)phenyl]chromen-4-one with“CORE” in step 1. The“Tail” and“CORE” are the reagents indicated in Table 8.

The following compounds C025 to C024 were prepared in analogy to the procedure described for the preparation of example C003-A and C003-B. By replacing methyl 3-[2-(p- tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate (Int-Tl) with“Tail”, 2-(4-bromo-2-hydroxy- phenyl)-8-chloro-chromen-4-one (Int-4) with“CORE” in step 1. The“CORE” and“Tail” are the reagents indicated in Table 9.

Table 9. Compounds synthesis and characterization

Example C060-A and Example C060-B: C7s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4- methoxy-phenoxy]ethoxy]cyclobutanecarboxylic acid and 7 Y»/s-3-[2-[2-(8-chloro-4-oxo- chromen-2-yl)-4-methoxy-phenoxy]ethoxy]cyclobutanecarboxylic acid

C060-A,C060-B

Step 1: Preparation of 2-hydroxy-5-methoxy-benzaldehyde

C060a

Compound C060a was prepared in analogy to the procedure described for the preparation of compound Int-5a by using 4-methoxyphenol as the starting material instead of 3-chloro-4- methyl-phenol in Step 1.

Step 2: Preparation of methyl 3-[2-(2-formyl-4-methoxy- phenoxy)ethoxy]cyclobutanecarboxylate

C060b

To a mixture of 2-hydroxy-5-methoxybenzaldehyde (550mg, 3.61 mmol), methyl 3-[2-(p- tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate ( Int-Tl, 600 mg, 1.95 mmol) in DMF (10 mL) was added K CO (1.5 g, 10.8 mmol) and the mixture was then stirred at 50 °C for 16 hours. After the reaction was completed, the mixture was diluted with water (50 mL) and extracted with EtOAc (50 mL) three times. The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with PE:EtOAc= 100:1 to 3:1) to give methyl 3-[2-(2-formyl-4-methoxy- phenoxy)ethoxy]cyclobutanecarboxylate (600 mg, 53.8 % yield) as a yellow oil.

(ESI ⁺ )[(M+H) ⁺ ]309.1.

Step 3: Preparation of 3-[2-[2-[(£')-3-(3-chloro-2-hydroxy-phenyl)-3-oxo-prop-l-en yl]-4- methoxy-phenoxy]ethoxy]cyclobutanecarboxylic acid

C060c

A mixture of KOH (395 mg, 7.03 mmol), methyl 3-(2-(2-formyl-4- methoxyphenoxy)ethoxy)cyclobutane-l-carboxylate (361 mg, 1.17 mmol) and l-(3-chloro-2- hydroxyphenyl)ethan-l-one (200 mg, 1.17 mmol) in ethanol (50 mL) was stirred at 80 °C overnight. After the reaction was completed, the mixture was adjusted to PH~2 by addition of 6N HC1, the resulting suspension was then filtered, the solid was collected and dried in vacuo to give 3-[2-[2-[(£)-3-(3-chloro-2-hydroxy-phenyl)-3-oxo-prop-l-eny l]-4-methoxy- phenoxyjethoxyjcyclobutanecarboxylic acid (500 mg, 95.4 % yield) as a yellow solid.

(ESI ⁺ )[(M+H) ⁺ ]447.1.

Step 4: Preparation of C¾-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid and 7>Y»/s-3-[2-[2-(8-chloro-4-oxo-chromen-2- yl)-4-methoxy-phenoxy]ethoxy]cyclobutanecarboxylic acid

C060-A,C060-B

To a mixture solution of 3 - 12 - 12-|(/7)-3-(3-chloro-2-hydroxy-phenyl)-3-oxo-prop- 1 -cnyl]-4- methoxy-phenoxyjethoxyjcyclobutanecarboxylic acid (500 mg, 1.12 mmol) in DMSO (30 mL) was added E (28.4 mg, 112 pmol) and the mixture was then stirred at 125 °C for 3hours. After the reaction was completed, the reaction was quenched with 2N Na ₂ S ₂ C>3 solution (15 mL) and the resulting suspension was filtered. The solid cake was collected to give the crude 3-[2-[2-(8- chloro-4-oxo-chromen-2-yl)-4-methoxy-phenoxy]ethoxy]cyclobut anecarboxylic acid, which was further purified by Prep-HPLC to give two sets of diastereomers of the 3-[2-[2-(8-chloro-4-oxo- chromen-2-yl)-4-methoxy-phenoxy]ethoxy]cyclobutanecarboxylic acid with cis- and irans- configuration, one of which is characterized as Example C060-A (90 mg, 17.7 %) and the other is Example C060-B (90 mg, 17.7 %) as yellow powder.

Example OOόO-A^H NMR (DMSO-ife, 400MHz): d ppm. 12.17 (s, 1H), 7.94-8.03 (m, 2H), 7.44-7.58 (m, 2H), 7.15-7.26 (m, 3H), 4.16-4.27 (m, 2H), 3.88-4.01 (m, 1H), 3.81 (s, 3H), 3.62- 3.72 (m, 2H), 2.51-2.54 (m, 1H), 2.35-2.45 (m, 2H), 1.92-2.04 (m, 2H). (ESI ⁺ ) [(M+H) ⁺ ]: 445.1.

Example OOόO-B^H NMR (DMSO-ifc, 400MHz): d ppm 12.15 (s, 1H), 8.00 (d, J = 8.1 Hz, 2H), 7.57 (d, J = 2.9 Hz, 1H), 7.49 (t, J = 7.9 Hz, 1H), 7.39 (s, 1H), 7.06-7.25 (m, 2H), 4.19-4.28 (m, 2H), 4.09-4.19 (m, 1H), 3.89 (s, 3H), 3.58-3.69 (m, 2H), 2.76-3.01 (m, 1H), 2.32-2.42 (m, 2H), 2.14-2.28 (m, 2H). (ESI ⁺ )[(M+H) ⁺ ]445. l.

Example C061: 3-[2-[[4-(8-chloro-4-oxo-chromen-2-yl)-3- pyridyl]oxy]ethoxy]cyclobutanecarboxylic acid

Step 1: Preparation of methyl 3-[2-[(4-formyl-3- pyridyl)oxy]ethoxy]cyclobutanecarboxylate

C061a

Compound C061a was prepared in analogy to the procedure described for the preparation of compound C060b by using 3-hydroxypyridine-4-carbaldehyde as the starting material instead of 2-hydroxy-5-methoxybenzaldehyde in Step 2.

Step 2: Preparation of methyl 3-[2-[[4-[(£')-3-(3-chloro-2-hydroxy-phenyl)-3-oxo-prop-l- enyl]-3-pyridyl]oxy]ethoxy]cyclobutanecarboxylate

C061b

To a solution of l-(3-chloro-2-hydroxy-phenyl)ethanone (128.27 mg, 0.750 mmol), potassium tert-butoxide (126.56 mg, 1.13 mmol) in THF (30 mL) was added methyl 3-[2-[(4-formyl-3- pyridyl)oxy]ethoxy]cyclobutanecarboxylate (210.0 mg, 0.750 mmol) and the mixture was stirred at room temperature for 3 hours. The mixture was concentrated in vacuo and the residue was adjusted to pH~5 by addition of 1N HC1. The mixture was extracted with EtOAc (20 mL) three times. The combined organic layer was dried over Na ₂ S0 ₄ and concentrated in vacuo to give methyl 3-|2-| |4-|(/7)-3-(3-chloro-2-hydroxy-phenyl)-3-oxo-prop- 1 -cnyl]-3- pyridyl]oxy]ethoxy]cyclobutanecarboxylate (273 mg, 84.0% yield) as a light brown oil.MS obsd. (ESI ⁺ ) [(M+H) ⁺ j: 432.1.

Step 3: Preparation of methyl 3-[2-[[4-(8-chloro-4-oxo-chromen-2-yl)-3- pyridyl]oxy]ethoxy]cyclobutanecarboxylate

C061c

A mixture of methyl 3- 12- 114- 1 ( A)-3 -(3-chloro-2-hydrox y-phcny 1 )-3 -oxo-prop- 1 -cnyl]-3- pyridyl]oxy]ethoxy]cyclobutanecarboxylate (273.0 mg, 0.630 mmol) and iodine (8.02 mg, 0.030 mmol) in DMSO (5 mL) was stirred at 140 °C for 3 hours. The mixture was diluted with water (20 mL) and the resulting suspension was filtered. The solid was collected and dried in vacuo to give methyl 3-[2-[[4-(8-chloro-4-oxo-chromen-2-yl)-3- pyridyl]oxy]ethoxy]cyclobutanecarboxylate (200 mg, 73.6% yield) as a yellow solid. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 430.0.

Step 4: Preparation of 3-[2-[[4-(8-chloro-4-oxo-chromen-2-yl)-3- pyridyl]oxy]ethoxy]cyclobutanecarboxylic acid

A mixture of methyl 3-[2-[[4-(8-chloro-4-oxo-chromen-2-yl)-3- pyridyl]oxy]ethoxy]cyclobutanecarboxylate (300.0 mg, 0.700 mmol) and LiOH (0.02 mL, 2.09 mmol) in a mixed solvent of THF (5 mL) and water (5 mL) was stirred at room temperature for 0.5 hour. The mixture was concentrated in vacuo and the residue was purified by Prep-HPLC to give 3-[2-[[4-(8-chloro-4-oxo-chromen-2-yl)-3-pyridyl]oxy]ethoxy] cyclobutanecarboxylic acid (16.4 mg, 5.48% yield) as a yellow solid ' l l NMR (DMSO-d ₆ , 400MHz): d ppml2.l9 (s, 1H), 8.60 (s, 1H), 8.44 (d, 7 = 5.1 Hz, 1H), 8.07 (d, 7 = 5.1 Hz, 1H), 7.97 (d, 7 = 7.9 Hz, 1H), 7.82 (d, 7 = 7.5 Hz, 1H), 7.37 (t, 7 = 7.7 Hz, 1H), 7.15 (d, 7 = 9.0 Hz, 1H), 4.33-4.46 (m, 2H),

4.15-4.24 (m, 0.4H), 3.94-4.04 (m, 0.6H), 3.72 (d, 7 = 4.2 Hz, 2H), 2.81-3.04 (m, 1H), 2.44 (dd, 7 = 10.8, 6.4 Hz, 2H), 2.11-2.29 (m, 1H), 1.91-2.05 (m, 1H). MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 416.1. Example C062: 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(2-oxooxazolidin-3- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid

Step 1: preparation of methyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(2-oxooxazolidin-3- yl)phenoxy]ethoxy]cyclobutanecarboxylate

C062a

To a solution of methyl 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylate (C003a, 300.0 mg, 0.590 mmol), 2-oxazolidone (154.35 mg, 1.77 mmol) and CS CO (385.01 mg, 1.18 mmol) in DMF (4 mL) were added Cul (202.1 mg, 1.18 mmol), N,N-dimethylethylenediamine (208.33 mg, 2.36 mmol) under N atmosphere. The mixture was then stirred at 110 °C for 4 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with PE:EtOAc =5:1 to 2:1) to give methyl 3-[2-[2- (8-chloro-4-oxo-chromen-2-yl)-5-(2-oxooxazolidin-3- yl)phenoxy]ethoxy]cyclobutanecarboxylate (290 mg, 93.6% yield) as yellow solid. ¹ 11 NMR (DMSO-ife, 400MHz): d ppm 7.94-8.06 (m, 3H), 7.41-7.54 (m, 2H), 7.28-7.38 (m, 1H), 7.23 (s, 1H), 4.40-4.58 (m, 2H), 4.10-4.33 (m, 5H), 3.73 (br d, 7 = 2.8 Hz, 2H), 3.52-3.65 (s, 3H), 2.23- 2.48 (m, 4H), 1.99-2.09 (m, 1H). (ESI ⁺ )[(M+H) ⁺ ]:5l4.2.

Step 2: preparation of 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(2-oxooxazolidin-3- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid

To a solution of methyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(2-oxooxazolidin-3- yl)phenoxy]ethoxy]cyclobutanecarboxylate (150.0 mg, 0.290 mmol) in THF (5 mL)/water (0.500 mL) was added LiOH (11 mg, 0.500 mmol). The mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the mixture was adjusted to pH~5 by addition of 2M HC1. The resulting suspension was then filtered and the solid was collected. The solid was then purified by preparative HPLC to give 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(2- oxooxazolidin-3-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid (60 mg, 38.24% yield) as a yellow solid, ' l l NMR (DMSO-ife, 400MHz): d ppm 12.15 (br s, 1H), 8.07 (t, 7=8.9 Hz, 1H),

8.01 - 7.94 (m, 2H), 7.53 (s, 1H), 7.48 (t, 7=7.9 Hz, 1H), 7.39 - 7.31 (m, 2H), 4.55 - 4.45 (m, 2H),

4.28 (br s, 2H), 3.91 - 4.22 (m, 3H), 3.80 - 3.68 (m, 2H), 3.04 - 2.91 (m, 1H), 2.43 - 2.36 (m, 2H),

2.29 - 2.20 (m, 1H), 2.10 - 1.92 (m, 1H). (ESI ⁺ )[(M+H) ⁺ ]:500.3.

Example C063-A and Example C063-B: C7s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(2- oxopyrrolidin-l-yl)phenoxy]ethoxy]cyclobutanecarboxylic acid and 7>YM.V-3-[2-[2-(8- chloro-4-oxo-chromen-2-yl)-5-(2-oxopyrrolidin-l-yl)phenoxy]e thoxy]cyclobutanecarboxylic acid

C063-A, C063-B

Step 1: preparation of methyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(2-oxopyrrolidin-l- yl)phenoxy]ethoxy]cyclobutanecarboxylate

C063a

Compound C063a was prepared in analogy to the procedure described for the preparation of example C062a by using pyrrolidin-2-one as the starting material instead of 2-oxazolidone. (ESI ⁺ )[(M+H) ⁺ ] :512.1.

Step 2: preparation of C¾-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(2-oxopyrrolidin -l- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid and 7>Y»/s-3-[2-[2-(8-chloro-4-oxo-chromen- 2-yl)-5-(2-oxopyrrolidin-l-yl)phenoxy]ethoxy]cyclobutanecarb oxylic acid

C063-A, C063-B

Example C063-A and C063-B were prepared in analogy to the procedure described for the preparation of example C003-A and C003-B by using methyl 3-[2-[2-(8-chloro-4-oxo-chromen- 2-yl)-5-(2-oxopyrrolidin-l-yl)phenoxy]ethoxy]cyclobutanecarb oxylate as the starting material instead of methyl 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylate in Step 2.

Example ppm 7.96-8.07 (m, 3H), 7.69-7.74 (m,

1H), 7.43-7.52 (m, 2H), 7.25 (s, 1H), 4.23-4.29 (m, 2H), 3.87-4.01 (m, 3H), 3.70-3.79 (m, 2H), 2.55-2.59 (m, 2H), 2.41-2.47 (m, 2H), 2.07-2.17 (m, 2H), 1.94-2.06 (m, 3H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:498.2.

Example C063-B: 1H NMR (DMSO-rfc, 400MHz): d ppm 8.07 (d, J = 8.8 Hz, 1H), 7.99 (d, J = 7.8 Hz, 2H), 7.71 (d, J = 1.7 Hz, 1H), 7.44-7.51 (m, 2H), 7.38 (s, 1H), 4.24-4.30 (m, 2H), 4.19 (t, 7 = 6.8 Hz, 1H), 3.92 (t, J = 7.1 Hz, 2H), 3.70-3.75 (m, 2H), 2.93-3.01 (m, 1H), 2.55-2.60 (m, 2H), 2.36-2.44 (m, 2H), 2.21-2.28 (m, 2H), 2.06-2.15 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:498.2.

Example C064-A and Example C064-B: C¾-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- methylsulfanyl-phenoxy]ethoxy]cyclobutanecarboxylic acid and traras-3-[2-[2-(8-chloro-4- oxo-chromen-2-yl)-5-methylsulfanyl-phenoxy]ethoxy]cyclobutan ecarboxylic acid

C064-A,C064-B

Step 1: preparation of methyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methylsulfanyl- phenoxy]ethoxy]cyclobutanecarboxylate

C064a

A mixture of methyl 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylate (C003a, 50 mg, 98.5 pmol),DABCO (22.1 mg, 197 pmol), Cul (37.5 mg, 197 pmol) in DMSO (5 mL) was microwaved at 170 °C for 2.5 hour. After the reaction was completed, the mixture was diluted with EtOAc (30 mL) and the suspension was then filtered through silica pad. The filtrate was concentrated in vacuo to give a dark solution of methyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methylsulfanyl- phenoxy]ethoxy]cyclobutanecarboxylate in DMSO, which was used in the next step directly without further purification. (ESI ⁺ )[(M+H) ⁺ ]:475.l

Step 2: preparation of C¾-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methylsulfanyl- phenoxy]ethoxy]cyclobutanecarboxylic acid and iraras-3-[2-[2-(8-chloro-4-oxo-chromen-2- yl)-5-methylsulfanyl-phenoxy]ethoxy]cyclobutanecarboxylic acid

C064-A,C064-B

Example C064-A and C064-B were prepared in analogy to the procedure described for the preparation of example C003-A and C003-B by using methyl 3-[2-[2-(8-chloro-4-oxo-chromen- 2-yl)-5-(2-oxopyrrolidin-l-yl)phenoxy]ethoxy]cyclobutanecarb oxylate as the starting material instead of methyl 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylate in Step 2.

Example ppm 7.95-8.05 (m, 3H), 7.49 (t, J = 7.9 Hz, 1H), 7.19-7.29 (m, 1H), 7.05-7.14 (m, 2H), 4.26-4.39 (m, 2H), 3.93-4.04 (m, 1H), 3.68- 3.79 (m, 2H), 2.57-2.62 (m, 4H), 2.39-2.47 (m, 2H), 1.97-2.08 (m, 2H). MS obsd. (ESI ⁺ )

[(M+H) ⁺ ]: 461.2.

Example C064-B: 1H NMR (DMSO-rfc, 400MHz): d ppm 7.96-8.02 (m, 3H), 7.49 (t, J = 7.9 Hz, 1H), 7.36 (s, 1H), 7.07-7.13 (m, 2H), 4.31-4.36 (m, 2H), 4.15-4.24 (m, 1H), 3.67-3.72 (m, 2H), 2.89-3.00 (m, 1H), 2.58 (s, 3H), 2.40 (qd, J = 6.6, 3.7 Hz, 2H), 2.16-2.28 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 461.2.

Example C065-A and Example C065-B: C7v- methyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)- 5-methylsulfonyl-phenoxy]ethoxy]cyclobutanecarboxylate and Trans-methyl 3-[2-[2-(8- chloro-4-oxo-chromen-2-yl)-5-methylsulfonyl-phenoxy]ethoxy]c yclobutanecarboxylate

C065-A,C065-B

To the solution of methyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methylsulfanyl- phenoxy]ethoxy]cyclobutanecarboxylate (142 mg, 299 pmol) in the DCM (25 mL) was added m-CPBA (103 mg, 598 pmol), the mixture was then stirred at room temperature overnight. After the reaction was completed, the mixture was purified Prep-HPLC to give two sets of diastereomers of the methyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methylsulfanyl- phenoxy]ethoxy]cyclobutanecarboxylate with cis- and trans- configuration, one of which is characterized as Example C065-A (3.5 mg, 1.9 % yield) and the other is Example C065-B (6.5 mg, 3.9 % yield) as white solid.

Example C065-A: 1H NMR (DMSO-ifc, 400MHz): d ppm 8.19 (d, J = 8.7 Hz, 1H), 8.03 (ddd, / = 7.9, 6.5, 1.5 Hz, 2H), 7.72-7.76 (m, 2H), 7.52 (s, 1H), 7.24 (s, 1H), 4.39-4.43 (m, 2H), 3.92-3.99 (m, 1H), 3.70-3.75 (m, 2H), 3.56 (s, 3H), 3.31 (s, 3H), 2.58-2.64 (m, 1H), 2.38-2.43 (m, 2H), 1.98-2.03 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 507.3.

Example ppm 8.18-8.24 (m, 1H), 7.99-8.06 (m, 2H), 7.73-7.77 (m, 2H), 7.52 (t, 7 = 7.9 Hz, 1H), 7.34 (s, 1H), 4.38-4.45 (m, 2H), 4.19 (quin, J = 6.6 Hz, 1H), 3.69-3.75 (m, 2H), 3.59 (s, 3H), 3.33 (s, 3H), 2.99-3.07 (m, 1H), 2.35-2.42 (m, 2H), 2.09-2.26 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 507.3.

Example C066-A and Example C066-B: C¾-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- thiazol-2-yl-phenoxy]ethoxy]cyclobutanecarboxylic acid and trans- 3-[2-[2-(8-chloro-4-oxo- chromen-2-yl)-5-thiazol-2-yl-phenoxy]ethoxy]cyclobutanecarbo xylic acid

Step 1: preparation of methyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-thiazol-2-yl- phenoxy]ethoxy]cyclobutanecarboxylate

C066a

A mixture of methyl 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylate (C003a, 80 mg, 158 pmol),Pd(OAc) ₂ (35.4 mg, 158 pmol), Cul (60 mg, 315 pmol), thiazole (26.8 mg, 315miho1) in DMF (2 ml) was stirred at 150 °C under microwave condition for 3 hours. After the reaction was completed, the mixture was diluted with EtOAc (30 ml) and then filtered, the filtrate was concentrated in vacuo to give the crude methyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-thiazol-2-yl- phenoxy]ethoxy]cyclobutanecarboxylate (80 mg, 100% yield ) as a yellow solid. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 512.2.

Step 2: preparation of C¾-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-thiazol-2-yl- phenoxy]ethoxy]cyclobutanecarboxylic acid and Ivans- 3-[2-[2-(8-chloro-4-oxo-chromen-2- yl)-5-thiazol-2-yl-phenoxy]ethoxy]cyclobutanecarboxylic acid

Example C066-A and C066-B were prepared in analogy to the procedure described for the preparation of example C003-A and C003-B by using methyl 3-[2-[2-(8-chloro-4-oxo-chromen- 2-yl)-5-thiazol-2-yl-phenoxy]ethoxy]cyclobutanecarboxylate as the starting material instead of methyl 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy] cyclobutanecarboxylate in Step 2.

Example C066-A: 1H NMR (DMSO-ifc, 400MHz): d ppm 8.14 (d, J = 8.6 Hz, 1H), 7.98- 8.05 (m, 3H), 7.93 (d, J = 3.2 Hz, 1H), 7.79 (td, J= 4.2, 1.5 Hz, 2H), 7.48-7.54 (m, 1H), 7.31 (s, 1H), 4.39-4.44 (m, 2H), 3.93-4.00 (m, 1H), 3.73-3.79 (m, 2H), 2.47-2.49 (m, 1H), 2.36-2.46 (m, 2H), 1.98-2.05 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 498.1.

Example ppm 8.17 (d, J = 8.7 Hz, 1H), 8.00- 8.05 (m, 3H), 7.94 (d, J = 3.2 Hz, 1H), 7.76-7.83 (m, 2H), 7.48-7.54 (m, 1H), 7.44 (s, 1H), 4.41- 4.46 (m, 2H), 4.16-4.24 (m, 1H), 3.72-3.76 (m, 2H), 2.94-2.99 (m, 1H), 2.38-2.44 (m, 2H), 2.21- 2.27 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 498.1.

Example C067-A and Example C067-B: C¾-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- morpholino-phenoxy]ethoxy]cyclobutanecarboxylic acid and iraras-3-[2-[2-(8-chloro-4-oxo- chromen-2-yl)-5-morpholino-phenoxy]ethoxy]cyclobutanecarboxy lic acid

C067-A,C067-B

The mixture of methyl 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylate (C003a, 80 mg, 158 mihoΐ, ), morpholine (41.2 mg, 473 pmol),K2C03 (65.3 mg, 473 pmol) and RuPhos Pd G2 (12.2 mg, 15.8 pmol) in l,4-Dioxane (3 ml) was stirred at l00°C overnight. After the reaction was completed, to the reaction mixture was added LiOH solution (1N, lmL) and then the mixture was stirred at 50°C for 2hours. The mixture was adjusted to pH~5 by addition of AcOH and the mixture was concentrated in vacuo. The residue was purified by prep-HPLC to give two sets of diastereomers of the 3-[2-[2-(8- chloro-4-oxo-chromen-2-yl)-5-morpholino-phenoxy]ethoxy]cyclo butanecarboxylic acid with cis- and trans- configuration, one of which is characterized as Example C067-A (9.5 mg, 11.5 % yield) and the other is Example C067-B (3.5 mg, 4.2 % yield) as white solid.

Example C067-A: 1H NMR (DMSO-tfc, 400MHz): d ppm 12.11 (br s, 1H), 7.90-8.00 (m, 3H), 7.45 (t, / = 7.9 Hz, 1H), 7.19 (s, 1H), 6.78 (dd, / = 9.0, 2.2 Hz, 1H), 6.66 (d, / = 2.2 Hz,

1H), 4.23-4.33 (m, 2H), 3.95-4.06 (m, 1H), 3.70-3.82 (m, 6H), 2.52-2.58 (m, 1H), 2.40-2.46 (m, 2H), 1.93-2.11 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ j: 500.3.

Example C067-B: 1H NMR (DMSO-tfe, 400MHz): d ppm 12.01-12.32 (m, 1H), 7.90-7.99 (m, 3H), 7.37-7.50 (m, 1H), 7.28-7.34 (m, 1H), 6.78 (dd, / = 9.0, 2.2 Hz, 1H), 6.65 (d, / = 2.0 Hz, 1H), 4.26-4.37 (m, 2H), 4.15-4.24 (m, 1H), 3.68-3.81 (m, 6H), 2.93-3.05 (m, 1H), 2.40 (ddd, / = 9.8, 6.7, 3.4 Hz, 2H), 2.17-2.30 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ j: 500.3.

Example C068: s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-pyrrolidin- l-yl- phenoxy]ethoxy]cyclobutanecarboxylic acid

Step 1: preparation of cis-tert-butyl 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylate

C068a

Compound C068a was prepared in analogy to the procedure described for the preparation of compound C003a by using cis-tert- butyl 3-[2-(p- tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate as the starting material instead of methyl 3-[2- (p-tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate.

Step 2: preparation of ds-tert-hut \ 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-pyrrolidin-l- yl-phenoxy]ethoxy]cyclobutanecarboxylate

C068b

A mixture of cis-tert- butyl 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylate (330.0 mg, 0.600 mmol), pyrrolidine (213.42 mg, 3 mmol), Pd ₂₍ dba)454.96 mg, 0.060 mmol), 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene (34.73 mg, 0.060 mmol) and CS CO (586.6 mg, 1.8 mmol) in l,4-dioxane (7 mL) was stirred at 105 °C for 5 hours. The mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with PE:EtOAc =10:1 to 1: 1) to give cis-tert- butyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-pyrrolidin-l-yl- phenoxy]ethoxy]cyclobutanecarboxylate (250 mg, 77.13% yield) as light yellow oil. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 540.1.

Step 3: preparation of s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-pyrrolidin-l-yl- phenoxy]ethoxy]cyclobutanecarboxylic acid

To a solution of cis-tert- butyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-pyrrolidin-l-yl- phenoxy]ethoxy]cyclobutanecarboxylate (250.0 mg, 0.460 mmol) in DCM (5 mL) was added TFA (2.5 mL, 32.45 mmol) and the mixture was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue was triturated with mixed solvent of EtOAc (3 mL) and PE (15 mL). The suspension was then filtered, the solid was collected and dried in vacuo to give s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-pyrrolidin-l-yl- phenoxy]ethoxy]cyclobutanecarboxylic acid (137.5 mg, 59.6% yield) as light red solid. ¹ 11 NMR (DMSO-ife, 400MHz): d ppm 12.39 - 11.69 (m, 1H), 7.89-7.96 (m, 3H), 7.42 (t, 7 = 7.9 Hz, 1H), 7.15 (s, 1H), 6.37 (d, 7 = 9.0 Hz, 1H), 6.19 (s, 1H), 4.16-4.36 (m, 2H), 3.86-4.12 (m, 1H), 3.65- 3.83 (m, 2H), 2.53-2.64 (m, 4H), 2.39-2.48 (m, 3H), 1.93-2.08 (m, 6H). MS obsd. (ESI ⁺ )

[(M+H) ⁺ ]: 484.7.

Example C069-A and Example C069-B: C¾-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- cyclopropyl-phenoxy]ethoxy]cyclobutanecarboxylic acid and 7’rans-3-[2-[2-(8-chloro-4-oxo- chromen-2-yl)-5-cyclopropyl-phenoxy]ethoxy]cyclobutanecarbox ylic acid

C069-A,C069-B

A mixture of methyl 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylate (C003a, 80 mg, 158 pmol), potassium

cyclopropyltrifluoroborate (35 mg, 236 pmol), Pd/PhTOr (18.2 mg, 15.8 pmol) and K ₂ CO ₃ (54.4 mg, 394 pmol) in l,4-Dioxane (5 mL) and water( lmL) was stirred at l00°C for 3hours. Then to the resulting mixture was added LiOH(22 mg, lmmol) and the mixture was stirred at 50°C for 30minutes. After the reaction was completed, the mixture was adjusted to PH~5 by addition of 6N HC1. The mixture was then concentrated in vacuo and the residue was purified by Prep- HPLC to give two sets of diastereomers of the 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5- cyclopropyl-phenoxyjethoxyjcyclobutanecarboxylic acid with cis- and trans- configuration, one of which is characterized as Example C069-A (10 mg, 13.5 % yield) and the other is Example C069-B (22 mg, 30 % yield) as white solid.

Example ppm 7.98 (d, 7=7.34 Hz, 2H), 7.90 (d, 7=7.58 Hz, 1H), 7.45-7.53 (m, 1H), 7.21 (br. s., 1H), 6.96 (br. s., 1H), 6.90 (d, 7=7.58 Hz, 1H), 4.29 (br. s., 2H), 3.95 (d, 7=5.87 Hz, 1H), 3.72 (br. s., 2H), 2.43 (br. s., 3H), 2.01 (br. s., 3H), 1.06 (d, 7=6.11 Hz, 2H), 0.80-0.90 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ j: 455.1.

Example C069-B: 1H NMR (DMSO-tfe, 400MHz): d ppm 7.88-8.05 (m, 3H), 7.41-7.54 (m, 1H), 7.29-7.37 (m, 1H), 6.90 (dd, J = 8.3, 1.4 Hz, 2H), 4.26-4.38 (m, 2H), 4.13-4.24 (m, 1H), 3.64-3.73 (m, 2H), 2.90-3.02 (m, 1H), 2.35-2.44 (m, 2H), 2.15-2.27 (m, 2H), 1.91-2.06 (m, 1H), 1.02-1.11 (m, 2H), 0.69-0.90 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 455.1.

Example C070: C7s-3-[2-[2-bromo-6-(8-chloro-6-fluoro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid

C070

Step 1: Preparation of 2-(3-bromo-2-hydroxy-phenyl)-8-chloro-6-fluoro-chromen-4-one

C070a

Compound C070a was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 3-bromo-2-hydroxy-benzaldehyde (CAS #: 1829-34-1, Cat.#: SY013143, from Accela ChemBio Inc) as the starting material instead of 4-chloro-2-hydroxy-5- methyl-benzaldehyde in Step 2 and using l-(3-chloro-5-fluoro-2-hydroxy-phenyl)ethanone as the starting material instead of l-(3-chloro-2-hydroxy-phenyl)ethanone in Step 3.

Step 2: Preparation of C7s-3-[2-[2-bromo-6-(8-chloro-6-fluoro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid

Example C070a was prepared in analogy to the procedure described for the preparation of example C004 by using 2-(3-bromo-2-hydroxy-phenyl)-8-chloro-6-fluoro-chromen-4-one as the starting material instead of 8-chloro-2-(4-chloro-2-hydroxy-phenyl)chromen-4-one in Step 1. ¹ 11 NMR (DMSO-ifc, 400MHz): d ppm 12.10 (br s, 1H), 7.79-7.89 (m, 4H), 7.47-7.66 (m, 1H), 7.34 (t, J = 7.7 Hz, 1H), 3.97-4.09 (m, 2H), 3.90 (quin, J = 6.7 Hz, 1H), 3.26-3.45 (m, 3H), 2.08-2.29 (m, 2H), 1.73-2.00 (m, 2H). (ESI ⁺ )[(M+H) ⁺ ]: 511.1. Example C071: C¾-3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-3-fluoro- phenoxy]ethoxy]cyclobutanecarboxylic acid

C071

Step 1: Preparation of 2-(4-bromo-2-fluoro-6-hydroxy-phenyl)-8-chloro-chromen-4-one

C071a

Compound C070a was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 4-bromo-2-fluoro-6-hydroxy-benzaldehyde (CAS #: 1427438-90-1, Cat.#: BD260521, from Bide Pharmtach) as the starting material instead of 4-chloro-2-hydroxy- 5-methyl-benzaldehyde in Step 2.

Step 2: Preparation of cis-tert- butyl 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-3- fluoro-phenoxy]ethoxy]cyclobutanecarboxylate

C071b

A solution of 2-(4-bromo-2-fluoro-6-hydroxy-phenyl)-8-chloro-chromen-4-one (200.0 mg, 0.540 mmol), cis-tert- butyl 3-[2-(p-tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate (200.48 mg, 0.540 mmol) and K ₂ CO ₃ (74.79 mg, 0.540 mmol) in DMF (15 mL) was stirred at 80 °C for 8 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluted with PE:EtOAc = 20:1 to 3:1) to give cis-tert- butyl 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-3-fluoro- phenoxy]ethoxy]cyclobutanecarboxylate (170 mg, 55.32% yield, purity 36.42%) as a light yellow oil.MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 567.0. Step 3: Preparation of s-3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-3-fluoro- phenoxy]ethoxy]cyclobutanecarboxylic acid

To a solution of cis-tert- butyl 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-3-fluoro- phenoxy]ethoxy]cyclobutanecarboxylate (170.0 mg, 0.300 mmol) in DCM (5 mL) was added TFA (2.5 mL, 32.45 mmol) and the mixture was stirred at 20 °C for 5 hours. After the reaction was completed, the mixture was concentrated in vacuo and the residue was purified by Prep- HPLC to give s-3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-3-fluoro- phenoxy]ethoxy]cyclobutanecarboxylic acid (89.7 mg, 58.55% yield) as an off-white solid. ¹ 11 NMR (DMSO-rfc, 400MHz): d ppm 12.07 (br s, 1H), 7.99-8.07 (m, 2H), 7.53 (t, 7 = 7.9 Hz, 1H), 7.38-7.45 (m, 2H), 6.71 (s, 1H), 4.19-4.32 (m, 2H), 3.77 (quin, J = 7.2 Hz, 1H), 3.41-3.62 (m, 2H), 2.16-2.34 (m, 3H), 1.74-1.85 (m, 2H). (ESI ⁺ )[(M+H) ⁺ ]: 511.5.

Example C072: C¾-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dimethoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid

C072

Example C072 was prepared in analogy to the procedure described for the preparation of example C071 by using 8-chloro-2-(2-hydroxy-4,5-dimethoxy-phenyl)chromen-4-one(Int -10) as the starting material instead of 2-(4-bromo-2-fluoro-6-hydroxy-phenyl)-8-chloro-chromen-4-one in Step 2. 1H NMR (DMSO-rfc, 400MHz): d ppm 7.98 (dd, J = 7.9, 2.9 Hz, 2H), 7.60 (s, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.25 (s, 1H), 6.91 (s, 1H), 4.28-4.35 (m, 2H), 3.88-4.00 (m, 4H), 3.82 (s, 3H), 3.67-3.76 (m, 2H), 2.38-2.47 (m, 2H), 1.96-2.06 (m, 2H). (ESI ⁺ )[(M+H) ⁺ ]: 475.1.

Example C073: C7s-3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid

C073

Example C073 was prepared in analogy to the procedure described for the preparation of example C071 by using 2-(4-bromo-2-hydroxy-5-methoxy-phenyl)-8-chloro-chromen-4-on e as the starting material instead of 2-(4-bromo-2-fluoro-6-hydroxy-phenyl)-8-chloro-chromen-4-one in Step 2. 1H NMR (DMSO-ife, 400MHz): d ppml2.08 (br s, 1H), 8.00 (br t, / = 7.5 Hz, 2H), 7.54-7.70 (m, 2H), 7.50 (t, / = 7.8 Hz, 1H), 7.23-7.30 (m, 1H), 4.17-4.36 (m, 2H), 3.87-3.96 (m, 4H), 3.63-3.73 (m, 2H), 2.54-2.61 (m, 1H), 2.33-2.48 (m, 2H), 1.93-2.03 (m, 2H).

(ESI ⁺ )[(M+H) ⁺ ]:523.2.

Example C074: C7s-3-[2-[[7-(8-chloro-4-oxo-chromen-2-yl)-2,3-dihydro-l,4-b enzodioxin-6- yl]oxy]ethoxy]cyclobutanecarboxylic acid

Step 1: Preparation of 6-hydroxy-2, 3-dihydro- l,4-benzodioxine-7-carbaldehyde

C074a

Compound C074a was prepared in analogy to the procedure described for the preparation of compound Int-5a by using 2, 3-dihydro- l,4-benzodioxin-6-ol as the starting material instead of 3-chloro-4-methyl-phenol in Step 1.

Step 2: Preparation of 8-chloro-2-(6-hydroxy-2,3-dihydro-l,4-benzodioxin-7-yl)chrom en-4- one

C074b

Compound C070a was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 6-hydroxy-2,3-dihydro-l,4-benzodioxine-7-carbaldehyde as the starting material instead of 4-chloro-2-hydroxy-5 -methyl- benzaldehyde in Step 2.

Step 3: Preparation of s-3-[2-[[7-(8-chloro-4-oxo-chromen-2-yl)-2,3-dihydro-l,4- benzodioxin-6-yl]oxy]ethoxy]cyclobutanecarboxylic acid

Example C074 was prepared in analogy to the procedure described for the preparation of example C071 by using 8-chloro-2-(6-hydroxy-2, 3-dihydro- l,4-benzodioxin-7-yl)chromen-4- one as the starting material instead of 2-(4-bromo-2-fluoro-6-hydroxy-phenyl)-8-chloro- chromen-4-one in Step 2. 1H NMR (DMSO-ife, 400MHz): d ppm 7.95-7.98 (m, 2H), 7.52 (s, 1H), 7.49 (s, 1H), 7.45 (m, 1H), 7.22 (s, 1H), 6.80 (s, 1H), 4.35 (dd, / = 5.3, 2.1 Hz, 2H), 4.27 (dd, / = 5.3, 2.1 Hz, 2H), 4.17-4.19 (m, 2H), 3.95 (m, 1H), 3.67-3.70 (m, 2H), 2.53 (br s, 1H), 2.41-2.44 (m, 2H), 2.01-2.02 (m, 2H). (ESI ⁺ )[(M+H) ⁺ ]:473.0.

Example C075: C¾-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-(difluoromethyl) -5-methyl- phenoxy]ethoxy]cyclobutanecarboxylic acid

C075

Step 1: Preparation of 4-benzyloxy-2-methyl-benzaldehyde

C075a

To a solution of 4-hydroxy-2-methyl-benzaldehyde (2000.0 mg, 14.69 mmol) in DMF (15 mL) were added potassium carbonate (2436.24 mg, 17.63 mmol) and benzyl bromide (1.83 mL, 15.42 mmol), then the mixture was stirred at 25 °C for 16 hours. After the reaction was completed, the reaction was quenched with water (150 mL) and the resulting solution was extracted with EtOAc (80 mL) three times. The combined organic layer was washed with brine (100 mb), dried over MgS0 ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with PE:EtOAc = 5:1) to give 4- benzyloxy-2-methyl-benzaldehyde (3200 mg, 96.27% yield) as a white solid. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 227.1.

Step 2: Preparation of 4-benzyloxy-5-bromo-2-methyl-benzaldehyde

C075b

To a solution of 4-benzyloxy-2-methyl-benzaldehyde (3200.0 mg, 14.14 mmol) in methanol (40 mL) cooled in ice-bath was added pyridinium tribromide (6784.53 mg, 21.21 mmol) and the mixture was stirred at 25 °C for 3 hours. After the reaction was completed, the reaction was quenched with 10% Na ₂ S0 ₃ solution (150 mL) and the resulting solution was extracted with EtOAc (100 mL) three times. The combined organic layer was washed with brine (100 mb), dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with PE:EtOAc = 5:1) to give 4-benzyloxy-5-bromo-2- methyl-benzaldehyde (3519 mg, 81.54% yield) as a white solid. MS obsd. (ESI ⁺ ) [(M+El) ⁺ ]: 305.0. Step 3: Preparation of methyl 2-benzyloxy-5-formyl-4-methyl-benzoate

C075c

A mixture of 4-benzyloxy-5-bromo-2-methyl-benzaldehyde (3519.0 mg, 11.53 mmol), (dppfhPdCb (2845.97 mg, 3.46 mmol), TEA(4.82 mL, 34.59 mmol) in methanol (100 mL) was stirred under CO (0.5 MPa) at 80 °C for 16 hours. After the reaction was completed and the reaction mixture was concentrated in vacuo. The residue was purified by column

chromatography on silica gel (eluted with PE:EtOAc = 5:1) to give methyl 2-benzyloxy-5- formyl-4-methyl- benzoate (2044 mg, 62.35% yield) as a white solid. MS obsd. (ESI ⁺ ) [(M+H) ¹ ]: 285.2.

Step 4: Preparation of methyl 2-benzyloxy-5-(difluoromethyl)-4-methyl-benzoate

C075d

To a solution of methyl 2-benzyloxy-5-formyl-4-methyl-benzoate (2300.0 mg, 8.09 mmol) in DCM (40 mL) was added DAST (5.34 mL, 40.45 mmol) and then the reaction mixture was stirred at 25 °C for 16 hours. After the reaction was completed, the mixture was poured into ice water (100 mL) and the resulting mixture was extracted with DCM (50 mL) three times. The combined organic layer was washed with brine (50 mL), dried over MgS0 ₄ , filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (PE/EtOAc = 10/1) to give methyl 2-benzyloxy-5-(difluoromethyl)-4-methyl-benzoate (2229 mg, 89.96% yield) as a white solid. MS obsd. (ESI ⁺ ) [(M+Na) ⁺ ]: 329.1.

Step 5: Preparation of [2-benzyloxy-5-(difluoromethyl)-4-methyl-phenyl]methanol

C075e

To a solution of methyl 2-benzyloxy-5-(difluoromethyl)-4-methyl-benzoate (2229.0 mg, 7.28 mmol) in THF (50 mL) was added LiAlEL (1104.68 mg, 29.11 mmol) at 0 °C and the mixture was stirred at 0 °C for 2 hours. After the reaction was completed, the reaction was quenched with 15 % NaOH aqueous solution (1.1 mL) and water (3.3 mL). The resulting mixture was filtered and the filtrate was concentrated in vacuo to give [2-benzyloxy-5- (difluoromethyl)-4-methyl-phenyl]methanol (1824 mg, 90.07% yield) as a white solid, which was used in the next step directly without further purification. MS obsd. (ESI ⁺ )[(M+Na) ⁺ ]: 301.1. Step 6: Preparation of 2-benzyloxy-5-(difluoromethyl)-4-methyl-benzaldehyde

C075f

To a solution of [2-benzyloxy-5-(difluoromethyl)-4-methyl-phenyl]methanol (1824.0 mg, 6.55 mmol) in DCM (50 mL) was added Mn() ₂₍ 5698.06 mg, 65.54 mmol) and the mixture was stirred at 25 °C for 16 hours. After the reaction was completed, the mixture was filtered and the filtrate was concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with PE:EtOAc = 10:1) to give 2-benzyloxy-5-(difluoromethyl)-4-methyl- benzaldehyde (1696 mg, 93.66% yield,) as a white solid. MS obsd. (ESI ⁺ ) [(M+Na) ⁺ ]: 299.1. Step 7: Preparation of (£')-3-[2-benzyloxy-5-(difluoromethyl)-4-methyl-phenyl]-l-( 3-chloro- 2-hydroxy-phenyl)prop-2-en-l-one

C075g

To a solution of l-(3-chloro-2-hydroxy-phenyl)ethanone (950.0 mg, 5.57 mmol) and 2- benzyloxy-5-(difluoromethyl)-4-methyl-benzaldehyde (1692.4 mg, 6.13 mmol) in ethanol (100 mL) was added KOH (3124.4 mg, 55.69 mmol) and the mixture was stirred at 35 °C for 16 hours. After the reaction was completed and the reaction mixture was adjusted to pH~6 by addition of 1N HC1 to give a yellow suspension. The suspension was filtered, the solid was washed with water and then dried in vacuo to give the crude (T')-3-[2-benzyloxy-5-(dinuoromethyl)-4- methyl- phenyl]- 1 -(3-chloro-2-hydroxy-phcnyl)prop-2-cn- 1 -one (2240 mg, 93.79% yield) as a yellow solid which was used in the next step directly without further purification.

Step 8: Preparation of 2-[2-benzyloxy-5-(difluoromethyl)-4-methyl-phenyl]-8-chloro- chromen-4-one

C075h

To a solution of (/O-3-|2-benzyloxy-5-(difluoromethyl)-4- methyl-phenyl ]- 1 -(3-chloro-2- hydroxy-phenyl)prop-2-en-l-one (1250.0 mg, 2.91 mmol) in DMSO (250 mL) was added L

(51.78 mg, 0.200 mmol) and then the reaction mixture was stirred at 140 °C for 6 hours. After the reaction was completed, the reaction mixture was quenched with water (500 mL) and the resulting suspension was filtered. The solid was washed with EtOH and then dried in vacuo to give 2-[2-benzyloxy-5-(difluoromethyl)-4-methyl-phenyl]-8-chloro- chromen-4-one (1114 mg, 89.54% yield) as a light yellow solid which was used in the next step directly without further purification.MS obsd. (ESI ⁺ ) [(M+H) ⁺ j: 427.0.

Step 9: Preparation of 8-chloro-2-[5-(difluoromethyl)-2-hydroxy-4-methyl- phenyl]chromen-4-one

C075i

To a solution of 2-[2-benzyloxy-5-(difluoromethyl)-4-methyl-phenyl]-8-chloro- chromen- 4-one (1100.0 mg, 2.58 mmol) in methanol (80 mL) was added Pd/C (10% Pd on carbon, 55% water) (110.0 mg, 2.58 mmol) and the reaction was stirred under 11 ₂ atmosphere at 25 °C for 12 hours. After the reaction was completed, the mixture was filtered through celite, the filtrate was concentrated in vacuo to give the crude 8-chloro-2-[5-(difluoromethyl)-2-hydroxy-4-methyl- phenyl]chromen-4-one (600 mg, 69.14% yield) as a dark brown solid, which was used in the next step directly without further purification. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 337.0.

Step 10: Preparation of C¾-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-(difluoromethyl) -5- methyl-phenoxy]ethoxy]cyclobutanecarboxylic acid

Example C075 was prepared in analogy to the procedure described for the preparation of example C071 by using 8-chloro-2-[5-(difluoromethyl)-2-hydroxy-4-methyl-phenyl]chr omen-4- one as the starting material instead of 2-(4-bromo-2-fluoro-6-hydroxy-phenyl)-8-chloro- chromen-4-one in Step 2. 1H NMR (DMSO-i¾, 400MHz): d ppml2.08 (br s, 1H), 8.18 (s, 1H), 7.97-8.03 (m, 2H), 7.49 (t, / = 7.9 Hz, 1H), 7.11-7.39 (m, 1H), 7.24 (s, 2H), 4.30-4.37 (m, 2H), 3.96 (quin, J = 7.3 Hz, 1H), 3.69-3.78 (m, 2H), 2.38-2.52 (m, 6H), 1.95-2.05 (m, 2H).

(ESI ⁺ )[(M+H) ⁺ ]:478.9.

Example C076: C¾-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-hydroxy-4-methox y- phenoxy]ethoxy]cyclobutanecarboxylic acid

Step 1: Preparation of 2-hydroxy-5-methoxy-4-[(4-methoxyphenyl)methoxy]benzaldehyde

C076a

To a mixture of 2,4-dihydroxy-5-methoxybenzaldehyde (785 mg, 4.67 mmol), sodium bicarbonate (471 mg, 5.6 mmol) in DMF (15 mL) was added l-(chloromethyl)-4- methoxybenzene (877 mg, 5.6 mmol) and the mixture was stirred at 85°C for 24hours. After the reaction was completed, the reaction mixture was diluted with water (lOOmL) and the resulting suspension was filtered. The solid was collected and dried in vacuo to give the crude 2-hydroxy- 5-methoxy-4-[(4-methoxyphenyl)methoxy]benzaldehyde (1.06 g, 71%) as a brown solid, which was directly used for next step directly without further purification. MS obsd. (ESI ⁺ ) [(M+H) ¹ ]: 288.7.

Step 2: Preparation of cis-tert- butyl 3-[2-[2-formyl-4-methoxy-5-[(4- methoxyphenyl)methoxy]phenoxy]ethoxy] cyclobutanecarboxylate

C076b

A mixture of 2-hydroxy-5-methoxy-4-((4-methoxybenzyl)oxy)benzaldehyde (1.06 g, 3.31 mmol), cis-tert- butyl 3-[2-(p-tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate (1.35 g, 3.64 mmol) and K ₂ CO ₃ (915 mg, 6.62 mmol) in DMF (10 mL) was heated to 50°C for 20 hours. After the reaction was completed, the reaction mixture was diluted with water (50 mL) and EtOAc (50 ml) three times. The combined organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the crude cis-tert- butyl 3-[2-[2-formyl-4-methoxy-5- [(4-methoxyphenyl)methoxy]phenoxy]ethoxy]cyclobutanecarboxyl ate (1.91 g, 93.9% yield) as a dark brown oil, which was used in the next step directly without further purification. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 486.8.

Step 3: Preparation of C¾-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-hydroxy-4-methox y- phenoxy]ethoxy]cyclobutanecarboxylic acid

C076

A mixture of cis-tert- butyl 3-[2-[2-formyl-4-methoxy-5-[(4- methoxyphenyl)methoxy]phenoxy]ethoxy]cyclobutanecarboxylate (1.6 g, 2.63 mmol), l-(3- chloro-2-hydroxyphenyl)ethan-l-one (494 mg, 2.89 mmol) and pyrrolidine (93.6 mg, 1.32 mmol) in DMSO (10 mL) was stirred at l00°C for 30minutes. After the reaction was completed, the reaction mixture was diluted with water (50 ml), extracted with EtOAc(50 mL) three times. The combined organic layer was washed with 2 N HC1, water, brine, dried over anhydrous Na ₂ S0 ₄ and then concentrated in vacuo to give light brown oil. The brown oil was dissolved in DMSO (10 mL) and to the resulting solution was added I ₂ (66.8 mg, 0.26 mmol), the mixture was then stirred at l40°C for 3 hours. After the reaction was completed, the reaction mixture was cooled to room temperature and then diluted with water (50 mL). The resulting mixture was extracted with EtOAc (50 mL) three times. The combined organic layer was directly concentrated in vacuo to give the crude C7.v-3-|2-|2-(8-chloro-4-oxo-chromen-2-yl)-5-hydroxy-4-metho xy- phenoxy]ethoxy]cyclobutanecarboxylic acid (2.76 g) as a dark oil which was directly used for next step without purification. NMR (DMSO- _< %, 400MHz): d ppm 10.17 (s, 1H), 7.94-8.01 (m, 2H), 7.61 (s, 1H), 7.46 (s, 1H), 7.20-7.23 (m, 1H), 7.06-7.10 (m, 1H), 6.93-6.98 (m, 1H), 4.11-4.19 (m, 2H), 3.96 (br t, J = 6.8 Hz, 1H), 3.83 (s, 3H), 3.66-3.73 (m, 2H), 2.76-2.80 (m,

1H), 2.38-2.45 (m, 2H), 1.91-2.05 (m, 2H). (ESI ⁺ )[(M+H) ⁺ ]:.MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 461.1 Example C077: C7s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-5-propox y- phenoxy]ethoxy]cyclobutanecarboxylic acid

C077

Step 1: Preparation of cis-propyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-5- propoxy-phenoxy]ethoxy]cyclobutanecarboxylate

C077a

To a mixture of s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-hydroxy-4-methoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid (346 mg, 0.3 mmol), K CO (166 mg, 1.2 mmol) and Nal (45 mg, 0.3 mmol) in DMF (3 mL) was added l-bromopropane (111 mg, 0.9 mmol) and the mixture was then stirred at 70°C for 16 hours. After the reaction was completed, the reaction mixture was diluted with water (30 mL) and extracted with EtOAc (100 mL) three times. The combined organic layer was washed with water, brine, dried over anhydrous Na S0 and concentrated in vacuo to give the crude .v-propyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4- methoxy-5-propoxy-phenoxy]ethoxy]cyclobutanecarboxylate (152 mg, 92.9% yield) as a dark brown oil, which was used in the next step directly without further purification. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 545.2

Step 2: Preparation of C¾-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-5-propox y- phenoxy]ethoxy]cyclobutanecarboxylic acid

C077

To a solution of r/.v-propyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-5-propoxy- phenoxy]ethoxy]cyclobutanecarboxylate (152 mg, 0.28 mmol) in THF (4 ml) and water (1 ml) was added lithium hydroxide monohydrate (58.2 mg, 1.39 mmol) and the mixture was then stirred at room temperature for 16 hours. After the reaction was completed, the mixture was ad _j usted to PH~3 by addition of 1N HC1. The reaction was then concentrated in vacuo and the residue was purified by Prep-HPLC to give s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4- methoxy-5-propoxy-phenoxy]ethoxy]cyclobutanecarboxylic acid(50 mg, 35.6% yield) as a yellow solid. (DMSO- , 400MHz) d ppm 12.10 (s, 1H), 8.00 - 7.94 (m, 2H), 7.60 (s, 1H), 7.47 (t, 7=7.9 Hz, 1H), 7.24 (s, 1H), 6.89 (s, 1H), 4.32 - 4.25 (m, 2H), 4.08 (t, 7=6.6 Hz, 2H), 4.01 - 3.91 (m, 1H), 3.82 (s, 3H), 3.73 - 3.67 (m, 2H), 2.59 - 2.52 (m, 1H), 2.47 - 2.39 (m, 2H), 2.06 - 1.95 (m, 2H), 1.85 - 1.73 (m, 2H), 1.01 (t, 7=7.4 Hz, 3H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 503.3.

Example 078: C7s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-ethoxy-4-methoxy - phenoxy]ethoxy]cyclobutanecarboxylic acid

C078

Example C078 was prepared in analogy to the procedure described for the preparation of example C077 by using iodoethane as the starting material instead of l-bromopropane in Step 1. 1H NMR (DMSO-ife, 400MHz): d ppm 12.10 (br s, 1H), 7.97 (dq, 7 = 7.9, 1.7 Hz, 2H), 7.55-7.62 (m, 1H), 7.47 (t, 7 = 7.9 Hz, 1H), 7.24 (s, 1H), 6.88 (s, 1H), 4.26-4.33 (m, 2H), 4.13-4.22 (m, 2H), 3.90-4.03 (m, 1H), 3.78-3.86 (m, 3H), 3.64-3.75 (m, 2H), 2.53-2.58 (m, 1H), 2.38-2.47 (m, 2H), 1.92-2.07 (m, 2H), 1.38 (t, 7 = 7.0 Hz, 3H). (ESI ⁺ )[(M+H) ⁺ ]:489.2.

Example 079: C7s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(cyclopropylmeth oxy)-4- methoxy-phenoxy]ethoxy]cyclobutanecarboxylic acid

C079

Example C079 was prepared in analogy to the procedure described for the preparation of example C077 by using bromomethylcyclopropane as the starting material instead of 1- bromopropane in Step 1. 1H NMR (DMSO-i¾, 400MHz) d ppm 12.04 (br s, 1H), 8.01 - 7.94 (m, 2H), 7.60 (s, 1H), 7.47 (t, 7=7.9 Hz, 1H), 7.24 (s, 1H), 6.85 (s, 1H), 4.30 - 4.25 (m, 2H), 4.01 - 3.91 (m, 3H), 3.83 (s, 3H), 3.72 - 3.68 (m, 2H), 2.59 - 2.52 (m, 1H), 2.47 - 2.38 (m, 2H), 2.05 - 1.95 (m, 2H), 1.34 - 1.26 (m, 1H), 0.65 - 0.58 (m, 2H), 0.39 - 0.32 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 515.1.

Example 080: C7s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-methoxy-5-(2,2,2 - trifluoroethoxy)phenoxy]ethoxy]cyclobutanecarboxylic acid

Example C080 was prepared in analogy to the procedure described for the preparation of example C077 by using l,l,l-trifluoro-2-iodoethane as the starting material instead of 1- bromopropane in Step 1. 1H NMR (DMSO-4, 400MHz) d ppm 12.05 (br s, 1H), 8.02 - 7.95 (m, 2H), 7.65 (s, 1H), 7.48 (t, 7=7.9 Hz, 1H), 7.24 (s, 1H), 7.05 (s, 1H), 4.92 (q, 7=8.8 Hz, 2H), 4.32 - 4.26 (m, 2H), 4.00 - 3.89 (m, 1H), 3.85 (s, 3H), 3.73 - 3.68 (m, 2H), 2.52 (d, 7=1.8 Hz, 1H), 2.46 - 2.37 (m, 2H), 2.06 - 1.94 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 543.1

Example C081: C7s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(difluoromethoxy )-4-methoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid

C081

Example C081 was prepared in analogy to the procedure described for the preparation of example C077 by using sodium chorodifluoroacetate as the starting material instead of 1- bromopropane in Step 1. 1H NMR (DMSO-ife, 400MHz) d ppm 12.01 (br s, 1H), 8.05 - 7.97 (m, 2H), 7.73 (s, 1H), 7.53 - 7.47 (m, 1H), 7.31 - 7.10 (m, 2H), 4.29 - 4.22 (m, 2H), 3.97 - 3.87 (m, 4H), 3.71 - 3.65 (m, 2H), 2.52-2.59 (m, 1H), 2.44 - 2.35 (m, 2H), 2.04 - 1.93 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 511.2.

Example C082: ^' s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-(cyclopropyl methoxy)-5- methoxy-phenoxy]ethoxy]cyclobutanecarboxylic acid

Step 1: preparation of 2-fluoro-5-hydroxy-4-methoxy-benzaldehyde

C082a

A mixture of 6-fluoroveratraldehyde (3600.0 mg, 19.55 mmol) in sulfuric acid (36.0 mL) was stirred at 95 °C under nitrogen for 6 hours. Then the resulting mixture was poured into ice water (150 g) and the resulting suspension was filtered. The filtered cake was washed with water (100 mL) twice and dried in vacuo to give 2-fluoro-5-hydroxy-4-methoxy-benzaldehyde (3025 mg, 1 90.95% yield, purity) as a brown solid. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 171.1.

Step 2: preparation of 5-(cyclopropylmethoxy)-2-fhioro-4-methoxy-benzaldehyde

C082b

To a solution of 2-fluoro-5-hydroxy-4-methoxy-benzaldehyde (1000.0 mg, 5.88 mmol), bromomethylcyclopropane (0.86 mL, 8.82 mmol) in DMF (25 mL) was added K ₂ CO ₃ (3249.23 mg, 23.51 mmol) and the mixture was stirred at 80°C for 2 hours. After the reaction was completed, the reaction mixture was diluted with water (100 mL) and the resulting mixture was extracted with EtOAc (50 mL) three times. The combined organic layer was washed with brine (50 mL) twice, dried over Na S0 and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with PE:EtOAc = 6:1) to give 5- (cyclopropylmethoxy)-2-fluoro-4-methoxy-benzaldehyde (1050 mg, 79.67% yield) as a white solid. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 225.2.

Step 3: preparation of 5-(cyclopropylmethoxy)-4-methoxy-2-[(4- methoxyphenyl)methoxy]benzaldehyde

C082c

To a mixture of 5-(cyclopropylmethoxy)-2-fluoro-4-methoxy-benzaldehyde (1000.0 mg, 4.46 mmol), CS CO (726.53 mg, 2.23 mmol) was added 4-methoxybenzyl alcohol (6161.53 mg, 44.6 mmol) and the mixture was stirred at 120 °C under microwave condition for 1 hour. The mixture was purified by reversed phase column chromatography (eluent with water/MeOEl = 1:3) to give 5-(cyclopropylmethoxy)-4-methoxy-2-[(4-methoxyphenyl)methoxy ]benzaldehyde (515 mg, 33.73% yield) as a white solid. MS obsd. (ESI ⁺ ) [(M+Na) ⁺ ]: 365.0.

Step 4: preparation of 8-chloro-2-[5-(cyclopropylmethoxy)-2-hydroxy-4-methoxy- phenyl]chromen-4-one

C082d

Compound C082d was prepared in analogy to the procedure described for the preparation of compound C075i by using 5-(cyclopropylmethoxy)-4-methoxy-2-[(4- methoxyphenyl)methoxy]benzaldehyde as the starting material instead of 2-benzyloxy-5- (difluoromethyl)-4-methyl-benzaldehyde in Step 7.

Step 5: preparation of cis-tert-hutyX 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4- (cyclopropylmethoxy)-5-methoxy-phenoxy]ethoxy]cyclobutanecar boxylate

C082e

Compound C082e was prepared in analogy to the procedure described for the preparation of compound C071b by using 8-chloro-2-[5-(cyclopropylmethoxy)-2-hydroxy-4-methoxy- phenyl]chromen-4-one as the starting material instead of 2-(4-bromo-2-fluoro-6-hydroxy- phenyl)-8-chloro-chromen-4-one in Step 7.

Step 6: preparation of s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-(cyclopropylmethox y)-5- methoxy-phenoxy]ethoxy]cyclobutanecarboxylic acid

C082

To a solution of cis-tert- butyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-(cyclopropylmethoxy) - 5-methoxy-phenoxy]ethoxy]cyclobutanecarboxylate (80.0 mg, 0.140 mmol) in DCM (15 mL) was added TFA (1.2 mL, 15.58 mmol) and the mixture was stirred at 25 °C for 1 hour. The mixture was then concentrated in vacuo and the residue was purified by Prep-HPLC to give cis- 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-(cyclopropylmethoxy) -5-methoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid (43 mg, 58.35% yield) as a light yellow solid. ¹ 11 NMR (DMSO-ife, 400MHz): d ppm. 12.12 (br s, 1H), 7.97 (dq, 7 = 7.9, 1.7 Hz, 2H), 7.59 (s, 1H), 7.47 (t, 7 = 7.9 Hz, 1H), 7.22 (s, 1H), 6.90 (s, 1H), 4.28-4.34 (m, 2H), 3.89-3.98 (m, 4H), 3.84 (d, 7 = 7.0 Hz, 2H), 3.68-3.74 (m, 2H), 2.35-2.47 (m, 3H), 1.96-2.05 (m, 2H), 1.20-1.30 (m, 1H), 0.55-0.60 (m, 2H), 0.29-0.37 (m, 2H).MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 514.9.

Example C083: s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-hydroxy-5-methoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid

C083

A mixture of cis-tert- butyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4- (cyclopropylmethoxy)-5-methoxy-phenoxy]ethoxy]cyclobutanecar boxylate (50.0 mg, 0.090 mmol) in TFA (3.0 mL, 38.94 mmol) was stirred at 40 °C for 1 hour. The mixture was then concentrated in vacuo and the residue was purified by Prep-HPLC to give s-3-[2-[2-(8-chloro- 4-oxo-chromen-2-yl)-4-hydroxy-5-methoxy-phenoxy]ethoxy]cyclo butanecarboxylic acid (25.2 mg, 62.38% yield) as a yellow solid. ¹ 11 NMR (l )MSO- _< %, 400MHz): d ppm 9.11 (s, 1H), 7.97 (ddd, 7 = 7.9, 1.6 Hz, 2H), 7.53 (s, 1H), 7.46 (t, 7 = 7.9 Hz, 1H), 7.25 (s, 1H), 6.85 (s, 1H), 4.24- 4.29 (m, 2H), 3.96 (t, 7 = 7.0 Hz, 1H), 3.90 (s, 3H), 3.67-3.73 (m, 2H), 2.52-2.56 (m, 1H), 2.35-

2.47 (m, 2H), 1.97-2.08 (m, 2H).. (ESI ⁺ )[(M+H) ⁺ ]:.460.9.

Example C084: s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-ethoxy-5-methoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid

C084

Example C084 was prepared in analogy to the procedure described for the preparation of example C082by using iodoethane as the starting material instead of bromomethylcyclopropane in Step 2. 1H NMR (DMSO-ife, 400MHz): d ppm 7.94-8.00 (m, 2H), 7.59 (s, 1H), 7.47 (t, 7 = 7.9 Hz, 1H), 7.24 (s, 1H), 6.89 (s, 1H), 4.24-4.36 (m, 2H), 3.88-4.09 (m, 6H), 3.65-3.77 (m, 2H), 2.52-2.58 (m, 1H), 2.38-2.48 (m, 2H), 1.96-2.08 (m, 2H), 1.36 (t, J = 7.0 Hz, 3H).

(ESI ⁺ )[(M+H) ⁺ ]:489.0.

Example C085: s-3-[2-[2-(8-cbloro-4-oxo-cbromen-2-yl)-5-metboxy-4-(2,2,2- trifluoroethoxy)phenoxy]ethoxy]cyclobutanecarboxylic acid

Example C085 was prepared in analogy to the procedure described for the preparation of example C082by using 2,2,2-trifluoroethyl trifluoromethanesulfonate as the starting material instead of bromomethylcyclopropane in Step 2. ¹ 11 NMR (DMSO-ife, 400MHz): d ppml2.l l (br s, 1H), 7.96-8.01 (m, 2H), 7.69 (s, 1H), 7.48 (t, J = 7.9 Hz, 1H), 7.20 (s, 1H), 6.96 (s, 1H), 4.70 (q, J = 9.0 Hz, 2H), 4.28-4.38 (m, 1H), 3.95 (s, 3H), 3.67-3.77 (m, 2H), 2.52-2.57 (m, 3H), 2.38- 2.47 (m, 2H), 1.95-2.04 (m, 2H). (ESI ⁺ )[(M+H) ⁺ ]:543. l.

Example C086: s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4-(difluoromethoxy)- 5-methoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid

C086 Example C086 was prepared in analogy to the procedure described for the preparation of example C082by using sodium chorodifluoro acetate as the starting material instead of bromomethylcyclopropane in Step 2. 1H NMR (DMSO-i¾, 400MHz): d ppm 12.12 (br s, 1H), 7.94-8.03 (m, 2H), 7.85 (s, 1H), 7.48 (t, 7 = 7.9 Hz, 1H), 7.24 (s, 1H), 6.95 (br d, 1H), 6.87 (s, 1H), 4.34-4.42 (m, 2H), 3.89-4.06 (m, 4H), 3.70-3.83 (m, 2H), 2.52-2.59 (m, 1H), 2.37-2.47 (m,

2H), 1.95-2.07 (m, 2H). (ESI ⁺ )[(M+H) ⁺ ]:5ll.l.

Example C087: s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5- bis(difluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylic acid

C087

Step 1: preparation of cis-tert-butyl 3-[2-[[6-(8-chloro-4-oxo-chromen-2-yl)-l,3- benzodioxol-5-yl]oxy]ethoxy]cyclobutanecarboxylate

C087a

Compound C087a was prepared in analogy to the procedure described for the preparation of compound C071b by using 8-chloro-2-(6-hydroxy-l,3-benzodioxol-5-yl)chromen-4-one as the starting material instead of 2-(4-bromo-2-fluoro-6-hydroxy-phenyl)-8-chloro-chromen-4-one in Step 7.

Step 2: preparation of s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dihydroxy- phenoxy]ethoxy]cyclobutanecarboxylic acid

C087b

To a solution of cis-tert- butyl 3-[2-[[6-(8-chloro-4-oxo-chromen-2-yl)-l,3-benzodioxol-5- yl]oxy]ethoxy]cyclobutanecarboxylate (250.0 mg, 0.490 mmol) in DCM (20 mL) was added AICI ₃ (517.88 mg, 3.88 mmol) and the mixture was stirred at 30 °C for 1 hour. The reaction was quenched with water (25 mL) and the resulting mixture was extracted with DCM (25 mL) twice. The combined organic layer was washed with brine, dried over MgS0 ₄ , filtered and the filtrate was concentrated in vacuo to give the crude ds-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5- dihydroxy-phenoxy]ethoxy]cyclobutanecarboxylic acid (210 mg, 89.1% yield) as a red solid. (ESI ⁺ )[(M+H) ⁺ ]:477.l.

Step 3: preparation of ds-methyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dihydroxy- phenoxy]ethoxy]cyclobutanecarboxylate

C087c

To a solution of ds-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dihydroxy- phenoxy]ethoxy]cyclobutanecarboxylic acid (350.0 mg, 0.780 mmol) in MeOH (40 mL) was added SOCl ₂ (1.0 mL, 0.780 mmol) and the resulting mixture was stirred at 30 °C for 3 hours. Then the reaction mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluted with PE/EtOAc = 3:1 to 1 :10) to give r/ ^' v- methyl 3-[2-[2-(8- chloro-4-oxo-chromen-2-yl)-4,5-dihydroxy-phenoxy]ethoxy]cycl obutanecarboxylate (280 mg, 77.56% yield) as a light yellow solid.

Step 4: preparation of ds-methyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5- bis(difluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylate

C087d

To a solution of r/.v- methyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dihydroxy- phenoxy]ethoxy]cyclobutanecarboxylate (120.0 mg, 0.260 mmol), (2-chloro-2,2-difluoro- acetyl)oxysodium (79.4 mg, 0.520 mmol) in DMF (8 mL) was added CS ₂ CO ₃ (254.51 mg, 0.780 mmol) and the mixture was stirred at 80 °C for 3 hours. The mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluted with PE:EtOAc = 3:1) to give r/.v- methyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5- bis(difluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylate (65 mg, 044.51% yield) as a yellow solid. MS obsd. (ESf)[(M+H) ⁺ ]: 561.1.

Step 5: preparation of s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5- bis(difluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylic acid

C087

To a solution of r/.v- methyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5- bis(difluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylate (60.0 mg, 0.110 mmol) in TE!F (5 mL) and water (1 mL) was added LiOEl (11 mg, 0.50 mmol). The reaction mixture was stirred at room temperature for 2 hours. Then the mixture was adjusted to pEl ~5 by addition of 2N HC1. The resulting mixture was concentrated in vacuo and the residue was purified by Prep-ElPLC to give 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5- bis(difluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylic acid (12 mg, 20.1% yield) as an off-white solid. NMR (DMSO-rfc, 400MHz): d ppm 7.99-8.04 (m, 2H), 7.96 (s, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.43 (dd, 1H), 7.28 (m, 1H), 7.23 (s, 1H), 7.18 (dd, 1H), 4.28-4.40 (m, 2H), 3.82- 4.06 (m, 1H), 3.66-3.76 (m, 2H), 2.25-2.46 (m, 3H), 1.93-2.04 (m, 2H).. MS obsd.

(ESI ⁺ )[(M+H) ⁺ ]: 547.1.

Example C088: C¾-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-diethoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid

C088

Example C088 was prepared in analogy to the procedure described for the preparation of example C077 by using s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dihydroxy- phenoxy]ethoxy]cyclobutanecarboxylic acid and iodoethane as the starting material instead of s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-hydroxy-4-methoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid and l-bromopropane in Step 1. ¹ 11 NMR (DMSO- d ₆ , 400MHz): d ppml2.09 (s, 1H), 7.97 (dd, 7 = 7.8, 3.3 Hz, 2H), 7.60 (s, 1H), 7.47 (t, J = 7.9 Hz, 1H), 7.24 (s, 1H), 6.88 (s, 1H), 4.25-4.29 (m, 2H), 4.19 (dd, J = 13.9, 6.9 Hz, 2H), 4.08 (dd, J = 13.9, 6.9 Hz, 2H), 3.93-4.09 (m, 1H), 3.70 (s, 2H), 2.42 (dd, J = 12.1, 4.8 Hz, 3H), 1.94-2.07 (m, 2H), 1.37 (dd, J = 15.3, 7.0 Hz, 6H). (ESI ⁺ )[(M+H) ⁺ ]:503.0.

Example C089: C7s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methoxy-4- (trifhioromethoxy)phenoxy]ethoxy]cyclobutanecarboxylic acid

C089

Step 1 : Preparation of cis-tert- butyl 3-[2-[5-bromo-2-formyl-4- (trifluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylate

To a mixture of 4-bromo-2-hydroxy-5-(trifluoromethoxy)benzaldehyde (221.8 mg, 0.780 mmol), cis-tert- butyl 3-[2-(p-tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate (432.44 mg, 1.17 mmol) in DMF (20 mL) was added K ₂ C(T(537.77 mg, 3.89 mmol) and the reaction was stirred at 80 °C for 4 hours. The reaction was diluted with water (200 mL) and the resulting mixture was extracted with EtOAc (150 mL) three times. The combined organic layer was washed with water (100 mL) twice, brine (100 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluent with PE:EtOAc = 4:1) to give cis-tert- butyl 3-[2-[5-bromo-2-formyl-4-(trifluoromethoxy)phenoxy]ethoxy]cy clobutanecarboxylate (300 mg, 79.77% yield) as a colorless oil. MS obsd. (ESI ⁺ ) [(M+Na) ⁺ ]: 505.0.

Step 2 : Preparation of cis-tert- butyl 3-[2-[2-formyl-5-hydroxy-4- (trifbioromethoxy)phenoxy]ethoxy]cyclobutanecarboxylate

To a solution of cis-tert- butyl 3-[2-[5-bromo-2-formyl-4- (trifluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylate (200.0 mg, 0.410 mmol), 4- methoxybenzyl alcohol (171.53 mg, 1.24 mmol), tBuXPhos (7.03 mg, 0.020 mmol) in 1,4- dioxane (15 mL) was added Pd ₂ (dba) ₃ (7.58 mg, 0.010 mmol) under N ₂ atmosphere. The mixture was stirred at 100 °C for 16 hours. The mixture was cooled to room temperature and

concentrated in vacuo. The residue was purified by prep-HPLC to give cis-tert- butyl 3-[2-[2- formyl-5-hydroxy-4-(trifluoromethoxy)phenoxy]ethoxy]cyclobut anecarboxylate (70 mg, 40.24% yield) as dense oil. MS obsd. (ESI ⁺ ) [ (M+Na) ⁺ ]: 443.1.

Step 3 : Preparation of cis-tert- butyl 3-[2-[2-formyl-5-methoxy-4- (trifluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylate

To a solution of ds-ZerZ-butyl 3-[2-[2-formyl-5-hydroxy-4- (trifluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylate (70.0 mg, 0.170 mmol), K CO (45.96 mg, 0.330 mmol) in ACN (2 mL) was added iodomethane (28.36 mg, 0.200 mmol) and the mixture was stirred at 30 °C for 10 hours. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluted with PE:EtOAc = 3:1) to give ds-ZerZ-butyl 3-[2-[2-formyl-5-methoxy-4-

(trifluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylate (65 mg, 89.8% yield) as a colorless oil. MS obsd. (ESI ⁺ )[(M+Na) ⁺ ]: 457.0.

Step 4 : Preparation of cis-tert- butyl 3-[2-[2-[(£')-3-(3-chloro-2-hydroxy-phenyl)-3-oxo- prop-l-enyl]-5-methoxy-4-(trifbioromethoxy)phenoxy]ethoxy]cy clobutanecarboxylate

A mixture of l-(3-chloro-2-hydroxy-phenyl)ethanone (27.49 mg, 0.160 mmol), cis-tert- butyl 3-[2-[2-formyl-4-methoxy-5-(trifluoromethoxy)phenoxy]ethoxy] cyclobutanecarboxylate (70.0 mg, 0.160 mmol), KOH (90.42 mg, 1.61 mmol) in EtOH (5 mL) was stirred at 40 °C for 20 hours. The mixture was poured into 1N HC1 (15 mL) and the resulting suspension was filtered. The solid was collected and dried in vacuo to give ds-ZerZ-butyl 3-|2-|2-|(77)-3-(3-chloro-2- hydroxy-phenyl)-3-oxo -prop - 1 - eny 1] - 5 - metho xy-4 -

(trifluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylate (80 mg, 84.58% yield) as a yellow solid. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 531.1.

Step 4 : Preparation of ds-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-methoxy-4- (trifluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylic acid

C089

A mixture of r7.v-3-| 2- 12- |(/7)-3-(3-chloro- 2-hydroxy-phenyl )-3-oxo-prop- 1 -cnyl |-5- methoxy-4-(trifluoromethoxy)phenoxy]ethoxy]cyclobutanecarbox ylic acid (80.0 mg, 0.150 mmol) and iodine (4.3 mg, 0.020 mmol) in DMSO (2 mL) was stirred at 140 °C for 3 hours. The resulting mixture was purified by prep-HPLC to give r/x-3-|2-|2-(8-chloro-4-oxo-chromcn-2-yl)- 5-methoxy-4-(trifluoromethoxy)phenoxy]ethoxy]cyclobutanecarb oxylic acid (26 mg, 32.3% yield) as an off-white solid, ' l l NMR (DMSO-rfe, 400MHz) d ppm 12.11 (br s, 1H), 7.99 (dd, .1 = 7.2, 5.7 Hz, 3H), 7.48 (t, J = 7.9 Hz, 1H), 7.24 (s, 1H), 7.07 (s, 1H), 4.41 (s, 2H), 4.01 (s, 3H), 3.92-3.99 (m, 1H), 3.76 (d, J = 4.5 Hz, 2H), 2.39-2.47 (m, 3H), 2.01 (dd, J = 20.0, 8.8 Hz, 2H).

MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 529.0.

Example C090: C7s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-hydroxy-4- (trifluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylic acid

C090

Step 1 : Preparation of cis-tert- butyl 3-[2-[2-formyl-5-[(4-methoxyphenyl)methoxy]-4- (trifluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylate

C090a To a solution of cis-tert- butyl 3-[2-[2-formyl-5-hydroxy-4- (trifluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylate (140.0 mg, 0.330 mmol), K CO (91.92 mg, 0.670 mmol) in ACN (12 mL) was added 4-methoxybenzylchloride (0.05 mL, 0.400 mmol) and the mixture was stirred at 60 °C for 16 hours. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluted with PE:EtOAc = 3: 1) to give cis-tert- butyl 3-[2-[2-formyl-5-[(4-methoxyphenyl)methoxy]-4- (trifluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylate (160 mg, 0.300 mmol) as a colorless oil. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 563.2.

Step 2 : Preparation of s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-[(4- methoxyphenyl)methoxy]-4-(trifluoromethoxy)phenoxy]ethoxy]cy clobutanecarboxylic acid

C090b

Compound C090b was prepared in analogy to the procedure described for the preparation of example C082by using cis- tert- butyl 3-[2-[2-formyl-5-[(4-methoxyphenyl)methoxy]-4- (trifluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylate as the starting material instead of cis-tert- butyl 3-[2-[2-formyl-4-methoxy-5-

(trifluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylate in Step 3. MS obsd. (ESI ⁺ )

[(M+H) ⁺ ]: 635.1.

Step 3 : Preparation of s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-hydroxy-4- (trifhioromethoxy)phenoxy]ethoxy]cyclobutanecarboxylic acid

C090 A mixture of s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-[(4-methoxyphenyl) methoxy]- 4-(trifluoromethoxy)phenoxy]ethoxy]cyclobutanecarboxylic acid (95.99 mg, 0.150 mmol) and TFA (0.001 mL, 0.020 mmol) in DMSO (2 mL) was stirred at 140 °C for 3 hours. The mixture was concentrated in vacuo, the residue was purified by Prep-HPLC to give rv ^' v-3-[ 2-[ 2-(8-chloro- 4-oxo-chromen-2-yl)-5-hydroxy-4-(trifluoromethoxy)phenoxy]et hoxy]cyclobutanecarboxylic acid (5 mg, 6.06% yield) as a grey solid. 1H NMR (DMSO-tfe, 400MHz) d ppm 12.09 (br s, 1H), 11.29 (s, 1H), 7.97 (dd, J = 14.9, 7.0Hz, 3H), 7.47 (t, J = 7.9 Hz, 1H), 7.21 (s, 1H), 6.80 (s, 1H), 4.18-4.28 (m, 2H), 3.92-3.99 (m, 1H), 3.68-3.77 (m, 2H), 2.39-2.44 (m, 3H), 1.94-2.05 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 515.1.

Example C091: C¾-3-[2-[6-(8-chloro-4-oxo-chromen-2-yl)-2-oxo-indolin-5- yl]oxyethoxy]cyclobutanecarboxylic acid

Step 1: Preparation of s-methyl 4-bromo-2-[2-(3-tert- butoxycarbonylcyclobutoxy)ethoxy]benzoate

C091a

To a mixture of methyl 4-bromo-2-hydroxybenzoate (2 g, 8.66 mmol), K ₂ CO ₃ (2.39 g,

17.3 mmol) in DMF (20 mL) was added cis-tert- butyl 3-[2-(p- tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate (3.85 g, 10.4 mmol) and the resulting mixture was stirred at 50°C for l6hours. After the reaction was completed, the reaction mixture was diluted with water (60 mL) and extracted with EtOAc (100 mL) three times. The combined organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the crude r/.v- methyl 4-hromo-2-[2-(3-/c/7-hutoxycarhonylcyclohutoxy)cthoxy] benzoate (4.41 g, 95.6% yield) as a yellow oil, which was used in the next step directly without further purification.MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 428.9.

Step 2: Preparation of s-3-[2-(5-bromo-2-methoxycarbonyl-4-nitro- phenoxy)ethoxy]cyclobutanecarboxylic acid

C091b

To a solution of cis- methyl 4-bromo-2-[2-(3 -tert- butoxycarbonylcyclobutoxy)ethoxy]benzoate (4.31 g, 8.43 mmol) in Conc.H ₂ S0 ₄ (50 mL) was added KNOT938 mg, 9.28 mmol) at 0°C in small portions while keeping inner temperature below 5°C. After addition, the mixture stirred at 0°C for another 20 minutes and then the reaction mixture was poured into ice-water (200 g). The resulted suspension was extracted with EtOAc (100 mL) three times, the combined organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the crude s-3-[2-(5-bromo-2-methoxycarbonyl-4- nitro-phenoxy)ethoxy]cyclobutanecarboxylic acid (3.54 g, 100% yield) as a yellow solid, which was used in the next step directly without further purification. MS obsd. (ESI ⁺ ) [(M+H) ¹ ]: 417.8 Step 3: Preparation of s-3-[2-[5-bromo-2-[3-(3-chloro-2-hydroxy-phenyl)-3-oxo- propanoyl]-4-nitro-phenoxy]ethoxy]cyclobutanecarboxylic acid

C091c

To LiHMDS solution (1 mol/L in THF, 5 mL, 5 mmol) was added cooled at -78°C was added l-(3-chloro-2-hydroxyphenyl)ethan-l-one solution (2 mol/L in THF, 2 mL, 2 mmol) dropwise and resulting solution was stirred at -78°C 30min. Then to the resulting mixture was added s-3-[2-(5-bromo-2-methoxycarbonyl-4-nitro-phenoxy)ethoxy]cyc lobutanecarboxylic acid (935 mg, 2 mmol, dissolved in THF (3 mL)) at -78°C and the reaction was then warmed to room temperature and stirred at room temperature for 16 hours. Then reaction mixture was diluted with water (25 mL) and adjusted to pH 5.0 by addition of AcOH, the resulting mixture was extracted with EtOAc (60 mL) three times. The combined organic layer was washed with brine, dried over anhydrous Na S0 and concentrated in vacuo to give the crude r/.v-3-|2-|5- bromo-2-[3-(3-chloro-2-hydroxy-phenyl)-3-oxo-propanoyl]-4-ni tro- phenoxyjethoxyjcyclobutanecarboxylic acid (710 mg, 63.8% yield) as a brown solid, which was used in the next step directly without further purification. MS obsd. (ESI ⁺ ) [(M+H) ¹ ]: 556.0. Step 4: Preparation of s-3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-nitro- phenoxy]ethoxy]cyclobutanecarboxylic acid

C091d

To a mixture of s-3-[2-[5-bromo-2-[3-(3-chloro-2-hydroxy-phenyl)-3-oxo-propa noyl]-4- nitro-phenoxy]ethoxy]cyclobutanecarboxylic acid (710 mg, 1.28 mmol) in AcOH (10 mL) was added Con. H SO (0.05 mL) and the resulting mixture was stirred at l00°C for lhour. The mixture was concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluted with PE:EtOAc 5:1 to 1:10) to give ds-3-[2-[5-bromo-2-(8-chloro-4-oxo- chromen-2-yl)-4-nitro-phenoxy]ethoxy]cyclobutanecarboxylic acid (360 mg, 52% yield) as a brown foam, which was used in the next step directly without further purification. MS obsd. (ESI ⁺ ) [(M+H) ¹ ]: 537.9

Step 5: Preparation of s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(2-methoxy- l- methoxycarbonyl-2-oxo-ethyl)-4-nitro-phenoxy]ethoxy]cyclobut anecarboxylic acid

C091e

A mixture of ds-3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)-4-nitro- phenoxy]ethoxy]cyclobutanecarboxylic acid (333 mg, 0.62 mmol), dimethyl malonate (98 mg, 0.74 mmol) and K ₂ CO ₃ (342 mg, 2.47 mmol) in DMF (5 mL) was stirred at 70°C overnight. After cooling to room temperature, the reaction mixture was diluted with water (30 mL), adjusted to PH~3 by addition of 1N HC1 and the resulting mixture was extracted with EtOAc (50 mL) three times. The combined organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the crude s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)- 5-(2-methoxy-l-methoxycarbonyl-2-oxo-ethyl)-4-nitro-phenoxy] ethoxy]cyclobutanecarboxylic acid (265 mg, 73% yield) as a brown oil, which was used in the next step directly without further purificatioaMS obsd. (ESI ⁺ ) [(M+H) ⁺ j: 590.1

Step 6: Preparation of cis- 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(2-methoxy-2-oxo- ethyl)-4-nitro-phenoxy]ethoxy]cyclobutanecarboxylic acid

C091f

A mixture of cis- 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(2-methoxy-l- methoxycarbonyl-2-oxo-ethyl)-4-nitro-phenoxy]ethoxy]cyclobut anecarboxylic acid (240 mg, 0.41 mmol), lithium chloride (51.7 mg, 1.22 mmol) in DMSO (3 mL) and water (0.3 mL) was stirred at l00°C for 16 hours. After cooling to room temperature, the reaction mixture was diluted with water (20 mL) and adjusted to pEl~3 by addition of 1N E1C1. The resulting mixture was extracted with EtOAc (50 mL) three times. The combined organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the crude d.v-3-|2-|2-(8- chloro-4-oxo-chromen-2-yl)-5-(2-methoxy-2-oxo-ethyl)-4-nitro - phenoxyjethoxyjcyclobutanecarboxylic acid (306 mg) as a brown oil, which was used in the next step directly without further purification. MS obsd. (ESI ⁺ ) [(M+El) ⁺ ]: 532.1

Step 7: Preparation of s-3-[2-[6-(8-chloro-4-oxo-chromen-2-yl)-2-oxo-indolin-5- yl]oxyethoxy]cyclobutanecarboxylic acid

C091

A mixture of ds-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(2-methoxy-2-oxo- ethyl)-4- nitro-phenoxy]ethoxy]cyclobutanecarboxylic acid (168 mg, 0.32 mmol), sodium hydrosulfite (275 mg, 1.58 mmol) in EtOH (6 mL) and water (2 mL) was stirred at 1 l0°C for 4 hours. After cooling to room temperature, the reaction mixture was diluted with water and adjusted to PH~3 by addition of 2 N HC1. The resulting mixture was extracted with EtOAc (50 mL) three times. The combined organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by Prep-HPLC to give d.v-3- 12- [ 6-(8-chloro-4- oxo-chromen-2-yl)-2-oxo-indolin-5-yl]oxyethoxy]cyclobutaneca rboxylic acid (6 mg, 4%) as a yellow solid. 1H NMR (DMSO-rfe, 400MHz) d ppm 10.46 (s, 1H), 8.02 - 7.97 (m, 2H), 7.49 (t, 7=7.9 Hz, 1H), 7.44 (s, 1H), 7.28 - 7.24 (m, 2H), 4.25 - 4.19 (m, 2H), 3.95 - 3.85 (m, 1H), 3.69 - 3.66 (m, 2H), 3.59 (s, 2H), 2.42 - 2.32 (m, 3H), 2.05 - 1.93 (m, 2H). MS obsd. (ESI ⁺⁾ [(M+H) ⁺ j: 470.1

Example C092: s-3-[2-[6-(8-chloro-4-oxo-chromen-2-yl)-3,3-dimeth\i-2-oxo-i ndolin-5- yl]oxyethoxy]cyclobutanecarboxylic acid

( 092

Step 1: Preparation of ds-methyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(2-methoxy-l,l- dimethyl-2-oxo-ethyl)-4-nitro-phenoxy]ethoxy]cyclobutanecarb oxylate

C092a

To a solution of s-3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(2-methoxy-2-oxo-e thyl)-4- nitro-phenoxy]ethoxy]cyclobutanecarboxylic acid (160 mg, 0.3 mmol), Mel (170 mg, 1.2 mmol) in DMF (2 mL) was added NaH (48 mg, 1.2 mmol) at 0°C and the mixture was then stirred at room temperature for 6hours. The reaction mixture was diluted with water (20 mL) and extracted with EtOAc (20 mL) three times. The combined organic layer was washed with brine, dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo to give the crude r/.v-methyl 3-[2-[2-(8-chloro-4- oxo-chromen-2-yl)-5-(2-methoxy- 1 , l-dimethyl-2-oxo-ethyl)-4-nitro- phenoxy]ethoxy]cyclobutanecarboxylate (162 mg, 92.9% yield) as a brown oil, which was used in the next step directly without further purification.MS obsd. (ESI ⁺ ) [(M+El) ⁺ ]: 574.2

Step 2: Preparation of s-methyl 3-[2-[6-(8-chloro-4-oxo-chromen-2-yl)-3,3-dimethyl-2- oxo-indolin-5-yl]oxyethoxy]cyclobutanecarboxylate

C092b

A mixture of r/ ^' v- methyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(2-methoxy-l,l- dimethyl-2-oxo-ethyl)-4-nitro-phenoxy]ethoxy]cyclobutanecarb oxylate (crude, 162 mg, 0.28 mmol) and iron (221 mg, 3.95 mmol) in AcOH (3 mL) was stirred at l00°C for 6 hours. After cooling to room temperature, the reaction mixture was diluted with THF (30 mL) and then filtered. The filtrate was concentrated in vacuo to give the crude r/.v- methyl 3-[2-[6-(8-chloro-4- oxo-chromen-2-yl)-3,3-dimethyl-2-oxo-indolin-5-yl]oxyethoxy] cyclobutanecarboxylate (213 mg) as a brown oil, which was used in the next step directly without further purifiation. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 512.4

Step 3: Preparation of ds-3-[2-[6-(8-cbloro-4-oxo-cbronien-2-yl)-3,3-dinietbyl-2-ox o-indolin-5- yl]oxyethoxy]cyclobutanecarboxylic acid

( 092

A mixture of d.v- methyl 3-[2-[6-(8-chloro-4-oxo-chromen-2-yl)-3,3-dimethyl-2-oxo- indolin-5-yl]oxyethoxy]cyclobutanecarboxylate (213 mg, 0.17 mmol, crude prepared above), lithium hydroxide monohydrate (140 mg, 3.33 mmol) in THF (4 mL) and water (1 mL) was stirred at room temperature for 3hours. The mixture was adjusted to PH~3 by addition of 1N HC1 and concentrated in vacuo. The residue was purified by Prep-HPLC to give d.v-3-|2-|6-(8- chloro-4-oxo-chromen-2-yl)-3,3-dimethyl-2-oxo-indolin-5-yl]o xyethoxy]cyclobutanecarboxylic acid (12 mg, 14% yield) as a yellow solid.1H NMR (l)MSO- _< %, 400MHz) d ppm 10.42 (s, 1H), 8.00 (d, 7=7.9 Hz, 2H), 7.52 - 7.39 (m, 3H), 7.21 (s, 1H), 4.30 - 4.22 (m, 2H), 4.00 - 3.88 (m,

1H), 3.72 - 3.63 (m, 2H), 2.44 - 2.35 (m, 3H), 2.03 - 1.93 (m, 2H), 1.31 (s, 6H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ j: 512.4

Example C093: C¾-3-[2-[6-(8-chloro-4-oxo-chromen-2-yl)-l,3,3-trimethyl-2- oxo-indolin-5- yl]oxyethoxy]cyclobutanecarboxylic acid

( 093

Step 1: Preparation of ds-methyl 3-[2-[6-(8-chloro-4-oxo-chromen-2-yl)-l,3,3-trimethyl-2- oxo-indolin-5-yl]oxyethoxy]cyclobutanecarboxylate

C093a

To a solution of cis- 3-[2-[6-(8-chloro-4-oxo-chromen-2-yl)-2-oxo-indolin-5- yl]oxyethoxy]cyclobutanecarboxylic acid (390 mg, 0.58 mmol) in DMF (6 mL) was added NaH (232 mg, 5.81 mmol) at 0°C and the mixture was stirred at 0°C for 30minutes. Then to the resulting mixture was added Mel (660 mg, 4.65 mmol) and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was diluted with water (50 mL) and the resulting suspension was filtered. The solid was collected and dried in vacuo to give the crude cis- methyl 3-[2-[6-(8-chloro-4-oxo-chromen-2-yl)-l,3,3-trimethyl-2-oxo- indolin-5-(01 yl]oxyethoxy]cyclobutanecarboxylate (331 mg, 87% yield) as a brown solid, which was used in the next step directly without further purification. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 526.5

Step 2: Preparation of s-3-[2-[6-(8-chloro-4-oxo-chromen-2-yl)-l,3,3-trimethyl-2-ox o- indolin-5-yl]oxyethoxy]cyclobutanecarboxylic acid

5 C093

A mixture of r/.v- methyl 3-[2-[6-(8-chloro-4-oxo-chromen-2-yl)-l,3,3-trimethyl-2-oxo- indolin-5-yl]oxyethoxy]cyclobutanecarboxylate (331 mg, 0.5 mmol) and lithium hydroxide monohydrate (211 mg, 5 mmol) in THF (4 mL) and water (1 mL) was stirred at room temperature for 2 hours. The mixture was adjusted to pFl~3 by addition of 1N F1C1 and concentrated in vacuo. The residue was purified by Prep-FlPLC to give r/.v-3- 12- [ 6-(8-chloro-4- oxo-chromen-2-yl)-l,3,3-trimethyl-2-oxo-indolin-5-yl]oxyetho xy]cyclobutanecarboxylic acid (12 mg, 4% yield) as a yellow solid. 1H NMR (DMSO-tfe, 400MFlz) d ppm 8.05 - 7.98 (m, 2F1), 7.54 . 7.47 ( _m , 3H), 7.17 (s, 1H), 4.33 - 4.25 (m, 2H), 3.96 - 3.87 (m, 1H), 3.72 - 3.64 (m, 2H), 3.18 (s, 3H), 2.45 - 2.30 (m, 3H), 2.03 - 1.90 (m, 2H), 1.34 (s, 6H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 512.1.

Example C094: as-3-[2-[2-[8-chloro-4-oxo-5-(trifluoromethyl)chromen-2- yl]phenoxy]ethoxy]cyclobutanecarboxylic acid

Step 1: Preparation of 5-bromo-8-chloro-2-(2-hydroxyphenyl)chromen-4-one

C094a

Compound C094a was prepared in analogy to the procedure described for the preparation of compound Int-1 by using l-(6-bromo-3-chloro-2-hydroxy-phenyl)ethanone and 2- hydroxybenzaldehyde as the starting material instead of l-(3-chloro-2-hydroxy-phenyl)ethanone and 2-methoxy-4-(trifluoromethyl)benzaldehyde in Step 1.

Step 2: Preparation of cis-tert-hutyX 3-[2-[2-(5-bromo-8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylate

C094b

A solution of 5-bromo-8-chloro-2-(2-hydroxyphenyl)chromen-4-one (200.0 mg, 0.570 mmol), cis-tert- butyl 3-[2-(p-tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate (210.74 mg, 0.570 mmol) and potassium carbonate (235.86 mg, 1.71 mmol) in DMF (10 mL) was stirred at 80 °C for 3 hours. The mixture was then concentrated in vacuo and the residue was purified by column chromatography on silica gel (eluted with PE:EtOAc = 20:1 to 3:1) to give cis-tert- butyl 3-[2-[2- (5-bromo-8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclobut anecarboxylate ( 145 mg, 46.36% yield) as light yellow oil. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 549.0.

Step 3: Preparation of s-3-[2-[2-[8-chloro-4-oxo-5-(trifluoromethyl)chromen-2- yl]phenoxy]ethoxy]cyclobutanecarboxylic acid

C094

A mixture of cis-tert- butyl 3-[2-[2-(5-bromo-8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylate (145.0 mg, 0.260 mmol), methyl 2,2-difluoro-2- (fluorosulfonyl) acetate (253.31 mg, 1.32 mmol) and copper (I) iodide (100.45 mg, 0.530 mmol) in DMF (3.5 mL) was stirred at 120 °C for 12 hours. The mixture was then concentrated in vacuo and the residue was purified by Prep-HPLC to give .v-3- 12-[2-[8-chloro-4-oxo-5- (trifluoromethyl)chromen-2-yl]phenoxy]ethoxy]cyclobutanecarb oxylic acid (24.9 mg, 19.56% yield) as an off-white solid. 1H NMR (DMSO-ife, 400MHz): d ppml2.02 (br s, 1H), 8.17 (d, 7 = 8.4 Hz, 1H), 8.05 (d, 7 = 7.8 Hz, 1H), 7.88 (d, 7 = 8.4 Hz, 1H), 7.60 (t, 7 = 7.9 Hz, 1H), 7.19- 7.34 (m, 3H), 4.24-4.34 (m, 2H), 3.96 (quin, 7 = 7.3 Hz, 1H), 3.68-3.77 (m, 2H), 2.36-2.46 (m,

3H), 1.92-2.04 (m, 2H). MS obsd. (ESI ⁺ ): [(M+H) ⁺ ]:483.5.

Example C095: s-3-[2-[2-[8-chloro-4-oxo-5-(trifluorometbyl)chromen-2-yl]-5 -etboxy- phenoxy]ethoxy]cyclobutanecarboxylic acid

C095

Step 1: Preparation of 5-bromo-8-chloro-2-(4-ethoxy-2-hydroxy-phenyl)chromen-4-one

C095a

Compound C095a was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 2-hydroxy-5-methoxy-benzaldehyde as the starting material instead of 4-chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2 and l-(6-bromo-3-chloro-2-hydroxy- phenyl)ethanone as the starting material instead of l-(3-chloro-2-hydroxy-phenyl)ethanone in step 3.

Step 2: Preparation of as-3-[2-[2-[8-chloro-4-oxo-5-(trifluoromethyl)chromen-2-yl]- 5- ethoxy-phenoxy]ethoxy]cyclobutanecarboxylic acid

Example C095 was prepared in analogy to the procedure described for the preparation of example C094 by using 5-bromo-8-chloro-2-(4-ethoxy-2-hydroxy-phenyl)chromen-4-one as the starting material instead of 5-bromo-8-chloro-2-(2-hydroxyphenyl)chromen-4-one in Step 2. ¹ 11 NMR (DMSO-ife, 400MHz): d ppm 12.06 (br s, 1H), 8.14 (d, / = 8.4 Hz, 1H), 8.01 (d, / = 8.7 Hz, 1H), 7.85 (d, J = 8.4 Hz, 1H), 7.21 (s, 1H), 6.77-6.83 (m, 2H), 4.24-4.33 (m, 2H), 4.16 (q, J = 6.9 Hz, 2H), 3.98 (quin, J = 7.2 Hz, 1H), 3.68-3.77 (m, 2H), 2.39-2.48 (m, 3H), 1.95-2.04 (m, 2H), 1.37 (t, J = 7.0 Hz, 3H).. (ESI ⁺ )[(M+H) ⁺ ]:527.l.

Example C096: C7s-3-[2-[2-[8-chloro-4-oxo-5-(trifluoromethyl)chromen-2-yl] -4,5- dimethoxy-phenoxy]ethoxy]cyclobutanecarboxylic acid

C096

Step 1: Preparation of 5-bromo-8-chloro-2-(2-hydroxy-4,5-dimethoxy-phenyl)chromen-4 - one

C096a

Compound C096a was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 2-hydroxy-4,5-dimethoxy-benzaldehyde as the starting material instead of 4-chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2 and l-(6-bromo-3-chloro-2- hydroxy-phenyl)ethanone as the starting material instead of l-(3-chloro-2-hydroxy- phenyl)ethanone in step 3.

Step 2: Preparation of as-3-[2-[2-[8-chloro-4-oxo-5-(trifluoromethyl)chromen-2-yl]- 4,5- dimethoxy-phenoxy]ethoxy]cyclobutanecarboxylic acid

C096

Example C096 was prepared in analogy to the procedure described for the preparation of example C094 by using 5-bromo-8-chloro-2-(2-hydroxy-4,5-dimethoxy-phenyl)chromen-4 -one as the starting material instead of 5-bromo-8-chloro-2-(2-hydroxyphenyl)chromen-4-one in Step 2. 1H NMR (DMSO-ife, 400MHz): d ppm8.11-8.17 (m, / = 8.3 Hz, 1H), 7.81-7.89 (m, / = 8.4

Hz, 1H), 7.62 (s, 1H), 7.26 (s, 1H), 6.91 (s, 1H), 4.21-4.41 (m, 2H), 3.86-4.00 (m, 4H), 3.82 (s, 3H), 3.68-3.77 (m, 2H), 2.38-2.46 (m, 3H), 1.90-2.12 (m, 2H). (ESI ⁺ )[(M+H) ⁺ ]:543.l.

Example C097: 3-[2-[2-[8-chloro-4-oxo-7-(trifluoromethyl)chromen-2-yl]-5-e thoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid

C097

Step 1: Preparation of 8-chloro-2-(4-ethoxy-2-hydroxy-phenyl)-7- (trifluoromethyl)chromen-4-one

C097a

Compound C095a was prepared in analogy to the procedure described for the preparation of compound Int-5 by using 2-hydroxy-5-methoxy-benzaldehyde as the starting material instead of 4-chloro-2-hydroxy-5-methyl-benzaldehyde in Step 2 and l-[3-chloro-2-hydroxy-4- (trifluoromethyl)phenyl]ethanone as the starting material instead of l-(3-chloro-2-hydroxy- phenyl)ethanone in step 3.

Step 2: Preparation of 3-[2-[2-[8-chloro-4-oxo-7-(trifbioromethyl)chromen-2-yl]-5-e thoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid

Example C097 was prepared in analogy to the procedure described for the preparation of example C004 by using 8-chloro-2-(4-ethoxy-2-hydroxy-phenyl)-7-(trifluoromethyl)ch romen-4- one as the starting material instead of 8-chloro-2-(4-chloro-2-hydroxy-phenyl)chromen-4-one in Step 2. 1H NMR (DMSO- , 400MHz): d ppm8. l3 (d, / = 8.4 Hz, 1H), 8.03 (d, / = 8.8 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 7.29 (s, 1H), 6.77-6.85 (m, 2H), 4.29 (br s, 2H), 4.17 (q, / = 7.0 Hz, 2H), 3.97 (br t, J = 7.2 Hz, 1H), 3.73 (br s, 2H), 2.43 (br d, / = 7.0 Hz, 3H), 1.95-2.06 (m, 2H),

1.37 (t, / = 6.9 Hz, 3H). (ESI ⁺ )[(M+H) ⁺ ]:527.l.

Example C098: s-3-[2-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-4,5-dimeth oxy- phenoxy]ethoxy]cyclobutanecarboxylic acid

Step 1: preparation of cis-tert-butyl 3-[2-(2-formyl-4,5-dimethoxy- phenoxy)ethoxy]cyclobutanecarboxylate

C098a

A mixture of cis-tert- butyl 3-[2-(p-tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate (2.44 g, 6.59 mmol), 2-hydroxy-4,5-dimethoxybenzaldehyde (600 mg, 3.29 mmol) and K CO (1.37 g, 9.88 mmol) in DMF (20 mL) was stirred at 60 °C overnight.

After the reaction was completed, the mixture was diluted with water (40 mL) and extracted with EtOAc (50 mL) three times. The combined organic layer was washed with brine, dried over Na S0 and concentrated in vacuo. The residue was purified by column

chromatography on silica gel (eluted with PE:EtOAc = 10:1 to 3: 1) to give cis-tert- butyl 3-[2-(2- formyl-4,5-dimethoxy-phenoxy)ethoxy]cyclobutanecarboxylate (600 mg, 47.9% yield) as a colorless oil. MS obsd. (ESI ⁺ ): [(M+H) ⁺ ]:38L3.

Step 2: preparation of cis-tert-butyl 3-[2-[2-[(/t)-3-[3-chloro-2,6- bis(methoxymethoxy)phenyl]-3-oxo-prop-l-enyl]-4,5-dimethoxy- phenoxy]ethoxy]cyclobutanecarboxylate

C098b A mixture of l-(3-chloro-2-hydroxy-6-(methoxymethoxy)phenyl)ethan-l-one (160 mg,

694 mihoΐ), cis-tert- butyl 3-[2-(2-formyl-4,5-dimethoxy-phenoxy)ethoxy]cyclobutanecarbo xylate (200 mg, 526 pmol) and KOH (29.5 mg, 526 pmol) in EtOH (10 mL) was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was diluted with water (50 mL) and extracted with EtOAc (30 mL) three times. The combined organic layer was concentrated in vacuo to give the crude cis-tert- butyl 3- [ 2- [ 2- [ ( /T ) - 3 - 13-chloro-2,6- bis(methoxymethoxy)phenyl]-3-oxo-prop-l-enyl]-4,5-dimethoxy- phenoxy]ethoxy]cyclobutanecarboxylate (305 mg, 100% yield) as a brown solid, which was used in the next step directly without further purification. MS obsd. (ESI ⁺ ): [(M+H) ⁺ ]:58l.2.

Step 3: preparation of cts-3-[2-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-4,5-dime thoxy- phenoxy]ethoxy]cyclobutanecarboxylic acid

To a suspension of cis-tert- butyl 3- [ 2- [ 2- [ (T)-3- [ 3-chloro-2,6- bis(methoxymethoxy)phenyl]-3-oxo-prop-l-enyl]-4,5-dimethoxy- phenoxy]ethoxy]cyclobutanecarboxylate (300 mg, 471 pmol) in DCM ( 20 Ml) was added TFA (1 mL) and the mixture was then stirred at room temperature for 2 hours. Then the mixture was then washed with water (10 mL) and the organic phase was concentrated in vacuo. The residue was dissolved in DMSO (5 mL) and to the resulting solution was added I ₂ (12 mg, 471 pmol).

The mixture was stirred at l40°C for 1 hour. After cooling to room temperature, the mixture was purified by Prep-HPLC to give s-3-[2-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-4,5- dimethoxy-phenoxy]ethoxy]cyclobutanecarboxylic acid (19.1 mg, 7.4% yield) as an orange solid. 1H NMR (DMSO-ifc, 400MHz): d ppm 12.80 (s, 1H), 11.97-12.19 (m, 1H), 7.81 (d, J = 8.9 Hz, 1H), 7.61 (s, 1H), 7.34 (s, 1H), 6.88-6.94 (m, 1H), 6.83 (d, J = 8.8 Hz, 1H), 4.26-4.37 (m, 2H), 3.95-4.00 (m, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 3.70-3.74 (m, 2H), 2.56-2.61 (m, 1H), 2.41-2.45 (m, 2H), 1.97-2.07 (m, 2H). MS obsd. (ESI ⁺ ): [(M+H) ⁺ ]:49l.3.

Example C099: s-3-[2-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-5- (trifhioromethyl)phenoxy]ethoxy]cyclobutanecarboxylic acid

C099

Example C099 was prepared in analogy to the procedure described for the preparation of example C098 by using 2-hydroxy-4-(trifluoromethyl)benzaldehyde as the starting material instead of 2-hydroxy-4,5-dimethoxybenzaldehyde in step 1. ¹ 11 NMR (l )MSO- _< 7„ 400MHz): d ppml2.54 (s, 1H), 8.18 (br d, / = 7.8 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.48-7.73 (m, 2H), 7.36 (s, 1H), 6.89 (d, J = 9.0 Hz, 1H), 4.30-4.49 (m, 2H), 3.95 (br t, 7 = 7.5 Hz, 1H), 3.62-3.78 (m, 2H), 2.36-2.46 (m, 3H), 1.93-2.17 (m, 2H). (ESI ⁺ )[(M+H) ⁺ ]:499.0.

Example C100: 2-[3-[2-(8-chloro-5-hydroxy-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propoxy]acetic acid

Example C100 was prepared in analogy to the procedure described for the preparation of example C098 by using 2-hydroxy-4-(trifluoromethyl)benzaldehyde and ferf-butyl 2-[3-(p- tolylsulfonyloxy)propoxy]acetate as the starting material instead of 2-hydroxy-4,5- dimethoxybenzaldehyde and cis-tert- butyl 3-[2-(p- tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate in step 1. ¹ 11 NMR (DMSO-ife, 400MHz): d ppml2.51-12.60 (m, 2H), 8.14 (d, J = 8.4 Hz, 1H), 7.87 (d, J = 8.8 Hz, 1H), 7.56-7.61 (m, 2H), 7.19 (s, 1H), 6.89 (d, J = 8.9 Hz, 1H), 4.36 (t, J = 6.2 Hz, 2H), 4.01 (s, 2H), 3.64 (t, J = 6.1 Hz, 2H), 2.01-2.11 (m, 2H). (ESI ⁺ )[(M+H) ⁺ ]:473.l.

Example C101: C7s-3-[2-[5-bromo-2-(8-chloro-3-methoxy-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid

Step 1: Preparation of cis-tert- butyl 3-[2-(5-bromo-2-formyl- phenoxy)ethoxy]cyclobutanecarboxylate

CIO la

To a solution of 4-bromo-2-hydroxybenzaldehyde (200.0 mg, 0.990 mmol), K ₂ CO ₃ (412.51 mg, 2.98 mmol) in DMF (10 mL) was added cis-tert- butyl 3-[2-(p- tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate (368.58 mg, 0.990 mmol) and the reaction mixture was stirred at 80 °C for 6 hours. Then the reaction was diluted with water (25 mL) and the resulting mixture was extracted with EtOAc (20 mL) three times. The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo to give cis-tert- butyl 3-[2-(5-bromo-2-formyl-phenoxy)ethoxy]cyclobutanecarboxylate (350 mg, 88.1% yield) as a yellow solid. MS obsd. (ESf) [(M+Na) ⁺ ]: 421.0.

Step 2: Preparation of s-3-[2-[5-bromo-2-[(£')-3-(3-chloro-2-hydroxy-phenyl)-3-oxo -prop- l-enyl]phenoxy]ethoxy]cyclobutanecarboxylic acid

ClOlb

A mixture of l-(3-chloro-2-hydroxy-phenyl)ethanone (250.0 mg, 1.47 mmol), cis-tert- butyl 3-[2-(5-bromo-2-formyl-phenoxy)ethoxy]cyclobutanecarboxylate (312.5 mg, 0.780 mmol) and KOE1 (411.15 mg, 7.33 mmol) in EtOEl (20 mL) was stirred at 30 °C for 8 hours. Then the mixture was adjusted to PEl~2 by addition of 1N E1C1 and the resulting suspension was filtered. The solid was washed with water and dried in vacuo to give the crude .v-3- 12- [ 5-bromo-2-| ( E)- 3-(3-chloro-2-hydroxy-phenyl)-3-oxo-prop-l-enyl]phenoxy]etho xy]cyclobutanecarboxylic acid (400 mg, 55.06% yield) as a light yellow solid, which was used in the next step directly without further purification.MS obsd. (ESI ⁺ )[(M+Na) ⁺ ]: 516.9.

Step 3: Preparation of s-3-[2-[5-bromo-2-(8-chloro-3-hydroxy-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid

ClOlc

To a solution of s-3-[2-[5-bromo-2-[(£)-3-(3-chloro-2-hydroxy-phenyl)-3-oxo- prop-l- enyl]phenoxy]ethoxy]cyclobutanecarboxylic acid (70.0 mg, 0.140 mmol) in EtOH (2 mL) were added hydrogen peroxide (35.22 mg, 0.310 mmol) and sodium hydroxide (11.3 mg, 0.280 mmol). The mixture was stirred at 25 °C for 16 hours. Then the mixture was poured into water (15 mL) and the resulting suspension was filtered. The solid was collected and purified by Prep-HPLC to give s-3-[2-[5-bromo-2-(8-chloro-3-hydroxy-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid (15 mg, 18.4% yield) as a white solid. ¹ 11 NMR (400 MHz, DMSO) d ppm: 8.04-8.20 (m, 1H), 7.96 (dd, 7 = 7.7, 1.3 Hz, 1H), 7.39-7.56 (m, 3H), 7.32 (dd, 7 = 8.2, 1.6 Hz, 1H), 4.17-4.20 (m, 2H), 3.73 (t, 7 = 6.9 Hz, 1H), 3.51-3.61 (m, 2H), 2.05-2.21 (m, 3H), 1.74 (dd, 7 = 18.1, 7.8 Hz, 2H). MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 509.0.

Step 4: Preparation of s-inethyl 3-[2-[5-bromo-2-(8-chloro-3-methoxy-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylate

ClOld

To a solution of s-3-[2-[5-bromo-2-(8-chloro-3-hydroxy-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid (25.0 mg, 0.050 mmol), CS CO (47.94 mg,

0.150 mmol) in DMF (2 mL) was added iodomethane (13.92 mg, 0.100 mmol) and the mixture was stirred at 40 °C for 2 hours. The reaction mixture was then quenched with water (30 mL) and extracted with EtOAc(40 mL) three times. The combined organic layer was washed with brine (40 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo . The residue was purified by column chromatography on silica gel (eluted with PE:EtOAc = 3:1) to give r/.v- methyl 3-[2-[5-bromo-2- (8-chloro-3-methoxy-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclob utanecarboxylate (18 mg, 70.07% yield) as a colorless oil. MS obsd. (ESI ⁺ ) [(M+Na) ⁺ ]: 559.0.

Step 5: Preparation of C¾-3-[2-[5-bromo-2-(8-chloro-3-methoxy-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylic acid

To a solution of r/ ^' v- methyl 3-[2-[5-bromo-2-(8-chloro-3-methoxy-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclobutanecarboxylate (18.0 mg, 0.030 mmol) in THF (8 mL) and water (1 mL) was added lithium hydroxide (8.02 mg, 0.330 mmol) and the mixture was stirred at 25 °C for 16 hours. The mixture was adjusted to pH~6 by addition of 1N HC1 and the resulting solution was concentrated in vacuo. The residue was purified by Prep-HPLC to give s-3-[2-[5-bromo-2- (8-chloro-3-methoxy-4-oxo-chromen-2-yl)phenoxy]ethoxy]cyclob utanecarboxylic acid (12.1 mg, 68.33% yield) as a white solid. NMR (DMSO-tfc, 400MHz): d ppm 8.09 (dd, J = 7.9, 1.5 Hz, 1H), 8.00 (dd, J = 7.7, 1.5 Hz, 1H), 7.48-7.53 (m, 3H), 7.35 (dd, J = 8.1, 1.7 Hz, 1H), 4.18-4.25 (m, 2H), 3.71-3.78 (m, 4H), 3.36-3.58 (m, 2H), 2.10-2.26 (m, 3H), 1.70-1.81 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ j: 523.0.

Example C102: C¾-3-[2-[[6-(8-chloro-4-oxo-chromen-2-yl)-2,2-difluoro-l,3- benzodioxol-5- yl]oxy]ethoxy]cyclobutanecarboxylic acid

C102

Step 1: Preparation of s-inethyl 3-[2-[[6-(8-chloro-4-oxo-chromen-2-yl)-2-thioxo-l,3- benzodioxol-5-yl]oxy]ethoxy]cyclobutanecarboxylate

C102a

To a solution of r/.v- methyl 3-[2-[2-(8-chloro-4-oxo-chromen-2-yl)-4,5-dihydroxy- phenoxy]ethoxy]cyclobutanecarboxylate (100.0 mg, 0.220 mmol), DMAP (58.32 mg, 0.480 mmol) in DCM (20 mL) was added thiophosgene (29.94 mg, 0.260 mmol) and the mixture was stirred at room temperature for 4 hours. The resulting solution was washed with water (20 mL), brine (15 mL), dried over MgS0 ₄ and concentrated in vacuo to give the crude cis- methyl 3-[2- [[6-(8-chloro-4-oxo-chromen-2-yl)-2-thioxo-l,3-benzodioxol-5 - yl]oxy]ethoxy]cyclobutanecarboxylate (102 mg, 93.47% yield) as a light yellow solid. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 503.1.

Step 2: Preparation of s-inethyl 3-[2-[[6-(8-chloro-4-oxo-chromen-2-yl)-2,2-difluoro-l,3- benzodioxol-5-yl]oxy]ethoxy]cyclobutanecarboxylate

To a solution of r/ ^' v- methyl 3-[2-[[6-(8-chloro-4-oxo-chromen-2-yl)-2-thioxo-l,3- benzodioxol-5-yl]oxy]ethoxy]cyclobutanecarboxylate (230.0 mg, 0.460 mmol), NIS (246.9 mg, 1.1 mmol) in DCM (10 mL) was added tetrabutylammonium dihydrogen trifluoride (413.6 mg, 1.37 mmol) at 0 °C and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with water (10 mL) and the resulting mixture was extracted with DCM (20 mL) twice. The combined organic layer was dried over Na ₂ S0 ₄ and concentrated in vacuo, the residue was purified by prep-HPLC to give r/.v- methyl 3-[2-[[6-(8-chloro-4-oxo-chromen-2-yl)- 2,2-difluoro-l,3-benzodioxol-5-yl]oxy]ethoxy]cyclobutanecarb oxylate (21.3 mg, 9.15% yield) as a yellow solid. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 509.1.

Step 3: Preparation of s-3-[2-[[6-(8-chloro-4-oxo-chromen-2-yl)-2,2-difluoro-l,3- benzodioxol-5-yl]oxy]ethoxy]cyclobutanecarboxylic acid

C102

L solution of r/.v- methyl 3-[2-[[6-(8-chloro-4-oxo-chromen-2-yl)-2,2-difluoro-l,3- benzodioxol-5-yl]oxy]ethoxy]cyclobutanecarboxylate (20.0 mg, 0.040 mmol) in hydrochloric acid (lOmL, 120 mmol) was stirred at 100 °C for 20 minutes. The reaction mixture was concentrated in vacuo and the residue was purification by prep-HPLC to give r/ ^' v-3-|2-| |6-(8- chloro-4-oxo-chromen-2-yl)-2,2-difluoro-l,3-benzodioxol-5- yl]oxy]ethoxy]cyclobutanecarboxylic acid (14.1 mg, 70.96% yield) as a white solid. ¹ 11 NMR (400 MHz, DMSO) d ppm: 12.11 (s, 1H), 7.97-8.04 (m, 2H), 7.88 (s, 1H), 7.58 (s, 1H), 7.50 (t, J = 7.9 Hz, 1H), 7.15 (s, 1H), 4.28-4.30 (m, 2H), 3.86-3.93 (m, 1H), 3.68-3.70 (m, 2H), 2.36-2.46

(m, 3H), 1.92-1.99 (m, 2H). MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 495.1.

Example C103:

3-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propoxy]cyclobutanecarboxylic acid

Example C103 was prepared in analogy to the procedure described for the preparation of example C004 by using 8-chloro-2-[2-hydroxy-4-(trifluoromethyl)phenyl]chromen-4-on e and methyl 3-[3-(p-tolylsulfonyloxy)propoxy]cyclobutanecarboxylate as the starting material instead of 8-chloro-2-(4-chloro-2-hydroxy-phenyl)chromen-4-one and methyl 3-[2-(p- tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate in step 1. ¹ 11 NMR (400 MHz, DMSO) d ppm: 12.03-12.13 (m, 1H), 8.10-8.15 (m, 1H), 8.03 (ddt, J = 7.8, 3.0, 1.5 Hz, 2H), 7.48-7.59 (m, 3H), 7.05-7.12 (m, 1H), 4.27-4.37 (m, 2H), 4.01-4.05 (m, 0.3H), 3.76-3.85 (m, 0.7H), 3.41-3.48 (m, 2H), 2.80-2.90 (m, 0.3H), 2.51-2.54 (m, 0.7H), 2.26-2.39 (m, 2H), 1.86-2.11 (m, 4H). MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 496.9.

Example C104: 3-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propoxy]cyclopentanecarboxylic acid

Example C104 was prepared in analogy to the procedure described for the preparation of example C004 by using 8-chloro-2-[2-hydroxy-4-(trifluoromethyl)phenyl]chromen-4-on e and methyl 3-[3-(p-tolylsulfonyloxy)propoxy]cyclopentanecarboxylate as the starting material instead of 8-chloro-2-(4-chloro-2-hydroxy-phenyl)chromen-4-one and methyl 3-[2-(p- tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate in step 1. ¹ 11 NMR (DMSO-ife, 400MHz): d ppm 8.11-8.23 (m, 1H), 8.05 (br dd, 1H, 7=6.4, 8.0 Hz), 7.88-8.00 (m, 1H), 7.38-7.50 (m, 3H), 7.21-7.26 (m, 1H), 4.32 (br d, 2H, 7=5.6 Hz), 3.89-4.01 (m, 1H), 3.59 (t, 2H, 7=5.9 Hz), 2.83 (br t, 1H, 7=7.9 Hz), 2.13 (br t, 2H, 7=5.3 Hz), 1.93 (br d, 2H, 7=7.3 Hz), 1.79-1.99 (m, 2H), 1.64- 1.77 (m, 2H).. (ESI ⁺ )[(M+H) ⁺ ]:5l0.9.

Example C105: 3-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]propoxy]cyclopentanecarboxylic acid

Example C105 was prepared in analogy to the procedure described for the preparation of example C004 by using 2-(4-bromo-2-hydroxy-phenyl)-8-chloro-chromen-4-one and methyl 3- [3-(p-tolylsulfonyloxy)propoxy]cyclopentanecarboxylate as the starting material instead of 8- chloro-2-(4-chloro-2-hydroxy-phenyl)chromen-4-one and methyl 3-[2-(p- tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate in step 1. ¹ 11 NMR (DMSO-ife, 400MHz): d ppml2.0l (br s, 1H), 7.96-8.03 (m, 2H), 7.83-7.91 (m, 1H), 7.38-7.55 (m, 3H), 7.02-7.06 (m,

1H), 4.19-4.29 (m, 2H), 3.80-3.93 (m, 1H), 3.48 (t, J = 6.2 Hz, 2H), 2.68-2.78 (m, 1H), 1.94-2.07 (m, 2H), 1.68-1.89 (m, 4H), 1.53-1.66 (m, 2H). (ESI ⁺ )[(M+H) ⁺ ]:52l.O.

Example C106: 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]cyclopentanecarboxylic acid

Example C106 was prepared in analogy to the procedure described for the preparation of example C004 by using 2-(4-bromo-2-hydroxy-phenyl)-8-chloro-chromen-4-one and methyl 3- [2-(p-tolylsulfonyloxy)ethoxy]cyclopentanecarboxylate as the starting material instead of 8- chloro-2-(4-chloro-2-hydroxy-phenyl)chromen-4-one and methyl 3-[2-(p- tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate in step 1. ¹ 11 NMR (DMSO-ife, 400MHz): d ppml2.0l (br s, 1H), 7.91-8.02 (m, 3H), 7.41-7.54 (m, 3H), 7.25 (s, 1H), 4.27-4.37 (m, 2H), 4.04 (dq, J = 5.4, 2.6 Hz, 1H), 3.67-3.78 (m, 2H), 2.76-2.85 (m, 1H), 1.74-1.95 (m, 4H), 1.59-1.71 (m, 2H). (ESI ⁺ )[(M+H) ⁺ ]:507.l.

Example C107: 4-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy] benzoic acid

Step 1: Preparation of 2-[4-bromo-2-(2-bromoethoxy)phenyl]-8-chloro-chromen-4-one

C107a To the solution of 2-(4-bromo-2-hydroxy-phenyl)-8-chloro-chromen-4-one (500 mg, 1.42 mmol), l,2-dibromoethane (1.07 g, 5.69 mmol) in DMF was added K ₂ CO ₃ (197 mg, 1.42 mmol) and the mixture was then stirred at 50°C overnight. After the reaction was completed, the mixture was partitioned between EtOAc (10 mL) and water (30 ml). The resulting suspension was filtered. The solid was collected and dried in vacuo to give 2-[4-bromo-2-(2- bromoethoxy)phenyl]-8-chloro-chromen-4-one (450 mg, 69% yield) as a yellow solid. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:457.0.

Step 2: Preparation of methyl 4-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]benzoate

C107b

A mixture of 2-[4-bromo-2-(2-bromoethoxy)phenyl]-8-chloro-chromen-4-one (110 mg, 239 pmol), methyl 4-hydroxybenzoate (60 mg, 392 pmol), K ₂ CO ₃ (54.3 mg, 393 pmol) in a mixed solvent of TE1F (5 mL) and DMF (2 mL) was stirred at 30 °C overnight. After the reaction was completed, the reaction mixture was diluted with EtOAc (40 mL). The resulting solution was washed with water (20 mL), brine (15 mL), dried over Na ₂ S0 ₄ and concentrated in vacuo to give the crude methyl 4-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy] benzoate (120 mg, 100% yield) as a yellow oil, which was used in the next step directly. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:527.0.

Step 3: Preparation of 4-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]benzoic acid

To a solution of methyl 4-(2-(5-bromo-2-(8-chloro-4-oxo-4ELchromen-2- yl)phenoxy)ethoxy)benzoate (120 mg, 227 pmol) in a mixed solvent of TE1F (5 ml), MeOEl (5 ml) and water (1 mL) was added LiOEl (43.4 mg, 1.81 mmol). The mixture was then stirred at room temperature for 48 hours. The reaction mixture was diluted with water (10 mL) and methanol (10 mL) and the resulting suspension was filtered. The solid was collected and purified by Prep-HPLC to give 4-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy] benzoic acid (16 mg, 12.3% yield) as an off-white solid. 1H NMR (400 MHz, DMSO) d ppm: 7.97 (td, J = 7.5, 1.5 Hz, 2H), 7.91 (d, J = 8.4 Hz, 1H), 7.85 (d, J = 8.8 Hz, 2H), 7.60-7.65 (m, 1H), 7.45- 7.50 (m, 2H), 7.19 (s, 1H), 7.08 (d, J = 8.8 Hz, 2H), 4.61 (dd, J = 5.9, 2.3 Hz, 2H), 4.47 (dd, J = 5.6, 2.5 Hz, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:5l5.l.

Example C108: 3-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy] benzoic acid

Example C108 was prepared in analogy to the procedure described for the preparation of example C107 by using methyl 3-hydroxybenzoate as the starting material instead of methyl 4- hydroxybenzoate in step 2. ¹ 11 NMR (400 MHz, DMSO) d ppm: 7.89-8.02 (m, 3H), 7.61-7.67 (m, 1H), 7.43-7.54 (m, 4H), 7.36-7.40 (m, 1H), 7.27 (br d, 7 = 1.7 Hz, 1H), 7.20 (s, 1H), 4.56- 4.66 (m, 2H), 4.31-4.49 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:5l5.l.

Example C109: 2-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5- (trifluoromethyl)phenoxy]propoxy] -2-methyl-propanoic acid

Example C109 was prepared in analogy to the procedure described for the preparation of example C107 by using 8-chloro-2-[2-hydroxy-4-(trifluoromethyl)phenyl]chromen-4-on e and l,3-dibromopropane as the starting material instead of 2-(4-bromo-2-hydroxy-phenyl)-8-chloro- chromen-4-one and l,2-dibromoethane in step 1 and using methyl 2-hydroxy- 2- methyl- propanoate as the starting material instead of methyl 4-hydroxybenzoate in step 2. ¹ 11 NMR (DMSO-ife, 400MHz): d ppm 8.23 (d, 1H, 7=7.9 Hz), 8.13 (dd, 1H, 7=1.5, 8.0 Hz), 7.95 (dd, 1H, 7=1.5, 7.8 Hz), 7.48-7.55 (m, 3H), 7.25 (s, 1H), 4.35-4.41 (m, 4H), 2.31 (m, 2H), 1.38 (s, 6H).. (ESI ⁺ )[(M+H) ⁺ ]:485.3.

Example C110: s-3-[3-[5-bromo-2-(8-cliloro-4-oxo-cliromen-2-yl)phenoxy]-2, 2-dimethyl- propoxy]cyclobutanecarboxylic acid and iraras-3-[3-[5-bromo-2-(8-chloro-4-oxo-chromen- 2-yl)phenoxy]-2,2-dimethyl-propoxy]cyclobutanecarboxylic acid

C110-A,C110-B

Step 1: Preparation of 3-benzyloxy-2,2-dimethyl-propan-l-ol

CllOa

To a solution of 2,2-dimethylpropane-l,3-diol (2800.0 mg, 26.88 mmol) in THF (60 mL) were added NaH (1290.45 mg, 32.26 mmol), benzyl bromide (3.2 mL, 26.88 mmol) and tetrabutylammonium iodide (9930.17 mg, 26.88 mmol) at 0 °C. The resulting mixture was stirred at 25 °C for 16 hours. Then the reaction mixture was quenched with saturated aqueous NH ₄ Cl (50 mL) and extracted with EtOAc (50 mL) three times. The combined organic layer was washed with brine (80 mL), dried over anhydrous Na ₂ S0 ₄ and concentrated in vacuo. The residue was purified by column chromatography on silica gel (eluted with PE:EtOAc = 100:1 to 5: 1) to give 3-benzyloxy-2,2-dimethyl-propan-l-ol (3800 mg, 72.74% yield) as a colorless oil. MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]: 195.2.

Step 2: Preparation of methyl 3-[2,2-dimethyl-3-(p- tolylsulfonyloxy)propoxy]cyclobutanecarboxylate

CllOb

Compound CllOb was prepared in analogy to the procedure described for the preparation of compound Int-Tl by using 3-benzyloxy-2,2-dimethyl-propan-l-ol as the starting material instead of 2-benzyloxyethanol in Step 1.

Step 3: Preparation of s-3-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-2,2- dimethyl-propoxy]cyclobutanecarboxylic acid and traras-3-[3-[5-bromo-2-(8-chloro-4-oxo- chromen-2-yl)phenoxy]-2,2-dimethyl-propoxy]cyclobutanecarbox ylic acid

C110-A,C110-B

Example C110-A and C110-B were prepared in analogy to the procedure described for the preparation of example C003-A and example C003-B by using 8-chloro-2-[2-hydroxy-4- (trifluoromethyl)phenyl]chromen-4-one and methyl 3-[2,2-dimethyl-3-(p- tolylsulfonyloxy)propoxy]cyclobutanecarboxylate as the starting materials instead of 2-(4- bromo-2-hydroxy-phenyl)-8-chloro-chromen-4-one and methyl 3-[2-(p- tolylsulfonyloxy)ethoxy]cyclobutanecarboxylate in Step 1.

Example C110-A: NMR (DMSO-ifc, 400MHz): d ppm 12.06 (br s, 1H), 8.01 (dq, / = 7.9, 1.4 Hz, 2H), 7.84 (d, J = 8.6 Hz, 1H), 7.39-7.56 (m, 3H), 7.00 (s, 1H), 3.94 (s, 2H), 3.69- 3.86 (m, 1H), 3.14 (s, 2H), 2.44 - 2.48 (m, 1H), 2.15-2.38 (m, 2H), 1.76-1.95 (m, 2H), 0.87-1.04 (m, 6H). (ESI ⁺ )[(M+H) ⁺ ]:535.0.

Example C110-B: 1H NMR (DMSO-ifc, 400MHz): d ppm 12.11 (br s, 1H), 8.01 (d, J = 8.1 Hz, 2H), 7.85 (d, J = 8.6 Hz, 1H), 7.40-7.59 (m, 3H), 7.02 (s, 1H), 3.91-4.06 (m, 3H), 3.13 (s, 2H), 2.73-2.98 (m, 1H), 2.16-2.34 (m, 2H), 1.95-2.10 (m, 2H), 0.98 (s, 6H).

(ESI ⁺ )[(M+H) ⁺ ]:535.0.Example Clll: (3/?)-l-[2-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]acetyl]pyrrolidine-3-carboxylic acid

Clll

Example 111 was prepared in analogy to the procedure described for the preparation of example A075 by using 2-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy] acetic acid as the starting material instead of 3-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]propanoic acid (Example A004) in step 1. ¹ 11 NMR (400 MHz, DMSO) d ppm: 7.96-8.02 (m, 2H), 7.88-7.92 (m, 1H), 7.40-7.55 (m, 3H), 7.17 (d, / = 6.0 Hz, 1H), 4.33-4.40 (m, 2H), 4.14-4.21 (m, 2H), 3.85-3.93 (m, 2H), 3.24-3.61 (m, 4H), 2.90-3.09 (m, 1H), 1.85-2.04 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:550.l.

Example 012: (3S)-l-[2-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2- yl)phenoxy]ethoxy]acetyl]pyrrolidine-3-carboxylic acid

Example 111 was prepared in analogy to the procedure described for the preparation of example A075 by using 2-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy] acetic acid and ferf-butyl (2.S')-pyrrolidinc-2-carhoxylatc as the starting material instead of 3-[5-bromo- 2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]propanoic acid (Example A004) and ferf-butyl (2R)~ pyrrolidine-2-carboxylate in step 1. ¹ 11 NMR (400 MHz, DMSO) d ppm: 12.40-12.56 (m, 1H), 7.97-8.04 (m, 2H), 7.86-7.93 (m, 1H), 7.41-7.55 (m, 3H), 7.17 (d, / = 6.1 Hz, 1H), 4.31-4.44 (m, 2H), 4.11-4.20 (m, 2H), 3.89 (br d, / = 2.6 Hz, 2H), 3.37-3.61 (m, 4H), 2.90-3.08 (m, 1H), 1.86- 2.09 (m, 2H). MS obsd. (ESI ⁺ ) [(M+H) ⁺ ]:550.0.

Example 013: 2-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-2-hydr oxy- propoxy]acetic acid

Step 1: Preparation of 2-[4-bromo-2-(oxiran-2-ylmethoxy)phenyl]-8-chloro-chromen-4- one

C113a

A mixture of 2-(4-bromo-2-hydroxy-phenyl)-8-chloro-chromen-4-one (300 mg, 853 mihoΐ), 2-(chloromethyl)oxirane (789 mg, 8.53 mmol) and K ₂ CO ₃ (1.77 g, 12.8 mmol) in DMF (25 mL) was stirred at 50 °C overnight. The mixture was then poured into water (75mL) and extracted with EtOAc (100 mL) twice. The combined organic layer was washed with brine, dried over Na ₂ S0 ₄ and concentrated in vacuo. The residue was then triturated with MTBE (20 mL) and the suspension was then filtered. The filtered cake was collected and dried in vacuo to give 2- [4- bromo-2-(oxiran-2-ylmethoxy)phenyl]-8-chloro-chromen-4-one (300 mg, 86.2% yield) as a yellow solid. MS obsd. (ESf) [(M+H) ⁺ ]: 406.9.

Step 2: Preparation of methyl 2-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-2- hydroxy-propoxy]acetate

C113b

To a solution of 2-[4-bromo-2-(oxiran-2-ylmethoxy)phenyl]-8-chloro-chromen-4- one

(220.0 mg, 0.540 mmol) in methyl glycolate (486.15 mg, 5.4 mmol) was added boron fluoride ethyl ether (182.98 mg, 2.7 mmol) and the mixture was stirred at 25 °C for lhour. The mixture was concentrated in vacuo and the residue was purified column chromatography on silica gel (eluted with PE:EtOAc = 5:1 to 1:1) to give methyl 2-[3-[5-bromo-2-(8-chloro-4-oxo-chromen- 2-yl)phenoxy]-2-hydroxy-propoxy]acetate (150 mg, 55.84% yield) as a colorless oil. MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 497.0.

Step 3: Preparation of 2-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-2-hydr oxy- propoxy]acetic acid

To a solution of methyl 2-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-2- hydroxy-propoxy] acetate (250.0 mg, 0.500 mmol) in THF (5 mL) and water (1 mL) was add LiOH (55 mg, 2.51 mmol) and the mixture was stirred at 25 °C for 3 hours. The mixture was then adjusted to pH~6 by addition of 2N HC1 and the resulting mixture was concentrated in vacuo.

The residue was then purified by Prep-HPLC to give 2-[3-[5-bromo-2-(8-chloro-4-oxo-chromen- 2-yl)phenoxy]-2-hydroxy-propoxy]acetic acid (130 mg, .03% yield) as a white solid. ¹ 11 NMR (DMSO-ife, 400MHz) d ppm 8.00 (d, J= 7.7 Hz, 2H), 7.90 (d, J= 8.5 Hz, 1H), 7.56 - 7.46 (m, 2H), 7.42 (dd, J= 8.5, 1.8 Hz, 1H), 7.19 (s, 1H), 4.16 (ddd, J= 15.8, 9.9, 5.3 Hz, 2H), 4.02-3.90 (m, 1H), 3.83-3.72 (m, 2H), 3.64-3.50 (m, 2H). MS obsd. (ESI ⁺ )[(M+H) ⁺ ]: 483.0.

Example 014: 2-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-2-hydr oxy- propoxyjacetamide

A solution of methyl 2-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-2-hydr oxy- propoxy] acetate (100.0 mg, 0.200 mmol) in ammonia (1 mL) was stirred at room temperature for 3hours. The mixture was concentrated in vacuo and the residue was then purified by Prep-HPLC to give 2-[3-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]-2-hydr oxy- propoxy] acetamide (30 mg, 29.08% yield) as a white solid. ¹ 11 NMR (l )MSO- _< %, 400MHz) d ppm 8.01 (dd, J= 7.9, 1.9 Hz, 2H), 7.91 (d, J= 8.5 Hz, 1H), 7.54 (d, J= 1.6 Hz, 1H), 7.50 (t, J= 7.9 Hz, 1H), 7.44 (dd, J= 8.5, 1.7 Hz, 1H), 7.32 (d, J= 17.4 Hz, 2H), 7.23 (s, 1H), 5.40 (d, J= 5.0 Hz, 1H), 4.29 (dd, J= 10.1, 3.9 Hz, 1H), 4.19 (dd, J= 10.0, 6.1 Hz, 1H), 4.07 (dd, J= 9.4, 5.1 Hz, 1H), 3.83 (d, J= 1.7 Hz, 2H), 3.55 (qd, J= 9.8, 5.4 Hz, 2H). MS obsd. (ESI ⁺ )[(M+H) ⁺ ]:482.0. Example 015:

2-[3-[2-(8-chloro-4-oxo-chromen-2-yl)-5-(trifluoromethyl)phe noxy]-2-hydroxy- propoxy]acetic acid

Example 115 was prepared in analogy to the procedure described for the preparation of example 013 by using 8-chloro-2-[2-hydroxy-4-(trifluoromethyl)phenyl]chromen-4-on e as the starting material instead of 2-(4-bromo-2-hydroxy-phenyl)-8-chloro-chromen-4-one in step 1. ¹ 11 NMR (DMSO-ifc, 400MHz) d ppm 8.13-8.18 (m, 1H), 7.99-8.06 (m, 2H), 7.56-7.61 (m, 2H), 7.49-7.55 (m, 1H), 7.20-7.27 (m, 1H), 5.22-5.32 (m, 1H), 4.31-4.37 (m, 1H), 4.21-4.26 (m, 1H), 4.05 (s, 2H), 3.52-3.59 (m, 1H), 3.52-3.55 (m, 1H). MS obsd. (ESI ⁺ )[(M+H) ⁺ ]:473.2.

Example 016: 2-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy] -N- cyclopropylsulfonyl-acetamide

To a mixture of 2-[2-[5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy] acetic acid (100 mg, 220 pmol, as the“EX” in Table 10), cyclopropanesulfonamide (34.7 mg, 287 pmol, as the“AMINE” in Table 10), DMAP (40.4 mg, 331 pmol) in DCM (10 mL) was added HATU (134 mg, 353 m mol ) and the mixture was then stirred at room temperature overnight. After the reaction was completed, the reaction solution was diluted with DCM (30 mL), the resulting solution was washed by water (15 mL), brine (15 ml), dried over MgS0 ₄ and filtered. The filtrate was concentrated in vacuo and the residue was purified by Prep-HPLC to give 2- [2- [5-bromo-2-(8-chloro-4-oxo-chromen-2-yl)phenoxy]ethoxy]-N-cy clopropylsulfonyl-acetamide (26.5 mg, 20.5% yield) as a white solid. NMR (DMS()- _< %, 400MHz) d ppm 11.68 (s, 1H), 8.00 (ddd, 7 = 7.8, 6.4, 1.5 Hz, 2H), 7.88-7.94 (m, 1H), 7.38-7.57 (m, 3H), 7.19 (s, 1H), 4.30- 4.43 (m, 2H), 4.12-4.19 (m, 2H), 3.78-3.96 (m, 2H), 2.88-2.99 (m, 1H), 1.03-1.13 (m, 4H). MS obsd. (ESI ⁺ )[(M+H) ⁺ ]:556.l. The following compounds 017 to 026 were prepared in analogy to the procedure described for the preparation of Example 016, replacing 2-[2-[5-bromo-2-(8-chloro-4-oxo- chromen-2-yl)phenoxy]ethoxy]acetic acid with“EX”, cyclopropanesulfonamide with“AMINE”. The“EX” and“AMINE” are the reagents indicated in Table 10.

Table 10: Compounds synthesis and characterization

Similar flavone compounds, 7-hydroxy-2-(2-hydroxyphenyl)chromen-4-one (compound F-l) in patent WO2015061294 for treating HBV infection as STING agonist and 6-methoxy-2- (2-methoxyphenyl)chromen-4-one (compound F-2) disclosed in patent WO 2001003681 for treating infections, were chosen as reference compounds in present invention.

(compound F-l) (compound F-2)

BIOLOGICAL EXAMPLES Biological Example 1: Engineered HepDESl9 primary screen assay

The assay was employed to screen for novel cccDNA inhibitors. HepDESl9 is a cccDNA- producing cell line. In this cell line, HBeAg in the cell culture supernatant as surrogate marker, as HBeAg production depends on cccDNA level and activity. HepDESl9 is an engineered cell line which contains a 1.1 unit length HBV genome, and pgRNA transcription from the transgene is controlled by Tetracycline (Tet). In the absence of Tet, pgRNA transcription will be induced, but HBV e antigen (HBeAg) could not be produced from this pgRNA due to very short leader sequence before the HBeAg start codon and the start codon is dismpted. Only after cccDNA is formed, the missing leader sequence and start codon mutation would be restored from the 3’- terminal redundancy of pgRNA, and then HBeAg could be synthesized. Therefore, HBeAg could be used as a surrogate marker for cccDNA (Zhou, T. et al., Antiviral Res. (2006), 72(2), 116-124; Guo, H. et al., J. Virol. (2007), 81(22), 12472-12484).

HepDESl9 cells were seeded at 2x10 ⁶ cells per T150 flask and cultured with the culture medium (Dulbecco’s Modified Eagle Medium: Nutrient Mixture F-12 [DMEM-F12, Gibco Cat. 11320-82], 10% Fetal Bovine Serum [FBS, Clontech Cat. 631101], O.lmM Non-Essential

Amino Acids Solution [NEAA, Gibco Cat. 11140-050], 50pg/mL Penicillin-Streptomycin [PS, Invitrogen Cat. 15140-163], 500 pg/mL Geneticin [G418, Invitrogen Cat. 10131-027]) containing 3pg/mL Tet (Sigma, Cat. 87128) for 5 days. Cells were then seeded at 4xl0 ⁶ cells per T150 in the same culture medium as described above in the absence of Tet for 8 days. Cells were then harvested and frozen at density of 2x 10 ⁶ cells per mL. For compound testing, the frozen cells were thawed and seeded into 96- well plates at a density of 6 xlO ⁴ cells per well. At 24hours after seeding, half log serial dilutions of compounds made with Dimethyl sulfoxide (DMSO, Sigma, Cat. D2650) were further diluted with the same culture medium as described above before they were added to the cells to reach desired final compound concentrations and 1% DMSO concentration. Plates were then incubated at 37°C for another 5 days before measurement of HBeAg level and cell viability. Intracellular HBeAg level were measured with enzyme-linked immunosorbent assay (ELISA) kit (Shanghai Kehua Diagnostic Medical Products Co., Ltd). Cell viability was assessed using Cell Counting Kit-8 (Doa/indo, Cat. CK04-20). IC50 values were derived from the dose-response curve using 4 parameter logistic curve fit method. The compounds of the present invention were tested for their capacity to inhibit extracellular FlBeAg level as described herein. The compounds of this invention were found to have IC50 below 50 mM. Particular compounds of formula (I) were found to have IC50 below 5.0 mM. Results of FlepDESl9 primary screen assay are given in Table Dl.

Table Dl: Activity data in FlepDESl9 primary screen assay

Biological Example 2: Cryopreserved primary human hepatocytes (PHH) assay

This assay is used to confirm the anti-HBV effect of the compounds in HBV PHH infection assay. Cryopreserved PHH (BioreclamationIVT, Lot Y/M) was thawed at 37°C and gently transferred into pre-warmed InVitroGRO HT medium(BioreclamationIVT, Cat. S03317). The mixture was centrifuged at 70 relative centrifugal force (RCF) for 3 minutes at RT, and the supernatant was discarded. Pre-warmed InVitroGRO CP medium (BioreclamationIVT, Cat# S03316) was added to the cell pellet to gently re-suspend cells. The cells were seeded at the density of 5.8xl0 ⁴ cells per well to collagen I coated 96-well plate (Gibco, Cat. A1142803) with the InVitroGRO CP medium. All plates were incubated at 37°C with 5% C0 ₂ and 85% humidity.

At 20 hours after plating, the medium was changed to PHH culture medium (Dulbecco's Modified Eagle Medium (DMEM)/Fl2 (1:1) (Gibco, Cat. 11320-033), 10% fetal bovine semm (Gibco Cat. 10099141), 100 U/mL penicillin, 100 pg/mL streptomycin (Gibco, Cat. 151401-122), 5 ng/mL human epidermal growth factor (Invitrogen Cat. PHG0311L), 20 ng/mL dexamethasone (Sigma, Cat. D4902) and 250 ng/mL human recombinant insulin (Gibco, Cat. 12585-014)). And the cells were incubated at 37°C with 5% C0 ₂ and 85% humidity for 4 hours. The medium was then changed to pre-warmed PHH culture medium containing 4% polyethylene glycol (PEG) MW8000 (Sigma, Cat. P1458-50ML) and 1% DMSO (Sigma, Cat. D2650). 5.8 x 10 ⁶ genomic equivalents of HBV were added into the medium. At 24 hours post-infection, the cells were gently washed with PBS and refreshed with PHH culture medium supplemented with 1% DMSO, and 0.25mg/mL Matrix gel (Coming, Cat.

356237) at 200pL per well. All plates were immediately placed in at 37°C C0 ₂ incubator. 24 hours later, serial dilutions of compounds made with DMSO were further diluted with the same culture medium (PHH culture medium supplemented with 1% DMSO and 0.25mg/mL Matrix gel as described above) before they were added to the cells to reach desired final compound concentrations and 1% DMSO concentration. The medium containing the compounds were refreshed every three days.

At 9 days post-compound treatment, extracellular HBsAg level were measured with Chemiluminescence Immuno Assay (CLIA) kit (Autobio, HBsAg Quantitative CLIA).

Extracellular HBV DNA was extracted by MagNA Pure 96 system (Roche) and then determined by quantitative PCR with the following primers and probe:

HBV-Forward Primer (SEQ ID NO: 1): AAGAAAAACCCCGCCTGTAA (5' to 3');

HBV-Re verse Primer (SEQ ID NO: 2): CCTGTTCTGACTACTGCCTCTCC (5' to 3'); HBV-Probe: 5’+ tetramethylrhodamine + SEQ ID NO: 3 + black hole quencher 2-3', wherein SEQ ID NO: 3 is CCTGATGTGATGTTCTCCATGTTCAGC.

HBsAg IC ₅₀ and HBV DNA IC ₅₀ values were derived from the dose-response curve using 4 parameter logistic curve fit method. The compounds of formula (I) have HBsAg IC ₅₀ <20 mM, particularly <1 mM; and HBV DNA IC ₅₀ < 50 mM. Results of Cryopreserved PHH assay are given in Table D2.

Table D2: HBsAg IC50 data in Cryopreserved PHH assay

Biological Example 3: cccDNA Southern Blot assay:

HepDESl9 cells were seeded at 4*10 ⁶ cells per T150 in the culture medium (Dulbecco’s Modified Eagle Medium: Nutrient Mixture F-12 [DMEM-F12, Gibco Cat. 11320-82], 10% Fetal Bovine Serum [FBS, Clontech Cat. 631101], O.lmM Non-Essential Amino Acids Solution

[NEAA, Gibco Cat. 11140-050], 50pg/mL Penicillin-Streptomycin [PS, Invitrogen Cat. 15140- 163], 500 pg/mL Geneticin [G418, Invitrogen Cat. 10131-027]) in the absence of Tet for 8 days. These cells were seeded at the density of lxlO ⁶ cells per well in 6-well plate. At 24hours after seeding, serial dilutions of compounds made with DMSO (Sigma, Cat. D2650) were further diluted with the same culture medium as described above before they were added to the cells to reach desired final compound concentrations and 1% DMSO concentration. After 5 days’ compound treatment, the cells growing in one well from 6-well plate were re-suspended with 500pL re-suspension buffer (50mM tris [hydroxymethyl] amino methane pH 7.5), lOmM ethylenediaminetetraacetic acid (EDTA), 50pg/mL RNase A [Qiagen, Cat. 158922] 500pL of 1.2% sodium dodecyl sulfate (SDS) was then added into the re-suspended cells to lyse the cells. After 15 minutes’ incubation, 700pL precipitation buffer (3M cesium chloride, 1M potassium acetate, 0.67M acetic acid) was added and the lysate was incubated at 4°C for 2h. The lysate was centrifuged at 15000 revolutions per minute (RPM) at 4 °C for 15 minutes. The supernatant was collected and loaded onto Qiagen miniprep columns (QIAprep spin Mini prep kit, Cat. No.

27016). After centrifugation for 1 minute at 15000 RPM, the column was washed once with 750 pL wash buffer PE (QIAprep spin Mini prep kit, Cat. No. 27016). 80 pL of double distilled water was loaded to the columns to elute Hirt DNA.

Hirt DNA of each sample was loaded into 1.2% lx tris-acetate electrophoresis (TAE) agarose gel and separated at 90 voltages for 3 hours. The gel was then treated in 50mM NaAc- HAc, pH4.2 for 30min at room temperature (RT), and then denatured by soaking in denaturation buffer (0.5 M sodium hydroxide, 1.5 M sodium chloride) at room temperature for 30-45 minutes. The gel was then treated with neutralization buffer (1M tris [hydroxymethyl] amino methane pH7.4 and 1.5M NaCl) at room temperature for 30-45 minutes.

The gel was transferred onto a pre-wet Nylon membrane (GE life science, Hybond N+) by capillary transfer method overnight, followed by UV crosslinking. The membrane was transferred into a hybridization tube, then rinsed with double distilled water at 60 °C for 5 min.

10 mL of hybridization buffer (Lab kits, China) was added, the resulting sample was rotated in hybridization oven at 60 °C for 1 hour. Digoxigenin (DIG)-labelled HBV probe was denatured at 95 °C for 10 minutes, and then 7 pL of denatured probe was added to the hybridization tube, which was rotated in hybridization oven at 60 °C overnight.

On the second day, the membrane was washed according to the procedure of DIG wash and block buffer set kit (Roche, Cat. 11 585 762 001), and then incubated with 50mL antibody solution (Antibody anti-Digoxigenin-AP Fab fragment [Roche Cat. 11093274910] diluted in fresh l xblocking buffer at 1: 10,000) for 1 hour. The membrane was washed with 50 mL washing buffer (lxMaleic buffer with 0.3% Tween- 20) for 15 minutes twice, and equilibrated with 20mL detection buffer (0.1M tris [hydroxymethyl] amino methane pH9.5, 0.1M sodium chloride) for 5 minutes. CDP-Star substrate (Roche, Cat. 12041677001) was added to the membrane for 5 minutes, and then the membrane was scanned by Bio-Rad Visualize Image System (Biorad, ChemiDoc-MP, Serial No. 731BR00916).

Results of cccDNA Southern Blot assay are given in Figure 1. The results indicate that the compounds of this invention dose-dependently reduced cccDNA level in FlepDESl9 cells.

Biological Example 4: Human microsome stability assay

The human microsomal stability assay is used for early assessment of metabolic stability of a test compound in human liver microsomes.

Fhiman liver microsomes (Cat.NO.: 452117, Coming, USA;Cat.NO.:Fl26lO, Xenotech, USA) were preincubated with test compound for 10 minutes at 37°C in 100 mM potassium phosphate buffer, pFl 7.4. The reactions were initiated by adding NADPF1 regenerating system. The final incubation mixtures contained 1 mM test compound, 0.5 mg/mL liver microsomal protein, 1 mM MgCT, 1 mM NADP, 1 unit/mL isocitric dehydrogenase and 6 mM isocitric acid in 100 mM potassium phosphate buffer, pFl 7.4. After incubation times of 0, 3, 6, 9, 15 and 30 minutes at 37°C, 300 pL of cold ACN (including internal standard) was added to 100 pL incubation mixture to terminate the reaction. Following precipitation and centrifugation, the amount of compound remaining in the samples was determined by LC-MS/MS. Controls of no NADPF1 regenerating system at zero and 30 minutes were also prepared and analyzed. The compounds of present invention showed good human liver microsome stability determined in the above assay, results are shown in Table D3 below.

Table D3. Human liver microsome stability of the compounds of present invention