Nbd1 modulators and methods of using the same

Abstract

The present disclosure includes, among other things, CFTR modulators, pharmaceutical compositions, and methods of making and using the same.

Description

[0001] NBD1 MODULATORS AND METHODS OF USING THE SAME

[0001] This application claims the benefit of and priority to U.S. Provisional Patent Application No.63 / 449,494, filed on March 2, 2023, the disclosure of each of which is hereby incorporated by reference in its entirety for all purposes. Background

[0002] Cystic fibrosis (CF), an autosomal recessive disorder, is caused by functional deficiency of the cAMP-activated plasma membrane chloride channel, cystic fibrosis transmembrane conductance regulator (CFTR), which results in pulmonary and other complications. The gene encoding CFTR has been identified and sequenced (See Gregory, R. J. et al. (1990) Nature 347:382-386; Rich, D. P. et al. (1990) Nature 347:358-362), (Riordan, J. R. et al. (1989) Science 245:1066-1073). CFTR, a member of the ATP binding cassette (ABC) superfamily is composed of two six membrane-spanning domains (MSD1 and MSD2), two nucleotide bind domains (NBD1 and NBD2), a regulatory region (R) and four cytosolic loops (CL1-4). CFTR protein is located primarily in the apical membrane of epithelial cells where it functions to conduct anions, including chloride, bicarbonate, and thiocyanate into and out of the cell. CFTR may have a regulatory role over other electrolyte channels, including the epithelial sodium channel ENaC.

[0003] In cystic fibrosis patients, the absence or dysfunction of CFTR leads to exocrine gland dysfunction and a multisystem disease, characterized by pancreatic insufficiency and malabsorption, as well as abnormal mucociliary clearance in the lung, mucostasis, chronic lung infection and inflammation, decreased lung function and ultimately respiratory failure.

[0004] While more than 1,900 mutations have been identified in the CFTR gene, a detailed understanding of how each CFTR mutation may impact channel function is known for only a few. (Derichs, European Respiratory Review, 22:127, 58-65 (2013)). The most frequent CFTR mutation is the in-frame deletion of phenylalanine at residue 508 (ΔF508) in the first nucleotide binding domain (NBD1). Over 70% of cystic fibrosis patients have a deletion at residue 508 in at least one CFTR allele. The loss of this key phenylalanine renders NBD1 conformationally unstable at physiological temperature and compromises the integrity of the interdomain interface between NDB1 and CFTR’s second transmembrane domain (ICL4). The ΔF508 mutation causes production of misfolded CFTR protein which, rather than traffic to the plasma membrane, is instead retained in the endoplasmic reticulum and targeted for degradation by the ubiquitin-proteasome system.

[0005] The loss of a functional CFTR channel at the plasma membrane disrupts ionic homeostasis and airway surface hydration leading to reduced lung function. Reduced periciliary liquid volume and increased mucus viscosity impede mucociliary clearance resulting in chronic infection and inflammation. In the lung, the loss of CFTR-function leads to numerous physiological effects downstream of altered anion conductance that result in the dysfunction of additional organs such as the pancreas, intestine and gall bladder.

[0006] By studying the mechanistic aspects of CFTR misfolding and corrections, small molecules have been identified as CF modulators, that can act as stabilizers.

[0007] Despite the identification of compounds that modulate CFTR, there is no cure for this fatal disease and identification of new compounds and new methods of therapy are needed as well as new methods for treating or lessening the severity of cystic fibrosis and other CFTR mediated conditions and diseases in a patient. Summary

[0008] The present disclosure includes a compound of formula I: or a pharmaceutically acceptable salt thereof. Additionally, the present disclosure includes, among other things, pharmaceutical compositions, methods of using and methods of making a compound of formula I. Detailed Description

[0009] In some embodiments, the present disclosure includes a compound of Formula I: (I) or a pharmaceutically acceptable salt thereof wherein W1is selected from the group consisting of -C(H)=, and -N=; W2is selected from the group consisting of -C(H)=, -C(Rd)=, and -N=; W3is selected from the group consisting of -C(H)=, -C(Rd)=, and -N=; W4is selected from the group consisting of -C(H)=, -C(Rd4)=, and -N=; W5is selected from the group consisting of -C(H)=, -C(Rd5)=, and -N=; W6is selected from the group consisting of -C(H)=, -C(Rc)=, and -N=; W7is selected from the group consisting of -C(H)=, -C(Rc)=, and -N=; W8is selected from the group consisting of -C(H)=, -C(Rc)=, and -N=; W9is selected from the group consisting of -C(H)=, -C(Rc9)=, and -N=; Ring A is an optionally substituted 8-10 membered fused heterocyclyl; Ring B is optionally substituted 5-membered heteroaryl; each Rais independently selected from the group consisting of halogen, oxo, -CN, -NO2- OR1, -SR1, -N(R1)2, -C(O)OR1, C(O)N(R1)2, -N(H)C(O)R1, -SO2R1, -SO2N(R2), - SO(NR2)R1, -N(H)C(O)N(R1)2, -CD3, optionally substituted C1-C6aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each Rais independently substituted with 0-4 instances of Raa, each Raais independently selected from the group consisting of deuterium, halogen, oxo, - COOH, -CN, -CD3, optionally substituted C1-C6aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-7 membered heterocyclyl, -OR1, -SR1, -N(R1)2, - C(O)OR1, C(O)N(R1)2, -N(H)C(O)R1, and -N(H)C(O)N(R1)2, wherein two instances of Raaare optionally taken together with any intervening atoms to form an optionally substituted 5-6 membered heterocyclyl ring; each Rbis independently selected from the group consisting of halogen, oxo, -CN, -NO2- OR1, -SR1, -N(R1)2, -C(O)OR1, C(O)N(R1)2, -N(H)C(O)R1, -SO2R1, -SO2N(R2), - SO(NR2)R1, -N(H)C(O)N(R1)2, optionally substituted C1-C6aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl; each Rcis independently selected from the group consisting of halogen, oxo, -CN, -NO2- OR1, -SR1, -N(R1)2, -C(O)OR1, C(O)N(R1)2, -N(H)C(O)R1, -SO2R1, -SO2N(R2), - SO(NR2)R1, -N(H)C(O)N(R1)2, optionally substituted C1-C6aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each Rcis independently substituted with 0-4 instances of Raa; each Rdis independently selected from the group consisting of halogen, oxo, -CN, -NO2- OR1, -SR1, -N(R1)2, -C(O)OR1, C(O)N(R1)2, -N(H)C(O)R1, -SO2R1, -SO2N(R2), - SO(NR2)R1, -N(H)C(O)N(R1)2, optionally substituted C1-C6aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each Rdis independently substituted with 0-4 instances of Raa; Rc9is halogen; Rd4is halogen; Rd5is halogen; each R1is independently selected from the group consisting of hydrogen, -CD3, -(CH2)1-3R2, - C(O)R2, -(CH2)1-3OR2, optionally substituted C1-C6aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl; wherein two instances of R1are optionally taken together with any intervening atoms to form an optionally substituted 3-7 membered heterocyclyl ring; each R2is independently selected from the group consisting of hydrogen, optionally substituted C1-C6aliphatic, optionally substituted phenyl, optionally substituted 5-6- membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl; X is selected from the group consisting of -O-, -S-, -S(O)-, -S(O)2-; -SO(NR2)- , -C(R1)(R2)- , and -C(O)-; n is 0, 1, 2, or 3; and m is 0, 1, 2, or 3.

[0010] In some embodiments, a compound of the present disclosure is of Formula (I-a), (I-b), (I-c), (I-d), (I-e), or (I-f): b) -d) f), or a pharmaceutically acceptable salt thereof. X

[0011] In some embodiments, X is selected from the group consisting of -O-, -S-, -S(O)-, - S(O)2-; -SO(NR2)- , -C(R1)(R2)- , and -C(O)-. In some embodiments, X is -O-. In some embodiments, X is -S-. In some embodiments, X is -S(O)-. In some embodiments, X is -S(O)2- . In some embodiments, X is -CH2-. In some embodiments, X is -C(O)-. Ring A

[0012] In some embodiments, Ring A is an optionally substituted 8-10 membered fused heterocyclyl. In some embodiments, Ring A is optionally substituted 9-10-membered heterocyclyl selected from the group consisting of dihydrochromenyl, dihydrobenzofuranyl, and dihydroisoindolyl. In some embodiments, Ring A is dihydrochromenyl. In some embodiments, Ring A is dihydrobenzofuranyl. In some embodiments, Ring A is dihydroisoindolyl.

[0013] In some embodiments, Ring A is selected from the group consisting of Ring B

[0014] In some embodiments, Ring B is optionally substituted 5-membered heteroaryl. In some embodiments, Ring B is optionally substituted 5-membered heteroaryl comprising 1-3 nitrogen atoms. In some embodiments, Ring B is a optionally substituted 5-membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, isooxadiazolyl and isothiadiazolyl. In some embodiments, Ring B is a optionally substituted pyrazolyl. In some embodiments, Ring B is a optionally substituted triazolyl. In some embodiments, Ring B is a optionally substituted imidazolyl. In some embodiments, Ring B is a optionally substituted oxazolyl. In some embodiments, Ring B is a optionally substituted thiazolyl. In some embodiments, Ring B is a optionally substituted oxadiazolyl. In some embodiments, Ring B is a optionally substituted thiadiazolyl. In some embodiments, Ring B is a optionally substituted isooxadiazolyl. In some embodiments, Ring B is a optionally substituted isothiadiazolyl. In some embodiments, Ring B is .

[0016] In some embodiments, Ring B is selected from the group consisting of

[0017] In some embodiments, Ring

[0018] In some embodiments, Ring B is selected from the group consisting

[0019] In some embodiments, Ring B is selected from the group consisting

[0020] In some embodiments, Ring B is selected from the group consisting

[0021] In some embodiments, Ring B is selected from the group consisting

[0022] Ring B is selected from the group consisting of

[0023] In some embodiments, Ring B is selected from the group consisting of Ra

[0024] In some embodiments, each Rais independently selected from the group consisting of halogen, oxo, -CN, -NO2-OR1, -SR1, -N(R1)2, -C(O)OR1, C(O)N(R1)2, -N(H)C(O)R1, -SO2R1, -SO2N(R2), -SO(NR2)R1, -N(H)C(O)N(R1)2, -CD3, optionally substituted C1-C6aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each Rais independently substituted with 0-4 instances of Raa. In some embodiments, each Rais independently selected from halogen, optionally substituted C1-C6alkyl, and optionally substituted C1-C6alkenyl, wherein each Rais independently substituted with 0-4 instances of Raa. In some embodiments, wherein each Rais independently -CH2COOH, - CH2CH2COOH, and -C(H)=C(H)-COOH. In some embodiments, wherein Rais -CH2COOH. In some embodiments, wherein Rais -CH2CH2COOH. In some embodiments, wherein Rais - C(H)=C(H)-COOH. Rb

[0025] In some embodiments, each Rbis independently selected from the group consisting of halogen, oxo, -CN, -NO2-OR1, -SR1, -N(R1)2, -C(O)OR1, C(O)N(R1)2, -N(H)C(O)R1, -SO2R1, -SO2N(R2), -SO(NR2)R1, -N(H)C(O)N(R1)2, optionally substituted C1-C6aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl. In some embodiments, Rbis optionally substituted C1-C6aliphatic. In some embodiments, Rbis optionally substituted C1-C6alkyl. In some embodiments, Rbis optionally substituted C1-C3alkyl. In some embodiments, Rbis optionally substituted methyl. Rc

[0026] In some embodiments, each Rcis independently selected from the group consisting of halogen, oxo, -CN, -NO2-OR1, -SR1, -N(R1)2, -C(O)OR1, C(O)N(R1)2, -N(H)C(O)R1, -SO2R1, -SO2N(R2), -SO(NR2)R1, -N(H)C(O)N(R1)2, optionally substituted C1-C6aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each Rcis independently substituted with 0-4 instances of Raa.

[0027] In some embodiments, Rcis halogen. In some embodiments, Rcis fluoro.

[0028] In some embodiments, Rcis CH2N(R1)(R2). In some embodiments, Rcis CH2N(H)(i- propyl). In some embodiments, Rcis CH2N(H)(t-butyl). Rd

[0029] In some embodiments, each Rdis independently selected from the group consisting of halogen, oxo, -CN, -NO2-OR1, -SR1, -N(R1)2, -C(O)OR1, C(O)N(R1)2, -N(H)C(O)R1, -SO2R1, -SO2N(R2), -SO(NR2)R1, -N(H)C(O)N(R1)2, optionally substituted C1-C6aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each Rdis independently substituted with 0-4 instances of Raa. In some embodiments, Rdis independently selected from the group consisting of halogen, -OR1, -SRI, -C(O)N(R1)2, - N(H)C(O)R1, -SO2R1, -SO2N(R2), -SO(NR2)R1, and optionally substituted C1-C6aliphatic, wherein each Rdis independently substituted with 0-4 instances of Raa. In some embodiments, each Rdis independently selected from the group consisting of fluoro, methyl, -CHF2, - CH2CHF2, -SCH3, -S(i-propyl),-S(cyclopropyl), -SCD3, -S(O)CH3, , -S(O)CD3, -S(O)2CH3, - S(O)2CD3, -S(O)2(i-propyl), -S(O)2(cyclopropyl), -CH3S(O)2CH3, -SO(N(CH3))CH3, - C(O)N(H)CH3, CH2N(H)(t-Butyl), and .

[0030] In some embodiments, the present disclosure includes compounds listed in Table 1. Table 1

[0002] 91 92 93 94 210 or a pharmaceutically acceptable salt thereof. Definitions

[0031] The term "aliphatic" or "aliphatic group", as used herein, means a straight-chain (i.e., unbranched) or branched, substituted or unsubstituted hydrocarbon chain that is completely saturated or that contains one or more units of unsaturation, or a monocyclic hydrocarbon or bicyclic hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic (also referred to herein as "carbocycle" "cycloaliphatic" or "cycloalkyl"), that has a single point of attachment to the rest of the molecule. Unless otherwise specified, aliphatic groups contain 1-6 aliphatic carbon atoms. In some embodiments, aliphatic groups contain 1-5 aliphatic carbon atoms. In other embodiments, aliphatic groups contain 1-4 aliphatic carbon atoms. In still other embodiments, aliphatic groups contain 1-3 aliphatic carbon atoms, and in yet other embodiments, aliphatic groups contain 1-2 aliphatic carbon atoms. In some embodiments, "cycloaliphatic" (or "carbocycle" or "cycloalkyl") refers to a monocyclic C3-C6hydrocarbon that is completely saturated or that contains one or more units of unsaturation, but which is not aromatic, that has a single point of attachment to the rest of the molecule. Suitable aliphatic groups include, but are not limited to, linear or branched, substituted or unsubstituted alkyl, alkenyl, alkynyl groups and hybrids thereof such as (cycloalkyl)alkyl, (cycloalkenyl)alkyl or (cycloalkyl)alkenyl.

[0032] The term "haloaliphatic" refers to an aliphatic group that is substituted with one or more halogen atoms.

[0033] The term "haloalkyl" refers to a straight or branched alkyl group that is substituted with one or more halogen atoms.

[0034] The term “alkyl” as used herein is a branched or unbranched saturated hydrocarbon group having a specified number of carbon atoms. In some embodiments, alkyl refers to a branched or unbranched saturated hydrocarbon group having three carbon atoms (C3). In some embodiments, alkyl refers to a branched or unbranched saturated hydrocarbon group having six carbon atoms (C6). In some embodiments, the term “alkyl” includes, but is not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, s- pentyl, neopentyl, and hexyl.

[0035] As used herein, the term “alkylene” refers to a bivalent alkyl group. An “alkylene chain” is a polymethylene group, i.e., —(CH2)n—, wherein n is a positive integer, preferably from 1 to 6, from 1 to 4, from 1 to 3, from 1 to 2, or from 2 to 3. A substituted alkylene chain is a polymethylene group in which one or more methylene hydrogen atoms are replaced with a substituent. Suitable substituents include those described below for a substituted aliphatic group. The term "halogen" means F, Cl, Br, or I.

[0036] The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", or "aryloxyalkyl", refers to monocyclic and bicyclic ring systems having a total of five to fourteen ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present disclosure, "aryl" refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, anthracyl and the like, which may bear one or more substituents. Also included within the scope of the term "aryl", as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl, and the like.

[0037] The terms "heteroaryl" and "heteroar-", used alone or as part of a larger moiety, e.g., "heteroaralkyl", or "heteroaralkoxy", refer to groups having 5 to 10 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 π electrons shared in a cyclic array; and having, in addition to carbon atoms, from one to five heteroatoms. The term "heteroatom" refers to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. Heteroaryl groups include, without limitation, thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolizinyl, purinyl, naphthyridinyl, and pteridinyl. The terms "heteroaryl" and "heteroar-", as used herein, also include groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclyl rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples include indolyl, isoindolyl, benzothienyl, benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzthiazolyl, quinolyl, isoquinolyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin- 3(4Η)-one. A heteroaryl group may be mono- or bicyclic. The term "heteroaryl" may be used interchangeably with the terms "heteroaryl ring", "heteroaryl group", or "heteroaromatic", any of which terms include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted.

[0038] As used herein, the terms "heterocycle", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a stable 5- to 7-membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 0-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4- dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or+NR (as in TV-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical", are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0039] A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a stable structure and any of the ring atoms can be optionally substituted. Examples of such saturated or partially unsaturated heterocyclic radicals include, without limitation, tetrahydrofuranyl, tetrahydrothiophenyl pyrrolidinyl, piperidinyl, pyrrolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, oxazolidinyl, piperazinyl, dioxanyl, dioxolanyl, diazepinyl, oxazepinyl, thiazepinyl, morpholinyl, and quinuclidinyl. The terms "heterocycle", "heterocyclyl", "heterocyclyl ring", "heterocyclic group", "heterocyclic moiety", and "heterocyclic radical", are used interchangeably herein, and also include groups in which a heterocyclyl ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, chromanyl, phenanthridinyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted.

[0040] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0041] As described herein, compounds of the disclosure may contain “optionally substituted” moieties. In general, the term “substituted”, whether preceded by the term “optionally” or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an “optionally substituted” group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at every position. Combinations of substituents envisioned by this disclosure are preferably those that result in the formation of stable or chemically feasible compounds. The term “stable”, as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0042] Suitable monovalent substituents on a substitutable carbon atom of an “optionally substituted” group are independently halogen; —(CH2)0-4R∘; —(CH2)0-4OR∘; —O(CH2)0-4R∘, —O—(CH2)0-4C(O)OR∘; —(CH2)0-4CH(OR∘)2; —(CH2)0-4SR∘; —(CH2)0-4Ph, which may be substituted with R∘; —(CH2)0-4O(CH2)0-1Ph which may be substituted with R∘; —CH═CHPh, which may be substituted with R∘; —(CH2)0-4O(CH2)0-1-pyridyl which may be substituted with R∘; —NO2; —CN; —N3; —(CH2)0-4N(R∘)2; —(CH2)0-4N(R∘)C(O)R∘; —N(R∘)C(S)R∘; — (CH2)0-4N(R∘)C(O)NR∘2; —N(R∘)C(S)NR∘2; —(CH2)0-4N(R∘)C(O)OR∘; — N(R∘)N(R∘)C(O)R∘; —N(R∘)N(R∘)C(O)NR∘2; —N(R∘)N(R∘)C(O)OR∘; —(CH2)0-4C(O)R∘; — C(S)R∘; —(CH2)0-4C(O)OR∘; —(CH2)0-4C(O)SR∘; —(CH2)0-4C(O)OSiR∘3; —(CH2)0-4OC(O)R∘; —OC(O)(CH2)0-4SR∘, SC(S)SR∘; —(CH2)0-4SC(O)R∘; —(CH2)0-4C(O)NR∘2; — C(S)NR∘2; —C(S)SR∘; —SC(S)SR∘, —(CH2)0-4OC(O)NR∘2; —C(O)N(OR∘)R∘; — C(O)C(O)R∘; —C(O)CH2C(O)R∘; —C(NOR∘)R∘; —(CH2)0-4SSR∘; —(CH2)0-4S(O)2R∘; — (CH2)0-4S(O)2OR∘; —(CH2)0-4OS(O)2R∘; —S(O)2NR∘2; —(CH2)0-4S(O)R∘; — N(R∘)S(O)2NR∘2; —N(R∘)S(O)2R∘; —S(O)(NR∘)R∘; —N(OR∘)R∘; —C(NH)NR∘2; — P(O)2R∘; —P(O)R∘2; —OP(O)R∘2; —OP(O)(OR∘)2; SiR∘3; —(C1-4straight or branched alkylene)O—N(R∘)2; or —(C1-4straight or branched alkylene)C(O)O—N(R∘)2, wherein each R∘may be substituted as defined below and is independently hydrogen, C1-6aliphatic, — CH2Ph, —O(CH2)0-1Ph, —CH2-(5-6 membered heteroaryl ring), or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R∘, taken together with their intervening atom(s), form a 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, which may be substituted as defined below.

[0043] Suitable monovalent substituents on R∘(or the ring formed by taking two independent occurrences of R∘together with their intervening atoms), are independently halogen, —(CH2))0-2R●, -(haloR●), —(CH2)0-2OH, —(CH2)0-2OR●, —(CH2)0-2CH(OR●)2; —O(haloR●), —CN, — N3, —(CH2)0-2C(O)R●, —(CH2)0-2C(O)OH, —(CH2)0-2C(O)OR●, —(CH2)0-2SR●, —(CH2))0-2SH, —(CH2)0-2NH2, —(CH2)0-2NHR●, —(CH2)0-2NR●2, —NO2, —SiR●3, —OSiR●3, — C(O)SR●, —(C1-4straight or branched alkylene)C(O)OR●, or —SSR●wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently selected from C1-4aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents on a saturated carbon atom of R∘include ═O and ═S.

[0044] Suitable divalent substituents on a saturated carbon atom of an “optionally substituted” group include the following: ═O, ═S, ═NNR*2, ═NNHC(O)R*, ═NNHC(O)OR*, ═NNHS(O)2R*, ═NR*, ═NOR*, —O(C(R*2))2-3O—, or —S(C(R*2))2-3S—, wherein each independent occurrence of R* is selected from hydrogen, C1-6aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur. Suitable divalent substituents that are bound to vicinal substitutable carbons of an “optionally substituted” group include: —O(CR*2)2-3O—, wherein each independent occurrence of R* is selected from hydrogen, C1-6aliphatic which may be substituted as defined below, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0045] Suitable substituents on the aliphatic group of R* include halogen, —R●, -(haloR●), — OH, —OR●, —O(haloR●), —CN, —C(O)OH, —C(O)OR●, —NH2, —NHR●, —NR●2, or — NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6- membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0046] Suitable substituents on a substitutable nitrogen of an “optionally substituted” group include —R†, —NR†2, —C(O)R†, —C(O)OR†, —C(O)C(O)R†, —C(O)CH2C(O)R†, — S(O)2R†, —S(O)2NR†2, —C(S)NR†2, —C(NH)NR†2, or —N(R†)S(O)2R†; wherein each R†is independently hydrogen, C1-6aliphatic which may be substituted as defined below, unsubstituted —OPh, or an unsubstituted 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or, notwithstanding the definition above, two independent occurrences of R†, taken together with their intervening atom(s) form an unsubstituted 3-12-membered saturated, partially unsaturated, or aryl mono- or bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0047] Suitable substituents on the aliphatic group of R†are independently halogen, —R●, - (haloR●), —OH, —OR●, —O(haloR●), —CN, —C(O)OH, —C(O)OR●, —NH2, —NHR●, — NR●2, or —NO2, wherein each R●is unsubstituted or where preceded by “halo” is substituted only with one or more halogens, and is independently C1-4aliphatic, —CH2Ph, —O(CH2)0-1Ph, or a 5-6-membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

[0048] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, incorporated herein by reference. Pharmaceutically acceptable salts of the compounds of this disclosure include those derived from suitable inorganic and organic acids and bases. Examples of pharmaceutically acceptable, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like.

[0049] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N(C1-4alkyl)4 salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate and aryl sulfonate.

[0050] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0051] The term "biological sample", as used herein, includes, without limitation, cell cultures or extracts thereof; biopsied material obtained from a mammal or extracts thereof; and blood, saliva, urine, feces, semen, tears, or other body fluids or extracts thereof. Examples of such purposes include, but are not limited to, blood transfusion, organ transplantation, biological specimen storage, and biological assays.

[0052] As used herein, a "therapeutically effective amount" means an amount of a substance (e.g., a therapeutic agent, composition, and / or formulation) that elicits a desired biological response. In some embodiments, a therapeutically effective amount of a substance is an amount that is sufficient, when administered as part of a dosing regimen to a subject suffering from or susceptible to a disease, disorder, and / or condition, to treat and / or diagnose the onset of the disease, disorder, and / or condition. As will be appreciated by those of ordinary skill in this art, the effective amount of a substance may vary depending on such factors as the desired biological endpoint, the substance to be delivered, the target cell or tissue, etc. For example, the effective amount of a provided compound in a formulation to treat a disease, disorder, and / or condition is the amount that alleviates, ameliorates, relieves, reduces severity of and / or reduces incidence of one or more symptoms or features of the disease, disorder, and / or condition. In some embodiments, a "therapeutically effective amount" is at least a minimal amount of a provided compound, or composition containing a provided compound, which is sufficient for treating one or more symptoms of an CFTR-associated disease or disorder.

[0053] The terms “treat”, “treatment” or “treating” mean to decrease, suppress, attenuate, diminish, arrest, or stabilize the development or progression of a disease (e.g., a disease or disorder delineated herein), lessen the severity of the disease or improve the symptoms associated with the disease. Treatment includes treating a symptom of a disease, disorder or condition. Without being bound by any theory, in some embodiments, treating includes augmenting deficient CFTR activity. If it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the subject) then the treatment is prophylactic (i.e., it protects the subject against developing the unwanted condition), whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilize the existing unwanted condition or side effects thereof).

[0054] The term "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or other primates (e.g., cynomolgus monkeys, rhesus monkeys); mammals, including commercially relevant mammals such as cattle, pigs, horses, sheep, goats, cats, and / or dogs; and / or birds, including commercially relevant birds such as chickens, ducks, geese, quail, and / or turkeys. Preferred subjects are humans.

[0055] The term “pharmaceutically acceptable carrier, adjuvant, or vehicle” refers to a non- toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound(s) with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of the compounds disclosed herein include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0056] A “pharmaceutically acceptable derivative” means any non-toxic salt, ester, salt of an ester or other derivative of a compound of this disclosure that, upon administration to a recipient, is capable of providing, either directly or indirectly, a compound of this disclosure or an active metabolite or residue thereof.

[0057] The expression “dosage unit form” as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that total daily usage of compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment. Specific effective dose level for any particular patient or organism will depend upon a variety of factors including disorder being treated and severity of the disorder; activity of specific compound employed; specific composition employed; age, body weight, general health, sex and diet of the patient; time of administration, route of administration, and rate of excretion of a specific compound employed; duration of treatment; drugs used in combination or coincidental with a specific compound employed, and like factors well known in the medical arts.

[0058] A “response” to a method of treatment can include a decrease in or amelioration of negative symptoms, a decrease in the progression of a disease or symptoms thereof, an increase in beneficial symptoms or clinical outcomes, a lessening of side effects, stabilization of disease, partial or complete remedy of disease, among others.

[0059] As used herein, “CFTR” means cystic fibrosis transmembrane conductance regulator. Defects in the function of the CFTR ion channel result from loss of function mutations of CFTR. Such mutations lead to exocrine gland dysfunction, abnormal mucociliary clearance, and cause cystic fibrosis. The most common CFTR mutation in Cystic Fibrosis (CF) patients leads to the specific deletion of three nucleotides of the codon for phenylalanine at position 508. This mutation, which is found in ~70% of CF patients worldwide, is referred to as “ΔF508”. The ΔF508 mutation decreases the stability of the CFTR NBD1 domain and limits CFTR interdomain assembly. Since CF is an autosomal recessive disease, a CF patient harboring the ΔF508 CFTR mutation must also carry a second defective copy of CFTR. Approximately 2000 different CF-causing CFTR mutations have been identified in CF patients. CF patients harboring the ΔF508 CFTR mutation can be homozygous for that mutation (ΔF508 / ΔF508). CF patients can also be ΔF508 heterozygous, if the second CFTR allele such patients carry instead contains a different CFTR loss of function mutation. Such CFTR mutations include, but are not limited to, G542X, G551D, N1303K, W1282X, R553X, R117H, R1162X, R347P, G85E, R560T, A455E, ΔI507, G178R, S549N, S549R, G551S, G970R, G1244E, S1251N, S1255P, and G1349D.

[0060] As used herein, the term “CFTR modulator” refers to a compound that increases the activity of CFTR. In certain aspects, a CFTR modulator is a CFTR corrector or a CFTR potentiator or a dual-acting compound having activities of a corrector and a potentiator.

[0061] As used herein, the term “CFTR corrector” refers to a compound that increases the amount of functional CFTR protein to the cell surface and thus enhances CFTR channel function. The CFTR correctors partially “rescue” misfolding of CFTR, thereby enabling the maturation and functional expression of CFTR protein harboring a CF causing mutation on the cell surface. Examples of correctors include, but are not limited to, VX-809, VX-661, VX-152, VX-440, VX-983, and GLPG2222. Such compounds may interact directly with CFTR protein, modifying its folding and conformational maturation during synthesis.

[0062] As used herein, the term “CFTR potentiator” refers to a compound that increases the ion channel activity of CFTR protein located at the cell surface, resulting in enhanced ion transport. CFTR potentiators repair the defective channel functions caused by mutations. Examples of potentiators include, but are not limited to, ivacaftor (VX770), deuterated ivacaftor (CPT 656), genistein and GLPG1837.

[0063] As used herein, the term “CFTR pharmacological chaperone” (PC) refers to compounds that stabilize the CFTR protein in its native state by binding directly to the protein.

[0064] As used herein, the term “CFTR proteostasis regulator” (PR) refers to compounds that enhance the protein folding efficiency within the cell. PRs can alter the activity of transcriptional, folding and / or membrane trafficking machinery, as well as impeding the degradation of partially folded, but functional, conformers at the endoplasmic reticulum (ER) or plasma membrane.

[0065] As used herein, “CFTR disease or condition” refers to a disease or condition associated with deficient CFTR activity, for example, cystic fibrosis, congenital bilateral absence of vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, smoking-related lung diseases, such as chronic obstructive pulmonary disease (COPD), chronic sinusitis, dry eye disease, protein C deficiency, A-beta.-lipoproteinemia, lysosomal storage disease, type 1 chylomicronemia, mild pulmonary disease, lipid processing deficiencies, type 1 hereditary angioedema, coagulation- fibrinolyis, hereditary hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjogren's syndrome.

[0066] As used herein, the term "combination," "combined," and related terms refers to the simultaneous or sequential administration of therapeutic agents in accordance with this disclosure. For example, a compound of the present disclosure may be administered with another therapeutic agent simultaneously or sequentially in separate unit dosage forms or together in a single unit dosage form. Accordingly, the present disclosure provides a single unit dosage form comprising a provided compound, an additional therapeutic agent, and a pharmaceutically acceptable carrier, adjuvant, or vehicle. Alternative Embodiments

[0067] In an alternative embodiment, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be2H (D or deuterium) or3H (T or tritium); carbon may be, for example,13C or14C; oxygen may be, for example,18O; nitrogen may be, for example,15N, and the like. In other embodiments, a particular isotope (e.g.,3H,13C,14C,18O, or15N) can represent at least 1%, at least 5%, at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at least 35%, at least 40%, at least 45%, at least 50%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or at least 99.9% of the total isotopic abundance of an element that occupies a specific site of the compound. Pharmaceutical Compositions

[0068] In some embodiments, the present disclosure provides a composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier, adjuvant, or vehicle. In some embodiments, the amount of compound in compositions contemplated herein is such that is effective to measurably modulate CFTR, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this disclosure is such that is effective to measurably modulate CFTR, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, a composition contemplated by this disclosure is formulated for administration to a patient in need of such composition. In some embodiments, a composition contemplated by this disclosure is formulated for oral administration to a patient.

[0069] In some embodiments, the amount of compound in compositions contemplated herein is such that is effective to measurably modulate a protein, particularly at CFTR, or a mutant thereof, in a biological sample or in a patient. In certain embodiments, the amount of compound in compositions of this disclosure is such that is effective to measurably modulate CFTR, or a mutant thereof, in a biological sample or in a patient.

[0070] In some embodiments, compositions of the present disclosure may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. In some preferred embodiments, compositions are administered orally, intraperitoneally or intravenously. In some embodiments, sterile injectable forms of the compositions comprising one or more compounds of the present disclosure may be aqueous or oleaginous suspension. In some embodiments, suspensions may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. In some embodiments, sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. In some embodiments, among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In some embodiments, additional examples include, but are not limited to, sterile, fixed oils are conventionally employed as a solvent or suspending medium.

[0071] The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques.

[0072] Pharmaceutically acceptable compositions comprising one or more compounds of the present disclosure may be orally administered in any orally acceptable dosage form including, but not limited to, capsules, tablets, aqueous suspensions or solutions. In some embodiments, carriers used include lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added. In some embodiments, useful diluents include lactose and dried cornstarch. In some embodiments, when aqueous suspensions are required for oral use, an active ingredient is combined with emulsifying and suspending agents. In some embodiments, certain sweetening, flavoring or coloring agents may also be added.

[0073] Alternatively, pharmaceutically acceptable compositions comprising a compound of the present disclosure may be administered in the form of suppositories for rectal administration. These can be prepared by mixing the agent with a suitable non-irritating excipient that is solid at room temperature but liquid at rectal temperature and therefore will melt in the rectum to release the drug. Such materials include cocoa butter, beeswax and polyethylene glycols.

[0074] Pharmaceutically acceptable compositions comprising a compound of the present disclosure may also be administered topically, especially when the target of treatment includes areas or organs readily accessible by topical application, including diseases of the eye, the skin, or the lower intestinal tract. Suitable topical formulations are readily prepared for each of these areas or organs. In some embodiments, pharmaceutically acceptable compositions may be formulated in a suitable ointment containing the active component suspended or dissolved in one or more carriers. Carriers for topical administration of compounds of this disclosure include, but are not limited to, mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene, polyoxypropylene compound, emulsifying wax and water. Alternatively, provided pharmaceutically acceptable compositions can be formulated in a suitable lotion or cream containing the active components suspended or dissolved in one or more pharmaceutically acceptable carriers. Suitable carriers include, but are not limited to, mineral oil, sorbitan monostearate, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2- octyldodecanol, benzyl alcohol and water.

[0075] Pharmaceutically acceptable compositions comprising a compound of the present disclosure may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0076] In some embodiments, an amount of a compound of the present disclosure that may be combined with the carrier materials to produce a composition in a single dosage form will vary depending upon the host treated, the particular mode of administration. Preferably, provided compositions should be formulated so that a dosage of between 0.01-100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions. Methods of Using Compounds of the Present Disclosure

[0077] As discussed above, CFTR is composed of two six membrane-spanning domains (MSD1 and MSD2), two nucleotide bind domains (NBD1 and NBD2), a regulatory region (R) and four cytosolic loops (CL1-4). CFTR protein is located primarily in the apical membrane of epithelial cells where it functions to conduct anions, including chloride, bicarbonate and thiocyanate into and out of the cell. The most frequent CFTR mutation is the in-frame deletion of phenylalanine at residue 508 (ΔF508) in the first nucleotide binding domain (NBD1). The mutation has several deleterious effects on the production of CFTR in the ER, its correct folding, its movement to the plasma membrane and its normal function as an ion channel for the cell.

[0078] One such negative effect is that the NBD1 domain is partially or mis-folded which is recognized within the cell as an aberrant protein and tagged for disposal by ER-associated degradation (ERAD) via the ubiquitin–proteasome system (UPS). Should a partially or mis- folded CFTR protein emerge from the ER, the protein must travel to the plasma membrane through complex glycosylation in the Golgi compartment and be functionally inserted. In wild- type CFTR, only 20-40% of CFTR reaches the plasma membrane, indicating that CFTR has energetic instability of individual NBDs, a slow domain assembly, and relatively fast ERAD kinetics which all contribute to inefficient folding and sensitize CFTR to structural perturbations by mutations.

[0079] In wild-type CFTR, the NBD1 domain folds co-translationally while other domains fold post-translationally. Mutated ΔF508 CFTR has impaired NBD1 folding but its backbone structure and thermodynamic stability are similar to wild-type CFTR. With delayed folding kinetics, mutated ΔF508 CFTR NBD1 has an increased folding activation energy. Lack of proper folding results in hydrophobic residues being exposed to the surface of NBD1 which causes aggregation with other CFTR proteins. Thus, the aggregation temperature of mutated CFTR drops from 41 °C to 33 °C. This level of instability creates a greater percentage of mis- folded mutant CFTR at physiological temperature (37 °C in humans). Mutant CFTR suffers from both kinetic and thermodynamic folding defects. CFTR stabilizers can address these folding defects, but complete energetic correction of mutant NBD1 folding has been shown to not result in the CFTR biosynthetic processing, underscoring the need for interface stability as well.

[0080] The disclosed CFTR correctors can interact with the NBD domain to stabilize the correct folded position R, such that CFTR is not labeled for elimination from the cell. The preservation of correct folding enables CFTR to function as a chloride ion channel at wild-type levels. In some embodiments, disclosed CFTR correctors can enhance the performance of wild-type CFTR.

[0081] CFTR stabilizers can function in combination with other therapeutic agents such as CFTR correctors that promote Δ508 CFTR exit from the ER and accumulation in the plasma membrane. Increasing the amount of CFTR cell surface expression can result in improved chloride conductance following channel activation by both potentiators and a cAMP agonist. Thus, disclosed herein are combinations of CFTR stabilizers with CFTR correctors and potentiators, optionally with cAMP agonists or another therapeutic agent as described below.

[0082] Disclosed herein are methods of treating deficient CFTR activity in a cell, comprising contacting the cell with a compound of the present disclosure, or a pharmaceutically acceptable salt thereof. In certain embodiments, contacting the cell occurs in a subject in need thereof, thereby treating a disease or disorder mediated by deficient CFTR activity.

[0083] Also, disclosed herein are methods of treating a disease or a disorder mediated by deficient CFTR activity comprising administering a compound of the present disclosure or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is a mammal, preferably a human. In some embodiments, the disease is associated with the regulation of fluid volumes across epithelial membranes, particularly an obstructive airway disease such as CF or COPD.

[0084] Such diseases and conditions include, but are not limited to, cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease, hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, I-cell disease / pseudo-Hurler, mucopolysaccharidoses, Sandhof / Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy / hyperinsulemia, Diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders, Huntington's, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, myotonic dystrophy, spongiform encephalopathies, hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler-Scheinker syndrome, COPD, dry-eye disease, Sjogren's disease, Osteoporosis, Osteopenia, bone healing and bone growth, bone repair, bone regeneration, reducing bone resorption, increasing bone deposition, Gorham's Syndrome, chloride channelopathies, myotonia congenita, Bartter's syndrome type III, Dent's disease, hyperekplexia, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome, Primary Ciliary Dyskinesia (PCD), PCD with situs inversus, PCD without situs inversus and ciliary aplasia.

[0085] Such diseases and conditions include, but are not limited to, cystic fibrosis, congenital bilateral absence of vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, chronic obstructive pulmonary disease (COPD), chronic sinusitis, dry eye disease, protein C deficiency, Abetalipoproteinemia, lysosomal storage disease, type 1 chylomicronemia, mild pulmonary disease, lipid processing deficiencies, type 1 hereditary angioedema, coagulation-fibrinolyis, hereditary hemochromatosis, CFTR-related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjogren's syndrome. In some embodiments, a disease is cystic fibrosis.

[0086] Provided herein are methods of treating cystic fibrosis, comprising administering to a subject in need thereof, a compound as disclosed herein or a pharmaceutically acceptable salt thereof. Also provided herein are methods of lessening the severity of cystic fibrosis, comprising administering to a subject in need thereof, a compound as disclosed herein or a pharmaceutically acceptable salt thereof. In some embodiments, the subject is a human. In some embodiments, the subject is at risk of developing cystic fibrosis, and administration is carried out prior to the onset of symptoms of cystic fibrosis in the subject.

[0087] Provided herein are compounds as disclosed herein for use in treating a disease or condition mediated by deficient CFTR activity. Also provided herein are uses of a compound as disclosed herein for the manufacture of a medicament for treating a disease or condition mediated by deficient CFTR activity.

[0088] Provided herein are kits for use in measuring the activity of CFTR or a fragment thereof in a biological sample in vitro or in vivo. The kit can contain: (i) a compound as disclosed herein, or a pharmaceutical composition comprising the disclosed compound, and (ii) instructions for: a) contacting the compound or composition with the biological sample; and b) measuring activity of said CFTR or a fragment thereof. In some embodiments, the biological sample is biopsied material obtained from a mammal or extracts thereof; blood, saliva, urine, feces, semen, tears, other body fluids, or extracts thereof. In some embodiments, the mammal is a human.

[0089] Provided herein are compounds as disclosed herein for use in treating kidney disease. In some embodiments, a kidney disease is autosomal dominant polycystic kidney disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD). In some embodiments, a kidney disease is autosomal dominant polycystic kidney disease (ADPKD). In some embodiments, a kidney disease is autosomal recessive polycystic kidney disease (ARPKD). Combination Treatments

[0090] As used herein, the term "combination therapy" means administering to a subject (e.g., human) two or more CFTR modulators, or a CFTR modulator and an agent such as antibiotics, ENaC inhibitors, GSNO (S-nitrosothiol, s-nitroglutathione) reductase inhibitors, and a CRISPR Cas correction therapy or system (as described in US 2007 / 0022507 and the like). In some embodiments, combination therapy includes administration of a compound described herein with a compound that modulates CFTR protein or ABC protein activities (e.g., as described in WO2018167690A1 and the like)

[0091] In certain embodiments, the method of treating a disease or condition mediated by deficient CFTR activity comprises administering a compound as disclosed herein conjointly with one or more other therapeutic agent(s). In some embodiments, one other therapeutic agent is administered. In other embodiments, at least two other therapeutic agents are administered.

[0092] In certain embodiments, the method of preventing a disease or condition mediated by deficient CFTR activity comprises administering a compound as disclosed herein conjointly with one or more other therapeutic agent(s). In some embodiments, one other therapeutic agent is administered. In other embodiments, at least two other therapeutic agents are administered.

[0093] Additional therapeutic agents include, for example, ENaC inhibitors, mucolytic agents, modulators of mucus rheology, bronchodilators, antibiotics, anti-infective agents, anti- inflammatory agents, ion channel modulating agents, therapeutic agents used in gene or mRNA therapy, agents that reduce airway surface liquid and / or reduce airway surface PH, CFTR correctors, and CFTR potentiators, or other agents that modulate CFTR activity. Other therapeutics include liposomal composition components such as those described in WO2012 / 170889, hybrid oligonucleotides that facilitate RNA cleavage such as those described in WO2016 / 130943, and single stranded oligonucleotides that modulate gene expression as described in WO2016 / 130929.

[0094] In some embodiments, at least one additional therapeutic agent is selected from one or more CFTR modulators, one or more CFTR correctors and one or more CFTR potentiators.

[0095] Non-limiting examples of additional therapeutics include VX-770 (Ivacaftor), VX-809 (Lumacaftor, 3-(6-(I-(2,2-5 difluorobenzo[d][1, 3]dioxo1-5-yl)cyclopropanecarboxamido)-3- methylpyridin-2-yl) benzoic acid, VX-661 (Tezacaftor, I-(2,2-difluoro-1, 3-benzodioxo1-5- yl)-N-[I-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(2-hydroxy-l, I-dimethylethyl)- IH-indol-5- yl]- cyclopropanecarboxamide), VX-983, VX-152, VX-440, VX-445, VX-659, VX-371, Orkambi, Ataluren (PTC 124) (3-[5-(2-fluorophenyl)-1, 2,4-oxadiazo1-3-yl]benzoic acid), PTI-130 (Proteostasis), PTI-801, PTI-808, PTI-428, N91115.74 (cavosonstat), QBW251 (Novartis) compounds described in WO2011113894, compounds N30 Pharmaceuticals (e.g., WO 2014 / 186704), deuterated ivacaftor (e.g., CTP-656 or VX-561), GLPG 2222, GLPG2451, GLPG3067, GLPG2851, GLPG2737, GLPG 1837 (N-(3-carbamoyl-5,5,7,7-tetramethyl-5,7- dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide), GLPG 2665 (Galapagos), FDL 169 (Flatley Discovery lab), FDL 176, FDL438, FDL304, FD2052160, FD1881042, FD2027304, FD2035659, FD2033129, FD1860293, CFFT-Pot01, CFFT-Pot-02, P-1037, glycerol, phenylbutyrate, and the like.

[0096] Non-limiting examples of additional therapeutics include compounds disclosed in US Patent Application Nos. PCT / US20 / 63586, PCT / US20 / 63589, and PCT / US20 / 63590, each of which is incorporated by reference in its entirety.

[0097] Non-limiting examples of anti-inflammatory agents are N6022 (3-(5-(4-(IH-imidazol- I-yl)10 phenyl)-I-(4-carbamoyl-2-methylphenyl)-'H-pyrrol-2-yl) propanoic acid), Ibuprofen, Lenabasum (anabasum), Acebilustat (CTX-4430), LAU-7b, POL6014, docosahexaenoic acid, alpha-1 anti-trypsin, sildenafil. Additional therapeutic agents also include, but are not limited to a mucolytic agent , a modifier of mucus rheology (such as hypertonic saline, mannitol, and oligosaccharide based therapy), a bronchodilator, an anti-infective (such as tazobactam, piperacillin, rifampin, meropenem, ceftazidime, aztreonam, tobramycin, fosfomycin, azithromycin, amitriptyline, vancomycin, gallium and colistin), an anti-infective agent, an anti- inflammatory agent, a CFTR modulator other than a compound of the present disclosure, and a nutritional agent. Additional therapeutic agents can include treatments for comorbid conditions of cystic fibrosis, such as exocrine pancreatic insufficiency which can be treated with Pancrelipase or Liprotamase.

[0098] Examples of CFTR potentiators include, but are not limited to, Ivacaftor (VX-770), CTP-656, NVS-QBW251, FD1860293, GLPG2451, GLPG1837, and N-(3-carbamoyl-5,5,7,7- tetramethyl-5,7-dihydro-4H-thieno[2,3-c]pyran-2-yl)-1H-pyrazole-5-carboxamide. Examples of potentiators are also disclosed in publications: WO2005120497, WO2008147952, WO2009076593, WO2010048573, WO2006002421, WO2008147952, WO2011072241, WO2011113894, WO2013038373, WO2013038378, WO2013038381, WO2013038386, WO2013038390, WO2014180562, WO2015018823, and U.S. patent application Ser. Nos. 14 / 271,080, 14 / 451,619 and 15 / 164,317.

[0099] Non-limiting examples of correctors include Lumacaftor (VX-809), 1-(2,2-difluoro- 1,3-benzodioxol-5-yl)-N-{1-[(2R)-2,3-dihydroxypropyl]-6-fluoro-2-(1-hydroxy-2- methylpropan-2-yl)-1H-indol-5-yl}cyclopropanecarboxamide (VX-661), VX-983, GLPG2222, GLPG2665, GLPG2737, VX-152, VX-440, FDL169, FDL304, FD2052160, and FD2035659. Examples of correctors are also disclosed in US20160095858A1, and U.S. application Ser. Nos.14 / 925,649 and 14 / 926,727.

[0100] In certain embodiments, the additional therapeutic agent is a CFTR amplifier. CFTR amplifiers enhance the effect of known CFTR modulators, such as potentiators and correctors. Examples of CFTR amplifier include PTI130 and PTI-428. Examples of amplifiers are also disclosed in publications: WO2015138909 and WO2015138934.

[0101] In certain embodiments, the additional therapeutic agent is an agent that reduces the activity of the epithelial sodium channel blocker (ENaC) either directly by blocking the channel or indirectly by modulation of proteases that lead to an increase in ENaC activity (e.g., serine proteases, channel-activating proteases). Exemplary of such agents include camostat (a trypsin- like protease inhibitor), QAU145, 552-02, GS-9411, INO-4995, Aerolytic, amiloride, AZD5634, and VX-371. Additional agents that reduce the activity of the epithelial sodium channel blocker (ENaC) can be found, for example, in PCT Publication No. WO2009074575 and WO2013043720; and U.S. Pat. No.8,999,976.

[0102] In one embodiment, the ENaC inhibitor is VX-371.

[0103] In one embodiment, the ENaC inhibitor is SPX-101 (S18).

[0104] In certain embodiments, the combination of a compound of the present disclosure, with a second therapeutic agent may have a synergistic effect in the treatment of cancer and other diseases or disorders mediated by adenosine. In other embodiments, the combination may have an additive effect. Exemplification Analytical Procedures1H NMR spectra were recorded with a Bruker AC 400 MHz apparatus. Chemical shifts (δ) are quoted in parts per million (ppm) and coupling constants (J) in hertz (Hz). LC-MS spectra were obtained with a UPLC Acquity device of Waters for the liquid chromatography analysis, coupling with a ZMD (Waters) mass spectrometer. This system was piloted by MassLynx v4.1 software. Detection was made in UV at 220 nm. Operational conditions for liquid chromatography analysis are as follows: Method 1: Column: Assentis Express C1850 x 2.1 mm, 2.7 µm Supelco Eluent: A: H2O + 0.02% TFA; B: CH3CN + 0.014% TFA; Gradient: T0 min: 2% B, T1 min : 98% B, T1.3min : 98% B, T1.33min : 2% B, T1.5min : following injection; Flow: 1 mL / min; Temperature: 55 °C. SQD : ESI+ 30V UV detection wavelength: 220 nm Injection volume: 0.2 µL. Method 2 (similar to Method 1, except for the following modifications): Column: Sunfire C18, 4.6 x 50mm, 3.5um Eluent: A: H2O + 0.01% TFA; B: CH3CN + 0.01% TFA; Gradient: T0 min: 5% B: T1.5min : 95%B; hold at 95%B. Flow: 2.0 mL / min; Temperature: 50 °C. Method 2A (identical to Method 2, except for the following modifications): Gradient: T0 min: 5% B: T1.3min : 95%B; hold at 95% B Flow: 2.0 mL / min. Method 3 (identical to Method 2, except for the following modifications): Gradient: T0 min: 5% B: T1.4 min : 95%B; hold at 95% B. Method 4 (similar to Method 1, except for the following modifications): Column: XBRIDGE C18 (4.6x 50 mm, 3.5um) Eluent: A: 10 mM aqueous ammonium bicarbonate; B: CH3CN; Gradient: T0 min: 10% B; 95% B, T1.5min; hold at 95% B Flow: 1.8 mL / min; Temperature: 50 °C. Method 4A (identical to Method 4, except the following modification): Gradient: T0 min: 10% B; 95% B, T1.4 min; hold at 95% B Method 5: Column: Poroshell 120 EC C184um 4.6*50mm Eluent: A: H2O + 0.01% TFA; B: CH3CN + 0.01% TFA; Gradient: T0 min: 5% B: T1.5min : 95%B; hold at 95%B. Flow: 2.0 mL / min; Temperature: 45 °C. UV detection wavelength: 214nm, 254nm Injection volume: 0.2 µL. Method 6: Column: HALO C18 (4.6x 30 mm, 2.7um) Eluent: A: H2O + 0.01% TFA; B: CH3CN + 0.01% TFA; Gradient: T0 min: 5% B: T1.4 min : 95%B; hold at 95%B. Flow: 2.2 mL / min; Temperature: 50 °C. UV detection wavelength: 214nm, 254nm Injection volume: 0.2 µL. Preparatory HPLC purification was carried out under the following conditions: Instrument: Gilson 281 (PHG011) Column Xtimate C1821.2 * 250 mm,10 µm Mobile Phase: A: water (10 mM NH4HCO3spiked with 0.025% NH3·H2O) ; B: acetonitrile Gradient: 5% B for 3 min, then 5-37% B in 10 min, stop at 18 min Flow Rate (ml / min): 30.00 Detection Wavelength (nm): 214 / 254 Retention Time (min): 8 Abbreviations: AcOH: acetic acid AIBN: azobisisobutyronitrile BINAP: 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl Boc: tert-butyloxycarbonyl n-BuOH: n-butanol DABAL-Me3: bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane adduct DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene DCM: dichloromethane DCE: 1,2-dichloroethane DEA: diethyl amine DHP: 3,4-dihydropyran DIPEA: N,N-diisopropylethylamine DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMF-DMA: N,N-dimethylformamide dimethyl acetal DMSO: dimethyl sulfoxide dppf: 1,1'-bis(diphenylphosphino)ferrocene DTT: dithiothreitol EA: ethyl acetate Ee: enantiomeric excess Eq: equivalents ESI: electron spray ionization EtOAc: ethyl acetate EtOH: ethanol FA: formic acid HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC: high performance liquid chromatography In vacuo: under vacuum ; under reduced pressure LAH: lithium aluminum hydride LC-MS: liquid chromatography-mass spectrometry LDA: lithium diisopropylamide LHMDS: lithium bis(trimethylsilyl)amide MeOH: methanol NBS: N-bromosuccinimide NIS: N-iodosuccinimide NMP: N-methyl-2-pyrrolidone Pd / C: palladium on carbon PE: petroleum ether PPTS: pyridinium p-toluenesulfonate Prep-HPLC: preparative HPLC RT or rt: room temperature / ambient temperature SFC: supercritical fluid chromatography TBAF: tetra-n-butylammonium fluoride TBS: tert-butyldimethylsilyl TCSF: tetramethylchloroformamidinium hexafluorophosphate TFA: trifluoroacetic acid TIPS: triisopropylsilyl THF: tetrahydrofuran THP: tetrahydropyran TLC: thin layer chromatography Ts: tosyl Example 1. Synthesis of 3-(3-(2-(2-fluoro-5-((6-fluoro-4-methyl-1H-indol-5- yl)oxy)phenyl)-1H-imidazol-5-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)propanoic acid Methyl 2-(3-bromo-2-hydroxyphenyl)acetate

[0105] Step A: To a solution of methyl 2-(2-hydroxyphenyl)acetate (3.4 g, 20.5 mmol) in DCM (50 mL) was added diisopropylamine (0.41 g, 4.10 mmol) and N-bromosuccinimide (3.63 g, 20.5 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was filtered, the filtrate was concentrated. The residue was purified by silica gel column chromatography, eluting with 25-50% EtOAc in petroleum ether, to give methyl 2-(3-bromo-2- hydroxyphenyl)acetate (4.3 g, 86%) as a light-yellow oil. MS (ESI): 244.9 , 247 m / z (M+H)+. Methyl 2-(3-bromo-2-(methoxymethoxy)phenyl)acetate

[0106] Step B: To a solution of methyl 2-(3-bromo-2-hydroxyphenyl)acetate (4.3 g, 17.6 mmol) in acetone (50 mL) was added bromomethyl methyl ether (2.40 g, 19.4 mmol) and K2CO3(4.86 g, 35.2 mmol). The mixture was stirred at 80 °C for 5 hours. The mixture was filtered, the filtrate was concentrated. The residue was purified by silica gel column chromatography, eluting with 15-25% EtOAc in petroleum ether, to give methyl 2-(3-bromo- 2-(methoxymethoxy)phenyl)acetate (4.11 g, 81%) as a light-yellow oil. MS (ESI): 289.2, 291.0 m / z (M+H)+. Methyl 2-(3-bromo-2-(methoxymethoxy)phenyl)propanoate

[0107] Step C: To a solution of methyl 2-(3-bromo-2-(methoxymethoxy)phenyl)acetate (4.11 g, 14.3 mmol) in THF (50 mL) was added dropwise 2M lithium diisopropylamide in THF (7.7 mL, 15.4 mmol) at -78 °C under an Ar atmosphere. The reaction mixture was stirred at this temperature for 30 min, and then MeI (2.43 g, 17.1 mmol) was added at -78 °C. The mixture was stirred at -78 °C for 2 hours. The reaction mixture was warmed to room temperature, stirred at room temperature overnight, and then quenched with water (50 mL). The reaction mixture pH was adjusted to ~6 with 1.0M hydrochloric acid, and the aqueous phase was extracted with ethyl acetate (60 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 6 / 1-4 / 1 petroleum ether / ethyl acetate) to afford methyl 2-(3-bromo-2-(methoxymethoxy)phenyl)propanoate (2.67 g, 62%) as a yellow solid. MS (ESI): 303.2 , 305.2 m / z (M+H)+. Methyl 2-(3-bromo-2-(methoxymethoxy)phenyl)-3-hydroxy-2-methylpropanoate

[0108] Step D: To a solution of methyl 2-(3-bromo-2-(methoxymethoxy)phenyl)propanoate (2.67 g, 8.84 mmol) in dry THF (30 mL) at -78 °C was added dropwise under an Ar atmosphere lithium diisopropylamide solution in THF (5.8 mL, 2.0 M, 11.6 mmol). The reaction mixture was stirred at this temperature for 30 min, then formaldehyde (0.53 g, 17.7 mmol) was added dropwise and stirring continued overnight at room temperature. The reaction was quenched with water (50 mL). The pH of the solution was adjusted to ~6 through the addition of 1N hydrochloric acid. The aqueous phase was extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 3:1-1:1 petroleum ether:ethyl acetate) to give methyl 2-(3- bromo-2-(methoxymethoxy)phenyl)-3-hydroxy-2-methylpropanoate (4.5 g, 72%) as a colorless solid. MS (ESI): 315.2 m / z (M-OH)+. Methyl 2-(3-bromo-2-(methoxymethoxy)phenyl)-2-methyl-3-((methylsulfonyl)oxy)propanoate

[0109] Step E: To the solution of methyl 2-(3-bromo-2-(methoxymethoxy)phenyl)-3-hydroxy- 2-methylpropanoate (2.0 g, 6.0 mmol) and Et3N (1.22 g, 12.1 mmol) in DCM (50 mL) was added methanesulfonyl chloride (4.82 g, 25.4 mmol) at 0 ºC, and the mixture was stirred at room temperature for 3 hours. The resulting mixture was diluted with DCM (50 mL), and the organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give crude methyl 2-(3-bromo-2-(methoxymethoxy)phenyl)-2-methyl-3- ((methylsulfonyl)oxy)propanoate (3.5 g) as a yellow oil, which was used directly in the next step. Methyl 2-(3-bromo-2-hydroxyphenyl)-2-methyl-3-((methylsulfonyl)oxy)propanoate

[0110] Step F: To the solution of crude methyl 2-(3-bromo-2-(methoxymethoxy)phenyl)-2- methyl-3-((methylsulfonyl)oxy)propanoate (3.5 g) in DCM (30 mL) was added at 0 ºC trifluoroacetic acid (2 mL), and the mixture was stirred at room temperature overnight. The resulting mixture was diluted with DCM (50 mL). The organic phase was washed with brine, dried over anhydrous Na2SO4, and concentrated in vacuo to give crude methyl 2-(3-bromo-2- hydroxyphenyl)-2-methyl-3-((methylsulfonyl)oxy)propanoate (2.2 g) as a brown oil which was used directly in the next step. Methyl 7-bromo-3-methyl-2,3-dihydrobenzofuran-3-carboxylate

[0111] Step G: To the solution of crude methyl 2-(3-bromo-2-hydroxyphenyl)-2-methyl-3- ((methylsulfonyl)oxy)propanoate (2.2 g) in acetone (20 mL) was added K2CO3(200 mg, 4.95 mmol). The resulting mixture was stirred at room temperature overnight and concentrated. To the residue were added H2O (50 mL) and EtOAc (50 mL), the organic phase was separated, and the aqueous phase was extracted with EtOAc (30 mL x 3). The combined organic phase was washed with H2O (100 mL), brine (100 mL), dried, and concentrated. The residue was purified by silica gel column chromatography, eluting with 25-50% EtOAc in petroleum ether, to give methyl 7-bromo-3-methyl-2,3-dihydrobenzofuran-3-carboxylate (940 mg, 58% over 3 steps) as a light-yellow oil. MS (ESI): 271.1 , 2731.1 m / z (M+H)+. 7-Bromo-3-methyl-2,3-dihydrobenzofuran-3-carboxylic acid

[0112] Step H: To a solution of methyl 7-bromo-3-methyl-2,3-dihydrobenzofuran-3- carboxylate (970 mg, 3.59 mmol) in THF (20 mL) was added a solution of LiOH (517 mg, 21.6 mmol) in H2O (4 mL), and the resulting solution was stirred at room temperature overnight. After diluting with water (50 mL), the aqueous phase was acidified with 1 N hydrochloric acid until no more precipitate formed. The precipitate was isolated to give crude 7-bromo-3-methyl- 2,3-dihydrobenzofuran-3-carboxylic acid (940 mg) as a light-yellow solid, which was used directly in the next step. 2-Bromo-1-(7-bromo-3-methyl-2,3-dihydrobenzofuran-3-yl)ethan-1-one

[0113] Step I: To a solution of 7-bromo-3-methyl-2,3-dihydrobenzofuran-3-carboxylic acid (940 mg, 3.59 mmol) in DCM (20 mL) was added oxalyl chloride (815 mg, 6.47 mmol) and DMF (2 drops) at 0 °C and stirring continued at 25 °C for 3 hours. The solution was concentrated, and the residue was dissolved in acetonitrile (20 mL). The acetonitrile solution was added dropwise over 30 min to a 2.0 N (trimethylsilyl)diazomethane solution in hexanes (5.5 mL, 11.0 mmol) at 0 °C. After the addition was complete, the mixture was allowed to warm to room temperature. After 2 hours, LC-MS analysis revealed that the reaction was complete. The yellow solution was chilled to 0 °C and hydrogen bromide solution (33 wt. % in acetic acid, 2.62 g, 10.8 mmol) was added dropwise to the mixture (vigorous gas evolution noted). After 1 hour, LC-MS analysis revealed that the reaction was complete. The mixture was diluted with brine (20 mL) and EtOAc (50 mL). The phases were separated, and the organic phase was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 5:1 petroleum ether:EtOAc) to give 2-bromo- 1-(7-bromo-3-methyl-2,3-dihydrobenzofuran-3-yl)ethan-1-one (480 mg, 41% over 2 steps) as a light-yellow oil. 5-(3-(5-(7-Bromo-3-methyl-2,3-dihydrobenzofuran-3-yl)-1H-imidazol-2-yl)-4-fluorophenoxy)-6- fluoro-4-methyl-1H-indole

[0114] Step J: A solution of 2-bromo-1-(7-bromo-3-methyl-2,3-dihydrobenzofuran-3- yl)ethan-1-one (480 mg, 1.45 mmol), 2-fluoro-5-((6-fluoro-4-methyl-1H-indol-5- yl)oxy)benzimidamide (Intermediate 1, 522 mg, 1.74 mmol) and NaHCO3(364 mg, 4.33 mmol) in DMF (5 mL) was stirred at 75 °C overnight. The mixture was diluted with EtOAc (50 mL), washed with water (20 mL x 3), brine (20 mL x 2), dried with anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 1:1:4-2:2:3 DCM:EtOAc:petroleum ether) to give 5-(3-(5-(7-bromo-3-methyl-2,3- dihydrobenzofuran-3-yl)-1H-imidazol-2-yl)-4-fluorophenoxy)-6-fluoro-4-methyl-1H-indole (330 mg, 43 %) as a light-yellow solid. MS (ESI): 536.2, 538.2 m / z (M+H)+. Ethyl (Z)-3-(3-(2-(2-fluoro-5-((6-fluoro-4-methyl-1H-indol-5-yl)oxy)phenyl)-1H-imidazol-5- yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acrylate

[0115] Step K: A mixture of 5-(3-(5-(7-bromo-3-methyl-2,3-dihydrobenzofuran-3-yl)-1H- imidazol-2-yl)-4-fluorophenoxy)-6-fluoro-4-methyl-1H-indole (330 mg, 0.62 mmol), ethyl acrylate (123 mg, 1.23 mmol), Pd(OAc)2(14 mg, 0.06 mmol), P(o-Tol)3 (28 mg, 0.09 mmol) and triethylamine (187 mg, 1.85 mmol) in DMF (5 mL) was stirred in a sealed tube under a N2 atmosphere at 110 °C for 5 hours. The mixture was filtered through Celite, and the filter cake was washed with EtOAc (30 mL). The filtrate was washed with H2O (20 ml x 4), brine (10 ml x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 4 / 2 / 1-3 / 2 / 2 petroleum ether / DCM / EtOAc, to afford ethyl (Z)-3-(3-(2-(2-fluoro-5-((6-fluoro-4-methyl-1H-indol-5- yl)oxy)phenyl)-1H-imidazol-5-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acrylate (210 mg, 61%) as a light-yellow solid. MS (ESI): 556.2 m / z (M+H)+. Ethyl 3-(3-(2-(2-fluoro-5-((6-fluoro-4-methyl-1H-indol-5-yl)oxy)phenyl)-1H-imidazol-5-yl)- 3-methyl-2,3-dihydrobenzofuran-7-yl)propanoate

[0116] Step L: To a solution of ethyl (Z)-3-(3-(2-(2-fluoro-5-((6-fluoro-4-methyl-1H-indol-5- yl)oxy)phenyl)-1H-imidazol-5-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acrylate (210 mg, 0.89 mmol) in EtOH (10 mL) was added Pd / C (10 wt. %, 50 mg), and the mixture was stirred at room temperature under H2overnight. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 4:2: / 1-3: / 2:2 petroleum ether:DCM:EtOAc, to give ethyl 3-(3- (2-(2-fluoro-5-((6-fluoro-4-methyl-1H-indol-5-yl)oxy)phenyl)-1H-imidazol-5-yl)-3-methyl- 2,3-dihydrobenzofuran-7-yl)propanoate (100 mg, 48%) as a light yellow solid. MS (ESI): 558.2 m / z (M+H)+. 3-(3-(2-(2-Fluoro-5-((6-fluoro-4-methyl-1H-indol-5-yl)oxy)phenyl)-1H-imidazol-5-yl)-3- methyl-2,3-dihydrobenzofuran-7-yl)propanoic acid

[0117] Step M: To a solution of ethyl 3-(3-(2-(2-fluoro-5-((6-fluoro-4-methyl-1H-indol-5- yl)oxy)phenyl)-1H-imidazol-5-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)propanoate (100 mg, 0.18 mmol) in THF (5 mL) was added a solution of LiOH (22 mg, 0.90 mmol) in H2O (0.9 mL), and the resulting mixture was stirred at room temperature overnight. After diluting with water (10 mL), the aqueous phase was acidified with 1 N hydrochloric acid until no more precipitate formed. The precipitate was purified by prep-HPLC to afford 3-(3-(2-(2-fluoro-5- ((6-fluoro-4-methyl-1H-indol-5-yl)oxy)phenyl)-1H-imidazol-5-yl)-3-methyl-2,3- dihydrobenzofuran-7-yl)propanoic acid (40 mg, 42%) as a white solid. MS (ESI): 530.1 m / z (M+H)+.1H NMR (400 MHz, MeOD-d4) δ 7.43 (dd, J = 6.0 Hz & 3.2 Hz, 1H), 7.28 (d, J = 3.2 Hz, 1H), 7.18-7.08 (m, 2H), 7.04 (dd, J = 7.6 Hz & 2.8 Hz, 2H), 6.87-6.77 (m, 3H), 6.52 (d, J = 3.2 Hz, 1H), 4.73 (d, J = 8.4 Hz, 1H), 4.43 (d, J = 8.4 Hz, 1H), 2.90 (t, J = 7.6 Hz, 2H), 2.61 (t, J = 7.6 Hz, 2H), 2.39 (s, 3H), 1.69 (s, 3H) ppm. Example 2. Synthesis of 3-[(3S)-3-[2-[2-fluoro-5-[(6-fluoro-4-methyl-1H-indol-5- yl)oxy]phenyl]-1H-imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]propanoic acid Example 3. Synthesis of 3-[(3R)-3-[2-[2-fluoro-5-[(6-fluoro-4-methyl-1H-indol-5- yl)oxy]phenyl]-1H-imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]propanoic acid

[0118] 3-[3-[2-[2-fluoro-5-[(6-fluoro-4-methyl-1H-indol-5-yl)oxy]phenyl]-1H-imidazol-5- yl]-3-methyl-2H-benzofuran-7-yl]propanoic acid (Example 1, 220 mg) was separated into its chiral components by chiral prep-HPLC. The absolute configuration of both enantiomers is unknown and was assigned arbitrarily. Thus, the faster eluting component of the mixture was assigned to be 3-[(3S)-3-[2-[2-fluoro-5-[(6-fluoro-4-methyl-1H-indol-5-yl)oxy]phenyl]-1H- imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]propanoic acid (Example 2, 90 mg, 41%) and the slower eluting component, 3-[(3R)-3-[2-[2-fluoro-5-[(6-fluoro-4-methyl-1H-indol-5- yl)oxy]phenyl]-1H-imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]propanoic acid (Example 3, 90 mg, 41%).

[0119] 3-[(3S)-3-[2-[2-fluoro-5-[(6-fluoro-4-methyl-1H-indol-5-yl)oxy]phenyl]-1H- imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]propanoic acid (Example 2):1H NMR (400 MHz, DMSO-d6) δ 12.09 (s, 1H), 11.47 (s, 1H), 7.39 (s, 2H), 7.23 (t, J = 10.4 Hz, 2H), 6.98 (dd, J = 12.4, 7.8 Hz, 3H), 6.74 (dd, J = 14.9, 8.0 Hz, 2H), 6.52 (s, 1H), 4.82 (d, J = 8.4 Hz, 1H), 4.37 (d, J = 8.6 Hz, 1H), 2.73 (t, J = 7.8 Hz, 2H), 2.45-2.39 (m, 2H), 2.32 (s, 3H), 1.58 (s, 3H). MS (ESI): 530.2 m / z (M+H)+.

[0120] 3-[(3R)-3-[2-[2-fluoro-5-[(6-fluoro-4-methyl-1H-indol-5-yl)oxy]phenyl]-1H- imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]propanoic acid (Example 3):1H NMR (400 MHz, DMSO-d6) δ 12.10 (s, 1H), 11.31 (s, 1H), 7.44-7.37 (m, 2H), 7.27-7.20 (m, 2H), 7.00 (dd, J = 18.9, 7.4 Hz, 2H), 6.94 (s, 1H), 6.75 (t, J = 7.5 Hz, 2H), 6.53 (s, 1H), 4.83 (d, J = 8.6 Hz, 1H), 4.38 (d, J = 8.6 Hz, 1H), 2.75 (t, J = 7.7 Hz, 2H), 2.47 (s, 2H), 2.33 (s, 3H), 1.58 (s, 3H). MS (ESI): 530.1 m / z (M+H)+. Example 4. Synthesis of 3-(3-(2-(2-fluoro-5-((6-fluoro-4-methyl-1H-indol-5- yl)oxy)phenyl)-1H-imidazol-5-yl)chroman-8-yl)propanoic acid 8-Bbromochromane-3-carboxylic acid

[0121] Step A: To a solution of methyl 8-bromochromane-3-carboxylate (1.4 g ,5.16 mmol) in MeOH (15 mL) and THF (15 mL) was added a solution of LiOH (867 mg, 20.7 mmol) in H2O (10 mL). The mixture was stirred for 6 hours at room temperature. The reaction mixture was diluted with water and the pH was adjusted to ~5 with concentrated hydrochloric acid. The mixture was extracted with EtOAc (30 ml x 3), washed with brine, dried over Na2SO4and concentrated to obtain 8-bromochromane-3-carboxylic acid (1.2 g, 81%). MS (ESI): 257, 259 m / z (M+H)+. (E)-8-(3-Methoxy-3-oxoprop-1-en-1-yl)chromane-3-carboxylic acid

[0122] Step B: To a solution of 8-bromochromane-3-carboxylic acid (1.2g, 4.2 mmol), palladium (II) acetate (94.3 mg, 0.42 mmol) and tri(2-methylphenyl)phosphine (256 mg, 0.84 mmol), Et3N (2.13 g, 21mmol) in DMF (30 ml) was added methyl prop-2-enoate (1.81 g, 21 mmol). The mixture was stirred at 120 °C under N2 for 15 hours. After cooling the reaction to room temperature, water was added and the mixture was extracted with EtOAc (50 ml x 3). The combined organic extracts were washed with saturated aqueous LiCl, brine, and dried over Na2SO4. The organic layer was concentrated under reduced pressure. The crude was further purified by flash column chromatography on silica, eluting with 25:2 DCM:methanol to obtain the title compound (750 mg, 41 %). MS (ESI): 263 m / z (M+H)+. 8-(3-Methoxy-3-oxopropyl)chromane-3-carboxylic acid

[0123] Step C: To a solution of 8-[(E)-3-methoxy-3-oxo-prop-1-enyl]chromane-3-carboxylic acid (700 mg, 2.4 mmol) in MeOH (10 mL) was added Pd / C (10 wt. %, 140 mg) and a drop of concentrated aqueous ammonia. The reaction mixture was stirred for 4 hours at room temperature under H2. After the reaction was judged complete by LC-MS, the mixture was filtered and concentrated under reduced pressure. The residue was purified by reverse phase column chromatography on C-18 silica column, eluting with a 5-40% gradient of 0.01% TFA- acetonitrile in water to afford the product, 8-(3-methoxy-3-oxopropyl)chromane-3-carboxylic acid (110 mg, 16 %). MS (ESI): 265 m / z (M+H)+. Methyl 3-(3-(2-bromoacetyl)chroman-8-yl)propanoate

[0124] Step D: A solution of 8-(3-methoxy-3-oxo-propyl)chromane-3-carboxylic acid (0.11 g, 3.79 mmol) in 5 mL of SOCl2was stirred at 70 °C for 1 hour. The mixture was concentrated under reduced pressure. The residue was dissolved in 10 mL of acetonitrile, and cooled to 0 °C. Trimethylsilyldiazomethane (0.86 g, 4 eq) was added dropwise, and the solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to 0 °C. Hydrobromic acid solution (255 mg, 43% in AcOH) was added dropwise, and the mixture was stirred for 20 minutes until gas evolution ceased. Water was added and the mixture was extracted with EtOAc (20 ml x 3). The combined organic layers were washed with NaHCO3and brine, dried over Na2SO4, and concentrated. The residue was further purified by column chromatography on silica gel, eluting with 10:1 petroleum ether:EtOAc to afford the pure product, methyl 3-(3-(2-bromoacetyl)chroman-8-yl)propanoate (70 mg, 48%). MS (ESI): 341 , 343 m / z (M+H)+. Methyl 3-(3-(2-(2-fluoro-5-((6-fluoro-4-methyl-1H-indol-5-yl)oxy)phenyl)-1H-imidazol-5- yl)chroman-8-yl)propanoate

[0125] Step E: To a solution of 2-fluoro-5-[(6-fluoro-4-methyl-1H-indol-5- yl)oxy]benzamidine (Intermediate 1, 110 mg, 0.365 mmol) and methyl 3-[3-(2- bromoacetyl)chroman-8-yl]propanoate (112 mg, 0.296 mmol) in DMF (3 mL) was added NaHCO3(92 mg, 1.1 mmol). The resulting mixture was stirred for 4 hours at 75 °C. After the reaction was judged complete by LC-MS, the mixture was poured into water (20 mL) and extracted with EtOAc (15 mL x 3). The organic phase was washed with saturated aqueous LiCl, brine, and dried over Na2SO4. After removal of the solids, the solvent was concentrated under reduced pressure to obtain a residue. The residue was further purified by column chromatography on silica gel, eluting with 3:1 petroleum ether:EtOAc to afford the pure title compound (35 mg, 17%). MS (ESI): 544 m / z (M+H)+. 3-(3-(2-(2-fluoro-5-((6-fluoro-4-methyl-1H-indol-5-yl)oxy)phenyl)-1H-imidazol-5- yl)chroman-8-yl)propanoic acid

[0126] Step F: To a solution of methyl 3-[3-[2-[2-fluoro-5-[(6-fluoro-4-methyl-1H-indol-5- yl)oxy]phenyl]-1H-imidazol-5-yl]chroman-8-yl]propanoate (35 mg) in THF (3 ml) and MeOH (1 ml) was added at room temperature a solution of LiOH (11 mg) in water (1 ml). The mixture was stirred at room temperature for 3 hours, and then concentrated. To the residue was added water (2 ml), and the pH was adjusted to less than 3 with 2N hydrochloric acid. The solid was filtered, washed with water, and dried to obtain 3-[3-[2-[2-fluoro-5-[(6-fluoro-4-methyl-1H- indol-5-yl)oxy]phenyl]-1H-imidazol-5-yl]chroman-8-yl]propanoic acid (16 mg, 47%). MS (ESI): 530 m / z (M+H)+.1H NMR (400 MHz, CDCl3) δ 7.43-7.41 (m, 1H), 7.26-7.25 (m, 1H), 7.18-7.09 (m, 2H), 6.97-6.93 (m, 3H), 6.87-6.83 (m, 1H), 6.76-7.73 (m, 1H),6.51-6.50(m, 1H), 4.48-4.45 (d, 1H), 4.10-4.05 (q, 1H), 3.12-3.01(m, 2H), 2.87-2.83 (t, 2H), 2.55-2.51 (m, 2H), 2.39 (s, 3H) ppm. Example 5. Synthesis of (S)-2-(3-(2-(2-fluoro-5-((6-fluoro-4-methyl-1H-indol-5- yl)oxy)phenyl)-1H-imidazol-5-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid Example 6. Synthesis of (R)-2-(3-(2-(2-fluoro-5-((6-fluoro-4-methyl-1H-indol-5- yl)oxy)phenyl)-1H-imidazol-5-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid Methyl 2-((2,6-dibromophenoxy)methyl)acrylate

[0127] Step A: To a solution of 2,6-dibromophenol (25.2 g, 100 mmol) in acetonitrile (200 mL) was added Cs2CO3(39.1 g, 120 mmol) and methyl-2-bromomethacrylate (17.9 g, 100 mmol). The mixture was stirred at 80 °C for 4 hours, then cooled to room temperature and filtered through a pad of Celite. The organic phase was concentrated in vacuo to give methyl 2-[(2,6-dibromophenoxy)methyl]prop-2-enoate (32 g, 91%) as an oil. MS (ESI): 351 m / z (M+H)+. Methyl 7-bromo-3-methyl-2H-benzofuran-3-carboxylate and methyl 8-bromochromane-3- carboxylate

[0128] Step B: To a solution of methyl 2-[(2,6-dibromophenoxy)methyl]prop-2-enoate (7 g, 20 mmol) in toluene (100 mL) was added tri-n-butyl tin hydride (5.8 g, 20 mmol) and 2,2'- azobis(2-methylpropionitrile) (0.657 g, 4 mmol). The mixture was stirred at 115 °C for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in EtOAc (200 mL), washed with saturated aqueous KF (200 mL), brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 0- 15% EtOAc in petroleum ether to give methyl 7-bromo-3-methyl-2H-benzofuran-3- carboxylate (1.9 g, 35%) as an oil and methyl 8-bromochromane-3-carboxylate (0.45 g, 8.3%) as an oil. methyl 7-bromo-3-methyl-2H-benzofuran-3-carboxylate: MS (ESI): 271, 273 m / z (M+H)+. methyl 8-bromochromane-3-carboxylate: MS (ESI): 271, 273 m / z (M+H)+. 7-Bromo-3-methyl-2H-benzofuran-3-carboxylic acid

[0129] Step C: To a solution of methyl 7-bromo-3-methyl-2H-benzofuran-3-carboxylate (1.5 g, 5.53 mmol) in THF (30 mL) and MeOH (10 mL) was added 1M aqueous LiOH · H2O (10 mL). The mixture was stirred at room temperature for 2 hours. Water (50 mL) was added, the pH was adjusted to 5, and the mixture was extracted with EtOAc (50 mL x 2). The combined organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated to give 7- bromo-3-methyl-2H-benzofuran-3-carboxylic acid (1.26 g, 89%) as an oil. MS (ESI): 257, 259 m / z (M+H)+. Benzyl 7-bromo-3-methyl-2,3-dihydrobenzofuran-3-carboxylate

[0130] Step D: To a solution of 7-bromo-3-methyl-2H-benzofuran-3-carboxylic acid (514 mg, 2 mmol) in acetone (5 mL) was added K2CO3(414 mg, 2.4 mmol) and benzyl bromide (410 mg, 3 mmol). The mixture was stirred at 70 °C overnight, cooled to room temperature, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 0-10% EtOAc in petroleum ether, to afford benzyl 7-bromo-3-methyl-2H-benzofuran-3- carboxylate (490 mg, 70.6%) as an oil. MS (ESI): 369, 371 m / z (M+Na)+. Benzyl 7-(2-ethoxy-2-oxoethyl)-3-methyl-2,3-dihydrobenzofuran-3-carboxylate

[0131] Step E: To a solution of benzyl 7-bromo-3-methyl-2H-benzofuran-3-carboxylate (490 mg, 1.41 mmol) in mesitylene (4 mL) was added ethyl potassium malonate (360 mg, 2.12 mmol), Allylpalladium chloride dimer (10.3 mg, 0.03 mmol), BINAP (52.7 mg, 0.08 mmol) and 4-dimethylaminopyridine (17.2 mg, 0.14 mmol). The mixture was stirred at 160 °C for 4 hours, then cooled room temperature, water (20 mL) was added, and the mixture extracted with EtOAc (20 mL x 2). The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 0-10% EtOAc in petroleum ether to give benzyl 7-(2-ethoxy-2-oxo-ethyl)-3-methyl-2H- benzofuran-3-carboxylate (200 mg, 40%) as an oil. MS (ESI): 355 m / z (M+H)+. 7-(2-Ethoxy-2-oxoethyl)-3-methyl-2,3-dihydrobenzofuran-3-carboxylic acid

[0132] Step F: To a solution of benzyl 7-(2-ethoxy-2-oxo-ethyl)-3-methyl-2H-benzofuran-3- carboxylate (200 mg, 0.564 mmol) in THF (5 mL) was added Pd(OH)2on activated carbon (20 wt. %, 40 mg). The flask was evacuated and backfilled with H2. The mixture was stirred at room temperature overnight, filtered, and concentrated in vacuo to give 7-(2-ethoxy-2-oxo- ethyl)-3-methyl-2H-benzofuran-3-carboxylic acid (140 mg, 94%) as a solid. MS (ESI): 265 m / z (M+H)+. Ethyl 2-(3-(2-bromoacetyl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate

[0133] Step G: A solution of 7-(2-ethoxy-2-oxo-ethyl)-3-methyl-2H-benzofuran-3-carboxylic acid (140 mg, 0.53 mmol) in SOCl2(2 mL) was stirred at 80 °C for 2 hours. The solvent was removed under reduced pressure. The residue was redissolved in acetonitrile (2 mL) and (trimethylsilyl)diazomethane (1.06 mL, 2.12 mmol) was added at 0 °C. The mixture was stirred at room temperature overnight. Aqueous HBr (0.5 mL) was added and stirring at room temperature continued for another hour. Water (20 mL) was added, and the resulting mixture was extracted with EtOAc (20 mL x 2). The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 0-10% EtOAc in petroleum ether, to give ethyl 2-[3-(2- bromoacetyl)-3-methyl-2H-benzofuran-7-yl]acetate (150 mg, 83%) as an oil. MS (ESI): 341, 343 m / z (M+H)+. Ethyl 2-(3-(2-(2-fluoro-5-((6-fluoro-4-methyl-1H-indol-5-yl)oxy)phenyl)-1H-imidazol-5-yl)- 3-methyl-2,3-dihydrobenzofuran-7-yl)acetate

[0134] Step H: To a solution of 2-fluoro-5-[(6-fluoro-4-methyl-1H-indol-5- yl)oxy]benzamidine (Intermediate 1, 140 mg, 0.465 mmol) in DMF (2 mL) was added ethyl 2- [3-(2-bromoacetyl)-3-methyl-2H-benzofuran-7-yl]acetate (159 mg, 0.465 mmol) and NaHCO3(78 mg, 0.929 mmol). The mixture was stirred at room temperature for 1 hour and then heated at 80 °C overnight. Water (20 mL) was added, and the mixture was extracted with EtOAc (20 mL x 2). The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 0- 25% EtOAc in petroleum ether, to give ethyl 2-[3-[2-[2-fluoro-5-[(6-fluoro-4-methyl-1H- indol-5-yl)oxy]phenyl]-1H-imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]acetate (150 mg, 59%) as a solid. MS (ESI): 544 m / z (M+H)+. Ethyl (S)-2-(3-(2-(2-fluoro-5-((6-fluoro-4-methyl-1H-indol-5-yl)oxy)phenyl)-1H-imidazol-5- yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate and ethyl (R)-2-(3-(2-(2-fluoro-5-((6-fluoro- 4-methyl-1H-indol-5-yl)oxy)phenyl)-1H-imidazol-5-yl)-3-methyl-2,3-dihydrobenzofuran-7- yl)acetate

[0135] Step I: Ethyl 2-[3-[2-[2-fluoro-5-[(6-fluoro-4-methyl-1H-indol-5-yl)oxy]phenyl]-1H- imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]acetate (230 mg, 0.36 mmol) was separated into its constituent enantiomers by chiral-HPLC. Details on the chiral separation method are given below: Instrument: SFC-80 (Thar, Waters); Column: OJ 20 * 250 mm, 10 µm (Daicel); Column temperature: 35 ºC; Mobile phase: 55 / 45 CO2 / MeOH (0.2% Methanol Ammonia); Flow rate: 80 g / min; Back pressure: 100 bar, Detection wavelength: 214 nm, Cycle time: 4.0 min, Sample solution: 120 mg dissolved in 20 ml Methanol, Injection volume: 1.8 mL

[0136] The absolute configurations of both enantiomers were assigned arbitrarily. Thus, the faster eluting enantiomer was assigned as ethyl 2-[(3S)-3-[2-[2-fluoro-5-[(6-fluoro-4-methyl- 1H-indol-5-yl)oxy]phenyl]-1H-imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]acetate (60 mg, 40%) and the slower eluting enantiomer was assigned as ethyl 2-[(3R)-3-[2-[2-fluoro-5-[(6- fluoro-4-methyl-1H-indol-5-yl)oxy]phenyl]-1H-imidazol-5-yl]-3-methyl-2H-benzofuran-7- yl]acetate (60 mg, 40%). ethyl 2-[(3S)-3-[2-[2-fluoro-5-[(6-fluoro-4-methyl-1H-indol-5-yl)oxy]phenyl]-1H-imidazol- 5-yl]-3-methyl-2H-benzofuran-7-yl]acetate MS (ESI): 544 m / z (M+H)+. ethyl 2-[(3R)-3-[2-[2-fluoro-5-[(6-fluoro-4-methyl-1H-indol-5-yl)oxy]phenyl]-1H-imidazol- 5-yl]-3-methyl-2H-benzofuran-7-yl]acetate: MS (ESI): 544 m / z (M+H)+. (S)-2-(3-(2-(2-Fluoro-5-((6-fluoro-4-methyl-1H-indol-5-yl)oxy)phenyl)-1H-imidazol-5-yl)-3- methyl-2,3-dihydrobenzofuran-7-yl)acetic acid

[0137] Step J: To a mixture of ethyl 2-[(3S)-3-[2-[2-fluoro-5-[(6-fluoro-4-methyl-1H-indol-5- yl)oxy]phenyl]-1H-imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]acetate (60 mg, 0.11 mmol) in THF (1 mL) and MeOH (0.3 mL) was added 1N aqueous LiOH solution (0.3 mL). The mixture was stirred at room temperature for 5 hours and the pH was adjusted to ~6 with hydrochloric acid. The crude was purified by reverse-phase flash chromatography on C18 silica gel to give 2-[(3S)-3-[2-[2-fluoro-5-[(6-fluoro-4-methyl-1H-indol-5-yl)oxy]phenyl]-1H- imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]acetic acid (Example 5, 46.3 mg, 81%) as a solid. MS (ESI): 516 m / z (M+H)+.1H NMR (400 MHz, MeOH-d4) δ 7.40 (dd, J = 6.0, 3.2 Hz, 1H), 7.26 (d, J = 3.2 Hz, 1H), 7.16 (t, J = 9.2 Hz, 1H), 7.13 (d, J = 19.2 Hz, 1H), 7.10-7.07 (m, 2H), 6.91- 6.89 (m, 1H), 6.88-6.81 (m, 2H), 6.51 (dd, J = 3.2, 0.8 Hz, 1H), 4.70 (d, J = 8.8 Hz, 1H), 4.44 (d, J = 8.8 Hz, 1H), 3.60 (s, 2H), 2.38 (s, 3H), 1.70 (s, 3H) ppm. (R)-2-(3-(2-(2-Fluoro-5-((6-fluoro-4-methyl-1H-indol-5-yl)oxy)phenyl)-1H-imidazol-5-yl)-3- methyl-2,3-dihydrobenzofuran-7-yl)acetic acid

[0138] Step K: To a solution of ethyl 2-[(3R)-3-[2-[2-fluoro-5-[(6-fluoro-4-methyl-1H-indol- 5-yl)oxy]phenyl]-1H-imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]acetate (60 mg, 0.11 mmol) in THF (1 mL) and MeOH (0.3 mL) was added 1N LiOH aqueous solution (0.3 mL), and the mixture was stirred at room temperature for 5 hours. The pH of the mixture was adjusted to ~6 with hydrochloric acid, and the crude purified by reverse-phase flash chromatography to give 2-[(3R)-3-[2-[2-fluoro-5-[(6-fluoro-4-methyl-1H-indol-5- yl)oxy]phenyl]-1H-imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]acetic acid (Example 6, 45.7 mg, 80%) as a solid. MS (ESI): 516 m / z (M+H)+.1H NMR (400 MHz, MeOH-d4) δ 7.41 (dd, J = 6.0, 3.2 Hz, 1H), 7.26 (d, J = 3.2 Hz, 1H), 7.13 (t, J = 8.8 Hz, 1H), 7.11 (d, J = 9.2 Hz, 1H), 7.09-7.06 (m, 2H), 6.86 (t, J = 7.2 Hz, 1H), 6.83-6.76 (m, 1H), 6.80 (s, 1H), 6.50 (dd, J = 3.2, 0.8 Hz, 1H), 4.70 (d, J = 8.6 Hz, 1H), 4.41 (d, J = 8.6 Hz, 1H), 3.58 (s, 2H), 2.38 (s, 3H), 1.69 (s, 3H) ppm. Example 7. Synthesis of (R)-2-(3-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-5-yl)chroman-8-yl)acetic acid Example 8. Synthesis of (S)-2-(3-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-5-yl)chroman-8-yl)acetic acid Benzyl 8-bromochromane-3-carboxylate

[0139] Step A: To a solution of 8-bromochromane-3-carboxylic acid (1.12 g, 4.27 mmol) in DMF (20 mL) was added K2CO3(1.18 g, 8.54 mmol) and benzyl bromide (0.949 g, 5.55 mmol). The mixture was stirred at room temperature for 3 hours. Water (100 mL) was added, and the mixture was extracted with EtOAc (50 mL x 2). The organic phase was washed with saturated aqueous LiCl, brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel flash column chromatography, eluting with 0-10% EtOAc in petroleum ether, to give benzyl 8-bromochromane-3-carboxylate (1.2 g, 76%) as a light-yellow solid. MS (ESI): 369, 371 m / z (M+Na)+. Benzyl 8-(2-ethoxy-2-oxoethyl)chromane-3-carboxylate

[0140] Step B: To a solution of benzyl 8-bromochromane-3-carboxylate (1.2 g, 3.28 mmol) in mesitylene (20 mL) was added ethyl potassium malonate (0.838 g, 4.93 mmol), allylpalladium chloride dimer (240 mg, 0.066 mmol), BINAP (123 mg, 0.197 mmol) and DMAP (40.1 mg, 0.328 mmol). The mixture was degassed with N2 and then heated with stirring at 160 °C for 4 hours and then cooled to room temperature. Water (50 mL) was added, and the mixture was extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 0-10% EtOAc in petroleum ether, to give benzyl 8-(2-ethoxy-2- oxo-ethyl)chromane-3-carboxylate (300 mg, 25%) as a light-yellow solid. MS (ESI): 355 m / z (M+H)+. 8-(2-Ethoxy-2-oxoethyl)chromane-3-carboxylic acid

[0141] Step C: To a solution of benzyl 8-(2-ethoxy-2-oxoethyl)chromane-3-carboxylate (200 mg, 0.564 mmol) in THF (5 mL) was added Pd(OH)2on activated carbon (20 wt. %, 40 mg). The flask was evacuated and backfilled with H2. The mixture was stirred at room temperature overnight, filtered, and concentrated in vacuo to give 8-(2-ethoxy-2-oxoethyl)chromane-3- carboxylic acid (130 mg, 87%) as a solid. MS (ESI): 265 m / z (M+H)+. Ethyl 2-(3-(2-bromoacetyl)chroman-8-yl)acetate

[0142] Step D: A solution of 8-(2-ethoxy-2-oxo-ethyl)chromane-3-carboxylic acid (206 mg, 0.725 mmol) in 5 mL of SOCl2was stirred at 70 °C for 1 hour. After cooling to room temperature, the solvent was evaporated under high vacuum. The residue was dissolved in 2 mL of acetonitrile and cooled to 0 °C. Trimethylsilyldiazomethane (331 mg, 2.9 mmol) was added dropwise, and the solution was slowly allowed to warm to room temperature and stirred overnight. The reaction mixture was cooled to 0 °C. Hydrobromic acid solution (48% in AcOH, 489 mg, 2.9 mmol) was added dropwise and the mixture was stirred for 20 minutes until gas evolution ceased. Water was added and the mixture was extracted with EtOAc (20 ml x 3). The combined organic phases were washed with NaHCO3, brine, dried over Na2SO4, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 10:1 petroleum ether:EtOAc to get ethyl 2-[3-(2-bromoacetyl)chroman-8-yl]acetate (150 mg, 60%). MS (ESI): 341, 343 m / z (M+H)+. Ethyl 2-(3-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-5- yl)chroman-8-yl)acetate

[0143] Step E: To a solution of 5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorobenzimidamide (Intermediate 2, 161 mg, 0.496 mmol) in DMF (5 mL) was added ethyl 2-[3-(2- bromoacetyl)chroman-8-yl]acetate (180 mg, 0.496 mmol) and NaHCO3(83.3 mg, 0.992mmol). The mixture was stirred at 75 °C for 5 hours. The reaction was cooled to room temperature and extracted with EtOAc (20 mL x 3). The organic phase was washed with saturated aqueous LiCl, brine, dried over Na2SO4. The solids were filtered off and the solvent was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica, eluting with 3:1 petroleum ether:EtOAc, to afford the desired product, ethyl 2-(3-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H- imidazol-5-yl)chroman-8-yl)acetate (120 mg, 41%). MS (ESI): 548 m / z (M+H)+. Ethyl (R)-2-(3-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-5- yl)chroman-8-yl)acetate and ethyl (S)-2-(3-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-5-yl)chroman-8-yl)acetate

[0144] Step F: Ethyl 2-[3-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-5-yl]chroman-8-yl]acetate (120 mg, 0.206 mmol) was separated into its constituent enantiomers by chiral HPLC under the following conditions: Column : AD-H (4.6 * 100 * 5 µm) Temperature: 39.9 °C. Co-Solvent: 0.2% ammonia in methanol. CO2Flow Rate: 2.8; Co-Solvent %: 30; Co-Solvent Flow Rate: 1.2; Total Flow: 4. Front Pressure: 152; Back Pressure: 152; Pressure Drop: 30. PDA Start Wavelength: 214 ; PDA Stop Wavelength: 359

[0145] The absolute configurations of both enantiomers were arbitrarily assigned as follows. The configuration of the faster eluting component was assigned as ethyl (R)-2-(3-(2-(5-((4,6- difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-5-yl)chroman-8-yl)acetate (28 mg, a white solid), and that of the slower eluting component (23 mg, a white solid) was assigned as ethyl (S)-2-(3-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-5- yl)chroman-8-yl)acetate. Ethyl (R)-2-(3-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-5- yl)chroman-8-yl)acetate, MS (ESI): 548 m / z (M+H)+. Ethyl (S)-2-(3-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-5- yl)chroman-8-yl)acetate, MS (ESI): 548 m / z (M+H)+. (R)-2-(3-(2-(5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-5-yl)chroman- 8-yl)acetic acid

[0146] Step G: To a solution of ethyl 2-[(3R)-3-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2- fluoro-phenyl]-1H-imidazol-5-yl]chroman-8-yl]acetate (28 mg, 0.051 mmol) in MeOH (0.5 mL) and THF (0.5 mL) was added a solution of LiOH (4.25 mg, 0.101 mmol) in water (0.3 mL) and the reaction was stirred for 8 hours at room temperature. The solvent was removed under reduced pressure, water (2 mL) was added, and the pH was adjusted to ~5 with 1N hydrochloric acid. The precipitate was collected and dried to afford 2-[(3R)-3-[2-[5-[(4,6- difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-5-yl]chroman-8-yl]acetic acid (Example 7, 11 mg, a white solid, 41%). MS (ESI): 520 m / z (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 12.12 (br s, 1H), 11.64 (s, 1H), 7.48-7.44 (m, 2H), 7.37-7.31 (m, 2H), 7.10 (s, 1H), 7.04-6.99 (m, 3H), 6.83-6.75 (m, 1H), 6.57 (s, 1H), 4.40-4.38 (m, 1H), 4.00 (t, J = 10 Hz, 1H), 3.51 (s, 2H), 3.20-3.10 (m, 1H), 3.10-2.88 (m, 2H) ppm. (S)-2-(3-(2-(5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-5-yl)chroman- 8-yl)acetic acid

[0147] Step H: To a solution of ethyl 2-[(3S)-3-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2- fluoro-phenyl]-1H-imidazol-5-yl]chroman-8-yl]acetate (23 mg, 0.042 mmol) in MeOH (0.5 mL) and THF (0.5 mL) was added a solution of LiOH (4.25 mg, 0.101mmol) in water (0.3 mL) and stirring continued for 8 hours at room temperature. The solvent was removed under reduced pressure, water (2 mL) was added, and the pH was adjusted to ~5 with 1N hydrochloric acid. The precipitate was collected and dried to give 2-[(3R)-3-[2-[5-[(4,6-difluoro-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1H-imidazol-5-yl]chroman-8-yl]acetic acid (Example 8, 11 mg, a white solid, 50%). MS (ESI): 520 m / z (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 12.12 (br s, 1H), 11.64 (s, 1H), 7.48-7.44 (m, 2H), 7.37-7.31 (m, 2H), 7.10 (s, 1H), 7.04-6.99 (m, 3H), 6.83-6.75 (m, 1H), 6.57 (s, 1H), 4.40-4.38 (m, 1H), 4.00 (t, J = 10 Hz, 1H), 3.51 (s, 2H), 3.20- 3.10 (m, 1H), 3.10-2.88 (m, 2H) ppm. Example 9. Synthesis of(S)-2-(3-(2-(5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-5-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid Example 10. Synthesis of (R)-2-(3-(2-(5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-5-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid

[0148] Step A: To a solution of 5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-benzamidine (Intermediate 2, 220 mg, 0.721 mmol) in DMF (2 mL) was added ethyl 2-[3-(2-bromoacetyl)- 3-methyl-2H-benzofuran-7-yl]acetate (Step G, Example 5, 246 mg, 0.721 mmol) and NaHCO3(121 mg, 1.44 mmol). The mixture was stirred at room temperature for 1 hour and then heated at 80°C overnight. After cooling to room temperature, water (20 mL) was added and the mixture was extracted with EtOAc (20 mL x 2). The organic phase was washed with brine, dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 0-25% EtOAc in petroleum ether, to give ethyl 2-[3-[2-[5-[(4,6- difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-5-yl]-3-methyl-2H-benzofuran-7- yl]acetate (200 mg, 50.7%) as a solid. MS (ESI): 548 m / z (M+H)+. Ethyl (S)-2-(3-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-5-yl)-3- methyl-2,3-dihydrobenzofuran-7-yl)acetate and ethyl (R)-2-(3-(2-(5-((4,6-difluoro-1H-indol- 5-yl)oxy)-2-fluorophenyl)-1H-imidazol-5-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate

[0149] Step B: Ethyl 2-[3-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]acetate (200 mg, 0.36 mmol) was separated into its constituent enantiomers by chiral-HPLC under the following conditions: Instrument: SFC-80 (Thar, Waters) Column: OJ 20*250mm, 10 um (Daicel) Column temperature: 35 ºC Mobile phase: 55 / 45 CO2 / 0.2% Ammonia in Methanol Flow rate: 80 g / min; Back pressure: 100 bar Detection wavelength: 214 nm Cycle time: 5.3 minutes Sample solution: 200 mg dissolved in 20 ml methanol; Injection volume: 2 mL

[0150] The absolute configurations of both enantiomers were arbitrarily assigned as follows. The configuration of the faster eluting component was assigned as ethyl 2-[(3S)-3-[2-[5-[(4,6- difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-5-yl]-3-methyl-2H-benzofuran-7- yl]acetate (80 mg, 40%), and that of the slower eluting component as ethyl 2-[(3R)-3-[2-[5- [(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-5-yl]-3-methyl-2H- benzofuran-7-yl]acetate (80 mg, 40%). Ethyl 2-[(3S)-3-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-5-yl]- 3-methyl-2H-benzofuran-7-yl]acetate: MS (ESI): 548 m / z (M+H)+. ethyl 2-[(3R)-3-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-5-yl]- 3-methyl-2H-benzofuran-7-yl]acetate: MS (ESI): 548 m / z (M+H)+. (S)-2-(3-(2-(5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-5-yl)-3- methyl-2,3-dihydrobenzofuran-7-yl)acetic acid

[0151] Step C: To a mixture of ethyl 2-[(3S)-3-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2- fluoro-phenyl]-1H-imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]acetate (80 mg, 0.146 mmol) in THF (1.5 mL) and MeOH (0.5 mL) was added 1N aqueous LiOH solution (0.5 mL). The mixture was stirred at room temperature for 5 hours, the pH was adjusted to ~6 with 1N hydrochloric acid, and the crude solution purified by reverse-phase flash column chromatography on C18 silica gel to give 2-[(3S)-3-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]- 2-fluoro-phenyl]-1H-imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]acetic acid (Example 9, 65.4 mg, 86%) as a solid. MS (ESI): 520 m / z (M+H)+.1H NMR (400 MHz, CD3OD) δ 7.48 (dd, J = 5.6 Hz, 3.4 Hz, 1H), 7.29 (d, J = 3.2 Hz, 1H), 7.20 (t, J = 9.6 Hz, 1H), 7.13 (d, J = 10.4 Hz, 1H), 7.08 (d, J = 7.6 Hz, 2H), 6.97 (dt, J = 9.0 Hz, 3.6 Hz, 1H), 6.91 (s, 1H), 6.87 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 3.2 Hz, 1H), 4.69 (d, J = 8.6 Hz, 1H), 4.43 (d, J = 8.6 Hz, 1H), 3.60 (s, 2H), 1.70 (s, 3H) ppm. (R)-2-(3-(2-(5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-5-yl)-3- methyl-2,3-dihydrobenzofuran-7-yl)acetic acid

[0152] Step D: To a mixture of ethyl 2-[(3R)-3-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2- fluoro-phenyl]-1H-imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]acetate (80 mg, 0.146 mmol) in THF (1.5 mL) and MeOH (0.5 mL) was added 1N aqueous LiOH solution (0.5 mL). The mixture was stirred at room temperature for 5 hours, the pH was adjusted to ~6 with 1N hydrochloric acid, and the crude solution purified by reverse-phase flash column chromatography on C18 silica gel to give 2-[(3R)-3-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]- 2-fluoro-phenyl]-1H-imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]acetic acid (Example 10, 64.3 mg, 84.7%) as a solid. MS (ESI): 520 m / z (M+H)+.1H NMR (400 MHz, CD3OD) δ 7.48 (dd, J = 5.6 Hz, 3.2 Hz, 1H), 7.29 (d, J = 3.0 Hz, 1H), 7.20 (t, J = 9.8 Hz, 1H), 7.13 (d, J = 10.0 Hz, 1H), 7.08 (d, J = 7.6 Hz, 2H), 6.97 (dt, J = 9.0 Hz, 3.6 Hz, 1H), 6.90 (s, 1H), 6.87 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 3.2 Hz, 1H), 4.69 (d, J = 8.6 Hz, 1H), 4.43 (d, J = 8.6 Hz, 1H), 3.59 (s, 2H), 1.70 (s, 3H) ppm. Example 11. Synthesis of (R)-2-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-4-yl)chroman-8-yl)acetic acid Example 12. (S)-2-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H- imidazol-4-yl)chroman-8-yl)acetic acid 3-(2-Bromophenoxy)propanoic acid

[0153] Step A: To the mixture of 2-bromophenol (17.3 g, 0.1 mol) in water (50 mL) was added NaOH (8 g, 0.2 mol) and 3-bromopropanoic acid (15.3 g, 0.1 mol). The reaction mixture was refluxed overnight. The reaction solution was diluted with H2O (50 mL) and washed with EtOAc (30 mL x 2). The aqueous layer was acidified to pH = 1~2 and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 3-(2-bromophenoxy)propanoic acid (10 g, 41%). MS (ESI): 269, 271 m / z (M+Na)+. 8-Bromochroman-4-one

[0154] Step B: A mixture of 3-(2-bromophenoxy)propanoic acid (9.5 g, 0.04 mol) and polyphosphoric acid (24 mL) was stirred at 100 °C for 2 hours. The reaction mixture was quenched with water (50 mL), extracted with EtOAc (50 mL x 3). The organic extracts were dried over Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography to afford 8-bromochroman-4-one (6.5 g, 74%). MS (ESI): 227, 229 m / z (M+H)+. 8-Bromochromane-4-carboxylic acid

[0155] Step C: To a solution of 8-bromochroman-4-one (6.6 g, 29.1 mmol) in DCM (10 mL) was added trimethylsilylcyanide (4.33 g, 43.6 mmol) and zinc iodide (1.86 g, 5.81 mmol). The reaction mixture was stirred at room temperature overnight, then concentrated under reduced pressure. The residue was dissolved in concentrated aqueous HCl (40 mL) and AcOH (40 mL). To the reaction mixture was added tin (II) chloride (18.7 g, 98.7 mmol), and the mixture was stirred at 90 °C overnight. After cooling to room temperature, water (80 mL) was added, the pH was adjusted to ~3 with 1N aqueous HCl, and the resulting mixture was extracted with EtOAc (50 mL x 4). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel to afford 8- bromochromane-4-carboxylic acid (3.5 g, 49%).1H NMR (400 MHz, DMSO-d6) δ 12.78 (s, 1H), 7.44 (dd, J = 7.6, 1.2 Hz, 1H), 7.22 (d, J = 7.2 Hz, 1H), 6.81 (t, J = 7.8 Hz, 1H), 4.36-4.29 (m, 1H), 4.19 (td, J = 10.4, 3.2 Hz, 1H), 3.82 (t, J = 5.4 Hz, 1H), 2.24-2.15 (m, 1H), 2.12-2.01 (m, 1H) ppm. Benzyl 8-bromochromane-4-carboxylate

[0156] Step D: To a solution of 8-bromochromane-4-carboxylic acid (7.8 g, 30.3 mmol) in acetone (40 mL) was added bromomethyl benzene (6.23 g, 36.4 mmol) and K2CO3(6.29 g, 45.5 mmol). The reaction mixture was stirred at 70 °C overnight. The reaction mixture was concentrated, and the residue was purified by column chromatography on silica gel to afford benzyl 8-bromochromane-4-carboxylate (10 g, 95%).1H NMR (400 MHz, CDCl3) δ 7.43 (dd, J = 8.0, 1.6 Hz, 1H), 7.40-7.28 (m, 5H), 7.22-7.16 (m, 1H), 6.74 (t, J = 7.6 Hz, 1H), 5.17 (d, J = 4.4 Hz, 2H), 4.42-4.31(m, 1H), 3.89-3.81 (m, 1H), 2.40-2.31 (m, 1H), 2.19-2.08 (m, 1H) ppm. Benzyl 8-(2-ethoxy-2-oxoethyl)chromane-4-carboxylate

[0157] Step E: To a solution of benzyl 8-bromochromane-4-carboxylate (3.0 g, 8.6 mmol) in mesitylene (15 mL) was added (3-ethoxy-3-oxo-propanoyl)oxypotassium (2.21 g, 13 mmol), allylpalladium chloride dimer (63.2 mg, 0.17 mmol), BINAP (0.323 g, 0.518 mmol) and 4- dimethylaminopyridine (0.106 g, 0.86 mmol). The reaction mixture was stirred at 140 °C. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (100 mL), washed with water (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with 0-50% EtOAc in petroleum ether, to afford benzyl 8-(2-ethoxy-2-oxo-ethyl)chromane-4-carboxylate (1.2 g, 39%). MS (ESI): 355 m / z (M+H)+. 8-(2-Ethoxy-2-oxoethyl)chromane-4-carboxylic acid

[0158] Step F: To a solution of benzyl 8-(2-ethoxy-2-oxo-ethyl)chromane-4-carboxylate (1.2 g, 3.39 mmol) in EtOH (10 mL) was added Pd / C (0.6 g, 10 wt.%). The reaction mixture was degassed under vacuum and purged with H2and stirred at room temperature for 2 hours. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography to afford 8-(2-ethoxy-2-oxo-ethyl) chromane-4-carboxylic acid (0.8 g, 89%). MS (ESI): 265 m / z (M+H)+. Ethyl 2-(4-(2-bromoacetyl)chroman-8-yl)acetate

[0159] Step G: A mixture of 8-(2-ethoxy-2-oxo-ethyl)chromane-4-carboxylic acid (0.4 g, 1.51 mmol) and SOCl2(10 mL) was stirred at 80 °C for 2 hours. The reaction mixture was concentrated to remove most of the SOCl2. The reaction mixture was dissolved in acetonitrile (10 mL) and concentrated, and this process was repeated once more. The residue was dissolved in acetonitrile (10 mL) and trimethylsilyldiazomethane (2M in hexane, 3.03 mL, 6.05 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature overnight, cooled to 0 °C, and 40% HBr in water (0.88 mL, 6.05 mmol) was added. The reaction mixture was stirred at room temperature for 0.5 hours, quenched with water (30 mL), extracted with EtOAc (40 mL x 3). The combined organic extracts were dried over Na2SO4, filtered, and concentrated. The residue was purified by column chromatography on silica gel, eluting with 0-30% ethyl acetate in petroleum ether, to afford ethyl 2-[4-(2-bromoacetyl)chroman-8-yl]acetate (0.31 g, 60%). MS (ESI): 341, 343 m / z (M+H)+. Ethyl 2-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4- yl)chroman-8-yl)acetate

[0160] Step H: To the solution of ethyl 2-[4-(2-bromoacetyl)chroman-8-yl]acetate (310 mg, 0.91 mmol) in DMF (5 mL) was added 5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro- benzamidine (291 mg, 0.95 mmol) and NaHCO3(153 mg, 1.82 mmol). The reaction was stirred at 80 °C overnight. Water (15 mL) was added, the reaction mixture extracted with EtOAc (30 mL x 3). The combined organic extract was washed with water (10 mL x 2), brine (10 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to afford ethyl 2-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)- 1H-imidazol-4-yl)chroman-8-yl)acetate (130 mg, 26%) as a yellow foam. Ethyl (S)-2-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4- yl)chroman-8-yl)acetate and ethyl (R)-2-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-4-yl)chroman-8-yl)acetate

[0161] Step I: The yellow foam isolated in the previous step was separated by SFC to afford its constituent enantiomers. The absolute configuration of the faster eluting enantiomer was arbitrarily assigned as ethyl (S)-2-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)- 1H-imidazol-4-yl)chroman-8-yl)acetate (47 mg, 9.5%, 100% ee), while the absolute configuration of the slower eluting enantiomer was assigned as ethyl (R)-2-(4-(2-(5-((4,6- difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)chroman-8-yl)acetate (50 mg, yield: 10.1%, 98% ee). MS (ESI): 548 m / z (M+H)+observed for both enantiomers. SFC separation conditions: Column: OJ 20 * 250mm, 10 µm (Daicel) Column temperature: 35 ºC Mobile phase: 70 / 30 CO2 / 0.2% ammonia in methanol Flow rate: 80 g / min; Back pressure: 100 bar Detection wavelength: 214 nm; Cycle time: 6.5 min Sample solution: 130 mg dissolved in 27 ml methanol; Injection volume: 1.0 ml. (S)-2-(4-(2-(5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)chroman- 8-yl)acetic acid

[0162] Step J: To a solution of ethyl 2-[(4S)-4-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2- fluoro-phenyl] -1H-imidazol-4-yl]chroman-8-yl]acetate (47 mg, 0.09 mmol) in THF (3 mL) and MeOH (1 mL) was added 1M aqueous LiOH (1 mL). The reaction was stirred at room temperature overnight. Water (15 mL) was added, the pH adjusted to ~2 with 1N aqueous HCl, and the resulting mixture extracted with EtOAc (30 mL x 3). The organic extract was washed with brine, dried over Na2SO4, filtered, and concentrated to afford 2-[(4S)-4-[2-[5-[(4,6- difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]chroman-8-yl]acetic acid (Example 11, 36.6 mg, 82%) MS (ESI): 520 m / z (M+H)+.1H NMR (400 MHz, CD3OD) δ 7.52 (dd, J = 6.0, 3.2 Hz, 1H), 7.32 (d, J = 3.2 Hz, 1H), 7.23 (dd, J = 9.2, 1.2 Hz, 1H), 7.16 (d, J = 10.0 Hz, 1H), 7.06 (dd, J = 7.2, 1.2 Hz, 1H), 7.03-6.98 (m, 2H), 6.79 (t, J = 7.6 Hz, 1H), 6.66 (s, 1H), 6.57 (dd, J = 3.2, 0.8 Hz, 1H), 4.26-4.21 (m, 2H), 4.14-4.09 (m, 1H), 3.59 (d, J = 1.2 Hz, 2H), 2.26-2.21 (m, 2H) ppm. (R)-2-(4-(2-(5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)chroman- 8-yl)acetic acid

[0163] Step K: To a solution of ethyl 2-[(4R)-4-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2- fluoro-phenyl] -1H-imidazol-4-yl]chroman-8-yl]acetate (50 mg, 0.09 mmol) in THF(3 mL) and MeOH (1 mL) was added 1M aqueous LiOH (1 mL). The reaction was stirred at room temperature overnight. Water (15 mL) was added, the pH adjusted to ~2 with 1N aqueous HCl, and the resulting mixture extracted with EtOAc (30 mL x 3). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and concentrated to afford 2-[(4R)-4-[2- [5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]chroman-8-yl]acetic acid (Example 12, 36.7 mg, 82%). MS (ESI): 520 m / z (M+H)+.1H NMR (400 MHz, CD3OD) δ 7.52 (dd, J = 6.0, 3.2 Hz, 1H), 7.32 (d, J = 3.6 Hz, 1H), 7.22 (dd, J = 9.2, 1.6 Hz, 1H), 7.16 (d, J = 10.0 Hz, 1H), 7.06 (dd, J = 7.2, 1.2 Hz, 1H), 7.03–7.00 (m, 2H), 6.79 (t, J = 7.6 Hz, 1H), 6.64 (s, 1H), 6.57 (dd, J = 3.2, 0.4 Hz, 1H), 4.26–4.21 (m, 2H), 4.14–4.09 (m, 1H), 3.59 (d, J = 1.2 Hz, 2H), 2.26-2.20 (m, 2H) ppm. Example 13. Synthesis of (S)-2-(3-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)oxazol-4-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid Example 14. (R)-2-(3-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)oxazol-4- yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid 2-(7-(2-Ethoxy-2-oxoethyl)-3-methyl-2,3-dihydrobenzofuran-3-yl)-2-oxoethyl 5-((4,6- difluoro-1H-indol-5-yl)oxy)-2-fluorobenzoate

[0164] Step A: A solution of ethyl 2-[3-(2-bromoacetyl)-3-methyl-2H-benzofuran-7-yl]acetate (1.1 g, 3.22 mmol), 5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-benzoic acid (Intermediate 3, 1.09 g, 3.55 mmol) and NaHCO3(0.677 g, 8.06 mmol) in DMF (10 mL) was stirred at room temperature for 3 hours. The mixture was poured into water, extracted with EtOAc (30 mL x 2). The combined organic extracts were dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 30- 80% EtOAc in petroleum ether, to give the product, [2-[7-(2-ethoxy-2-oxo-ethyl)-3-methyl- 2H-benzofuran-3-yl]-2-oxo-ethyl] 5-[(4,6-difluoro-1H-indol -5-yl)oxy]-2-fluoro-benzoate (1.2 g, 65.6%) as a yellow oil. MS (ESI): 568.2 m / z (M+H)+. Ethyl (S)-2-(3-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)oxazol-4-yl)-3-methyl- 2,3-dihydrobenzofuran-7-yl)acetate and ethyl (R)-2-(3-(2-(5-((4,6-difluoro-1H-indol-5- yl)oxy)-2-fluorophenyl)oxazol-4-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate

[0165] Step B: A solution of [2-[7-(2-ethoxy-2-oxo-ethyl)-3-methyl-2H-benzofuran-3-yl]-2- oxo-ethyl] 5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-benzoate (0.7 g, 1.23 mmol) and ammonium acetate (1.90 g, 24.7 mmol) in acetic acid (10 mL) was heated at 110 °C for 6 hours, and then cooled to room temperature. The solvent was removed in vacuo. The residue was poured into water, extracted with EtOAc (50 mL x 2). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with 30-80% EtOAc in petroleum ether, to give the crude product. The crude was further separated by chiral HPLC (SFC) to give two enantiomers. The absolute configurations of both enantiomers were arbitrarily assigned as follows. The absolute configuration of the faster eluting enantiomer was assigned as ethyl 2-[(3S)-3-[2-[5-[(4,6- difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl] oxazol-4-yl]-3-methyl-2H-benzofuran-7- yl]acetate (0.105 g, 15.5%, a white solid), and that of the slower eluting enantiomer was assigned as ethyl 2-[(3R)-3-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]oxazol- 4-yl]-3-methyl-2H-benzofuran-7-yl]acetate (0.1 g, 14.8%, a white solid). MS (ESI): 549.2 m / z (M+H)+, found for both enantiomers. Chiral resolution condition: Instrument: SFC-80 (Thar, Waters) Column: AD 20 * 250mm, 10 µm (Daicel); Column temperature: 35 ºC Mobile phase: 30 / 70 CO2 / methanol (0.2% ammonia in methanol) Flow rate: 80 g / min; Back pressure: 100 bar; Cycle time: 8.4 min Detection wavelength: 214 nm Sample solution: 2000 mg dissolved in 35 ml methanol; Injection volume: 3 ml (S)-2-(3-(2-(5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)oxazol-4-yl)-3-methyl-2,3- dihydrobenzofuran-7-yl)acetic acid

[0166] Step C: A solution of 2-[(3S)-3-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro- phenyl]oxazol -4-yl]-3-methyl-2H-benzofuran-7-yl]acetic acid (0.105 g, 0.191 mmol) and LiOH.H2O (80.3 mg, 1.91 mmol) in THF (4 mL), MeOH (4 mL) and H2O (2 mL) was stirred at room temperature for 4 hours. The solvent was removed in vacuo. The residue was acidified with 1M aqueous HCl to pH 5~6, extracted with ethyl acetate (20 mL x 2). The combined organic extracts were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to give the product, 2-[(3S)- 3-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]- 2-fluoro-phenyl]oxazol-4-yl]-3-methyl-2H- benzofuran-7-yl]acetic acid (52.3 mg, 53%) as white solid. MS (ESI): 521.2 m / z (M+H)+.1H NMR (400 MHz, CD3OD) δ 7.61 (s, 1H), 7.48 (dd, J = 5.6, 3.2 Hz,1H), 7.33-7.32 (d, J = 3.2 Hz, 1H), 7.24 (t, J = 9.6 Hz,1H), 7.18-7.08 (m, 4H), 6.86 (t, J = 9.6 Hz, 1H), 6.57 (d, J = 3.2 Hz, 1H), 4.75 (d, J = 8.4 Hz, 1H), 4.42 (d, J = 8.8 Hz , 1H), 3.54 (d, J = 2.4 Hz, 2H), 1.70 (s, 3H) ppm. (R)-2-(3-(2-(5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)oxazol-4-yl)-3-methyl-2,3- dihydrobenzofuran-7-yl)acetic acid

[0167] Step D: A solution of 2-[(3R)-3-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro- phenyl]oxazol-4-yl]-3-methyl-2H-benzofuran-7-yl]acetic acid (0.10 g, 0.18 mmol) and LiOH. H2O (76.5 mg, 1.82 mmol) in THF (3 mL), MeOH (3 mL) and H2O (2 mL) was stirred at room temperature for 4 hours. The solvent was removed in vacuo. The residue was acidified with 1M aqueous HCl to pH 5~6, extracted with ethyl acetate (20 mL x 2). The combined organic extracts were washed with brine (10 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to give the product, 2-[(3R)- 3-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]oxazol-4-yl]-3-methyl-2H- benzofuran-7-yl]acetic acid (34.8 mg, 36.7%) as white solid. MS (ESI): 521.2 m / z (M+H)+.1H NMR (400 MHz, CD3OD) δ 7.61 (s, 1H), 7.48 (dd, J = 5.2, 3.2 Hz ,1H), 7.32 (d, J = 3.2 Hz, 1H), 7.24 (t, J = 9.6 Hz, 1H), 7.18-7.08 (m, 4H), 6.86 (t, J = 9.2 Hz,1H), 6.58 (d, J = 3.2 Hz, 1H), 4.75 (d, J = 8.8 Hz, 1H), 4.42 (d , J = 8.8 Hz, 1H), 3.54 (d, J = 2.8 Hz, 2H), 1.70 (s,3H) ppm. Example 15. Synthesis of 2-(3-(2-(2-fluoro-5-((6-fluoro-4-((methylsulfonyl)methyl)-1H- indol-5-yl)oxy)phenyl)oxazol-4-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid 2-(7-(2-Ethoxy-2-oxoethyl)-3-methyl-2,3-dihydrobenzofuran-3-yl)-2-oxoethyl 2-fluoro-5-((6- fluoro-4-((methylsulfonyl)methyl)-1H-indol-5-yl)oxy)benzoate

[0168] Step A: To a solution of ethyl 2-(3-(2-bromoacetyl)-3-methyl-2,3-dihydrobenzofuran- 7-yl)acetate (Step G, Example 5; 770 mg) in N,N-dimethylformamide (20 mL) were added 2- fluoro-5-((6-fluoro-4-((methylsulfonyl)methyl)-1H-indol-5-yl)oxy)benzoic acid (946 mg) and sodium hydrogen carbonate (450 mg). The reaction was stirred at room temperature for 3 hours. The mixture was diluted with water (30 mL) and extracted with ethyl acetate (20 mL x 2). The combined extracts were washed with lithium chloride solution (30 mL x 2), brine (30 mL x 2), dried over sodium sulfate, filtered, and concentrated to give 2-(7-(2-ethoxy-2-oxoethyl)-3- methyl-2,3-dihydrobenzofuran -3-yl)-2-oxoethyl 2-fluoro-5-((6-fluoro-4- ((methylsulfonyl)methyl)-1H-indol-5-yl)oxy)benzoate (1.453 g, 91%) as a brown solid, which was used in the next step without further purification. MS (ESI): 642 m / z (M+H)+. Ethyl 2-(3-(2-(2-fluoro-5-((6-fluoro-4-((methylsulfonyl)methyl)-1H-indol-5- yl)oxy)phenyl)oxazol-4-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate

[0169] Step B: To a solution of 2-(7-(2-ethoxy-2-oxoethyl)-3-methyl-2,3-dihydrobenzofuran- 3-yl)-2-oxoethyl 2-fluoro-5-((6-fluoro-4-((methylsulfonyl)methyl)-1H-indol-5- yl)oxy)benzoate (1.045 g, 86%, 1.4 mmol) in acetic acid (26 mL) was added ammonium acetate (2.16 g, 28 mmol). The reaction was stirred at 100 °C for 24 hours. The solvent was removed in vacuo, the residue was suspended in water (30 mL) and extracted with ethyl acetate (20 mL x 2). The organic phase was washed with saturated aqueous NaHCO3solution (30 mL x 3), brine (30 mL x 2), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 35% ethyl acetate in petroleum ether, to give ethyl 2-(3-(2-(2-fluoro-5-((6-fluoro-4-((methylsulfonyl)methyl)-1H-indol-5- yl)oxy)phenyl)oxazol-4-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate (340 mg, 37%) as a white solid. MS (ESI): 623 m / z (M+H)+. 2-(3-(2-(2-Fluoro-5-((6-fluoro-4-((methylsulfonyl)methyl)-1H-indol-5-yl)oxy)phenyl)oxazol- 4-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid

[0170] Step C: To a solution of lithium hydroxide hydrate (88 mg) in water (2mL), methanol (2 mL) and tetrahydrofuran (6 mL) was added ethyl 2-(3-(2-(2-fluoro-5-((6-fluoro-4- ((methylsulfonyl)methyl)-1H-indol-5-yl)oxy)phenyl)oxazol-4-yl)-3-methyl-2,3- dihydrobenzofuran-7-yl)acetate (280 mg). The reaction was stirred at room temperature for 1.5 hours. The mixture was diluted with water, and the volatile organics were removed under reduced pressure. The pH of the aqueous phase was adjusted to 3-4 with 1 M hydrochloric acid. The precipitate was isolated by filtration and washed with water, then purified by prep-HPLC to afford 2-(3-(2-(2-fluoro-5-((6-fluoro-4-((methylsulfonyl)methyl)-1H-indol-5- yl)oxy)phenyl)oxazol-4-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid (164 mg, 65%) as a white solid. MS (ESI): 595 m / z (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 11.44 (s, 1H), 8.04 (s, 1H), 7.48 (t, J = 2.8 Hz, 1H), 7.46 (d, J = 11.2 Hz, 1H), 7.40 (dd, J = 6.0, 3.2 Hz, 1H), 7.33 (t, J = 9.6 Hz, 1H), 7.04-7.09 (m, 2H), 7.02 (dt, J = 9.2, 3.6 Hz, 1H), 6.82 (t, J = 7.6 Hz, 1H), 6.72 (br, 1H), 4.74 (d, J = 8.8 Hz, 1H), 4.69 (s, 2H), 4.43 (d, J = 8.8 Hz, 1H), 3.47 (s, 2H), 2.99 (s, 3H), 1.61 (s, 3H) ppm. Example 16. Synthesis of 2-(3-(1-(2-fluoro-5-((6-fluoro-4-(methylsulfonyl)-1H-indol-5- yl)oxy)phenyl)-1H-pyrazol-3-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid 7-Bromo-N-methoxy-N,3-dimethyl-2,3-dihydrobenzofuran-3-carboxamide

[0171] Step A: To a solution of 7-bromo-3-methyl-2,3-dihydrobenzofuran-3-carboxylic acid (Step C, Example 5; 34.5 mmol, 8.8 g) in THF (100 mL) was added triethylamine (103 mmol, 10.5 g), N-methoxymethanamine hydrochloride (51.7 mmol, 5.05 g) and HATU (41.4 mmol, 15.7 g), and the mixture was stirred overnight at room temperature under an N2 atmosphere.80 mL water was added, and the mixture extracted with EtOAc (80 mL x 3). The combined organic phase was concentrated and purified by flash column chromatography on silica gel, eluting with 0-15% EtOAc in petroleum ether, to give 7-bromo-N-methoxy-N,3-dimethyl-2,3- dihydrobenzofuran-3-carboxamide (8.5 g, 61%) as a yellow oil. MS (ESI): 300.1, 302.1 m / z (M+H)+. 1-(7-Bromo-3-methyl-2,3-dihydrobenzofuran-3-yl)ethan-1-one

[0172] Step B: To a solution of 7-bromo-N-methoxy-N,3-dimethyl-2,3-dihydrobenzofuran-3- carboxamide (28.3 mmol, 8.5 g) in THF (100 ml) at 0 °C was added dropwise under an N2 atmosphere MeMgBr solution (3M in diethyl ether, 76 mL, 227 mmol). The mixture was stirred at 0 °C for 10 minutes, then allowed to warm to room temperature and stirred for another 2 hours. The reaction solution was poured into 100 mL saturated aqueous NH4Cl and extracted with EtOAc (80 mL x 3). The combined organic phase was concentrated, and the crude purified by flash column chromatography on silica gel, eluting with 0-7% EtOAc in petroleum ether, to give 1-(7-bromo-3-methyl-2,3-dihydrobenzofuran-3-yl)ethan-1-one (6.5 g, 67%) as a yellow oil. MS (ESI): 255.0, 257.0 m / z (M+H)+. (E)-1-(7-Bromo-3-methyl-2,3-dihydrobenzofuran-3-yl)-3-(dimethylamino)prop-2-en-1-one

[0173] Step C: To a solution of 1-(7-bromo-3-methyl-2,3-dihydrobenzofuran-3-yl)ethan-1-one (25.5 mmol, 6.5 g) in DMF (20 ml) was added DMF-DMA (127 mmol, 15.2 g) and the mixture was stirred at 100 °C overnight. The reaction solution was poured into 50 mL water and extracted with EtOAc (50 mL x 3). The combined organic phase was washed with brine (80 mL x 3) and concentrated to give crude (E)-1-(7-bromo-3-methyl-2,3-dihydrobenzofuran-3- yl)-3-(dimethylamino)prop-2-en-1-one (7.6 g) as a brown oil. MS (ESI): 310.1 m / z (M+H)+. 3-(7-Bromo-3-methyl-2,3-dihydrobenzofuran-3-yl)-1H-pyrazole

[0174] Step D: To a solution of (E)-1-(7-bromo-3-methyl-2,3-dihydrobenzofuran-3-yl)-3- (dimethylamino)prop-2-en-1-one (24.5 mmol, 7.6 g) in EtOH (150 ml) was added hydrazine hydrate (123 mmol, 6.13 g) and the mixture was stirred at 50 °C for 2 hours. The reaction solution was concentrated and purified by flash column chromatography on silica gel, eluting with 0-3% MeOH in DCM, to give 3-(7-bromo-3-methyl-2,3-dihydrobenzofuran-3-yl)-1H- pyrazole (6.7 g, 84.6%) as a yellow oil. MS (ESI): 279, 281 m / z (M+H)+. 2-(3-Methyl-3-(1H-pyrazol-3-yl)-2,3-dihydrobenzofuran-7-yl)acetonitrile

[0175] Step E: To a solution of 3-(7-bromo-3-methyl-2,3-dihydrobenzofuran-3-yl)-1H- pyrazole (10.2 mmol, 2.85 g) in DMSO (61.6 mL) and H2O (15.4 mL) was added 4-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)isoxazole(15.3 mmol, 2.99 g), KF (30.6 mmol, 1.78 g) and Pd(dppf)Cl2(1.02 mmol, 747 mg), and the mixture was stirred at 130 °C for 6 hours. The reaction solution was poured into 60 mL water and extracted with EtOAc (60 mL x 3). The combined organic phase was washed with brine (60 mL x 2), concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 0-50% EtOAc in petroleum ether) to give 2-(3-methyl-3-(1H-pyrazol-3-yl)-2,3-dihydrobenzofuran-7-yl)acetonitrile as a yellow oil (2 g, 73%). MS (ESI): 240.2 m / z (M+H)+. Ethyl 2-(3-methyl-3-(1H-pyrazol-3-yl)-2,3-dihydrobenzofuran-7-yl)acetate

[0176] Step F: To a solution of 2-(3-methyl-3-(1H-pyrazol-3-yl)-2,3-dihydrobenzofuran-7- yl)acetonitrile (8.36 mmol, 2 g) in EtOH (60 ml) and DCM (24 ml) was added chlorotrimethylsilane (251 mmol, 27.2 g) and the mixture was stirred overnight at 60 °C. The reaction solution was concentrated and purified by flash column chromatography on silica gel, eluting with 0-40% EtOAc in petroleum ether, to give ethyl 2-(3-methyl-3-(1H-pyrazol-3-yl)- 2,3-dihydrobenzofuran-7-yl)acetate as a white solid (1.8 g, 73%). MS (ESI): 287.1 m / z (M+H)+. Ethyl 2-(3-(1-(2-fluoro-5-((6-fluoro-4-(methylthio)-1-tosyl-1H-indol-5-yl)oxy)phenyl)-1H- pyrazol-3-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate

[0177] Step G: To a mixture of ethyl 2-[3-methyl-3-(1H-pyrazol-3-yl)-2H-benzofuran-7- yl]acetate (200 mg, 0.7 mmol), 6-fluoro-5-(4-fluoro-3-iodo-phenoxy)-4-methylsulfanyl-1-(p- tolylsulfonyl)indole (Intermediate 5, 399 mg, 0.70 mmol), and Na2CO3(148 mg, 1.4 mmol) in NMP was added (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (39.7 mg, 0.279 mmol), and CuI (26.6 mg, 0.14 mmol). The reaction mixture was stirred at 100 °C for 16 hours under an atmosphere of argon. After cooling to room temperature, the reaction mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (50 mL x 3). The organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 1 / 1 petroleum ether / ethyl acetate, to give ethyl 2-[3-[1-[2-fluoro-5-[6-fluoro-4-methylsulfanyl- 1-(p-tolylsulfonyl)indol-5-yl]oxy-phenyl]pyrazol-3-yl]-3-methyl-2H-benzofuran-7-yl]acetate (0.1 g, 20%) as a white solid. MS (ESI): 730 m / z (M+H)+. Ethyl 2-(3-(1-(2-fluoro-5-((6-fluoro-4-(methylsulfonyl)-1-tosyl-1H-indol-5-yl)oxy)phenyl)- 1H-pyrazol-3-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate

[0178] Step H: Ethyl 2-[3-[1-[2-fluoro-5-[6-fluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol- 5-yl]oxy-phenyl]pyrazol-3-yl]-3-methyl-2H-benzofuran-7-yl]acetate (300 mg, 0.411 mmol) was dissolved in MeOH and then ammonium molybdate tetrahydrate (600 mg, 0.485 mmol) in 30% aqueous hydrogen peroxide was added. The mixture was stirred at 40 °C for 16 hours. The reaction was quenched with NH4Cl and the result solution was extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography on silica gel, eluting with 1 / 1 petroleum ether / ethyl acetate, to afford ethyl 2- [3-[1-[2-fluoro-5-[6-fluoro-4-methylsulfonyl-1-(p-tolylsulfonyl)indol-5-yl]oxy- phenyl]pyrazol-3-yl]-3-methyl-2H-benzofuran-7-yl]acetate (300 mg, 95.8%) as a white solid. MS (ESI): 762 m / z (M+H)+. 2-(3-(1-(2-Fluoro-5-((6-fluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)phenyl)-1H-pyrazol-3- yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid

[0179] Step I: To a solution of ethyl 2-[3-[1-[2-fluoro-5-[6-fluoro-4-methylsulfonyl-1-(p- tolylsulfonyl) indol-5-yl]oxy-phenyl]pyrazol-3-yl]-3-methyl-2H-benzofuran-7-yl]acetate (300 mg, 0.40 mmol) in THF (9 mL) and MeOH (3 mL) was added LiOH (47.2 mg, 1.97 mmol) at 0 °C. The solution was allowed to warm to room temperature and stirred for 3 hours. After removal of the solvent, water was added, and the pH of the mixture was adjusted to ~6 with 1N hydrochloric acid. A precipitate formed, which was isolated by filtration to afford 2-[3-[1- [2-fluoro-5-[(6-fluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]phenyl]pyrazol-3-yl]-3-methyl- 2H-benzofuran-7-yl]acetic acid (118 mg, 51.5%) as a white solid. MS (ESI): 580 m / z (M+H)+.1H NMR (400 MHz, CD3OD) δ 8.03 (t, J = 2.8 Hz, 1H), 7.68 (dd, J = 10.6, 0.8 Hz, 1H), 7.56 (d, J = 3.2 Hz, 1H), 7.49 (dd, J = 6.4, 3.2 Hz, 1H), 7.28 (dd, J = 11.2, 9.2 Hz, 1H), 7.22 (dd, J = 3.2, 0.8 Hz, 1H), 7.10 (dd, J = 7.2, 0.8 Hz, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.84 (dt, J = 9.2, 3.2 Hz, 1H), 6.80 (d, J = 7.6 Hz, 1H), 6.37 (d, J = 2.8 Hz, 1H), 4.82 (d, J = 8.8 Hz, 1H), 4.47 (d, J = 8.8 Hz, 1H), 3.61 (d, J = 1.2 Hz, 2H), 3.34 (s, 3H), 1.72 (s, 3H) ppm. Example 17. Synthesis of (R)-2-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)acetic acid Example 18. (S)-2-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H- imidazol-4-yl)-4-methylchroman-8-yl)acetic acid 8-Bromo-4-methylchromane-4-carboxylic acid

[0180] Step A: To a solution of 8-bromochromane-4-carboxylic acid (6.0 g, 23.3 mmol) in THF (50 mL) was dropwise added lithium diisopropylamide (35 mL, 70 mmol) at -78 °C under N2. The reaction was stirred at -78 °C for 1 hour. To the reaction mixture was added dropwise CH3I (4.65 mL, 74.7 mmol). The reaction mixture was allowed to warm to room temperature and stirred overnight. The reaction mixture was quenched with a saturated NH4Cl aqueous solution (100 mL) and extracted with EtOAc (100 mL x 3). The combined organic extract was washed with water (15 mL x 2) and brine (20 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 0- 50% ethyl acetate in petroleum ether, to afford 8-bromo-4-methyl-chromane-4-carboxylic acid (5.15 g, 81%). MS (ESI): 225 m / z (M-46)+. Benzyl 8-bromo-4-methylchromane-4-carboxylate

[0181] Step B: To a solution of 8-bromo-4-methyl-chromane-4-carboxylic acid (5.15 g, 19 mmol) in acetone (50 mL) was added bromomethyl benzene (3.9 g, 22.8 mmol) and K2CO3(3.94 g, 28.5 mmol). The reaction was stirred at 80 °C overnight. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with 0-10% of ethyl acetate in petroleum ether, to afford benzyl 8-bromo-4-methyl- chromane-4-carboxylate (7.0 g, quantitative yield). MS (ESI): 361 m / z (M+H)+. Benzyl 8-(2-ethoxy-2-oxoethyl)-4-methylchromane-4-carboxylate

[0182] Step C: To a solution of benzyl 8-bromo-4-methyl-chromane-4-carboxylate (7.4 g) in mesitylene (80 mL) was added (3-ethoxy-3-oxo-propanoyl)oxypotassium (5.44 g, 32 mmol), allylpalladium chloride dimer (0.16 g, 0.43 mmol), BINAP (0.80 g, 1.28 mmol) and 4- dimethylaminopyridine (0.26 g, 2.13 mmol). The reaction mixture was stirred at 140 °C overnight and concentrated. The residue was purified by silica gel column chromatography, eluting with 0-10% ethyl acetate in petroleum ether, to afford benzyl 8-(2-ethoxy-2-oxo- ethyl)chromane-4-carboxylate (2.9 g, 38%).1H NMR (400 MHz, CD3OD) δ 7.35-7.25 (m, 5H), 7.22 (dd, J = 8.0, 1.6 Hz, 1H), 7.06 (dd, J = 7.4, 1.6 Hz, 1H), 6.83 (t, J = 7.6 Hz, 1H), 5.14 (s, 2H), 4.26-4.19 (m, 2H), 4.13 (q, J = 7.2 Hz, 2H), 3.57 (d, J = 7.2 Hz, 2H), 2.52-2.46 (m , 1H), 1.93-1.87 (m, 1H), 1.61 (s, 3H), 1.23 (t, J = 7.2 Hz, 3H) ppm. 8-(2-Ethoxy-2-oxoethyl)-4-methylchromane-4-carboxylic acid

[0183] Step D: To a solution of benzyl 8-(2-ethoxy-2-oxo-ethyl)-4-methyl-chromane-4- carboxylate (2.9 g, 7.87 mmol) in EtOH (20 mL) was added at room temperature Pd / C (10 wt. %, 1 g). The reaction mixture was stirred under H2for 3 hours. The reaction mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with 0-50% of ethyl acetate in petroleum ether) to afford 8-(2-ethoxy-2-oxo-ethyl)-4- methyl-chromane-4-carboxylic acid (1.96 g, 90%). MS (ESI): 279 m / z (M+H)+. Ethyl 2-[4-(2-bromoacetyl)-4-methyl-chroman-8-yl]acetate

[0184] Step E: To a round bottom flask were added 8-(2-ethoxy-2-oxo-ethyl)-4-methyl- chromane-4-carboxylic acid (0.9 g, 3.23 mmol) and SOCl2(10 mL). The reaction mixture was stirred at 80 °C for 2 hours. The reaction mixture was concentrated to remove SOCl2, the residue was dissolved in acetonitrile (10 mL) and trimethylsilyldiazomethane (2M in hexane, 6.47 mL, 12.9 mmol) was added at 0 °C. The reaction mixture was stirred overnight at room temperature. The reaction mixture was cooled to 0 °C and 40% HBr in water (1.87 mL, 12.9 mmol) was added. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was quenched with water (30 mL), extracted with EtOAc (40 mL x 3). The combined organic extract was washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with 0- 20% of ethyl acetate in petroleum ether) to afford ethyl 2-[4-(2-bromoacetyl)-4-methyl- chroman-8-yl]acetate (0.78 g, 70%).1H NMR (400 MHz, CDCl3) δ 7.13 (d, J = 7.2 Hz, 1H), 6.97-6.94 (m, 1H), 6.90 (t, J = 7.2 Hz, 1H), 4.31-4.26 (m, 1H), 4.18 (q, J = 7.2 Hz, 2H), 4.14- 4.07 (m, 1H), 3.90 (s, 2H), 3.61 (s, 1H), 2.48-2.42 (m, 1H), 1.83-1.78 (m, 1H), 1.58 (s, 3H), 1.27 (t, J = 7.2 Hz, 3H) ppm. Ethyl 2-[4-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4- methyl-chroman-8-yl]acetate

[0185] Step F: To a solution of 5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-benzamidine (Intermediate 2, 200 mg, 0.66 mmol) in DMF (10 mL) was added ethyl 2-[4-(2-bromoacetyl)- 4-methyl-chroman-8-yl]acetate (0.22 g, 0.62 mmol) and NaHCO3(0.11 g, 1.31 mmol). The reaction mixture was stirred overnight at room temperature. The reaction was quenched with water (30 mL), extracted with EA (30 mL x 4). The combined organic extract was washed with water (20 mL x 3), brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with 0-60% of ethyl acetate in petroleum ether) to afford ethyl 2-[4-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro- phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]acetate (200 mg, yield 54%). MS (ESI): 562 m / z (M+H)+. Ethyl (R)-2-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4- methylchroman-8-yl)acetate and ethyl (S)-2-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)acetate

[0186] Step G: The product from Step F (300 mg) was separated by chiral HPLC to afford two enantiomers whose absolute configuration was assigned arbitrarily as follows. The chiral configuration of the faster eluting enantiomer was arbitrarily assigned as ethyl 2-[(4S)-4-[2-[5- [(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8- yl]acetate (125 mg, 42%, 98% ee), and that of the slower eluting component as ethyl 2-[(4R)- 4-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl- chroman-8-yl]acetate (158 mg, 53%, 98% ee). For both enantiomers, MS (ESI): 562 m / z (M+H)+. Chiral separation method: Column: CHIRALPAK IB N-5 Column size: 5.0 cm I.D. × 25 cm Solution concentration: 9.6 mg / ml; Injection volume: 8 ml Mobile phase: DCM / Hexane / MeOH / diethylamine = 60 / 40 / 1 / 0.1(V / V / V / V) Flow rate: 60 ml / min Detection wavelength: 254 nm Temperature: 35 °C (S)-2-(4-(2-(5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4- methylchroman-8-yl)acetic acid

[0187] Step H: To a solution of ethyl 2-[(4S)-4-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2- fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]acetate (absolute configuration assigned arbitrarily, 125 mg, 0.22 mmol) in THF (10 mL) and MeOH (3 mL) was added LiOH (1M in water, 3 mL, 3 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (15 mL), the pH adjusted to ~3 with 1N hydrochloric acid and extracted with EtOAc (30 mL x 3). The combined organic extract was washed with a 0.1% NH4HCO3aqueous solution (15 mL x 2) and brine (15 mL), dried over Na2SO4, filtered, and concentrated to afford 2-[(4S)-4-[2-[5-[(4,6-difluoro-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]acetic acid (119.1 mg, quantitative yield, 98% ee). MS (ESI): 534 m / z (M+H)+.1H NMR (400 MHz, CD3OD) δ 7.47 (dd, J = 5.6, 2.8 Hz, 1H), 7.32 (d, J = 3.2 Hz, 1H), 7.21- 7.13 (m, 3H), 7.06 (dd, J = 7.6, 1.6 Hz, 1H), 6.94 (J = 8.8, 3.6 Hz, 1H), 6.82 (t, J = 7.6 Hz, 1H), 6.61 (s, 1H), 6.56 (dd, J = 3.2, 0.4Hz, 1H), 4.26-4.21 (m, 1H), 4.06-4.00 (m, 1H), 3.58 (s, 2H), 2.47-2.42 (m, 1H), 2.04-1.98 (m, 1H), 1.74 (s, 3H) ppm. (R)-2-(4-(2-(5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4- methylchroman-8-yl)acetic acid

[0188] Step I: To a solution of ethyl 2-[(4R)-4-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2- fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]acetate (absolute configuration assigned arbitrarily, 158 mg, 0.28 mmol) in THF (10 mL) and MeOH (3 mL) was added LiOH (1M in water, 3 mL, 3 mmol). The reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water (15 mL), pH adjusted to ~3 with 1N aqueous HCl, and extracted with EtOAc (30 mL x 3). The extract was washed with 0.1% NH4HCO3aqueous solution (15 mL x 2), brine (15 mL), dried over Na2SO4, filtered, and concentrated to afford 2- [(4R)-4-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4- methyl-chroman-8-yl]acetic acid (150.3 mg, quantitative yield, 98% ee). MS (ESI): 534 m / z (M+H)+.1H NMR (400 MHz, CD3OD) δ 7.47 (dd, J = 6.0, 3.2 Hz, 1H), 7.32 (d, J = 3.2 Hz, 1H), 7.21-7.13 (m, 3H), 7.06 (dd, J = 7.6, 1.6 Hz, 1H), 6.94 (dt, J = 8.4, 3.6 Hz, 1H), 6.82 (t, J = 7.6 Hz, 1H), 6.63 (s, 1H), 6.57 (dd, J = 3.2, 0.4 Hz, 1H), 4.26-4.22 (m, 1H), 4.06-4.00 (m, 1H), 3.58 (s, 2H), 2.48-2.42 (m, 1H), 2.05-1.98 (m, 1H), 1.74 (s, 3H) ppm. Example 19. Synthesis of (R)-2-(3-(1-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-pyrazol-3-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid Example 20. Synthesis of (S)-2-(3-(1-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-pyrazol-3-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid Ethyl 2-(3-(1-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-pyrazol-3-yl)-3- methyl-2,3-dihydrobenzofuran-7-yl)acetate

[0189] Step A: To a solution of 4,6-difluoro-5-(4-fluoro-3-iodophenoxy)-1H-indole (Intermediate 8, 0.771 mmol, 300 mg) in toluene (3 mL) was added ethyl 2-(3-methyl-3-(1H- pyrazol-3-yl)-2,3-dihydrobenzofuran-7-yl)acetate (Step F, Example 16; 0.771 mmol, 210 mg), potassium carbonate (1.54 mmol, 213 mg), cuprous iodide (0.154 mmol, 29.4 mg), (1R,2R)- N,N'-dimethyl-1,2-cyclohexanediamine (0.308 mmol, 43.9 mg), and the mixture was stirred in a microwave tube at 130 °C for 5 hours. The reaction solution was concentrated to remove toluene. Water (30 mL) was added, and the mixture extracted with EtOAc (20 mL x 2). The combined organic phase was concentrated and purified by flash column chromatography on silica gel, eluting with 0-3% MeOH in DCM, to give the title compound as a yellow oil (150 mg, 31.9%). MS (ESI): 548.2 m / z (M+H)+. Ethyl (R)-2-(3-(1-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-pyrazol-3-yl)-3- methyl-2,3-dihydrobenzofuran-7-yl)acetate and ethyl (S)-2-(3-(1-(5-((4,6-difluoro-1H-indol- 5-yl)oxy)-2-fluorophenyl)-1H-pyrazol-3-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate

[0190] Step B: The racemic mixture obtained in Step A was separated by SFC into its constituent enantiomers. The absolute configuration of the faster eluting enantiomer was arbitrarily assigned as ethyl (R)-2-(3-(1-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)- 1H-pyrazol-3-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate (130 mg), while the absolute configuration of the slower eluting enantiomer was assigned as ethyl (S)-2-(3-(1-(5-((4,6- difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-pyrazol-3-yl)-3-methyl-2,3- dihydrobenzofuran-7-yl)acetate (130 mg). MS (ESI): 548.2 m / z (M+H)+was observed for both enantiomers. SFC conditions: Instrument: SFC-80 (Thar, Waters) Column: IG 20 * 250 mm, 10 µm (Daicel) Column temperature: 35 ºC Mobile phase: 55 / 45 CO2 / MeOH (0.2% ammonia in methanol) Flow rate: 80 g / min; Back pressure: 100 bar Detection wavelength: 214 nm; Cycle time: 4 min Sample solution: 350 mg dissolved in 35 mL Methanol; Injection volume: 2 mL (R)-2-(3-(1-(5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-pyrazol-3-yl)-3-methyl- 2,3-dihydrobenzofuran-7-yl)acetic acid

[0191] Step C: To a solution of ethyl (R)-2-(3-(1-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-pyrazol-3-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate (0.237 mmol, 130 mg) in THF (10 mL) and H2O (3 mL) was added 1M aqueous LiOH (2 ml), and the mixture was stirred at room temperature overnight. The pH of the reaction solution was adjusted to ~5 with 3M aqueous HCl and extracted with EtOAc (20 mL x 3).The combined organic phase was concentrated and purified by prep-HPLC to give (R)-2-(3-(1-(5-((4,6-difluoro-1H-indol-5- yl)oxy)-2-fluorophenyl)-1H-pyrazol-3-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid as a white solid (75.6 mg, 61%). MS (ESI): 520.0 m / z (M+H)+.1H NMR (400 MHz, CD3OD) δ 7.98 (m, 1H), 7.41-7.39 (dd, J = 6.0, 2.8 Hz, 1H), 7.30 (d, J = 3.2 Hz, 1H), 7.24-7.19 (m, 1H), 7.14-7.12 (d, J = 10.4 Hz, 1H), 7.04-7.01 (m, 2H), 6.83-6.79 (m, 1H), 6.77-6.73 (t, J = 7.6 Hz, 1H), 6.54 (d, J = 3.2 Hz, 1H), 6.31 (d, J = 2.4 Hz, 1H), 4.76 (d, J = 8.8 Hz, 1H), 4.42 (d, J = 8.4 Hz, 1H), 3.55 (s, 2H), 1.67 (s, 3H) ppm. (S)-2-(3-(1-(5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-pyrazol-3-yl)-3-methyl- 2,3-dihydrobenzofuran-7-yl)acetic acid

[0192] Step D: To a solution of ethyl (S)-2-(3-(1-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-pyrazol-3-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate (0.237 mmol, 130 mg) in THF (10 mL) and H2O (3 mL) was added 1M aqueous LiOH (2 ml), and the mixture was stirred at room temperature overnight. The pH of the reaction solution was adjusted to ~5 with 3M aqueous HCl and extracted with EtOAc (20 mL x 3).The combined organic phase was concentrated. The residue was purified by prep-HPLC to give (S)-2-(3-(1-(5-((4,6-difluoro- 1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-pyrazol-3-yl)-3-methyl-2,3-dihydrobenzofuran-7- yl)acetic acid as a white solid (74.5 mg, 60.4%). MS (ESI): 520.2 m / z (M+H)+.1H NMR (400 MHz, CD3OD) δ 7.96 (m, 1H), 7.40-7.38 (dd, J = 6.4, 2.8 Hz, 1H), 7.28-7.27 (m, 1H),7.23- 7.16 (m, 1H), 7.13-7.10 (d, J = 10.4 Hz, 1H), 7.03-7.00 (m, 2H), 6.83-6.77 (m, 1H), 6.75-6.72 (t, J = 7.6 Hz, 1H), 6.53 (d, J = 3.2 Hz, 1H), 6.29 (d, J = 2.4 Hz, 1H), 4.75 (d, J = 8.8 Hz, 1H), 4.40(d, J = 8.8 Hz, 1H), 3.54 (s, 2H), 1.65 (s, 3H) ppm. Example 21. Synthesis of (R)-2-(3-(2-(2-fluoro-5-((6-fluoro-4-(methylsulfonyl)-1H- indol-5-yl)oxy)phenyl)oxazol-4-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid Example 22. Synthesis of (S)-2-(3-(2-(2-fluoro-5-((6-fluoro-4-(methylsulfonyl)-1H- indol-5-yl)oxy)phenyl)oxazol-4-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid 2-Fluoro-5-((6-fluoro-4-(methylthio)-1H-indol-5-yl)oxy)benzoic acid

[0193] Step A: To a solution of potassium hydroxide (1.77 g, 31.6 mmol) in ethanol (10 mL) and water (5 mL) was added 2-fluoro-5-((6-fluoro-4-(methylthio)-1H-indol-5- yl)oxy)benzonitrile (Intermediate 7, 2.0 g, 6.3 mmol). The reaction was stirred at 100 °C for 2.5 hours. The mixture was cooled to room temperature and diluted with water (30 mL). The pH was adjusted to 4-5 with 1 M hydrochloric acid. The mixture was extracted with ethyl acetate (30 mL x 3), the organic layer was washed with brine (30 mL x 2), dried over sodium sulfate, filtered, and concentrated to give 2-fluoro-5-((6-fluoro-4-(methylthio)-1H-indol-5- yl)oxy)benzoic acid (2.3 g, 99%) as a brown solid. MS (ESI): 336 m / z (M+H)+. 2-(7-(2-Ethoxy-2-oxoethyl)-3-methyl-2,3-dihydrobenzofuran-3-yl)-2-oxoethyl 2-fluoro-5-((6- fluoro-4-(methylthio)-1H-indol-5-yl)oxy)benzoate

[0194] Step B: To a solution of ethyl 2-(3-(2-bromoacetyl)-3-methyl-2,3-dihydrobenzofuran- 7-yl)acetate (Step G, Example 5; 1.00 g, 90% purity, 2.64 mmol) in N,N-dimethylformamide (30 mL) were added 2-fluoro-5-((6-fluoro-4-(methylthio)-1H-indol-5-yl)oxy)benzoic acid (973 mg, 92% purity, 2.67 mmol) and sodium hydrogen carbonate (554 mg, 6.59 mmol). The reaction was stirred at room temperature for 3 hours, diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic extracts were washed with saturated aqueous lithium chloride (50 mL x 2), brine (50 mL x 2), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 0-25% ethyl acetate in petroleum ether, to afford 2-(7-(2-ethoxy-2-oxoethyl)-3-methyl-2,3- dihydrobenzofuran-3-yl)-2-oxoethyl 2-fluoro-5-((6-fluoro-4-(methylthio)-1H-indol-5- yl)oxy)benzoate (1.68 g, 93%) as a yellow oil. MS (ESI): 596 m / z (M+H)+. Ethyl 2-(3-(2-(2-fluoro-5-((6-fluoro-4-(methylthio)-1H-indol-5-yl)oxy)phenyl)oxazol-4-yl)-3- methyl-2,3-dihydrobenzofuran-7-yl)acetate

[0195] Step C: To a solution of 2-(7-(2-ethoxy-2-oxoethyl)-3-methyl-2,3-dihydrobenzofuran- 3-yl)-2-oxoethyl 2-fluoro-5-((6-fluoro-4-(methylthio)-1H-indol-5-yl)oxy)benzoate (1.66 g, 87% purity, 2.42 mmol) in acetic acid (43 mL) was added ammonium acetate (3.74 g, 48.5 mmol). The reaction was stirred at 110 °C for 16 hours. The solvent was removed in vacuo, the residue was dissolved in water (40 mL) and extracted with ethyl acetate (20 mL x 2). The organic extracts were washed with saturated aqueous NaHCO3solution (30 mL x 3), brine (30 mL x 2), dried over sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography, eluting with 20% ethyl acetate in petroleum ether, to give ethyl 2-(3-(2-(2-fluoro-5-((6-fluoro-4-(methylthio)-1H-indol-5-yl)oxy)phenyl)oxazol-4- yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate (458 mg, 33%) as a white solid. MS (ESI): 577 m / z (M+H)+. Ethyl 2-(3-(2-(2-fluoro-5-((6-fluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)phenyl)oxazol-4- yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate

[0196] Step D: To a solution of ethyl 2-(3-(2-(2-fluoro-5-((6-fluoro-4-(methylthio)-1H-indol- 5-yl)oxy) phenyl) oxazol-4-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate (458 mg, 0.79 mmol) in methanol (11.4 mL) was added a solution of ammonium molybdate tetrahydrate (923 mg, 0.31 mmol) in hydrogen peroxide (30% aqueous solution, 4.6 mL) dropwise at 0 °C. The reaction was then stirred at room temperature for 3 hours. The mixture was diluted with water (80 mL) and extracted with ethyl acetate (30 mL x 2). The combined extract was washed with a Na2S2O3aqueous solution (30 mL x 2), brine (30 mL x2), dried over sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography (40 g silica gel column @ 100 mL / min, eluting with 35% ethyl acetate in petroleum ether) to give ethyl 2-(3-(2-(2-fluoro-5-((6-fluoro-4-(methylsulfonyl)-1H-indol-5-yl) oxy)phenyl)oxazol-4-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate (199 mg, 39%) as a light yellow solid. MS (ESI): 609 m / z (M+H)+. Ethyl (R)-2-(3-(2-(2-fluoro-5-((6-fluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)phenyl)oxazol- 4-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate and ethyl (S)-2-(3-(2-(2-fluoro-5-((6- fluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)phenyl)oxazol-4-yl)-3-methyl-2,3- dihydrobenzofuran-7-yl)acetate

[0197] Step E: The racemic mixture, ethyl 2-(3-(2-(2-fluoro-5-((6-fluoro-4-(methylsulfonyl)- 1H-indol-5-yl) oxy)phenyl)oxazol-4-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate (199 mg, 95% purity, 0.31 mmol) was separated by SFC into its constituent enantiomers. The absolute configuration of the faster eluting enantiomer was arbitrarily assigned as ethyl (R)-2- (3-(2-(2-fluoro-5-((6-fluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)phenyl)oxazol-4-yl)-3- methyl-2,3-dihydrobenzofuran-7-yl)acetate (64 mg, 34%, a white solid), and that of the slower eluting enantiomer as ethyl (S)-2-(3-(2-(2-fluoro-5-((6-fluoro-4-(methylsulfonyl)-1H-indol-5- yl)oxy)phenyl)oxazol-4-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate (85 mg, 45%, a white solid). MS (ESI): 609 m / z (M+H)+observed for both enantiomers. SFC Method: Instrument: SFC-80 (Thar, Waters) Column: OJ 20 * 250 mm, 10 µm (Daicel) Column temperature: 35 ºC Mobile phase: 65 / 35 CO2 / MeOH (0.2% ammonia in methanol) Flow rate: 80 g / min ; Back pressure: 100 bar Detection wavelength: 214 nm Cycle time: 5.5 min Sample solution: 190 mg dissolved in 25 ml; Methanol injection volume: 1.9 ml. (R)-2-(3-(2-(2-Fluoro-5-((6-fluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)phenyl)oxazol-4-yl)- 3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid

[0198] Step F: To a solution of lithium hydroxide hydrate (22 mg) in water (1 mL), methanol (1 mL) and tetrahydrofuran (3 mL) was added ethyl (R)-2-(3-(2-(2-fluoro-5-((6-fluoro-4- (methylsulfonyl)- 1H-indol-5-yl)oxy)phenyl)oxazol-4-yl)-3-methyl-2,3-dihydrobenzofuran-7- yl)acetate (64 mg, 0.103 mmol). The reaction was stirred at room temperature for 2 hours. The mixture was diluted with water, and then the volatile organics were removed under reduced pressure. The pH of the water phase was adjusted to 5-6 with 1 M hydrochloric acid. The precipitate was isolated, washed with water, and dried in vacuo to give (R)-2-(3-(2-(2-fluoro- 5-((6-fluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)phenyl)oxazol-4-yl)-3-methyl-2,3- dihydrobenzofuran-7-yl)acetic acid (Example 21, 60 mg, 98%) as white solid. MS (ESI): 581 m / z (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 12.27 (s, 1H), 11.86 (s, 1H), 8.07 (s, 1H), 7.84 (d, J = 10.8 Hz, 1H), 7.68 (t, J = 2.8, 1H), 7.46 (dd, J = 5.6, 3.2 Hz, 1H), 7.36 (t, J = 9.6 Hz, 1H), 7.11 (dd, J = 7.2, 1.2 Hz, 1H), 7.09-7.03 (m, 3H), 6.83 (t, J = 7.6 Hz, 1H), 4.76 (d, J = 8.8 Hz, 1H), 4.44 (d, J = 8.8 Hz, 1H), 3.51 (s, 2H), 3.37 (s, 3H), 1.61 (s, 3H) ppm. (S)-2-(3-(2-(2-Fluoro-5-((6-fluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)phenyl)oxazol-4-yl)- 3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid

[0199] Step G: To a solution of lithium hydroxide hydrate (29 mg) in water (1 mL), methanol (1 mL) and tetrahydrofuran (3 mL) was added ethyl (S)-2-(3-(2-(2-fluoro-5-((6-fluoro-4- (methylsulfonyl)-1H-indol-5-yl)oxy)phenyl)oxazol-4-yl)-3-methyl-2,3-dihydrobenzofuran-7- yl)acetate (85 mg, 0.14 mmol). The reaction was stirred at room temperature for 2 hours. The mixture was diluted with water, then the volatile organics were removed under reduced pressure. The pH of the water phase was adjusted to 5-6 with 1 M aqueous HCl. The precipitate was isolated by filtration, washed with water, and dried in vacuo to give (S)-2-(3-(2-(2-fluoro- 5-((6-fluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)phenyl)oxazol-4-yl)-3-methyl-2,3- dihydrobenzofuran-7-yl)acetic acid (Example 22, 65 mg, 95%) as white solid. MS (ESI): 581 m / z (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 11.86 (s, 1H), 8.07 (s, 1H), 7.84 (d, J = 10.4 Hz, 1H), 7.68 (t, J = 2.8, 1H), 7.46 (dd, J = 5.6, 3.2 Hz, 1H), 7.36 (t, J = 9.6 Hz, 1H), 7.11 (dd, J = 7.6, 1.2 Hz, 1H), 7.09-7.03 (m, 3H), 6.83 (t, J = 7.6 Hz, 1H), 4.75 (d, J = 8.8 Hz, 1H), 4.44 (d, J = 8.8 Hz, 1H), 3.51 (s, 2H), 3.37 (s, 3H), 1.61 (s, 3H) ppm. Example 23. Synthesis of 2-(3-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)- 1-methyl-1H-imidazol-4-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid 5-((4,6-Difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-5-yl)oxy)-2-fluorobenzonitrile

[0200] Step A: To a mixture of NaH (125 mg, 3.12 mmol) in THF (2 mL) was added at 0 °C under a nitrogen atmosphere 5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-benzonitrile (Intermediate 2E, 600 mg, 2.08 mmol) in THF (4 mL). The mixture was stirred at 0 °C for 30 minutes. 2-(chloromethoxy)ethyl-trimethyl-silane (416 mg, 2.5 mmol) in THF (2 mL) was added dropwise to the mixture at 0 °C. The mixture was warmed to room temperature and stirred for 3 hours. LC-MS analysis showed that most of the starting material had disappeared, and the mixture was quenched with water. The mixture was extracted with ethyl acetate (45 mL x 2). The combined organic layers were washed with brine, dried, concentrated, and purified by flash column chromatography on silica, eluting with 0-15% ethyl acetate in petroleum ether to give 5-[4,6-difluoro-1-(2-trimethylsilylethoxymethyl)indol-5-yl]oxy-2- fluoro-benzonitrile (770 mg, 88.4 %) as a colorless oil. MS (ESI): 419 m / z (M+H)+. 5-((4,6-Difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-5-yl)oxy)-2- fluorobenzimidamide

[0201] Step B: To a solution of 5-[4,6-difluoro-1-(2-trimethylsilylethoxymethyl)indol-5- yl]oxy-2-fluoro-benzonitrile (770 mg, 1.84 mmol) in THF (10 mL) was added dropwise at 0 °C LHMDS (1.3 M solution, 5.6 mL). The solution was stirred at room temperature for 16 hours. LC-MS revealed that most of the starting material had disappeared. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (45 mL x 2). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give the crude 5-[4,6-difluoro-1-(2-trimethylsilylethoxymethyl)indol-5-yl]oxy-2-fluoro- benzamidine (830 mg, 104%) as a brown oil. MS (ESI): 436 m / z (M+H)+. Ethyl 2-(3-(2-(5-((4,6-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-4-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate

[0202] Step C: A mixture of ethyl 2-[3-(2-bromoacetyl)-3-methyl-2H-benzofuran-7-yl]acetate (Step G, Example 5 ; 320 mg, 0.94 mmol), 5-[4,6-difluoro-1-(2- trimethylsilylethoxymethyl)indol-5-yl]oxy-2-fluoro-benzamidine (490 mg, 11.3 mmol), and NaHCO3(158 mg, 1.88 mmol) in DMF (5 mL) was stirred at 75 °C for 5 hours. The mixture was extracted with ethyl acetate (35 mL x 2) and water (50 mL). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica, eluting with 0-30% ethyl acetate in petroleum ether, to give ethyl 2-[3-[2-[5-[4,6-difluoro-1-(2-trimethylsilylethoxymethyl)indol-5-yl]oxy-2- fluoro-phenyl]-1H-imidazol-4-yl]-3-methyl-2H-benzofuran-7-yl]acetate (377 mg, 59 %) as a white solid. MS (ESI): 678 m / z (M+H)+. Ethyl 2-(3-(2-(5-((4,6-difluoro-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indol-5-yl)oxy)-2- fluorophenyl)-1-methyl-1H-imidazol-4-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate

[0203] Step D: A mixture of ethyl 2-[3-[2-[5-[4,6-difluoro-1-(2- trimethylsilylethoxymethyl)indol-5-yl]oxy-2-fluoro-phenyl]-1H-imidazol-4-yl]-3-methyl-2H- benzofuran-7-yl]acetate (600 mg, 0.89 mmol), iodomethane (188 mg, 1.33 mmol), and K2CO3(244 mg, 1.77 mmol) in DMF (8 mL) was stirred at room temperature for 16 hours. The mixture was quenched with water (60 mL) and extracted with ethyl acetate (50 mL x 2). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated. The residue was purified by flash column chromatography on silica, eluting with 0-30% ethyl acetate in petroleum ether, to give ethyl 2-[3-[2-[5-[4,6-difluoro-1-(2- trimethylsilylethoxymethyl)indol-5-yl]oxy-2-fluoro-phenyl]-1-methyl-imidazol-4-yl]-3- methyl-2H-benzofuran-7-yl]acetate (450 mg, 73.5%) as a white solid. MS (ESI): 692 m / z (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.65-7.56 (m, 2H), 7.33 (t, J = 9.2 Hz, 1H), 7.11- 7.04 (m, 2H), 7.04-6.99 (m, 3H), 6.79 (t, J = 7.6 Hz, 1H), 6.63 (d, J = 2.8 Hz, 1H), 5.57 (s, 2H), 4.74 (d, J = 8.4 Hz, 1H), 4.34 (d, J = 8.4 Hz, 1H), 4.07 (q, J = 7.2 Hz, 2H), 3.57 (s, 2H), 3.49-3.43 (m, 5H), 1.56 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H), 0.81 (t, J = 8.0 Hz, 2H), -0.12 (s, 9H) ppm. Ethyl 2-(3-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1-methyl-1H-imidazol-4- yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate

[0204] Step E: A mixture of ethyl 2-[3-[2-[5-[4,6-difluoro-1-(2- trimethylsilylethoxymethyl)indol-5-yl]oxy-2-fluoro-phenyl]-1-methyl-imidazol-4-yl]-3- methyl-2H-benzofuran-7-yl]acetate (370 mg, 0.54 mmol) and TBAF (5.4 mL, 1 M in THF) in THF (5 mL) was stirred at 80 °C for 7 hours. The solution was cooled to room temperature, treated with saturated aqueous ammonium chloride solution (40 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated to give crude ethyl 2-[3-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2- fluoro-phenyl]-1-methyl-imidazol-4-yl]-3-methyl-2H-benzofuran-7-yl]acetate (300 mg, 99.9%) as a light brown solid. MS (ESI): 562 m / z (M+H)+. 2-(3-(2-(5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1-methyl-1H-imidazol-4-yl)-3- methyl-2,3-dihydrobenzofuran-7-yl)acetic acid

[0205] Step F: A mixture of ethyl 2-[3-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro- phenyl]-1-methyl-imidazol-4-yl]-3-methyl-2H-benzofuran-7-yl]acetate (300 mg, 0.53 mmol) and NaOH (85.5 mg, 2.1 mmol) in THF / methanol / H2O was stirred at room temperature for 16 hours. The mixture was purified by prep-HPLC to afford 2-[3-[2-[5-[(4,6-difluoro-1H-indol- 5-yl)oxy]-2-fluoro-phenyl]-1-methyl-imidazol-4-yl]-3-methyl-2H-benzofuran-7-yl]acetic acid (3.6 mg, 1.2 %) as a white solid. MS (ESI): 534 m / z (M+H)+.1H NMR (400 MHz, MeOH- d4) δ 7.30 (d, J = 3.2 Hz, 1H), 7.22 (t, J = 9.2 Hz, 1H), 7.17-7.00 (m, 5H), 6.84 (t, J = 7.2 Hz, 1H), 6.80 (s, 1H), 6.54 (dd, J = 3.2, 0.8 Hz, 1H), 4.68 (d, J = 8.4 Hz, 1H), 4.37 (d, J = 8.8 Hz, 1H), 3.55 (s, 2H), 3.51 (d, J = 1.6 Hz, 3H), 1.65 (s, 3H) ppm. Example 24. Synthesis of (S)-2-(3-(1-(2-fluoro-5-((6-fluoro-4-((methylsulfonyl)methyl)- 1H-indol-5-yl)oxy)phenyl)-1H-pyrazol-3-yl)-3-methyl-2,3-dihydrobenzofuran-7- yl)acetic acid Example 25. Synthesis (R)-2-(3-(1-(2-fluoro-5-((6-fluoro-4-((methylsulfonyl)methyl)- 1H-indol-5-yl)oxy)phenyl)-1H-pyrazol-3-yl)-3-methyl-2,3-dihydrobenzofuran-7- yl)acetic acidy yyyyl 2-(3-(1-(2-fluoro-5-((6-fluoro-4-((methylsulfonyl)methyl)-1H-indol-5-yl)oxy)phenyl)- 1H-pyrazol-3-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate

[0206] Step A: A mixture of 6-fluoro-5-(4-fluoro-3-iodo-phenoxy)-4-(methylsulfonylmethyl)- 1H-indole (Intermediate 6; 1.2 g, 2.6 mmol), ethyl 2-[3-methyl-3-(1H-pyrazol-3-yl)-2H- benzofuran-7-yl]acetate (Step F, Example 16 ; 742 mg, 2.59 mmol), and Na2CO3(549 mg, 5.18 mmol) in NMP was added (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (147 mg, 1.04 mmol), CuI (98.7 mg, 0.52 mmol) and the mixture was stirred at 100 °C for 16 hours under Ar. After cooling to room temperature, the mixture was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with H2O (50 mL x 2), brine (50 mL x 2), dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting 1 / 1 with petroleum ether / ethyl acetate, to give ethyl 2-[3-[1-[2-fluoro-5-[[6-fluoro-4- (methylsulfonylmethyl)-1H-indol-5-yl]oxy]phenyl]pyrazol-3-yl]-3-methyl-2H-benzofuran-7- yl]acetate (0.4 g, 25%) as a white solid. MS (ESI): 622 m / z (M+H)+. Ethyl (S)-2-(3-(1-(2-fluoro-5-((6-fluoro-4-((methylsulfonyl)methyl)-1H-indol-5- yl)oxy)phenyl)-1H-pyrazol-3-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate and ethyl (R)- 2-(3-(1-(2-fluoro-5-((6-fluoro-4-((methylsulfonyl)methyl)-1H-indol-5-yl)oxy)phenyl)-1H- pyrazol-3-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetate

[0207] Step B: The racemic mixture, ethyl 2-[3-[1-[2-fluoro-5-[[6-fluoro-4- (methylsulfonylmethyl)-1H-indol-5-yl]oxy] phenyl]pyrazol-3-yl]-3-methyl-2H-benzofuran-7- yl]acetate was separated by SFC into its constituent enantiomers. The absolute configuration of the faster eluting enantiomer was arbitrarily assigned as ethyl 2-[(3S)-3-[1-[2-fluoro-5-[[6- fluoro-4-(methylsulfonylmethyl)-1H-indol-5-yl]oxy]phenyl]pyrazol-3-yl]-3-methyl-2H- benzofuran-7-yl]acetate (160 mg, 40%), and that of the slower eluting enantiomer as ethyl 2- [(3R)-3-[1-[2-fluoro-5-[[6-fluoro-4-(methylsulfonylmethyl)-1H-indol-5- yl]oxy]phenyl]pyrazol-3-yl]-3-methyl-2H-benzofuran-7-yl]acetate (160 mg, 40%). MS (ESI): 622 m / z (M+H)+observed for both enantiomers. SFC separation conditions: Instrument: SFC-80 (Thar, Waters) Column: OJ 20 * 250 mm, 10 µm (Daicel) Column temperature: 35 ºC Mobile phase: 45 / 55 CO2 / MeOH (0.2% ammonia in methanol) Flow rate: 80 g / min; Back pressure: 100 bar Detection wavelength: 214 nm Cycle time: 4.5 min Sample solution: 400 mg dissolved in 35 ml; Methanol Injection volume: 1.9 ml (S)-2-(3-(1-(2-Fluoro-5-((6-fluoro-4-((methylsulfonyl)methyl)-1H-indol-5-yl)oxy)phenyl)-1H- pyrazol-3-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid

[0208] Step C: To a solution of ethyl 2-[(3S)-3-[1-[2-fluoro-5-[[6-fluoro-4- (methylsulfonylmethyl)- 1H-indol-5-yl]oxy]phenyl]pyrazol-3-yl]-3-methyl-2H-benzofuran-7- yl]acetate (160 mg, 0.26 mmol) in THF (9 mL) and MeOH (3 mL) was added LiOH (30.8 mg, 1.3 mmol) at 0 °C. The solution was warmed to room temperature and stirred for 3 hours. After removing the solvent under reduced pressure, water was added and the pH of the mixture was adjusted to ~6 with 1N hydrochloric acid. The precipitate was isolated by filtration and air- dried to give 2-[(3S)-3-[1-[2-fluoro-5-[[6-fluoro-4-(methylsulfonylmethyl)-1H-indol-5- yl]oxy]phenyl]pyrazol-3-yl]-3-methyl-2H-benzofuran-7-yl]acetic acid (102 mg, 66%) as a white solid. MS (ESI): 594 m / z (M+H)+. NMR (400 MHz, CD3OD) δ 8.02 (t, J = 2.8 Hz, 1H), 7.50-7.33 (m, 3H), 7.25 (dd, J = 11.2, 9.2 Hz, 1H), 7.04-7.08 (m, 2H), 6.83 (dt, J = 9.2, 3.2 Hz, 1H), 6.78 (t, J = 7.6 Hz, 1H), 6.74 (dd, J = 3.2, 0.8 Hz, 1H), 6.36 (d, J = 2.8 Hz, 1H), 4.81 (d, J = 8.8 Hz, 1H), 4.70 (s, 2H), 4.46 (d, J = 8.8 Hz, 1H), 3.60 (s, 2H), 2.97 (s, 3H), 1.71 (s, 3H) ppm. (R)-2-(3-(1-(2-Fluoro-5-((6-fluoro-4-((methylsulfonyl)methyl)-1H-indol-5-yl)oxy)phenyl)-1H- pyrazol-3-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)acetic acid

[0209] Step D: To a solution of ethyl 2-[(3R)-3-[1-[2-fluoro-5-[[6-fluoro-4- (methylsulfonylmethyl)- 1H-indol-5-yl]oxy]phenyl]pyrazol-3-yl]-3-methyl-2H-benzofuran-7- yl]acetate (160 mg, 0.26 mmol) in THF (9 mL) and MeOH (3 mL) was added LiOH (30.8 mg, 1.3 mmol) at 0 °C. The solution was warmed to room temperature and stirred for 3 hours. After removing the solvent, water was added, and the pH of the mixture was adjusted to ~6 with 1N hydrochloric acid. The precipitate was filtered and air-dried to give 2-[(3R)-3-[1-[2-fluoro-5- [[6-fluoro-4-(methylsulfonylmethyl)-1H-indol-5-yl]oxy]phenyl]pyrazol-3-yl]-3-methyl-2H- benzofuran-7-yl]acetic acid (83.8 mg, 54.9%) as a white solid. MS (ESI): 594 m / z (M+H)+.1H NMR (400 MHz, CD3OD) δ 8.02 (t, J = 2.8 Hz, 1H), 7.50-7.33 (m, 3H), 7.25 (dd, J = 11.2, 9.2 Hz, 1H), 7.04-7.08 (m, 2H), 6.83 (dt, J = 3.2, 9.2 Hz, 1H), 6.78 (t, J = 7.6 Hz, 1H), 6.74 (dd, J = 0.8, 3.2 Hz, 1H), 6.36 (d, J = 2.8 Hz, 1H), 4.81 (d, J = 8.8 Hz, 1H), 4.70 (s, 2H), 4.46 (d, J = 8.8 Hz, 1H), 3.60 (s, 2H), 2.97 (s, 3H), 1.71 (s, 3H) ppm. Example 26. Synthesis of (R)-3-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)propanoic acid Example 27. Synthesis of (S)-3-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)propanoic acid 2-Bromo-1-(8-bromo-4-methylchroman-4-yl)ethan-1-one

[0210] Step A: To a solution of 8-bromo-4-methyl-chromane-4-carboxylic acid (Step A, Example 17 ; 1.50 g, 5.53 mmol, 1 eq) in DCM (20 mL) was added oxalyl chloride (0.97 mL, 11.1 mmol) and a drop of DMF. The mixture was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in acetonitrile (30 mL). Trimethylsilyldiazomethane (11 mL, 22.1 mmol) was added at 0 °C. The mixture was stirred at room temperature overnight. A hydrogen bromide solution (35% in water, 10 mL) was added at 0 °C and stirring continued for 30 minutes. The reaction was diluted with 200 mL of water and extracted with ethyl acetate (200 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated. The crude was purified by silica gel column chromatography, eluting with 0-15% ethyl acetate in petroleum ether, to give 2-bromo- 1-(8-bromo-4-methyl-chroman-4-yl)ethanone as a colorless liquid (1.60 g, 4.60 mmol, 83%). MS (ESI): 347.0 m / z (M+H)+. 5-(3-(4-(8-Bromo-4-methylchroman-4-yl)-1H-imidazol-2-yl)-4-fluorophenoxy)-4,6-difluoro- 1H-indole

[0211] Step B: To a solution of 2-bromo-1-(8-bromo-4-methyl-chroman-4-yl)ethanone (1.00 eq, 1.75 g, 5.03 mmol) in DMF (20 mL) was added 5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2- fluoro-benzamidine (Intermediate 2; 1.53 g, 5.03 mmol) and sodium bicarbonate (845 mg, 10.1 mmol). The mixture was stirred at 75 °C overnight, cooled to room temperature, diluted with 100 mL of water, and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated. The crude was purified by silica gel column chromatography, eluting with 0-35% ethyl acetate in petroleum ether, to give 5-[3- [4-(8-bromo-4-methyl-chroman-4-yl)-1H-imidazol-2-yl]-4-fluoro-phenoxy]-4,6-difluoro-1H- indole as a yellow solid (2.10 g, 3.79 mmol, 75%). MS (ESI): 554.0, 556 m / z (M+H)+. Ethyl (E)-3-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4- methylchroman-8-yl)acrylate

[0212] Step C: To a solution of 5-[3-[4-(8-bromo-4-methyl-chroman-4-yl)-1H-imidazol-2-yl]- 4-fluoro-phenoxy]-4,6-difluoro-1H-indole (1.00 eq, 900 mg, 1.62 mmol) in 1,4-dioxane (30 mL) and water (6 mL) was added under N2 ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)prop-2-enoate (734 mg, 3.25 mmol), Pd(dppf)Cl2dichloromethane complex (133 mg, 0.162 mmol) and potassium carbonate (224 mg, 1.62 mmol). The mixture was stirred at 95 °C for 4 hours, cooled to room temperature, diluted with 100 mL of water, and extracted with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated. The crude was purified by silica gel column chromatography, eluting with 0-40% ethyl acetate in petroleum ether, to give ethyl (E)-3-[4-[2-[5-[(4,6-difluoro- 1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]prop-2- enoate as a white solid (510 mg, 0.889 mmol, 55%). MS (ESI): 574.0 m / z (M+H)+. Ethyl (R,E)-3-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)- 4-methylchroman-8-yl)acrylate and ethyl (S,E)-3-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)- 2-fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)acrylate

[0213] Step D: The racemic mixture, ethyl (E)-3-[4-[2-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]- 2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]prop-2-enoate (510 mg, 0.889 mmol) was separated by chiral SFC into its constituent enantiomers. The absolute configuration of the faster eluting enantiomer (Stereoisomer 1) was arbitrarily assigned as ethyl (R,E)-3-(4- (2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4- methylchroman-8-yl)acrylate (190 mg, 0.331 mmol, 37%, a white solid), while the absolute configuration of the slower eluting enantiomer (Stereoisomer 2) was assigned as ethyl (S,E)- 3-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4- methylchroman-8-yl)acrylate (205 mg, 0.357 mmol, 40%, a white solid). Chiral SFC Conditions: Instrument: SFC-150 (Waters) Column: OJ 20 * 250 mm, 10 µm (Daicel) Column temperature: 35 ºC Mobile phase: 65 / 35 CO2 / (7M ammonia in MeOH) Flow rate: 100 g / min; Back pressure: 100 bar Detection wavelength: 214 nm Cycle time: 4.7 min Sample solution 500 mg dissolved in 40 ml methanol; Injection volume: 2 ml Ethyl (R)-3-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-

[0214] Step E: To a solution of ethyl (R,E)-3-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)acrylate (1.00 eq, 135 mg, 0.235 mmol) in methanol (20mL) was added Pd / C (10 wt. %, 0.10 eq, 25 mg) and the mixture was stirred under a H2atmosphere at room temperature for 2 hours. The reaction suspension was filtered, and the filtrate was concentrated to give ethyl (R)-3-(4-(2-(5-((4,6-difluoro-1H-indol- 5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)propanoate as a white solid (114 mg, 0.198 mmol, 84%). MS (ESI): 576.3 m / z (M+H)+. Ethyl (S)-3-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-

[0215] Step F: To a solution of ethyl (S,E)-3-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)acrylate (120 mg, 0.209 mmol) in methanol (20 mL) was added Pd / C (10 wt. %, 22 mg, 0.0209 mmol) and stirred under a H2atmosphere at room temperature for 2 hours. The reaction suspension was filtered, and the filtrate was concentrated to give ethyl (S)-3-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)propanoate as a white solid (103 mg, 0.179 mmol, 85.5%). MS (ESI): 576.3 m / z (M+H)+. (R)-3-(4-(2-(5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-

[0216] Step G: To a solution of ethyl (R,E)-3-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)acrylate (114 mg, 0.198 mmol) in methanol (8 mL), THF (8 mL) and water (4 mL) was added lithium hydroxide monohydrate (42 mg, 0.990 mmol). The mixture was stirred at room temperature for 2 hours, diluted with 30 mL of water, acidified with hydrochloric acid to pH~4, and extracted with ethyl acetate (40 mL x 3). The combined organic phase was washed with brine, dried over Na2SO4, and concentrated to give (R)-3-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H- imidazol-4-yl)-4-methylchroman-8-yl)propanoic acid as a white solid (86 mg, 0.157 mmol, 79 %). MS (ESI): 548.2 m / z (M+H)+, retention time: 1.59 min. LC-MS Method: Column: HALO C18 (4.6 x 30 mm, 3.7 µm) Mobile phase A: 0.01% TFA in water ; Mobile Phase B: 0.01% TFA in acetonitrile Elution program: Gradient from 5 to 95% of B in 1.5 minutes at 2 ml / min Column temperature: 40 ºC Detection wavelength: 214 nm, 254 nm ; MS: ESI, Positive mode, 110 to 1000 amu (S)-3-(4-(2-(5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-

[0217] Step H: To a solution of ethyl (S)-3-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)propanoate (103 mg, 0.179 mmol) in methanol (8 mL), THF (8 mL) and water (4 mL) was added lithium hydroxide monohydrate (38 mg, 0.895 mmol). The mixture was stirred at room temperature for 2 hours, diluted with 30 mL of water, acidified with HCl solution to pH=4, and extracted with Ethyl acetate (40 mL * 3). The combined organic phase was washed with brine, dried over Na2SO4and concentrated to give (S)-3-(4-(2-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)- 4-methylchroman-8-yl)propanoic acid as a white solid (67 mg, 0.122 mmol, 68%). MS (ESI): 548.2 m / z (M+H)+, retention time: 1.59 min. LC-MS Method: Column: HALO C18 (4.6 x 30 mm, 3.7 µm) Mobile phase A: 0.01% TFA in water ; Mobile Phase B: 0.01%TFA in acetonitrile Elution program: Gradient from 5 to 95% of B in 1.5 minutes at 2 ml / min Column temperature: 40 ºC Detection wavelength: 214 nm, 254 nm ; MS: ESI, Positive mode, 110 to 1000 amu Example 28. Synthesis of (R)-3-(3-(2-(2-fluoro-5-((6-fluoro-4-(methylsulfonyl)-1H- indol-5-yl)oxy)phenyl)-1H-imidazol-5-yl)-3-methyl-2,3-dihydrobenzofuran-7- yl)propanoic acid Example 29. Synthesis of (S)-3-(3-(2-(2-fluoro-5-((6-fluoro-4-(methylsulfonyl)-1H- indol-5-yl)oxy)phenyl)-1H-imidazol-5-yl)-3-methyl-2,3-dihydrobenzofuran-7- yl)propanoic acid (E)-7-(3-Methoxy-3-oxoprop-1-en-1-yl)-3-methyl-2,3-dihydrobenzofuran-3-carboxylic acid

[0218] Step A: To a solution of 7-bromo-3-methyl-2H-benzofuran-3-carboxylic acid(Step H, Example 1 ; 3400 mg, 13.2 mmol), palladium (II) acetate (297 mg, 0.1 eq), tri(2- methylphenyl)phosphine (1.89 g, 0.2 eq), and Et3N (6.69 g, 5 eq) in DMF (5 ml), was added ethyl acrylate (5.69 g, 5.0 eq). The mixture was stirred at 120 °C under microwave irradiation for two hours. Water was added to the cooled reaction, and the resulting mixture was extracted with EtOAc (100 ml x 3) and washed with saturated aqueous LiCl. The organic layer was concentrated under reduced pressure. The crude was further purified by column chromatography on silica gel, eluting with 25:2 DCM:methanol, to provide the pure title compound (3100 mg, 89%). MS (ESI): 263.1 m / z (M+H)+. 7-(3-Methoxy-3-oxopropyl)-3-methyl-2,3-dihydrobenzofuran-3-carboxylic acid

[0219] Step B: To a solution of 7-[(E)-3-methoxy-3-oxo-prop-1-enyl]-3-methyl-2H- benzofuran-3-carboxylic acid (6.2 g, 23.6 mmol) in MeOH (200 mL) was added Pd / C (10 wt. %, 1.0 g) and the resulting suspension was stirred at room temperature under H2for 4 hours. After the reaction was judged complete by LC-MS, the mixture was filtered and concentrated under reduced pressure to provide the product, 7-(3-methoxy-3-oxopropyl)-3- methyl-2,3-dihydrobenzofuran-3-carboxylic acid (1.2 g, 19.2%). MS (ESI): 265.1 m / z (M+H)+.1H NMR (400 MHz, DMSO-d6) δ 7.15 (dd, J = 7.5, 1.2 Hz, 1H), 7.02 (d, J = 7.6 Hz, 1H), 6.81 (t, J = 7.5 Hz, 1H), 4.94 (d, J = 9.1 Hz, 1H), 4.25 (d, J = 9.1 Hz, 1H), 3.58 (s, 3H), 2.77 (t, J = 7.7 Hz, 2H), 2.59 (t, J = 7.7 Hz, 2H), 1.50 (s, 3H) ppm. Methyl 3-(3-(2-bromoacetyl)-3-methyl-2,3-dihydrobenzofuran-7-yl)propanoate

[0220] Step C: A solution of 7-(3-methoxy-3-oxopropyl)-3-methyl-2,3-dihydrobenzofuran-3- carboxylic acid (0.5 g, 1.9 mmol) in 5 mL of SOCl2was stirred at 70 °C for 1 hour. The volatiles were removed under reduced pressure. The residue was dissolved in 10 mL of acetonitrile and cooled to 0 °C. Trimethylsilyldiazomethane (0.86 g, 7.6 mmol) was added dropwise, and the solution was slowly allowed to warm to room temperature and stirred overnight. The solvent was removed under reduced pressure. The mixture was dissolved in 50 mL of acetonitrile and cooled to 0 °C. Hydrobromic acid (43% wt.) was added dropwise, and the mixture was stirred for 20 minutes until gas evolution stopped. Water was added and the mixture was extracted with EtOAc (50 ml x 3). The combined organic extracts were washed with NaHCO3, brine, dried over Na2SO4, and concentrated. The residue was further purified by column chromatography on silica, eluting with 10:1 petroleum ether:ethyl acetate (PE: EA = 10:1) to provide the pure product, methyl 3-(3-(2-bromoacetyl)-3-methyl-2,3- dihydrobenzofuran-7-yl)propanoate (0.6 g, 92.9%). MS (ESI): 341.1, 343.1 m / z (M+H)+. 2-Fluoro-5-((6-fluoro-4-(methylthio)-1H-indol-5-yl)oxy)benzimidamide

[0221] Step D: To a solution of 2-fluoro-5-[(6-fluoro-4-methylsulfanyl-1H-indol-5- yl)oxy]benzonitrile (Intermediate 7; 1.0 g, 3.16 mmol) in THF (30 mL) was added at 0 °C under a nitrogen atmosphere lithium bis(trimethylsilyl)amide (25.3 mL, 25.3 mmol). The reaction was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was filtered and concentrated under reduced pressure to give the product, 2-fluoro-5- ((6-fluoro-4-(methylthio)-1H-indol-5-yl)oxy)benzimidamide (960 mg, 91%). MS (ESI): 334.1 m / z (M+H)+. Methyl 3-(3-(2-(2-fluoro-5-((6-fluoro-4-(methylthio)-1H-indol-5-yl)oxy)phenyl)-1H-imidazol- 5-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)propanoate

[0222] Step E: To a solution of 2-fluoro-5-[(6-fluoro-4-methylsulfanyl-1H-indol-5- yl)oxy]benzamidine (Step D; 734 mg, 2.2 mmol) and methyl 3-[3-(2-bromoacetyl)-3-methyl- 2H-benzofuran-7-yl]propanoate (Step C; 676 mg, 2 mmol) in DMF (5 mL) was added NaHCO3(227 mg, 2.7 mmol). The mixture was stirred for 16 hours at 75 °C. After the reaction was judged complete by LC-MS, water was added and the mixture was extracted with EtOAc (50 ml x 3), The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated. The residue was further purified by column chromatography on silica gel, eluting with 3:1 petroleum ether in EtOAc to provide the pure product, methyl 3-(3-(2-(2- fluoro-5-((6-fluoro-4-(methylthio)-1H-indol-5-yl)oxy)phenyl)-1H-imidazol-5-yl)-3-methyl- 2,3-dihydrobenzofuran-7-yl)propanoate (767 mg, 60.5%). MS (ESI): 576.2 m / z (M+H)+. Methyl 3-(3-(2-(2-fluoro-5-((6-fluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)phenyl)-1H- imidazol-5-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)propanoate

[0223] Step F: To a solution of methyl 3-[3-[2-[2-fluoro-5-[(6-fluoro-4-methylsulfanyl-1H- indol-5-yl)oxy]phenyl]-1H-imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]propanoate (767 mg, 1.33 mmol) in MeOH (10 mL) was added dropwise at 0 °C a solution of ammonium molybdate tetrahydrate (1650 mg, 1.33 mmol) in aqueous hydrogen peroxide (7.67 mL), and the resulting mixture stirred for 2 hours at 25 °C . After the reaction was judged complete by LC-MS, water was added and the mixture was extracted with EtOAc (50 ml x 3), washed with brine, dried over Na2SO4, and concentrated. The residue was further purified by column chromatography on silica gel, eluting with 1:1 petroleum ether:ethyl acetate, to provide the pure product, methyl 3-(3-(2-(2-fluoro-5-((6-fluoro-4-(methylsulfonyl)-1H-indol-5- yl)oxy)phenyl)-1H-imidazol-5-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)propanoate (250 mg, 30.9%). MS (ESI): 608.2 m / z (M+H)+. Methyl (R)-3-(3-(2-(2-fluoro-5-((6-fluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)phenyl)-1H- imidazol-5-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)propanoate and methyl (S)-3-(3-(2-(2- fluoro-5-((6-fluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)phenyl)-1H-imidazol-5-yl)-3- methyl-2,3-dihydrobenzofuran-7-yl)propanoate

[0224] Step G: The racemic mixture, ethyl 3-[3-[2-[2-fluoro-5-[(6-fluoro-4-methylsulfonyl- 1H-indol-5-yl)oxy]phenyl]-1H-imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]propanoate (330 mg, 0.543 mmol) was separated into its constituent enantiomers by chiral-HPLC. The absolute configuration of the faster eluting enantiomer was arbitrarily assigned as methyl 3-[(3R)-3-[2- [2-fluoro-5-[(6-fluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]phenyl]-1H-imidazol-5-yl]-3- methyl-2H-benzofuran-7-yl]propanoate (80 mg, 24%), and the absolute configuration of the slower eluting enantiomer was assigned as methyl 3-[(3S)-3-[2-[2-fluoro-5-[(6-fluoro-4- methylsulfonyl-1H-indol-5-yl)oxy]phenyl]-1H-imidazol-5-yl]-3-methyl-2H-benzofuran-7- yl]propanoate (80 mg, 24%). MS (ESI): 608.2 m / z (M+H)+observed for both enantiomers. (R)-3-(3-(2-(2-Fluoro-5-((6-fluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)phenyl)-1H- imidazol-5-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)propanoic acid

[0225] Step H: To a mixture of methyl 3-[(3R)-3-[2-[2-fluoro-5-[(6-fluoro-4-methylsulfonyl- 1H-indol-5-yl)oxy]phenyl]-1H-imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]propanoate (80 mg, 0.132 mmol) in THF (1.5 mL) and MeOH (0.5 mL) was added 1N aqueous LiOH (0.5 mL). The reaction mixture was stirred at room temperature for 4 hours, the pH was adjusted to ~6 with hydrochloric acid and purified by reverse-phase flash chromatography on C18 silica to provide 3-[(3R)-3-[2-[2-fluoro-5-[(6-fluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]phenyl]-1H- imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]propanoic acid (Example 28, 64.5 mg, 82.5%) as a solid. MS (ESI): 594 m / z (M+H)+.1H NMR (400 MHz, CD3OD) δ 7.67 (d, J = 10.6 Hz, 1H), 7.58-7.50 (m, 2H), 7.27-7.18 (m, 2H), 7.05 (t, J = 8.0 Hz, 2H), 7.02-6.98 (m, 1H), 6.95 (s, 1H), 6.85 (t, J = 7.6 Hz, 1H), 4.73 (d, J = 8.8 Hz, 1H), 4.45 (d, J = 8.8 Hz, 1H), 3.34 (s, 3H), 2.90 (t, J = 7.8 Hz, 2H), 2.62 (t, J = 7.8 Hz, 2H), 1.71 (s, 3H) ppm. (S)-3-(3-(2-(2-Fluoro-5-((6-fluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)phenyl)-1H- imidazol-5-yl)-3-methyl-2,3-dihydrobenzofuran-7-yl)propanoic acid Step I: To a mixture of methyl 3-[(3S)-3-[2-[2-fluoro-5-[(6-fluoro-4-methylsulfonyl-1H-indol- 5-yl)oxy]phenyl]-1H-imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]propanoate (80 mg, 0.132 mmol) in THF (1.5 mL) and MeOH (0.5 mL) was added 1N aqueous LiOH (0.5 mL). The reaction mixture was stirred at room temperature for 4 hours, the pH was adjusted to ~6 with hydrochloric acid and purified by reverse-phase flash chromatography on C18 silica to provide 3-[(3S)-3-[2-[2-fluoro-5-[(6-fluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]phenyl]-1H- imidazol-5-yl]-3-methyl-2H-benzofuran-7-yl]propanoic acid (Example 29, 63.4 mg, 81.1%) as a solid. MS (ESI): 594 m / z (M+H)+.1H NMR (400 MHz, CD3OD) δ 7.66 (d, J = 10.6 Hz, 1H), 7.59-7.50 (m, 2H), 7.26-7.18 (m, 2H), 7.04 (t, J = 7.2 Hz, 2H), 6.98 (dt, J = 8.0 Hz, 3.4 Hz, 1H), 6.91 (s, 1H), 6.85 (t, J = 7.4 Hz, 1H), 4.73 (d, J = 8.8 Hz, 1H), 4.45 (d, J = 8.6 Hz, 1H), 3.34 (s, 3H), 2.90 (t, J = 7.8 Hz, 2H), 2.62 (t, J = 7.8 Hz, 2H), 1.70 (s, 3H) ppm. Example 30. Synthesis of 3-[(4S)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)oxy]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Ethyl 3-[(4S)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1H-imidazol-4- yl]-4-methyl-chroman-8-yl]propanoate and ethyl 3-[(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro- Step A: To a stirred solution of ethyl 3-[4-(2-bromoacetyl)-4-methyl-chroman-8-yl]propanoate (Intermediate 9) (1.00 eq, 250 mg, 0.677 mmol) and 2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)oxy]benzamidine (Intermediate 12) (1.00 eq, 0.22 g, 0.677 mmol) in DMF (10 mL) was added sodium bicarbonate (1.67 eq, 95 mg, 1.13 mmol). The mixture was stirred at 70 °C for 16 hours. The mixture was cooled to ambient temperature, diluted with ethyl acetate (60 ml), washed with water (2 x 20 ml), dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 0-80% ethyl acetate in petroleum ether, to afford the racemic mixture of ethyl 3-[4-[2-[2- fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman- 8-yl]propanoate (0.21 g, 0.354 mmol, 52 %) as a solid. MS (ESI): 594.0 m / z (M+H)+; retention time: 1.57 min (modified Method 2 – Gradient: T0min: 5% B: 95% B, T1.3min; Flow Rate: 1.8ml / min). The racemic mixture was separated by SFC into its chiral components, ethyl 3-[(4R)-4-[2-[2- fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman- 8-yl]propanoate (Product P1, 80 mg, 0.135 mmol, 38.10 % yield) (absolute configuration assigned arbitrarily) as a solid, and ethyl 3-[(4S)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)oxy]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (Product P2, 85 mg, 0.143 mmol, 40 % yield) (absolute configuration assigned arbitrarily and consistent with that of Product P1). Chiral Separation Conditions: Instrument: SFC-150 (Waters); Column: OJ 25 * 250 mm, 10 µm (Daicel); Column temperature: 35 ºC; Mobile phase: 80 / 20 CO2 / MeOH spiked with 0.2% of 7M NH3in MeOH; Flow rate: 100 ml / min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 6.8 min; Sample solution: 210 mg dissolved in 30 ml Methanol; Injection volume: 3.0 ml 3-[(4S)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]-4- methyl-chroman-8-yl]propanoic acid Step B: To a stirred solution of ethyl 3-[(4S)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)oxy]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (1.00 eq, 85 mg, 0.143 mmol) (from Step A, Product P2 - absolute configuration unknown and assigned arbitrarily) in THF (3 mL) and water(1 mL) was added lithium hydroxide monohydrate (5.00 eq, 30 mg, 0.716 mmol). The reaction was stirred at room temperature for 16 h. The mixture was acidified with 1.0 M hydrochloric acid to pH ~6 and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC to give 3-[(4S)-4- [2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]-4-methyl- chroman-8-yl]propanoic acid (48 mg, 0.0840 mmol, 59 % yield) (absolute configuration assigned consistent with starting material ester) as a solid.1H NMR (500 MHz, CD3OD) δ 7.49 (dd, J = 6.0, 3.5 Hz, 1H), 7.37 (d, J = 3.0 Hz, 1H), 7.19 (dd, J = 10.5, 9.0 Hz, 1H), 7.05 (d, J = 8.0 Hz, 1H), 7.00-6.94 (m, 2H), 6.75 (t, J = 7.5 Hz, 1H), 6.62 (t, J = 3.5Hz, 1H), 6.55 (s, 1H), 4.27-4.20 (m, 1H), 4.07-3.93 (m, 1H), 2.86 (t, J = 8.0 Hz, 2H), 2.54 (t, J =8.0 Hz, 2H), 2.49- 2.40 (m, 1H), 2.02-1.94(m, 1H), 1.70 (s, 3H) ppm. MS (ESI): 566.2 m / z (M+H)+; retention time: 1.57 min (modified Method 2 – Gradient: T0 min: 5% B: 95% B, T1.3 min; Flow Rate: 1.8 ml / min). Example 31. Synthesis of 3-[(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)oxy]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Prepared according to procedure described in Step B, Example 30 from ethyl 3-[(4R)-4-[2-[2- fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman- 8-yl]propanoate (Product P1, Step A, Example 30). The absolute configuration was assigned arbitrarily. MS (ESI): 566.2 m / z (M+H)+; retention time: 1.57 min (modified Method 2 – Gradient: T0 min: 5% B: 95% B, T1.3 min; Flow Rate: 1.8 ml / min). Example 32. Synthesis of 3-[(4S)-4-[2-[5-[[4-(difluoromethyl)-6,7-difluoro-1H-indol-5- yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Enantiomers of ethyl 3-[4-[2-[5-[[4-(difluoromethyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2- fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate Step A: To a stirred solution of 5-[[4-(difluoromethyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2- fluoro-benzamidine (Intermediate 10) (1.00 eq, 190 mg, 0.535 mmol) and ethyl 3-[4-(2- bromoacetyl)-4-methyl-chroman-8-yl]propanoate (Intermediate 9) (1.10 eq, 217 mg, 0.588 mmol) in DMF (4mL) was added under N2 sodium carbonate (2.00 eq, 90 mg, 1.07 mmol). The mixture was stirred overnight at rt. The reaction was concentrated to dryness. The residue was suspended in EtOAc (10 ml). The separated organics was washed with water (2 x 10 ml), brine (10 ml), dried over MgSO4, and concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with 0-50% EtOAc in petroleum ether to give ethyl 3-[4-[2-[5-[[4-(difluoromethyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (197 mg, 0.280 mmol, 52 % yield) . MS (ESI): 626.3 m / z (M+H)+; retention time: 1.76 min (modified Method 3 - Flow Rate: 1.8 ml / min). The racemic mixture was separated into its components via the chiral SFC method described in Example 30 affording (S)-3-(4-(2-(5-((4-(difluoromethyl)-6,7-difluoro-1H-indol-5-yl)oxy)- 2-fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)propanoic acid (Product P1, 76 mg) and (R)-3-(4-(2-(5-((4-(difluoromethyl)-6,7-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)propanoic acid (Product P2, 74 mg). The absolute configurations of the product enantiomers were assigned arbitrarily. (S)-3-(4-(2-(5-((4-(difluoromethyl)-6,7-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H- imidazol-4-yl)-4-methylchroman-8-yl)propanoic acid Step B: To a stirred solution of ethyl (S)-3-(4-(2-(5-((4-(difluoromethyl)-6,7-difluoro-1H- indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)propanoate (Product P1, Step A, 1.00 eq, 76 mg, 0.121 mmol) in THF (1.1 mL) was added methanol (0.4 mL) and lithium hydroxide monohydrate (3.00 eq). The mixture was stirred overnight at RT, partitioned between water and EtOAc. The separated organic phase was washed with water (2 x 10 mL), brine (10 mL), dried over sodium sulphate, filtered and concentrated. The residue was purified by Prep-HPLC to give (S)-3-(4-(2-(5-((4-(difluoromethyl)-6,7-difluoro-1H-indol- 5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)propanoic acid (20 mg, 0.0335 mmol, 27% yield) (product P1) as a white solid. MS (ESI): 598.2 m / z (M+H)+.1H NMR (500 MHz, CD3OD) δ 7.50 (dt, J = 8.5, 4.0 Hz, 1H), 7.47 (d, J = 3.0 Hz, 1H), 7.19 (dd, J = 6.5, 3.5Hz, 1H), 7.10-6.97 (m, 3H), 6.90 (dt, J = 9.0, 3.5 Hz, 1H), 6.76 (dd, J = 15.5, 8.0 Hz, 2H), 6.56 (s, 1H), 4.24 (ddd, J = 11.0, 6.0, 3.0 Hz, 1H), 4.06-4.00 (m, 1H), 2.86 (t, J = 7.5 Hz, 2H), 2.54 (dd, J = 8.5, 7.5 Hz, 2H), 2.46 (ddd, J = 13.5, 6.0, 2.5 Hz, 1H), 1.98 (ddd, J = 13.0, 9.0, 3.0 Hz, 1H), 1.70 (s, 3H). Example 33. Synthesis of 3-[(4R)-4-[2-[5-[[4-(difluoromethyl)-6,7-difluoro-1H-indol-5- yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Prepared according to procedure analogous to one described in Example 32, starting from ethyl (R)-3-(4-(2-(5-((4-(difluoromethyl)-6,7-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H- imidazol-4-yl)-4-methylchroman-8-yl)propanoate (Product P2, Step A, Example 32). The title compound was obtained as a white solid (28 mg, 0.0470 mmol, 40 % yield). MS (ESI): 598.2 m / z (M+H)+.1H NMR (400 MHz, CD3OD) δ 7.52 (d, J = 3.2 Hz, 1H), 7.49 (dd, J = 6.0, 3.2 Hz, 1H), 7.24 (dd, J = 10.4, 9.2 Hz, 1H), 7.05 (ddd, J = 12.4, 10.8, 9.2 Hz, 3H), 6.96-6.92 (m, 1H), 6.82-6.75 (m, 2H), 6.65 (s, 1H), 4.29-4.23 (m, 1H), 4.05 (ddd, J = 11.2, 9.2, 2.4 Hz, 1H), 2.87 (t, J = 7.6 Hz, 2H), 2.57 (t, J = 7.6 Hz, 2H), 2.45 (ddd, J = 13.6, 6.20, 2.4 Hz, 1H), 2.02- 1.96 (m, 1H), 1.72 (s, 3H). Example 34. Synthesis of (S)-3-(4-(5-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl)-4-methylchroman-8-yl)propanoic acid tert-Butyl N-[(8-bromo-4-methyl-chromane-4-carbonyl)amino]-N-methyl-carbamate Step A: To a solution of 8-bromo-4-methyl-chromane-4-carboxylic acid (Step A, Example 18) (1.00 eq, 1.50 g, 5.53 mmol) in MeCN (40 mL) was added 1-Boc-1-methylhydrazine (1.50 eq, 1213 mg, 8.30 mmol), N,N,N',N'-Tetramethylchloroformamidinium hexafluorophosphate (1.00 eq, 1552 mg, 5.53 mmol) and 1-methylimidazole (3.50 eq, 1.5 mL, 19.4 mmol). The mixture was stirred at room temperature for 2 hours, diluted with 100 mL of water and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine, dried over Na2SO4and concentrated. The residue was purified by silica gel column chromatography, eluting with 0~30% ethyl acetate in petroleum ether, to give tert-butyl N-[(8-bromo-4-methyl- chromane-4-carbonyl)amino]-N-methyl-carbamate (1.90 g, 4.76 mmol, 86.01 % yield) as a colorless liquid. MS (ESI): 421.0, 423 m / z (M+Na)+; retention time: 1.58 min (modified Method 2 – Gradient: T0 min: 5% B: 95% B, T1.3 min). 8-Bromo-N',4-dimethyl-chromane-4-carbohydrazide Step B: To a stirred solution of tert-butyl N-[(8-bromo-4-methyl-chromane-4- carbonyl)amino]-N-methyl-carbamate (1.00 eq, 1.90 g, 4.76 mmol) in DCM (20 mL) was added trifluoroacetic acid (4.00 eq, 1.5 mL, 19.0 mmol). The mixture was stirred at room temperature for 4 hours, diluted with 100 mL of water, and extracted with ethyl acetate (100 mL * 3). The combined organic phase was washed with the saturate NaHCO3solution and brine, dried over Na2SO4and concentrated to give 8-bromo-N',4-dimethyl-chromane-4- carbohydrazide (1.30 g, 4.35 mmol, 91 % yield) as a white solid. MS (ESI): 299.0, 301 m / z (M+H)+. 5-[3-[5-(8-Bromo-4-methyl-chroman-4-yl)-2-methyl-1,2,4-triazol-3-yl]-4-fluoro-phenoxy]- 4,6-difluoro-1H-indole Step C: To a solution of 8-bromo-N',4-dimethyl-chromane-4-carbohydrazide (1.00 eq, 1.30 g, 4.35 mmol) in pyridine (30 mL) was added methyl 5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2- fluoro-benzenecarboximidothioate (Intermediate 11, 1.00 eq, 1462 mg, 4.35 mmol) and magnesium sulfate (10.0 eq, 5231 mg, 43.5 mmol). The reaction mixture was stirred at 80 °C overnight, diluted with 300 mL of water and extracted with ethyl acetate (3 x 300 mL). The combined organic extracts were washed with brine, dried over Na2SO4and concentrated. The residue was purified by silica gel column chromatography, eluting with 0-30% ethyl acetate in petroleum ether, to give 5-[3-[5-(8-bromo-4-methyl-chroman-4-yl)-2-methyl-1,2,4-triazol-3- yl]-4-fluoro-phenoxy]-4,6-difluoro-1H-indole (1.90 g, 3.34 mmol, 77 % yield) as a yellow solid.1.3 min, MS (ESI): 569.2, 571.2 m / z (M+H)+; retention time: 2.00 min (modified Method 2 – Gradient: T0 min: 5% B: 95% B, T1.3 min). Enantiomers of ethyl (E)-3-[4-[5-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1- Step D: To a stirred solution of 5-[3-[5-(8-bromo-4-methyl-chroman-4-yl)-2-methyl-1,2,4- triazol-3-yl]-4-fluoro-phenoxy]-4,6-difluoro-1H-indole (1.00 eq, 950 mg, 1.67 mmol) in 1,4- dioxane (20 mL) and water (4 mL) was added ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)prop-2-enoate (2.00 eq, 754 mg, 3.34 mmol), 1,1′- bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (0.100 eq, 136 mg, 0.167 mmol) and potassium carbonate (3.00 eq, 692 mg, 5.01 mmol). The mixture was stirred at 100 °C for 3 hours, diluted with 100 mL of water and extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine, dried over Na2SO4and concentrated. The crude was purified by silica gel column chromatography, eluting with 0-40% ethyl acetate in petroleum ether, to give ethyl (E)-3-[4-[5-[5-[(4,6-difluoro-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1-methyl-1,2,4-triazol-3-yl]-4-methyl-chroman-8-yl]prop- 2-enoate (705 mg, 1.20 mmol, 72 % yield) as a yellow solid. 589.2 (M+H)+; retention time: 1.83 min (modified Method 2 – Gradient: T0 min: 5% B: 95% B, T1.3 min). The racemic ethyl (E)-3-[4-[5-[5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1- methyl-1,2,4-triazol-3-yl]-4-methyl-chroman-8-yl]prop-2-enoate (705 mg) was separated into its constituent enantiomers by SFC to give ethyl (S,E)-3-(4-(5-(5-((4,6-difluoro-1H-indol-5- yl)oxy)-2-fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl)-4-methylchroman-8-yl)acrylate (Product P1, 240 mg, 0.408 mmol, 34 % yield) as a white solid and ethyl (R,E)-3-(4-(5-(5- ((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl)-4- methylchroman-8-yl)acrylate (Product P2, 300 mg, 0.510 mmol, 43 % yield) as a white solid. The absolute configurations of these isolated pure enantiomers, product P1 and product P2, were assigned arbitrarily. Chiral SFC Separation Conditions: Instrument: SFC-150 (Waters); Column: (R,R)Whelk 20 * 250 mm, 10 µm; Column temperature: 35 ºC; Mobile phase: 65 / 35 CO2 / MeOH [spiked with 0.2% solution of 7M NH3in MeOH]; Flow rate: 100 g / min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 5.3 min; Sample solution 705 mg dissolved in 40 ml Methanol; Injection volume: 1 ml. Ethyl (S)-3-(4-(5-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1-methyl-1H-1,2,4- t Step E: To a stirred solution of ethyl (S,E)-3-(4-(5-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl)-4-methylchroman-8-yl)acrylate (1.00 eq, 205 mg, 0.348 mmol) in methanol (20 mL) was added Pd / C (10 wt. %, 0.100 eq, 37 mg, 0.0348 mmol). The suspension was stirred at ambient temperature and pressure under a H2atmosphere for 2 hours. The solids were filtered off and the filtrate was concentrated. The residue was purified by silica gel column chromatography, eluting with 0-35% of ethyl acetate in petroleum ether, to give ethyl (S)-3-(4-(5-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1- methyl-1H-1,2,4-triazol-3-yl)-4-methylchroman-8-yl)propanoate (180 mg, 0.305 mmol, 88 % yield) as a white solid. MS (ESI): 591.3 (M+H)+; retention time: 2.03 min (Method 4). (S)-3-(4-(5-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1-methyl-1H-1,2,4-triazol- Step F: To a stirred solution of ethyl (S)-3-(4-(5-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl)-4-methylchroman-8-yl)propanoate (1.00 eq, 180 mg, 0.305 mmol) in methanol (10 mL), THF (10 mL) and water (5 mL) was added lithium hydroxide monohydrate (5.00 eq, 64 mg, 1.52 mmol). The reaction mixture was stirred at room temperature for 2 hours, diluted with 40 mL of water, acidified with aqueous HCl to pH=5, and extracted with ethyl acetate (3 x 40 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated to give 3-[4-[5-[5-[(4,6-difluoro-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1-methyl-1,2,4-triazol-3-yl]-4-methyl-chroman-8-yl]propanoic acid (123 mg, 0.219 mmol, 72 % yield) as a white solid. MS (ESI): 563.3 (M+H)+; retention time: 1.57 min (Method 4). Example 35. Synthesis of (R)-3-(4-(5-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl)-4-methylchroman-8-yl)propanoic acid Prepared according to procedure described in Steps E and F, Example 34 from ethyl (R,E)-3- (4-(5-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl)- 4-methylchroman-8-yl)acrylate (Product P2, Step D, Example 34). MS (ESI): 563.3 (M+H)+; retention time: 1.57 min (Method 4). Example 36. Synthesis of (S,E)-3-(4-(5-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl)-4-methylchroman-8-yl)acrylic acid To a stirred solution of ethyl (S,E)-3-(4-(5-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl)-4-methylchroman-8-yl)acrylate (Product P1, Step D, Example 34, 1.00 eq, 70 mg, 0.122 mmol) in methanol (8 mL), THF (8 mL) and water (4 mL) was added lithium hydroxide monohydrate (5.00 eq, 26 mg, 0.610 mmol). The reaction mixture was stirred at room temperature for 3 hours, diluted with 20 mL of water, acidified with aqueous HCl to pH=4, and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with brine, dried over Na2SO4, and concentrated to give (S,E)-3-(4-(5- (5-((4,6-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl)-4- methylchroman-8-yl)acrylic acid (48 mg, 0.0876 mmol, 72 % yield) as a white solid. Retention time: 1.56 min (Method 4).1H NMR (400 MHz, CD3OD) δ 7.99 (d, 1H), 7.54 (dd, 1H), 7.45-7.42 (m, 1H), 7.38 (d, 1H), 7.34 (d, 2H), 7.26-7.22 (m, 1H), 7.16 (d, 2H), 6.95 (t, 1H), 6.57 (d, 1H), 6.53 (d, 1H), 4.45- 4.40 (m, 1H), 4.34-4.29 (m, 1H), 3.35 (3H, partial overlap with solvent peak), 2.52-2.45 (m, 1H), 2.19-2.14 (m, 1H), 1.86 (s, 3H). Example 37. Synthesis of (R,E)-3-(4-(5-(5-((4,6-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl)-4-methylchroman-8-yl)acrylic acid Prepared similarly to Example 36, starting from ethyl (R,E)-3-(4-(5-(5-((4,6-difluoro-1H- indol-5-yl)oxy)-2-fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl)-4-methylchroman-8- yl)acrylate (Product P2, Step D, Example 34). Retention time: 1.56 min (Method 4).1H NMR (400 MHz, CD3OD) δ 7.99 (d, 1H), 7.54 (dd, 1H), 7.45-7.42 (m, 1H), 7.38 (d, 1H), 7.34 (d, 2H), 7.26-7.22 (m, 1H), 7.16 (d, 2H), 6.95 (t, 1H), 6.57 (d, 1H), 6.53 (d, 1H), 4.45- 4.40 (m, 1H), 4.34-4.29 (m, 1H), 3.35 (3H, partial overlap with solvent peak), 2.52-2.45 (m, 1H), 2.19-2.14 (m, 1H), 1.86 (s, 3H). Example 38. Synthesis of 3-[(4R)-4-[5-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)oxy]phenyl]-1H-1,2,4-triazol-3-yl]-4-methyl-chroman-8-yl]propanoic acid Enantiomers of ethyl 3-[4-[5-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1H- 1,2,4-triazol-3-yl]-4-methyl-chroman-8-yl]propanoate Step A: To a stirred solution of 2-fluoro-5-((4,6,7-trifluoro-1H-indol-5-yl)oxy)benzimidamide (Intermediate 12, 1.00 eq, 440 mg, 1.36 mmol) and 8-(3-ethoxy-3-oxopropyl)-4- methylchromane-4-carboxylic acid (Intermediate 9E, 1.25 eq, 500 mg, 1.71 mmol) in DMF (5 mL) was added N,N-diisopropylethylamine (1.50 eq, 0.36 mL, 2.05 mmol) and HATU (1.50 eq, 781 mg, 2.06 mmol) at RT. The mixture was stirred at RT for 16 h, then treated with hydrazine sulfate (1.50 eq, 267 mg, 2.06 mmol) and acetic acid (4.00 eq, 0.31 mL, 5.48 mmol), and heated at 80 °C for 3 h. The mixture was diluted with ethyl acetate (5 mL), washed with water (3 x 5 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 0-70% ethyl acetate in petroleum ether, to give ethyl 3-(4-(5-(2-fluoro-5-((4,6,7-trifluoro-1H-indol-5-yl)oxy)phenyl)-1H-1,2,4-triazol-3-yl)- 4-methylchroman-8-yl)propanoate (300 mg, 0.505 mmol, 30 % yield) as a yellow solid. MS (ESI): 595 (M+H)+; retention time: 1.57 min (Method 4). The racemic mixture was separated into its constituent enantiomers by chiral SFC (method analogous to one described for Example 30) to give ethyl (R)-3-(4-(5-(2-fluoro-5-((4,6,7- trifluoro-1H-indol-5-yl)oxy)phenyl)-1H-1,2,4-triazol-3-yl)-4-methylchroman-8- yl)propanoate (100 mg, 0.168 mmol, Product P1, 33% yield), and ethyl (S)-3-(4-(5-(2-fluoro- 5-((4,6,7-trifluoro-1H-indol-5-yl)oxy)phenyl)-1H-1,2,4-triazol-3-yl)-4-methylchroman-8- yl)propanoate (90 mg, 0.152 mmol, Product P2, 30% yield). The absolute configurations of Product P1 and Product P2 were assigned arbitrarily and have not been determined experimentally. 3-[(4R)-4-[5-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1H-1,2,4-triazol-3-yl]- 4-methyl-chroman-8-yl]propanoic acid Step B: To a stirred solution of ethyl (R)-3-(4-(5-(2-fluoro-5-((4,6,7-trifluoro-1H-indol-5- yl)oxy)phenyl)-1H-1,2,4-triazol-3-yl)-4-methylchroman-8-yl)propanoate (100 mg, 0.168 mmol, Product P1) in water (2 mL) and THF (6 mL) was added lithium hydroxide monohydrate (0.055 g, 1.30 mmol). The reaction was stirred at room temperature overnight, acidified with 1.0 M hydrochloric acid to pH = 6, and extracted with ethyl acetate (3 x 10 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to give (R)-3-(4-(5-(2- fluoro-5-((4,6,7-trifluoro-1H-indol-5-yl)oxy)phenyl)-1H-1,2,4-triazol-3-yl)-4- methylchroman-8-yl)propanoic acid (71.9 mg, yield 75%) as solid. MS (ESI): 567 m / z (M+H)+; retention time: 1.99 min (modified Method 2 – Gradient: T0 min: 5% B: 95% B, T2.5 min).1H NMR (500 MHz, CD3OD) δ 7.50 (s, 1H), 7.37 (d, J = 3.0 Hz, 1H), 7.22 (s, 1H), 7.09-6.94 (m, 3H), 6.74 (s, 1H), 6.62 (t, J = 3.0 Hz, 1H), 4.35-4.15 (m, 2H), 2.87 (t, J = 7.5 Hz, 2H), 2.56 (dd, J = 8.5, 6.0 Hz, 3H), 2.06 (s, 1H), 1.81 (s, 3H) ppm. Example 39. Synthesis of 3-[(4S)-4-[5-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)oxy]phenyl]-1H-1,2,4-triazol-3-yl]-4-methyl-chroman-8-yl]propanoic acid Prepared in substantially the same way as Example 38, starting from ethyl (S)-3-(4-(5-(2- fluoro-5-((4,6,7-trifluoro-1H-indol-5-yl)oxy)phenyl)-1H-1,2,4-triazol-3-yl)-4- methylchroman-8-yl)propanoate (90 mg, 0.152 mmol, Product P2) to obtain the title compound, 72.1 mg, 84% yield. MS (ESI): 567 m / z (M+H)+; retention time: 1.99 min (modified Method 2 – Gradient: T0 min: 5% B: 95% B, T2.5 min).1H NMR (500 MHz, CD3OD) δ 7.51 (s, 1H), 7.37 (d, J = 3.0 Hz, 1H), 7.22 (t, J = 9.0 Hz, 1H), 7.08-6.94 (m, 3H), 6.75 (s, 1H), 6.62 (t, J = 3.0 Hz, 1H), 4.32-4.16 (m, 2H), 2.87 (t, J = 7.5 Hz, 2H), 2.61-2.50 (m, 3H), 2.07 (s, 1H), 1.81 (s, 3H) ppm. Example 40. Synthesis of 3-[(4R)-4-[5-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)oxy]phenyl]-1-methyl-1,2,4-triazol-3-yl]-4-methyl-chroman-8-yl]propanoic acid Prepared following similar procedure to one described in Step B, Example 38, starting from Product P1 (Step A, 120 mg, 0.197 mmol) to afford the title compound (72 mg,0.121 mmol, 61 % yield). The absolute configuration of the product was assigned arbitrarily. MS (ESI): 581.3 (M+H)+; retention time: 2.01 min (Method 3).1H NMR (400 MHz, CD3OD) δ 7.37 (d, J = 3.1 Hz, 1H), 7.29 (t, J = 9.2 Hz, 1H), 7.17 (dt, J = 9.0, 3.6 Hz, 1H), 7.12 (dd, J = 5.5, 3.2 Hz, 1H), 7.03-6.93 (m, 2H), 6.69 (t, J = 7.6 Hz, 1H), 6.61 (t, J = 2.6 Hz, 1H), 4.27 (t, J = 5.3 Hz, 2H), 3.76 (d, J = 1.7 Hz, 3H), 2.85 (t, J = 7.8 Hz, 2H), 2.64-2.49 (m, 3H), 2.01 (dt, J = 10.5, 5.0 Hz, 1H), 1.76 (s, 3H). Enantiomers of ethyl 3-(4-(5-(2-fluoro-5-((4,6,7-trifluoro-1H-indol-5-yl)oxy)phenyl)-1- methyl-1H-1,2,4-triazol-3-yl)-4-methylchroman-8-yl)propanoate Step A: To a stirred solution of ethyl 3-[4-methyl-4-(methylaminocarbamoyl)chroman-8- yl]propanoate (Intermediate 14, 1.00 eq, 350 mg, 1.09 mmol) in pyridine (5 mL) was added methyl 2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]benzenecarboximidothioate hydroiodide (1.00 eq, 527 mg, 1.09 mmol) and the mixture was stirred at 50 °C for 2 h. The reaction was diluted with EtOAc (60 ml), washed with water (2 x 30 ml) and brine (30 mL). The organic phase was dried over Na2SO4and concentrated to dryness. The residue was purified by flash column chromatography on silica eluting with 50% EtOAc in petroleum ether to afford racemic ethyl 3-(4-(5-(2-fluoro-5-((4,6,7-trifluoro-1H-indol-5-yl)oxy)phenyl)-1- methyl-1H-1,2,4-triazol-3-yl)-4-methylchroman-8-yl)propanoate. The racemic mixture was separated into its enantiomerically pure components by chiral SFC, following a method similar to the one described for Examples 35 and 36, to afford ethyl 3-[(4R)-4-[5-[2-fluoro-5-[(4,6,7- trifluoro-1H-indol-5-yl)oxy]phenyl]-1-methyl-1,2,4-triazol-3-yl]-4-methyl-chroman-8- yl]propanoate (Product P1, 120 mg, 0.197 mmol, 18.05 % yield) and ethyl 3-[(4S)-4-[5-[2- fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1-methyl-1,2,4-triazol-3-yl]-4-methyl- chroman-8-yl]propanoate (Product P2, 127 mg, 0.209 mmol, 19 % yield). The absolute configurations of both enantiomers have not been determined experimentally and were assigned arbitrarily. Ethyl 3-[(4R)-4-[5-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1-methyl-1,2,4- triazol-3-yl]-4-methyl-chroman-8-yl]propanoate (Product P1): MS (ESI): 609.2 (M+H)+; retention time 2.16 min (modified Method 2 - Gradient: T0 min: 5% B: 95% B, T1.3 min : 95%B; Flow: 1.8 mL / min). Ethyl 3-[(4S)-4-[5-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1-methyl-1,2,4- triazol-3-yl]-4-methyl-chroman-8-yl]propanoate (Product P2): MS (ESI): 609.2 (M+H)+; retention time 2.17 min (modified Method 2 - Gradient: T0 min: 5% B: 95% B, T1.3 min : 95%B; Flow: 1.8 mL / min). Example 41. Synthesis of 3-[(4S)-4-[5-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)oxy]phenyl]-1-methyl-1,2,4-triazol-3-yl]-4-methyl-chroman-8-yl]propanoic acid Prepared following similar procedure to one described in Step B, Example 38, starting from Product P2 (Step A, Example 40, 127 mg, 0.209 mmol) to afford the title compound (77 mg, 0.127 mmol, 61 % yield)). The absolute configuration of the product was assigned arbitrarily. MS (ESI): 581.3 (M+H)+; retention time: 2.01 min (Method 3). MS (ESI): 581.3 (M+H)+; retention time: 2.01 min (Method 3).1H NMR (400 MHz, CD3OD) δ 7.37 (d, J = 3.2 Hz, 1H), 7.29 (t, J = 9.2 Hz, 1H), 7.17 (dt, J = 9.1, 3.7 Hz, 1H), 7.12 (dd, J = 5.4, 3.2 Hz, 1H), 6.98 (ddd, J = 14.4, 7.6, 1.4 Hz, 2H), 6.69 (t, J = 7.6 Hz, 1H), 6.61 (t, J = 2.8 Hz, 1H), 4.27 (t, J = 5.3 Hz, 2H), 3.76 (d, J = 1.7 Hz, 3H), 2.85 (t, J = 7.8 Hz, 2H), 2.66-2.49 (m, 3H), 2.05-1.96 (m, 1H), 1.76 (s, 3H). Example 42. Synthesis of 3-[(4S)-4-[5-[5-[[4-(2,2-difluoroethyl)-6,7-difluoro-1H-indol- 5-yl]oxy]-2-fluoro-phenyl]-1-methyl-1,2,4-triazol-3-yl]-4-methyl-chroman-8- yl]propanoic acid Prepared following similar procedure to one described in Step B, Example 38, starting from Product P1 (Step A, 14 mg, 0.0214 mmol) to afford the title compound (3.0 mg, 0.00479 mmol, 22 % yield) as a white solid. The absolute configuration of the product was assigned arbitrarily. MS (ESI): 627.2 (M+H)+; retention time 1.92 (modified Method 2 - Gradient: T0 min: 5% B: 95% B, T1.3 min : 95%B; Flow: 1.8 mL / min).1H NMR (400 MHz, CD3OD) δ 7.40 (d, J = 3.2 Hz, 1H), 7.28 (t, J = 9.2 Hz, 1H), 7.08 (ddd, J = 8.8, 6.4, 3.2 Hz, 2H), 7.01-6.94 (m, 2H), 6.72-6.64 (m, 2H), 4.28 (t, J = 5.2 Hz, 2H), 3.76 (d, J = 1.6 Hz, 3H), 2.85 (dd, J = 8.0, 4.4 Hz, 2H), 2.60-2.54 (m, 2H), 2.04-1.98 (m, 2H), 1.76 (s, 3H). Enantiomers of ethyl 3-[4-[5-[5-[[4-(2,2-difluoroethyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2- Step A: The racemic ethyl 3-[4-[5-[5-[[4-(2,2-difluoroethyl)-6,7-difluoro-1H-indol-5-yl]oxy]- 2-fluoro-phenyl]-1-methyl-1,2,4-triazol-3-yl]-4-methyl-chroman-8-yl]propanoate (30 mg, 0.0438 mmol, 36 % yield) was obtained from methyl 5-((4-(2,2-difluoroethyl)-6,7-difluoro- 1H-indol-5-yl)oxy)-2-fluorobenzimidothioate hydroiodide (Intermediate 15, 1.00 eq, 49 mg, 0.093 mmol) and ethyl 3-[4-methyl-4-(methylaminocarbamoyl)chroman-8-yl]propanoate (Intermediate 14, 39 mg, 0.122 mmol) following procedure from Step A, Example 40. MS (ESI): 655.3 (M+H)+; retention time: 2.15 min (Method 3). The racemic mixture was separated into its enantiomerically pure components by chiral SFC, following a method similar to the one described for Examples 35 and 36, to afford ethyl (S)-3- (4-(5-(5-((4-(2,2-difluoroethyl)-6,7-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1-methyl- 1H-1,2,4-triazol-3-yl)-4-methylchroman-8-yl)propanoate (Product P1, 14 mg, 0.0214 mmol) and ethyl (R)-3-(4-(5-(5-((4-(2,2-difluoroethyl)-6,7-difluoro-1H-indol-5-yl)oxy)-2- fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl)-4-methylchroman-8-yl)propanoate (Product P2, 14 mg, 0.0214 mmol). The absolute configurations of both enantiomers have not been determined experimentally and were assigned arbitrarily. Example 43. Synthesis of 3-[(4R)-4-[5-[5-[[4-(2,2-difluoroethyl)-6,7-difluoro-1H-indol- 5-yl]oxy]-2-fluoro-phenyl]-1-methyl-1,2,4-triazol-3-yl]-4-methyl-chroman-8- yl]propanoic acid Prepared similarly to Example 42 starting from Product P2 (Step A, Example 42, 14 mg, 0.0214 mmol) to afford the title compound (1.1 mg, 0.00176 mmol, 8 % yield) as a white solid. The absolute configuration of the product was assigned arbitrarily. MS (ESI): 627.2 (M+H)+; retention time 1.92 (modified Method 2 - Gradient: T0 min: 5% B: 95% B, T1.3 min : 95%B; Flow: 1.8 mL / min).1H NMR (500 MHz, CD3OD) δ 7.40 (dd, J = 8.5, 3.0 Hz, 1H), 7.27 (t, J = 9.0 Hz, 1H), 7.14- 7.03 (m, 2H), 6.98 (dd, J = 15.0, 7.5 Hz, 2H), 6.69 (t, J = 7.5 Hz, 1H), 6.65 (t, J = 3.0 Hz, 1H), 6.25-5.92 (m, 1H), 4.27 (t, J = 5.0 Hz, 2H), 3.76 (d, J = 1.5 Hz, 3H), 3.37 (dt, J = 15.5, 7.5 Hz, 2H), 2.85 (t, J = 7.5 Hz, 2H), 2.66-2.49 (m, 3H), 2.03-1.96 (m, 1H), 1.76 (s, 3H). Example 44. Synthesis of 3-(4-(5-(5-((6,7-difluoro-4-(methylthio)-1H-indol-5-yl)oxy)-2- fluorophenyl)-1-methyl-1H-1,2,4-triazol-3-yl)-4-methylchroman-8-yl)propanoic acid Ethyl 3-[4-[5-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1- Step A: To a stirred solution of ethyl 3-[4-methyl-4-(methylaminocarbamoyl)chroman-8- yl]propanoate (Intermediate 14, 1.00 eq, 1.26 g, 3.92 mmol) in pyridine (18 mL) was added methyl 5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro- benzenecarboximidothioate hydroiodide (Intermediate 16 1.00 eq, 1.50 g, 3.92 mmol) and magnesium sulfate (1.69 eq, 800 mg, 6.65 mmol). The reaction mixture was stirred at 80 °C for 6 h, concentrated, diluted with water (20 mL), acidified (pH < 7) with hydrochloric acid (1 M), and extracted with ethyl acetate (50 mL). The organic extract was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-32% ethyl acetate in petroleum ether to give ethyl 3-[4-[5-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1- methyl-1,2,4-triazol-3-yl]-4-methyl-chroman-8-yl]propanoate (1.10 g, 1.73 mmol, 44 % yield) as a solid. MS (ESI): 637.3 (M+H)+; retention time: 2.22 min (Method 3). 3-(4-(5-(5-((6,7-Difluoro-4-(methylthio)-1H-indol-5-yl)oxy)-2-fluorophenyl)-1-methyl-1H- 1,2,4-triazol-3-yl)-4-methylchroman-8-yl)propanoic acid Step B: To a stirred solution of ethyl 3-[4-[5-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1-methyl-1,2,4-triazol-3-yl]-4-methyl-chroman-8-yl]propanoate (1.00 eq, 130 mg, 0.204 mmol) in THF (3 mL) was added 1 M aqueous lithium hydroxide (14.7 eq, 3.0 mL, 3.00 mmol). The mixture was stirred at RT and reaction progress was followed by LC-MS until the starting material disappeared. The reaction mixture was diluted water (80 mL), acidified with 1 M hydrochloric acid, and extracted with ethyl acetate (80 mL). The organic extract was washed with brine (100 mL), dried over anhydrous sodium sulfate, and concentrated to give 3-[4-[5-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro- phenyl]-1-methyl-1,2,4-triazol-3-yl]-4-methyl-chroman-8-yl]propanoic acid (86 mg, 0.137 mmol, 67 % yield) as a solid. MS (ESI): 609.3 (M+H)+; retention time: 2.04 min (modified Method 2 – Gradient: T0 min: 5% B; 95% B, T1.3 min ; Column Temperature: 45°C). Example 45. Synthesis of 3-[4-[5-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]- 2-fluoro-phenyl]-1-methyl-1,2,4-triazol-3-yl]-4-methyl-chroman-8-yl]propanoic acid Ethyl 3-[4-[5-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1- Step A: To a stirred solution of ethyl 3-[4-[5-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1-methyl-1,2,4-triazol-3-yl]-4-methyl-chroman-8-yl]propanoate (Example 44, 1.00 eq, 450 mg, 0.707 mmol) in methanol (5 mL) was added a solution of ammonium molybdate tetrahydrate (2.00 eq, 223 mg, 1.41 mmol) and hydrogen peroxide (277 eq, 6.0 mL, 196 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 1 h, quenched with aqueous Na2S2O3, and extracted with ethyl acetate (25 mL). The organic extract was washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-10% ethyl acetate in petroleum ether to give ethyl 3-[4-[5-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2- fluoro-phenyl]-1-methyl-1,2,4-triazol-3-yl]-4-methyl-chroman-8-yl]propanoate (80 mg, 0.123 mmol, 17 % yield) as a solid. MS (ESI): 653.2 (M+H)+; retention time: 8.80 min (modified Method 4 - Gradient: T0 min: 10% B; 95% B, T8.0 min; Flow: 1.0 mL / min; Temperature: 45 °C). All of the eluted products from the above chromatographic purification were combined and stored for further purification and isolation of desired compounds. 3-[4-[5-[5-[(6,7-Difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1-methyl- Step B: The title compound (16 mg, 0.0259 mmol, 37 % yield) was obtained from ethyl 3-[4- [5-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1-methyl-1,2,4- triazol-3-yl]-4-methyl-chroman-8-yl]propanoate (1.00 eq, 50 mg, 0.0705 mmol) following the general procedure described in Step B, Example 44. MS (ESI): 625.3 (M+H)+; retention time: 1.84 min (Method 3). Example 46. Synthesis of 3-[(4R)-4-[5-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1-methyl-1,2,4-triazol-3-yl]-4-methyl-chroman-8-yl]propanoic acid Enantiomers of ethyl 3-[4-[5-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro- Step A: The racemic ethyl 3-[4-[5-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2- fluoro-phenyl]-1-methyl-1,2,4-triazol-3-yl]-4-methyl-chroman-8-yl]propanoate (220 mg, 0.313 mmol, 44 % yield, a solid) was isolated by prep-HPLC purification from the product mixture obtained after the chromatographic purification in Step A, Example 45. MS (ESI): 669.3 (M+H)+; retention time: 2.06 (Method 3). The racemic mixture was separated into its enantiomerically pure components by chiral SFC to afford ethyl 3-[(4R)-4-[5-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro- phenyl]-1-methyl-1,2,4-triazol-3-yl]-4-methyl-chroman-8-yl]propanoate (Product P1, 80 mg, 0.120 mmol, 36 % yield) and ethyl 3-[(4S)-4-[5-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol- 5-yl)oxy]-2-fluoro-phenyl]-1-methyl-1,2,4-triazol-3-yl]-4-methyl-chroman-8-yl]propanoate (Product P2, 80 mg, 0.118 mmol, 36 % yield) as solids. MS (ESI): 669.3 (M+H)+; retention time: 2.06 min (Method 3) observed for both product P1 and product P2. The absolute configurations of these isolated pure enantiomers, product P1 and product P2, were assigned arbitrarily. Chiral SFC Separation Conditions: Instrument: SFC-150 (Waters); Column: IG 25 * 250 mm, 10 µm (Regis); Column temperature: 35 ºC; Mobile phase: 70 / 30 CO2 / MeOH [spiked with 0.2 % 7M NH3in MeOH]; Flow rate: 100 ml / min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 4.38 min; Sample solution: 200 mg dissolved in 12 ml methanol; Injection volume: 1 ml. 3-[(4R)-4-[5-[5-[(6,7-Difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1- Step B: The title compound (54 mg, 0.0838 mmol, 70 % yield, a solid) was obtained from Product P1 (Step A, 80 mg, 0.120 mmol) following the general procedure from Step B, Example 44. MS (ESI): 641.2 (M+H)+; retention time: 1.88 min (Method 3). Example 47. Synthesis of 3-[(4S)-4-[5-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1-methyl-1,2,4-triazol-3-yl]-4-methyl-chroman-8-yl]propanoic acid The title compound (45 mg, 0.0696 mmol, 58 % yield, a solid) was prepared similarly to Example 46 starting from Product P2 (Step A, Example 46, 80 mg, 0.120 mmol). MS (ESI): 641.2 (M+H)+; retention time: 1.88 min (Method 3). Example 48. Synthesis of 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate Step A: To a stirred solution of ethyl 3-[4-(2-bromoacetyl)-4-methyl-chroman-8-yl]propanoate (Intermediate 9, 1.00 eq, 350 mg, 0.948 mmol) in DMF (10 mL) was added 5-[(6,7-difluoro- 4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzamidine (Intermediate 17, 1.10 eq, 366 mg, 1.04 mmol) and sodium bicarbonate (2.00 eq, 159 mg, 1.90 mmol) . The reaction mixture was stirred at RT overnight, diluted with water (50 mL) and extracted with EtOAc (50 ml). The organic extract was washed with aqueous LiCl, brine (50 mL), dried over Na2SO4and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-35% EtOAc in PE to give ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (400 mg, 0.643 mmol, 68 % yield) as a solid. MS (ESI): 622.3 (M+H)+; retention time: 1.77 min (Method 3). Enantiomers of ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro- Step B: To a stirred solution of ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (1.00 eq, 170 mg, 0.273 mmol) in methanol (5 mL) was added a solution of ammonium molybdate tetrahydrate (1.01 eq, 340 mg, 0.275 mmol) in hydrogen peroxide (239 eq, 2.0 mL, 65.3 mmol) at 0 °C. The reaction mixture was stirred at RT for 1 h, quenched with saturated aqueous Na2SO3, and extracted with ethyl acetate (25 mL). The separated organic phase was washed with brine (25 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by prep-HPLC to give ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2- fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (90 mg, 0.138 mmol, 50 % yield) as a solid. MS (ESI): 654.3 (M+H)+; retention time: 1.68 min (Method 3). 190 mg (0.291 mmol) of racemic mixture obtained as described above was separated into its enantiomerically pure components by chiral SFC to afford ethyl 3-[(4R)-4-[2-[5-[(6,7-difluoro- 4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl- chroman-8-yl]propanoate (Product P1, 75 mg, 0.115 mmol, 40% yield) and ethyl 3-[(4S)-4-[2- [5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]- 4-methyl-chroman-8-yl]propanoate (Product P2, 90 mg, 0.138 mmol, 47 % yield) as solids. MS (ESI): 654.3 (M+H)+; retention time: 1.68 min (Method 3) observed for both Product P1 and Product P2. The absolute configurations of these isolated pure enantiomers, product P1 and product P2, were assigned arbitrarily. Chiral SFC Separation Conditions were identical to those used in Step A, Example 46 except for the following changes: Cycle time: 3.1 min; Sample solution: 190 mg dissolved in 22 mL methanol; Injection volume: 2.5 mL. 3-[(4R)-4-[2-[5-[(6,7-Difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- Step C: To a solution of ethyl 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (Product P1, 1.00 eq, 75 mg, 0.115 mmol) in THF (3 mL) and methanol (1 mL) was added a solution of lithium hydroxide (8.72 eq, 1.0 mL, 1.00 mmol) in water. The reaction mixture was stirred at RT for 1 day, diluted with water (10 mL), acidified (pH< 7) with hydrochloric acid (1M), and extracted with ethyl acetate (20 mL). The organic extract was dried over MgSO4and concentrated. The residue was purified by prep-HPLC to give 3-[(4R)-4-[2-[5-[(6,7-difluoro- 4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl- chroman-8-yl]propanoic acid (46 mg, 0.0730 mmol, 64 % yield) as a solid. MS (ESI): 626.2 (M+H)+; retention time: 1.56 min (Method 3). Example 49. Synthesis of 3-[(4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid The title compound (47 mg, 0.0754 mmol, 55 % yield, a solid) was prepared similarly to Example 48 starting from Product P2 (Step B, Example 48, 90 mg, 0.138 mmol). MS (ESI): 626.2 (M+H)+; retention time: 1.56 min (Method 3). Example 50. Synthesis of Diastereomer 1 of (2R)-3-[4-[2-[2-fluoro-5-[(4,6,7-trifluoro- 1H-indol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]-2-methyl- propanoic acid Diastereomers of methyl (2R)-3-[4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- Step A: To a stirred solution of methyl (2R)-3-[4-(2-bromoacetyl)-4-methyl-chroman-8-yl]-2- methyl-propanoate (Intermediate 18, 1.00 eq, 320 mg, 0.667 mmol) and 2-fluoro-5-[(4,6,7- trifluoro-1H-indol-5-yl)oxy]benzamidine (Intermediate 12, 1.00 eq, 216 mg, 0.667 mmol) in DMF (5 mL) was added sodium bicarbonate (2.00 eq, 112 mg, 1.33 mmol). The reaction mixture was stirred at 80 ºC for 5 h. The mixture was quenched with water (20 mL), extracted with ethyl acetate (20 mL), and the solids filtered off. The separated organic extract was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to give methyl (2R)-3-[4-[2-[2-fluoro-5-[(4,6,7-trifluoro- 1H-indol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]-2-methyl-propanoate (180 mg, 0.303 mmol, 45 % yield) as a solid. MS (ESI): 594.3 (M+H)+; retention time: 1.86 min (Method 3). The above mixture of diastereomers was resolved into its components by SFC to afford Diastereomer 1 of methyl (2R)-3-[4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)oxy]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]-2-methyl-propanoate (61 mg, 0.103 mmol, 34 % yield) and Diastereomer 2 of methyl (2R)-3-[4-[2-[2-fluoro-5-[(4,6,7- trifluoro-1H-indol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]-2-methyl- propanoate (62 mg,0.104 mmol, 34 % yield) as solids. Diastereomer 1: MS (ESI): 594.3 (M+H)+; retention time: 1.77 min (Method 3) Diastereomer 2: MS (ESI): 594.3 (M+H)+; retention time: 1.77 min (Method 3) SFC Conditions are similar to those applied in Example 46 except for the following changes: Column: IC 25 * 250 mm, 10 µm; Mobile phase: 75 / 25 CO2 / MeOH [spiked with 0.2 % 7M NH3in MeOH]; Cycle time: 3.63 min; Sample solution: 180 mg dissolved in 21 ml isopropanol. Enantiomer 1 of (2R)-3-[4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1H- Step B: Enantiomer 1 of (2R)-3-[4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]- 1H-imidazol-4-yl]-4-methyl-chroman-8-yl]-2-methyl-propanoic acid (40 mg, 0.0688 mmol, 65 % yield, a solid) was prepared from the Diastereomer 1 (Step A, 61 mg, 0.106 mmol) following the general procedure from Step C, Example 48. MS (ESI): 580.3 (M+H)+; retention time: 1.66 min (Method 3). Example 51. Synthesis of Diastereomer 2 of (2R)-3-[4-[2-[2-fluoro-5-[(4,6,7-trifluoro- 1H-indol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]-2-methyl- propanoic acid The title compound (38 mg, 0.0657 mmol, 63 % yield) was prepared similarly to Example 50 from Diastereomer 2 (Step A, Example 50, 62 mg, 0.104 mmol). MS (ESI): 580.3 (M+H)+; retention time: 1.66 min (Method 3). Example 52. Synthesis of Diastereomer 1 of (2S)-3-[4-[2-[2-fluoro-5-[(4,6,7-trifluoro- 1H-indol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]-2-methyl- propanoic acid Prepared in the same way as Example 50, starting from methyl (2S)-3-[4-(2-bromoacetyl)-4- methyl-chroman-8-yl]-2-methyl-propanoate (Intermediate 19) and 2-fluoro-5-[(4,6,7- trifluoro-1H-indol-5-yl)oxy]benzamidine (Intermediate 12) via Diastereomer 1 of methyl (2S)- 3-(4-(2-(2-fluoro-5-((4,6,7-trifluoro-1H-indol-5-yl)oxy)phenyl)-1H-imidazol-4-yl)-4- methylchroman-8-yl)-2-methylpropanoate. MS (ESI): 580.1 (M+H)+; retention time: 1.60 min (Method 3). Example 53. Synthesis of Diastereomer 2 of (2S)-3-[4-[2-[2-fluoro-5-[(4,6,7-trifluoro- 1H-indol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]-2-methyl- propanoic acid Prepared in the same way as Example 51 from Diastereomer 2 of methyl (2S)-3-(4-(2-(2- fluoro-5-((4,6,7-trifluoro-1H-indol-5-yl)oxy)phenyl)-1H-imidazol-4-yl)-4-methylchroman-8- yl)-2-methylpropanoate. MS (ESI): 580.1 (M+H)+; retention time: 1.60 min (Method 3). Example 54. Synthesis of 3-[(4R)-4-[2-[5-[[6,7-difluoro-4-(trideuteriomethylsulfonyl)- 1H-indol-5-yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-(trideuteriomethyl)chroman-8- yl]propanoic acid 3-[(4R)-4-[2-[5-[[6,7-difluoro-4-(trideuteriomethylsulfanyl)-1H-indol-5-yl]oxy]-2-fluoro- Step A: To a stirred and chilled (0 ºC) solution of ethyl 3-[(4R)-4-[2-[5-[[6,7-difluoro-4- (trideuteriomethylsulfanyl)-1H-indol-5-yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4- (trideuteriomethyl)chroman-8-yl]propanoate (1.00 eq, 130 mg, 0.207 mmol) in THF (3 mL) ) was added aqueous lithium hydroxide (205 eq, 2.0 mL, 42.4 mmol). The reaction mixture was allowed to warm to rt over 1 h, poured into water (30 mL), acidified with hydrochloric acid, and extracted with ethyl acetate (50 mL), The organic extract was washed with brine (90 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 40-50% ethyl acetate in petroleum ether to give 3-[(4R)-4-[2-[5-[[6,7-difluoro-4-(trideuteriomethylsulfanyl)-1H-indol-5-yl]oxy]-2-fluoro- phenyl]-1H-imidazol-4-yl]-4-(trideuteriomethyl)chroman-8-yl]propanoic acid (120 mg, 0.200 mmol, 97 % yield) as a colorless oil. MS (ESI): 600.2 (M+H)+; retention time: 1.58 min (modified Method 2 - Gradient: T0 min: 5% B, T1.3 min : 95%B ; Flow: 1.8 mL / min). The starting material for this step, ethyl 3-[(4R)-4-[2-[5-[[6,7-difluoro-4- (trideuteriomethylsulfanyl)-1H-indol-5-yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4- (trideuteriomethyl)chroman-8-yl]propanoate [absolute stereochemistry assigned arbitrarily, MS (ESI): 628.1 (M+H)+] was prepared by resolving the racemic mixture obtained similarly to the product from Step A, Example 48 by replacing Intermediate 9 with the deuterated Intermediate 20 and Intermediate 17 with the deuterated Intermediate 21. The chiral SFC method was analogous to the one used in Step B, Example 48. 3-[(4R)-4-[2-[5-[[6,7-difluoro-4-(trideuteriomethylsulfonyl)-1H-indol-5-yl]oxy]-2-fluoro- phenyl]-1H-imidazol-4-yl]-4-(trideuteriomethyl)chroman-8-yl]propanoic acid Step B: To a solution of 3-[(4R)-4-[2-[5-[[6,7-difluoro-4-(trideuteriomethylsulfanyl)-1H- indol-5-yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-(trideuteriomethyl)chroman-8- yl]propanoic acid (1.00 eq, 124 mg, 0.207 mmol) in methanol (5 mL) was added ammonium molybdate tetrahydrate (0.508 eq, 130 mg, 0.105 mmol) and hydrogen peroxide (205 eq, 1.3 mL, 42.4 mmol). The reaction mixture was stirred at 0 ºC for 1 h, poured into water (30 mL), and extracted with ethyl acetate (50 mL). The separated organic layer was washed with brine (90 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 40-50% ethyl acetate in petroleum ether to give 3-[(4R)-4-[2-[5-[[6,7-difluoro-4-(trideuteriomethylsulfonyl)-1H-indol-5-yl]oxy]- 2-fluoro-phenyl]-1H-imidazol-4-yl]-4-(trideuteriomethyl)chroman-8-yl]propanoic acid (55 mg, 0.0871 mmol, 42 % yield) as a solid. MS (ESI): 632.3 (M+H)+; retention time: 1.47 min (modified Method 2 - Gradient: T0 min: 5% B, T1.3 min : 95%B ; Flow: 1.8 mL / min).1H NMR (400 MHz, CD3OD) δ 7.57-7.52 (m, 2H), 7.25-7.17 (m, 2H), 7.05-6.96 (m, 3H), 7.06 (t, J = 8.0 Hz, 1H), 6.57 (s, 1H), 4.27-4.21 (m, 1H), 4.03 (td, J = 4.0 Hz, 1H), 2.86 (m, 2H), 2.54 (m, 2H), 2.46 (m, 1H), 1.97 (m, 1H). The absolute stereochemistry of the title compound has been assigned arbitrarily. Example 55. Synthesis of 3-[(4S)-4-[2-[5-[[6,7-difluoro-4-(trideuteriomethylsulfonyl)- 1H-indol-5-yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-(trideuteriomethyl)chroman-8- yl]propanoic acid The title compound was prepared according to the procedures for Example 54 starting from the opposite enantiomer to the one used in Step B, Example 54. The absolute stereochemistry of the title compound has been assigned arbitrarily. MS (ESI): 632.3 (M+H)+; retention time: 1.47 min (modified Method 2 - Gradient: T0 min: 5% B, T1.3 min : 95%B ; Flow: 1.8 mL / min).1H NMR (400 MHz, CD3OD) δ 7.57-7.52 (m, 2H), 7.25-7.17 (m, 2H), 7.05-6.96 (m, 3H), 7.06 (t, J = 8.0 Hz, 1H), 6.57 (s, 1H), 4.27-4.21 (m, 1H), 4.03 (td, J = 4.0 Hz, 1H), 2.86 (m, 2H), 2.54 (m, 2H), 2.46 (m, 1H), 1.97 (m, 1H). Example 56. Synthesis of 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]- 2-fluoro-phenyl]oxazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid [2-[8-(3-Ethoxy-3-oxo-propyl)-4-methyl-chroman-4-yl]-2-oxo-ethyl] 5-[(6,7-difluoro-4- Step A: To a stirred solution of 5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2- fluoro-benzoic acid (Intermediate 22, 1.00 eq, 410 mg, 1.16 mmol) in DMF (10 mL) was added ethyl 3-[4-(2-bromoacetyl)-4-methyl-chroman-8-yl]propanoate (Intermediate 9, 1.00 eq, 428 mg, 1.16 mmol) and sodium bicarbonate (3.00 eq, 292 mg, 3.48 mmol). The reaction mixture was stirred at rt overnight, concentrated to dryness. The residue was suspended in EtOAc (30 mL) and washed with water (30 mL). The separated organic phase was washed with brine (40 mL), dried over sodium sulfate, filtered, and concentrated. The crude was then purified by flash column chromatography on silica gel eluting 0-25% EA in PE to give [2-[8-(3-ethoxy-3-oxo- propyl)-4-methyl-chroman-4-yl]-2-oxo-ethyl] 5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5- yl)oxy]-2-fluoro-benzoate (610 mg, 0.894 mmol, 77 % yield). MS (ESI): 664.3 (M+Na)+; retention time: 2.21 min (Method 3). Ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]oxazol- Step B: To a stirred solution of [2-[8-(3-ethoxy-3-oxo-propyl)-4-methyl-chroman-4-yl]-2-oxo- ethyl] 5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzoate (1.00 eq, 610 mg, 0.951 mmol) in acetic acid (10 mL) was added ammonium acetate (3.00 eq, 220 mg, 2.85 mmol) and the reaction mixture was stirred at 110 °C for 2 days. The reaction was cooled to rt, concentrated and the residue was suspended in EtOAc (40 mL). The organic phase was basified with saturated aqueous NaHCO3, washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-55% EtOAc in PE to give ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]oxazol-4-yl]-4-methyl-chroman-8-yl]propanoate (420 mg, 0.644 mmol, 68 % yield). MS (ESI): 623.3 (M+H)+; retention time: 2.34 min (Method 3). 3-[4-[2-[5-[(6,7-Difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]oxazol-4-yl]- Step C: The title compound (3.6 mg,0.00605 mmol, 25 % yield, a solid) was prepared from ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]oxazol- 4-yl]-4-methyl-chroman-8-yl]propanoate (15 mg, 0.0241 mmol) via the procedure described in Step A, Example 54. MS (ESI): 595.2 (M+H)+; retention time: 2.14 min (Method 3). Example 57. Synthesis of 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]oxazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Example 58. Synthesis of 3-[(4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]oxazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]oxazol- 4-yl]-4-methyl-chroman-8-yl]propanoate and ethyl 3-[4-[2-[5-[(6,7-difluoro-4- methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]oxazol-4-yl]-4-methyl-chroman-8- yl]propanoate Step A: To a stirred solution of ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]oxazol-4-yl]-4-methyl-chroman-8-yl]propanoate (Step B, Example 56, 1.00 eq, 410 mg, 0.658 mmol) in methanol (6 mL) was added ammonium molybdate tetrahydrate (0.246 eq, 200 mg, 0.162 mmol) in hydrogen peroxide (99.1 eq, 2.0 mL, 65.3 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 5 h, quenched with sodium thiosulfate, diluted with water (20 mL), and extracted with EtOAc (50 mL). The separated organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-55% EtOAc in PE to give ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfonyl- 1H-indol-5-yl)oxy]-2-fluoro-phenyl]oxazol-4-yl]-4-methyl-chroman-8-yl]propanoate (309 mg, 0.458 mmol, 70 % yield) and ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]oxazol-4-yl]-4-methyl-chroman-8-yl]propanoate (30 mg, 0.0462 mmol, 7 % yield) . ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]oxazol- 4-yl]-4-methyl-chroman-8-yl]propanoate: MS (ESI): 655.3 (M+H)+; retention time: 2.14 min (Method 3). ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]oxazol- 4-yl]-4-methyl-chroman-8-yl]propanoate: MS (ESI): 639.3 (M+H)+; retention time: 2.13 min (Method 3). Enantiomers of ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro- Step B: The racemic ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2- fluoro-phenyl]oxazol-4-yl]-4-methyl-chroman-8-yl]propanoate (400 mg, 0.611 mmol) was resolved via chiral SFC into its components to obtain ethyl 3-[(4R)-4-[2-[5-[(6,7-difluoro-4- methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]oxazol-4-yl]-4-methyl-chroman-8- yl]propanoate (Product P1, 110 mg , 0.168 mmol, 28 % yield) and ethyl 3-[(4S)-4-[2-[5-[(6,7- difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]oxazol-4-yl]-4-methyl- chroman-8-yl]propanoate (Product P2, 90 mg, 0.137 mmol, 23 % yield) as solids. MS (ESI): 655.3 (M+H)+; retention time: 2.14 min (Method 3) observed for both enantiomers. The absolute configurations of Product P1 and Product P2 were assigned arbitrarily. SFC Separation Conditions: Instrument: SFC-150 (Waters); Column: OD 25 * 250 mm, 10 µm; Column temperature: 35 ºC; Mobile phase: 55 / 45 CO2 / MeOH [spiked with 0.2% of 7M NH3in MeOH; Flow rate: 120 ml / min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 3.1 min; Sample solution: 550 mg dissolved in 45 mL methanol; Injection volume: 2 mL. 3-[(4R)-4-[2-[5-[(6,7-Difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]oxazol- 4-yl]-4-methyl-chroman-8-yl]propanoic acid and Synthesis of 3-[(4S)-4-[2-[5-[(6,7-difluoro- 4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]oxazol-4-yl]-4-methyl-chroman-8- yl]propanoic acid Step C: The title compounds were prepared via the procedure described in Step A, Example 54 starting from Product P1 and Product P2 (Step B). 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]oxazol- 4-yl]-4-methyl-chroman-8-yl]propanoic acid (Example 57, 67 mg, 0.106 mmol, 63 % yield) was obtained via the basic hydrolysis of ethyl 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl- 1H-indol-5-yl)oxy]-2-fluoro-phenyl]oxazol-4-yl]-4-methyl-chroman-8-yl]propanoate (Product P1, 110 mg , 0.168 mmol). MS (ESI): 627.3 (M+H)+; retention time: 1.96 min (Method 3). 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]oxazol- 4-yl]-4-methyl-chroman-8-yl]propanoic acid (Example 58, 55 mg, 0.0870 mmol, 64 % yield) was obtained via the basic hydrolysis of ethyl 3-[(4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl- 1H-indol-5-yl)oxy]-2-fluoro-phenyl]oxazol-4-yl]-4-methyl-chroman-8-yl]propanoate (Product P2, 90 mg, 0.137 mmol). MS (ESI): 627.3 (M+H)+; retention time: 1.96 min (Method 3). Example 59. Synthesis of 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]- 2-fluoro-phenyl]oxazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid The title compound (19 mg, 0.0298 mmol, 64 % yield) was prepared from ethyl 3-[4-[2-[5- [(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]oxazol-4-yl]-4-methyl- chroman-8-yl]propanoate (Step A, Example 57, 30 mg, 0.0470 mmol) via the procedure described in Step A, Example 54. MS (ESI): 611.3 (M+H)+; retention time: 1.93 min (Method 3). Example 60. Synthesis of 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]- 2-fluoro-phenyl]-1-methyl-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1- Step A: The title compound (150 mg,0.236 mmol, 31 % yield) was prepared from 5-[(6,7- difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-N-methyl-benzamidine (Intermediate 23, 1.00 eq, 280 mg, 0.766 mmol) and ethyl 3-[4-(2-bromoacetyl)-4-methyl-chroman-8- yl]propanoate (Intermediate 9, 1.10 eq, 311 mg, 0.843 mmol) following a similar procedure to Step A, Example 48. MS (ESI): 636.3 (M+H)+; retention time: 1.75 min (Method 3). 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1-methyl- i Step B: The title compound (2.7 mg, 0.00444 mmol, 19 %) was prepared via a procedure analogous to the one in Step C, Example 48 starting from ethyl 3-[4-[2-[5-[(6,7-difluoro-4- methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1-methyl-imidazol-4-yl]-4-methyl- chroman-8-yl]propanoate (15 mg, 0.0236 mmol). MS (ESI): 608.3 (M+H)+; retention time: 1.64 min (Method 3). Example 61. Synthesis of 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1-methyl-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Example 62. Synthesis of 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1-methyl-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1- methyl-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate and ethyl 3-[4-[2-[5-[(6,7- difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1-methyl-imidazol-4-yl]-4- methyl-chroman-8-yl]propanoate Step A: The title compounds were obtained from ethyl 3-[4-[2-[5-[(6,7-difluoro-4- methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1-methyl-imidazol-4-yl]-4-methyl- chroman-8-yl]propanoate (Step A, Example 60, 1.00 eq, 250 mg, 0.393 mmol) via an analogous procedure to the one in Step A, Example 57, except that the purification of the crude product was performed by prep-HPLC and not flash chromatography. Ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1- methyl-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (140 mg, 0.210 mmol, 53 % yield). MS (ESI): 668.3 (M+H)+; retention time: 1.68 min (Method 3). Ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1- methyl-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (11 mg, 0.0169 mmol, 4 % yield). MS (ESI): 652.3 (M+H)+(Method 3). Enantiomers of ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro- Step B: The racemic mixture, ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1-methyl-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (140 mg, 0.210 mmol), was resolved via chiral SFC into its components to obtain ethyl (R)-3-(4-(2- (5-((6,7-difluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)-2-fluorophenyl)-1-methyl-1H- imidazol-4-yl)-4-methylchroman-8-yl)propanoate (Product P1, 65 mg, 0.0973 mmol, 46 % yield) and ethyl (S)-3-(4-(2-(5-((6,7-difluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)-2- fluorophenyl)-1-methyl-1H-imidazol-4-yl)-4-methylchroman-8-yl)propanoate (Product P2, 55 mg, 0.0824 mmol, 39 % yield) as solids. MS (ESI): 668.3 (M+H)+; retention time: 1.66 min (Method 3) observed for both products. The absolute configurations of both enantiomers were assigned arbitrarily. SFC Separation Conditions were similar to the ones used in Step B, Example 58, except for the following changes: Mobile phase: 75 / 25 CO2 / MeOH [spiked with 0.2% of 7M NH3in MeOH; Flow rate: 100 ml / min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 5 min; Sample solution: 140 mg dissolved in 40 ml methanol; Injection volume: 2 ml. 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1- methyl-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid and 3-[(4R)-4-[2-[5-[(6,7- difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1-methyl-imidazol-4-yl]-4- methyl-chroman-8-yl]propanoic acid Step C: The title compounds were prepared via a procedure analogous to the one in Step C, Example 48 starting from Product P1 and Product P2 (Step B). 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1- methyl-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid (Example 61, 31 mg, 0.0485 mmol, 50 % yield) was obtained via the basic hydrolysis of ethyl (R)-3-(4-(2-(5-((6,7-difluoro- 4-(methylsulfonyl)-1H-indol-5-yl)oxy)-2-fluorophenyl)-1-methyl-1H-imidazol-4-yl)-4- methylchroman-8-yl)propanoate (Product P1, 65 mg, 0.0973 mmol). MS (ESI): 640.3 (M+H)+; retention time: 1.53 min (Method 3). 3-[(4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1- methyl-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid (Example 62, 33 mg, 0.0516 mmol, 69 % yield) was obtained via the basic hydrolysis of ethyl (S)-3-(4-(2-(5-((6,7-difluoro- 4-(methylsulfonyl)-1H-indol-5-yl)oxy)-2-fluorophenyl)-1-methyl-1H-imidazol-4-yl)-4- methylchroman-8-yl)propanoate (Product P2, 50 mg, 0.0749 mmol). MS (ESI): 640.3 (M+H)+; retention time: 1.53 min (Method 3). Example 63. Synthesis of 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]- 2-fluoro-phenyl]-1-methyl-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid The title compound (2.3 mg, 0.00369 mmol, 24 % yield) was prepared from ethyl 3-(4-(2-(5- ((6,7-difluoro-4-(methylsulfinyl)-1H-indol-5-yl)oxy)-2-fluorophenyl)-1-methyl-1H-imidazol- 4-yl)-4-methylchroman-8-yl)propanoate (Step A, Example 61, 10 mg, 0.0153 mmol) via a procedure analogous to the one in Step C, Example 48. MS (ESI): 624.3 (M+H)+; retention time: 1.53 min (Method 3). Example 64. Synthesis of 6,7-difluoro-5-[4-fluoro-3-[4-[(4R)-4-methylchroman-4-yl]- 1H-imidazol-2-yl]phenoxy]-4-methylsulfinyl-1H-indole Example 65. Synthesis of 6,7-difluoro-5-[4-fluoro-3-[4-[(4S)-4-methylchroman-4-yl]- 1H-imidazol-2-yl]phenoxy]-4-methylsulfinyl-1H-indole Enantiomers of 6,7-difluoro-5-[4-fluoro-3-[4-(4-methylchroman-4-yl)-1H-imidazol-2- Step A: To a stirred solution of 5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2- fluoro-benzamidine (1.00 eq, 281 mg, 0.800 mmol) in DMF (5 mL) was added 2-bromo-1-(4- methylchroman-4-yl)ethanone (Intermediate 24, 1.00 eq, 215 mg, 0.800 mmol) and sodium bicarbonate (2.00 eq, 134 mg, 1.60 mmol), and the reaction mixture was stirred at 75 °C for 16 hours. The mixture was cooled to RT, poured into water, and extracted with ethyl acetate (2 x 20 ml). The separated organic layer was washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-50% ethyl acetate in petroleum ether to give 6,7- difluoro-5-[4-fluoro-3-[4-(4-methylchroman-4-yl)-1H-imidazol-2-yl]phenoxy]-4- methylsulfanyl-1H-indole (220 mg, 0.422 mmol, 53 % yield) as a white solid. MS (ESI): 522.3 (M+H)+; retention time: 1.81 min (modified Method 2 - Column Temperature:45 °C). The racemic mixture (110 mg) was separated into its components via chiral SFC to afford 6,7- difluoro-5-[4-fluoro-3-[4-[(4R)-4-methylchroman-4-yl]-1H-imidazol-2-yl]phenoxy]-4- methylsulfanyl-1H-indole (Product P1, 26 mg, 0.0499 mmol, 24 % yield) as a white solid and 6,7-difluoro-5-[4-fluoro-3-[4-[(4S)-4-methylchroman-4-yl]-1H-imidazol-2-yl]phenoxy]-4- methylsulfanyl-1H-indole (Product P2, 23 mg, 0.0441 mmol, 21 % yield) as a white solid. MS (ESI): 522.3 (M+H)+; retention time: 1.82 min (modified Method 2 - Oven Temperature:45 °C) observed for both enantiomers. SFC Separation conditions: Instrument: SFC-150 (Waters); Column: (R,R) WHELK-01 25 * 250 mm, 10 µm (Regis); Column temperature: 35 ºC; Mobile phase: 45 / 55 CO2 / MeOH [spiked with 0.2% of 7M NH3in MeOH]; Flow rate: 120 ml / min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 5 min; Sample solution: 800 mg dissolved in 60 ml methanol; Injection volume: 1.5 ml. 6,7-Difluoro-5-[4-fluoro-3-[4-[(4R)-4-methylchroman-4-yl]-1H-imidazol-2-yl]phenoxy]-4- methylsulfinyl-1H-indole and 6,7-difluoro-5-[4-fluoro-3-[4-[(4S)-4-methylchroman-4-yl]- Step B: The title compounds were obtained via sulfide to sulfone oxidation from Product P1 and Product P2 (Step A) using the following procedure. To a solution of 6,7-difluoro-5-[4-fluoro-3-[4-[(4S)-4-methylchroman-4-yl]-1H-imidazol-2- yl]phenoxy]-4-methylsulfanyl-1H-indole (Product P2, 1.00 eq, 20 mg, 0.0383 mmol) in methanol (3 mL) was added a mixture of ammonium molybdate tetrahydrate (0.844 eq, 40 mg, 0.0324 mmol) in aqueous hydrogen peroxide (1.00 eq, 0.20 mL, 0.0383 mmol) at 0 °C. The reaction was stirred at room temperature for 0.5 h, diluted with ethyl acetate (30 mL), washed with water (2 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to get 6,7-difluoro-5-[4-fluoro-3-[4-[(4S)-4- methylchroman-4-yl]-1H-imidazol-2-yl]phenoxy]-4-methylsulfinyl-1H-indole (Example 65, 7.4 mg, 0.0138 mmol, 36 % yield) as a white solid. MS (ESI): 538.3 (M+H)+; retention time: 1.68 min (modified Method 2 - Column: Poroshell 120 EC C184 µm 4.6 * 50 mm; Column Temperature:45 °C). Following the above procedure, 6,7-Difluoro-5-[4-fluoro-3-[4-[(4R)-4-methylchroman-4-yl]- 1H-imidazol-2-yl]phenoxy]-4-methylsulfinyl-1H-indole (Example 64, 7.2 mg, 0.0134 mmol, 35 % yield) was obtained from 6,7-difluoro-5-[4-fluoro-3-[4-[(4R)-4-methylchroman-4-yl]- 1H-imidazol-2-yl]phenoxy]-4-methylsulfanyl-1H-indole (Product P2, 1.00 eq, 20 mg, 0.0383 mmol). MS (ESI): 538.3 (M+H)+; retention time: 1.68 min (modified Method 2 - Column: Poroshell 120 EC C184 µm 4.6 * 50 mm; Column Temperature: 45 °C). Example 66. Synthesis of 6,7-difluoro-5-[4-fluoro-3-[4-(4-methylchroman-4-yl)-1H- imidazol-2-yl]phenoxy]-4-methylsulfonyl-1H-indole To a solution of 6,7-difluoro-5-[4-fluoro-3-[4-(4-methylchroman-4-yl)-1H-imidazol-2- yl]phenoxy]-4-methylsulfanyl-1H-indole (Step A, Example 65, 1.00 eq, 80 mg, 0.153 mmol) in methanol (10 mL) was added a mixture of ammonium orthomolybdate (7.90 eq, 160 mg, 1.21 mmol) in 1 mL of aqueous hydrogen peroxide (1 eq) at 0 °C. The reaction was stirred at room temperature for 2 h, diluted with ethyl acetate (30 mL), washed with water (3 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to give 6,7-difluoro-5-[4-fluoro-3-[4-(4-methylchroman-4-yl)-1H-imidazol-2- yl]phenoxy]-4-methylsulfonyl-1H-indole (30 mg, 0.0547 mmol, 36 % yield) as a white solid. MS (ESI): 554.3 (M+H)+; retention time: 1.70 min (modified Method 2 - Oven Temperature:45 °C). Example 67. Synthesis of 3-[(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)sulfinyl]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Example 68. Synthesis of 3-[(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)sulfonyl]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Enantiomers of ethyl 3-[4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)sulfanyl]phenyl]- 1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate Step A: To a solution of 2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)sulfanyl]benzamidine (Intermediate 25, 1.00 eq, 300 mg, 0.884 mmol) in DMF (6mL) was added ethyl 3-[4-(2- bromoacetyl)-4-methyl-chroman-8-yl]propanoate (Intermediate 9, 1.00 eq, 326 mg, 0.884 mmol) and sodium bicarbonate (2.00 eq, 149 mg, 1.77 mmol). The mixture was stirred at 70 °C overnight. The reaction was quenched with water (20 mL), extracted with ethyl acetate (20 mL). The separated organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to give ethyl 3-[4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)sulfanyl]phenyl]-1H-imidazol-4-yl]-4- methyl-chroman-8-yl]propanoate (200 mg, 0.328 mmol, 37 % yield) as a solid. MS (ESI): 610 (M+H)+; retention time: 1.82 min (Method 2). The racemic mixture (390 mg, 0.640 mmol) was separated into its components via chiral SFC to give ethyl (R)-3-(4-(2-(2-fluoro-5-((4,6,7-trifluoro-1H-indol-5-yl)thio)phenyl)-1H- imidazol-4-yl)-4-methylchroman-8-yl)propanoate (Product P1, 140 mg, 0.230 mmol, 36 % yield) and ethyl (S)-3-(4-(2-(2-fluoro-5-((4,6,7-trifluoro-1H-indol-5-yl)thio)phenyl)-1H- imidazol-4-yl)-4-methylchroman-8-yl)propanoate (Product P2, 130 mg, 0.213 mmol, 33 % yield). The absolute configurations of Product P1 and Product P2 are unknown and were assigned arbitrarily. MS (ESI): 610 (M+H)+; retention time: 1.79 min (Method 3) observed for both enantiomers. SFC Separation Conditions: Instrument: SFC-150 (Waters) Column: IG 25 * 250 mm, 10 µm; Column temperature: 35 ºC; Mobile phase: 60 / 40 CO2 / MeOH [spiked with 0.2% of 7M NH3in MeOH]; Flow rate: 100 ml / min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 3.7 min; Sample solution:390 mg dissolved in 35 ml methanol; Injection volume: 4.5 ml) 3-[(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)sulfanyl]phenyl]-1H-imidazol-4-yl]- 4-methyl-chroman-8-yl]propanoic acid Step B: The title compound () was obtained from ethyl (R)-3-(4-(2-(2-fluoro-5-((4,6,7- trifluoro-1H-indol-5-yl)thio)phenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)propanoate (Product P1, 120 mg, 0.206 mmol, 90 % yield) through a procedure analogous to the one in Step C, Example 48. MS (ESI): 582 (M+H)+; retention time: 1.66 min (Method 2A). 3-[(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)sulfinyl]phenyl]-1H-imidazol-4-yl]- 4-methyl-chroman-8-yl]propanoic acid and 3-[(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H- Step C: To a stirred solution of 3-[(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)sulfanyl]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid (1.00 eq, 110 mg, 0.189 mmol) in methanol (2.5 mL) was added at 0°C ammonium molybdate tetrahydrate (0.299 eq, 70 mg, 0.0566 mmol) in aqueous hydrogen peroxide (86.3 eq, 0.50 mL, 16.3 mmol). The reaction mixture was stirred at room temperature for 4 h, diluted with water (30 mL), and extracted with EtOAc (50 mL). The organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to give 3-[(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)sulfinyl]phenyl]-1H- imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid (Example 67, 48 mg, 0.0803 mmol, 43 % yield) and 3-[(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)sulfonyl]phenyl]-1H- imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid (Example 68, 32 mg, 0.0523 mmol, 28 % yield). 3-[(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)sulfinyl]phenyl]-1H-imidazol-4-yl]- 4-methyl-chroman-8-yl]propanoic acid (Example 67): MS (ESI): 598.2 (M+H)+; retention time: 1.57 min (modified Method 3 – Column Temperature: 45 ºC). 3-[(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)sulfonyl]phenyl]-1H-imidazol-4-yl]- 4-methyl-chroman-8-yl]propanoic acid (Example 68): MS (ESI): 614.2 (M+H)+; retention time: 1.64 min (modified Method 3 – Column Temperature: 45 ºC). Example 69. Synthesis of 3-[(4S)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)sulfinyl]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Example 70. Synthesis of 3-[(4S)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)sulfonyl]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Example 69 and Example 70 were prepared from ethyl (S)-3-(4-(2-(2-fluoro-5-((4,6,7- trifluoro-1H-indol-5-yl)thio)phenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)propanoate (Product P2, Step A, Example 67) following the procedure in Steps B and C in Examples 67 and 68. 3-[(4S)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)sulfinyl]phenyl]-1H-imidazol-4-yl]- 4-methyl-chroman-8-yl]propanoic acid (Example 69): MS (ESI): 598.2 (M+H)+; retention time: 1.57 min (modified Method 3 – Column Temperature: 45 ºC). 3-[(4S)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)sulfonyl]phenyl]-1H-imidazol-4-yl]- 4-methyl-chroman-8-yl]propanoic acid (Example 70): MS (ESI): 614.2 (M+H)+; retention time: 1.64 min (modified Method 3 – Column Temperature: 45 ºC). Example 71. Synthesis of 3-[(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)sulfanyl]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Preparation described in Step B, Example 68. Example 72. Synthesis of 3-[(4S)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)sulfanyl]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Prepared from ethyl (S)-3-(4-(2-(2-fluoro-5-((4,6,7-trifluoro-1H-indol-5-yl)thio)phenyl)-1H- imidazol-4-yl)-4-methylchroman-8-yl)propanoate (Product P2, Step A, Example 67) following the ester hydrolysis procedure in Steps B Example 67. MS (ESI): 582 (M+H)+; retention time: 1.66 min (Method 2A). The following Examples were synthesized from Intermediate 17 and Intermediates 26-29 via the procedures described for the preparation of Example 48 and Example 49, as well as Step A, Example 45 or Step A, Example 62 (for sulfoxide-containing compounds).

[0003] Example 84. Synthesis of 3-[(4R)-4-[2-[5-[[6,7-difluoro-4-(methylcarbamoyl)-1H-indol- 5-yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Example 85. Synthesis of 3-[(4S)-4-[2-[5-[[6,7-difluoro-4-(methylcarbamoyl)-1H-indol- 5-yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Enantiomers of ethyl 3-[4-[2-[5-[[6,7-difluoro-4-(methylcarbamoyl)-1H-indol-5-yl]oxy]-2- fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate Step A: A mixture of 5-(3-carbamimidoyl-4-fluoro-phenoxy)-6,7-difluoro-N-methyl-1H- indole-4-carboxamide (Intermediate 30, 1.00 eq, 140 mg, 0.386 mmol) , ethyl 3-[4-(2- bromoacetyl)-4-methyl-chroman-8-yl]propanoate (Intermediate 9, 1.00 eq, 143 mg, 0.386 mmol) and sodium bicarbonate (2.00 eq, 65 mg, 0.773 mmol) in DMF (5 mL) was stirred at 70 °C for 16 h. The reaction mixture was diluted with brine (20 mL), extracted with EA (3 x 5 mL), the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 10:1 DCM:MeOH to give ethyl 3-[4-[2-[5-[[6,7-difluoro-4-(methylcarbamoyl)-1H-indol-5- yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (120 mg, 0.190 mmol, 49 % yield) as a solid. MS (ESI): 633.4 (M+H)+; retention time: 1.74 min (Method 5). The racemic ethyl 3-[4-[2-[5-[[6,7-difluoro-4-(methylcarbamoyl)-1H-indol-5-yl]oxy]-2- fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (1.00 eq, 120 mg, 0.190 mmol) was resolved by chiral HPLC into its constituent enantiomers, ethyl 3-[(4R)-4-[2-[5- [[6,7-difluoro-4-(methylcarbamoyl)-1H-indol-5-yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]- 4-methyl-chroman-8-yl]propanoate (Product P1, 37 mg, 0.0585 mmol, 31 % yield) and ethyl 3-[(4S)-4-[2-[5-[[6,7-difluoro-4-(methylcarbamoyl)-1H-indol-5-yl]oxy]-2-fluoro-phenyl]- 1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (Product P2, 35 mg, 0.0553 mmol, 29 % yield). The absolute configurations of Product P1 and Product P2 are unknown and were assigned arbitrarily. MS (ESI): 633.4 (M+H)+; retention time: 1.73 min (Method 5) observed for both enantiomers. 3-[(4R)-4-[2-[5-[[6,7-difluoro-4-(methylcarbamoyl)-1H-indol-5-yl]oxy]-2-fluoro-phenyl]- 1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid and 3-[(4S)-4-[2-[5-[[6,7- difluoro-4-(methylcarbamoyl)-1H-indol-5-yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4- methyl-chroman-8-yl]propanoic acid Step B: The enantiomerically pure ethyl esters obtained in Step A were hydrolyzed to afford the title compounds via a procedure analogous to the one in Step B, Example 30. 3-[(4R)-4-[2-[5-[[6,7-difluoro-4-(methylcarbamoyl)-1H-indol-5-yl]oxy]-2-fluoro-phenyl]- 1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid (24 mg, 0.0400 mmol, 68 % yield) was derived from Product P1, Step A: MS (ESI): 605.3 (M+H)+; retention time: 1.61 min (Method 5).1H NMR (400 MHz, CD3OD) δ 7.43 (d, J = 3.1 Hz, 1H), 7.40 (dd, J = 5.9, 3.2 Hz, 1H), 7.21- 7.13 (m, 1H), 7.05-6.92 (m, 3H), 6.75 (t, J = 7.6 Hz, 1H), 6.67 (t, J = 3.2 Hz, 1H), 6.60 (s, 1H), 4.25 (ddd, J = 9.6, 6.3, 3.0 Hz, 1H), 4.04 (dd, J = 14.3, 5.7 Hz, 1H), 2.85 (t, J = 7.7 Hz, 2H), 2.81 (s, 3H), 2.54 (t, J = 7.7 Hz, 2H), 2.49-2.41 (m, 1H), 2.02-1.93 (m, 1H), 1.70 (s, 3H) ppm. 3-[(4S)-4-[2-[5-[[6,7-difluoro-4-(methylcarbamoyl)-1H-indol-5-yl]oxy]-2-fluoro-phenyl]- 1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid (23 mg, 0.0379 mmol, 69 % yield) was derived from Product P2, step A: MS (ESI): 605.3 (M+H)+; retention time: 1.63 min (Method 5)1H NMR (400 MHz, CD3OD) δ 7.43 (d, J = 3.1 Hz, 1H), 7.40 (dd, J = 5.9, 3.1 Hz, 1H), 7.21- 7.14 (m, 1H), 6.98 (ddd, J = 11.8, 9.0, 5.7 Hz, 3H), 6.75 (t, J = 7.6 Hz, 1H), 6.67 (t, J = 3.1 Hz, 1H), 6.62 (s, 1H), 4.29-4.21 (m, 1H), 4.09-4.01 (m, 1H), 2.85 (t, J = 7.7 Hz, 2H), 2.81 (s, 3H), 2.54 (t, J = 7.7 Hz, 2H), 2.45 (ddd, J = 13.5, 6.3, 2.5 Hz, 1H), 1.98 (ddd, J = 13.5, 10.3, 5.9 Hz, 1H), 1.70 (s, 3H) ppm. Example 86. Synthesis of 6,7-difluoro-5-[4-fluoro-3-[4-[(4R)-4-methylchroman-4-yl]- 1H-imidazol-2-yl]phenoxy]-N-methyl-1H-indole-4-carboxamide Example 87. Synthesis of 6,7-difluoro-5-[4-fluoro-3-[4-[(4S)-4-methylchroman-4-yl]- 1H-imidazol-2-yl]phenoxy]-N-methyl-1H-indole-4-carboxamide The title compounds were obtained from Intermediate 30 and Intermediate 24 following a procedure analogous to the one in Step A, Examples 84 and 85. 6,7-difluoro-5-[4-fluoro-3-[4-[(4R)-4-methylchroman-4-yl]-1H-imidazol-2-yl]phenoxy]-N- methyl-1H-indole-4-carboxamide (7.5 mg, 0.0141 mmol, 42 % yield): MS (ESI): 533.3 (M+H)+; retention time: 1.70 min (Method 4).1H NMR (400 MHz, CD3OD) δ 7.43 (d, J = 3.1 Hz, 2H), 7.20-7.13 (m, 2H), 7.08 (t, J = 6.9 Hz, 1H), 6.98-6.92 (m, 1H), 6.82 (t, J = 7.5 Hz, 1H), 6.76 (d, J = 7.2 Hz, 1H), 6.67 (t, J = 3.2 Hz, 1H), 6.56 (s, 1H), 4.18 (dd, J = 8.6, 5.4 Hz, 1H), 3.98 (t, J = 8.9 Hz, 1H), 2.81 (s, 3H), 2.49-2.40 (m, 1H), 1.98 (dd, J = 12.0, 7.8 Hz, 1H), 1.70 (s, 3H) ppm. 6,7-difluoro-5-[4-fluoro-3-[4-[(4S)-4-methylchroman-4-yl]-1H-imidazol-2-yl]phenoxy]-N- methyl-1H-indole-4-carboxamide (7.8 mg, 0.0146 mmol, 46 % yield): MS (ESI): 533.3 (M+H)+; retention time: 1.70 min (Method 4).1H NMR (400 MHz, CD3OD) δ 7.45-7.39 (m, 2H), 7.21-7.14 (m, 2H), 7.08 (ddd, J = 8.7, 7.3, 1.6 Hz, 1H), 6.95 (dt, J = 9.0, 3.6 Hz, 1H), 6.86-6.80 (m, 1H), 6.76 (dd, J = 8.2, 1.1 Hz, 1H), 6.67 (t, J = 3.2 Hz, 1H), 6.57 (s, 1H), 4.22-4.14 (m, 1H), 4.03-3.94 (m, 1H), 2.81 (s, 3H), 2.45 (ddd, J = 13.7, 6.1, 2.7 Hz, 1H), 1.98 (ddd, J = 13.7, 11.2, 6.6 Hz, 1H), 1.70 (s, 3H)ppm. Example 88. Synthesis of (R)-2-(((R)-4-(2-(5-((6,7-difluoro-4-((methyl-d3)thio)-1H- indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-(methyl-d3)chroman-8- yl)methyl)propanoic-3,3,3-d3 acid Example 89. Synthesis of (R)-2-(((S)-4-(2-(5-((6,7-difluoro-4-((methyl-d3)thio)-1H- indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-(methyl-d3)chroman-8- yl)methyl)propanoic-3,3,3-d3 acid Diastereomers of methyl (2R)-3,3,3-trideuterio-2-[[4-[2-[5-[[6,7-difluoro-4- (trideuteriomethylsulfanyl)-1H-indol-5-yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4- (trideuteriomethyl)chroman-8-yl]methyl]propanoate Step A: The diastereomer mixture, methyl (2R)-3,3,3-trideuterio-2-[[4-[2-[5-[[6,7-difluoro-4- (trideuteriomethylsulfanyl)-1H-indol-5-yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4- (trideuteriomethyl)chroman-8-yl]methyl]propanoate (740 mg, 1.17 mmol, 86 % yield, a colorless oil), was prepared from Intermediate 31 and Intermediate 33 following a procedure similar to the one in Step A, Example 48. MS (ESI): 631.3 (M+H)+; retention time: 2.08 min (modified Method 2 - Gradient: 5%-95% B in 2.5 min). The diastereomer mixture (1.00 eq, 670 mg, 1.06 mmol) was separated via chiral HPLC to give methyl (R)-2-(((R)-4-(2-(5-((6,7-difluoro-4-((methyl-d3)thio)-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-4-yl)-4-(methyl-d3)chroman-8-yl)methyl)propanoate-3,3,3-d3 (Product P1, 326 mg, 0.517 mmol, 49 % yield) and methyl (R)-2-(((S)-4-(2-(5-((6,7-difluoro- 4-((methyl-d3)thio)-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-(methyl- d3)chroman-8-yl)methyl)propanoate-3,3,3-d3 (Product P2, 324 mg, 0.514 mmol, 48 % yield) as white solids. The absolute configuration of the quaternary carbon center is unknown and was assigned arbitrarily. Product P1: MS (ESI): 631.3 (M+H)+; retention time: 2.03 min (modified Method 2 - Gradient: 5%-95% B in 2.5 min); Chiral HPLC retention time: 5.34 min. Product P2: MS (ESI): 631.3 (M+H)+; retention time: 2.03 min (modified Method 2 - Gradient: 5%-95% B in 2.5 min). Chiral HPLC retention time: 6.12 min. Chiral HPLC Separation Conditions: Instrument: Shimadzu LC-20AT; Column: CHIRALCEL OD-H (ODH0CD-TC012); Column size: 0.46 cm I.D. × 15 cm L; Injection volume: 2 µl; Mobile phase: 85 / 15(V / V) Hexane / EtOH; Flow rate: 1.0 ml / min; Detection wavelength: 214 nm; Temperature: 35 °C. (R)-2-(((R)-4-(2-(5-((6,7-difluoro-4-((methyl-d3)thio)-1H-indol-5-yl)oxy)-2-fluorophenyl)- 1H-imidazol-4-yl)-4-(methyl-d3)chroman-8-yl)methyl)propanoic-3,3,3-d3 acid and (R)-2- (((S)-4-(2-(5-((6,7-difluoro-4-((methyl-d3)thio)-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H- imidazol-4-yl)-4-(methyl-d3)chroman-8-yl)methyl)propanoic-3,3,3-d3 acid Step B: The title compounds were obtained following an ester hydrolysis procedure similar to the one in Step C, Example 48. (R)-2-(((R)-4-(2-(5-((6,7-difluoro-4-((methyl-d3)thio)-1H-indol-5-yl)oxy)-2-fluorophenyl)- 1H-imidazol-4-yl)-4-(methyl-d3)chroman-8-yl)methyl)propanoic-3,3,3-d3 acid (Example 88, 310 mg, 0.503 mmol, 97 % yield, a white solid ) was prepared from Product P1: MS (ESI): 617.3 (M+H)+; retention time: 1.63 min (modified Method 2 - Gradient: 5%B increase to 95%B within 1.3 min; Temperature: 45 °C).1H NMR (400 MHz , CD3OD) δ 7.46-7.40 (m, 2H), 7.17- 7.12 (m, 1H), 7.08-7.06 (m, 1H), 6.98-6.95 (m, 1H), 6.86-6.82 (m, 1H), 6.77-6.71 (m, 2H), 6.50 (s, 1H), 4.24-4.19 (m, 1H), 4.03-3.97 (m, 1H), 2.93 (dd, J = 12.8, 6.8 Hz, 1H), 2.75 (t, J = 7.2 Hz, 1H), 2.67-2.62 (m, 1H), 2.45-2.40 (m, 1H), 2.01-1.95 (m, 1H) ppm. (R)-2-(((S)-4-(2-(5-((6,7-difluoro-4-((methyl-d3)thio)-1H-indol-5-yl)oxy)-2-fluorophenyl)- 1H-imidazol-4-yl)-4-(methyl-d3)chroman-8-yl)methyl)propanoic-3,3,3-d3 acid (Example 89, 296 mg, 0.480 mmol, 93 % yield, a white solid) was prepared from Product P2: MS (ESI): 617.3 (M+H)+; retention time: 1.63 min (modified Method 2 - Gradient: 5% B increase to 95% B within 1.3 min; Temperature: 45 °C).1H NMR (400 MHz ,CD3OD) δ 7.45-7.40 (m, 2H), 7.17-7.12 (m, 1H), 7.07-7.05 (m, 1H), 6.97-6.95 (m, 1H), 6.86-6.82 (m, 1H), 6.76-6.71 (m, 2H), 6.52 (s, 1H), 4.25-4.20 (m, 1H), 4.03-3.98 (m, 1H), 2.92 (dd, J = 12.8, 6.8 Hz, 1H), 2.74 (t, J = 7.2 Hz, 1H), 2.65 (dd, J = 12.8, 7.2 Hz, 1H), 2.47-2.41 (m, 1H), 2.01-1.94 (m, 1H) ppm. Example 90. Synthesis of (R)-2-(((R)-4-(2-(5-((6,7-difluoro-4-((methyl-d3)sulfonyl)-1H- indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-(methyl-d3)chroman-8- yl)methyl)propanoic-3,3,3-d3 acid Example 91. Synthesis of (2R)-2-(((4R)-4-(2-(5-((6,7-difluoro-4-((methyl-d3)sulfinyl)- 1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-(methyl-d3)chroman-8- yl)methyl)propanoic-3,3,3-d3 acid To a stirred and chilled (0 ºC) solution of (R)-2-(((R)-4-(2-(5-((6,7-difluoro-4-((methyl- d3)thio)-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-(methyl-d3)chroman-8- yl)methyl) propanoic-3,3,3-d3 acid (1.00 eq, 280 mg, 0.454 mmol) in methanol (28 mL) was added ammonium molybdate tetrahydrate (0.508 eq, 285 mg, 0.231 mmol) and aqueous hydrogen peroxide (2.01 eq). The reaction mixture was stirred at 0 ºC for 0.5 h, the temperature was raised to RT and stirring continued for 3 h. The reaction mixture was poured into water (20 mL), extracted with ethyl acetate (20 mL). The separated organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC to give (2R)-2-(((4R)-4-(2-(5-((6,7-difluoro-4-((methyl-d3)sulfinyl)- 1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-(methyl-d3)chroman-8- yl)methyl)propanoic-3,3,3-d3 acid (Example 91, 32 mg, 0.0506 mmol, 11 % yield) as a white solid and (R)-2-(((R)-4-(2-(5-((6,7-difluoro-4-((methyl-d3)sulfonyl)-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-4-yl)-4-(methyl-d3)chroman-8-yl)methyl)propanoic-3,3,3-d3 acid (Example 90, 151 mg, 0.232 mmol, 51 % yield) as a white solid. The absolute configuration of the quaternary carbon center of Example 90 and Example 91 has been assigned arbitrarily, consistent with the arbitrary chirality assignment within the starting material. (R)-2-(((R)-4-(2-(5-((6,7-difluoro-4-((methyl-d3)sulfonyl)-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-4-yl)-4-(methyl-d3)chroman-8-yl)methyl)propanoic-3,3,3-d3 acid (Example 90): MS (ESI): 649.3 (M+H)+; retention time: 1.53 min (modified Method 2 - Gradient: 5% B increase to 95% B within 1.3 min; Temperature: 45 °C).1H NMR (400 MHz , CD3OD) δ 7.57-7.53 (m, 2H), 7.26-7.17 (m, 2H), 7.07-6.96 (m, 3H), 6.75 (t, J = 7.2 Hz, 1H), 6.53 (s, 1H), 4.25-4.20 (m, 1H), 4.03-3.98 (m, 1H), 2.92 (dd, J = 12.8, 6.8 Hz, 1H), 2.77-2.62 (m, 2H), 2.45-2.41 (m, 1H), 2.01-1.93 (m, 1H) ppm. (2R)-2-(((4R)-4-(2-(5-((6,7-difluoro-4-((methyl-d3)sulfinyl)-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-4-yl)-4-(methyl-d3)chroman-8-yl)methyl)propanoic-3,3,3-d3 acid (Example 91): MS (ESI): 633.3 (M+H)+; retention time: 1.47 min (modified Method 2 - Gradient: 5% B increase to 95% B within 1.3 min; Temperature: 45 °C).1H NMR (400 MHz , CD3OD) δ 7.56-7.50 (m, 2H), 7.24-7.19 (m, 2H), 7.06 (d, J = 8.0 Hz, 1H), 6.98-6.95 (m, 2H), 6.76-6.73 (m, 1H), 6.53 (s, 1H), 4.24-4.20 (m, 1H), 4.03-3.98 (m, 1H), 2.92 (dd, J = 12.4, 6.4 Hz, 1H), 2.76-2.61 (m, 2H), 2.45-2.41 (m, 1H), 2.00-1.93 (m, 1H) ppm. Example 92. Synthesis of (R)-2-(((S)-4-(2-(5-((6,7-difluoro-4-((methyl-d3)sulfonyl)-1H- indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-(methyl-d3)chroman-8- yl)methyl)propanoic-3,3,3-d3 acid Example 93. Synthesis of (2R)-2-(((4S)-4-(2-(5-((6,7-difluoro-4-((methyl-d3)sulfinyl)- 1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-(methyl-d3)chroman-8- yl)methyl)propanoic-3,3,3-d3 acid Example 93 and Example 94 were prepared from (R)-2-(((S)-4-(2-(5-((6,7-difluoro-4- ((methyl-d3)thio)-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-(methyl- d3)chroman-8-yl)methyl)propanoic-3,3,3-d3 acid (Example 89) following the procedure for Examples 90 and 91. The absolute configuration of the quaternary carbon center of Example 90 and Example 91 has been assigned arbitrarily, consistent with the arbitrary chirality assignment within the starting material. (R)-2-(((S)-4-(2-(5-((6,7-difluoro-4-((methyl-d3)sulfonyl)-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-4-yl)-4-(methyl-d3)chroman-8-yl)methyl)propanoic-3,3,3-d3 acid (Example 92, 117 mg, 0.180 mmol, 41 yield, a white solid): MS (ESI): 649.3 (M+H)+; retention time: 1.50 min (modified Method 2 - Gradient: 5% B increase to 95% B within 1.3 min; Temperature: 45 °C).1H NMR (400 MHz ,MeOD‑d4) δ 7.57-7.53 (m, 2H), 7.25-7.17 (m, 2H), 7.07-7.04 (m, 1H), 7.00-6.96 (m, 2H), 6.75 (t, J = 7.6 Hz, 1H), 6.54 (s, 1H), 4.25-4.20 (m, 1H), 4.03-3.99 (m, 1H), 2.92 (dd, J = 12.8, 6.8 Hz, 1H), 2.76-2.62 (m, 2H), 2.47-2.42 (m, 1H), 2.01-1.93 (m, 1H) ppm. (2R)-2-(((4S)-4-(2-(5-((6,7-difluoro-4-((methyl-d3)sulfinyl)-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-4-yl)-4-(methyl-d3)chroman-8-yl)methyl)propanoic-3,3,3-d3 acid (Example 93, 40 mg, 0.0627 mmol, 14 % yield, a white solid): MS (ESI): 633.3 (M+H)+; retention time: 1.50 min (modified Method 2 - Gradient: 5% B increase to 95% B within 1.3 min; Temperature: 45 °C).1H NMR (400 MHz , MeOD‑d4) δ 7.56-7.50 (m, 2H), 7.24-7.19 (m, 2H), 7.07-6.96 (m, 3H), 6.74 (t, J = 7.6 Hz, 1H), 6.55 (s, 1H), 4.24-4.21 (m, 1H), 4.03-3.99 (m, 1H), 2.92 (dd, J = 12.8, 6.8 Hz, 1H), 2.75-2.62 (m, 2H), 2.47-2.42 (m, 1H), 2.00-1.93 (m, 1H) ppm. Examples 94-99 were prepared following the procedures described for Examples 88-93 starting from Intermediate 32 and Intermediate 33. LC-MS data on the final compounds were obtained with a modified Method 2 - Gradient: 5% B increase to 95% B within 1.3 min; Temperature: 45 °C. The absolute and relative configurations of these examples are unknown and were assigned arbitrarily.

[0004] Example 100. Synthesis of (3R)-3-[(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H- indol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]butanoic acid The title compound was prepared in substantially the same way as Example 30 starting from Intermediate 28 and Intermediate 12. MS (ESI): 633.3 (M+H)+; retention time: 1.58 min (modified Method 2 – Gradient: 5% increase to 95% B within 1.3 min; Flow Rate: 1.8 ml / min). The absolute configuration is unknown and was assigned arbitrarily. Example 101. Synthesis of (3R)-3-[(4S)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H- indol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]butanoic acid The title compound was prepared in substantially the same way as Example 30 starting from Intermediate 27 and Intermediate 12. MS (ESI): 580 (M+H)+; retention time: 1.57 min (modified Method 2 – Gradient: 5% increase to 95%B within 1.3 min; Flow Rate: 1.8ml / min). The absolute configuration is unknown and was assigned arbitrarily. Example 102. Synthesis of 3-[(4S)-4-[2-[5-[(4-cyclopropylsulfanyl-6,7-difluoro- 1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8- yl]propanoic acid Enantiomers of ethyl 3-[4-[2-[5-[(4-cyclopropylsulfanyl-6,7-difluoro-1H-indol-5-yl)oxy]-2- Step A: To a stirred solution of 5-[(4-cyclopropylsulfanyl-6,7-difluoro-1H-indol-5-yl)oxy]-2- fluoro-benzamidine (Intermediate 35, 1.00 eq, 100 mg, 0.265 mmol) in DMF (5 mL) was added ethyl 3-[4-(2-bromoacetyl)-4-methyl-chroman-8-yl]propanoate (Intermediate 9, 1.00 eq, 98 mg, 0.265 mmol) and sodium bicarbonate (2.00 eq, 45 mg, 0.530 mmol), and the reaction mixture was stirred at 75 °C for 4 hours. The mixture was extracted with ethyl acetate (2 x 20 ml). The combined organic extracts were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-50% ethyl acetate in petroleum ether to give ethyl 3-[4-[2-[5-[(4- cyclopropylsulfanyl-6,7-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4- methyl-chroman-8-yl]propanoate (100 mg,0.154 mmol, 58 % yield) as a white solid. MS (ESI): 648.3 (M+H)+; retention time: 1.91 min (Method 5). 240 mg of the racemic ethyl 3-[4-[2-[5-[(4-cyclopropylsulfanyl-6,7-difluoro-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate were separated by chiral SFC to afford ethyl 3-[(4R)-4-[2-[5-[(4-cyclopropylsulfanyl-6,7-difluoro- 1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (Product P1, 80 mg, 0.124 mmol, 33 % yield) as a yellow oil and ethyl 3-[(4S)-4-[2-[5-[(4- cyclopropylsulfanyl-6,7-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4- methyl-chroman-8-yl]propanoate (Product P2, 75 mg, 0.116 mmol, 31 % yield) as a yellow oil. The absolute configurations of the enantiomerically pure Product P1 and Product P2 are unknown and were assigned arbitrarily. MS (ESI): 648.3 (M+H)+; retention time: 1.91 min (Method 5) observed for both Product P1 and Product P2. SFC Separation Conditions: Instrument: SFC-150 (Waters); Column: OJ 25 * 250 mm, 10 µm (Daicel); Column temperature: 35 ºC; Mobile phase: 75 / 25 CO2 / [1:1 MeOH (spiked with 0.5% 7M NH3in MeOH):ACN]; Flow rate: 120 ml / min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 2.1 min; Sample solution: 200 mg dissolved in 50 ml methanol; Injection volume: 2 mL. 3-[(4S)-4-[2-[5-[(4-cyclopropylsulfanyl-6,7-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]- Step B: To a solution of ethyl 3-[(4S)-4-[2-[5-[(4-cyclopropylsulfanyl-6,7-difluoro-1H-indol- 5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (Product P2, Step A, 1.00 eq, 75 mg, 0.116 mmol) in water (2 mL) and THF (2 mL) was added lithium hydroxide monohydrate (5.00 eq, 24 mg, 0.579 mmol) and the reaction was stirred at room temperature for 16 hours. The mixture was acidified with 1M HCl to pH~5, extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-20% methanol in DCM to give 3- [(4S)-4-[2-[5-[(4-cyclopropylsulfanyl-6,7-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid (60 mg, 0.0968 mmol, 84 % yield) as a white solid. MS (ESI): 620.0 (M+H)+; retention time: 1.69 min (modified Method 4 - Temperature: 45 ºC). Example 103. Synthesis of 3-[(4R)-4-[2-[5-[(4-cyclopropylsulfanyl-6,7-difluoro- 1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8- yl]propanoic acid The title compound (60 mg, 0.0968 mmol, 78 % yield, a white solid) was obtained in substantially the same way as Example 102 starting from ethyl 3-[(4R)-4-[2-[5-[(4- cyclopropylsulfanyl-6,7-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4- methyl-chroman-8-yl]propanoate (Product P1, Step A, Example 102, 80 mg, 0.124 mmol). MS (ESI): 620.0 (M+H)+; retention time: 1.69 min (modified Method 4 - Temperature: 45 ºC). Example 104. Synthesis of 3-[(4S)-4-[2-[5-[(4-cyclopropylsulfonyl-6,7-difluoro- 1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8- yl]propanoic acid To a stirred and chilled (0 °C) solution of 3-[(4S)-4-[2-[5-[(4-cyclopropylsulfanyl-6,7-difluoro- 1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid (Example 102, 1.00 eq, 30 mg, 0.0484 mmol) in methanol (1 mL) was added a mixture of ammonium molybdate tetrahydrate (1.01 eq, 60 mg, 0.0487 mmol) in 0.5 mL of aqueous peroxide (). The reaction was stirred at room temperature for 30 min, diluted with ethyl acetate (30 mL), washed with water (3 x 30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC to give 3-[(4S)-4-[2-[5-[(4- cyclopropylsulfonyl-6,7-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4- methyl-chroman-8-yl]propanoic acid (9.1 mg, 0.0140 mmol, 29 % yield) as a white solid. MS (ESI): 652.3 (M+H)+; retention time: 1.72 min (Method 5). The absolute configuration of the title compound is unknown and was assigned arbitrarily. Example 105. Synthesis of 3-[(4R)-4-[2-[5-[(4-cyclopropylsulfonyl-6,7-difluoro- 1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8- yl]propanoic acid Prepared in substantially the same way as Example 104 starting from Example 103. MS (ESI): 652.3 (M+H)+; retention time: 1.72 min (Method 5). The absolute configuration of the title compound is unknown and was assigned arbitrarily. Example 106. Synthesis of 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-isopropylsulfonyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Prepared in substantially the same way as Example 104 starting from Intermediate 9 and Intermediate 34. MS (ESI): 654.3 (M+H)+; retention time: 1.63 min (Method 4) The absolute configuration of the title compound is unknown and was assigned arbitrarily. Example 107. Synthesis of 3-[(4S)-4-[2-[5-[(6,7-difluoro-4-isopropylsulfonyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Prepared in substantially the same way as Example 104 starting from Intermediate 9 and Intermediate 34. MS (ESI): 654.3 (M+H)+; retention time: 1.63 min (Method 4) The absolute configuration of the title compound is unknown and was assigned arbitrarily. Example 108. Synthesis of 3-[(4S)-4-[2-[5-[(6,7-difluoro-4-isopropylsulfanyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Prepared in substantially the same way as Example 102 starting from Intermediate 9 and Intermediate 34. MS (ESI): 621.9 (M+H)+; retention time: 1.74 min (Method 4) The absolute configuration of the title compound is unknown and was assigned arbitrarily. Example 109. Synthesis of 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-3,3-difluoro-4-methyl-chroman-8- yl]propanoic acid Enantiomers of ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro- Step A: Racemic ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2- fluoro-phenyl]-1H-imidazol-4-yl]-3,3-difluoro-4-methyl-chroman-8-yl]propanoate, obtained from Intermediate 9 and Intermediate 36 in substantially the same way as the product from Step A, Example 102, (160 mg, 70 % yield, a solid) was separated via chiral SFC into ethyl 3- [(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-3,3-difluoro-4-methyl-chroman-8-yl]propanoate (Stereoisomer 1, 52 mg, 33 % yield) and ethyl 3-[(4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro- phenyl]-1H-imidazol-4-yl]-3,3-difluoro-4-methyl-chroman-8-yl]propanoate (Stereoisomer 2, 49 mg, 31 % yield) as a solid. The absolute configurations of the Stereoisomer 1 and Stereoisomer 2 are unknown and were assigned arbitrarily. Ethyl 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]- 1H-imidazol-4-yl]-3,3-difluoro-4-methyl-chroman-8-yl]propanoate (Stereoisomer 1): MS (ESI): 658.2 (M+H)+; retention time: 1.89 min (modified Method 2 – Gradient: 5% B to 95% B within 1.3 min; Flow Rate: 1.8ml / min). Ethyl 3-[(4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]- 1H-imidazol-4-yl]-3,3-difluoro-4-methyl-chroman-8-yl]propanoate (Stereoisomer 2): MS (ESI): 658.2 (M+H)+; retention time: 1.89 min (modified Method 2 – Gradient: 5% B to 95% B within 1.3 min; Flow Rate: 1.8ml / min). 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-3,3-difluoro-4-methyl-chroman-8-yl]propanoic acid Step B: The title compound was prepared from ethyl 3-[(4R)-4-[2-[5-[(6,7-difluoro-4- methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-3,3-difluoro-4- methyl-chroman-8-yl]propanoate (Stereoisomer 1, Step A) following the procedure from Step B, Example 102. MS (ESI): 630.2 (M+H)+; retention time: 1.74 min (modified Method 2 – Gradient: 5% B to 95% B within 1.3 min; Flow Rate: 1.8 ml / min). Example 110. Synthesis of 3-[(4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-3,3-difluoro-4-methyl-chroman-8- yl]propanoic acid Prepared in substantially the same way as Example 109 from Stereoisomer 2, Step A, Example 109. MS (ESI): 630.2 (M+H)+; retention time: 1.74 min (modified Method 2 – Gradient: 5% B to 95% B within 1.3 min; Flow Rate: 1.8 ml / min). Example 111. Synthesis of 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-3,3-difluoro-4-methyl-chroman-8- yl]propanoic acid Example 112. Synthesis of 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-3,3-difluoro-4-methyl-chroman-8- yl]propanoic acid To a stirred solution of 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2- fluoro-phenyl]-1H-imidazol-4-yl]-3,3-difluoro-4-methyl-chroman-8-yl]propanoic acid (Example 109, 40 mg, 0.0635 mmol) in MeOH (3 mL) was added a mixture of 0.1 g ammonium molybdate tetrahydrate in 0.5 mL of aqueous peroxide (~2 eq) at 0 °C. The reaction was allowed to warm up to rt and stirred for 0.5 h. The mixture was diluted with ethyl acetate (30 mL), washed with water (50 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to give 3-[(4R)-4-[2-[5-[(6,7-difluoro- 4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-3,3-difluoro-4- methyl-chroman-8-yl]propanoic acid (Example 111, 4.9 mg, 12 % yield) and 3-[(4R)-4-[2-[5- [(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-3,3- difluoro-4-methyl-chroman-8-yl]propanoic acid (Example 112, 12.8 mg, 30 % yield) as a solid. The absolute configurations of the title compounds are unknown and were assigned arbitrarily, consistent with the stereochemistry assignment for the starting material. 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-3,3-difluoro-4-methyl-chroman-8-yl]propanoic acid (Example 111): MS (ESI): 646.2 (M+H)+; retention time: 1.58 min (modified Method 2 – Gradient: 5% B to 95% B within 1.3 min). 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-3,3-difluoro-4-methyl-chroman-8-yl]propanoic acid (Example 112): MS (ESI): 662.2 (M+H)+; retention time: 1.60 min (modified Method 2 – Gradient: 5% B to 95% B within 1.3 min). Example 113. Synthesis of 3-[(4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-3,3-difluoro-4-methyl-chroman-8- yl]propanoic acid Example 114. Synthesis of 3-[(4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-3,3-difluoro-4-methyl-chroman-8- yl]propanoic acid Example 113 and Example 114 were prepared similarly to Example 111 and Example 112 starting from Example 110. 3-[(4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-3,3-difluoro-4-methyl-chroman-8-yl]propanoic acid ( 8.9 mg, 24 % yield): MS (ESI): 646.2 (M+H)+; retention time: 1.57 min (modified Method 2 – Gradient: 5% B to 95% B within 1.3 min). 3-[(4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-3,3-difluoro-4-methyl-chroman-8-yl]propanoic acid (16.2 mg, 43 % yield): MS (ESI): 662.2 (M+H)+; retention time: 1.60 min (modified Method 2 – Gradient: 5% B to 95% B within 1.3 min). Example 115. Synthesis of 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-3-fluoro-4-methyl-chroman-8-yl]propanoic acid Example 116. Synthesis of 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-3-fluoro-4-methyl-chroman-8-yl]propanoic acid Example 115 (20.9 mg, 17 % yield) and Example 116 (38.2 mg, 30 % yield) were prepared in substantially the same way as Example 111 and Example 112 starting from 3-[4-[2-[5-[(6,7- difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-3-fluoro- 4-methyl-chroman-8-yl]propanoic acid. This starting material was obtained in substantially the same way as Example 102 starting from Intermediate 9 and Intermediate 37. 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-3-fluoro-4-methyl-chroman-8-yl]propanoic acid: MS (ESI): 612.2 (M+H)+; retention time: 1.46 min (Method 4). 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol- 4-yl]-3-fluoro-4-methyl-chroman-8-yl]propanoic acid (Example 115): MS (ESI): 628.2 (M+H)+; retention time: 1.43 min (modified Method 2 – Gradient: 5% B to 95% B within 1.3 min; Flow Rate: 1.8 ml / min). 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-3-fluoro-4-methyl-chroman-8-yl]propanoic acid (Example 116): MS (ESI): 644.1 (M+H)+; retention time: 1.46 min (modified Method 2 – Gradient: 5% B to 95% B within 1.3 min; Flow Rate: 1.8 ml / min). Example 117. Synthesis of 3-[(2R,4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-2,4-dimethyl-chroman-8- yl]propanoic acid Diastereomers of ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2- Step A: A mixture of 5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro- benzamidine (Intermediate 17, 1.00 eq, 1018 mg, 2.90 mmol), ethyl 3-[4-(2-bromoacetyl)-2,4- dimethyl-chroman-8-yl]propanoate (Intermediate 38, 1.00 eq, 1.11 g, 2.90 mmol) and sodium bicarbonate (2.00 eq, 487 mg, 5.79 mmol) in DMF (10 mL) was stirred at 75 °C for 16 h. The reaction mixture was diluted with brine (50 mL) and extracted with EA (3 x 10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 0-10% ethyl acetate in petroleum ether to give ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol- 5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-2,4-dimethyl-chroman-8-yl]propanoate (Product 1, an equimolar mixture of 2 enantiomers, 436 mg, 24 % yield) as a brown solid and ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-2,4-dimethyl-chroman-8-yl]propanoate (Product 2, an equimolar mixture of 2 enantiomers, 953 mg, 52 % yield) as a brown solid. The relative configurations of the two stereocenters contained within each Product 1 and Product 2 racemic mixtures are unknown. Product 1: MS (ESI): 636.4 (M+H)+; retention time: 1.95 min (Method 5). Product 2: MS (ESI): 636.4 (M+H)+; retention time: 1.94 min (Method 5). Enantiomers of ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro- Step B: Product 1 (Step A), an equimolar mixture of 2 enantiomers (436 mg, 0.686 mmol), was separated by supercritical fluid chromatography to give ethyl 3-[(2R,4R)-4-[2-[5-[(6,7- difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-2,4- dimethyl-chroman-8-yl]propanoate (Stereoisomer 1, 159 mg, 0.250 mmol, 37 % yield) as a white solid and ethyl 3-[(2S,4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]- 2-fluoro-phenyl]-1H-imidazol-4-yl]-2,4-dimethyl-chroman-8-yl]propanoate (Stereoisomer 2, 195 mg, 0.307 mmol, 45 % yield) as a white solid. The absolute and relative configurations of Stereoisomer 1 and Stereoisomer 2 are unknown and were assigned arbitrarily. Chiral prep-HPLC Conditions: Column: OD-H 4.6 * 100 mm 5 µm; Mobile phase: 1 / 1 ACN / MeOH [spiked with 0.2 % 7M NH3in MeOH]; Injection volume: 5.00 µl; Run time: 5.0 Minutes; Detection wavelength: 254 nm; Flow rate: 3.0 mL / min; Back Pressure: 2000 psi; Column Temperature: 40 °C. Under these conditions, Stereoisomer 1 elutes first at 2.09 min and Stereoisomer 2 elutes second at 2.45 min. 3-[(2R,4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- i Step C: A mixture of ethyl 3-[(2R,4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-2,4-dimethyl-chroman-8-yl]propanoate (Stereoisomer 1, Step B, 1.00 eq, 30 mg, 0.0472 mmol) and lithium hydroxide monohydrate (4.00 eq, 7.9 mg, 0.189 mmol) in THF (1 mL), methanol (1 mL) and water (0.5 mL) was stirred at room temperature for 16 h. The pH of the mixture was adjusted to ~5 with 1M hydrochloric acid and the mixture extracted with EA (3 x 5 mL). The combined organic extracts were dried over Na2SO4and concentrated in vacuo. The residue was purified by reverse-phase column chromatography on C18 to give 3-[(2R,4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol- 5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-2,4-dimethyl-chroman-8-yl]propanoic acid (18 mg, 0....

Claims

Claims 1. A compound of Formula (I):or a pharmaceutically acceptable salt thereof wherein W1is selected from the group consisting of -C(H)=, and -N=; W2is selected from the group consisting of -C(H)=, -C(Rd)=, and -N=; W3is selected from the group consisting of -C(H)=, -C(Rd)=, and -N=; W4is selected from the group consisting of -C(H)=, -C(Rd4)=, and -N=; W5is selected from the group consisting of -C(H)=, -C(Rd5)=, and -N=; W6is selected from the group consisting of -C(H)=, -C(Rc)=, and -N=; W7is selected from the group consisting of -C(H)=, -C(Rc)=, and -N=; W8is selected from the group consisting of -C(H)=, -C(Rc)=, and -N=; W9is selected from the group consisting of -C(H)=, -C(Rc9)=, and -N=; Ring A is an optionally substituted 8-10 membered fused heterocyclyl; Ring B is optionally substituted 5-membered heteroaryl; each Rais independently selected from the group consisting of halogen, oxo, -CN, -NO2- OR1, -SR1, -N(R1)2, -C(O)OR1, C(O)N(R1)2, -N(H)C(O)R1, -SO2R1, -SO2N(R2), - SO(NR2)R1, -N(H)C(O)N(R1)2, -CD3, optionally substituted C1-C6aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each Rais independently substituted with 0-4 instances of Raa;each Raais independently selected from the group consisting of deuterium, halogen, oxo, - COOH, -CN, -CD3, optionally substituted C1-C6aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, optionally substituted 3-7 membered heterocyclyl, -OR1, -SR1, -N(R1)2, - C(O)OR1, C(O)N(R1)2, -N(H)C(O)R1, and -N(H)C(O)N(R1)2, wherein two instances of Raaare optionally taken together with any intervening atoms to form an optionally substituted 5-6 membered heterocyclyl ring; each Rbis independently selected from the group consisting of halogen, oxo, -CN, -NO2- OR1, -SR1, -N(R1)2, -C(O)OR1, C(O)N(R1)2, -N(H)C(O)R1, -SO2R1, -SO2N(R2), - SO(NR2)R1, -N(H)C(O)N(R1)2, optionally substituted C1-C6aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl; each Rcis independently selected from the group consisting of halogen, oxo, -CN, -NO2- OR1, -SR1, -N(R1)2, -C(O)OR1, C(O)N(R1)2, -N(H)C(O)R1, -SO2R1, -SO2N(R2), - SO(NR2)R1, -N(H)C(O)N(R1)2, optionally substituted C1-C6aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each Rcis independently substituted with 0-4 instances of Raa; each Rdis independently selected from the group consisting of halogen, oxo, -CN, -NO2- OR1, -SR1, -N(R1)2, -C(O)OR1, C(O)N(R1)2, -N(H)C(O)R1, -SO2R1, -SO2N(R2), - SO(NR2)R1, -N(H)C(O)N(R1)2, optionally substituted C1-C6aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each Rdis independently substituted with 0-4 instances of Raa; Rc9is halogen; Rd4is halogen; Rd5is halogen; each R1is independently selected from the group consisting of hydrogen, -CD3, -(CH2)1-3R2, - C(O)R2, -(CH2)1-3OR2, optionally substituted C1-C6aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl; wherein two instances of R1are optionally taken together with any intervening atoms to form an optionally substituted 3-7 membered heterocyclyl ring;each R2is independently selected from the group consisting of hydrogen, optionally substituted C1-C6aliphatic, optionally substituted phenyl, optionally substituted 5-6- membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl; X is selected from the group consisting of -O-, -S-, -S(O)-, -S(O)2-; -SO(NR2)- , -C(R1)(R2)- , and -C(O)-; n is 0, 1, 2, or 3; and m is 0, 1, 2, or 3.

2. The compound of claim 1, wherein W1is -N=.

3. The compound of claim 1, wherein W2is -N=.

4. The compound of claim 1, wherein W3is -N=.

5. The compound of claim 1, wherein W4is -N=.

6. The compound of claim 1, wherein when W8is -N=, W1, W2, W3, and W4are each not -N=.

7. The compound of claim 1, wherein the compound is of Formula (I-a), (I-b), (I-c), (I-d), (I-e), or (I-f):or a pharmaceutically acceptable salt thereof.

8. The compound of any of claims 1-7, wherein W6is -C(H)=; W7is -C(H)=; W8is -C(H)=; and W9is -N=.

9. The compound of any of claims 1-7, wherein W6is -C(H)=; W7is -C(H)=; W8is -N=; and W9is -C(H)=.

10. The compound of any of claims 1-7, wherein W6is -C(H)=; W7is -C(H)=; W8is -C(H)=; and W9is -C(H)=.

11. The compound of any of claims 1-7, wherein W6is -C(Rc)=; W7is -C(H)=; W8is -C(H)=; and W9is -C(H)=.

12. The compound of any of claims 1-7, wherein W6is -C(H)=; W7is -C(H)=; W8is -C(Rc)=; and W9is -C(H)=.

13. The compound of any of claims 1-12, wherein X is -O-.

14. The compound of any of claims 1-13, wherein Ring B is optionally substituted 5- membered heteroaryl comprising 1-3 nitrogen atoms.

15. The compound of any of claims 1-14, wherein Ring B is a optionally substituted 5- membered heteroaryl selected from the group consisting of pyrazolyl, triazolyl, imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, thiadiazolyl, isooxadiazolyl and isothiadiazolyl.

16. The compound of claim 15, wherein Ring B is pyrazolyl.

17. The compound of claim 15, wherein Ring B is18. The compound of claim 15, wherein Ring B is.

19. The compound of claim 15, wherein Ring B is triazolyl.

20. The compound of claims 15, wherein Ring B is 1,2,4 triazolyl.

21. The compound of claims 15, wherein Ring B is 1,2,3 triazolyl.

22. The compound of claim 15, wherein Ring B is selected from the group consisting of23. The compound of claim 15, wherein Ring24. The compound of claim 15, wherein Ring B is pyrrolyl.

25. The compound of claim 15, wherein Ring B is selected from the group consisting of26. The compound of claim 15, wherein Ring B is imidazolyl.

27. The compound of claim 15, wherein Ring B is selected from the group consisting of28. The compound of claim 15, wherein Ring B is selected from the group consisting of29. The compound of claim 15, wherein Ring B is oxazolyl.

30. The compound of claim 15, wherein Ring B is selected from the group consisting of31. The compound of claim 15, wherein Ring B is thiazolyl.

32. The compound of claim 15, wherein Ring B is selected from the group consisting of33. The compound of claim 15, wherein Ring B is selected from the group consisting of oxazolyl, pyrazolyl, 1,2,4-triazolyl or imidazolyl.

34. The compound of claim 15, wherein Ring B is selected from the group consisting of35. The compound of any of claims 1-34, wherein Ring A is optionally substituted 9-10- membered heterocyclyl selected from the group consisting of dihydrochromenyl, dihydrobenzofuranyl, and dihydroisoindolyl.

36. The compound of claim 35, wherein Ring A is optionally substituted 9-10-membered heterocyclyl selected from the group consisting of37. The compound of any of claims 1-37, wherein each Rais independently selected from halogen, optionally substituted C1-C6alkyl, and optionally substituted C1-C6alkenyl, wherein each Rais independently substituted with 0-4 instances of Raa.

38. The compound of claim 36, wherein each Rais independently selected from the group consisting of -CH2COOH, -CH2CH2COOH, and -C(H)=C(H)-COOH.

39. The compound of any of claims 1-38, wherein each Rdis independently selected from the group consisting of halogen, -OR1, -SRI, -C(O)N(R1)2, -N(H)C(O)R1, -SO2R1, - SO2N(R2), -SO(NR2)R1, and optionally substituted C1-C6aliphatic, wherein each Rdis independently substituted with 0-4 instances of Raa.

40. The compound of claim 39, wherein each Rdis independently selected from the group consisting of fluoro, methyl, -CHF2, -CH2CHF2, -SCH3, -S(i-propyl),-S(cyclopropyl), - SCD3,-S(O)CH3,,-S(O)CD3, -S(O)2CH3, -S(O)2CD3, -S(O)2(i-propyl), - S(O)2(cyclopropyl), -CH3S(O)2CH3, -SO(N(CH3))CH3, -C(O)N(H)CH3, CH2N(H)(t- Butyl),41. The compound of any of claims 1-40, wherein each Rd4is halogen.

42. The compound of claim 41, wherein Rd4is fluoro.

43. The compound of any of claims 1-42, wherein each Rd5is halogen.

44. The compound of claim 43, wherein Rd5is fluoro.

45. The compound of any of the previous claims, wherein the compound is selected from the group consisting ofor a pharmaceutically acceptable salt thereof.

46. A pharmaceutical composition comprising a compound of any of the previous claims and a pharmaceutically acceptable excipient.

47. A method of treating a CFTR-mediated disease or disorder comprising administering a patient in need there of a compound any of claims 1-39 or a pharmaceutical composition of claim 46.

48. The method of claim 47, wherein the disease or condition is selected from cystic fibrosis, asthma, smoke induced COPD, chronic bronchitis, rhinosinusitis, constipation, pancreatitis, pancreatic insufficiency, male infertility caused by congenital bilateral absence of the vas deferens (CBAVD), mild pulmonary disease, idiopathic pancreatitis, allergic bronchopulmonary aspergillosis (ABPA), liver disease,hereditary emphysema, hereditary hemochromatosis, coagulation-fibrinolysis deficiencies, protein C deficiency, Type 1 hereditary angioedema, lipid processing deficiencies, familial hypercholesterolemia, Type 1 chylomicronemia, abetalipoproteinemia, lysosomal storage diseases, I-cell disease / pseudo-Hurler, mucopolysaccharidoses, Sandhof / Tay-Sachs, Crigler-Najjar type II, polyendocrinopathy / hyperinsulemia, Diabetes mellitus, Laron dwarfism, myeloperoxidase deficiency, primary hypoparathyroidism, melanoma, glycanosis CDG type 1, congenital hyperthyroidism, osteogenesis imperfecta, hereditary hypofibrinogenemia, ACT deficiency, Diabetes insipidus (DI), neurophyseal DI, neprogenic DI, Charcot-Marie Tooth syndrome, Perlizaeus-Merzbacher disease, neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, progressive supranuclear palsy, Pick's disease, several polyglutamine neurological disorders, Huntington's, spinocerebellar ataxia type I, spinal and bulbar muscular atrophy, dentatorubal pallidoluysian, myotonic dystrophy, spongiform encephalopathies, hereditary Creutzfeldt-Jakob disease, Fabry disease, Straussler- Scheinker syndrome, COPD, dry-eye disease, Sjogren's disease, Osteoporosis, Osteopenia, bone healing and bone growth, bone repair, bone regeneration, reducing bone resorption, increasing bone deposition, Gorham's Syndrome, chloride channelopathies, myotonia congenita, Bartter's syndrome type III, Dent's disease, hyperekplexia, epilepsy, hyperekplexia, lysosomal storage disease, Angelman syndrome, Primary Ciliary Dyskinesia (PCD), PCD with situs inversus, PCD without situs inversus and ciliary aplasia.

49. The method of claim 47 or 48, wherein the disease or condition is selected from cystic fibrosis, congenital bilateral absence of vas deferens (CBAVD), acute, recurrent, or chronic pancreatitis, disseminated bronchiectasis, asthma, allergic pulmonary aspergillosis, chronic obstructive pulmonary disease (COPD), chronic sinusitis, dry eye disease, protein C deficiency, Abetalipoproteinemia, lysosomal storage disease, type 1 chylomicronemia, mild pulmonary disease, lipid processing deficiencies, type 1 hereditary angioedema, coagulation-fibrinolyis, hereditary hemochromatosis, CFTR- related metabolic syndrome, chronic bronchitis, constipation, pancreatic insufficiency, hereditary emphysema, and Sjogren's syndrome.

50. The method of any one of claims 47-49, wherein the disease or condition is cystic fibrosis.

51. A method of treating kidney disease in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any of claims 1-39 or a pharmaceutical composition of claim 46.

52. The method of claim 51, wherein the kidney disease is autosomal dominant polycystic kidney disease or autosomal recessive polycystic kidney disease.

53. The method of claim 51, wherein the kidney disease is autosomal dominant polycystic kidney disease.

54. The method of claim 51, wherein the kidney disease is autosomal recessive polycystic kidney disease.

55. A method of treating cystic fibrosis in a subject, comprising administering to the subject a therapeutically effective amount of a compound of any of claims 1-39 or a pharmaceutical composition of claim 46.

56. The method of claim 55, wherein the subject is human.

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