Thyromimetic agents

Abstract

Provided are compounds having the following structure of Formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein A, X 1 , X 2 , Q, R 1 , R 2 , and n are as defined herein. Such compounds are useful as thyromimetic agents and have utility for treating diseases such as neurodegenerative diseases and fibrotic diseases. Also provided are pharmaceutical compositions containing such compounds, as well as methods of their use and preparation.

Description

background Technical Field

[0002] This invention relates to thyroxine compounds and products containing them, as well as their use and preparation methods.

[0003] Description of related technologies

[0004] Thyroid hormone (TH) is a key signaling agent for oligodendrocyte differentiation and myelin formation during development, and it also stimulates myelin regeneration in an adult model of multiple sclerosis (MS) (Calzà et al., Brain Res Revs 48:339-346, 2005). However, TH is not an acceptable long-term therapy due to the limited therapeutic window for achieving myelin regeneration while avoiding cardiotoxicity and bone demineralization associated with chronic hyperthyroidism. Some thyroid hormone analogs can activate thyroid hormone-responsive genes by utilizing the molecular and physiological characteristics of thyroid hormone receptors, while avoiding the associated drawbacks of TH (Malm et al., 2005). Mini Rev Med Chem 7:79-86, 2007). These receptors are expressed in two main forms, with heterogeneous tissue distribution and overlapping but different groups of target genes (Yen, Physiol Rev 81:1097-1142, 2001). TRα is abundant in the heart, brain, and bones, while TRβ is abundant in the liver (O'Shea et al., 2001). Nucl Recept Signal 4:e011, 2006).

[0005] It has also been reported that TH can inhibit transforming growth factor β (TGF-β) signaling, thereby attenuating fibrosis (Alonso-Merino et al., Proc Natl Acad Sci US A. 113(24):E3451-60, 2016). TGF-β is a pleiotropic cytokine that plays a key role in pathological processes such as fibrosis (Massagué, Nat Rev Mol Cell Biol. 13(10):616–630, 2012). By inhibiting TGF-β signaling, TR ligands or agonists may have beneficial effects in blocking the progression of fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) or systemic sclerosis (Varga et al., 2012). Curr Opin Rheumatol. 20(6): 720–728, 2008).

[0006] Developing selective thyrotropin drugs is challenging due to the high sequence homology of thyroid hormone receptor subtypes; that is, only one amino acid residue on the inner surface of the ligand-binding domain lumen varies between the α1 and β1 forms. Despite this challenge, several groups have reported TRβ-selective agonists. Scanlan et al. identified GC-1 (sobetirome) as one of the most potent analogs, which showed good performance in vitro (Chiellini et al., Chem Biol 5:299-306, 1998; Yoshihara et al., J Med Chem 46:3152-3161, 2003) and in vivo (Trost et al., Endocrinology 141:3057-3064, 2000; Grover et al., Endocrinology 145:1656-1661, 2004; Baxter et al., Trends Endocrinol Metab 15:154-157, 2004) showed significant TRβ selectivity. As used herein, the term "subitilor" refers to a synthetic diarylmethane derivative that is being investigated clinically as a potential therapeutic agent for hypercholesterolemia (see U.S. Patent 5,883,294, which is incorporated herein by reference). Other names for subitilor found in the literature and regulatory filings include QRX-431 and GC-1. Metabasis employed a similar core and novel liver-targeting prodrug strategy in MB07811 (Erion et al., PNAS 104(39), 15490-15495, 2007). Madrigal has reported the in vivo TRβ-selective activity of MGL-3196 (Taub et al., 2007). Atherosclerosis 230(2):373-380, 2013). KaroBio has reported on eprotirome (KB2115; Berkenstam et al., PNAS 105(2):663-668, 2008) and KB-141 (Ye et al., J Med Chem Both (46:1580-1588, 2003) showed improved TRβ selectivity in vitro. Further research by this group highlighted other selective compounds (Hangeland et al., BMCL 14:3549-3553, 2004). It has been reported that two TRβ selective agonists, identified as SKL-12846 and SKL-13784, accumulate in the liver and lower cholesterol levels in rodents (Takahashi et al., 2004). BMC 22(1):488-498, 2014; Xenobiotica2015, 1-9). Kissei also reported selective compounds (Shiohara et al., 2015, 1-9). BMC 20(11), 3622-3634, 2012).

[0007] Although progress has been made in this field, there is still a need for further selective thyrotropin compounds, products containing them, and methods related to their use and preparation. Summary of the Invention

[0008] This article discloses compounds according to Formula I:

[0009] (I)

[0010] Or pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes or salts thereof, wherein A, X 1 X 2 Q, R 1 R 2 And n is defined below.

[0011] In one embodiment, a pharmaceutical composition is provided comprising a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, in combination with a pharmaceutically acceptable carrier, diluent, or excipient. In another embodiment, the pharmaceutical composition is used to treat neurodegenerative diseases, including those classified as demyelinating diseases such as X-linked adrenoleukodystrophy or multiple sclerosis. In yet another embodiment, the pharmaceutical composition is used to treat medical conditions associated with increased TGF-β activity, such as fibrotic diseases.

[0012] In the implementation scheme, a method for treating neurodegenerative diseases in a subject of need is provided, comprising administering a compound having the structure of formula (I), or a pharmaceutically acceptable salt or a composition comprising the compound. In some aspects, the neurodegenerative diseases may be classified as demyelinating diseases, such as X-linked adrenoleukodystrophy or multiple sclerosis.

[0013] In another embodiment, a method is provided for treating a medical condition associated with TGF-β overexpression in a subject of need, comprising administering a compound having the structure of formula (I), or a pharmaceutically acceptable salt or composition comprising the compound. In some aspects, the medical condition associated with TGF-β overexpression is a fibrotic disease. Detailed Implementation

[0014] As described above, the present invention relates to thyroxine compounds, products containing such compounds, and methods of using and synthesizing them.

[0015] In one embodiment, a compound having the structure of formula (I) is provided:

[0016] (I)

[0017] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0018] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0019] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0020] R 1 For -NR 1a R 1b or -OR 1c ;

[0021] R 1a and R 1b Each can be independently H, lower alkyl, lower alkenyl, lower alkynyl, or -OR. a -NR a R b Carbocyclic, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R 1a and R 1b Together with the nitrogen atoms they are attached to, they form heterocycles;

[0022] R 1c It can be H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl;

[0023] Q is the key, –C(R) 3 R 4 )- or –{C(R 3 R 4 )}2-;

[0024] A is aryl or heteroaryl;

[0025] Each R 2 Independently, it can be halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, or -OR. a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2Ra or -S(O)2OR a ;

[0026] Each R 3 and R 4 Independently H, halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR a -NR a R b Carbocyclic, heterocyclic, carbocycloalkyl or heterocycloalkyl, or R 3 and R 4 Together they form =O or =S;

[0027] n is 0–5; and

[0028] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0029] Where R 1a R 1b R 1c R 2 R 3 R 4 R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' The alkyl group is replaced by -NR'R'', -S(O)2R', or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group, or a lower haloalkyl group; and

[0030] Where Q is -CH2-, A is phenyl, and R is... 1 = -OH, and when n is 0, X 1 It is a lower haloalkyl or halogenated.

[0031] The acid compound (R) of the present invention 1 = -OR 1c And R 1c = H) is an active agonist that selectively activates the TRβ receptor. The amide compound (R) of the present invention 1 = –NR 1a R 1b This compound can act as a substrate for a specific hydrolase, fatty acid-amide hydrolase (FAAH), which cleaves the amide to release thyroxine. Therefore, in tissues expressing high levels of FAAH, such as the central nervous system, the conversion of the prodrug to the drug is enhanced. The ester compound (R) of the present invention... 1 = -OR 1c And R 1c(≠ H) is also a prodrug, usually processed by the action of esterases, which can selectively exist in specific tissues.

[0032] As used herein, "lower alkyl" refers to a straight-chain or branched alkyl group having 1 to 8 carbon atoms, 1 to 6 carbon atoms in some embodiments, 1 to 4 carbon atoms in some embodiments, and 1 to 3 carbon atoms in some embodiments. Examples of straight-chain lower alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched lower alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl.

[0033] As used herein, "lower alkenyl" refers to a straight-chain or branched alkenyl group having 2 to 8 carbon atoms, in some embodiments 2 to 6 carbon atoms, in some embodiments 2 to 4 carbon atoms, and in some embodiments 2 to 3 carbon atoms. An alkenyl group is an unsaturated hydrocarbon chain containing at least one carbon-carbon double bond. Examples of lower alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, and hexenyl.

[0034] As used herein, "lower alkynyl" refers to a straight-chain or branched alkynyl group having 2 to 8 carbon atoms, in some embodiments 2 to 6 carbon atoms, in some embodiments 2 to 4 carbon atoms, and in some embodiments 2 to 3 carbon atoms. An alkynyl group is an unsaturated hydrocarbon chain containing at least one carbon-carbon triple bond. Examples of lower alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0035] "Halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0036] "Hydroxy group" refers to -OH.

[0037] "Cyano" refers to -CN.

[0038] "Lower haloalkyl" refers to a lower alkyl group as defined above in which one or more hydrogen atoms are replaced by a halogen. Examples of lower haloalkyl groups include, but are not limited to, -CF3, -CHF2, etc.

[0039] "Lower alkoxy group" refers to a lower alkyl group (i.e., -O-(lower alkyl group)) as defined above, which is connected by an oxygen atom. Examples of lower alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, tert-butoxy, etc.

[0040] "Lower haloalkoxy group" refers to a lower haloalkyl group (i.e., -O-(lower haloalkyl group)) as defined above, which is connected by an oxygen atom. Examples of lower haloalkoxy groups include, but are not limited to, -OCF3.

[0041] “Cycloalkyl” refers to an alkyl group that forms a ring structure, which may be substituted or unsubstituted, wherein the ring is fully saturated, partially unsaturated, or completely unsaturated, wherein if unsaturation is present, the conjugation of π electrons in the ring does not produce aromaticity. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups further include polycyclic cycloalkyl groups, such as, but not limited to, norbornel, adamantyl, bornel, camphenyl, isocamphenyl, and carenyl, as well as fused rings, such as, but not limited to, decahydronaphthyl.

[0042] "Cycloalkylalkyl" is an alkyl group as defined above in which the hydrogen or carbon bond of the alkyl group is replaced by a cycloalkyl bond as defined above.

[0043] "Aryl" refers to a cyclic aromatic hydrocarbon that does not contain heteroatoms. Therefore, aryl includes, but is not limited to, phenyl, azulel, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrene, triphenylene, pyrene, tetraphenyl, phenylene, biphenylene, anthracene, and naphthyl. In some embodiments, the aryl group contains 6-14 carbons in the ring portion of the group. The terms "aryl" and "aryl group" include fused rings, wherein at least one ring, but not necessarily all rings, is aromatic, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). In one embodiment, the aryl group is phenyl or naphthyl, while in another embodiment, the aryl group is phenyl.

[0044] "Carbocyclic," "carbocyclic," or "carbocyclic" refers to an alkyl group that forms a cyclic structure, which may be substituted or unsubstituted, wherein the ring is fully saturated, partially unsaturated, or completely unsaturated, and wherein, if unsaturation is present, the conjugation of π electrons in the ring can produce aromaticity. In one embodiment, the carbocyclic group comprises a cycloalkyl group as defined above. In another embodiment, the carbocyclic group comprises an aryl group as defined above.

[0045] "Carbocycloalkyl" is an alkyl group as defined above in which the hydrogen or carbon bond of the alkyl group is replaced by a bond attached to a carbocyclic group as defined above.

[0046] The terms "heterocyclic group," "heterocyclic," or "heterocyclic" refer to an aromatic or non-aromatic ring moiety containing three or more ring members, wherein one or more ring members are heteroatoms, such as, but not limited to, N, O, S, or P. In some embodiments, a heterocyclic group comprises 3 to 20 ring members, while other such groups have 3 to 15 ring members. At least one ring contains a heteroatom, but each ring in a polycyclic system need not contain a heteroatom. For example, dioxolane rings and benzodioxolane ring systems (methylenedioxyphenyl ring systems) are heterocyclic groups within the scope referred to herein.

[0047] Heterocyclic groups also include fused ring types, including those with fused aromatic and non-aromatic groups. Heterocyclic groups also include polycyclic systems containing heteroatoms, such as, but not limited to, quinuclidyl, and include heterocyclic groups with substituents, including but not limited to alkyl, halogen, amino, hydroxyl, cyano, carboxyl, nitro, thio, or alkoxy groups bonded to one of the ring members. Heterocyclic groups as defined herein can be heteroaryl or partially or fully saturated cyclic groups containing at least one cyclic heteroatom. Heterocyclic groups include, but are not limited to, pyrrolyl, furanyl, tetrahydrofuranyl, dioxolane, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indoleyl, dihydroindoleyl, azaindoleyl, inzolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazolopyridyl, thianaphthalenyl, purine, xanthineyl, adenine, guanine, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxolinyl, and quinazolinyl.

[0048] "Heterocyclic alkyl" is an alkyl group as defined above in which the hydrogen or carbon bond of the alkyl group is replaced by a bond attached to a heterocyclic group as defined above.

[0049] "Heteroaryl" refers to an aromatic ring moiety containing five or more ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, and S. Heteroaryl groups include, but are not limited to, groups such as pyrroleyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, thiopheneyl, triazolyl, tetraazolyl, triazinyl, thiazolyl, thiopheneyl, oxazolyl, isoxazolyl, benzothiopheneyl, benzofuranyl, indoleyl, azaindolyl, indoleyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazolylpyridyl, thianaphthyl, purinel, xanthinel, adeninel, guaninel, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxolinyl, and quinazolinyl. The terms “heteroaryl” and “heteroaryl group” include fused-ring compounds, such as those in which at least one ring, but not all rings, is aromatic, including tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, and 2,3-dihydroindolyl.

[0050] In one embodiment, a compound having the structure of formula (IA) is provided:

[0051] (IA)

[0052] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0053] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0054] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0055] R 1a and R 1b Each can be independently H, lower alkyl, lower alkenyl, lower alkynyl, or -OR. a -NR a R b Carbocyclic, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R 1a and R 1b Together with the nitrogen atoms they are attached to, they form heterocycles;

[0056] Q is the key, –C(R) 3 R 4 )- or –{C(R 3 R 4 )}2-;

[0057] A is aryl or heteroaryl;

[0058] Each R 2Independently, it can be halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, or -OR. a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0059] Each R 3 and R 4 Independently H, halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR a -NR a R b Carbocyclic, heterocyclic, carbocycloalkyl or heterocycloalkyl, or R 3 and R 4 Together they form =O or =S;

[0060] n is 0–5; and

[0061] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0062] Where R 1a R 1b R 1c R 2 R 3 R 4 R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' It is replaced by -NR'R'', -S(O)2R' or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group or a lower haloalkyl group.

[0063] In one embodiment, a compound having the structure of formula (IB) is provided:

[0064] (IB)

[0065] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0066] X 1It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0067] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0068] R 1c It can be H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl;

[0069] Q is the key, –C(R) 3 R 4 )- or –{C(R 3 R 4 )}2-;

[0070] A is aryl or heteroaryl;

[0071] Each R 2 Independently, it can be halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, or -OR. a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0072] Each R 3 and R 4 Independently H, halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR a -NR a R b Carbocyclic, heterocyclic, carbocycloalkyl or heterocycloalkyl, or R 3 and R 4 Together they form =O or =S;

[0073] n is 0–5; and

[0074] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0075] Where R 1a R 1b R 1c R 2 R 3 R 4 R aand R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' The alkyl group is replaced by -NR'R'', -S(O)2R', or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group, or a lower haloalkyl group; and

[0076] Where Q is -CH2-, A is phenyl, and R is... 1c When H is denoted as H and n is 0, X 1 It is a lower haloalkyl or halogenated.

[0077] In one embodiment, a compound having the structure of formula (IB) is provided, wherein A is a heteroaryl group, and in a more specific embodiment, it is a furanyl or thiophene group.

[0078] In one embodiment, a compound having the structure of formula (II) is provided:

[0079] (II)

[0080] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0081] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0082] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0083] R 1 For -NR 1a R 1b or -OR 1c ;

[0084] R 1a and R 1b Each can be independently H, lower alkyl, lower alkenyl, lower alkynyl, or -OR. a -NR a R b Carbocyclic, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R 1a and R 1b Together with the nitrogen atoms they are attached to, they form heterocycles;

[0085] R 1c It can be H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl;

[0086] A is aryl or heteroaryl;

[0087] Each R 2Independently, it can be halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, or -OR. a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0088] n is 0–5; and

[0089] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0090] Where R 1a R 1b R 1c R 2 R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' It is replaced by -NR'R'', -S(O)2R' or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group or a lower haloalkyl group.

[0091] In one embodiment, a compound having the structure of formula (II-A) is provided:

[0092] (II-A)

[0093] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0094] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0095] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0096] R 1a and R 1b Each can be independently H, lower alkyl, lower alkenyl, lower alkynyl, or -OR. a -NR a R b Carbocyclic, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R 1aand R 1b Together with the nitrogen atoms they are attached to, they form heterocycles;

[0097] A is aryl or heteroaryl;

[0098] Each R 2 Independently, it can be halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, or -OR. a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0099] n is 0–5; and

[0100] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0101] Where R 1a R 1b R 1c R 2 R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' It is replaced by -NR'R'', -S(O)2R' or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group or a lower haloalkyl group.

[0102] In one embodiment, a compound having the structure of formula (II-B) is provided:

[0103] (II-B)

[0104] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0105] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0106] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0107] R 1cIt can be H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl;

[0108] A is aryl or heteroaryl;

[0109] Each R 2 Independently, it can be halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, or -OR. a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0110] n is 0–5; and

[0111] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0112] Where R 1a R 1b R 1c R 2 R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' It is replaced by -NR'R'', -S(O)2R' or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group or a lower haloalkyl group.

[0113] In one embodiment, a compound having the structure of formula (III) is provided:

[0114] (III)

[0115] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0116] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0117] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0118] R 1 For -NR 1a R1b or -OR 1c ;

[0119] R 1a and R 1b Each can be independently H, lower alkyl, lower alkenyl, lower alkynyl, or -OR. a -NR a R b Carbocyclic, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R 1a and R 1b Together with the nitrogen atoms they are attached to, they form heterocycles;

[0120] R 1c It can be H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl;

[0121] Each R 2 Independently, it can be halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, or -OR. a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0122] n is 0–5; and

[0123] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0124] Where R 1a R 1b R 1c R 2 R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' It is replaced by -NR'R'', -S(O)2R' or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group or a lower haloalkyl group.

[0125] In one embodiment, a compound having the structure of formula (III-A) is provided:

[0126] (III-A)

[0127] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0128] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0129] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0130] R 1a and R 1b Each can be independently H, lower alkyl, lower alkenyl, lower alkynyl, or -OR. a -NR a R b Carbocyclic, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R 1a and R 1b Together with the nitrogen atoms they are attached to, they form heterocycles;

[0131] Each R 2 Independently, it can be halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, or -OR. a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0132] n is 0–5; and

[0133] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0134] Where R 1a R 1b R 1c R 2 R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' It is replaced by -NR'R'', -S(O)2R' or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group or a lower haloalkyl group.

[0135] In one embodiment, a compound having the structure of formula (III-B) is provided:

[0136] (III-B)

[0137] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0138] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0139] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0140] R 1c It can be H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl;

[0141] Each R 2 Independently, it can be halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, or -OR. a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0142] n is 0–5; and

[0143] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0144] Where R 1a R 1b R 1c R 2 R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' It is replaced by -NR'R'', -S(O)2R' or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group or a lower haloalkyl group.

[0145] In a more specific embodiment, a compound having the structure of any one of formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), or (III-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, is provided, wherein n is 1–5, and an R 2 For R to be replaced at position 3 of ring A 2a .

[0146] In one embodiment, a compound having the structure of formula (IV) is provided:

[0147] (IV)

[0148] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0149] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0150] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0151] R 1 For -NR 1a R 1b or -OR 1c ;

[0152] R 1a and R 1b Each can be independently H, lower alkyl, lower alkenyl, lower alkynyl, or -OR. a -NR a R b Carbocyclic, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R 1a and R 1b Together with the nitrogen atoms they are attached to, they form heterocycles;

[0153] R 1c It can be H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl;

[0154] R 2a Halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, -OR a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NRa C(O)R b -S(O)2R a or -S(O)2OR a ;

[0155] Each R 2b Independently, it can be halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, or -OR. a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0156] m is 0–4; and

[0157] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0158] Where R 1a R 1b R 1c R 2a R 2b R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' It is replaced by -NR'R'', -S(O)2R' or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group or a lower haloalkyl group.

[0159] In one embodiment, a compound having the structure of formula (IV-A) is provided:

[0160] (IV-A)

[0161] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0162] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0163] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0164] R1a and R 1b Each can be independently H, lower alkyl, lower alkenyl, lower alkynyl, or -OR. a -NR a R b Carbocyclic, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R 1a and R 1b Together with the nitrogen atoms they are attached to, they form heterocycles;

[0165] R 2a Halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, -OR a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0166] Each R 2b Independently, it can be halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, or -OR. a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0167] m is 0–4; and

[0168] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0169] Where R 1a R 1b R 1c R 2a R 2b R a and R bEach can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' It is replaced by -NR'R'', -S(O)2R' or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group or a lower haloalkyl group.

[0170] In one embodiment, a compound having the structure of formula (IV-B) is provided:

[0171] (IV-B)

[0172] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0173] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0174] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0175] R 1c It can be H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl;

[0176] R 2a Halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, -OR a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0177] Each R 2b Independently, it can be halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, or -OR. a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2ORa ;

[0178] m is 0–4; and

[0179] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0180] Where R 1a R 1b R 1c R 2a R 2b R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' It is replaced by -NR'R'', -S(O)2R' or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group or a lower haloalkyl group.

[0181] In one embodiment, a compound having the structure of formula (V) is provided:

[0182] (V)

[0183] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0184] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0185] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0186] R 1 For -NR 1a R 1b or -OR 1c ;

[0187] R 1a and R 1b Each can be independently H, lower alkyl, lower alkenyl, lower alkynyl, or -OR. a -NR a R b Carbocyclic, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R 1a and R 1b Together with the nitrogen atoms they are attached to, they form heterocycles;

[0188] R 1c It can be H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl;

[0189] A is aryl or heteroaryl;

[0190] Each R 2 Independently, it is halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0191] R 3 and R 4 Each can be independently H, halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, or -OR. a -NR a R b Carbocyclic, heterocyclic, carbocycloalkyl or heterocycloalkyl, or R 3 and R 4 Together they form =O or =S;

[0192] n is 0–5; and

[0193] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0194] Where R 1a R 1b R 1c R 2 R 3 R 4 R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' The alkyl group is replaced by -NR'R'', -S(O)2R', or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group, or a lower haloalkyl group; and

[0195] Where R 3 and R 4 Each is H, A is phenyl, and R is... 1 When X is -OH and n is 0, 1 It is a lower haloalkyl or halogenated.

[0196] In one embodiment, a compound having the structure of formula (V) is provided, wherein A is a heteroaryl group, and in a more specific embodiment, it is a furanyl or thiophene group.

[0197] In one embodiment, a compound having the structure of formula (VA) is provided:

[0198] (VA)

[0199] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0200] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0201] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0202] R 1a and R 1b Each can be independently H, lower alkyl, lower alkenyl, lower alkynyl, or -OR. a -NR a R b Carbocyclic, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R 1a and R 1b Together with the nitrogen atoms they are attached to, they form heterocycles;

[0203] A is aryl or heteroaryl;

[0204] Each R 2 Independently, it is halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0205] R 3 and R 4 Each can be independently H, halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, or -OR. a -NR a R b Carbocyclic, heterocyclic, carbocycloalkyl or heterocycloalkyl, or R 3 and R4 Together they form =O or =S;

[0206] n is 0–5; and

[0207] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0208] Where R 1a R 1b R 1c R 2 R 3 R 4 R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' It is replaced by -NR'R'', -S(O)2R' or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group or a lower haloalkyl group.

[0209] In one implementation, a compound having the structure of formula (VB) is provided:

[0210] (VB)

[0211] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0212] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0213] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0214] R 1c It can be H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl;

[0215] A is aryl or heteroaryl;

[0216] Each R 2 Independently, it is halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R aor -S(O)2OR a ;

[0217] R 3 and R 4 Each can be independently H, halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, or -OR. a -NR a R b Carbocyclic, heterocyclic, carbocycloalkyl or heterocycloalkyl, or R 3 and R 4 Together they form =O or =S;

[0218] n is 0–5; and

[0219] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0220] Where R 1a R 1b R 1c R 2 R 3 R 4 R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' The alkyl group is replaced by -NR'R'', -S(O)2R', or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group, or a lower haloalkyl group; and

[0221] Where R 3 and R 4 Each is H, A is phenyl, and R is H. 1c When H is denoted as H and n is 0, X 1 It is a lower haloalkyl or halogenated.

[0222] In one embodiment, a compound having the structure of formula (VI) is provided:

[0223] (VI)

[0224] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0225] Q 1 Q 2 Q 3 Q 4 and Q 5 Each independently constitutes CH and CR. 2 Or N;

[0226] X1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0227] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0228] R 1 For -NR 1a R 1b or -OR 1c ;

[0229] R 1a and R 1b Each can be independently H, lower alkyl, lower alkenyl, lower alkynyl, or -OR. a -NR a R b Carbocyclic, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R 1a and R 1b Together with the nitrogen atoms they are attached to, they form heterocycles;

[0230] R 1c It can be H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl;

[0231] Each R 2 Independently, it is halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0232] R 3 and R 4 Each can be independently H, halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, or -OR. a -NR a R b Carbocyclic, heterocyclic, carbocycloalkyl or heterocycloalkyl, or R 3 and R 4 Together they form =O or =S; and

[0233] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0234] Where R 1a R 1b R 1c R 2 R 3 R 4 R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' The alkyl group is replaced by -NR'R'', -S(O)2R', or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group, or a lower haloalkyl group; and

[0235] Where R 3 and R 4 Each is H, R 1 It is -OH, and Q 1 Q 2 Q 3 Q 4 and Q 5 When each is CH, X 1 It is a lower haloalkyl or halogenated.

[0236] In one embodiment, a compound having the structure of formula (VI-A) is provided:

[0237] (VI-A)

[0238] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0239] Q 1 Q 2 Q 3 Q 4 and Q 5 Each independently constitutes CH and CR. 2 Or N;

[0240] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0241] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0242] R 1a and R 1b Each can be independently H, lower alkyl, lower alkenyl, lower alkynyl, or -OR. a -NR a R b Carbocyclic, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R 1a and R 1b Together with the nitrogen atoms they are attached to, they form heterocycles;

[0243] Each R 2 Independently, it is halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0244] R 3 and R 4 Each can be independently H, halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, or -OR. a -NR a R b Carbocyclic, heterocyclic, carbocycloalkyl or heterocycloalkyl, or R 3 and R 4 Together they form =O or =S; and

[0245] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0246] Where R 1a R 1b R 1c R 2 R 3 R 4 R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' It is replaced by -NR'R'', -S(O)2R' or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group or a lower haloalkyl group.

[0247] In one embodiment, a compound having the structure of formula (VI-B) is provided:

[0248] (VI-B)

[0249] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0250] Q 1 Q 2Q 3 Q 4 and Q 5 Each independently constitutes CH and CR. 2 Or N;

[0251] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0252] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0253] R 1c It can be H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl;

[0254] Each R 2 Independently, it is halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0255] R 3 and R 4 Each can be independently H, halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, or -OR. a -NR a R b Carbocyclic, heterocyclic, carbocycloalkyl or heterocycloalkyl, or R 3 and R 4 Together they form =O or =S; and

[0256] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0257] Where R 1a R 1b R 1c R 2 R 3 R 4 R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. 'The alkyl group is replaced by -NR'R'', -S(O)2R', or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group, or a lower haloalkyl group; and

[0258] Where R 3 and R 4 Each is H, R 1c Let H be Q, and Q be Q 1 Q 2 Q 3 Q 4 and Q 5 When each is CH, X 1 It is a lower haloalkyl or halogenated.

[0259] In one embodiment, a compound having the structure of formula (VII) is provided:

[0260] (VII)

[0261] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0262] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0263] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0264] R 1 For -NR 1a R 1b -OR 1c Or heterocyclic rings;

[0265] R 1a and R 1b Each can be independently H, lower alkyl, lower alkenyl, lower alkynyl, or -OR. a -NR a R b Carbocyclic, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R 1a and R 1b Together with the nitrogen atoms they are attached to, they form heterocycles;

[0266] R 1c It can be H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl;

[0267] Each R 2 Independently, it is halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR a -NR a R b -C(O)Ra -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0268] R 3 and R 4 Each can be independently H, halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, or -OR. a -NR a R b Carbocyclic, heterocyclic, carbocycloalkyl or heterocycloalkyl, or R 3 and R 4 Together they form =O or =S;

[0269] n is 0–5; and

[0270] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0271] Where R 1a R 1b R 1c R 2 R 3 R 4 R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' The alkyl group is replaced by -NR'R'', -S(O)2R', or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group, or a lower haloalkyl group; and

[0272] Where R 3 and R 4 Each is H, R 1 When X is -OH and n is 0, 1 It is a lower haloalkyl or halogenated.

[0273] In one embodiment, a compound having the structure of formula (VII-A) is provided:

[0274] (VII-A)

[0275] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0276] X1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0277] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0278] R 1a and R 1b Each can be independently H, lower alkyl, lower alkenyl, lower alkynyl, or -OR. a -NR a R b Carbocyclic, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R 1a and R 1b Together with the nitrogen atoms they are attached to, they form heterocycles;

[0279] Each R 2 Independently, it is halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0280] R 3 and R 4 Each can be independently H, halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, or -OR. a -NR a R b Carbocyclic, heterocyclic, carbocycloalkyl or heterocycloalkyl, or R 3 and R 4 Together they form =O or =S;

[0281] n is 0–5; and

[0282] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0283] Where R 1a R 1b R 1c R 2 R 3 R 4 R a and R bEach can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' It is replaced by -NR'R'', -S(O)2R' or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group or a lower haloalkyl group.

[0284] In one embodiment, a compound having the structure of formula (VII-B) is provided:

[0285] (VII-B)

[0286] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0287] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0288] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0289] R 1c It can be H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl;

[0290] Each R 2 Independently, it is halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0291] R 3 and R 4 Each can be independently H, halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, or -OR. a -NR a R b Carbocyclic, heterocyclic, carbocycloalkyl or heterocycloalkyl, or R 3 and R 4 Together they form =O or =S;

[0292] n is 0–5; and

[0293] R a and R bEach is independently H, a lower alkyl group, or a lower haloalkyl group;

[0294] Where R 1a R 1b R 1c R 2 R 3 R 4 R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' The alkyl group is replaced by -NR'R'', -S(O)2R', or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group, or a lower haloalkyl group; and

[0295] Where R 3 and R 4 Each is H, R 1 When X is -OH and n is 0, 1 It is a lower haloalkyl or halogenated.

[0296] In one embodiment, a compound having the structure of formula (VIII) is provided:

[0297] (VIII)

[0298] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0299] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0300] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0301] R 1 For -NR 1a R 1b or -OR 1c ;

[0302] R 1a and R 1b Each can be independently H, lower alkyl, lower alkenyl, lower alkynyl, or -OR. a -NR a R b Carbocyclic, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R 1a and R 1b Together with the nitrogen atoms they are attached to, they form heterocycles;

[0303] R 1c It can be H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl;

[0304] R 2a Halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, -OR a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0305] Each R 2b Independently, it can be halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, or -OR. a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0306] R 3 and R 4 Each can be independently H, halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, or -OR. a -NR a R b Carbocyclic, heterocyclic, carbocycloalkyl or heterocycloalkyl, or R 3 and R 4 Together they form =O or =S;

[0307] m is 0–4; and

[0308] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0309] Where R 1a R 1b R 1c R 2a R 2b R 3 R4 R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' It is replaced by -NR'R'', -S(O)2R' or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group or a lower haloalkyl group.

[0310] In one embodiment, a compound having the structure of formula (VIII-A) is provided:

[0311] (VIII-A)

[0312] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0313] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0314] X 2 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0315] R 1a and R 1b Each can be independently H, lower alkyl, lower alkenyl, lower alkynyl, or -OR. a -NR a R b Carbocyclic, carbocycloalkyl, heterocyclic or heterocycloalkyl, or R 1a and R 1b Together with the nitrogen atoms they are attached to, they form heterocycles;

[0316] R 2a Halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, -OR a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0317] Each R 2b Independently, it can be halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, or -OR. a -NRa R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0318] R 3 and R 4 Each can be independently H, halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, or -OR. a -NR a R b Carbocyclic, heterocyclic, carbocycloalkyl or heterocycloalkyl, or R 3 and R 4 Together they form =O or =S;

[0319] m is 0–4; and

[0320] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0321] Where R 1a R 1b R 1c R 2a R 2b R 3 R 4 R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' It is replaced by -NR'R'', -S(O)2R' or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group or a lower haloalkyl group.

[0322] In one embodiment, a compound having the structure of formula (VIII-B) is provided:

[0323] (VIII-B)

[0324] Or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, wherein:

[0325] X 1 It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0326] X 2It is a lower alkyl group, a lower haloalkyl group, or a halo;

[0327] R 1c It can be H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl;

[0328] R 2a Halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, -OR a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0329] Each R 2b Independently, it can be halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocycloalkyl, heterocyclic alkyl, or -OR. a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)R b -S(O)2R a or -S(O)2OR a ;

[0330] R 3 and R 4 Each can be independently H, halogenated, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, or -OR. a -NR a R b Carbocyclic, heterocyclic, carbocycloalkyl or heterocycloalkyl, or R 3 and R 4 Together they form =O or =S;

[0331] m is 0–4; and

[0332] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0333] Where R1a R 1b R 1c R 2a R 2b R 3 R 4 R a and R b Each can be independently and optionally converted to one or more halogenated, cyano, or -OR groups. ' It is replaced by -NR'R'', -S(O)2R' or -S(O)2OR', wherein R' and R'' are each independently H, a lower alkyl group or a lower haloalkyl group.

[0334] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 3 For H.

[0335] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 3 It is a carbon ring.

[0336] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 3 It is cyclopropyl or cyclobutyl.

[0337] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 3 It is a lower alkyl group.

[0338] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 3 It is a lower haloalkyl group.

[0339] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 3 For -OR a In a further implementation, R a For H.

[0340] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (VA), (VI), (VI-A), (VII), (VII-A), (VIII), or (VIII-A), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 1a It is a lower alkyl group.

[0341] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (VA), (VI), (VI-A), (VII), (VII-A), (VIII), or (VIII-A), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 1a It is a methyl group.

[0342] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (II), (II-A), (III), (III-A), (IV), (IV-A), (V), (VA), (VI), (VI-A), (VII), (VII-A), (VIII), or (VIII-A), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 1b For H.

[0343] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IB), (II), (II-B), (III), (III-B), (IV), (IV-B), (V), (VB), (VI), (VI-B), (VII), (VII-B), (VIII), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 1c For H.

[0344] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IB), (II), (II-B), (III), (III-B), (IV), (IV-B), (V), (VB), (VI), (VI-B), (VII), (VII-B), (VIII), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 1c It is a lower alkyl group.

[0345] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IB), (II), (II-B), (III), (III-B), (IV), (IV-B), (V), (VB), (VI), (VI-B), (VII), (VII-B), (VIII), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 1c It can be methyl or ethyl.

[0346] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 1 It is a lower alkyl group.

[0347] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 1 It is a methyl group.

[0348] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 1 It is a lower alkenyl group.

[0349] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 1 Halogenated.

[0350] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 1 It can be Cl or Br.

[0351] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 1 It is Cl.

[0352] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 1 It is Br.

[0353] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 1 It is a lower haloalkyl group.

[0354] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 1 For –CF3.

[0355] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 2 It is a lower alkyl group.

[0356] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 2 It is a methyl group.

[0357] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 2 Halogenated.

[0358] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 2 It can be Cl or Br.

[0359] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 2 It is Cl.

[0360] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 2 It is Br.

[0361] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 2 It is a lower haloalkyl group.

[0362] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X 2 For –CF3.

[0363] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 2a Or at least one R 2 It is a lower alkyl group.

[0364] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 2a Or at least one R 2 R' is a lower alkyl group substituted with -OR', and in a further embodiment, R' is H, or R' is a lower alkyl group.

[0365] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 2a Or at least one R 2 It is a lower haloalkyl group.

[0366] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 2a Or at least one R 2 For -OR a In a further implementation, R a It is a lower alkyl group, or R a It is a lower haloalkyl group.

[0367] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 2a Or at least one R 2 -C(O)R a In a further implementation, R a It is a lower alkyl group.

[0368] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 2a Or at least one R 2 For -NR a C(O)R b In a further implementation, R a Let H be the number of 'R', and R be the number of 'R'. b It is a lower alkyl group, or R b It is a methyl group.

[0369] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 2a Or at least one R 2 -C(O)ORa In a further implementation, R a It is a lower alkyl group, or R a It can be methyl or ethyl.

[0370] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 2a Or at least one R 2 is -S(O)2R a In a further implementation, R a It is a lower alkyl group, or R a It is a methyl group.

[0371] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 2a Or at least one R 2 For halogenation, and in a further embodiment, R 2a Or at least one R 2 It is F.

[0372] In a more specific embodiment, a compound having the structure of any one of the above formulas (I), (IA), (IB), (II), (II-A), (II-B), (III), (III-A), (III-B), (IV), (IV-A), (IV-B), (V), (VA), (VB), (VI), (VI-A), (VI-B), (VII), (VII-A), (VII-B), (VIII), (VIII-A), or (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 2a Or at least one R 2 It is a cyano group.

[0373] Representative compounds of formulas (I) and (II) through (VIII) that are applicable include the compounds listed in Table 1 below and their pharmaceutically acceptable salts. For this purpose, representative compounds are identified herein by their respective “compound number,” sometimes abbreviated as “compound No.” or “number.”

[0374] Table 1

[0375] Representative compounds

[0376]

[0377] The term "isomer" is used herein to encompass all chiral, diastereomeric, or racemic forms of a structure, unless a specific stereochemical or isomeric form is specifically indicated. Such compounds can be optical isomers enriched or resolved to any degree at any or all of the asymmetric atoms (as clearly seen in the description). Racemic mixtures and diastereomeric mixtures, as well as individual optical isomers, can be synthesized to be substantially free of their enantiomers or diastereomeric counterparts, and these are all within the scope of certain embodiments of the invention. Isomers resulting from the presence of a chiral center comprise a pair of non-overlapping isomers referred to as "enantiomers." The single enantiomers of a pure compound are optically active (i.e., they are capable of rotating about the plane of plane-polarized light and are referred to as...). R or S ).

[0378] "Separated optical isomer" refers to a compound that has been substantially purified from the corresponding optical isomer of the same general formula. For example, the separated isomer may be at least about 80%, at least 80%, or at least 85% pure by weight. In other embodiments, the separated isomer is at least 90%, at least 98%, or at least 99% pure by weight.

[0379] "Essentially enantiomers or diastereomers" means that the enantiomer is enriched at a level of at least about 80% relative to another enantiomer or diastereomer, and more specifically, more than 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, or 99.9%.

[0380] The terms "racemate" and "racemic mixture" refer to an equal mixture of two enantiomers. A racemate is marked with "(±)" because it is not optically active (i.e., it does not cause plane-polarized light to rotate in either direction because its constituent enantiomers cancel each other out). All compounds marked with an asterisk (*) adjacent to a tertiary or quaternary carbon are optical isomers, which can be purified from their respective racemates and / or synthesized by appropriate chiral synthesis.

[0381] A "hydrate" is a compound that exists in combination with water molecules. This combination may include stoichiometric amounts of water, such as monohydrate or dihydrate, or may include random amounts of water. When used herein, "hydrate" refers to a solid form; that is, for a compound in aqueous solution, although it may be hydrated, it is not the hydrate referred to by the term as used herein.

[0382] "Solvate" is similar to hydrate, except that a solvent other than water is present. For example, methanol or ethanol can form an "alcohol," which can be stoichiometric or non-stoichiometric. When used herein, "solvate" refers to a solid form; that is, for a compound in a solvent solution, although it may be solvated, it is not a solvate as referred to herein.

[0383] "Isotope" refers to an atom having the same number of protons but different numbers of neutrons, and the isotopes of compounds of formula (I) include any such compound in which one or more atoms are replaced by isotopes of that atom. For example, carbon-12—the most common form of carbon—has six protons and six neutrons, while carbon-13 has six protons and seven neutrons, and carbon-14 has six protons and eight neutrons. Hydrogen has two stable isotopes: deuterium (one proton and one neutron) and tritium (one proton and two neutrons). Fluorine has many isotopes, with fluorine-19 having the longest half-life. Therefore, the isotopes of compounds having the structure of formula (I) include, but are not limited to, compounds of formula (I) in which one or more carbon-12 atoms are replaced by carbon-13 and / or carbon-14 atoms, one or more hydrogen atoms are replaced by deuterium and / or tritium, and / or one or more fluorine atoms are replaced by fluorine-19.

[0384] A "salt" generally refers to an organic compound in its ionic form, such as a carboxylic acid or amine, combined with a counterion. For example, a salt formed between an acid in its anionic form and a cation is called an "acid addition salt." Conversely, a salt formed between a base in its cationic form and an anion is called a "base addition salt."

[0385] The term "pharmaceutically acceptable" refers to a pharmaceutical agent that has been approved for human use and is generally non-toxic. For example, the term "pharmaceutically acceptable salt" refers to a non-toxic inorganic or organic acid and / or base addition salt (see, for example, Lit et al., Salt Selection for Basic Drugs). Int. J. Pharm ., 33, 201-217, 1986 (which is incorporated herein by reference).

[0386] Pharmaceutically acceptable base addition salts of the compounds of this invention include, for example, metal salts, including salts of alkali metals, alkaline earth metals, and transition metals, such as calcium salts, magnesium salts, potassium salts, sodium salts, and zinc salts. Pharmaceutically acceptable base addition salts also include those derived from basic amines, such as... N,N' - An organic salt formed from dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucosamine), and procaine.

[0387] Pharmaceutically acceptable acid addition salts can be prepared from inorganic acids or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from aliphatic, alicyclic, aromatic, aromatic aliphatic, heterocyclic, carboxylic acid, and sulfonic acid categories. Examples include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, hippuric acid, malonic acid, oxalic acid, methylene dihydroxynaphthyl acid (Pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylsulfamic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactopyric acid, and galacturonic acid.

[0388] Although pharmaceutically unacceptable salts are not typically used as drugs, such salts may be useful, for example, as intermediates in the synthesis of compounds having the structure of formula (I), such as in their purification by recrystallization.

[0389] In some embodiments, the present invention provides a pharmaceutical composition comprising the compound of the present invention and at least one pharmaceutically acceptable carrier, diluent, or excipient. For example, the active compound is typically mixed with, diluted by, or encapsulated within a carrier, which may be in the form of an ampoule, capsule, pouch, paper, or other container. When the active compound is mixed with a carrier, or when the carrier acts as a diluent, it can be a solid, semi-solid, or liquid material that serves as a medium, excipient, or carrier for the active compound. The active compound may be adsorbed onto a particulate solid carrier, such as a pouch. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, kaolin, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, gum arabic, lower alkyl ethers of stearic acid or cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethyl cellulose, and polyvinylpyrrolidone. Similarly, the carrier or diluent may comprise any sustained-release material known in the art, alone or in mixture with waxes, such as glyceryl monostearate or glyceryl distearate.

[0390] As used herein, the term "pharmaceutical composition" means a composition comprising one or more of the compounds described herein or their pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts, formulated together with a pharmaceutically acceptable carrier, and may also contain other additives, manufactured or sold with the approval of a government regulatory agency as part of a treatment regimen for a mammalian disease. For example, pharmaceutical compositions may be formulated for oral administration in unit dosage forms (e.g., tablets, capsules, pouches, soft capsules, or syrups); for topical administration (e.g., as creams, gels, lotions, or ointments); for intravenous administration (e.g., as a sterile solution without particulate emboli in a solvent system suitable for intravenous use); or any other formulation described herein. The routine procedures and ingredients used for selecting and preparing suitable formulations are described in, for example... Remington: The Science and Practice of Pharmacy , 21st edition, edited by Gennaro, Lippencott Williams & Wilkins (2005) and The United States Pharmacopeia: The National Formulary (USP 36 NF31), published in 2013.

[0391] As used herein, the term "pharmaceutically acceptable carrier" means any component other than the disclosed compound or its pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts (e.g., a carrier capable of suspending or dissolving the active compound) and having non-toxic and non-inflammatory properties in patients. Excipients may include, for example: anti-adhesives, antioxidants, adhesives, coatings, compression aids, disintegrants, dyes (pigments), softeners, emulsifiers, fillers (diluents), film-forming agents or coatings, flavorings, fragrances, flow enhancers (flow improvers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or hydrated water. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, croscarmellose, citric acid, crospovidone, cysteine, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silica, sodium carboxymethyl cellulose, sodium citrate, sodium glycolate starch, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0392] The formulation may be mixed with adjuvants that do not react adversely with the active compound. These adjuvants may include wetting agents, emulsifiers, and suspending agents; salts, buffers, and / or coloring agents that affect osmotic pressure; preservatives; sweeteners; or flavoring agents. The composition may also be sterilized if necessary.

[0393] The route of administration can be any route by which the active compound of the present invention is efficiently delivered to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subcutaneous, intradermal, percutaneous, or parenteral, including intravenous, subcutaneous, and / or intramuscular administration. In one embodiment, the route of administration is oral.

[0394] The dosage form can be administered once daily or more than once daily, such as twice or three times daily. Alternatively, if the prescribing physician deems it appropriate or the prescribing information for the drug indicates it is suitable, the dosage form can be administered at a less frequent frequency than once daily, such as every other day or once weekly. Dosage regimens include, for example, titrating the dose to a level necessary or useful for the indication to be treated, thereby adapting the patient's body to treatment, minimizing or avoiding treatment-related adverse side effects, and / or maximizing the therapeutic effect of the compounds of the invention. Other dosage forms include delayed or controlled-release formulations. Suitable dosing regimens and / or forms include, for example, those described in the latest version of... Physicians' Desk Reference The ones listed in are cited here for reference.

[0395] In another embodiment, a method for preparing a composition of the compounds described herein is provided, comprising formulating the compounds of the invention with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the method may further include the step of formulating the composition into tablets or capsules. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the method further includes the step of lyophilizing the composition to form a lyophilized article.

[0396] In another embodiment, a method of treating a subject suffering from a neurodegenerative disease is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the neurodegenerative disease is a demyelinating disease. In another embodiment, the demyelinating disease is a chronic demyelinating disease. In yet another embodiment, the demyelinating disease is an X-linked genetic disorder, leukodystrophy, dementia, tau proteinosis, or ischemic stroke, or is associated with such disease. In another implementation, the demyelinating disease is or is associated with the following diseases: adult Refsum disease, Alexander disease, Alzheimer's disease, Barlow concentric sclerosis, Canavan disease, central pontine myelinolysis (CPM), cerebral palsy, cerebral tendinitis xanthomas, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic syndrome, diffuse demyelinating sclerosis, encephalomyelitis, idiopathic inflammatory demyelinating disease (IIDD), infantile Refsum disease, Krabbe disease, Leber hereditary optic neuropathy, Marburg multiple sclerosis, Marchifava-Bignami disease, metachromatic leukodystrophy, multifocal motor neuropathy, paraproteinemic demyelinating polyneuropathy, Pelizaeus-Merzbacher disease, peroneal muscular atrophy, progressive multifocal leukoencephalopathy, transverse myelitis, tropical spastic paraplegia, van der Knaap disease, or Zellweger syndrome. In another implementation, the demyelinating disease is or is associated with the following diseases: multiple sclerosis, MCT8 deficiency, X-linked adrenoleukodystrophy (ALD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia, or lacunar stroke.

[0397] As used in this article, the term “neurodegenerative disease” refers to any type of disease characterized by progressive deterioration of the nervous system.

[0398] As used herein, the term "demyelinating disease" refers to any disease or medical condition of the nervous system in which the myelin sheath is damaged or lost, or in which the growth or development of the myelin sheath is impaired. Demyelination inhibits the transmission of signals in the affected nerves, resulting in impairment of sensory, motor, cognitive, or other functions involving the nerves. Demyelinating diseases have many different causes and can be genetic or acquired. In some cases, demyelinating diseases are caused by infectious agents, autoimmune responses, toxic agents, or traumatic injury. In others, the cause of a demyelinating disease is unknown ("idiopathic") or develops from a combination of factors.

[0399] As used in this article, the term "leukodystrophy" refers to a group of diseases that affect the growth or development of myelin.

[0400] As used herein, the term "leukoencephalopathy" refers to any one of a group of diseases that affect the white matter of the brain; it may specifically refer to several diseases, for example, including "leukoencephalopathy with loss of white matter" and "toxic leukoencephalopathy." Leukoencephalopathy is a disease similar to leukodystrophy.

[0401] As used in this article, the term "tau protein disease" refers to conditions or illnesses associated with tau, such as Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease (PiD), argyrophilic granulation disease (AGD), frontotemporal dementia and Parkinson's disease linked to chromosome 17 (FTDP-17), Parkinson's disease, stroke, traumatic brain injury, mild cognitive impairment, etc.

[0402] As used herein, the terms “multiple sclerosis” and “MS” refer to a slowly progressive central nervous system disease characterized by diffuse demyelinating plaques in the brain and spinal cord, resulting in a variety of neurological symptoms and signs, typically with remissions and exacerbations. The etiology of MS is unknown, but an immune abnormality is suspected. An increased familial incidence suggests a genetic predisposition, with women being slightly more susceptible than men. Symptoms of MS include weakness, lack of coordination, paresthesia, speech disturbances, and visual disturbances, most commonly diplopia. More specific signs and symptoms depend on the location of the lesions and the severity and destructiveness of the inflammatory and sclerotic process. Relapsing-remitting multiple sclerosis (RRMS) is the clinical course of MS characterized by well-defined acute exacerbations with complete or partial remission and no disease progression between exacerbations. Secondary progressive multiple sclerosis (SPMS) is the clinical course of MS that initially presents as relapsing-remitting, then progresses at varying rates, possibly with occasional relapses and mild remissions. Primary progressive multiple sclerosis (PPMS) initially presents as a progressive condition. Clinically isolated syndromes are the first neurological seizures caused by inflammation / demyelinating in one or more sites of the central nervous system. Progressive relapsing multiple sclerosis (PRMS) is a rare form of MS (approximately 5%) characterized by a steadily worsening disease state from onset, with acute relapses but no remission.

[0403] In yet another embodiment, a method for treating a subject with an X-linked genetic disease is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the X-linked genetic disease is MCT8 deficiency or X-linked adrenoleukodystrophy (ALD).

[0404] In another embodiment, a method of treating a subject with leukodystrophy is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the leukodystrophy is adrenoleukodystrophy (ALD), adrenospinal neuropathy (AMN), cerebral adrenoleukodystrophy (cALD), metachromatic leukodystrophy (MLD), Canavan disease, or Krabbe disease (globuloid cell leukodystrophy). As used herein, the term "adrenospinal neuropathy" or "AMN" refers to an adult variant of X-linked adrenoleukodystrophy characterized by a mutation in the ABCD1 gene that results in impaired peroxisome function, with accumulation of very long-chain fatty acids (VLCFAs) and demyelination.

[0405] In one embodiment, a method for treating a subject with a tau protein disorder is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the tau protein disorder is Alzheimer's disease, frontotemporal dementia, primary age-related tau protein disorder (PART), Pick's disease, or frontotemporal dementia and Parkinson's disease linked to chromosome 17 (FTDP-17).

[0406] In yet another embodiment, a method for treating a subject suffering from ischemic stroke is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the ischemic stroke is lacunar stroke (also known as "lacunar infarction"). In another embodiment, the method is used to treat a subject suffering from lacunar stroke syndrome (LACS).

[0407] In another embodiment, a treatment is provided for adults with Refsum disease, infantile Refsum disease, Alexander disease, Alzheimer's disease, Barlow concentric sclerosis, Canavan disease, central pontine myelinolysis (CPM), cerebral palsy, cerebral tendinitis xanthomas, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic syndrome, diffuse demyelinating sclerosis, encephalomyelitis, idiopathic inflammatory demyelinating disease (IIDD), Krabbe disease, Leber hereditary optic neuropathy, leukodystrophy, Marburg multiple sclerosis, Marchiafava-Bignami disease, and metachromatic leukodystrophy. Methods for administering to a subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemic mixture, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.

[0408] In one embodiment, the demyelinating disease is multiple sclerosis. In another embodiment, the demyelinating disease is X-linked adrenoleukodystrophy (ALD).

[0409] In another embodiment, a method for treating a subject with amyotrophic lateral sclerosis (ALS) is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the ALS is sporadic or familial ALS, or ALS with a superoxide dismutase-1 mutation.

[0410] In one embodiment, a method is provided for treating a subject with a medical condition associated with increased TGF-β activity, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the medical condition associated with increased TGF-β activity is a fibrotic disease. In another embodiment, the fibrotic disease is nonalcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis (IPF), systemic scleroderma, or Alport syndrome, or is associated with such disease. As used herein, the term "Alport syndrome" refers to a hereditary condition caused by a mutation in the a3a4a5(IV) collagen network gene that results in a structural defect in the glomerular basement membrane (GBM) during early development, subsequently leading to disruption of the filtration barrier, renal fibrosis, and the development of renal failure.

[0411] As used herein, the term "fibrotic disease" refers to a condition, disease, or symptom that is readily treatable by the application of compounds with antifibrotic activity. Fibrotic diseases include, but are not limited to, pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis of known etiologies, liver fibrosis, and kidney fibrosis. Other exemplary fibrotic diseases include musculoskeletal fibrosis, myocardial fibrosis, postoperative adhesions, scleroderma, glaucoma, and skin lesions such as keloids.

[0412] In another embodiment, a method is provided for treating a subject suffering from NASH, NAFLD, NAFLD with hyperlipidemia, alcoholic liver disease / alcoholic steatohepatitis, liver fibrosis associated with viral infection (HBV, HCV), fibrosis associated with cholestatic diseases (primary biliary cholangitis, primary sclerosing cholangitis), (familial) hypercholesterolemia, dyslipidemia, hereditary lipid disorders, cirrhosis, alcohol-induced fibrosis, hemochromatosis, glycogen storage disease, α-1 antitrypsin deficiency, autoimmune hepatitis, Wilson's disease, Crigler-Najjar syndrome, lysosomal acid lipase deficiency, or cystic fibrotic liver disease, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

[0413] In another embodiment, a method is provided for treating a subject suffering from Alport syndrome, diabetic nephropathy, FSGS, fibrosis associated with IgA nephropathy, chronic kidney disease (CKD), post-AKI, HIV-related CKD, chemotherapy-induced CKD, nephrotoxic agent-related CKD, renal systemic fibrosis, tubulointerstitial fibrosis, glomerulosclerosis, or polycystic kidney disease (PKD), the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

[0414] In another embodiment, a treatment is provided for patients with IPF, ILD, pulmonary fibrosis, pulmonary fibrosis associated with autoimmune diseases such as rheumatoid arthritis, scleroderma, or Sjögren's syndrome, asthma-related pulmonary fibrosis, COPD, asbestos- or silica-induced pulmonary fibrosis, silicosis, respiratory bronchiolitis, idiopathic interstitial pneumonia (IIP), idiopathic nonspecific interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia, acute interstitial pneumonia, and rare IIP: idiopathic lymphoid interstitial pneumonia. A method for administering to a subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemic mixture, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.

[0415] In another embodiment, a method is provided for treating a subject suffering from scleroderma / systemic sclerosis, graft-versus-host disease, hypertrophic scars, keloids, renal systemic fibrosis, porphyria cutanea tarda, restrictive dermatitis, Dupuytren's contracture, cutaneous fibrosis, renal systemic fibrosis / renal fibrotic dermatitis, mixed connective tissue disease, sclerosing myxedema, eosinophilic fasciitis, fibrosis caused by exposure to chemical or physical substances, GvHD-induced fibrosis, adult scleroderma, lipoid scleroderma, or a progeria condition (progeria, acrogeria, Werner syndrome), the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

[0416] In another embodiment, a method is provided for treating a subject suffering from atrial fibrosis, endocardial myocardial fibrosis, myocardial fibrosis, atherosclerosis, restenosis, or joint fibrosis, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

[0417] In another embodiment, a method is provided for treating a subject suffering from mediastinal fibrosis, myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

[0418] In another embodiment, a method is provided for treating a subject suffering from Crohn's disease, retroperitoneal fibrosis, intestinal fibrosis, fibrosis in inflammatory bowel disease, ulcerative colitis, gastrointestinal fibrosis caused by cystic fibrosis, or pancreatic fibrosis caused by pancreatitis, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

[0419] In another embodiment, a method is provided for treating a subject suffering from endometrial fibrosis, uterine fibroids, or Peyronie's disease, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

[0420] In another embodiment, a method is provided for treating a subject suffering from macular degeneration, diabetic retinopathy, retinal fibrovascular disease, or vitreoretinopathy, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

[0421] In another embodiment, a method is provided for treating a subject with trauma-related scars (surgical complications, chemotherapy-induced fibrosis, radiation-induced fibrosis), the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.

[0422] As used herein, the term "administration" means providing a compound, a prodrug of a compound, or a pharmaceutical composition comprising such compound or prodrug as described herein. The compound or composition may be administered to a subject by another person or may be administered by the subject himself / herself. Non-limiting examples of routes of administration are oral, parenteral (e.g., intravenous), or topical.

[0423] As used herein, the term "treatment" refers to an intervention that improves the indications or symptoms of a disease or pathological condition. As used herein, the terms "treatment" and "management" in relation to a disease, pathological condition, or symptom also refer to any observable beneficial effect of treatment. For example, a beneficial effect can be demonstrated by: delayed onset of clinical symptoms of the disease in susceptible subjects; a reduction in the severity of some or all of the clinical symptoms of the disease; slower disease progression; a reduction in the number of disease relapses; an improvement in the overall health or well-being of the subject; or other parameters specific to a particular disease known in the art. Prophylactic treatment is administered to subjects who do not exhibit indications of disease or only exhibit early indications, with the aim of reducing the risk of developing pathology. Therapeutic treatment is administered to subjects after the development of indications and symptoms of disease.

[0424] As used herein, the term "subject" refers to an animal (e.g., a mammal, such as a human). Subjects treated according to the methods described herein may be subjects diagnosed with neurodegenerative diseases involving demyelination, insufficient myelination, or incomplete myelination, such as subjects diagnosed with multiple sclerosis or cerebral palsy, or subjects at risk of developing such a condition. Diagnosis can be made by any method or technique known in the art. Those skilled in the art will understand that subjects to be treated according to this disclosure may have already undergone standard testing or may be identified without examination as subjects at risk due to the presence of one or more risk factors associated with the disease or condition.

[0425] As used herein, the term "effective amount" refers to an amount of the pharmaceutical agent sufficient to achieve the desired effect in a subject treated with the specified agent. Ideally, an effective amount of the agent is an amount sufficient to inhibit or treat the disease without causing substantial toxicity in the subject. The effective amount of the agent will depend on the subject being treated, the severity of the disease, and the route of administration of the pharmaceutical composition. Based on this disclosure, those skilled in the art will understand the methods for determining an effective amount of the disclosed compound sufficient to achieve the desired effect in a subject.

[0426] As used in this article, the term "chronic" refers to a medical condition or illness that persists or recurs frequently over time.

[0427] Compounds having structures of formulas (I), (II), (III), (IV), (V), and (VI) can be synthesized using standard synthetic techniques known to those skilled in the art. For example, the compounds of the present invention can be synthesized using appropriately modified WO 2014 / 178892, WO 2014 / 178931, WO 2016 / 134292, WO 2017 / 201320, WO 2018 / 032012, and the synthetic procedures set forth in Schemes 1-7 below.

[0428] Therefore, the reactions, processes, and synthetic methods described herein are not limited to the specific conditions described in the following experimental sections, but are intended as guidance for those skilled in the art. For example, reactions can be carried out in any suitable solvent or other reagent to achieve the necessary transformations. Typically, suitable solvents are proton or aprotic solvents that do not substantially react with the reactants, intermediates, or products at the temperatures at which the reaction proceeds (i.e., temperatures ranging from freezing to boiling). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction, suitable solvents may be used for specific post-reaction processing.

[0429] Option 1.

[0430]

[0431] The compounds of the present invention can be prepared according to Scheme 1. Protected phenol A is obtained by treating a commercially available 4-iodophenol with an alkylating agent such as methoxymethyl chloride, benzyl bromide, or triisopropylsilyl chloride in a solvent such as THF or DMF using a base such as sodium hydride or triethylamine. A 3,5-disubstituted phenol is similarly protected using an orthogonal protecting group to obtain B. Compound B is deprotonated at the 4-position using a substance such as n-butyllithium or n-butylmagnesium bromide, and the resulting anion is condensed with a formylating agent such as DMF to obtain aldehyde C. If the protecting group PG2 is acid-sensitive, free phenol can be released during acid treatment; alternatively, PG2 can be cleaved in a separate step. The phenolic moiety of C is alkylated with a protected acetic acid equivalent such as methyl chloroacetate or tert-butyl bromoacetate in a solvent such as THF, DMF, or acetone using a base such as potassium carbonate or sodium hydride to obtain ester D.

[0432] Metal transfer of iodide A is performed in solvents such as THF or DME using isopropyl magnesium bromide or sec-butyllithium, and the resulting anion condenses with aldehyde D to give diarylmethanol compound E. In acidic solvents such as TFA or aqueous HCl solutions, E is deoxygenated using a hydride source such as triethylsilane to produce diarylmethane compound F. If PG1 is an acid-sensitive protecting group (e.g., MOM), the deoxygenation product is directly isolated as phenol. Alternatively, PG1 can be removed in a separate step. Phenol F is then reacted with a substituted benzyl alcohol or benzyl halide G, such as p-fluorobenzyl chloride, 1-(1-chloroethyl)-4-fluorobenzene, or 2,4-difluorobenzyl alcohol, in the presence of Lewis acids such as zinc chloride, aluminum chloride, or boron trifluoride ethers, to give a 3'-benzylated product, such as ester H.

[0433] Option 2.

[0434]

[0435] As described in Scheme 2, the ortho-iodination of phenol F provides the key intermediate I, for example, using N-iodosuccinimide or solid iodine. To prepare the compounds of the present invention, I is reacted with meta-substituted boronic acid (or boronic ester) J under various Suzuki conditions to provide the ester K of the present invention.

[0436] Option 3

[0437]

[0438] Referring to Scheme 3, a disubstituted phenol (e.g., 3,5-dichlorophenol, 3-methyl-5-chlorophenol, or 3-methyl-5-bromophenol, etc.) reacts with a formaldehyde equivalent (e.g., aqueous formaldehyde, oligooxymethane, or dimethoxymethane, etc.) to give a hydroxymethyl derivative (L), which is then selectively reacted at the phenol oxygen with an activated acetate moiety (e.g., ethyl chloroacetate or methyl bromoacetate, etc.) in the presence of a base to give an intermediate (M). The hydroxymethyl group is activated (e.g., by reaction with thionyl chloride, oxaloyl chloride, or p-toluenesulfonyl chloride, etc.) to give a chloromethyl derivative (N) (or the corresponding toluenesulfonate, or methanesulfonate, or bromomethyl analog, etc.), which condenses with a 2-substituted phenol (O) in the presence of a Lewis acid (e.g., zinc chloride or aluminum chloride, etc.) to give an ester (P).

[0439] Option 4.

[0440]

[0441] As shown in Scheme 4, for example, using an aqueous solution of sodium hydroxide (if R 1 (methyl) or TFA (if R 1 The acid (Q) of the present invention is provided by hydrolysis of the ester group of (tert-butyl), (H), (K), or (P). If desired, the acid (Q) can be converted into an amide (R) by condensation with the corresponding amine (e.g., methylamine, propylamine, or 2-sulfonylethylamine, etc.) in the presence of a coupling agent such as DDC or EDCI, or by forming an activated intermediate (e.g., the corresponding acyl chloride) using thionyl chloride, etc. Alternatively, if desired, the ester (H), (K), or (P) or acid (Q) can be reacted with amine R. 1a R 1b Heating NH2, such as methylamine, propylamine, or 2-sulfonylethylamine, together yields the amide (R) of the present invention.

[0442] Option 5.

[0443]

[0444] The benzyl alcohol or halide (G) used in Scheme 1 can be derived from a commercial supplier or can be prepared as described in Scheme 5. For example, benzyl alcohols such as 1-(4-fluorophenyl)ethanol are combined with reagents such as thionyl chloride or phosphorus tribromide to obtain the corresponding benzyl halide (G).

[0445] Option 6.

[0446]

[0447] The arylboronic acid or ester (J) used in Scheme 2 can be of commercial origin or can be prepared as described in Scheme 6. The aryl halide (S) can be reacted with di(pinacol)diboron or a similar reagent using a palladium catalyst to give (J). Alternatively, (S) can be metallized using isopropyl magnesium bromide or n-butyllithium, followed by reaction with a trialkoxyboronate, etc., to provide (J).

[0448] Option 7.

[0449]

[0450] The substituted phenol (O) used in Scheme 3 can be prepared as shown in Scheme 7. 2-Halophenols, such as 2-bromophenol, can be condensed with boric acid or ester (J) under Suzuki conditions in the presence of a palladium catalyst, etc., to obtain 2-substituted phenol (O). Alternatively, 2-bromophenol can be metallized using isopropyl magnesium bromide or n-butyllithium, etc., and then condensed with an aldehyde or ketone (T) to obtain an intermediate such as (U). The substituted phenol (O) is produced by deoxygenation of (U) under hydrogenolysis conditions using hydrogen in the presence of a palladium or platinum catalyst, etc., or under reduction-deoxygenation conditions in the presence of a reducing agent such as triethylsilane, etc., in the presence of an acid such as TFA.

[0451] Example

[0452] The invention is further illustrated by the following examples. These examples are non-limiting and represent various aspects of the invention only. The solid and dashed wedges within the structures disclosed herein indicate relative stereochemistry; absolute stereochemistry is described only in specific illustration or depiction.

[0453] General Method

[0454] All reagents not described in the experimental section are either commercially available, known compounds, or can be formed by those skilled in the art from known compounds using known methods.

[0455] The compounds and intermediates produced by the method according to the invention may require purification. Purification of organic compounds is well known to those skilled in the art, and there are several ways to purify the same compound. In some cases, purification may not be necessary. In some cases, the compound can be purified by crystallization. In some cases, impurities can be removed by stirring with a suitable solvent.

[0456] In some cases, compounds can be purified by chromatography, particularly rapid column chromatography, using a specially designed or pre-packed silica column and a gradient of eluents, such as heptane, diethyl ether, ethyl acetate, acetonitrile, ethanol, etc. In other cases, compounds can be purified using preparative HPLC methods.

[0457] The purification methods described herein can provide the compounds of the invention in salt form with sufficient basic or acidic functionality, for example, in the case of sufficiently basic compounds of the invention, trifluoroacetate or formate, or in the case of sufficiently acidic compounds of the invention, ammonium salts. Such salts can be converted to their free basic or free acidic forms, respectively, by various methods known to those skilled in the art, or used as salts in subsequent biological assays. It should be understood that the specific form of the isolated and described compounds of the invention is not necessarily the only form in which the compounds can be used in biological assays to quantify specific biological activities.

[0458] All starting materials and reagents were commercially available and used as is. Unless otherwise specified, the solvents were used at approximately room temperature, and the experiments were conducted using a Bruker instrument running at 400 MHz. 1 1H nuclear magnetic resonance (NMR) spectroscopy. In all cases, the NMR data were consistent with the proposed structure. Characteristic chemical shifts (δ) were expressed in parts per million (ppm), and conventional abbreviations were used to denote the main peak: e.g., s, singlet; d, doublet; t, triplet; q, tetrad; dd, doubletet; dt, doubletuplet; m, multiplet; br, broad. Preparative HPLC purification was performed by reversed-phase HPLC using a gradient of acetonitrile in aqueous TFA solution, or an equivalent HPLC system, such as methanol in aqueous ammonium acetate solution.

[0459] Chemical names were generated using ChemDraw naming software (version 17.0.0.206) from PerkinElmer Informatics, Inc. In some cases, the generally accepted name of a commercially available reagent was used instead of the name generated by the naming software.

[0460] Intermediate A1

[0461] Synthesis of 1-iodo-4-(methoxymethoxy)benzene (intermediate A1)

[0462]

[0463] A solution of 4-iodophenol (50 g, 227 mmol) in THF (400 mL) was cooled to 0°C. Sodium hydride (60% in mineral oil) (10.9 g, 273 mmol) was added in portions. The mixture was stirred at 0°C for 20 min. Chloromethyl ether (21.96 g, 273 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. The mixture was poured into ice water (600 mL) and extracted with EtOAc (200 mL x 3). The combined organic phases were washed with brine (200 mL), dried over Na2SO4, and concentrated under vacuum to give intermediate A1 (60 g, 227 mmol, 99% yield) as a colorless liquid.

[0464] TLC: EtOAc / petroleum ether = 1 / 10 (v / v), Rf = 0.95

[0465] 1 H NMR: (400 MHz, DMSO- d 6) δ 7.63 – 7.59 (m, 2H), 6.89 – 6.84 (m, 2H), 5.17 (s, 2H), 3.36 (s, 3H).

[0466] Intermediate A2

[0467] Synthesis of (3,5-dichlorophenoxy)-triisopropyl-silane (compound A2)

[0468]

[0469] A solution of 3,5-dichlorophenol (35.0 g, 215 mmol) and imidazole (21.93 g, 322 mmol) in DCM (400 mL) was cooled to 0°C. Chloro(triisopropyl)silane (45.5 g, 236 mmol) was added. The mixture was stirred at room temperature for 2 h. Water (200 mL) was added, and the resulting mixture was extracted with DCM (100 mL x 3). The combined DCM phases were washed with brine (200 mL), dried over Na2SO4, and concentrated under vacuum to give intermediate A2 (68 g, 213 mmol, 99.2% yield) as a pale yellow liquid.

[0470] TLC: EtOAc / petroleum ether = 1 / 20 (v / v), Rf = 0.95

[0471] 1 H NMR: (400 MHz, DMSO- d 6) δ 7.21 (t, J = 1.8 Hz, 1H), 6.89 (d,J = 1.8Hz, 2H), 1.29 – 1.23 (m, 3H), 1.06 (d, J = 7.4 Hz, 18H).

[0472] Intermediate A3

[0473] Synthesis of 2,6-dichloro-4-hydroxybenzaldehyde (intermediate A3)

[0474]

[0475] The solution of intermediate A2 (70 g, 219 mmol) in THF (600 mL) was cooled to -70°C. Butyllithium (96.5 mL, 241 mmol, 2.5 M in THF) was added dropwise at -70°C. The solution was stirred at -70°C for 45 min. DMF (20.83 g, 285 mmol) was added dropwise. The mixture was stirred at -70°C for 3 h. The reaction mixture was heated to -10°C, quenched with 1 N HCl (440 mL), stirred at room temperature for 15 min, and then extracted with EtOAc (300 mL x 2). The combined organic phases were washed with brine (500 mL), dried over Na2SO4, and concentrated under vacuum. The residue was washed with hexane and dried to give intermediate A3 (28.5 g, 149 mmol, 68.1% yield) as a white solid.

[0476] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.5

[0477] 1 H NMR: (400 MHz, DMSO- d 6) δ 10.25 (s, 1H), 6.94 (s, 2H).

[0478] Intermediate A4

[0479] Synthesis of methyl 2-(3,5-dichloro-4-formyl-phenoxy)acetate (intermediate A4)

[0480]

[0481] To a solution of intermediate A3 (18.2 g, 95.3 mmol) in acetone (180 mL), methyl 2-chloroacetate (12.4 g, 114 mmol) and potassium carbonate (26.34 g, 191 mmol) were added. The reaction mixture was heated to 60°C and stirred for 2 h. Water (100 mL) was added, and the resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, and concentrated under vacuum to give intermediate A4 (25.0 g, 95.1 mmol, 99.9% yield) as a yellow solid.

[0482] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.45

[0483] 1 H NMR: (400 MHz, DMSO- d 6) δ 10.28 (s, 1H), 7.28 (s, 2H), 5.04 (s, 2H), 3.72 (s, 3H).

[0484] Intermediate A5

[0485] 2-(3,5-Dichloro-4-(hydroxy(4-(methoxymethoxy)phenyl)methyl)phenoxy)methyl acetate (middle) Synthesis of interstitial A5

[0486]

[0487] A solution of intermediate A1 (50 g, 189 mmol) in THF (250 mL) was cooled to -20°C. Isopropyl magnesium chloride (20.8 g, 202 mmol, 1.0 M THF) was added dropwise. The mixture was stirred at room temperature for 2 h, then cooled to -67°C. A solution of intermediate A4 (33.2 g, 126 mmol) in THF (250 mL) was added dropwise at -67°C. The mixture was stirred at -67°C for 2 h. The reaction was quenched by adding saturated aqueous NH4Cl solution (100 mL). The mixture was extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (200 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (EtOAc / petroleum ether = 1 / 50 to 1 / 10) to give intermediate A5 as a white solid (12.0 g, 29.9 mmol, 23.7% yield).

[0488] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.3

[0489] 1H NMR: (400 MHz, DMSO- d 6) δ 7.16 (d, J = 8.3 Hz, 2H), 7.07 (s, 2H), 6.94 (d, J = 8.7 Hz, 2H), 6.36 (d, J = 4.9 Hz, 1H), 6.01 (d, J = 4.9 Hz, 1H), 5.14 (s, 2H), 4.91 (s, 2H), 3.71 (s, 3H), 3.35 (s, 3H).

[0490] Intermediate A6

[0491] Synthesis of methyl 2-[3,5-dichloro-4-[(4-hydroxyphenyl)methyl]phenoxy]acetate (intermediate A6)

[0492]

[0493] Triethylsilane (11.6 g, 100 mmol, 15.9 mL) was added to a solution of intermediate A5 (10.0 g, 24.9 mmol) in DCM (100 mL) at room temperature. The solution was cooled to 0°C. TFA (85.3 g, 748 mmol, 57.6 mL) was added dropwise. The mixture was stirred at room temperature for 2 h. The mixture was concentrated under vacuum. The residue was washed with hexane (10 mL) and dried to give intermediate A6 (6.86 g, 20.1 mmol, 80.7% yield) as a white solid.

[0494] TLC: petroleum ether / EtOAc = 1 / 5 (v / v), Rf = 0.32

[0495] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.16 (s, 1H), 7.14 (s, 2H), 6.91 (d, J =8.3 Hz, 2H), 6.65 (d, J = 8.4 Hz, 2H), 4.89 (s, 2H), 4.05 (s, 2H), 3.71 (s, 3H).

[0496] Intermediate A7

[0497] Synthesis of methyl 2-(3,5-dichloro-4-(4-hydroxy-3-iodobenzyl)phenoxy)acetate (intermediate A7)

[0498]

[0499] The solution of intermediate A6 (2.0 g, 5.86 mmol) and p-toluenesulfinic acid (183 mg, 1.17 mmol) in DCM (20 mL) was cooled to 0°C. N-iodosuccinimide (1.32 g, 5.86 mmol) was added in portions. The mixture was stirred at 0°C for 4 h. Water (15 mL) was added, and the mixture was extracted with DCM (10 mL x 2). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, and concentrated under vacuum to give intermediate A7 (2.4 g, 5.14 mmol, 87.7% yield) as an orange solid.

[0500] TLC: petroleum ether / EtOAc = 1 / 5 (v / v), Rf = 0.32

[0501] 1 H NMR: (400 MHz, DMSO- d 6) δ 10.15 (s, 1H), 7.40 (d, J = 2.1 Hz, 1H),7.17 (s, 2H), 6.96 – 6.90 (m, 1H), 6.78 (d, J = 8.3 Hz, 1H), 4.90 (s, 2H), 4.05 (s, 2H), 3.71 (s, 3H).

[0502] Intermediate A8

[0503] Synthesis of 3,5-dichloro-4-(hydroxymethyl)phenol (intermediate A8)

[0504]

[0505] 3,5-Dichlorophenol (25.0 g, 153 mmol) was added to a solution of NaOH (6.7 g, 169 mmol) in water (20 mL). The mixture was heated to 45°C, and 36% formaldehyde aqueous solution (12.4 g, 153 mmol) was slowly added dropwise. The mixture was stirred at 45°C for 2 h, then cooled to room temperature. The pH was adjusted to approximately 3–4 with 1 N HCl, and the mixture was stirred at room temperature for 20 min. The solid was filtered, washed with water (50 mL), and dried to give intermediate A8 (11.5 g, 59.6 mmol, 39% yield) as a grayish-white solid.

[0506] TLC: EtOAc / petroleum ether 1 / 3, Rf 0.36

[0507] 1H NMR: (400 MHz, DMSO- d 6) δ 10.02 (s, 1H), 6.82 (s, 2H), 4.98 (s, 1H), 4.57 (d, J = 2.1 Hz, 2H)

[0508] Intermediate A9

[0509] Synthesis of methyl 2-[3,5-dichloro-4-(hydroxymethyl)phenoxy]acetate (intermediate A9)

[0510]

[0511] Potassium carbonate (3.22 g, 23.3 mmol) and methyl 2-chloroacetate (2.02 g, 18.6 mmol) were added to a solution of intermediate A8 (3.0 g, 15.5 mmol) in acetone (40 mL). The mixture was refluxed for 2 h. The mixture was cooled to room temperature, diluted with water (120 mL), and extracted with EtOAc (80 mL x 3). The combined organic phases were washed with brine (200 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1 to 5 / 1) to give intermediate A9 (2.0 g, 7.54 mmol, 48.5% yield) as a white solid.

[0512] TLC: EtOAc / petroleum ether 1 / 5, Rf 0.28

[0513] 1 H NMR: (400 MHz, DMSO- d 6) δ 7.10 (s, 2H), 5.08 (t, J = 5.3 Hz, 1H), 4.91 (s, 2H), 4.61 (d, J = 5.3 Hz, 2H), 3.70 (s, 3H).

[0514] Intermediate A10

[0515] Synthesis of methyl 2-[3,5-dichloro-4-(chloromethyl)phenoxy]acetate (intermediate A10)

[0516]

[0517] Thionyl chloride (0.67 g, 5.66 mmol) was added to a mixture of intermediate A9 (1.0 g, 3.77 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 1 h and then concentrated under vacuum to give crude intermediate A10 (1.0 g, 3.53 mmol, 93.5% yield) as a pale yellow solid.

[0518] TLC: EtOAc / petroleum ether 1 / 5, Rf 0.72

[0519] 1 H NMR: (400 MHz, DMSO- d 6) δ 7.21 (s, 2H), 4.94 (s, 2H), 4.85 (s, 2H), 3.71 (s, 3H).

[0520] Intermediate A11

[0521] Synthesis of ethyl 2-(3,5-dichloro-4-(hydroxymethyl)phenoxy)acetate (intermediate A11)

[0522]

[0523] Ethyl 2-bromoethyl acetate (11.25 g, 67.4 mmol) and K₂CO₃ (11.17 g, 80.8 mmol) were added to a solution of intermediate A8 (13.0 g, 67.4 mmol) in DMF (120 mL) at room temperature. The mixture was stirred at room temperature for 2 h, then diluted with water (200 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with water (100 mL x 3) and brine (200 mL), dried over Na₂SO₄, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 5 / 1) to give intermediate A11 (15 g, 79% yield) as a grayish-white solid.

[0524] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.42

[0525] 1 H NMR: (400 MHz, DMSO- d 6) δ 7.09 (s, 2H), 5.09 (t, J = 5.2 Hz, 1H), 4.88 (s, 2H), 4.60 (d, J = 5.2 Hz, 2H), 4.17 (q, J= 7.1 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H).

[0526] Intermediate A12

[0527] Synthesis of ethyl 2-(3,5-dichloro-4-(chloromethyl)phenoxy)acetate (intermediate A12)

[0528]

[0529] Intermediate A11 (15.0 g, 3.77 mmol) was added to DCM (150 mL) at 0 o Thionyl chloride (9.59 g, 80.6 mmol) was added dropwise to reaction mixture C. The mixture was stirred at room temperature for 1 h, diluted with DCM (100 mL), and concentrated under vacuum to give intermediate A12 (15.0 g, 93.5% yield) as a pale yellow solid.

[0530] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.72

[0531] 1 H NMR: (400 MHz, DMSO- d 6) δ 7.20 (s, 2H), 4.92 (s, 2H), 4.86 (s, 2H), 4.17 (q, J = 7.2 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H).

[0532] Intermediate A13

[0533] Synthesis of 3-chloro-4-(hydroxymethyl)-5-methylphenol (intermediate A13)

[0534]

[0535] To a mixture of 3-chloro-5-methylphenol (3.55 g, 24.9 mmol) in water (10 mL) at room temperature, NaOH (1.10 g, 27.4 mmol) was added. The mixture was heated to 45°C, and then an aqueous formaldehyde solution (0.75 g, 24.9 mmol, 37%) was added dropwise. The resulting mixture was stirred at 45°C for 2 h. The mixture was cooled to room temperature, acidified to pH ~3 with HCl (3N), and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (15 mL), dried over Na₂SO₄, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 50 / 1 to 5 / 1) to give intermediate A13 (0.76 g, 4.40 mmol, 17.7% yield) as a grayish-white solid.

[0536] TLC: EtOAc / petroleum ether = 1 / 1 (v / v), Rf = 0.8

[0537] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.68 (s, 1H), 6.62 (d, J = 2.4 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 4.73 (t, J = 5.2 Hz, 1H), 4.49 (d, J = 5.2 Hz, 2H), 2.31 (s, 3H).

[0538] Intermediate A14

[0539] Synthesis of 2-[3-chloro-4-(hydroxymethyl)-5-methylphenoxy]acetic acid ester (intermediate A14)

[0540]

[0541] Cesium carbonate (1.87 g, 5.74 mmol), sodium iodide (57 mg, 380 μmol), and methyl 2-chloroacetate (540 mg, 4.97 mmol) were added to a solution of intermediate A13 (0.66 g, 3.82 mmol) in acetone (10 mL) at room temperature. The mixture was stirred at room temperature for 4 h. Water (30 mL) was added, and the mixture was extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 100 / 1 to 5 / 1) to give intermediate A14 (280 mg, 1.14 mmol, 29.9% yield) as a white solid.

[0542] TLC: EtOAc / petroleum ether = 1 / 2 (v / v), Rf = 0.67

[0543] 1 H NMR: (400 MHz, DMSO- d 6) δ 6.84 (d, J = 2.6 Hz, 1H), 6.78 (d, J = 2.6Hz, 1H), 4.85-4.81 (m, 3H), 4.53 (d, J = 4.9 Hz, 2H), 3.69 (s, 2H), 2.37 (s, 3H).

[0544] Intermediate A15

[0545] Synthesis of 2-[3-chloro-4-(chloromethyl)-5-methylphenoxy]acetate (intermediate A15)

[0546]

[0547] Thionyl chloride (263 mg, 2.21 mmol) was added to a solution of intermediate A14 (360 mg, 1.47 mmol) in DCM (6 mL) at room temperature. The mixture was stirred at room temperature for 1 h and then concentrated under vacuum to give intermediate A15 (300 mg, 1.14 mmol, 77.5% yield) as a yellow solid.

[0548] TLC: EtOAc / petroleum ether = 1 / 2 (v / v), Rf = 0.8

[0549] 1 H NMR: (400 MHz, DMSO- d 6) δ 6.96 (d, J= 2.4 Hz, 1H), 6.87 (d, J = 2.4Hz, 1H), 4.86 (s, 2H), 4.82 (s, 2H), 3.71 (s, 3H), 2.41 (s, 3H).

[0550] Intermediate A16

[0551] Synthesis of 3-bromo-4-(hydroxymethyl)-5-methylphenol (intermediate A16)

[0552]

[0553] Formaldehyde aqueous solution (6.5 g, 80.2 mmol) was added dropwise to a solution of 3-bromo-5-methylphenol (15 g, 80.2 mmol) and NaOH (3.5 g, 88.2 mmol) in water (100 mL) at 45 °C. The reaction mixture was heated to 45 °C overnight. The reaction mixture was acidified to pH ~6-7 with 1N HCl and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (EtOAc / petroleum ether = 1 / 20 to 1 / 5) to give intermediate A16 (3.0 g, 14% yield) as a grayish-white solid.

[0554] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.41

[0555] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.67 (s, 1H), 6.80 (d, J = 2.5 Hz, 1H), 6.60 (d, J = 2.4 Hz, 1H), 4.73 (t, J = 5.1 Hz, 1H), 4.51 (d, J = 5.1 Hz, 2H), 2.30 (s, 3H).

[0556] Intermediate A17

[0557] Synthesis of ethyl 2-(3-bromo-4-(hydroxymethyl)-5-methylphenoxy) (intermediate A17)

[0558]

[0559] To a solution of intermediate A16 (3.0 g, 13.8 mmol) in DMF (20 mL) at room temperature, K₂CO₃ (2.3 g, 16.56 mmol) and ethyl 2-bromoacetate (2.5 g, 15.2 mmol) were added; the mixture was stirred at room temperature for 2 h. Water (100 mL) was added, and the resulting mixture was extracted with EtOAc (40 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na₂SO₄, and concentrated under vacuum; the residue was purified by reversed-phase column chromatography to give intermediate A17 (2.7 g, 64% yield).

[0560] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.44

[0561] 1 H NMR: (400 MHz, DMSO- d 6) δ 6.99 (d, J = 2.7 Hz, 1H), 6.82 (dd, J =2.7, 0.7 Hz, 1H), 4.84 (t, J = 5.1 Hz, 1H), 4.81 (s, 2H), 4.79 (s, 2H), 4.55(d, J = 5.2 Hz, 2H), 4.17 (q, J = 7.1 Hz, 2H), 2.39 (s, 3H), 1.21 (t, J = 7.1Hz, 3H).

[0562] Intermediate A18

[0563] Synthesis of ethyl 2-(3-bromo-4-(chloromethyl)-5-methylphenoxy) (intermediate A18)

[0564]

[0565] Thionyl chloride (2.19 g, 18.48 mmol) was added to a solution of intermediate A17 (2.8 g, 9.24 mmol) in DCM (10 mL) at room temperature; the resulting mixture was stirred at room temperature for 1 h. The reaction was concentrated under vacuum to give intermediate A18 (2.9 g, 97% yield).

[0566] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.6

[0567] 1 H NMR: (400 MHz, DMSO- d6) δ 7.10 (d, J = 2.7 Hz, 1H), 6.90 (d, J = 2.7Hz, 1H), 4.83 (d, J = 1.3 Hz, 4H), 4.17 (q, J = 7.1 Hz, 2H), 2.42 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H).

[0568] Intermediate A19

[0569] Synthesis of 2-(4-formyl-3,5-dimethylphenoxy)tert-butyl acetate (intermediate A19)

[0570]

[0571] Cesium carbonate (130 g, 0.40 mol) was added to a solution of 2,6-dimethyl-4-hydroxybenzaldehyde (30 g, 0.20 mol) and tert-butyl bromoacetate (35 mL, 0.25 mol) in DMF (600 mL) at room temperature. The reaction mixture was stirred at room temperature for 3 h. The reaction mixture was diluted with EtOAc (1000 mL) and filtered. The filtrate was washed with water (1000 mL x 3) and brine (500 mL x 2), dried over Na2SO4, and concentrated under vacuum to give intermediate A19 (47 g, 89% yield) as a white solid.

[0572] TLC: EtOAc / Petroleum Ether = 1 / 20

[0573] 1 H NMR: (400 MHz, CDCl3) δ 10.48 (s, 1H), 6.58 (s, 2H), 4.55 (s, 2H), 2.60 (s, 6H), 1.49 (s, 9H).

[0574] Intermediate A20

[0575]

[0576] NaBH4 (0.14 g, 3.8 mmol) was added fractionally to an intermediate A19 (1.00 g, 3.78 mmol) in methanol (30 mL) at 0°C. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was quenched with water (50 mL), extracted with EtOAc (50 mL x 3), dried over Na2SO4, and concentrated under vacuum to give intermediate A20 (0.9 g, 89% yield) as a colorless oil.

[0577] TLC:EtOAc / petroleum ether = 1 / 10 (v / v)

[0578] 1 H NMR: (400 MHz, DMSO) δ 6.53 (d, J = 7.6 Hz, 2H), 4.57 (d, J = 7.6Hz, 2H), 4.40 (s, 2H), 4.32 (s, 1H), 2.30 (d, J = 7.6 Hz, 6H), 1.43 (d, J =7.8 Hz, 9H).

[0579] Intermediate A21

[0580]

[0581] Add thionyl chloride (0.44 g, 3.72 mmol) to a solution of intermediate A20 (0.9 g, 3.38 mmol) in DCM (20 mL) at room temperature; stir the resulting solution at room temperature for 30 min. Concentrate the reaction mixture under vacuum to give intermediate A21 (0.9 g, 93% yield) as a white solid.

[0582] TLC:EtOAc / petroleum ether = 1 / 10 (v / v)

[0583] 1 H NMR: (400 MHz, DMSO) δ 6.61 (s, 2H), 4.75 (s, 2H), 4.61 (s, 2H), 2.31 (d, J = 13.6 Hz, 6H), 1.42 (s, 9H).

[0584] Intermediate B1

[0585]

[0586] A mixture of (3-bromophenyl)-difluoromethyl ether (3.0 g, 13.4 mmol), bis(pinacol)diboron (6.8 g, 26.9 mmol), Pd(dppf)Cl2 (984 mg, 1.35 mmol), and KOAc (4.0 g, 40.4 mmol) in anhydrous 1,4-dioxane (30 mL) was stirred overnight at 85°C. The resulting solution of intermediate B1 was used without further purification.

[0587] TLC: EtOAc / petroleum ether = 1 / 2 (v / v), Rf = 0.2

[0588] Intermediate B2

[0589]

[0590] A mixture of 3'-bromo-1-methylstyrene (500 mg, 2.54 mmol), Pd(dppf)Cl2 (186 mg, 0.25 mmol), bis(pinacol)diboron (1.29 g, 5.07 mmol), and KOAc (748 mg, 7.62 mmol) in 1,4-dioxane (10 mL) was stirred at 80°C for 4 h. The mixture was filtered through a silica gel pad, concentrated to dryness, and purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1) to give intermediate B2 (400 mg, 65%) as a yellow solid.

[0591] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.87

[0592] 1 H NMR: (400 MHz, DMSO- d 6) δ 7.76 – 7.72 (m, 1H), 7.65 – 7.62 (m, 1H), 7.63 – 7.58 (m, 1H), 7.41 – 7.34 (m, 1H), 5.39 (dd, J = 1.7, 0.8 Hz, 1H), 5.11 (t, J = 1.5 Hz, 1H), 2.11 (s, 3H), 1.30 (s, 12H).

[0593] Intermediate B3

[0594]

[0595] A mixture of 3-(2,2,2-trifluoroethyl)-1-bromobenzene (500 mg, 2.09 mmol), Pd(dppf)Cl2 (153 mg, 0.21 mmol), bis(pinacol)diboron (1.06 g, 4.18 mmol), and KOAc (616 mg, 6.28 mmol) in 1,4-dioxane (10 mL) was stirred at 80°C for 4 h. The mixture was filtered through a silica gel pad, concentrated to dryness, and purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1) to give intermediate B3 (400 mg, 84%) as a colorless oil.

[0596] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.88

[0597] intermediate B4

[0598]

[0599] Potassium acetate (430 mg, 4.36 mmol) was added to a mixture of 3-pentafluoroethyl-bromobenzene (400 mg, 1.45 mmol), bis(pinacol)diboron (406 mg, 1.60 mmol), and Pd(dppf)Cl2 (53 mg, 0.07 mmol) in 1,4-dioxane (10 mL). The mixture was heated to 100°C and maintained for 3 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum to give crude intermediate B4 (468 mg, 99% yield), which was used without further purification.

[0600] TLC: petroleum ether / EtOAc = 10 / 1 (v / v), Rf = 0.9

[0601] Intermediate B5

[0602]

[0603] To a solution of 3-chlorothiophene (237 mg, 2.0 mmol) in hexane (3 mL), 4,4'-di-tert-butyl-2,2'-bipyridine (16 mg, 60 μmol), 4,4,5,5-tetramethyl-1,3,2-dioxabortane (128 mg, 1.0 mmol), and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (40 mg, 60 μmol) were added. The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum, and intermediate B5 was used without further purification.

[0604] Intermediate B6

[0605]

[0606] To a solution of 3-methylfuran (400 mg, 4.87 mmol) in THF (10 mL), bis(pinacol)diboron (1.23 g, 4.87 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (65 mg, 97.4 μmol), and 4,4'-di-tert-butyl-2,2'-bipyridine (33 mg, 122 μmol) were added. The mixture was heated to reflux for 2 h, then cooled to room temperature and concentrated under vacuum to give intermediate B6 as a mixture with the 2,4-substituted isomer. This mixture was used without further purification.

[0607] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.30

[0608] Intermediate B7

[0609]

[0610] A mixture of sodium dichlorofluoroacetate (1.0 g, 5.2 mmol), 3-bromo-4-fluorophenol (1.60 g, 10.5 mmol), and K₂CO₃ (868 mg, 6.3 mmol) in DMF (10 mL) was stirred at 100°C for 2 h. The mixture was cooled to room temperature. Concentrated HCl (1.5 mL) and water (3 mL) were added, and the mixture was stirred at room temperature for 1 h. The mixture was cooled to 0°C. NaOH (4 M, 5 mL) and water (25 mL) were added, and the mixture was extracted with Et₂O (5 mL x 3). The organic layer was washed with brine (15 mL), dried over Na₂SO₄, and purified by silica gel column chromatography (petroleum ether / EtOAc = 200 / 1 to 100 / 1) to give intermediate B7 (150 mg, 11% yield) as a colorless oil.

[0611] TLC: Petroleum ether / EtOAc = 100 / 1 (v / v), Rf = 0.55

[0612] 1 H NMR: (400 MHz, DMSO- d 6) δ 7.62 (dd, J = 6.0, 3.2 Hz, 1H), 7.46 (t, J = 8.8 Hz, 1H), 7.28 (dt, J = 9.2, 3.6 Hz, 1H), 7.24 (t, J = 73.6 Hz, 1H).

[0613] 19 F NMR: (376 MHz, DMSO- d 6) δ -82.81, -112.84.

[0614] Intermediate B8

[0615]

[0616] Potassium acetate (183 mg, 1.8 mmol) was added to a mixture of intermediate B7 (150 mg, 622 μmol), bis(pinacol)diboron (175 mg, 684 μmol), and Pd(dppf)Cl2·CH2Cl2 (25 mg, 31 μmol) in 1,4-dioxane (5.0 mL) at room temperature. The mixture was heated to 110°C and maintained for 3 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum to give crude intermediate B8 (175 mg, 97% yield), which was used without further purification.

[0617] TLC: EtOAc / petroleum ether = 1 / 10 (v / v), Rf = 0.65

[0618] Intermediate B9

[0619]

[0620] A mixture of (3-bromo-5-fluorophenyl)-difluoromethyl ether (120 mg, 0.50 mmol), KOAc (146 mg, 1.50 mmol), bis(pinacol)diboron (189 mg, 0.75 mmol), and Pd(dppf)Cl2 (18 mg, 0.03 mmol) in 1,4-dioxane (3 mL) was incubated at 85 °C under a nitrogen atmosphere. o Stir at C for 2 h. The crude solution of intermediate B9 is used without further purification.

[0621] TLC: Petroleum ether / EtOAc = 20 / 1 (v / v), Rf = 0.65

[0622] Intermediate B10

[0623]

[0624] A mixture of (3-bromo-6-fluorophenyl)-difluoromethyl ether (300 mg, 1.2 mmol), bis(pinacol)diboron (348 mg, 1.4 mmol), Pd(dppf)Cl2 (91 mg, 0.1 mmol), and KOAc (365 mg, 3.6 mmol) in 1,4-dioxane (3 mL) was stirred overnight at 80 °C. The mixture was filtered and concentrated under vacuum to give intermediate B10 (330 mg, 95% yield) as a black oil, which was used without further purification.

[0625] TLC: petroleum ether / EtOAc = 10 / 1 (v / v), Rf = 0.8

[0626] LCMS:RT=4.324 min; [M+1]=289.1

[0627] Intermediate B11

[0628] Synthesis of 1-bromo-3-(difluoromethoxy)-2-fluorobenzene (intermediate B11)

[0629]

[0630] A mixture of sodium dichlorofluoroacetate (1.0 g, 5.2 mmol), 3-bromo-2-fluorophenol (1.60 g, 10.47 mmol), and K₂CO₃ (868 mg, 6.3 mmol) in DMF (10 mL) was stirred at 100°C for 2 h. The mixture was cooled to room temperature. Concentrated HCl (1.5 mL) and water (3 mL) were added, and the mixture was stirred at room temperature for 1 h. The mixture was cooled to 0°C, and NaOH (4 M, 5 mL) and H₂O (25 mL) were added. The mixture was extracted with Et₂O (5 mL x 3). The combined organic phases were washed with brine (15 mL), dried over Na₂SO₄, and purified by silica gel column chromatography (petroleum ether / EtOAc = 200 / 1 to 100 / 1) to give intermediate B11 (800 mg, 47% yield) as a colorless oil.

[0631] TLC: Petroleum ether / EtOAc = 100 / 1 (v / v), Rf = 0.55

[0632] 1 H NMR: (400 MHz, DMSO- d 6) δ 7.66 – 7.60 (m, 1H), 7.42 (t, J = 8.0 Hz, 1H), 7.303 (t, J= 15.6 Hz, 1H), 7.24 (td, J = 8.4, 1.6 Hz, 1H).

[0633] 19 F NMR: (376 MHz, DMSO- d 6) δ -82.56 (d, J = 3.6 Hz), -124.68.

[0634] Intermediate B12

[0635] 2-(3-(difluoromethoxy)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaboranecyclopentane (middle) Synthesis of intermediate B12

[0636]

[0637] Potassium acetate (500 mg, 5.1 mmol) was added to a solution of intermediate B11 (400 mg, 1.7 mmol), bis(pinacol)diboron (1.25 g, 4.93 mmol), and Pd(dppf)Cl2·CH2Cl2 (457 mg, 1.8 mmol) in 1,4-dioxane (5.0 mL) at room temperature. The mixture was heated to 110°C and maintained for 3 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum to give crude intermediate B12 (470 mg, 95% yield), which was used without further purification.

[0638] TLC: EtOAc / petroleum ether = 1 / 10 (v / v), Rf = 0.65

[0639] Intermediate C1

[0640] Synthesis of 3'-(difluoromethoxy)-[1,1'-biphenyl]-2 alcohol (intermediate C1)

[0641]

[0642] A mixture of intermediate B1 (3.5 g, 13 mmol), 2-bromophenol (1.5 g, 8.67 mmol), Pd(dppf)Cl2 (634 mg, 0.87 mmol), and K2CO3 (3.6 g, 26 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was stirred overnight at 90°C. Water (50 mL) was added, and the mixture was extracted with EtOAc (30 mL x 2). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1 to 5 / 1, v / v) to give intermediate C1 (700 mg, 34% yield) as a yellow oil.

[0643] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.54

[0644] LCMS: RT=2.551 min; [M-1]=235.0

[0645] intermediate C2

[0646] Synthesis of 3'-ethyl-[1,1'-biphenyl]-2-ol (intermediate C2)

[0647]

[0648] A mixture of 2-bromophenol (660 mg, 3.81 mmol), (3-ethylphenyl)boric acid (630 mg, 4.20 mmol), Na₂CO₃ (809 mg, 7.63 mmol), and Pd(dppf)Cl₂ (278 mg, 381 μmol) in 1,4-dioxane (10 mL) / water (2 mL) was incubated at 85 °C under a N₂ atmosphere. o Stir at C for 2 hours. Concentrate the mixture and purify it by silica gel column chromatography (petroleum ether / EtOAc = 100 / 1, v / v) to give intermediate C2 (600 mg, 79% yield) as a yellow oil.

[0649] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.35

[0650] 1 H NMR: (400 MHz, DMSO) δ 9.43 (s, 1H), 7.41 – 7.07 (m, 6H), 6.92 (d, J = 7.7 Hz, 1H), 6.86 (t, J= 7.4 Hz, 1H), 2.64 (q, J = 7.6 Hz, 2H), 1.21 (t, J = 6.8 Hz, 3H).

[0651] intermediate C3

[0652] Synthesis of 3'-(trifluoromethyl)-[1,1'-biphenyl]-2-ol (intermediate C3)

[0653]

[0654] A mixture of 2-bromophenol (500 mg, 2.89 mmol), 3-trifluoromethyl-phenylboronic acid (659 mg, 3.47 mmol), Pd(dppf)Cl2 (211 mg, 289 μmol), and K2CO3 (1.20 g, 8.67 mmol) in water (1 mL) and 1,4-dioxane (5 mL) was stirred overnight at 90°C. Water (30 mL) was added, and the mixture was extracted with EtOAc (20 mL * 2). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1) to give intermediate C3 (600 mg, 87% yield) as a yellow oil.

[0655] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.37

[0656] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.75 (s, 1H), 7.93 – 7.82 (m, 2H), 7.72 –7.62 (m, 2H), 7.32 (dd, J = 7.6, 1.8 Hz, 1H), 7.24 –7.20 (m, 1H), 6.98 (dd, J = 8.2, 1.2 Hz, 1H), 6.91 (td, J = 7.4, 1.2 Hz, 1H).

[0657] intermediate C4

[0658] Synthesis of 4-(hydroxy(2-hydroxyphenyl)methyl)benzonitrile (intermediate C4)

[0659]

[0660] A solution of 2-bromophenol (2.0 g, 11.6 mmol) in diethyl ether (20 mL) was cooled to -78°C. n-BuLi (2.5 M) (25.5 mmol) was added dropwise. The mixture was heated to room temperature and stirred for 2 h. The mixture was then cooled to -78°C. A solution of 4-cyanobenzaldehyde (1.7 g, 12.7 mmol) in THF (6 mL) was added dropwise. The mixture was stirred at -78°C for 1 h and then heated to room temperature. The reaction was quenched with a saturated aqueous solution of NH4Cl (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (EtOAc / petroleum ether = 1 / 50 to 1 / 5) to give intermediate C4 (1.7 g, 65% yield) as a white solid.

[0661] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.20

[0662] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.56 (s, 1H), 7.76 – 7.69 (m, 2H), 7.59 –7.53 (m, 2H), 7.35 (dd, J = 8.0, 1.6 Hz, 1H), 7.05 (td, J = 7.6, 1.6 Hz, 1H),6.81- 6.77(m, 2H), 6.04 (d, J = 4.4 Hz, 1H), 5.93 (d, J = 4.0 Hz, 1H).

[0663] intermediate C5

[0664] Synthesis of 4-(2-hydroxybenzyl)benzonitrile (intermediate C5)

[0665]

[0666] Et3SiH (3.5 g, 30.7 mmol) was added to a solution of intermediate C4 (1.7 g, 7.5 mmol) in DCM (20 mL). The mixture was cooled to 0°C, and TFA (26.3 g, 231 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. Water (20 mL) was added, and the resulting mixture was extracted with DCM (10 mL x 3). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, and concentrated under vacuum; the residue was washed with hexane (10 mL) to give intermediate C5 (1.2 g, 76% yield) as a white solid.

[0667] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), R f =0.45

[0668] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.47 (s, 1H), 7.72 (d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.4 Hz, 2H), 7.12 – 7.02 (m, 2H), 6.81 (d, J = 7.6 Hz, 1H), 6.74(t, J = 7.4 Hz, 1H), 3.95 (s, 2H).

[0669] intermediate C6

[0670] Synthesis of 2-(hydroxy(pyridin-4-yl)methyl)phenol (intermediate C6)

[0671]

[0672] A solution of 2-bromophenol (2.0 g, 11.6 mmol) in ether (20 mL) was cooled to -70°C; n-BuLi (25.5 mmol, 10 mL, 2.5 M) was added dropwise. The mixture was stirred at -70°C for 2 h. 4-pyridinecarboxaldehyde (1.4 g, 12.7 mmol) in THF (5 mL) was added dropwise. The mixture was stirred at -70°C for 1 h. The reaction was quenched with a saturated aqueous solution of NH4Cl (15 mL); the pH was adjusted to ~7 with HCl (1N). The resulting mixture was extracted with EtOAc (30 mL x 2); the combined organic phases were washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 20:1) to give intermediate C6 (1.2 g, 51% yield) as a white solid.

[0673] TLC:DCM / MeOH=15 / 1(v / v), Rf=0.3

[0674] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.56 (s, 1H), 8.46 – 8.43 (m, 2H), 7.34(d, J = 6.2 Hz, 3H), 7.07 – 7.02 (m, 1H), 6.81 – 6.75 (m, 2H), 5.97 (s, 1H), 5.89 (d, J = 4.4 Hz, 1H).

[0675] intermediate C7

[0676] Synthesis of 2-(pyridin-4-ylmethyl)phenol (intermediate C7)

[0677]

[0678] Et3SiH (2.8 g, 23.8 mmol) and TFA (2.7 g, 23.8 mmol) were added to a solution of intermediate C6 (1.2 g, 5.96 mmol) in DCM (15 mL) at 0°C. The mixture was stirred at room temperature for 1 h and then concentrated under vacuum. Water (15 mL) was added, and the mixture was adjusted to pH ~7 with NaHCO3 (2N) and extracted with EtOAc (50 mL x 2). The combined organic phases were washed with brine (100 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM:MeOH = 100:1 to 30:1) to give intermediate C7 (530 mg, 48% yield) as a yellow oil.

[0679] TLC:DCM / MeOH=10 / 1(v / v), Rf=0.7

[0680] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.45 (s, 1H), 8.43 – 8.38 (m, 2H), 7.21 –7.17 (m, 2H), 7.11 – 7.02 (m, 2H), 6.81 (dd, J = 8.2, 1.2 Hz, 1H), 6.75 (dd, J = 7.4, 1.2 Hz, 1H), 3.87 (s, 2H).

[0681] intermediate C8

[0682] Synthesis of pyrimidine-5-carboxaldehyde (intermediate C8)

[0683]

[0684] MnO2 (15.6 g, 181 mmol) was added to a solution of pyrimidine-5-methanol (2.0 g, 18.1 mmol) in chloroform (30 mL) at room temperature. The mixture was stirred overnight at 50°C. The reaction mixture was cooled to room temperature, filtered, and the filtrate was concentrated under vacuum to give a crude product, which was purified by silica gel column chromatography (petroleum ether / EtOAc = 2 / 1, v / v) to give intermediate C8 (800 mg, 40% yield) as a white solid.

[0685] TLC: EtOAc / petroleum ether = 1 / 10 (v / v), Rf = 0.44

[0686] 1H NMR: (400 MHz, DMSO) δ 10.15 (s, 1H), 9.45 (s, 1H), 9.26 (s, 2H).

[0687] intermediate C9

[0688] Synthesis of 2-(hydroxy(pyrimidin-5-yl)methyl)phenol (intermediate C9)

[0689]

[0690] n-BuLi (16 mmol, 6.51 mL, 2.5 M) was added to a solution of 2-bromophenol (1.28 g, 7.40 mmol) in THF (30 mL) at -70°C. The mixture was stirred at room temperature for 30 min, then cooled to -70°C. Intermediate C8 (800 mg, 7.40 mmol) was added at -70°C; the mixture was slowly heated to room temperature and stirred for 16 h. The reaction was quenched with water (50 mL); the pH was adjusted to pH 6-7 with 2N HCl, and the resulting mixture was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 / 2, v / v) to give intermediate C9 (800 mg, 53% yield) as a white solid.

[0691] TLC: EtOAc / petroleum ether = 1 / 10 (v / v), Rf = 0.4

[0692] 1 H NMR: (400 MHz, DMSO) δ 9.60 (s, 1H), 9.02 (s, 1H), 8.70 (s, 2H), 7.48 (m, 1H), 7.09 (m, 1H), 6.84 (t, J = 7.4 Hz, 1H), 6.77 (d, J = 8.0 Hz, 1H), 6.04 (d, J = 4.4 Hz, 1H), 5.98 (d, J = 4.4 Hz, 1H).

[0693] Intermediate C10

[0694] Synthesis of 2-(pyrimidin-5-ylmethyl)phenol (intermediate C10)

[0695]

[0696] Et3SiH (1.84 g, 15.8 mmol) and TFA (118 mmol, 9.0 mL) were added to a solution of intermediate C9 (800 mg, 3.95 mmol) in DCM (10 mL) at 0°C. The mixture was stirred at room temperature for 0.5 h. The reaction was concentrated under vacuum and extracted with chloroform / isopropanol (30 mL / 10 mL * 3). The combined organic phases were dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (DCM / MeOH = 20 / 1, v / v) to give intermediate C10 (1.0 g, 100% yield) as a white solid.

[0697] TLC: EtOAc / petroleum ether = 1 / 10 (v / v), Rf = 0.5

[0698] 1 H NMR: (400 MHz, DMSO) δ 9.57 (s, 1H), 9.00 (s, 1H), 8.66 (s, 2H), 7.16 (m, 1H), 7.06 (d, J = 1.7 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 6.76 (d, J = 7.4 Hz, 1H), 3.88 (s, 2H).

[0699] Intermediate C11

[0700] Synthesis of methyl 4-(2,2,2-trifluoroethyl)benzoate (intermediate C11)

[0701]

[0702] A mixture of (4-carbonmethoxyphenyl)boropinara ester (1.0 g, 3.82 mmol), 1,1,1-trifluoro-2-iodoethane (1.6 g, 7.6 mmol), Pd2(dba)3 (175 mg, 191 μmol), xantphos (221 mg, 382 μmol), CuCl (38 mg, 382 μmol), and CsF (1.74 g, 11.5 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was stirred overnight at 65°C under a nitrogen atmosphere. The mixture was cooled to room temperature and filtered; the filtrate was concentrated under vacuum. The residue was dissolved in DCM (100 mL), washed with H2O (50 mL) and brine (50 mL), and then dried over Na2SO4. The solution was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1) to give intermediate C11 (330 mg, 40% yield) as a pale yellow solid.

[0703] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.82

[0704] 1 H NMR: (400 MHz, DMSO- d 6) δ 7.97 (d, J = 8.1 Hz, 2H), 7.52 (d, J = 7.9Hz, 2H), 3.86 (s, 3H), 3.78 (q, J = 11.6 Hz, 2H).

[0705] intermediate C12

[0706] Synthesis of (4-(2,2,2-trifluoroethyl)phenyl)methanol (intermediate C12)

[0707]

[0708] LiAlH4 (69 mg, 1.82 mmol) was added to an anhydrous THF solution (6 mL) at 0°C to intermediate C11 (330 mg, 1.51 mmol); the mixture was stirred at 0°C for 1 h. A saturated NH4Cl (water) solution (5 mL) was added, and the resulting mixture was extracted with DCM (5 mL x 2). The organic layer was dried over Na2SO4 and concentrated under vacuum to give intermediate C12 (250 mg, 87% yield) as a pale yellow solid.

[0709] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.49

[0710] 1 H NMR: (400 MHz, DMSO- d 6) δ 7.33 – 7.29 (m, 4H), 5.18 (t, J = 5.7 Hz, 1H), 4.49 (d, J = 5.7 Hz, 2H), 3.61 (q, J = 11.7 Hz, 2H).

[0711] intermediate C13

[0712] Synthesis of 1-(chloromethyl)-4-(2,2,2-trifluoroethyl)benzene (intermediate C13)

[0713]

[0714] Add thionyl chloride (235 mg, 1.97 mmol) to a solution of intermediate C12 (250 mg, 1.31 mmol) in DCM (4 mL). Stir the mixture at room temperature for 2 h. Concentrate the mixture to dryness to give intermediate C13 (250 mg, 92% yield) as a pale yellow solid.

[0715] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.78

[0716] 1 H NMR: (400 MHz, DMSO- d 6) δ 7.45 (d, J = 7.9 Hz, 2H), 7.37 (d, J = 7.9Hz, 2H), 4.76 (s, 2H), 3.66 (q, J = 11.6 Hz, 2H).

[0717] intermediate C14

[0718] Synthesis of 2-(1-(4-fluorophenyl)-1-hydroxypropyl)phenol (intermediate C14)

[0719]

[0720] A solution of 2-bromophenol (3.41 g, 19.7 mmol) in THF (40 mL) at -30 °C was added dropwise to n-BuLi (2.5 M, 17.35 mL). After 2 h, the mixture was cooled to -50 °C and (4-fluorophenyl)-ethyl ketone (3.0 g, 19.7 mmol) was added dropwise. The mixture was stirred overnight at room temperature, then diluted with an aqueous solution of NH4Cl (30 mL), acidified with HCl (1N) to pH 6–7, and extracted with EtOAc (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1 to 5 / 1) to give intermediate C14 (2.1 g, 43% yield) as a yellow oil.

[0721] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.36

[0722] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.58 (s, 1H), 7.41 – 7.30 (m, 3H), 7.11 –7.02 (m, 3H), 6.80 (td, J = 7.6, 1.3 Hz, 1H), 6.67 (dd, J = 8.0, 1.3 Hz, 1H), 6.19 (s, 1H), 2.42 (dq, J = 14.4, 7.3 Hz, 1H), 2.14 (dq, J = 14.3, 7.2 Hz, 1H), 0.77 (t, J = 7.2 Hz, 3H).

[0723] Intermediate C15

[0724] Synthesis of 2-(1-(4-fluorophenyl)propyl)phenol (intermediate C15)

[0725]

[0726] Et3SiH (3.97 g, 34 mmol) was added to a solution of intermediate C14 (2.10 g, 8.53 mmol) in DCM (20 mL) at room temperature. The mixture was cooled to 0. oTFA (29.17 g, 256 mmol) was added dropwise. The mixture was stirred at room temperature for 3 h, diluted with DCM (20 mL), and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 50 / 1 to 10 / 1) to give intermediate C15 (1.7 g, 86% yield) as a yellow oil.

[0727] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), R f =0.60

[0728] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.31 (s, 1H), 7.31 – 7.22 (m, 2H), 7.17(dd, J = 8.0, 1.6 Hz, 1H), 7.10 – 7.01 (m, 2H), 6.97 (td, J = 7.5, 1.7 Hz, 1H), 6.75 (dd, J = 7.8, 6.6 Hz, 2H), 4.16 (t, J = 7.9 Hz, 1H), 2.01 – 1.89(m, 2H), 0.80 (t, J = 7.3 Hz, 3H).

[0729] intermediate C16

[0730] Synthesis of 2-(1-(4-fluorophenyl)-1-hydroxybutyl)phenol (intermediate C16)

[0731]

[0732] A solution of 2-bromophenol (2.0 g, 11.6 mmol) in THF (20 mL) was cooled to -78°C. n-BuLi (10.2 mL, 2.5 M; 25.5 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h, then cooled to -78°C. (4-fluorophenyl)- nA solution of 1.7 g (12.7 mmol) of propyl ketone in THF (6 mL). The mixture was stirred at -78°C for 1 h, then heated to 70°C and stirred overnight. The reaction was quenched with saturated NH4Cl aqueous solution (20 mL) and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (EtOAc / petroleum ether = 1 / 50 to 1 / 10) to give intermediate C16 (750 mg, 25% yield) as a white solid.

[0733] TLC: EtOAc / petroleum ether = 1 / 10 (v / v), Rf = 0.20

[0734] LCMS:RT=4.018 min; [M-1]=259.0

[0735] Intermediate C17

[0736] Synthesis of 2-(1-(4-fluorophenyl)butyl)phenol (intermediate C17)

[0737]

[0738] Et3SiH (1.3 g, 11.4 mmol) was added to a solution of intermediate C16 (750 mg, 2.9 mmol) in DCM (10 mL). The mixture was cooled to 0°C, and TFA (9.8 g, 85.5 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. Water (20 mL) was added, and the resulting mixture was extracted with DCM (10 mL x 3). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, and concentrated under vacuum. The residue was washed with hexane (10 mL) to give intermediate C17 (1.2 g, 76% yield) as a white solid.

[0739] TLC:EtOAc / petroleum ether = 1 / 10 (v / v), R f =0.6

[0740] 1 H NMR: (400 MHz, DMSO) δ 9.35 (s, 1H), 7.28 (dd, J = 8.4, 6.0 Hz, 2H), 7.17 (t, J = 9.2 Hz, 1H), 7.05 (t, J = 8.8 Hz, 2H), 6.97 (m, 1H), 6.80 –6.71 (m, 2H), 4.30 (t,J = 8.0 Hz, 1H), 1.99 – 1.84 (m, 2H), 1.20 (td, J =14.0, 7.2 Hz, 2H), 0.88 (t, J = 7.2 Hz, 2H).

[0741] intermediate C18

[0742] Synthesis of 2-(1-(4-fluorophenyl)-1-hydroxy-2-methylpropyl)phenol (intermediate C18)

[0743]

[0744] n-BuLi (8.79 mmol, 3.52 mL, 2.5 M) was added dropwise to a solution of 2-bromophenol (691 mg, 4.00 mmol) in anhydrous THF (5 mL) at -50°C. The mixture was heated to room temperature and stirred for 1 h to obtain solution A. In parallel, a mixture of (4-fluorophenyl)-isopropyl ketone (332 mg, 2.00 mmol) and ZnCl2 (1 mL, 1.00 mmol) was stirred at room temperature for 1 h and then added dropwise to solution A. The resulting mixture was stirred at room temperature for 2 h and then quenched by adding saturated NH4Cl aqueous solution (15 mL). The mixture was acidified to pH ~4-5 with 1N HCl and then extracted with DCM (15 mL * 2). The combined organic layers were dried over Na2SO4, concentrated under vacuum, and purified by reversed-phase column chromatography to give intermediate C18 (350 mg, 67% yield) as a colorless oil.

[0745] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.48

[0746] 1 H NMR: (400 MHz, chloroform- d ) δ 8.78 (s, 1H), 7.40 – 7.33 (m, 2H), 7. 15 –7.11 (m, 2H), 7.02 – 6.93 (m, 2H), 6.86 – 6.77 (m, 2H), 2.81 – 2.72 (m, 1H),1.10 (d, J = 6.8 Hz, 3H), 0.82 (d, J = 6.7 Hz, 3H).

[0747] Intermediate C19

[0748] Synthesis of 2-(1-(4-fluorophenyl)-2-methylpropyl)phenol (intermediate C19)

[0749]

[0750] The mixture of intermediate C18 (250 mg, 960 μmol) and 5% Pd / C (250 mg) in THF (10 mL) was stirred overnight at 60°C. The mixture was cooled to room temperature and filtered, then concentrated to dryness to give intermediate C19 (200 mg, 85% yield).

[0751] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.66

[0752] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.39 (s, 1H), 7.36 – 7.30 (m, 3H), 7.06 –7.01 (m, 2H), 6.95 – 6.91 (m, 1H), 6.75 – 6.71 (m, 2H), 3.88 (d, J = 11.3 Hz,1H), 2.58 – 2.51 (m, 1H), 0.79 (dd, J = 14.9, 6.4 Hz, 6H).

[0753] Intermediate C20

[0754] Synthesis of 2-(cyclopropyl(4-fluorophenyl)(hydroxy)methyl)phenol (intermediate C20)

[0755]

[0756] A solution of 2-bromophenol (1.58 g, 9.13 mmol) in THF (30 mL) was cooled to -70°C, and n-BuLi (20 mmol, 8.0 mL, 2.5 M) was added dropwise. The mixture was stirred at room temperature for 30 min, then cooled to -70°C; 4-fluorophenylcyclopropyl ketone (1.50 g, 9.13 mmol) in THF (3 mL) was added dropwise. The mixture was stirred at room temperature for 16 h. The reaction was quenched with water (50 mL); the mixture was adjusted to pH 6-7 with 2N HCl and extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1, v / v) to give intermediate C20 (2.0 g, 87% yield) as a white solid.

[0757] TLC: EtOAc / petroleum ether = 1 / 10 (v / v), Rf = 0.4

[0758] LCMS:(RT= 3.74 min; [M-1]=257.0)

[0759] Intermediate C21

[0760] Synthesis of 2-(cyclopropyl(4-fluorophenyl)methyl)phenol (intermediate C21)

[0761]

[0762] Et3SiH (1.8 g, 15.5 mmol) and TFA (116 mmol, 8.6 mL) were added to a solution of intermediate C20 (1.0 g, 3.87 mmol) in DCM (10 mL) at 0°C. The mixture was stirred at room temperature for 30 min. The mixture was concentrated under vacuum; water (10 mL) was added, and the mixture was extracted with DCM (30 mL * 3). The combined organic phases were dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1, v / v) to give intermediate C21 (400 mg, 25% yield, 60% purity) as a white solid.

[0763] TLC: EtOAc / petroleum ether = 1 / 10 (v / v), Rf = 0.5

[0764] 1 H NMR: (400 MHz, DMSO) δ 9.24 (s, 1H), 7.36 – 7.23 (m, 3H), 7.10 –6.95 (m, 3H), 6.76 (m, 2H), 3.48 (d, J = 10.0 Hz, 1H), 0.53 (m, 2H), 0.25 (m, 1H), 0.12 (m, 1H).

[0765] Intermediate C22

[0766] Synthesis of cyclobutyl(4-fluorophenyl)methanol (intermediate C22)

[0767]

[0768] I₂ (1.61 mmol) was added to a mixture of 4-fluorobenzaldehyde (2 g, 16.1 mmol), 1-bromocyclobutane (2.4 g, 17.7 mmol), and Mg (1.0 g, 40.3 mmol) in THF (20 mL) at room temperature. The mixture was refluxed for 4 h. Water (40 mL) was added, and the mixture was extracted with EtOAc (20 mL x 3). The combined organic phases were washed with brine (5 mL), dried over Na₂SO₄, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / EtOAc = 50 / 1 to 5 / 1) to give intermediate C₂₂ (2.0 g, 69% yield) as a pale yellow liquid.

[0769] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.25

[0770] 1 H NMR: (400 MHz, chloroform- d ) δ 7.25 – 7.19 (m, 2H), 6.99 – 6.90 (m, 2H), 4.49 (d, J = 8.0 Hz, 1H), 2.52 (h, J = 8.0 Hz, 1H), 2.04 – 1.70 (m, 6H).

[0771] Intermediate C23

[0772] Synthesis of cyclobutyl(4-fluorophenyl) ketone (intermediate C23)

[0773]

[0774] Add Dess-Martin periodinane (4.2 g, 10.0 mmol) to a solution of intermediate C22 (1.5 g, 8.32 mmol) in DCM (20 mL). Stir the mixture at room temperature for 2 h. Add water (30 mL) and extract the resulting mixture with DCM (15 mL x 3). Wash the combined organic phases with brine (20 mL), dry to Na2SO4 and concentrate under vacuum to give intermediate C23 (1.4 g, 94% yield) as a colorless liquid.

[0775] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), R f =0.7

[0776] 1 H NMR: (400 MHz, chloroform- d) δ 7.87 – 7.79 (m, 2H), 7.03 (t, J = 8.6 Hz, 2H), 3.88 (p, J = 8.0 Hz, 1H), 2.40 – 2.26 (m, 2H), 2.26 – 2.15 (m, 2H), 2.07 – 1.93 (m, 1H), 1.83 (m, 1H).

[0777] Intermediate C24

[0778] Synthesis of 2-(cyclobutyl(4-fluorophenyl)(hydroxy)methyl)phenol (intermediate C24)

[0779]

[0780] ZnCl2 (2.8 mL, 1.3 mmol) was added to a solution of intermediate C23 (1 g, 5.61 mmol) in THF (10 mL) at room temperature; the mixture was stirred at room temperature for 30 min (solution A). Separately, a solution of 2-bromophenol (1.2 g, 6.73 mmol) in THF (2.5 mL) was cooled to -78°C and then added... n -BuLi (2.5 M, in THF) (7.4 mL, 18.5 mmol) was added, and the solution was stirred at room temperature for 1 h (solution B). Solution B was cooled to -78°C, and solution A was added. The resulting mixture was stirred at -78°C for 2 h. Water (20 mL) was added, and the mixture was extracted with EtOAc (10 mL * 3). The combined organic phases were washed with brine (5 mL), dried over Na2SO4, concentrated under vacuum, and purified by reversed-phase column chromatography (MeCN / H2O) to give intermediate C24 (800 mg, 52% yield) as a pale yellow oil.

[0781] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), R f =0.50

[0782] LCMS:RT=4.030 min; [M-1]=271.1

[0783] Intermediate C25

[0784] Synthesis of 2-(cyclobutyl(4-fluorophenyl)methyl)phenol (intermediate C25)

[0785]

[0786] The solution of intermediate C24 (800 mg, 3.0 mmol) and Et3SiH (1.37 g, 11.75 mmol, 1.88 mL) in DCM (8 mL) was cooled to 0°C. TFA (10.1 g, 88.5 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. Water (20 mL) was added, and the mixture was extracted with DCM (10 mL x 3). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / EtOAc = 50 / 1 to 10 / 1) to give intermediate C25 (650 mg, 86% yield) as a pale yellow oil.

[0787] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), R f =0.45

[0788] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.28 (s, 1H), 7.23 (dd, J = 8.4, 5.8 Hz, 2H), 7.17 (d, J = 7.0 Hz, 1H), 7.02 (t, J = 8.9 Hz, 2H), 6.97 (t, J = 7.6 Hz, 1H), 6.74 (t, J = 7.0 Hz, 2H), 4.25 (d, J = 11.4 Hz, 1H), 3.15 – 3.04 (m,1H), 1.97 – 1.85 (m, 2H), 1.83 – 1.72 (m, 2H), 1.72 – 1.63 (m, 1H), 1.56 (q, J = 8.0, 16.0 Hz, 1H).

[0789] Intermediate C26

[0790] Synthesis of 6-fluoro-1-(2-hydroxyphenyl)-1,2,3,4-tetrahydronaphthalene-1-ol (intermediate C26)

[0791]

[0792] n-BuLi (2.5 M, 7.3 mL) was added dropwise to solution A of 2-bromophenol (1.4 g, 8.3 mmol) in THF (15 mL) at -78°C. The mixture was stirred at room temperature for 1 h. ZnCl2 (1 M, 3.3 mL) was added dropwise to solution B of 6-fluoro-1-tetrahydronaphthone (1.5 g, 9.14 mmol) in THF (3 mL). The mixture was stirred at room temperature for 30 min. Solution A was cooled to -78°C and solution B was added dropwise. The mixture was stirred at -78°C for 2 h. Water (30 mL) was added, and the resulting mixture was extracted with EtOAc (15 mL * 3). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, concentrated under vacuum, and purified by reversed-phase column chromatography (MeCN / H2O) to give intermediate C26 (220 mg, 10% yield) as a brown oil.

[0793] TLC: EtOAc / petroleum ether = 1 / 10 (v / v), Rf = 0.20

[0794] LCMS:RT=3.835 min; [M-1]=257.0

[0795] Intermediate C27

[0796] Synthesis of 2-(6-fluoro-1,2,3,4-tetrahydronaphth-1-yl)phenol (intermediate C27)

[0797]

[0798] A solution of intermediate C26 (220 mg, 852 μmol) and Et3SiH (396 mg, 3.41 mmol) in DCM (4 mL) was cooled to 0°C. TFA (2.91 g, 25.6 mmol) was added dropwise. The solution was stirred at room temperature for 2 h. The reaction was quenched with water (20 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / EtOAc = 50 / 1 to 10 / 1) to give intermediate C27 (110 mg, 53% yield) as a pale yellow oil.

[0799] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), R f =0.6

[0800] Intermediate C28

[0801] 6-Fluoro-1-(2-hydroxyphenyl)-2,3-dihydro-1 H Synthesis of 1-indanol (intermediate C28)

[0802]

[0803] Add n-BuLi (12.8 mmol, 5.1 mL, 2.5 M) to solution A of 2-bromophenol (1.0 g, 5.8 mmol) in THF (15 mL) at -78°C. Stir the mixture at room temperature for 1 h. Add ZnCl2 (1 M, 2.3 mL) to solution B of 6-fluoro-1-indanone (1.0 g, 6.4 mmol) in THF (3 mL) at room temperature. Stir the mixture at room temperature for 30 min. Cool solution A to -78°C and add solution B. Stir the reaction mixture at -78°C for 2 h. Add water (20 mL) and adjust the pH to ~6-7 with 1N HCl. Extract the mixture with EtOAc (10 mL x 3). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, concentrated under vacuum, and purified by reversed-phase column chromatography (MeCN / H2O) to give intermediate C28 (180 mg, 11% yield) as a yellow oil.

[0804] TLC: EtOAc / petroleum ether = 1 / 10 (v / v), Rf = 0.20

[0805] LCMS:RT=3.661 min; [M-1]=243.0

[0806] Intermediate C29

[0807] 2-(6-Fluoro-2,3-dihydro-1- H Synthesis of 1-inden-1-yl)phenol (intermediate C29)

[0808]

[0809] A solution of intermediate C28 (220 mg, 852 μmol) and Et3SiH (396 mg, 3.41 mmol) in DCM (4 mL) was cooled to 0°C. TFA (2.91 g, 25.6 mmol) was added dropwise. The solution was stirred at room temperature for 2 h. The reaction was quenched with water (10 mL) and extracted with DCM (5 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / EtOAc = 50 / 1 to 10 / 1) to give intermediate C29 (130 mg, 63% yield) as a pale yellow oil.

[0810] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), R f =0.6

[0811] LCMS:RT=3.997 min; [M-1]=227.0

[0812] Intermediate C30

[0813] Synthesis of 2-((4-fluorophenyl)(hydroxy)methyl)phenol (intermediate C30)

[0814]

[0815] n-BuLi (2.5 M in hexane) (29.0 mmol, 11.6 mL) was added dropwise to a solution of 2-bromophenol (4.18 g, 24.2 mmol) in THF (40 mL) at -30 °C. After 0.5 h, 4-fluorobenzaldehyde (3.0 g, 24.2 mmol) was added dropwise to THF (10 mL). The mixture was stirred for 1 h, then quenched with a saturated aqueous solution of NH4Cl (50 mL), acidified to pH ~6-7 with 1N HCl, and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1 to 5 / 1) to give intermediate C30 (2.47 g, 46% yield) as a yellow oil.

[0816] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.36

[0817] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.43 (s, 1H), 7.36 (td, J = 5.6, 2.4 Hz,3H), 7.14 – 6.97 (m, 3H), 6.82 – 6.70 (m, 2H), 5.96 (d, J = 4.2 Hz, 1H), 5.72 (d, J = 4.3 Hz, 1H).

[0818] Intermediate C31

[0819] Synthesis of 2-(4-fluorobenzyl)phenol (intermediate C31)

[0820]

[0821] Et3SiH (5.26 g, 45.3 mmol) was added to a solution of intermediate C30 (2.47 g, 11.3 mmol) in DCM (25 mL) at room temperature. The mixture was stirred at 0°C for 10 min, and then TFA (38.7 g, 340 mmol) was added dropwise. The mixture was stirred at room temperature for 3 h, diluted with DCM (20 mL), and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 50 / 1 to 10 / 1) to give intermediate C31 (1.86 g, 81% yield) as a yellow oil.

[0822] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), R f =0.64

[0823] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.39 (s, 1H), 7.25 – 7.20 (m, 2H), 7.10 –6.98 (m, 4H), 6.81 – 6.78 (m, 1H), 6.71 (td, J = 7.4, 1.3 Hz, 1H), 3.84 (s, 2H).

[0824] intermediate C32

[0825] Synthesis of 2-(hydroxy(thiophen-3-yl)methyl)phenol (intermediate C32)

[0826]

[0827] n-BuLi (14.5 mmol, 5.8 mL 2.5 M) was added to a solution of 2-bromophenol (1.0 g, 5.78 mmol) in THF (10 mL) at -78°C; the mixture was stirred at -78°C for 1 h. Thiophene-3-carboxaldehyde (1.3 g, 11.6 mmol) in THF (5 mL) at -78°C was added to the resulting solution. The mixture was stirred at -78°C for 2 h. The reaction mixture was quenched with water (20 mL) and the pH of the solution was adjusted to pH 6-7 with 1N HCl. The resulting mixture was extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, concentrated under vacuum, and purified by reversed-phase column chromatography to give intermediate C32 (850 mg, 71% yield) as a yellow solid.

[0828] TLC: Petroleum ether / EtOAc = 5 / 1 (v / v), Rf = 0.4

[0829] LCMS:RT= 2.809 min, [M-1] = 205.1

[0830] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.41 (s, 1H), 7.37 (dd, J = 4.8, 2.8 Hz, 1H), 7.34 (dd, J = 8.0, 1.6 Hz, 1H), 7.18 (dt, J = 3.2, 1.2 Hz, 1H), 7.06 –6.98 (m, 2H), 6.79-6.75 (m, 2H), 6.01 (d, J = 4.4Hz, 1H), 5.68 (d, J = 4.8Hz, 1H).

[0831] Intermediate C33

[0832] Synthesis of 2-(thiophene-3-ylmethyl)phenol (intermediate C33)

[0833]

[0834] Et3SiH (930 mg, 8.0 mmol) and TFA (3.0 g, 26.7 mmol) were added to a solution of intermediate C32 (550 mg, 2.67 mmol) in DCM (15 mL) at 0°C; the mixture was stirred at room temperature for 2 h. The reaction was concentrated and purified by reversed-phase column chromatography to give intermediate C33 (230 mg, 45% yield).

[0835] TLC: Petroleum ether / EtOAc = 5 / 1 (v / v), Rf = 0.59

[0836] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.38 (s, 1H), 7.40 (dd, J = 4.8, 3.2 Hz, 1H), 7.10 – 7.08 (m, 1H), 7.02 – 6.98(m, 2H), 6.96 (dd, J = 4.8, 1.6 Hz, 1H), 6.83 – 6.77 (m, 1H), 6.70 (td, J = 7.2, 1.2 Hz, 1H), 3.84 (s, 2H).

[0837] intermediate C34

[0838] Synthesis of 2-(hydroxy(thiophen-2-yl)methyl)phenol (intermediate C34)

[0839]

[0840] To a solution of 2-bromophenol (2.0 g, 11.6 mmol) in THF (20 mL) at -78°C, n-BuLi (28.9 mmol, 12 mL, 2.5 M) was added; the mixture was stirred at -78°C for 1 h. Thiophene-2-carboxaldehyde (2.6 g, 23.1 mmol) was added, and the mixture was stirred at -78°C for 2 h. The reaction mixture was quenched with water (20 mL), the pH was adjusted to ~6-7 with 1N HCl, and the mixture was extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum; the residue was purified by reversed-phase column chromatography to give intermediate C34 (2.0 g, 83% yield) as a yellow solid.

[0841] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.4

[0842] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.47 (s, 1H), 7.39 (dd, J = 7.6, 1.6 Hz, 1H), 7.32 (dd, J = 4.8, 1.2 Hz, 1H), 7.05 (dd, J = 7.6, 1.6 Hz, 1H), 6.88(dd, J = 4.8, 3.6 Hz, 1H), 6.83 – 6.75 (m, 3H), 6.17 (d, J = 4.8 Hz, 1H), 5.98 (d, J= 4.8 Hz, 1H).

[0843] Intermediate C35

[0844] Synthesis of 2-(thiophene-2-ylmethyl)phenol (intermediate C35)

[0845]

[0846] Et3SiH (3.4 g, 29.1 mmol) and TFA (11.1 g, 97.0 mmol) were added to a solution of intermediate C34 (2.0 g, 9.70 mmol) in DCM (20 mL) at 0°C; the mixture was stirred at room temperature for 1 h. The reaction mixture was concentrated under vacuum and purified by reversed-phase column chromatography to give intermediate C35 (700 mg, 37% yield).

[0847] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.7

[0848] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.47 (s, 1H), 7.26 (dd, J = 5.2, 1.2 Hz,1H), 7.11 – 6.98 (m, 2H), 6.90 (dd, J = 5.2, 3.2 Hz, 1H), 6.86 – 6.77 (m,2H), 6.72 (td, J = 7.2, 1.2 Hz, 1H), 4.03 (s, 2H).

[0849] Intermediate C36

[0850] Synthesis of 2-(2,2,2-trifluoro-1-(4-fluorophenyl)-1-hydroxyethyl)phenol (intermediate C36)

[0851]

[0852] To a mixture of 2-bromophenol (2.2 g, 12.5 mmol) in THF (30 mL) at -70°C under N2 atmosphere, n-butyllithium (26.0 mmol, 10.4 mL, 2.5 M) was added dropwise. The mixture was stirred at room temperature for 1 h. (4-fluorophenyl)-trifluoromethyl ketone (2.0 g, 10.4 mmol) was added at 0°C. The mixture was stirred at room temperature for 3 h. The mixture was quenched with a saturated aqueous solution of NH4Cl (30 mL). The mixture was acidified to pH ~5-6 with 2 M HCl and then extracted with EtOAc (15 mL x 2). The organic phase was washed with water (30 mL x 2), then with brine (30 mL), concentrated under vacuum, and purified by reversed-phase column chromatography to give intermediate C36 (1.0 g, 34% yield) as a white solid.

[0853] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.48

[0854] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.62 (s, 1H), 7.42 – 7.34 (m, 3H), 7.24 –7.14 (m, 3H), 6.87 (td, J = 7.6, 1.3 Hz, 1H), 6.79 (dd, J = 8.1, 1.2 Hz, 1H).

[0855] Intermediate C37

[0856] Synthesis of 2-(2,2,2-trifluoro-1-(4-fluorophenyl)ethyl)phenol (intermediate C37)

[0857]

[0858] A mixture of intermediate C36 (1.0 g, 3.49 mmol), NaI (4.2 g, 28.0 mmol), and TMSCl (2.3 g, 21.0 mmol) in acetonitrile (10 mL) was microwaved at 120°C for 2 h. The mixture was cooled to room temperature and concentrated to dryness; the residue was purified by Prep-TLC to give intermediate C37 (300 mg, 32% yield) as a colorless oil.

[0859] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.66

[0860] 1 H NMR: (400 MHz, DMSO- d6) δ 9.89 (s, 1H), 7.45 – 7.40 (m, 3H), 7.23 –7.13 (m, 3H), 6.91 – 6.82 (m, 2H), 5.33 (q, J = 10.8 Hz, 1H).

[0861] Intermediate C38

[0862] Synthesis of 2-(3,3,3-trifluoro-1-(4-fluorophenyl)propyl)phenol (intermediate C38)

[0863]

[0864] Cu(CH3CN)4PF6 (61 mg, 164 μmol) was added to a mixture of 4-fluorostyrene (200 mg, 1.6 mmol), Tognis reagent (792 mg, 2.4 mmol), and 2-hydroxyphenylboronic acid (452 ​​mg, 3.3 mmol) in DMA (10.0 mL). The mixture was stirred at 40°C for 1 h. Water (10 mL) was added, and the resulting mixture was extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / EtOAc = 50 / 1 to 10 / 1) to give intermediate C38 (360 mg, 77% yield) as a yellow oil.

[0865] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.3

[0866] LCMS:RT=1.569 min, [M-1]:283.1

[0867] Intermediate C39

[0868] Synthesis of 1-(4-fluorophenyl)-2-methoxyethane-1-one (intermediate C39)

[0869]

[0870] To a solution of 4-fluoroacetophenone (2.0 g, 14.5 mmol) in MeOH (60 mL) at room temperature, TsNHNH2 (2.7 g, 14.5 mmol), TBHP (7.8 g, 86.9 mmol), and TBAI (1.1 g, 2.89 mmol) were added. The mixture was stirred overnight at room temperature. Water (100 mL) was added, and the resulting mixture was extracted with EtOAc (50 mL x 2). The organic phase was washed with brine (20 mL x 2), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (EtOAc / petroleum ether = 1 / 100–1 / 10) to give intermediate C39 (1.7 g, 70% yield) as a yellow liquid.

[0871] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.49.

[0872] 1 H NMR: (400 MHz, DMSO- d 6 ) δ 8.04 – 7.96 (m, 2H), 7.40 – 7.32 (m, 2H), 4.77 (s, 2H), 3.35 (s, 3H).

[0873] Intermediate C40

[0874] Synthesis of 2-(1-(4-fluorophenyl)-1-hydroxy-2-methoxyethyl)phenol (intermediate C40)

[0875]

[0876] Add n-BuLi (38.2 mmol, 15 mL 2.5 M) to a solution of 2-bromophenol (3.0 g, 17.3 mmol) in THF (30 mL) at -78°C; stir the mixture at room temperature for 1 h. Add intermediate C39 (1.9 g, 11.6 mmol) in THF (5 mL) at -78°C to the reaction mixture. Stir the mixture overnight at -5°C. Add water (100 mL) dropwise to the reaction mixture, then acidify to pH ~6-7 with 2N HCl and extract with EtOAc (30 mL * 2). Concentrate the organic phase and purify by reversed-phase column chromatography to give intermediate C40 (800 mg, 28% yield) as a yellow liquid.

[0877] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), R f =0.39

[0878] 1H NMR: (400 MHz, DMSO- d 6 ) δ 9.45 (s, 1H), 7.39 – 7.32 (m, 2H), 7.29(dd, J = 8.0, 2.0 Hz, 1H), 7.12 – 7.05 (m, 3H), 6.79 (td, J = 7.6, 1.2 Hz,1H), 6.70 (dd, J = 8.0, 1.2 Hz, 1H), 6.40 (s, 1H), 3.98 – 3.88 (m, 2H), 3.29 (s, 3H).

[0879] Intermediate C41

[0880] Synthesis of 2-(1-(4-fluorophenyl)-2-methoxyethyl)phenol (intermediate C41)

[0881]

[0882] Pd / C (400 mg, 5% w / w) was added to a solution of intermediate C40 (400 mg, 1.53 mmol) in MeOH (8 mL) at room temperature; the mixture was stirred at 50°C for 3 days. The reaction was filtered, concentrated under vacuum, and purified by Prep-TLC to give intermediate C41 (90 mg, 24% yield) as a white solid.

[0883] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), R f =0.50

[0884] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.40 (s, 1H), 7.31 – 7.23 (m, 2H), 7.11 –7.04 (m, 3H), 7.00 (td, J = 7.6, 1.6 Hz, 1H), 6.80 – 6.69 (m, 2H), 4.56 (t, J = 7.6 Hz, 1H), 3.86 – 3.75 (m, 2H), 3.23 (s, 3H).

[0885] intermediate C42

[0886] Synthesis of 2-(1-(4-fluorophenyl)-1-hydroxyethyl)phenol (intermediate C42)

[0887]

[0888] 2-Bromophenol (20.0 g, 116 mmol) in 100 mL of THF was cooled to -78°C. n-BuLi (232 mmol, 92.5 mL 2.5 M) was added. The mixture was stirred at room temperature for 1 h, then cooled to -78°C. 4-Fluoroacetophenone (16.0 g, 116 mmol) was added to 10 mL of THF. The mixture was stirred at room temperature for 16 h. The reaction mixture was acidified to pH 6-7 with 2N HCl, then extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (100 mL), dried over Na₂SO₄, concentrated under vacuum, and purified by reversed-phase column chromatography to give intermediate C42 (2.0 g, 7.3% yield).

[0889] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.3

[0890] LCMS:RT=3.46 min; [M-1]=231.1

[0891] intermediate C43

[0892] Synthesis of 2-(1-(4-fluorophenyl)ethyl)phenol (intermediate C43)

[0893]

[0894] Et3SiH (11.4 g, 98.0 mmol) and TFA (84.0 g, 735 mmol) were added to a solution of intermediate C42 (5.7 g, 24.5 mmol) in DCM (50 mL) at 0 °C. The mixture was stirred at room temperature for 2 h. The reaction was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1) to give intermediate C43 (5.0 g, 94.3% yield).

[0895] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.25

[0896] 1 H NMR: (400 MHz, DMSO) δ 9.33 (s, 1H), 7.28 – 7.19 (m, 2H), 7.12 –7.02 (m, 3H), 6.99 (m, 1H), 6.79 – 6.71 (m, 2H), 4.44 (d, J = 7.3 Hz, 1H), 1.49 (d, J = 7.3 Hz, 3H).

[0897] intermediate C44

[0898] Synthesis of 2-(2-(4-fluorophenyl)-1-hydroxyethyl)phenol (intermediate C44)

[0899]

[0900] A solution of 2-bromophenol (571 mg, 3.3 mmol) in THF (5 mL) was cooled to -78°C. n-BuLi (2.5 M in THF) (7.3 mmol, 3.2 mL) was added dropwise. The mixture was stirred at room temperature for 30 min, then cooled to -78°C. A solution of 4-fluorophenylacetaldehyde (500 mg, 3.6 mmol) in THF (5 mL) was added dropwise. The mixture was stirred at -78°C for 1 h. The reaction was quenched with a saturated aqueous solution of NH4Cl (10 mL) and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (EtOAc / petroleum ether = 1 / 50 to 1 / 20) to give intermediate C44 (200 mg, 24% yield) as a colorless oil.

[0901] TLC: EtOAc / petroleum ether = 1 / 10 (v / v), Rf = 0.20

[0902] Intermediate C45

[0903] Synthesis of 2-(4-fluorophenylethyl)phenol (intermediate C45)

[0904]

[0905] Et3SiH (418 mg, 3.6 mmol) was added to a solution of intermediate C44 (200 mg, 0.9 mmol) in DCM (4 mL). The mixture was cooled to 0°C, and TFA (3.1 g, 27 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. Water (10 mL) was added, and the resulting mixture was extracted with DCM (5 mL x 3). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-TLC (EtOAc / petroleum ether = 1 / 10) to give intermediate C45 (120 mg, 65% yield) as a white solid.

[0906] TLC:EtOAc / petroleum ether = 1 / 10 (v / v), R f =0.6

[0907] 1H NMR: (400 MHz, DMSO) δ 9.29 (s, 1H), 7.26 – 7.19 (m, 1H), 7.11 –7.05 (m, 1H), 7.03 – 6.97 (m, 1H), 6.78 (d, J = 8.0 Hz, 1H), 6.68 (dt, J =7.6, 1.2 Hz, 1H), 2.84 – 2.74 (m, 1H).

[0908] Intermediate D1

[0909] Synthesis of 1-(1-chloroethyl)-4-fluorobenzene (intermediate D1)

[0910]

[0911] Thionyl chloride (1.27 g, 10.7 mmol) was added to a solution of 1-(4-fluorophenyl)-1-ethanol (1.00 g, 7.13 mmol) in DCM (10 mL) at room temperature. The mixture was stirred for 1 h and concentrated under vacuum to give intermediate D1 (1.13 g, 7.12 mmol, 99% yield).

[0912] TLC: EtOAc / petroleum ether = 3 / 1 (v / v), Rf = 0.54

[0913] 1 H NMR: (400 MHz, DMSO- d 6) δ 7.56 – 7.50 (m, 2H), 7.20-7.16 (m, 2H),5.36 (q, J = 6.8 Hz, 1H), 1.78 (d, J = 6.8 Hz, 3H).

[0914] Intermediate D2

[0915] Synthesis of 1-(2-chloropropan-2-yl)-4-fluorobenzene (intermediate D2)

[0916]

[0917] A solution of 2-(4-F-phenyl)-2-propanol (500 mg, 3.24 mmol) and SOCl2 (579 mg, 4.86 mmol) in DCM (5 mL) was stirred overnight at room temperature. The mixture was concentrated to dryness to give crude intermediate D2 (500 mg, 89% yield) as a colorless oil.

[0918] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.57

[0919] 1 H NMR: (400 MHz, DMSO- d 6) δ 7.68 – 7.62 (m, 2H), 7.22-7.17 (m, 2H), 1.96 (s, 6H).

[0920] Intermediate D3

[0921] Synthesis of furan-3-ylmethanol (intermediate D3)

[0922]

[0923] NaBH4 (95 mg, 2.50 mmol) was added to a solution of furan-3-carboxaldehyde (200 mg, 2.08 mmol) in THF (2 mL) at 0°C. The mixture was stirred at 0°C for 2 h, then quenched with water (10 mL) and extracted with EtOAc (10 mL). The organic layer was washed with water (10 mL), then with brine (10 mL), dried over Na2SO4, and concentrated to dryness to give intermediate D3 (150 mg, 73% yield) as a colorless oil.

[0924] TLC: EtOAc / petroleum ether = 1 / 10 (v / v), Rf = 0.49

[0925] 1 H NMR: (400 MHz, DMSO- d 6) δ 7.58 (t, J = 1.7 Hz, 1H), 7.53 – 7.50 (m,1H), 6.45 – 6.41 (m, 1H), 4.93 (t, J = 5.6 Hz, 1H), 4.33 (dd, J = 5.6, 1.0Hz, 2H).

[0926] Intermediate D4

[0927] Synthesis of 3-(chloromethyl)furan (intermediate D4)

[0928]

[0929] Thionyl chloride (364 mg, 3.06 mmol) was added to a solution of intermediate D3 (200 mg, 2.04 mmol) in DCM (2 mL). The mixture was stirred at 0°C for 2 h. The mixture was concentrated to dryness to give intermediate D4 (150 mg, 63% yield) as a colorless solid.

[0930] TLC: EtOAc / petroleum ether = 1 / 10 (v / v), Rf = 0.78

[0931] Example 1

[0932] 2-(3,5-Dichloro-4-((6-hydroxy-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl)phenoxy) Synthesis of acetic acid (compound 1)

[0933]

[0934] Sodium bicarbonate (1 mL, 2 M aqueous solution) was added to a solution of intermediate A7 (300 mg, 642 μmol), 3-trifluoromethylphenylboronic acid (183 mg, 963 μmol), and Pd(dppf)Cl2 (47.0 mg, 64.2 μmol) in dioxane (5 mL) at room temperature. The mixture was heated to 70°C and stirred for 3 h. The mixture was cooled to room temperature. NaOH (1.9 mL, 1.0 M aqueous solution) was added, and the mixture was stirred at room temperature for 30 min. The reaction was quenched with water (5 mL), acidified to pH ~4-5 with aqueous HCl (1 M), and extracted with EtOAc (3 mL x 3). The combined organic phases were washed with brine (5 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-TLC (DCM / MeOH = 10 / 1) to give compound 1 as a white solid (20 mg, 42.4 μmol, 6.6% yield).

[0935] TLC:DCM / MeOH=10 / 1(v / v), Rf=0.15

[0936] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.65 (s, 1H), 7.84 (s, 1H), 7.76 (d, J =5.5 Hz, 1H), 7.64 (d, J = 5.5 Hz, 2H), 7.15 (s, 1H), 7.11 (s, 2H), 6.98 –6.84 (m, 2H), 4.74 (s, 2H), 4.13 (s, 2H).

[0937] Example 2

[0938] 2-(3,5-Dichloro-4-((3'-ethyl-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetic acid Synthesis of ester (compound 2)

[0939]

[0940] A mixture of 3-ethylphenylboronic acid (101 mg, 0.64 mmol), intermediate A7 (300 mg, 0.57 mmol), 2NNaHCO3 (1 mL, 1.92 mmol), and Pd(dppf)Cl2 (47 mg, 0.06 mmol) in 1,4-dioxane (5 mL) was incubated at 70°C under a N2 atmosphere. o Stir at C for 8 hours. Concentrate the mixture under vacuum. Purify the residue by reversed-phase column chromatography to give compound 2 (57 mg, 19% yield) as a yellow oil.

[0941] TLC: Petroleum ether / EtOAc = 1 / 5 (v / v), Rf = 0.45

[0942] 1 H NMR: (400 MHz, DMSO) δ 9.33 (s, 1H), 7.27 (m, 3H), 7.15 (s, 2H), 7.12 (d, J = 7.0 Hz, 1H), 7.02 (s, 1H), 6.89 (d, J = 8.3 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 4.89 (s, 2H), 4.11 (s, 2H), 3.71 (s, 3H), 2.63 (q, J = 7.5 Hz, 2H), 1.22 – 1.14 (m, 3H).

[0943] Example 3

[0944] 2-(3,5-Dichloro-4-((3'-ethyl-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetic acid (Chemical) Synthesis of compound 3)

[0945]

[0946] Sodium bicarbonate (642 μL, 2 M aqueous solution) was added to a solution of intermediate A7 (200 mg, 428 μol), 3-ethylphenylboronic acid (96 mg, 642 μol), and Pd(dppf)Cl2 (31 mg, 43 μol) in dioxane (5 mL) at room temperature. The mixture was heated to 70°C and stirred overnight. The mixture was cooled to room temperature. NaOH (1.3 mL, 1 M aqueous solution) was added, and the resulting mixture was stirred for 30 min. The reaction was quenched with water (10 mL), acidified to pH 4-5 with aqueous HCl (1 M), and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-HPLC to give compound 3 (30 mg, 67 μol, 15.7% yield) as a white solid.

[0947] TLC:DCM / MeOH=10 / 1(v / v), Rf=0.26

[0948] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.34 (s, 1H), 7.35 – 7.22 (m, 3H), 7.13(d, J = 2.2 Hz, 1H), 7.10 (s, 2H), 7.03 (d, J = 2.2 Hz, 1H), 6.88 (dd, J =8.3, 2.2 Hz, 1H), 6.83 (d, J = 8.3 Hz, 1H), 4.75 (s, 2H), 4.11 (s, 2H), 2.62(q, J = 7.6 Hz, 2H), 1.19 (t, J = 7.6 Hz, 3H).

[0949] Example 4

[0950] 2-(3,5-Dichloro-4-((3'-ethyl-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenoxy)N-methyl Synthesis of acetamide (compound 4)

[0951]

[0952] Add 1N MeNH2 aqueous solution (1.3 mL, 1.30 mmol) to a solution of compound 2 (57 mg, 0.13 mmol) in THF (2 mL) at room temperature; incubate the resulting mixture at 75°C. oThe mixture was stirred overnight at C. The reaction was concentrated under vacuum and purified by Prep-TLC (DCM / MeOH = 20 / 1, v / v) to give compound 4 (37 mg, 65% yield) as a pale yellow oil.

[0953] TLC: petroleum ether / EtOAc = 1 / 5 (v / v), Rf = 0.4

[0954] 1 H NMR: (400 MHz, DMSO) δ 9.34 (s, 1H), 8.05 (d, J = 4.7 Hz, 1H), 7.31– 7.22 (m, 3H), 7.14 (s, 2H), 7.13 – 7.10 (m, 1H), 7.02 (d, J = 2.3 Hz, 1H), 6.89 (m, 1H), 6.82 (d, J = 8.3 Hz, 1H), 4.53 (s, 2H), 4.11 (s, 2H), 2.64 (d, J = 4.6 Hz, 3H), 2.63 – 2.58 (m, 2H), 1.19 (t, J = 7.6 Hz, 3H).

[0955] LCMS: RT=4.10 min; [M+1]=443.

[0956] Example 5

[0957] 2-(3,5-Dichloro-4-((3'-(difluoromethoxy)-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenoxy Synthesis of hydroxyacetic acid (compound 5)

[0958]

[0959] To a solution of intermediate B1 (173 mg, 642 μmol), intermediate A7 (300 mg, 642 μmol), and Pd(dppf)Cl2 (23 mg, 32 μmol) in 1,4-dioxane (10 mL) at room temperature, NaHCO3 (0.96 mL, 2 M aqueous solution) was added. The mixture was heated to 70°C and stirred overnight. The reaction was cooled to room temperature. NaOH (1.25 mL, 1 N aqueous solution) was added, and the mixture was stirred at room temperature for 30 min. The reaction was quenched with water (10 mL), acidified to pH 4-5 with aqueous HCl (1 M), and extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-HPLC to give compound 5 as a white solid (40 mg, 85.2 μmol, 20% yield).

[0960] TLC:DCM / MeOH=10 / 1(v / v), Rf=0.2

[0961] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.10 (s, 1H), 9.55 (s, 1H), 7.45 – 7.42(t, J =8.0 Hz, 1H), 7.24 (t, J =74.0 Hz, 1H), 7.37 – 7.28 (m, 2H), 7.12 (s,1H), 7.12 – 7.05 (m, 3H), 6.92 (dd, J = 8.4, 2.3 Hz, 1H), 6.86 (d, J = 8.3Hz, 1H), 4.77 (s, 2H), 4.12 (s, 2H).

[0962] Example 6

[0963] 2-(3,5-Dichloro-4-((3'-(ethoxycarbonyl)-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenoxy) Synthesis of acetic acid (compound 6)

[0964]

[0965] To a mixture of intermediate A7 (200 mg, 428 μmol), 3-ethoxycarbonylphenylboronic acid (125 mg, 644 μmol), and Pd(dppf)Cl2·CH2Cl2 (35 mg, 43 μmol) in 1,4-dioxane (3.0 mL) at room temperature, an aqueous solution of NaHCO3 (2 M, 0.5 mL) was added. The mixture was heated to 70°C overnight. The reaction mixture was cooled to room temperature. NaOH (1 M, 0.4 mL) was added, and the resulting mixture was stirred for 30 min. The reaction was quenched with water (10 mL), acidified to pH ~4-5 with aqueous HCl (1 M), and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-HPLC to give compound 6 (30 mg, 14% yield) as a white solid.

[0966] TLC:MeOH / DCM=1 / 10(v / v), Rf=0.20

[0967] LCMS:RT=3.997 min; [M-1]=472.8

[0968] 1 H NMR: (400 MHz, DMSO) δ 9.58 (s, 1H), 8.10 (s, 1H), 7.88 (d, J = 7.6Hz, 1H), 7.74 (d, J = 7.4 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.12 (s, 1H), 7.09 (d, J = 1.8 Hz, 1H), 6.94 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.77 (s, 1H), 4.33 (dd, J = 14.2, 7.0 Hz, 1H), 4.13 (s, 1H), 1.33 (t, J = 7.0Hz, 1H).

[0969] Example 7

[0970] 2-(3,5-Dichloro-4-((6-hydroxy-3'-methoxy-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetic acid Synthesis of (Compound 7)

[0971]

[0972] To a mixture of intermediate A7 (250 mg, 540 μmol), 3-methoxyphenylboronic acid (122 mg, 800 μmol), and Pd(dppf)Cl2·CH2Cl2 (39 mg, 54 μmol) in 1,4-dioxane (5.0 mL) at room temperature, an aqueous solution of NaHCO3 (2 M, 0.5 mL) was added. The mixture was heated to 70°C and stirred overnight. The reaction mixture was cooled to room temperature; LiOH·H2O (67 mg, 1.6 mmol) was added, and the mixture was stirred for 30 min. The reaction was quenched with water (10 mL), acidified to pH 4–5 with aqueous HCl (1 M), and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-HPLC to give compound 7 (30 mg, 29% yield) as a white solid.

[0973] TLC:MeOH / DCM=1 / 10(v / v), Rf=0.20

[0974] LCMS:RT=3.887 min; [M-1]=430.8

[0975] 1 H NMR: (400 MHz, DMSO) δ 13.11 (s, 1H), 9.40 (s, 1H), 7.29 (dd, J =10.2, 6.0 Hz, 1H), 7.12 (s, 1H), 7.05 – 7.00 (m, 1H), 6.93 – 6.89 (m, 1H), 6.85 (dd, J = 14.0, 5.0 Hz, 1H), 4.77 (s, 1H), 4.11 (s, 1H), 3.76 (s, 1H).

[0976] Example 8

[0977] 2-(3,5-Dichloro-4-((6-hydroxy-3'-(hydroxymethyl)-[1,1'-biphenyl]-3-yl)methyl)phenoxy) Synthesis of acetic acid (compound 8)

[0978]

[0979] A mixture of intermediate A7 (200 mg, 428 μmol), 3-hydroxymethyl-phenylboronic acid (78 mg, 514 μmol), Pd(dppf)Cl2 (31 mg, 43 μmol), and NaHCO3 (aqueous solution) (1 M, 1 mL) in 1,4-dioxane (3 mL) was stirred overnight at 75°C. The mixture was cooled to room temperature, LiOH·H2O (54 mg, 1.3 mmol) was added, and the mixture was stirred at room temperature for 30 min. Water (10 mL) was added, the pH was adjusted to ~4-5 with 1N HCl, and the mixture was extracted with EtOAc (10 mL * 2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by Prep-HPLC to give compound 8 (50 mg, 27% yield) as a pale yellow solid.

[0980] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0

[0981] LCMS:RT=3.298 min; [M-1]=430.8 / 432.8

[0982] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.13 (s, 1H), 9.35 (s, 1H), 7.42 (s, 1H), 7.34 – 7.29 (m, 2H), 7.24 – 7.19 (m, 1H), 7.11 (s, 2H), 7.03 (d, J = 2.0 Hz, 1H), 6.89 (dd, J = 8.4, 2.2 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 5.17 (s, 1H), 4.75 (s, 2H), 4.51 (s, 2H), 4.11 (s, 2H).

[0983] Example 9

[0984] 2-(4-((3'-acetamido-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3,5-dichlorophenoxy)ethyl Synthesis of acid (compound 9)

[0985]

[0986] To a mixture of intermediate A7 (200 mg, 428 μmol), 3-acetamido-phenylboronic acid (115 mg, 642 μmol), and Pd(dppf)Cl2·CH2Cl2 (39 mg, 54 μmol) in 1,4-dioxane (5.0 mL) at room temperature, an aqueous solution of NaHCO3 (2 M, 0.5 mL) was added. The mixture was heated to 70°C and stirred overnight. The reaction was cooled to room temperature; LiOH·H2O (55 mg, 1.3 mmol) was added, and the resulting mixture was stirred for 30 min. The reaction was quenched by adding water (10 mL); the mixture was acidified to pH ~4-5 with an aqueous solution of HCl (1 M) and extracted with EtOAc (5 mL * 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-HPLC to give compound 9 as a white solid (10 mg, 5% yield).

[0987] TLC:MeOH / DCM=1 / 10(v / v), Rf=0.15

[0988] LCMS:RT=3.276 min; [M-1]=457.9

[0989] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.94 (s, 1H), 8.86 (s, 1H), 7.19 (dd, J =4.4, 2.0 Hz, 4H), 6.65 (d, J = 8.4 Hz, 1H), 6.48 (d, J = 8.4 Hz, 1H), 6.19(d, J = 8.4 Hz, 1H), 6.07 (d, J = 8.4 Hz, 1H), 5.24 – 5.21 (m, 1H), 4.93 (d, J = 3.6 Hz, 4H), 4.69 (dd, J = 2.4, 1.1 Hz, 1H), 4.05 (s, 2H), 3.97 (s, 2H), 3.72 (d, J = 0.8 Hz, 4H), 2.45 (s, 2H), 2.23 (s, 3H), 1.93 (s, 3H).

[0990] Example 10

[0991] 2-(4-((3'-acetyl-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3,5-dichlorophenoxy)acetic acid Synthesis of methyl ester (compound 10)

[0992]

[0993] To a solution of intermediate A7 (200 mg, 0.43 mmol) in 1,4-dioxane (3 mL) at room temperature, 3-acetylphenylboronic acid (106 mg, 0.65 mmol), Pd(dppf)Cl2 (29 mg, 0.04 mmol), and NaHCO3(2N) (1.29 mmol, 0.6 mL) were added. The mixture was stirred overnight at 85 °C, then diluted with EtOAc (20 mL) and filtered. The filtrate was washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by Prep-HPLC to give compound 10 (17 mg, 9% yield) as a white solid.

[0994] TLC: petroleum ether / EtOAc = 5 / 1 (v / v), Rf=0.6

[0995] Example 11

[0996] 2-(4-((3'-acetyl-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3,5-dichlorophenoxy)acetic acid Synthesis of (Compound 11)

[0997]

[0998] LiOH·H₂O (5 mg, 0.12 mmol) was added to a solution of compound 10 (17 mg, 0.04 mmol) in THF (3 mL) and water (2 mL). The mixture was stirred at room temperature for 2 h. The pH was adjusted to approximately 4 with 1 N HCl, and the resulting mixture was extracted with EtOAc (20 mL x 2). The organic layer was washed with brine (20 mL), dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by Prep-HPLC to give compound 11 (8 mg, 44% yield) as a white solid.

[0999] TLC:DCM / MeOH=10 / 1(v / v), Rf=0.1

[1000] LCMS: RT=3.744 min; [M-1]=442.8

[1001] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.76 (s, 1H), 8.05 (s, 1H), 7.88 (d,J =7.8 Hz, 1H), 7.73 (d, J = 7.8 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.11 (s,1H), 6.94 (d, J = 16.0 Hz, 4H), 4.28 (s, 2H), 4.11 (s, 2H), 2.60 (s, 3H).

[1002] Example 12

[1003] 2-(3,5-Dichloro-4-((6-hydroxy-3'-(trifluoromethoxy)-[1,1'-biphenyl]-3-yl)methyl)phenoxy Synthesis of hydroxyacetic acid (compound 12)

[1004]

[1005] A solution of intermediate A7 (200 mg, 0.43 mmol), Pd(dppf)Cl2 (35 mg, 0.64 mmol), NaHCO3 (108 mg, 1.28 mmol), and 3-trifluoromethoxyphenylboronic acid (132 mg, 0.64 mmol) in H2O (0.5 mL) and 1,4-dioxane (5 mL) was refluxed overnight. The mixture was cooled to room temperature; LiOH·H2O (54 mg, 1.28 mmol) was added, and the resulting mixture was stirred at room temperature for 30 min. Water (10 mL) was added, and the mixture was extracted with ether (10 mL x 2); the aqueous phase was adjusted to pH ~3 with HCl (1N), and then extracted again with EtOAc (10 mL x 2). The combined EtOAc phases were washed with brine (5 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-HPLC (MeCN / H2O) to give compound 12 (5 mg, 2% yield) as a white solid.

[1006] TLC: Petroleum ether / EtOAc = 5 / 1 (v / v), Rf = 0.1

[1007] LCMS:RT=4.21 min; [M-1]=485

[1008] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.13 (s, 1H), 9.66 (s, 1H), 7.53 – 7.47 (m, 4H), 7.28 (d, J = 7.8 Hz, 1H), 7.11 (d, J= 3.8 Hz, 3H), 6.95 – 6.91 (m,1H), 6.87 (d, J = 8.4 Hz, 1H), 4.73 (s, 2H), 4.12 (s, 2H).

[1009] Example 13

[1010] 2-(3,5-Dichloro-4-((6-hydroxy-3'-isopropyl-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetic acid Synthesis of (Compound 13)

[1011]

[1012] To a mixture of intermediate A7 (200 mg, 428 μmol), 3-isopropylphenylboronic acid (105 mg, 642 μmol), and Pd(dppf)Cl2·CH2Cl2 (39 mg, 54 μmol) in 1,4-dioxane (5.0 mL) at room temperature, an aqueous solution of NaHCO3 (2 M, 0.5 mL) was added. The mixture was heated to 70°C and stirred overnight. The reaction mixture was cooled to room temperature; LiOH·H2O (55 mg, 1.3 mmol) was added, and the resulting mixture was stirred for 30 min. The reaction mixture was quenched with water (10 mL), acidified to pH 4–5 with an aqueous solution of HCl (1 M), and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-HPLC (MeCN / H2O) to give compound 13 (25 mg, 13% yield) as a white solid.

[1013] TLC:MeOH / DCM=1 / 10(v / v), Rf=0.3

[1014] LCMS:RT=4.358 min; [M-1]=442.9

[1015] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.11 (s, 1H), 9.36 (s, 1H), 7.34 – 7.25 (m, 3H), 7.15 (d, J = 6.8 Hz, 1H), 7.12 (s, 2H), 7.03 (d, J = 2.2 Hz, 1H), 6.89 (dd, J = 8.4, 2.4 Hz, 1H), 6.82 (d, J= 8.4 Hz, 1H), 4.76 (s, 2H), 4.11(s, 2H), 2.90 (p, J = 6.8 Hz, 1H), 1.22 (d, J = 6.8 Hz, 6H).

[1016] Example 14

[1017] 2-(3,5-Dichloro-4-((6-hydroxy-3'-(methylsulfonyl)-[1,1'-biphenyl]-3-yl)methyl)phenoxy Synthesis of hydroxyacetic acid (compound 14)

[1018]

[1019] Under a nitrogen atmosphere, Pd(dppf)Cl2 (31 mg, 0.04 mmol) was added to a solution of intermediate A7 (200 mg, 0.40 mmol), 3-methylsulfonyl-phenylboronic acid (128 mg, 0.60 mmol), and NaHCO3 (2 M, 0.5 mL) in 1,4-dioxane (3 mL) at room temperature. The resulting mixture was heated at 70°C overnight. The reaction mixture was cooled to room temperature, LiOH·H2O (84 mg, 2.0 mmol) was added, and the resulting mixture was stirred at room temperature for 30 min. The reaction was quenched with water (10 mL), the pH was adjusted to pH 4-5 with 1N HCl, and the mixture was extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (10 mL x 2), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by Prep-TLC (methanol / DCM = 1 / 10) to give 87 mg of crude product. Compound 14 (21 mg, 10% yield) was further purified by Prep-HPLC (ACN / water range 20 / 80 to 90 / 10, 25 min) to give a grayish-white solid.

[1020] TLC:MeOH / DCM=1 / 10(v / v), Rf=0.21

[1021] LCMS:RT=3.39 min; [M-1]=478.8

[1022] 1 H NMR: (400 MHz, DMSO) δ 13.11 (s, 1H), 9.69 (s, 1H), 8.06 (t, J =2.0 Hz, 1H), 7.85-7.80 (m, 2H), 7.67 (t, J = 7.6 Hz, 1H), 7.17 (d, J= 2.0Hz, 1H), 7.12 (s, 2H), 6.93 (dd, J = 8.4, 2.4 Hz, 1H), 6.88 (d, J = 8.4 Hz,1H), 4.78 (s, 2H), 4.14 (s, 2H), 3.23 (s, 3H).

[1023] Example 15

[1024] 2-(3,5-Dichloro-4-((6-hydroxy-3'-(methoxymethyl)-[1,1'-biphenyl]-3-yl)methyl)phenoxy Synthesis of hydroxyacetic acid (compound 15)

[1025]

[1026] A solution of intermediate A7 (200 mg, 0.43 mmol), NaHCO3 (1.29 mmol, 0.6 mL), Pd(dppf)Cl2 (30 mg, 0.04 mmol), and 3-methoxymethyl-phenylboronic acid (106 mg, 0.64 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) was refluxed overnight. The mixture was cooled to room temperature; LiOH·H2O (54 mg, 1.29 mmol) was added, and the resulting mixture was stirred at room temperature for 30 min. Water (10 mL) was added, and the mixture was extracted with ether (10 mL x 2). The aqueous phase was adjusted to pH ~3 with HCl (1N), and then extracted again with EtOAc (10 mL x 2). The combined EtOAc phases were washed with brine (5 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-TLC (DCM / MeOH=10 / 1) and Prep-HPLC (MeCN / H2O) to give compound 15 (10 mg, 5% yield) as a white solid.

[1027] TLC: Petroleum ether / EtOAc = 5 / 1 (v / v), Rf = 0.1

[1028] LCMS:RT=3.77 min; [M-1]=444.8

[1029] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.11 (s, 1H), 9.40 (s, 1H), 7.42 (s, 1H), 7.36 (dd, J= 4.8, 2.1 Hz, 2H), 7.24 – 7.20 (m, 1H), 7.12 (s, 2H), 7.04 (d, J = 2.2 Hz, 1H), 6.89 (dd, J = 8.4, 2.2 Hz, 1H), 6.83 (d, J = 8.4 Hz, 1H), 4.77(s, 2H), 4.43 (s, 2H), 4.11 (s, 2H), 3.30 (s, 3H).

[1030] Example 16

[1031] 2-(3,5-dichloro-4-((6-hydroxy-3'-propyl-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetic acid (C) Synthesis of compound 16

[1032]

[1033] To a mixture of intermediate A7 (200 mg, 428 μmol), 3-n-propylphenylboronic acid (105 mg, 642 μmol), and Pd(dppf)Cl2·CH2Cl2 (39 mg, 54 μmol) in 1,4-dioxane (5.0 mL) at room temperature, an aqueous solution of NaHCO3 (2 M, 0.5 mL) was added. The mixture was heated to 70°C and stirred overnight. The reaction was cooled to room temperature; LiOH·H2O (55 mg, 1.3 mmol) was added, and the resulting mixture was stirred for 30 min. The reaction was quenched with water (10 mL), acidified to pH 4–5 with an aqueous solution of HCl (1 M), and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-HPLC (MeCN / H2O) to give compound 16 (35 mg, 18% yield) as a white solid.

[1034] TLC:MeOH / DCM=1 / 10(v / v), Rf=0.25

[1035] LCMS: RT=4.361 min; [M-1]=442.9

[1036] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.11 (s, 1H), 9.34 (s, 1H), 7.29 – 7.22 (m, 3H), 7.10 (s, 2H), 7.08 (dd, J= 4.0, 1.2 Hz, 1H), 7.02 (d, J = 2.0Hz, 1H), 6.87 (dd, J = 8.4, 2.4 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 4.75 (s, 2H), 4.09 (s, 2H), 2.55 (d, J = 7.6 Hz, 2H), 1.63 – 1.54 (m, 2H), 0.90 (t, J = 7.2Hz, 3H).

[1037] Example 17

[1038] 2-(3,5-Dichloro-4-((6-hydroxy-3'-methyl-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetic acid (C) Synthesis of compound 17)

[1039]

[1040] To a solution of intermediate A7 (200 mg, 428 μmol) in 1,4-dioxane (4 mL) at room temperature, Pd(dppf)Cl2 (34.97 mg, 42.82 μmol), NaHCO3 (2N, 1 mL), and toluene-3-boronic acid (87.3 mg, 642 μmol) were added. The mixture was heated to 70 °C overnight and then cooled to room temperature. LiOH·H2O (135 mg, 7.5 mmol) was added; the mixture was stirred at room temperature for 30 min, diluted with water (5 mL), acidified to pH ~4-5 with 1N HCl, and extracted with DCM (5 mL * 3). The combined organic phases were washed with brine (5 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by Prep-HPLC (ACN / water range 30 / 70 to 85 / 15) to give compound 17 (30 mg, 16% yield) as a grayish-white solid.

[1041] TLC:DCM / MeOH =10 / 1(v / v), Rf=0.33

[1042] LCMS: RT=2.441 min; [M-1] =414.8.

[1043] 1 H NMR: (400 MHz, DMSO- d6) δ 13.11 (s, 1H), 9.35 (s, 1H), 7.29 – 7.20 (m, 3H), 7.11 (s, 2H), 7.09 (d, J = 7.0 Hz, 1H), 7.02 (d, J = 2.2 Hz, 1H), 6.88 (dd, J = 8.3, 2.3 Hz, 1H), 6.82 (d, J = 8.3 Hz, 1H), 4.77 (s, 2H), 4.10 (s, 2H), 2.32 (s, 3H).

[1044] Example 18

[1045] 2-(3,5-Dichloro-4-((3'-cyano-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetic acid Synthesis of ester (compound 18)

[1046]

[1047] A mixture of 3-cyanophenylboronic acid (77 mg, 0.48 mmol), intermediate A7 (150 mg, 0.32 mmol), 2NNaHCO3 (0.48 mL, 0.96 mmol), and Pd(dppf)Cl2 (11 mg, 0.02 mmol) in 1,4-dioxane (2 mL) was incubated at 85°C under a N2 atmosphere. o Stir at C for 16 h. The resulting solution of compound 18 was used in the next step without further purification.

[1048] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.44

[1049] LCMS:RT=2.48 min; [M-1]=440.0

[1050] Example 19

[1051] 2-(3,5-Dichloro-4-((3'-cyano-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetic acid (C) Synthesis of compound 19

[1052]

[1053] LiOH (39 mg, 0.96 mmol) was added to a solution of compound 18 (141 mg, 0.32 mmol) dissolved in THF (1 mL) / water (5 mL) at room temperature; the resulting mixture was stirred at room temperature for 1 h. The reaction was acidified to pH ~6-7 with 2N HCl, concentrated under vacuum, and purified by Prep-HPLC to give compound 19 (10 mg, 10% yield) as a pale yellow solid.

[1054] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0

[1055] 1 H NMR: (400 MHz, DMSO) δ 13.07 (s, 1H), 9.68 (s, 1H), 7.92 (s, 1H), 7.80 (m, 1H), 7.75 (m, 1H), 7.60 (t, J = 7.8 Hz, 1H), 7.17 – 7.07 (m, 3H), 6.91 (m, 2H), 4.75 (s, 2H), 4.12 (s, 2H).

[1056] LCMS: RT=3.64 Min; [M-1]=427.

[1057] Example 20

[1058] 2-(3,5-Dichloro-4-((6-hydroxy-3'-vinyl-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetic acid Synthesis of methyl ester (compound 20)

[1059]

[1060] Under a nitrogen atmosphere, Pd(PPh3)2Cl2 (15 mg, 0.21 mmol) and K3PO4 (91 mg, 0.43 mmol) were added to a solution of intermediate A7 (100 mg, 0.21 mmol) and styrene-2-boronic acid (48 mg, 0.32 mmol) in 1,4-dioxane (3 mL) at room temperature. The mixture was heated to 70°C overnight. The reaction mixture was diluted with EtOAc (10 mL), washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by Prep-TLC (EtOAc / petroleum ether = 1 / 10) to give compound 20 (20 mg, 21% yield) as a pale yellow solid.

[1061] TLC:MeOH / DCM=1 / 10(v / v), Rf=0.41

[1062] LCMS:RT=2.97 min; [M-1]=441.0

[1063] Example 21

[1064] 2-(3,5-Dichloro-4-((6-hydroxy-3'-vinyl-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetic acid Synthesis of (Compound 21)

[1065]

[1066] To a solution of compound 20 (20 mg, 0.04 mmol) in water (0.5 mL) / THF (2 mL) at room temperature, LiOH·H₂O (4 mg, 0.08 mmol) was added; the resulting mixture was stirred overnight. The reaction mixture was diluted with water (10 mL), acidified with HCl (2N) to pH ~5, and extracted with EtOAc (5 mL * 2). The combined extracts were dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by Prep-TLC (methanol / DCM = 1 / 10) to give compound 21 (12 mg, 61% yield) as a white solid.

[1067] TLC: Methanol / DCM = 1 / 10 (v / v), Rf = 0.23

[1068] LCMS:RT=3.99 min; [M-1]=427.0

[1069] 1 H NMR: (400 MHz, DMSO) δ 9.53 (s, 1H), 7.53 (s, 1H), 7.45 – 7.31 (m,3H), 7.06 (s, 1H), 6.95 (s, 2H), 6.88 (s, 2H), 6.76 (dd, J = 17.6, 10.8 Hz, 1H), 5.82 (d, J = 17.6 Hz, 1H), 5.26 (d, J = 10.8 Hz, 1H), 4.24 (s, 2H), 4.09 (s, 2H).

[1070] Example 22

[1071] 2-(3,5-Dichloro-4-((6-hydroxy-3'-(prop-1-en-2-yl)-[1,1'-biphenyl]-3-yl)methyl)phenoxy Synthesis of hydroxyacetic acid (compound 22)

[1072]

[1073] A mixture of intermediate B2 (118 mg, 482 μmol), intermediate A7 (150 mg, 321 μmol), NaHCO3 (2 M, 0.48 mL), and Pd(dppf)Cl2 (24 mg, 32.1 μmol) in 1,4-dioxane (2 mL) was stirred overnight at 100 °C. The mixture was cooled to room temperature; LiOH·H2O (40 mg, 963 μmol) was added, and the mixture was stirred for 1 h. The mixture was acidified to pH ~5-6 with 1N HCl; water (30 mL) was added, and the mixture was extracted with EtOAc (25 mL * 2). The combined organic layers were washed with water (25 mL), then with brine (50 mL), dried over Na2SO4, and purified by Prep-HPLC to give compound 22 (20 mg, 14% yield) as a white solid.

[1074] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0

[1075] LCMS:RT=4.151 min; [M-1]=441.0 / 443.0

[1076] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.08 (s, 1H), 9.39 (s, 1H), 7.57 (d, J =2.1 Hz, 1H), 7.44 – 7.31 (m, 3H), 7.11 (s, 2H), 7.06 (d, J = 2.2 Hz, 1H), 6.91 (dd, J = 8.3, 2.3 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 5.41 (s, 1H), 5.11(t, J = 1.6 Hz, 1H), 4.77 (s, 2H), 4.12 (s, 2H), 2.12 (s, 3H).

[1077] Example 23

[1078] 2-(3,5-Dichloro-4-((3'-formyl-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetic acid Synthesis of methyl ester (compound 23)

[1079]

[1080] To a mixture of intermediate A7 (500 mg, 1.0 mmol), 2-formylphenylboronic acid (225 mg, 1.5 mmol), and Pd(dppf)Cl2·CH2Cl2 (82 mg, 100 μmol) in 1,4-dioxane (5.0 mL) at room temperature, an aqueous solution of NaHCO3 (2 M, 1.5 mL) was added. The mixture was heated to 70°C overnight. The reaction mixture was cooled to room temperature, quenched with water (10 mL), acidified to pH ~4-5 with an aqueous solution of HCl (1 M), and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-TLC (petroleum ether / EtOAc = 5 / 1) to give compound 23 (130 mg, 27% yield) as a white solid.

[1081] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.3

[1082] LCMS:RT=2.018 min; [M-1]=457.1

[1083] 1 H NMR: (400 MHz, DMSO- d 6) δ 10.05 (s, 1H), 9.60 (s, 1H), 8.03 (s, 1H),7.86 – 7.75 (m, 2H), 7.63 (t, J = 7.6 Hz, 1H), 7.15 (s, 2H), 7.13 (s, 1H),6.92 (s, 1H), 6.89 (s, 1H), 4.88 (s, 2H), 4.21 – 4.15 (m, 2H), 4.14 (s, 2H),1.19 (t, J = 7.2 Hz, 3H).

[1084] Example 24

[1085] 2-(3,5-Dichloro-4-((3'-ethynyl-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetic acid Synthesis of methyl ester (compound 24)

[1086]

[1087] To a mixture of compound 23 (120 mg, 261 μmol) and K₂CO₃ (72 mg, 523 μmol) in MeOH (1 mL) and THF (1 mL), 1-dimethylphosphono-1-diazo-acetone (60 mg, 314 μmol) was added. The mixture was stirred overnight at room temperature. Water (10 mL) was added, and the resulting mixture was extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na₂SO₄, and concentrated under vacuum. The crude product was purified by Prep-TLC (EtOAc / petroleum ether = 1 / 3) to give compound 24 (50 mg, 42% yield) as a pale yellow oil.

[1088] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.35

[1089] Example 25

[1090] 2-(3,5-Dichloro-4-((3'-ethynyl-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetic acid Synthesis of (Compound 25)

[1091]

[1092] LiOH·H2O (14 mg, 330 μmol) was added to a solution of compound 24 (50 mg, 110 μmol) in THF / H2O (1 mL / 0.5 mL) at room temperature. The mixture was stirred at room temperature for 1 h. The mixture was diluted with water (5 mL), acidified to pH 4–5 with 1 N HCl, and extracted with EtOAc (3 mL x 3). The combined organic phases were washed with brine (5 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by Prep-HPLC (MeCN / H2O) to give compound 25 (10 mg, 21% yield) as a white solid.

[1093] TLC:MeOH / DCM =1 / 10(v / v), Rf=0.30

[1094] LCMS:RT=1.691min; [M-1]=425.0

[1095] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.52 (s, 1H), 7.58 (d, J = 1.6 Hz, 1H), 7.49 (dt, J= 6.4, 2.4 Hz, 1H), 7.43 – 7.38 (m, 2H), 7.12 (s, 2H), 7.07 (d, J = 2.4 Hz, 1H), 6.91 (dd, J = 8.4, 2.4 Hz, 1H), 6.85 (d, J = 8.4 Hz, 1H), 4.77(s, 2H), 4.17 (s, 1H), 4.12 (s, 2H).

[1096] Example 26

[1097] 2-(3,5-Dichloro-4-((6-hydroxy-3'-(2,2,2-trifluoroethyl)-[1,1'-biphenyl]-3-yl)methyl)benzene Synthesis of (oxy)acetic acid (compound 26)

[1098]

[1099] A mixture of intermediates B3 (138 mg, 482 μmol), A7 (150 mg, 321 μmol), NaHCO3 (2 M, 0.48 mL), and Pd(dppf)Cl2 (24 mg, 32.1 μmol) in 1,4-dioxane (2 mL) was stirred overnight at 100 °C. The mixture was cooled to room temperature; LiOH·H2O (40 mg, 963 μmol) was added, and the resulting mixture was stirred for 1 h. The mixture was acidified to pH ~5-6 with 1N HCl; water (30 mL) was added, and the mixture was extracted with EtOAc (25 mL * 2). The combined organic layers were washed with water (25 mL), then with brine (50 mL), dried over Na2SO4, and purified by Prep-HPLC to give compound 26 (20 mg, 13% yield) as a white solid.

[1100] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0

[1101] LCMS:RT=3.884 min; [M-1]=483.0 / 484.9

[1102] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.04 (s, 1H), 9.45 (s, 1H), 7.45 (d, J =10.6 Hz, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.27 (d,J = 7.5 Hz, 1H), 7.11 (s,2H), 7.05 (d, J = 2.1 Hz, 1H), 6.90 (dd, J = 8.2, 2.2 Hz, 1H), 6.84 (d, J =8.3 Hz, 1H), 4.77 (s, 2H), 4.11 (s, 2H), 3.67 (q, J = 11.6 Hz, 2H).

[1103] Example 27

[1104] 2-(3,5-Dichloro-4-((6-hydroxy-3'-(perfluoroethyl)-[1,1'-biphenyl]-3-yl)methyl)phenoxy) Synthesis of methyl acetate (compound 27)

[1105]

[1106] Pd(dppf)Cl2 (66 mg, 0.09 mmol) was added to a solution of intermediate A7 (300 mg, 0.64 mmol), intermediate B4 (310 mg, 0.96 mmol), and NaHCO3 (2 M, 1 mL) in 1,4-dioxane (10 mL) at room temperature. The mixture was refluxed overnight. The mixture was cooled to room temperature, poured into water (10 mL), and extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-HPLC (MeCN / H2O) to give compound 27 (30 mg, 16% yield) as a white solid.

[1107] TLC: Petroleum ether / EtOAc = 5 / 1 (v / v), Rf = 0.4

[1108] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.68 (s, 1H), 7.80 (d, J = 7.2 Hz, 2H), 7.67 (t, J = 7.8 Hz, 1H), 7.61 (d, J = 7.8 Hz, 1H), 7.16 (s, 2H), 7.12 (d, J = 2.2 Hz, 1H), 6.95 (dd, J = 8.4, 2.4 Hz, 1H), 6.87 (d, J= 8.4 Hz, 1H), 4.89 (s, 2H), 4.13 (s, 2H), 3.70 (s, 3H).

[1109] Example 28

[1110] 2-(3,5-Dichloro-4-((6-hydroxy-3'-(perfluoroethyl)-[1,1'-biphenyl]-3-yl)methyl)phenoxy) Synthesis of acetic acid (compound 28)

[1111]

[1112] A solution of LiOH·H₂O (13 mg, 0.30 mmol) in water (0.2 mL) was added to a solution of compound 27 (30 mg, 0.05 mmol) in THF (5 mL); the mixture was stirred at room temperature for 2 h. Water (5 mL) was added, and the reaction was acidified to pH ~6-7 with 2N HCl, followed by extraction with EtOAc (10 mL * 2). The combined organic phases were washed with brine (20 mL), dried over Na₂SO₄, concentrated under vacuum, and purified by Prep-HPLC (MeCN / H₂O) to give compound 28 (25 mg, 85% yield) as a white solid.

[1113] TLC: petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.1

[1114] LCMS:RT=4.253 min; [M-1]=519

[1115] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.08 (s, 1H), 9.66 (s, 1H), 7.82 – 7.76 (m, 2H), 7.69 – 7.59 (m, 2H), 7.13 (d, J = 2.4 Hz, 1H), 7.12 (s, 2H), 6.95(dd, J = 8.4, 2.3 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.77 (s, 2H), 4.13 (s, 2H).

[1116] Example 29

[1117] 2-(3,5-dichloro-4-((3'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetic acid (compound) Synthesis of substance 29

[1118]

[1119] To a solution of intermediate A7 (150 mg, 321 μmol) in 1,4-dioxane (3 mL) at room temperature, Pd(dppf)Cl2 (27 mg, 32 μmol), NaHCO3 (2N, 1 mL), and 3-chlorophenylboronic acid (76 mg, 482 μmol) were added. The mixture was heated to 70 °C overnight. The mixture was cooled to room temperature, LiOH·H2O (67 mg, 1.6 mmol) was added, and the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was diluted with water (5 mL), acidified to pH ~3 with 1N HCl, and extracted with DCM (5 mL * 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by Prep-HPLC to give compound 29 (40 mg, 28% yield) as a grayish-white solid.

[1120] TLC:DCM / MeOH =10 / 1(v / v), Rf=0.33

[1121] LCMS: RT=2.319 min; [M-1]=435.

[1122] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.61 (s, 1H), 7.53 (q, J = 1.3 Hz, 1H),7.44 – 7.39 (m, 2H), 7.35 (dt, J = 6.5, 2.4 Hz, 1H), 7.12 (s, 2H), 7.09 (d, J = 2.2 Hz, 1H), 6.92 (dd, J = 8.3, 2.2 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 4.78 (s, 2H), 4.11 (s, 2H).

[1123] Example 30

[1124] 2-(3,5-dichloro-4-((3'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetic acid methyl ester Synthesis of (Compound 30)

[1125]

[1126] To a solution of intermediate A7 (500 mg, 1.07 mmol) in 1,4-dioxane (5 mL) at room temperature, Pd(dppf)Cl2 (88 mg, 107 μmol), NaHCO3 (2N, 1 mL), and 3-chlorophenylboronic acid (251 mg, 1.61 mmol) were added. The mixture was heated to 70 °C overnight. The mixture was diluted with water (5 mL), acidified with 1N HCl to pH < 7, and extracted with DCM (5 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by Prep-HPLC to give compound 30 (200 mg, 41% yield) as a grayish-white solid.

[1127] TLC: petroleum ether / EtOAc = 5 / 1 (v / v), Rf = 0.44

[1128] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.58 (s, 1H), 7.54 – 7.52 (m, 1H), 7.41(dd, J = 5.0, 1.9 Hz, 2H), 7.37 – 7.32 (m, 1H), 7.16 (s, 2H), 7.08 (d, J =2.0 Hz, 1H), 6.92 (dd, J = 8.3, 2.2 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 4.89 (s, 2H), 4.12 (s, 2H), 3.70 (s, 3H).

[1129] Example 31

[1130] 2-(3,5-dichloro-4-((3'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenoxy)- N -First Synthesis of methylacetamide (compound 31)

[1131]

[1132] To a solution of compound 30 (100 mg, 221 μmol) in THF (0.5 mL) at room temperature, an aqueous solution of methylamine (40% wt / wt, 1.5 mL) was added. The mixture was heated to 70°C overnight in a sealed tube, then cooled to room temperature, diluted with water (10 mL), and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (20 mL), dried over Na₂SO₄, and concentrated under vacuum. The crude product was purified by Prep-TLC (MeOH / DCM = 1 / 30) to give compound 31 (20 mg, 20% yield) as a brown solid.

[1133] TLC:DCM / MeOH =5 / 1(v / v), Rf=0.44

[1134] LCMS:RT=4.059; [M-1]=448.

[1135] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.57 (s, 1H), 8.05 (s, 1H), 7.55 – 7.51 (m, 1H), 7.44 – 7.39 (m, 2H), 7.35 (dt, J = 6.4, 2.4 Hz, 1H), 7.15 (s, 2H), 7.08 (d, J = 2.2 Hz, 1H), 6.96 – 6.89 (m, 1H), 6.86 (d, J = 8.3 Hz, 1H), 4.54(s, 2H), 4.12 (s, 2H), 2.65 (d, J = 4.6 Hz, 3H).

[1136] Example 32

[1137] 2-(3,5-dichloro-4-((3'-chloro-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenoxy)- N,N - Synthesis of dimethylacetamide (compound 32)

[1138]

[1139] Add one drop of DMF and oxaloyl chloride (46 mg, 366 μmol) to a solution of compound 29 (80 mg, 183 μmol) in DCM (2 mL) cooled in an ice bath. Stir the mixture at room temperature for 2 h and concentrate under vacuum. Add the crude product (80 mg, 175 μmol) from DCM (1 mL) to a solution of methylamine (2 mL, 34 mmol) in DCM (3 mL) stirred in an ice bath. Heat the mixture to room temperature and stir for 2 h, then concentrate under vacuum. Purify the crude product by Prep-TLC (MeOH / DCM = 1 / 30) to give compound 32 (50 mg, 61% yield) as a grayish-white solid.

[1140] TLC:DCM / MeOH =30 / 1(v / v), Rf=0.34

[1141] LCMS:RT=4.109; [M-1]=462.

[1142] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.57 (s, 1H), 7.56 – 7.50 (m, 1H), 7.39-7.45 (m, 2H), 7.32-7.36 (m, 1H), 7.10 (s, 2H), 7.09 (d, J = 2.2 Hz, 1H), 6.92(dd, J = 8.4, 2.3 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 4.90 (s, 2H), 4.11 (s, 2H), 2.96 (s, 3H), 2.84 (s, 3H).

[1143] Example 33

[1144] 2-(3,5-Dichloro-4-(4-hydroxy-3-(thiophen-2-yl)benzyl)phenoxy)methyl acetate (compound 33) Synthesis

[1145]

[1146] Thiophene-2-boronic acid (82 mg, 0.64 mmol), Pd(dppf)Cl2 (32 mg, 0.04 mmol), and NaHCO3(2N) (1.29 mmol, 0.6 mL) were added to a room temperature solution of intermediate A7 (200 mg, 0.43 mmol) in 1,4-dioxane (3 mL). The mixture was stirred overnight at 85°C. The mixture was diluted with EtOAc (20 mL) and filtered. The filtrate was washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to give compound 33 (100 mg, 55% yield), which was used without further purification.

[1147] TLC: Petroleum ether / EtOAc = 5 / 1 (v / v), Rf = 0.4

[1148] LCMS:RT=4.333 min; [M-1]=421.0

[1149] Example 34

[1150] Synthesis of 2-(3,5-dichloro-4-(4-hydroxy-3-(thiophen-2-yl)benzyl)phenoxy)acetic acid (compound 34)

[1151]

[1152] LiOH·H2O (44 mg, 1.05 mmol) was added to a solution of compound 33 (100 mg, 0.35 mmol) in THF (3 mL) and H2O (2 mL). The mixture was stirred at room temperature for 2 h; the pH was adjusted to approximately 4 with 1 N HCl. The aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by Prep-HPLC to give compound 34 (40 mg, 28% yield) as a white solid.

[1153] TLC:DCM / MeOH=10 / 1(v / v), Rf=0.2

[1154] LCMS:RT=3.857 min; [M-1]=407.0

[1155] 1 H NMR: (400 MHz, DMSO- d 6) δ 12.99 (s, 1H), 10.01 (s, 1H), 7.47 (d, J=3.6 Hz, 1H), 7.45 (s, 1H), 7.40 (s, 1H), 7.13 (s, 2H), 7.07 (t, J =4.8 Hz,1H), 6.85 (s, 2H), 4.78 (s, 2H), 4.11 (s, 2H).

[1156] Example 35

[1157] 2-(3,5-Dichloro-4-(3-(4-chlorothiophen-2-yl)-4-hydroxybenzyl)phenoxy)methyl acetate (compound) Synthesis of 35)

[1158]

[1159] To a solution of intermediate A7 (150 mg, 0.31 mmol) and intermediate B5 (152 mg, 0.62 mmol) in water (1 mL) and 1,4-dioxane (6 mL) at room temperature, NaHCO3 (52 mg, 0.62 mmol) and Pd(dppf)Cl2 (11 mg, 15.6 μmol) were added. The reaction was stirred overnight at 75°C. The mixture was concentrated under vacuum. The residue was purified by Prep-HPLC to give compound 35 (30 mg, 20% yield) as a pale yellow solid.

[1160] TLC: EtOAc / petroleum ether = 1 / 5, Rf = 0.52

[1161] Example 36

[1162] 2-(3,5-dichloro-4-(3-(4-chlorothiophen-2-yl)-4-hydroxybenzyl)phenoxy)acetic acid (compound 36) synthesis

[1163]

[1164] To a solution of compound 35 (100 mg, 0.21 mmol) in water (2 mL) / THF (4 mL) at room temperature, NaOH (34 mg, 0.84 mmol) was added; the resulting mixture was stirred overnight at room temperature. The reaction mixture was acidified to pH ~3 with HCl (1N) and extracted with EtOAc (10 mL * 3); the combined organic phases were dried over Na₂SO₄ and concentrated under vacuum. The crude product was purified by Prep-TLC (methanol / DCM = 1 / 10) to give compound 36 (25 mg, 26% yield) as a white solid.

[1165] TLC: EtOAc / petroleum ether = 1 / 5, Rf = 0.21

[1166] LCMS:RT=3.92 min; [M-1]:=440.9

[1167] 1 H NMR: (400 MHz, DMSO- d 6) δ 10.66 (brs, 1H), 7.51 – 7.43 (m, 3H), 6.95(s, 2H), 6.91 (d, J = 8.4 Hz, 1H), 6.83 (dd, J = 8.4, 2.4 Hz, 1H), 4.22 (s, 2H), 4.08 (s, 2H).

[1168] Example 37

[1169] 2-(3,5-Dichloro-4-(4-hydroxy-3-(5-(trifluoromethyl)thiophene-2-yl)benzyl)phenoxy)acetic acid (chemical) Synthesis of compound 37)

[1170]

[1171] A mixture of [5-(trifluoromethyl)thienyl]boronipinurate (58 mg, 0.21 mmol), intermediate A7 (100 mg, 0.21 mmol), Cs₂CO₃ (135 mg, 0.42 mmol), and Pd(dppf)Cl₂ (16 mg, 0.02 mmol) in 1,4-dioxane (3 mL) / water (1 mL) was incubated at 85°C under a N₂ atmosphere. o The mixture was stirred at C for 16 h. The reaction was acidified to pH 6-7 with 2N HCl, concentrated under vacuum, and purified by Prep-HPLC to give compound 37 (7 mg, 5% yield) as a pale yellow solid.

[1172] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0

[1173] 1 H NMR: (400 MHz, DMSO) δ 10.62 (s, 1H), 7.65 (d, J = 4.0 Hz, 1H),7.60 (s, 1H), 7.56 (d, J = 4.1 Hz, 1H), 7.14 (s, 2H), 6.91 (d, J = 2.0 Hz, 2H), 4.79 (s, 2H), 4.14 (s, 2H).

[1174] LCMS: RT=4.07 min; [M-1]=477.

[1175] Example 38

[1176] Synthesis of 2-(3,5-dichloro-4-(3-(furan-2-yl)-4-hydroxybenzyl)phenoxy)acetic acid (compound 38)

[1177]

[1178] To a solution of intermediate A7 (150 mg, 321 μmol) in 1,4-dioxane (4 mL) at room temperature, Pd(dppf)Cl2 (27 mg, 32 μmol), NaHCO3 (2 M, 0.5 mL), and furan-2-boronic acid (54 mg, 482 μmol) were added. The mixture was heated to 70°C overnight. The mixture was cooled to room temperature, LiOH·H2O (67 mg, 1.6 mmol) was added, and the mixture was stirred at room temperature for 30 min. The reaction was quenched with water (5 mL), acidified to pH ~4-5 with 1N HCl, and extracted with DCM (5 mL * 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by Prep-HPLC (ACN / water range 30 / 70 to 85 / 15) to give compound 38 (40 mg, 31% yield) as a grayish-white solid.

[1179] TLC:DCM / MeOH =10 / 1(v / v), Rf=0.33

[1180] LCMS:RT=3.494 min; [M-1] =391

[1181] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.97 (s, 1H), 7.67 (dd, J = 1.8, 0.8 Hz, 1H), 7.43 (d, J = 2.1 Hz, 1H), 7.13 (s, 2H), 6.91 (dd, J = 3.3, 0.8 Hz, 1H), 6.87 (d, J = 2.2 Hz, 1H), 6.84 (d, J = 8.3 Hz, 1H), 6.54 (dd, J = 3.3, 1.8Hz, 1H), 4.78 (s, 2H), 4.11 (s, 2H).

[1182] Example 39

[1183] 2-(3,5-dichloro-4-(3-(furan-3-yl)-4-hydroxybenzyl)phenoxy)methyl acetate (compound 39) synthesis

[1184]

[1185] Pd(dppf)Cl2 (31 mg, 0.04 mmol) was added to a solution of intermediate A7 (200 mg, 0.43 mmol), furan-3-boronic acid (72 mg, 0.64 mmol), and NaHCO3 (2 M, 0.6 mL) in 1,4-dioxane (10 mL) at room temperature. The mixture was refluxed overnight. The mixture was cooled to room temperature, water (10 mL) was added, and the mixture was extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-HPLC (MeCN / H2O) to give compound 39 (100 mg, 57% yield) as a yellow liquid.

[1186] TLC: Petroleum ether / EtOAc = 5 / 1 (v / v), Rf = 0.4

[1187] Example 40

[1188] Synthesis of 2-(3,5-dichloro-4-(3-(furan-3-yl)-4-hydroxybenzyl)phenoxy)acetic acid (compound 40)

[1189]

[1190] LiOH·H₂O (30 mg, 0.72 mmol) was added to a solution of compound 39 (100 mg, 0.24 mmol) in THF (5 mL) / water (0.2 mL) at room temperature; the resulting mixture was stirred at room temperature for 1 h. The reaction was acidified to pH ~6-7 with 2N HCl and extracted with EtOAc (3 × 10 mL). The combined organic layers were washed with brine (5 mL), dried over Na₂SO₄, and concentrated under vacuum. The crude product was purified by Prep-HPLC to give compound 40 (50 mg, 52% yield) as a white solid.

[1191] TLC: petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.1

[1192] LCMS:RT=3.579 min; [M-1]=391

[1193] 1 H NMR: (400 MHz, DMSO- d6) δ 13.10 (s, 1H), 9.80 (s, 1H), 8.08 (d, J =1.8 Hz, 1H), 7.68 (t, J = 1.7 Hz, 1H), 7.35 (d, J = 2.2 Hz, 1H), 7.12 (s,2H), 6.85 – 6.78 (m, 2H), 6.74 (dd, J = 8.4, 2.2 Hz, 1H), 4.78 (s, 2H), 4.11 (s, 2H).

[1194] Example 41

[1195] 2-(3,5-Dichloro-4-(4-hydroxy-3-(thiophen-3-yl)benzyl)phenoxy)methyl acetate (compound 41) Synthesis

[1196]

[1197] A solution of thiophene-3-boronic acid (82 mg, 642 μmol), intermediate A7 (150 mg, 321 μmol), Pd(dppf)Cl2 (24 mg, 32.1 μmol), and NaHCO3 (2 M, 0.48 mL) in 1,4-dioxane (5 mL) was stirred overnight at 85°C. The mixture was concentrated to dryness. Water (30 mL) was added, and the mixture was extracted with EtOAc (25 mL * 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, and purified by Prep-TLC (petroleum ether / EtOAc = 5 / 1) to give compound 41 (80 mg, 29% yield, 50% purity) as a yellow solid.

[1198] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.42

[1199] Example 42

[1200] Synthesis of 2-(3,5-dichloro-4-(4-hydroxy-3-(thiophen-3-yl)benzyl)phenoxy)acetic acid (compound 42)

[1201]

[1202] LiOH·H₂O (12 mg, 283 μmol) was added to a solution of compound 41 (80 mg, 50% purity, 94.4 μmol) in water (1 mL) and MeOH (2 mL). The mixture was stirred at room temperature for 1 h. The mixture was acidified to pH 5-6 with 1 N HCl and extracted with DCM (5 mL). The organic layer was concentrated to dryness and purified by Prep-HPLC to give compound 42 (15 mg, 38% yield) as a white solid.

[1203] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0

[1204] LCMS:RT=1.728 min; [M-1]=407.0 / 409.0

[1205] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.10 (s, 1H), 9.62 (s, 1H), 7.73 (dd, J =3.0, 1.3 Hz, 1H), 7.53 (dd, J = 5.0, 3.0 Hz, 1H), 7.42 (dd, J = 5.0, 1.3 Hz,1H), 7.30 (s, 1H), 7.12 (s, 2H), 6.83 (d, J = 1.3 Hz, 2H), 4.77 (s, 2H), 4.11 (s, 2H).

[1206] Example 43

[1207] 2-(3,5-dichloro-4-(3-(5-chlorothiophen-3-yl)-4-hydroxybenzyl)phenoxy)acetic acid (compound 43) synthesis

[1208]

[1209] A mixture of 2-chlorothiophene-4-boronipinurate (50 mg, 240 μmol), intermediate A7 (98 mg, 240 μmol), NaHCO3 (2 M, 0.36 mL), and Pd(dppf)Cl2 (15 mg, 24.5 μmol) in 1,4-dioxane (2 mL) was stirred overnight at 100 °C. The mixture was cooled to room temperature, LiOH·H2O (25 mg, 613 μmol) was added, and the resulting mixture was stirred for 1 h. The mixture was acidified to pH ~5-6 with 1N HCl, water (30 mL) was added, and the resulting mixture was extracted with EtOAc (25 mL * 2). The combined organic layers were washed with water (25 mL * 2), then with brine (50 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-HPLC to give compound 43 (35 mg, 39% yield) as a white solid.

[1210] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0

[1211] LCMS:RT=2.419 min; [M-1]=440.9 / 442.9

[1212] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.11 (s, 1H), 9.77 (s, 1H), 7.62 (d, J =1.8 Hz, 1H), 7.43 (d, J = 1.8 Hz, 1H), 7.30 (d, J = 1.7 Hz, 1H), 7.12 (s,2H), 6.85 – 6.80 (m, 2H), 4.78 (s, 2H), 4.10 (s, 2H).

[1213] Example 44

[1214] 2-(3,5-dichloro-4-(4-hydroxy-3-(3-methylfuran-2-yl)benzyl)phenoxy)acetic acid (compound 44) synthesis

[1215]

[1216] Pd(dppf)Cl2 (16 mg, 0.022 mmol) and NaHCO3 (109 mg, 1.29 mmol) were added to a solution of intermediate A7 (200 mg, 0.43 mmol) and intermediate B6 (179 mg, 0.86 mmol) in 1,4-dioxane / H2O (5 / 2 mL). The reaction mixture was heated to 80°C overnight. The reaction mixture was cooled to room temperature; LiOH·H2O (90 mg, 2.15 mmol) was added, and the resulting mixture was stirred at room temperature for 30 min. Water (10 mL) was added, the pH was adjusted to pH 3-4 with 1N HCl, and the mixture was extracted with EtOAc (10 mL * 3). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated under vacuum; the residue was purified by Prep-HPLC to give compound 44 (10 mg) as a pale yellow solid—a minor product among two similar products.

[1217] LCMS:RT=3.795 min; [M-1]=405.1 / 406.9

[1218] 1 H NMR: (400 MHz, DMSO- d 6) δ 12.96 (s, 1H), 9.51 (s, 1H), 7.56 (d, J =1.7 Hz, 1H), 7.11 (s, 2H), 7.03 – 6.91 (m, 2H), 6.84 (d, J = 8.3 Hz, 1H), 6.36 (d, J = 1.4 Hz, 1H), 4.77 (s, 2H), 4.09 (s, 2H), 1.94 (s, 3H)

[1219] Example 45

[1220] 2-(3,5-Dichloro-4-((2'-fluoro-6-hydroxy-5'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl) Synthesis of phenoxyacetic acid (compound 45)

[1221]

[1222] To a room-temperature solution of intermediate A7 (150 mg, 321 μmol) in 1,4-dioxane (3 mL), Pd(dppf)Cl2 (27 mg, 32 μmol), NaHCO3 (2 M, 0.5 mL), and 2-fluoro-5-trifluoromethyl-phenylboronic acid (100 mg, 482 μmol) were added. The mixture was heated to 70 °C overnight. The mixture was cooled to room temperature, LiOH·H2O (67 mg, 1.6 mmol) was added, and the resulting mixture was stirred at room temperature for 30 min. The reaction was quenched with water (5 mL), acidified to pH 4-5 with 1N HCl, and extracted with DCM (5 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by Prep-HPLC (ACN / water range 30 / 70 to 85 / 15) to give compound 45 (10 mg, 6% yield) as a grayish-white solid.

[1223] TLC:DCM / MeOH =10 / 1(v / v), Rf=0.33

[1224] LCMS: RT=2.291 min; [M-1] = 487.

[1225] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.09 (s, 1H), 9.66 (s, 1H), 7.77 (dt, J =7.8, 3.1 Hz, 1H), 7.72 – 7.66 (m, 1H), 7.48 (t, J = 9.1 Hz, 1H), 7.12 (s,2H), 7.05 (s, 1H), 6.98 (dd, J = 8.4, 2.1 Hz, 1H), 6.87 (d, J = 8.4 Hz, 1H), 4.77 (s, 2H), 4.11 (s, 2H).

[1226] Example 46

[1227] 2-(3,5-Dichloro-4-((2'-fluoro-6-hydroxy-5'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl) phenoxy)- N Synthesis of methylacetamide (compound 46)

[1228]

[1229] Add a catalytic amount of DMF (1 drop) to compound 45 (100 mg, 0.2 mmol) in DCM (2 mL). Cool the mixture to 0. o C and oxalyl chloride (51 mg, 0.4 mmol) were added. The mixture was stirred at room temperature for 30 min. The mixture was concentrated under vacuum to give 2-(3,5-dichloro-4-((2'-fluoro-6-hydroxy-5'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetyl chloride (100 mg, 99% yield) as a pale yellow solid. TLC: MeOH / DCM = 1 / 10 (v / v), R f =0.90

[1230] MeNH2 (40% w / w, 2 mL in H2O) was added dropwise to 2-(3,5-dichloro-4-((2'-fluoro-6-hydroxy-5'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetyl chloride (50 mg, 0.1 mmol) in DCM (2 mL) at 0°C. The reaction was stirred at room temperature for 30 min. Water (10 mL) was added, and the mixture was extracted with DCM (5 mL x 3). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-HPLC to give compound 46 (12 mg, 24% yield) as a white solid.

[1231] TLC:MeOH / DCM =1 / 10(v / v), R f =0.60

[1232] LCMS:RT=3.004 min; [M-1]=502.1

[1233] 1 H NMR: (400 MHz, DMSO) δ 9.66 (s, 1H), 8.05 (s, 1H), 7.77 (s, 1H), 7.70 (d, J = 6.8 Hz, 1H), 7.49 (t, J = 9.2, 19.2 Hz, 1H), 7.15 (s, 1H), 7.05(s, 1H), 6.99 (d, J = 7.2 Hz, 1H), 6.87 (d, J = 8.0 Hz, 1H), 4.54 (s, 1H), 4.12 (s, 1H), 2.65 (d, J= 4.8 Hz, 1H).

[1234] 19 F NMR: (376 MHz, DMSO) δ -60.31 (s), -108.13 (s).

[1235] Example 47

[1236] 2-(3,5-Dichloro-4-((2'-fluoro-6-hydroxy-5'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl) phenoxy)- N,N Synthesis of dimethylacetamide (compound 47)

[1237]

[1238] Add a catalytic amount of DMF (1 drop) to compound 45 (100 mg, 0.2 mmol) in DCM (2 mL). Cool the mixture to 0. o C and oxalyl chloride (51 mg, 0.4 mmol) were added. The mixture was stirred at room temperature for 30 min. The mixture was concentrated under vacuum to give 2-(3,5-dichloro-4-((2'-fluoro-6-hydroxy-5'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetyl chloride (100 mg, 99% yield) as a pale yellow solid. TLC: MeOH / DCM = 1 / 10 (v / v), R f =0.90

[1239] Dimethylamine (50 mg, 0.1 mmol in THF, 2 M) was added dropwise to 2-(3,5-dichloro-4-((2'-fluoro-6-hydroxy-5'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetyl chloride (2 mL) at 0°C. The mixture was stirred at room temperature for 30 min. Water (10 mL) was added, and the mixture was extracted with DCM (5 mL x 3). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-HPLC to give compound 47 (20 mg, 39% yield) as a white solid.

[1240] TLC:MeOH / DCM =1 / 10(v / v), R f =0.60

[1241] LCMS: T=3.004 min; [M-1]=502.1

[1242] 1 H NMR: (400 MHz, DMSO) δ 9.64 (s, 1H), 7.76 (d,J = 3.0 Hz, 1H), 7.70(dd, J = 6.4, 2.0 Hz, 1H), 7.49 (t, J = 8.8 Hz, 1H), 7.10 (s, 1H), 7.05 (s,1H), 6.98 (dd, J = 8.0, 2.4 Hz, 1H), 6.88 (d, J = 8.4 Hz, 1H), 4.90 (s, 1H), 4.11 (s, 1H), 2.96 (s, 1H), 2.84 (s, 1H).

[1243] 19 F NMR: (376 MHz, DMSO) δ -60.31 (s), -108.11 (s).

[1244] Example 48

[1245] 2-(3,5-Dichloro-4-((4'-fluoro-6-hydroxy-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl)benzene Synthesis of (oxy)acetic acid (compound 48)

[1246]

[1247] A solution of [3-(trifluoromethyl)-4-fluorophenyl]boronpinaol ester (140 mg, 482 μmol), intermediate A7 (150 mg, 321 μmol), Pd(dppf)Cl2 (24 mg, 32 μmol), and NaHCO3 (aqueous solution) (2 M, 0.48 mL) in 1,4-dioxane (5 mL) was stirred overnight at 85°C. The mixture was cooled to room temperature, LiOH·H2O (23 mg, 963 μmol) was added, and the resulting mixture was stirred for 20 min. The mixture was acidified to pH ~5-6 with 1M HCl. Water (30 mL) was added; the mixture was extracted with EtOAc (25 mL * 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-TLC (DCM / MeOH = 10 / 1) to give compound 48 (10 mg, 6% yield) as a brown solid.

[1248] TLC:DCM / MeOH =10 / 1(v / v), Rf=0.32

[1249] LCMS:T=2.427 min; [M-1]:486.8 / 488.8

[1250] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.19 (s, 1H), 9.72 (s, 1H), 7.88-7.85 (m,1H), 7.84 – 7.77 (m, 1H), 7.56-7.51 (m, 1H), 7.15 (d, J = 2.0 Hz, 1H), 7.10(s, 2H), 6.95 – 6.85 (m, 2H), 4.73 (s, 2H), 4.12 (s, 2H).

[1251] Example 49

[1252] 2-(3,5-Dichloro-4-((2'-fluoro-6-hydroxy-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl) Synthesis of phenoxyacetic acid (compound 49)

[1253]

[1254] To a mixture of intermediate A7 (150 mg, 321 μmol), [3-(trifluoromethyl)-2-fluorophenyl]boronic acid (100 mg, 482 μmol), and Pd(dppf)Cl2·CH2Cl2 (26 mg, 32 μmol) in 1,4-dioxane (5.0 mL) at room temperature, an aqueous solution of NaHCO3 (2 M, 0.5 mL) was added. The mixture was heated to 70°C and stirred overnight. The reaction mixture was cooled to room temperature; LiOH·H2O (55 mg, 1.3 mmol) was added, and the resulting mixture was stirred for 30 min. The reaction was quenched with water (10 mL), acidified to pH 4–5 with aqueous HCl (1 N), and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-HPLC (MeCN / H2O) to give compound 49 (10 mg, 6% yield) as a white solid.

[1255] TLC:MeOH / DCM=1 / 10(v / v), Rf=0.3

[1256] LCMS:RT=4.534 min; [M-1]=487.8

[1257] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.66 (s, 1H), 7.74 (t, J = 6.8 Hz, 1H), 7.65 (t, J= 6.4 Hz, 1H), 7.43 (t, J = 8.0 Hz, 1H), 7.10 (s, 2H), 7.04 – 6.95(m, 2H), 6.87 (d, J = 8.0 Hz, 1H), 4.72 (s, 2H), 4.11 (s, 2H).

[1258] 19 F NMR: (376 MHz, DMSO- d 6) δ -59.85, -59.89, -116.66, -116.70, -116.73, -116.76.

[1259] Example 50

[1260] 2-(3,5-Dichloro-4-((3'-fluoro-6-hydroxy-5'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl) Synthesis of phenoxyacetic acid (compound 50)

[1261]

[1262] Pd(dppf)Cl2 (16 mg, 0.03 mmol) was added to a room-temperature solution of 3-fluoro-5-trifluoromethylphenylboronic acid (100 mg, 0.48 mmol), intermediate A7 (150 mg, 0.32 mmol), and NaHCO3 (0.7 mL, 1.44 mmol) in 1,4-dioxane (5 mL); the mixture was refluxed overnight. The reaction was cooled to room temperature; LiOH·H2O (61 mg, 1.44 mmol) was added, and the resulting mixture was stirred at room temperature for 30 min. Water (10 mL) was added, and the mixture was extracted with ether (10 mL x 2). The aqueous phase was adjusted to pH ~3 with HCl (2N), and then extracted again with EtOAc (10 mL x 2). The combined EtOAc extracts were washed with brine (10 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-HPLC (MeCN / H2O) to give compound 50 (4 mg, 4% yield) as a white solid.

[1263] TLC: Petroleum ether / EtOAc = 1 / 5 (v / v), Rf = 0.1

[1264] LCMS:RT=4.156 min; [M-1]=487

[1265] 1 H NMR: (400 MHz, DMSO- d6) δ 13.10 (s, 1H), 9.81 (s, 1H), 7.70 (s, 1H), 7.65 (d, J = 9.8 Hz, 1H), 7.60 (d, J = 8.8 Hz, 1H), 7.24 (d, J = 2.0 Hz, 1H), 7.12 (s, 2H), 6.94 – 6.87 (m, 2H), 4.77 (s, 2H), 4.13 (s, 2H).

[1266] Example 51

[1267] 2-(3,5-Dichloro-4-((5'-ethyl-2'-fluoro-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenoxy) Synthesis of acetic acid (compound 51)

[1268]

[1269] Pd(dppf)Cl2 (16 mg, 0.02 mmol) was added to a solution of intermediate A7 (100 mg, 0.21 mmol), 2-fluoro-5-ethylphenylboronic acid (80 mg, 0.32 mmol), and NaHCO3 (0.3 mL, 0.63 mmol) in 1,4-dioxane (5 mL); the mixture was refluxed overnight. The reaction was cooled to room temperature; LiOH·H2O (27 mg, 0.63 mmol) was added, and the resulting mixture was stirred for 30 min. Water (10 mL) was added, and the mixture was extracted with ether (10 mL x 2). The aqueous phase was adjusted to pH ~3 with HCl (2N), and then extracted again with EtOAc (10 mL x 2). The combined EtOAc extracts were washed with brine (10 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-HPLC (MeCN / H2O) to give compound 51 (4 mg, 4% yield) as a white solid.

[1270] TLC: Petroleum ether / EtOAc = 1 / 5 (v / v), Rf = 0.1

[1271] LCMS:RT=4.011 min; [M-1]=417

[1272] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.11 (s, 1H), 9.40 (s, 1H), 7.17 (dd, J=8.4, 4.8 Hz, 1H), 7.11 (s, 3H), 7.08 (d, J = 8.6 Hz, 1H), 6.93 (d, J = 10.0Hz, 2H), 6.82 (d, J = 8.2 Hz, 1H), 4.77 (s, 2H), 4.10 (s, 2H), 2.60 (q, J =7.6 Hz, 2H), 1.17 (t, J = 7.6 Hz, 3H).

[1273] Example 52

[1274] 2-(3,5-Dichloro-4-((5'-(difluoromethoxy)-2'-fluoro-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl Synthesis of phenyl phenoxyacetic acid (compound 52)

[1275]

[1276] To a mixture of intermediate B8 (470 mg, 1.6 mmol), intermediate A7 (150 mg, 0.32 mmol), and Pd(dppf)Cl2·CH2Cl2 (13 mg, 0.016 mmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL) at room temperature, NaHCO3 (0.96 mmol, 0.48 mL) was added. The reaction mixture was heated to 80°C overnight under N2 (gas). The reaction mixture was cooled to room temperature. LiOH·H2O (25 mg, 0.6 mmol) was added, and the resulting mixture was stirred for 30 min. Water (20 mL) was added, and the mixture was extracted with EtOAc (10 mL * 3). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by Prep-HPLC to give compound 52 (20 mg, 12% yield) as a white solid.

[1277] TLC:DCM / MeOH=10 / 1(v / v), Rf=0.2

[1278] LCMS:RT=3.779 min; [M-1]=485.0

[1279] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.09 (s, 1H), 9.58 (s, 1H), 7.29 (t, J=9.2 Hz, 1H), 7.16 (ddd, J = 11.6, 6.0, 3.6 Hz, 2H), 6.98 (dd, J = 12.0, 3.6Hz, 2H), 6.86 (d, J = 8.2 Hz, 1H), 4.76 (s, 2H), 4.11 (s, 2H).

[1280] 19 F NMR: (376 MHz, DMSO- d 6) δ -81.96, -118.49.

[1281] Example 53

[1282] 2-(3,5-Dichloro-4-((3'-(difluoromethoxy)-5'-fluoro-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl) Synthesis of methyl phenoxyacetate (compound 53)

[1283]

[1284] A mixture of intermediate B9 (144 mg, 0.50 mmol), intermediate A7 (155 mg, 0.33 mmol), 2N NaHCO3 (0.5 mL, 1.0 mmol), and Pd(dppf)Cl2 (17 mg, 0.02 mmol) in 1,4-dioxane (5 mL) was incubated at 85°C under a N2 atmosphere. o Stir at C for 16 hours. Concentrate the reaction mixture under vacuum; compound 53 was used in the next step without further purification.

[1285] TLC: Petroleum ether / EtOAc = 5 / 1 (v / v), Rf = 0.4

[1286] LCMS: RT=2.87 min; [M-1]=499.0.

[1287] Example 54

[1288] 2-(3,5-Dichloro-4-((3'-(difluoromethoxy)-5'-fluoro-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl) Synthesis of phenoxyacetic acid (compound 54)

[1289]

[1290] LiOH (155 mg, 1.0 mmol) was added to a room temperature solution of compound 53 (165 mg, 0.33 mmol) in THF (1 mL) / water (5 mL); the resulting mixture was stirred at 50°C for 1 h. The reaction was acidified to pH ~6-7 with 2N HCl, concentrated under vacuum, and purified by Prep-HPLC to give compound 54 (45 mg, 57% yield).

[1291] TLC: Petroleum ether / EtOAc = 5 / 1 (v / v), Rf = 0.4

[1292] LCMS: RT=2.09 min; [M-1]=485.

[1293] 1 H NMR: (400 MHz, DMSO) δ 13.10 (s, 1H), 9.71 (s, 1H), 7.50 (s, 0.24H), 7.32 (s, 0.52H), 7.22 (M, 1H), 7.16 (t, J = 2.2 Hz, 2H), 7.14 (s,0.33H), 7.12 (s, 2H), 7.06 (m, 1H), 6.92 (m, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.77 (s, 2H), 4.12 (s, 2H).

[1294] Example 55

[1295] 2-(3,5-Dichloro-4-((3'-(difluoromethoxy)-4'-fluoro-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl) Synthesis of phenoxyacetic acid (compound 55)

[1296]

[1297] A mixture of compound A7 (138 mg, 0.48 mmol), intermediate B10 (150 mg, 0.32 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol), and NaHCO3(2 N) (0.96 mmol, 0.48 mL) in 1,4-dioxane (4 mL) was stirred overnight at 85°C under N2. The mixture was cooled to room temperature, LiOH·H2O (67 mg, 1.6 mmol) was added, and the resulting mixture was stirred at room temperature for 30 min. The pH of the mixture was adjusted to ~4 with 1N HCl. The aqueous layer was extracted with EtOAc (20 mL * 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by Prep-HPLC to give compound 55 (8 mg, 5% yield) as a white solid.

[1298] TLC:DCM / MeOH=10 / 1(v / v), Rf=0.2

[1299] LCMS:RT=3.885 min; [M-1]=485.0

[1300] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.08 (s, 1H), 9.62 (s, 1H), 7.51-7.49(dd, J 1 = 8.0 Hz J 2= ​​7.2 Hz, 1H), 7.45-7.42 (dd, J 1 = 8.0 Hz, J 2 =12 Hz, 1H), 7.40-7.38 (dd, J 1 = 3.2 Hz, J 2 = 5.2 Hz, 1H), 7.27(t, J =73.6 Hz, 1H), 7.27 (s, 1H),7.13 (s, 2H), 7.10 (d, J = 2.0 Hz, 1H), 6.93-6.91 (dd, J 1 = 8.0 Hz J 2 =8.4 Hz, 1H), 6.86 (d, J = 8.4 Hz, 1H), 4.78 (s, 2H), 4.12 (s, 2H).

[1301] Example 56

[1302] 2-(3,5-Dichloro-4-((3'-(difluoromethoxy)-2'-fluoro-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl) Synthesis of phenoxyacetic acid (compound 56)

[1303]

[1304] An aqueous solution of NaHCO3 (2 M, 0.48 mL) was added to a mixture of intermediate B12 (470 mg, 1.6 mmol), intermediate A7, and Pd(dppf)Cl2·CH2Cl2 (150 mg, 321.14 μmol) in 1,4-dioxane (5 mL) and H2O (0.5 mL) at room temperature. The reaction mixture was heated to 80°C overnight under N2 (gas). The reaction mixture was cooled to room temperature. LiOH·H2O (55 mg, 1.3 mmol) was added, and the resulting mixture was stirred for 30 min. The mixture was adjusted to pH ~4 with 1N HCl, and extracted with EtOAc (10 mL * 3). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by Prep-HPLC to give compound 56 (30 mg, 19% yield) as a white solid.

[1305] TLC:DCM / MeOH=10 / 1(v / v), Rf=0.2

[1306] LCMS:RT=3.835 min; [M-1]=485.0

[1307] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.09 (s, 1H), 9.55 (s, 1H), 7.31 (t, J =8.0 Hz, 1H), 7.25 (t, J = 73.2 Hz, 1H), 7.25 – 7.16 (m, 2H), 7.11 (s, 2H), 6.99 (m, 2H), 6.86 (d, J = 8.2 Hz, 1H), 4.77 (s, 2H), 4.11 (s, 2H).

[1308] 19 F NMR: (376 MHz, DMSO- d 6) δ -81.95, -132.15.

[1309] Example 57

[1310] 2-(3,5-Dichloro-4-((3'-(difluoromethoxy)-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenoxy Synthesis of methyl acetate (compound 57)

[1311]

[1312] A solution of intermediate C1 (750 mg, 3.17 mmol), intermediate A10 (300 mg, 1.06 mmol), and ZnCl2 (2.65 mmol, 2.6 mL) in DCE (10 mL) was stirred overnight at 85°C. The mixture was concentrated to dryness and purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1 to 5 / 1, v / v) to give compound 57 as a white solid (180 mg, 35% yield).

[1313] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.45

[1314] Example 58

[1315] 2-(3,5-Dichloro-4-((3'-(difluoromethoxy)-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenoxy Synthesis of α-N-methylacetamide (compound 58)

[1316]

[1317] A solution of compound 57 (200 mg, 414 μmol) and methylamine (321 mg, 4.14 mmol, 40% aqueous solution) in THF (2 mL) was stirred overnight at 70 °C in a tube. The mixture was concentrated and purified by Prep-HPLC to give compound 58 (50 mg, 25% yield) as a white solid.

[1318] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.35

[1319] LCMS:RT=3.894 min; [M-1]=479.8 / 481.9

[1320] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.09 (s, 1H), 7.28 (d, J = 2.8 Hz, 1H), 7.17 (d, J = 2.4 Hz, 1H), 6.96 (s, 1H), 6.68 – 6.61 (m, 2H), 4.88 (s, 2H), 4.17 (q, J= 7.2 Hz, 2H), 4.08 (s, 2H), 3.16-3.09 (m, 1H), 1.20 (t, J = 7.2Hz, 3H), 1.10 (d, J = 6.8 Hz, 6H).

[1321] Example 59

[1322] 2-(3-chloro-4-((3'-ethyl-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-5-methylphenoxy)acetic acid Synthesis of methyl ester (compound 59)

[1323]

[1324] Intermediate C2 (60 mg, 0.23 mmol) and ZnCl2 / THF (1 M) (0.57 mL, 0.58 mmol) were added to a solution of intermediate A15 (135 mg, 0.69 mmol) in DCE (5 mL) at room temperature. The resulting mixture was heated at 80 °C. o The mixture was stirred overnight at C. The mixture was concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc = 5 / 1, v / v) to give compound 59 (80 mg, 83% yield) as a yellow oil.

[1325] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.4

[1326] 1 H NMR: (400 MHz, DMSO) δ 9.29 (s, 1H), 7.27 (m, 3H), 7.11 (d, J = 6.9Hz, 1H), 6.94 (m, 2H), 6.81 (m, 3H), 4.81 (s, 2H), 4.00 (s, 2H), 3.69 (s,3H), 2.61 (m, 2H), 2.23 (s, 3H), 1.16 (m, 3H).

[1327] Example 60

[1328] 2-(3-chloro-4-((3'-ethyl-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-5-methylphenoxy)ethyl Synthesis of acid (compound 60)

[1329]

[1330] LiOH (23 mg, 0.57 mmol) was added to a solution of compound 59 (80 mg, 0.19 mmol) in water (5 mL) / THF (1 mL) at room temperature; the resulting mixture was stirred at room temperature for 1 h. The reaction was acidified to pH ~6-7 with 2N HCl, and then extracted with DCM (30 mL * 3). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-HPLC to give compound 60 (20 mg, 25% yield) as a pale yellow solid.

[1331] TLC: Petroleum ether / EtOAc = 1 / 5 (v / v), Rf = 0.0

[1332] LCMS: RT=4.09 min; [M+1]=410.13.

[1333] 1 H NMR: (400 MHz, DMSO) δ 13.02 (s, 1H), 9.29 (s, 1H), 7.31 – 7.22 (m,3H), 7.11 (m, 1H), 6.95 (d, J = 2.1 Hz, 1H), 6.89 (m, 1H), 6.84 – 6.76 (m,3H), 4.67 (s, 2H), 4.00 (s, 2H), 2.62 (m, 2H), 2.22 (s, 3H), 1.19 (t, J = 7.6Hz, 3H).

[1334] Example 61

[1335] 2-(3-chloro-4-((3'-(difluoromethoxy)-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-5-methylbenzene Synthesis of methyl oxyethyl acetate (compound 61)

[1336]

[1337] A solution of intermediate C1 (162 mg, 0.68 mmol), intermediate A15 (60 mg, 0.23 mmol), and ZnCl2 (1 M, 0.57 mL) in DCE (2 mL) was stirred overnight at 85°C. The mixture was concentrated to dryness and purified by silica gel column chromatography (petroleum ether / EtOAc = 5 / 1, v / v) to give compound 61 (50 mg, 47% yield) as a white solid.

[1338] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.39

[1339] Example 62

[1340] 2-(3-chloro-4-((3'-(difluoromethoxy)-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-5-methylbenzene Synthesis of (oxy)acetic acid (compound 62)

[1341]

[1342] LiOH·H₂O (6 mg, 0.26 mmol) was added to a solution of compound 61 (40 mg, 86.4 μmol) in water (1 mL) and MeOH (2 mL). The mixture was stirred at room temperature for 1 h. The mixture was adjusted to pH 5–6 with 1 N HCl (20 mL) and extracted with DCM (20 mL). The organic phase was concentrated to dryness and purified by Prep-HPLC and Prep-TLC (DCM / MeOH = 5 / 1) to give compound 62 (5 mg, 12% yield) as a white solid.

[1343] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0

[1344] LCMS: RT=3.829 min; [M-1]=446.9

[1345] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.19 (s, 1H), 9.57 (s, 1H), 7.43 (t, J =8.0 Hz, 1H), 7.34 – 7.27 (m, 2H), 7.24(t, J = 74.4 Hz, 1H), 7.10 – 7.05 (m,1H), 7.01 (d, J = 2.0 Hz, 1H), 6.89 – 6.75 (m, 4H), 4.60 (s, 2H), 4.00 (s, 2H), 2.22 (s, 3H).

[1346] Example 63

[1347] 2-(3-chloro-4-((6-hydroxy-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl)-5-methylphenoxy Synthesis of methyl acetate (compound 63)

[1348]

[1349] A solution of intermediate A15 (70 mg, 266 μmol), intermediate C3 (190 mg, 800 μmol), and ZnCl2 (1 M, 0.65 mL) in DCE (2 mL) was stirred overnight at 85°C. The mixture was concentrated to dryness and then purified by silica gel column chromatography (petroleum ether / EtOAc = 5 / 1, v / v) to give intermediate 63 (50 mg, 40% yield) as a white solid.

[1350] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.4

[1351] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.61 (s, 1H), 7.82 (s, 1H), 7.75 (s, 1H), 7.64 (d, J = 1.2 Hz, 2H), 7.06 (d, J = 2.0 Hz, 1H), 6.94 (d, J = 2.4 Hz, 1H), 6.86 – 6.82 (m, 3H), 4.81 (s, 2H), 4.03 (s, 2H), 3.70 (s, 3H), 2.23 (s, 3H).

[1352] Example 64

[1353] 2-(3-chloro-4-((6-hydroxy-3'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl)-5-methylphenoxy Synthesis of hydroxyacetic acid (compound 64)

[1354]

[1355] To a solution of compound 63 (50 mg, 107 μmol) in H₂O (1 mL) and MeOH (2 mL), NaOH (13 mg, 323 μmol) was added. The mixture was stirred at room temperature for 1 h. The mixture was adjusted to pH 5–6 with 1 N HCl (20 mL) and extracted with DCM (20 mL). The organic layer was concentrated to dryness and then purified by Prep-HPLC to give compound 64 (15 mg, 31% yield) as a white solid.

[1356] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0

[1357] LCMS:RT=4.053 min; [M-1]=448.9

[1358] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.04 (s, 1H), 9.60 (s, 1H), 7.83 (s, 1H), 7.78 – 7.71 (m, 1H), 7.67 – 7.57 (m, 2H), 7.07 (d, J = 2.0 Hz, 1H), 6.93 –6.76 (m, 4H), 4.68 (s, 2H), 4.02 (s, 2H), 2.23 (s, 3H).

[1359] Example 65

[1360] 2-(3-bromo-4-((3'-(difluoromethoxy)-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-5-methylbenzene Synthesis of ethyl(oxy)acetate (compound 65)

[1361]

[1362] Intermediate A18 (800 mg, 2.49 mmol) and 1 M ZnCl2 (6.22 mL, 6.22 mmol) were added to a solution of intermediate C1 (1.7 g, 7.47 mmol) in DCE (5 mL) at room temperature. The resulting mixture was heated at 85°C. o Stirred overnight at C. The mixture was poured into water (20 mL) and extracted with DCM (30 mL x 3). The combined organic phases were dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1, v / v) to give compound 65 (1.1 g, 84% yield) as a yellow oil.

[1363] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.4

[1364] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.51 (s, 1H), 7.46 – 7.38 (m, 1.44H), 7.36– 7.27 (m, 2H), 7.24 (s, 0.54H), 7.12 – 7.04 (m, 3H), 6.99 (m, 1H), 6.88 –6.80 (m, 4H), 4.79 (s, 2H), 4.16 (m, 2H), 4.05 (m, 2H), 2.23 (s, 3H), 1.19 –1.15 (m, 3H).

[1365] Example 66

[1366] 2-(3-bromo-4-((3'-(difluoromethoxy)-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-5-methyl Synthesis of phenoxyacetic acid (compound 66)

[1367]

[1368] LiOH·H₂O (278 mg, 6.90 mmol) was added to a room temperature solution of compound 65 (1.2 g, 2.30 mmol) in water (10 mL) / THF (5 mL); the resulting mixture was stirred at room temperature for 1 h. The reaction was acidified to pH ~3-4 with 2N HCl, concentrated under vacuum, and purified by reversed-phase column chromatography to give compound 66 (731 mg, 67% yield).

[1369] TLC: petroleum ether / EtOAc = 1 / 5 (v / v), Rf = 0

[1370] LCMS:RT: 3.91 min; [M-1]=491.0

[1371] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.51 (s, 1H), 7.45 – 7.39 (m, 1.25H), 7.36– 7.28 (m, 2H), 7.23 (s, 0.48H), 7.10 (m, 1H), 7.06 – 7.03 (m, 1H), 7.01 (m,1H), 6.83 (m, 3H), 4.68 (s, 2H), 4.05 (s, 2H), 2.23 (s, 3H).

[1372] Example 67

[1373] 2-(3-bromo-4-((3'-(difluoromethoxy)-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-5-methyl Synthesis of phenoxy)-N-methylacetamide (compound 67)

[1374]

[1375] Oxaloyl chloride (62 mg, 0.48 mmol) and DMF (cat.) were added to a solution of compound 66 (80 mg, 0.16 mmol) in DCM (15 mL). After stirring at room temperature for 1 h, the reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (5 mL) and methylamine / THF (1 M, 1.6 mL) was added. After stirring at room temperature for 2 h, the mixture was poured into water (20 mL) and extracted with DCM (30 mL x 3). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-TLC to give compound 67 (53 mg, 64% yield) as a white solid.

[1376] TLC: EtOAc / petroleum ether = 1 / 1 (v / v), Rf = 0.3

[1377] LCMS:RT=3.86 min; [M-1]=504.0

[1378] 1 H NMR: (400 MHz, DMSO) δ 9.51 (s, 1H), 8.02 (d, J = 5.1 Hz, 1H), 7.43(m, 1H), 7.35 – 7.27 (m, 2H), 7.24 (s, 0.54H), 7.13 – 7.04 (m, 2.47H), 7.02 –6.98 (m, 1H), 6.86 (m, 3H), 4.46 (s, 2H), 4.05 (s, 2H), 2.65 (d, J = 4.6 Hz, 3H), 2.23 (s, 3H).

[1379] Example 68

[1380] 2-(3-bromo-4-((3'-(difluoromethoxy)-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-5-methyl Synthesis of phenoxy)-1-(pyrrolidone-1-yl)ethane-1-one (compound 68)

[1381]

[1382] Oxaloyl chloride (62 mg, 0.48 mmol) and DMF (cat.) were added to a solution of compound 66 (80 mg, 0.16 mmol) in DCM (10 mL). After stirring at room temperature for 1 h, the reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (5 mL), and this solution was added dropwise to a mixture of Na2CO3 (52 mg, 0.48 mmol) and pyrrolidine (11 mg, 0.16 mmol) in DCM (10 mL). The reaction was stirred at room temperature for 1 h, then poured into water (20 mL) and extracted with DCM (10 mL x 3). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-TLC (petroleum ether / EtOAc = 1:1) to give compound 68 (60 mg, 67% yield) as a white solid.

[1383] TLC: EtOAc / petroleum ether = 1 / 1 (v / v), Rf = 0.2

[1384] LCMS:RT=4.08 min; [M-1]=544.1

[1385] 1 H NMR: (400 MHz, DMSO) δ 9.51 (s, 1H), 7.42 (m, 1.34H), 7.36 – 7.27 (m, 2.27H), 7.24 (s, 0.24H), 7.11 – 7.04 (m, 2H), 7.00 (s, 1H), 6.83 (s, 3H),4.72 (s, 2H), 4.04 (s, 2H), 3.48 – 3.40 (m, 2H), 3.29 (s, 1H), 2.22 (s, 3H),1.94 – 1.83 (m, 2H), 1.81 – 1.72 (m, 2H).

[1386] Example 69

[1387] 2-(3,5-dichloro-4-(3-(4-fluorobenzyl)-4-hydroxybenzyl)phenoxy)methyl acetate (compound 69) synthesis

[1388]

[1389] ZnCl2 (1N / hexane) was added to a solution of intermediate A6 (300 mg, 0.88 mmol) in 1,2-dichloroethane (5 mL) at room temperature. (1.76 mmol, 1.8 mL) and 4-fluorobenzyl chloride (166 mg, 0.88 mmol). The reaction was heated to 90°C overnight. The reaction mixture was cooled to room temperature, quenched with water (20 mL), and extracted with DCM (20 mL x 2). The combined organic phases were washed with water (2 x 10 mL) and brine (2 x 10 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by Prep-TLC (petroleum ether / EtOAc = 3 / 1) to give compound 69 (60 mg, 0.15 mmol, 43% yield) as a brown liquid.

[1390] TLC: Petroleum ether / EtOAc = 1 / 3 (v / v), Rf = 0.5

[1391] Example 70

[1392] Synthesis of 2-(3,5-dichloro-4-(3-(4-fluorobenzyl)-4-hydroxybenzyl)phenoxy)acetic acid (compound 70)

[1393]

[1394] A solution of LiOH·H₂O (46 mg, 1.1 mmol) in water (1 mL) was added to a solution of compound 69 (100 mg, 0.22 mmol) in THF (5 mL). The reaction was stirred at room temperature for 1 h. Water (10 mL) was added, and the pH was adjusted to ~6 with HCl (1N). The mixture was extracted with EtOAc (10 mL * 2); the combined organic phases were washed with brine (10 mL), dried over Na₂SO₄, and concentrated under vacuum. The crude product was purified by preparative-HPLC (ACN / water range 15 / 85 to 75 / 25) to give compound 70 (25 mg, 0.057 mmol, 26% yield) as a gray solid.

[1395] TLC: petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.1

[1396] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.36 (s, 1H), 7.18 (dd, J = 8.5, 5.6 Hz, 2H), 7.05 (t, J = 8.9 Hz, 2H), 7.00 (s, 2H), 6.85 (s, 1H), 6.72 (s, 2H), 4.51(s, 2H), 3.98 (s, 2H), 3.78 (s, 2H).

[1397] Example 71

[1398] 2-(3,5-Dichloro-4-(3-(4-fluorobenzyl)-4-hydroxybenzyl)phenoxy)-N-methylacetamide (Compound 71) Synthesis

[1399]

[1400] Methylamine (40% in H2O) (8 mL) was added to a solution of compound 69 (100 mg, 223 μmol) in THF (5 mL) at room temperature. The mixture was stirred overnight at 65°C in a sealed tube. The mixture was diluted with water (10 mL) and extracted with EtOAc (5 mL x 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by Prep-TLC (petroleum ether / EtOAc = 1 / 1) to give compound 71 (80 mg, 80% yield) as a grayish-white solid.

[1401] TLC:EtOAc / petroleum ether = 1 / 1 (v / v), R f =0.39

[1402] LCMS: RT=2.039 min; [M-1]=446.

[1403] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.27 (s, 1H), 8.06 (d, J = 5.3 Hz, 1H),7.21 – 7.15 (m, 2H), 7.11 (s, 2H), 7.05 (m, 2H), 6.85 (d, J = 2.1 Hz, 1H), 6.73 (dd, J = 8.3, 2.2 Hz, 1H), 6.68 (d, J = 8.2 Hz, 1H), 4.53 (s, 2H), 4.00(s, 2H), 3.78 (s, 2H), 2.65 (d, J = 4.6 Hz, 3H).

[1404] Example 72

[1405] 2-(3,5-dichloro-4-(3-(1-(4-fluorophenyl)ethyl)-4-hydroxybenzyl)phenoxy)methyl acetate (compound) Synthesis of 72)

[1406]

[1407] Intermediate A6 (806 mg, 5.08 mmol) and ZnCl2 (10 mL, 10.2 mmol) were added to a solution of intermediate D1 (2.6 g, 7.62 mmol) in DCE (50 mL) at room temperature. The reaction mixture was heated to 85°C and stirred overnight. The reaction mixture was cooled to room temperature, diluted with DCM (20 mL), washed with brine (2 x 10 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (EtOAc / petroleum ether = 1 / 10) to give compound 72 (1.2 g, 50% yield) as a colorless oil.

[1408] TLC: Petroleum ether / EtOAc = 5 / 1 (v / v), Rf = 0.55

[1409] LCMS:RT=4.47 min; [M-1]=462.1

[1410] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.24 (s, 1H), 7.21-7.19 (m, 2H), 7.12 (s, 2H), 7.05 (t, J = 8.8 Hz, 2H), 6.96 (d, J = 2.2 Hz, 1H), 6.70 (dd, J = 2.4, 8.4 Hz, 1H), 6.65 (d, J = 8.2 Hz, 1H), 4.89 (s, 2H), 4.37-4.39 (m, 1H), 4.02(d, J = 3.2 Hz, 2H), 3.70 (s, 3H), 1.44 (d, J = 7.2 Hz, 3H).

[1411] Example 73

[1412] 2-(3,5-Dichloro-4-(3-(1-(4-fluorophenyl)ethyl)-4-hydroxybenzyl)phenoxy)acetic acid (compound) Synthesis of 73)

[1413]

[1414] To a room-temperature solution of compound 72 (100 mg, 0.22 mmol) in THF / H₂O (4 / 1 mL), NaOH (17.2 mg, 432 μmol) was added. The mixture was stirred for 4 h and then diluted with water (15 mL). 1 N HCl was added to adjust the pH to ~3-4. The mixture was extracted with EtOAc (10 mL * 3). The combined organic phases were washed with brine (20 mL), dried over Na₂SO₄, and concentrated under vacuum to give compound 73 (20 mg, 45 μmol, 20.6% yield) as a white solid.

[1415] TLC:DCM / MeOH =10 / 1(v / v), Rf=0.21

[1416] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.10 (s, 1H), 9.21 (s, 1H), 7.21-7.19(m, 2H), 7.08 (s, 2H), 7.07 – 7.02 (m, 2H), 6.96 (d, J = 2.2 Hz, 1H), 6.70 (dd, J = 2.2, 8.2 Hz, 1H), 6.64 (d, J = 8.2 Hz, 1H), 4.76 (s, 2H), 4.37-4.39(m, 1H), 4.01 (d, J = 3.4 Hz, 2H), 1.44 (d, J = 7.2 Hz, 3H).

[1417] Example 74

[1418] ( S )-2-(3,5-dichloro-4-(3-(1-(4-fluorophenyl)ethyl)-4-hydroxybenzyl)phenoxy)acetic acid (compound) Synthesis of substance 74

[1419]

[1420] LiOH·H₂O (326 mg, 7.74 mmol) was added to a room temperature solution of compound 72 (1.2 g, 2.58 mmol) in THF (3 mL) / water (20 mL). The mixture was stirred at room temperature for 1 h. The reaction was acidified to pH ~3-4 with 2N HCl and concentrated under vacuum to give crude compound 73. Compound 73 was purified by chiral HPLC (chiral HPLC preparation conditions: column: Superchiral S-AD (Chiralway Biotech) 21x250 mm, 5 μm, temperature: 35 ℃, wavelength: 220 nm, mobile phase: isohexane / EtOH / formic acid = 70:30:0.05, flow rate: 15 ml / min; chiral HPLC analysis conditions: Superchiral S-AD (Chiralway Biotech) 4.6x150 mm, 5 μm, temperature: 35 ℃, wavelength: 220 nm, mobile phase: isohexane / EtOH / formic acid = 70:30:0.05, flow rate: 0.9 ml / min), yielding compound 74 (380 mg, 32% yield) as the early elution peak (analytical chiral HPLC peak 1 retention time: 3.4 min, >98% ee).

[1421] Example 75

[1422] ( R )-2-(3,5-dichloro-4-(3-(1-(4-fluorophenyl)ethyl)-4-hydroxybenzyl)phenoxy)acetic acid (compound) Synthesis of substance 75

[1423]

[1424] Compound 75 (380 mg, 32% yield) was separated from the above chiral HPLC purification of compound 73 as the late elution peak (analytical chiral HPLC peak 2 retention time: 5.2 min, >98% ee).

[1425] Example 76

[1426] ( R 2-(3,5-dichloro-4-(3-(1-(4-fluorophenyl)ethyl)-4-hydroxybenzyl)phenoxy)methyl acetate Synthesis of (Compound 76)

[1427]

[1428] Thionyl chloride (52 mg, 0.44 mmol) was added to a solution of compound 75 (100 mg, 0.22 mmol) in MeOH (5 mL) at room temperature; the mixture was stirred at 80°C for 1 h. The reaction was concentrated under vacuum to give compound 76 (101 mg, 100% yield).

[1429] TLC: petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.1

[1430] LCMS:RT=3.01 min; [M-1]=461.0

[1431] Example 77

[1432] ( R )-2-(3,5-dichloro-4-(3-(1-(4-fluorophenyl)ethyl)-4-hydroxybenzyl)phenoxy)- N -Methylethyl Synthesis of amide (compound 77)

[1433]

[1434] An aqueous solution of methylamine (1 M, 4.45 mL) in THF (1 mL) at room temperature was added to a solution of compound 76 (103 mg, 0.23 mmol). The resulting mixture was stirred at 75°C for 16 h. The reaction was concentrated and purified by silica gel column chromatography (petroleum ether / EtOAc = 2 / 1) to give compound 77 (60 mg, 57% yield).

[1435] TLC: petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.2

[1436] LCMS:(RT=2.23 min; [M-1]=459.9)

[1437] 1 H NMR: (400 MHz, DMSO) δ 9.22 (s, 1H), 8.05 (d, J = 5.1 Hz, 1H), 7.22– 7.16 (m, 2H), 7.12 (s, 2H), 7.09 – 7.02 (m, 2H), 6.96 (d, J = 2.2 Hz, 1H), 6.71 (m, 1H), 6.64 (d, J = 8.2 Hz, 1H), 4.53 (s, 2H), 4.38 (m, 1H), 4.07 –3.96 (m, 2H), 2.65 (d, J = 4.7 Hz, 3H), 1.45 (d, J = 7.3 Hz, 3H).

[1438] Example 78

[1439] ( R )-2-(3,5-dichloro-4-(3-(1-(4-fluorophenyl)ethyl)-4-hydroxybenzyl)phenoxy)- N,N -Second Class Synthesis of hydroxyacetamide (compound 78)

[1440]

[1441] Dimethylamine / THF (1M, 3.58 mL) was added to a solution of compound 76 (103 mg, 0.23 mmol) in THF (5 mL) at room temperature. The resulting mixture was stirred at 75°C for 16 h. The reaction was concentrated and purified by Prep-TLC (petroleum ether / EtOAc = 1 / 1) to give compound 78 (4 mg, 4% yield).

[1442] TLC: petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.2

[1443] LCMS:RT=2.45 min; [M-1]=474.0)

[1444] 1 H NMR: (400 MHz, DMSO) δ 9.21 (s, 1H), 7.23 – 7.15 (m, 2H), 7.05 (m, 4H), 6.97 (d, J = 2.2 Hz, 1H), 6.71 (m, 1H), 6.64 (d, J = 8.2 Hz, 1H), 4.90(s, 2H), 4.38 (d, J = 7.2 Hz, 1H), 4.01 (d, J = 3.8 Hz, 2H), 2.97 (s, 3H), 2.84 (s, 3H), 1.45 (d, J = 7.3 Hz, 3H).

[1445] Example 79

[1446] 2-(3,5-Dichloro-4-(3-(4-cyanobenzyl)-4-hydroxybenzyl)phenoxy)methyl acetate (Compound 79) Synthesis

[1447]

[1448] ZnCl2 (1 M in THF) (1.8 mmol) was added to a solution of intermediate C5 (443 mg, 2.2 mmol) and intermediate A6 (200 mg, 0.71 mmol) in DCE (6 mL). The mixture was stirred at 85°C for 3 h. Water (5 mL) was added, and the resulting mixture was extracted with DCM (3 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by Prep-TLC (petroleum ether / EtOAc = 3 / 1). The product was washed with MeOH to give compound 79 (70 mg, 22% yield) as a white solid.

[1449] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), R f =0.2

[1450] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.35 (s, 1H), 7.71 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 7.13 (s, 2H), 6.89 (s, 1H), 6.76 (dd, J = 8.4, 2.0Hz, 1H), 6.70 (d, J = 8.3 Hz, 1H), 4.89 (s, 2H), 4.01 (s, 2H), 3.89 (s, 2H), 3.70 (s, 3H).

[1451] Example 80

[1452] Synthesis of 2-(3,5-dichloro-4-(3-(4-cyanobenzyl)-4-hydroxybenzyl)phenoxy)acetic acid (compound 80)

[1453]

[1454] LiOH (20 mg, 461 μmol) was added to a room-temperature solution of compound 79 (70 mg, 153 μmol) in THF / H₂O (2 mL / 0.5 mL). The mixture was stirred at room temperature for 2 h. The mixture was diluted with water (5 mL), acidified to pH 5-6 with 1 N HCl, and extracted with EtOAc (3 mL x 3). The combined organic phases were washed with brine (5 mL), dried over Na₂SO₄, and concentrated under vacuum. The crude product was purified by Prep-TLC (DCM / MeOH = 10 / 1) to give compound 80 (60 mg, 89% yield) as a white solid.

[1455] TLC:MeOH / DCM =1 / 10(v / v), Rf=0.25

[1456] LCMS:RT=3.86 min; [M-1]=439.8

[1457] 1 H NMR: (400 MHz, DMSO) δ 9.36 (s, 1H), 7.71 (d, J = 8.2 Hz, 1H), 7.35 (d,J = 8.0 Hz, 1H), 7.06 (s, 1H), 6.90 (s, 1H), 6.79 – 6.74 (m, 1H), 6.70(d, J = 8.2 Hz, 1H), 4.70 (s, 1H), 4.01 (s, 1H), 3.89 (s, 1H).

[1458] Example 81

[1459] 2-(3,5-dichloro-4-(4-hydroxy-3-(pyridin-4-ylmethyl)benzyl)phenoxy)methyl acetate (compound) Synthesis of 81)

[1460]

[1461] ZnCl2 (1.9 mL, 1.85 mmol) was added to a solution of intermediate C7 (200 mg, 0.74 mmol) and intermediate A10 (411 mg, 2.22 mmol) in DCE (8 mL) at room temperature. The mixture was heated to 85°C overnight. The reaction mixture was cooled to room temperature and DCM (10 mL) was added. The mixture was washed with water (2 × 10 mL) and brine (2 × 10 mL), dried over Na2SO4, and concentrated under vacuum. The residue was washed with MeOH to give compound 81 (40 mg, 12% yield) as a white solid.

[1462] TLC:MeOH / DCM=1 / 15(v / v), Rf=0.6

[1463] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.34 (s, 1H), 8.40 (d, J = 5.4 Hz, 2H), 7.15 (d, J = 5.4 Hz, 2H), 7.13 (s, 2H), 6.90 (d, J = 2.2 Hz, 1H), 6.77 (d, J = 8.4 Hz, 1H), 6.71 (d, J = 8.2 Hz, 1H), 4.89 (s, 2H), 4.02 (s, 2H), 3.82 (s, 2H), 3.70 (s, 3H).

[1464] Example 82

[1465] 2-(3,5-Dichloro-4-(4-hydroxy-3-(pyridin-4-ylmethyl)benzyl)phenoxy)acetic acid (compound 82) Synthesis

[1466]

[1467] LiOH·H2O (12 mg, 0.27 mmol) was added to a solution of compound 81 (40 mg, 0.09 mmol) in THF (5 mL) and H2O (0.5 mL). The mixture was stirred at room temperature for 1 h; water (5 mL) was added, and the mixture was adjusted to pH 5-6 with HCl (1N) and extracted with EtOAc (10 mL * 2). The combined organic phases were washed with brine (20 mL), dried over Na2SO4, and concentrated under vacuum to give compound 82 (30 mg, 77% yield) as a white solid.

[1468] TLC:MeOH / DCM=1 / 15(v / v), Rf=0.1

[1469] LCMS:RT=2.518 min; [M-1]=416

[1470] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.40 (s, 1H), 8.46 (d, J = 5.0 Hz, 2H),7.24 (s, 2H), 7.09 (s, 2H), 6.92 (s, 1H), 6.79 – 6.70 (m, 2H), 4.77 (s, 2H),4.02 (s, 2H), 3.86 (s, 2H).

[1471] Example 83

[1472] 2-(3,5-dichloro-4-(3-(2-fluorobenzyl)-4-hydroxybenzyl)phenoxy)methyl acetate (compound 83) synthesis

[1473]

[1474] A mixture of intermediate A6 (100 mg, 0.3 mmol), 2-fluorobenzyl chloride (52 mg, 0.36 mmol), and ZnCl2 (1 M in THF, 0.6 mL, 0.6 mmol) in DCE (3 mL) was stirred overnight at 95°C. The mixture was diluted with DCM (10 mL) and washed with water (10 mL) and brine (10 mL). The organic layer was dried over Na2SO4 and concentrated under vacuum. The residue was purified by Prep-HPLC to give intermediate 83 (30 mg, 22% yield) as a white solid.

[1475] TLC: Petroleum ether / EtOAc = 5 / 1 (v / v), Rf = 0.4

[1476] LCMS:RT=2.998 min; [M-1]=447.7

[1477] Example 84

[1478] Synthesis of 2-(3,5-dichloro-4-(3-(2-fluorobenzyl)-4-hydroxybenzyl)phenoxy)acetic acid (compound 84)

[1479]

[1480] LiOH·H₂O (9 mg, 0.21 mmol) was added to a mixture of intermediate 83 (30 mg, 0.07 mmol) in THF (2 mL) and water (1 mL). The mixture was stirred at room temperature for 2 h. The pH was adjusted to ~4 with 1N HCl; the aqueous layer was extracted with EtOAc (20 mL x 2). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by Prep-HPLC to give compound 84 (14 mg, 47% yield) as a white solid.

[1481] TLC:DCM / MeOH=10 / 1(v / v), Rf=0.1

[1482] LCMS:RT=3.974 min; [M-1]=432.8

[1483] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.37 (s, 1H), 7.22 (d, J = 10.2 Hz, 1H), 7.13 (d, J = 7.0 Hz, 2H), 7.08 (d, J = 7.8 Hz, 1H), 6.99 (s, 2H), 6.77 (d, J = 16.8 Hz, 2H), 6.70 (d, J = 7.8 Hz, 1H), 4.54 (s, 2H), 3.97 (s, 2H), 3.80 (s, 2H).

[1484] Example 85

[1485] 2-(3,5-dichloro-4-(3-(3-fluorobenzyl)-4-hydroxybenzyl)phenoxy)methyl acetate (compound 85) synthesis

[1486]

[1487] ZnCl2 (1 M, 6 mL) in THF and intermediate A6 (200 mg, 586 μmol) were added to a room-temperature solution of 3-fluorobenzyl chloride (42 mg, 293 μmol) in DCE (6 mL). The mixture was heated to reflux overnight. The mixture was diluted with DCM (5 mL), washed with brine (5 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by Prep-TLC (petroleum ether / EtOAc = 5 / 1) to give compound 85 (23 mg, 17% yield) as a colorless oil.

[1488] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.36

[1489] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.30 (s, 1H), 7.28 (q, J = 7.3 Hz, 1H),7.12 (s, 2H), 7.01 (d, J = 7.7 Hz, 1H), 6.96 (t, J = 8.9 Hz, 2H), 6.89 (d, J = 2.0 Hz, 1H), 6.77 – 6.73 (dd, J=8.4 Hz, 1.6 Hz,1H), 6.70 (d, J = 8.2 Hz,1H), 4.88 (s, 2H), 4.01 (s, 2H), 3.82 (s, 2H), 3.70 (s, 3H).

[1490] Example 86

[1491] Synthesis of 2-(3,5-dichloro-4-(3-(3-fluorobenzyl)-4-hydroxybenzyl)phenoxy)acetic acid (compound 86)

[1492]

[1493] LiOH (2 mg, 76.79 μmol) was added to a room-temperature solution of compound 85 (23 mg, 51.19 μmol) in THF (3 mL) and water (1 mL). The mixture was stirred at room temperature for 2 h. The mixture was diluted with water (3 mL), acidified to pH ~6-7 with 1N HCl, and extracted with EtOAc (3 mL x 3). The combined organic phases were washed with brine (5 mL), dried over Na2SO4, and concentrated under vacuum to give compound 86 (15 mg, 68% yield) as a gray solid.

[1494] TLC:MeOH / DCM =1 / 10(v / v), R f =0.25

[1495] LCMS: RT=2.067 min; [M-1] =433.

[1496] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.38 (s, 1H), 7.28 (q, J = 7.7 Hz, 1H), 7.01 (d, J = 7.6 Hz, 1H), 6.99 – 6.92 (m, 2H), 6.89 (d, J = 5.5 Hz, 3H), 6.72(q, J = 8.2 Hz, 2H), 4.19 (s, 2H), 3.98 (s, 2H), 3.82 (s, 2H).

[1497] Example 87

[1498] 2-(3,5-Dichloro-4-(3-(2,4-difluorobenzyl)-4-hydroxybenzyl)phenoxy)methyl acetate (compound) Synthesis of 87)

[1499]

[1500] A mixture of 2,4-difluorobenzyl chloride (96 mg, 0.6 mmol), intermediate A6 (200 mg, 0.6 mmol), and ZnCl2 (1 M in THF) in DCE (5 mL) was stirred overnight at 95°C. The mixture was cooled to room temperature, diluted with DCM (10 mL), and washed with water (10 mL). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by Prep-HPLC to give compound 87 (20 mg, 7% yield) as a white solid.

[1501] TLC: Petroleum ether / EtOAc = 5 / 1 (v / v), Rf = 0.4

[1502] LCMS:RT=3.360 min; [M-1]=464.8

[1503] Example 88

[1504] 2-(3,5-dichloro-4-(3-(2,4-difluorobenzyl)-4-hydroxybenzyl)phenoxy)acetic acid (compound 88) synthesis

[1505]

[1506] LiOH·H₂O (5 mg, 0.12 mmol) was added to a solution of compound 87 (20 mg, 0.04 mmol) in THF (2 mL) and water (1 mL). The mixture was stirred at room temperature for 2 h, then adjusted to pH ~4 with 1N HCl and extracted with EtOAc (20 mL * 2). The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by Prep-HPLC to give compound 88 (5 mg, 28% yield) as a white solid.

[1507] TLC:DCM / MeOH=10 / 1(v / v), Rf=0.1

[1508] LCMS:RT=3.992 min; [M-1]=450.8

[1509] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.35 (s, 1H), 7.20 – 7.13 (dd, J 1 = 16.4Hz, J 2 =19.2 Hz,2 H), 7.06 (s, 2H), 6.97 (t, J = 7.6 Hz, 1H), 6.77 (d, J = 8.0Hz, 2H), 6.70 (d, J = 7.6 Hz, 1H), 4.74 (s, 2H), 3.98 (s, 2H), 3.77 (s, 2H).

[1510] Example 89

[1511] 2-(3,5-dichloro-4-(3-(4-chlorobenzyl)-4-hydroxybenzyl)phenoxy)methyl acetate (compound 89) synthesis

[1512]

[1513] ZnCl2 (1 M, 1.17 mL) in THF and intermediate A6 (200 mg, 586 μmol) were added to a solution of 4-chlorobenzyl chloride (95 mg, 586 μmol) in DCE (5 mL) at room temperature. The mixture was heated to reflux overnight. The mixture was diluted with DCM (5 mL). The combined organic phases were washed with brine (5 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by Prep-TLC (petroleum ether / EtOAc = 5 / 1) to give compound 89 (30 mg, 11% yield) as a white solid.

[1514] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.36

[1515] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.28 (s, 1H), 7.29 (d, J = 8.3 Hz, 2H), 7.18 (d, J = 8.4 Hz, 2H), 7.12 (s, 2H), 6.87 – 6.85 (m, 1H), 6.74 (dd, J =8.3, 1.9 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 4.89 (s, 2H), 4.01 (s, 2H), 3.79 (s, 2H), 3.70 (s, 3H).

[1516] Example 90

[1517] Synthesis of 2-(3,5-dichloro-4-(3-(4-chlorobenzyl)-4-hydroxybenzyl)phenoxy)acetic acid (compound 90)

[1518]

[1519] LiOH (3 mg, 97 μmol) was added to a room-temperature solution of compound 89 (30 mg, 64 μmol) in THF (2 mL) and water (1 mL). The mixture was stirred at room temperature for 2 h, diluted with water (5 mL), acidified to pH ~6-7 with 1N HCl, and then extracted with EtOAc (5 mL * 2). The combined organic phases were washed with brine (5 mL), dried over Na₂SO₄, and concentrated under vacuum to give compound 90 (20 mg, 69% yield) as a white solid.

[1520] TLC:MeOH / DCM =1 / 10(v / v), R f =0.25

[1521] LCMS: RT=2.515 min; [M-1]=449.

[1522] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.43 (s, 1H), 7.32 – 7.25 (m, 2H), 7.22 –7.15 (m, 2H), 6.88 (m, 3H), 6.75 – 6.67 (m, 2H), 4.20 (s, 2H), 3.97 (s, 2H), 3.78 (s, 2H).

[1523] Example 91

[1524] 2-(3,5-Dichloro-4-(4-hydroxy-3-(4-methylbenzyl)benzyl)phenoxy)methyl acetate (Compound 91) Synthesis

[1525]

[1526] ZnCl2 (1 M, 1.17 mL) in THF and intermediate A6 (200 mg, 586 μmol) were added to a solution of 4-methylbenzyl chloride (83 mg, 586 μmol) in DCE (5 mL) at room temperature. The mixture was heated to reflux overnight. The mixture was diluted with DCM (5 mL). The combined organic phases were washed with brine (5 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by Prep-TLC (petroleum ether / EtOAc = 5 / 1) to give compound 91 (40 mg, 16% yield) as a colorless oil.

[1527] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.31

[1528] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.19 (s, 1H), 7.12 (s, 2H), 7.04 (s, 4H), 6.84 (s, 1H), 6.73 – 6.69 (m, 1H), 6.67 (d, J= 8.3 Hz, 1H), 4.89 (s, 2H), 3.99 (s, 2H), 3.74 (s, 2H), 3.70 (s, 3H), 2.23 (s, 3H).

[1529] Example 92

[1530] The synthesis of 2-(3,5-dichloro-4-(4-hydroxy-3-(4-methylbenzyl)benzyl)phenoxy)acetic acid (compound 92) become

[1531]

[1532] LiOH (1.4 mg, 57 μmol) was added to a room-temperature solution of compound 91 (17 mg, 38 μmol) in THF (3 mL) and water (1 mL). The mixture was stirred at room temperature for 2 h. The mixture was diluted with water (3 mL), acidified to pH ~6-7 with 1N HCl, and extracted with EtOAc (3 mL x 3). The combined organic phases were washed with brine (5 mL), dried over Na2SO4, and concentrated under vacuum to give compound 92 (15 mg, 91% yield) as a gray solid.

[1533] TLC:MeOH / DCM =1 / 10(v / v), R f =0.25

[1534] LCMS: RT= 2.296 min; [M-1] =429.

[1535] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.33 (s, 1H), 7.04 (d, J = 1.4 Hz, 4H), 6.89 – 6.83 (m, 3H), 6.68 (d, J = 1.7 Hz, 2H), 4.16 (s, 2H), 3.96 (s, 2H), 3.74 (s, 2H), 2.23 (s, 3H).

[1536] Example 93

[1537] 2-(3,5-dichloro-4-(4-hydroxy-3-(pyrimidin-5-ylmethyl)benzyl)phenoxy)methyl acetate (compound) Synthesis of 93)

[1538]

[1539] Intermediate A6 (100 mg, 0.35 mmol) and ZnCl2 / THF (1 M, 0.87 mL) were added to a room-temperature solution of intermediate C10 (197 mg, 1.05 mmol) in DCE (10 mL). The reaction was heated to 100°C and maintained for 2 days. The mixture was cooled to room temperature and diluted with DCM (20 mL); the resulting mixture was washed with brine (2 x 10 mL). The organic phase was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by Prep-TLC (EtOAc / petroleum ether = 1 / 3) to give compound 93 (150 mg, 20% purity) as a pale yellow oil.

[1540] TLC: petroleum ether / EtOAc = 1 / 5 (v / v), Rf = 0.4

[1541] LCMS:RT=3.53min; [M-1]=432.0

[1542] Example 94

[1543] 2-(3,5-Dichloro-4-(4-hydroxy-3-(pyrimidin-5-ylmethyl)benzyl)phenoxy)acetic acid (compound 94) Synthesis

[1544]

[1545] LiOH·H₂O (30 mg, 0.70 mmol) was added to a room temperature solution of compound 93 (150 mg, 0.35 μmol) in THF / water (2 / 1 mL). The mixture was stirred at room temperature for 1 h. The reaction mixture was acidified to pH ~3-4 with 2N HCl, concentrated under vacuum, and purified by Prep-HPLC to give compound 94 (13 mg, 2.9% yield in two steps).

[1546] TLC: petroleum ether / EtOAc = 1 / 5 (v / v), Rf = 0

[1547] LCMS:RT=3.00 min; [M-1]=418.9

[1548] 1 H NMR: (400 MHz, DMSO) δ 13.11 (s, 1H), 9.45 (s, 1H), 8.99 (s, 1H), 8.61 (s, 2H), 7.09 (s, 2H), 6.98 (d, J = 2.2 Hz, 1H), 6.77 (m, 1H), 6.70 (d, J= 8.2 Hz, 1H), 4.77 (s, 2H), 4.03 (s, 2H), 3.83 (s, 2H).

[1549] Example 95

[1550] 2-(3,5-Dichloro-4-(4-hydroxy-3-(4-(2,2,2-trifluoroethyl)benzyl)benzyl)phenoxy)acetic acid Synthesis of methyl ester (compound 95)

[1551]

[1552] ZnCl2 (1.2 mmol, 1.20 mL) was added to a solution of intermediate C13 (100 mg, 479 μmol) and intermediate A6 (327 mg, 958 μmol) in chlorobenzene (5 mL). The mixture was stirred overnight at 120°C. The mixture was concentrated to dryness, water (20 mL) was added, and the resulting mixture was extracted with DCM (20 mL x 2). The organic layer was dried over Na2SO4 and concentrated under vacuum to give compound 95 (200 mg, 16% yield, 20% purity), which was used without further purification.

[1553] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.38

[1554] Example 96

[1555] 2-(3,5-Dichloro-4-(4-hydroxy-3-(4-(2,2,2-trifluoroethyl)benzyl)benzyl)phenoxy)acetic acid Synthesis of (Compound 96)

[1556]

[1557] LiOH·H₂O (16 mg, 389.6 μmol) was added to a solution of compound 95 (200 mg, 77.9 μmol, 20% purity) in MeOH (3 mL) and water (1 mL). The mixture was stirred at room temperature for 2 h. Water (10 mL) was added, and the mixture was acidified to pH 4–5 with 1 N HCl. The mixture was extracted with DCM (10 mL x 2). The organic layer was concentrated to dryness and then purified by Prep-TLC (DCM / MeOH = 10 / 1) and Prep-HPLC to give compound 96 (30 mg, 77% yield) as a white solid.

[1558] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0

[1559] LCMS:RT=3.994 min; [M-1]=496.8 / 498.8

[1560] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.12 (s, 1H), 9.27 (s, 1H), 7.22 (d, J =7.9 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.08 (s, 2H), 6.88 (d, J = 2.1 Hz, 1H), 6.74 (dd, J = 8.3, 2.2 Hz, 1H), 6.69 (d, J = 8.2 Hz, 1H), 4.77 (s, 2H), 4.00 (s, 2H), 3.80 (s, 2H), 3.56 (q, J = 11.6 Hz, 2H).

[1561] Example 97

[1562] 2-(3,5-Dichloro-4-(3-(1-(4-fluorophenyl)propyl)-4-hydroxybenzyl)phenoxy)methyl acetate (compound) Synthesis of substance 97

[1563]

[1564] Intermediate A10 (100 mg, 0.36 mmol) and ZnCl2 (1.0 M in THF) (1.0 M, 0.9 mL) were added to a solution of intermediate C15 (244 mg, 1.06 mmol) in DCE (2 mL) at room temperature. The mixture was heated to reflux overnight. The mixture was cooled to room temperature and diluted with DCM (5 mL); the organic phase was washed with brine (5 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by Prep-TLC (petroleum ether / EtOAc = 5 / 1) to give compound 97 (52 mg, 30% yield) as a colorless oil.

[1565] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), R f =0.36

[1566] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.19 (s, 1H), 7.20 (ddd, J = 8.2, 5.2, 2.3Hz, 2H), 7.14 (s, 2H), 7.08 – 7.01 (m, 3H), 6.71 (dd,J = 8.3, 2.2 Hz, 1H), 6.63 (d, J = 8.3 Hz, 1H), 4.89 (s, 2H), 4.10 (t, J = 7.9 Hz, 1H), 4.03 (s,2H), 3.70 (s, 3H), 1.89 (td, J = 7.5, 3.3 Hz, 2H), 0.78 (t, J = 7.2 Hz, 3H).

[1567] Example 98

[1568] 2-(3,5-Dichloro-4-(3-(1-(4-fluorophenyl)propyl)-4-hydroxybenzyl)phenoxy)acetic acid (compound) Synthesis of 98)

[1569]

[1570] To a room-temperature solution of compound 97 (43 mg, 90 μmol) in THF (2 mL), LiOH·H₂O (7.5 mg, 180 μmol) in water (1 mL) was added. The mixture was stirred at room temperature for 2 h, diluted with water (10 mL), acidified to pH ~3 with HCl (1N), and extracted with EtOAc (5 mL * 3). The combined organic phases were washed with brine (10 mL), dried over Na₂SO₄, and concentrated under vacuum. The crude product was purified by Prep-HPLC to give compound 98 (10 mg, 23% yield) as a grayish-white solid.

[1571] TLC:DCM / MeOH =10 / 1(v / v), R f =0.39

[1572] LCMS: RT=2.543 min; [M-1] =461.

[1573] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.15 (s, 1H), 9.18 (s, 1H), 7.21 (t, J =7.1 Hz, 2H), 7.05 (dd, J = 16.7, 7.2 Hz, 5H), 6.70 (d, J = 8.1 Hz, 1H), 6.63(d, J = 8.3 Hz, 1H), 4.74 (s, 2H), 4.09 (d,J = 8.7 Hz, 1H), 4.03 (s, 2H), 1.89 (s, 2H), 0.78 (t, J = 7.2 Hz, 3H).

[1574] Example 99

[1575] 2-(3,5-Dichloro-4-(3-(1-(4-fluorophenyl)propyl)-4-hydroxybenzyl)phenoxy)- N -Methylacetamide Synthesis of (Compound 99)

[1576]

[1577] A solution of compound 97 (150 mg, 305 μmol) and an aqueous solution of methylamine (1 mL, 40%) in THF (5 mL) was stirred overnight at 70°C in a sealed tube. Water (30 mL) was added, and the mixture was extracted with EtOAc (25 mL * 2). The combined organic layers were washed with water (20 mL * 2) and brine (20 mL), dried over Na₂SO₄, concentrated under vacuum, and purified by Prep-TLC (DCM / MeOH = 20 / 1) to give compound 99 (50 mg, 34% yield) as a white solid.

[1578] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.17

[1579] LCMS:RT=4.134 min; [M-1]=476.1

[1580] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.17 (s, 1H), 8.05 (d, J = 6.4 Hz, 1H),7.24 – 7.18 (m, 2H), 7.12 (s, 2H), 7.08 – 7.00 (m, 3H), 6.71 (dd, J = 8.4, 2.4 Hz, 1H), 6.63 (d, J = 8.4 Hz, 1H), 4.53 (s, 2H), 4.10 (t, J = 7.9 Hz,1H), 4.04 (s, 2H), 2.65 (d, J = 4.8 Hz, 3H), 1.92 – 1.87 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H).

[1581] Example 100

[1582] 2-(3,5-Dichloro-4-(3-(1-(4-fluorophenyl)propyl)-4-hydroxybenzyl)phenoxy)- N,N -Dimethylethyl Synthesis of amide (compound 100)

[1583]

[1584] Oxaloyl chloride (107 mg, 842 μol) was added to a mixture of compound 98 (130 mg, 281 μol) in DCM (5 mL). The mixture was stirred at room temperature for 2 h. The mixture was concentrated to dryness to give crude acyl chloride (130 mg, 96% yield), which was combined with 2 mL of dimethylamine solution (2 M in THF) and stirred at room temperature for 5 min. The mixture was concentrated to dryness. Water (30 mL) was added, and the resulting mixture was extracted with EtOAc (15 mL * 2). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-TLC (DCM / MeOH = 20 / 1) and Prep-HPLC to give compound 100 (80 mg, 60% yield) as a white solid.

[1585] TLC:DCM / MeOH =20 / 1(v / v), Rf=0.4

[1586] LCMS:RT=4.261 min; [M-1]=488.1

[1587] 1 H NMR: (400 MHz, DMSO- d 6) δ 9.16 (s, 1H), 7.24 – 7.18 (m, 2H), 7.10 –7.01 (m, 5H), 6.74 – 6.69 (m, 1H), 6.64 (d, J = 8.4 Hz, 1H), 4.90 (s, 2H), 4.11 (t, J = 8.0 Hz, 1H), 4.03 (s, 2H), 2.96 (s, 3H), 2.84 (s, 3H), 1.92 –1.87 (m, 2H), 0.78 (t, J = 7.2 Hz, 3H).

[1588] Example 101

[1589] 2-(3,5-Dichloro-4-(3-(1-(4-fluorophenyl)butyl)-4-hydroxybenzyl)phenoxy)methyl acetate (compound) Synthesis of substance 101

[1590]

[1591] ZnCl2 (1 M, in THF) (1.3 mmol, 1.3 mL) was added to a solution of intermediate C17 (338 mg, 1.6 mmol) and intermediate A10 (150 mg, 0.5 mmol) in DCE (5 mL). The mixture was stirred overnight at 85°C. Water (5 mL) was added, and the mixture was extracted with DCM (3 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by Prep-TLC (EtOAc / petroleum ether = 1 / 10) to give compound 101 (55 mg, 22% yield) as a white solid.

[1592] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), R f =0.2

[1593] Example 102

[1594] 2-(3,5-Dichloro-4-(3-(1-(4-fluorophenyl)butyl)-4-hydroxybenzyl)phenoxy)acetic acid (compound) Synthesis of 102)

[1595]

[1596] LiOH (14 mg, 336 μmol) was added to a solution of compound 101 (55 mg, 112 μmol) in THF / H₂O (2 mL / 0.5 mL) at room temperature. The mixture was stirred at room temperature for 2 h; the mixture was quenched with water (5 mL), acidified to pH 5-6 with 1N HCl, and extracted with EtOAc (3 mL x 3). The combined organic phases were washed with brine (5 mL), dried over Na₂SO₄, and concentrated under vacuum. The crude product was purified by Prep-HPLC (MeCN / H₂O / TFA) to give compound 102 (45 mg, 85% yield) as a white solid.

[1597] TLC:MeOH / DCM =1 / 10(v / v), Rf=0.30

[1598] LCMS:RT=4.338 min; [M-1]=474.9

[1599] 1 H NMR: (400 MHz, DMSO) δ 9.24 (s, 1H), 7.21 (dd, J =6.0, 2.8 Hz, 2H), 7.05 (dd, J= 4.8, 2.4 Hz, 2H), 7.03 (s, 2H), 7.02 (s, 1H), 6.70 (dd, J =8.4, 2.0 Hz, 1H), 6.64 (d, J = 8.0 Hz, 1H), 4.60 (s, 2H), 4.23 (t, J = 8.0Hz, 1H), 4.02 (s, 2H), 1.92 – 1.78 (m, 2H), 1.15 (m, 2H), 0.84 (t, J = 7.2Hz, 3H).

[1600] Example 103

[1601] 2-(3,5-Dichloro-4-(3-(1-(4-fluorophenyl)-2-methylpropyl)-4-hydroxybenzyl)phenoxy)acetic acid ethyl Synthesis of ester (compound 103)

[1602]

[1603] ZnCl2 (1.3 mmol, 1.30 mL, 1 M in THF) was added to a solution of intermediate C19 (382 mg, 1.56 mmol) and intermediate A12 (155 mg, 521 μmol) in DCE (10 mL). The mixture was stirred overnight at 90°C. The mixture was cooled to room temperature and concentrated to dryness, water (20 mL) was added, and the resulting mixture was extracted with DCM (20 mL x 2). The organic layer was dried over Na2SO4, concentrated under vacuum, and purified by Prep-TLC (petroleum ether / EtOAc = 5 / 1) to give compound 103 as a white solid (140 mg, 32% yield, 60% purity).

[1604] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.38

[1605] Example 104

[1606] 2-(3,5-Dichloro-4-(3-(1-(4-fluorophenyl)-2-methylpropyl)-4-hydroxybenzyl)phenoxy)acetic acid Synthesis of (Compound 104)

[1607]

[1608] LiOH (21 mg, 499 μmol) was added to a solution of compound 103 (140 mg, 166 μmol, 60% purity) in MeOH (3 mL) and water (1 mL). The mixture was stirred at room temperature for 1 h. Water (10 mL) was added, and the mixture was acidified to pH 4–5 with 1N HCl and extracted with DCM (10 mL). The organic layer was dried over Na₂SO₄, concentrated under vacuum, and purified by Prep-HPLC to give compound 104 (40 mg, 50% yield) as a white solid.

[1609] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0

[1610] LCMS:RT=4.181 min; [M-1]=475.1 / 477.1

[1611] 1 H NMR: (400 MHz, DMSO- d 6) δ 13.10 (s, 1H), 9.14 (s, 1H), 7.30 – 7.22(m, 2H), 7.18 (d, J = 2.2 Hz, 1H), 7.10 (s, 2H), 7.07 – 6.98 (m, 2H), 6.68(dd, J = 8.3, 2.2 Hz, 1H), 6.61 (d, J = 8.3 Hz, 1H), 4.77 (s, 2H), 4.04 (s,2H), 3.82 (d, J = 11.3 Hz, 1H), 2.45 – 2.36 (m, 1H), 0.77 (dd, J = 14.4, 6.4Hz, 6H).

[1612] Example 105

[1613] 2-(3,5-Dichloro-4-(3-(2-(4-fluorophenyl)propane-2-yl)-4-hydroxybenzyl)phenoxy)acetic acid (chemical) Synthesis of compound 105

[1614]

[1615] ZnCl2 (1M, 2.32 mL) was added to a solution of intermediate D2 (200 mg, 1.16 mmol) and intermediate A6 (395 mg, 1.16 mmol) in DCE (5 mL). The mixture was then heated to 85 °C. oThe mixture was stirred overnight at C. It was cooled to room temperature and concentrated to dryness; THF / H₂O (5 / 2 mL) and LiOH·H₂O (146 mg, 3.48 mmol) were added, and the resulting mixture was stirred at room temperature for 30 min. Water (10 mL) was added, and the mixture was acidified to pH 4–5 with 1N HCl and extracted with DCM (10 mL * 2). The organic layer was concentrated under vacuum and then purified by Prep-TLC (DCM / MeOH = 5 / 1) and Prep-HPLC to give compound 105 as a white solid (10 mg, 2% yield).

[1616] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0

[1617] 1 H NMR: (400 MHz, DMSO- d 6) δ 8.83 (s, 1H), 7.21 (d, J = 2.1 Hz, 1H),7.11 – 7.08 (m, 2H), 7.04 – 6.91 (m, 4H), 6.80 – 6.75 (m, 1H), 6.55 (d, J =8.2 Hz, 1H), 4.35 (s, 2H), 4.07 (s, 2H), 1.57 (s, 6H).

[1618] Example 106

[1619] 2-(3,5-Dichloro-4-(3-(cyclopropyl(4-fluorophenyl)methyl)-4-hydroxybenzyl)phenoxy)methyl acetate Synthesis of (Compound 106)

[1620]

[1621] Intermediate A10 (40 mg, 0.13 mmol) and ZnCl2 / THF (1 M, 0.32 mL) were added to a solution of intermediate C21 (100 mg, 0.39 mmol) in DCE (10 mL) at room temperature. The reaction mixture was heated to 95°C and maintained for 2 days. The reaction mixture was cooled to room temperature and diluted with DCM (20 mL); the resulting mixture was washed with brine (2 x 10 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by Prep-TLC (EtOAc / petroleum ether = 1 / 5) to give compound 106 (20 mg, 28% yield) as a pale yellow oil.

[1622] TLC: petroleum ether / EtOAc = 1 / 5 (v / v), Rf = 0.4

[1623] 1 H NMR: (400 MHz, DMSO) δ 9.10 (s, 1H), 7.21 (m, 3H), 7.14 (m, 3H), 7.08 – 7.01 (m, 2H), 6.77 – 6.71 (m, 1H), 6.61 (m, 1H), 4.89 (s, 2H), 4.08 –4.04 (m, 2H), 3.70 (s, 3H), 3.50 – 3.41 (m, 3H), 1.41 – 1.29 (m, 1H), 1.09(m,2H), 0.58 (m, 2H), 0.23 (m, 1H), 0.08 (m, 1H).

[1624] Example 107

[1625] 2-(3,5-Dichloro-4-(3-(cyclopropyl(4-fluorophenyl)methyl)-4-hydroxybenzyl)phenoxy)acetic acid (compound) Synthesis of substance 107

[1626]

[1627] LiOH·H₂O (5 mg, 0.12 mmol) was added to a room temperature solution of compound 106 (20 mg, 0.04 mmol) in THF / water (2 / 1 mL); the resulting mixture was stirred at room temperature for 1 h. The reaction mixture was acidified to pH ~3-4 with 2N HCl, concentrated under vacuum, and purified by Prep-HPLC to give compound 107 (4 mg, 21% yield).

[1628] TLC: petroleum ether / EtOAc = 1 / 5 (v / v), Rf = 0

[1629] LCMS:RT: 2.41min; [M+1]=472.9

[1630] 1 H NMR (400 MHz, DMSO) δ 9.02 (s, 1H), 7.12 (s, 3H), 6.96 (m, 4H), 6.64 (d, J = 7.1 Hz, 1H), 6.53 (d, J = 8.0 Hz, 1H), 4.65 (s, 2H), 3.96 (s,2H), 3.40 (s, 1H), 1.26 (s, 1H), 0.41 (d, J = 28.8 Hz, 2H), 0.13 (s, 1H), 0.00 (s, 1H).

[1631] Example 108

[1632] 2-(3,5-Dichloro-4-(3-(cyclobutyl(4-fluorophenyl)methyl)-4-hydroxybenzyl)phenoxy)methyl acetate Synthesis of (Compound 108)

[1633]

[1634] Intermediate A10 (100 mg, 0.4 mmol) and ZnCl2 (1 M, in THF) (0.8 mL) were added to a solution of intermediate C25 (287.11 mg, 1.1 mmol) in DCE (4 mL) at room temperature. The reaction mixture was heated to 85°C and stirred overnight. The reaction mixture was diluted with DCM (10 mL), washed with brine (5 mL x 3), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (EtOAc / petroleum ether = 1 / 30 to 1 / 10) to give compound 108 (90 mg, 50% yield) as a colorless oil.

[1635] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), R f =0.2

[1636] 1 H NMR (400 MHz, DMSO-) d 6) δ 9.13 (s, 1H), 7.16 (dd, J = 8.4, 6.4 Hz,2H), 7.10 (s, 2H), 7.05 – 6.98 (m, 3H), 6.72 (dd, J = 8.0, 1.6 Hz, 1H), 6.61(d, J = 8.2 Hz, 1H), 4.76 (s, 2H), 4.16 (d, J = 11.2 Hz, 1H), 4.04 (s, 2H), 2.96 (q, J = 9.4, 8.6 Hz, 1H), 1.92 – 1.61 (m, 6H).

[1637] Example 109

[1638] 2-(3,5-Dichloro-4-(3-(cyclobutyl(4-fluorophenyl)methyl)-4-hydroxybenzyl)phenoxy)acetic acid (compound) Synthesis of substance 109

[1639]

[1640] LiOH·H2O (13.3 mg, 556 μmol) was added to a mixture of compound 108 (90 mg, 185 μmol) in THF / H2O (2 mL / 0.5 mL). The mixture was stirred at room temperature for 2 h. Water (2 mL) was added, and the pH was adjusted to ~3-4 with 1N HCl. The resulting mixture was extracted with EtOAc (5 mL*3); the combined organic phases were washed with brine (15 mL), dried over Na2SO4, concentrated under vacuum, and purified by Prep-TLC (DCM / MeOH = 10 / 1) to give compound 109 (30 mg, 34% yield) as a white solid.

[1641] TLC:MeOH / DCM =1 / 10(v / v), Rf=0.25

[1642] LCMS:RT=4.394 min; [M-1]=487.0

[1643] 1 H NMR (400 MHz, DMSO-) d 6) δ 13.19 (s, 1H), 9.13 (s, 1H), 7.20 – 7.13(m, 2H), 7.10 (s, 2H), 7.06 – 6.97 (m, 3H), 6.72 (d, J = 7.2 Hz, 1H), 6.62(d, J = 8.2 Hz, 1H), 4.77 (s, 2H), 4.16 (d, J = 11.2 Hz, 1H), 4.04 (s, 2H), 3.02 – 2.93 (m, 1H), 1.90 – 1.65 (m, 5H), 1.55 – 1.45 (m, 1H).

[1644] Example 110

[1645] 2-(3,5-Dichloro-4-(3-(6-fluoro-1,2,3,4-tetrahydronaphthyl-1-yl)-4-hydroxybenzyl)phenoxy)acetic acid Synthesis of methyl ester (compound 110)

[1646]

[1647] ZnCl2 (1 M / THF) (567 μmol, 0.6 mL) was added to a solution of intermediate C27 (110 mg, 454 μmol) and intermediate A10 (65 mg, 227 μmol) in DCE (5 mL). The mixture was stirred overnight at 85°C. Water (10 mL) was added, and the mixture was extracted with DCM (5 mL x 3). The combined organic phases were washed with brine, dried over Na2SO4, concentrated under vacuum, and purified by Prep-TLC (EtOAc / petroleum ether = 1 / 5) to give compound 110 (35 mg, 31% yield) as a colorless oil.

[1648] TLC:EtOAc / petroleum ether = 1 / 5 (v / v), R f =0.2

[1649] LCMS:RT=3.298 min; [M-1]=486.9

[1650] Example 111

[1651] 2-(3,5-Dichloro-4-(3-(6-fluoro-1,2,3,4-tetrahydronaphth-1-yl)-4-hydroxybenzyl)phenoxy)acetic acid Synthesis of (Compound 111)

[1652]

[1653] LiOH·H2O (5 mg, 221 μmol) was added to a solution of compound 110 (35 mg, 74 μmol) in THF / H2O (2 mL / 0.5 mL) at room temperature. The mixture was stirred at room temperature for 2 h. The mixture was diluted with water (10 mL), acidified to pH ~3-4 with 1 N HCl, and extracted with EtOAc (5 mL * 3). The combined organic phases were washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by Prep-HPLC to give compound 111 (15 mg, 44% yield) as a white solid.

[1654] TLC:MeOH / DCM =1 / 10(v / v), Rf=0.30

[1655] LCMS:RT=4.170 min; [M-1]=473.0

[1656] 1 H NMR (400 MHz, DMSO-) d 6) δ 13.12 (s, 1H), 9.30 (s, 1H), 7.03 (s, 2H), 6.92 (dd, J= 10.0, 2.8 Hz, 1H), 6.81 (td, J = 8.4, 2.8 Hz, 1H), 6.77 – 6.69(m, 3H), 6.37 (s, 1H), 4.75 (s, 2H), 4.33 (t, J = 5.6 Hz, 1H), 3.89 (s, 2H), 3.34 (s, 2H), 2.77 (m, 2H), 1.85 (m, 2H), 1.63 (m, 2H).

[1657] 19 F NMR (376 MHz, DMSO) δ -117.90 (s).

[1658] Example 112

[1659] 2-(3,5-dichloro-4-(3-(5-fluoro-2...

Claims

1. Compounds of formula (IV): (IV) Or its pharmaceutically acceptable salt, wherein: X 1 It is a lower alkyl or halogenated; X 2 Halogenated; R 1 is - OR 1c ; R 1c For H; R 2a It is a lower alkyl group, a lower haloalkyl group, or -OR a -C(O)R a -NR a C(O)R b -C(O)OR a -S(O)2R a Halogenated or cyano; m is 0; and R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group; Lower alkyl refers to straight-chain or branched alkyl with 1 to 8 carbon atoms; and lower haloalkyl refers to straight-chain or branched alkyl with 1 to 8 carbon atoms in which one or more hydrogen atoms are replaced by halogens.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 1 Halogenated.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein X 2 It is -Cl.

4. The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein the compound has a structure selected from: 。 5. A pharmaceutical composition comprising a compound of any one of claims 1-4 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

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