EP4673141A1

EP4673141A1 - Nbd1 modulators and methods of using the same

Info

Publication number: EP4673141A1
Application number: EP24764683.9A
Authority: EP
Inventors: Junkai Liao; Mark Munson; Sukanthini Thurairatnam; Bradford Hirth; Zhongli Gao; Gregory Donald HURLBUT; Jinyu Liu; Michael Kothe; George Topalov; John E. Macor; Yi Li; Andrew Good
Original assignee: Genzyme Corp; Sionna Therapeutics Inc
Current assignee: Genzyme Corp; Sionna Therapeutics Inc
Priority date: 2023-03-02
Filing date: 2024-03-01
Publication date: 2026-01-07
Also published as: WO2024182751A1

Abstract

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

Description

NBD1 MODULATORS AND METHODS OF USING THE SAME [001] 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 [002] 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. [003] 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. [004] 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. [005] 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. [006] By studying the mechanistic aspects of CFTR misfolding and corrections, small molecules have been identified as CF modulators, that can act as stabilizers. [007] 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 [008] 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 [009] In some embodiments, the present disclosure includes a compound of Formula I: (I) or a pharmaceutically acceptable salt thereof wherein W¹ is selected from the group consisting of -C(H)=, and -N=; W² is selected from the group consisting of -C(H)=, -C(R^d)=, and -N=; W³ is selected from the group consisting of -C(H)=, -C(R^d)=, and -N=; W⁴ is selected from the group consisting of -C(H)=, -C(R^d4)=, and -N=; W⁵ is selected from the group consisting of -C(H)=, -C(R^d5)=, and -N=; W⁶ is selected from the group consisting of -C(H)=, -C(R^c)=, and -N=; W⁷ is selected from the group consisting of -C(H)=, -C(R^c)=, and -N=; W⁸ is selected from the group consisting of -C(H)=, -C(R^c)=, and -N=; W⁹ is selected from the group consisting of -C(H)=, -C(R^c9)=, and -N=; Ring A is an optionally substituted 8-10 membered fused heterocyclyl; Ring B is optionally substituted 5-membered heteroaryl; each R^a is 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-C₆ aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each R^a is independently substituted with 0-4 instances of R^aa, each R^aa is independently selected from the group consisting of deuterium, halogen, oxo, - COOH, -CN, -CD₃, optionally substituted C₁-C₆ aliphatic, 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 R^aa are optionally taken together with any intervening atoms to form an optionally substituted 5-6 membered heterocyclyl ring; each R^b is 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-C₆ aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl; each R^c is 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-C₆ aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each R^c is independently substituted with 0-4 instances of R^aa; each R^d is 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-C₆ aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each R^d is independently substituted with 0-4 instances of R^aa; R^c9 is halogen; R^d4 is halogen; R^d5 is halogen; each R¹ is independently selected from the group consisting of hydrogen, -CD₃, -(CH₂)_1-3R², - C(O)R², -(CH₂)_1-3OR², optionally substituted C₁-C₆ aliphatic, 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 R¹ are optionally taken together with any intervening atoms to form an optionally substituted 3-7 membered heterocyclyl ring; each R² is independently selected from the group consisting of hydrogen, optionally substituted C₁-C₆ aliphatic, 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. [010] 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 [011] 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 [012] 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. [013] In some embodiments, Ring A is selected from the group consisting of Ring B [014] 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 . [016] In some embodiments, Ring B is selected from the group consisting of [017] In some embodiments, Ring [018] In some embodiments, Ring B is selected from the group consisting [019] In some embodiments, Ring B is selected from the group consisting [020] In some embodiments, Ring B is selected from the group consisting [021] In some embodiments, Ring B is selected from the group consisting [022] Ring B is selected from the group consisting of [023] In some embodiments, Ring B is selected from the group consisting of R^a [024] In some embodiments, each R^a is 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-C₆ aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each R^a is independently substituted with 0-4 instances of R^aa. In some embodiments, each R^a is independently selected from halogen, optionally substituted C₁-C₆ alkyl, and optionally substituted C₁-C₆ alkenyl, wherein each R^a is independently substituted with 0-4 instances of R^aa. In some embodiments, wherein each R^a is independently -CH₂COOH, - CH₂CH₂COOH, and -C(H)=C(H)-COOH. In some embodiments, wherein R^a is -CH₂COOH. In some embodiments, wherein R^a is -CH₂CH₂COOH. In some embodiments, wherein R^a is - C(H)=C(H)-COOH. R^b [025] In some embodiments, each R^b is 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-C₆ aliphatic, 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, R^b is optionally substituted C₁-C₆ aliphatic. In some embodiments, R^b is optionally substituted C₁-C₆ alkyl. In some embodiments, R^b is optionally substituted C₁-C₃ alkyl. In some embodiments, R^b is optionally substituted methyl. R^c [026] In some embodiments, each R^c is 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-C₆ aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each R^c is independently substituted with 0-4 instances of R^aa. [027] In some embodiments, R^c is halogen. In some embodiments, R^c is fluoro. [028] In some embodiments, R^c is CH₂N(R¹)(R²). In some embodiments, R^c is CH₂N(H)(i- propyl). In some embodiments, R^c is CH₂N(H)(t-butyl). R^d [029] In some embodiments, each R^d is 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-C₆ aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each R^d is independently substituted with 0-4 instances of R^aa. In some embodiments, R^d is independently selected from the group consisting of halogen, -OR¹, -SR^I, -C(O)N(R¹)₂, - N(H)C(O)R¹, -SO₂R¹, -SO₂N(R²), -SO(NR²)R¹, and optionally substituted C₁-C₆ aliphatic, wherein each R^d is independently substituted with 0-4 instances of R^aa. In some embodiments, each R^d is 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 . [030] In some embodiments, the present disclosure includes compounds listed in Table 1. Table 1

91 92 93 94 210 or a pharmaceutically acceptable salt thereof. Definitions [031] 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-C₆ hydrocarbon 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. [032] The term "haloaliphatic" refers to an aliphatic group that is substituted with one or more halogen atoms. [033] The term "haloalkyl" refers to a straight or branched alkyl group that is substituted with one or more halogen atoms. [034] 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. [035] 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. [036] 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. [037] 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. [038] 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. [039] 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. [040] 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. [041] 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. [042] 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; —(C_1-4 straight or branched alkylene)O—N(R^∘)₂; or —(C_1-4 straight or branched alkylene)C(O)O—N(R^∘)₂, wherein each R^∘ may be substituted as defined below and is independently hydrogen, C_1-6 aliphatic, — 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. [043] 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^●, —(C_1-4 straight 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 C_1-4 aliphatic, —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. [044] 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, C_1-6 aliphatic 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, C_1-6 aliphatic 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. [045] 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 C_1-4 aliphatic, —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. [046] 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, C_1-6 aliphatic 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. [047] 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 C_1-4 aliphatic, —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. [048] 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. [049] Salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N(C_1-4alkyl)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. [050] 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. [051] 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. [052] 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. [053] 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). [054] 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. [055] 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. [056] 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. [057] 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. [058] 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. [059] 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. [060] 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. [061] 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. [062] 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. [063] 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. [064] 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. [065] 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. [066] 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 [067] In an alternative embodiment, compounds described herein may also comprise one or more isotopic substitutions. For example, hydrogen may be ²H (D or deuterium) or ³H (T or tritium); carbon may be, for example, ¹³C or ¹⁴C; 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, or ¹⁵N) 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 [068] 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. [069] 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. [070] 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. [071] The term “parenteral” as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. [072] 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. [073] 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. [074] 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. [075] 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. [076] 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 [077] 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. [078] 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. [079] 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. [080] 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. [081] 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. [082] 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. [083] 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. [084] 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. [085] 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. [086] 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. [087] 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. [088] 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. [089] 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 [090] 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) [091] 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. [092] 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. [093] 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. [094] 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. [095] 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. [096] 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. [097] 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. [098] 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. [099] 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. [100] 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. [101] 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. [102] In one embodiment, the ENaC inhibitor is VX-371. [103] In one embodiment, the ENaC inhibitor is SPX-101 (S18). [104] 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 Procedures ¹H 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, T_1.3 min : 98% B, T_1.33 min : 2% B, T_1.5 min : 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: T_1.5 min : 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: T_1.3 min : 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, T_1.5 min; 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: T_1.5 min : 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 NH₄HCO₃ spiked 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 [105] 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 [106] 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 [107] 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 [108] 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 [109] 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 [110] 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 [111] 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 [112] 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 [113] 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 [114] 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 [115] 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 [116] 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 H₂ overnight. 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 [117] 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 [118] 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%). [119] 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)⁺. [120] 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 [121] 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 Na₂SO₄ and 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 [122] 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 [123] 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 [124] 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 SOCl₂ was 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 NaHCO₃ and 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 [125] 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 [126] 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 [127] 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 [128] 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 [129] 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 [130] 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 [131] 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 [132] 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)₂ on 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 [133] 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 [134] 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 [135] 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 [136] 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 [137] 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 [138] 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 [139] 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 [140] 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 [141] 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)₂ on 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 [142] Step D: A solution of 8-(2-ethoxy-2-oxo-ethyl)chromane-3-carboxylic acid (206 mg, 0.725 mmol) in 5 mL of SOCl₂ was 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 [143] 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 [144] 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. CO₂ Flow 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 [145] 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 [146] 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 [147] 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 [148] 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 [149] 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 [150] 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 [151] 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 [152] 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 [153] 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 [154] 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 [155] 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 [156] 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 [157] 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 [158] 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 H₂ and 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 [159] 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 [160] 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 [161] 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 [162] 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 [163] 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 [164] 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 [165] 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 [166] 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 [167] 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 [168] 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 [169] 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 NaHCO₃ solution (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 [170] 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 [171] 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 [172] 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 [173] 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 [174] 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 [175] 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 [176] 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 [177] 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 [178] 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 [179] 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 [180] 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 [181] 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 [182] 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 [183] 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 H₂ for 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 [184] 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 [185] 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 [186] 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 [187] 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% NH₄HCO₃ aqueous 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 [188] 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% NH₄HCO₃ aqueous 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 [189] 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 [190] 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 [191] 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 [192] 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 [193] 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 [194] 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 [195] 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 NaHCO₃ solution (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 [196] 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 Na₂S₂O₃ aqueous 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 [197] 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 [198] 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 [199] 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 [200] 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 [201] 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 [202] 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 [203] 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 [204] 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 [205] 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 [206] 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 [207] 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 [208] 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 [209] 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 [210] 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 [211] 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 [212] 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)Cl₂ dichloromethane 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 [213] 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- [214] 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 H₂ atmosphere 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- [215] 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 H₂ atmosphere 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- [216] 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- [217] 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 Na₂SO₄ and 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 [218] 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 [219] 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 H₂ for 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 [220] 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 SOCl₂ was 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 [221] 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 [222] 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 [223] 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 [224] 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 [225] 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: T⁰ min: 5% B: 95% B, T^1.3 min; 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 NH₃ in 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 Na₂SO₄ and 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 NaHCO₃ solution and brine, dried over Na₂SO₄ and 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 Na₂SO₄ and 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 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-[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 NH₃ in 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 H₂ atmosphere 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 Na₂SO₄ and 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 NH₃ in 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 Na₂SO₄ and 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 MgSO₄ and 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 NH₃ in 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 NH₃ in 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 NH₃ in 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 NH₃ in 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 NH₃ in 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).

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.

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 NH₃ in 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 NH₃ in 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 Na₂SO₄ and 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, 0.0288 mmol, 61 % yield) as a white solid. MS (ESI): 608.3 (M+H)⁺; retention time: 1.74 min (Method 5).¹H NMR (500 MHz, CD₃OD) δ 7.49-7.47 (m, 1H), 7.41 (d, J = 3.1 Hz, 1H), 7.18-7.14 (m, 1H), 7.16 (dd, J = 10.4, 9.2 Hz, 1H), 7.07-7.01 (m, 1H), 6.87-6.84 (m, 1H), 6.81 (t, J = 7.6 Hz, 1H), 6.73 (t, J = 3.1 Hz, 1H), 6.26 (s, 1H), 3.96-3.92 (m, 1H), 2.88 (t, J = 7.7 Hz, 2H), 2.62-2.50 (m, 2H), 2.40-2.38 (m, 4H), 1.74-1.69 (m, 1H), 1.67 (s, 3H), 1.31 (d, J = 6.2 Hz, 3H) ppm. The absolute and relative configuration of the title compound are unknown and were assigned arbitrarily. Example 118. Synthesis of 3-[(2R,4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-2,4-dimethyl-chroman-8- yl]propanoic acid A mixture of aqueous hydrogen peroxide (19.8 eq, 0.40 mL, 3.92 mmol) and ammonium molybdate tetrahydrate (0.500 eq, 122 mg, 0.0987 mmol) was added to a solution 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 (Example 117, 1.00 eq, 120 mg, 0.197 mmol) in methanol (2 mL) at 0 °C. The mixture was stirred at 0 °C for 10 min, diluted with brine (3 mL), and extracted with EA (3 x 10 mL). The combined organic extracts were washed with saturated aqueous Na₂S₂O₃ (3 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by reverse-phase column chromatography on C18 silica gel eluting with water/MeCN to give 3-[(2R,4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-2,4-dimethyl-chroman-8-yl]propanoic acid (110 mg, 0.176 mmol, 89 % yield) as a white solid. MS (ESI): 624.4 (M+H)⁺; retention time: 1.56 min (Method 2).¹H NMR (400 MHz, CD₃OD) δ 7.72-7.50 (m, 2H), 7.25-7.20 (m, 3H), 7.05-7.03 (m, 1H), 7.01-6.93 (m, 1H), 6.82-6.79 (m, 1H), 6.30-6.25 (m, 1H), 3.96-3.92 (m, 1H), 3.02 (s, 3H), 2.90-2.86 (m, 2H), 2.66-2.49 (m, 2H), 2.38 (d, J = 13.3 Hz, 1H), 1.75- 1.69 (m, 1H), 1.67 (s, 3H), 1.31 (d, J = 6.2 Hz, 3H) ppm. The absolute and relative configuration of the title compound are unknown and were assigned arbitrarily. Example 119. Synthesis of 3-[(2R,4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-2,4-dimethyl-chroman-8- yl]propanoic acid A mixture of aqueous hydrogen peroxide (50.9 eq, 0.72 mL, 7.02 mmol) and ammonium molybdate tetrahydrate (1.00 eq, 170 mg, 0.138 mmol) was added to a solution of 3-[(2R,4R)- 4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4- yl]-2,4-dimethyl-chroman-8-yl]propanoic acid (1.00 eq, 86 mg, 0.138 mmol) in methanol (2 mL) at 0 °C. The resulting mixture was stirred at 0 °C for 2 h when LC-MS analysis showed that the reaction had run to completion. The reaction mixture was diluted with brine (3 mL), extracted with EA (3 x 10 mL). The combined organic extracts were washed with saturated aqueous Na₂S₂O₃ (3 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by reverse-phase column chromatography on C18 silica gel eluting with H₂O/MeCN to give 3-[(2R,4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]- 2-fluoro-phenyl]-1H-imidazol-4-yl]-2,4-dimethyl-chroman-8-yl]propanoic acid (63 mg, 0.0980 mmol, 71 % yield) as a white solid. MS (ESI): 640.3 (M+H)⁺; retention time: 1.59 min (Method 2).¹H NMR (400 MHz, CD₃OD) δ 7.59-7.57 (m, 2H), 7.27-7.25 (m, 1H), 7.24-7.13 (m, 2H), 7.05-7.03 (m, 1H), 6.99-6.97 (m, 1H), 6.83-6.79 m, 1H), 6.26 (s, 1H), 3.96-3.92 (m, 1H), 3.32 (s, 3H), 2.90-2.86 (m, 2H), 2.63-2.51 (m, 2H), 2.39 (d, J = 13.3 Hz, 1H), 1.75-1.69 (m, 1H), 1.68 (s, 3H), 1.32 (d, J = 6.2 Hz, 3H) ppm. Example 120-127 were prepared in substantially the same way as Example 117, Example 118 and Example 119. Thus, Examples 123-127 were prepared starting from Product 2 (Step A, Example 117) and Examples 120-122 from Stereoisomer 2 (Step B, Example 117). The absolute and relative configurations of the stereocenters contained in these Examples are unknown and have been assigned arbitrarily.

Example 128. Synthesis of 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-2,2,4-trimethyl-chroman-8- yl]propanoic acid Ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- i Step A: To a stirred solution of ethyl 3-[4-(2-bromoacetyl)-2,2,4-trimethyl-chroman-8- yl]propanoate (Intermediate 39, 1.00 eq, 330 mg, 0.831 mmol) in DMF (7 mL) was added 5- [(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzamidine (Intermediate 17, 1.00 eq, 292 mg, 0.831 mmol) and sodium bicarbonate (2.00 eq, 140 mg, 1.66 mmol), and the mixture was stirred at 75 °C for 16 hours, diluted with 20 mL of water, and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine (3 x 20 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0-20% of EA 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]-2,2,4-trimethyl- chroman-8-yl]propanoate (300 mg, 0.462 mmol, 56 % yield) as a white solid. MS (ESI): 650.3 (M+H)⁺; retention time: 1.95 min (Method 5). Enantiomers of 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-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]-2,2,4-trimethyl-chroman-8-yl]propanoate (1.00 eq, 200 mg, 0.308 mmol) in THF (2 mL) , ethanol (1 mL) and water (1 mL) was added lithium hydroxide monohydrate (4.00 eq, 52 mg, 1.23 mmol). The mixture was stirred at room temperature for 16 hours, diluted with 10 mL of water, acidified with HCl solution to pH = 5, and extracted with ethyl acetate (3 x 10 mL). The combined organic phase was washed with water (3 x 10 mL) and concentrated. The residue was freeze-dried to give 3-[4-[2-[5-[(6,7- difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-2,2,4- trimethyl-chroman-8-yl]propanoic acid (182 mg, 0.293 mmol, 95 % yield) as a white solid. MS (ESI): 622.1 (M+H)⁺; retention time: 1.72 min (modified Method 2 - Flow Rate: 1.8 mL/min). 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-2,2,4-trimethyl-chroman-8-yl]propanoic acid (1.00 eq, 220 mg, 0.354 mmol) was purified by chiral HPLC to give 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-2,2,4-trimethyl-chroman-8-yl]propanoic acid (Stereoisomer 1, 100 mg, 0.161 mmol, 46 % yield) and 3-[(4S)-4-[2-[5-[(6,7-difluoro-4- methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-2,2,4-trimethyl- chroman-8-yl]propanoic acid (Stereoisomer 2, 98 mg,0.158 mmol, 45 % yield). MS (ESI): 622.1 (M+H)⁺; retention time: 1.73 min (Method 2) observed for both separation products. The absolute configurations of Stereoisomer 1 (Example 131) and Stereoisomer 2 (Example 132) are unknown and have been assigned arbitrarily. 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- Step C: A mixture of hydrogen peroxide (35.0 eq, 0.15 mL, 4.79 mmol) and ammonium molybdate tetrahydrate (0.500 eq, 84 mg, 0.0684 mmol) was slowly added to a solution of 3- [(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-2,2,4-trimethyl-chroman-8-yl]propanoic acid (Stereoisomer 1, 1.00 eq, 85 mg, 0.137 mmol) in methanol (2 mL) at 0 °C, and the reaction was stirred at 0 °C for 1 h. The reaction mixture was diluted with brine (3 mL), extracted with EA (3 x 10 mL). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by reverse-phase column on C18 eluting with water-acetonitrile to give 3-[(4R)-4-[2- [5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]- 2,2,4-trimethyl-chroman-8-yl]propanoic acid (43 mg, 0.0650 mmol, 48 % yield) as a white solid. MS (ESI): 654.4 (M+H)⁺; retention time: 1.70 min (Method 2). ¹H NMR (400 MHz, CD₃OD) δ 7.57 (t, J = 3.5 Hz, 2H), 7.26 (t, J = 5.6 Hz, 2H), 7.20 (dd, J = 10.5, 9.2 Hz, 1H), 7.06 (d, J = 5.9 Hz, 1H), 7.01-6.94 (m, 1H), 6.84 (t, J = 7.6 Hz, 1H), 6.46 (s, 1H), 3.32 (s, 3H), 2.87 (t, J = 7.1 Hz, 2H), 2.67 (d, J = 14.1 Hz, 1H), 2.59-2.52 (m, 2H), 1.94 (d, J = 14.0 Hz, 1H), 1.65 (s, 3H), 1.38 (s, 3H), 0.99 (s, 3H) ppm. The absolute configuration of the reaction product, Example 128, is unknown and has been assigned arbitrarily. Example 129. Synthesis of 3-[(4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-2,2,4-trimethyl-chroman-8- yl]propanoic acid Prepared in substantially the same way as Example 128 starting from Stereoisomer 2, Step B, Example 128. The absolute configuration of Example 129 is unknown and has been assigned arbitrarily. MS (ESI): 654.4 (M+H)⁺; retention time: 1.70 min (Method 2). ¹H NMR (400 MHz, CD₃OD) δ 7.57 (t, J = 4.3 Hz, 2H), 7.23 (ddd, J = 19.6, 8.8, 6.6 Hz, 3H), 7.06 (d, J = 7.3 Hz, 1H), 7.02 – 6.95 (m, 1H), 6.84 (t, J = 7.6 Hz, 1H), 6.48 (s, 1H), 3.32 (s, 3H), 2.87 (t, J = 7.2 Hz, 2H), 2.66 (d, J = 14.1 Hz, 1H), 2.59 – 2.52 (m, 2H), 1.94 (d, J = 14.1 Hz, 1H), 1.66 (s, 3H), 1.38 (s, 3H), 0.99 (s, 3H) ppm. Example 130. Synthesis of 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-2,2,4-trimethyl-chroman-8- yl]propanoic acid Example 131. Synthesis of 3-[(4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-2,2,4-trimethyl-chroman-8- yl]propanoic acid The preparation of Example 130 and Example 131 has been described in Step B, Example 128. Example 132. Synthesis of trans-(1R,2S)-2-[(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]cyclopropanecarboxylic acid Example 133. Synthesis of trans-(1S,2R)-2-[(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]cyclopropanecarboxylic acid Enantiomers of 5-[3-[4-(8-bromo-4-methyl-chroman-4-yl)-1H-imidazol-2-yl]-4-fluoro- Step A: To a stirred solution of 2-bromo-1-(8-bromo-4-methyl-chroman-4-yl)ethanone (1.00 eq, 1.80 g, 5.17 mmol) and 2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]benzamidine (1.20 eq, 2006 mg, 6.21 mmol) in DMF (10 mL) was added sodium bicarbonate (2.00 eq, 869 mg, 10.3 mmol) and the mixture was stirred at 75 °C for 16 h. The reaction mixture was concentrated to dryness and the residue was suspended in EtOAc (50 ml). The separated organics were washed with water (2 x 20 mL) and brine (30 mL). The organic phase was dried MgSO₄ and concentrated. The residue was purified by flash column chromatography on silica gel eluting with EtOAc in isohexane to give 5-[3-[4-(8-bromo-4-methyl-chroman-4-yl)-1H- imidazol-2-yl]-4-fluoro-phenoxy]-4,6,7-trifluoro-1H-indole (1.50 g, 2.62 mmol, 51 % yield). MS (ESI): 572.1, 574.1 (M+H)⁺; retention time: 1.71 min (modified Method 2 - Flow Rate: 1.8mL/min). The racemic mixture (1.50 g, 2.62 mmol) was separated by chiral SFC to give 5-[3-[4-[(4R)- 8-bromo-4-methyl-chroman-4-yl]-1H-imidazol-2-yl]-4-fluoro-phenoxy]-4,6,7-trifluoro-1H- indole (Stereoisomer 1, 600 mg,1.05 mmol) and 5-[3-[4-[(4S)-8-bromo-4-methyl-chroman-4- yl]-1H-imidazol-2-yl]-4-fluoro-phenoxy]-4,6,7-trifluoro-1H-indole (Stereoisomer 2, 620 mg, 1.08 mmol). The absolute configurations of Stereoisomer 1 and Stereoisomer 2 are unknown and have been assigned arbitrarily. SFC Separation Conditions: Instrument: SFC-150 (Waters); Column: OJ 25 * 250 mm, 10 µm (Daicel); Column temperature: 35 ºC; Mobile phase: 65/35 CO₂/MeOH [spiked with 0.2 % 7M NH₃ in MeOH]; Flow rate: 100 mL/min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 6.5 min; Sample solution: 1550 mg dissolved in 50 ml methanol; Injection volume: 4.0 mL. Chiral HPLC Analysis Conditions: Column : Chiralcell OJ-34.6 * 100 mm 3 µm; Mobile Phase: MeOH [spiked with 0.2 % 7M NH₃ in MeOH]; Injection Volume: 1.00 µl; Detection Wavelength; 214 nm; Run Time: 4.0 minutes; Flow rate: 3.0 mL/min; Back Pressure: 2000 psi; Column Temperature: 40 °C. 5-[3-[4-[(4R)-8-bromo-4-methyl-chroman-4-yl]-1H-imidazol-2-yl]-4-fluoro-phenoxy]-4,6,7- trifluoro-1H-indole (Stereoisomer 1) - retention time: 1.81 min. 5-[3-[4-[(4S)-8-Bromo-4-methyl-chroman-4-yl]-1H-imidazol-2-yl]-4-fluoro-phenoxy]-4,6,7- trifluoro-1H-indole (Stereoisomer 2) – retention time: 2.39 min. Trans-Ethyl (1S,2R)-2-[(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]cyclopropanecarboxylate and trans-ethyl (1R,2S)- 2-[(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]-4- Step B: A mixture of 5-[3-[4-[(4R)-8-bromo-4-methyl-chroman-4-yl]-1H-imidazol-2-yl]-4- fluoro-phenoxy]-4,6,7-trifluoro-1H-indole (Stereoisomer 1, 1.00 eq, 50 mg, 0.0874 mmol), cis- ethyl 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate (1.20 eq, 25 mg, 0.105 mmol), tri-potassium phosphate (3.00 eq, 56 mg, 0.262 mmol), dioxane:water (5:1) (10 mL) and 1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (0.150 eq, 8.5 mg, 0.0131 mmol) was stirred at 100 °C for 16 h under N². The reaction mixture was cooled, concentrated to dryness, the residue was suspended in EtOAc (50 mL), washed with water (2 x 20 mL), brine (20 mL), the organic phase was dried with MgSO₄ and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 20% EtOAc in isohexane to give trans-ethyl (1R,2S)-2-[(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]cyclopropanecarboxylate (30 mg, 0.0495 mmol, 57 % yield) as a mixture of diastereomers. MS (ESI): 606.3 (M+H)+; retention time: 1.71 min (modified Method 2 - Gradient: 5% increase to 95% B within 1.3 min). Trans-(1S,2R)-2-[(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]cyclopropanecarboxylic acid and trans-(1R,2S)-2- [(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]-4- Step C: To a solution of trans-ethyl (1R,2S)-2-[(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]cyclopropanecarboxylate (1.00 eq, 30 mg, 0.0495 mmol) in THF (5 mL) was added 1M aqueous LiOH (1.00 eq, 5.0 mL) and the mixture was stirred overnight at room temperature. The aqueous phase was acidified to pH~5 with hydrochloric acid and the mixture was extracted with EA (3 × 10 mL). The combined organic extracts were washed with brine (20 mL), dried over Na₂SO₄ and concentrated to dryness. The residue was purified by prep-HPLC to give trans-(1R,2S)-2- [(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]cyclopropanecarboxylic acid (Diastereomer 1, Example 132, 8.1 mg, 0.0140 mmol, 28 % yield) and trans-(1S,2R)-2-[(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]cyclopropanecarboxylic acid (Diastereomer 2, Example 133, 3.8 mg, 0.00658 mmol, 13 % yield). Diastereomer 1 (Example 132): MS (ESI): 578.3 (M+H)⁺; retention time: 1.58 min (modified Method 2 - Gradient: 5% increase to 95% B within 1.3 min).¹H NMR (400 MHz, CD₃OD) δ 7.49 (s, 1H), 7.36 (d, J = 3.1 Hz, 1H), 7.22-7.14 (m, 1H), 7.06-7.00 (m, 2H), 6.97 (dt, J = 6.9, 3.2 Hz, 1H), 6.74 (t, J = 7.7 Hz, 1H), 6.61 (t, J = 3.1 Hz, 1H), 6.58 (s, 1H), 4.19 (ddd, J = 9.3, 6.5, 3.0 Hz, 1H), 4.03 (t, J = 9.5 Hz, 1H), 2.46 (dd, J = 17.4, 8.2 Hz, 2H), 2.04 (ddd, J = 9.0, 7.7, 5.7 Hz, 1H), 1.93 (ddd, J = 13.9, 8.0, 2.1 Hz, 1H), 1.66 (s, 3H), 1.49 (dt, J = 7.8, 5.4 Hz, 1H), 1.33 (ddd, J = 12.6, 8.3, 4.1 Hz, 1H) ppm. Diastereomer 2 (Example 133): MS (ESI): 578.3 (M+H)+; retention time: 1.61 min (modified Method 2 - Gradient: 5% increase to 95% B within 1.3 min).¹H NMR (400 MHz, CD₃OD) δ 7.49 (dd, J = 5.7, 3.2 Hz, 1H), 7.37 (d, J = 3.1 Hz, 1H), 7.18 (dd, J = 10.3, 9.3 Hz, 1H), 7.10 (dd, J = 15.1, 7.7 Hz, 2H), 6.96 (dt, J = 8.8, 3.4 Hz, 1H), 6.78 (t, J = 7.6 Hz, 1H), 6.62 (t, J = 3.1 Hz, 1H), 6.33 (s, 1H), 4.19 (dt, J = 11.0, 3.7 Hz, 1H), 3.85 (td, J = 11.0, 2.0 Hz, 1H), 2.40 (dd, J = 16.7, 8.1 Hz, 1H), 2.33 (ddd, J = 13.6, 4.0, 2.2 Hz, 1H), 2.09-1.96 (m, 2H), 1.71 (s, 3H), 1.44 (dt, J = 7.5, 5.4 Hz, 1H), 1.36-1.27 (m, 1H) ppm. Example 134. Synthesis of (1R,2R)-2-((R)-4-(2-(2-fluoro-5-((4,6,7-trifluoro-1H- indol-5-yl)oxy)phenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)cyclopropane-1- carboxylic acid cis-Ethyl (1R,2R)-2-[(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]cyclopropanecarboxylate and cis-ethyl (1S,2S)-2- [(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]-4- Step A: A mixture of 5-[3-[4-[(4R)-8-bromo-4-methyl-chroman-4-yl]-1H-imidazol-2-yl]-4- fluoro-phenoxy]-4,6,7-trifluoro-1H-indole (1.00 eq, 150 mg, 0.262 mmol), trans-ethyl2- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)cyclopropanecarboxylate (1.20 eq, 76 mg, 0.314 mmol), tri-potassium phosphate (3.00 eq, 167 mg, 0.786 mmol), dioxane:water (5:1, 20 mL) and 1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (0.200 eq, 34 mg, 0.0524 mmol) was stirred at 100 °C for 16 h and concentrated to dryness. The residue was suspended in EtOAc (50 ml), washed with water (2 x 20 mL), brine (30 mL), dried with MgSO₄ and concentrated to dryness. The residue was purified by SFC to give cis-ethyl (1R,2R)-2-[(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]cyclopropanecarboxylate (Stereoisomer 1, 50 mg, 0.0826 mmol, 31 % yield) and cis-ethyl (1S,2S)-2-[(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]cyclopropanecarboxylate (Stereoisomer 2, 10 mg, 0.0165 mmol, 6.3 % yield). The absolute and relative configurations of Stereoisomer 1 and Stereoisomer 2 are unknown and have been assigned arbitrarily. MS (ESI): 606.3 (M+H)+; retention time: 1.73 min (modified Method 2 - Gradient: 5% increase to 95% B within 1.3 min) observed for both Stereoisomer 1 and Stereoisomer 2. SFC Separation Method: Instrument: SFC-150 (Waters); Column: OX 25 * 250 mm, 10 µm (Daicel); Column temperature: 35 ºC; Mobile phase: 70/30 CO₂/MEOH [spoked with 0.2% 7M NH₃ in MeOH]; Flow rate: 100 mL/min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 3.6 min; Sample solution: 95 mg dissolved in 30 mL methanol; Injection volume: 3.0 mL. (1R,2R)-2-((R)-4-(2-(2-fluoro-5-((4,6,7-trifluoro-1H-indol-5-yl)oxy)phenyl)-1H-imidazol-4- Step B: To a solution of cis-ethyl (1R,2R)-2-[(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]cyclopropanecarboxylate (1.00 eq, 50 mg, 0.0826 mmol) in THF (3 mL) was added 1M aqueous LiOH (1.00 eq, 3.0 mL), methanol (1 mL) and the mixture was stirred overnight at room temperature. The aqueous phase was acidified to pH 5 with hydrochloric acid, the mixture was extracted with EA (3 × 10 mL). The combined organics were washed with brine (20 mL), dried over Na₂SO₄, and concentrated to dryness. The residue was purified by prep-HPLC to give cis-(1R,2R)-2-[(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]cyclopropanecarboxylic acid (11 mg, 0.0180 mmol, 22 % yield). MS (ESI): 578.3 (M+H)+; retention time: 1.62 min (modified Method 2 - Gradient: 5% increase to 95% B within 1.4 min). ¹H NMR (400 MHz, CD₃OD) δ 7.47 (dd, J = 5.5, 3.1 Hz, 1H), 7.37 (d, J = 3.1 Hz, 1H), 7.18 (dd, J = 10.5, 9.1 Hz, 1H), 7.03 (dd, J = 6.9, 2.5 Hz, 1H), 6.97 (dt, J = 9.0, 3.6 Hz, 1H), 6.82- 6.71 (m, 2H), 6.61 (t, J = 3.1 Hz, 1H), 6.58 (s, 1H), 4.26 (ddd, J = 10.6, 6.3, 3.1 Hz, 1H), 4.12- 4.02 (m, 1H), 2.63 (ddd, J = 9.2, 6.9, 4.4 Hz, 1H), 2.47 (ddd, J = 13.8, 6.3, 2.6 Hz, 1H), 1.97 (ddd, J = 13.4, 8.7, 2.9 Hz, 1H), 1.75-1.60 (m, 4H), 1.48-1.38 (m, 1H), 1.33 (ddd, J = 8.2, 6.9, 4.2 Hz, 1H) ppm. Example 135. Synthesis of cis-(1S,2S)-2-[(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]cyclopropanecarboxylic acid Prepared in substantially the same way as Example 134 starting from cis-ethyl (1S,2S)-2-[(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]cyclopropanecarboxylate (Stereoisomer 2, Step A, Example 134). MS (ESI): 578.3 (M+H)+; retention time: 1.59 min (modified Method 2 - Gradient: 5% increase to 95% B within 1.4 min).¹H NMR (400 MHz, CD₃OD) δ 7.48 (s, 1H), 7.37 (d, J = 3.1 Hz, 1H), 7.19 (dd, J = 10.4, 9.2 Hz, 1H), 7.06 (dd, J = 7.1, 2.2 Hz, 1H), 6.97 (dt, J = 9.0, 3.5 Hz, 1H), 6.82- 6.72 (m, 2H), 6.62 (t, J = 3.1 Hz, 1H), 6.55 (s, 1H), 4.26 (ddd, J = 10.4, 5.9, 3.2 Hz, 1H), 4.09- 4.00 (m, 1H), 2.63 (ddd, J = 9.1, 6.8, 4.4 Hz, 1H), 2.46 (ddd, J = 8.3, 5.6, 2.2 Hz, 1H), 2.04- 1.91 (m, 1H), 1.74-1.62 (m, 4H), 1.43 (dt, J = 9.3, 4.7 Hz, 1H), 1.34 (ddd, J = 8.1, 6.9, 4.2 Hz, 1H) ppm. Examples 136-139 were prepared in substantially the same way as Examples 132-135 starting from 5-[3-[4-[(4S)-8-bromo-4-methyl-chroman-4-yl]-1H-imidazol-2-yl]-4-fluoro-phenoxy]- 4,6,7-trifluoro-1H-indole (Stereoisomer 2, Example 132). The absolute and relative configurations of these compounds are unknown and assigned arbitrarily. Except when noted otherwise LC/MS data were collected using a modified Method 2 - Gradient: 5% increase to 95% B within 1.4 min; Flow Rate: 1.8mL/min. Example 140. Synthesis of (1S,2R)-2-[(4S)-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]cyclopropanecarboxylic acid Example 141. Synthesis of (1R,2S)-2-[(4S)-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]cyclopropanecarboxylic acid Diastereomers of ethyl 2-[(4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2- Step A: A mixture of ethyl cis-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)cyclopropanecarboxylate (1.50 eq, 120 mg, 0.500 mmol), 1,4-dioxane (4 mL), water (0.40 mL), 1,1'‑bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.150 eq, 36 mg, 0.0500 mmol), tripotassium phosphate (3.00 eq, 212 mg, 0.999 mmol) and 6,7-difluoro-5-[4-fluoro-3- [4-[(4S)-8-bromo-4-methyl-chroman-4-yl]-1H-imidazol-2-yl]phenoxy]-4-methylsulfanyl-1H- indole (obtained similarly to product from Step A, Example 133 starting from Intermediate 17 and 2-bromo-1-(8-bromo-4-methylchroman-4-yl)ethan-1-one; absolute configuration assigned arbitrarily, 1.00 eq, 200 mg, 0.333 mmol) was stirred overnight at 100 °C under an Ar atmosphere. The reaction mixture was extracted with ethyl acetate (2 x 20 mL). The combined organic phases 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 37-45% ethyl acetate in petroleum ether to give ethyl (1S,2R)-2-[rac-(4S)-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]cyclopropanecarboxylate (Diastereomer 1, 40 mg, 0.0631 mmol, 19 % yield) as a white solid and ethyl (1S,2R)-2-[(4S)-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]cyclopropanecarboxylate (Diastereomer 2, 40 mg, 0.0631 mmol, 19 % yield) as a white solid. Both products were characterized by a modified Method 2 - Gradient: 5% increase to 95% B within 1.3 min; Flow Rate: 1.8 mL/min. Diastereomer 1: MS (ESI): 634.2 (M+H)+; retention time: 1.57 min. Diastereomer 2: MS (ESI): 634.2 (M+H)+; retention time: 1.60 min. (1S,2R)-2-[(4S)-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]cyclopropanecarboxylic acid and (1R,2S)-2-[(4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro- Step B: To a stirred solution of an unresolved diastereomer mixture of ethyl 2-[(4S)-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]cyclopropanecarboxylate (Step A, 1.00 eq, 18 mg, 0.0281 mmol) in THF (1.5 mL) was added aqueous lithium hydroxide (53.4 eq, 1.5 mL, 1.50 mmol) and methanol (0.5 mL), and the mixture was stirred at RT for 4 days. The mixture was diluted with water (10 mL), extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to give (1R,2S)-2-[(4S)-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]cyclopropanecarboxylic acid (Product 1, 1.8 mg, 0.00297 mmol, 11 % yield) as a white solid and (1S,2R)-2-[ (4S)-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]cyclopropanecarboxylic acid (Product 2, 1.5 mg, 0.00248 mmol, 9 % yield) as a white solid. The absolute and relative configurations of Stereoisomer 1 and Stereoisomer 2 are unknown and have been assigned arbitrarily. Product 1: MS (ESI): 606.2 (M+H)+; retention time: 1.71 min (modified Method 4 - Gradient from 5 to 90% of B in 1.4 min at 2.0 mL/min); Product 2: MS (ESI): 606.2 (M+H)+; retention time: 1.76 min (modified Method 4 - Gradient from 5 to 90% of B in 1.4 min at 2.0 mL/min); Example 142. Synthesis of (1R,2S)-2-[(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]cyclopropanecarboxylic acid To a solution of (1R,2S)-2-[(4S)-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]cyclopropanecarboxylic acid (1.00 eq, 20 mg, 0.0330 mmol) in methanol (2 mL) was added ammonium molybdate tetrahydrate (1.23 eq, 50 mg, 0.0405 mmol) in aqueous hydrogen peroxide (76 eq, 0.5 mL) at 0 ºC, and the mixture was stirred at 0 °C for 1 h. The reaction was quenched with saturated aqueous sodium sulfite (10 mL), extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to give (1R,2S)-2-[(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]cyclopropanecarboxylic acid (16 mg, 0.0236 mmol, 72 % yield). MS (ESI): 638.1 (M+H)+; retention time: 1.62 min (modified Method 4 - Gradient from 5 to 90% of B in 1.4 min at 2.0 mL/min); ¹H NMR (400 MHz, CD₃OD) δ 7.57 (d, J = 3.2 Hz, 1H), 7.54 (dd, J = 6.0, 3.2 Hz, 1H), 7.25 (t, J = 3.2 Hz, 1H), 7.19 (dd, J = 10.4, 9.2 Hz, 1H), 7.11 (dd, J = 18.8, 7.4 Hz, 2H), 7.00-6.95 (m, 1H), 6.79 (t, J = 7.6 Hz, 1H), 6.32 (s, 1H), 4.21-4.16 (m, 1H), 3.84 (dd, J = 11.6, 9.6 Hz, 1H), 3.31 (s, 3H), 2.43-2.31 (m, 2H), 2.08-1.99 (m, 2H), 1.71 (s, 3H), 1.46-1.41 (m, 1H), 1.38-1.33 (m, 1H) ppm. The absolute and relative configuration of the product is unknown and was assigned arbitrarily. Example 143. Synthesis of (1S,2R)-2-[(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]cyclopropanecarboxylic acid Prepared in substantially the same way as Example 142 starting from (1S,2R)-2-[ (4S)-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]cyclopropanecarboxylic acid. The absolute and relative configuration of the product is unknown and was assigned arbitrarily. MS (ESI): 638.1 (M+H)+; retention time: 1.61 min (modified Method 4 - Gradient from 5 to 90% of B in 1.4 min at 2.0 mL/min) Examples 144-149 were prepared in substantially the same way as Examples 142-143 using where appropriate trans-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)cyclopropanecarboxylate as well as 6,7-difluoro-5-[4-fluoro-3-[4-[(4S)-8-bromo-4-methyl- chroman-4-yl]-1H-imidazol-2-yl]phenoxy]-4-methylsulfanyl-1H-indole (as defined in Step A, Example 141) or its enantiomer. Example 150. Synthesis of 3-[(4R)-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]-2,2- dimethyl-propanoic acid Enantiomers of methyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2- Step A: To a stirred solution of methyl 3-[4-(2-bromoacetyl)-4-methyl-chroman-8-yl]-2,2- dimethyl-propanoate (1.00 eq, 460 mg, 1.20 mmol) in DMF (6 mL) was added 5-[(6,7-difluoro- 4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzamidine (1.10 eq, 464 mg, 1.32 mmol) and sodium bicarbonate (2.00 eq, 202 mg, 2.40 mmol). The reaction mixture was stirred at 70 °C for 4 h, diluted with water (30 mL), and extracted with EtOAc (50 mL). The organic layer was washed with saturated aqueous LiCl (20 mL) and brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-33% EtOAc in PE to give methyl 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]-2,2-dimethyl-propanoate (510 mg, 0.802 mmol, 67 % yield) as a solid. MS (ESI): 636.3 (M+H)⁺; retention time: 1.74 min (modified Method 2 - 5% to 95% B within 1.3 min; Flow Rate: 1.8 mL/min). Racemic 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]-2,2-dimethyl-propanoate (450 mg, 0.708 mmol) was separated into its constituent enantiomers by SFC to give methyl 3-[(4R)-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]-2,2-dimethyl-propanoate (Stereoisomer 1, 200 mg, 0.315 mmol, 44 % yield) and methyl 3-[(4S)-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]-2,2-dimethyl-propanoate (Stereoisomer 2, 100 mg, 0.157 mmol, 22 % yield) as solids. The absolute configuration of Stereoisomer 1 and Stereoisomer 2 is unknown and was assigned arbitrarily. MS (ESI): 636.3 (M+H)⁺ and a retention time of 1.74 min (modified Method 2 - 5% to 95% B within 1.3 min; Flow Rate: 1.8 mL/min) was observed for both enantiomers. SFC Separation Conditions: Instrument: SFC-150 (Waters); Column: OJ 25 * 250 mm, 10 µm (Daicel); Column temperature: 35 ºC; Mobile phase: 70/30 CO₂/isopropanol [spiked with 0.5% 7M NH₃ in MeOH]; Flow rate: 120 mL/min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 3.4 min; Sample solution: 510 mg dissolved in 45 mL MeOH; Injection volume: 1.2 mL. 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- Step B: To a solution of methyl 3-[(4R)-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]-2,2-dimethyl- propanoate (Stereoisomer 1, 1.00 eq, 200 mg, 0.315 mmol) in THF (1 mL) was added methanol (1 mL), 1 M aqueous LiOH (3.18 eq, 1.0 mL, 1.00 mmol) and NaOH (0.795 eq, 10 mg, 0.250 mmol). The reaction mixture was stirred at room temperature for 7 days, diluted with water (30 mL), acidified with hydrochloric acid (1M) until pH~5, and extracted with EtOAc (50 mL). The organic layer was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 3-[(4R)-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]-2,2-dimethyl-propanoic acid (195 mg, 0.314 mmol, 99 % yield) as a solid. MS (ESI): 622.2 (M+H)⁺ and a retention time of 1.66 min (modified Method 2 - 5% to 95% B within 1.3 min; Flow Rate: 1.8 mL/min). The absolute configuration of the reaction product is unknown and was assigned arbitrarily. Example 151. Synthesis of 3-[(4S)-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]-2,2- dimethyl-propanoic acid The title compound was prepared similarly to Example 150 starting from methyl 3-[(4S)-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]-2,2-dimethyl-propanoate (Stereoisomer 2, Step A, Example 150). MS (ESI): 622.2 (M+H)⁺ and a retention time of 1.66 min (modified Method 2 - 5% to 95% B within 1.3 min; Flow Rate: 1.8 mL/min). The absolute configuration of Example 151 is unknown and was assigned arbitrarily. Example 152. 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]-2,2- dimethyl-propanoic acid Example 153. Synthesis of 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]-2,2- dimethyl-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]-4-methyl-chroman-8-yl]-2,2-dimethyl-propanoic acid (Example 150, 1.00 eq, 190 mg, 0.306 mmol) in methanol (4 mL) was added a solution of ammonium molybdate tetrahydrate (0.318 eq, 120 mg, 0.0971 mmol) in aqueous hydrogen peroxide (53.4 eq, 0.50 mL, 16.3 mmol) at 0 °C. The reaction mixture was stirred at 0 °C for 3 h, diluted with water (30 mL), and extracted with EtOAc (50 mL). The separated organic phase was washed with saturated aqueous sodium thiosulfate (30 mL), brine (30 mL), 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-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]- 1H-imidazol-4-yl]-4-methyl-chroman-8-yl]-2,2-dimethyl-propanoic acid (Example 152, 69 mg, 0.105 mmol, 35 % yield) and 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]-2,2-dimethyl-propanoic acid (Example 153, 32 mg, 0.0499 mmol, 16 % yield) as solids. The absolute configurations of Example 152 and Example 153 are unknown and were assigned arbitrarily. LC/MS analysis of the title compounds was carried out following a modified Method 2 - 5% to 95% B within 1.3 min; Flow Rate: 1.8 mL/min. 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]-2,2-dimethyl-propanoic acid (Example 152): MS (ESI): 654.3 (M+H)⁺ and a retention time of 1.56 min. 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-4-methyl-chroman-8-yl]-2,2-dimethyl-propanoic acid (Example 153): MS (ESI): 638.2 (M+H)⁺ and a retention time of 1.54 min. Example 154. Synthesis of (S)-3-(4-(2-(5-((6,7-difluoro-4-(methylsulfonyl)-1H- indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)-2,2- dimethylpropanoic acid Example 155. Synthesis of 3-((4S)-4-(2-(5-((6,7-difluoro-4-(methylsulfinyl)-1H- indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)-2,2- dimethylpropanoic acid Example 154 and Example 155 were prepared similarly to Examples 152-153 starting from Example 151. LC/MS analysis of the title compounds was carried out following a modified Method 2 - 5% to 95% B within 1.3 min; Flow Rate: 1.8 mL/min. 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]-2,2-dimethyl-propanoic acid (Example 152): MS (ESI): 654.3 (M+H)⁺ and a retention time of 1.57 min. 3-[(4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-4-methyl-chroman-8-yl]-2,2-dimethyl-propanoic acid (Example 153): MS (ESI): 638.2 (M+H)⁺ and a retention time of 1.54 min. Examples 156-161 were prepared in substantially the same way as Examples 150-155 starting from Intermediate 17 and Intermediate 41. The absolute configurations of these Examples are unknown and have been assigned arbitrarily. A modified Method 2 (5% to 95% B within 1.3 min; Flow Rate: 1.8 mL/min) was used to collect LC/MS data. Example 162. Synthesis of (1R)-2-(4-(2-(5-((6,7-difluoro-4-(methylsulfonyl)-1H- indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)cyclopentane- 1-carboxylic acid Example 163. Synthesis of (2S)-2-(4-(2-(5-((6,7-difluoro-4-(methylsulfonyl)-1H- indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)cyclopentane- 1-carboxylic acid Example 164. Synthesis of 2-((R)-4-(2-(5-((6,7-difluoro-4-(methylsulfonyl)-1H- indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)cyclopentane- 1-carboxylic acid Methyl 2-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- Step A: A mixture of methyl 2-[4-(2-bromoacetyl)-4-methyl-chroman-8- yl]cyclopentanecarboxylate (1.00 eq, 80 mg, 0.202 mmol), DMF (3 mL), 5-[(6,7-difluoro-4- methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzamidine (1.20 eq, 85 mg, 0.243 mmol) and sodium bicarbonate (2.00 eq, 34 mg, 0.405 mmol) was stirred overnight at 70 ºC. The mixture was quenched with water (50 mL), diluted with ethyl acetate (50 mL) and filtered. The separated organic phase was washed with saturated aqueous LiCl (50 mL), 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 methyl 2-[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]cyclopentanecarboxylate (90 mg, 0.139 mmol, 69 % yield) as a solid. MS (ESI): 648.2 (M+H)⁺ and a retention time of 1.80 min (modified Method 2 - 5% to 95% B within 1.3 min; Flow Rate: 1.8 mL/min). (1R)-2-(4-(2-(5-((6,7-difluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H- imidazol-4-yl)-4-methylchroman-8-yl)cyclopentane-1-carboxylic acid, (2S)-2-(4-(2-(5-((6,7- difluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4- methylchroman-8-yl)cyclopentane-1-carboxylic acid and 2-((R)-4-(2-(5-((6,7-difluoro-4- (methylsulfonyl)-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8- Step B: To a solution of 2-[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]cyclopentanecarboxylic acid (1.00 eq, 80 mg, 0.126 mmol) in methanol (3 mL) was added a solution of ammonium molybdate tetrahydrate (0.449 eq, 70 mg, 0.0566 mmol) in aqueous hydrogen peroxide (10 eq, 0.20 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h, diluted with water (20 mL), and extracted with ethyl acetate (25 mL). The separated organic layer was washed with brine (25 mL), dried over Na₂SO₄, and concentrated. The residue was purified by prep-HPLC to give (1R)-2-(4-(2-(5-((6,7-difluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)cyclopentane-1-carboxylic acid (Product 1, Example 162, 5.4 mg, 0.00811 mmol, 6 % yield), (2S)-2-(4-(2-(5-((6,7-difluoro-4- (methylsulfonyl)-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman- 8-yl)cyclopentane-1-carboxylic acid (Product 2, Example 163, 6.6 mg, 0.00991 mmol, 8 % yield) and 2-[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]cyclopentanecarboxylic acid (Product 3, Example 164, 8.9 mg, 0.0134 mmol, 11 % yield) as solids. The absolute and relative configurations of the compounds contained in the above isolated Product 1, Product 2 and Product 3 are unknown and have been assigned arbitrarily. The following analytical data were collected with a modified Method 2 – Gradient: from 5 to 95% of B in 7.5 min at 1mL/min; Temperature: 40 º Product P1 is a mixture of at least two compounds: MS (ESI): 666.2 (M+H)⁺ observed for two peaks at 6.23 and 6.29 min. Product P2 is a mixture of at least two compounds: MS (ESI): 666.2 (M+H)⁺ observed for two peaks at 6.34 and 6.39 min. Product P3: MS (ESI): 666.2 (M+H)⁺ observed for a single peak at 6.50 min. Example 165. Synthesis of 3-(4-(2-(5-((4-(N,S-dimethylsulfonimidoyl)-6,7- difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4-methylchroman-8- yl)propanoic acid Ethyl 3-(4-(2-(5-((4-(N,S-dimethylsulfonimidoyl)-6,7-difluoro-1H-indol-5-yl)oxy)-2- Step A: To a solution of 5-[[4-(N,S-dimethylsulfonimidoyl)-6,7-difluoro-1H-indol-5-yl]oxy]- 2-fluoro-benzamidine (Intermediate 43, 70 mg, 0.176 mmol) in DMF (3 mL) was added ethyl 3-[4-(2-bromoacetyl)-4-methyl-chroman-8-yl]propanoate (Intermediate 9, 65 mg, 0.176 mmol) and NaHCO₃ (30 mg, 0.352 mmol). The reaction mixture was stirred for 4 hours at 75 °C, cooled to rt, and extracted with ethyl acetate (50 mL). The organic extract was washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-75% ethyl acetate in petroleum ether to give ethyl 3-[4-[2-[5-[[4-(N,S-dimethylsulfonimidoyl)-6,7-difluoro-1H- indol-5-yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (15 mg, 13 % yield) as a solid. MS (ESI): 667.2 (M+H)⁺ and a retention time of 1.61 min (modified Method 2 - 5% to 95% B in 1.3 min). 3-(4-(2-(5-((4-(N,S-dimethylsulfonimidoyl)-6,7-difluoro-1H-indol-5-yl)oxy)-2-fluorophenyl)- Step B: To a stirred solution of ethyl 3-[4-[2-[5-[[4-(N,S-dimethylsulfonimidoyl)-6,7-difluoro- 1H-indol-5-yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (11 mg, 0.0165 mmol) in THF (0.5 mL) was added aqueous lithium hydroxide (0.165 mL,1M) and the reaction was stirred at RT for 16 h. The mixture was acidified with 1M hydrochloric acid to pH ~ 4, extracted with ethyl acetate (30 mL). The organic extract was washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to give 3-[4-[2-[5-[[4-(N,S-dimethylsulfonimidoyl)-6,7-difluoro-1H- indol-5-yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid (4.2 mg, 40 % yield) as a solid. MS (ESI): 639.2 (M+H)⁺ and a retention time of 1.46 min (modified Method 2 - 5% to 95% B in 1.3 min). Example 166. Synthesis of 2-[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]oxyacetic acid Prepared in substantially the same way as Example 152 starting from Intermediate 17 and Intermediate 44. MS (ESI): 628.3 (M+H)⁺, retention time of 1.50 min (Method 3). ¹H NMR (400 MHz, CD₃OD). δ 7.56-7.52 (m, 2H), 7.25-7.20 (m, 2H), 7.06-7.03 (m, 1H), 6.83-6.81 (m, 1H), 6.77-6.75 (m, 1H), 6.68 (s, 1H), 4.59 (s, 2H), 4.23-4.16 (m, 1H), 4.03-3.95 (m, 1H), 3.30 (s, 3H), 2.46-2.38 (m, 1H), 2.02-1.96 (m, 1H), 1.71 (s, 3H) ppm. Example 167. Synthesis of 6,7-difluoro-5-[4-fluoro-5-[4-(4-methylchroman-4-yl)- 1H-imidazol-2-yl]-2-(quinuclidin-3-ylmethyl)phenoxy]-4-methylsulfonyl-1H-indole 5-[2-Benzyloxy-4-fluoro-5-[4-(4-methylchroman-4-yl)-1H-imidazol-2-yl]phenoxy]-6,7- difluoro-4-methylsulfanyl-1H-indole Step A: A mixture of 2-bromo-1-(4-methylchroman-4-yl)ethanone (Intermediate 24, 1.00 eq, 2553 mg, 9.49 mmol) 4-benzyloxy-5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2- fluoro-benzamidine (Intermediate 45, 1.00 eq, 4.34 g, 9.49 mmol) and sodium bicarbonate (2.00 eq, 1594 mg, 19.0 mmol) in DMF (40 mL) was stirred at 75 °C for 16 h. The reaction mixture was diluted with brine (200 mL) and extracted with EA (3 x 50 mL). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 20:1 PE:EA to give 5-[2-benzyloxy-4- fluoro-5-[4-(4-methylchroman-4-yl)-1H-imidazol-2-yl]phenoxy]-6,7-difluoro-4- methylsulfanyl-1H-indole (5.42 g, 8.63 mmol, 91 % yield) as a brown solid. MS (ESI): 628.3 (M+H)⁺, retention time of 2.11 min (Method 4). 2-[(6,7-Difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4-methylchroman-4-yl)- 1H-imidazol-2-yl]phenol Step B: A mixture of 5-[2-benzyloxy-4-fluoro-5-[4-(4-methylchroman-4-yl)-1H-imidazol-2- yl]phenoxy]-6,7-difluoro-4-methylsulfanyl-1H-indole (1.00 eq, 5.42 g, 8.63 mmol) and anisole (6.00 eq, 5.7 mL, 51.8 mmol) in TFA (60.1 eq, 40 mL, 519 mmol) and DCM (5 mL) was stirred at 50 °C for 16 h. After concentration under reduced pressure, the residue was dissolved in EA (100 mL) and washed with saturated aqueous NaHCO₃ (3 x 20 mL). The organic phase was dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 2:1 PE:EA to give 2-[(6,7-difluoro-4- methylsulfanyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4-methylchroman-4-yl)-1H-imidazol-2- yl]phenol (836 mg, 1.56 mmol, 18 % yield) as a brown solid. MS (ESI): 538.2 (M+H)⁺, retention time of 1.56 min (Method 2). [2-[(6,7-Difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4-methylchroman-4- Step C: A mixture of 2-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4- methylchroman-4-yl)-1H-imidazol-2-yl]phenol (1.00 eq, 50 mg, 0.0930 mmol), N,N- diisopropylethylamine (4.00 eq, 0.065 mL, 0.372 mmol) in anhydrous DMF (2 mL) and 1,1,1- trifluoro-N-phenyl-N-((trifluoromethyl)sulfonyl)methanesulfonamide (1.80 eq, 60 mg, 0.167 mmol) was stirred at 0 °C for 2 h. The reaction mixture was diluted with brine (10 mL) and extracted with EA (3 x 3 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 5:1 PE:EA to give [2-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-5- fluoro-4-[4-(4-methylchroman-4-yl)-1H-imidazol-2-yl]phenyl] trifluoromethanesulfonate (55 mg, 0.0821 mmol, 88 % yield) as a brown solid. MS (ESI): 670.2 (M+H)⁺, retention time of 2.03 min (Method 2). 6,7-Difluoro-5-[4-fluoro-5-[4-(4-methylchroman-4-yl)-1H-imidazol-2-yl]-2-[(E)-quinuclidin- Step D: A mixture of [2-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4- methylchroman-4-yl)-1H-imidazol-2-yl]phenyl] trifluoromethanesulfonate (1.00 eq, 20 mg, 0.0299 mmol), (3Z)-3-[(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)methylene]quinuclidine (4.00 eq, 30 mg, 0.119 mmol), [1'1-Bis(diphenylphosphino)ferrocene]dichloro palladium(II) (0.100 eq, 2.2 mg, 0.00299 mmol) and potassium phosphate (4.00 eq, 25 mg, 0.119 mmol) in toluene (1 mL) and water (0.5 mL) was stirred at 90 °C under nitrogen for 2 h. The reaction mixture was extracted with EA (3 x 1 mL). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 2:1 DCM:MeOH to give 6,7-difluoro-5-[4-fluoro-5-[4-(4- methylchroman-4-yl)-1H-imidazol-2-yl]-2-[(E)-quinuclidin-3-ylidenemethyl]phenoxy]-4- methylsulfanyl-1H-indole (14 mg, 0.0218 mmol, 73 % yield) a brown solid. MS (ESI): 643.4 (M+H)⁺, retention time of 1.44 min (Method 2). 6,7-Difluoro-5-[4-fluoro-5-[4-(4-methylchroman-4-yl)-1H-imidazol-2-yl]-2-[(E)-quinuclidin- 3-ylidenemethyl]phenoxy]-4-methylsulfonyl-1H-indole Step E: A mixture of ammonium molybdate tetrahydrate (1.00 eq, 77 mg, 0.0622 mmol) and aqueous hydrogen peroxide (1.00 eq, 0.20 mL, 0.0622 mmol) was added to a solution of 6,7- difluoro-5-[4-fluoro-5-[4-(4-methylchroman-4-yl)-1H-imidazol-2-yl]-2-[(E)-quinuclidin-3- ylidenemethyl]phenoxy]-4-methylsulfanyl-1H-indole (1.00 eq, 40 mg, 0.0622 mmol) in methanol (3 mL) at 0 °C, the resulting mixture was stirred at 0 °C for 1 h, diluted with brine (1 mL) and extracted with EA (3 x 5 mL). The combined organic extracts were washed with saturated aqueous Na₂S₂O₃ (1 mL), dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by reversed-phase column chromatography on C18 silica gel to give 6,7- difluoro-5-[4-fluoro-5-[4-(4-methylchroman-4-yl)-1H-imidazol-2-yl]-2-[(E)-quinuclidin-3- ylidenemethyl]phenoxy]-4-methylsulfonyl-1H-indole (34 mg, 0.0504 mmol, 81 % yield) as a brown solid. MS (ESI): 628.3 (M+H)⁺, retention time of 1.50 min (Method 4). 6,7-Difluoro-5-[4-fluoro-5-[4-(4-methylchroman-4-yl)-1H-imidazol-2-yl]-2-(quinuclidin-3- ylmethyl)phenoxy]-4-methylsulfonyl-1H-indole Step F: A mixture of 6,7-difluoro-5-[4-fluoro-5-[4-(4-methylchroman-4-yl)-1H-imidazol-2- yl]-2-[(E)-quinuclidin-3-ylidenemethyl]phenoxy]-4-methylsulfonyl-1H-indole (1.00 eq, 36 mg, 0.0534 mmol) and palladium on activated carbon (5 wt. %, wetted with ca. 55% water, 1.00 eq, 15 mg) in methanol (2 mL) was stirred at room temperature for 6 h. The solids were filtered off, rinsed with MeOH and the combined filtrates were concentrated. The residue was purified by reversed-phase column chromatography on C18 silica gel to give 6,7-difluoro-5- [4-fluoro-5-[4-(4-methylchroman-4-yl)-1H-imidazol-2-yl]-2-(quinuclidin-3- ylmethyl)phenoxy]-4-methylsulfonyl-1H-indole (17 mg, 0.0248 mmol, 47 % yield) as a white solid. MS (ESI): 677.0 (M+H)⁺, retention time of 1.77 min (Method 4).¹H NMR (400 MHz, CD₃OD) δ 7.58-7.57 (m, 1H), 7.37-7.13 (m, 3H), 7.11-7.09 (m, 1H), 7.04-7.02 (m, 1H), 6.79- 6.76 (m, 1H), 6.72-6.70 (m, 1H), 6.47 (s, 1H), 4.13-4.08 (m, 1H), 3.95-3.88 (m, 1H), 3.25 (s, 3H), 3.18-3.10 (m, 1H), 3.10-2.95 (m, 3H), 2.88-2.84 (m, 3H), 2.61-2.58 (m, 1H), 2.46 – 2.30 (m, 2H), 2.08-2.0 (m, 1H), 1.92-1.85 (m, 1H), 1.79-1.75 (m, 2H), 1.62-1.53 (m, 5H). Example 168. Synthesis of 3-(4-(2-(2-fluoro-5-(4,6,7-trifluoro-1H-indole-5- carbonyl)phenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)propanoic acid Ethyl 3-[4-[2-[2-fluoro-5-[tetrahydropyran-2-yloxy-(4,6,7-trifluoro-1H-indol-5- Step A: A mixture of ethyl 3-[4-(2-bromoacetyl)-4-methyl-chroman-8-yl]propanoate (1.00 eq, 0.17 g, 0.460 mmol), DMF (10 mL), 2-fluoro-5-[tetrahydropyran-2-yloxy-(4,6,7-trifluoro-1- triisopropylsilyl-indol-5-yl)methyl]benzamidine (1.20 eq, 0.32 g, 0.552 mmol) sodium bicarbonate (2.00 eq, 77 mg, 0.921 mmol) was stirred at 70 °C for 16 h. The reaction mixture was diluted with water (50 mL), extracted with ethyl acetate (3 x 50 mL). The combined extracts were washed with brine (50 mL), dried over Na₂SO₄, 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-[2-fluoro-5-[tetrahydropyran-2-yloxy-(4,6,7-trifluoro- 1H-indol-5-yl)methyl]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (0.20 g, 0.289 mmol, 63 % yield) ^as^ a solid. MS (ESI): 692.4 (M+H)⁺, retention time of 1.79 min (Method 3). Ethyl 3-[4-[2-[2-fluoro-5-[hydroxy-(4,6,7-trifluoro-1H-indol-5-yl)methyl]phenyl]-1H- imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate Step B: To a solution of^ethyl 3-[4-[2-[2-fluoro-5-[tetrahydropyran-2-yloxy-(4,6,7-trifluoro- 1H-indol-5-yl)methyl]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (1.00 eq, 0.20 g, 0.289 mmol) in DCM (5 mL) was added^ hydrochloric acid (4 M, 27.7 eq, 2.0 mL, 8.00 mmol) and the mixture was stirred at room temperature for 5 min. The reaction mixture was diluted with water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (20 mL), dried over Na₂SO₄, 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-[2-fluoro-5-[hydroxy-(4,6,7-trifluoro-1H-indol-5- yl)methyl]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (0.17 g, 0.280 mmol, 97 % yield) as a solid. MS (ESI): 608 (M+H)⁺, retention time of 1.66 min (Method 3). Ethyl 3-[4-[2-[2-fluoro-5-(4,6,7-trifluoro-1H-indole-5-carbonyl)phenyl]-1H-imidazol-4-yl]- 4-methyl-chroman-8-yl]propanoate Step C: A mixture of ethyl 3-[4-[2-[2-fluoro-5-[hydroxy-(4,6,7-trifluoro-1H-indol-5- yl)methyl]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (1.00 eq, 85 mg, 0.140 mmol), DMSO (2 mL) ^ and 1-hydroxy-1,2-benziodoxol-3(1H)-one 1-oxide (2.00 eq, 170 mg, 0.280 mmol) ^was stirred at RT for 16 h. The mixture was diluted with DCM (60 mL) and water (20 mL), and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over Na₂SO₄, 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-[2-fluoro-5-(4,6,7-trifluoro-1H-indole-5- carbonyl)phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (0.040 g, 0.0661 mmol, 47 % yield) ^^as a solid. MS (ESI): 606 (M+H)⁺, retention time of 1.43 min (Method 4). 3-(4-(2-(2-Fluoro-5-(4,6,7-trifluoro-1H-indole-5-carbonyl)phenyl)-1H-imidazol-4-yl)-4- methylchroman-8-yl)propanoic acid Step D: To a solution of ethyl 3-(4-(2-(2-fluoro-5-(4,6,7-trifluoro-1H-indole-5- carbonyl)phenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)propanoate (40 mg, 0.066 mmol) in THF (3 mL)^was added^lithium hydroxide (3.0 mL, 3.0 mmol). The reaction was stirred at RT for 16 h.^The mixture was acidified with 1.0 M hydrochloric acid to pH = 5, extracted with ethyl acetate (3 x 20 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 3-(4-(2-(2-fluoro-5-(4,6,7-trifluoro-1H-indole-5-carbonyl)phenyl)-1H- imidazol-4-yl)-4-methylchroman-8-yl)propanoic acid (2.9 mg, 16 % yield)^as a white solid.^ MS (ESI): 578 (M+H)⁺, retention time of 1.62 min (Method 4).¹H NMR (500 MHz, CD₃OD) δ 8.43 (d, J = 5.5 Hz, 1H), 7.93-7.88 (m, 1H), 7.44-7.36 (m, 2H), 7.05 (d, J = 7.5 Hz, 1H), 7.00 (d, J = 7.5 Hz, 1H), 6.75 (t, J = 7.5 Hz, 1H), 6.65 (t, J = 3.0 Hz, 1H), 6.61 (s, 1H), 4.27-4.22 (m, 1H), 4.08-4.02 (m, 1H), 2.86 (t, J = 7.5 Hz, 2H), 2.54 (t, J = 7.5 Hz, 2H), 2.50-2.43 (m, 1H), 2.05-1.93 (m, 1H), 1.71 (s, 3H) ppm. Example 169. Synthesis of 3-[4-[2-[2-fluoro-5-[hydroxy-(4,6,7-trifluoro-1H-indol- 5-yl)methyl]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid To a stirred solution of ethyl 3-(4-(2-(2-fluoro-5-(hydroxy(4,6,7-trifluoro-1H-indol-5- yl)methyl)phenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)propanoate (Step B, Example 168, 40 mg, 0.066 mmol)^in THF (3 mL)^was added^aqueous lithium hydroxide (3.0 mL, 3.0 mmol). The reaction mixture was stirred at RT for 16 h, acidified with 1.0 M hydrochloric acid to pH = 5, and extracted with ethyl acetate (3 x 20 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 3-(4-(2-(2-fluoro-5- (hydroxy(4,6,7-trifluoro-1H-indol-5-yl)methyl)phenyl)-1H-imidazol-4-yl)-4-methylchroman- 8-yl)propanoic acid (REQ-01520-6-P) (3.3 mg, 12 % yield)^as a white solid.^ MS (ESI): 580 (M+H)⁺, retention time of 1.53 min (Method 4). ¹H NMR (500 MHz, CD₃OD) δ 7.91 (d, J = 7.0 Hz, 1H), 7.50 (s, 1H), 7.28 (d, J = 3.0 Hz, 1H), 7.21-7.15 (m, 1H), 7.07 (t, J = 8.0 Hz, 1H), 7.00 (t, J = 6.0 Hz, 1H), 6.75 (q, J = 7.5 Hz, 1H), 6.56-6.50 (m, 2H), 6.34 (s, 1H), 4.30-4.20 (m, 1H), 4.06-4.00 (m, 1H), 2.91-2.82 (m, 2H), 2.57-2.51 (m, 2H), 2.51-2.43 (m, 1H), 2.03- 1.94 (m, 1H), 1.71 (d, J = 6.0 Hz, 3H) ppm. Example 170. Synthesis of 3-[4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)methyl]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Step A: To a solution of 2-fluoro-5-(hydroxy(4,6,7-trifluoro-1-(triisopropylsilyl)-1H-indol-5- yl)methyl)benzonitrile (0.46 g, 0.966 mmol) in DCM (5 mL) was added Et₃N (0.4 mL, 2.898 mmol) and acetyl chloride (114 mg, 1.449 mmol). The mixture was stirred at RT for 1 h and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0- 15% ethyl acetate in petroleum ether to give (3-cyano-4-fluorophenyl)(4,6,7-trifluoro-1- (triisopropylsilyl)-1H-indol-5-yl)methyl acetate (420 mg, 86 % yield) as a solid. MS (ESI): 541 (M+Na)⁺, retention time of 2.57 min (modified Method 2 - Gradient: 5%-95% B in 2.5 min). Step B: To a stirred solution of (3-cyano-4-fluorophenyl)(4,6,7-trifluoro-1-(triisopropylsilyl)- 1H-indol-5-yl)methyl acetate (0.25 g, 0.483 mmol) in chloroform (5 mL) was added indium tribromide (8.6 mg, 0.024 mmol) and Et₃SiH (225 mg, 1.932 mmol). The mixture was stirred at 60 °C for 5 min, quenched with water (10 mL), and extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-20% ethyl acetate in petroleum ether to give 2-fluoro-5-((4,6,7-trifluoro-1-(triisopropylsilyl)- 1H-indol-5-yl)methyl)benzonitrile (170 mg, 76 % yield) as a solid. MS (ESI): 305 (M- TIPS+H) ⁺, retention time of 2.03 min (modified Method 2 - Gradient: 5%-95% B in 2.5 min). Step C: To a stirred solution of 2-fluoro-5-((4,6,7-trifluoro-1-(triisopropylsilyl)-1H-indol-5- yl)methyl)benzonitrile (1.00 eq, 170 mg, 0.370 mmol) in THF (3 mL) was added at RT LHMDS (10.00 eq, 3.7 mL, 3.70 mmol). The reaction mixture was stirred at room temperature for 1 hour, quenched with water (20 mL), and extracted with EA (2 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over magnesium sulfate and concentrated under reduced pressure to give 2-fluoro-5-((4,6,7-trifluoro-1-(triisopropylsilyl)- 1H-indol-5-yl)methyl)benzimidamide (170 mg, 86 % yield). MS (ESI): 478 (M-TIPS+H) ⁺, retention time of 1.86 min (modified Method 2 - Gradient: 5%-95% B in 1.3 min). ^Ethyl 3-(4-(2-(2-fluoro-5-((4,6,7-trifluoro-1H-indol-5-yl)methyl)phenyl)-1H-imidazol-4-yl)- 4-methylchroman-8-yl)propanoate Step D: A mixture of^ethyl 3-(4-(2-bromoacetyl)-4-methylchroman-8-yl)propanoate (1.00 eq, 110 mg, 0.297 mmol) and^2-fluoro-5-((tetrahydro-2H-pyran-2-yloxy)(4,6,7-trifluoro-1- (triisopropylsilyl)-1H-indol-5-yl)methyl)benzimidamide (1.20 eq, 170 mg, 0.356 mmol), DMF (10 mL) and sodium bicarbonate (2.00 eq, 50 mg, 0.594 mmol) was stirred at 70 °C for 16 h. The reaction mixture was cooled, diluted with water (100 mL), extracted with ethyl acetate (3 x 30 mL). The combined organic extracts were washed with brine (30 mL), dried over Na₂SO₄, 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-(2-fluoro-5-((4,6,7- trifluoro-1H-indol-5-yl)methyl)phenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)propanoate (100 mg, 57 % yield) as a solid. MS (ESI): 592.2 (M +H) ⁺, retention time of 2.03 min (Method 2). 3-(4-(2-(2-Fluoro-5-((4,6,7-trifluoro-1H-indol-5-yl)methyl)phenyl)-1H-imidazol-4-yl)-4- methylchroman-8-yl)propanoic acid Step E: To a solution of ethyl 3-(4-(2-(2-fluoro-5-((4,6,7-trifluoro-1H-indol-5- yl)methyl)phenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)propanoate (100 mg, 0.169 mmol) in THF (3 mL) was added^aqueous lithium hydroxide (3.0 mL, 3.0 mmol) and the reaction was stirred at RT for 16 h.^The mixture was acidified with 1.0 M hydrochloric acid to pH = 5, extracted with ethyl acetate (20 mL x 3), the combined organic phases were^washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC to give 3-(4-(2-(2-fluoro-5-((4,6,7-trifluoro-1H-indol-5- yl)methyl)phenyl)-1H-imidazol-4-yl)-4-methylchroman-8-yl)propanoic acid (REQ-01521) (45 mg, 62 % yield)^as a white solid. MS (ESI): 564 (M+H) ⁺, retention time of 1.61 min (Method 4).¹H NMR (500 MHz, CD₃OD) δ 7.77 (dd, J = 7.0, 2.0 Hz, 1H), 7.30-7.23 (m, 2H), 7.12 (dd, J = 11.0, 8.5 Hz, 1H), 7.07 (dd, J = 8.0, 1.5 Hz, 1H), 7.02 (d, J = 7.5 Hz, 1H), 6.77 (t, J = 7.5 Hz, 1H), 6.59 (s, 1H), 6.53 (t, J = 3.0 Hz, 1H), 4.30-4.22 (m, 1H), 4.14 (s, 2H), 4.10- 4.02 (m, 1H), 2.87 (t, J = 7.5 Hz, 2H), 2.56 (t, J = 8.0 Hz, 2H), 2.52-2.46 (m, 1H), 2.03-1.96 (m, 1H), 1.73 (s, 3H) ppm. Example 171. Synthesis of 3-[4-[2-[5-[[6,7-difluoro-4-(methylsulfonimidoyl)-1H- indol-5-yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Step A: To a solution of 5-[[6,7-difluoro-4-(methylsulfonimidoyl)-1H-indol-5-yl]oxy]-2- fluoro-benzonitrile (Intermediate 43C, 92 mg, 0.25 mmol) in THF (2.5 mL) was added LHMDS (2.5 mL, 2.5 mmol) at 0 °C. The mixture was stirred at room temperature for 16 h, quenched with water, and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 5-[[6,7-difluoro-4-(methylsulfonimidoyl)-1H-indol-5-yl]oxy]-2-fluoro- benzamidine (85 mg, 88 % yield) as a solid. MS (ESI): 383.2 (M+H) ⁺, retention time of 1.37 min (modified Method 2 - Gradient: 5% to 95% B within 1.3min). Ethyl 3-[4-[2-[5-[[6,7-difluoro-4-(methylsulfonimidoyl)-1H-indol-5-yl]oxy]-2-fluoro- Step B: A mixture of 5-[[6,7-difluoro-4-(methylsulfonimidoyl)-1H-indol-5-yl]oxy]-2-fluoro- benzamidine (70 mg, 0.183 mmol), DMF (3 mL), ethyl 3-[4-(2-bromoacetyl)-4-methyl- chroman-8-yl]propanoate (81 mg, 0.219 mmol) and NaHCO₃ (30.7 mg, 0.366 mmol) was stirred for 4 hours at 75 °C. The mixture was quenched with water and extracted with ethyl acetate (50 mL). The combined organic extracts were washed with brine (50 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-75% ethyl acetate in petroleum ether to give ethyl 3-[4-[2-[5-[[6,7-difluoro-4-(methylsulfonimidoyl)-1H-indol-5-yl]oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (49 mg, 41.0 % yield) as a solid. MS (ESI): 653.3 (M+H) ⁺, retention time of 1.62 min (modified Method 2 - Gradient: 5% to 95% B within 1.3min). 3-[4-[2-[5-[[6,7-Difluoro-4-(methylsulfonimidoyl)-1H-indol-5-yl]oxy]-2-fluoro-phenyl]-1H- Step C: The title compound was prepared via the ester hydrolysis method described in Example 170, Step E. MS (ESI): 625.2 (M+H) ⁺, retention time of 1.45 min (modified Method 2 - Gradient: 5% to 95% B within 1.3min). Example 172. Synthesis of N-[[2-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5- yl)oxy]-5-fluoro-4-[4-(4-methylchroman-4-yl)-1H-imidazol-2-yl]phenyl]methyl]propan- 2-amine 2-[(6,7-Difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4-methylchroman-4-yl)- 1H-imidazol-2-yl]benzonitrile Step A: A mixture of 1,1′-bis(diphenylphosphino)ferrocene (0.100 eq, 17 mg, 0.0299 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (0.100 eq, 12 mg, 0.0299 mmol), tris(dibenzylideneacetone) dipalladium (0.100 eq, 27 mg, 0.0299 mmol), zinc (3.00 eq, 59 mg, 0.896 mmol), [2-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4- methylchroman-4-yl)-1H-imidazol-2-yl]phenyl] trifluoromethanesulfonate (Step C, Example 167, 1.00 eq, 200 mg, 0.299 mmol) and zinc cyanide (2.00 eq, 70 mg, 0.597 mmol) in anhydrous DMA (3 mL) was stirred at 120 °C under a nitrogen atmosphere for 16 h. The reaction mixture was diluted with brine (20 mL) and extracted with EA (3 x 5 mL). The combined organic phases were dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 5:1 PE:EA to give the titled 2-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4- methylchroman-4-yl)-1H-imidazol-2-yl]benzonitrile (122 mg, 0.223 mmol, 75 % yield) as a brown solid. MS (ESI): 547.3 (M+H) ⁺, retention time of 2.01 min (Method 2). tert-Butyl N-[[2-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4- Step B: A mixture of 2-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4- methylchroman-4-yl)-1H-imidazol-2-yl]benzonitrile (1.00 eq, 170 mg, 0.311 mmol), Boc anhydride (2.00 eq, 0.14 mL, 0.622 mmol) and Raney nickel (1.00 eq, 40 mg) was stirred at room temperature under hydrogen for 16 h. After filtration and concentration, the residue was purified by flash column chromatography on silica gel eluting with 5:1 PE:EA to give tert- butyl N-[[2-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4- methylchroman-4-yl)-1H-imidazol-2-yl]phenyl]methyl]carbamate (160 mg, 0.246 mmol, 79 % yield) as a brown solid. MS (ESI): 651.4 (M+H) ⁺, retention time of 1.77 min (Method 2). tert-Butyl N-[[2-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4- Step C: A mixture of aqueous hydrogen peroxide (30 wt. %, 1.00 eq, 1.0 mL, 0.246 mmol) and ammonium molybdate tetrahydrate (1.00 eq, 304 mg, 0.246 mmol) was slowly added to a solution of tert-butyl N-[[2-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4- (4-methylchroman-4-yl)-1H-imidazol-2-yl]phenyl]methyl]carbamate (1.00 eq, 160 mg, 0.246 mmol) in methanol (4 mL) at 0 °C. The mixture was stirred at 0 °C for 1 h, diluted with brine (3 mL) and extracted with EA (3 x 10 mL). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 1:1 PE:EA to give the titled tert-butyl N-[[2-[(6,7-difluoro-4- methylsulfonyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4-methylchroman-4-yl)-1H-imidazol-2- yl]phenyl]methyl]carbamate (80 mg, 0.117 mmol, 48 % yield) as a brown solid. MS (ESI): 683.4 (M+H) ⁺, retention time of 1.66 min (Method 2). [2-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4-methylchroman-4- yl)-1H-imidazol-2-yl]phenyl]methanamine Step D: To a stirred solution of tert-butyl N-[[2-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5- yl)oxy]-5-fluoro-4-[4-(4-methylchroman-4-yl)-1H-imidazol-2-yl]phenyl]methyl]carbamate (1.00 eq, 20 mg, 0.0293 mmol) in methanol (0.5 mL) was added HCl in 1.4-dioxane (10.0 eq, 0.073 mL, 0.293 mmol). The mixture was stirred at room temperature for 1 h and concentrated. The residue was dissolved in NH₃-MeOH (7.0 M, 2 mL) and stirred for 10 min. The mixture was concentrated in vacuo. The residue was purified by reversed-phase column chromatography on C18 silica gel to give [2-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5- yl)oxy]-5-fluoro-4-[4-(4-methylchroman-4-yl)-1H-imidazol-2-yl]phenyl]methanamine (9.9 mg, 0.0168 mmol, 57 % yield) as a white solid. MS (ESI): 583.3 (M+H) ⁺, retention time of 1.76 min (Method 2). ¹H NMR (400 MHz, CD₃OD) δ 7.59 (d, J = 3.1 Hz, 1H), 7.36 (d, J = 11.4 Hz, 1H), 7.23-7.21 (m, 2H), 7.11-7.10 (m, 1H), 7.07-7.01 (m, 1H), 6.80-6.76 (m, 1H), 6.72-6.70 (m, 1H), 6.49 (s, 1H), 4.18-3.87 (m, 4H), 3.23 (s, 3H), 2.37-2.33 (m, 1H), 1.89 (s, 1H), 1.62 (s, 3H) ppm. N-[[2-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4-methylchroman- Step E: A mixture of [2-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4- methylchroman-4-yl)-1H-imidazol-2-yl]phenyl]methanamine (1.00 eq, 7.9 mg, 0.0136 mmol) and acetone (5.00 eq, 3.9 mg, 0.0678 mmol) in DCE (1 mL) was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (3.00 eq, 8.6 mg, 0.0407 mmol) was added and the mixture. was stirred at room temperature for 16 h. The reaction mixture was quenched with 2 mL MeOH and concentrated. The residue was purified by reverse-phase column chromatography on C18 silica gel eluting with H₂O-MeCN to give N-[[2-[(6,7-difluoro-4- methylsulfonyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4-methylchroman-4-yl)-1H-imidazol-2- yl]phenyl]methyl]propan-2-amine (4.3 mg, 0.00688 mmol, 51 % yield) as a white solid. MS (ESI): 625.3 (M+H) ⁺, retention time of 1.89 min (Method 4).¹H NMR (400 MHz, CD₃OD) δ 7.60-7.59 (m, 1H), 7.39-7.36 (m, 1H), 7.27-7.21 (m, 2H), 7.12-6.99 (m, 2H), 6.78-6.71 (m, 2H), 6.57-6.44 (m, 1H), 4.13-3.90 (m, 4H), 3.21 (s, 3H), 3.02-2.91 (m, 1H), 2.37-2.33 (m, 1H), 1.95-1.87 (m, 1H), 1.60 (s, 3H), 1.19 (d, J = 6.2 Hz, 6H) ppm. Example 173. Synthesis of N-[[6,7-difluoro-5-[4-fluoro-3-[4-[(4R)-4- methylchroman-4-yl]-1H-imidazol-2-yl]phenoxy]-1H-indol-4-yl]methyl]-2-methyl- propan-2-amine Example 174. Synthesis of N-[[6,7-difluoro-5-[4-fluoro-3-[4-[(4S)-4- methylchroman-4-yl]-1H-imidazol-2-yl]phenoxy]-1H-indol-4-yl]methyl]-2-methyl- propan-2-amine [6,7-difluoro-5-[4-fluoro-3-[4-(4-methylchroman-4-yl)-1H-imidazol-2-yl]phenoxy]-1H- indol-4-yl]methanol Step A: To a solution of4-bromo-6,7-difluoro-5-[4-fluoro-3-[4-(4-methylchroman-4-yl)-1H- imidazol-2-yl]phenoxy]-1H-indole (1.00 eq, 550 mg, 0.992 mmol) in 1,4-dioxane (5 mL) was added (tributylstannyl)methanol (2.00 eq, 637 mg, 1.98 mmol) and XPhos Pd G2 (0.100 eq, 78 mg, 0.0992 mmol). The reaction was stirred 100 °C for 2 h under an argon atmosphere, cooled to rt, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 20-60% ethyl acetate in petroleum ether to give [6,7-difluoro-5-[4-fluoro-3-[4-(4- methylchroman-4-yl)-1H-imidazol-2-yl]phenoxy]-1H-indol-4-yl]methanol (250 mg, 0.495 mmol, 50 % yield) as a colorless solid. MS (ESI): 506.2 (M+H) ⁺, retention time of 1.66 min (Method 4). 6,7-difluoro-5-[4-fluoro-3-[4-(4-methylchroman-4-yl)-1H-imidazol-2-yl]phenoxy]-1H- indole-4-carbaldehyde Step B: To a solution of[6,7-difluoro-5-[4-fluoro-3-[4-(4-methylchroman-4-yl)-1H-imidazol- 2-yl]phenoxy]-1H-indol-4-yl]methanol (1.00 eq, 250 mg, 0.495 mmol) in DMSO (10 mL) was added Dess-Martin periodinane (1.50 eq, 315 mg, 0.742 mmol) and the reaction was stirred room temperature for 2 h. The reaction was quenched with saturated aqueous NaHCO₃ (10 mL) and water (30 mL) and extracted with EtOAc (2 x 40 mL). The combined organic extracts were washed with water (30 mL), brine, dried over 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 6,7-difluoro-5-[4-fluoro-3-[4-(4-methylchroman-4-yl)-1H-imidazol-2- yl]phenoxy]-1H-indole-4-carbaldehyde (230 mg, 0.457 mmol, 92 % yield) as a colorless solid. MS (ESI): 504.2 (M+H) ⁺, retention time of 1.75 min (Method 2). Enantiomer s of N-[[6,7-difluoro-5-[4-fluoro-3-[4-(4-methylchroman-4-yl)-1H-imidazol-2- Step C: A mixture of 6,7-difluoro-5-[4-fluoro-3-[4-(4-methylchroman-4-yl)-1H-imidazol-2- yl]phenoxy]-1H-indole-4-carbaldehyde (1.00 eq, 60 mg, 0.119 mmol) tert-butylamine (3.00 eq, 0.038 mL, 0.358 mmol) and titanium(IV) isopropoxide (3.00 eq, 0.10 mL, 0.358 mmol) in toluene (2 mL) was stirred at 120 °C for 16 h. The solvent was removed under reduced pressure and the residue was dissolved in methanol (1 mL). Sodium cyanoborohydride (5.00 eq, 37 mg, 0.596 mmol) was added and the mixture was stirred at rt for an additional 1 h. The reaction mixture was quenched with saturated aqueous NaHCO₃ (20 mL), extracted with ethyl acetate (20 mL x 3), the combined organic extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to give N-[[6,7-difluoro-5-[4-fluoro-3-[4-(4-methylchroman-4-yl)-1H-imidazol-2- yl]phenoxy]-1H-indol-4-yl]methyl]-2-methyl-propan-2-amine (30 mg, 0.0535 mmol, 45 % yield) as a colorless solid. MS (ESI): 561.2 (M+H) ⁺, retention time of 1.42 min (Method 3). N-[[6,7-difluoro-5-[4-fluoro-3-[4-(4-methylchroman-4-yl)-1H-imidazol-2-yl]phenoxy]-1H- indol-4-yl]methyl]-2-methyl-propan-2-amine (1.00 eq, 35 mg, 0.0624 mmol) was separated into its constituent enantiomers via SFC to give N-[[6,7-difluoro-5-[4-fluoro-3-[4-[(4R)-4- methylchroman-4-yl]-1H-imidazol-2-yl]phenoxy]-1H-indol-4-yl]methyl]-2-methyl-propan-2- amine (Example 173, 8.0 mg, 0.0143 mmol, 23 % yield) and N-[[6,7-difluoro-5-[4-fluoro-3- [4-[(4S)-4-methylchroman-4-yl]-1H-imidazol-2-yl]phenoxy]-1H-indol-4-yl]methyl]-2- methyl-propan-2-amine (Example 174, 15 mg, 0.0268 mmol, 43 % yield) as a white solid. SFC Separation Conditions: Instrument: SFC-150 (Waters); Column: OJ 25 * 250 mm, 10 µm (Daicel); Column temperature: 35 ºC; Mobile phase: 75/25 CO₂/EtOH [spiked with 0.5% 7M NH₃ in MeOH]; Flow rate: 100 mL/min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 2.2 min; Sample solution: 35 mg dissolved in 35 mL methanol; Injection volume: 2 mL. Example 175. Synthesis of 3-[(4R)-4-[3-[5-[(6,7-difluoro-4-methylsulfanyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1,2,4-triazol-1-yl]-4-methyl-chroman-8-yl]propanoic acid Step A: A mixture of 8-(3-ethoxy-3-oxo-propyl)-4-methyl-chromane-4-carboxylic acid (1.00 eq, 1500 mg, 5.13 mmol), 2-hydroxyisoindoline-1,3-dione (1.10 eq, 921 mg, 5.64 mmol), dicyclohexyl carbodiimide (1.20 eq, 1270 mg, 6.16 mmol) and 4,4-dimethylaminopyridine (0.100 eq, 63 mg, 0.513 mmol) in DCM (20 mL) was stirred at RT for 16 hours. The mixture was diluted with DCM (100 mL), washed with water (2 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0-40% ethyl acetate in petroleum ether to give (1,3- dioxoisoindolin-2-yl) 8-(3-ethoxy-3-oxo-propyl)-4-methyl-chromane-4-carboxylate (1600 mg, 3.66 mmol, 71 % yield) as a colorless oil. MS (ESI): 438.3 (M+H) ⁺, retention time of 2.02 min (Method 5). Ethyl 3-[4-[3-[5-[6,7-difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- Step B: A mixture of (1,3-dioxoisoindolin-2-yl) 8-(3-ethoxy-3-oxo-propyl)-4-methyl- chromane-4-carboxylate (1.00 eq, 80 mg, 0.183 mmol) , 6,7-difluoro-5-[4-fluoro-3-(1H-1,2,4- triazol-3-yl)phenoxy]-4-methylsulfanyl-1-(p-tolylsulfonyl)indole (1.00 eq, 97 mg, 0.183 mmol), 12-phenyl-12H-benzo[b]phenothiazine (0.05 eq, 3.0 mg, 0.00914 mmol) and lithium tetrafluoroborate (2.00 eq, 34 mg, 0.366 mmol) in DCE (3 mL) was stirred and irradiated for 48 h with 40W LED (450 nm) at room temperature under Ar. The mixture was diluted with ethyl acetate (10 mL), washed with water (2 x 10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0-50% ethyl acetate in petroleum ether to give ethyl 3-[4-[3-[5-[6,7-difluoro-4- methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-phenyl]-1,2,4-triazol-1-yl]-4- methyl-chroman-8-yl]propanoate (60 mg, 0.0772 mmol, 42 % yield) as a yellow oil. MS (ESI): 799.3 (M+Na) ⁺, retention time of 2.41 min (Method 5). Enantiomers of Ethyl 3-[4-[3-[5-[6,7-difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5- Step C: The product mixture from the previous reaction step was separated by SFC into its constituent enantiomers, ethyl 3-[(4R)-4-[3-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1,2,4-triazol-1-yl]-4-methyl-chroman-8-yl]propanoate (Stereoisomer 1, 60 mg ,0.0964 mmol, 38 % yield) as a white solid and ethyl 3-[(4S)-4-[3-[5- [(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1,2,4-triazol-1-yl]-4- methyl-chroman-8-yl]propanoate (Stereoisomer 2, 55 mg, 0.0883 mmol, 34 % yield) as a white solid. SFC Separation Conditions: Instrument: SFC-150 (Waters); Column: OD 25 * 250 mm, 10 µm (Daicel); Column temperature: 35 ºC; Mobile phase: 60/40 CO₂/MeOH [spiked with 0.2% (7M NH₃ in MeOH]; Flow rate: 110 mL/min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 4.8 min; Sample solution: 200 mg dissolved in 35 mL methanol; Injection volume: 2 mL. MS (ESI): 645.3 (M+Na)⁺, retention time of 2.20 min (Method 5) observed for both enantiomers. The absolute configurations of both enantiomers are unknown and were assigned arbitrarily. 3-[(4R)-4-[3-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1,2,4- t Step D: A mixture of ethyl 3-[(4R)-4-[3-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1,2,4-triazol-1-yl]-4-methyl-chroman-8-yl]propanoate (Stereoisomer 1, Step C, 1.00 eq, 60 mg, 0.0964 mmol), water (3 mL), MeCN (3 mL) and lithium hydroxide monohydrate (5.00 eq, 20 mg, 0.482 mmol) was stirred at room temperature for 16 hours. The mixture was acidified with 1M hydrochloric acid to pH ~ 5-6, extracted with ethyl acetate (2 x 20 mL), washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC to give 3-[(4R)-4-[3-[5- [(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1,2,4-triazol-1-yl]-4- methyl-chroman-8-yl]propanoic acid (55 mg, 0.0925 mmol, 96 % yield) as a white solid. MS (ESI): 594.9 (M+H) ⁺, retention time of 1.61 min (Method 4). Example 176. Synthesis of 3-[(4R)-4-[3-[5-[(6,7-difluoro-4-methylsulfonyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1,2,4-triazol-1-yl]-4-methyl-chroman-8-yl]propanoic acid Example 177. Synthesis of 3-[(4R)-4-[3-[5-[(6,7-difluoro-4-methylsulfinyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1,2,4-triazol-1-yl]-4-methyl-chroman-8-yl]propanoic acid To a stirred solution of 3-[(4R)-4-[3-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2- fluoro-phenyl]-1,2,4-triazol-1-yl]-4-methyl-chroman-8-yl]propanoic acid (Example 175, 1.00 eq, 40 mg, 0.0673 mmol) in methanol (0.5000mL) was added at 0 °C a mixture of ammonium molybdate tetrahydrate (0.855 eq, 71 mg, 0.0575 mmol) in aqueous hydrogen peroxide (1.00 eq, 0.20 mL, 0.0673 mmol). The reaction was stirred at 0 °C for 30 min, diluted with ethyl acetate (20 mL), washed with water (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to give 3-[(4R)-4-[3-[5-[(6,7- difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1,2,4-triazol-1-yl]-4-methyl- chroman-8-yl]propanoic acid (23 mg, 0.0365 mmol, 54 % yield) as a white solid and 3-[(4R)- 4-[3-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1,2,4-triazol-1- yl]-4-methyl-chroman-8-yl]propanoic acid (2.7 mg, 0.00442 mmol, 7 % yield) as a white solid. MS (ESI): 626.8 (M+H) ⁺, retention time of 1.39 min (Method 4). 3-[(4R)-4-[3-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1,2,4- triazol-1-yl]-4-methyl-chroman-8-yl]propanoic acid (Example 176): MS (ESI): 611.0 (M+H) +, retention time of 1.32 min (Method 4). Example 178. Synthesis of 2-[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]sulfanylpropanoic acid The title compound was prepared in 3 steps, starting from Intermediate 48 and Intermediate 17, following procedures outlined in Step A and B, Example 44 followed by the sulfide to sulfone oxidation protocol described in Example 176. MS (ESI): 658 (M+H) ⁺, retention time of 1.51 min (Method 2A). Example 179. Synthesis of (E)-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]prop-2- enoic acid Example 180. Synthesis of (E)-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]prop-2-enoic acid Example 181. Synthesis of (E)-3-[4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]prop-2-enoic acid 5-[3-[4-(8-bromo-4-methyl-chroman-4-yl)-1H-imidazol-2-yl]-4-fluoro-phenoxy]-6,7- difluoro-4-methylsulfanyl-1H-indole Step A: The title compound was prepared via a procedure analogous to one in Step D, Example 170 starting from Intermediate 17 and Intermediate 49. MS (ESI): 600.2, 602.2 (M+H) ⁺, retention time of 1.79 min (Method 2). (E)-3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- Step B: A mixture of ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (1.00 eq, 113 mg, 0.500 mmol), 1,4-dioxane (4 mL), water (0.4 mL), 1,1'- 1,1'‑bis(diphenylphosphino)ferrocene]palladium(II) dichloride (0.150 eq, 54 mg, 0.0749 mmol) , and 5-[3-[4-(8-bromo-4-methyl-chroman-4-yl)-1H-imidazol-2-yl]-4-fluoro- phenoxy]-6,7-difluoro-4-methylsulfanyl-1H-indole (1.00 eq, 300 mg, 0.500 mmol) was stirred overnight at 100 °C under Ar. The reaction mixture was extracted with ethyl acetate (20 mL x 4). The combined organic phases were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 37-45% ethyl acetate in petroleum ether to give ethyl (E)-3-(4-(2-(5- ((6,7-difluoro-4-(methylthio)-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-imidazol-4-yl)-4- methylchroman-8-yl)acrylate (250 mg, 0.410 mmol, 82 % yield) as a white solid. MS (ESI): 620.2 (M+H) ⁺, retention time of 1.78 min (Method 2). (E)-3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- i Step C: The title compound (220 mg, 0.372 mmol, 92 % yield) was prepared following an ester hydrolysis procedure similar to one used in Step D, Example 175. MS (ESI): 592.2 (M+H) ⁺, retention time of 1.63 min (Method 2). (E)-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]prop-2-enoic acid, (E)-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]prop-2-enoic acid and (E)-3-[4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5- Step D: To a solution of (E)-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]prop-2-enoic acid (1.00 eq, 220 mg, 0.372 mmol) in MeCN (5 mL) was added at 0 °C ammonium molybdate tetrahydrate (0.479 eq, 220 mg, 0.178 mmol), and aqueous hydrogen peroxide (176 eq, 2.0 mL, 65.3 mmol). The reaction mixture was allowed to warm to rt over 1 h, poured into water (20 mL), extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by SFC to give (E)-3-[4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro- phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]prop-2-enoic acid (Product 1, 52 mg, 0.0851 mmol, 23 % yield), (E)-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]prop-2-enoic acid (Product 2, 38 mg, 0.0616 mmol, 17 % yield), and (E)-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]prop-2-enoic acid (Product 3, 25 mg, 0.0393 mmol, 11 % yield) as a white solid. The absolute and relative configurations of Products 1-3 are unknown and were assigned arbitrarily. SFC Separation Condition: Instrument: SFC-150 (Waters); Column: IH 25 * 250 mm, 10 µm (Daicel); Column temperature: 35 ºC; Mobile phase: 75/25 CO₂/MeOH [spiked with 0.2% (7M NH₃ in MeOH)]; Flow rate: 100 ml/min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 5.3 min; Sample solution: 700 mg dissolved in 65 ml methanol; Injection volume: 4.0 ml. Product 1: Chiral HPLC retention time – 1.38 min; MS (ESI): 624 (M+H) ⁺, retention time of 1.63 min (modified Method 2 - Flow Rate: 1.8mL/min). Product 2: Chiral HPLC retention time – 2.23 min; MS (ESI): 624 (M+H) ⁺, retention time of 1.63 min (modified Method 2 - Flow Rate: 1.8mL/min). Product 3: MS (ESI): 609 (M+H) ⁺, retention time of 1.89 min (modified Method 2 - Flow Rate: 1.8mL/min). Chiral HPLC Conditions: Column: OJ-34.6 * 100 mm, 3 µm; Co-Solvent: MeOH [0.2%NH₃ (7M in MeOH)]; Injection Volume: 5.00 ul; Run Time: 4.0 Minutes; Flow rate: 3.0 mL/min; Detection wavelength: 214 nm; Back Pressure: 2000 psi; Column Temperature: 40 °C. Example 182. Synthesis of (R)-3-(4-(1-(5-((6,7-difluoro-4-(methylsulfonyl)-1H- indol-5-yl)oxy)-2-fluorophenyl)-1H-pyrazol-3-yl)-4-methylchroman-8-yl)propanoic acid Example 183. Synthesis of (S)-3-(4-(1-(5-((6,7-difluoro-4-(methylsulfonyl)-1H- indol-5-yl)oxy)-2-fluorophenyl)-1H-pyrazol-3-yl)-4-methylchroman-8-yl)propanoic acid Ethyl 3-[4-[1-[5-[6,7-difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- Step A: A mixture of 6,7-difluoro-5-(4-fluoro-3-iodo-phenoxy)-4-methylsulfanyl-1-(p- tolylsulfonyl)indole (Intermediate 51, 282 mg, 0.4771 mmol), ethyl 3-[4-methyl-4-(1H- pyrazol-3-yl)chroman-8-yl]propanoate (Intermediate 50, 150 mg, 0.4771 mmol), Na₂CO₃ (102 mg, 0.9543 mmol), NMP (3 mL), trans-(1R,2R)-N1,N2-dimethylcyclohexane-1,2-diamine (28 mg, 0.1909 mmol) and CuI (18.2 mg, 0.0954 mmol) was stirred at 100 °C for 16 h under Ar. The mixture was partitioned between saturated aqueous NH₄Cl and ethyl acetate (10 mL). The organic phase was washed with water (20 mL x 2) and brine (20 mL x 2), dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with 2/1 petroleum ether/ethyl acetate to give ethyl 3-[4-[1-[5-[6,7- difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-phenyl]pyrazol-3-yl]-4- methyl-chroman-8-yl]propanoate (120 mg, 25 % yield) as a white solid. MS (ESI): 776.3 (M+H) ⁺, retention time of 3.46 min (modified Method 2 – Gradient: 5%-95% B in 2.5 min). 3-[4-[1-[5-[(6,7-Difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]pyrazol-3- yl]-4-methyl-chroman-8-yl]propanoic acid Step B: The title compound (90 mg,0.114 mmol, 74 % yield) was obtained from ethyl 3-[4-[1- [5-[6,7-difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-phenyl]pyrazol- 3-yl]-4-methyl-chroman-8-yl]propanoate following an ester hydrolysis procedure similar to the one in Step D, Example 175. MS (ESI): 594.2 (M+H) ⁺, retention time of 2.01 min (modified Method 2 – Flow Rate: 1.8 mL/min).¹H NMR (400 MHz, CD₃OD) δ 7.96 (t, J = 2.6 Hz, 1H), 7.44 (d, J = 3.0 Hz, 1H), 7.30 (dd, J = 6.4, 3.0 Hz, 1H), 7.22 (dd, J = 11.49.2 Hz, 1H), 7.02- 6.97 (m, 1H), 6.93 (d, J = 6.2 Hz, 1H), 6.83-6.72 (m, 2H), 6.62 (t, J = 7.6 Hz, 1H), 6.18 (d, J = 2.4 Hz, 1H), 4.25-4.18 (m, 1H), 4.14-4.08 (m, 1H), 2.88-2.81 (m, 2H), 2.57-2.49 (m, 2H), 2.42-2.36 (m, 1H), 2.35 (s, 3H), 2.07-2.00 (m, 1H), 1.70 (s, 3H) ppm. Enantiomers of 3-(4-(1-(5-((6,7-difluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)-2- Step C: Racemic 3-(4-(1-(5-((6,7-difluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)-2- fluorophenyl)-1H-pyrazol-3-yl)-4-methylchroman-8-yl)propanoic acid was obtained from ethyl 3-[4-[1-[5-[6,7-difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- phenyl]pyrazol-3-yl]-4-methyl-chroman-8-yl]propanoate following a sulfide oxidation procedure similar to one used in Step D, Example 181 starting from ethyl 3-[4-[1-[5-[6,7- difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-phenyl]pyrazol-3-yl]-4- methyl-chroman-8-yl]propanoate. MS (ESI): 626 (M+H) ⁺, retention time of 1.91 min (modified Method 2 – Flow Rate: 1.8 mL/min). The racemic mixture was separated by chiral HPLC to give (R)-3-(4-(1-(5-((6,7-difluoro-4- (methylsulfonyl)-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H-pyrazol-3-yl)-4-methylchroman-8- yl)propanoic acid (Product 1, 11.9 mg, 12 % yield over oxidation and resolution steps) and (S)- 3-(4-(1-(5-((6,7-difluoro-4-(methylsulfonyl)-1H-indol-5-yl)oxy)-2-fluorophenyl)-1H- pyrazol-3-yl)-4-methylchroman-8-yl)propanoic acid (Product 2, 10 mg, 10 % yield over oxidation and resolution steps). Product 1: ¹H NMR (500 MHz, CD₃OD) δ 7.98 (t, J = 2.5 Hz, 1H), 7.60 (d, J = 3.0 Hz, 1H), 7.45 (dd, J = 6.5, 3.0 Hz, 1H), 7.28-7.22 (m, 2H), 7.04-7.01 (m, 1H), 6.93 (d, J = 6.5 Hz, 1H), 6.87-6.83 (m, 1H), 6.65 (t, J = 7.5 Hz, 1H), 6.18 (d, J = 2.5 Hz, 1H), 4.26-4.21 (m, 1H), 4.17- 4.10 (m, 1H), 3.29 (s, 3H), 2.87-2.82 (m, 2H), 2.56-2.50 (m, 2H), 2.44-2.38 (m, 1H), 2.09-2.00 (m, 1H), 1.72 (s, 3H) ppm. Product 2: ¹H NMR (500 MHz, CD₃OD) δ 7.97 (t, J = 2.5 Hz, 1H), 7.60 (d, J = 3.0 Hz, 1H), 7.44 (dd, J = 6.5, 3.0 Hz, 1H), 7.28-7.22 (m, 2H), 7.01 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 6.5 Hz, 1H), 6.87-6.83 (m, 1H), 6.64 (t, J = 7.5 Hz, 1H), 6.18 (d, J = 2.5 Hz, 1H), 4.25-4.20 (m, 1H), 4.16-4.10 (m, 1H), 3.28 (s, 3H), 2.88-2.80 (m, 2H), 2.56-2.48 (m, 2H), 2.43-2.38 (m, 1H), 2.08- 2.01 (m, 1H), 1.72 (s, 3H) ppm. Example 184. Synthesis of N-[[2-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5- yl)oxy]-5-fluoro-4-[4-(4-methylchroman-4-yl)-1H-imidazol-2-yl]phenyl]methyl]-2- methyl-propan-2-amine 2-[(6,7-Difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4-methylchroman-4-yl)- 1H-imidazol-2-yl]benzaldehyde Step A: To a solution of 2-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4- (4-methylchroman-4-yl)-1H-imidazol-2-yl]benzonitrile (Step A, Example 172, 1.00 eq, 109 mg, 0.199 mmol) in anhydrous DCM (5 mL) and Chloroform (1 mL) was slowly added DIBAL-H (1.0 N in hexane, 3.00 eq, 0.60 mL, 0.598 mmol) at -78 °C. The mixture was stirred at -78 °C for 1 h. The reaction was quenched with 1 N hydrochloric acid and 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 5:1 PE:EA to give 2-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-5- fluoro-4-[4-(4-methylchroman-4-yl)-1H-imidazol-2-yl]benzaldehyde (85 mg, 0.155 mmol, 78 % yield) as a brown solid. MS (ESI): 550.3 (M+H) ⁺, retention time of 1.96 min (modified Method 2 – Temperature: 40 °C). N-[[2-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4-methylchroman- Step B: A mixture of 2-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4- methylchroman-4-yl)-1H-imidazol-2-yl]benzaldehyde (1.00 eq, 15 mg, 0.0273 mmol), 2- methylpropan-2-amine (2.00 eq, 4.0 mg, 0.0546 mmol) and titanium tetraisopropanolate (3.00 eq, 23 mg, 0.0819 mmol) in anhydrous toluene (1 mL) was stirred at 120 °C for 16 h. The reaction mixture was concentrated in vacuo, the residue was dissolved in methanol (1mL) and sodium cyanoborohydride (3.00 eq, 5.1 mg, 0.0819 mmol) was added. The resulting mixture was stirred at room temperature for 1 h, diluted with DCM (10 mL) and washed with saturated aqueous sodium bicarbonate (3 x 2 mL). The organic phase was 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 N-[[2-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5- yl)oxy]-5-fluoro-4-[4-(4-methylchroman-4-yl)-1H-imidazol-2-yl]phenyl]methyl]-2-methyl- propan-2-amine (13 mg, 0.0214 mmol, 79 % yield) as a brown solid. MS (ESI): 607.4 (M+H) +, retention time of 1.48 min (modified Method 2 – Temperature: 40 °C). N-[[2-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-5-fluoro-4-[4-(4-methylchroman- Step C: The title compound (5.0 mg, 0.00783 mmol, 37 % yield) was prepared from the product of Step B following a sulfide oxidation procedure similar to the one described in Step D, Example 181. MS (ESI): 639.4 (M+H) ⁺, retention time of 1.43 min (modified Method 2 – Temperature: 40 °C). Example 185. Synthesis of 2-[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]sulfanyl-2-methyl- propanoic acid The title compound was prepared from Intermediate 52 and Intermediate 53 via a two-step sequence analogous to Step A, Example 167 (imidazole ring formation) followed by Step D, Example 175 (ester hydrolysis). MS (ESI): 672.2 (M+H) ⁺, retention time of 1.56 min (Method 3). Example 186. Synthesis of 3-[4-[3-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]pyrazol-1-yl]-4-methyl-chroman-8-yl]propanoic acid Example 187. Synthesis of 3-[4-[3-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]pyrazol-1-yl]-4-methyl-chroman-8-yl]propanoic acid Example 186 (4.0 mg, 0.00656 mmol, 16 % yield) and Example 187 (4.3 mg, 0.00687 mmol, 16 % yield) were prepared from 3-[4-[3-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]pyrazol-1-yl]-4-methyl-chroman-8-yl]propanoic acid via a sulfide oxidation procedure analogous to the one in Step D, Example 180/181. Example 186: MS (ESI): 609.9 (M+H) ⁺, retention time of 1.52 min (Method 4).¹H NMR (500 MHz, CD₃OD) δ 7.57 (d, J = 3.1 Hz, 1H), 7.53-7.48 (m, 1H), 7.27-7.22 (m, 2H), 7.20 (t, J = 8.3 Hz, 1H), 7.16-7.09 (m, 2H), 6.86-6.81 (m, 2H), 6.57 (s, 1H), 4.29-4.22 (m, 1H), 3.87-3.78 (m, 1H), 2.98 (d, J = 8.7 Hz, 3H), 2.88 (d, J = 7.6 Hz, 2H), 2.70 (d, J = 14.2 Hz, 1H), 2.54 (dd, J = 14.5, 7.3 Hz, 2H), 2.27-2.18 (m, 1H), 1.97 (s, 3H) ppm. Example 187: MS (ESI): 626.0 (M+H) ⁺, retention time of 1.55 min (Method 4).¹H NMR (500 MHz, CD₃OD) δ 7.61 (dd, J = 5.9, 3.3 Hz, 1H), 7.58 (d, J = 3.1 Hz, 1H), 7.26 (t, J = 3.2 Hz, 1H), 7.24-7.20 (m, 2H), 7.17 (d, J = 7.4 Hz, 1H), 7.12-7.05 (m, 1H), 6.86 (t, J = 7.6 Hz, 1H), 6.84-6.79 (m, 1H), 6.58-6.55 (m, 1H), 4.33-4.23 (m, 1H), 3.85-3.79 (m, 1H), 3.31 (s, 3H), 2.89 (t, J = 7.0 Hz, 2H), 2.77-2.69 (m, 1H), 2.56-2.49 (m, 2H), 2.27-2.18 (m, 1H), 1.99 (s, 3H) ppm. Ethyl 3-[4-[3-[5-[6,7-difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- Step A: A mixture of (1,3-dioxoisoindolin-2-yl) 8-(3-ethoxy-3-oxo-propyl)-4-methyl- chromane-4-carboxylate (Step A, Example 175, 2.00 eq, 661 mg, 1.51 mmol), 6,7-difluoro-5- [4-fluoro-3-(1H-pyrazol-3-yl)phenoxy]-4-methylsulfanyl-1-(p-tolylsulfonyl)indole (Intermediate 54, 1.00 eq, 400 mg, 0.755 mmol), LiBF4 (2.00 eq, 140 mg, 1.51 mmol), 10- phenylphenothiazine (0.100 eq, 25 mg, 0.0755 mmol) in DCE (4 mL) was stirred and irradiated with a 40W LED (450 nm) at room temperature under Ar for 48 h. The mixture was diluted with ethyl acetate (200 mL), washed with water (2 x 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 20 % EA in PE to give ethyl 3-[4-[3-[5-[6,7-difluoro-4- methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-phenyl]pyrazol-1-yl]-4-methyl- chroman-8-yl]propanoate (30 mg, 0.0387 mmol, 5 % yield) and ethyl 3-[4-[5-[5-[6,7-difluoro- 4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-phenyl]pyrazol-1-yl]-4-methyl- chroman-8-yl]propanoate (7.0 mg, 0.00902 mmol, 1.2 % yield). MS (ESI): 798.2 (M+Na)⁺, retention time of 2.50 min (Method 2A) observed for title compound. Ethyl 3-[4-[3-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro- Step B: To a solution of ethyl 3-[4-[3-[5-[6,7-difluoro-4-methylsulfanyl-1-(p- tolylsulfonyl)indol-5-yl]oxy-2-fluoro-phenyl]pyrazol-1-yl]-4-methyl-chroman-8- yl]propanoate (1.00 eq, 40 mg, 0.0516 mmol) in THF (3 mL) was added TBAF (2.00 eq, 0.10 mL, 0.103 mmol) at 0 °C. The mixture was allowed to warm up and stirred at RT for 2 h, diluted with ethyl acetate (20 mL), washed with water (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude was purified by silica gel chromatography eluting with 10 % EA in PE to give ethyl 3-[4-[3-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol- 5-yl)oxy]-2-fluoro-phenyl]pyrazol-1-yl]-4-methyl-chroman-8-yl]propanoate (30 mg, 0.0483 mmol, 94 % yield). MS (ESI): 644.3 (M+H) ⁺, retention time of 2.28 min (Method 2A). 3-[4-[3-[5-[(6,7-Difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]pyrazol-1- yl]-4-methyl-chroman-8-yl]propanoic acid Step C: The title compound (25 mg, 0.0421 mmol, 87 % yield) was prepared via an ester hydrolysis procedure analogous to the one in Step A, Example 54. MS (ESI): 616.3 (M+Na)⁺, retention time of 1.48 min (Method 2). Example 188. Synthesis of 3-[(4R)-6-chloro-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 Enantiomers of ethyl 3-[6-chloro-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5- Step A: Racemic ethyl 3-[6-chloro-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 was assembled from Intermediate 55 and Intermediate 17 following a similar procedure to that in StepA, Example 133. The racemic mixture (959 mg, 1.46 mmol) was separated by SFC to give ethyl 3-[(4R)-6-chloro-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 (Stereoisomer 1, 425 mg, 0.648 mmol, 44 % yield) and ethyl 3-[(4S)-6-chloro-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 (Stereoisomer 2, 390 mg, 0.594 mmol, 41 % yield) as white solids. The absolute configurations of Stereoisomer 1 and Stereoisomer 2 are unknown and have been assigned arbitrarily. MS (ESI): 656.2 (M+H)⁺, retention time of 1.78 min (Method 2A) were observed for both enantiomers. SFC Separation Conditions: Instrument: SFC-150 (Waters); Column: AS 25 * 250 mm, 10 µm (Daicel); Column temperature: 35 ºC; Mobile phase: 65/35 CO₂/isopropanol [spiked with 0.2% 7M NH₃ in MeOH]; Flow rate: 100 mL/min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 5.7 min; Sample solution: 950 mg dissolved in 40 mL methanol; Injection volume: 3 mL. 3-[(4R)-6-chloro-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro- Step B: The title compound (absolute configuration assigned arbitrarily) was obtained following an ester hydrolysis procedure similar to the one in Step A, Example 54. MS (ESI): 628.2 (M+H)⁺, retention time of 1.67 min (Method 2A). 3-[(4R)-6-chloro-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 and 3-[(4R)-6-chloro-4- [2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4- yl]-4-methyl-chroman-8-yl]propanoic acid Step C: To a solution of 3-[(4R)-6-chloro-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]propanoic acid (1.00 eq, 386 mg, 0.615 mmol) in methanol (35 mL) was added ammonium heptamolybdate (0.509 eq, 386 mg, 0.313 mmol), and aqueous hydrogen peroxide (62.1 eq, 3.9 mL, 38.2 mmol). 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 (40 mL), extracted with ethyl acetate (40 mL), the organic phase was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to give 3- [(4R)-6-chloro-4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]- 1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid (94 mg, 0.146 mmol, 24 % yield) as a white solid and 3-[(4R)-6-chloro-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 (89 mg, 0.135 mmol, 22 % yield) as a white solid. The absolute and relative configurations of the products are unknown and have been assigned arbitrarily. 3-[(4R)-6-chloro-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 (Example 188): MS (ESI): 660.2 (M+H)⁺, retention time of 1.55 min (Method 2A).¹H NMR (400 MHz , CD₃OD) δ 7.57- 7.55 (m, 2H), 7.25-7.18 (m, 2H), 7.02-6.96 (m, 3H), 6.63 (s, 1H), 4.28-4.23 (m, 1H), 4.08-4.02 (m, 1H), 3.30 (s, 3H), 2.84 (t, J = 7.6 Hz, 2H), 2.55 (t, J = 7.6 Hz, 2H), 2.50-2.45 (m, 1H), 1.99-1.93 (m, 1H), 1.69 (s, 3H) ppm. 3-[(4R)-6-chloro-4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro- phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid: MS (ESI): 644.2 (M+H)⁺, retention time of 1.53 min (Method 2A). Example 189. Synthesis of 3-[(4R)-6-chloro-4-[2-[5-[[6,7-difluoro-4-[(S)- methylsulfinyl]-1H-indol-5-yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl- chroman-8-yl]propanoic acid Example 190. Synthesis of 3-[(4R)-6-chloro-4-[2-[5-[[6,7-difluoro-4-[(R)- methylsulfinyl]-1H-indol-5-yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl- chroman-8-yl]propanoic acid Example 189 and Example 190 were prepared via the separation of the mixture obtained in Step C, Example 188. 3-[(4R)-6-chloro-4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid (94 mg, 0.146 mmol) was separated by SFC to give 3-[(4R)-6-chloro-4-[2-[5-[[6,7-difluoro-4-[(S)- methylsulfinyl]-1H-indol-5-yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman- 8-yl]propanoic acid (Diastereomer 1, 33 mg, 0.0505 mmol, 35 % yield) and 3-[(4R)-6-chloro- 4-[2-[5-[[6,7-difluoro-4-[(R)-methylsulfinyl]-1H-indol-5-yl]oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid (Diastereomer 2, 40 mg, 0.0618 mmol, 42 % yield) as white solids. SFC Separation Conditions are identical to those in Step A, Example 188 except for the following changes: Mobile phase: 65/35 CO₂/methanol [spiked with 0.2% 7M NH₃ in MeOH]; Cycle time: 3 min; Sample solution: 90 mg dissolved in 30 mL methanol; Injection volume: 1 mL. Diastereomer 1: MS (ESI): 644.2 (M+H)⁺, retention time of 1.53 min (modified Method 2A - Flow Rate: 1.8mL/min); Chiral HPLC retention time: 1.72 min. Diastereomer 2: MS (ESI): 644.2 (M+H)⁺, retention time of 1.63 min (modified Method 2 - Flow Rate: 1.8mL/min); Chiral HPLC retention time: 2.11 min. Chiral HPLC Conditions: Column: IG 4.6 * 100 mm 5 µm; Co-Solvent: MeOH [0.2%NH₃ (7M in MeOH)]; Injection Volume: 5.00 µl; Run Time: 4.0 minutes; Flow rate: 3.0 mL/min; Detection wavelength: 214 nm; Back Pressure: 2000 psi; Column Temperature: 40 °C. Examples 190-193 were prepared in a similar manner to Examples 188-190 starting from ethyl 3-[(4S)-6-chloro-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, Example 188, absolute configuration assigned arbitrarily). Example 194. Synthesis of 3-[(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)oxy]phenyl]-1H-imidazol-4-yl]-2,2,4-trimethyl-chroman-8-yl]propanoic acid Example 195. Synthesis of 3-[(4S)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)oxy]phenyl]-1H-imidazol-4-yl]-2,2,4-trimethyl-chroman-8-yl]propanoic acid Enantiomers of ethyl 3-[4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1H- Step A: The racemic ethyl 3-[4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]- 1H-imidazol-4-yl]-2,2,4-trimethyl-chroman-8-yl]propanoate was assembled from Intermediate 39 and Intermediate 12 following a similar procedure to the one in Step A, Example 133. The racemic mixture (205 mg, 0.330 mmol) was separated by chiral HPLC to give ethyl 3-[(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1H-imidazol- 4-yl]-2,2,4-trimethyl-chroman-8-yl]propanoate (Stereoisomer 1, 85 mg, 0.137 mmol, 42 % yield) and ethyl 3-[(4S)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1H- imidazol-4-yl]-2,2,4-trimethyl-chroman-8-yl]propanoate (Stereoisomer 2, 80 mg, 0.129 mmol, 39 % yield). The absolute configurations of Stereoisomers 1 and 2 are unknown and have been assigned arbitrarily. MS (ESI): 622.4 (M+H)⁺, retention time of 1.92 min (modified Method 2 - Gradient: 5%-95% B in 2.5 min). 3-[(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]- 2,2,4-trimethyl-chroman-8-yl]propanoic acid and 3-[(4S)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro- Step B: The title compounds were prepared from Stereoisomer 1 and Stereoisomer 2 by an ester hydrolysis procedure similar to the one in Step A, Example 54. The absolute configuration of each product acid has been assigned arbitrarily. 3-[(4R)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]- 2,2,4-trimethyl-chroman-8-yl]propanoic acid: MS (ESI): 594.4 (M+H)⁺, retention time of 1.79 min (Method 4). ¹H NMR (400 MHz, CD₃OD) δ 7.51 (dd, J = 5.8, 3.2 Hz, 1H), 7.37 (d, J = 3.1 Hz, 1H), 7.27 (dd, J = 7.8, 1.4 Hz, 1H), 7.23-7.16 (m, 1H), 7.05 (d, J = 6.1 Hz, 1H), 6.98 (dt, J = 8.9, 3.5 Hz, 1H), 6.83 (t, J = 7.6 Hz, 1H), 6.62 (t, J = 3.1 Hz, 1H), 6.44 (s, 1H), 2.87 (t, J = 7.2 Hz, 2H), 2.66 (d, J = 14.1 Hz, 1H), 2.55 (t, J = 7.7 Hz, 2H), 1.93 (d, J = 14.0 Hz, 1H), 1.64 (s, 3H), 1.37 (s, 3H), 0.97 (s, 3H) ppm. 3-[(4S)-4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]- 2,2,4-trimethyl-chroman-8-yl]propanoic acid: MS (ESI): 594.4 (M+H)⁺, retention time of 1.79 min (Method 4). ¹H NMR (400 MHz, CD₃OD) δ 7.51 (dd, J = 5.9, 3.2 Hz, 1H), 7.37 (d, J = 3.1 Hz, 1H), 7.27 (dd, J = 7.8, 1.5 Hz, 1H), 7.20 (dd, J = 10.4, 9.2 Hz, 1H), 7.05 (dd, J = 7.4, 1.4 Hz, 1H), 6.98 (dt, J = 9.0, 3.5 Hz, 1H), 6.84 (d, J = 7.6 Hz, 1H), 6.62 (t, J = 3.1 Hz, 1H), 6.45 (s, 1H), 2.87 (t, J = 7.2 Hz, 2H), 2.66 (d, J = 14.1 Hz, 1H), 2.59-2.52 (m, 2H), 1.93 (d, J = 14.1 Hz, 1H), 1.64 (s, 3H), 1.37 (s, 3H), 0.97 (s, 3H) ppm. Example 196. Synthesis of N-[[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]methyl]-2,2- difluoro-ethanamine Example 197. Synthesis of N-[[4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]methyl]-2,2- difluoro-ethanamine Methyl 4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- i Step A: The title compound (3.00 g,5.18 mmol, 65 % yield) was obtained from Intermediate 17 and Intermediate 56 following a similar procedure to the one in Step A, Example 133. MS (ESI): 580.2 (M+H)⁺, retention time of 1.67 min (modified Method 2A - Flow Rate: 1.8 mL/min). [4-[2-[5-[(6,7-Difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol- 5-yl]-4-methyl-chroman-8-yl]methanol Step B: To a solution of methyl 4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2- fluoro-phenyl]-1H-imidazol-5-yl]-4-methyl-chromane-8-carboxylate (1.00 eq, 2.70 g, 4.66 mmol) in THF (27 mL) was added lithium aluminum hydride (1.10 eq, 194 mg, 5.12 mmol) at 0 °C. The mixture was stirred at 0 °C for 1 hour, quenched with water (100 mL) and extracted with ethyl acetate (50 mL x 3). The combined extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-43% ethyl acetate in petroleum ether to give [4- [2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-5- yl]-4-methyl-chroman-8-yl]methanol (490 mg, 0.888 mmol, 19 % yield) and recovered starting material (2 g). MS (ESI): 552.2 (M+H)⁺, retention time of 1.67 min (Method 2). 4-[2-[5-[(6,7-Difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-5- Step C: To a solution of [4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro- phenyl]-1H-imidazol-5-yl]-4-methyl-chroman-8-yl]methanol (1.00 eq, 100 mg, 0.181 mmol) in DMSO (1.5 mL) was added Dess-Martin periodinane (2.00 eq, 154 mg, 0.363 mmol) . The mixture was stirred at room temperature for 2 hours, diluted with water (50 mL), and extracted with ethyl acetate (30 mL x 3). The combined extracts were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to afford 4-[2-[5-[(6,7-difluoro- 4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-5-yl]-4-methyl- chromane-8-carbaldehyde (90 mg, 0.164 mmol, 90 % yield). MS (ESI): 550.0 (M+H)⁺, retention time of 1.92 min (Method 2). N-[[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- Step D: To a solution of 4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro- phenyl]-1H-imidazol-5-yl]-4-methyl-chromane-8-carbaldehyde (1.00 eq, 150 mg, 0.273 mmol) in DCE (4 mL) was added 2,2-difluoroethanamine (1.99 eq, 44 mg, 0.543 mmol) and acetic acid (1 drop). The mixture was stirred at room temperature for 1 hour, and sodium triacetoxyborohydride (2.01 eq, 116 mg, 0.547 mmol) was added. The mixture was stirred at room temperature for 16 hours, diluted with water (10 mL), and extracted with ethyl acetate (10 mL x 3). The combined extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-80% ethyl acetate in petroleum ether to give N-[[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]methyl]-2,2-difluoro-ethanamine (146 mg,0.238 mmol, 87.03 % yield) as a light yellow solid. MS (ESI): 615.2 (M+H)⁺, retention time of 1.45 min (Method 3). N-[[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]methyl]-2,2-difluoro-ethanamine and N-[[4-[2-[5- [(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4- Step E: To a solution of N-[[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]methyl]-2,2-difluoro-ethanamine (1.00 eq, 146 mg, 0.238 mmol) in methanol (15 mL) ) and was added ammonium molybdate tetrahydrate (0.497 eq, 146 mg, 0.118 mmol), and aqueous hydrogen peroxide (61.8 eq, 1.5 mL, 14.7 mmol). The reaction mixture was stirred at 0 ºC for 1 h, then at room temperature for 2 h. The mixture was poured into water (20 mL), extracted with ethyl acetate (3 x 20 mL), the organic layer was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by prep-HPLC to give N-[[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]methyl]-2,2-difluoro-ethanamine (11 mg, 0.0170 mmol, 7 % yield) as a white solid and N-[[4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]- 1H-imidazol-4-yl]-4-methyl-chroman-8-yl]methyl]-2,2-difluoro-ethanamine (1.1 mg,0.00174 mmol, 0.7 % yield) as a white solid. N-[[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]methyl]-2,2-difluoro-ethanamine: MS (ESI): 647.3 (M+H)⁺, retention time of 1.36 min (modified Method 2A - Flow Rate: 1.8mL/min).¹H NMR (400 MHz, MeOH‑d4) δ 7.57-7.53 (m, 2H), 7.25-7.17 (m, 3H), 7.12-7.10 (m, 1H), 6.99-6.95 (m, 1H), 6.84 (t, J = 7.6 Hz, 1H), 6.58 (s, 1H), 5.99-5.89 (m, 1H), 4.31-4.26 (m, 1H), 4.10-4.05 (m, 1H), 3.83 (s, 2H), 3.30 (s, 3H), 2.96 (td, J = 15.6, 4.0 Hz, 2H), 2.52-2.47 (m, 1H), 2.02- 1.96 (m, 1H), 1.71 (s, 3H) ppm. N-[[4-[2-[5-[(6,7-difluoro-4-methylsulfinyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-4-methyl-chroman-8-yl]methyl]-2,2-difluoro-ethanamine: MS (ESI): 631.2 (M+H)⁺, retention time of 1.35 min (modified Method 2A - Flow Rate: 1.8mL/min).¹H NMR (400 MHz, MeOH‑d4) δ 7.56-7.50 (m, 2H), 7.24-7.09 (m, 4H), 6.99-6.95 (m, 1H), 6.83 (t, J = 7.6 Hz, 1H), 6.59 (s, 1H), 5.99-5.89 (m, 1H), 4.30-4.25 (m, 1H), 4.10-4.04 (m, 1H), 3.82 (s, 2H), 3.00-2.89 (m, 5H), 2.51-2.46 (m, 1H), 2.02-1.97 (m, 1H), 1.71 (s, 3H) ppm. Example 198. Synthesis of 3-[4-[2-[5-[(6-fluoro-1H-pyrrolo[3,2-b]pyridin-5- yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid The title compound was prepared from 2-fluoro-5-[(6-fluoro-1H-pyrrolo[3,2-b]pyridin-5- yl)oxy]benzamidine (WO2023034992) and Intermediate 9 following a similar procedure to the one in Step A, Example 133. MS (ESI): 531.0 (M+H)⁺, retention time of 1.34 min (modified Method 4 - Flow Rate: 2.0 mL/min).¹H NMR (400 MHz, CD₃OD) δ 7.81-7.74 (m, 1H), 7.64- 7.58 (m, 1H), 7.52 (d, J = 3.3 Hz, 1H), 7.48-7.40 (m, 2H), 7.31 (s, 1H), 7.12-7.05 (m, 1H), 6.98-6.92 (m, 1H), 6.81 (t, J = 7.6 Hz, 1H), 6.44-6.36 (m, 1H), 4.38-4.27 (m, 1H), 4.25-4.14 (m, 1H), 2.89 (t, J = 7.6 Hz, 2H), 2.57 (t, J = 7.6 Hz, 2H), 2.49-2.37 (m, 1H), 2.16-2.07 (m, 1H), 1.82 (s, 3H) ppm. Example 199. Synthesis of 3-[4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indazol-5- yl)oxy]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid Ethyl 3-[4-[2-[2-fluoro-5-(4,6,7-trifluoro-1-tetrahydropyran-2-yl-indazol-5-yl)oxy-phenyl]- Step A: The title compound (83 mg,0.107 mmol, 39 % yield) was prepared from Intermediate 9 and Intermediate 57 following a similar procedure to the one in Step A, Example 133. MS (ESI): 679.3 (M+H)⁺, retention time of 1.75 min (modified Method 2A - Flow Rate: 1.8 mL/min). Ethyl 3-[4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indazol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]-4- methyl-chroman-8-yl]propanoate Step B: To a stirred solution of ethyl 3-[4-[2-[2-fluoro-5-(4,6,7-trifluoro-1-tetrahydropyran-2- yl-indazol-5-yl)oxy-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (1.00 eq, 83 mg, 0.122 mmol) in ethanol (2 mL) was added 4-methylbenzenesulfonic acid (1.20 eq, 25 mg, 0.147 mmol). The mixture was stirred at 60 ºC for 1 h. The mixture was added water (20 mL) and extracted with ethyl acetate (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over 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 ethyl 3-[4-[2-[2-fluoro-5-[(4,6,7-trifluoro-1H-indazol-5- yl)oxy]phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (20 mg, 0.0345 mmol, 28 % yield) as a white solid. MS (ESI): 595.3 (M+H)⁺, retention time of 1.62 min (modified Method 2A - Flow Rate: 1.8 mL/min). 3-[4-[2-[2-Fluoro-5-[(4,6,7-trifluoro-1H-indazol-5-yl)oxy]phenyl]-1H-imidazol-4-yl]-4- methyl-chroman-8-yl]propanoic acid Step C: The title compound (13 mg, 0.0222 mmol, 65 % yield) was obtained via a similar ester hydrolysis procedure to the one in Step A, Example 54. MS (ESI): 567.2 (M+H)⁺, retention time of 1.52 min (modified Method 2A - Flow Rate: 1.8 mL/min). ¹H NMR (500 MHz, CD₃OD) δ 7.50 (dd, J = 5.5, 3.0 Hz, 1H), 7.22 (dd, J = 10.5, 9.0 Hz, 1H), 7.06-7.00 (m, 3H), 6.77 (t, J = 7.5 Hz, 1H), 6.58 (s, 1H), 4.26 (ddd, J = 11.0, 6.0, 3.0 Hz, 1H), 4.08-4.02 (m, 1H), 2.87 (t, J = 8.0 Hz, 2H), 2.57-2.53 (m, 2H), 2.48 (ddd, J = 13.5, 6.0, 2.5 Hz, 1H), 2.00 (ddd, J = 13.5, 9.0, 3.0 Hz, 1H), 1.72 (s, 3H) ppm. Example 200. Synthesis of 5-[[4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1H-imidazol-5-yl]-4-methyl-chroman-8-yl]-hydroxy- methyl]imidazolidine-2,4-dione 5-[[4-[2-[5-[(6,7-Difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-5-yl]-4-methyl-chroman-8-yl]-hydroxy-methyl]imidazolidine-2,4-dione Step A: A mixture of 4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro- phenyl]-1H-imidazol-5-yl]-4-methyl-chromane-8-carbaldehyde (Step C, Example 197; 1.00 eq, 150 mg, 0.273 mmol), methanol (2 mL), water (0.5 mL), imidazolidine-2,4-dione (3.00 eq, 82 mg, 0.819 mmol) and trimethylamine (2M in THF, 5.00 eq, 0.68 mL, 1.36 mmol) was irradiated in a microwave reactor at 60 °C for 7 days. The mixture was diluted with water (50 mL), extracted with ethyl acetate (30 mL x 3), the combined extracts were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-43% ethyl acetate in petroleum ether to give 5-[[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro- phenyl]-1H-imidazol-5-yl]-4-methyl-chroman-8-yl]-hydroxy-methyl]imidazolidine-2,4-dione (Product 1, 15 mg, 0.0231 mmol, 9 % yield) and (5Z)-5-[[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]methylene]imidazolidine-2,4-dione (Product 2, 20 mg, 0.0317 mmol, 12 % yield). Product 1: MS (ESI): 650.1 (M+H)⁺, retention time of 1.60 min (Method 2). Product 2: MS (ESI): 632.2 (M+H)⁺, retention time of 1.77 min (Method 2). 5-[[4-[2-[5-[(6,7-Difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- Step B: To a solution of 5-[[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2- fluoro-phenyl]-1H-imidazol-5-yl]-4-methyl-chroman-8-yl]-hydroxy-methyl]imidazolidine- 2,4-dione (1.00 eq, 15 mg, 0.0231 mmol) in methanol (1.5 mL) was added a solution of ammonium molybdate tetrahydrate (0.300 eq, 8.6 mg, 0.00693 mmol) in hydrogen peroxide (30% in water, 0.15 mL) at room temperature. The reaction was stirred at room temperature for 2 h, diluted with water (50 mL), and extracted with ethyl acetate (30 mL x 3). The combined extracts were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC to give 5-[[4-[2-[5-[(6,7-difluoro-4- methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-5-yl]-4-methyl-chroman- 8-yl]-hydroxy-methyl]imidazolidine-2,4-dione (5.1 mg, 0.00748 mmol, 32 % yield). MS (ESI): 682.2 (M+H)⁺, retention time of 1.41 min (modified Method 2A - Flow Rate: 1.8 mL/min). Example 201. Synthesis of (5Z)-5-[[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]methylene]imidazolidine-2,4-dione The title compound (8.0 mg, 0.0121 mmol, 76 % yield) was prepared from Product 2 (Step A, Example 200) via the sulfide oxidation method of Step B, Example 200. MS (ESI): 664.2 (M+H)⁺, retention time of 1.58 min (modified Method 2 - Flow Rate: 1.8 mL/min). Example 202. Synthesis of 5-[[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]methyl]imidazolidine-2,4-dione A mixture of (5Z)-5-[[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]methylene]imidazolidine-2,4-dione (1.00 eq, 3.0 mg, 0.00452 mmol), ethanol (1 mL) and palladium on carbon (wet, 10 wt. %, 5.0 mg) was stirred under a hydrogen atmosphere for 4 hours at 50 °C. The catalyst was removed by filtration and the solids were washed with ethanol (20 mL). The combined filtrate was concentrated to give 5-[[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]methyl]imidazolidine-2,4-dione (2.0 mg, 0.00300 mmol, 67 % yield).666.2 (M+H)⁺, retention time of 1.46 min (Method 3). Example 203. Synthesis of 5-[[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]methyl]oxazolidin-2- one 5-[3-[4-(8-Allyl-4-methyl-chroman-4-yl)-1H-imidazol-2-yl]-4-fluoro-phenoxy]-6,7-difluoro- 4-methylsulfanyl-1H-indole Step A: A mixture of 2-allyl-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (896 mg, 5.33 mmol), 1,4-dioxane (20 mL), water (2 mL), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.100 eq, 218 mg, 0.266 mmol), 5-[3-[4-(8-bromo-4-methyl-chroman-4-yl)-1H-imidazol-2- yl]-4-fluoro-phenoxy]-6,7-difluoro-4-methylsulfanyl-1H-indole (1.00 eq, 1600 mg, 2.66 mmol) and Cs₂CO₃ (1737 mg, 5.33 mmol) was stirred overnight at 100 °C under an Ar atmosphere. The reaction mixture was cooled and extracted with ethyl acetate (20 mL x 2). The combined organic extracts were washed with brine (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 37-45% ethyl acetate in petroleum ether to give 5-[3-[4-(8-allyl-4- methyl-chroman-4-yl)-1H-imidazol-2-yl]-4-fluoro-phenoxy]-6,7-difluoro-4-methylsulfanyl- 1H-indole (1200 mg, 1.92 mmol, 79 % yield) as a white solid. MS (ESI): 562.2 (M+H)⁺, retention time of 1.87 min (modified Method 2 - Flow Rate: 1.8 mL/min). Benzyl N-[3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]- Step B: Osmium tetroxide (37 mg, 0.143 mmol) was added to a solution of benzyloxycarbonylamino 4-chlorobenzoate (0.98 g, 3.2 mmol) in acetonitrile (24 mL) and stirred at room temperature for 10 min.5-[3-[4-(8-allyl-4-methyl-chroman-4-yl)-1H-imidazol- 2-yl]-4-fluoro-phenoxy]-6,7-difluoro-4-methylsulfanyl-1H-indole (1.2 g, 2.14 mmol) was added as a solution in acetonitrile (24 mL) to the carbamate solution followed by the addition of water (5 mL), and the reaction was stirred at room temperature for 16 h. The reaction was quenched with saturated Na₂S₂O₃ (50 mL) and stirred for a further 5 min. The reaction mixture was diluted with water (150 mL) and extracted with ethyl acetate (2 x 80 mL). The organic extracts were combined and washed with saturated aqueous NaHCO₃ (30 mL) and brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with from 0% to 60% EA in PE to give benzyl N-[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]-2-hydroxy-propyl]carbamate (556 mg, 36 % yield) as a solid. MS (ESI): 729 (M+H)⁺, retention time of 1.77 min (modified Method 2 - Flow Rate: 1.8 mL/min). 5-[[4-[2-[5-[(6,7-Difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- i Step C: To a solution of benzyl N-[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]-2-hydroxy-propyl] carbamate (50 mg, 0.0686 mmol) in THF (5 mL) was added NaH (60% dispersion in oil, 9 mg, 0.2058 mmol) at RT. The mixture was stirred at RT overnight, quenched with saturated aqueous NH₄Cl (30 mL) and extracted with ethyl acetate (40 mL x 3). The combined extracts were washed with brine (30 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-70 % ethyl acetate in petroleum ether to give 5-[[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]methyl]oxazolidin-2-one (30 mg, 63 % yield) as a solid. MS (ESI): 621 (M+H)⁺, retention time of 1.79 min (modified Method 2 - Flow Rate: 1.8 mL/min). 5-[[4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- Step D: The title compound (16.1 mg, 51 %, a white solid) was prepared via a sulfide to sulfone oxidation procedure similar to the one in Step B, Example 200. MS (ESI): 653 (M+H)⁺, retention time of 1.54 min (modified Method 2 - Flow Rate: 1.8 mL/min).¹H NMR (500 MHz, CD₃OD) δ 7.57-7.56 (m, 1H), 7.54 (s, 1H), 7.25 (t, J = 3.0 Hz, 1H), 7.19 (dd, J = 10.5, 9.0 Hz, 1H), 7.11 (dd, J = 8.0, 1.5 Hz, 1H), 7.07-7.04 (m, 1H), 6.99-6.95 (m, 1H), 6.79 (t, J = 7.5 Hz, 1H), 6.57 (s, 1H), 4.96-4.91 (m, 1H), 4.28-4.22 (m, 1H), 4.08-4.02 (m, 1H), 3.55 (td, J = 8.5, 5.5 Hz, 1H), 3.36-3.33 (m, 1H), 3.30 (s, 3H), 3.10-3.04 (m, 1H), 2.96-2.90 (m, 1H), 2.51-2.45 (m, 1H), 2.01-1.94 (m, 1H), 1.71 (s, 3H) ppm. Example 204. Synthesis of 3-[4-[2-[5-[(6,7-difluoro-4-sulfamoyl-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-[(4-methoxyphenyl)methylsulfanyl]-1H-indol-5-yl]oxy]-2- Step A: The title compound (800 mg, 1.10 mmol, 63 % yield) was prepared from Intermediate 9 and Intermediate 58 following a similar procedure to that in Step A, Example 133. MS (ESI): 728.3 (M+H)⁺, retention time of 1.97 min (Method 5). Ethyl 3-[4-[2-[5-[(3-chloro-4-chlorosulfonyl-6,7-difluoro-1H-indol-5-yl)oxy]-2-fluoro- Step B: To a stirred and chilled (0 °C) solution of ethyl 3-[4-[2-[5-[[6,7-difluoro-4-[(4- methoxyphenyl)methylsulfanyl]-1H-indol-5-yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4- methyl-chroman-8-yl]propanoate (1.00 eq, 50 mg, 0.0687 mmol) in acetic acid (3 mL) and water (0.30 mL) was added N-chlorosuccinimide (4.00 eq, 37 mg, 0.275 mmol) in one portion. The mixture was stirred at 0 °C for 2 hours, diluted with ethyl acetate (30 mL), washed with water (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated to give ethyl 3-[4-[2-[5-[(3-chloro-4-chlorosulfonyl-6,7-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (40 mg, 0.0565 mmol, 82 % yield) as a gray oil. MS (ESI): 708.3 (M+H)⁺, retention time of 1.91 min (Method 5). Ethyl 3-[4-[2-[5-[(3-chloro-6,7-difluoro-4-sulfamoyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]- Step C: A mixture of ethyl 3-[4-[2-[5-[(3-chloro-4-chlorosulfonyl-6,7-difluoro-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (1.00 eq, 40 mg, 0.0565 mmol) and ammonia (46.1 eq, 2.0 mL, 2.60 mmol) in THF (5 mL) was stirred at rt for 4 hours. The solvent was removed in vacuo and the residue was purified by prep-HPLC to give ethyl 3-[4-[2-[5-[(3-chloro-6,7-difluoro-4-sulfamoyl-1H-indol-5-yl)oxy]-2-fluoro- phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (7.5 mg, 0.0109 mmol, 19 % yield) as a gray solid. MS (ESI): 688.8 (M+H)⁺, retention time of 2.01 min (Method 4). Ethyl 3-[4-[2-[5-[(6,7-difluoro-4-sulfamoyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate Step D: A suspension of ethyl 3-[4-[2-[5-[(3-chloro-6,7-difluoro-4-sulfamoyl-1H-indol-5- yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (1.00 eq, 7.5 mg, 0.0109 mmol) and palladium on carbon (4.32 eq, 5.0 mg, 0.0470 mmol) in methanol (2 mL) was stirred for 2 hours under hydrogen at ambient temperature and pressure. The mixture was filtered, the solids washed with methanol (3 x 5 mL) and the filtrate was concentrated to give ethyl 3-[4-[2-[5-[(6,7-difluoro-4-sulfamoyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (5.0 mg,0.00764 mmol, 70 % yield) as a gray solid. MS (ESI): 654.9 (M+H)⁺, retention time of 2.01 min (Method 4). 3-[4-[2-[5-[(6,7-Difluoro-4-sulfamoyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4- yl]-4-methyl-chroman-8-yl]propanoic acid Step E: To a solution of ethyl 3-[4-[2-[5-[(6,7-difluoro-4-sulfamoyl-1H-indol-5-yl)oxy]-2- fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoate (1.00 eq, 5.0 mg, 0.00764 mmol) in 1:1 water : THF (2 mL) was added lithium hydroxide monohydrate (5.00 eq, 1.6 mg, 0.0382 mmol). The reaction was stirred at room temperature for 4 hours. The mixture was acidified with 1M hydrochloric acid to pH ~ 5-6, 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 prep-HPLC to get the product 3-[4-[2-[5-[(6,7-difluoro-4-sulfamoyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid (3.2 mg,0.00511 mmol, 67 % yield) as white solid. MS (ESI): 627.3 (M+H)⁺, retention time of 1.44 min (Method 5). Example 205. Synthesis of 3-[4-[2-[5-[[6,7-difluoro-4-(methylsulfamoyl)-1H- indol-5-yl]oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-chroman-8-yl]propanoic acid The title compound was prepared similarly to Example 204 exchanging ammonia in Step C with methylamine. MS (ESI): 641.3 (M+H)⁺, retention time of 1.52 min (Method 2). Examples 206-209 were obtained from Intermediate 17 and Intermediate 59 by following the procedure for the preparation of Examples 188-193 (Step A-C) and omitting the sulfoxide diastereomer separation step (described specifically for Examples 189-190). The absolute and relative configurations of Examples 206-209 are unknown and were assigned arbitrarily. Example 210. Synthesis of 3-[4-[2-[5-[[4-[(1,1-dioxo-1,2-thiazolidin-2-yl)methyl]- 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 was prepared from Intermediate 9 and Intermediate 60 via a two step sequence analogous to Step A, Example 167 (imidazole ring formation) followed by Step D, Example 175 (ester hydrolysis). MS (ESI): 681.2 (M+H) ⁺, retention time of 1.51 min (modified Method 2A - Flow Rate: 1.8 mL/min). Example 211. Synthesis of (E)-2-[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]ethenesulfonamide (E)-2-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- Step A: A mixture of 5-[3-[4-(8-bromo-4-methyl-chroman-4-yl)-1H-imidazol-2-yl]-4-fluoro- phenoxy]-6,7-difluoro-4-methylsulfanyl-1H-indole (Step A, Example 181, 100 mg, 0.166 mmol), toluene (3 mL), ethenesulfonamide (27 mg, 0.25 mmol), bis(tri-tert- butylphosphine)palladium(0) (17 mg, 0.033 mmol) and triethylamine (168 mg, 1.66 mmol) was stirred at 100 °C for 5 hours. The reaction was cooled to rt and volatiles were removed under reduced pressure. The mixture was extracted with ethyl acetate (30 mL). The organic extract was washed with brine (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-65% ethyl acetate in petroleum ether to give (E)-2-[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]ethenesulfonamide (56 mg, 54 % yield) as a solid. MS (ESI): 627.0 (M+H) ⁺, retention time of 1.72 min (Method 2A). (E)-2-[4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- Step B: To a solution of (E)-2-[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]ethenesulfonamide (100 mg, 0.159 mmol) in MeOH (3 mL) was added a mixture of 100 mg ammonium molybdate heptahydrate in 0.5 mL of aqueous hydrogen peroxide (30 wt. %) at room temperature. The reaction mixture was stirred at room temperature for 1 h, diluted with ethyl acetate (30 mL), washed with water (3 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-70% ethyl acetate in petroleum ether to give (E)-2-[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]ethenesulfonamide (65 mg, 62 % yield) as a solid. MS (ESI): 659.2 (M+H) ⁺, retention time of 1.51 min (Method 2A). Example 212. Synthesis of 2-[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]ethanesulfonamide A mixture of (E)-2-[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]ethenesulfonamide (Example 211, 50 mg, 0.076 mmol), toluene (3 mL) and p-toluenesulfonyl hydrazide (141 mg, 0.76 mmol) was stirred for 2 hours at 110 °C, cooled to rt and concentrated. The residue was suspended in 1M hydrochloric acid (15 mL), extracted with ethyl acetate (30 mL), washed with brine (30 mL×2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC to give 2-[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]ethanesulfonamide (2 mg, 44 % yield) as a solid. MS (ESI): 661.3 (M+H) ⁺, retention time of 1.51 min (Method 2A). Example 213. Synthesis of 6,7-difluoro-5-[4-fluoro-3-[4-[4-methyl-8-[(E)-2- methylsulfonylvinyl]chroman-4-yl]-1H-imidazol-2-yl]phenoxy]-4-methylsulfonyl-1H- indole Example 214. Synthesis of (E)-6,7-difluoro-5-(4-fluoro-3-(4-(4-methyl-8-(2- (methylsulfonyl)vinyl)chroman-4-yl)-1H-imidazol-2-yl)phenoxy)-4-(methylsulfinyl)-1H- indole 6,7-Difluoro-5-[4-fluoro-3-[4-[4-methyl-8-[(E)-2-methylsulfonylvinyl]chroman-4-yl]-1H- Step A: A mixture of 5-[3-[4-(8-bromo-4-methyl-chroman-4-yl)-1H-imidazol-2-yl]-4-fluoro- phenoxy]-6,7-difluoro-4-methylsulfanyl-1H-indole (1.00 eq, 200 mg, 0.333 mmol), toluene (4 mL), 1-methylsulfonylethylene (1.02 eq, 36 mg, 0.339 mmol), bis(tri-tert- butylphosphine)palladium(0) (0.200 eq, 34 mg, 0.0666 mmol) and TEA (10.0 eq, 0.46 mL, 3.33 mmol) was stirred at 100 °C for 4 hours. The mixture was cooled to rt, concentrated in vacuo. The residue was dissolved in ethyl acetate (10 mL), washed with brine (10 mL × 2), dried over anhydrous sodium 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 give 6,7-difluoro-5-[4-fluoro-3-[4-[4-methyl-8-[(E)-2-methylsulfonylvinyl]chroman-4-yl]- 1H-imidazol-2-yl]phenoxy]-4-methylsulfanyl-1H-indole (92 mg, 0.147 mmol, 44 % yield) as a solid. MS (ESI): 626.1 (M+H) ⁺, retention time of 1.95 min (modified Method 2 - Gradient: 5%-95% B in 2.5 min). 6,7-difluoro-5-[4-fluoro-3-[4-[4-methyl-8-[(E)-2-methylsulfonylvinyl]chroman-4-yl]-1H- imidazol-2-yl]phenoxy]-4-methylsulfonyl-1H-indole and (E)-6,7-difluoro-5-(4-fluoro-3-(4-(4- methyl-8-(2-(methylsulfonyl)vinyl)chroman-4-yl)-1H-imidazol-2-yl)phenoxy)-4- (methylsulfinyl)-1H-indole Step B: To a solution of 6,7-difluoro-5-[4-fluoro-3-[4-[4-methyl-8-[(E)-2- methylsulfonylvinyl]chroman-4-yl]-1H-imidazol-2-yl]phenoxy]-4-methylsulfanyl-1H-indole (1.00 eq, 92 mg, 0.147 mmol) in methanol (10 mL) was added ammonium molybdate tetrahydrate (0.506 eq, 92 mg, 0.0744 mmol) and aqueous hydrogen peroxide (30 wt. %, 1.0 mL, 9.79 mmol). The reaction mixture was stirred at 0 ºC for 0.5 h, then at room temperature for 2 h. The mixture was poured into water (10 mL), extracted with ethyl acetate (3 x 10 mL). The organic extracts were washed with brine (20 mL) and concentrated to give 280 mg of residue. This residue was purified by prep-HPLC to give 6,7-difluoro-5-[4-fluoro-3-[4-[4- methyl-8-[(E)-2-methylsulfonylvinyl] chroman-4-yl]-1H-imidazol-2-yl]phenoxy]-4- methylsulfonyl-1H-indole (Product 1, 45.8 mg,0.0669 mmol, 47 % yield) and 6,7-difluoro-5- [4-fluoro-3-[4-[4-methyl-8-[(E)-2-methylsulfonylvinyl]chroman-4-yl]-1H-imidazol-2- yl]phenoxy]-4-methylsulfinyl-1H-indole (Product 2, 15.5 mg, 0.0218 mmol, 16 % yield) as a white solid. MS (ESI): 658.1 (M+H) ⁺, retention time of 1.95 min (modified Method 2 - Gradient: 5%-95% B in 2.5 min). Product 1 (Example 213): MS (ESI): 658.1 (M+H) ⁺, retention time of 1.54 min (modified Method 2A - Flow Rate: 1.8 mL/min). ¹H NMR (400 MHz, CD₃OD) δ 7.78 (d, J = 15.6 Hz, 1H), 7.57-7.54 (m, 2H), 7.45-7.43 (m, 1H), 7.32-7.17 (m, 4H), 7.00-6.89 (m, 2H), 6.62 (s, 1H), 4.39-4.34 (m, 1H), 4.17-4.13 (m, 1H), 3.31 (s, 3H), 3.04 (s, 3H), 2.56-2.51 (m, 1H), 2.03-1.98 (m, 1H), 1.73 (s, 3H) ppm. Product 2 (Example 214): MS (ESI): 642.2 (M+H) ⁺, retention time of 1.51 min (modified Method 2A - Flow Rate: 1.8mL/min). ¹H NMR (400 MHz, CD₃OD) δ 7.78 (d, J = 15.6 Hz, 1H), 7.56-7.43 (m, 3H), 7.31-7.20 (m, 4H), 7.00-6.89 (m, 2H), 6.64 (s, 1H), 4.39-4.34 (m, 1H), 4.18-4.13 (m, 1H), 3.05 (s, 3H), 2.99 (d, J = 6.4 Hz, 3H), 2.54-2.50 (m, 1H), 2.03-1.98 (m, 1H), 1.73 (s, 3H) ppm. Example 215. Synthesis of 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-isochroman-8-yl]propanoic acid Example 216. Synthesis of 3-[(4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-isochroman-8-yl]propanoic acid Ethyl 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- i Step A: The title compound was prepared from Intermediate 17 and Intermediate 61 in substantially the same way as the product of Step A, Example 128. MS (ESI): 622 (M+H) ⁺, retention time of 1.70 min (modified Method 2A - Flow Rate: 1.8 mL/min). Enantiomers of 3-[4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro- Step B: The product ester from Step A was hydrolyzed following the procedure from Step D, Example 175. The resulting racemic mixture (125 mg, 0.211 mmol) was separated via SFC into 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]- 1H-imidazol-4-yl]-4-methyl-isochroman-8-yl]propanoic acid (Stereoisomer 1, 31 mg, 0.0522 mmol, 25 % yield) and 3-[(4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2- fluoro-phenyl]-1H-imidazol-4-yl]-4-methyl-isochroman-8-yl]propanoic acid (Stereoisomer 2, 30 mg, 0.0505 mmol, 24 % yield) as white solids. The absolute configurations of Stereoisomer 1 and Stereoisomer 2 are unknown and were assigned arbitrarily. MS (ESI): 594 (M+H) ⁺, retention time of 1.57 min (modified Method 2A - Flow Rate: 1.8 mL/min) observed for both stereoisomers. SFC Separation Conditions: Instrument: SFC-150 (Waters); Column: IG 25 * 250 mm, 10 µm (Daicel); Column temperature: 35 ºC; Mobile phase: 60/40 CO₂/MeOH [spiked with 0.2% 7M NH₃ in MeOH; Flow rate: 100 mL/min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 4.5 min; Sample solution: 150 mg dissolved in 18 mL MeOH-DCM; Injection volume: 1 mL. 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-4-methyl-isochroman-8-yl]propanoic acid (Stereoisomer 1, Example 215): Chiral HPLC retention time – 2.11 min. 3-[(4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-4-methyl-isochroman-8-yl]propanoic acid (Stereoisomer 2, Example 216): Chiral HPLC retention time – 2.73 min. Chiral HPLC Conditions: Column: IG 4.6 * 100 mm 5 µm; Co-solvent: MeOH [spiked with 0.2% 7M NH₃ in MeOH]; Injection Volume: 5.00 µl; Detection Wavelength: 214 nm; Run Time: 5.0 min; Flow rate: 3.0 mL/min; Back pressure: 2000 psi; Column temperature: 40 °C. Example 217. 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-isochroman-8-yl]propanoic acid Example 218. 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-isochroman-8-yl]propanoic acid Example 217 and Example 218 were prepared from Example 215 and Example 216, respectively, following a similar sulfide to sulfone oxidation procedure to the one described in Step D, Example 180/181. 3-[(4R)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-4-methyl-isochroman-8-yl]propanoic acid (Example 217): MS (ESI): 626.2 (M+H)⁺, retention time of 1.44 min (modified Method 2A - Flow Rate: 1.8 mL/min).¹H NMR (400 MHz, CD₃OD) δ 7.56 (d, J = 3.2 Hz, 1H), 7.50 (dd, J = 6.0, 3.2 Hz, 1H), 7.24 (t, J = 3.2 Hz, 1H), 7.22-7.15 (m, 1H), 7.13-7.02 (m, 2H), 6.97 (t, J = 7.2 Hz, 2H), 6.91 (s, 1H), 4.93 (s, 2H), 4.18 (d, J = 12.0 Hz, 1H), 3.71 (d, J = 12.0 Hz, 1H), 3.29 (s, 3H), 2.80 (t, J = 7.6 Hz, 2H), 2.57 (t, J = 7.6 Hz, 2H), 1.65 (s, 3H) ppm. 3-[(4S)-4-[2-[5-[(6,7-difluoro-4-methylsulfonyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]-1H- imidazol-4-yl]-4-methyl-isochroman-8-yl]propanoic acid (Example 218): MS (ESI): 626.2 (M+H)⁺, retention time of 1.44 min (modified Method 2A - Flow Rate: 1.8 mL/min).¹H NMR (500 MHz, CD₃OD) δ 7.56 (d, J = 3.2 Hz, 1H), 7.50 (dd, J = 6.0, 3.2 Hz, 1H), 7.23 (t, J = 3.2 Hz, 1H), 7.22-7.15 (m, 1H), 7.10 (t, J = 7.6 Hz, 1H), 7.04 (d, J = 6.8 Hz, 1H), 7.00-6.94 (m, 2H), 6.92 (s, 1H), 4.92 (s, 2H), 4.18 (d, J = 12.0 Hz, 1H), 3.71 (d, J = 12.0 Hz, 1H), 3.29 (s, 3H), 2.80 (t, J = 7.6 Hz, 2H), 2.57 (t, J = 7.6 Hz, 2H), 1.65 (s, 3H) ppm. Preparation of Intermediates Intermediate 1 2-Fluoro-5-((6-fluoro-4-methyl-1H-indol-5-yl)oxy)benzimidamide [226] A solution of 2-fluoro-5-((6-fluoro-4-methyl-1H-indol-5-yl)oxy)benzonitrile (Intermediate 1D) (600 mg, 2.1 mmol) and LiHMDS (1M in THF) (8.4 mL, 8.4 mmol) in THF (12 mL) was stirred at room temperature overnight. The reaction was quenched by addition of water (15 mL). The resulting mixture was extracted with a mixture of EtOAc and THF (1:1). The organic phase was dried over anhydrous Na₂SO₄ and concentrated in vacuo to give the title compound (635 mg, crude) as brown solid. This crude product was used directly in the next reaction step without further purification. MS (ESI): 302.1 m/z (M+H)⁺. Intermediate 1A 1,2-Difluoro-3,4-dimethyl-5-nitrobenzene [227] A mixture of 3-bromo-1,2-difluoro-4-methyl-5-nitrobenzene (10 g, 40 mmol), MeB(OH)₂ (12 g, 200 mmol), Pd(dppf)Cl₂ (2.9 mg, 4.0 mmol) and NaHCO₃ (10 g, 120 mmol) in 1,4-dioxane (160 mL) and H₂O (40 mL) was stirred under a N2 atmosphere at 80 °C for 3 days. The mixture was filtered, and ethyl acetate (300 mL) was added to the filtrate. The organic phase was washed with H₂O (100 mL x 2), brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. This residue was purified by silica gel column chromatography (eluting with 12:1 petroleum ether : ethyl acetate) to afford 1,2- difluoro-3,4-dimethyl-5-nitrobenzene (6.4 g, 85%) as a light-yellow oil.¹H NMR (400 MHz, CDCl₃) d 7.59 (t, J = 8.4 Hz, 1H), 2.42 (s, 3H), 2.32 (d, J = 2.4 Hz, 3H) ppm. Intermediate 1B 2-(3-Bromo-4-fluorophenoxy)-1-fluoro-3,4-dimethyl-5-nitrobenzene [228] To a solution of 1,2-difluoro-3,4-dimethyl-5-nitrobenzene (14 g, 74.9 mmol) in DMF (100 mL) was added 3-bromo-4-fluorophenol (14.9 g, 32.5 mmol) and K₂CO₃ (20.7 g, 149.7 mmol), and the resulting mixture was stirred at 100 °C for 2 hours. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (250 mL). The organic layer was washed with water (100 mL x 2), brine (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with 100/1 petroleum ether/ethyl acetate) to afford 2-(3-bromo-4- fluorophenoxy)-1-fluoro-3,4-dimethyl-5-nitrobenzene (22 g, 83%) as a pale solid. ¹H NMR (400 MHz, CDCl₃) δ 7.57 (d, J = 9.2 Hz, 1H), 7.10-7.00 (m, 2H), 6.82-6.75 (m, 1H), 2.44 (s, 3H), 2.26 (s, 3H) ppm. Intermediate 1C 5-(3-Bromo-4-fluorophenoxy)-6-fluoro-4-methyl-1H-indole [229] A mixture of 2-(3-bromo-4-fluorophenoxy)-1-fluoro-3,4-dimethyl-5-nitrobenzene (10.0 g, 28.0 mmol), DMF-DMA (16.7 g, 140.1 mmol) and pyrrolidine (4.00 g, 56.0 mmol) was stirred at 100 °C for 2 hours. The resulting mixture was concentrated in vacuo. The residue was dissovled in a mixture of acetic acid (100 mL) and toluene (60 mL), and to the solution was added Fe powder (7.84 g, 140.1 mmol). The reaction mixture was stirred at 100 °C overnight, and then cooled to room temperature, filtered through a pad of Celite and the filter cake washed with ethyl acetate (100 mL x 3). The combined organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with 15/1 petroleum ether/ ethyl acetate) to afford 5-(3-bromo-4-fluorophenoxy)-6-fluoro-4-methyl-1H-indole (6.0 g, 64%) as a green solid.¹H NMR (400 MHz, CDCl³) d 8.29 (s, 1H), 7.30-7.23 (m, 1H), 7.08 (d, J = 10.0 Hz, 1H), 7.04-6.99 (m, 2H), 6.84-6.77 (m, 1H), 6.57 (s, 1H), 2.39 (s, 3H) ppm. Intermediate 1D 2-Fluoro-5-((6-fluoro-4-methyl-1H-indol-5-yl)oxy)benzonitrile [230] A mixture of 5-(3-bromo-4-fluorophenoxy)-6-fluoro-4-methyl-1H-indole (6.0 g, 17.8 mmol), Zn(CN)₂ (3.10 mg, 26.7 mmol), Pd(dppf)Cl₂ (1.45 g, 1.78 mmol) and Zn (114 mg, 1.78 mmol) in DMF (25 mL) was heated at 150 °C for 45 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, filtered through a pad of Celite and the filter cake was washed with ethyl acetate (80 mL x 3). The combined organic phase was washed with water (80 mL x 2), brine (150 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with petroleum 6/1 ether/ ethyl acetate) to afford 2-fluoro-5-((6-fluoro-4-methyl-1H-indol-5- yl)oxy)benzonitrile (4.2 g, 83%) as a yellow solid. MS (ESI): 285.1 m/z (M+H)⁺. ¹H NMR (400 MHz, CDCl₃) d 8.28 (s, 1H), 7.27 (s, 1H), 7.20-7.07 (m, 3H), 6.98 (dd, J = 4.8 Hz & 2.8 Hz, 1H), 6.58 (s, 1H), 2.39 (s, 3H) ppm. Intermediate 2 5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2-fluorobenzimidamide [231] To a solution of 5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-benzonitrile (Intermediate 2E) (440 mg, 1.53 mmol) in THF (10 mL) was added the solution of lithium bis(trimethylsilyl)amide (6.12 mL, 1 M in THF) at 0 °C. The resulting mixture was stirred at 25 °C overnight. The reaction was quenched with water (0.2 mL) and diluted with ethyl acetate (30 mL). The mixture was washed with brine (10 mL X 2), dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo to give the crude title compound (500 mg), which was used directly in the next step. MS (ESI): 306 m/z (M+H)⁺. 5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2-fluorobenzimidamide [232] Alternative procedure: To a solution of 5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro- benzonitrile (0.5 g, 1.73 mmol) in THF (14 mL) was added dropwise lithium bis(trimethylsilyl)amide (13.9 mL, 13.9 mmol). The mixture was stirred at room temperature for 1 hour. Water (50 mL) was added, and the resulting mixture extracted with EtOAc (50 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 0-50% 2M NH₃- MeOH in DCM, to give 5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-benzamidine (0.45 g, 85%) as a solid. MS (ESI): 306 m/z (M+H)⁺. Intermediate 2A 5-(2,6-Difluoro-4-nitrophenoxy)-2-fluorobenzonitrile [233] To a solution of 1,2,3-trifluoro-5-nitrobenzene (45 g, 0.254 mol) and 2-fluoro-5- hydroxybenzonitrile (38.3 g, 0.28 mol) in DMF (200 mL) was added K₂CO₃ (70 g, 0.5 mol). The resulting mixture was heated for 2 hours at 100 °C. To the cooled reaction was added water (1500 mL), and the mixture extracted with EtOAc (1000 mL x 2). The combined organic phase was washed with^brine (500 mL x 3), dried over anhydrous Na₂SO₄, filtered, and concentrated under reduced pressure to afford the desired product, 5-(2,6-difluoro-4- nitrophenoxy)-2-fluorobenzonitrile (74 g, 99%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ 8.03-7.98 (m, 2H), 7.28-7.23 (m, 2H), 7.21-7.19 (m, 1H) ppm. Intermediate 2B 5-(4-Amino-2,6-difluorophenoxy)-2-fluorobenzonitrile [234] To a suspension of 5-(2,6-difluoro-4-nitrophenoxy)-2-fluorobenzonitrile (37 g, 126 mmol) in EtOH (450 mL) was added iron power (28.1 g, 543 mmol) and a solution of NH₄Cl (53.8 g, 1.01 mol) in water (150 mL). The resulting mixture was heated to reflux for 4 hours. The reaction mixture was filtered through a pad of Celite, and the filtrate was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (1 L). The organic phase was washed with water (200 mL x 3), brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo to afford the desired product, 5-(4-amino-2,6-difluorophenoxy)-2- fluorobenzonitrile (33.2 g, quantitative yield) as a yellow solid. ¹H NMR (500 MHz, CDCl₃) δ 7.23-7.20 (m, 1H), 7.14 (t, J = 8.5 Hz, 1H), 7.08 (dd, J = 5.0, 3.5 Hz, 1H), 6.33-6.28 (m, 2H), 3.90 (br, 2H) ppm. Intermediate 2C 5-(4-Amino-2,6-difluoro-3-iodophenoxy)-2-fluorobenzonitrile [235] A solution of 5-(4-amino-2,6-difluorophenoxy)-2-fluorobenzonitrile (33.2 g, 126 mmol) and N-iodosuccinimide (31.1 g, 126 mmol) in AcOH (250 mL) was stirred at room temperature for 1 hour. The solution was concentrated under reduced pressure. The residue was suspended in saturated aqueous NaHCO₃ (500 mL), and extracted with ethyl acetate (500 mL x 3). The organic phase was washed with brine (200 mL x 3), dried over anhydrous Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography (eluting with 4/1 petroleum ether/ethyl acetate) to afford the desired product, 5-(4-amino-2,6-difluoro-3-iodophenoxy)-2-fluorobenzonitrile (45.5 g, 92%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ 7.63 (dd, J = 5.0, 3.5 Hz, 1H), 7.49 (t, J = 9.0 Hz, 1H), 7.39- 7.36 (m, 1H), 6.63 (dd, J = 13, 2.0 Hz, 1H), 5.88 (br s, 2H) ppm. Intermediate 2D 5-[4-Amino-2,6-difluoro-3-(2-trimethylsilylethynyl)phenoxy]-2-fluorobenzonitrile [236] To a solution of 5-(4-amino-2,6-difluoro-3-iodophenoxy)-2-fluorobenzonitrile (61 g, 156 mmol) in DMF (300 mL) was added Pd(dppf)Cl₂ (3.43 g, 4.7 mmol), CuI (2.98 g, 15.6 mmol) and Et₃N (23.7 g, 235 mmol), followed by the addition of ethynyl(trimethyl)silane (28 mL, 187 mmol). The resulting mixture was stirred at ambient temperature overnight under a nitrogen atmosphere. The reaction was quenched with water (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic phase was washed with brine (150 mL x 3), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with 1/3/3 petroleum ether/EtOAc/DCM) to afford the desired product, 5-[4-amino-2,6-difluoro-3-(2-trimethylsilylethynyl)phenoxy]-2- fluorobenzonitrile (42 g, 74.5%) as a yellow solid. MS (ESI): 361 m/z (M+H)⁺. Intermediate 2E 5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2-fluorobenzonitrile [237] A mixture of 5-[4-amino-2,6-difluoro-3-(2-trimethylsilylethynyl)phenoxy]-2-fluoro- benzonitrile (Intermediate 2D) (28.0 g, 77.7 mmol) and CuI (29.6 g, 155 mmol) in DMF (250 mL) was flushed with argon for 2 min and heated for 5 hours at 100 °C under argon. The insoluble materials were removed by suction filtration and the filtrate was diluted with ethyl acetate (1500 mL). The organic phase was washed with brine (300 mL x 5), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography (eluting with 4/1 petroleum ether/ethyl acetate) to afford the desired product, 5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluorobenzonitrile (18 g, 80%) as a yellow solid. ¹H NMR (500 MHz, DMSO-d₆) δ 11.64 (br, 1H), 7.62 (dd, J = 5.0, 3.5 Hz, 1H), 7.51-7.47 (m, 2H), 7.39-7.36 (m, 1H), 7.32 (d, J = 10.0 Hz, 1H), 6.58 (t, J = 2.0 Hz, 1H) ppm. Intermediate 3 5-((4,6-Difluoro-1H-indol-5-yl)oxy)-2-fluorobenzoic acid [238] A solution of Intermediate 2E (500 mg, 1.74 mmol) in 3M aqueous NaOH (4.4 mL, 13.2 mmol) was stirred at 90 °C overnight. The reaction mixture was cooled, and the pH adjusted to ~2 with 3M aqueous HCl. The reaction mixture was diluted with EtOAc, washed with water and brine, dried over Na₂SO₄, filtered and concentrated. The residue was purified by silica gel column chromatography, eluting with 0-10% MeOH in DCM, to give the title compound (512 mg, 96%) as a yellow solid. MS (ESI): 308.1 m/z (M+H)⁺. Intermediate 4 2-Fluoro-5-((6-fluoro-4-((methylsulfonyl)methyl)-1H-indol-5-yl)oxy)benzoic acid [239] To a solution of potassium hydroxide (5.90 g, 105 mmol) in ethanol (30 mL) and water (15 mL) was added 2-fluoro-5-((6-fluoro-4-((methylsulfonyl)methyl)-1-(phenylsulfonyl)-1H- indol-5-yl)oxy) benzonitrile (Intermediate 4C, 3.52 g, 7 mmol). The reaction was stirred at 100 °C for 2.5 hours. The mixture was cooled to room temperature and diluted with water (100 mL), the pH was adjusted to 4-5 with 1 M aqueous HCl. The mixture was extracted with ethyl acetate (50 mL x 3). The combined organic layer was washed with brine (50 mL x 2), dried over sodium sulfate, filtered, and concentrated. The residue was suspended in a 5:1 mixture of petroleum ether:ethyl acetate (10 mL), stirred for 30 min, then filtered. The filtrate was dried over sodium sulfate and concentrated under reduced pressure to give 2-fluoro-5-((6-fluoro-4- ((methylsulfonyl)methyl)-1H-indol-5-yl)oxy)benzoic acid (2.695 g, 90 %) as pink solid. MS (ESI): 382 m/z (M+H)⁺. Intermediate 4A 5-((1-((4-Phenyl)sulfonyl)-6-fluoro-4-methyl-1H-indol-5-yl)oxy)-2-fluorobenzonitrile [240] To a solution of 2-fluoro-5-((6-fluoro-4-methyl-1H-indol-5-yl)oxy)benzonitrile (Intermediate 1D, 12 g, 42 mmol) in dry THF (120 ml) at 0 °C was added NaH (1.5 g, 63 mmol) slowly. After 0.5 hours, benzenesulfonyl chloride (9.6 g,54.3 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction was quenched with an ice-water mixture (100 ml). The water layer was extracted with ethyl acetate (100 ml x 3). The combined extracts were washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by silica gel column chromatography (eluting with 4/1 petroleum ether/ethyl acetate) to give 2-fluoro-5-((6-fluoro-4-methyl-1-(phenylsulfonyl)-1H- indol-5-yl)oxy)benzonitrile (15 g, 84%) as a white solid. MS (ESI): 425.2 m/z (M+H)⁺. Intermediate 4B 5-((4-(Bromomethyl)-1-((4-phenyl)sulfonyl)-6-fluoro-1H-indol-5-yl)oxy)-2- fluorobenzonitrile [241] To a stirred solution of 2-fluoro-5-((6-fluoro-4-methyl-1-(phenylsulfonyl)-1H-indol-5- yl)oxy)benzonitrile (8 g, 18.8 mmol) in dry CCl4 (650 ml) were added NBS (3.7 g, 20.7 mmol) and AIBN (0.92 g, 5.6 mmol) at room temperature . The reaction mixture was stirred at 80 °C for 5 hours, quenched with a saturated aqueous K₂CO₃ solution (200 ml), and extracted with ethyl acetate (100 ml x 3). The combined organic layer was washed with brine, dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was washed with cold diethyl ether (50 mL) and filtered. The filter cake was dried under vacuum to give 5-((4-(bromomethyl)-6- fluoro-1-(phenylsulfonyl)-1H-indol-5-yl)oxy)-2-fluorobenzonitrile (6.4 g, 68%) as a brown solid. ¹H NMR (400 MHz, CDCl₃) δ 7.94 (d, J = 7.6 Hz, 2H), 7.86 (d, J = 10.4 Hz, 1H), 7.72 (d, J = 3.6 Hz, 1H), 7.64 (m, 1H), 7.55 (m, 2H), 7.19-7.16 (m, 1H), 7.13 (m, 1H), 7.08-7.04 (m, 1H), 6.82 (d, J = 3.6 Hz, 1H), 4.64 (s, 2H) ppm. Intermediate 4C 5-((1-((4-Phenyl)sulfonyl)-6-fluoro-4-((methylsulfonyl)methyl)-1H-indol-5-yl)oxy)-2- fluorobenzonitrile [242] A mixture of 5-((4-(bromomethyl)-6-fluoro-1-(phenylsulfonyl)-1H-indol-5-yl)oxy)-2- fluorobenzonitrile (0.502 g, 1.0 mmol) and methanesulfinic acid, sodium salt (0.51 g, 5.0 mmol) in DMF (5 mL) was stirred at room temperature overnight. The mixture was quenched with water (10 mL), extracted with ethyl acetate (10 mL x 3). The combined organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel column, eluting with 6/1-3/1 petroleum ether/ethyl acetate, to afford 2-fluoro-5-((6-fluoro-4- ((methylsulfonyl)methyl)-1-(phenylsulfonyl)-1H-indol-5-yl)oxy)benzonitrile (0.4 g, 80%) as a yellow oil. MS (ESI): 524.5 m/z (M+Na)⁺. Intermediate 5 6-Fluoro-5-(4-fluoro-3-iodophenoxy)-4-(methylthio)-1-tosyl-1H-indole [243] To a stirred solution of 2-fluoro-5-[6-fluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol- 5-yl]oxy-aniline (Intermediate 5E, 9 g, 19.5 mmol) in acetonitrile (100 mL) and water (20 mL) was added tert-butyl nitrite (10.1 g, 98 mmol) and KI (16.2 g, 98 mmol). The mixture was heated and stirred at 50 °C for 2 hours. After cooling to room temperature, water (400 mL) was added, and the mixture was extracted with EtOAc (200 mL x 3). The combined organic phase was washed with saturated aqueous NaHSO3 solution (100 mL), brine (200 mL), dried over Na₂SO₄, filtered, and concentrated. The crude material was purified by flash column chromatography on silica gel, eluting with 0-30% ethyl acetate in petroleum ether, to give the desired product as an oil (7 g, 63%). MS (ESI): 571.8 m/z (M+H)⁺. Intermediate 5A 5-(2-Bromo-6-fluoro-3-methyl-4-nitrophenoxy)-2-fluoroaniline [244] To a suspension of 3-bromo-1,2-difluoro-4-methyl-5-nitro-benzene (47 g, 186 mmol) and K₂CO₃ (51.6 g, 373 mmol) in DMF (500 mL) was added 3-amino-4-fluoro-phenol (23.7 g, 186 mmol), and the mixture was stirred at 100 °C for 1 hour. The mixture was quenched with saturated aqueous NH₄Cl and then extracted with ethyl acetate (300 mL x 3). The combined organic phase was washed with H₂O (200 mL x 2), brine (200 mL x 2), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel, eluting with 2/1/1 petroleum ether/ethyl acetate/dichloromethane, to give 5-(2-bromo-6-fluoro-3-methyl-4-nitro-phenoxy)-2-fluoro- aniline (65 g, 97%) as a yellow oil. MS (ESI): 359 m/z (M+H)⁺. Intermediate 5B N-(5-(2-Bromo-3-(2-(dimethylamino)vinyl)-6-fluoro-4-nitrophenoxy)-2- fluorophenyl)formamide [245] To a stirred solution of 5-(2-bromo-6-fluoro-3-methyl-4-nitro-phenoxy)-2-fluoro- aniline (25 g, 70 mmol) in DMF (50 mL) was added N,N-dimethylformamide dimethyl acetal (41.5 g, 348 mmol). The mixture was stirred at 100 °C for 16 hours. After cooling to room temperature, the mixture was concentrated in vacuo to afford the desire product without purification (30 g, 97%). MS (ESI): 442.0 m/z (M+H)⁺. Intermediate 5C 5-((4-Bromo-6-fluoro-1H-indol-5-yl)oxy)-2-fluoroaniline [246] To a solution of N-[5-[2-bromo-3-[(E)-2-(dimethylamino)vinyl]-6-fluoro-4-nitro- phenoxy]-2-fluoro-phenyl]formamide (30 g, crude, 39 mmol) in toluene (300 mL) was added Fe powder (18.9 g, 339 mmol) and AcOH (38.8 mL, 678 mmol). The mixture was heated at 100 °C and stirred for 16 hours. After cooling to room temperature, the mixture was filtered through a pad of Celite, and the filtrate was concentrated. The residue was treated with water (300 mL), extracted with EtOAc (300 mL x 3). The combined organic phase was washed with brine (200 mL), dried over Na₂SO₄, filtered, and concentrated to give the crude product. The crude material was purified by flash column chromatography on silica gel, eluting with 0-40% ethyl acetate in petroleum ether, to afford the desired product as a solid (14 g, 61% yield over 2 steps). MS (ESI): 339.1, 341.1 m/z (M+H)⁺. Intermediate 5D 2-Fluoro-5-((6-fluoro-4-(methylthio)-1H-indol-5-yl)oxy)aniline [247] To a solution of 5-[(4-bromo-6-fluoro-1H-indol-5-yl)oxy]-2-fluoro-aniline (14.0 g, 41.1 mmol, 1.0 eq) in DMF (85 mL) was added under a N2 atmosphere tributyl(methylsulfanyl)stannane (0.507 g, 61.8 mmol, 1.5 eq) and Pd(dppf)Cl₂ (73.4 mg, 0.1 mmol, 0.1 eq). The suspension was degassed and purged with N2 several times. The suspension was stirred under N2 at 160 °C for 3 hours. After cooling to room temperature, water (50 mL) was added and the mixture was extracted with EtOAc (30 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel, eluting with 0-30% ethyl acetate in petroleum ether , to afford the desired product as a solid (200 mg, 65%). MS (ESI): 307.1 m/z (M+H)⁺. Intermediate 5E 2-Fluoro-5-((6-fluoro-4-(methylthio)-1-tosyl-1H-indol-5-yl)oxy)aniline [248] To a solution of 2-fluoro-5-[(6-fluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]aniline (6 g, 20 mmol) in THF (50 mL) was added dropwise at -78 °C sodium bis(trimethylsilyl)amide (1M in THF, 20 mL, 20 mmol). The resulting mixture was stirred for 0.5 hours at the same temperature, followed by the addition of toluene-4-sulfonyl chloride (3.73 g, 20 mmol) in THF (10 mL). The reaction mixture was stirred at -78 °C for 1 hour. After the reaction was judged complete by LC-MS, saturated NH₄Cl solution (100 mL) was added, and the mixture was extracted with EtOAc (100 mL x 3). The combined organic phase was washed with brine (100 mL), dried over Na₂SO₄, filtered, and concentrated. The crude material was purified by flash column chromatography on silica gel, eluting with 0-30% ethyl acetate in petroleum ether, to give the desired product as an oil (8.5 g, 94%). MS (ESI): 461.1 m/z (M+H)⁺. Intermediate 6 6-Fluoro-5-(4-fluoro-3-iodophenoxy)-4-((methylsulfonyl)methyl)-1H-indole [249] 6-fluoro-5-(4-fluoro-3-iodo-phenoxy)-4-(methylsulfonylmethyl)-1-(p- tolylsulfonyl)indole (Intermediate 6G, 1.7 g, 2.75 mmol) was dissolved in 3/1/1 THF/MeOH/H₂O and LiOH (330 mg, 13.8 mmol) was added. The mixture was stirred at room temperature for 16 hours, quenched with saturated aqueous NH₄Cl, and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with H₂O, brine (50 mL x 2), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with 1/1 petroleum ether/ethyl acetate, to give 6-fluoro- 5-(4-fluoro-3-iodo-phenoxy)-4-(methylsulfonylmethyl)-1H-indole (1.2 g, 94%) as a solid. MS (ESI): 464 m/z (M+H)⁺. Intermediate 6A 2-Fluoro-5-((6-fluoro-4-vinyl-1H-indol-5-yl)oxy)aniline [250] To a mixture of 5-[(4-bromo-6-fluoro-1H-indol-5-yl)oxy]-2-fluoro-aniline (Intermediate 5C, 5.8 g, 17.1 mmol) and Cs₂CO₃ (11.1 g, 34.2 mmol) in 1,4-dioxane/H₂O (5/1) was added 4,4,5,5-tetramethyl-2-vinyl-1,3,2-dioxaborolane (5.27 g, 34.2 mmol), Pd(dppf)₂Cl₂ dichloromethane adduct (1.4 g, 1.71 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 3). The combined organic phase was washed with H₂O (100 mL), brine (100 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 2-fluoro-5-[(6-fluoro-4-vinyl-1H-indol-5- yl)oxy]aniline (4.8 g, 98%) as a yellow oil. MS (ESI): 287 m/z (M+H)⁺. Intermediate 6B 2-Fluoro-5-((6-fluoro-1-tosyl-4-vinyl-1H-indol-5-yl)oxy)aniline [251] To a stirred and chilled (-78 °C) solution of 2-fluoro-5-[(6-fluoro-4-vinyl-1H-indol-5- yl)oxy]aniline (2.5 g, 8.73 mmol) in THF was added a solution of sodium bis(trimethylsilyl)amide (1M in THF, 1 eq) dropwise under Ar. The mixture was stirred at -78 °C for 0.5 hours, treated with TsCl (1.66 g, 8.73 mmol) in THF. The mixture was stirred at -78 °C for another 0.5 hours, quenched with saturated aqueous NH₄Cl, and extracted with ethyl acetate (50 mL x 3). 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 column chromatography on silica gel, eluting with 1/1 petroleum ether/ethyl acetate, to give 2- fluoro-5-[6-fluoro-1-(p-tolylsulfonyl)-4-vinyl-indol-5-yl]oxy-aniline (2.3 g, 60%) as a yellow oil. MS (ESI): 441 m/z (M+H)⁺. Intermediate 6C 6-Fluoro-5-(4-fluoro-3-iodophenoxy)-1-tosyl-4-vinyl-1H-indole [252] To a stirred solution of 2-fluoro-5-[6-fluoro-1-(p-tolylsulfonyl)-4-vinyl-indol-5- yl]oxy-aniline (2.3 g, 5.22 mmol) in acetonitrile/water (10/1) was added tert-butyl nitrite (2.69 g, 26.1 mmol) and KI (4.33 g, 26.1 mmol). The mixture was stirred at 50 °C for 16 hours, quenched with saturated aqueous NH₄Cl, and extracted with ethyl acetate (50 mL x 3). The combined organic phase was washed with 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 with 1/1 petroleum ether/ethyl acetate, to give 6-fluoro-5-(4-fluoro-3- iodo-phenoxy)-1-(p-tolylsulfonyl)-4-vinyl-indole (2 g, 70%) as a solid. MS (ESI): 552 m/z (M+H)⁺. Intermediate 6D 6-Fluoro-5-(4-fluoro-3-iodophenoxy)-1-tosyl-1H-indole-4-carbaldehyde [253] To a stirred solution of 6-fluoro-5-(4-fluoro-3-iodo-phenoxy)-1-(p-tolylsulfonyl)-4- vinyl-indole (3.3 g, 6 mmol) in THF/H₂O (10/1) was added NaIO4 (2.56 g, 12 mmol) and OsO4 (76.1 mg, 0.30 mmol). The mixture was stirred at room temperature for 16 hours, quenched with saturated aqueous NH₄Cl, and extracted with ethyl acetate (50 mL x 2). The organic phase was washed with brine (50 mL), dried with anhydrous Na₂SO₄, filtered and concentrated in vacuo to give crude 6-fluoro-5-(4-fluoro-3-iodo-phenoxy)-1-(p-tolylsulfonyl)indole-4- carbaldehyde (2.8 g, 85%) as a yellow oil. MS (ESI): 554 m/z (M+H)⁺. Intermediate 6E (6-Fluoro-5-(4-fluoro-3-iodophenoxy)-1-tosyl-1H-indol-4-yl)methanol [254] To a stirred solution of 6-fluoro-5-(4-fluoro-3-iodo-phenoxy)-1-(p- tolylsulfonyl)indole-4-carbaldehyde (2.8 g, 5.06 mmol) in THF/EtOH(10/1) was added NaBH4 (191 mg, 5.06 mmol). The mixture was stirred at room temperature for 1 hour, quenched with saturated aqueous NH₄Cl, and extracted with ethyl acetate (50 mL x 2). The combined organic phase was washed with H₂O (50 mL), 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 [6-fluoro-5-(4-fluoro-3-iodo- phenoxy)-1-(p-tolylsulfonyl)indol-4-yl]methanol (2.7 g, 96%) as a solid. MS (ESI): 556 m/z (M+H)⁺. Intermediate 6F 4-(Bromomethyl)-6-fluoro-5-(4-fluoro-3-iodophenoxy)-1-tosyl-1H-indole [255] To a stirred solution of [6-fluoro-5-(4-fluoro-3-iodo-phenoxy)-1-(p- tolylsulfonyl)indol-4-yl]methanol (2.7 g, 4.86 mmol) in DCM were added 2,6-Lutidine (1.56 g, 14.6 mmol) and PBr3 (2.63 g, 9.72 mmol). The mixture was stirred at room temperature for 16 hours, quenched with NaHCO₃, and 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 column chromatography on silica gel, eluting with 2/1 petroleum ether/ethyl acetate, to give 4-(bromomethyl)-6-fluoro-5-(4-fluoro- 3-iodo-phenoxy)-1-(p-tolylsulfonyl)indole (2.2 g, 73%) as a solid. MS (ESI): 618, 620 m/z (M+H)⁺. Intermediate 6G 6-Fluoro-5-(4-fluoro-3-iodophenoxy)-4-((methylsulfonyl)methyl)-1-tosyl-1H-indole [256] To a stirred solution of 4-(bromomethyl)-6-fluoro-5-(4-fluoro-3-iodo-phenoxy)-1-(p- tolylsulfonyl)indole (2.2 g, 3.56 mmol) in DMF was added methanesulfinic acid, sodium salt (1.82 g, 17.8 mmol). The mixture was stirred at 90 °C for 16 hours, cooled to room temperature, quenched with saturated aqueous NH₄Cl and extracted with ethyl acetate (50 mL x 2). 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 6-fluoro-5-(4-fluoro-3-iodo-phenoxy)- 4-(methylsulfonylmethyl)-1-(p-tolylsulfonyl)indole (1.7 g, 77%) as a solid. MS (ESI): 618 m/z (M+H)⁺. Intermediate 7 2-Fluoro-5-((6-fluoro-4-(methylthio)-1H-indol-5-yl)oxy)benzonitrile [257] A mixture of 5-(3-bromo-4-fluorophenoxy)-6-fluoro-4-(methylthio)-1H-indole (800 mg, 2.17 mmol), Zn(CN)₂ (380 mg, 3.25 mmol) , Zn (28 mg, 0.43 mmol) and Pd(dppf)Cl₂ (159 mg, 0.217 mmol) in DMF (10 mL) was stirred at 150 °C for 45 minutes in a microwave reactor. The reaction mixture was cooled to room temperature, quenched with water (20 mL), and extracted with ethyl acetate (20 mL x 3). The combined EtOAc extracts were washed with brine (20 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 0-100% ethyl acetate in petroleum ether, to give 2-fluoro-5-((6-fluoro-4-(methylthio)-1H-indol-5-yl)oxy)benzonitrile (219 mg, 32%) as a yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.36 (s, 1H), 7.31 (t, J1 = 4 Hz, J2 = 8 Hz 1H), 7.16- 7.04 (m, 3H), 7.00 (t, J1= 4 Hz, J2 = 8 Hz 1H), 6.78 (s, 1H), 2.46 (s, 3H) ppm. Intermediate 7A 3-Bromo-1,2-difluoro-4-methyl-5-nitrobenzene [258] To a stirred solution of 1,2-difluoro-4-methyl-5-nitrobenzene (150 g, 866 mmol) in trifluoroacetic acid (800 mL) were added 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione (136 g, 476 mmol) and concentrated sulfuric acid (200 mL). The solution was stirred at 25 °C for 10 hours. Three batches of reaction suspension (total 450 g of 1,2-difluoro-4-methyl-5- nitrobenzene) were combined and poured into ice water (5 L) and stirred for 15 minutes and extracted with petroleum ether (4 L x 2). The combined organic extracts were washed with brine (5 L), dried over sodium sulfate, filtered and concentrated. The resulting oil was purified by flash chromatography over silica (100% petroleum ether) to afford the title compound as a yellow oil (417 g, 64%).¹H NMR (400 MHz CDCl³) δ 7.68 (q, J = 6.0 Hz, 1H), 2.55 (s, 3H) ppm. Intermediate 7B 5-(2-Bromo-6-fluoro-3-methyl-4-nitrophenoxy)-2-fluoroaniline [259] To a stirred solution of 3-Bromo-1,2-difluoro-4-methyl-5-nitrobenzene (6 g, 24 mmol) and 3-amino-4-fluorophenol (3.4 g, 26 mmol) in DMF (80 mL) was added Cs₂CO₃ (11.6 g, 35.7 mmol). The mixture was stirred at room temperature overnight, quenched with 150 mL of water, and extracted with EtOAc (20 mL × 3). The combined organic extracts were dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by silica gel column chromatography, eluting with 4/1 petroleum ether/ethyl acetate, to give 5-(2-bromo-6-fluoro- 3-methyl-4-nitrophenoxy)-2-fluoroaniline (7.2 g, 85%) as a yellow solid. MS (ESI): 359, 361 m/z (M+H)⁺. Intermediate 7C 2-Fluoro-5-(6-fluoro-2-((4-methoxybenzyl)thio)-3-methyl-4-nitrophenoxy)aniline [260] To a solution of 5-(2-bromo-6-fluoro-3-methyl-4-nitrophenoxy)-2-fluoroaniline (6.3 g, 0.0175 mol), tris(dibenzylideneacetone)dipalladium(0) (0.8 g, 0.88 mmol), Xantphos (1g, 1.75 mmol), DIPEA (4.5g, 0.035 mmol) in dry dioxane (100 mL) was added 4-methoxybenzyl mercaptan (2.97g , 0.0193 mol). The reaction was stirred at 100 °C overnight and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 0-30% ethyl acetate in petroleum ether, to give the product, 2-fluoro-5-(6-fluoro-2-((4- methoxybenzyl)thio)-3-methyl-4-nitrophenoxy)aniline (4.8 g, 63 % yield) as a yellow solid. MS (ESI): 433 m/z (M+H)⁺. Intermediate 7D 2-(3-Amino-4-fluorophenoxy)-3-fluoro-6-methyl-5-nitrobenzenethiol [261] To a mixture of 2-fluoro-5-(6-fluoro-2-((4-methoxybenzyl)thio)-3-methyl-4- nitrophenoxy)aniline (4.8 g, 0.01 mol) in anisole (25 mL) was added TFA (25 mL). The mixture was stirred at 50 °C overnight. The mixture was concentrated to give the crude mixture of 2-(3-amino-4-fluorophenoxy)-3-fluoro-6-methyl-5-nitrobenzenethiolwhich was used directly in the next step. MS (ESI): 313 m/z (M+H)⁺. Intermediate 7E 2-Fluoro-5-(6-fluoro-3-methyl-2-(methylthio)-4-nitrophenoxy)aniline [262] To a stirred solution of crude 2-(3-amino-4-fluorophenoxy)-3-fluoro-6-methyl-5- nitrobenzenethiol (4.8 g, 0.38 mmol) in acetone (20 mL) was added K₂CO₃ (4.6 g, 0.033 mol) and CH₃I (1.74 g, 0.012 mol). The mixture was stirred at room temperature for 1 hour, filtered, and rinsed with acetone (5 mL x 2). The filtrate was concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 0-30% ethyl acetate in petroleum ether, to give the product, 2-fluoro-5-(6-fluoro-3-methyl-2-(methylthio)-4-nitrophenoxy)aniline (2.3 g, 64% yield, based on 4.8 g of 2-(3-amino-4-fluorophenoxy)-3-fluoro-6-methyl-5- nitrobenzenethiol starting material) as a brown solid. MS (ESI): 327 m/z (M+H)⁺. Intermediate 7F (2-(3-Bromo-4-fluorophenoxy)-3-fluoro-6-methyl-5-nitrophenyl)(methyl)sulfane [263] To a mixture of 2-fluoro-5-(6-fluoro-3-methyl-2-(methylthio)-4-nitrophenoxy)aniline (2.3 g, 7.1 mmol) in 100 mL of aqueous HBr (40 wt. %) was added dropwise a solution of NaNO₂ (0.73 g, 10.6 mmol) in 20 mL of water at 0 °C. After stirring for 0.5 hours, CuBr (1.5 g, 10.6 mmol) and 50 mL of DCM were added. The reaction was stirred at 0 °C for 1 hour. The mixture was concentrated. The residue was extracted with EtOAc (50 mL), washed with brine (20 mL x 4), dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with 0-50% ethyl acetate in petroleum ether, to give the product, (2-(3-bromo-4-fluorophenoxy)-3-fluoro-6-methyl-5- nitrophenyl)(methyl)sulfane (2.3 g , 83% yield) as a solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.17 (d, J = 4.0 Hz, 1H), 7.35 (m, 2H), 7.01 (m, 1H), 2.59 (s, 3H), 2.35 (s, 3H) ppm. Intermediate 7G 5-(3-Bromo-4-fluorophenoxy)-6-fluoro-4-(methylthio)-1H-indole [264] To a solution of (2-(3-bromo-4-fluorophenoxy)-3-fluoro-6-methyl-5- nitrophenyl)(methyl)sulfane (2.3 g, 2.9 mmol) in DMF (60 mL) was added DMF-DMA (8.5 g, 0.071 mol). The mixture was stirred at 120 °C overnight. The mixture was diluted with EtOAc (150 mL), washed with brine (10 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was dissolved into 50 mL of toluene and 50 mL of AcOH, and Fe powder (3.9 g, 0.071mol) was added. The reaction was stirred at 100 °C for 2 days, cooled to room temperature and concentrated under reduced pressure. The residue was extracted with EtOAc (50 mL). The organic extract was washed with brine (20 mL x 4), dried over Na₂SO₄, filtered, and concentrated. The crude product was purified by flash column chromatography on silica gel, eluting with 0-50% ethyl acetate in petroleum ether, to give 5-(3-bromo-4-fluorophenoxy)-6- fluoro-4-(methylthio)-1H-indole (1 g, 50% yield) as a yellow oil. MS (ESI): 370, 372 m/z (M+H)⁺. Intermediate 8 4,6-Difluoro-5-(4-fluoro-3-iodophenoxy)-1H-indole [265] To a solution of (E)-2-(2,4-difluoro-3-(4-fluoro-3-iodophenoxy)-6-nitrophenyl)-N,N- dimethylethen-1-amine (15.1 mmol, 7 g) in a mixture of toluene (10 mL) and acetic acid (10 mL) was added Fe powder (151 mmol, 8.42 g), and the mixture was stirred at 100 °C for 4 hours. The cooled reaction mixture was concentrated, treated with 50 mL of water, and extracted with EtOAc (40 mL x 3). The combined organic phase was concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 0-20% EtOAc in petroleum ether, to give 4,6-difluoro-5-(4-fluoro-3-iodophenoxy)-1H-indole (4 g, 65% yield, a white solid). MS (ESI): 390.0 m/z (M+H)⁺. Intermediate 8A 4-Fluoro-3-iodophenol [266] To a stirred solution of 3-amino-4-fluoro-phenol (94.4 mmol, 12 g) in 2.5M hydrochloric acid (120 mL) and water (90 mL) was added dropwise at 0 °C a solution of NaNO₂ (113 mmol, 7.82 g) in water (48 mL). The mixture was stirred at 0 °C for 10 minutes, treated with a solution of KI (189 mmol, 31.3 g) in water (90 mL) (keeping the temperature of the reaction solution between 0-5 °C during the addition), stirred at 0-5 °C for 10 minutes, then at 90 °C for another 2.5 hours. The reaction solution was cooled to room temperature and extracted with EtOAc (100 mL x 3). The combined organic phase was concentrated and purified by flash column chromatography on silica gel, eluting with 0-7% EtOAc in petroleum ether, to give 4-fluoro-3-iodophenol as a yellow oil (8.5 g, 36% yield). The product was used in next step without further characterization. Intermediate 8B 1,3-Difluoro-2-(4-fluoro-3-iodophenoxy)-4-methyl-5-nitrobenzene [267] To a solution of 4-fluoro-3-iodophenol (23.1 mmol, 5.5 g) in DMF (30 mL) was added 1,2,3-trifluoro-4-methyl-5-nitro-benzene (20.9 mmol, 4 g) and K₂CO₃ (46.2 mmol, 6.39 g). The mixture was stirred at 100 °C for 3 hours, cooled to rt, quenched with 100 mL of water, and extracted with EtOAc (80 mL x 3). The combined organic phase was concentrated and purified by flash column chromatography on silica gel, eluting with 0-7% EtOAc in petroleum ether, to give 1,3-difluoro-2-(4-fluoro-3-iodophenoxy)-4-methyl-5-nitrobenzene as a yellow oil (6.5 g, 62% yield). The product was used in next step without further characterization. Intermediate 8C (E)-2-(2,4-Difluoro-3-(4-fluoro-3-iodophenoxy)-6-nitrophenyl)-N,N-dimethylethen-1- amine To a solution of 1,3-difluoro-2-(4-fluoro-3-iodophenoxy)-4-methyl-5-nitrobenzene (15 mmol, 6.0 g) in DMF (40 mL) was added N,N-dimethylformamide dimethyl acetal (73.3 mmol, 8.4 g) and the mixture was stirred at 100 °C for 4 hours. The reaction solution was poured into water (50 mL) and extracted with EtOAc (40 mL x 3). The combined organic phase was washed with water (50 mL x 2), brine (40 mL x 2), filtered, and concentrated to give (E)-2-(2,4- difluoro-3-(4-fluoro-3-iodophenoxy)-6-nitrophenyl)-N,N-dimethylethen-1-amine as a red- brown oil (crude, 7 g). The crude was used directly in the next step. MS (ESI): 465 m/z (M+H)⁺. Intermediate 9 Ethyl 3-[4-(2-bromoacetyl)-4-methyl-chroman-8-yl]propanoate To a solution of 8-(3-ethoxy-3-oxo-propyl)-4-methyl-chromane-4-carboxylic acid (1.00 eq, 22.60 g, 77.3 mmol) in DCM (460mL) was added oxalyl chloride (2.00 eq, 14 mL, 155 mmol) and 6 drops DMF at 0 °C. The reaction mixture was stirred for 1.5 h and concentrated. The residue was dissolved in MeCN (300 mL), treated with trimethylsilyl diazomethane (4.00 eq, 155 mL, 309 mmol) dropwise at 0 ºC, and stirred for 1 h. To the mixture was added hydrobromic acid (4.00 eq, 75.82 g, 309 mmol) while keeping the temperature under 0 ºC. Stirring in cold bath was continued for 1 h. The reaction mixture was poured into water (400 mL), and extracted with ethyl acetate (500 mL x 2). The combined organic extracts were washed with water (200 mL), brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 0-12% ethyl acetate in petroleum ether, to give the desired product ethyl 3-[4-(2-bromoacetyl)- 4-methyl-chroman-8-yl]propanoate (25.60 g,69.3 mmol, 89.68 % yield) as a white solid. MS (ESI): 369.1, 371.1 m/z (M+H)⁺; retention time 2.16 min (modified Method 3 - Column Temperature:45 °C). Intermediate 9A tert-Butyl 8-bromochromane-4-carboxylate To a solution of 8-bromochromane-4-carboxylic acid (1.00 eq, 31 mL, 132 mmol) in tert- butanol (200 mL) was added 4-dimethylaminopyridine (0.300 eq, 4.85 g, 39.7 mmol), followed by Boc anhydride (1.50 eq, 46 mL, 198 mmol) dropwise. The reaction mixture was stirred at rt for 4 h and concentrated. The residue was taken up in EtOAc (500 mL), washed with water (2 x 500 mL), brine (2 x 500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude was purified by flash column chromatography on silica gel, eluting with petroleum ether, to give tert-butyl 8-bromochromane-4-carboxylate (34.00 g,109 mmol, 82 % yield) as an oil.¹H NMR (400 MHz, CDCl₃) δ 7.41 (dd, J = 8.0, 1.2 Hz, 1H), 7.21 (d, J = 7.6 Hz, 1H), 6.76 (t, J = 8.0 Hz, 1H), 4.36 (dd, J = 8.8, 3.2 Hz, 2H), 3.71-3.66 (m, 1H), 2.31 (ddd, J = 14.0, 7.2, 4.0 Hz, 1H), 2.09 (ddt, J = 14.0, 8.4, 5.6 Hz, 1H), 1.45 (s, 9H). Intermediate 9B tert-Butyl 8-bromo-4-methyl-chromane-4-carboxylate To a stirred solution of tert-butyl 8-bromochromane-4-carboxylate (1.00 eq, 5.00 g, 16.0 mmol) in dry THF (50 mL) was added dropwise at -78 °C LDA (1.20 eq, 9.6 mL, 19.2 mmol). The mixture was stirred at -78 °C for 1 h, treated with methyl iodide (1.10 eq, 1.1 mL, 17.6 mmol), and stirred at -78 °C for another 1 h. The reaction mixture was quenched with water, extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 0-5% ethyl acetate in petroleum ether, to give tert- butyl 8-bromo-4-methyl-chromane-4-carboxylate (4.10 g, 12.5 mmol, 78 % yield) as colorless oil. ¹H NMR (400 MHz, CDCl₃) δ 7.39 (dd, J = 7.6, 1.2 Hz, 1H), 7.27 (dd, J = 7.6, 1.6 Hz, 1H), 6.77 (t, J = 8.0 Hz, 1H), 4.35-4.28 (m, 2H), 2.48 (m, 1H), 1.94-1.80 (m, 1H), 1.55 (s, 3H), 1.40 (s, 9H). Intermediate 9C tert-Butyl 8-[(E)-3-ethoxy-3-oxo-prop-1-enyl]-4-methyl-chromane-4-carboxylate To a solution of tert-butyl 8-bromo-4-methyl-chromane-4-carboxylate (1.00 eq, 20.00 g, 61.1 mmol) in 1,4-Dioxane (5mL) ) and water (0.5000mL) was added ethyl (E)-3-(4,4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)acrylate (2.00 eq, 27636 mg, 122 mmol), potassium carbonate (3.00 eq, 25343 mg, 183 mmol) and Pd(dppf)Cl₂.CH₂Cl₂ (0.100 eq, 4987 mg, 6.11 mmol). The reaction mixture was stirred at 100 ºC for 2 h, poured into water (300 mL), and extracted with ethyl acetate (500 mL). The organic layer was washed with brine (90 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography eluting with 0-5% ethyl acetate in petroleum ether to give tert-butyl 8-[(E)-3- ethoxy-3-oxo-prop-1-enyl]-4-methyl-chromane-4-carboxylate (11.80 g, 34.1 mmol, 56 % yield) as solid. MS (ESI): 291.2 (M+H-t-Bu)⁺ ; retention time 1.86 min (Method 3) Intermediate 9D tert-Butyl 8-(3-ethoxy-3-oxo-propyl)-4-methyl-chromane-4-carboxylate To a solution of tert-butyl 8-[(E)-3-ethoxy-3-oxo-prop-1-enyl]-4-methyl-chromane-4- carboxylate (1.00 eq, 18.50 g, 53.4 mmol) in THF (200 mL) was added under N2 palladium on activated carbon (10 wt.%, 0.528 eq, 3.00 g, 28.2 mmol). The suspension was stirred under H₂ at ambient temperature and pressure for 16 hours. The Pd catalyst. was removed by filtration. The filtrate was concentrated to afford tert-butyl 8-(3-ethoxy-3-oxo-propyl)-4-methyl- chromane-4-carboxylate (18.50 g, 53.1 mmol, 99 % yield) as an oil. MS (ESI): 371.1 (M + Na)⁺. ; retention time 2.21 min (Method 2) Intermediate 9E 8-(3-Ethoxy-3-oxo-propyl)-4-methyl-chromane-4-carboxylic acid A solution of tert-butyl 8-(3-ethoxy-3-oxo-propyl)-4-methyl-chromane-4-carboxylate (1.00 eq, 6.60 g, 18.9 mmol) in 4M HCl in EtOAc (10.0 eq, 47 mL, 189 mmol) was stirred at rt for 6 h. The solvent was removed under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 0-25% ethyl acetate in petroleum ether) to give 8- (3-ethoxy-3-oxo-propyl)-4-methyl-chromane-4-carboxylic acid (4.60 g,15.7 mmol, 83 % yield) as a colorless oil.¹H NMR (400 MHz, DMSO-d₆) δ 12.58 (s, 1H), 7.15 (dd, J = 8.0, 1.6 Hz, 1H), 6.99 (dd, J = 7.2, 1.2 Hz, 1H), 6.78 (t, J = 7.6 Hz, 1H), 4.19 (t, J = 5.2 Hz, 2H), 4.08- 4.02 (m, 2H), 2.76 (t, J = 7.6 Hz, 2H), 2.52 (dd, J = 12.8, 5.2 Hz, 3H), 2.36 (dt, J = 9.6, 4.4 Hz, 1H), 1.81 (dt, J = 12.0, 5.6 Hz, 1H), 1.16 (t, J = 6.4 Hz, 3H). Intermediate 10 5-[[4-(Difluoromethyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2-fluoro-benzamidine To a stirred solution of 5-[[4-(difluoromethyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2-fluoro- benzonitrile (1.00 eq, 184 mg, 0.544 mmol) in THF (11 mL) was added LHMDS (1.00 eq, 91 mg, 0.544 mmol). The mixture was stirred for 2 h at RT and concentrated to dryness. The residue was suspended in EtOAc (20 ml), washed with water (2 x 20 ml), brine (20 mL), dried over MgSO₄, and concentrated. The residue was purified by flash chromatography on silica gel to give 5-[[4-(difluoromethyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2-fluoro-benzamidine (190 mg, 0.492 mmol, 90 % yield). MS (ESI): 356.1 (M+H)⁺ ; retention time 1.48 min (modified Method 3 - Gradient: T0 min: 5% B: 95% B, T1.3 min; Flow Rate: 1.8 ml/min). Intermediate 10A 5-[[6,7-Difluoro-4-(hydroxymethyl)-1H-indol-5-yl]oxy]-2-fluoro-benzonitrile To a solution of 5-[(4-bromo-6,7-difluoro-1H-indol-5-yl)oxy]-2-fluoro-benzonitrile (prepared as in WO2023034992, 1.00 eq, 2.00 g, 5.45 mmol) and (tributylstannyl)methanol (2.00 eq, 3.50 g, 10.9 mmol) in dry 1,4-dioxane (40 mL) was added under a N2 atmosphere XPhos-Pd-G2 (0.0500 eq, 214 mg, 0.272 mmol). The reaction mixture was stirred at 80 °C overnight, cooled to rt, and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 0-40% ethyl acetate in petroleum ether, to give the 5-[[6,7-difluoro-4- (hydroxymethyl)-1H-indol-5-yl]oxy]-2-fluoro-benzonitrile (0.90 g,2.83 mmol, 52 % yield) as a solid. Intermediate 10B 5-[6,7-Difluoro-4-formyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile To a stirred solution of 5-[[6,7-difluoro-4-(hydroxymethyl)-1H-indol-5-yl]oxy]-2-fluoro- benzonitrile (1.00 eq, 3.92 g, 12.3 mmol) in DMSO (80 mL) was added Dess-Martin periodinane (1.30 eq, 6.79 g, 16.0 mmol) . The resulting mixture was stirred for 4 h at RT and concentrated under reduced pressure. The residue was taken up in water (20 ml), extracted with DCM (2 x 20ml). The combined organic extracts were washed with brine (20 mL), dried over MgSO₄ and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with 0-50% EtOAc in Petroleum ether, to give 5-[(6,7-difluoro-4-formyl-1H-indol- 5-yl)oxy]-2-fluoro-benzonitrile (3.40 g, 10.2 mmol, 83 % yield). MS (ESI): 317.1 (M+H)⁺. Intermediate 10C 5-[6,7-Difluoro-4-formyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile To a stirred, chilled (0 ºC) solution of 5-[(6,7-difluoro-4-formyl-1H-indol-5-yl)oxy]-2-fluoro- benzonitrile (1.00 eq, 3.40 g, 10.8 mmol) in THF (80 mL) was added sodium (1.10 eq, 0.28 g, 11.8 mmol) under a nitrogen atmosphere. The mixture was stirred for 30 min at 0 ºC, treated with. p-toluenesulfonyl chloride (1.20 eq, 2.46 g, 12.9 mmol), allowed to warm to rt, and stirred for another 2 h. The reaction was quenched with aqueous NH₄Cl, extracted with EtOAc (2 x 20 ml). The combined organic extracts were washed with water, brine, dried over MgSO₄, and concentrated to dryness. The residue was triturated with a 1:10 EtOAc:petroleum ether mixture to give 5-[6,7-difluoro-4-formyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile (4.42 g,8.55 mmol, 79 % yield) . MS (ESI): 471.1 (M+H)⁺ Intermediate 10D 5-[4-(Difluoromethyl)-6,7-difluoro-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- benzonitrile To a solution of 5-[6,7-difluoro-4-formyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- benzonitrile (1.00 eq, 240 mg, 0.510 mmol) in DCM (4 mL) was added diethylaminosulfur trifluoride (5.00 eq, 0.34 mL, 2.55 mmol) The mixture was stirred overnight at RT. After adjusting the pH to ~8 with aqueous NaHCO₃, the mixture was extracted with DCM (2 x 50 mL). The combined organic phase was dried, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel, eluting with 20% EtOAc in petroleum ether, to give 5-[4-(difluoromethyl)-6,7-difluoro-1-(p-tolylsulfonyl)indol-5-yl]oxy- 2-fluoro-benzonitrile (236 mg, 0.476 mmol, 93 % yield) as a white solid. MS (ESI): 515.1 (M+Na)⁺ ; retention time 2.18 min (modified Method 3 - Gradient: T0 min: 5% B: 95% B, T1.3 min; Flow Rate: 1.8 ml/min). Intermediate 10E 5-[[4-(Difluoromethyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2-fluoro-benzonitrile To a solution of 5-[4-(difluoromethyl)-6,7-difluoro-1-(p-tolylsulfonyl)indol-5-yl]oxy-2- fluoro-benzonitrile (1.00 eq, 422 mg, 0.857 mmol) in THF (1.7 mL) was added TBAF (1M in THF, 2.00 eq, 1.7 mL, 1.71 mmol). The resulting mixture was stirred for 2 h at RT and concentrated to dryness. The residue was suspended in EtOAc (10 ml), washed with water (2 x 10 ml), brine (10 mL), dried over MgSO₄ and concentrated. The residue was purified by flash chromatography on silica gel, eluting with 0-30% ethyl acetate in petroleum ether, to give 5- [[4-(difluoromethyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2-fluoro-benzonitrile (184 mg, 0.539 mmol, 62 % yield. MS (ESI): 339.1 (M+H)⁺ ; retention time 2.00 min (modified Method 3 - Flow Rate: 1.8 ml/min). Intermediate 11 Methyl 5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-benzenecarboximidothioate To a solution of 5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-benzenecarboximidothioic acid (1.00 eq, 2.10 g, 6.52 mmol) in acetone (30 mL) was added methyl iodide (5.00 eq, 2.0 mL, 32.6 mmol). The reaction mixture was stirred at 50 °C for 3 hours. The solvent was removed under reduced pressure to give crude methyl 5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro- benzenecarboximidothioate (2.50 g, 7.43 mmol, 114 % yield) as a yellow solid. MS (ESI): 337.2 (M+H)⁺. The crude product was advanced directly to the next step. Intermediate 11A 5-[(4,6-Difluoro-1H-indol-5-yl)oxy]-2-fluoro-benzenecarboximidothioic acid To a solution of 5-[(4,6-difluoro-1H-indol-5-yl)oxy]-2-fluoro-benzonitrile (prepared as in WO2023034992) (1.00 eq, 2.00 g, 6.94 mmol) in DMF (20 mL) was added magnesium chloride hexahydrate (1.00 eq, 1411 mg, 6.94 mmol) and sodium hydrosulfide (2.00 eq, 778 mg, 13.9 mmol). The mixture was stirred at room temperature for 1 hour, diluted with 100 mL of water, extracted with ethyl acetate (3 x 100 mL). The combined organic extracts were washed with brine, dried over Na₂SO₄ and concentrated to give 5-[(4,6-difluoro-1H-indol-5- yl)oxy]-2-fluoro-benzenecarboximidothioic acid (2.10 g, 6.52 mmol, 93 % yield) as a yellow liquid. MS (ESI): 323.0 (M+H)⁺ Intermediate 12 2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]benzamidine To a stirred solution of 2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]benzonitrile (1.00 eq, 2.18 g, 7.12 mmol) in THF (71 mL) was added LHMDS (10.0 eq, 71 mL, 71.2 mmol) at 0 ºC. The mixture was stirred for 2 h at RT, quenched with saturated aqueous ammonium chloride (50 mL), and extracted with ethyl acetate (2 x 100 mL). The combined organic extracts were washed with water (50 mL), brine (50 mL), dried over anhydrous sodium sulfate, and concentrated to give 2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]benzamidine (2.10 g, 6.50 mmol, 91 % yield). MS (ESI): 324.1 (M+H)⁺ ; retention time 1.49 min (Method 3). Intermediate 12A 2-Fluoro-5-(2,3,6-trifluoro-4-nitro-phenoxy)benzonitrile To a stirred solution of 2,3,4,5-tetrafluoronitrobenzene (1.00 eq, 62 mL, 513 mmol) in DMF (2 L) was added 2-fluoro-5-hydroxy-benzonitrile (1.00 eq, 70.29 g, 513 mmol) and potassium carbonate (2.00 eq, 141.70 g, 1025 mmol). The mixture was stirred at room temperature for 1 h, quenched with water (1 L), and extracted with ethyl acetate (3 x 1 L). The combined organic phases were washed with water (3 x 1 L), brine (2 x 1 L), dried over anhydrous Na₂SO₄, filtered, and concentrated. The residue was purified by column chromatography on silica, eluting with 0-20% EtOAc in petroleum ether, to give 2-fluoro-5-(2,3,6-trifluoro-4-nitro- phenoxy)benzonitrile (123.30 g, 395 mmol, 77 % yield) as a white solid. Retention time 2.16 min (modified Method 4 - Gradient: T0 min: 5% B: 90% B, T1.4 min). Intermediate 12B 5-(4-Amino-2,3,6-trifluoro-phenoxy)-2-fluoro-benzonitrile To a mixture of 2-fluoro-5-(2,3,6-trifluoro-4-nitro-phenoxy)benzonitrile (1.00 eq, 40.00 g, 128 mmol) in ethanol (500 mL) was added iron powder (5.00 eq, 35.78 g, 641 mmol) and a solution of ammonium chloride (8.00 eq, 54.83 g, 1025 mmol) in water (100 mL). The resulting mixture was stirred at room temperature for 2 h. The insoluble materials were removed by suction filtration through a pad of Celite and the filter cake was washed with ethanol. The combined filtrates were concentrated under reduced pressure to afford 5-(4-amino-2,3,6-trifluoro- phenoxy)-2-fluoro-benzonitrile (38.00 g,121 mmol, 94 % yield) as a yellow solid. MS (ESI): 281.1 (M-H)-; retention time 1.82 min (modified Method 4 - Gradient: T0 min: 5% B: 90% B, T1.5 min). Intermediate 12C 5-(4-Amino-2,3,6-trifluoro-5-iodo-phenoxy)-2-fluoro-benzonitrile A mixture of 5-(4-amino-2,3,6-trifluoro-phenoxy)-2-fluoro-benzonitrile (1.00 eq, 38.00 g, 135 mmol) and NIS (1.20 eq, 36.35 g, 162 mmol) in acetic acid (500 mL) was stirred at 25 °C for 1 h. The mixture was diluted with ethyl acetate (200 mL), washed with water (3 x 50 mL), brine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 3:1 petroleum ether : ethyl acetate to afford 5-(4-amino-2,3,6-trifluoro-5-iodo-phenoxy)-2-fluoro-benzonitrile (40.00 g, 98.0 mmol, 72 % yield) as a yellow solid. MS (ESI): 409.0 (M+H)⁺ ; retention time 2.13 min (Method 4). Intermediate 12D 5-[4-Amino-2,3,6-trifluoro-5-(2-trimethylsilylethynyl)phenoxy]-2-fluoro-benzonitrile To a solution of 5-(4-amino-2,3,6-trifluoro-5-iodo-phenoxy)-2-fluoro-benzonitrile (1.00 eq, 32.00 g, 78.4 mmol) in DMF (200 mL) was added copper(I) iodide (0.200 eq, 2.99 g, 15.7 mmol) triethylamine (3.00 eq, 33 mL, 235 mmol), 1,1-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (0.100 eq, 5.74 g, 7.84 mmol), followed by trimethylsilylacetylene (3.00 eq, 33 mL, 235 mmol). The mixture was stirred overnight at 25 °C under a nitrogen atmosphere, diluted with ethyl acetate (300 mL), washed with water (3 x 300 mL), brine (2 x 300 mL), and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 5:1 petroleum ether : ethyl acetate to afford 5-[4- amino-2,3,6-trifluoro-5-(2-trimethylsilylethynyl)phenoxy]-2-fluoro-benzonitrile (18.00 g, 47.6 mmol, 60 % yield) as a brown oil. MS (ESI): 379.1 (M+H)⁺ ; retention time 2.93 min (Method 4). Intermediate 12E 2-Fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]benzonitrile To a solution of 5-[4-amino-2,3,6-trifluoro-5-(2-trimethylsilylethynyl)phenoxy]-2-fluoro- benzonitrile (1.00 eq, 18.00 g, 47.6 mmol) in DMF (120 mL) was added copper(I) iodide (2.00 eq, 18.12 g, 95.1 mmol) . The resulting mixture was stirred overnight at 100 °C in a glove box under an atmosphere of inert gas. The insoluble material was removed by suction filtration, the filtrate was diluted with ethyl acetate (200 mL), washed with water (3 x 200 mL), brine (2 x 200 mL) and concentrated in vacuo. The residue was purified by silica gel column chromatography, eluting with 5:1 petroleum ether : ethyl acetate to afford 2-fluoro-5-[(4,6,7- trifluoro-1H-indol-5-yl)oxy]benzonitrile (12.00 g, 39.2 mmol, 82 % yield) as a yellow solid. MS (ESI): 307.1 (M+H)⁺ ; retention time 2.99 min (Method 4). Intermediate 13 Methyl 2-fluoro-5-((4,6,7-trifluoro-1H-indol-5-yl)oxy)benzimidothioate hydroiodide To a solution of 2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]benzenecarboximidothioic acid (1.00 eq, 3.80 g, 11.2 mmol) in acetone (50 mL) was added methyl iodide (5.00 eq, 3.0 mL, 48.3 mmol), the mixture was stirred at 50 °C for 6 h and concentrated under reduced pressure to give crude methyl 2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy] benzenecarboximidothioate (5.00 g, 14.1 mmol, 126 % yield). MS (ESI): 355.0 (M+H)⁺ ; retention time 1.69 min (modified Method 2 - Gradient: T0 min: 5% B: 95% B, T1.3 min : 95% B; Flow: 1.8 mL/min). The crude product was advanced to the next step without purification or further characterization. Intermediate 13A 2-Fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]benzenecarboximidothioic acid To a mixture of magnesium chloride hexahydrate ( 1.00 eq, 2.15 g, 10.6 mmol) in DMF (20 mL) was added sodium hydrosulfide (2.00 eq, 1.19 g, 21.1 mmol). The mixture was stirred for 10 minutes, treated with 2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)oxy]benzonitrile (Intermediate 12) (1.00 eq, 3.80 g, 10.6 mmol), and stirred for another 1 h at room temperature. The reaction was diluted with EtOAc (100 mL), washed with water (2 x 100 mL), brine (2 x 100 mL), and concentrated. The residue was purified by flash chromatography on silica gel eluting with 50% EtOAc in PE to give 2-fluoro-5-[(4,6,7- trifluoro-1H-indol-5-yl)oxy]benzenecarboximidothioic acid (3.80 g, 11.2 mmol, 90 % yield). MS (ESI): 341.1 (M+H)⁺ ; retention time 1.84 min (modified Method 2 - Gradient: T0 min: 5% B: 95% B, T1.3 min : 95% B; Flow: 1.8 mL/min). Intermediate 14 Ethyl 3-[4-methyl-4-(methylaminocarbamoyl)chroman-8-yl]propanoate To a solution of ethyl 3-[4-[[tert-butoxycarbonyl(methyl)amino]carbamoyl]-4-methyl- chroman-8-yl]propanoate (1.00 eq, 1.35 g, 3.21 mmol) in DCM (10 mL) was added a solution of HCl in dioxane (6.23 eq, 10 mL, 20.0 mmol). The reaction mixture was stirred at room temperature for 2 hours and concentrated under reduced pressure. The residue was diluted with water (30 mL). The pH was adjusted to basic (>7) with aqueous NaHCO₃ and extracted with ethyl acetate (2 x 100 mL). The organic extracts were washed with brine (100 mL), dried over sodium sulfate and concentrated to give ethyl 3-[4-methyl-4- (methylaminocarbamoyl)chroman-8-yl]propanoate (950 mg, 2.76 mmol, 86 % yield) as a solid. MS (ESI): 321.2 (M+H)⁺ ; retention time 1.67 min. (Method 3). Intermediate 14A Ethyl 3-[4-[[tert-butoxycarbonyl(methyl)amino]carbamoyl]-4-methyl-chroman-8- yl]propanoate To a solution of 8-(3-ethoxy-3-oxo-propyl)-4-methyl-chromane-4-carboxylic acid (Intermediate 9E) (1.00 eq, 2.00 g, 6.84 mmol), TCSF (1.00 eq, 260 mg, 6.84 mmol) and 1- methylimidazole (3.50 eq, 1.9 mL, 23.9 mmol) in MeCN (20 mL) was added 1-Boc-1- methylhydrazine (1.10 eq, 1100 mg, 7.53 mmol). The mixture was stirred at RT for 1 h, diluted with EtOAc (60 ml), washed with water (2 x 30 ml), brine (30ml), dried over Na₂SO₄, and concentrated to dryness. The residue was purified by flash column chromatography on silica gel eluting with 50% EtOAc in PE to obtain ethyl 3-[4-[[tert- butoxycarbonyl(methyl)amino]carbamoyl]-4-methyl-chroman-8-yl]propanoate (1.50 g, 2.68 mmol, 39 % yield). MS (ESI): 443.2 (M+Na)⁺; retention time 1.97 min (modified Method 2 - Gradient: T0 min: 5% B: 95% B, T1.3 min : 95% B; Flow: 1.8 mL/min). Intermediate 15 Methyl 5-[[4-(2,2-difluoroethyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2-fluoro- benzenecarboximidothioate hydroiodide To a solution of 5-[[4-(2,2-difluoroethyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2-fluoro- benzenecarbothioamide (1.00 eq, 47 mg, 0.122 mmol) in acetone (2 mL) was added methyl iodide (5.00 eq, 0.038 mL, 0.608 mmol). The mixture was stirred for 2 h at 50 ºC and concentrated to give methyl 5-[[4-(2,2-difluoroethyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2- fluoro-benzenecarboximidothioate;hydroiodide (49 mg, 0.0636 mmol, 52 %) as a solid. MS (ESI): 401.1 (M+H)⁺; retention time 1.74 min (Method 3). Intermediate 15A 5-[4-(2,2-Difluorovinyl)-6,7-difluoro-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- benzonitrile To a stirred solution of sodium 3,3-difluoro-3-iodopropanoate (3.00 eq, 164 mg, 0.638 mmol) in DCM (2 mL) was added 5-[6,7-difluoro-4-formyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2- fluoro-benzonitrile (Intermediate 10C, 1.00 eq, 100 mg, 0.213 mmol) and triphenylphosphine (1.00 eq, 56 mg, 0.213 mmol). The mixture was stirred overnight at 90 ºC and concentrated to dryness. The residue was suspended in EtOAc (10 ml), washed with water (2 x 10 ml), brine (10 mL), dried over MgSO₄, and concentrated to dryness. The residue was purified by flash column chromatography on silica gel eluting with 0-30% EtOAc in PE to give 5-[4-(2,2- difluorovinyl)-6,7-difluoro-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile (28 mg, 0.0388 mmol, 18 % yield). MS (ESI): 505.1 (M+H)⁺; retention time 2.13 min (modified Method 2 - Flow Rate: 1.8mL/min). Intermediate 15B 5-[4-(2,2-Difluoroethyl)-6,7-difluoro-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- benzonitrile To a solution of 5-[4-(2,2-difluorovinyl)-6,7-difluoro-1-(p-tolylsulfonyl)indol-5-yl]oxy-2- fluoro-benzonitrile (1.00 eq, 567 mg, 1.12 mmol) in ethyl acetate (10 mL) was added Pd/C (2.34 eq, 280 mg, 2.63 mmol) . The reaction suspension was stirred at 50 ºC under an atmosphere of H₂ for 4 h. The solids were filtered off and rinsed with EA (2 x 6 mL). The filtrate was concentrated to afford 5-[4-(2,2-difluoroethyl)-6,7-difluoro-1-(p- tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile (447 mg,0.265 mmol, 23 % yield) as an oil. MS (ESI): 507.1 (M+H)⁺; retention time 2.14 min (Method 3). Intermediate 15C 5-[[4-(2,2-Difluoroethyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2-fluoro-benzonitrile To a solution of 5-[4-(2,2-difluoroethyl)-6,7-difluoro-1-(p-tolylsulfonyl)indol-5-yl]oxy-2- fluoro-benzonitrile (1.00 eq, 447 mg, 0.883 mmol) in THF (2.7 mL) was added TBAF (1M in THF, 3.00 eq, 692 mg, 2.65 mmol) and the resulting mixture was stirred for 1 h at 80 ºC and concentrated to dryness. The residue was suspended in EtOAc (10 ml), washed with water (2 x 10 mL), brine (10 mL), dried over MgSO₄, and concentrated to dryness. The residue was purified by flash column chromatography on silica gel eluting with 0-30% EtOAc in PE to give 5-[[4-(2,2-difluoroethyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2-fluoro-benzonitrile (130 mg, 0.332 mmol, 38 % yield). MS (ESI): 353.1 (M+H)⁺; retention time 2.00 min (Method 3). Intermediate 15D 5-[[4-(2,2-Difluoroethyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2-fluoro- benzenecarbothioamide To a solution of 5-[[4-(2,2-difluoroethyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2-fluoro- benzonitrile (1.00 eq, 130 mg, 0.369 mmol) in DMF (2 ml) was added magnesium chloride (1.00 eq, 35 mg, 0.369 mmol) and sodium hydrosulfide (2.00 eq, 41 mg, 0.738 mmol), and the mixture was stirred for 1 h at RT. The reaction was concentrated to dryness and the residue was suspended in water (10 ml) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO₄ and concentrated to dryness. The residue was purified by flash chromatography on silica gel eluting with 0-60% ethyl acetate in petroleum ether to give 5-[[4-(2,2-difluoroethyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2-fluoro- benzenecarbothioamide (47 mg, 0.116 mmol, 31 % yield). MS (ESI): 387.1 (M+H)⁺; retention time 1.89 min (Method 3). Intermediate 16 Methyl 5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro- benzenecarboximidothioate hydroiodide The title compound (1.50 g, 2.94 mmol, 90% yield, a yellow solid) was prepared in substantially the same way as Intermediate 15 starting from 5-[(6,7-difluoro-4-methylsulfanyl- 1H-indol-5-yl)oxy]-2-fluoro-benzenecarboximidothioic acid (1.00 eq, 1.20 g, 3.26 mmol). MS (ESI): 383.1 (M+H)⁺; retention time 1.77 min (Method 3). Intermediate 16A 5-(6-Bromo-2,3-difluoro-4-nitro-phenoxy)-2-fluoro-benzonitrile and 4-(4-bromo-2,3- difluoro-6-nitrophenoxy)-2-fluorobenzonitrile To a suspension of 1-bromo-2,3,4-trifluoro-5-nitro-benzene (1.00 eq, 18.67 g, 72.9 mmol) and potassium carbonate (2.00 eq, 20160 mg, 146 mmol) in DMF (80 mL) was added 2-fluoro-5- hydroxy-benzonitrile (1.00 eq, 10.00 g, 72.9 mmol) in DMF (20 mL) at rt. The reaction mixture was stirred at rt under Ar for 16 h, quenched with water (500 mL) and extracted with ethyl acetate (3 x 500 mL). The combined extracts were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-40% ethyl acetate in petroleum ether to give an unresolved mixture of 5-(6-bromo-2,3-difluoro-4-nitro-phenoxy)-2-fluoro-benzonitrile and 4- (4-bromo-2,3-difluoro-6-nitrophenoxy)-2-fluorobenzonitrile (17.20 g, 46.1 mmol, 63 % yield) as a yellow solid. MS (ESI): 373 (M+H)⁺; retention time 2.13 min (Method 3). Intermediate 16B 5-(4-Amino-6-bromo-2,3-difluoro-phenoxy)-2-fluoro-benzonitrile and 4-(6-amino-4- bromo-2,3-difluorophenoxy)-2-fluorobenzonitrile To a solution of 5-(6-bromo-2,3-difluoro-4-nitro-phenoxy)-2-fluoro-benzonitrile (1.00 eq, 17.20 g, 39.0 mmol) in acetic acid (100 mL) was added iron (5.00 eq, 10878 mg, 195 mmol), and the suspension was stirred at rt for 4 hours. The reaction mixture was diluted with water (400 mL), extracted with EA (300 mL x 2). The combined organic extracts were 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 an unresolved mixture of 5-(4-amino-6-bromo-2,3-difluoro-phenoxy)-2-fluoro-benzonitrile and 4-(6-amino-4-bromo-2,3-difluorophenoxy)-2-fluorobenzonitrile (10.60 g, 30.9 mmol, 79 % yield) as a yellow solid. MS (ESI): 343, 345 (M+H)⁺; retention time 1.94 min (modified Method 3 – Flow Rate: 2.2 mL/min). Intermediate 16C 5-(4-Amino-2-bromo-5,6-difluoro-3-iodo-phenoxy)-2-fluoro-benzonitrile and 5-(2- amino-4-bromo-5,6-difluoro-3-iodo-phenoxy)-2-fluoro-benzonitrile To a solution of a mixture of 5-(4-amino-6-bromo-2,3-difluoro-phenoxy)-2-fluoro-benzonitrile and 5-(2-amino-4-bromo-5,6-difluoro-3-iodo-phenoxy)-2-fluoro-benzonitrile (Intermediate 16B, 1.00 eq, 68.60 g, 200 mmol) in acetic acid (900 mL) was added NIS (1.00 eq, 44.98 g, 200 mmol), and the resulting mixture was stirred at RT for 3 h. A precipitate formed. The mixture was filtered, the solid was washed with acetic acid (100 mL), methyl tert-butyl ether (150 mL) and dried in vacuo to give an unresolved mixture of 5-(4-amino-2-bromo-5,6- difluoro-3-iodo-phenoxy)-2-fluoro-benzonitrile and 5-(2-amino-4-bromo-5,6-difluoro-3-iodo- phenoxy)-2-fluoro-benzonitrile (40.50 g, 84.9 mmol, 42 % yield) as a white solid. MS (ESI): 468.8, 470.8 (M+H)⁺; retention time 2.08 min (Method 3). The filtrate was concentrated to give a residue (350 mL) containing acetic acid. Upon standing at RT a precipitate formed. The precipitate was isolated by filtration, washed with acetic acid (100 mL) and methyl tert-butyl ether (150 mL), and dried in vacuo to afford additional product mixture (25 g, 26 %) as a white solid. MS (ESI): 468.8, 470.8 (M+H)⁺; retention time 2.08 min (Method 3). Intermediate 16D 5-[4-Amino-2-bromo-5,6-difluoro-3-(2-trimethylsilylethynyl)phenoxy]-2-fluoro- benzonitrile To a solution of a mixture of 5-(4-amino-2-bromo-5,6-difluoro-3-iodo-phenoxy)-2-fluoro- benzonitrile and 5-(2-amino-4-bromo-5,6-difluoro-3-iodo-phenoxy)-2-fluoro-benzonitrile (Intermediate 16C, 1.00 eq, 25.00 g, 53.3 mmol) in DMF (75 mL) was added TEA (3.00 eq, 22 mL, 160 mmol), copper(I) iodide (0.200 eq, 2.03 g, 10.7 mmol), trimethylsilylacetylene (2.40 eq, 18 mL, 128 mmol) and bis(triphenylphosphine)palladium(II) dichloride (0.200 eq, 7.48 g, 10.7 mmol). The reaction mixture was stirred at room temperature for 3 h under an Ar atmosphere, quenched with water (150 mL), and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-10% ethyl acetate in petroleum ether to give 5-[4-amino-2-bromo- 5,6-difluoro-3-(2-trimethylsilylethynyl)phenoxy]-2-fluoro-benzonitrile (14.10 g, 27.3 mmol, 51 % yield) as a solid.. MS (ESI): 439.0, 441.0 (M+H)⁺; retention time 2.30 min (Method 3). Intermediate 16E 5-[(4-Bromo-6,7-difluoro-1H-indol-5-yl)oxy]-2-fluoro-benzonitrile To a solution of 5-[4-amino-2-bromo-5,6-difluoro-3-(2-trimethylsilylethynyl)phenoxy]-2- fluoro-benzonitrile (1.00 eq, 14.00 g, 31.9 mmol) in DMF (210 mL) was added copper(I) iodide (0.200 eq, 1.21 g, 6.37 mmol) and the reaction was stirred at 100 °C for 1 h under and Ar atmosphere. The reaction mixture was cooled to rt, quenched with water (600 mL), and extracted with ethyl acetate (2 x 300 mL). The combined organic extracts were washed with brine (200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-20% ethyl acetate in petroleum ether to give 5-[(4-bromo-6,7-difluoro-1H-indol-5-yl)oxy]-2-fluoro-benzonitrile (4.50 g, 11.0 mmol, 35 % yield) as solid. MS (ESI): 367.0, 369.0 (M+H)⁺; retention time 2.06 min (modified Method 3 - Gradient: T0 min: 10% B; T1.4 min : 95%B). Intermediate 16F 5-[4-Bromo-6,7-difluoro-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile To a stirred and chilled (0 °C) solution of 5-[(4-bromo-6,7-difluoro-1H-indol-5-yl)oxy]-2- fluoro-benzonitrile (1.00 eq, 20.00 g, 54.5 mmol) in THF (200 mL) was added sodium hydride (60 % dispersion in oil, 1.10 eq, 2.40 g, 59.9 mmol). The mixture was stirred for 1 h at 0 °C, then treated with 4-toluenesulfonyl chloride (1.05 eq, 10.91 g, 57.2 mmol). The mixture was allowed to warm to RT and was stirred at RT for 2 hours, quenched with a saturated aqueous ammonium chloride solution (100 mL), and extracted with ethyl acetate (200 mL). The separated organic phase was washed with water (200 mL), brine (200 mL), dried over anhydrate sodium sulfate, filtered, and concentrated to afford crude 5-[4-bromo-6,7-difluoro- 1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile (28.40 g, 54.5 mmol, quantitative yield) as a solid. ¹H NMR (400 MHz, CDCl₃) δ 7.89 (dd, J = 11.6, 5.6 Hz, 3H), 7.35 (d, J = 8.0 Hz, 2H), 7.21- 7.13 (m, 2H), 7.02-6.96 (m, 1H), 6.78 (dd, J = 3.6, 2.0 Hz, 1H), 2.43 (s, 3H). Intermediate 16G 5-[6,7-Difluoro-4-[(4-methoxyphenyl)methylsulfanyl]-1-(p-tolylsulfonyl)indol-5-yl]oxy- 2-fluoro-benzonitrile A mixture of 5-[4-bromo-6,7-difluoro-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile (1.00 eq, 10.00 g, 19.2 mmol) , 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.100 eq, 1.11 g, 1.92 mmol), 4-methoxybenzyl mercaptan (1.20 eq, 3.2 mL, 23.0 mmol), tris(dibenzylideneacetone)dipalladium (0.0500 eq, 0.88 g, 0.959 mmol), N,N- Diisopropylethylamine (2.00 eq, 6.7 mL, 38.4 mmol) and 1,4-dioxane (300 mL) was stirred overnight at 100 °C. The reaction mixture was cooled to RT, partitioned between water and EA. The separated organic phase was washed with brine, dried over Na₂SO₄, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-30% ethyl acetate in petroleum ether to give5-[6,7-difluoro-4-[(4-methoxyphenyl)methylsulfanyl]- 1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile (10.00 g, 15.6 mmol, 82 % yield) as a solid. MS (ESI): 617.2 (M+Na)⁺; retention time 2.28 min (modified Method 2 - Gradient: T0 min: 5% B; 95% B, T1.3 min ; Column Temperature: 45 °C). Intermediate 16H 5-[6,7-Difluoro-1-(p-tolylsulfonyl)-4-sulfanyl-indol-5-yl]oxy-2-fluoro-benzonitrile To a solution of 5-[6,7-difluoro-4-[(4-methoxyphenyl)methylsulfanyl]-1-(p- tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile (1.00 eq, 2.00 g, 3.36 mmol) in anisole (10 mL) was added TFA (38.6 eq, 10 mL, 130 mmol). The reaction was stirred overnight at 50 °C and concentrated. The residue was dissolved into THF (20 mL), treated with triphenylphosphine (1.13 eq, 1.00 g, 3.81 mmol), stirred at room temperature for 2 hours, and concentrated to give 5-[6,7-difluoro-1-(p-tolylsulfonyl)-4-sulfanyl-indol-5-yl]oxy-2-fluoro- benzonitrile (2.90 g,1.83 mmol, 55 % yield) which was used directly in the next step. MS (ESI): 497.1 (M+Na)⁺; retention time 2.19 min (modified Method 2 – Gradient: T0 min: 5% B; 95% B, T1.3 min ; Column Temperature: 45 °C). Intermediate 16I 5-[6,7-Difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile To a solution of 5-[6,7-difluoro-1-(p-tolylsulfonyl)-4-sulfanyl-indol-5-yl]oxy-2-fluoro- benzonitrile (1.00 eq, 2.90 g, 6.11 mmol) in acetone (20 mL) was added iodomethane (1.20 eq, 0.46 mL, 7.33 mmol) and potassium carbonate (3.00 eq, 2534 mg, 18.3 mmol). The reaction mixture was stirred at room temperature for 2 hours, the solids were filtered off, the filtrate was concentrated, and the residue was purified by flash chromatography on silica gel eluting with 0-20% ethyl acetate in petroleum ether to give 5-[6,7-difluoro-4-methylsulfanyl-1-(p- tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile (1.3 g, 2.67 mmol, 92% yield) as a yellow oil. MS (ESI): 489.1 (M+H)⁺; retention time 2.23 min (Method 3). Intermediate 16J 5-[(6,7-Difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzonitrile A mixture of 5-[6,7-difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- benzonitrile (1.00 eq, 5.80 g, 11.9 mmol) and a solution of TBAF in THF (60 mL, 1 M) was stirred at room temperature for 2 hours, quenched with water (100 mL), and extracted with ethyl acetate (100 mL). The organic extract was washed with brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-15% ethyl acetate in petroleum ether to give crude 5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzonitrile (4.65 g, 13.5 mmol, 114 % yield) as a solid, which was used directly in the next step. MS (ESI): 335.1 (M+H)⁺; retention time 2.05 min (Method 3). Intermediate 16K 5-[(6,7-Difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro- benzenecarboximidothioic acid To a solution of magnesium chloride (1.00 eq, 577 mg, 2.84 mmol) in DMF (10 mL) was added at 0°C sodium hydrosulfide (2.00 eq, 318 mg, 5.68 mmol) and 5-[(6,7-difluoro-4- methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzonitrile (1.00 eq, 950 mg, 2.84 mmol). The reaction mixture was stirred at room temperature for 2 hours, diluted with water (50 mL), and extracted with ethyl acetate (2 x 50 mL). The combined organic extracts were washed with aqueous LiCl (50 mL), brine (50 mL), dried over sodium sulfate and concentrated to give 5- [(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzenecarboximidothioic acid (1.10 g, 2.69 mmol, 95 % yield) as a solid which was used directly in the next step. MS (ESI): 369.1 (M+H)⁺; retention time 1.92 min (Method 3). Intermediate 17 5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzamidine To a solution of 5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzonitrile (Intermediate 16J, 1.00 eq, 656 mg, 1.96 mmol) in THF (10 mL) was added LHMDS (8.00 eq, 16 mL, 15.7 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 3 h, diluted with water (50 mL), and extracted with ethyl acetate (100 mL). The separated organic extract was washed with brine (100 mL), dried over Na₂SO₄ and concentrated to give 5-[(6,7- difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzamidine (670 mg, 1.91 mmol, 97 % yield) as a solid. MS (ESI): 352.1 (M+H)⁺; retention time 1.47 min (Method 3). Intermediate 18 Methyl (2R)-3-[4-(2-bromoacetyl)-4-methyl-chroman-8-yl]-2-methyl-propanoate A solution of 8-[(2R)-3-methoxy-2-methyl-3-oxo-propyl]-4-methyl-chromane-4-carboxylic acid (1.00 eq, 370 mg, 1.27 mmol) in thionyl chloride (32.5 eq, 3.0 mL, 41.1 mmol) was stirred at 80 °C for 1 h and concentrated. The residue was dissolved in MeCN (4 mL), treated with trimethylsilyldiazomethane (2.00 eq, 289 mg, 2.53 mmol) at 0 °C. The reaction was stirred at 0 °C for 30 min, treated with hydrobromic acid (29.9 eq, 2.1 mL, 37.9 mmol) , stirred at 0 °C for another 30 min. and quenched with water (30 mL). The mixture was extracted with ethyl acetate (35 mL). The separated organic phase was washed with brine (35 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-15% EtOAc in PE to give methyl (2R)-3-[4-(2- bromoacetyl)-4-methyl-chroman-8-yl]-2-methyl-propanoate (320 mg, 0.667 mmol, 53 % yield) as a solid. MS (ESI): 369.1, 371.1 (M+H)⁺; retention time 2.06 min (Method 3). Intermediate 18A Benzyl 8-[(2R)-3-methoxy-2-methyl-3-oxo-propyl]-4-methyl-chromane-4-carboxylate To a suspension of zinc powder (6.00 eq, 326 mg, 4.98 mmol) in DMF (3 mL) was added iodine (0.100 eq, 21 mg, 0.0830 mmol) under Ar. The mixture was stirred at room temperature for 40 min and methyl (2S)-3-iodo-2-methyl-propanoate (1.20 eq, 227 mg, 0.997 mmol) was added. The mixture was stirred at room temperature for another 40 min, then 2- dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (0.100 eq, 34 mg, 0.0830 mmol) and tris(dibenzylideneacetone) dipalladium (0.0500 eq, 38 mg, 0.0415 mmol) were added followed by benzyl 8-bromo-4-methyl-chromane-4-carboxylate (Step B, Example 18, 1.00 eq, 300 mg, 0.830 mmol). The reaction mixture was stirred overnight at 70 °C, cooled to RT, and diluted with water (20 mL) and ethyl acetate (20 mL). The solids were filtered off, the filtrate phases were separated, and the aqueous phase was extracted with ethyl acetate (2 x 10 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-10% ethyl acetate in petroleum ether to give benzyl 8-[(2R)-3-methoxy-2- methyl-3-oxo-propyl]-4-methyl-chromane-4-carboxylate (230 mg, 0.601 mmol, 72 % yield). MS (ESI): 383.2 (M+H)⁺; retention time 2.18 min (Method 3). Intermediate 18B 8-[(2R)-3-Methoxy-2-methyl-3-oxo-propyl]-4-methyl-chromane-4-carboxylic acid To a solution of benzyl 8-[(2R)-3-methoxy-2-methyl-3-oxo-propyl]-4-methyl-chromane-4- carboxylate (1.00 eq, 1.04 g, 2.72 mmol) in THF (10 mL) was added Palladium on active carbon (10 wt. %, 200 mg) under H₂. The reaction mixture was stirred under hydrogen at ambient temperature and pressure for 5 h, the solids were filtered off and the filtrate was concentrated to give 8-[(2R)-3-methoxy-2-methyl-3-oxo-propyl]-4-methyl-chromane-4- carboxylic acid (690 mg, 2.36 mmol, 87 % yield) as a solid. MS (ESI): 293.2 (M+H)⁺; retention time 1.86 min (Method 3). Intermediate 19 Methyl (2S)-3-(4-(2-bromoacetyl)-4-methylchroman-8-yl)-2-methylpropanoate Prepared following the procedures for Example 18 by replacing methyl (2S)-3-iodo-2-methyl- propanoate with methyl (2R)-3-iodo-2-methyl-propanoate. MS (ESI): 369.1, 371.1 (M+H)⁺; retention time 2.06 min (Method 3). Intermediate 20 Ethyl 3-[4-(2-bromoacetyl)-4-(trideuteriomethyl)chroman-8-yl]propanoate Prepared in substantially the same way as Intermediate 9 but using iodomethane-D₃ in the place of iodomethane when running the second step in the synthesis (Intermediate 9B). MS (ESI): 372.2, 374.2 (M+H)⁺; retention time 2.05 min (modified Method 3- Temperature: 45 °C). Intermediate 21 5-[[6,7-Difluoro-4-(trideuteriomethylsulfanyl)-1H-indol-5-yl]oxy]-2-fluoro-benzamidine Prepared in substantially the same way as Intermediate 17, starting from Intermediate 16H but using iodomethane-D₃ in the place of iodomethane. MS (ESI): 355.2 (M+H)⁺; retention time 1.47 min (modified Method 3- Temperature: 45 °C). Intermediate 22 5-[(6,7-Difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzoic acid A mixture of 5-[6,7-difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- benzonitrile (Intermediate 16, 1.00 eq, 2.30 g, 4.71 mmol) and sodium hydroxide (3.00 eq, 0.56 g, 14.1 mmol) in methanol (40 mL) and water (40 mL) was stirred at 45 °C for 16 hours and concentrated in vacuo. The residue was acidified with 1M hydrochloric acid to pH 5-6 and 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 0-10% methanol in dichloromethane to give the product 5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2- fluoro-benzoic acid (1.50 g,4.25 mmol, 90 % yield) as a yellow solid. MS (ESI): 354.3 (M+H)⁺; retention time 1.87 min (Method 2 - Temperature: 45 °C). Intermediate 23 5-[(6,7-Difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-N-methyl-benzamidine To a solution of methylamine hydrochloride (20.0 eq, 2.42 g, 35.9 mmol) in toluene (100 mL) was added trimethylaluminum (20.0 eq, 36 mL, 35.9 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 2 h. 5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2- fluoro-benzonitrile (Intermediate 16J, 1.00 eq, 600 mg, 1.79 mmol) was then added and the reaction mixture was heated at reflux overnight and poured into ice water (500 mL). The solids were removed by filtration, the filtrate was extracted with ethyl acetate (2 x 500 mL). The combined organic extracts were washed with brine (500 mL), dried over Na₂SO₄, fileted, and concentrated. The crude was purified by flash column chromatography on silica gel eluting with 0-15% MeOH in DCM to give 5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2- fluoro-N-methyl-benzamidine (500 mg, 1.37 mmol, 76 % yield) as a solid. MS (ESI): 366.2 (M+H)⁺; retention time 1.48 min (Method 3). Intermediate 24 2-Bromo-1-(4-methylchroman-4-yl)ethanone Prepared in substantially the same way as Intermediate 9 starting from 4-methylchromane-4- carboxylic acid. MS (ESI): 269.2, 271.2 (M+H)⁺. Intermediate 25 2-Fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)sulfanyl]benzamidine To a solution of 2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)sulfanyl]benzonitrile (1.00 eq, 850 mg, 2.64 mmol) in dry THF (10 mL) was added LHMDS (8.00 eq, 21 mL, 21.1 mmol) dropwise at 0 °C under Ar. The mixture was stirred at room temperature for 2 h, quenched with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (2 x 40 mL). The combined organic phases were washed with brine (80 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5- yl)sulfanyl]benzamidine (800 mg, 2.36 mmol, 89 % yield) as a solid. MS (ESI): 340 (M+H)⁺; retention time 1.47 min (Method 2). Intermediate 25A 2-Fluoro-5-(2,3,6-trifluoro-4-nitro-phenyl)sulfanyl-benzonitrile To a solution of 2-fluoro-5-sulfanyl-benzonitrile (14 g, 91.4 mmol) in DMF (200 mL) was added 2,3,4,5-tetrafluoronitrobenzene (17.8 g, 91.4 mmol) and potassium carbonate (25.2 g, 182.8 mmol). The mixture was stirred at room temperature for 1 h, quenched with water (500 mL) and extracted with ethyl acetate (500 mL x 3). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-20% ethyl acetate in petroleum ether to give 2-fluoro-5-(2,3,6-trifluoro-4-nitro-phenyl)sulfanyl-benzonitrile (24 g, 80 % yield) as a solid. MS (ESI): 329.1 (M+H)⁺; retention time 1.97 min (Method 2A). Intermediate 25B 5-(4-Amino-2,3,6-trifluoro-phenyl)sulfanyl-2-fluoro-benzonitrile To a solution of 2-fluoro-5-(2,3,6-trifluoro-4-nitro-phenyl)sulfanyl-benzonitrile (24 g, 73.1 mmol) in toluene (300 mL) and acetic acid (100 mL) was added Fe powder (20.4 g, 365.6 mmol) at room temperature. The reaction mixture was stirred at room temperature for 1 h. The volatiles were removed under reduced pressure and the residue was diluted with ethyl acetate (500 mL), washed with water (500 mL x 2), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 0-30% ethyl acetate in petroleum ether to give 5-(4-amino-2,3,6-trifluoro-phenyl)sulfanyl-2- fluoro-benzonitrile (18.5 g, 85 % yield) as a solid. MS (ESI): 299.0 (M+H)⁺; retention time 1.96 min (Method 2A). Intermediate 25C 5-(4-Amino-2,3,6-trifluoro-5-iodo-phenyl)sulfanyl-2-fluoro-benzonitrile To a solution of 5-(4-amino-2,3,6-trifluoro-phenyl)sulfanyl-2-fluoro-benzonitrile (18.5 g, 62 mmol) in acetic acid (500 mL) was added NIS (15.3 g, 68.2 mmol) at room temperature. The reaction mixture was stirred at room temperature for 16 h and concentrated. The mixture was diluted with ethyl acetate (1000 mL), washed with water (500 mL x 2), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 0-50% ethyl acetate in petroleum ether to give 5-(4-amino-2,3,6- trifluoro-5-iodo-phenyl)sulfanyl-2-fluoro-benzonitrile (22 g, 84 % yield) as a solid. MS (ESI): 425.1 (M+H)⁺; retention time 2.23 min (Method 2A). Intermediate 25D 5-[4-Amino-2,3,6-trifluoro-5-(2-trimethylsilylethynyl)phenyl]sulfanyl-2-fluoro- benzonitrile To a solution of 5-(4-amino-2,3,6-trifluoro-5-iodo-phenyl)sulfanyl-2-fluoro-benzonitrile (22 g, 51.8 mmol) in DMF (200 mL) was added trimethylsilylacetylene (17.5 mL, 124.48 mmol), dichlorobis(triphenylphosphine)palladium(II) (3.64 g, 5.18 mmol), CuI (1.97 g, 10.37 mmol) and TEA (21.7 mL, 155.6 mmol) at room temperature. The reaction mixture was stirred at room temperature for 2 h, extracted with ethyl acetate (1000 mL), washed with brine (1000 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-20% ethyl acetate in petroleum ether to give 5-[4-amino-2,3,6-trifluoro-5-(2-trimethylsilylethynyl)phenyl]sulfanyl-2-fluoro- benzonitrile (17 g, 83 % yield) as an oil. MS (ESI): 395.0 (M+H)⁺; retention time 2.21 min (Method 2A). Intermediate 25E 2-Fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)sulfanyl]benzonitrile A mixture of 5-[4-amino-2,3,6-trifluoro-5-(2-trimethylsilylethynyl)phenyl]sulfanyl-2-fluoro- benzonitrile (17 g, 43 mmol), DMF (200 mL) and CuI (1.64 g, 8.6 mmol) was stirred at 100 °C for 16 h. The mixture was extracted with ethyl acetate (500 mL), washed with brine (500 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-40% ethyl acetate in petroleum ether to give 2-fluoro-5-[(4,6,7-trifluoro-1H-indol-5-yl)sulfanyl]benzonitrile (9 g, 65 % yield) as a solid. MS (ESI): 323.0 (M+H)⁺; retention time 2.00 min (Method 2A). Intermediate 26 Methyl (3R)-3-[(4S)-4-(2-bromoacetyl)-4-methyl-chroman-8-yl]butanoate To a solution of (4S)-8-[(1R)-3-methoxy-1-methyl-3-oxo-propyl]-4-methyl-chromane-4- carboxylic acid (Intermediate 26F, 1.00 eq, 500 mg, 1.71 mmol) in DCM (5 mL) was added oxalyl chloride (2.00 eq, 0.30 mL, 3.42 mmol) and a drop of DMF at 0 °C. The reaction mixture was stirred at room temperature for 30 min and concentrated. The residue was dissolved in MeCN (5 mL) and trimethylsilyldiazomethane (4.00 eq, 3.4 mL, 6.84 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature for 1 h and hydrobromic acid (4.00 eq, 0.37 mL, 6.84 mmol) was added. The reaction mixture was stirred at 0 °C for another 30 min, water (20 mL) was added and the solution was extracted with ethyl acetate (20 mL). The organic layer was washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give methyl (3R)-3-[(4S)-4-(2-bromoacetyl)-4-methyl-chroman-8- yl]butanoate (590 mg, 1.60 mmol, 93 % yield) as solid.. MS (ESI): 369, 371 (M+H)⁺; retention time 2.00 min (Method 3). Intermediate 26A Benzyl 8-bromo-4-methyl-chromane-4-carboxylate To a solution of 8-bromo-4-methyl-chromane-4-carboxylic acid (1.00 eq, 2.00 g, 7.38 mmol) in acetone (20 mL) was added potassium carbonate (1.50 eq, 1.53 g, 11.1 mmol) and benzyl bromide (1.19 eq, 1.0 mL, 8.77 mmol), and the mixture was stirred at 60 °C for 6 h. The reaction was quenched with water (10 mL), extracted with ethyl acetate (10 mL), the organic phase was washed with brine (20 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-13% ethyl acetate in petroleum ether to give benzyl 8-bromo-4-methyl-chromane-4-carboxylate (2.30 g, 6.18 mmol, 84 % yield) as a solid. MS (ESI): 383, 385 (M+Na)⁺; retention time 2.17 min (Method 3). Intermediate 26B Benzyl (4S)-8-bromo-4-methyl-chromane-4-carboxylate The racemic benzyl 8-bromo-4-methyl-chromane-4-carboxylate (1.00 eq, 3.00 g, 8.30 mmol) was resolved into its constituent stereoisomers via chiral SFC according to the following conditions: Instrument: SFC-150 (Waters); Column: OJ 25 * 250 mm, 10 µm (Daicel); Column temperature: 35 ºC; Mobile phase: 85/15 CO₂/MeOH [spiked with 0.2% 7M NH₃ in MeOH] ; Flow rate: 90 ml/min; Back pressure: 100 bar; Detection wavelength: 214 nm; Cycle time: 8.2 min; Sample solution: 3000 mg dissolved in 77 ml Methanol; Injection volume: 3.5 ml Thus were obtained benzyl (4R)-8-bromo-4-methyl-chromane-4-carboxylate (Product P1, Intermediate 26C, 1.50 g, 4.07 mmol, 49 % yield) and benzyl (4S)-8-bromo-4-methyl- chromane-4-carboxylate (Product P2, Intermediate 26B, 1.30 g, 3.38 mmol, 41 % yield) as solids. MS (ESI): 384.1 (M+H)⁺; retention time 2.17 min (Method 3) observed for both enantiomers. The absolute configurations of Intermediate 26B and Intermediate 26C are unknown and were assigned arbitrarily for identification purposes. Intermediate 26C Benzyl (4R)-8-bromo-4-methyl-chromane-4-carboxylate The title compound (absolute configuration unknown and assigned arbitrarily) was prepared as described for Intermediate 26B. Intermediate 26D Isomers of benzyl (S,Z)-8-(4-methoxy-4-oxobut-2-en-2-yl)-4-methylchromane-4- carboxylate To a solution of benzyl (4S)-8-bromo-4-methyl-chromane-4-carboxylate (Intermediate 26B, 1.00 eq, 1.30 g, 3.60 mmol) in toluene (10 mL) was added bis(tri-tert- butylphosphine)palladium(0) (0.100 eq, 185 mg, 0.360 mmol), trans-methyl crotonate (1.50 eq, 540 mg, 5.40 mmol) and TEA (10.0 eq, 5.0 mL, 36.0 mmol), and the reaction mixture was stirred at 120 °C overnight. After cooling to rt the reaction mixture was concentrated to dryness. The residue was purified by flash column chromatography on silica gel eluting with 0-25% EtOAc in PE to give two products whose masses were consistent with the structure of the desired benzyl (S,Z)-8-(4-methoxy-4-oxobut-2-en-2-yl)-4-methylchromane-4-carboxylate and its isomers. Thus, were isolated Product P1 (800 mg, 2.06 mmol, 57 % yield) and Product P2 (120 mg, 0.274 mmol, 8 % yield). Product P1: MS (ESI): 381.3 (M+H)⁺; retention time 2.17 min (Method 3). Product P2: MS (ESI): 381.3 (M+H)⁺; retention time 2.11 min (Method 3). Intermediate 26E (4S)-8-(3-methoxy-1-methyl-3-oxo-propyl)-4-methyl-chromane-4-carboxylic acid To a solution of Intermediate 26D (1.00 eq, 800 mg, 2.10 mmol) in THF (10 mL) and methanol (10 mL) was added Pd/C (0.894 eq, 200 mg, 1.88 mmol). The reaction mixture was stirred at room temperature for 5 h under hydrogen, filtered and concentrated to give (4S)-8-(3-methoxy- 1-methyl-3-oxo-propyl)-4-methyl-chromane-4-carboxylic acid (660 mg, 2.03 mmol, 97 % yield) as a solid. MS (ESI): 293.2 (M+H)⁺; retention time 1.85 min (Method 3). Intermediate 26F (4S)-8-[(1S)-3-methoxy-1-methyl-3-oxo-propyl]-4-methyl-chromane-4-carboxylic acid The diastereomer mixture (4S)-8-(3-methoxy-1-methyl-3-oxo-propyl)-4-methyl-chromane-4- carboxylic acid (Intermediate 26E, 1.00 eq, 770 mg, 2.63 mmol) was purified by prep-HPLC to give (4S)-8-[(1R)-3-methoxy-1-methyl-3-oxo-propyl]-4-methyl-chromane-4-carboxylic acid (Product P1, 100 mg, 0.342 mmol) and (4S)-8-[(1S)-3-methoxy-1-methyl-3-oxo-propyl]- 4-methyl-chromane-4-carboxylic acid (Product P2, Intermediate 26F, 500 mg, 1.71 mmol) as solids. The absolute and relative configurations of Product P1 and Product P2 are unknown and assigned arbitrarily for identification purposes only. (4S)-8-[(1R)-3-methoxy-1-methyl-3-oxo-propyl]-4-methyl-chromane-4-carboxylic acid (Product P1): MS (ESI): 293.3 (M+H)⁺; retention time 1.83 min (Method 4). (4S)-8-[(1S)-3-methoxy-1-methyl-3-oxo-propyl]-4-methyl-chromane-4-carboxylic acid (Product P2: MS (ESI): 293.3 (M+H)⁺; retention time 1.85 min (Method 4). The following additional intermediates were prepared from Intermediate 26C and Product P1 isolated with Intermediate 26F using the general procedure outlined for Intermediate 26. The absolute and relative configurations of these Intermediates are unknown and assigned arbitrarily for identification purposes.

Intermediate 30 5-(3-Carbamimidoyl-4-fluoro-phenoxy)-6,7-difluoro-N-methyl-1H-indole-4- carboxamide To a chilled (0 °C) solution of 5-(3-cyano-4-fluoro-phenoxy)-6,7-difluoro-N-methyl-1H- indole-4-carboxamide (1.00 eq, 150 mg, 0.434 mmol) in THF (2 mL) was added LHMDS (8.00 eq, 3.4 mL, 3.48 mmol) and the mixture was stirred and allowed to warm to RT over 16 h. The reaction was quenched with saturated aqueous NH₄Cl (2 mL) and 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 3:1 DCM:MeOH to give 5-(3-carbamimidoyl-4-fluoro-phenoxy)-6,7-difluoro-N-methyl-1H- indole-4-carboxamide (140 mg, 0.386 mmol, 89 % yield) as a solid. MS (ESI): 363.3 (M+H)⁺; retention time 1.38 min (Method 5). Intermediate 30A 5-[1-(Benzenesulfonyl)-4-bromo-6,7-difluoro-indol-5-yl]oxy-2-fluoro-benzonitrile To a solution of methyl 5-[(4-bromo-6-fluoro-7-methyl-1H-indol-5-yl)oxy]-2-fluoro- benzonitrile (1.00 eq, 5.00 g, 13.8 mmol) in DMF (50 mL) was added sodium (1.20 eq, 392 mg, 16.3 mmol) at 0 °C under an Ar atmosphere, and the mixture was stirred for 1 hour. Benzenesulfonyl chloride (1.10 eq, 1.9 mL, 15.0 mmol) was added at 0 °C . The mixture was allowed to warm to rt and stirred for an additional 1 h, diluted with 50 mL of water, and extracted with ethyl acetate (3 x 80 mL). The combined organic extracts were washed with brine (3 x 80 mL), dried over Na₂SO₄, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 10-18% of ethyl acetate in petroleum ether) to give 5-[1-(benzenesulfonyl)-4-bromo-6,7-difluoro-indol-5-yl]oxy-2-fluoro-benzonitrile (6.50 g, 12.8 mmol, 94 % yield) as an earthy yellow solid. MS (ESI): 507.1, 509.1 (M+H)⁺; retention time 1.88 min (Method 2). Intermediate 30B 5-[1-(Benzenesulfonyl)-6,7-difluoro-4-(hydroxymethyl)indol-5-yl]oxy-2-fluoro- benzonitrile To a solution of 5-[1-(benzenesulfonyl)-4-bromo-6,7-difluoro-indol-5-yl]oxy-2-fluoro- benzonitrile (1.00 eq, 5.00 g, 9.86 mmol) and (tributylstannyl)methanol (2.00 eq, 6.33 g, 19.7 mmol) in 1,4-dioxane (50 mL) was added XPhos Pd G2 (0.0500 eq, 387 mg, 0.493 mmol) and the mixture was stirred for 16 h at 80 °C under N2. The mixture was cooled to rt and concentrated. The residue was suspended in ethyl acetate (50 mL), washed with water (2 x 50 mL), brine (2 x 50 mL), dried over sodium sulphate, 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 5-[1-(benzenesulfonyl)-6,7-difluoro-4-(hydroxymethyl)indol-5- yl]oxy-2-fluoro-benzonitrile (2.10 g, 4.58 mmol, 47 % yield) as a solid. MS (ESI): 481.2 (M+Na)⁺; retention time 2.01 min (Method 5). Intermediate 30C 1-(Benzenesulfonyl)-5-(3-cyano-4-fluoro-phenoxy)-6,7-difluoro-indole-4-carboxylic acid To a solution of 5-[1-(benzenesulfonyl)-6,7-difluoro-4-(hydroxymethyl)indol-5-yl]oxy-2- fluoro-benzonitrile (1.00 eq, 2.10 g, 4.58 mmol) in DMF (50 mL) was added pyridinium dichromate (10.0 eq, 17.23 g, 45.8 mmol) and the mixture was stirred overnight at rt. The mixture was diluted with 20 mL ethyl acetate and filtered through Celite, the filtrate was washed with brine (25 mL), the organic phase was separated, dried and concentrated. The residue was purified by flash chromatography 2:1 PE:EA to afford 1-(benzenesulfonyl)-5-(3- cyano-4-fluoro-phenoxy)-6,7-difluoro-indole-4-carboxylic acid (1.50 g, 3.18 mmol, 69 % yield) ) as a solid. MS (ESI): 473.2 (M+H)⁺; retention time 1.97 min (Method 5). Intermediate 30D 1-(Benzenesulfonyl)-5-(3-cyano-4-fluoro-phenoxy)-6,7-difluoro-N-methyl-indole-4- carboxamide EDCI (1.00 eq, 41 mg, 0.212 mmol) was added to a solution of 1-(benzenesulfonyl)-5-(3- cyano-4-fluoro-phenoxy)-6,7-difluoro-indole-4-carboxylic acid (1.00 eq, 100 mg, 0.212 mmol) and 1-hydroxybenzotriazole (1.00 eq, 29 mg, 0.212 mmol) in DCM (1 mL) and DMF (2 mL) at 0 °C. The reaction mixture was stirred for 20 min at 0 °C, treated with methanamine (10.0 eq, 66 mg, 2.12 mmol). The reaction was allowed to warm to RT over 16 hours, diluted with ethyl acetate (10 ml), washed with a 10% aqueous solution of sodium hydrogen sulphate (10 ml), and extracted with ethyl acetate (3 x 10 ml), the combined organic phases were washed with a saturated aqueous solution of sodium hydrogen carbonate, dried over magnesium sulphate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel (12 g) using 1:1 ethyl acetate:heptane as eluent to give 1-(benzenesulfonyl)-5-(3-cyano-4- fluoro-phenoxy)-6,7-difluoro-N-methyl-indole-4-carboxamide (90 mg, 0.185 mmol, 88 % yield) . MS (ESI): 486.2 (M+H)⁺; retention time 1.97 min (Method 5). Intermediate 30E 5-(3-Cyano-4-fluoro-phenoxy)-6,7-difluoro-N-methyl-1H-indole-4-carboxamide To a solution of 1-(benzenesulfonyl)-5-(3-cyano-4-fluoro-phenoxy)-6,7-difluoro-N-methyl- indole-4-carboxamide (1.00 eq, 90 mg, 0.185 mmol) in THF (1 mL) was added TBAF (2.00 eq, 97 mg, 0.371 mmol). The mixture was stirred at rt for 2 h, diluted with water (20 ml), and extracted with EA (3 x 40 mL). The combined organic extracts were washed with brine (30 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 1:1 PE:EA to afford 5-(3-cyano-4-fluoro-phenoxy)- 6,7-difluoro-N-methyl-1H-indole-4-carboxamide (40 mg, 0.116 mmol, 63 % yield) as a solid. MS (ESI): 346.1 (M+H)⁺; retention time 1.48 min (Method 2). Intermediate 31 tert-Butyl 8-[(2R)-3,3,3-trideuterio-2-methoxycarbonyl-propyl]-4- (trideuteriomethyl)chromane-4-carboxylate To a suspension of zinc powder (6.00 eq, 950 mg, 14.5 mmol) in DMF (10 mL) was added iodine (0.1000 eq, 61 mg, 0.242 mmol) under Ar. The mixture was stirred at room temperature for 40 min, treated with methyl (2S)-3,3,3-trideuterio-2-(iodomethyl)propanoate (1.50 eq, 840 mg, 3.63 mmol), and stirred at room temperature for another 40 min. 2- Dicyclohexylphosphino-2',6'-dimethoxy-1,1'-biphenyl (0.200 eq, 199 mg, 0.484 mmol) and tris(dibenzylideneacetone) dipalladium (0.1000 eq, 222 mg, 0.242 mmol) were added, followed by tert-butyl 8-bromo-4-(trideuteriomethyl)chromane-4-carboxylate (1.00 eq, 800 mg, 2.42 mmol) and the reaction mixture was stirred at 70 °C overnight. The reaction mixture was diluted with water (10 mL) and ethyl acetate (10 mL), the solids were filtered off, and the aqueous phase of the filtrate was extracted with ethyl acetate (2 x 20 mL). The combined organic phases were washed with brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-10% ethyl acetate in petroleum ether to give tert-butyl 8-[(2R)-3,3,3-trideuterio- 2-methoxycarbonyl-propyl]-4-(trideuteriomethyl)chromane-4-carboxylate (307 mg, 0.866 mmol, 36 % yield) as an oil. MS (ESI): 377.3 (M+Na)⁺; retention time 2.68 min. Intermediate 31A tert-Butyl 8-bromo-4-(trideuteriomethyl)chromane-4-carboxylate Prepared similarly to Intermediate 9B by replacing iodomethane with iodomethane-D₃. MS (ESI): 330, 332 (M+H)⁺. Intermediate 32 tert-Butyl 8-((S)-2-(methoxycarbonyl)propyl-3,3,3-d3)-4-(methyl-d3)chromane-4- carboxylate Prepared similarly to Intermediate 31 by replacing methyl (2S)-3,3,3-trideuterio-2- (iodomethyl)propanoate with methyl (2R)-3,3,3-trideuterio-2-(iodomethyl)propanoate. MS (ESI): 377.3 (M+Na)⁺; retention time 2.68 min. Intermediate 33 5-[[6,7-Difluoro-4-(trideuteriomethylsulfanyl)-1H-indol-5-yl]oxy]-2-fluoro-benzamidine Prepared in the same way as Intermediate 17 by replacing iodomethane with iodomethane-D₃ when converting Intermediate 16H to Intermediate 16I. MS (ESI): 355.1 (M+H)⁺. Intermediate 34 5-[(6,7-Difluoro-4-isopropylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzamidine To a solution of 5-[(6,7-difluoro-4-isopropylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzonitrile (1.00 eq, 130 mg, 0.359 mmol) in THF (2 mL) was added LHMDS (10.0 eq, 1.8 mL, 3.59 mmol) at 0 °C. and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (30 mL), washed with water (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the product 5-[(6,7-difluoro-4- isopropylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzamidine (130 mg, 0.343 mmol, 96 % yield) as a gray solid. MS (ESI): 380.3 (M+H)⁺; retention time 1.67 min (Method 5). Intermediate 34A 5-[6,7-Difluoro-4-isopropylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- benzonitrile To a solution of 5-[6,7-difluoro-1-(p-tolylsulfonyl)-4-sulfanyl-indol-5-yl]oxy-2-fluoro- benzonitrile (Intermediate 16H, 1.00 eq, 200 mg, 0.422 mmol) in acetone (5 mL) was added potassium carbonate (2.00 eq, 117 mg, 0.843 mmol) and 2-iodopropane (2.00 eq, 0.084 mL, 0.843 mmol), and the mixture was stirred for 2 hours at room temperature. The mixture was diluted with ethyl acetate (20 mL), washed with water (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 0-30% ethyl acetate in petroleum ether to give 5-[6,7-difluoro-4- isopropylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile (200 mg, 0.387 mmol, 92 % yield) as a yellow solid. MS (ESI): 539.2 (M+Na)⁺; retention time 2.32 min (Method 5). Intermediate 34B 5-[(6,7-Difluoro-4-isopropylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzonitrile To a solution of 5-[6,7-difluoro-4-isopropylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2- fluoro-benzonitrile (1.00 eq, 200 mg, 0.387 mmol) in THF (10 mL) was added TBAF (3.00 eq, 1.2 mL, 1.16 mmol) and the mixture was stirred for 2 hours at room temperature. The mixture was diluted with ethyl acetate (20 mL), washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 0-40% ethyl acetate in petroleum ether to give the product 5- [(6,7-difluoro-4-isopropylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzonitrile (120 mg, 0.331 mmol, 86 % yield) as a white solid. MS (ESI): 363.3 (M+H)⁺; retention time 2.14 min (Method 5). Intermediate 35 5-[(4-Cyclopropylsulfanyl-6,7-difluoro-1H-indol-5-yl)oxy]-2-fluoro-benzamidine To a solution of 5-[(4-cyclopropylsulfanyl-6,7-difluoro-1H-indol-5-yl)oxy]-2-fluoro- benzonitrile (1.00 eq, 100 mg, 0.278 mmol) in THF (2 mL) was added LHMDS (10.0 eq, 2.8 mL, 2.78 mmol) at 0 °C, and the mixture was stirred at room temperature for 2 hours. The mixture was diluted with ethyl acetate (30 mL), washed with water (2 x 50 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the product 5-[(4- cyclopropylsulfanyl-6,7-difluoro-1H-indol-5-yl)oxy]-2-fluoro-benzamidine (100 mg, 0.265 mmol, 96 % yield) as a gray solid. MS (ESI): 378.3 (M+H)⁺; retention time 1.63 min (Method 5). Intermediate 35A 5-[4-Cyclopropylsulfanyl-6,7-difluoro-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- benzonitrile A mixture of cyclopropylboronic acid (1.50 eq, 109 mg, 1.26 mmol) , cesium carbonate (1.00 eq, 275 mg, 0.843 mmol), copper (II) acetate (1.00 eq, 153 mg, 0.843 mmol) , 2,2'-bipyridine (1.00 eq, 132 mg, 0.843 mmol) and 5-[6,7-difluoro-1-(p-tolylsulfonyl)-4-sulfanyl-indol-5- yl]oxy-2-fluoro-benzonitrile (1.00 eq, 400 mg, 0.843 mmol) in DCE (5 mL) was heated at 70 °C for 4 hours. The reaction mixture was cooled to room temperature, diluted with water (30 mL), and extracted with DCM (3 x 20 mL). The combined organic layers were washed with brine (2 × 10 mL), dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 0-30% ethyl acetate in petroleum ether to give the product 5-[4-cyclopropylsulfanyl-6,7-difluoro-1-(p- tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile (360 mg, 0.700 mmol, 83 % yield) as a white solid. MS (ESI): 515.2 (M+H)⁺; retention time 2.29 min (Method 5). Intermediate 36 Ethyl 3-[4-(2-bromoacetyl)-3,3-difluoro-4-methyl-chroman-8-yl]propanoate To a solution of 8-(3-ethoxy-3-oxo-propyl)-3,3-difluoro-4-methyl-chromane-4-carboxylic acid (420 mg, 1.28 mmol) in dichloromethane (5 mL) was added oxalyl chloride (0.336 mL, 3.83 mmol) and three drops of N,N-dimethylformamide at room temperature. After stirring for 1 h, the solution was concentrated, the residue was dissolved in MeCN (5 mL), and a solution of 2.0 M (trimethylsilyl)diazomethane (2.6 mL, 5.2 mmol) was added dropwise to the mixture at 0 °C. The mixture was allowed to warm to room temperature and stirred for 16 h. The yellow solution was re-cooled to 0 °C, while hydrobromic acid (40%, 1.16 g, 5.75 mmol) was added dropwise over 10 min. After stirring for 30 min, the mixture was diluted with brine (30 mL) and ethyl acetate (30 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. 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-bromoacetyl)-3,3- difluoro-4-methyl-chroman-8-yl]propanoate (410 mg, 79 % yield ) as an oil. MS (ESI): 427.0, 429 (M+Na)⁺; retention time 2.20 min (Method 2). Intermediate 36A Ethyl 8-bromo-4-methyl-3-oxo-chromane-4-carboxylate To a solution of ethyl 8-bromo-3-oxo-chromane-4-carboxylate (CN104829574, 9 g, 30 mmol) in DMF (90 mL) was added iodomethane (6.4 g, 45.1 mmol) and potassium carbonate (8.3 g, 60.1 mmol). The mixture was stirred at room temperature for 2 h, diluted with water (500 mL), and extracted with ethyl acetate (3 x 250 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-10% ethyl acetate in petroleum ether to give ethyl 8-bromo-4-methyl-3-oxo-chromane-4-carboxylate (7.8 g, yield 83 % ) as an oil. MS (ESI): 313.1, 315.1 (M+H)⁺; retention time 2.09 min (modified Method 2 - Gradient: 5%B increase to 95% B within 1.3min). Intermediate 36B Ethyl 8-bromo-3,3-difluoro-4-methyl-chromane-4-carboxylate To a solution of ethyl 8-bromo-4-methyl-3-oxo-chromane-4-carboxylate (7.8 g, 24.9 mmol) in DCM (100 mL) was added DAST (20 g, 124.54 mmol). The reaction was stirred at 40 °C for 48 h, cooled to rt, extracted with DCM (200 mL), washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by prep-HPLC to give ethyl 8-bromo-3,3-difluoro-4-methyl-chromane-4-carboxylate (1 g, 12 % yield) and ethyl 8-bromo-3-fluoro-4-methyl-chromene-4-carboxylate (1.9 g, 24 % yield) as an oil. Ethyl 8-bromo-3,3-difluoro-4-methyl-chromane-4-carboxylate: MS (ESI): 334.9, 336.9 (M+H)⁺; retention time 2.52 min (modified Method 2 - Gradient: 5%B increase to 95% B within 1.3min). Ethyl 8-bromo-3-fluoro-4-methyl-chromene-4-carboxylate: MS (ESI): 315, 317 (M+H)⁺; retention time 2.57 min (modified Method 2 - Gradient: 5%B increase to 95% B within 1.3min). Intermediate 36C 8-Bromo-3,3-difluoro-4-methyl-chromane-4-carboxylic acid To a solution of ethyl 8-bromo-3,3-difluoro-4-methyl-chromane-4-carboxylate (1 g, 2.98 mmol) in THF (27 mL) and methanol (9 mL) was added aqueous lithium hydroxide (9 mL, 1 M solution), and the reaction was stirred at RT for 16 h. LCMS monitored. The mixture was acidified with 1M hydrochloric acid to pH=4, extracted with ethyl acetate (100 mL), washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 8-bromo-3,3-difluoro-4-methyl-chromane-4-carboxylic acid (820 mg, 89 % yield) as a solid. MS (ESI): 307, 309 (M+H)⁺; retention time 2.52 min (modified Method 2 - Gradient: 5%B to 95% B within 1.3min). Intermediate 36D Benzyl 8-bromo-3,3-difluoro-4-methyl-chromane-4-carboxylate To a solution of 8-bromo-3,3-difluoro-4-methyl-chromane-4-carboxylic acid (820 mg, 2.67 mmol) in DMF (16 mL) was added benzyl bromide (503 mg, 2.93 mmol) and potassium carbonate (553 mg, 4 mmol). The mixture was stirred for 2 h at room temperature, diluted with ethyl acetate (100 mL), washed with water (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 0-10% ethyl acetate in petroleum ether to give benzyl 8-bromo-3-fluoro-4-methyl- chromene-4-carboxylate (850 mg, 80 % yield) as an oil. MS (ESI): 397, 399 (M+H)⁺; retention time 2.34 min (Method 2). Intermediate 36E Benzyl 8-[(E)-3-ethoxy-3-oxo-prop-1-enyl]-3,3-difluoro-4-methyl-chromane-4- carboxylate To a solution of benzyl 8-bromo-3,3-difluoro-4-methyl-chromane-4-carboxylate (850 mg, 2.14 mmol) in dioxane (10 mL) and water (2.5 mL) was added ethyl (E)-3-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)acrylate (724 mg, 3.2 mmol), 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (175 mg, 0.21 mmol) and potassium carbonate (0.59 g, 4.28 mmol) at room temperature. The mixture was stirred at 100 °C for 16 h. The mixture was extracted with ethyl acetate (100 mL), washed with water (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-10% ethyl acetate in petroleum ether to give benzyl 8-[(E)-3-ethoxy-3-oxo-prop-1-enyl]-3,3-difluoro-4-methyl-chromane-4- carboxylate (570 mg, 64% yield) as an oil. MS (ESI): 417.2 (M+H)⁺; retention time 2.33 min (Method 2). Intermediate 36F 8-(3-Ethoxy-3-oxo-propyl)-3,3-difluoro-4-methyl-chromane-4-carboxylic acid To a solution of benzyl 8-[(E)-3-ethoxy-3-oxo-prop-1-enyl]-3,3-difluoro-4-methyl-chromane- 4-carboxylate (570 mg, 1.36 mmol) in ethanol (10 mL) was added palladium on carbon (wet, 10 wt. %, 100 mg). The reaction mixture was stirred under hydrogen for 2 hours at room temperature. The catalyst was removed by filtration and washed with THF (30 mL). The combined filtrates were concentrated to give 8-(3-ethoxy-3-oxo-propyl)-3,3-difluoro-4- methyl-chromane-4-carboxylic acid (420 mg, 93 % yield) as an oil. MS (ESI): 329.2 (M+H)⁺; retention time 1.82 min (modified Method 2 - Gradient: 5% B to 95% B within 1.3 min; Flow Rate: 1.8mL/min). Intermediate 37 Ethyl 3-(4-(2-bromoacetyl)-3-fluoro-4-methylchroman-8-yl)propanoate To a solution of 8-(3-ethoxy-3-oxo-propyl)-3-fluoro-4-methyl-chromane-4-carboxylic acid (520 mg, 1.67 mmol) in dichloromethane (5 mL) was added oxalyl chloride (0.44 mL, 5 mmol) and three drops of N,N-dimethylformamide at room temperature. After stirring for 1 h, the solution was concentrated, the residue was dissolved in MeCN (5 mL), and a 2.0 M solution of (trimethylsilyl)diazomethane (3.35 mL, 6.7 mmol) was added dropwise to the mixture at 0 °C. The mixture was allowed to warm to room temperature and stirred for 16 h. The yellow solution was re-cooled to 0 °C and hydrobromic acid (40 %, 1.5 g, 7.54 mmol) was added dropwise over 10 min. After stirring for 30 min, the mixture was diluted with brine (30 mL) and ethyl acetate (30 mL), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. 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-bromoacetyl)-3-fluoro-4- methyl-chroman-8-yl]propanoate (320 mg, 49 % yield) as an oil. MS (ESI): 387.1, 389.1 (M+H)⁺; retention time 1.99 min (modified Method 2 - Gradient: 5% to 95%B within 1.3 min; Flow Rate: 1.8mL/min). Intermediate 37A 8-Bromo-3-fluoro-4-methyl-chromene-4-carboxylic acid To a solution of ethyl 8-bromo-3-fluoro-4-methyl-chromene-4-carboxylate (isolated during synthesis of Intermediate 36B, 1.9 g, 6 mmol) in THF (54 mL) and methanol (18 mL) was added aqueous lithium hydroxide (18 mL, 1 M solution). The reaction was stirred at RT for 16 h. The mixture was acidified with 1 M hydrochloric acid to pH = 4, and extracted with ethyl acetate (100 mL). The separated organic layer was washed with brine (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give 8-bromo-3-fluoro-4-methyl- chromene-4-carboxylic acid (1.6 g, 92 % yield) as a solid. MS (ESI): 287.0, 289 (M+H)⁺; retention time 2.15 min (modified Method 2 - Gradient: 5%-95% B in 2.5 min). Intermediate 37B Benzyl 8-bromo-3-fluoro-4-methyl-chromene-4-carboxylate To a solution of 8-bromo-3-fluoro-4-methyl-chromene-4-carboxylic acid (1.6 g, 5.57 mmol) in DMF (16 mL) was added benzyl bromide (1 g, 6.13 mmol) and potassium carbonate (1.2 g, 8.36 mmol). The mixture was stirred for 2 h at room temperature, diluted with ethyl acetate (100 mL), washed with water (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 0- 10% ethyl acetate in petroleum ether to give benzyl 8-bromo-3-fluoro-4-methyl-chromene-4- carboxylate (REQ-01608-5-BP-1a, 1.8 g, 86 % yield) as an oil. MS (ESI): 377.2, 379.2 (M+H)⁺; retention time 2.36 min (Method 2). Intermediate 37C Benzyl 8-[(E)-3-ethoxy-3-oxo-prop-1-enyl]-3-fluoro-4-methyl-chromene-4-carboxylate To a solution of benzyl 8-bromo-3-fluoro-4-methyl-chromene-4-carboxylate (8 g, 4.77 mmol) in dioxane (20 mL) and water (5 mL) was added ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)acrylate (1.6 g, 7.15 mmol), 1,1'-bis(diphenylphosphino)ferrocene- palladium(II)dichloride dichloromethane complex (389 mg, 0.477 mmol) and potassium carbonate (1.3 g, 9.54 mmol), and the mixture was stirred at 100 °C for 16 h. The mixture was extracted with ethyl acetate (100 mL), washed with water (2 x 100 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on a silica gel column eluting with 0-10% ethyl acetate in petroleum ether to give benzyl 8- [(E)-3-ethoxy-3-oxo-prop-1-enyl]-3-fluoro-4-methyl-chromene-4-carboxylate (1.4 g, 74 % yield) as an oil. MS (ESI): 397.2 (M+H)⁺; retention time 2.38 min (Method 2). Intermediate 37D 8-(3-Ethoxy-3-oxo-propyl)-3-fluoro-4-methyl-chromane-4-carboxylic acid To a solution of benzyl 8-[(E)-3-ethoxy-3-oxo-prop-1-enyl]-3-fluoro-4-methyl-chromene-4- carboxylate (700 mg, 1.76 mmol) in ethanol (10 mL) was added palladium on carbon (wet, 10 wt. %, 100 mg). The reaction mixture was stirred under hydrogen for 2 hours at room temperature. The catalyst was removed by filtration and washed with THF (30 mL). The combined filtrates were concentrated to give 8-(3-ethoxy-3-oxo-propyl)-3-fluoro-4-methyl- chromane-4-carboxylic acid (520 mg, 95 % yield) as an oil. MS (ESI): 311.1 (M+H)⁺; retention time 1.93 min (Method 2). Intermediate 38 Ethyl 3-[4-(2-bromoacetyl)-2,4-dimethyl-chroman-8-yl]propanoate To a solution of 8-(3-ethoxy-3-oxo-propyl)-2,4-dimethyl-chromane-4-carboxylic acid (1.00 eq, 1.03 g, 3.36 mmol) in anhydrous DCM (10 mL) was added oxalyl chloride (4.00 eq, 1.2 mL, 13.4 mmol) and one drop of anhydrous DMF, and the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated, the residue was dissolved in anhydrous MeCN (10 mL), treated with trimethylsilyl diazomethane (4.00 eq, 6.7 mL, 13.4 mmol), and stirred at room temperature for 1 h. The mixture was concentrated, the residue was dissolved in anhydrous MeCN (15mL), treated with hydrobromic acid (5.00 eq, 1.9 mL, 16.8 mmol) , and stirred at 0 °C for 1 h. The reaction was diluted with brine (60 mL), extracted with EA (3 x 20 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 PE:EA to give ethyl 3-[4-(2-bromoacetyl)-2,4-dimethyl-chroman-8- yl]propanoate (1.00 g, 2.61 mmol, 78 % yield) as a brown liquid. MS (ESI): 383.1, 385.1 (M+H)⁺; retention time 2.34 min (modified Method 2 - Temperature: 40 °C). Intermediate 38A 8-Bromo-2-methyl-chroman-4-one A mixture of 1-(3-bromo-2-hydroxy-phenyl)ethanone (1.00 eq, 10.00 g, 46.5 mmol) acetaldehyde (6.00 eq, 16 mL, 279 mmol) and N,N-diisopropylethylamine (2.00 eq, 16 mL, 93.0 mmol) in ethanol (20 mL) was stirred at 170 °C in a microwave reactor for 1 h. The cooled reaction mixture was diluted with EA (200 mL), washed with aqueous sodium hydroxide (10 wt. %, 3 x 50 mL), hydrochloric acid (1.0 M, 50 mL) and brine (50 mL). The organic phase was dried over Na₂SO₄, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 20:1 PE:EA to give 8-bromo-2-methyl- chroman-4-one (4.50 g, 18.7 mmol, 40 % yield) as a yellow solid. MS (ESI): 241.1, 243.1 (M+H)⁺; retention time 1.94 min (Method 5). Intermediate 38B 8-Bromo-2-methyl-4-trimethylsilyloxy-chromane-4-carbonitrile To a solution of 8-bromo-2-methyl-chroman-4-one (1.00 eq, 9.10 g, 37.7 mmol) and trimethylsilyl cyanide (4.00 eq, 20 mL, 151 mmol) in anhydrous DCM (2 mL) was added zinc iodide (0.100 eq, 1205 mg, 3.77 mmol), and the mixture was stirred at room temperature for 4 h. The reaction mixture was diluted with EA (100 mL), washed with saturated aqueous NaHCO₃ (3 x 20 mL), the organic phase was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue, crude 8-bromo-2-methyl-4-trimethylsilyloxy-chromane-4-carbonitrile (12.00 g,35.3 mmol, 93.42 % yield), was used in the next step without further purification. MS (ESI): 315.2 , 313.2 (M-CN)⁺; retention time 2.26 min (Method 5). Intermediate 38C 8-Bromo-2-methyl-2H-chromene-4-carboxylic acid To a solution of 8-bromo-2-methyl-4-trimethylsilyloxy-chromane-4-carbonitrile (1.00 eq, 12.00 g, 35.3 mmol) in acetic acid (90 mL) was added tin(II) chloride dihydrate (4.00 eq, 31829 mg, 141 mmol) and hydrochloric acid (30.6 eq, 90 mL, 1080 mmol) The resulting mixture was stirred at 90 °C for 16 h. The cooled reaction mixture was diluted with brine (500 mL), extracted with EA (3 x 100 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 5:1 PE:EA to give 8-bromo-2-methyl-2H-chromene-4-carboxylic acid (8.05 g, 29.9 mmol, 85 % yield) as a brown solid. MS (ESI): 269.1, 271.0 (M+H)⁺; retention time 1.86 min (Method 5). Intermediate 38D 8-Bromo-2-methyl-chromane-4-carboxylic acid To a solution of 8-bromo-2-methyl-2H-chromene-4-carboxylic acid (1.00 eq, 2.00 g, 7.43 mmol) in ethanol (20 mL) was added sodium borohydride (4.00 eq, 1125 mg, 29.7 mmol) and cobalt (II) chloride (1.00 eq, 966 mg, 7.43 mmol), and the mixture was stirred at 60 °C for 16 h. The reaction was quenched with ice water (100 mL), the pH was adjusted to 2-3 with 1 N hydrochloric acid, and the mixture was extracted with EA (3 x 30 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 5:1 PE:EA to give 8-bromo-2- methyl-chromane-4-carboxylic acid (2.00 g, 7.38 mmol, 99 % yield) as a brown solid. MS (ESI): 271.2, 273.2 (M+H)⁺; retention time 1.83 min (Method 5). Intermediate 38E tert-Butyl 8-bromo-2-methyl-chromane-4-carboxylate A mixture of 8-bromo-2-methyl-chromane-4-carboxylic acid (1.00 eq, 2.00 g, 7.38 mmol) Boc anhydride (1.50 eq, 2.6 mL, 11.1 mmol) and 4-dimethylaminopyridine (0.300 eq, 270 mg, 2.21 mmol) in tert-butanol (15 mL) was stirred at room temperature for 16 h. The mixture was concentrated and purified by flash column chromatography on silica gel eluting with 50:1 PE:EA to give tert-butyl 8-bromo-2-methyl-chromane-4-carboxylate (1.95 g, 5.96 mmol, 81 % yield) as a brown liquid. MS (ESI): 225.2, 227.2 (M-Boc)-; retention time 2.23 min (Method 5). Intermediate 38F tert-Butyl 8-bromo-2,4-dimethyl-chromane-4-carboxylate To a solution of tert-butyl 8-bromo-2-methyl-chromane-4-carboxylate (1.00 eq, 1.95 g, 5.96 mmol) in anhydrous THF (20 mL) was added LDA (1.50 eq, 4.5 mL, 8.94 mmol) at - 78 °C, and the mixture was stirred at -78 °C for 30 min. Iodomethane (1.50 eq, 0.56 mL, 8.94 mmol) was added and the resulting mixture was warmed up to room temperature over 1 h. The reaction was quenched with saturated aqueous NaHCO₃ (5 mL), diluted with brine (60 mL), and extracted with EA (3 x 20 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 20:1 PE:EA to give tert-butyl 8-bromo-2,4-dimethyl-chromane-4- carboxylate (1.94 g, 5.67 mmol, 95 % yield) as a brown liquid. MS (ESI): 239.3, 241.3 (M- Boc)-; retention time 2.26 min (Method 5). Intermediate 38G tert-Butyl 8-[(E)-3-ethoxy-3-oxo-prop-1-enyl]-2,4-dimethyl-chromane-4-carboxylate A mixture of tert-butyl 8-bromo-2,4-dimethyl-chromane-4-carboxylate (1.00 eq, 1.94 g, 5.67 mmol), ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (1.50 eq, 1924 mg, 8.51 mmol), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.100 eq, 463 mg, 0.567 mmol) and potassium carbonate (3.00 eq, 2352 mg, 17.0 mmol) in 1,4-dioxane (35 mL) and water (8.5 mL) was stirred at 100 °C under a N2 atmosphere for 16 h. The mixture was cooled to rt, diluted with brine (100 mL) and extracted with EA (3 x 30 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 20:1 PE:EA to give tert-butyl 8-[(E)-3-ethoxy-3-oxo-prop-1-enyl]-2,4-dimethyl- chromane-4-carboxylate (1.71 g, 4.74 mmol, 84 % yield) as a brown liquid. MS (ESI): 361.4 (M+H)⁺; retention time 2.27 min (Method 5). Intermediate 38H tert-Butyl 8-(3-ethoxy-3-oxo-propyl)-2,4-dimethyl-chromane-4-carboxylate A mixture of tert-butyl 8-[(E)-3-ethoxy-3-oxo-prop-1-enyl]-2,4-dimethyl-chromane-4- carboxylate (1.00 eq, 1.71 g, 4.74 mmol) and palladium on activated carbon (5 wt. %, wetted with ca.55% water, 342 mg) in THF (20 mL) was stirred at ambient temperature and pressure under a H₂ atmosphere for 16 h. The solids were filtered off and the filtrate was concentrated to afford tert-butyl 8-(3-ethoxy-3-oxo-propyl)-2,4-dimethyl-chromane-4-carboxylate (1.57 g, 4.33 mmol, 91 % yield) which was used in the next step without purification. MS (ESI): 261.1 (M-Boc)-; retention time 2.51 min (modified Method 2 - Temperature:40 °C). Intermediate 38I 8-(3-Ethoxy-3-oxo-propyl)-2,4-dimethyl-chromane-4-carboxylic acid To a solution of tert-butyl 8-(3-ethoxy-3-oxo-propyl)-2,4-dimethyl-chromane-4-carboxylate (1.00 eq, 1.47 g, 4.06 mmol) in EA (1 mL) was added a solution of HCl in 1,4-dioxane (5.00 eq, 5.1 mL, 20.3 mmol), the mixture was stirred at room temperature for 16 h and concentrated in vacuo. The residue was dissolved in EA (50 mL), washed with brine (3 x 10 mL), the organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 10:1 PE:EA to give 8-(3-ethoxy-3-oxo- propyl)-2,4-dimethyl-chromane-4-carboxylic acid (1.13 g, 3.69 mmol, 91 % yield) as a brown liquid. MS (ESI): 307.1 (M+H)⁺; retention time 2.06 min (modified Method 2 - Temperature:40 °C). Intermediate 39 Ethyl 3-[4-(2-bromoacetyl)-2,2,4-trimethyl-chroman-8-yl]propanoate The title compound was prepared in ten steps from 8-bromo-2,2-dimethyl-chroman-4-one in substantially the same way as the preparation of Intermediate 38 from 8-Bromo-2-methyl- chroman-4-one. MS (ESI): 397.3, 399.3 (M+H)⁺; retention time 2.23 min (modified Method 2 - Gradient: 5%-95% B in 2.5 min). Intermediate 40 Methyl 3-[4-(2-bromoacetyl)-4-methyl-chroman-8-yl]-2,2-dimethyl-propanoate The title compound was prepared in 2 steps from tert-butyl 8-(3-methoxy-2,2-dimethyl-3-oxo- propyl)-4-methyl-chromane-4-carboxylate in substantially the same way as the preparation of Intermediate 38 from Intermediate 38H. MS (ESI): 383.1, 385.1 (M+H)⁺; retention time 2.07 min (modified Method 2A - Flow Rate: 1.8mL/min). Intermediate 40A tert-Butyl 8-(3-methoxy-2,2-dimethyl-3-oxo-propyl)-4-methyl-chromane-4-carboxylate To a suspension of zinc powder (6.00 eq, 1.92 g, 29.3 mmol) in DMF (10 mL) was added iodine (0.100 eq, 0.12 g, 0.489 mmol) and the mixture was stirred at room temperature for 30 min. A solution of methyl 3-iodo-3-methyl-butanoate (1.10 eq, 1.30 g, 5.38 mmol) in DMF (2 mL) was then added and the mixture was stirred at room temperature for an additional 1 h. To the resulting mixture were added tert-butyl 8-bromo-4-methyl-chromane-4-carboxylate (1.00 eq, 1.60 g, 4.89 mmol), S-Phos (0.100 eq, 201 mg, 0.489 mmol) and tris(dibenzylideneacetone)dipalladium(0) (0.0500 eq, 224 mg, 0.244 mmol), and the mixture was stirred at 70 °C overnight, diluted with water (40 mL), filtered, and extracted with EA (100 mL). The organic extract was washed with saturated aqueous LiCl (60 mL), brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-7% EtOAc in PE to give tert-butyl 8-(3-methoxy-2,2-dimethyl-3-oxo-propyl)-4-methyl-chromane-4-carboxylate (530 mg, 1.46 mmol, 30 % yield). MS (ESI): 385.2 (M+Na)⁺; retention time 2.26 min (modified Method 2A - Flow Rate: 1.8 mL/min). Intermediate 41 Ethyl 2-[4-(2-bromoacetyl)-4-methyl-chroman-8-yl]acetate The title compound’s preparation and characterization has been described in Steps A-E, Example 18. Intermediate 42 Methyl 2-[4-(2-bromoacetyl)-4-methyl-chroman-8-yl]cyclopentanecarboxylate The title compound was prepared from 8-(2-methoxycarbonylcyclopentyl)-4-methyl- chromane-4-carboxylic acid following a similar procedure to the one in Step E, Example 18. MS (ESI): 417.2, 419.2 (M+Na)⁺; retention time 2.14 min (modified Method 3). Intermediate 42A Benzyl 8-(2-methoxycarbonylcyclopenten-1-yl)-4-methyl-chromane-4-carboxylate A mixture of benzyl 8-bromo-4-methyl-chromane-4-carboxylate (Step B, Example 18, 1.00 eq, 440 mg, 1.22 mmol), 1,4-dioxane (20 mL), water (5 mL), methyl 2-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)cyclopentene-1-carboxylate (2.00 eq, 614 mg, 2.44 mmol), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.300 eq, 298 mg, 0.365 mmol) and potassium carbonate (2.00 eq, 337 mg, 2.44 mmol) was stirred at 100 °C for 16 h. The mixture was extracted with ethyl acetate (60 mL), washed with water (60 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-26% ethyl acetate in petroleum ether to give benzyl 8-(2-methoxycarbonylcyclopenten-1-yl)-4-methyl-chromane- 4-carboxylate (170 mg, 0.418 mmol, 34 % yield) as a solid. MS (ESI): no significant ionization observed; retention time 2.18 min (Method 2A). Intermediate 42B 8-(2-Methoxycarbonylcyclopentyl)-4-methyl-chromane-4-carboxylic acid A mixture of benzyl 8-(2-methoxycarbonylcyclopenten-1-yl)-4-methyl-chromane-4- carboxylate (1.00 eq, 170 mg, 0.418 mmol), THF (5 mL) and palladium on activated carbon (10 wt. %, 70 mg). was stirred under H₂ at ambient temperature and pressure for 2h. The solids were filtered off and the filtrate was concentrated to give 8-(2-methoxycarbonylcyclopentyl)- 4-methyl-chromane-4-carboxylic acid (120 mg, 0.256 mmol, 61 % yield) as a solid. MS (ESI): 241.1 (M+Na)⁺; two product peaks observed with retention times of 1.87 and 1.94 (Method 3). Intermediate 43 5-((4-(N,S-dimethylsulfonimidoyl)-6,7-difluoro-1H-indol-5-yl)oxy)-2- To a solution of [(Z)-[amino-[5-[[4-(N,S-dimethylsulfonimidoyl)-6,7-difluoro-1H-indol-5- yl]oxy]-2-fluoro-phenyl]methylene]amino] acetate (129 mg, 0.28 mmol) in THF (5 mL) was added Pd/C (wet, 10 wt. %, 30 mg)and the reaction mixture was stirred under hydrogen for 2 h at ambient temperature and pressure. The catalyst was removed by filtration and rinsed with EtOH (20 mL). The combined filtrate was concentrated to give 5-((4-(N,S- dimethylsulfonimidoyl)-6,7-difluoro-1H-indol-5-yl)oxy)-2-fluorobenzimidamide (110 mg, 98 % yield) as a white solid. MS (ESI): 307.1 (M+H)⁺; retention time 2.06 min (modified Method 2 - Gradient: 5% to 95% B within 1.3 min). Intermediate 43A 5-[6,7-Difluoro-4-methylsulfinyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile To a solution of 5-[6,7-difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- benzonitrile (Intermediate 16I, 2 g, 4.0 mmol) in MeOH (10 mL) and THF (10 mL) was added at 0 °C a mixture of ammonium heptamolybdate tetrahydrate (1 g) in 5 mL of aqueous hydrogen peroxide (4.1 mmol). The reaction was stirred at 0 °C for 2 h, diluted with ethyl acetate (100 mL), washed with water (3 x 100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified flash column chromatography on silica gel eluting with 0-60% ethyl acetate in petroleum ether to give 5-[6,7-difluoro-4-methylsulfinyl- 1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile (1.6 g, 77 % yield) as a solid. MS (ESI): 505.1 (M+H)⁺; retention time 2.00 min (modified Method 2 - Gradient: 5% to 95% B within 1.3 min). Intermediate 43B N-[[5-(3-cyano-4-fluoro-phenoxy)-6,7-difluoro-1-(p-tolylsulfonyl)indol-4-yl]-methyl-oxo- λ6-sulfanylidene]-2,2,2-trifluoro-acetamide To a solution of 5-[6,7-difluoro-4-methylsulfinyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- benzonitrile (1.6 g, 3.17 mmol) in DCM (16 mL) was added trifluoroacetamide (717 mg, 6.34 mmol) followed by MgO (511 mg, 12.68 mmol), PhI(OAc)₂ (1.53 g, 4.75 mmol) and dirhodium tetraacetate (70 mg, 0.158 mmol). The mixture was stirred at room temperature for 16 h, filtered, and the solids were rinsed with DCM (2 x 20 mL). The combined filtrates were concentrated and the residue was purified by flash column chromatography on silica gel eluting with 0-50% ethyl acetate in petroleum ether to give N-[[5-(3-cyano-4-fluoro-phenoxy)-6,7- difluoro-1-(p-tolylsulfonyl)indol-4-yl]-methyl-oxo-λ6-sulfanylidene]-2,2,2-trifluoro- acetamide (1.2 g, 61 % yield) as a solid. MS (ESI): 616.1 (M+H)⁺; retention time 2.21 min (modified Method 2 - Gradient: 5% to 95% B within 1.3 min). Intermediate 43C 5-[[6,7-Difluoro-4-(methylsulfonimidoyl)-1H-indol-5-yl]oxy]-2-fluoro-benzonitrile To a solution of N-[[5-(3-cyano-4-fluoro-phenoxy)-6,7-difluoro-1-(p-tolylsulfonyl)indol-4- yl]-methyl-oxo-λ6-sulfanylidene]-2,2,2-trifluoro-acetamide (1.2 g, 1.94 mmol) in THF (16 mL) was added TBAF (15.6 mL, 15.6 mmol) and the reaction mixture was stirred at 70 °C for 1 h. The mixture was extracted with ethyl acetate (50 mL), washed with brine (2 x 50 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 5-[[6,7-difluoro-4-(methylsulfonimidoyl)-1H-indol-5-yl]oxy]-2-fluoro-benzonitrile (452 mg, 63 % yield) as a solid. MS (ESI): 366.1 (M+H)⁺; retention time 1.73 min (modified Method 2 - Gradient: 5% to 95% B within 1.3 min). Intermediate 43D 5-[6,7-Difluoro-4-(methylsulfonimidoyl)-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- benzonitrile To a solution of 5-[[6,7-difluoro-4-(methylsulfonimidoyl)-1H-indol-5-yl]oxy]-2-fluoro- benzonitrile (452 mg, 1.23 mmol) in DMF (10 mL) was added NaH (74 mg, 1.85 mmol) at 0 °C. The reaction mixture was stirred for 0.5 h at 0 °C. Tosyl chloride (236 mg, 1.24 mmol) was added and stirring continued for 3 h at 0 °C. The mixture was extracted with ethyl acetate (50 mL). The organic extract was washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-75% ethyl acetate in petroleum ether to give 5-[6,7-difluoro-4- (methylsulfonimidoyl)-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile (550 mg, 86 % yield) as a solid. MS (ESI): 520.0 (M+H)⁺; retention time 2.09 min (modified Method 2 - Gradient: 5% to 95% B within 1.3 min). Intermediate 43E 5-((4-(N,S-dimethylsulfonimidoyl)-6,7-difluoro-1-tosyl-1H-indol-5-yl)oxy)-2- fluorobenzonitrile A mixture of 5-[6,7-difluoro-4-(methylsulfonimidoyl)-1-(p-tolylsulfonyl)indol-5-yl]oxy-2- fluoro-benzonitrile (550 mg, 1 mmol), dioxane (8 mL), cupric acetate (317 mg, 1.58 mmol), pyridine (201 mg, 2.54 mmol) and methylboronic acid (127 mg, 2.11 mmol) was stirred at 100 °C for 30 min. The mixture was filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-60% ethyl acetate in petroleum ether to give 5-[4-(N,S-dimethylsulfonimidoyl)-6,7-difluoro-1-(p-tolylsulfonyl)indol-5-yl]oxy-2- fluoro-benzonitrile (398 mg, 70 % yield) as a solid. MS (ESI): 534.1 (M+H)⁺; retention time 1.72 min (modified Method 2 - Gradient: 5% to 95% B within 1.3 min). Intermediate 43F 5-((4-(N,S-dimethylsulfonimidoyl)-6,7-difluoro-1H-indol-5-yl)oxy)-2-fluorobenzonitrile To a solution of 5-[4-(N,S-dimethylsulfonimidoyl)-6,7-difluoro-1-(p-tolylsulfonyl)indol-5- yl]oxy-2-fluoro-benzonitrile (398 mg, 0.746 mmol) in THF (4 mL) was added TBAF (3.7 mL, 3.7 mmol) and the reaction mixture was stirred at room temperature for 2 h. The mixture was extracted with ethyl acetate (50 mL), washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-70% ethyl acetate in petroleum ether to give 5-[[4- (N,S-dimethylsulfonimidoyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2-fluoro-benzonitrile (198 mg, 70 % yield) as a solid. MS (ESI): 380.1 (M+H)⁺; retention time 1.52 min (modified Method 2 - Gradient: 5% to 95% B within 1.3 min). Intermediate 43G (Z)-5-((4-(N,S-dimethylsulfonimidoyl)-6,7-difluoro-1H-indol-5-yl)oxy)-2-fluoro-N'- hydroxybenzimidamide To a solution of 5-[[4-(N,S-dimethylsulfonimidoyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2-fluoro- benzonitrile (140 mg, 0.369 mmol) in ethanol was added hydroxylamine hydrochloride (103 mg, 1.48 mmol) and TEA (187 mg, 1.84 mmol). The reaction mixture was stirred at rt for 2 h, extracted with ethyl acetate (30 mL), washed with brine (2 x 30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give 5-[[4-(N,S-dimethylsulfonimidoyl)-6,7- difluoro-1H-indol-5-yl]oxy]-2-fluoro-N'-hydroxy-benzamidine (152 mg, crude) as an oil. MS (ESI): 413.1 (M+H)⁺; retention time 1.44 min (modified Method 2 - Gradient: 5% to 95% B within 1.3 min). Intermediate 43H (Z)-N'-acetoxy-5-((4-(N,S-dimethylsulfonimidoyl)-6,7-difluoro-1H-indol-5-yl)oxy)-2- fluorobenzimidamide To a solution of 5-[[4-(N,S-dimethylsulfonimidoyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2-fluoro- N'-hydroxy-benzamidine (152 mg, 0.368 mmol) in acetic acid (5 mL) was added Ac2O (0.0692 mL, 0.737 mmol) and the reaction was stirred at rt for 1 h. The mixture was diluted with ethyl acetate (30 mL), washed with water (3 x 30 mL), dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-100% ethyl acetate in petroleum ether to give [(Z)-[amino-[5-[[4-(N,S- dimethylsulfonimidoyl)-6,7-difluoro-1H-indol-5-yl]oxy]-2-fluoro-phenyl]methylene]amino] acetate (129 mg, 77 % yield) as an oil. MS (ESI): 455.1 (M+H)⁺; retention time 1.57 min (modified Method 2 - Gradient: 5% to 95% B within 1.3 min). Intermediate 44 Ethyl 2-[4-(2-bromoacetyl)-4-methyl-chroman-8-yl]oxyacetate The title compound was prepared in two steps from tert-butyl 8-(2-ethoxy-2-oxo-ethoxy)-4- methyl-chromane-4-carboxylate (Intermediate 44C) following the methods used to transform Intermediate 9D into Intermediate 9. MS (ESI): 371, 373 (M+H)⁺; retention time 2.21 min (modified Method 2 - Gradient: 5% to 95% B within 2.5 min). Intermediate 44A (4-tert-Butoxycarbonyl-4-methyl-chroman-8-yl)boronic acid To a stirred and chilled (-78 °C) solution of tert-butyl 8-bromo-4-methyl-chromane-4- carboxylate (Intermediate 9B, 1.00 eq, 0.97 g, 2.97 mmol) in THF (15 mL) was added n- butyllithium (1.20 eq, 1.4 mL, 3.56 mmol). The mixture was stirred at (-78 °C) for 0.5 h, treated with trimethyl borate (3.00 eq, 1.0 mL, 8.91 mmol) and stirred at -78 °C for an additional 15 min, and quenched with saturated aqueous NH₄Cl (50 mL). The mixture was extracted with ethyl acetate (3 x 60 mL). The combined organic extracts were washed with brine (50 mL), dried over sodium sulfate, filtered and concentrated to give (4-tert-butoxycarbonyl-4-methyl- chroman-8-yl)boronic acid (0.80 g,2.74 mmol, 92 % yield) as a solid. MS (ESI): 310.2 (M+H₂O)⁺; retention time 1.65 min (Method 3). Intermediate 44B tert-Butyl 8-hydroxy-4-methyl-chromane-4-carboxylate To a solution of (4-tert-butoxycarbonyl-4-methyl-chroman-8-yl)boronic acid (1.00 eq, 750 mg, 2.57 mmol) in THF (6 mL) and water (6 mL) was added sodium perborate tetrahydrate (3.00 eq, 1185 mg, 7.70 mmol) and the mixture was stirred at RT for 0.5 h. The mixture was extracted with ethyl acetate (3 x 20 mL). The combined extracts were washed with brine (3 x 20mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-25% ethyl acetate in petroleum ether to give tert- butyl 8-hydroxy-4-methyl-chromane-4-carboxylate (300 mg,v1.13 mmol, 44 % yield) as a solid. MS (ESI): 287.2 (M+Na)⁺; retention time 1.95 min (Method 3). Intermediate 44C tert-Butyl 8-(2-ethoxy-2-oxo-ethoxy)-4-methyl-chromane-4-carboxylate To a solution of tert-butyl 8-hydroxy-4-methyl-chromane-4-carboxylate (1.00 eq, 0.30 g, 1.13 mmol) and cesium carbonate (2.00 eq, 740 mg, 2.27 mmol) in DMF (6mL) was added ethyl bromoacetate (1.50 eq, 0.19 mL, 1.70 mmol) and the mixture was stirred at RT for 16 h. The mixture was diluted with water (50 mL) and extracted with ethyl acetate (3 x 25 mL) The combined organic extracts were washed with water (15 mL), brine (15 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-25% ethyl acetate in petroleum ether to give tert- butyl 8-(2-ethoxy-2-oxo-ethoxy)-4-methyl-chromane-4-carboxylate (0.33 g, 0.942 mmol, 83 % yield) as a light yellow solid. MS (ESI): 368.2 (M+H₂O)⁺; retention time 2.45 min (modified Method 2 – Gradient: 5%-95% B in 2.5 min). Intermediate 45 4-Benzyloxy-5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzamidine To a stirred solution of 4-benzyloxy-5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2- fluoro-benzonitrile (1.00 eq, 437 mg, 0.992 mmol) in THF (1 mL) was added LHMDS (8.00 eq, 7.9 mL, 7.94 mmol) at 0 °C and the resulting mixture was allowed to warm to room temperature over 16 h. The reaction was quenched with saturated aqueous NH₄Cl (5 mL) and extracted with EA (3 x 10 mL). The combined organic layers extracts were dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 2:1 DCM:MeOH to give 4-benzyloxy-5-[(6,7-difluoro-4- methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzamidine (400 mg, 0.874 mmol, 88 % yield) as a brown solid. MS (ESI): 458.3 (M+H)⁺; retention time 1.77 min (Method 5). Intermediate 45A 4-Benzyloxy-5-bromo-2-fluoro-benzonitrile To a solution of 5-bromo-2-fluoro-4-hydroxy-benzonitrile (1.00 eq, 30.00 g, 139 mmol) in MeCN (300 mL) was added potassium carbonate (2.00 eq, 38.39 g, 278 mmol) and benzyl bromide (1.50 eq, 25 mL, 208 mmol). The reaction was stirred at rt for 6 h, diluted with 200 mL of water, and extracted with ethyl acetate (3 x 200 mL). The combined organic phase was washed with brine (3 x 200 mL), dried over anhydrous Na₂SO₄, filtered and concentrated. The crude was purified by silica gel column chromatography (eluting with 0-50% of ethyl acetate in petroleum ether) to give 4-benzyloxy-5-bromo-2-fluoro-benzonitrile (24.00 g ,78.4 mmol, 57 % yield) as a yellow solid. MS (ESI): 306, 308 (M+H)⁺; retention time 2.06 min (Method 4). Intermediate 45B 4-Benzyloxy-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzonitrile A mixture of 4-benzyloxy-5-bromo-2-fluoro-benzonitrile (1.00 eq, 500 mg, 1.63 mmol) in 1,4- dioxane (20 mL), 1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.0500 eq, 67 mg, 0.0817 mmol), bis(pinacolato)diboron (1.50 eq, 622 mg, 2.45 mmol) and potassium acetate (3.00 eq, 481 mg, 4.90 mmol) was stirred under Ar at 85 °C for 5 hours, then cooled, 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 Na₂SO₄ and concentrated to give 4-benzyloxy-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzonitrile (450 mg, 1.27 mmol, 78 % yield) as a brown solid. This crude product was used in the next step without further purification. MS (ESI): 354.2 (M+H)⁺; retention time 2.20 min (Method 2A). Intermediate 45C 4-Benzyloxy-2-fluoro-5-hydroxy-benzonitrile To a solution of 4-benzyloxy-2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzonitrile (1.00 eq, 55.00 g, 156 mmol) in THF (200 mL) and water (50mL) was added sodium perborate tetrahydrate (3.00 eq, 47571 mg, 467 mmol). The reaction mixture was stirred at room temperature for 1 hour, diluted with 400 mL of water, extracted with ethyl acetate (3 x 300 mL), the combined organic phase was washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography eluting with 0-20% of ethyl acetate in petroleum ether to give 4-benzyloxy-2-fluoro-5-hydroxy-benzonitrile (31.50 g, 130 mmol, 83 % yield) as a yellow solid. MS (ESI): 244.1 (M+H)⁺; retention time 1.82 min (Method 2A). Intermediate 45D 4-Benzyloxy-5-(6-bromo-2,3-difluoro-4-nitro-phenoxy)-2-fluoro-benzonitrile A mixture of 1-bromo-2,3,4-trifluoro-5-nitro-benzene (1.00 eq, 2105 mg, 8.22 mmol), DMF (50 mL), 4-benzyloxy-2-fluoro-5-hydroxy-benzonitrile (1.00 eq, 2.00 g, 8.22 mmol) and potassium carbonate (2.00 eq, 2273 mg, 16.4 mmol) was stirred at room temperature overnight, diluted with 300 mL of water, and extracted with ethyl acetate (3 x 300 mL). The combined organic phase was washed with brine, dried over Na₂SO₄ and concentrated. The crude was purified by silica gel column chromatography eluting with 0-20% of ethyl acetate in petroleum ether to give 4-benzyloxy-5-(6-bromo-2,3-difluoro-4-nitro-phenoxy)-2-fluoro-benzonitrile (1.90 g, 3.96 mmol, 48 % yield) as a white solid. MS (ESI): 501.1, 503.1 (M+Na)⁺; retention time 2.12 min (Method 2A). Intermediate 45E 5-(4-Amino-6-bromo-2,3-difluoro-phenoxy)-4-benzyloxy-2-fluoro-benzonitrile A mixture of 4-benzyloxy-5-(6-bromo-2,3-difluoro-4-nitro-phenoxy)-2-fluoro-benzonitrile (1.00 eq, 1.90 g, 3.96 mmol) in acetic acid (40 mL), iron powder (5.00 eq, 1107 mg, 19.8 mmol) and ammonium chloride (8.00 eq, 1697 mg, 31.7 mmol) was stirred at room temperature for 2 hours, diluted with 200 mL of water, and extracted with ethyl acetate (3 x 200 mL). The combined organic phase was washed with brine, dried over Na₂SO₄ and concentrated to give 5-(4-amino-6-bromo-2,3-difluoro-phenoxy)-4-benzyloxy-2-fluoro-benzonitrile (1.70 g,3.78 mmol, 95 % yield) as a light yellow solid. MS (ESI): 449.0, 451.0 (M+H)⁺; retention time 2.04 min (Method 6). Intermediate 45F 5-(4-Amino-2-bromo-5,6-difluoro-3-iodo-phenoxy)-4-benzyloxy-2-fluoro- benzonitrile To a solution of 5-(4-amino-6-bromo-2,3-difluoro-phenoxy)-4-benzyloxy-2-fluoro- benzonitrile (1.00 eq, 1.70 g, 3.78 mmol) in acetic acid (20 mL) was added NIS (1.15 eq, 979 mg, 4.35 mmol) and stirred at room temperature for 3 hours, diluted with 100 mL of water, alkalized with NaHCO₃ to pH=7, extracted with ethyl acetate (3 x 100 mL). 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% of ethyl acetate in petroleum ether to give 5-(4-amino-2-bromo-5,6-difluoro-3-iodo-phenoxy)-4-benzyloxy-2-fluoro- benzonitrile (1.50 g, 2.61 mmol, 68.92 % yield) as a yellow solid. MS (ESI): 575.0, 577.0 (M+H)⁺; retention time 2.14 min (Method 2A). Intermediate 45G 5-[4-Amino-2-bromo-5,6-difluoro-3-(2-trimethylsilylethynyl)phenoxy]-4-benzyloxy-2- fluoro-benzonitrile A mixture of 5-(4-amino-2-bromo-5,6-difluoro-3-iodo-phenoxy)-4-benzyloxy-2-fluoro- benzonitrile (1.00 eq, 44.50 g, 77.4 mmol), TEA (1.50 eq, 16 mL, 116 mmol) and DMF (10 mL) copper (I) iodide (0.200 eq, 2.95 g, 15.5 mmol), palladium(II)bis(triphenylphosphine) dichloride (0.150 eq, 8.15 g, 11.6 mmol) and trimethylsilyl acetylene (3.00 eq, 33 mL, 232 mmol was stirred at 30 °C for 2 h under Ar. The volatiles were removed in vacuo and the residue was suspended in EA (200 mL). The solids were filtered off and the filtrate was evaporated in vacuo to afford 5-[4-amino-2-bromo-5,6-difluoro-3-(2- trimethylsilylethynyl)phenoxy]-4-benzyloxy-2-fluoro-benzonitrile (29.00 g, 47.7 mmol, 62 % yield). MS (ESI): 545, 547 (M+H)⁺; retention time 2.30 min (Method 3). Intermediate 45H 4-Benzyloxy-5-[(4-bromo-6,7-difluoro-1H-indol-5-yl)oxy]-2-fluoro-benzonitrile A mixture of 5-[4-amino-2-bromo-5,6-difluoro-3-(2-trimethylsilylethynyl)phenoxy]-4- benzyloxy-2-fluoro-benzonitrile (1.00 eq, 1.10 g, 2.02 mmol) in DMF (20 mL) and cuprous iodide (0.200 eq, 77 mg, 0.403 mmol) was stirred at 100 °C under Ar for 1 hour, diluted with 100 mL of water, and extracted with EA (3 x 100mL). The combined organic phase was washed with brine, dried over Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography eluting with 0-50% of ethyl acetate in petroleum ether to give 4-benzyloxy-5- [(4-bromo-6,7-difluoro-1H-indol-5-yl)oxy]-2-fluoro-benzonitrile (640 mg, 1.35 mmol, 67 % yield) as a yellow solid. MS (ESI): 473.1, 475.1 (M+H)⁺; retention time 2.13 min (Method 3). Intermediate 45I 4-Benzyloxy-5-[4-bromo-6,7-difluoro-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- To a solution of 4-benzyloxy-5-[(4-bromo-6,7-difluoro-1H-indol-5-yl)oxy]-2-fluoro- benzonitrile (1.00 eq, 500 mg, 1.06 mmol) in anhydrous DMF (5 mL) was added slowly at 0 °C under N2 sodium hydride (1.20 eq, 51 mg, 1.27 mmol, 60% dispersion in oil). The resulting mixture was stirred at 0 °C for 10 min. p-Toluenesulfonyl chloride (1.10 eq, 222 mg, 1.16 mmol) was added portion wise, and the resulting mixture warmed up to rt with stirring over 4 h. The reaction was quenched with saturated aqueous NaHCO₃ (50 mL) and extracted with EA (3 x 10 mL). The combined organic layer was dried over Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 10:1 PE:EA to give 4-benzyloxy-5-[4-bromo-6,7-difluoro-1-(p-tolylsulfonyl)indol-5-yl]oxy- 2-fluoro-benzonitrile (636 mg, 1.01 mmol, 96 % yield) as a brown solid. MS (ESI): 649.1, 651.1 (M+Na)⁺; retention time 2.32 min. Intermediate 45J 4-Benzyloxy-5-[6,7-difluoro-4-[(4-methoxyphenyl)methylsulfanyl]-1-(p- tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile A mixture of 4-benzyloxy-5-[4-bromo-6,7-difluoro-1-(p-tolylsulfonyl)indol-5-yl]oxy-2- fluoro-benzonitrile (1.00 eq, 500 mg, 0.797 mmol) 4-methoxybenzyl mercaptan (1.20 eq, 0.13 mL, 0.956 mmol) tris(dibenzylideneacetone) dipalladium (0.0500 eq, 36 mg, 0.0398 mmol) 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (0.100 eq, 46 mg, 0.0797 mmol) and N,N- diisopropylethylamine (2.00 eq, 0.28 mL, 1.59 mmol) in 1,4-dioxane (10mL) was stirred at 100 °C under a N2 atmosphere 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 5:1 PE:EA to give 4-benzyloxy-5-[6,7-difluoro-4-[(4- methoxyphenyl)methylsulfanyl]-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile (476 mg, 0.679 mmol, 85 % yield) as a brown solid. MS (ESI): 723.3 (M+Na)⁺; retention time 2.34 min (Method 5). Intermediate 45K 4-benzyloxy-5-[6,7-difluoro-1-(p-tolylsulfonyl)-4-sulfanyl-indol-5-yl]oxy-2-fluoro- benzonitrile To a solution of 4-benzyloxy-5-[6,7-difluoro-4-[(4-methoxyphenyl)methylsulfanyl]-1-(p- tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile (1.00 eq, 1.00 g, 1.43 mmol) in DCM (10mL) was added TFA (91.0 eq, 10 mL, 130 mmol) and anisole (3.21 eq, 0.50 mL, 4.58 mmol). The resulting mixture was stirred at room temperature for 6 h. After concentration, the residue, 4-benzyloxy-5-[6,7-difluoro-1-(p-tolylsulfonyl)-4-sulfanyl-indol-5-yl]oxy-2-fluoro- benzonitrile (800 mg,0.450 mmol, 31 % yield), was carried into the next step without purification. MS (ESI): 581.2 (M)⁺; retention time 1.81 min (Method 5). Intermediate 45L 4-Benzyloxy-5-[6,7-difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- benzonitrile A mixture of 4-benzyloxy-5-[6,7-difluoro-1-(p-tolylsulfonyl)-4-sulfanyl-indol-5-yl]oxy-2- fluoro-benzonitrile (1.00 eq, 823 mg, 1.42 mmol), potassium carbonate (2.00 eq, 392 mg, 2.83 mmol) in acetone (10mL) and iodomethane (1.00 eq, 0.089 mL, 1.42 mmol) was stirred at room temperature for 1 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 10:1 PE:EA to give 4-benzyloxy-5-[6,7-difluoro-4-methylsulfanyl-1-(p- tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile (690 mg,1.16 mmol, 81 % yield) as a brown solid. MS (ESI): 617.3 (M)⁺; retention time 2.27 min (Method 5). Intermediate 45M 4-Benzyloxy-5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzonitrile To a solution of 4-benzyloxy-5-[6,7-difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5- yl]oxy-2-fluoro-benzonitrile (1.00 eq, 100 mg, 0.168 mmol) in THF (1 mL) was added TBAF (2.00 eq, 0.34 mL, 0.336 mmol) and the mixture was stirred at room temperature for 2 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 PE:EA to give 4- benzyloxy-5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzonitrile (70 mg, 0.159 mmol, 95 % yield) as a brown solid. MS (ESI): 441.3 (M+H)⁺; retention time 2.11 min (Method 5). Intermediate 46 2-Fluoro-5-((tetrahydro-2H-pyran-2-yloxy)(4,6,7-trifluoro-1-(triisopropylsilyl)-1H- indol-5-yl)methyl)benzimidamide To a solution of 2-fluoro-5-((tetrahydro-2H-pyran-2-yloxy)(4,6,7-trifluoro-1- (triisopropylsilyl)-1H-indol-5-yl)methyl)benzonitrile (1.00 eq, 270 mg, 0.482 mmol) in^THF (3 mL) was added at rt^LHMDS (8.00 eq, 3.9 mL, 3.856 mmol) and the reaction mixture was stirred for 1 hour. The mixture was quenched with water (20 mL) and extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over magnesium sulfate and concentrated under reduced pressure to give 2-fluoro-5- ((tetrahydro-2H-pyran-2-yloxy)(4,6,7-trifluoro-1-(triisopropylsilyl)-1H-indol-5- yl)methyl)benzimidamide (290 mg, quantitative yield). MS (ESI): 578.4 (M+H)⁺; retention time 1.93 min (Method 3). Intermediate 46A 4,6,7-Trifluoro-1H-indole To a solution of^1,2,5-trifluoro-3-nitrobenzene (23 g, 130 mmol) in THF (200 mL) was added vinyl magnesium bromide (1.0 M solution in THF, 390 mL, 390 mmol) at -78 °C and the reaction mixture was stirred at -78 °C for^1h.^The mixture was quenched with saturated ammonium chloride solution (200 mL), extracted with ethyl acetate (200 mL). The separated organic layer was washed with brine (2 x 200 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-10% ethyl acetate in petroleum ether to give ^4,6,7-trifluoro-1H-indole (2.8 g, yield 12 %)^as an oil. MS (ESI): 172 (M+H)⁺; retention time 1.98 min (modified Method 2 - Gradient: 5%-95% B in 2.5min). Intermediate 46B 4,6,7-Trifluoro-1-(triisopropylsilyl)-1H-indole To a stirred and chilled (0 °C) solution of^4,6,7-trifluoro-1H-indole (2.8 g, 16.4 mmol)^in^THF (30 mL)^was added NaH (590 mg, 24.6 mmol, 60 % dispersion in oil) and the mixture was stirred at 0 °C for^1 h. TIPSCl (3.8 g, 19.68 mmol) in THF (5 mL) was added, and stirring at 0 °C was continued for^1 h. The mixture was quenched with saturated aqueous ammonium chloride solution (50 mL) and extracted with ethyl acetate (50 mL). The separated organic layer was washed with brine (2 x 50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0- 10% ethyl acetate in petroleum ether to give 4,6,7-trifluoro-1-(triisopropylsilyl)-1H-indole (3.4 g, 64 % yield)^as an oil. MS (ESI): 328 (M+H)⁺; retention time 2.39 min (modified Method 2 - Gradient: 5%-95% B in 2.5 min). Intermediate 46C 2-Fluoro-5-(hydroxy(4,6,7-trifluoro-1-(triisopropylsilyl)-1H-indol-5- yl)methyl)benzonitrile To a solution of 4,6,7-trifluoro-1-(triisopropylsilyl)-1H-indole (0.8 g, 2.45 mmol) in^THF (10 mL) was added at -78 °C LDA (1.5 mL, 2.94 mmol). The mixture was stirred at -78 °C 1 h treated with 2-Fluoro-5-formyl-benzonitrile (1.05 eq, 0.39 g, 2.57 mmol), and stirred at -78 °C for additional1 h.^The mixture was quenched with saturated aqueous NH₄Cl (30 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed with brine (30 mL), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-25% ethyl acetate in petroleum ether to give 2-fluoro-5-(hydroxy(4,6,7-trifluoro-1-(triisopropylsilyl)-1H-indol-5- yl)methyl)benzonitrile (920 mg, 79 % yield) as a solid. MS (ESI): 477 (M+H)⁺; retention time 2.73 min (modified Method 2 - Gradient: 5%-95% B in 2.5min). Intermediate 46D 2-Fluoro-5-((tetrahydro-2H-pyran-2-yloxy)(4,6,7-trifluoro-1-(triisopropylsilyl)-1H- indol-5-yl)methyl)benzonitrile A mixture of 2-fluoro-5-(hydroxy(4,6,7-trifluoro-1-(triisopropylsilyl)-1H-indol-5- yl)methyl)benzonitrile (0.46 g, 0.966 mmol), PPTS (24 mg, 0.1 mmol) and DHP (325 mg, 3.864 mmol) in THF (10 mL) was stirred at 60 °C for 16 h. The mixture was concentrated and the residue was purified by flash chromatography on silica gel eluting with 0-15% ethyl acetate in petroleum ether to give 2-fluoro-5-((tetrahydro-2H-pyran-2-yloxy)(4,6,7-trifluoro-1- (triisopropylsilyl)-1H-indol-5-yl)methyl)benzonitrile (540 mg, 99 % yield) as a solid. MS (ESI): 561 (M+H)⁺; retention time 3.81 min (modified Method 2 - Gradient: 5%-95% B in 3 min). Intermediate 47 6,7-Difluoro-5-[4-fluoro-3-(1H-1,2,4-triazol-3-yl)phenoxy]-4-methylsulfanyl-1-(p- tolylsulfonyl)indole To a solution of 5-[6,7-difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-N- (dimethylaminomethylene)-2-fluoro-benzamide (1.00 eq, 1500 mg, 2.67 mmol) in acetic acid (3 mL) was added hydrazine monohydrate (1.50 eq, 201 mg, 4.01 mmol) . The reaction mixture was stirred at 80 °C for 2 hours. The solvent was removed in vacuo, the residue was diluted with ethyl acetate (20 mL), washed with water (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 0-80% ethyl acetate in petroleum ether to give 6,7-difluoro-5-[4- fluoro-3-(1H-1,2,4-triazol-3-yl)phenoxy]-4-methylsulfanyl-1-(p-tolylsulfonyl)indole (800 mg, 1.51 mmol, 57 % yield) as a yellow solid. MS (ESI): 531.2 (M+H)⁺; retention time 2.05 min (Method 5). Intermediate 47A 5-[(6,7-Difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzoic acid A solution of 5-[6,7-difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- benzonitrile (Intermediate 16, 1.00 eq, 400 mg, 0.819 mmol), NaOH (3.00 eq, 98 mg, 2.46 mmol) in methanol (10 mL) and water (3 mL) was stirred at 45 °C for 16 h. The solvent was removed in vacuo and the residue was acidified with 1M hydrochloric acid to pH ~ 5-6, extracted with ethyl acetate (2 x 20 mL). The combined organic extracts were washed with brine (20 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-10% methanol in dichloromethane to give 5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro- benzoic acid (270 mg, 0.764 mmol, 93 % yield) as a yellow solid. MS (ESI): 354.0 (M+H)⁺; retention time 1.93 min (modified Method 2 - Flow Rate: 1.8mL/min). Intermediate 47B 5-[(6,7-Difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzamide A mixture of 5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzoic acid (1.00 eq, 270 mg, 0.764 mmol), EDCI (2.00 eq, 293 mg, 1.53 mmol), 1-hydroxybenzotriazole (2.00 eq, 207 mg, 1.53 mmol) N N-diisopropylethylamine (3.00 eq, 296 mg, 2.29 mmol) and ammonium chloride (10.0 eq, 409 mg, 7.64 mmol) in DMF (5 mL) was stirred at room temperature for 16 hours. The mixture was diluted with ethyl acetate (20 mL), washed with water (2 x 20 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel column chromatography eluting with 0-80% ethyl acetate in petroleum ether to give 5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro- benzamide (200 mg, 0.568 mmol, 74 % yield) as a white solid. MS (ESI): 353.2 (M+H)⁺; retention time 1.81 min (Method 5). Intermediate 47C 5-[6,7-Difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzamide To a solution of 5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-benzamide (1.00 eq, 1.40 g, 3.97 mmol) in THF (20 mL) was added sodium hydride (1.20 eq, 191 mg, 4.77 mmol) at 0 °C. After stirring at 0 °C for 30 min, tosyl chloride (1.20 eq, 909 mg, 4.77 mmol) was added, and the mixture was stirred at room temperature for 1 additional hour. The mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL x 2). The combined organic phases were washed with brine (50mL x 2), dried over Na₂SO₄ and concentrated. The residue was purified by silica gel column chromatography eluting with 0- 50% ethyl acetate in petroleum ether to give 5-[6,7-difluoro-4-methylsulfanyl-1-(p- tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzamide (1.60 g, 3.16 mmol, 80 % yield) as a white solid. MS (ESI): 507.3 (M+H)⁺; retention time 2.05 min (Method 5). Intermediate 47D 5-[6,7-Difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-N- (dimethylaminomethylene)-2-fluoro-benzamide A mixture of 5-[6,7-difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- benzamide (1.00 eq, 1.50 g, 2.96 mmol) and DMF-DMA (50.4 eq, 20 mL, 149 mmol) was stirred at 80 °C for 5 hours. The solvent was removed under reduced pressure and the residue was used in the next step without purification. MS (ESI): 562.3 (M+H)⁺; retention time 1.97 min (Method 5). Intermediate 48 Ethyl 2-[4-(2-bromoacetyl)-4-methyl-chroman-8-yl]sulfanylpropanoate The title compound was prepared in substantially the same way as the transformation of Intermediate 9D into Intermediate 9 starting from tert-butyl 8-(2-ethoxy-1-methyl-2-oxo- ethyl)sulfanyl-4-methyl-chromane-4-carboxylate. MS (ESI): 401, 403 (M+H)⁺; retention time 2.00 min (Method 2A). Intermediate 48A tert-Butyl 8-(2-ethoxy-1-methyl-2-oxo-ethyl)sulfanyl-4-methyl-chromane-4-carboxylate To a solution of tert-butyl 8-bromo-4-methyl-chromane-4-carboxylate (1.00 eq, 350 mg, 1.07 mmol) in 1,4-dioxane (5 mL) was added ethyl 2-sulfanylpropanoate (1.50 eq, 215 mg, 1.60 mmol), N,N-diisopropylethylamine (2.00 eq, 0.37 mL, 2.14 mmol), 4,5- bis(diphenylphosphino)-9,9-dimethylxanthene (0.100 eq, 62 mg, 0.107 mmol) and tris(dibenzylideneacetone)dipalladium (0.0500 eq, 49 mg, 0.0535 mmol). The reaction was stirred at 100 °C for 16 h, cooled to rt, diluted with water (20 mL), and extracted with ethyl acetate (20 mL). The separated organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography eluting with 0-20% ethyl acetate in petroleum ether to give tert-butyl 8-(2-ethoxy-1-methyl-2- oxo-ethyl)sulfanyl-4-methyl-chromane-4-carboxylate (300 mg, 0.788 mmol, 74 % yield) as an oil. MS (ESI): 325 (M-55)⁺; retention time 2.19 min (Method 2A). Intermediate 49 2-Bromo-1-(8-bromo-4-methylchroman-4-yl)ethan-1-one The title compound was prepared following a procedure similar to one for the preparation of Intermediate 38, starting from 8-bromo-4-methylchromane-4-carboxylic acid (Step A, Example 18). MS (ESI): 349 (M+H)⁺; retention time 2.01 min (Method 3). Intermediate 50 Ethyl 3-[4-methyl-4-(1H-pyrazol-3-yl)chroman-8-yl]propanoate A mixture of ethyl (E)-3-[4-methyl-4-(1H-pyrazol-3-yl)chroman-8-yl]prop-2-enoate (1.3 g, 4.16 mmol), Pd/C (10 wt. %, 500 mg) and EtOH (15 mL) was stirred under H₂ at ambient temperature and pressure for 16 h. The solids were filtered off and the filtrate was concentrated in vacuo to give ethyl 3-[4-methyl-4-(1H-pyrazol-3-yl)chroman-8-yl]propanoate (1.2 g, 92%) as a yellow oil. MS (ESI): 315 (M+H)⁺; retention time 1.89 min (Method 3). Intermediate 50A 8-Bromo-N-methoxy-N,4-dimethyl-chromane-4-carboxamide A mixture of 8-bromo-4-methyl-chromane-4-carboxylic acid (10 g, 36.885 mmol), THF (100 mL), N,O-dimethylhydroxylamine hydrochloride (5.4 g, 55.328 mmol), HATU (16.83 g, 44.262 mmol) and Et₃N (11.2 g, 110.66 mmol) was stirred at RT 16 h. The mixture was quenched with saturated aqueous NH₄Cl and extracted with ethyl acetate (50 mL). The organic phase was washed with H₂O (200 mL x 2) and brine (200 mL x 2), dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography eluting with 2/1/1 petroleum ether/ethyl acetate/dichloromethane to give 8- bromo-N-methoxy-N,4-dimethyl-chromane-4-carboxamide (7.5 g, 69 %) as a yellow oil. MS (ESI): 314, 316 (M+H)⁺; retention time 2.22 min (Method 2). Intermediate 50B 1-(8-Bromo-4-methylchroman-4-yl)ethan-1-one To a cooled (0 °C) solution of 8-Bromo-N-methoxy-N,4-dimethyl-chromane-4-carboxamide (7.5 g, 23.872 mmol) in THF (75 mL) was added dropwise MeMgBr (1M in THF, 119.4 mL, 119.4 mmol ). The mixture was stirred at RT 16 h, quenched with NH₄Cl, and extracted with ethyl acetate (50 mL). The organic phase was washed with water (200 mL x 2), brine (200 mL x 2), dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 2/1 petroleum ether/ethyl acetate to give 1-(8-bromo-4-methyl-chroman-4-yl)ethanone (6.4 g, 90 %) as a yellow oil. MS (ESI): 269, 271 (M+H)⁺; retention time 1.96 min (Method 3). Intermediate 50C (E)-1-(8-Bromo-4-methyl-chroman-4-yl)-3-(dimethylamino)prop-2-en-1-one A mixture of 1-(8-bromo-4-methyl-chroman-4-yl)ethanone (6.4 g, 23.78 mmol), DMF (64 mL) and N,N-dimethylformamide dimethyl acetal (16 mL, 16mmol) was stirred at 120 °C for 2 h. The mixture was quenched with NH₄Cl and extracted with ethyl acetate (50 mL). The organic phase was washed with water (200 mL x 2) and brine (200 mL x 2), dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 2/1 petroleum ether/ethyl acetate to give (E)-1-(8- bromo-4-methyl-chroman-4-yl)-3-(dimethylamino)prop-2-en-1-one (7.7 g, 95 %) as a yellow oil. MS (ESI): 324, 326 (M+H)⁺; retention time 1.90 min (Method 3). Intermediate 50D 3-(8-Bromo-4-methyl-chroman-4-yl)-1H-pyrazole A mixture of (E)-1-(8-bromo-4-methyl-chroman-4-yl)-3-(dimethylamino)prop-2-en-1-one (7.7 g, 23.75 mmol), EtOH (80 mL) and hydrazine hydrate (2.38 g, 47.5 mmol) was stirred at 80 °C for 5 h. The mixture was cooled, quenched with saturated aqueous NH₄Cl and extracted with ethyl acetate (50 mL). The organic phase was washed with water (200 mL x 2) and brine (200 mL x 2), 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 3-(8-bromo-4-methyl-chroman-4-yl)-1H-pyrazole (6 g, 78 %) as a yellow oil. MS (ESI): 293, 295 (M+H)⁺; retention time 1.87 min (Method 3). Intermediate 50E Ethyl (E)-3-[4-methyl-4-(1H-pyrazol-3-yl)chroman-8-yl]prop-2-enoate A mixture of 3-(8-bromo-4-methyl-chroman-4-yl)-1H-pyrazole (1.5 g, 5.12 mmol), K₂CO₃ (2.12 g, 15.35 mmol), ethyl (E)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)prop-2-enoate (1.74 g, 7.675 mmol) and 1,1′-bis(diphenylphosphino)ferrocene] dichloropalladium(II), complex with dichloromethane (418 mg, 0.512 mmol) in 1,4-dioxane/water (15 mL/1.5 mL) was stirred for 16 h at 100 °C under Ar. The mixture was quenched with saturated aqueous NH₄Cl and extracted with ethyl acetate (50 mL). The separated organic phase was washed with water (20 mL x 2) and brine (20 mL x 2), dried with 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 (E)-3-[4-methyl-4-(1H-pyrazol-3- yl)chroman-8-yl]prop-2-enoate (1.3 g, 73 %) as a yellow oil. MS (ESI): 313 (M+H)⁺; retention time 1.91 min (Method 3). Intermediate 51 6,7-Difluoro-5-(4-fluoro-3-iodo-phenoxy)-4-methylsulfanyl-1-(p-tolylsulfonyl)indole 5-[6,7-difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-aniline (2.7 g, 5.64 mmol) was dissolved in MeCN/water (10/1) and tert-butyl nitrite (3.3 g, 28.2 mmol) and KI (4.7 g, 28.2 mmol) were added. The mixture was stirred at 50 °C for 2 h, cooled to RT, quenched with saturated aqueous NH₄Cl and extracted with ethyl acetate (50 mL). The organic phase was washed with water (20 mL x 2) and brine (20 mL x 2), dried with anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 2/1/1 petroleum ether/ethyl acetate/dichloromethane to give 6,7- difluoro-5-(4-fluoro-3-iodo-phenoxy)-4-methylsulfanyl-1-(p-tolylsulfonyl)indole (2 g, 58 %) as a yellow solid. MS (ESI): 590 (M+H)⁺; retention time 3.10 min (modified Method 2 - Gradient: 5%-95% B in 2.5 min). Intermediate 51A 5-(6-Bromo-2,3-difluoro-4-nitro-phenoxy)-2-fluoro-aniline A mixture of 1-bromo-2,3,4-trifluoro-5-nitro-benzene (1.00 eq, 47.7 g, 186.44 mmol), K₂CO₃ (2.00 eq, 51.5 g, 372.88 mmol), DMF (500 mL) and 3-amino-4-fluoro-phenol (1.00 eq, 23.7 g, 131 mmol) was stirred at RT for 16 h, diluted with water (1000 mL), extracted with ethyl acetate (3 x 500 mL). The combined organic extracts were washed with brine (500 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-40% ethyl acetate in petroleum ether to give 5-(6-bromo-2,3-difluoro-4-nitro-phenoxy)-2-fluoro-aniline (54 g, 76 % yield) as yellow solid. MS (ESI): 363, 365 (M+H)⁺; retention time 2.27 min (Method 2). Intermediate 51B tert-Butyl N-[5-(6-bromo-2,3-difluoro-4-nitro-phenoxy)-2-fluoro-phenyl]carbamate A suspension of 5-(6-bromo-2,3-difluoro-4-nitro-phenoxy)-2-fluoro-aniline (40 g, 110.17 mmol) and Boc anhydride (120.22 g, 550.85 mmol) in acetonitrile was stirred at 100 °C for 16 h. The mixture was concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-40% ethyl acetate in petroleum ether to give tert-butyl N-[5-(6- bromo-2,3-difluoro-4-nitro-phenoxy)-2-fluoro-phenyl]carbamate (50 g, 80 % yield) as a yellow solid. MS (ESI): 485, 487 (M+Na)⁺; retention time 2.18 min (Method 3). Intermediate 51C tert-Butyl N-[5-[(4-bromo-6,7-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]carbamate To a stirred and chilled (-78 °C) solution of tert-butyl N-[5-(6-bromo-2,3-difluoro-4-nitro- phenoxy)-2-fluoro-phenyl]carbamate (40 g, 86.354 mmol) in THF (400 mL) was added vinyl magnesium bromide (1.0 M solution in THF, 259 mL, 259 mmol). The reaction mixture was stirring at -78 °C for 1 h, quenched with saturated aqueous ammonium chloride (800 mL), extracted with ethyl acetate (500 mL). The separated organic layer was washed with brine (2 x 200 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 tert-butyl N-[5-[(4-bromo-6,7-difluoro-1H-indol-5-yl)oxy]-2-fluoro- phenyl]carbamate (4.56 g, 11 % yield) as a solid. MS (ESI): 479, 481 (M+Na)⁺; retention time 2.61 min (modified Method 2 - Gradient: 5%-95% B in 2.5 min). Intermediate 51D tert-Butyl N-[5-[4-bromo-6,7-difluoro-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- phenyl]carbamate NaHMDS (12 mL, 12 mmol) was added dropwise under Ar to a chilled (-78 °C) solution of tert-Butyl N-[5-[(4-bromo-6,7-difluoro-1H-indol-5-yl)oxy]-2-fluoro-phenyl]carbamate (5.5 g, 12 mmol) in THF (55 mL). The mixture was stirred at -78 °C for 0.5 h, tosyl chloride (as a solution in THF, 2.3 g, 12 mmol) was added and the mixture was stirred at -78 °C for another 0.5 h. The reaction was quenched with saturated aqueous NH₄Cl and extracted with ethyl acetate (150 mL). The organic phase was washed with water (200 mL) and brine (200 mL), dried over anhydrous Na₂SO₄, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with 2/1/1 petroleum ether/ethyl acetate/dichloromethane to give tert-butyl N-[5-[4-bromo-6,7-difluoro-1-(p- tolylsulfonyl)indol-5-yl]oxy-2-fluoro-phenyl] carbamate (5.6 g, 72 %) as a yellow solid. MS (ESI): 633, 635 (M+Na)⁺; retention time 3.05 min (modified Method 2 - Gradient: 5%-95% B in 2.5 min). Intermediate 51E tert-Butyl N-[5-[6,7-difluoro-4-[(4-methoxyphenyl)methylsulfanyl]-1-(p- tolylsulfonyl)indol-5-yl]oxy-2-fluoro-phenyl]carbamate A mixture of tert-butyl N-[5-[4-bromo-6,7-difluoro-1-(p-tolylsulfonyl)indol-5-yl]oxy-2- fluoro-phenyl]carbamate (5.6 g, 9.16 mmol), dioxane (60 mL), DIPEA(3.2 mL, 18.32 mmol), Pd2(dba)3 (419.3 mg, 0.458 mmol), 4-methoxybenzyl mercaptan (1.7 g, 1.2 eq, 10.99 mmol) and Xantphos (0.53 g, 0.92 mmol) was stirred at 100 °C for 16 h under Ar. The mixture was cooled to RT and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-20% ethyl acetate in petroleum ether to give tert-butyl N-[5-[6,7- difluoro-4-[(4-methoxyphenyl)methylsulfanyl]-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- phenyl]carbamate (5.7 g, 82 % yield) as a solid. MS (ESI): 707.3 (M+Na)⁺; retention time 2.35 min (Method 3). Intermediate 51F 5-[6,7-Difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-aniline A solution of tert-butyl N-[5-[6,7-difluoro-4-[(4-methoxyphenyl)methylsulfanyl]-1-(p- tolylsulfonyl)indol-5-yl]oxy-2-fluoro-phenyl]carbamate (5 g, 7.3 mmol) in TFA (50 mL) and anisole(5 mL) was stirred at RT for 16 h. The mixture was concentrated, the residue was dissolved in acetone(50 mL) and iodomethane (0.55 mL, 8.76 mmol) and potassium carbonate (2.4 g, 18.32 mmol) were added. The mixture was stirred at RT for 1 h then quenched with saturated aqueous sodium thiosulfate (200 mL), extracted with ethyl acetate (200 mL), washed with brine (200 mL × 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-20% ethyl acetate in petroleum ether to give 5-[6,7-difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5- yl]oxy-2-fluoro-aniline (2.37 g, 70 % yield over two steps) as a solid. MS (ESI): 479 (M+H)⁺; retention time 2.65 min (modified Method 2 - Gradient: 5%-95% B in 2.5 min). Intermediate 52 5-[6,7-Difluoro-4-methylsulfonyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzamidine The title compound was prepared from 5-((6,7-difluoro-4-(methylsulfonyl)-1-tosyl-1H-indol- 5-yl)oxy)-2-fluorobenzonitrile via a three steps sequence analogous to the one converting Intermediate 43F into Intermediate 43. MS (ESI): 538.1 (M+H)⁺; retention time 1.54 min (Method 3). Intermediate 53 Ethyl 2-[1-(2-bromoacetyl)-1-methyl-tetralin-5-yl]sulfanyl-2-methyl-propanoate The title compound was prepared from Intermediate 53A in substantially the same way as the transformation of Intermediate 48A into Intermediate 48. MS (ESI): 413.1, 415.1 (M+H)⁺; retention time 2.08 min (Method 3). Intermediate 53A tert-Butyl 8-(2-ethoxy-1,1-dimethyl-2-oxo-ethyl)sulfanyl-4-methyl-chromane-4- carboxylate To a solution of tert-butyl 8-(2-ethoxy-1-methyl-2-oxo-ethyl)sulfanyl-4-methyl-chromane-4- carboxylate (Intermediate 48A, 1.00 eq, 200 mg, 0.526 mmol) in dry THF (5 mL) was added LDA (1.20 eq, 0.32 mL, 0.631 mmol) dropwise at -78 °C under Ar. After stirring for 30 min, iodomethane (1.20 eq, 0.039 mL, 0.631 mmol) was added and the mixture was stirred at RT for 2 h. The reaction was quenched with a saturated aqueous NH₄Cl solution (20 mL), extracted with ethyl acetate(30 mL). The separated organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-20% ethyl acetate in petroleum ether to give tert- butyl 8-(2-ethoxy-1,1-dimethyl-2-oxo-ethyl)sulfanyl-4-methyl-chromane-4-carboxylate (190 mg, 0.482 mmol, 92 % yield) as an oil. MS (ESI): 339 (M-55)⁺ - protonated acid after loss of t-Bu, retention time 2.24 min (Method 3). Intermediate 54 6,7-Difluoro-5-[4-fluoro-3-(1H-pyrazol-3-yl)phenoxy]-4-methylsulfanyl-1-(p- tolylsulfonyl)indole To a solution of (E)-1-[5-[6,7-difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2- fluoro-phenyl]-3-(dimethylamino)prop-2-en-1-one (1.00 eq, 250 mg, 0.446 mmol) in ethanol (4 mL) and THF (2 mL) was added hydrazine (10.0 eq, 0.14 mL, 4.46 mmol) at RT. The reaction mixture was stirred for 3 h at 50 °C, cooled to RT, diluted with ethyl acetate (20 mL), washed with water (20 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 20 % EA in PE to give 6,7- difluoro-5-[4-fluoro-3-(1H-pyrazol-3-yl)phenoxy]-4-methylsulfanyl-1-(p-tolylsulfonyl)indole (150 mg, 0.283 mmol, 64 % yield). MS (ESI): 530.1 (M+H)⁺; retention time 1.50 min (Method 2A). Intermediate 54A 1-[5-[(6,7-Difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro-phenyl]ethanone Methylmagnesium bromide (2.50 eq, 2.6 mL, 2.56 mmol) was added to a solution of 5-[6,7- difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-benzonitrile (1.00 eq, 500 mg, 1.02 mmol) in a mixture of toluene (5 mL) and THF (0.5 mL) at 80 °C, and the mixture was stirred for 20 min. The mixture was cooled to RT and saturated aqueous ammonium chloride (200 ml) and 100 ml of water were added. The aqueous phase was extracted with ethyl acetate (2 x 100 mL). The combined organic phase was washed with brine (50 ml), dried with anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 15 % EA in PE to give 1-[5-[(6,7-difluoro-4-methylsulfanyl-1H- indol-5-yl)oxy]-2-fluoro-phenyl]ethanone (260 mg, 0.740 mmol, 72 % yield). MS (ESI): 352.1 (M+H)⁺; retention time 1.41 min (Method 2A). Intermediate 54B 1-[5-[6,7-Difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- phenyl]ethanone A mixture of 1-[5-[(6,7-difluoro-4-methylsulfanyl-1H-indol-5-yl)oxy]-2-fluoro- phenyl]ethanone (1.00 eq, 260 mg, 0.740 mmol) , tosyl chloride (1.50 eq, 211 mg, 1.11 mmol), NaOH (2.00 eq, 59 mg, 1.48 mmol), DCM (5mL) and benzyl triethylammonium chloride (0.150 eq, 25 mg, 0.111 mmol) was stirred for 4 h at RT, diluted with ethyl acetate (200 mL), washed with water (200 mLx2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography eluting with 15 % EA in PE to give 1- [5-[6,7-difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- phenyl]ethanone (300 mg ,0.593 mmol, 80 % yield). MS (ESI): 506.1 (M+H)⁺; retention time 1.55 min (Method 2A). Intermediate 54C (E)-1-[5-[6,7-difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro- phenyl]-3-(dimethylamino)prop-2-en-1-one To a solution of 1-[5-[6,7-difluoro-4-methylsulfanyl-1-(p-tolylsulfonyl)indol-5-yl]oxy-2- fluoro-phenyl]ethanone (1.00 eq, 300 mg, 0.593 mmol) in DMF (3 mL) was added DMF-DMA (10.0 eq, 706 mg, 5.93 mmol) at RT. The reaction mixture was stirred for 16 h at 100 °C, cooled to RT, diluted with ethyl acetate (200 mL), washed with water (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with 15 % EA in PE to give (E)-1-[5-[6,7-difluoro-4-methylsulfanyl- 1-(p-tolylsulfonyl)indol-5-yl]oxy-2-fluoro-phenyl]-3-(dimethylamino)prop-2-en-1-one (250 mg, 0.446 mmol, 75 % yield). MS (ESI): 561.2 (M+H)⁺; retention time 1.47 min (Method 2A). Intermediate 55 Ethyl 3-[4-(2-bromoacetyl)-6-chloro-4-methyl-chroman-8-yl]propanoate The title compound was obtained from Intermediate 55A via a sequence analogous to the one transforming Intermediate 9D into Intermediate 9. MS (ESI): 403.1, 405.1 (M+H)⁺; retention time 2.10 min (Method 6). Intermediate 55A tert-Butyl 6-chloro-8-(3-ethoxy-3-oxo-propyl)-4-methyl-chromane-4-carboxylate To a solution of tert-butyl 8-(3-ethoxy-3-oxo-propyl)-4-methyl-chromane-4-carboxylate (1.00 eq, 120 mg, 0.344 mmol) in acetic acid (2 mL) was added N-chlorosuccinimide (20.0 eq, 920 mg, 6.89 mmol) and the mixture was stirred with at RT for 2 h. The reaction mixture was quenched with water (5 mL), extracted with ethyl acetate (3 x 5 mL), the combined organic extracts were washed with saturated aqueous NaHCO₃ (3 x 10 mL), water (3 x 10 mL), brine (5 mL), dried over anhydrate sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-15% ethyl acetate in petroleum ether to give tert-butyl 6-chloro-8-(3-ethoxy-3-oxo-propyl)-4-methyl-chromane-4-carboxylate (90 mg, 0.235 mmol, 68 % yield) as a solid. MS (ESI): 405.1 (M+Na)⁺; retention time 2.85 min (modified Method 2 - Gradient: 5%-95% B in 2.5 min). Intermediate 56 Methyl 4-(2-bromoacetyl)-4-methyl-chromane-8-carboxylate The title compound was prepared in two steps from Intermediate 56A similarly to the transformation of Intermediate 9D into Intermediate 9. MS (ESI): 327.1, 329.1 (M+H)⁺; retention time 1.97 min (Method 2). Intermediate 56A O4-tert-butyl O8-methyl 4-methylchromane-4,8-dicarboxylate A mixture of tert-butyl 8-bromo-4-methyl-chromane-4-carboxylate (1.00 eq, 6.50 g, 19.9 mmol), triethylamine (7.22 eq, 20 mL, 143 mmol), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.200 eq, 3219 mg, 3.97 mmol) in methanol (40 mL) was stirred at 90 °C for 16 hours under an atmosphere of carbon monoxide. The mixture was diluted with water (100 mL), extracted with ethyl acetate (50 mL x 3). The combined organic extracts were 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 0-18% ethyl acetate in petroleum ether to give O4-tert-butyl O8-methyl 4-methylchromane-4,8-dicarboxylate (550 mg, 1.80 mmol, 9 % yield). MS (ESI): 307.1 (M+H)⁺; retention time 2.02 min (modified Method 2A - Flow Rate: 1.8 mL/min). Intermediate 57 2-Fluoro-5-(4,6,7-trifluoro-1-tetrahydropyran-2-yl-indazol-5-yl)oxy-benzamidine To a stirred solution of 2-fluoro-5-(4,6,7-trifluoro-1-tetrahydropyran-2-yl-indazol-5-yl)oxy- benzonitrile (1.00 eq, 460 mg, 1.18 mmol) in THF (9 mL) was added LHMDS (1M in THF, 8.00 eq, 9.4 mL, 9.40 mmol) and the resulting mixture was stirred for 1 h at RT. The mixture was diluted with ethyl acetate (10 mL), washed with water (2 x 10 mL), brine (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 50-100% ethyl acetate in petroleum ether, then eluting with ethyl acetate, followed by 80:20:10:1 DCM:THF:MeCN:NH₄OH to give 2- fluoro-5-(4,6,7-trifluoro-1-tetrahydropyran-2-yl-indazol-5-yl)oxy-benzamidine (112 mg, 0.194 mmol, 17 % yield). MS (ESI): 409.1 (M+H)⁺; retention time 1.41 min (Method 3). Intermediate 57A [(3-Cyano-4-fluoro-phenyl)-(2,4,6-trimethoxyphenyl)-λ3-iodanyl] 4- methylbenzenesulfonate To a solution of 2-fluoro-5-iodo-benzonitrile (1.00 eq, 25.00 g, 101 mmol) in MeCN (300 mL) was added in one portion p-toluenesulfonic acid monohydrate (1.50 eq, 28.88 g, 152 mmol), followed by 3-chloroperoxybenzoic acid (1.50 eq, 30.82 g, 152 mmol) in a single portion. The reaction was stirred at 55 °C for 1 hour. After 30 minutes, 1,3,5-trimethoxybenzene (1.50 eq, 25.53 g, 152 mmol) was added in one portion and stirring was continued at 55 °C for 1 hour. The reaction mixture was cooled to RT and concentrated under reduced pressure. The residue was triturated with methyl triphenylmethyl ether. The precipitate was isolated by vacuum filtration, washed with methyl triphenylmethyl ether and dried to give [(3-cyano-4-fluoro- phenyl)-(2,4,6-trimethoxyphenyl)-λ3-iodanyl] 4-methylbenzenesulfonate (46.00 g, 78.6 mmol, 78 % yield) as a yellow solid. MS (ESI): 414.0[M-OTs]⁺; retention time 1.47 min (modified Method 2 - Gradient: 5%-95% B in 2.5 min). Intermediate 57B 4,6,7-Trifluoro-1-tetrahydropyran-2-yl-indazole A mixture of 4,6,7-trifluoro-1H-indazole (1.00 eq, 3.50 g, 20.3 mmol), DCM (100 mL), p- toluenesulfonic acid monohydrate (0.100 eq, 0.39 g, 2.03 mmol) and 3,4-dihydropyran (3.00 eq, 5.6 mL, 61.0 mmol) was stirred at room temperature for 1 h, quenched with water (20 mL) and extracted with dichloromethane (20 mL x 3). The combined organic extracts were washed with brine (20 mL x 3), dried over sodium sulfate, filtered and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-25% ethyl acetate in petroleum ether to give 4,6,7-trifluoro-1-tetrahydropyran-2-yl-indazole (4.50 g, 17.6 mmol, 86 % yield) as a solid. MS (ESI): 173.1 [M-THP+2H]⁺; retention time 2.45 min (modified Method 2 - Gradient: 5%-95% B in 2.5 min). Intermediate 57C (4,6,7-Trifluoro-1-tetrahydropyran-2-yl-indazol-5-yl)boronic acid To a solution of 4,6,7-trifluoro-1-tetrahydropyran-2-yl-indazole (1.00 eq, 4.40 g, 17.2 mmol) in THF (75 mL) at -78 °C was added LDA (1.20 eq, 10 mL, 20.6 mmol). The mixture was stirred at -78 °C for 0.5 h, trimethyl borate (3.00 eq, 5.8 mL, 51.5 mmol) was added and the mixture was stirred at -78 °C for another 15mintues. The reaction was quenched with saturated aqueous NH₄Cl (50 mL) and extracted with ethyl acetate (100 mL x 3). The combined organic extracts were washed with brine (50 mL x 3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-70% ethyl acetate in petroleum ether to give (4,6,7-trifluoro-1-tetrahydropyran-2-yl- indazol-5-yl)boronic acid (4.25 g, 14.2 mmol, 83 % yield) as a solid. MS (ESI): 323.1 (M+Na)⁺; retention time 1.91 min (modified Method 2 - Gradient: 5%-95% B in 2.5 min). Intermediate 57D 4,6,7-Trifluoro-1-tetrahydropyran-2-yl-indazol-5-ol To a solution of (4,6,7-trifluoro-1-tetrahydropyran-2-yl-indazol-5-yl)boronic acid (1.00 eq, 4.25 g, 14.2 mmol) in ethanol (60 mL) was added aqueous hydrogen peroxide (9.00 eq, 3.9 mL, 127 mmol) and the mixture was stirred overnight at room temperature. The mixture was extracted with ethyl acetate (40 mL x 3), the combined extracts were washed with brine (20 mL x 3), dried over sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-25% ethyl acetate in petroleum ether to give 4,6,7-trifluoro-1-tetrahydropyran-2-yl-indazol-5-ol (3.20 g, 11.8 mmol, 83 % yield) as a solid. MS (ESI): 271.1 (M-H)-; retention time 1.52 min (Method 4). Intermediate 57E 2-Fluoro-5-(4,6,7-trifluoro-1-tetrahydropyran-2-yl-indazol-5-yl)oxy-benzonitrile A mixture of 4,6,7-trifluoro-1-tetrahydropyran-2-yl-indazol-5-ol (1.00 eq, 3.10 g, 11.4 mmol), [(3-cyano-4-fluoro-phenyl)-(2,4,6-trimethoxyphenyl)-λ3-iodanyl] 4-methylbenzenesulfonate (1.00 eq, 6.67 g, 11.4 mmol), and potassium carbonate (3.00 eq, 4.72 g, 34.2 mmol) in acetone (50 mL) was stirred at 55 °C for 16 h. The reaction mixture was concentrated to dryness, the residue was suspended in EtOAc (100 mL), the organics were washed with water (2 x 50 mL), brine (50 mL), dried over MgSO₄ and concentrated. The residue was purified by reverse phase flash column chromatography eluting with 60% MeCN in water (spiked with 0.1% NH₄HCO₃) to give 2-fluoro-5-(4,6,7-trifluoro-1-tetrahydropyran-2-yl-indazol-5-yl)oxy-benzonitrile (2.20 g, 5.62 mmol, 49 % yield) as a solid. MS (ESI): 414.0 (M+Na)⁺; retention time 2.13 min (modified Method 2A - Flow Rate: 1.8 mL/min). Intermediate 58 5-[[6,7-Difluoro-4-[(4-methoxyphenyl)methylsulfanyl]-1H-indol-5-yl]oxy]-2-fluoro- benzamidine To a solution of 5-[[6,7-difluoro-4-[(4-methoxyphenyl)methylsulfanyl]-1H-indol-5-yl]oxy]-2- fluoro-benzonitrile (1.00 eq, 1.32 g, 3.00 mmol) in THF (30 mL) was added LHMDS (8.00 eq, 24 mL, 24.0 mmol) at 0 °C and the mixture was stirred at 0 °C for 2 hours. The mixture was diluted with ethyl acetate (50 mL), washed with water (50 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give 5-[[6,7-difluoro-4-[(4- methoxyphenyl)methylsulfanyl]-1H-indol-5-yl]oxy]-2-fluoro-benzamidine (1.30 g, 2.84 mmol, 95 % yield) as a gray solid. MS (ESI): 458.3 (M+H)⁺; retention time 1.70 min (Method 6). Intermediate 58A 5-[[6,7-difluoro-4-[(4-methoxyphenyl)methylsulfanyl]-1H-indol-5-yl]oxy]-2-fluoro- benzonitrile A mixture of 5-[6,7-difluoro-4-[(4-methoxyphenyl)methylsulfanyl]-1-(p-tolylsulfonyl)indol- 5-yl]oxy-2-fluoro-benzonitrile (1.00 eq, 2.50 g, 4.20 mmol)and tetrabutylammonium fluoride (2.00 eq, 8.4 mL, 8.41 mmol) in THF (20 mL) was stirred for 2 hours at room temperature. The mixture was diluted with ethyl acetate (20 mL), washed with brine (2 x 20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography eluting with 0-40% ethyl acetate in petroleum ether to give 5-[[6,7- difluoro-4-[(4-methoxyphenyl)methylsulfanyl]-1H-indol-5-yl]oxy]-2-fluoro-benzonitrile (1600 mg, 3.63 mmol, 86 % yield) as a white solid. MS (ESI): 463.2 (M+Na)⁺; retention time 2.12 min (Method 6). Intermediate 59 Ethyl 3-[4-(2-bromoacetyl)-6-fluoro-4-methyl-chroman-8-yl]propanoate The title compound was prepared similarly to Intermediate 9 starting from 8-bromo-6- fluorochromane-4-carboxylic acid. MS (ESI): 387.1, 389.1 (M+H)⁺; retention time 2.05 min (Method 3). Intermediate 60 5-[[4-[(1,1-Dioxo-1,2-thiazolidin-2-yl)methyl]-6,7-difluoro-1H-indol-5-yl]oxy]-2-fluoro- benzamidine The title compound was obtained from Intermediate 60C via a four step sequence analogous to the one converting Intermediate 43E into Intermediate 43. MS (ESI): 439.1 (M+H)⁺; retention time 1.35 min (modified Method 2A - Flow Rate: 1.8mL/min). Intermediate 60A 5-[1-(Benzenesulfonyl)-6,7-difluoro-4-methyl-indol-5-yl]oxy-2-fluoro-benzonitrile A mixture of 5-[1-(benzenesulfonyl)-4-bromo-6,7-difluoro-indol-5-yl]oxy-2-fluoro- benzonitrile (Intermediate 30A, 1.00 eq, 2.00 g, 3.94 mmol), DMF (100 mL), methylboronic acid (5.00 eq, 1.18 g, 19.7 mmol), 1,1′- bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (0.100 eq, 322 mg, 0.394 mmol) and a solution of potassium carbonate (3.00 eq, 1.63 g, 11.8 mmol) in water (10 mL) was stirred at 100 °C for 3 h under an Ar atmosphere. The reaction mixture was diluted with water (80 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic extracts were washed water (4 x 80 mL), brine (100 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel eluting with 0-30% ethyl acetate in petroleum ether to afford 5- [1-(benzenesulfonyl)-6,7-difluoro-4-methyl-indol-5-yl]oxy-2-fluoro-benzonitrile (1.20 g,2.71 mmol, 69 % yield). MS (ESI): 443.1 (M+H)⁺; retention time 2.10 min (modified Method 2A - Flow Rate: 1.8 mL/min). Intermediate 60B 5-[1-(Benzenesulfonyl)-4-(bromomethyl)-6,7-difluoro-indol-5-yl]oxy-2-fluoro- benzonitrile To a stirred solution of 5-[1-(benzenesulfonyl)-6,7-difluoro-4-methyl-indol-5-yl]oxy-2-fluoro- benzonitrile (1.00 eq, 200 mg, 0.452 mmol) in carbon tetrachloride (10 mL) was added azobisisobutyronitrile (0.100 eq, 7.4 mg, 0.0452 mmol) and N-bromosuccinimide (1.20 eq, 97 mg, 0.542 mmol) at room temperature. The reaction mixture was stirred at 80 °C overnight, cooled to rt, diluted with water (50 mL), and extracted with ethyl acetate (3 x 30 mL). The combined extracts were washed with brine (30 mL), dried over 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 afford 5-[1-(benzenesulfonyl)-4- (bromomethyl)-6,7-difluoro-indol-5-yl]oxy-2-fluoro-benzonitrile (70 mg, 0.134 mmol, 30 % yield). MS (ESI): no significant ionization observed; retention time 2.16 min (modified Method 2A - Flow Rate: 1.8 mL/min). The material was carried into the next step without further characterization. Intermediate 60C 5-[1-(Benzenesulfonyl)-4-[(1,1-dioxo-1,2-thiazolidin-2-yl)methyl]-6,7-difluoro-indol-5- yl]oxy-2-fluoro-benzonitrile To a stirred and chilled (0 °C) solution of 1,2-thiazolidine 1,1-dioxide (2.00 eq, 326 mg, 2.69 mmol) in DMF (10 mL) was added sodium hydride (1.10 eq, 57 mg, 1.48 mmol) under a N2 atmosphere. The reaction mixture was stirred at 0 °C for 1 h. A solution of 5-[[1- (benzenesulfonyl)-4-(bromomethyl)-6,7-difluoro-1H-inden-5-yl]oxy]-2-fluoro-benzonitrile (1.00 eq, 700 mg, 1.35 mmol) in DMF (10 mL) was added slowly at 0 °C to the reaction mixture and the reaction was allowed to warm to room temperature overnight. The reaction mixture was quenched with water (30 mL), extracted with EA (3 x 30 mL). the combined organic extract was washed with brine (30 mL), dried over Na₂SO₄, filtered and concentrated. The residue was purified by flash chromatography on silica gel eluting with 0-20% EA in PE to give 5-[1-(benzenesulfonyl)-4-[(1,1-dioxo-1,2-thiazolidin-2-yl)methyl]-6,7-difluoro-indol-5- yl]oxy-2-fluoro-benzonitrile (237 mg,0.422 mmol, 31 % yield). MS (ESI): 301 (loss of phenylsulfonyl and sultam)⁺; retention time 1.80 min (modified Method 2A - Flow Rate: 1.8 mL/min). Intermediate 61 Ethyl 3-[4-(2-bromoacetyl)-4-methyl-isochroman-8-yl]propanoate The title compound was prepared from 8-bromoisochroman-4-one in substantially the same way in which Intermediate 9 was prepared from 8-Bromochroman-4-one. MS (ESI): 369, 371 (M+H)⁺; retention time 2.06 min (Method 3). Biological Assays Example 30A. Aggregation analysis using differential static light scattering (DSLS) Purified recombinant NBD1 was produced using previously described methods (A. Schmidt, J.L. Mendoza, P. J. Thomas (2011) Biochemical and Biophysical Approaches to Probe CFTR Structure (365-376) M.D. Amaral, K. Kunzelmann (eds.), Cystic Fibrosis, Methods in Molecular Biology 741, Springer Science+Business Media). The effect of test compounds on thermal stability of NBD1 was evaluated by differential static light scattering (DSLS) using the Harbinger Stargazer-384 instrument (Epiphyte Three, Toronto, Canada). Test compounds were dissolved and diluted to desired concentrations in 100% DMSO. The compounds or DMSO controls (100nL) were stamped into wells of a 385-well low volume optical plate (Corning Inc., Corning, NY) using the Echo 555 acoustic liquid handler (Labcyte Inc., San Jose, CA). [268] NBD1 protein was diluted to 0.2mg/ml in S200 buffer (50mM Tris-HCl, 150mM NaCl, 5mM MgCl₂, 2mM ATP, 2mM DTT, pH7.6) containing 1% glycerol.10uL of protein solution was aliquoted into the 384-well plate harboring the test compounds and 10uL mineral oil was overlayed onto the protein solution, using the epMotion robotic liquid handler (Eppendorf North America, Hauppauge, NY). After placing into the Stargazer instrument, the plate was heated at 1°C per minute to 70°C. Images were captured from 25°C to 70°C every 0.5°C. At the end of the experiment run, instrument software integrated image files and analyzed data automatically. A linear regression curve was generated for each well, representing the increase in light scattering over time. A temperature of aggregation (Tagg) was calculated based on the inflection point of the curve. To better compare data across experiments the average Tagg for DMSO control wells was calculated and subtracted from values for wells containing compounds to obtain a “∆Tagg” value. These ∆Tagg values reflect stabilizing efficacy of the compounds. Data for Compounds 1-83 are provided in Table 2 below. Table 2 *A: T ≥8 °C; B: 4-8 °C; C: ≤ 4 °C; D: Not Determined. Example 30B. TECC24 AUC fold over DMSO @ 10 µM [269] The effects of a test agent on CFTR-mediated transepithelial chloride transport was measured using TECC24 recording analysis. Test agents were solubilized in DMSO. Solubilized test agents were mixed with incubation medium containing DMEM/F12, Ultroser G (2%; Crescent Chemical, catalog #67042), Hyclone Fetal Clone II (2%; GE Healthcare, catalog # SH30066.02), bovine brain extract (0.25%; Lonza, catalog #CC-4098), insulin (2.5 μg/mL), IL-13 (10 ng/mL), hydrocortisone (20 nM), transferrin (2.5 μg/mL), triiodothyronine (500 nM), ethanolamine (250 nM), epinephrine (1.5 μΜ), phosphoethanolamine (250 nM), and retinoic acid (10 nM). Primary human bronchial epithelial cells from a ΔF508 homozygous CF donor (CF-HBE cells; from University of North Carolina Cystic Fibrosis Tissue Procurement Center), grown on Transwell HTS 24-well cell culture inserts (Costar, catalog #3378), were exposed to test agents or controls dissolved in incubation medium. The CF-HBE cells were cultured at 36.5°C for 48 hours before TECC24 recordings were performed in the presence or absence of test agent, a positive control or vehicle (DMSO). [270] Following incubation, the transwell cell culture inserts containing the test agent or control-treated CF-HBE cells were loaded onto a TECC24 apparatus (TECC v7 or MTECC v2; EP Design) to record the transepithelial voltage (VT) and resistance (TEER) using 4 AgCl electrodes per well configured in current-clamp mode. The apical and basolateral bath solutions both contained (in mM) 140 NaCl, 5 KCl, 2 CaCl², 1 MgCl², 10 Hepes, and 10 glucose (adjusted to pH 7.4 with NaOH). To inhibit basal Na+ absorption, the ENaC inhibitor benzamil (10 μM) was added to the bath. Then, the adenylate cyclase activator, forskolin (10 μΜ), was added to the bath to activate CFTR. The forskolin-stimulated Cl- transport was halted by addition of CFTR inhibitor-172 (20 μM) to the bath at the end of the experiment to confirm specificity. VT and TEER recordings were digitally acquired at routine intervals using TECC or MTECC software (EP Design). VT and TEER were transformed into equivalent transepithelial Cl- current (IEQ), and the Area Under the Curve (AUC) of the IEQ time course between forskolin and CFTR inhibitor-172 addition is generated using Excel (Microsoft). Efficacy is expressed as the ratio of the test agent AUC divided by vehicle AUC. EC50s based on AUC are generated using the non-linear regression log(agonist) vs. response function in Prism software (Graphpad) with HillSlope fixed = 1. [271] If a test agent increased the AUC of the forskolin-stimulated ΙEQ relative to vehicle in CF-HBE cells, and this increase was inhibited by CFTR inhibitor-172, then the test agent was considered a CFTR corrector. The data is shown in Table XX below. Table 3

ND = Not determined; “A" refers to AUC @10 µM >=12; “B” refers to AUC @10 µM between 4-12; “C” refers to AUC @10 µM <= 4. Equivalents and Scope [272] In the claims articles such as “a,” “an,” and “the” may mean one or more than one unless indicated to the contrary or otherwise evident from the context. Claims or descriptions that include “or” between one or more members of a group are considered satisfied if one, more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process unless indicated to the contrary or otherwise evident from the context. The present disclosure includes embodiments in which exactly one member of the group is present in, employed in, or otherwise relevant to a given product or process. The present disclosure includes embodiments in which more than one, or all of the group members are present in, employed in, or otherwise relevant to a given product or process. [273] Furthermore, the present disclosure encompasses all variations, combinations, and permutations in which one or more limitations, elements, clauses, and descriptive terms from one or more of the listed claims is introduced into another claim. For example, any claim that is dependent on another claim can be modified to include one or more limitations found in any other claim that is dependent on the same base claim. Where elements are presented as lists, e.g., in Markush group format, each subgroup of the elements is also disclosed, and any element(s) can be removed from the group. It should it be understood that, in general, where the present disclosure, or aspects of the present disclosure, is/are referred to as comprising particular elements and/or features, certain embodiments of the present disclosure or aspects of the present disclosure consist, or consist essentially of, such elements and/or features. For purposes of simplicity, those embodiments have not been specifically set forth in haec verba herein. It is also noted that the terms “comprising” and “containing” are intended to be open and permits the inclusion of additional elements or steps. Where ranges are given, endpoints are included. Furthermore, unless otherwise indicated or otherwise evident from the context and understanding of one of ordinary skill in the art, values that are expressed as ranges can assume any specific value or sub–range within the stated ranges in different embodiments of the present disclosure, to the tenth of the unit of the lower limit of the range, unless the context clearly dictates otherwise. [274] This application refers to various issued patents, published patent applications, journal articles, and other publications, all of which are incorporated herein by reference. If there is a conflict between any of the incorporated references and the instant specification, the specification shall control. In addition, any particular embodiment of the present disclosure that falls within the prior art may be explicitly excluded from any one or more of the claims. Because such embodiments are deemed to be known to one of ordinary skill in the art, they may be excluded even if the exclusion is not set forth explicitly herein. Any particular embodiment of the present disclosure can be excluded from any claim, for any reason, whether or not related to the existence of prior art. [275] Those skilled in the art will recognize or be able to ascertain using no more than routine experimentation many equivalents to the specific embodiments described herein. The scope of the present embodiments described herein is not intended to be limited to the above Description, but rather is as set forth in the appended claims. Those of ordinary skill in the art will appreciate that various changes and modifications to this description may be made without departing from the spirit or scope of the present disclosure, as defined in the following claims.

Claims

Claims 1. A compound of Formula (I): or a pharmaceutically acceptable salt thereof wherein W¹ is selected from the group consisting of -C(H)=, and -N=; W² is selected from the group consisting of -C(H)=, -C(R^d)=, and -N=; W³ is selected from the group consisting of -C(H)=, -C(R^d)=, and -N=; W⁴ is selected from the group consisting of -C(H)=, -C(R^d4)=, and -N=; W⁵ is selected from the group consisting of -C(H)=, -C(R^d5)=, and -N=; W⁶ is selected from the group consisting of -C(H)=, -C(R^c)=, and -N=; W⁷ is selected from the group consisting of -C(H)=, -C(R^c)=, and -N=; W⁸ is selected from the group consisting of -C(H)=, -C(R^c)=, and -N=; W⁹ is selected from the group consisting of -C(H)=, -C(R^c9)=, and -N=; Ring A is an optionally substituted 8-10 membered fused heterocyclyl; Ring B is optionally substituted 5-membered heteroaryl; each R^a is 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-C₆ aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each R^a is independently substituted with 0-4 instances of R^aa; each R^aa is independently selected from the group consisting of deuterium, halogen, oxo, - COOH, -CN, -CD₃, optionally substituted C₁-C₆ aliphatic, 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 R^aa are optionally taken together with any intervening atoms to form an optionally substituted 5-6 membered heterocyclyl ring; each R^b is 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-C₆ aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl; each R^c is 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-C₆ aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each R^c is independently substituted with 0-4 instances of R^aa; each R^d is 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-C₆ aliphatic, optionally substituted phenyl, optionally substituted 5-6-membered heteroaryl, optionally substituted 3-7 membered carbocyclyl, and optionally substituted 3-7 membered heterocyclyl, wherein each R^d is independently substituted with 0-4 instances of R^aa; R^c9 is halogen; R^d4 is halogen; R^d5 is halogen; each R¹ is independently selected from the group consisting of hydrogen, -CD₃, -(CH₂)_1-3R², - C(O)R², -(CH₂)_1-3OR², optionally substituted C₁-C₆ aliphatic, 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 R¹ are optionally taken together with any intervening atoms to form an optionally substituted 3-7 membered heterocyclyl ring; each R² is independently selected from the group consisting of hydrogen, optionally substituted C₁-C₆ aliphatic, 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 W¹ is -N=.

3. The compound of claim 1, wherein W² is -N=.

4. The compound of claim 1, wherein W³ is -N=.

5. The compound of claim 1, wherein W⁴ is -N=.

6. The compound of claim 1, wherein when W⁸ is -N=, W¹, W², W³, and W⁴ are 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 W⁶ is -C(H)=; W⁷ is -C(H)=; W⁸ is -C(H)=; and W⁹ is -N=.

9. The compound of any of claims 1-7, wherein W⁶ is -C(H)=; W⁷ is -C(H)=; W⁸ is -N=; and W⁹ is -C(H)=.

10. The compound of any of claims 1-7, wherein W⁶ is -C(H)=; W⁷ is -C(H)=; W⁸ is -C(H)=; and W⁹ is -C(H)=.

11. The compound of any of claims 1-7, wherein W⁶ is -C(R^c)=; W⁷ is -C(H)=; W⁸ is -C(H)=; and W⁹ is -C(H)=.

12. The compound of any of claims 1-7, wherein W⁶ is -C(H)=; W⁷ is -C(H)=; W⁸ is -C(R^c)=; and W⁹ is -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 is

18. 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 of

23. The compound of claim 15, wherein Ring

24. 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 of

26. 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 of

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

29. 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 of

31. 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 of

33. 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 of

35. 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 of

37. The compound of any of claims 1-37, wherein each R^a is independently selected from halogen, optionally substituted C₁-C₆ alkyl, and optionally substituted C₁-C₆ alkenyl, wherein each R^a is independently substituted with 0-4 instances of R^aa.

38. The compound of claim 36, wherein each R^a is 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 R^d is independently selected from the group consisting of halogen, -OR¹, -SR^I, -C(O)N(R¹)₂, -N(H)C(O)R¹, -SO₂R¹, - SO₂N(R²), -SO(NR²)R¹, and optionally substituted C₁-C₆ aliphatic, wherein each R^d is independently substituted with 0-4 instances of R^aa.

40. The compound of claim 39, wherein each R^d is 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 R^d4 is halogen.

42. The compound of claim 41, wherein R^d4 is fluoro.

43. The compound of any of claims 1-42, wherein each R^d5 is halogen.

44. The compound of claim 43, wherein R^d5 is fluoro.

45. The compound of any of the previous claims, wherein the compound is selected from the group consisting of

or 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.