Novel thyroid hormone mimetic

Abstract

A compound having the structure of formula (I): [Formula 1] JPEG2023503962000378.jpg3590 or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R 1 , R 2 , X 1 , X 2 , Y 1 , and Y 2 is as defined herein. Such compounds function as thyromimetics and are useful in treating diseases such as neurodegenerative disorders and fibrotic diseases. Pharmaceutical compositions comprising such compounds and methods for their use and preparation are also provided.

Description

[Technical Field]

[0001] This invention relates to thyromimetic compounds, products containing the same, and methods for their use and preparation.

[0002] Details of related technologies Thyroid hormones (TH) are important signals in ongoing oligodendrocyte differentiation and myelination, and also stimulate remyelination in adult models of multiple sclerosis (MS) (Calza et al., Brain Res Revs 48:339-346, 2005). However, TH is not an acceptable long-term therapy because there are limited therapeutic opportunities to achieve remyelination while avoiding the cardiotoxicity and bone demineralization associated with chronic hyperthyroidism. Some thyroid hormone analogs can activate thyroid hormone response genes while avoiding the associated downsides of TH by leveraging the molecular and physiological characteristics of thyroid hormone receptors (Malm et al., Mini Rev Med Chem 7:79-86, 2007). These receptors are expressed in two main but separate sets of target genes due to heterogeneous tissue distribution and overlap (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., Nucl Recept Signal 4:e011, 2006).

[0003] Furthermore, it has been reported that TH can inhibit transforming growth factor β (TGF-β) signaling and weaken fibrotic responses (Alonso-Merino et al., Proc Natl Acad Sci USA. 113(24):E3451-60, 2016). TGF-β is a cytokine with multifaceted effects on tissue homeostasis, which plays an important role in pathological processes such as fibrosis (Massague, Nat Rev Mol Cell Biol. 13(10):616-630, 2012). By inhibiting TGF-β signaling, TR ligands or agonists may have beneficial effects in preventing the progression of fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) or systemic sclerosis (Varga et al., Curr Opin Rheumatol. 20(6): 720-728, 2008).

[0004] The development of selective thyromimetics has been challenging due to the high sequence homology of thyroid hormone receptor subtypes, specifically the variation between the α1 and β1 forms in only one amino acid residue on the inner surface of the ligand-binding domain lumen. Despite these difficulties, TRβ-selective agonists have been reported in various populations. Scanlan et al. identified GC-1 (sovethyrom) as one of the first promising analogs to demonstrate significant TRβ selectivity 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). In this specification, the term “sovethyrom” refers to a synthetic diarylmethane derivative that has been clinically tested as a candidate therapeutic agent for hypercholesterolemia (see U.S. Patent No. 5,883,294, cited herein by reference). Other names for sovethyrom found in the literature and regulatory reports are QRX-431 and GC-1. Metabasis utilizes a similar core to its novel liver-targeted prodrug strategy in MB07811 (Erion et al., PNAS 104(39), 15490-15495, 2007). Madrigal has reported in vivo TRβ-selective activity against MGL-3196 (Taub et al., Atherosclerosis 230(2):373-380, 2013). KaroBio has reported on eprothilome (KB2115; Berkenstam et al., PNAS 105(2):663-668, 2008) and KB-141 (Ye et al., J Med Chem 46:1580-1588, 2003), both of which demonstrate improved TRβ selectivity in vitro.Further testing of this population highlights additional selective compounds (Hangeland et al., BMCL 14:3549-3553, 2004). Two TRβ-selective agonists have been identified as SKL-12846 and SKL-13784, which have been reported to accumulate in the liver of rodents and lower cholesterol levels (Takahashi et al., BMC 22(1):488-498, 2014; Xenobiotica 2015, 1-9). Kissei has also reported selective compounds (Shiohara et al., BMC 20(11), 3622-3634, 2012).

[0005] Although progress has been made in this field, there is still a need for more selective thyroid hormone mimetic compounds, as well as products containing them, and methods related to their use and preparation. [Overview of the project]

[0006] This specification describes compounds of formula I,

[0007] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is disclosed, where R 1 , R 2 , X 1 , X 2 , Y 1 , and Y 2 It is defined as follows:

[0008] 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 one embodiment, the pharmaceutical composition is intended for use in the treatment of neurodegenerative disorders, including neurodegenerative disorders classified as demyelinating diseases such as X-linked adrenoleukodystrophy or multiple sclerosis. In another embodiment, the pharmaceutical composition is intended for use in the treatment of medical conditions associated with increased TGF-β activity, such as fibrous diseases.

[0009] In one embodiment, a method is provided for treating a target neurodegenerative disorder, the method comprising the step of administering a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, or a composition containing the same. In some embodiments, the neurodegenerative disorder can be classified as a demyelinating disease such as X-linked adrenoleukodystrophy or multiple sclerosis.

[0010] In another embodiment, a method is provided for treating a medical condition associated with the overexpression of a particular TGF-β, the method comprising the step of administering a compound having the structure of formula (I), or a pharmaceutically acceptable salt thereof, or a composition containing the same. In some embodiments, the medical condition associated with the overexpression of TGF-β is a fibrous disease. [Brief explanation of the drawing]

[0011] [Figure 1] Compounds 16 and 17, which are amide prodrugs, have been shown to provide higher levels of the acidophilic compound 15 in the brain than would be achieved if compound 15 itself were administered. [Modes for carrying out the invention]

[0012] As described above, the present invention relates to thyroid hormone mimetic compounds, products containing the same, and methods for their use and synthesis.

[0013] In one embodiment, a compound having the structure of formula (I),

[0014]

Chemical formula

[0015] The acidic compound of the present invention (R 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 ) can act as a substrate for the specific hydrolase enzyme fatty acid amide hydrolase (FAAH), thereby cleaving the amide and releasing a thyroid hormone mimetic. Therefore, the prodrug conversion to the drug is enhanced in tissues that express high levels of FAAH, such as the central nervous system. Figure 1 shows that compounds 16 and 17, which are amide prodrugs, provide significantly higher levels of the acidophilic compound 15 in the brain than can be achieved by administering compound 15 itself. The ester compound (R) of the present invention 1 =-OR 1c and R 1c ≠H) is also a prodrug that is typically processed through the action of esterases that can selectively exist in specific tissues.

[0016] As used herein, “lower alkyl” means a linear 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 linear lower alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched lower alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.

[0017] As used herein, “lower alkenyl” means a linear or branched alkenyl group having 2 to 8 carbon atoms, 2 to 6 carbon atoms in some embodiments, 2 to 4 carbon atoms in some embodiments, and 2 to 3 carbon atoms in some embodiments. An alkenyl group is an unsaturated hydrocarbon containing at least one carbon-carbon double bond. Examples of lower alkenyl groups, but not limited to, include vinyl, propenyl, isopropenyl, butenyl, pentenyl, and hexenyl.

[0018] As used herein, “lower alkynyl” means a linear or branched alkynyl group having 2 to 8 carbon atoms, 2 to 6 carbon atoms in some embodiments, 2 to 4 carbon atoms in some embodiments, and 2 to 3 carbon atoms in some embodiments. An alkynyl group is an unsaturated hydrocarbon containing at least one carbon-carbon triple bond. Examples of lower alkynyl groups, but not limited to, include ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

[0019] "Halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0020] "Hydroxy" refers to the -OH group.

[0021] "Cyano" refers to -CN.

[0022] A "lower haloalkyl" refers to a lower alkyl group as defined above, which has one or more hydrogen atoms replaced by a halogen. Examples of lower haloalkyl groups include, but are not limited to, -CF3 and -CHF2.

[0023] "Lower alkoxy" refers to a lower alkyl group bonded by an oxygen atom, as defined above (i.e., -O-(lower alkyl)). Examples of lower alkoxy groups, though not limited to them, include methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, and tert-butoxy.

[0024] A "lower haloalkoxy" refers to a lower haloalkyl group bonded by an oxygen atom, as defined above (i.e., -O-(lower haloalkyl)). Examples of lower haloalkoxy groups, though not limited to them, include -OCF3 and -OCHF2.

[0025] "Cycloalkyl" refers to alkyl groups that form a ring structure that may or may not be substituted, and the ring may be fully saturated, partially unsaturated, or completely unsaturated, and if unsaturation is present, aromaticity does not arise due to π electron conjugation within the ring. Examples of cycloalkyl groups, but are not limited to, include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, cycloalkyl groups have 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms is 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups further include, but are not limited to, polycyclic cycloalkyl groups such as norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and condensed rings such as decalinyl.

[0026] A "cycloalkylalkyl" is an alkyl group as defined above, wherein the hydrogen bond or carbon bond of the alkyl group is exchanged with a bond to a cycloalkyl group as defined above.

[0027] An "aryl" group is a cyclic aromatic hydrocarbon that does not contain heteroatoms. Therefore, examples of aryl groups, though not limited to them, include phenyl, azlenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenantrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, an aryl group contains 6 to 14 carbon atoms in its ring portion. The terms "aryl" and "aryl group" include fused rings, and at least one ring is aromatic, such as a fused aromatic-aliphatic ring system (e.g., indanyl, tetrahydronaphthyl, etc.), although not all rings are aromatic. In one embodiment, the aryl is phenyl or naphthyl, and in another embodiment, it is phenyl.

[0028] A "carbocykyl," "carbocyclic," or "carbocyclic formula" is an alkyl group that forms a ring structure, and the alkyl group may or may not be substituted, and the ring may be fully saturated, partially unsaturated, or fully unsaturated, and if unsaturation is present, aromaticity may arise from the conjugation of π electrons within the ring. In one embodiment, the carbocyclic includes a cycloalkyl as defined above. In another embodiment, the carbocyclic includes an aryl as defined above.

[0029] A "carbocyclic alkyl group" is an alkyl group as defined above, in which the hydrogen bonds or carbon bonds of the alkyl group are replaced by bonds with a carbocyclyl group as defined above. Examples of carbocyclic alkyl groups, but not limited to them, include cyclopropylmethyl, cyclobutylmethyl, and benzyl.

[0030] "Heterocyclyl," "heterocyclic," or "heterocyclic formula" refers to an aromatic and non-aromatic ring portion containing three or more ring members, one or more of which are heteroatoms such as N, O, S, or P, but not limited to these. In some embodiments, a heterocyclyl group contains 3 to 20 ring members, while other such groups have 3 to 15 ring members. At least one ring contains a heteroatom, but not all rings in a polycyclic system need to contain heteroatoms. For example, the dioxolanyl ring system and the benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups to the extent defined herein.

[0031] Heterocyclyl groups further include fused ring species, including species having fused aromatic and non-aromatic groups. Heterocyclyl groups further include, but are not limited to, polycyclic ring systems containing heteroatoms such as quinuclidyl, and further include heterocyclyl groups having substituents bonded to one of the ring members, which include, but are not limited to, alkyl, halo, amino, hydroxyl, cyano, carboxyl, nitro, thio, or alkoxy groups. Heterocyclyl groups as defined herein may be heteroaryl groups or partially or fully saturated cyclic groups containing at least one ring heteroatom. The heterocyclyl group is not limited to pyrrolidinyl, furanil, tetrahydrofuranil, dioxolanil, piperidinil, piperazinil, morpholinil, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranil, dihydrobenzofuranil, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl Examples of groups include azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl.

[0032] A "heterocycle alkyl" is an alkyl group as defined above, in which the hydrogen bonds or carbon bonds of the alkyl group are replaced by bonds with a heterocyclic group as defined above.

[0033] A "heteroaryl" refers to an aromatic ring moiety containing five or more ring members, one or more of which are heteroatoms such as N, O, and S, but are not limited to these. Examples of heteroaryl groups, though not limited to them, include pyrrolyl, pyrazolyl, pyridinyl, pyridadinyl, pyrimidyl, pyrazyl, pyrazinyl, pyrimidinyl, thienyl, triazolyl, tetrazolyl, triazinyl, thiazolyl, thiophenyl, oxazolyl, isoxazolyl, benzothiophenyl, benzofuranil, indolyl, azaindolyl, indazolyl, benzimimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, and quinazolinyl. The terms "heteroaryl" and "heteroaryl group" include fused ring compounds in which at least one ring is aromatic, though not all rings are necessarily aromatic, and include tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, and 2,3-dihydroindolyl.

[0034] In one embodiment, a compound having the structure of formula (I), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, where R 2 R is a lower alkyl group optionally substituted with one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O)2R', or -S(O)2OR', where R' and R'' are independently H, a lower alkyl group, or a lower haloalkyl group. In another embodiment, R 2 R is an unsubstituted lower alkyl. In a more specific embodiment, R 2 These are methyl, ethyl, propyl, isopropyl, or butyl.

[0035] In one embodiment, a compound having the structure of formula (II),

[0036] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, in the formula, X 1 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. X 2 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. Y 1 and Y 2 Each of these is independently H, cyano, halogen, lower alkyl, or lower alkoxy, and Y 1 and Y 2 At least one of them is not H, R 1 -NR 1a R 1b OR 1c And, R 1a and R 1b Each of these is independently H, lower alkyl, lower alkenyl, lower alkynyl, and -OR. a , -NR a R b , a carbocyclic ring, a carbocyclic alkyl, a heterocyclic ring, or a heterocyclic alkyl, or R 1a and R 1b They, together with the nitrogen atom to which they are bonded, form a heterocycle. R 1c is H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl, Here, R 1a , R 1b , and R 1c Each of these is independently substituted with one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O)2R', or -S(O)2OR', where R' and R'' are independently H, a lower alkyl, or a lower haloalkyl.

[0037] In one embodiment, a compound having the structure of formula (II-A)

[0038] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, in the formula, X 1 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. X 2 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. Y 1 and Y 2 Each of these is independently H, cyano, halogen, lower alkyl, or lower alkoxy, and Y 1 and Y 2 At least one of them is not H, and also, R 1a and R 1b Each of these is independently H, lower alkyl, lower alkenyl, lower alkynyl, and -OR. a , -NR a R b , a carbocyclic ring, a carbocyclic alkyl, a heterocyclic ring, or a heterocyclic alkyl, or R 1a and R 1b They, together with the nitrogen atom to which they are bonded, form a heterocycle. Here, R 1a and R 1b Each of these is independently substituted with one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O)2R', or -S(O)2OR', where R' and R'' are independently H, a lower alkyl, or a lower haloalkyl.

[0039] In one embodiment, a compound having the structure of formula (II-B)

[0040] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, in the formula, X 1 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. X 2 is lower alkyl, lower alkenyl, lower haloalkyl, or halo, Y 1 and Y 2 are each independently H, cyano, halogen, lower alkyl, or lower alkoxy, and at least one of Y 1 and Y 2 is not H, and R 1c is H, lower alkyl, carbocycle, heterocycle, carbocyclic alkyl, or heterocyclic alkyl, wherein R 1c is optionally substituted with one or more halo, cyano, -OR’, -NR’R”, =O, =S, -S(O)2R’, or -S(O)2OR’, and R’ and R” are each independently H, lower alkyl, or lower haloalkyl.

[0041] In one embodiment, a compound having the structure of formula (III),

[0042]

Chemical formula

[0043] In one embodiment, a compound having the structure of formula (III-A)

[0044] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, in the formula, X 1 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. X 2 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. Y 1 and Y 2 Each of these is independently H, cyano, halogen, lower alkyl, or lower alkoxy, and Y 1 and Y 2 At least one of them is not H, R 1a and R 1b Each of these is independently H, lower alkyl, lower alkenyl, lower alkynyl, and -OR. a , -NR a R b , a carbocyclic ring, a carbocyclic alkyl, a heterocyclic ring, or a heterocyclic alkyl, or R 1a and R 1b They, together with the nitrogen atom to which they are bonded, form a heterocycle. Q is -C(R 3 R4 )-, or -{C(R 3 R 4 )}2-, A is an aryl or heteroaryl, R 3 and R 4 Each of these is independently H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, and -OR. a , -NR a R b , a carbocyclic ring, a heterocyclic ring, a carbocyclic alkyl or a heterocyclic alkyl, or R 3 and R 4 They come together to form =O or =S, R 5 Each of these independently includes halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocyclic alkyl, heterocyclic alkyl, and -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 And, n is between 0 and 5, and also, R a and R b Each of these is independently H, a lower alkyl, or a lower haloalkyl. Here, R 1a , R 1b , R 3 , R 4 , R 5 , R a , and R b Each of these is independently substituted with one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O)2R', or -S(O)2OR', where R' and R'' are independently H, a lower alkyl, or a lower haloalkyl.

[0045] In one embodiment, a compound having the structure of formula (III-B)

[0046] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, in the formula, X 1 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. X 2 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. Y 1 and Y 2 Each of these is independently H, cyano, halogen, lower alkyl, or lower alkoxy, and Y 1 and Y 2 At least one of them is not H, R 1c is H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl, Q is -C(R 3 R 4 )-, or -{C(R 3 R 4 )}2-, A is an aryl or heteroaryl, R 3 and R 4 Each of these is independently H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, and -OR. a , -NR a R b , a carbocyclic ring, a heterocyclic ring, a carbocyclic alkyl or a heterocyclic alkyl, or R 3 and R 4 They come together to form =O or =S, R 5 Each of these independently includes halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocyclic alkyl, heterocyclic alkyl, and -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 And, n is between 0 and 5, and also, R a and R b Each of these is independently H, a lower alkyl, or a lower haloalkyl. Here, R 1c , R 3 , R 4 , R 5 , R a , and R b Each of these is independently substituted with one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O)2R', or -S(O)2OR', where R' and R'' are independently H, a lower alkyl, or a lower haloalkyl.

[0047] In one embodiment, a compound having the structure of formula (IV),

[0048] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, in the formula, X 1 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. X 2 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. Y 1 and Y 2 Each of these is independently H, cyano, halogen, lower alkyl, or lower alkoxy, and Y 1 and Y 2 At least one of them is not H, R 1 -NR 1a R 1b OR1c And, R 1a and R 1b Each of these is independently H, lower alkyl, lower alkenyl, lower alkynyl, and -OR. a , -NR a R b , a carbocyclic ring, a carbocyclic alkyl, a heterocyclic ring, or a heterocyclic alkyl, or R 1a and R 1b They, together with the nitrogen atom to which they are bonded, form a heterocycle. R 1c is H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl, A is an aryl or heteroaryl, R 3 and R 4 Each of these is independently H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, and -OR. a , -NR a R b , a carbocyclic ring, a heterocyclic ring, a carbocyclic alkyl or a heterocyclic alkyl, or R 3 and R 4 They come together to form =O or =S, R 5 Each of these independently includes halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocyclic alkyl, heterocyclic alkyl, and -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 And, n is between 0 and 5, and also, R a and R b Each of these is independently H, a lower alkyl, or a lower haloalkyl. Here, R 1a, R 1b , R 1c , R 3 , R 4 , R 5 , R a , and R b Each of these is independently substituted with one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O)2R', or -S(O)2OR', where R' and R'' are independently H, a lower alkyl, or a lower haloalkyl.

[0049] In one embodiment, a compound having the structure of formula (IV-A)

[0050] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, in the formula, X 1 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. X 2 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. Y 1 and Y 2 Each of these is independently H, cyano, halogen, lower alkyl, or lower alkoxy, and Y 1 and Y 2 At least one of them is not H, R 1a and R 1b Each of these is independently H, lower alkyl, lower alkenyl, lower alkynyl, and -OR. a , -NR a R b , a carbocyclic ring, a carbocyclic alkyl, a heterocyclic ring, or a heterocyclic alkyl, or R 1a and R 1b They, together with the nitrogen atom to which they are bonded, form a heterocycle. A is an aryl or heteroaryl, R 3 and R 4Each of these is independently H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, and -OR. a , -NR a R b , a carbocyclic ring, a heterocyclic ring, a carbocyclic alkyl or a heterocyclic alkyl, or R 3 and R 4 They come together to form =O or =S, R 5 Each of these independently includes halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocyclic alkyl, heterocyclic alkyl, and -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 And, n is between 0 and 5, and also, R a and R b Each of these is independently H, a lower alkyl, or a lower haloalkyl. Here, R 1a , R 1b , R 3 , R 4 , R 5 , R a , and R b Each of these is independently substituted with one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O)2R', or -S(O)2OR', where R' and R'' are independently H, a lower alkyl, or a lower haloalkyl.

[0051] In one embodiment, a compound having the structure of formula (IV-B)

[0052] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, in the formula, X 1 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. X 2 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. Y 1 and Y 2 Each of these is independently H, cyano, halogen, lower alkyl, or lower alkoxy, and Y 1 and Y 2 At least one of them is not H, R 1c is H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl, A is an aryl or heteroaryl, R 3 and R 4 Each of these is independently H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, and -OR. a , -NR a R b , a carbocyclic ring, a heterocyclic ring, a carbocyclic alkyl or a heterocyclic alkyl, or R 3 and R 4 They come together to form =O or =S, R 5 Each of these independently includes halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocyclic alkyl, heterocyclic alkyl, and -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 And, n is between 0 and 5, and also, R a and R bEach of these is independently H, a lower alkyl, or a lower haloalkyl. Here, R 1c , R 3 , R 4 , R 5 , R a , and R b Each of these is independently substituted with one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O)2R', or -S(O)2OR', where R' and R'' are independently H, a lower alkyl, or a lower haloalkyl.

[0053] In one embodiment, a compound having the structure of formula (V),

[0054] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, in the formula, Q 1 Q 2 Q 3 Q 4 , and Q 5 CH and CR are independent of each other. 5 , or N, X 1 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. X 2 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. Y 1 and Y 2 Each of these is independently H, cyano, halogen, lower alkyl, or lower alkoxy, and Y 1 and Y 2 At least one of them is not H, R 1 -NR 1a R 1b OR 1c And, R 1a and R 1b Each of these is independently H, lower alkyl, lower alkenyl, lower alkynyl, and -OR.a , -NR a R b , a carbocyclic ring, a carbocyclic alkyl, a heterocyclic ring, or a heterocyclic alkyl, or R 1a and R 1b They, together with the nitrogen atom to which they are bonded, form a heterocycle. R 1c is H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl, R 3 and R 4 Each of these is independently H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, and -OR. a , -NR a R b , a carbocyclic ring, a heterocyclic ring, a carbocyclic alkyl or a heterocyclic alkyl, or R 3 and R 4 They come together to form =O or =S, R 5 Each of these independently includes halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocyclic alkyl, heterocyclic alkyl, and -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 And, n is between 0 and 5, and also, R a and R b Each of these is independently H, a lower alkyl, or a lower haloalkyl. Here, R 1a , R 1b , R 1c , R 3 , R 4 , R 5 , R a , and R bEach of these is independently substituted with one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O)2R', or -S(O)2OR', where R' and R'' are independently H, a lower alkyl, or a lower haloalkyl.

[0055] In one embodiment, a compound having the structure of formula (VA)

[0056] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, in the formula, Q 1 Q 2 Q 3 Q 4 , and Q 5 CH and CR are independent of each other. 5 , or N, X 1 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. X 2 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. Y 1 and Y 2 Each of these is independently H, cyano, halogen, lower alkyl, or lower alkoxy, and Y 1 and Y 2 At least one of them is not H, R 1a and R 1b Each of these is independently H, lower alkyl, lower alkenyl, lower alkynyl, and -OR. a , -NR a R b , a carbocyclic ring, a carbocyclic alkyl, a heterocyclic ring, or a heterocyclic alkyl, or R 1a and R 1b They, together with the nitrogen atom to which they are bonded, form a heterocycle. R 3 and R 4Each of these is independently H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, and -OR. a , -NR a R b , a carbocyclic ring, a heterocyclic ring, a carbocyclic alkyl or a heterocyclic alkyl, or R 3 and R 4 They come together to form =O or =S, R 5 Each of these independently includes halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocyclic alkyl, heterocyclic alkyl, and -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 And, n is between 0 and 5, and also, R a and R b Each of these is independently H, a lower alkyl, or a lower haloalkyl. Here, R 1a , R 1b , R 3 , R 4 , R 5 , R a , and R b Each of these is independently substituted with one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O)2R', or -S(O)2OR', where R' and R'' are independently H, a lower alkyl, or a lower haloalkyl.

[0057] In one embodiment, a compound having the structure of formula (VB)

[0058] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, in the formula, Q 1 Q 2 Q 3 Q 4 , and Q 5 CH and CR are independent of each other. 5 , or N, X 1 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. X 2 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. Y 1 and Y 2 Each of these is independently H, cyano, halogen, lower alkyl, or lower alkoxy, and Y 1 and Y 2 At least one of them is not H, R 1c is H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl, R 3 and R 4 Each of these is independently H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, and -OR. a , -NR a R b , a carbocyclic ring, a heterocyclic ring, a carbocyclic alkyl or a heterocyclic alkyl, or R 3 and R 4 They come together to form =O or =S, R 5 Each of these independently includes halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocyclic alkyl, heterocyclic alkyl, and -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 And, n is between 0 and 5, and also, R a and R b Each of these is independently H, a lower alkyl, or a lower haloalkyl. Here, R 1c , R 3 , R 4 , R 5 , R a , and R b Each of these is independently substituted with one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O)2R', or -S(O)2OR', where R' and R'' are independently H, a lower alkyl, or a lower haloalkyl.

[0059] In one embodiment, a compound having the structure of formula (VI),

[0060] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, in the formula, X 1 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. X 2 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. Y 1 and Y 2 Each of these is independently H, cyano, halogen, lower alkyl, or lower alkoxy, and Y 1 and Y 2 At least one of them is not H, R 1 -NR 1a R 1b OR 1c And, R 1a and R 1b Each of these is independently H, lower alkyl, lower alkenyl, lower alkynyl, and -OR. a , -NR aR b , a carbocyclic ring, a carbocyclic alkyl, a heterocyclic ring, or a heterocyclic alkyl, or R 1a and R 1b They, together with the nitrogen atom to which they are bonded, form a heterocycle. R 1c is H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl, R 3 and R 4 Each of these is independently H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, and -OR. a , -NR a R b , a carbocyclic ring, a heterocyclic ring, a carbocyclic alkyl or a heterocyclic alkyl, or R 3 and R 4 They come together to form =O or =S, R 5 Each of these independently includes halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocyclic alkyl, heterocyclic alkyl, and -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 And, n is between 0 and 5, and also, R a and R b Each of these is independently H, a lower alkyl, or a lower haloalkyl. Here, R 1a , R 1b , R 1c , R 3 , R 4 , R 5 , R a , and R bEach of these is independently substituted with one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O)2R', or -S(O)2OR', where R' and R'' are independently H, a lower alkyl, or a lower haloalkyl.

[0061] In one embodiment, a compound having the structure of formula (VI-A)

[0062] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, in the formula, X 1 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. X 2 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. Y 1 and Y 2 Each of these is independently H, cyano, halogen, lower alkyl, or lower alkoxy, and Y 1 and Y 2 At least one of them is not H, R 1a and R 1b Each of these is independently H, lower alkyl, lower alkenyl, lower alkynyl, and -OR. a , -NR a R b , a carbocyclic ring, a carbocyclic alkyl, a heterocyclic ring, or a heterocyclic alkyl, or R 1a and R 1b They, together with the nitrogen atom to which they are bonded, form a heterocycle. R 3 and R 4 Each of these is independently H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, and -OR. a , -NR a R b , a carbocyclic ring, a heterocyclic ring, a carbocyclic alkyl or a heterocyclic alkyl, or R 3 and R 4They come together to form =O or =S, R 5 Each of these independently includes halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocyclic alkyl, heterocyclic alkyl, and -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 And, n is between 0 and 5, and also, R a and R b Each of these is independently H, a lower alkyl, or a lower haloalkyl. Here, R 1a , R 1b , R 3 , R 4 , R 5 , R a , and R b Each of these is independently substituted with one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O)2R', or -S(O)2OR', where R' and R'' are independently H, a lower alkyl, or a lower haloalkyl.

[0063] In one embodiment, a compound having the structure of formula (VI-B)

[0064] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, in the formula, X 1 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. X 2 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. Y 1 and Y 2 Each of these is independently H, cyano, halogen, lower alkyl, or lower alkoxy, and Y 1 and Y 2 At least one of them is not H, R 1c is H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl, R 3 and R 4 Each of these is independently H, halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, and -OR. a , -NR a R b , a carbocyclic ring, a heterocyclic ring, a carbocyclic alkyl or a heterocyclic alkyl, or R 3 and R 4 They come together to form =O or =S, R 5 Each of these independently includes halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocyclic alkyl, heterocyclic alkyl, and -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 And, n is between 0 and 5, and also, R a and R b Each of these is independently H, a lower alkyl, or a lower haloalkyl. Here, R 1c , R 3 , R 4 , R 5 , R a , and R bEach of these is independently substituted with one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O)2R', or -S(O)2OR', where R' and R'' are independently H, a lower alkyl, or a lower haloalkyl.

[0065] In one embodiment, a compound having the structure of formula (VII),

[0066] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, in the formula, X 1 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. X 2 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. Y 1 and Y 2 Each of these is independently H, cyano, halogen, lower alkyl, or lower alkoxy, and Y 1 and Y 2 At least one of them is not H, R 1 -NR 1a R 1b OR 1c And, R 1a and R 1b Each of these is independently H, lower alkyl, lower alkenyl, lower alkynyl, and -OR. a , -NR a R b , a carbocyclic ring, a carbocyclic alkyl, a heterocyclic ring, or a heterocyclic alkyl, or R 1a and R 1b They, together with the nitrogen atom to which they are bonded, form a heterocycle. R 1c is H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl, A is an aryl or heteroaryl, R 5Each of these independently includes halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocyclic alkyl, heterocyclic alkyl, and -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 And, n is between 0 and 5, and also, R a and R b Each of these is independently H, a lower alkyl, or a lower haloalkyl. Here, R 1a , R 1b , R 1c , R 5 , R a , and R b Each of these is independently substituted with one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O)2R', or -S(O)2OR', where R' and R'' are independently H, a lower alkyl, or a lower haloalkyl.

[0067] In one embodiment, a compound having the structure of formula (VII-A)

[0068] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, in the formula, X 1 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. X 2 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. Y 1 and Y 2Each of these is independently H, cyano, halogen, lower alkyl, or lower alkoxy, and Y 1 and Y 2 At least one of them is not H, R 1a and R 1b Each of these is independently H, lower alkyl, lower alkenyl, lower alkynyl, and -OR. a , -NR a R b , a carbocyclic ring, a carbocyclic alkyl, a heterocyclic ring, or a heterocyclic alkyl, or R 1a and R 1b They, together with the nitrogen atom to which they are bonded, form a heterocycle. A is an aryl or heteroaryl, R 5 Each of these independently includes halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocyclic alkyl, heterocyclic alkyl, and -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 And, n is between 0 and 5, and also, R a and R b Each of these is independently H, a lower alkyl, or a lower haloalkyl. Here, R 1a , R 1b , R 5 , R a , and R b Each of these is independently substituted with one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O)2R', or -S(O)2OR', where R' and R'' are independently H, a lower alkyl, or a lower haloalkyl.

[0069] In one embodiment, a compound having the structure of formula (VII-B)

[0070] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, in the formula, X 1 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. X 2 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. Y 1 and Y 2 Each of these is independently H, cyano, halogen, lower alkyl, or lower alkoxy, and Y 1 and Y 2 At least one of them is not H, R 1c is H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl, A is an aryl or heteroaryl, R 5 Each of these independently includes halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocyclic alkyl, heterocyclic alkyl, and -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 And, n is between 0 and 5, and also, R a and R b Each of these is independently H, a lower alkyl, or a lower haloalkyl. Here, R 1a , R 1b , R 1c , R5 , R a , and R b Each of these is independently substituted with one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O)2R', or -S(O)2OR', where R' and R'' are independently H, a lower alkyl, or a lower haloalkyl.

[0071] In one embodiment, a compound having the structure of formula (VIII),

[0072] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, in the formula, X 1 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. X 2 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. Y 1 and Y 2 Each of these is independently H, cyano, halogen, lower alkyl, or lower alkoxy, and Y 1 and Y 2 At least one of them is not H, R 1 -NR 1a R 1b OR 1c And, R 1a and R 1b Each of these is independently H, lower alkyl, lower alkenyl, lower alkynyl, and -OR. a , -NR a R b , a carbocyclic ring, a carbocyclic alkyl, a heterocyclic ring, or a heterocyclic alkyl, or R 1a and R 1b They, together with the nitrogen atom to which they are bonded, form a heterocycle. R 1c is H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl, R5 Each of these independently includes halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocyclic alkyl, heterocyclic alkyl, and -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 And, n is between 0 and 5, and also, R a and R b Each of these is independently H, a lower alkyl, or a lower haloalkyl. Here, R 1a , R 1b , R 1c , R 5 , R a , and R b Each of these is independently substituted with one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O)2R', or -S(O)2OR', where R' and R'' are independently H, a lower alkyl, or a lower haloalkyl.

[0073] In one embodiment, a compound having the structure of formula (VIII-A)

[0074] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, in the formula, X 1 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. X 2 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. Y 1 and Y 2Each of these is independently H, cyano, halogen, lower alkyl, or lower alkoxy, and Y 1 and Y 2 At least one of them is not H, R 1a and R 1b Each of these is independently H, lower alkyl, lower alkenyl, lower alkynyl, and -OR. a , -NR a R b , a carbocyclic ring, a carbocyclic alkyl, a heterocyclic ring, or a heterocyclic alkyl, or R 1a and R 1b They, together with the nitrogen atom to which they are bonded, form a heterocycle. R 5 Each of these independently includes halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocyclic alkyl, heterocyclic alkyl, and -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 And, n is between 0 and 5, and also, R a and R b Each of these is independently H, a lower alkyl, or a lower haloalkyl. Here, R 1a , R 1b , R 5 , R a , and R b Each of these is independently substituted with one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O)2R', or -S(O)2OR', where R' and R'' are independently H, a lower alkyl, or a lower haloalkyl.

[0075] In one embodiment, a compound having the structure of formula (VIII-B)

[0076] [ka] Alternatively, a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, in the formula, X 1 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. X 2 These are lower alkyl, lower alkenyl, lower haloalkyl, or halo. Y 1 and Y 2 Each of these is independently H, cyano, halogen, lower alkyl, or lower alkoxy, and Y 1 and Y 2 At least one of them is not H, R 1c is H, lower alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl, R 5 Each of these independently includes halo, cyano, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocyclic, heterocyclic, carbocyclic alkyl, heterocyclic alkyl, and -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 And, n is between 0 and 5, and also, R a and R b Each of these is independently H, a lower alkyl, or a lower haloalkyl. Here, R 1a , R 1b , R 1c , R 5 , R a , and R bEach of these is independently substituted with one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O)2R', or -S(O)2OR', where R' and R'' are independently H, a lower alkyl, or a lower haloalkyl.

[0077] In one embodiment, compounds having any one structure of formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), or pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts thereof are provided. 3 is H

[0078] In one embodiment, compounds having the structures of formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), or pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts thereof are provided. 3 is a carbon ring. In one embodiment, R 3 It is cyclopropyl or cyclobutyl.

[0079] In one embodiment, compounds having any one structure of formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), or pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts thereof are provided. 3 is a lower alkyl group. In one embodiment, R 3 It is methyl, ethyl, or propyl.

[0080] In one embodiment, compounds having any one structure of formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), or pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts thereof are provided. 3 は-OR a In one embodiment, R a is H. In one embodiment, R a is a lower alkyl group. In a more specific embodiment, R a It is methyl.

[0081] In one embodiment, compounds having any one structure of formula (I), formula (II), formula (II-A), formula (III), formula (III-A), formula (IV), formula (IV-A), formula (V), formula (VA), formula (VI), formula (VI-A), formula (VII), formula (VII-A), formula (VIII), formula (VIII-A), or pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts thereof are provided. 1 -NR 1a R 1b And R 1b H is H.

[0082] In one embodiment, compounds having any one structure of formula (I), formula (II), formula (II-A), formula (III), formula (III-A), formula (IV), formula (IV-A), formula (V), formula (VA), formula (VI), formula (VI-A), formula (VII), formula (VII-A), formula (VIII), formula (VIII-A), or pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts thereof are provided. 1 -NR 1a R 1b And R 1a H is H.

[0083] In one embodiment, compounds having any one structure of formula (I), formula (II), formula (II-B), formula (III), formula (III-B), formula (IV), formula (IV-B), formula (V), formula (VB), formula (VI), formula (VI-B), formula (VII), formula (VII-B), formula (VIII), formula (VIII-B), or pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts thereof are provided. 1 は-OR 1c And R 1c H is H.

[0084] In one embodiment, compounds having any one structure of formula (I), formula (II), formula (II-B), formula (III), formula (III-B), formula (IV), formula (IV-B), formula (V), formula (VB), formula (VI), formula (VI-B), formula (VII), formula (VII-B), formula (VIII), formula (VIII-B), or pharmaceutically acceptable isomers, racemates, hydrates, solvates, isotopes, or salts thereof are provided. 1 は-OR 1c And R 1c is a lower alkyl group. In one embodiment, R 1c It is methyl or ethyl.

[0085] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, where X 1 is a lower alkyl group. In one embodiment, X 1 It is methyl.

[0086] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, where X 1 is a halo. In one embodiment, X 1 is Cl or Br. In one embodiment, X 1 is Cl. In one embodiment, X 1 It is Br.

[0087] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, where X 1 is a lower haloalkyl. In one embodiment, X 1 It is -CF3.

[0088] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, where X 1is a lower alkenyl. In one embodiment, X 1 In another embodiment, X is vinyl, and in another embodiment, X 1 It is isopropenyl.

[0089] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, X 2 is a lower alkyl group. In one embodiment, X 2 It is methyl.

[0090] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, X 2 is a halo. In one embodiment, X 2 is Cl or Br. In one embodiment, X 2 is Cl. In one embodiment, X 2 It is Br.

[0091] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, X 2 is a lower haloalkyl. In one embodiment, X 2 It is -CF3.

[0092] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, X 2 is a lower alkenyl. In one embodiment, X 2 In another embodiment, X is vinyl, and in another embodiment, X 2 It is isopropenyl.

[0093] In one embodiment, a compound having any one structure of formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, and at least one R 5 It is a lower alkyl group.

[0094] In one embodiment, a compound having any one structure of formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, and at least one R 5 R' is a lower alkyl group substituted with -OR'. In one embodiment, R' is H. In another embodiment, R' is a lower alkyl group.

[0095] In one embodiment, a compound having any one structure of formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, and at least one R 5 It is a lower haloalkyl.

[0096] In one embodiment, a compound having any one structure of formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, and at least one R 5 は-OR a In one embodiment, R a is a lower alkyl group. In one embodiment, R a It is a lower haloalkyl.

[0097] In one embodiment, a compound having any one structure of formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, and at least one R 5 -C(O)R a In one embodiment, R a It is a lower alkyl group.

[0098] In one embodiment, a compound having any one structure of formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, and at least one R 5 -NR a C(O)R b In one embodiment, R a H is R b is a lower alkyl group. In one embodiment, R b It is methyl.

[0099] In one embodiment, a compound having any one structure of formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, and at least one R 5 is -C(O)OR a In one embodiment, Ra is a lower alkyl group. In one embodiment, R a It is methyl or ethyl.

[0100] In one embodiment, a compound having any one structure of formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, and at least one R 5 -S(O)2R a In one embodiment, R a is a lower alkyl group. In one embodiment, R a It is methyl.

[0101] In one embodiment, a compound having any one structure of formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, and at least one R 5 is a halo. In one embodiment, at least one R 5 It is F.

[0102] In one embodiment, a compound having any one structure of formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, and at least one R5 It is cyano.

[0103] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided. 1 is a halogen. In one embodiment, Y 1 is F. In one embodiment, Y 1 It is Cl.

[0104] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided. 1 It is cyano.

[0105] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided. 1 It is a lower alkyl group.

[0106] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided. 1 It is a lower alkoxy.

[0107] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided. 1 H is H.

[0108] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided. 2 is a halogen. In one embodiment, Y 2 is F. In one embodiment, Y 2 It is Cl.

[0109] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided. 2 It is cyano.

[0110] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided. 2 It is a lower alkyl group.

[0111] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided. 2 It is a lower alkoxy.

[0112] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided. 2 H is H.

[0113] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided. 1 F is Y 2 H is H.

[0114] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided. 1 Cl is Y 2 H is H.

[0115] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided. 1 is cyano, Y 2 H is H.

[0116] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided. 1 Y is a lower alkyl group. 2 H is H.

[0117] In one embodiment, a compound having any one structure of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (VA), formula (VB), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided. 1 Y is a lower alkoxy, 2 H is H.

[0118] In one embodiment, a compound having any one of the structures of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (V-A), formula (V-B), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, where Y 1 is H, and Y 2 is F.

[0119] In one embodiment, a compound having any one of the structures of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (V-A), formula (V-B), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, where Y 1 is H, and Y 2 is Cl.

[0120] In one embodiment, a compound having any one of the structures of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (V-A), formula (V-B), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, where Y 1 is H, and Y 2 is cyano.

[0121] In one embodiment, a compound having any one of the structures of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (V-A), formula (V-B), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, wherein Y 1 is H, and Y 2 is lower alkyl.

[0122] In one embodiment, a compound having any one of the structures of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (V-A), formula (V-B), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, wherein Y 1 is H, and Y 2 is lower alkoxy.

[0123] In one embodiment, a compound having any one of the structures of formula (I), formula (II), formula (II-A), formula (II-B), formula (III), formula (III-A), formula (III-B), formula (IV), formula (IV-A), formula (IV-B), formula (V), formula (V-A), formula (V-B), formula (VI), formula (VI-A), formula (VI-B), formula (VII), formula (VII-A), formula (VII-B), formula (VIII), formula (VIII-A), formula (VIII-B), or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof is provided, wherein Y 1 is F, and Y 2 is F.

[0124] Representative compounds of formulas (I) and (II) to (VIII-B) (where applicable) include the compounds listed in Table 1 below and their pharmaceutically acceptable salts. Therefore, representative compounds are identified herein by their respective "Compound Numbers," which are sometimes abbreviated as "Compound No.", "Cmpd. No.", or "No.".

[0125] [Table 1-1]

[0126] [Table 1-2]

[0127] [Table 1-3]

[0128] [Table 1-4]

[0129] [Table 1-5]

[0130] [Table 1-6]

[0131] [Table 1-7]

[0132] [Table 1-8]

[0133] Table 1-9

[0134] Table 1-10

[0135] Table 1-11

[0136] Table 1-12

[0137] Table 1-13

[0138] Table 1-14

[0139] Table 1-15

[0140] Table 1-16

[0141] Table 1-17

[0142] Table 1-18

[0143] Table 1-19

[0144] Table 1-20

[0145] Table 1-21

[0146] Table 1-22

[0147] Table 1-23

[0148] Table 1-24

[0149] Table 1-25

[0150] Table 1-26

[0151] Table 1-27

[0152] Table 1-28

[0153] Unless otherwise specified, the term “isomer” is used herein to encompass all chiral, diasthretheomer, or racemic forms of a given structure. As is evident from the description, such compounds may contain concentrated or divided optical isomers at any degree of concentration with respect to any or all chiral atoms. Both racemic and diastereomer mixtures can be synthesized substantially free of enantiomer or diastereomer partners, as well as individual optical isomers, and these are all within the scope of specific embodiments of the present invention. Isomers resulting from the presence of a chiral center include a pair of non-superimal isomers called “enantiomers.” A single enantiomer of a pure compound is optically active (i.e., they can rotate the plane of plane polarization and are designated R or S).

[0154] "Isolated optical isomer" means a compound substantially purified from the corresponding optical isomer of the same formula. For example, the isolated isomer may be at least about 80% by weight, at least 80% by weight, or at least 85% by weight pure. In other embodiments, the isolated isomer may be at least 90% by weight pure, at least 98% by weight pure, or at least 99% by weight pure.

[0155] "Substantially enantiomerically" pure means a level of enantiomerically or diasleteomerically enrichment of one enantiomer with respect to another enantiomer or diasleteomer of at least about 80%, more specifically, greater than 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, or 99.9%.

[0156] The terms “racemate” and “racemic mixture” refer to an equal mixture of two enantiomers. Racemates are not non-optically active (i.e., their constituent enantiomers cancel each other out, so they do not rotate plane-polarized light in any direction) and are therefore labeled with “(±)”. All compounds with an asterisk (*) adjacent to a tertiary or quaternary carbon are optically active isomers and can be purified from their respective racemates and / or synthesized by appropriate chiral synthesis.

[0157] A "hydrate" is a compound that exists in combination with water molecules. This combination may include water in scientific quantities, such as monohydrates or dihydrates, or in any quantity. When used herein, "hydrate" refers to the solid form. That is, a compound in an aqueous solution can be hydrated, but is not considered a hydrate in the context of this specification.

[0158] A “solvate” is similar to a hydrate, except that a solvent other than water is present. For example, methanol or ethanol can form an “alcolate,” which can again be stoichiometric or nonstoichiometric. When this term is used herein, “solvate” refers to the solid form. That is, a compound in a solvent solution can be solvated, but is not a solvate when used herein.

[0159] An "isotope" refers to an atom that has the same number of protons but different numbers of neutrons. The isotopes of the compound in 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 6 protons and 6 neutrons, carbon-13 has 6 protons and 7 neutrons, and carbon-14 has 6 protons and 8 neutrons. Hydrogen has two stable isotopes: deuterium (1 proton and 1 neutron) and tritium (1 proton and 2 neutrons). Fluorine has many isotopes, but fluorine-19 is the longest-lived. Therefore, 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 with carbon-13 and / or carbon-14 atoms, one or more hydrogen atoms are replaced with deuterium and / or tritium, and / or one or more fluorine atoms are replaced with fluorine-19.

[0160] The term "salt" usually refers to an organic compound, such as a carboxylic acid or amine, in the form of an ion 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."

[0161] The term "pharmaceutically acceptable" refers to a drug that is approved for human use and is typically non-toxic. For example, the term "pharmaceutically acceptable salt" refers to a non-toxic inorganic or organic acid and / or base addition salt (see, e.g., Lit et al., Salt Selection for Basic Drugs, Int J.Pharm., 33, 1986 201-217, incorporated herein by reference).

[0162] The pharmaceutically acceptable base addition salts of the compounds of the present invention include metal salts, such as alkali metal salts, alkaline earth metal salts, and transition metal salts, including calcium salts, magnesium salts, potassium salts, sodium salts, and zinc salts. The pharmaceutically acceptable base addition salts also include organic salts made from basic amines such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), tromethamine (tris-hydroxymethylmethylamine), and procaine.

[0163] pharmaceutically acceptable acid addition salts may be prepared from inorganic 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 may be selected from the aliphatic, alicyclic, aromatic, aromaticaliphatic, heterocyclic, carboxylated, and sulfone classes of organic acids, examples of which 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, pyruvate, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, and phenylacetic acid. It contains mandelic acid, hippuric acid, malonic acid, oxalic acid, embonic acid (pamoic acid), methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylaminosulfonic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactaric acid, and galacturonic acid.

[0164] Salts that are not pharmaceutically acceptable are generally not useful as pharmaceuticals, but such salts may be useful as intermediates in the synthesis of compounds having the structure of formula I, for example, in purification by recrystallization. In certain embodiments, the present invention provides pharmaceutical compositions comprising the compound of the present invention and at least one pharmaceutically acceptable carrier, diluent, or excipient. For example, the active compound is usually mixed with a carrier, diluted by a carrier, or encapsulated in 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 may be a solid, semi-solid, or liquid material which acts as a vehicle, excipient, or culture medium for the active compound. The active compound may be adsorbed, for example, on a granular solid carrier in a pouch. Some examples of suitable carriers include water, salt solutions, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, clay, sucrose, dextrin, magnesium carbonate, sugars, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone. Similarly, carriers or diluents may include any sustained-release material known in the art, such as glyceryl monostearate or glyceryl distearate, either alone or mixed with wax.

[0165] 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 on a pharmaceutically acceptable carrier which may also contain other excipients, and manufactured and marketed with the approval of a government regulatory authority as part of a therapeutic regimen for the treatment of diseases of mammals. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage forms (e.g., tablets, capsules, caplets, gel caps, or syrups), for topical administration (e.g., as creams, gels, lotions, or ointments), for intravenous administration (e.g., as sterile solutions without microparticle studs, and in solvent systems suitable for intravenous use), or in other formulations described herein. Conventional procedures and components for the selection and preparation of appropriate formulations are described in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005), published in 2013, and in The United States Pharmacopeia: The National Formulary (USP 36 NF31).

[0166] 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., carriers capable of suspending or dissolving the active compound) that has non-toxic and non-inflammatory properties in the patient. Excipients may include, for example: anti-tackifiers, antioxidants, binders, coatings, compression aids, disintegrants, pigments (colorants), emollients, emulsifiers, fillers (diluents), film-forming agents or coatings, flavorings, fragrances, lubricants (flow enhancers), preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or waters of hydration. Exemplary excipients include, but are not limited to, butylated hydroxytoluene (BHT), calcium carbonate, dibase calcium phosphate, calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose (methylcelluloFse), methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0167] The formulation can be mixed with adjuvants that do not react adversely with the active compound. These adjuvants may include wetting agents, emulsifiers and suspending agents, salts affecting osmotic pressure, buffers, and / or colorants, preservatives, sweeteners, or flavorings. The composition may also be sterilized as needed.

[0168] The route of administration may be any route that effectively delivers the active compound of the present invention to the appropriate or desired site of action, for example, orally, nasally, pulmonaryly, buccally, subcutaneously, intradermally, transdermally, or parenterally, including intravenously, subcutaneously, and / or intramuscularly. In one embodiment, the route of administration is orally.

[0169] The dosage form can be administered once daily, or more than once daily, for example, twice or three times daily. Alternatively, the dosage form can be administered less frequently than daily, such as every other day or weekly, if preferred by the prescribing physician or the drug's prescribing information. Dosage regimens may include, for example, dose escalations to the extent necessary or useful for the symptoms being treated, thereby allowing the patient's body to adapt to the treatment, minimizing or avoiding undesirable side effects associated with the treatment, and / or maximizing the therapeutic effect of the compound. Other dosage forms include delayed-release or controlled-release forms. Appropriate dosing regimens and / or forms include, for example, those described in the latest edition of the Physicians' Desk Reference incorporated herein by reference.

[0170] In another embodiment, a method is provided for producing a composition of the compounds described herein, comprising the step of formulating the compound of the present invention using 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 may further include the step of lyophilizing the composition to form a lyophilized preparation.

[0171] In another embodiment, a method is provided for treating a subject with a neurodegenerative disease, the method comprising administering 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, to the subject. 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 or is related to an X-linked genetic disease, leukodystrophy, dementia, tauopathy, or ischemic stroke. In another embodiment, demyelinating diseases include adult Refsum disease, Alexander disease, Alzheimer's disease, Barlow concentric sclerosis, Canavan disease, central pontine myelinoclastic disintegration (CPM), cerebral palsy, cerebral tendon xanthomatous neuropathy, chronic inflammatory demyelinating polyneuropathy (CIDP), Devick syndrome, diffuse myelinoclastic sclerosis, encephalomyelitis, idiopathic inflammatory demyelinating disease (IIDD), infantile Refsum disease, Krabbe disease, Leber hereditary optic neuropathy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy, multifocal motor neuropathy, and paraproteinemic demyelinating polyneuropathy. The demyelinating disease is or is related to polyneuropathy, Pelizaeus-Merzbach disease, peroneal atrophy, progressive multifocal leukoencephalopathy, transverse myelitis, tropical spastic paraplegia, van der Knaap disease, or Zellweger syndrome. In one embodiment, the demyelinating disease is or is related to multiple sclerosis, MCT8 deficiency, X-linked adrenoleukodystrophy (ALD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia, or pituitary stroke.

[0172] As used herein, the term “neurodegenerative disease” refers to any type of disease characterized by progressive deterioration of the nervous system.

[0173] In this specification, the term “desylenesis” refers to any disorder or condition of the nervous system in which myelin is damaged, lost, or the growth or development of the myelin sheath is impaired. Demyelinating disorders disrupt the conduction of signals in the affected nerves, causing impairment in sensory, motor, cognitive, or other nerve-related functions. Demyelinating disorders can have a variety of causes and can be hereditary or acquired. In some cases, demyelinating disorders are caused by infectious agents, autoimmune reactions, toxic substances, or trauma. In other cases, the cause of demyelinating disorders is unknown ("idiopathic") or they develop as a result of a combination of factors.

[0174] As used herein, the term “leukodystrophy” refers to a group of diseases that affect the growth or development of the myelin sheath.

[0175] As used herein, the term “leukoencephalopathy” refers to any of the group of diseases affecting the white matter of the brain, and may specifically refer to several diseases, including, for example, “leukodystrophy” and “toxic leukoencephalopathy.” Leukoencephalopathy is a leukodystrophy-like disease.

[0176] As used herein, the term “tauopathy” refers to tau-related disorders or diseases, such as Alzheimer’s disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick’s disease (PiD), argyrophilic grain disease (AGD), frontotemporal dementia and parkinsonism associated with chromosome 17 (FTDP-17), Parkinson’s disease, stroke, traumatic brain injury, and mild cognitive impairment.

[0177] As used herein, the terms “multiple sclerosis” and “MS” refer to a slowly progressive CNS disease characterized by scattered demyelination patches in the brain and spinal cord, resulting in a wide variety of neurological symptoms and signs, usually with periods of remission and exacerbation. The cause of MS is unknown, but an immune disorder is suspected. Familial occurrence suggests genetic susceptibility, and the disease is slightly more prevalent in women than in men. Symptoms of MS include weakness, lack of coordination, paresthesia, speech disorders, and visual disturbances, most commonly diplopia. More specific signs and symptoms vary depending on the location of the lesions and the severity and destructiveness of the inflammatory and sclerotic processes. Relapsing-remitting multiple sclerosis (RRMS) is a clinical course of MS characterized by clearly defined acute attacks, complete or partial recovery, and no disease progression between attacks. Secondary progressive multiple sclerosis (SPMS) is a clinical course of MS that initially presents as a relapsing-remitting type, and then progresses at varying rates with occasional relapses and minor remissions. Primary progressive multiple sclerosis (PPMS) initially presents as a progressive type. Clinically isolated syndrome is the first neurological episode, caused by inflammation / demyelination in one or more sites of the central nervous system (CNS). Relapsing-progressive multiple sclerosis (PRMS) is a rare form of MS (~5%) characterized by steady disease progression from onset, with acute relapses but no remissions.

[0178] In yet another embodiment, a method is provided for treating a subject with an X-linked genetic disorder, the method comprising administering 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, to the subject. In one embodiment, the X-linked genetic disorder is MCT8 deficiency or X-linked adrenoleukodystrophy (ALD).

[0179] In another embodiment, a method is provided for treating a subject with leukodystrophy, the method comprising administering 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, to the subject. In one embodiment, the leukodystrophy is adrenoleukodystrophy (ALD), adrenoleukodystrophy (AMN), cerebral morphology of adrenoleukodystrophy (cALD), metachromatic leukodystrophy (MLD), Canavan disease, or Krabbe disease (globoid leukodystrophy). In this specification, the terms “adrenoleukodystrophy” or “AMN” refer to an adult variant of X-linked adrenoleukodystrophy characterized by an ABCD1 gene mutation, resulting in peroxisome dysfunction with accumulation of very long-chain fatty acids (VLCFAs) and demyelination.

[0180] In one embodiment, a method is provided for treating a subject with a tauopathy, the method comprising administering 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, to the subject. In one embodiment, the tauopathy is Alzheimer's disease, frontotemporal dementia, primary age-related tauopathy (PART), Pick's disease, or frontotemporal dementia and parkinsonism associated with chromosome 17 (FTDP-17).

[0181] In yet another embodiment, a method is provided for treating a subject with ischemic stroke, the method comprising administering 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, to the subject. In one embodiment, the ischemic stroke is a lacunar stroke (also known as a lacunar infarction). In another embodiment, the method is used to treat a subject suffering from lacunar stroke syndrome (LACS).

[0182] In another embodiment, the following conditions are included: adult Refsum disease, infant Refsum disease, Alexander disease, Alzheimer's disease, Barlow concentric sclerosis, Canavan disease, central pontine myelinoclastic disintegration (CPM), cerebral palsy, cerebral tendon xanthomatous neuropathy, chronic inflammatory demyelinating polyneuropathy (CIDP), Devick syndrome, diffuse myelinoclastic sclerosis, encephalomyelitis, idiopathic inflammatory demyelinating disease (IIDD), Krabbe disease, Leber hereditary optic neuropathy, leukodystrophy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy (MLD), multifocal motor neuropathy (MMN), multiple sclerosis (MS), and paraproteinemic demyelinating polyneuropathy. A method is provided for treating polyneuropathy, Pelizaeus-Merzbach disease (PMD), progressive multifocal leukoencephalopathy (PML), tropical spastic paraplegia (TSP), X-linked adrenoleukodystrophy (X-ALD, ALO, or X-linked ALO), or Zellweger syndrome, the method comprising administering 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, to a target.

[0183] In one embodiment, the demyelinating disease is multiple sclerosis. In another embodiment, the demyelinating disease is X-linked adrenoleukodystrophy (ALD).

[0184] Another embodiment provides a method for treating a subject with amyotrophic lateral sclerosis (ALS), the method comprising administering 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, to the subject. In one embodiment, ALS is sporadic or familial ALS, or ALS associated with superoxide dismutase-1 mutations.

[0185] 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 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, to the subject. In one embodiment, the medical condition associated with increased TGF-β activity is a fibrous disease. In another embodiment, the fibrous disease is or is associated with non-alcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis (IPF), systemic scleroderma, or Alport syndrome. As used herein, the term “Alport syndrome” refers to a genetic disorder caused by mutations in the a3a4a5(IV) collagen network gene, resulting in structural defects of the glomerular basement membrane (GBM) early in development, followed by disruption of the hyperbarrier, development of renal fibrosis, and renal failure.

[0186] In this specification, the term “fibrous disease” refers to a disease, disorder, or condition that is treatable with the administration of compounds having antifibrotic activity. Fibrous diseases include, but are not limited to, pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis of known etiology, hepatic fibrosis, and renal fibrosis. Other exemplary fibrous diseases include musculoskeletal fibrosis, cardiac fibrosis, postoperative adhesions, scleroderma, glaucoma, and skin lesions such as keloids.

[0187] In another embodiment, a method is provided for treating subjects with liver diseases including NASH, NAFLD, NAFLD with hyperlipidemia, alcoholic liver disease / alcoholic steatohepatitis, hepatic fibrosis associated with viral infection (HBV, HCV), fibrosis associated with biliary diseases (primary biliary cholangitis, primary sclerosing cholangitis), (familial) hypercholesterolemia, dyslipidemia, hereditary dyslipidemia, cirrhosis, alcohol-induced fibrosis, hemochromatosis, glycogen storage disease, α-1 antitrypsin deficiency, autoimmune hepatitis, Wilson's disease, Crigler-Nadjar syndrome, lysosomal acid lipase deficiency, and cystic fibrosis, the method comprising administering 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, to the subject.

[0188] Another embodiment provides a method for treating subjects with Alport syndrome, diabetic nephropathy, FSGS, fibrosis associated with IgA nephropathy, chronic kidney disease (CKD), post-AKI, HIV-related CKD, chemotherapy-induced CKD, nephrotoxic drug-related CKD, nephrogenic systemic fibrosis, tubulointerstitial fibrosis, glomerulosclerosis, or polycystic kidney disease (PKD), the method comprising administering 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, to the subject.

[0189] In another embodiment, IPF, ILD, pulmonary fibrosis, rheumatoid arthritis, scleroderma, or pulmonary fibrosis with autoimmune diseases such as Sjögren's syndrome, asthma-associated pulmonary fibrosis, COPD, asbestos or silica-induced PF, silicosis, respiratory bronchiolitis, idiopathic interstitial pneumonia (IIP), idiopathic nonspecific interstitial pneumonia, respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia, acute interstitial pneumonia, rare IIP: idiopathic lymphocytic interstitial pneumonia, idiopathic upper lobe pulmonary fibrosis, unclassifiable idiopathic interstitial A method is provided for treating subjects with pneumonia, hypersensitivity pneumonitis, radiation-induced lung injury, progressive nodular fibrosis-pneumoconiosis, bronchiectasis, compositosis, chronic respiratory disease, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary arterial hypertension (PAH), or cystic fibrosis, the method comprising administering 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, to the subject.

[0190] Another embodiment provides a method for treating subjects with scleroderma / systemic sclerosis, graft-versus-host disease, hypertrophic scars, keloids, nephrogenic systemic fibrosis, porphyria, restrictive dermopathy, Dupuytren's contracture, cutaneous fibrosis, nephrogenic systemic fibrosis / nephrogenic fibrotic dermatosis, mixed connective tissue disease, sclerosing myxedema, eosinophilic fasciitis, fibrosis caused by exposure to chemical or physical factors, GvHD-induced fibrosis, adult edematous sclerosis, lipodermatosclerosis, or progeria (progeria, acroprogeria, Werner syndrome), the method comprising administering 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 pharmaceutically effective amount thereof, to the subject.

[0191] Another embodiment provides a method for treating subjects with atrial fibrosis, endocardial fibrosis, cardiac fibrosis, atherosclerosis, restenosis, or arthral fibrosis, the method comprising administering 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, to the subject.

[0192] Another embodiment provides a method for treating subjects with mediastinal fibrosis, myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis, the method comprising administering 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, to the subject.

[0193] Another embodiment provides a method for treating subjects with Crohn's disease, retroperitoneal fibrosis, intestinal fibrosis, fibrosis in inflammatory bowel disease, GI fibrosis due to ulcerative colitis, cystic fibrosis, or pancreatic fibrosis due to pancreatitis, the method comprising administering 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, to the subject.

[0194] Another embodiment provides a method for treating a subject with endometrial fibroid, uterine fibroid, or Peyronie's disease, the method comprising administering 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, to the subject.

[0195] Another embodiment provides a method for treating subjects with macular degeneration, diabetic retinopathy, retinal fibrovascular disease, or vitreoretinopathy, the method comprising administering 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, to the subject.

[0196] Another embodiment provides a method for treating subjects with scars associated with trauma (surgical complications, chemotherapy-induced fibrosis, radiation-induced fibrosis), the method comprising administering 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, to the subject.

[0197] As used herein, the term “administer” means providing a compound, a prodrug of a compound, or a pharmaceutical composition containing a compound or prodrug described herein. The compound or composition may be administered to a subject by another person or self-administered by the subject. Non-limiting examples of routes of administration include oral, parenteral (e.g., intravenous), or topical.

[0198] As used herein, the term “treatment” refers to an intervention that improves the signs or symptoms of a disease or pathological condition. As used herein, the terms “treatment,” “to treat,” or “to treat” also refer to any observable beneficial effect of treatment with respect to a disease, pathological condition, or symptom. Beneficial effects can be demonstrated, for example, by delaying the onset of clinical symptoms of a disease in a susceptible subject, by reducing the severity of some or all clinical symptoms of the disease, by delaying disease progression, by reducing the number of disease relapses, by improving the subject’s overall health or well-being, or by other parameters well known in the art and specific to a particular disease. Preventive treatment is treatment performed on a subject who shows no signs of disease or only early signs, with the aim of reducing the risk of pathological development. Therapeutic treatment is treatment performed on a subject after the signs and symptoms of a disease have appeared.

[0199] 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 persons diagnosed with a neurodegenerative disease including demyelination, myelinization failure, or myelin sheath failure, for example, persons diagnosed with multiple sclerosis or cerebral palsy, or persons at risk of developing such diseases. Diagnosis may be performed by any method or technique known in the art. A person skilled in the art will understand that subjects treated according to this disclosure may have undergone standard examinations or, without examination, have been identified as persons at risk due to the presence of one or more risk factors for the disease or disease.

[0200] As used herein, the term “effective dose” refers to a sufficient amount of a specified drug to achieve the desired effect in a subject being treated with the specified drug. Ideally, an effective dose of a drug is sufficient to inhibit or treat a disease without causing substantial toxicity in the subject. The effective dose of a drug depends on the subject being treated, the severity of the disease, and the method of administration of the pharmaceutical composition. Methods for determining an effective dose of a disclosed compound sufficient to achieve the desired effect in a subject will be understood by those skilled in the art in light of this disclosure.

[0201] As used herein, the term “chronic” refers to a medical disorder or condition that persists for a long period of time or recurs frequently.

[0202] Compounds having the structures of formulas (I), (II), (III), (IV), (V), (VI), (VII), and (VIII) 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 synthetic procedures described in WO2014 / 178892, WO2014 / 178931, WO2016 / 134292, WO2017 / 201320, WO2018 / 032012, and schemes 1-7 below.

[0203] For this purpose, the reactions, processes, and synthesis methods described herein are not limited to the specific conditions described in the experimental sections below, but are rather intended as a guide for those with the appropriate skills in the art. For example, reactions can be carried out using any suitable solvent or other reagents to carry out the necessary transformations. Generally, a suitable solvent is a protic or aprotic solvent that is substantially inactive with the reactants, intermediates, or products at the temperature in which the reaction is carried out (i.e., from freezing to boiling point, or at a higher temperature if the reaction is carried out in a sealed container). A given reaction may be carried out in one solvent or a mixture of two or more solvents. Depending on the particular reaction, a solvent suitable for the specific workup after the reaction may be employed.

[0204] [ka]

[0205] The compounds of the present invention can be prepared according to Scheme 1. Referring to Scheme 1, a disubstituted or trisubstituted phenol (A) (e.g., 3,5-dichlorophenol, 3-methyl-5-chlorophenol, or 3,5-dichloro-2-fluorophenol) is reacted with a formaldehyde equivalent (e.g., aqueous formaldehyde, paraformaldehyde, or dimethoxymethane) to obtain a hydroxymethyl derivative (B), which is then reacted with an activated acetate moiety (e.g., ethyl chloroacetate or methyl bromoacetate) selectively with phenolic oxygen in the presence of a base to obtain an intermediate (C). The hydroxymethyl group is activated (e.g., via a reaction using thionyl chloride, oxalyl chloride, or p-toluenesulfonyl chloride) to obtain a chloromethyl derivative (D) (or the corresponding tosylate, mesylate, or bromomethyl analog), which is then condensed with a 2-substituted phenol (E) in the presence of a Lewis acid (such as zinc chloride or aluminum chloride) to obtain an ester (F). Alternatively, the intermediate alcohol (C) can be reacted directly with phenol (E) in the presence of a provic acid such as sulfuric acid or a Lewis acid such as boron trifluoride etherate.

[0206] [ka]

[0207] The compounds of the present invention can be prepared according to Scheme 2. Referring to Scheme 2, phenol G(=F,R 2=H (prepared according to Scheme 1) is reacted with a reactive halide H, such as p-fluorobenzyl chloride, 1-(1-chloroethyl)-4-fluorobenzene, or 2,4-difluorobenzyl alcohol, in the presence of a Lewis acid such as zinc chloride, aluminum chloride, or boron trifluoride etherate, to obtain a 3'-alkylation product such as ester F.

[0208] [ka]

[0209] The compounds of the present invention can be prepared according to Scheme 3. Referring to Scheme 3, for example, an important intermediate I is obtained by ortho-iodination of phenol G using N-iodosuccinimide or solid iodine. To prepare the compounds of the present invention, ester (K) of the present invention is obtained by reacting I with boronic acid (or boronate) J under various Suzuki conditions.

[0210] [ka]

[0211] As shown in Scheme 4, for example, an aqueous solution of sodium hydroxide (R 1 (If it is methyl) or TFA(R 1 Acid (L) of the present invention is obtained by hydrolysis of the ester group of (K) using (when is t-butyl). If necessary, acid (L) can be converted to amide (M) by condensation with the corresponding amine (e.g., methylamine, propylamine, or 2-sulfonylethylamine) in the presence of a coupling agent such as DDC or EDCI, or by forming an activated intermediate (e.g., the corresponding acid chloride) using thionyl chloride, etc. Alternatively, if necessary, either ester (K) or acid (L) can be converted to amine R 1b R 1cThe amide (M) of the present invention may be obtained by heating with NH, for example, methylamine, propylamine, or 2-sulfonylethylamine.

[0212] [ka]

[0213] The phenol (A) of the present invention may be commercially available or may be prepared according to Scheme 5. Referring to Scheme 5, the corresponding boronate (O) may be obtained by oxidatively borylating a disubstituted or trisubstituted arene (N) with an activated boronating agent such as (bis-pinacolate)diboron in the presence of an activated metal catalyst such as (1,5-cyclooctadiene)(methoxy)iridium(I) dimer. For example, the corresponding phenol (A) can be obtained by oxidative deborylation of O using hydrogen peroxide.

[0214] [ka]

[0215] Alternative approaches to the preparation of the important intermediate phenol (A) are described in Scheme 6. Referring to Scheme 6, alkyl, alkenyl, or alkynyl products (A) may be obtained by reacting a disubstituted or trisubstituted phenol (P) having one substituent as bromine or iodine under Suzuki coupling conditions, for example, with a boronic acid or boronate reagent, in the presence of a palladium catalyst such as Pd(OAc)2 or Pd(dppf)Cl2. 1 If is an alkene or alkyne, the corresponding alkyl-substituted (A') can be obtained by subsequent hydrogenation in a hydrogen atmosphere, for example, using a Pd-C catalyst.

[0216] [ka]

[0217] As shown in Scheme 7, a substituted phenol (E) as employed in Scheme 3 may be prepared. Referring to Scheme 7, a 2-substituted phenol (E) may be obtained by condensing a 2-halophenol (Q), such as 2-bromophenol or 2-bromo-3-fluorophenol, with a boronic acid or ester (J) under Suzuki conditions in the presence of a palladium catalyst or the like. 2 If the group is an alkene or alkyne, the corresponding alkyl-substituted phenol (E) can be obtained by subsequent hydrogenation in a hydrogen atmosphere, for example, using a Pd-C catalyst. Alternatively, a 2-halophenol (Q), such as 2-bromophenol or 2-bromo-3-fluorophenol, may be metallated using isopropylmagnesium bromide or n-butyllithium, and then condensed with an aldehyde or ketone (R) to obtain an intermediate such as (S). The substituted phenol (E) is produced by deoxygenation of (S) under hydrocracking conditions using hydrogen gas in the presence of a palladium or platinum catalyst, or under reductive deoxygenation conditions in the presence of an acid such as TFA or a reducing agent such as triethylsilane.

[0218] [ka]

[0219] The arylboronic acid or ester (J) used in Scheme 3 may be commercially available or prepared as described in Scheme 8. Referring to Scheme 8, (J) may be obtained by reacting an aryl halide (T) with di(pinacolate)diborone or a similar reagent using a palladium catalyst or the like. Alternatively, (T) may be metallized using isopropylmagnesium bromide or n-butyllithium, and then reacted with a trialkoxyborate or the like to obtain (J). [Examples]

[0220] The present invention is further illustrated by the following examples, which are non-limiting and represent only various aspects of the present invention. Solid and dotted V-shapes in the structures disclosed herein illustrate relative stereochemistry, while absolute stereochemistry is depicted only where specifically described or defined.

[0221] General method All reagents for synthesis not described in the experimental section may be commercially available, well-known compounds, or formed from well-known compounds by methods well known to those skilled in the art.

[0222] Compounds and intermediates produced according to the method of the present invention may require purification. The purification of organic compounds is well known to those skilled in the art, and several methods exist for purifying the same compound. In some cases, purification may not be necessary. In some cases, the compound may be purified by crystallization. In some cases, impurities may be stirred with a suitable solvent.

[0223] In some cases, the compound may be purified by chromatography, particularly flash column chromatography, using silica gel cartridges prepared or pre-packed for the purpose, and eluents such as gradients of solvents such as heptane, ether, ethyl acetate, acetonitrile, or ethanol. In some cases, the compound may be purified by preparative HPLC (normal-phase or reversed-phase) using the methods described. Preparative HPLC purification by reversed-phase HPLC was performed using an acetonitrile gradient in aqueous TFA solution, or an equivalent HPLC system such as methanol in aqueous ammonium acetate solution.

[0224] Purification methods as described herein can provide compounds of the present invention having a sufficiently basic or acidic function, such as in the form of a salt, i.e., a sufficiently basic compound, i.e., a trifluoroacetate or formate, or in the form of a sufficiently acidic compound, i.e., an ammonium salt. These types of salts can be converted to their free base or free acid form, respectively, by various methods known to those skilled in the art, or can be used as salts in subsequent biological assays. It should be understood that the isolated and specific forms of the compounds of the present invention described herein are not necessarily the only forms in which the compounds can be applied to biological assays to quantify specific biological activities.

[0225] All starting materials and reagents were commercially available and used as is. 1 Unless otherwise specified, 1H nuclear magnetic resonance (NMR) spectroscopy was performed at room temperature using the described solvent and a Bruker instrument operating at 400 MHz. In all cases, the NMR data were consistent with the proposed structure. Characteristic chemical shifts (δ) are given in ppm (parts-per-million) using conventional abbreviations to specify the major peaks: e.g., s, singleline; d, doubleline; t, tripleline; q, quadrupleline; dd, doubleline of doubleline; dt, doubleline of tripleline; m, multiline; br, broadband.

[0226] Chemical names were generated using ChemDraw naming software (version 17.0.0.206) by PerkinElmer Informatics, Inc. In some cases, commonly accepted names or acronyms for commercially available reagents were used instead of names generated by the naming software.

[0227] Intermediate A1 Synthesis of methyl 2-(4-formyl-3,5-dimethylphenoxy)acetate (intermediate A1)

[0228] [ka]

[0229] To a solution of 2,6-dimethyl-4-hydroxybenzaldehyde (5.0 g, 33.3 mmol) in acetone (50 mL), methyl chloroacetate (3.9 g, 36.6 mmol), NaI (1.1 g, 6.66 mmol), and Cs2CO3 (11.0 g, 33.3 mmol) were added. The mixture was stirred at 55°C for 5 hours. Water (200 mL) was added, and the mixture was extracted with RINKAN (50 mL). * 3) The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / SiO7 = 4:1) to obtain intermediate A1 (7.1 g, 96.0% yield) as a yellow solid. TLC: Petroleum ether / acetate = 3 / 1 (v / v), Rf = 0.5 LCMS:RT=3.177 min, [M+1]=223.0 1 H NMR:(400MHz,DMSO-d6) δ 10.34(s,1H),6.70(s,2H),4.85(s,2H),3.67(s, 3H).

[0230] Intermediate A2 Synthesis of methyl 2-(4-(hydroxymethyl)-3,5-dimethylphenoxy)acetate (intermediate A2)

[0231] [ka]

[0232] NaBH4 (1.2g, 31.1mmol) was added to a mixture of intermediate A1 (6.9g, 31.1mmol) in MeOH (50mL) at 0°C. The mixture was stirred at room temperature for 2 hours. Water (50mL) was added, and the reaction mixture was extracted with SiO4 (20mL). *2) The organic layer was washed with brine (20 mL), dried on Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / SiO1 = 3:1) to obtain intermediate A2 (5.8 g) as a white solid. TLC: Petroleum ether / acetate = 3 / 1 (v / v), Rf = 0.3 1 H NMR:(400MHz,DMSO-d6) δ 6.56(s,2H),4.73(s,2H),4.59(t,J=8.0,1H),4.39(d,J=7.6Hz,2H),3.68(s,3H),2.30(s,6H).

[0233] Intermediate A3 Synthesis of methyl 2-(4-(chloromethyl)-3,5-dimethylphenoxy)acetate (intermediate A3)

[0234] [ka]

[0235] To a solution of intermediate A2 (5.8 g, 25.9 mmol) in 0°C DCM (50 mL), SOCl2 (9.2 g, 77.6 mmol) was added dropwise. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum, and the product was washed with n-hexane (50 mL) to obtain intermediate A3 (5.3 g, 84.4% yield) as a white solid. TLC: Petroleum ether / acetate = 3 / 1 (v / v), Rf = 0.6 1 H NMR:(400MHz,DMSO-d6) δ 6.65(s,2H),4.77(s,2H),4.75(s,2H),3.69(s,3H),2.33(s,6H),

[0236] Intermediate A4 Synthesis of 3-bromo-4-(hydroxymethyl)-5-methylphenol (intermediate A4)

[0237] [ka]

[0238] To a solution of sodium hydroxide (1.76 g, 44.1 mmol) in water (30 mL), 7.5 g, 40.1 mmol, 3-bromo-5-methylphenol was added. The solution was heated to 45°C, and formaldehyde (3.25 g, 40.1 mmol, 37% / w in water) was added dropwise. The mixture was stirred at 45°C for 2 hours. The mixture was cooled, and water (10 mL) was added. The mixture was acidified with HCl (3N) until the pH became 3. The mixture was extracted with HCl (20 mL). * 2) The combined organic phases were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:SiO = 30:1 to 4:1) to obtain intermediate A4 (1.0 g, 4.6 mmol, 11.5% yield) as a white solid. TLC: Petroleum ether / toluene = 1 / 1 (v / v), Rf = 0.8 1 H NMR:(400MHz,DMSO-d6) δ 9.67(s,1H),6.80(d,J=2.4Hz,1H),6.60(d,J=2.5Hz,1H),4.73(t,J=5.1Hz,1H),4.51(d,J=5.1Hz,2H),2.33(s,3H).

[0239] Intermediate A5 Synthesis of ethyl 2-(3-bromo-4-(hydroxymethyl)-5-methylphenoxy)acetate (intermediate A5)

[0240] [ka]

[0241] Ethyl 2-bromoacetate (1.0 g, 6.0 mmol) was added to a solution of intermediate A4 (1.0 g, 4.6 mmol) and sodium bicarbonate (657 mg, 7.8 mmol) in DMF (10 mL) at room temperature. The mixture was stirred overnight at room temperature. Water (20 mL) was added, and the mixture was extracted with SiO2 (20 mL). * 2) The combined organic phase was washed with brine (30 mL), dried with Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether:SiO = 100:1 to 5:1) to obtain intermediate A5 (600 mg, 42% yield) as a white solid. TLC: Petroleum ether / acetate = 2 / 1 (v / v), Rf = 0.7 1 H NMR:(400MHz,DMSO-d6)δ 6.99(d,J=2.8Hz,1H),6.83-6.80(m,1H),4.85(t,J=5.2Hz,1H),4.79(s,2H),4 .55(d,J=5.2Hz,2H),4.17(q,J=7.2Hz,2H),2.38(s,3H),1.21(t,J=7.2Hz,3H).

[0242] Intermediate A6 Synthesis of ethyl 2-(3-bromo-4-(chloromethyl)-5-methylphenoxy)acetate (intermediate A6)

[0243] [ka]

[0244] To a solution of intermediate A5 (600 mg, 1.98 mmol) in dichloromethane (10 mL) at room temperature, thionyl chloride (471 mg, 3.96 mmol) was added. The mixture was stirred at room temperature for 1 hour and then concentrated under vacuum to obtain intermediate A6 (600 mg, 94% yield) as a white solid. TLC: Petroleum ether / acetate = 2 / 1 (v / v), Rf = 0.8 1H NMR:(400MHz,DMSO-d6) δ 7.10(d,J=2.8Hz,1H),6.92-6.89(m,1H),4.84(s,4H),4.17(q,J=7.2Hz,2H),2.42(s,3H),1.21(t,J=7.2Hz,3H).

[0245] Intermediate A7 Synthesis of 3,5-dichloro-4-(hydroxymethyl)phenol (intermediate A7)

[0246] [ka]

[0247] 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 hours, and then cooled to room temperature. The pH was adjusted with 1 N HCl to 3-4, and the mixture was stirred at room temperature for 20 minutes. The solid was filtered, washed with water (50 mL), and dried to obtain intermediate A7 (11.5 g, 59.6 mmol, 39% yield) as an off-white solid. TLC: HCl / petroleum ether 1 / 3, Rf 0.36 1 H NMR:(400MHz,DMSO-d6) δ 10.02(s,1H),6.82(s,2H),4.98(s,1H),4.57(d,J=2.1Hz,2H)

[0248] Intermediate A8 Synthesis of methyl 2-(3,5-dichloro-4-(hydroxymethyl)phenoxy)acetate (intermediate A8)

[0249] [ka]

[0250] To a solution of intermediate A7 (3.0 g, 15.5 mmol) in acetone (40 mL), potassium carbonate (3.22 g, 23.3 mmol) and methyl 2-chloroacetate (2.02 g, 18.6 mmol) were added. The mixture was refluxed for 2 hours. The mixture was cooled to room temperature and diluted with water (120 mL), and SiO2 (80 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (200 mL), dried with Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether: SiO=20 / 1~5 / 1) to obtain intermediate A8 (2.0 g, 7.54 mmol, 48.5% yield) as a white solid. TLC: HCl / petroleum ether 1 / 5, Rf 0.28 1 H NMR:(400MHz,DMSO-d6) δ 7.10(s,2H),5.08(t,J=5.3Hz,1H),4.91(s,2H),4.61(d,J=5.3Hz,2H),3.70(s,3H).

[0251] Intermediate A9 Synthesis of ethyl 2-(3,5-dichloro-4-(hydroxymethyl)phenoxy)acetate (intermediate A9)

[0252] [ka]

[0253] To a solution of intermediate A7 (13.0 g, 67.4 mmol) in DMF (120 mL) at room temperature, ethyl 2-bromoacetic acid (11.25 g, 67.4 mmol) and K2CO3 (11.2 g, 80.8 mmol) were added. The mixture was stirred at room temperature for 2 hours, diluted with water (200 mL), and extracted with SiO2 (100 mL). * 3) Add the combined organic phase to water (100 mL) *3) The product was washed with brine (200 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / siRNA = 5 / 1) to obtain intermediate A9 (15 g, 79% yield) as an off-white solid. TLC: HCl / petroleum ether = 1 / 5 (v / v), Rf = 0.42 1 H NMR:(400MHz,DMSO-d6) δ 7.09(s,2H),5.09(t,J=5.2Hz,1H),4.88(s,2H),4.60(d,J=5.2Hz,2H),4.17(q,J=7.1Hz,2H),1.21(t,J=7.1Hz,3H).

[0254] Intermediate A10 Synthesis of methyl 2-(3,5-dichloro-4-(chloromethyl)phenoxy)acetate (intermediate A10)

[0255] [ka]

[0256] Thionyl chloride (0.67 g, 5.66 mmol) was added to a mixture of intermediate A8 (1.0 g, 3.77 mmol) in DCM (10 mL). The mixture was stirred at room temperature for 1 hour, and then concentrated under vacuum to obtain crude intermediate A10 (1.0 g, 3.53 mmol, 93.5% yield) as a pale yellow solid. TLC: HCl / petroleum ether 1 / 5, Rf 0.72 1 H NMR:(400MHz,DMSO-d6) δ 7.21(s,2H),4.94(s,2H),4.85(s,2H),3.71(s,3H).

[0257] Intermediate A11 Synthesis of ethyl 2-(3,5-dichloro-4-(chloromethyl)phenoxy)acetate (intermediate A11)

[0258] [ka]

[0259] Thionyl chloride (9.59 g, 80.6 mmol) was added dropwise to the reaction mixture of intermediate A9 (15.0 g, 3.77 mmol) in DCM (150 mL) at 0°C. The mixture was stirred at room temperature for 1 hour, diluted with DCM (100 mL), and concentrated under vacuum to obtain intermediate A11 (15.0 g, 93.5% yield) as a pale yellow solid. TLC: HCl / petroleum ether = 1 / 5 (v / v), Rf = 0.72 1 H NMR:(400MHz,DMSO-d6) δ 7.20(s,2H),4.92(s,2H),4.86(s,2H),4.17(q,J=7.2Hz,2H),1.21(t,J=7.1Hz,3H).

[0260] Intermediate A12 Synthesis of 3-chloro-4-(hydroxymethyl)-5-methylphenol (intermediate A12)

[0261] [ka] A mixture of 3-chloro-5-methylphenol (3.55 g, 24.9 mmol) in 10 mL of water at room temperature was mixed with NaOH (1.10 g, 27.42 mmol). The mixture was heated to 45°C, and formaldehyde (0.75 g, 24.93 mmol, 37% / w in water) was added dropwise. The mixture was stirred at 45°C for 2 hours. The mixture was cooled to room temperature, then acidified with HCl (3N) until the pH was 3, and extracted with HCl (10 mL). * 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 / SiO7 = 50 / 1 to 5 / 1) to obtain intermediate A12 (0.76 g, 4.40 mmol, 17.7% yield) as an off-white solid. TLC: HCl / petroleum ether = 1 / 1(v / v), Rf = 0.8 1 H NMR:(400MHz,DMSO-d6) δ 9.68(s,1H),6.62(d,J=2.4Hz,1H),6.56(d,J=2.4Hz,1H),4.73(t,J=5.2Hz,1H),4.49(d,J=5.2Hz,2H),2.31(s,3H).

[0262] Intermediate A13 Synthesis of ethyl 2-(3-chloro-4-(hydroxymethyl)-5-methylphenoxy)acetate (intermediate A13)

[0263] [ka]

[0264] To a solution of intermediate A12 (1.00 g, 5.79 mmol) in DMF (10 mL) at room temperature, K2CO3 (0.97 g, 6.95 mmol) and ethyl bromoethyl (0.98 g, 5.79 mmol) were added. The mixture was stirred at room temperature for 4 hours, diluted with water (30 mL), and extracted with SiO4 (10 mL). * 3) The combined organic phases were washed with brine (20 mL), dried on Na2SO4, and concentrated in vacuum to obtain intermediate A13 (1.2 g, 75.9% yield). TLC: HCl / petroleum ether = 1 / 2 (v / v), Rf = 0.54

[0265] Intermediate A14 Synthesis of ethyl 2-(3-chloro-4-(chloromethyl)-5-methylphenoxy)acetate (intermediate A14)

[0266] [ka]

[0267] To a solution of intermediate A13 (1.00 g, 3.87 mmol) in DCM (10 mL) at room temperature, SOCl2 (0.55 g, 4.64 mmol) was added. The mixture was stirred at room temperature for 2 hours, and then concentrated under vacuum to obtain intermediate A14 (1.0 g, 93.4% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 10 (v / v), Rf = 0.67 1 H NMR:(400MHz,DMSO-d6)δ 6.95(d,J=2.6Hz,1H),6.86(d,J=2.6Hz,1H),4.82(d,J=5.3Hz,4H),4.16(q,J=7.0Hz,2H),2.39(s,2H),1.20(t,J=7.2Hz,3H).

[0268] Intermediate A15 Synthesis of 3-bromo-5-chloro-4-(hydroxymethyl)phenol (intermediate A15)

[0269] [ka]

[0270] To a solution of NaOH (463 mg, 11.6 mmol) in water (20 mL) at room temperature, 3-chloro-5-bromophenol (2.4 g, 11.6 mmol) was added. The mixture was heated to 45°C, and formaldehyde (347 mg, 11.6 mmol) was added dropwise. The mixture was stirred overnight at 45°C, then diluted with water (20 mL), acidified with 1 N HCl until the pH was 6-7, and toluene (20 mL) was added. * Extraction was performed as described in 2). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / dimethyl = 100 / 1 to 5 / 1) to obtain intermediate A15 (850 mg, 31% yield) as a white solid. TLC: Petroleum ether / acetate = 3 / 1 (v / v), Rf = 0.35. LCMS:RT= 1.619 min, [M-1]=234.9.

[0271] Intermediate A16 Synthesis of ethyl 2-(3-bromo-5-chloro-4-(hydroxymethyl)phenoxy)acetate (intermediate A16)

[0272] [ka]

[0273] To a solution of intermediate A15 (850 mg, 3.58 mmol) in DMF (10 mL) at room temperature, K2CO3 (742 mg, 5.37 mmol) and ethyl bromoethyl (717 mg, 4.30 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water (30 mL) was added, and the resulting mixture was extracted with HCl (30 mL). * 2) Extracted. The combined organic phase was removed with water (20 mL). * 3) and brine (30 mL) * 3) The mixture was washed, dried on Na2SO4, and concentrated in a vacuum to obtain intermediate A16 (920 mg, 79% yield) as a white solid. TLC: Petroleum ether / acetate = 3 / 1 (v / v), Rf = 0.51 1 H NMR:(400MHz,DMSO-d6)δ 7.23(d,J=2.8Hz,1H),7.13(d,J=2.4Hz,1H),5.07(t,J=5.2Hz,1H),4.88( s,2H),4.63(d,J=5.2Hz,2H),4.17(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H).

[0274] Intermediate A17 Synthesis of ethyl 2-(3-bromo-5-chloro-4-(chloromethyl)phenoxy)acetate (intermediate A17)

[0275] [ka]

[0276] SOCl2 (276 mg, 2.32 mmol) was added to a solution of intermediate A16 (500 mg, 1.55 mmol) in DCM (7 mL) at 0°C. The mixture was stirred at room temperature for 2 hours and then concentrated under vacuum to obtain crude intermediate A17 (500 mg, 94.6% yield) as a white solid. TLC: Petroleum ether / African ether = 3 / 1 (v / v), Rf = 0.79 1 H NMR:(400MHz,DMSO-d6) δ 7.34(d,J=2.4Hz,1H),7.24(d,J=2.4Hz,1H),4.92(s,2H),4.88(s,2H),4.17(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H).

[0277] Intermediate A18 Synthesis of 4-bromo-2-fluoro-3,5-dimethylphenol (intermediate A18)

[0278] [ka]

[0279] To a solution of 4-bromo-3,5-dimethylphenol (20 g, 99.5 mmol) in room temperature DCE (200 mL), N-fluoropyridinium triflate (24.6 g, 99.5 mmol) was added, and the resulting solution was heated overnight to 80°C. The reaction mixture was cooled to room temperature, diluted with siRNA (1000 mL), and filtered. The filtrate was then diluted with water (400 mL). * 3) and brine (400mL) * The product was washed (2), dried on Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (SiO2SO4 = 1 / 50) to obtain intermediate A18 (6.0 g, 27.5% yield) as a yellow solid. TLC: HCl / petroleum ether = 1 / 10, Rf = 0.45 1H NMR:(400MHz,DMSO-d6) δ 9.88(d,J=1.2Hz,1H),6.81(d,J=9.2Hz,1H),2.24(d,J=3.2Hz,6H). 19 F NMR:(376MHz,DMSO-d6) δ -137.26.

[0280] Intermediate A19 Synthesis of 1-(benzyloxy)-4-bromo-2-fluoro-3,5-dimethylbenzene (intermediate A19)

[0281] [ka]

[0282] To a solution of intermediate A18 (6.0 g, 27.4 mmol) in DMF (35 mL) at room temperature, benzyl bromide (5.2 g, 30.1 mmol) and Cs2CO3 (17.9 g, 54.8 mmol) were added, and the resulting mixture was stirred overnight at room temperature. The reaction mixture was diluted with SiO2 (300 mL) and filtered. The filtrate was then diluted with water (100 mL). * 2) And then, brine (100 mL) * The product was washed (2), dried on Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (SiO2SO4 = 1 / 100) to obtain intermediate A19 (6.6 g, 77.9% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 10, Rf = 0.78 1 H NMR:(400MHz,DMSO-d6) δ 7.57-7.30(m,5H),7.20(d,J=8.9Hz,1H),5.16(s,2H),2.31(s,3H),2.27(d,J=2.8Hz,3H). 19 F NMR:(376MHz,DMSO-d6) δ -135.63.

[0283] Intermediate A20 Synthesis of 4-(benzyloxy)-3-fluoro-2,6-dimethylbenzaldehyde (intermediate A20)

[0284] [ka]

[0285] To a solution of intermediate A19 (6.6 g, 21.3 mmol) in THF (70 mL) at -60°C, n-BuLi (23.5 mmol, 9.4 mL of 2.5 M) was added dropwise. The resulting mixture was stirred at -60°C for 1 hour, after which DMF (3.1 g, 42.7 mmol) was added. The reaction was stirred at -60°C for 1 hour, then quenched with water (100 mL), and siRNA (100 mL) was added. * 2) Extracted. Wash the combined organic phase with brine (100 mL) * 2) The mixture was dried with Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography (SiO2SO4 / petroleum ether = 1 / 10) to obtain intermediate A20 (4.1 g, 74.3% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 10, Rf = 0.65 1 H NMR:(400MHz,DMSO-d6) δ 10.34(d,J=1.2Hz,1H),7.60-7.28(m,5H),7.10(d,J=8.0Hz,1H),5.26(s,2H),2.54(s,3H),2.45(d,J=2.4Hz,3H). 19 F NMR:(376MHz,DMSO-d6) δ -142.02.

[0286] Intermediate A21 Synthesis of 3-fluoro-4-hydroxy-2,6-dimethylbenzaldehyde (intermediate A21)

[0287] [ka]

[0288] To a solution of intermediate A20 (4.1 g, 15.9 mmol) in room temperature THF (60 mL), Pd / C (600 mg (5% w / w), 0.28 mmol) was added. The flask was degassed, washed three times with H2 (g), and then stirred for 1.5 hours. The reaction mixture was filtered, and the filtrate was concentrated under vacuum. The crude product was recrystallized from hexane (5 mL) to obtain intermediate A21 (2.4 g, 89.9% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 10, Rf = 0.35 1 H NMR:(400MHz,DMSO-d6) δ 10.78(s,1H),10.29(d,J=0.8Hz,1H),6.69(d,J=8.4Hz,1H),2.47(s,3H),2.44(d,J=2.4Hz,3H). 19 F NMR:(376MHz,DMSO-d6) δ -143.64.

[0289] Intermediate A22 Synthesis of 2-fluoro-4-(hydroxymethyl)-3,5-dimethylphenol (intermediate A22)

[0290] [ka]

[0291] To a solution of intermediate A21 (2.4 g, 14.3 mmol) in ethanol (30 mL) at 0°C, NaBH4 (540 mg, 14.3 mmol) was added in small increments. The reaction mixture was warmed to room temperature for 1.5 hours with stirring. The reaction was quenched with water (50 mL), acidified with HCl (1 N) to pH 2, and extracted with HCl (100 mL). * 2) The combined organic phases were dried on Na2SO4 and concentrated in a vacuum to obtain intermediate A22 (2.4 g, 98.8% yield) as a yellow solid. TLC: HCl / petroleum ether = 1 / 10, Rf = 0.23 1H NMR:(400MHz,DMSO-d6) δ 9.45(d,J=0.8Hz,1H),6.56(d,J=9.2Hz,1H),4.60 (brs, 1H),4.37(s,2H),2.22(s,3H),2.20(d,J=2.4Hz,3H). 19 F NMR:(376MHz,DMSO-d6) δ -143.28.

[0292] Intermediate A23 Synthesis of ethyl 2-(2-fluoro-4-(hydroxymethyl)-3,5-dimethylphenoxy)acetate (intermediate A23)

[0293] [ka]

[0294] To a solution of intermediate A22 (2.0 g, 11.7 mmol) and ethyl 2-bromoacetic acid (2.0 g, 11.7 mmol) in DMF (20 mL) at room temperature, Cs2CO3 (4.6 g, 14.1 mmol) was added, and the resulting mixture was stirred at room temperature for 3 hours. The reaction was diluted with SiO2 (80 mL) and filtered. The filtrate was then diluted with water (30 mL). * The product was washed (2), dried on Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (SiO2SO4 = 1 / 5) to obtain intermediate A23 (1.6 g, 53% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 10, Rf = 0.57 1 H NMR:(400MHz,DMSO-d6) δ 6.72(d,J=8.4Hz,1H),4.81(s,2H),4.72(t,J=5.2Hz,1H),4.40(dd,J=5.2, 0.8Hz,2H),4.16(q,J=6.8Hz,2H),2.28(s,3H),2.23(d,J=2.4Hz,3H),1.21(t,J=6.8Hz,3H).

[0295] Intermediate A24 Synthesis of ethyl 2-(4-(chloromethyl)-2-fluoro-3,5-dimethylphenoxy)acetate (intermediate A24)

[0296] [ka]

[0297] To a solution of intermediate A23 (1.9 g, 7.4 mmol) in room temperature DCM (10 mL), SOCl2 (0.9 g, 7.4 mmol) and a catalytic amount of DMF (0.05 mL) were added, and the resulting solution was stirred at room temperature for 2 hours. The reaction mixture was concentrated under vacuum to obtain intermediate A24 (2.0 g, 98.5% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 10, Rf = 0.88 1 H NMR:(400MHz,DMSO-d6)δ 6.82(d,J=8.2Hz,1H),4.85(s,2H),4.76(d,J=0.8Hz,2H),4.17(q,J=7.2Hz,2H),2.31(s,3H),2.26(d,J=2.4Hz,3H),1.21(t,J=7.2Hz,3H). 19 F NMR:(376MHz,DMSO-d6) δ -140.27.

[0298] Synthesis of intermediate A25: 2-(3,5-dichloro-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate A25)

[0299] [ka]

[0300] A mixture of 2,4-dichloro-1-fluorobenzene (30 g, 182 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (1.2 g, 4.5 mmol), bis(pinacolate)diborone (46.2 g, 182 mmol), and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (2.4 g, 3.6 mmol) in THF (300 mL) was stirred at 80°C for 6 hours under an N2 atmosphere. The reaction product was concentrated under vacuum, and the residue was purified by silica gel column chromatography (petroleum ether: SiO=20:1, v / v) to obtain intermediate A25 (50 g, 94% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 10 (v / v), Rf = 0.35 1 H NMR:(400MHz,DMSO) δ 7.94(m,1H),7.51(m,1H),1.30(s,14H).

[0301] Intermediate A26 Synthesis of 3,5-dichloro-2-fluorophenol (intermediate A26)

[0302] [ka]

[0303] To a solution of intermediate A25 (50.0 g, 172 mmol) in THF (1 L) at room temperature, 100 mL of H2O2 (30% of the water concentration) was added, and the resulting mixture was stirred at room temperature for 3 hours. The reaction product was extracted with SiO4 (50 mL). * 3) The combined organic phase was washed with brine (200 mL), dried on Na2SO4, and concentrated in vacuum to obtain intermediate A26 (50 g, 99.7% yield, 62% purity) as a white solid. TLC: SiO / Petroleum ether = 1 / 10 (v / v), Rf = 0.2 1 H NMR:(400MHz,DMSO) δ 10.93(s,1H),7.12(m,1H),6.96(m,1H).

[0304] Intermediate A27 Synthesis of 3,5-dichloro-2-fluoro-4-(hydroxymethyl)phenol (intermediate A27)

[0305] [ka]

[0306] To a solution of intermediate A26 (45.0 g, 157 mmol) in water (200 mL) at room temperature, formaldehyde (4.7 g, 157 mmol) and NaOH (6.2 g, 157 mmol) were added, and the resulting mixture was stirred at 50°C for 32 hours. The reaction mixture was extracted with SiO4 (100 mL). * 3) The combined organic phase was washed with brine (200 mL), dried on Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / siRNA = 5:1) to obtain intermediate A27 (22 g, 66% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 5 (v / v), Rf = 0.41 1 H NMR:(400MHz,DMSO) δ 10.85(s,1H),7.01(d,J=7.7Hz,1H),5.12(s,1H),4.58(d,J=5.0Hz,2H).

[0307] Intermediate A28 Synthesis of ethyl 2-(3,5-dichloro-2-fluoro-4-(hydroxymethyl)phenoxy)acetate (intermediate A28)

[0308] [ka]

[0309] A solution of intermediate A27 (10.3 g, 49.1 mmol) in DMF (50 mL) at room temperature was added with K2CO3 (8.1 g, 58.9 mmol) and ethyl 2-bromoacetate (9.0 g, 54 mmol), and the resulting mixture was stirred at room temperature for 16 h. The reaction was poured into water (50 mL) and extracted with EtOAc (50 mL * 3), and the combined organic phases were washed with brine (200 mL), dried over Na2SO4, and concentrated in vacuo to afford intermediate A28 (14.0 g, 49.1 mmol, 96% yield) as a white solid. TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.44 1 1H NMR: (400 MHz, DMSO) δ 7.36 (d, J = 7.6 Hz, 1H), 5.22 (t, J = 5.4 Hz, 1H), 5.00 (s, 2H), 4.62 (d, J = 5.3 Hz, 2H), 4.18 (d, J = 7.1 Hz, 2H), 1.21 - 1.14 (m, 3H).

[0310] Intermediate A29 Synthesis of ethyl 2-(3,5-dichloro-4-(chloromethyl)-2-fluorophenoxy)acetate (Intermediate A29)

[0311]

Chemical formula

[0312] A solution of intermediate A28 (14.5 g, 48.8 mmol) in DCM (50 mL) was added with thionyl chloride (8.71 g, 73.6 mmol). After stirring at room temperature for 3 h, the reaction mixture was concentrated in vacuo to afford intermediate A29 (14 g, 90% yield) as a white solid. TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.6 1 1H NMR: (400 MHz, DMSO) δ 7.49 (d, J = 7.6 Hz, 1H), 5.04 (s, 2H), 4.87 (s, 2H), 4.18 (m, 2H), 1.21 (t, J = 7.1 Hz, 3H).

[0313] Intermediate A30 Synthesis of 2-(3-bromo-5-chloro-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate A30)

[0314] [ka]

[0315] A mixture of 1-fluoro-2-bromo-4-chlorobenzene (10.0 g, 47.8 mmol), bis(pinacolate)diborone (12.1 g, 47.8 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (633 mg, 955 mmol), and 4,4'-di-tert-butyl-2,2'-bipyridine (320 mg, 1.2 mmol) in THF (100 mL) was stirred overnight at 80°C under an N2 atmosphere. Water (60 mL) was added, and the resulting mixture was extracted with ELISA (30 mL). * 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 (SiO2SO4 = 1 / 100 to 1 / 30) to obtain intermediate A30 (14.0 g, 87.4% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 10 (v / v), Rf = 0.75 1 H NMR:(400MHz,DMSO-d6) δ 7.99(dd,J=6.0, 2.8Hz,1H),7.54(dd,J=4.4, 2.8Hz,1H),1.30(s,12H).

[0316] Intermediate A31 Synthesis of 3-bromo-5-chloro-2-fluorophenol (intermediate A31)

[0317] [ka]

[0318] To a solution of intermediate A30 (14.0 g, 41.7 mmol) in room temperature THF (100 mL), H2O2 (23.7 mL of 30% aqueous solution, 209 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction product was quenched with Na2S2O3 (8.0 g) and extracted with SiO2 (50 mL). * 3) The combined organic phases were washed with brine (100 mL), dried on Na2SO4, and concentrated in vacuum to obtain intermediate A31 (9.0 g, 95.6% yield) as a yellow liquid. TLC: HCl / petroleum ether = 1 / 10 (v / v), Rf = 0.5 1 H NMR:(400MHz,DMSO-d6) δ 10.90(s,1H),7.20(dd,J=4.8, 2.4Hz,1H),7.00(dd,J=7.2, 2.4Hz,1H).

[0319] Intermediate A32 Synthesis of 3-bromo-5-chloro-2-fluoro-4-(hydroxymethyl)phenol (intermediate A32)

[0320] [ka]

[0321] Intermediate A31 (9.1 g, 40.4 mmol) was added to a solution of NaOH (6.2 g, 156.6 mmol) in H2O (100 mL) at room temperature. The mixture was heated to 45°C, and HCHO (4.7 mL of 37% aqueous solution, 40.4 mmol) was added dropwise. The mixture was stirred overnight at 45°C. The reaction product was cooled to room temperature, diluted with water (50 mL), and then acidified with 1 N HCl until the pH was 5-6, and HCl (30 mL) was added. * Extraction was performed as described in 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / SiO7 = 50 / 1 to 5 / 1) to obtain intermediate A32 (4.1 g, 39.7% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 5 (v / v), Rf = 0.20 1 H NMR:(400MHz,DMSO-d6) δ 10.83(s,1H),7.05(d,J=7.8Hz,1H),5.10(t,J=5.2Hz,1H),4.62(d,J=5.1Hz,2H).

[0322] Intermediate A33 Synthesis of ethyl 2-(3-bromo-5-chloro-2-fluoro-4-(hydroxymethyl)phenoxy)acetate (intermediate A33)

[0323] [ka]

[0324] To a solution of intermediate A32 (4.0 g, 15.7 mmol) in DMF (5 mL) at room temperature, K2CO3 (2.6 g, 18.8 mmol) and ethyl 2-bromoacetic acid (2.6 g, 15.7 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water (50 mL), and the mixture was extracted with SiO2 (20 mL). * 3) The combined organic phases were washed with brine (50 mL), dried on Na2SO4, and concentrated in vacuum to obtain intermediate A33 (5.0 g, 93.5% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 5 (v / v), Rf = 0.25

[0325] Intermediate A34 Synthesis of ethyl 2-(3-bromo-5-chloro-4-(chloromethyl)-2-fluorophenoxy)acetate (intermediate A34)

[0326] [ka]

[0327] SOCl2 (2.6 g, 21.9 mmol) was added to a solution of intermediate A33 (5.0 g, 14.6 mmol) in DCM (50 mL). The mixture was stirred at room temperature for 1 hour. Water (50 mL) was added, and the resulting mixture was extracted with DCM (20 mL). * 3) The combined organic phases were washed with brine (50 mL), dried on Na2SO4, and concentrated in vacuum to obtain intermediate A34 (5.0 g, 94.9% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 5 (v / v), Rf = 0.5

[0328] Intermediate A35 Synthesis of 2-(5-bromo-3-chloro-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate A35)

[0329] [ka]

[0330] A mixture of 1-fluoro-2-chloro-4-bromobenzene (10.0 g, 47.8 mmol), bis(pinacolate)diborone (12.1 g, 47.8 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (633 mg, 955 mmol), and 4,4'-di-tert-butyl-2,2'-bipyridine (320 mg, 1.2 mmol) in THF (100 mL) was stirred overnight at 80°C under an N2 atmosphere. Water (60 mL) was added, and the mixture was extracted with ELISA (30 mL). * 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 (siRNA / petroleum ether = 1 / 100 to 1 / 30) to obtain intermediate A35 (14.5 g, 90.6% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 10 (v / v), Rf = 0.75 1H NMR:(400MHz,DMSO-d6) δ 8.03(dd,J=6.4, 2.4Hz,1H),7.64(dd,J=4.4, 2.8Hz,1H),1.31(s,12H).

[0331] Intermediate A36 Synthesis of 5-bromo-3-chloro-2-fluorophenol (intermediate A36)

[0332] [ka]

[0333] To a solution of intermediate A35 (14.5 g, 43.2 mmol) in room temperature THF (100 mL), an aqueous H2O2 solution (24.5 mL of 37% aqueous solution, 216 mmol) was added, and the mixture was stirred at room temperature for 2 hours. Na2S2O3 (8.0 g) was added, the mixture was stirred for 20 minutes, and then extracted with SiO2 (50 mL). * 3) The combined organic phases were washed with brine (100 mL), dried on Na2SO4, and concentrated in vacuum to obtain intermediate A36 (9.7 g, 99.5% yield) as a yellow liquid. TLC: HCl / petroleum ether = 1 / 10 (v / v), Rf = 0.5

[0334] Intermediate A37 Synthesis of 5-bromo-3-chloro-2-fluoro-4-(hydroxymethyl)phenol (intermediate A37)

[0335] [ka]

[0336] Intermediate A36 (10.0 g, 40.6 mmol) was added to a solution of NaOH (2.0 g, 49.1 mmol) in H2O (100 mL) at room temperature. The mixture was heated to 45°C, and formaldehyde (3.3 mL of 37% aqueous solution, 40.6 mmol) was added dropwise. The mixture was stirred overnight at 45°C. The reaction product was cooled to room temperature, diluted with water (50 mL), and then acidified with 1 N HCl until the pH was 5-6, and HCl (30 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (100 mL), dried with Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (SiO2SO4 = 1 / 50 to 1 / 5) to obtain intermediate A37 (7.6 g, 73.1% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 5 (v / v), Rf = 0.20 1 H NMR:(400MHz,DMSO-d6) δ 10.87(s,1H),7.18(d,J=8.0Hz,1H),5.12(t,J=5.2Hz,1H),4.62-4.58(m,2H).

[0337] Intermediate A38 Synthesis of ethyl 2-(5-bromo-3-chloro-2-fluoro-4-(hydroxymethyl)phenoxy)acetate (intermediate A38)

[0338] [ka]

[0339] To a solution of intermediate A37 (7.6 g, 29.7 mmol) in DMF (70 mL) at room temperature, K2CO3 (4.9 g, 29.7 mmol) and ethyl 2-bromoacetic acid (5.0 g, 29.7 mmol) were added, and the mixture was stirred at room temperature for 1 hour. The reaction product was poured into water (50 mL) and extracted with SiO2 (20 mL). * 3) The combined organic phases were washed with brine (50 mL), dried on Na2SO4, and concentrated in vacuum to obtain intermediate A38 (10.0 g, 99.0% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 5 (v / v), Rf = 0.25

[0340] Intermediate A39 Synthesis of ethyl 2-(5-bromo-3-chloro-4-(chloromethyl)-2-fluorophenoxy)acetate (intermediate A39)

[0341] [ka]

[0342] SOCl2 (5.3g, 43.9mmol) was added to a solution of intermediate A38 (10.0g, 29.3mmol) in DCM (100mL). The mixture was stirred at room temperature for 1 hour. Water (50mL) was added, and the mixture was extracted with DCM (20mL). * 3) The combined organic phases were washed with brine (50 mL), dried on Na2SO4, and concentrated in vacuum to obtain intermediate A39 (10.0 g, 95.2% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 5 (v / v), Rf = 0.5

[0343] Intermediate A40 Synthesis of 2,3,5-trichloro-4-(hydroxymethyl)phenol (intermediate A40)

[0344] [ka]

[0345] To a solution of NaOH (41 mg, 1.01 mmol) in water (10 mL) at room temperature, 2,3,5-trichlorophenol (200 mg, 1.01 mmol) was added. The mixture was heated to 45°C, and formaldehyde (37% aqueous solution of 82 mg, 1.01 mmol) was added dropwise. The mixture was stirred overnight at 45°C, and the resulting solution was diluted with water (20 mL), acidified with 1 N HCl until the pH was 5-6, and extracted with ethyl acetate (20 mL). *2) The combined organic phases were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by preparative TLC (petroleum ether / siRNA = 3 / 1) to obtain intermediate A40 (100 mg, 43.4% yield) as a white solid. TLC: Petroleum ether / acetate = 3 / 1 (v / v), Rf = 0.30. LCMS:RT= 1.467 min, [M-1]=226.8. 1 H NMR:(400MHz,DMSO-d6) δ 11.11(s,1H),7.02(s,1H),5.10(t,J=5.2Hz,1H),4.62(d,J=4.8Hz,2H).

[0346] Intermediate A41 Synthesis of ethyl 2-(2,3,5-trichloro-4-(hydroxymethyl)phenoxy)acetate (intermediate A41)

[0347] [ka]

[0348] To a solution of intermediate A40 (100 mg, 0.44 mmol) in DMF (5 mL) at room temperature, K2CO3 (91 mg, 0.66 mmol) and ethyl bromoethyl (88 mg, 0.53 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water (10 mL) was added, and the mixture was extracted with ELISA (20 mL). * 2) Add the combined organic phase to water (20 mL) * 3) and brine (20 mL) * 2) The mixture was washed, dried on Na2SO4, and concentrated in a vacuum to obtain intermediate A41 (130 mg, 94.3% yield) as a white solid. TLC: Petroleum ether / acetate = 3 / 1 (v / v), Rf = 0.42. 1H NMR:(400MHz,DMSO-d6) δ 7.31(s,1H),5.21(t,J=5.4Hz,1H),5.04(s,2H),4.66(d,J=5.2Hz,2H),4.18(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H).

[0349] Intermediate A42 Synthesis of ethyl 2-(2,3,5-trichloro-4-(chloromethyl)phenoxy)acetate (intermediate A42)

[0350] [ka]

[0351] To a solution of intermediate A41 (130 mg, 0.41 mmol) in 3 mL of DCM at 0°C, SOCl2 (74 mg, 0.62 mmol) was added, and the resulting mixture was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum to obtain intermediate A42 (115 mg, 83.5% yield) as a white solid. TLC: Petroleum ether / acetate = 3 / 1 (v / v), Rf = 0.72. 1 H NMR:(400MHz,DMSO-d6) δ 7.44(s,1H),5.08(s,2H),4.91(s,2H),4.18(q,J=7.2Hz,2H),1.21(t,J=7.2Hz,3H).

[0352] Intermediate A43 Synthesis of 3,5-dichloro-2-(hydroxymethyl)phenol (intermediate A43)

[0353] [ka]

[0354] To a solution of dichlorosalicyaldehyde (2.5 g, 13.09 mmol) in THF (5 mL) at 0°C, NaBH4 (594.19 mg, 15.71 mmol) was added. The mixture was stirred at room temperature for 2 hours, and then diluted with water (20 mL). The mixture was acidified with 2N HCl to pH 4–5, and extracted with HCl (20 mL). * 2) The combined organic extracts were washed with brine (30 mL), dried on Na2SO4, and concentrated in a vacuum to obtain intermediate A43 (2.3 g, 93% yield) as a white solid. TLC: Petroleum ether / acetate = 3 / 1 (v / v), Rf = 0.24. LCMS:RT= 1.403 min, [M-1]=190.9. 1 H NMR:(400MHz,DMSO-d6) δ 10.44(s,1H),6.98(d,J=2.0Hz,1H),6.83(d,J=2.0Hz,1H),4.51(s,2H).

[0355] Intermediate A44 Synthesis of 3,5-dichloro-2-methylphenol (intermediate A44)

[0356] [ka]

[0357] A mixture of intermediates A43 (2.1 g, 10.9 mmol), Et3SiH (5.1 g, 43.5 mmol), and TFA (12.4 g, 109 mmol) in DCM (20 mL) was stirred at room temperature for 2 days. The reaction mixture was diluted with SiO (30 mL) and brine (10 mL) * The product was washed (2) and dried on Na2SO4. The crude product was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether / siRNA = 50 / 1 to 20 / 1) to obtain intermediate A44 (890 mg, 46.2% yield) as a yellow solid. TLC: Petroleum ether / acetate = 3 / 1 (v / v), Rf = 0.65. LCMS:RT= 1.505 min, [M-1]=175.0. 1 H NMR:(400MHz,DMSO-d6) δ 10.36(d,J=1.2Hz,1H),6.97(d,J=2.0Hz,1H),6.80(d,J=2.0Hz,1H),2.12(s,3H).

[0358] Intermediate A45 Synthesis of 3,5-dichloro-4-(hydroxymethyl)-2-methylphenol (intermediate A45)

[0359] [ka]

[0360] Intermediate A44 (890 mg, 5.03 mmol) was added to a solution of NaOH (201 mg, 5.03 mmol) in water (20 mL) at room temperature. The mixture was heated to 45°C, and formaldehyde (408 mg of 37% aqueous solution, 5.03 mmol) was added dropwise. The mixture was stirred at 45°C, then diluted with water (20 mL), acidified with 1 N HCl until the pH was 5-6, and HCl (20 mL) was added. * Extraction was performed as described in 2). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / siRNA = 20 / 1 to 5 / 1) to obtain intermediate A45 (400 mg, 38.4% yield) as a white solid. TLC: Petroleum ether / toluene = 3 / 1 (v / v), Rf = 0.31. LCMS:RT=0.637 min, [M-1]=205.0. 1 H NMR:(400MHz,DMSO-d6) δ 10.28(s,1H),6.84(s,1H),4.94(t,J=5.2Hz,1H),4.59(d,J=4.8Hz,2H),2.15(s,3H).

[0361] Intermediate A46 Synthesis of ethyl 2-(3,5-dichloro-4-(hydroxymethyl)-2-methylphenoxy)acetate (intermediate A46)

[0362] [ka]

[0363] To a solution of intermediate A45 (400 mg, 1.93 mmol) in DMF (5 mL) at room temperature, K2CO3 (400 mg, 2.90 mmol) and ethyl bromoethyl (387 mg, 2.32 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with  (30 mL) and washed with brine (10 mL). * 2) The mixture was dried on Na2SO4 and concentrated in a vacuum to obtain intermediate A46 (520 mg, 91.8% yield) as a white solid. TLC: Petroleum ether / acetate = 3 / 1 (v / v), Rf = 0.53. 1 H NMR:(400MHz,DMSO-d6)δ 7.07(s,1H),5.06(t,J=5.2Hz,1H),4.92(s,2H),4.64(d,J=5.2Hz,2H),4.17(q,J=7.2Hz,2H),2.24(s,3H),1.21(t,J=7.2Hz,3H).

[0364] Intermediate A47 Synthesis of ethyl 2-(3,5-dichloro-4-(chloromethyl)-2-methylphenoxy)acetate (intermediate A47)

[0365] [ka]

[0366] SOCl2 (316 mg, 2.66 mmol) was added to a solution of intermediate A46 (520 mg, 1.77 mmol) in DCM (5 mL) at 0°C. The mixture was stirred at room temperature for 2 hours. By concentrating the mixture under vacuum, intermediate A47 (530 mg, 95.8% yield) was obtained as a white solid. TLC: Petroleum ether / acetate = 3 / 1 (v / v), Rf = 0.67. 1 H NMR:(400MHz,DMSO-d6) δ 7.18(s,1H),4.96(s,2H),4.89(s,2H),4.17(q,J=7.2Hz,2H),2.26(s,3H),1.21(t,J=7.2Hz,3H).

[0367] Intermediate A48 Synthesis of 2-(3-chloro-2-fluoro-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate A48)

[0368] [ka]

[0369] A mixture of 3-chloro-4-fluorotoluene (10.0 g, 69.2 mmol), 4,4'-di-tert-2,2'-bipyridine (464 mg, 1.73 mmol), and (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (917 mg, 1.38 mmol) in THF (100 mL) was mixed with bis(pinacolate)diborone (17.6 g, 69.2 mmol). The mixture was heated overnight at 80°C. The mixture was cooled to room temperature, water (20 mL) was added, and the resulting mixture was extracted with ELISA (20 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 silica gel column chromatography (petroleum ether / SiO1 = 100 / 1 to 30 / 1) to obtain intermediate A48 (17.5 g, 93.5% yield) as a white solid. TLC: Petroleum ether / acetate = 3 / 1 (v / v), Rf = 0.40. 1H NMR:(400MHz,DMSO-d6) δ 7.52(ddd,J=7.2, 2.4, 0.8Hz,1H),7.37(ddd,J=5.2, 2.4, 0.8Hz,1H),2.28(s,3H),1.29(s,12H).

[0370] Intermediate A49 Synthesis of 3-chloro-2-fluoro-5-methylphenol (intermediate A49)

[0371] [ka]

[0372] A mixture of intermediate A48 (2.8 g, 10.35 mmol) in THF (30 mL) was mixed with an aqueous H2O2 solution (1.8 g, 30% w / w, 52 mmol). The mixture was stirred at room temperature for 2 hours. Na2S2O3 (8.0 g) was added, the mixture was stirred for 20 minutes, and then extracted with SiO2 (20 mL). * 3) The combined organic phase was washed with brine (50 mL), dried on Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / alkyl = 100:1 to 10 / 1) to obtain intermediate A49 (1.6 g, 96.2% yield) as a yellow oil. TLC: Petroleum ether / acetate = 5 / 1 (v / v), Rf = 0.41. 1 H NMR:(400MHz,DMSO-d6) δ 10.19(d,J=4.8Hz,1H),6.74(ddd,J=6.0, 2.0, 0.8Hz,1H),6.71(ddd,J=8.0, 2.4, 0.8Hz,1H),2.18(s,3H).

[0373] Intermediate A50 Synthesis of 3-chloro-2-fluoro-4-(hydroxymethyl)-5-methylphenol (intermediate A50)

[0374] [ka]

[0375] Intermediate A49 (1.6 g, 10 mmol) was added to a solution of NaOH (398 mg, 9.96 mmol) in water (20 mL) at room temperature. The mixture was heated to 45°C, and aqueous HCHO solution (889 mg, 37% w / w, 11 mmol) was added dropwise. The mixture was stirred overnight at 45°C, then diluted with water (20 mL), acidified to pH 5-6 with 1 N HCl, and extracted with ELISA (20 mL). * 2) 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 / siRNA = 100 / 1 to 5 / 1) to obtain intermediate A50 (1.0 g, 52.6% yield) as a white solid. TLC: Petroleum ether / acetate = 3 / 1 (v / v), Rf = 0.37. 1 H NMR:(400MHz,DMSO-d6) δ 10.15(s,1H),6.82-6.63(m,1H),4.87(t,J=5.2Hz,1H),4.52-4.47(m,2H),2.29(s,3H).

[0376] Intermediate A51 Synthesis of ethyl 2-(3-chloro-2-fluoro-4-(hydroxymethyl)-5-methylphenoxy)acetate (intermediate A51)

[0377] [ka]

[0378] To a solution of intermediate A50 (900 mg, 4.72 mmol) in DMF (10 mL), K2CO3 (783 mg, 5.67 mmol) and ethyl bromoethyl (788 mg, 4.72 mmol) were added. The mixture was stirred at room temperature for 1 hour. Water (30 mL) was added, and the resulting mixture was extracted with SiO4 (10 mL). *2) The combined organic phases were washed with brine (30 mL), dried on Na2SO4, and concentrated in vacuum to obtain intermediate A51 (1.3 g, 99.9% yield) as a white solid. TLC: Petroleum ether / acetate = 3 / 1 (v / v), Rf = 0.45. 1 H NMR:(400MHz,DMSO-d6)δ 6.98(d,J=8.0Hz,1H),4.96(s,1H),4.90(s,2H),4.53(s,2H),4.21-4.13(m,2H),2.36-2.33(m,3H),1.21(t,J=7.2Hz,3H).

[0379] Intermediate A52 Synthesis of ethyl 2-(3-chloro-2-fluoro-4-(hydroxymethyl)-5-methylphenoxy)acetate (intermediate A52)

[0380] [ka]

[0381] SOCl2 (1.1 g, 9.4 mmol) was added to a solution of intermediate A51 (1.3 g, 4.7 mmol) in DCM (20 mL) at room temperature. The resulting mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum to obtain crude intermediate A52 (1.3 g, 92.8% yield) as a white solid. TLC: Petroleum ether / acetate = 3 / 1 (v / v), Rf = 0.57. 1 H NMR:(400MHz,DMSO-d6)δ 7.09(d,J=8.4Hz,1H),4.94(s,2H),4.83(d,J=0.8Hz,2H),4.18(q,J=7.2Hz,2H),2.39-2.36(m,3H),1.21(t,J=7.2Hz,3H).

[0382] Intermediate A53 Synthesis of 2-(5-chloro-2-fluoro-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate A53)

[0383] [ka]

[0384] A mixture of 2-fluoro-5-chlorotoluene (6.0 g, 41.5 mmol), bis(pinacolate)diborone (10.5 g, 41.5 mmol), (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (550 mg, 830 mmol), and 4,4'-di-tert-butyl-2,2'-bipyridine (268 mg, 1.0 mmol) in THF (60 mL) was stirred overnight at 80°C under an N2 atmosphere. Water (60 mL) was added, and the resulting mixture was extracted with ethyl acetate (30 mL). * 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 (SiO2SO4 = 1 / 100 to 1 / 30) to obtain intermediate A53 (9.4 g, 83.9% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 10 (v / v), Rf = 0.75 1 H NMR:(400MHz,DMSO-d6) δ 7.50(dd,J=6.0, 2.8Hz,1H),7.37-7.34(m,1H),2.20(d,J=2.4Hz,3H),1.28(s,12H).

[0385] Intermediate A54 Synthesis of 5-chloro-2-fluoro-3-methylphenol (intermediate A54)

[0386] [ka]

[0387] To a solution of intermediate A53 (9.4 g, 34.7 mmol) in room temperature THF (100 mL), H2O2 aqueous solution (30% w / w) (19.7 g, 174 mmol) was added, and the resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was cooled to 0°C, and Na2S2O3 (15.0 g) was added. Water (100 mL) was added, and the mixture was stirred for 20 minutes, after which SiO2 was extracted (50 mL). * 3) The combined organic phases were washed with brine (100 mL), dried on Na2SO4, and concentrated in vacuum to obtain intermediate A34 (5.0 g, 89.3% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 10 (v / v), Rf = 0.5 LCMS:RT=1.246 min, [M-1]=159.0

[0388] Intermediate A55 Synthesis of 5-chloro-2-fluoro-4-(hydroxymethyl)-3-methylphenol (intermediate A55)

[0389] [ka]

[0390] Intermediate A54 (50.0 g, 31.3 mmol) was added to a solution of NaOH (1.4 g, 34.3 mmol) in H2O (50 mL) at room temperature. The mixture was heated to 45°C, and aqueous HCHO (2.5 g, 37% w / w, 31.3 mmol) was added dropwise. The mixture was stirred overnight at 45°C. The reaction product was cooled to room temperature, diluted with water (60 mL), acidified with 1 N HCl to pH 5-6, and HCl (30 mL) was added. * Extraction was performed as described in 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (siRNA / petroleum ether = 1 / 50 to 1 / 5) to obtain intermediate A55 (2.0 g, 33.9% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 5 (v / v), Rf = 0.20 1 H NMR:(400MHz,DMSO-d6) δ 10.20(s,1H),6.82(d,J=8.0Hz,1H),4.92(t,J=5.2Hz,1H),4.51(d,J=3.2Hz,2H),2.27(d,J=2.8Hz,3H).

[0391] Intermediate A56 Synthesis of ethyl 2-(5-chloro-2-fluoro-4-(hydroxymethyl)-3-methylphenoxy)acetate (intermediate A56)

[0392] [ka]

[0393] To a solution of intermediate A55 (2.0 g, 10.5 mmol) in DMF (20 mL) at room temperature, K2CO3 (1.7 g, 12.6 mmol) and ethyl bromoacetate (1.8 g, 10.5 mmol) were added. The mixture was stirred at room temperature for 1 hour. The reaction product was poured into water (50 mL) and extracted with SiO4 (20 mL). * 3) The combined organic phases were washed with brine (50 mL), dried on Na2SO4, and concentrated in vacuum to obtain intermediate A56 (2.8 g, 96.6% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 5 (v / v), Rf = 0.25

[0394] Intermediate A57 Synthesis of ethyl 2-(5-chloro-4-(chloromethyl)-2-fluoro-3-methylphenoxy)acetate (intermediate A57)

[0395] [ka]

[0396] SOCl2 (1.8g, 15.2mol) was added to a solution of intermediate A56 (2.8g, 10.1mol) in DCM (100mL). The mixture was stirred at room temperature for 1 hour. Water (50mL) was added, and the resulting mixture was added to DCM (20mL). * 3) Extraction was performed. The combined organic phase was washed with brine (50 mL), dried with Na2SO4, and concentrated in vacuum to obtain intermediate A57 (2.8 g, 93.3% yield) as a white solid. TLC: Â / petroleum ether = 1 / 5 (v / v), Rf = 0.5

[0397] Intermediate A58 Synthesis of 2-(2,3-difluoro-5-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate A58)

[0398] [ka]

[0399] 1,2-difluoro-4-methylbenzene (8.0 g, 62 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (419 mg, 1.56 mmol), and [Ir(OMe)](1,5-cod)2 (828 mg, 1.25 mmol) were added to THF (80 mL) with B2Pin2 (15.9 g, 62.4 mmol). The mixture was heated at 80°C overnight and cooled to room temperature. Water (100 mL) was added to the mixture, and SiO2Pin2 (50 mL) was added. * Extraction was performed as described in 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (SiO2SO4 = 1 / 100) to obtain intermediate A58 (11.0 g, 69% yield) as a white solid. 1 H NMR:(400 MHz,DMSO-d6)δ 7.42-7.33(m,1H),7.22(ddt,J=4.5,2.2,1.1 Hz,1H),2.29(s,3H),1.30(s,12H).

[0400] Intermediate A59 Synthesis of 2,3-difluoro-5-methylphenol (intermediate A59)

[0401] [ka]

[0402] Hydrogen peroxide (24.5 g, 216 mmol, 22 mL, 30% wt / wt) was added to intermediate A58 (11 g, 43 mmol) in THF (100 mL). The mixture was stirred at room temperature for 2 hours. Na2S2O3 (4.0 g) was added, and the mixture was extracted with SiO2 (50 mL). * 3) The combined organic layers were washed with brine (100 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel column (petroleum ether / alkyl = 100 / 1 to 5 / 1) to obtain intermediate A59 (6 g, 96% yield) as a yellow oil. LCMS: T=0.98 min, [M-1]=143.1

[0403] Intermediate A60 Synthesis of 2,3-difluoro-4-(hydroxymethyl)-5-methylphenol (intermediate A60)

[0404] [ka]

[0405] Intermediate A59 (3g, 21 mmol) was added to a solution of NaOH (916 mg, 22.90 mmol) in water (30 mL) at room temperature. The mixture was heated to 45°C, and 37% formaldehyde (1.7 g, 20.8 mmol, 2 mL, 37% wt / wt) was added dropwise. The mixture was stirred at 45°C overnight and then cooled. The mixture was diluted with water (20 mL), acidified to pH=6-7 with 1 M HCl, and toluene (50 mL) was added. *Extraction was performed as described in 3). The organic phase was washed with brine (50 mL), dried with Na2SO4, and concentrated under vacuum. The crude product was purified using a silica gel column (petroleum ether / siRNA = 20 / 1 to 5 / 1) to obtain intermediate A60 (1.2 g, 33%) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 10.15(s,1H),6.59(dd,J=8.1,1.9 Hz,1H),4.89(t,J=5.4 Hz,1H),4.42-4.38(m,2H),2.25(s,3H).

[0406] Intermediate A61 Synthesis of ethyl 2-(2,3-difluoro-4-(hydroxymethyl)-5-methylphenoxy)acetate (intermediate A61)

[0407] [ka]

[0408] To a solution of intermediate A60 (800 mg, 4.6 mmol) in DMF (10 mL), K2CO3 (762 mg, 5.51 mmol) and ethyl 2-bromoacetate (767 mg, 4.59 mmol) were added. The mixture was stirred overnight at room temperature, diluted with water (30 mL), and siRNA (20 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (10 mL), dried with Na2SO4, and concentrated under reduced pressure to obtain compound 5 (1.0 g, 83.7% yield) as a white solid.

[0409] Intermediate A62 Synthesis of 2-(2,5-difluoro-3-methylphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate A62)

[0410] [ka]

[0411] To a solution of 1-bromo-2,5-difluoro-3-methylbenzene (500 mg, 2.42 mmol) and bis(pinacolate)diborone (920 mg, 3.62 mmol) in 1,4-dioxane (19 mL), KOAc (948 mg, 9.66 mmol) and Pd(dppf)Cl2 (197 mg, 0.24 mmol) were added. The mixture was stirred overnight at 85°C and cooled to room temperature. The mixture was diluted with water (100 mL) and extracted with ethyl acetate (100 mL). The organic phase was dried over Na2SO4, concentrated under vacuum, and purified by silica gel chromatography (ethyl acetate / petroleum ether = 1 / 5) to obtain intermediate A62 (350 mg, 57% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 7.34-7.26(m,1H),7.10(dt,J=7.9,3.7 Hz,1H),2.21(d,J=2.3 Hz,3H),1.29(s,12H).

[0412] Intermediate A63 Synthesis of ethyl 2-(2,5-difluoro-4-(hydroxymethyl)-3-methylphenoxy)acetate (intermediate A63)

[0413] [ka]

[0414] To a solution of intermediate A62 (350 mg, 1.38 mmol) in THF (5 mL), H2O2 (234 mg, 6.89 mmol) was added. The mixture was stirred at room temperature for 2 hours and diluted with water (30 mL) and DCM (30 mL). The organic phase was washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum. The resulting yellow solid (177 mg, 1.23 mmol) was dissolved in water (5 mL) with NaOH (54 mg, 1.35 mmol) and heated to 45 °C. Formaldehyde (40 mg, 1.35 mmol) was added, and the mixture was stirred overnight at 45 °C. After cooling to room temperature, the mixture was acidified to pH ~7 with 1N HCl, diluted with water (30 mL), and extracted with RINKAN (30 mL). The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resulting solid was dissolved in DMF (3 mL), and ethyl 2-bromoacetate (253 mg, 1.52 mmol) and K2CO3 (261 mg, 1.89 mmol) were added. The mixture was stirred at room temperature for 2 hours and then separated into water (30 mL) and butyl (30 mL). The organic phase was then separated into water (30 mL) * 3) The mixture was washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to obtain product intermediate A63 (328 mg, 91% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 7.95(s,4H),6.89(dd,J=11.2,7.2 Hz,1H),4.88(s,2H),4.43(s,2H),4.16(s,3H),4.11(s,1H),2.27(d,J=2.6 Hz,3H),1.21(s,5H).

[0415] Intermediate A64 Synthesis of ethyl 2-(4-(chloromethyl)-2,5-difluoro-3-methylphenoxy)acetate (intermediate A64)

[0416] [ka]

[0417] To a solution of intermediate A63 (328 mg, 1.26 mmol) in DCM (4 mL), thionyl chloride (225 mg, 1.89 mmol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum to obtain intermediate A64 (276 mg, 79% yield) as a yellow solid. 1 H NMR(400 MHz,DMSO-d6)δ 7.01(dd,J=11.4,7.2 Hz,1H),4.92(s,2H),4.77(d,J=1.7 Hz,2H),4.17(q,J=7.1 Hz,2H),2.30(d,J=2.6 Hz,3H),1.21(t,J=7.1 Hz,3H).

[0418] Intermediate A65 Synthesis of (6-chloro-2,3-difluorophenyl)methanol (intermediate A65)

[0419] [ka]

[0420] To a solution of 6-chloro-2,3-difluorobenzaldehyde (3.0 g, 16 mmol) in room temperature THF (30 mL), NaBH4 (707 mg, 18.7 mmol) was added. The mixture was heated to 50 °C, stirred overnight, and cooled to room temperature. H2O (50 mL) was added. The mixture was then mixed with siRNA (25 mL). * 2) Extracted. The combined organic layer was diluted with water (25 mL). * 2) The mixture was washed with brine (50 mL), dried over Na2SO4, and concentrated to dryness to obtain intermediate A65 (2.8 g, 92% yield) as a white solid. 1 H NMR:(400 MHz,DMSO-d6)δ 7.45(dt,J=10.1,8.8 Hz,1H),7.35(ddd,J=9.0,4.5,1.9 Hz,1H),5.36(s,1H),4.59(d,J=2.5 Hz,2H).

[0421] Intermediate A66 Synthesis of tert-butyl((6-chloro-2,3-difluorobenzyl)oxy)dimethylsilane (intermediate A66)

[0422] [ka]

[0423] Intermediate A65 (2.8 g, 16 mmol) and imidazole (2.1 g, 31 mmol) were added to room temperature DCM (30 mL), to which TBSCl (2.6 g, 17 mmol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with H2O (30 mL) and then diluted with DCM (25 mL). * 2) Extracted. The combined organic layer was diluted with water (25 mL). * 2) The mixture was washed with brine (50 mL), dried with Na2SO4, and concentrated to dryness to obtain intermediate A66 (4.5 g, 98% yield) as a colorless oil. 1 H NMR:(400 MHz,DMSO-d6)δ 7.49(dt,J=10.0,8.8 Hz,1H),7.38(ddd,J=9.0,4.2,1.7 Hz,1H),4.81-4.76(m,2H),0.85(s,9H),0.08(s,6H).

[0424] Intermediate A67 Synthesis of ethyl 2-(5-chloro-2,3-difluoro-4-(hydroxymethyl)phenoxy)acetate (intermediate A67)

[0425] [ka]

[0426] Intermediate A66 (5.8 g, 19.81 mmol), bis(pinacolate)diborone (5.0 g, 20 mmol), [Ir(OMe)](1,5-cod)2 (263 mg, 0.400 mmol), and 4,4'-di-tert-butyl-2,2'-bipyridine (133 mg, 0.501 mmol) were stirred in THF (40 mL) at 80°C for 4 hours. The mixture was allowed to cool to room temperature. The mixture was diluted with H2O (30 mL) and sorbed with ELISA (10 mL). * 2) Extracted. The combined organic layer was then mixed with water (20 mL). * 2) The mixture was washed with brine (20 mL), dried over Na2SO4, and purified by silica gel column (petroleum ether ~ petroleum ether / SiO7 = 10 / 1) to obtain intermediate A67 (7.0 g, 84% yield) as a colorless oil. 1 H NMR:(400 MHz,DMSO-d6)δ 7.42(dd,J=4.4,2.0 Hz,1H),4.79(d,J=2.2 Hz,2H),1.31(s,12H),0.85(s,9H),0.08(s,6H).

[0427] Intermediate A68 Synthesis of 4-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-2,3-difluorophenol (intermediate A68)

[0428] [ka]

[0429] Hydrogen peroxide (3.2 g, 93 mmol) was added to intermediate A67 (7.8 g, 19 mmol) in THF (80 mL). The mixture was stirred overnight at room temperature. The mixture was diluted with H2O (100 mL) and toluene (50 mL) was added. * 2) Extracted. The combined organic layer was treated with water (50 mL). * 2) The mixture was washed with brine (50 mL), dried over Na2SO4, and purified by silica column (petroleum ether / SiO7 = 10 / 1) to obtain intermediate A68 (4.7 g, 82% yield) as a white solid. 1H NMR:(400 MHz,DMSO-d6)δ 10.98(s,1H),6.88(dd,J=7.3,2.1 Hz,1H),4.68(d,J=2.2 Hz,2H),0.85(d,J=1.3 Hz,9H),0.06(d,J=1.4 Hz,6H).

[0430] Intermediate A69 Synthesis of ethyl 2-(4-(((tert-butyldimethylsilyl)oxy)methyl)-5-chloro-2,3-difluorophenoxy)acetate (intermediate A69)

[0431] [ka]

[0432] Intermediate A68 (3.0 g, 9.7 mmol), K2CO3 (2.0 g, 15 mmol), and ethyl 2-bromoacetate (2.0 g, 11.66 mmol) in DMF (30 mL) were stirred at room temperature for 3 hours. The mixture was diluted with H2O (100 mL) and extracted with SiO (25 mL). The combined organic layer was then diluted with water (25 mL). * 5) The mixture was washed with brine (50 mL), dried over Na2SO4, and concentrated to dryness to obtain product intermediate A69 (3.5 g, 91% yield) as a yellow solid. 1 H NMR:(400 MHz,DMSO-d6)δ 7.24(dd,J=7.1,2.1 Hz,1H),5.00(s,2H),4.72(d,J=2.2 Hz,2H),4.21-4.15(m,2H),1.21(dd,J=7.4,6.8 Hz,3H),0.85(s,9H),0.08(s,6H).

[0433] Intermediate A70 Synthesis of ethyl 2-(5-chloro-4-(chloromethyl)-2,3-difluorophenoxy)acetate (intermediate A70)

[0434] [ka]

[0435] To a solution of intermediate A69 (3.5 g, 8.9 mmol) in DCM (20 mL), TBAF (1 M in THF, 9.8 mL) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with H2O (50 mL) and extracted with DCM (25 mL). The combined organic layer was then diluted with water (25 mL). * 2) The mixture was washed with brine (50 mL), dried over Na2SO4, and concentrated to dryness to obtain compound 7 (2.4 g, 97% yield) as a colorless oil. To a solution of compound 7 (2.4 g, 8.6 mmol) in DCM (20 mL), SOCl2 (1.5 g, 12.8 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness to obtain intermediate A70 (2.5 g, 94% yield) as a white solid. 1 H NMR:(400 MHz,DMSO-d6)δ 7.35(dd,J=7.2,2.2 Hz,1H),5.04(s,2H),4.80(d,J=1.9 Hz,2H),4.18(q,J=7.1 Hz,2H),1.21(t,J=7.1 Hz,3H).

[0436] Intermediate A71 Synthesis of 3-chloro-2,5-difluoro-4-(hydroxymethyl)phenol (intermediate A71)

[0437] [ka]

[0438] 2-chloro-1,4-difluorobenzene (19.8 g, 133 mmol), 4,4'-di-tert-butyl-2,2'-bipyridine (894 mg, 3.33 mmol), and [Ir(OMe)](1,5-cod)2 (1.7 g, 2.67 mmol) were added to THF (100 mL), to which 4,4'-di-tert-butyl-2,2'-bipyridine (33.8 g, 133.30 mmol) was added. The mixture was heated at 80°C overnight and cooled to room temperature. Water (80 mL) was added, and the mixture was dissolved in phenylethylamine (50 mL). *3) Extraction was performed. The combined organic phase was washed with brine (80 mL), dried over Na2SO4, and concentrated under vacuum. The resulting solid was dissolved in THF (100 mL), and hydrogen peroxide (22.6 g, 664.85 mmol, 68.5 mL) was added at 0°C. The mixture was stirred at room temperature for 4 hours. The reaction was quenched with saturated Na2S2O3 aqueous solution (10 mL), and toluene (100 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (100 mL), dried with Na2SO4, and concentrated in vacuum. The resulting solid was dissolved in water (30 mL) at room temperature, and NaOH (1.8 g, 45.58 mmol) was added. The mixture was heated to 45°C, and CH2O (3.7 g, 45.58 mmol) was added dropwise. The mixture was stirred at 45°C overnight and cooled to room temperature. The mixture was diluted with water (20 mL), acidified to pH=5-6 with 1N HCl, and toluene (50 mL) was added. * Extraction was performed as described in 2). The combined organic phase was washed with brine (60 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified using a silica gel column (petroleum ether / SiO1 = 20 / 1 to 5 / 1) to obtain intermediate A71 (1.5 g, 6% yield) as a white solid. LCMS: T=0.36min, [M-1]=193.0

[0439] Intermediate A72 Synthesis of ethyl 2-(3-chloro-2,5-difluoro-4-(hydroxymethyl)phenoxy)acetate (intermediate A72)

[0440] [ka]

[0441] To a solution of intermediate A71 (500 mg, 2.57 mmol) in DMF (6 mL), K2CO3 (533 mg, 3.85 mmol) and ethyl 2-bromoacetate (515 mg, 3.08 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with  (30 mL) and brine (10 mL) *2) The mixture was washed, dried with Na2SO4, and concentrated in a vacuum to obtain intermediate A72 (710 mg, 98% yield) as a white solid. 1 H NMR:(400MHz,DMSO-d6)δ 7.20(dd,J=11.2,7.0 Hz,1H),5.21(s,1H),4.97(s,2H),4.51(s,2H),4.18(t,J=7.2 Hz,2H),1.21(t,J=7.2 Hz,3H).

[0442] Intermediate A73 Synthesis of ethyl 2-(3-chloro-4-(chloromethyl)-2,5-difluorophenoxy)acetate (intermediate A73)

[0443] [ka]

[0444] To a solution of intermediate A72 (710 mg, 2.53 mmol) in 5 mL of DCM at 0°C, thionyl chloride (451 mg, 3.79 mmol) was added. The mixture was stirred at room temperature for 2 hours. The mixture was concentrated under vacuum to obtain crude intermediate A73 (688 mg, 91% yield) as a yellow solid. HNMR: 1 H NMR(400 MHz,DMSO-d6)δ 7.34(dd,J=11.5,7.0 Hz,1H),5.00(s,2H),4.79(d,J=1.6 Hz,2H),4.18(q,J=7.1 Hz,2H),1.21(t,J=7.1 Hz,3H).

[0445] Intermediate A74 Synthesis of 4-(benzyloxy)-2,6-dichlorobenzaldehyde (intermediate A74)

[0446] [ka]

[0447] To a solution of 2,6-dichloro-4-hydroxybenzaldehyde (6.5 g, 34 mmol) in DMF (50 mL), K2CO3 (5.6 g, 41 mmol) and BnBr (5.8 g, 34 mmol) were added. The mixture was stirred at room temperature for 2 hours, diluted with water (50 mL), and toluene (30 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (50 mL), dried with Na2SO4, concentrated in vacuum, and washed with n-hexane to obtain intermediate A74 (8.6 g, 90% yield) as a white solid. 1 H NMR:(400 MHz,DMSO-d6)δ 10.28(s,1H),7.49-7.35(m,5H),7.30(s,2H),5.27(s,2H).

[0448] Intermediate A75 Synthesis of 2,4-dichloro-6-iodophenol (intermediate A75)

[0449] [ka]

[0450] To a solution of 2,4-dichlorophenol (5.0 g, 30.67 mmol) in DCM (30 mL), NIS (8.3 g, 36.81 mmol) and TsOH (1.2 g, 6.13 mmol) were added. The mixture was stirred overnight at room temperature. The mixture was diluted with H2O (50 mL) and extracted with DCM (50 mL). The organic phase was washed with brine (20 mL), dried over Na2SO4, and concentrated under vacuum to obtain intermediate A75 (2.0 g, 23% yield) as a white solid. LCMS: T = 2.376 min, [M-1] = 286.7

[0451] Intermediate A76 Synthesis of 1,5-dichloro-3-iodo-2-methoxybenzene (intermediate A76)

[0452] [ka]

[0453] To a solution of intermediate A75 (1.5 g, 5.33 mmol) in DMF (10 mL), K2CO3 (1.1 g, 8.00 mmol) and MeI (1.1 g, 8.00 mmol) were added. The reaction mixture was stirred at room temperature for 3 hours. The mixture was diluted with H2O (50 mL) and toluene (20 mL) was added. * 2) Extracted. The combined organic phase was prepared in brine (50 mL). * 2) The mixture was washed, dried with Na2SO4, and concentrated in a vacuum to obtain intermediate A76 (1.5 g, 97% yield) as a brown solid. 1 H NMR:(400 MHz,DMSO-d6)δ 7.89(d,J=2.5 Hz,1H),7.71(d,J=2.5 Hz,1H),3.77(s,3H).

[0454] Intermediate A77 Synthesis of 3,5-dichloro-2-methoxyphenol (intermediate A77)

[0455] [ka]

[0456] To a solution of intermediate A76 (1.7 g, 5.8 mmol) in water (1 mL) at room temperature, KOH (1.3 g, 23 mmol), Pd2(dba)3 (532 mg, 0.58 mmol), and tBuXPhos (247 mg, 0.58 mmol) were added. The reaction mixture was heated at 100 °C overnight and cooled to room temperature. The reaction mixture was diluted with H2O (50 mL) and SiO2 (20 mL) was added. * 2) Extracted. The combined organic phase was treated with brine (20 mL). * The product was washed (2), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified using a silica gel column (petroleum ether / siRNA = 50 / 1) to obtain intermediate A77 (560 mg, 50% yield) as a brown solid. LCMS: T=1.256 min, [M-1]=190.9

[0457] Intermediate A78 Synthesis of 3,5-dichloro-4-(hydroxymethyl)-2-methoxyphenol (intermediate A78)

[0458] [ka]

[0459] Intermediate A77 (546 mg, 2.83 mmol) was added to a solution of NaOH (113 mg, 2.83 mmol) in water (20 mL) at room temperature. The mixture was heated to 45°C and CH2O (230 mg, 2.83 mmol) was added dropwise. The mixture was stirred at 45°C overnight and cooled to room temperature. The mixture was diluted with water (20 mL), acidified to pH=5-6 with 1N HCl, and toluene (20 mL) was added. * Extraction was performed as described in 2). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, and concentrated under reduced pressure. The crude product was purified using a silica gel column (petroleum ether / SiO7 = 20 / 1 to 5 / 1) to obtain intermediate A78 (280 mg, 44% yield) as a white solid. LCMS: T = 1.052 min, [M-1] = 220.9

[0460] Intermediate A79 Synthesis of ethyl 2-(3,5-dichloro-4-(hydroxymethyl)-2-methoxyphenoxy)acetate (intermediate A79)

[0461] [ka]

[0462] To a solution of intermediate A78 (280 mg, 1.26 mmol) in DMF (5 mL), K2CO3 (260 mg, 1.88 mmol) and ethyl 2-bromoacetate (251 mg, 1.51 mmol) were added. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with SiO2 (30 mL) and brine (20 mL) *2) The mixture was washed, dried with Na2SO4, and concentrated in a vacuum to obtain intermediate A79 (380 mg, 98% yield) as a white solid. 1 H NMR;(400 MHz,DMSO-d6)δ 7.17(s,1H),5.12(t,J=5.2 Hz,1H),4.96(s,2H),4.60(d,J=5.2 Hz,2H),4.18(t,J=7.2 Hz,2H),3.79(s,3H),1.21(t,J=7.2 Hz,3H).

[0463] Intermediate A80 Synthesis of ethyl 2-(3,5-dichloro-4-(chloromethyl)-2-methoxyphenoxy)acetate (intermediate A80)

[0464] [ka]

[0465] SOCl2 (219 mg, 1.84 mmol) was added to a solution of intermediate A79 (380 mg, 1.23 mmol) in DCM (5 mL) at 0°C. The mixture was stirred at room temperature for 2 hours. By concentrating the mixture under vacuum, intermediate A80 (378 mg, 94% yield) was obtained as a white solid. 1 H NMR;(400 MHz,DMSO-d6)δ 7.29(s,1H),5.00(s,2H),4.86(s,2H),4.18(q,J=7.2 Hz,2H),3.82(s,3H),1.21(t,J=7.2 Hz,3H).

[0466] Intermediate B1 Synthesis of 3-fluoro-2-(prop-1-en-2-yl)phenol (intermediate B1)

[0467] [ka]

[0468] A mixture of 2-bromo-3-fluorophenol (38.0 g, 200 mmol), isopropenyl-2-borone (pinacolate) (50.4 g, 300 mmol), and Pd(dppf)Cl2·CH2Cl2 (16.3 g, 20 mmol) in 1,4-dioxane (300 mL) and water (30 mL) at room temperature was mixed with K2CO3 (55.3 g, 400 mmol). The mixture was heated to 70°C and stirred overnight. The reaction mixture was cooled to room temperature, quenched with water (100 mL), and siRNA (100 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (200 mL), dried with Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (SiO2 / petroleum ether = 1 / 100 to 1 / 20) to obtain intermediate B1 (23.0 g, 76% yield) as a white solid. TLC: Â / petroleum ether = 1 / 10 (v / v), Rf = 0.55 1 H NMR:(400 MHz,DMSO-d6)δ 9.72(s,1H),7.06(td,J=8.4,6.8 Hz,1H),6.66(td,J=8.4,1.2 Hz,1H),6.59(m,1.0 Hz,1H),5.28(m,1H),4.89(m,1H),1.98(s,3H).

[0469] Intermediate B2 Synthesis of 3-fluoro-2-isopropylphenol (intermediate B2)

[0470] [ka]

[0471] To a solution of intermediate B1 (23.0 g, 151 mmol) in MeOH (300 mL), Pd / C (10%) (6.0 g) was added. The reaction mixture was stirred overnight at 60°C. The mixture was cooled to 0°C, filtered, and concentrated under vacuum to obtain intermediate B2 (21.0 g, 90% yield) as a yellow oil. TLC: Â / petroleum ether = 1 / 50 (v / v), Rf = 0.25 1H NMR:(400 MHz,DMSO-d6)δ 9.69(s,1H),7.00-6.93(m,1H),6.65-6.60(m,1H),6.52(ddd,J=10.8,8.0,1.2 Hz,1H),3.40(m,1H),1.25(dd,J=7.2,1.2 Hz,6H).

[0472] Intermediate B3 Synthesis of 2-(3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate B3)

[0473] [ka]

[0474] A mixture of 3-bromophenyl difluoromethyl ether (250 mg, 1.12 mmol), bis(pinacolate)diborone (311 mg, 1.23 mmol), Pd(dppf)Cl2 (73 mg, 0.10 mmol), and KOAc (323 mg, 3.36 mmol) in 1,4-dioxane (5 mL) was stirred overnight at 80°C. The mixture was filtered and concentrated under vacuum to obtain intermediate B3 (270 mg, 89.4% yield) as a black oil, which was used without further purification. TLC: Petroleum ether / alkyl = 10 / 1 (v / v), Rf = 0.8

[0475] Intermediate B4 Synthesis of 1-(1-bromovinyl)-4-fluorobenzene (intermediate B4)

[0476] [ka]

[0477] Br2 (17.4g, 109mmol) was added to a solution of 4-fluoroacetophenone (10.0g, 72.4mmol), P(OPh)3 (35.4g, 109mmol), and triethylamine (11.7g, 116mmol) in DCM (100mL) at -15℃. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated to dryness and purified by silica gel column chromatography (petroleum ether eluent) to obtain intermediate B4 (8.0g, 54.9% yield) as a colorless oil that stores best at 0℃. TLC: Petroleum ether, R f =0.91 1 H NMR:(400 MHz,Chloroform-d)δ 7.63-7.50(m,2H),7.03(t,J=8.7 Hz,2H),6.05(d,J=2.1 Hz,1H),5.76(d,J=2.0 Hz,1H).

[0478] Intermediate B5 Synthesis of 2-(1-(4-fluorophenyl)vinyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate B5)

[0479] [ka]

[0480] A solution of intermediate B4 (3.0 g, 14.9 mmol), bis(pinacolate)diborone (5.7 g, 22.4 mmol), Pd(PPh3)2Cl2 (1.1 g, 1.49 mmol), KOAc (4.4 g, 44.8 mmol), and PPh3 (1.2 g, 4.48 mmol) in toluene (50 mL) was stirred overnight at 100 °C. The mixture was concentrated under vacuum. Water (30 mL) was added to the mixture, and SiO2 (25 mL) was added. *3) Extraction was performed. The combined organic phase was washed with brine (50 mL), dried with Na2SO4, concentrated in vacuum, and purified by silica gel column chromatography (petroleum ether / HCl = 20 / 1) to obtain intermediate B5 (1.5 g, 40.5% yield) as a yellow oil. TLC: Petroleum ether, Rf=0.69 1 H NMR:(400 MHz,Chloroform-d)δ 7.45(dd,J=8.7,5.6 Hz,2H),7.00(t,J=8.8 Hz,2H),6.04(s,2H),1.32(s,12H).

[0481] Intermediate B6 Synthesis of 3-fluoro-2-(4-fluorobenzyl)phenol (intermediate B6)

[0482] [ka]

[0483] To a solution of 4-fluorobenzyl bromide (1.0 g, 5.29 mmol) and 6-fluoro-2-hydroxyphenylboronic acid (1.2 g, 7.94 mmol) in toluene (10 mL) at room temperature, Pd(dppf)Cl2 (387 mg, 0.53 mmol) and K3PO4 (3.4 g, 15.87 mmol) were added. The reaction mixture was heated overnight at 100°C under N2 (g). Water (20 mL) was added, and the resulting mixture was dissolved in toluene (10 mL). * Extraction was performed as described in 2). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / SiO₂ = 100 / 1 to 20 / 1) and subsequent reverse-phase column chromatography to obtain intermediate B6 (180 mg, 15.4% yield) as a pale yellow oil. TLC: Petroleum ether / African ether = 5 / 1(v / v), Rf = 0.29.

[0484] Intermediate B7 Synthesis of 3-fluoro-2-(1-(4-fluorophenyl)-1-hydroxypropyl)phenol (intermediate B7)

[0485] [ka]

[0486] To a solution of 2-bromo-3-fluorophenol (1.00 g, 5.24 mmol) in THF (10 mL) at -30°C, n-BuLi (2.5 M, 4.00 mL, 10.0 mmol) was added dropwise. The reaction mixture was stirred at -30°C for 30 minutes, then cooled to -50°C, and (4-fluorophenyl)ethyl ketone (0.73 g, 4.36 mmol) in THF (3 mL) was added dropwise. The mixture was stirred at -50°C for 2 hours, quenched with aqueous NH4Cl solution (30 mL), acidified to pH ~6 with HCl (1 N), and then toluene (20 mL) was added. * Extraction was performed as described in 3). The combined organic phase was washed with brine (30 mL), dried with Na2SO4, and concentrated under vacuum. The crude product was purified by reverse-phase column chromatography to obtain intermediate B7 (230 mg, 20% yield) as a yellow oil. TLC: alkyl / petroleum ether = 1 / 5 (v / v), Rf = 0.36 1 H NMR:(400 MHz,DMSO-d6)δ 11.07(s,1H),7.47-7.40(m,2H),7.36(s,1H),7.18-7.04(m,3H),6.58(dt,J=8.3,1.1 Hz,1H),6.49(ddd,J=12.0,8.2,1.3 Hz,1H),2.49-2.42(m,2H),2.22-2.15(m,1H),0.89(t,J=7.2 Hz,3H).

[0487] Intermediate B8 Synthesis of 3-fluoro-2-(1-(4-fluorophenyl)propyl)phenol (intermediate B8)

[0488] [ka]

[0489] To a solution of intermediate B7 (230 mg, 1.14 mmol) in DCM (5 mL) at room temperature, Et3SiH (528 mg, 4.54 mmol) was added, the mixture was cooled to 0°C, and TFA (3.88 g, 34.1 mmol) was added dropwise. The mixture was stirred at room temperature for 3 hours, and then concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / HCl = 50 / 1 to 10 / 1) to obtain intermediate B8 (80 mg, 37% yield) as a yellow oil. TLC: alkyl / petroleum ether = 1 / 5 (v / v), Rf = 0.60

[0490] Intermediate B9 Synthesis of 3-fluoro-2-(1-(4-fluorophenyl)-1-hydroxybutyl)phenol (intermediate B9)

[0491] [ka]

[0492] To a solution of 2-bromo-3-fluorophenol (1.00 g, 5.24 mmol) in THF (10 mL) at -30°C, n-BuLi (2.5 M, 4.0 mL, 10.0 mmol) was added dropwise. The reaction mixture was stirred at -30°C for 30 minutes, then cooled to -50°C, and (4-fluorophenyl)propyl ketone (0.73 g, 4.36 mmol) in THF (3 mL) was added dropwise. The mixture was stirred at -50°C for 2 hours, quenched with aqueous NH4Cl solution (30 mL), acidified to pH ~6 with HCl (1 N), and then toluene (10 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (20 mL), dried with Na2SO4, and concentrated under vacuum. The crude product was purified by reverse-phase column chromatography to obtain intermediate B9 (250 mg, 20% yield) as a yellow oil. TLC: alkyl / petroleum ether = 1 / 5 (v / v), Rf = 0.36 1 H NMR:(400 MHz,DMSO-d6)δ 11.06(s,1H),7.46-7.40(m,2H),7.40(s,1H),7.17-7.06(m,3H),6.57(dt,J=8.2,1.1 Hz,1H),6.49(ddd,J=12.0,8.2,1.3 Hz,1H),2.47-2.37(m,1H),2.19-2.07(m,1H),2.03-1.96(m,1H),1.62-1.44(m,1H),0.90(t,J=7.4 Hz,3H).

[0493] Intermediate B10 Synthesis of 3-fluoro-2-(1-(4-fluorophenyl)butyl)phenol (intermediate B10)

[0494] [ka]

[0495] To a solution of intermediate B9 (230 mg, 826 ml) in DCM (5 mL) at room temperature, Et3SiH (384 mg, 3.31 mmol) was added. The mixture was cooled to 0°C, and TFA (2.83 g, 24.8 mmol) was added dropwise. The mixture was stirred at room temperature for 3 hours, and then concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / alkyl = 50 / 1 to 10 / 1) to obtain intermediate B10 (130 mg, 60% yield) as a yellow oil. TLC: alkyl / petroleum ether = 1 / 5 (v / v), Rf = 0.60 1 H NMR:(400 MHz,DMSO-d6)δ 9.88(d,J=1.6 Hz,1H),7.33-7.27(m,2H),7.10-7.04(m,2H),7.03-6.97(m,1H),6.66-6.61(m,1H),6.54(ddd,J=10.9,8.3,1.1 Hz,1H),4.48-4.39(m,1H),2.23-2.08(m,1H),2.06-1.96(m,1H),1.18(d,J=7.4 Hz,1H),0.88(t,J=7.3 Hz,3H).

[0496] Intermediate B11 Synthesis of 3-chloro-2-(prop-1-en-2-yl)phenol (intermediate B11)

[0497] [ka]

[0498] A mixture of 2-bromo-3-chlorophenol (1.0 g, 4.8 mmol), isopropenyl-2-borone (pinacolate) (1.2 g, 7.2 mmol), and Pd(dppf)Cl2·CH2Cl2 (170 mg, 0.24 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) at room temperature was mixed with K2CO3 (1.3 g, 9.6 mmol). The mixture was heated at 75°C overnight. The reaction mixture was cooled to room temperature, quenched with water (30 mL), and siRNA (30 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (20 mL), dried with Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (SiO2 / petroleum ether = 1 / 20) to obtain intermediate B11 (800 mg, 98% yield) as a white solid. TLC: Â / petroleum ether = 1 / 10 (v / v), Rf = 0.55 1 H NMR:(400 MHz,DMSO)δ 9.65(s,1H),7.06(t,J=8.1 Hz,1H),6.86(d,J=8.0 Hz,1H),6.79(d,J=8.2 Hz,1H),5.27(s,1H),4.78(s,1H),1.93(s,3H).

[0499] Intermediate B12 Synthesis of 3-chloro-2-isopropylphenol (intermediate B12)

[0500] [ka]

[0501] Raney-Ni (40 mg) was added to a solution of intermediate B11 (800 mg, 4.7 mmol) in THF (20 mL). The reaction mixture was stirred overnight at 60°C under H2 gas (1 atm). The mixture was cooled to 0°C, filtered, and then concentrated under vacuum to obtain intermediate B12 (800 mg, 98% yield) as a yellow oil. TLC: Â / petroleum ether = 1 / 50 (v / v), Rf = 0.25 1 H NMR:(400 MHz,DMSO)δ 9.69(s,1H),6.96(m,1H),6.82-6.71(m,2H),3.61-3.48(m,1H),1.29(d,J=7.1 Hz,6H).

[0502] Intermediate B13 Synthesis of 3-methoxy-2-(prop-1-en-2-yl)phenol (intermediate B13)

[0503] [ka]

[0504] To a solution of 2-bromo-3-methoxyphenol (500 mg, 2.46 mmol) and propenyl-2-borone (pinacolate) (621 mg, 3.69 mmol) in 1,4-dioxane (10 mL) at room temperature under N2 (g), Pd(dppf)Cl2 (360 mg, 0.49 mmol) and K2CO3 (681 mg, 4.93 mmol) were added. The mixture was heated at 80°C overnight. The mixture was diluted with ELISA (20 mL) and brine (10 mL) * The product was washed (2), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (SiO2SO4 = 1 / 100 to 1 / 10) to obtain intermediate B13 (200 mg, 49.4% yield) as a pale yellow liquid. TLC: Petroleum ether / acetate = 10 / 1 (v / v), Rf = 0.75. 1H NMR:(400 MHz,DMSO-d6)δ 9.02(s,1H),6.98(t,J=8.0 Hz,1H),6.43(ddd,J=9.2,8.4,0.8 Hz,2H),5.15(dt,J=3.2,1.6 Hz,1H),4.71(dd,J=2.4,1.2 Hz,1H),3.67(s,3H),1.89(t,J=1.2 Hz,3H).

[0505] Intermediate B14 Synthesis of 2-isopropyl-3-methoxyphenol (intermediate B14)

[0506] [ka]

[0507] To a solution of intermediate B13 (400 mg, 2.44 mmol) in room temperature THF (10 mL), Pd / C (100 mg, 2.44 mmol) was added. The mixture was degassed several times under vacuum and then placed under an H2 atmosphere. The mixture was stirred overnight at 60°C. The reaction product was filtered and concentrated to obtain intermediate B14 (400 mg, 98.7% yield) as a white solid. TLC: Petroleum ether / African ether = 10 / 1 (v / v), Rf = 0.76. 1 H NMR:(400 MHz,DMSO-d6)δ 9.11(s,1H),6.89(t,J=8.0 Hz,1H),6.42-6.35(m,2H),3.70(s,3H),3.50-3.46(m,1H),1.21(d,J=7.2 Hz,6H).

[0508] Intermediate B15 Synthesis of 3-hydroxy-2-(prop-1-en-2-yl)benzonitrile (intermediate B15)

[0509] [ka]

[0510] K2CO3 (1.68 g, 12.12 mmol) was added to a mixture of 2-bromo-3-hydroxybenzonitrile (800 mg, 4.04 mmol), isopropenyl-2-borone (pinacolate) (1.36 g, 8.08 mmol), and Pd(dppf)Cl2·CH2Cl2 (260 mg, 0.40 mmol) in 1,4-dioxane (10 mL) and H2O (2 mL) at room temperature. The mixture was heated at 75°C overnight. The reaction mixture was cooled to room temperature, quenched with water (30 mL), and siRNA (30 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (20 mL), dried with Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (SiO2 / petroleum ether = 1 / 20) to obtain intermediate B15 (400 mg, 62.2% yield) as a white solid. TLC: Â / petroleum ether = 1 / 5 (v / v), Rf = 0.55 1 H NMR:(400 MHz,DMSO-d6)δ 10.13(s,1H),7.30-7.20(m,2H),7.12(dd,J=7.9,1.5 Hz,1H),5.34(q,J=1.6 Hz,1H),4.98-4.95(m,1H),2.03(s,3H).

[0511] Intermediate B16 Synthesis of 3-hydroxy-2-isopropylbenzonitrile (intermediate B16)

[0512] [ka]

[0513] To a solution of intermediate B15 (400 mg, 4.7 mmol) in THF (20 mL), Pd / C (5%) (40 mg) was added. The reaction mixture was stirred overnight at room temperature under an H2 atmosphere. The mixture was filtered, concentrated to dryness, and purified by preparative TLC (petroleum ether / SiO1 = 5 / 1) to obtain intermediate B16 (150 mg, 37.1% yield) as a white solid. TLC: alkyl / petroleum ether = 1 / 5 (v / v), Rf = 0.61 1 H NMR:(400 MHz,DMSO-d6)δ 10.06(s,1H),7.22-7.14(m,2H),7.08(dd,J=7.0,2.4 Hz,1H),3.41(p,J=7.1 Hz,1H),1.34(d,J=7.1 Hz,6H).

[0514] Intermediate B17 Synthesis of 2-(1-(4-fluorophenyl)-1-hydroxybutyl)phenol (intermediate B17)

[0515] [ka]

[0516] To a solution of 2-bromophenol (1.25 g, 7.22 mmol) in dry THF (15 mL) at -50°C, n-BuLi (15.0 mmol, 6.02 mL of 2.5 M) was added. The mixture was warmed to room temperature and stirred for 1 hour. The resulting solution was cooled to 0°C, and 4-fluorophenyl-n-propyl ketone (1.00 g, 6.02 mmol) in THF (5 mL) was added dropwise. The mixture was stirred at room temperature for 2 hours. NH4Cl(aq) (15 mL) was added. The mixture was acidified to pH 4-5 with 1N HCl, and then DCM (15 mL) was added. * Extraction was performed in step 2). The combined organic layers were dried with Na2SO4, concentrated under vacuum, and purified by reverse-phase column chromatography to obtain intermediate B17 (1.0 g, 63.9% yield) as a colorless oil. TLC: HCl / petroleum ether = 1 / 5 (v / v), Rf = 0.48 1H NMR:(400 MHz,DMSO-d6)δ 9.57(s,1H),7.40-7.32(m,3H),7.10-7.02(m,3H),6.79(td,J=7.6,1.3 Hz,1H),6.66(dd,J=8.0,1.3 Hz,1H),6.21(s,1H),2.42-2.31(m,1H),2.14-2.02(m,1H),1.27-1.20(m,2H),0.85(t,J=7.4 Hz,3H).

[0517] Intermediate B18 Synthesis of 2-(1-(4-fluorophenyl)butyl)phenol (intermediate B18)

[0518] [ka]

[0519] A mixture of intermediate B17 (1.0 g, 3.84 mmol), Et3SiH (1.79 g, 15.4 mmol), and TFA (4.38 g, 38.4 mmol) in DCM (10 mL) was stirred at room temperature for 3 hours. The mixture was concentrated under vacuum and purified by silica gel column chromatography to obtain the product intermediate B18 (800 mg, 85.2% yield) as a white solid. TLC: alkyl / petroleum ether = 1 / 5 (v / v), Rf = 0.66 1 H NMR:(400 MHz,DMSO-d6)δ 9.30(s,1H),7.31-7.24(m,2H),7.17(dd,J=8.1,1.6 Hz,1H),7.04(t,J=8.9 Hz,2H),7.00-6.94(m,1H),6.75(d,J=7.7 Hz,2H),4.29(t,J=7.9 Hz,1H),1.96-1.86(m,2H),1.17(t,J=7.1 Hz,2H),0.86(d,J=7.4 Hz,3H).

[0520] Intermediate B19 Synthesis of 3'-(difluoromethoxy)-[1,1'-biphenyl]-2-ol (intermediate B19)

[0521] [ka]

[0522] A mixture of intermediate B3 (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 to the mixture, and ¼ (30 mL) was added to the mixture. * Extraction was performed as described in 2). The combined organic phase was washed with brine (50 mL), dried with Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / SiO1 = 20 / 1 to 5 / 1, v / v) to obtain intermediate B19 (700 mg, 34% yield) as a yellow oil. TLC: Â / petroleum ether = 1 / 5 (v / v), Rf = 0.54 LCMS:RT=2.551 min;[M-1]=235.0

[0523] Intermediate B19 Synthesis of 4-iodo-2-isopropyl-1-(methoxymethoxy)benzene (intermediate B20)

[0524] [ka]

[0525] To a solution of 4-iodo-2-isopropylphenol (20.0 g, 76.3 mmol) in DCM (200 mL), DIEA (29.6 g, 229 mmol) and MOMCl (9.2 g, 114 mmol) were added. The mixture was stirred at room temperature for 3 hours. Water (500 mL) was added, and the mixture was dissolved in siRNA (200 mL). *Extraction was performed as described in 3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, and concentrated under vacuum until dry. The residue was purified by silica gel column (petroleum ether) to obtain intermediate B20 (14 g, 60% yield) as a yellow oil. 1 H NMR:(400 MHz,DMSO-d6)δ 7.45(d,J=8.0 Hz,2H),6.87(d,J=8.2 Hz,1H),5.20(s,2H),3.37(d,J=0.6 Hz,3H),1.15(d,J=6.9 Hz,6H).

[0526] Intermediate C1 Synthesis of methyl 2-(4-(3-bromo-2-fluoro-4-hydroxybenzyl)-3,5-dimethylphenoxy)acetate (intermediate C1)

[0527] [ka]

[0528] A solution of intermediate A3 (1 g, 4.12 mmol), 2-bromo-3-fluorophenol (2.3 g, 12.4 mmol), and ZnCl2 (1 M in THF, 10.3 mL) in DCE (5 mL) was stirred overnight at 95°C. The mixture was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether / SiO=5:1) and preparative TLC (petroleum ether / SiO=3:1) to obtain intermediate C1 (100 mg, 6.1% yield) as a colorless oil. TLC: Petroleum ether / acetate = 5 / 1 (v / v), Rf = 0.4 1 H NMR:(400 MHz,DMSO-d6)δ 10.44(s,1H),6.66(s,2H),6.64(d,J=8.8 Hz,1H),6.37(t,J=8.4 Hz,1H),4.75(s,2H),3.82(s,2H),3.71(s,3H),2.13(s,6H).

[0529] Intermediate C2 Synthesis of ethyl 2-(3-bromo-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-5-methylphenoxy)acetate (intermediate C2)

[0530] [ka]

[0531] To a solution of intermediate A6 (1.06 g, 3.3 mmol) in room temperature DCE (20 mL), intermediate B2 (1.52 g, 9.9 mmol) and ZnCl2 / THF (1 M) (8.2 mL, 8.25 mmol) were added. The reaction mixture was heated to 85 °C and stirred for 2 hours. The reaction mixture was diluted with DCM (20 mL) and brine (2 * The solution was washed with 10 mL of silica gel, dried over Na₂SO₄, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (siRNA / petroleum ether = 1 / 5) to obtain intermediate C7 as a solid (530 mg, 38.8% yield). TLC: Â / petroleum ether = 1 / 5 (v / v), Rf = 0.35 1 H NMR:(400 MHz,DMSO)δ 9.48(d,J=1.5 Hz,1H),7.08(d,J=2.7 Hz,1H),6.88(d,J=2.7 Hz,1H),6.49-6.43(m,1H),6.17(t,J=8.6 Hz,1H),4.80(s,2H),4.18(d,J=7.1 Hz,2H),3.93(s,2H),2.16(s,2H),1.26(m,6H),1.17(t,J=7.1 Hz,3H).

[0532] Intermediate C3 Synthesis of ethyl 2-(4-(3-bromo-2-fluoro-4-hydroxybenzyl)-3,5-dichlorophenoxy)acetate (intermediate C3)

[0533] [ka]

[0534] A solution of 2-bromo-3-fluorophenol (1.54 g, 8.07 mmol), intermediate A11 (800 mg, 2.69 mmol), and ZnCl2 (916 mg, 6.72 mmol) in DCE (20 mL) was stirred overnight at 90°C. The mixture was cooled to room temperature and concentrated under vacuum. Water (30 mL) was added, and the mixture was dissolved in dimethyl phosphate (25 mL). * 3) Extraction was performed. The combined organic phase was washed with brine (50 mL), dried with Na2SO4, concentrated in vacuum, and purified by silica gel column chromatography (petroleum ether / siRNA = 5 / 1) to obtain intermediate C3 (600 mg, 49.4% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 5 (v / v), Rf = 0.4 LCMS: RT=2.795 min, [M-1]=448.9 1 H NMR:(400 MHz,DMSO-d6)δ 10.55(s,1H),7.18(s,2H),6.68(dd,J=8.5,1.4 Hz,1H),6.57(t,J=8.6 Hz,1H),4.89(s,2H),4.18(q,J=7.1 Hz,2H),4.09(s,2H),1.21(t,J=7.1 Hz,3H).

[0535] Intermediate C4 Synthesis of methyl 2-(4-(3-bromo-4-hydroxy-2-methylbenzyl)-3,5-dichlorophenoxy)acetate (intermediate C4)

[0536] [ka]

[0537] To a solution of 2-bromo-3-methylphenol (1.0 g, 5.4 mmol) and intermediate A10 (758 mg, 2.7 mmol) in DCE (10.0 mL), ZnCl2 (1 M / THF) (6.7 mmol, 6.7 mL) was added. The mixture was stirred overnight at 85°C. The mixture was cooled to room temperature, water (20 mL) was added, and the resulting mixture was heated in DCM (10 mL). *3) Extraction was performed. The combined organic phase was washed with brine (20 mL), dried with Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (SiO2 / petroleum ether = 1 / 30 to 1 / 10) to obtain intermediate C4 (400 mg, 34% yield) as a white solid. TLC: Â / petroleum ether = 1 / 5 (v / v), Rf = 0.30 1 H NMR:(400 MHz,DMSO-d6)δ 9.94(s,1H),7.20(s,2H),6.65(d,J=8.4 Hz,1H),6.19(d,J=8.4 Hz,1H),4.93(s,2H),4.05(s,2H),3.72(s,3H),2.45(s,3H).

[0538] Intermediate C5 Synthesis of ethyl 2-(3-bromo-5-chloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)phenoxy)acetate (intermediate C5)

[0539] [ka]

[0540] To a solution of intermediate A34 (1.0 g, 2.9 mmol) in DCE (10 mL) at room temperature, 2-isopropylphenol (1.1 g, 8.3 mmol) and ZnCl2 (6.9 mmol, 6.9 mL) were added. The reaction mixture was heated to 85 °C and stirred overnight. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the resulting mixture was heated in DCM (20 mL). * Extraction was performed as described in 3). The combined organic phase was washed with brine (40 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (siRNA / petroleum ether = 1 / 100 to 1 / 10) to obtain intermediate C5 (550 mg, 43.1% yield) as a white solid. TLC: Petroleum ether / acetate = 5 / 1 (v / v), Rf = 0.20 1H NMR:(400 MHz,DMSO-d6)δ 9.11(s,1H),7.44(d,J=7.6 Hz,1H),6.97(s,1H),6.65(d,J=1.2 Hz,2H),4.99(s,2H),4.18(q,J=6.8 Hz,2H),4.11(s,2H),3.13(p,J=6.8 Hz,1H),1.19-1.15(m,3H),1.11(d,J=6.8Hz,6H).

[0541] Intermediate C6 Synthesis of ethyl 2-(5-bromo-3-chloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)phenoxy)acetate (intermediate C6)

[0542] [ka]

[0543] To a solution of intermediate A39 (6.0 g, 16.7 mmol) in DCE (100 mL) at room temperature, 2-isopropylphenol (6.8 g, 50.0 mmol) and ZnCl2 (41.7 mmol, 42 mL) were added. The reaction mixture was heated to 85 °C and stirred overnight. The reaction mixture was cooled to room temperature, water (60 mL) was added, and the mixture was heated in DCM (30 mL). * Extraction was performed as described in 3). The combined organic phase was washed with brine (100 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (SiO2SO4 = 1 / 100 to 1 / 10) to obtain intermediate C6 (2.6 g, 33.9% yield) as a white solid. TLC: Petroleum ether / acetate = 5 / 1 (v / v), Rf = 0.20 1H NMR:(400 MHz,DMSO-d6)δ 9.13(s,1H),7.54(d,J=7.6 Hz,1H),6.97(s,1H),6.67-6.63(m,2H),5.00(s,2H),4.18(q,J=7.2 Hz,2H),4.10(s,2H),3.13(p,J=6.8 Hz,1H),1.21(t,J=7.2 Hz,3H),1.11(d,J=6.8 Hz,6H).

[0544] Intermediate C7 Synthesis of ethyl 2-(4-(3-bromo-2-fluoro-4-hydroxybenzyl)-3,5-dichloro-2-fluorophenoxy)acetate (intermediate C7)

[0545] [ka]

[0546] ZnCl2 (1.0 g, 3.1 mmol) was added to a solution of 2-bromo-3-fluorophenol (1.8 g, 9.3 mmol) and intermediate A29 (1.0 g, 3.1 mmol) in chlorobenzene (20 mL). The mixture was stirred in a microwave at 160 °C for 2 hours. The mixture was allowed to cool to room temperature. Water (150 mL) was added, and the resulting mixture was heated in DCM (100 mL). * 3) Extraction was performed. The combined organic phase was washed with brine (100 mL), dried with Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (siRNA / petroleum ether = 1 / 5) to obtain intermediate C7 as a solid (950 mg, 67.7% yield). TLC: Â / petroleum ether = 1 / 5 (v / v), Rf = 0.25 1 H NMR:(400 MHz,DMSO)δ 10.58(s,1H),7.45(d,J=7.6 Hz,1H),6.69(d,J=8.7 Hz,1H),6.61(d,J=8.5 Hz,1H),5.02(d,J=6.8 Hz,2H),4.18(d,J=7.1 Hz,2H),4.11(s,2H),1.21(s,3H).

[0547] Intermediate C8 Synthesis of 3,5-dichloro-4-(3-isopropyl-4-(methoxymethoxy)benzyl)phenol (intermediate C8)

[0548] [ka]

[0549] A solution of intermediate B20 (8.2 g, 27 mmol) in THF (80 mL) was cooled to -20°C. i-PrMgCl (1 M in THF, 32 mL) was added dropwise. The mixture was stirred at room temperature for 2 hours, and then cooled to -70°C. A solution of intermediate A74 (5.0 g, 18 mmol) in THF (10 mL) was added dropwise. The solution was stirred at -70°C for 2 hours. Saturated NH4Cl aqueous solution (50 mL) was added, and the mixture was dissolved in SiO4Cl (50 mL). * 3) Extraction was performed. The combined organic phase was washed with brine (200 mL), dried with Na2SO4, and concentrated under vacuum. The resulting brown oil was filtered through a silica plug, and the filtrate was concentrated. Half of the resulting yellow solid was dissolved in THF (30 mL), and Pd / C (750 mg, 6.18 mmol) was added. The mixture was stirred overnight at 50°C under an H2 atmosphere. The reaction mixture was cooled to room temperature and filtered. Water (30 mL) was added, and the mixture was dissolved in toluene (20 mL). * 3) Extraction was performed. The combined organic phase was washed with brine (50 mL), dried with Na2SO4, and concentrated in vacuum. The resulting yellow oil was dissolved in DCM (20 mL), cooled to 0°C, and Et3SiH (3.60 g, 30.98 mmol) was added dropwise. Then TFA (1.4 g, 12.39 mmol) was added dropwise. The mixture was stirred at room temperature for 0.5 hours. The mixture was acidified to pH=7 with saturated NaHCO3 aqueous solution. The mixture was then dissolved in ELISA (30 mL). *Extraction was performed in step 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel column (petroleum ether / SiO7 = 30 / 1 to 10 / 1) to obtain intermediate C8 (1.7 g, 80% yield) as a yellow solid. 1 H NMR:(400 MHz,DMSO-d6)δ 10.24(s,1H),7.06(d,J=2.2 Hz,1H),6.90(d,J=8.4 Hz,1H),6.88(s,2H),6.79(dd,J=8.4,2.3 Hz,1H),5.15(s,2H),4.05(s,2H),3.36(s,3H),3.22(p,J=7.0 Hz,1H),1.13(d,J=6.9 Hz,6H).

[0550] Intermediate C9 Synthesis of 3,5-dichloro-2-iodo-4-(3-isopropyl-4-(methoxymethoxy)benzyl)phenol (intermediate C9)

[0551] [ka]

[0552] A solution of intermediate C8 (1.6 g, 4.50 mmol) in DCM (30 mL) was cooled to 0°C. NIS (912 mg, 4.05 mmol) was added little by little. The mixture was stirred at 0°C for 4 hours. Water (30 mL) was added, and the mixture was added to DCM (20 mL). * 3) Extraction was performed. The combined organic phase was washed with brine (50 mL), dried with Na2SO4, concentrated under vacuum, and purified by silica gel column (petroleum ether / siRNA = 50 / 1 to 5 / 1) to obtain intermediate C9 (200 mg, 9% yield) as a white solid. 1H NMR(400 MHz,DMSO-d6)δ 11.12(s,1H),7.06(d,J=2.3 Hz,1H),6.98(s,1H),6.90(d,J=8.4 Hz,1H),6.75(dd,J=8.5,2.3 Hz,1H),5.15(s,2H),4.19(s,2H),3.36(s,3H),3.25-3.18(m,1H),1.13(d,J=6.9 Hz,6H).

[0553] Intermediate C10 Synthesis of 2,4-dichloro-6-hydroxy-3-(3-isopropyl-4-(methoxymethoxy)benzyl)benzonitrile (intermediate C10)

[0554] [ka]

[0555] A mixture of intermediates C9 (50 mg, 88 μmol), Pd2(dba)3 (10 mg, 18 μmol), and dppf (8 mg, 8 μmol) in NMP (1 mL) was mixed with Zn(CN)2 (21 mg, 176 μmol). The mixture was heated to 150 °C and stirred under microwave conditions for 1 hour. The mixture was cooled to room temperature. Water (20 mL) was added to the mixture, and HCl (15 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (30 mL), dried with Na2SO4, and purified by preparative TLC (petroleum ether / siRNA = 2 / 1) to obtain intermediate C10 (30 mg, 90% yield) as a white solid. 1 H NMR(400 MHz,DMSO-d6)δ 12.01(s,1H),7.10(s,1H),7.06(d,J=2.3 Hz,1H),6.91(d,J=8.4 Hz,1H),6.77(dd,J=8.4,2.3 Hz,1H),5.16(s,2H),4.11(s,2H),3.36(s,3H),3.26-3.18(m,1H),1.14(d,J=7.0 Hz,6H).

[0556] Intermediate D1 Synthesis of 2-bromo-4-(difluoromethoxy)-1-fluorobenzene (intermediate D1)

[0557] [ka]

[0558] A mixture of sodium chlorodifluoroacetate (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 hours. The mixture was allowed to cool to room temperature. Concentrated hydrochloric acid (1.5 mL) and water (3 mL) were added, and the mixture was stirred at room temperature for 1 hour. The mixture was cooled to 0°C. NaOH (4 M, 5 mL) and water (25 mL) were added, and the mixture was stirred in Et2O (5 mL) * 3) Extraction was performed. The organic layer was washed with brine (15 mL), dried over Na2SO4, and purified by silica gel column chromatography (petroleum ether / alkyl = 200 / 1 to 100 / 1) to obtain intermediate D1 (150 mg, 11% yield) as a colorless oil. TLC: Petroleum ether / acetate = 100 / 1 (v / v), Rf = 0.55 1 H NMR:(400 MHz,DMSO-d6)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). 19 F NMR:(376 MHz,DMSO-d6)δ -82.81,-112.84.

[0559] Intermediate D2 Synthesis of 2-(5-(difluoromethoxy)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (intermediate D2)

[0560] [ka]

[0561] Potassium acetate (183 mg, 1.8 mmol) was added to a mixture of intermediate D1 (150 mg, 622 umol), bis(pinacolate)diborone (175 mg, 684 umol), and Pd(dppf)Cl2·CH2Cl2 (25 mg, 31 umol) in 1,4-dioxane (5.0 mL) at room temperature. The mixture was heated at 110 °C for 3 hours. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum to obtain crude intermediate D2 (175 mg, 97% yield), which was used without further purification. TLC: alkyl / petroleum ether = 1 / 10 (v / v), Rf = 0.65

[0562] Example 1 Synthesis of methyl 2-(4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate (Compound 1)

[0563] [ka]

[0564] To a solution of intermediate B2 (381 mg, 2.3 mmol) and intermediate A3 (200 mg, 0.78 mmol) in DCE (5.0 mL), ZnCl2 (1 M / THF) (1.9 mmol, 1.9 mL) was added. The mixture was stirred overnight at 85°C. The mixture was cooled to room temperature, water (20 mL) was added, and the resulting mixture was poured into DCM (10 mL). * 3) Extraction was performed. The combined organic phase was washed with brine (20 mL), dried with Na2SO4, concentrated in vacuum, and purified by preparative TLC (siRNA / petroleum ether = 1 / 5) to obtain compound 1 (35 mg, 12% yield) as a pale yellow oil. TLC: Â / petroleum ether = 1 / 5 (v / v), Rf = 0.30

[0565] Example 2 Synthesis of 2-(4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (compound 2)

[0566] [ka]

[0567] To a solution of compound 1 (35 mg, 94 umol) in THF / H2O (2.0 mL / 0.5 mL) at room temperature, LiOH·H2O (12 mg, 280 umol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (30 mL), acidified to pH 3-4 with 1N HCl, and toluene (15 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (30 mL), dried with Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 2 (10 mg, 30% yield) as a white solid. TLC:MeOH / DCM=1 / 10(v / v), Rf=0.30 LCMS: RT=4.025 min, [M-1]=345.1 1 H NMR:(400 MHz,DMSO-d6)δ 9.43(s,1H),6.62(s,2H),6.43(d,J=8.4 Hz,1H),6.14(d,J=8.8 Hz,1H),4.62(s,2H),3.74(s,2H),2.11(s,6H),1.26(d,J=7.0 Hz,6H).

[0568] Example 3 Synthesis of 2-(4-((3'-(difluoromethoxy)-2-fluoro-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)-3,5-dimethylphenoxy)acetic acid (compound 3)

[0569] [ka]

[0570] To a solution of intermediates C1 (136 mg, 0.50 mmol) and B3 (100 mg, 0.25 mmol) in 1,4-dioxane (4 mL) at room temperature, Pd(dppf)Cl2 (18 mg, 0.03 mmol) and NaHCO3 (2N) (0.75 mmol, 0.4 mL) were added. The reaction mixture was heated overnight at 80°C under N2. LiOH.H2O (32 mg, 0.75 mmol) was added, and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with HCl (10 mL), and the pH was adjusted to pH ~4 with 1N HCl. The aqueous layer was diluted with HCl (20 mL) * Extraction was performed as described in 2). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 3 (20 mg, 17.8% yield) as a white solid. TLC:DCM / MeOH = 10 / 1(v / v), Rf = 0.2 LCMS: RT=3.752 min, [M-1]=445.1 1 H NMR:(400 MHz,DMSO-d6)δ 9.96(s,1H),7.46(d,J=7.2 Hz,1H),7.27(d,J=0.4 Hz,1H),7.26(t,J=92.8,1 H),7.19(s,1H),7.16(d,J=8.0 Hz,1H),6.65(d,J=80 Hz,1H),6.57(s,2H),6.37(t,J=8.8 Hz,1H),4.25(s,2H),3.79(s,2H),2.13(s,6H).

[0571] Example 4 Synthesis of methyl 2-(4-(2-fluoro-3-(1-(4-fluorophenyl)vinyl)-4-hydroxybenzyl)-3,5-dimethylphenoxy)acetate (compound 4)

[0572] [ka]

[0573] A solution of intermediate B5 (234 mg, 944 umol), intermediate C1 (250 mg, 629 umol), Pd(dppf)Cl2 (46 mg, 63 umol), and NaHCO3(aq)(2M, 1 mL) in 1,4-dioxane (5 mL) was stirred overnight at 80°C. The mixture was cooled to room temperature and concentrated under vacuum. Water (30 mL) was added to the mixture, and SiO2 (25 mL) was added. * The compound was extracted using method 2). The combined organic phase was washed with brine (50 mL), dried with Na2SO4, concentrated under vacuum, and purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain compound 4 (100 mg, 36.2% yield) as a yellow solid. TLC: Â / petroleum ether = 1 / 5 (v / v), Rf = 0.55

[0574] Example 5 Synthesis of 2-(4-(2-fluoro-3-(1-(4-fluorophenyl)vinyl)-4-hydroxybenzyl)-3,5-dimethylphenoxy)acetic acid (compound 5)

[0575] [ka]

[0576] A solution of compound 4 (100 mg, 228 mmol) and LiOH.H2O (48 mg, 1.14 mmol) in water (1 mL) and methanol (3 mL) was stirred at room temperature for 1 hour. The mixture was acidified to pH ~5 with 1N HCl, water (30 mL) was added, and the mixture was mixed with HCl (25 mL). * The compound was extracted using method 2). The combined organic phase was washed with brine (50 mL), dried with Na2SO4, concentrated under vacuum, and purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain compound 5 (50 mg, 51.6% yield) as a white solid. TLC: alkyl / petroleum ether = 1 / 5 (v / v), Rf = 0 1H NMR:(400 MHz,DMSO-d6)δ 9.48(s,1H),7.60-7.45(m,3H),7.32(dd,J=8.4,5.5 Hz,2H),7.15(t,J=8.7 Hz,2H),6.62(s,2H),6.56(d,J=8.6 Hz,1H),6.37(t,J=8.6 Hz,1H),5.97(s,1H),5.23(s,1H),4.57(s,2H),3.77(s,2H),2.15(s,6H).

[0577] Example 6 Synthesis of 2-(4-(2-fluoro-3-(1-(4-fluorophenyl)ethyl)-4-hydroxybenzyl)-3,5-dimethylphenoxy)acetic acid (compound 6)

[0578] [ka]

[0579] A solution of compound 5 (50 mg, 118 umol) and Pd / C (5%) (50 mg) in MeOH (5 mL) was stirred overnight at 50°C under an H2 atmosphere. The mixture was cooled to room temperature, filtered, concentrated under vacuum, and then purified by preparative HPLC to obtain compound 6 (20 mg, 39.8% yield) as a white solid. TLC:MeOH / DCM=1 / 10(v / v), Rf=0.30 LCMS: RT=2.264 min, [M-1]=425.1 1 H NMR:(400 MHz,DMSO-d6)δ 12.91(s,1H),9.62(s,1H),7.32-7.25(m,2H),7.12-7.04(m,2H),6.61(s,2H),6.49(d,J=8.4 Hz,1H),6.20(t,J=8.6 Hz,1H),4.60(s,3H),3.71(d,J=4.6 Hz,2H),2.09(s,6H),1.64(dd,J=7.4,1.2 Hz,3H).

[0580] Example 7 Synthesis of ethyl 2-(3-bromo-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-5-methylphenoxy)acetate (compound 7)

[0581] [ka]

[0582] To a solution of intermediate B2 (720 mg, 4.66 mmol) in room temperature DCE (5 mL), intermediate A6 (500 mg, 1.55 mmol) and ZnCl2 (1.0 M, 3.11 mmol, 3.11 mL) in THF were added. The reaction mixture was heated at 90°C overnight. The reaction mixture was diluted with DCM (20 mL) and brine (10 mL) * The product was washed (2), dried over Na2SO4, and concentrated in vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / siRNA = 10 / 1) to obtain compound 7 (250 mg, 36.6% yield) as a colorless oil. TLC: Petroleum ether / acetate = 5 / 1 (v / v), Rf = 0.21 1 H NMR:(400 MHz,DMSO-d6)δ 9.48(s,1H),7.08(d,J=2.7 Hz,1H),6.88(d,J=2.7 Hz,1H),6.45(d,J=8.3 Hz,1H),6.17(t,J=8.6 Hz,1H),4.80(s,2H),4.18(q,J=7.1 Hz,2H),3.93(s,2H),3.38(p,J=7.1 Hz,1H),2.17(s,3H),1.26(d,J=7.1 Hz,6H),1.24-1.18(m,3H).

[0583] Example 8 Synthesis of 2-(4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-3-methyl-5-vinylphenoxy)acetic acid (compound 8)

[0584] [ka]

[0585] Compound 7 (180 mg, 0.4 mmol) and vinylboron (pinacolate) (92 mg, 0.6 mmol) were dissolved in water (0.5 mL) at room temperature and 1,4-dioxane (3 mL). Pd(dppf)Cl2 (32 mg, 0.04 mmol) and K2CO3 (110 mg, 0.8 mmol) were added. The reaction mixture was heated in a microwave at 120 °C for 2 hours. The mixture was cooled to room temperature, and NaOH (48 mg, 1.2 mmol) was added. The mixture was stirred at room temperature for 0.5 hours. The reaction mixture was diluted with HCl (10 mL) and filtered. The filtrate was acidified with 1N HCl to pH 3-4, and diluted with water (5 mL). * 2) and brine (5 mL) * The product was washed (2), dried with Na2SO4, and concentrated in vacuum. The crude product was purified by preparative TLC (MeOH / DCM = 1 / 10) to obtain compound 8 (146 mg, 99.4% yield) as a yellow oil. TLC:DCM / MeOH=1 / 10(v / v), Rf=0.24

[0586] Example 9 Synthesis of 2-(3-ethyl-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-5-methylphenoxy)acetic acid (compound 9)

[0587] [ka]

[0588] To a solution of compound 8 (146 mg, 0.4 mmol) in THF (3 mL) at room temperature, Pd / C (50 mg) was added, and the mixture was stirred overnight at room temperature under an H2 atmosphere. The reaction mixture was filtered through a Celite pad. The filtrate was concentrated under vacuum and purified by preparative HPLC to obtain compound 9 (70 mg, 48.6% yield) as a white solid. TLC:DCM / MeOH=10 / 1(v / v), Rf=0.48 LCMS: RT=2.011 min, [M-1]=359. 1 H NMR:(400 MHz,DMSO-d6)δ 9.41(s,1H),6.62(s,2H),6.43(d,J=8.3 Hz,1H),6.11(t,J=8.6 Hz,1H),4.61(s,2H),3.76(s,2H),3.47-3.34(m,1H),2.45(q,J=8.3,7.5 Hz,3H),2.10(s,3H),1.27(d,J=7.2 Hz,6H),1.02(t,J=7.5 Hz,3H).

[0589] Example 10 Synthesis of 2-(3-ethyl-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-5-methylphenoxy)-N-methylacetamide (compound 10)

[0590] [ka]

[0591] To a solution of compound 9 (50 mg, 0.14 mmol) in DCM (4 mL) at room temperature, oxalyl chloride (18 mg, 0.14 mmol) and a small amount of DMF (cat) were added. The mixture was stirred at room temperature for 1 hour, and then concentrated under vacuum. Crude acid chloride (50 mg, 0.14 mmol) was dissolved in THF (1 mL), and a solution of methylamine (12 mg, 0.39 mmol) in THF (3 mL) was added dropwise at 0°C. The mixture was warmed to room temperature, stirred for 1 hour, and then concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 10 (20 mg, 40.6% yield) as an off-white solid. TLC:MeOH / DCM=1 / 10(v / v), Rf=0.68 1H NMR:(400 MHz,DMSO-d6)δ 9.42(s,1H),7.99(s,1H),6.69(q,J=2.8 Hz,1H),6.61(s,1H),6.42(d,J=8.4 Hz,1H),6.11(t,J=8.4 Hz,1H),4.56(s,1H),4.42(s,1H),3.76(d,J=3.6 Hz,2H),3.44-3.37(m,1H),2.66(d,J=4.8 Hz,2H),2.45(dd,J=7.6,5.2 Hz,2H),2.10(d,J=5.6 Hz,3H),1.27(d,J=7.2 Hz,6H),1.03(td,J=7.6,4.8 Hz,3H). 19 F NMR:(376 MHz,DMSO-d6)δ -120.54,-120.63.

[0592] Example 11 Synthesis of ethyl 2-(4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-3-methyl-5-(prop-1-en-2-yl)phenoxy)acetate (compound 11)

[0593] [ka]

[0594] To a solution of intermediate C2 (530 mg, 1.21 mmol) in 1,4-dioxane (10 mL) at room temperature, potassium isopropenyltrifluoroborate (357 mg, 2.42 mmol), Cs2CO3 (786 mg, 2.42 mmol), and Pd(dppf)Cl2 (88 mg, 0.06 mmol) were added. The reaction mixture was stirred in a microwave under N2 (g) at 120°C for 2 hours. The resulting solution of compound 11 was used without further purification. TLC: Â / petroleum ether = 1 / 5 (v / v), Rf = 0.35 LCMS: RT=3.26 min, [M-1]=399.2

[0595] Example 12 Synthesis of 2-(4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-3-methyl-5-(prop-1-en-2-yl)phenoxy)acetic acid (compound 12)

[0596] [ka]

[0597] To a solution of compound 11 (500 mg, 1.25 mmol) in water (5 mL) / THF (1 mL) at room temperature, NaOH (149 mg, 3.75 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified with 2N HCl to pH 3-4, and then DCM (30 mL) was added. * The compound was extracted in step 3). The combined organic phase was concentrated in a vacuum and purified by preparative HPLC to obtain compound 12 (330 mg, 70.9% yield). TLC: Petroleum ether / acet = 1 / 5 (v / v), Rf = 0 LCMS: RT=4.09 min, [M-1]=371.1 1 H NMR:(400 MHz,DMSO)δ 9.43(s,1H),6.69(d,J=2.8 Hz,1H),6.51(d,J=2.7 Hz,1H),6.44(d,J=8.4 Hz,1H),6.15(t,J=8.6 Hz,1H),5.10-5.02(m,1H),4.64(d,J=2.3 Hz,1H),4.58(s,2H),3.74(s,2H),3.39(s,1H),2.05(s,3H),1.84(s,3H),1.25(d,J=7.1 Hz,6H).

[0598] Example 13 Synthesis of 2-(4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-3-isopropyl-5-methylphenoxy)acetic acid (compound 13)

[0599] [ka]

[0600] To a solution of compound 12 (270 mg, 0.72 mmol) in MeOH (5 mL) at room temperature, Pd / C (27 mg) was added, and the mixture was stirred at 70°C for 16 hours under an H2 atmosphere. The reaction product was cooled, filtered, concentrated, and purified by preparative HPLC to obtain compound 13 (100 mg, 37.1% yield). TLC:DCM / MeOH=20 / 1(v / v), Rf=0.35 LCMS: RT=4.16 min, [M-1]=373.2 1 H NMR:(400 MHz,DMSO)δ 12.88(s,1H),9.42(d,J=1.4 Hz,1H),6.69(d,J=2.8 Hz,1H),6.60(d,J=2.7 Hz,1H),6.43(d,J=8.3 Hz,1H),6.11(d,J=8.6 Hz,1H),4.62(s,2H),3.78(s,2H),3.45-3.36(m,1H),2.97-2.84(m,1H),2.11(s,3H),1.31-1.24(m,6H),1.05(d,J=6.8 Hz,6H).

[0601] Example 14 Synthesis of methyl 2-(3,5-dichloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)phenoxy)acetate (compound 14)

[0602] [ka]

[0603] To a solution of intermediate B2 (23.0 g, 149 mmol) and intermediate A10 (15.0 g, 53 mmol) in DCE (300 mL), ZnCl2 (1 M in THF) (133 mmol, 133 mL) was added. The mixture was stirred overnight at 85°C. The mixture was cooled to room temperature, water (150 mL) was added, and the resulting mixture was poured into DCM (100 mL). *3) Extraction was performed. The combined organic phase was washed with brine (100 mL), dried with Na2SO4, concentrated in vacuum, and purified by silica gel column chromatography (SiO2 / petroleum ether = 1 / 130 to 1 / 10) to obtain compound 14 (6.0 g, 28% yield) as a colorless oil. TLC: Â / petroleum ether = 1 / 5 (v / v), Rf = 0.25 LCMS:RT=4.529 min; [M-1]=398.9 1 H NMR:(400 MHz,DMSO-d6)δ 9.54(s,1H),7.18(s,2H),6.48(d,J=8.4 Hz,1H),6.27(t,J=8.4 Hz,1H),4.92(s,2H),4.02(s,2H),3.72(s,3H),3.39(m,1H),1.26(d,J=6.8 Hz,6H).

[0604] Example 15 Synthesis of 2-(3,5-dichloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)phenoxy)acetic acid (compound 15)

[0605] [ka]

[0606] To a solution of compound 14 (6.0 g, 15 mmol) in THF / H2O (60 mL / 10 mL) at room temperature, LiOH·H2O (1.9 g, 45 mmol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (30 mL), acidified to pH 3-4 with 1N HCl, and toluene (15 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (30 mL), dried with Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 15 (3.0 g, 17% yield) as a white solid. TLC:MeOH / DCM=1 / 10(v / v), Rf=0.30 LCMS:RT=3.974 min; [M-1]=385.0 1 H NMR:(400 MHz,DMSO-d6)δ 13.14(s,1H),9.54(s,1H),7.14(s,2H),6.48(d,J=8.4 Hz,1H),6.27(t,J=8.4 Hz,1H),4.79(s,2H),4.02(s,2H),3.40(m,1H),1.26(d,J=7.2 Hz,6H). 19 F NMR:(376 MHz,DMSO-d6)δ -120.25.

[0607] Example 16 Synthesis of 2-(3,5-dichloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)phenoxy)-N-methylacetamide (compound 16)

[0608] [ka]

[0609] A mixture of compound 15 (2.0 g, 5.2 mmol) in DCM (20 mL) was mixed with DMF (cat). The mixture was cooled to 0°C, and oxalyl chloride (1.3 g, 10.4 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then concentrated under vacuum to obtain the corresponding acid chloride (2.0 g, 95% yield) as a yellow solid. This material was dissolved in DCM (20 mL) and added dropwise to CH3NH2 (2 M / THF) (4.9 mL, 9.8 mmol). The mixture was stirred at room temperature for 1 hour. Water (30 mL) was added, and the resulting mixture was dissolved in DCM (20 mL). * 3) Extraction was performed. The combined organic phase was washed with brine (50 mL), dried with Na2SO4, concentrated under vacuum, and purified by preparative HPLC to obtain compound 16 (1.1 g, 55% yield) as a white solid. TLC:DCM / MeOH=10 / 1(v / v), Rf=0.45 LCMS:RT=3.974 min; [M-1]=398.0 1H NMR:(400 MHz,DMSO-d6)δ 9.54(s,1H),8.09(d,J=4.4 Hz,1H),7.17(s,2H),6.48(d,J=8.4 Hz,1H),6.28(t,J=8.4 Hz,1H),4.56(s,2H),4.03(s,2H),3.41(m,1H),2.67(d,J=4.4 Hz,3H),1.26(d,J=7.4 Hz,6H). 19 F NMR:(376 MHz,DMSO-d6)δ -120.23.

[0610] Example 17 Synthesis of 2-(3,5-dichloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)phenoxy)-N,N-dimethylacetamide (compound 17)

[0611] [ka]

[0612] A mixture of compound 15 (2.0 g, 5.2 mmol) in DCM (20 mL) was mixed with DMF (cat). The mixture was cooled to 0°C, and oxalyl chloride (1.3 g, 10.4 mmol) was added. The mixture was stirred at room temperature for 30 minutes, and then concentrated under vacuum to obtain the corresponding acid chloride (2.0 g, 95% yield) as a yellow solid. A sample of this material (150 mg, 370 umol) was dissolved in DCM (20 mL) and added dropwise to dimethylamine (2 M / THF) (0.37 mL, 740 umol). The mixture was stirred at room temperature for 1 hour. Water (10 mL) was added, and the resulting mixture was collected in DCM (10 mL). * 3) Extraction was performed. The combined organic phase was washed with brine (20 mL), dried with Na2SO4, concentrated under vacuum, and purified by preparative HPLC to obtain compound 17 (70 mg, 45% yield) as a white solid. TLC:DCM / MeOH=10 / 1(v / v), Rf=0.45 LCMS:RT=4.109 min; [M-1]=412.1 1 H NMR:(400 MHz,DMSO-d6)δ 9.52(s,1H),7.12(s,2H),6.48(d,J=8.4 Hz,1H),6.27(t,J=8.6 Hz,1H),4.92(s,2H),4.02(s,2H),3.42-3.37(m,1H),2.97(s,3H),2.85(s,3H),1.26(d,J=7.2 Hz,6H). 19 F NMR:(376 MHz,DMSO-d6)δ -120.28.

[0613] Example 18 Synthesis of 2-(3,5-dichloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)phenoxy)-N-ethylacetamide (compound 18)

[0614] [ka]

[0615] To a solution of compound 15 (70 mg, 181 umol) in DCM (2 mL), oxalyl chloride (69 mg, 542 umol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated under vacuum, and ethylamine in THF (2 mL) was added. The mixture was stirred at room temperature for 10 minutes. The resulting solution was concentrated under vacuum and purified by preparative TLC (DCM / MeOH = 10 / 1) to obtain compound 18 (40 mg, 56.3% yield) as a white solid. TLC:DCM / MeOH=10 / 1(v / v), Rf=0.56 LCMS: RT=2.545min, [M-1]=412.1 1H NMR:(400 MHz,DMSO-d6)δ 9.52(d,J=1.5 Hz,1H),8.14(t,J=5.7 Hz,1H),7.16(s,2H),6.47(d,J=8.3 Hz,1H),6.27(t,J=8.6 Hz,1H),4.54(s,2H),4.02(s,2H),3.42-3.35(m,1H),3.20-3.10(m,2H),1.26(d,J=7.2 Hz,6H),1.04(t,J=7.2 Hz,3H).

[0616] Example 19 Synthesis of 2-(3,5-dichloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)phenoxy)-N-ethyl-N-methylacetamide (compound 19)

[0617] [ka]

[0618] To a solution of compound 15 (70 mg, 0.18 mmol) in DMF (3 mL) at room temperature, HATU (103 mg, 0.27 mmol), DIEA (0.6 mL, 0.36 mmol), and N-methyl-N-ethylamine (0.5 mL, 0.54 mmol) were added. The mixture was stirred at room temperature for 2 hours, then diluted with water (10 mL), and toluene (3 mL) was added. * Extraction was performed as described in 3). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 19 (27 mg, 35% yield) as an off-white solid. TLC:DCM / MeOH = 10 / 1 (v / v), Rf = 0.7 1H NMR:(400 MHz,DMSO-d6)δ 9.56-9.50(m,1H),7.10(d,J=3.2 Hz,2H),6.48(dd,J=8.4,1.2 Hz,1H),6.27(t,J=8.4 Hz,1H),4.91(d,J=7.2 Hz,2H),4.01(s,2H),3.40(d,J=7.2 Hz,1H),3.30(dd,J=7.6,4.0 Hz,2H),2.95(s,1.5H),2.82(s,1.5H),1.33-1.20(m,6H),1.14(s,1.5H),1.01(s,1.5H). 19 F NMR:(376 MHz,DMSO-d6)δ -73.97,-120.27.

[0619] Example 20 Synthesis of 2-(3,5-dichloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)phenoxy)-N-(2-fluoroethyl)acetamide (compound 20)

[0620] [ka]

[0621] To a solution of compound 15 (100 mg, 258 umol) in DMF (5 mL) at room temperature, HATU (147 mg, 387 umol), DIEA (67 mg, 516 umol), and 2-fluoroethylamine (77 mg, 775 umol) were added. The mixture was stirred at room temperature for 2 hours, diluted with water (10 mL), and toluene (5 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with water (10 mL) and brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by preparative TLC (MeOH / DCM = 1 / 10) to obtain compound 20 (50 mg, 43% yield) as a white solid. TLC:DCM / MeOH=15 / 1(v / v), Rf=0.59 LCMS: RT=4.198 min, [M-1]=430. 1H NMR:(400 MHz,DMSO-d6)δ 9.52(d,J=1.5 Hz,1H),8.37(t,J=5.8 Hz,1H),7.17(s,2H),6.47(dd,J=8.5,1.1 Hz,1H),6.27(t,J=8.6 Hz,1H),4.60(s,2H),4.52(t,J=5.1 Hz,1H),4.40(t,J=5.1 Hz,1H),4.02(s,2H),3.48(q,J=5.3 Hz,1H),3.44-3.38(m,1H),3.38(s,1H),1.29-1.22(m,6H).

[0622] Example 21 Synthesis of 2-(3,5-dichloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)phenoxy)-N-methoxyacetamide (compound 21)

[0623] [ka]

[0624] To a solution of compound 15 (70 mg, 181 umol) in DMF (3 mL) at room temperature, HATU (103 mg, 271 umol), DIEA (47 mg, 362 umol), and methoxylamine (45 mg, 542 umol) were added. The mixture was stirred at room temperature for 2 hours, diluted with water (10 mL), and toluene (5 mL) was added. * 3) Extracted. The combined organic phase was removed with water (10 mL). * 3) The mixture was washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 21 (32 mg, 42% yield) as a white solid. TLC:DCM / MeOH=15 / 1(v / v), Rf=0.60 LCMS: RT=4.025 min, [M-1]=414. 1H NMR:(400 MHz,DMSO-d6)δ 11.46(s,1H),9.53(s,1H),7.16(s,2H),6.47(d,J=8.4 Hz,1H),6.26(t,J=8.6 Hz,1H),4.58(s,2H),4.02(s,2H),3.63(s,3H),3.41(s,1H),1.25(d,J=7.1 Hz,6H).

[0625] Example 22 Synthesis of 2-(3,5-dichloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)phenoxy)-N-methoxy-N-methylacetamide (compound 22)

[0626] [ka]

[0627] To a solution of compound 15 (70 mg, 181 umol) in DMF (5 mL) at room temperature, HATU (103 mg, 271 umol), DIEA (94 mg, 723 umol), and N,O-dimethylhydroxylamine (53 mg, 542 umol) were added. The mixture was stirred at room temperature for 2 hours, diluted with water (10 mL), and toluene (5 mL) was added. * 3) Extracted. The combined organic phase was removed with water (10 mL). * 3) The mixture was washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 22 (20 mg, 26% yield) as a white solid. TLC:DCM / MeOH=15 / 1(v / v), Rf=0.55 LCMS: RT=4.394 min, [M-1]=428. 1H NMR:(400 MHz,DMSO-d6)δ 9.52(d,J=1.5 Hz,1H),7.12(s,2H),6.48(d,J=8.4 Hz,1H),6.28(t,J=8.5 Hz,1H),5.01(s,2H),4.02(s,2H),3.75(s,3H),3.42-3.37(m,1H),3.13(s,3H),1.29-1.22(m,6H).

[0628] Example 23 Synthesis of 2-(3,5-dichloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)phenoxy)-N',N'-dimethylacetohydrazide (compound 23)

[0629] [ka]

[0630] To a solution of compound 15 (70 mg, 181 umol) in DMF (5 mL) at room temperature, HATU (103 mg, 271 umol), DIEA (94 mg, 723 umol), and N,N-dimethylhydrazine (52 mg, 542 umol) were added. The mixture was stirred at room temperature for 2 hours, diluted with water (10 mL), and toluene (5 mL) was added. * 3) Extracted. The combined organic phase was removed with water (10 mL). * 3) The mixture was washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 23 (12 mg, 15% yield) as a white solid. TLC:DCM / MeOH=10 / 1(v / v), Rf=0.65 LCMS: RT=4.031 min, [M-1]=427. 1H NMR:(400 MHz,DMSO-d6)δ 9.52(d,J=1.5 Hz,1H),7.12(s,2H),6.52-6.43(m,1H),6.28(t,J=8.6 Hz,1H),5.01(s,2H),4.02(s,2H),3.75(s,3H),3.41-3.33(m,1H),3.13(s,3H),1.26(d,J=7.1 Hz,6H).

[0631] Example 24 Synthesis of 2-(3,5-dichloro-4-((3'-(difluoromethoxy)-2-fluoro-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetic acid (compound 24)

[0632] [ka]

[0633] A mixture of intermediate A11 (150 mg, 0.34 mmol), intermediate B3 (138 mg, 0.51 mmol), Pd(dppf)Cl2 (22 mg, 0.03 mmol), and NaHCO3(2N)(0.51 mL, 1.02 mmol) in 1,4-dioxane (4 mL) was stirred overnight at 85°C under N2. LiOH.H2O(aqueous, 2M)(0.51 mL, 1.02 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The solution was adjusted to pH ~4 with 1N HCl, and the aqueous layer was dissolved in SiO2 (20 mL). * The compound was extracted using method 2). The organic layer was washed with brine (20 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative HPLC (ACN / water = 65:35, v / v) to obtain compound 24 (8 mg, 4.9% yield) as a white solid. TLC:DCM / MeOH = 10 / 1(v / v), Rf = 0.2 LCMS: RT=3.913 min, [M-1]=485.0 1H NMR:(400 MHz,DMSO-d6)δ 10.04(s,1H),7.48-7.45(m,1H),7.28(d,J=4.4 Hz,1H),7.25(t,J=62.0Hz,1 H),7.19-7.15(m,2H),6.95(s,2H),6.70(d,J=8.6 Hz,1H),6.54(t,J=8.8 Hz,1H),4.26(s,2H),4.06(s,2H).

[0634] Example 25 Synthesis of 2-(3,5-dichloro-4-((2,2'-difluoro-6-hydroxy-5'-(trifluoromethyl)-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetic acid (compound 25)

[0635] [ka]

[0636] A mixture of 1,4-dioxane (2 mL) and water (0.5 mL) containing 2-fluoro-5-trifluoromethylphenylboronic acid (69 mg, 332 umol), intermediate C3 (100 mg, 221 umol), K2CO3 (92 mg, 664 umol), and Pd(dppf)Cl2 (16 mg, 22 umol) was stirred overnight at 100°C. The mixture was cooled to room temperature, LiOH.H2O (28 mg, 664 umol) was added, and the resulting mixture was stirred for 20 minutes. The mixture was acidified to pH ~5 with 2N HCl, water (30 mL) was added, and the mixture was mixed with RINKAN (25 mL). * The compound was extracted in step 2). The combined organic layer was washed with brine (50 mL), dried over Na2SO4, concentrated under vacuum, and purified by preparative HPLC to obtain compound 25 (20 mg, 17.8% yield) as a white solid. TLC:DCM / MeOH=10 / 1(v / v), Rf=0.35 LCMS: RT=2.424 min, [M-1]=504.9 1H NMR:(400 MHz,DMSO-d6)δ 13.10(s,1H),10.08(d,J=1.7 Hz,1H),7.88-7.82(m,1H),7.78(dd,J=6.4,2.4 Hz,1H),7.56(t,J=9.0 Hz,1H),7.16(s,2H),6.72(d,J=8.6 Hz,1H),6.65(t,J=8.6 Hz,1H),4.80(s,2H),4.10(s,2H).

[0637] Example 26 Synthesis of 2-(3,5-dichloro-4-((5'-(difluoromethoxy)-2,2'-difluoro-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenoxy)acetic acid (compound 26)

[0638] [ka]

[0639] A mixture of intermediates C3 (50 mg, 111 umol), D2 (96 mg, 332 umol), Pd(dppf)Cl2 (8 mg, 11 umol), and K2CO3 (46 mg, 332 umol) in water (0.3 mL) and 1,4-dioxane (2 mL) was microwaved at 140 °C for 2 hours. The mixture was cooled to room temperature, LiOH.H2O (14 mg, 331.8 umol) was added, and the resulting mixture was stirred for 20 minutes. The mixture was acidified to pH ~5 with 2N HCl, water (30 mL) was added, and the mixture was mixed with SiO2 (25 mL). * The compound was extracted in step 2). The combined organic phase was washed with brine (50 mL), dried over Na2SO4, concentrated under vacuum, and purified by preparative TLC (DCM / MeOH = 10 / 1) and preparative HPLC to obtain compound 26 (7 mg, 13.4 µl, 12.1% yield) as a white solid. TLC:DCM / MeOH=10 / 1(v / v), Rf=0.35 LCMS: RT=2.050 min, [M-1]=502.9 1H NMR:(400 MHz,DMSO-d6)δ 13.12(s,1H),9.99(d,J=1.7 Hz,1H),7.36(t,J=9.0 Hz,1H),7.23(t,J=148.2 Hz,1H),7.28-7.19(m,2H),7.16(s,2H),6.70(d,J=8.6 Hz,1H),6.62(t,J=8.6 Hz,1H),4.80(s,2H),4.09(s,2H).

[0640] Example 27 Synthesis of ethyl 2-(3,5-dichloro-4-(2-fluoro-3-(4-fluorobenzyl)-4-hydroxybenzyl)phenoxy)acetate (compound 27)

[0641] [ka]

[0642] To a solution of intermediate B6 (444 mg, 2.02 mmol) in room temperature DCE (5 mL), intermediate A11 (200 mg, 0.67 mmol) and ZnCl2 (1.0 M in THF, 1.5 mL, 1.5 mmol) were added. The reaction mixture was heated at 90°C overnight. The reaction mixture was diluted with DCM (20 mL) and brine (10 mL) * The product was washed (2), dried over Na2SO4, and concentrated in vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / siRNA = 5 / 1) to obtain compound 27 (160 mg, 49.4% yield) as a colorless oil. TLC: Petroleum ether / acetate = 5 / 1 (v / v), Rf = 0.21 1 H NMR:(400 MHz,DMSO-d6)δ 9.81(s,1H),7.23(dd,J=8.5,5.7 Hz,2H),7.16(s,2H),7.11-7.03(m,2H),6.56(d,J=8.5 Hz,1H),6.40(t,J=8.7 Hz,1H),4.89(s,2H),4.18(q,J=7.0 Hz,3H),4.04(s,2H),3.88(s,2H),1.23-1.18(m,3H).

[0643] Example 28 Synthesis of 2-(3,5-dichloro-4-(2-fluoro-3-(4-fluorobenzyl)-4-hydroxybenzyl)phenoxy)acetic acid (compound 28)

[0644] [ka]

[0645] To a solution of compound 27 (170 mg, 0.35 mmol) in THF (3 mL) / water (1 mL), LiOH·H2O (18 mg, 0.42 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction product was acidified with 1N HCl to pH 3-4, and then extracted with SiO (20 mL). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, concentrated under vacuum, and purified by preparative HPLC and subsequent preparative TLC (DCM / MeOH = 5 / 1) to obtain compound 28 (25 mg, 15% yield) as a white solid. TLC:DCM / MeOH = 5 / 1(v / v), Rf = 0.31 LCMS: RT = 4.137 min, [M-1] = 451. 1 H NMR:(400 MHz,DMSO-d6)δ 9.81(s,1H),7.27-7.18(m,2H),7.11(s,2H),7.10-7.04(m,2H),6.57(d,J=8.5 Hz,1H),6.40(t,J=8.7 Hz,1H),4.75(s,2H),4.03(s,2H),3.88(s,2H).

[0646] Example 29 Synthesis of 2-(3,5-dichloro-4-(2-fluoro-3-(1-(4-fluorophenyl)vinyl)-4-hydroxybenzyl)phenoxy)acetic acid (compound 29)

[0647] [ka]

[0648] A solution of intermediate B5 (494 mg, 1.99 mmol), intermediate C3 (600 mg, 1.33 mmol), Pd(dppf)Cl2 (97.11 mg, 0.13 mmol), and NaHCO3 (2 M, 2 mL) in 1,4-dioxane (7 mL) was stirred overnight at 85 °C. The mixture was concentrated under vacuum. LiOH·H2O (167 mg, 3.99 mmol) was added to THF / H2O (5 mL / 1 mL), and the mixture was stirred at room temperature for 2 hours. Water (30 mL) was added, and the pH was adjusted to pH ~5 with 2N HCl, and the resulting mixture was dissolved in ELISA (25 mL) * The compound was extracted using method 2). The combined organic phase was washed with brine (50 mL), dried with Na2SO4, concentrated under vacuum, and purified by preparative TLC (DCM / MeOH = 5 / 1) to obtain compound 29 (200 mg, 32.4% yield) as a yellow solid. TLC:MeOH / DCM=1 / 10(v / v), Rf=0.30 LCMS: RT=3.930 min, [M-1]=463.0

[0649] Example 30 Synthesis of 2-(3,5-dichloro-4-(2-fluoro-3-(1-(4-fluorophenyl)ethyl)-4-hydroxybenzyl)phenoxy)acetic acid (compound 30)

[0650] [ka]

[0651] To a solution of compound 29 (220 mg, 0.47 mmol) in methanol (5 mL), Pd / C (200 mg) was added. The mixture was stirred overnight at 60°C under an H2 atmosphere. The mixture was filtered, concentrated under vacuum, and purified by preparative HPLC to obtain compound 30 (20 mg, 9.1% yield) as a yellow solid. TLC:MeOH / DCM=1 / 10(v / v), Rf=0.33 1H NMR:(400 MHz,DMSO-d6)δ 9.74(s,1H),7.28(dd,J=8.5,5.6 Hz,2H),7.15-7.03(m,4H),6.53(d,J=8.4 Hz,1H),6.35(t,J=8.5 Hz,1H),4.76(s,2H),4.60(q,J=7.3 Hz,1H),4.07-3.92(m,2H),1.63(d,J=7.3 Hz,3H). LCMS: RT=4.060 min, [M-1]=465.0

[0652] Example 31 Synthesis of ethyl 2-(3,5-dichloro-4-(2-fluoro-3-(1-(4-fluorophenyl)propyl)-4-hydroxybenzyl)phenoxy)acetate (compound 31)

[0653] [ka]

[0654] To a solution of intermediate B8 (80 mg, 322 umol) in DCE (3 mL) at room temperature, intermediate A11 (32 mg, 107 umol) and ZnCl2 (242 umol, 0.2 mL) were added. The mixture was heated under 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 preparative TLC (petroleum ether / siRNA = 5 / 1) to obtain compound 31 (40 mg, 73% yield) as a colorless oil. TLC: alkyl / petroleum ether = 1 / 5 (v / v), Rf = 0.36

[0655] Example 32 Synthesis of 2-(3,5-dichloro-4-(2-fluoro-3-(1-(4-fluorophenyl)propyl)-4-hydroxybenzyl)phenoxy)acetic acid (compound 32)

[0656] [ka]

[0657] To a solution of compound 31 (40 mg, 78.5 umol) in THF (5 mL) at room temperature, LiOH.H2O (10 mg, 236 umol) in water (1 mL) was added. The mixture was stirred at room temperature for 2 hours, then diluted with water (10 mL), acidified to pH 3-4 with HCl (1 N), and HCl (5 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (10 mL), dried with Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 32 (4 mg, 10% yield) as an off-white solid. TLC:DCM / MeOH=10 / 1(v / v), Rf=0.39 LCMS: RT=2.906 min, [M-1]=479. 1 H NMR:(400 MHz,DMSO-d6)δ 13.04(s,1H),9.72(s,1H),7.33(dd,J=8.5,5.6 Hz,2H),7.12(s,2H),7.11-7.05(m,2H),6.52(d,J=8.4 Hz,1H),6.35(t,J=8.5 Hz,1H),4.76(s,2H),4.33(t,J=8.0 Hz,1H),4.08-3.93(m,2H),2.14(dd,J=13.5,6.9 Hz,2H),0.83(t,J=7.3 Hz,3H).

[0658] Example 33 Synthesis of ethyl 2-(3,5-dichloro-4-(2-fluoro-3-(1-(4-fluorophenyl)butyl)-4-hydroxybenzyl)phenoxy)acetate (compound 33)

[0659] [ka]

[0660] To a solution of intermediate B10 (130 mg, 496 umol) in room temperature DCE (5 mL), intermediate A11 (50 mg, 165 umol) and ZnCl2 (45 mg, 330 umol) were added. The mixture was heated under reflux overnight. The mixture was diluted with DCM (5 mL), washed with brine (10 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by preparative TLC (petroleum ether / alkyl = 5 / 1) to obtain compound 33 (40 mg, 46% yield) as a colorless oil. TLC: alkyl / petroleum ether = 1 / 5 (v / v), Rf = 0.36

[0661] Example 34 Synthesis of 2-(3,5-dichloro-4-(2-fluoro-3-(1-(4-fluorophenyl)butyl)-4-hydroxybenzyl)phenoxy)acetic acid (compound 34)

[0662] [ka]

[0663] To a solution of compound 33 (40 mg, 76 umol) in THF (5 mL) at room temperature, LiOH.H2O (10 mg, 229 umol) in water (1 mL) was added. The mixture was stirred at room temperature for 2 hours, diluted with water (10 mL), acidified to pH 3-4 with HCl (1 N), and toluene (5 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (10 mL), dried with Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 34 (5 mg, 13% yield) as an off-white solid. TLC:DCM / MeOH=10 / 1(v / v), Rf=0.39 LCMS: RT=3.242 min, [M-1]=493. 1H NMR:(400 MHz,DMSO-d6)δ 9.72(s,1H),7.34(d,J=8.2 Hz,2H),7.10(d,J=16.5 Hz,4H),6.52(d,J=8.6 Hz,1H),6.40-6.29(m,1H),4.86-4.72(m,2H),4.50-4.40(m,1H),4.00( s,2H),2.23-2.10(m,1H),2.09-1.94(m,1H),1.23(s,2H),0.88(t,J=7.5 Hz,3H).

[0664] Example 35 Synthesis of ethyl 2-(3-chloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-5-methylphenoxy)acetate (compound 35)

[0665] [ka]

[0666] To a solution of intermediate A14 (1.0 g, 2.21 mmol) in room temperature DCE (5 mL), intermediate B2 (0.6 g, 1.47 mmol) and ZnCl2 (4.32 mL, 4.32 mmol) were added. The mixture was heated under 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 silica gel column chromatography (petroleum ether / siRNA = 20 / 1 to 5 / 1) to obtain compound 35 (320 mg, 37.5% yield) as a colorless oil. TLC: Â / petroleum ether = 1 / 5 (v / v), Rf = 0.31

[0667] Example 36 Synthesis of 2-(3-chloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-5-methylphenoxy)acetic acid (compound 36)

[0668] [ka]

[0669] To a solution of compound 35 (320 mg, 0.8 mmol) in THF (5 mL), LiOH.H2O (102 mg, 2.43 mmol) in water (1 mL) was added. The mixture was stirred at room temperature for 2 hours, diluted with water (10 mL), acidified to pH 3-4 with HCl (1 N), and HCl (5 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (10 mL), dried with Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 36 (80 mg, 27% yield) as an off-white solid. TLC:DCM / MeOH=10 / 1(v / v), Rf=0.39 LCMS: RT=3.974 min, [M-1]=365. 1 H NMR:(400 MHz,DMSO-d6)δ 9.62(s,1H),6.79(d,J=2.6 Hz,1H),6.72(d,J=2.7 Hz,1H),6.47(d,J=8.4 Hz,1H),6.20(t,J=8.6 Hz,1H),4.36(s,2H),3.88(s,2H),3.45-3.33(m,1H),2.13(s,3H),1.26(d,J=7.1 Hz,6H).

[0670] Example 37 Synthesis of 2-(3-chloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-5-methylphenoxy)-N-methylacetamide (compound 37)

[0671] [ka]

[0672] A solution of compound 36 (60 mg, 164 umol) in DCM (3 mL) was cooled to 0°C. Oxalyl chloride (42 mg, 327 umol) and DMF (cat) were added. The mixture was stirred at room temperature for 1 hour, and then concentrated under vacuum to obtain the crude acid chloride. One-third of this sample (20 mg, 52 umol) was dissolved in DCM (1 mL) and added dropwise at 0°C to a solution of methylamine (1 mL) in DCM (3 mL). The mixture was stirred at room temperature for 1 hour, and then concentrated under vacuum. The crude product was purified by preparative TLC (DCM / MeOH = 15 / 1) to obtain compound 37 (15 mg, 76% yield) as an off-white solid. LCMS: RT=3.969 min, [M-1]=378. 1 H NMR:(400 MHz,DMSO-d6)δ 9.48(s,1H),8.04(s,1H),6.95(s,1H),6.86(s,1H),6.45(d,J=8.5 Hz,1H),6.20(t,J=8.8 Hz,1H),4.47(s,2H),3.90(s,2H),3.41-3.36(m,1H),2.66(d,J=4.7 Hz,3H),2.17(s,3H),1.26(d,J=7.1 Hz,6H).

[0673] Example 38 Synthesis of 2-(3-chloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-5-methylphenoxy)-N,N-dimethylacetamide (compound 38)

[0674] [ka]

[0675] A solution of compound 36 (60 mg, 164 umol) in DCM (3 mL) was cooled to 0°C. Oxalyl chloride (42 mg, 327 umol) and DMF (cat) were added. The mixture was stirred at room temperature for 1 hour, and then concentrated in vacuum to obtain the crude acid chloride. One-third of this sample (25 mg, 65 umol) was dissolved in DCM (2 mL) and added dropwise at 0°C to a solution of dimethylamine (1 mL) in DCM (3 mL). The mixture was stirred at room temperature for 1 hour, and then concentrated in vacuum. The crude product was purified by preparative TLC (DCM / MeOH = 15 / 1) to obtain compound 38 (17 mg, 66.5% yield) as an off-white solid. LCMS: RT=3.974 min, [M-1]=392. 1 H NMR:(400 MHz,DMSO-d6)δ 9.03(s,1H),6.89(dd,J=13.7,2.4 Hz,2H),6.77(d,J=2.7 Hz,1H),6.63(d,J=8.2 Hz,1H),6.56(dd,J=8.2,2.2 Hz,1H),4.66(s,2H),3.93(s,2H),3.16-3.09(m,1H),2.19(s,3H),1.10(d,J=6.9 Hz,6H).

[0676] Example 39 Synthesis of ethyl 2-(3-bromo-5-chloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)phenoxy)acetate (compound 39)

[0677] [ka]

[0678] To a solution of intermediate A17 (820 mg, 2.40 mmol) in room temperature DCE (30 mL), intermediate B2 (739 mg, 4.80 mmol) and ZnCl2(s) (817 mg, 6.00 mmol) were added. The reaction mixture was heated to 90 °C and stirred overnight. The reaction mixture was diluted with DCM (20 mL), washed with brine (20 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (siRNA / petroleum ether = 1 / 50 to 1 / 10) to obtain compound 39 (600 mg, 54% yield) as a colorless oil. TLC:DCM / MeOH=5 / 1(v / v), Rf=0.24 LCMS:RT= 3.341 min,[M-1]=456.9.

[0679] Example 40 Synthesis of 2-(3-bromo-5-chloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)phenoxy)acetic acid (compound 40)

[0680] [ka]

[0681] A mixture of compound 39 (50 mg, 75% purity, 81.6 umol) in MeOH (3 mL) was mixed with NaOH (10 mg, 245 umol) in water (1 mL). The mixture was stirred at room temperature for 10 minutes. The mixture was acidified to pH ~5 with 2N HCl, and water (10 mL) was added, resulting in a mixture of HCl (15 mL). * The compound was extracted using method 2). The combined organic phase was washed with brine (50 mL), dried with Na2SO4, concentrated under vacuum, and purified by preparative HPLC to obtain compound 40 (15 mg, 45.5% yield) as a white solid. TLC: alkyl / petroleum ether = 1 / 5 (v / v), Rf = 0 LCMS: RT=2.372 min, [M-1]=428.9 1H NMR:(400 MHz,DMSO-d6)δ 9.52(d,J=1.4 Hz,1H),7.28(d,J=2.6 Hz,1H),7.17(d,J=2.6 Hz,1H),6.47(d,J=8.3 Hz,1H),6.23(t,J=8.6 Hz,1H),4.79(s,2H),4.06(s,2H),3.42-3.37(m,1H),1.26(d,J=7.1 Hz,6H).

[0682] Example 41 Synthesis of ethyl 2-(3-chloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-5-vinylphenoxy)acetate (compound 41)

[0683] [ka]

[0684] To a mixture of compound 39 (600 mg, 1.31 mmol) and vinylboron (pinacolate) (302 mg, 1.96 mmol) in water (1 mL) at room temperature / 1,4-dioxane (3 mL), Pd(dppf)Cl2 (106 mg, 0.13 mmol) and Cs2CO3 (850 mg, 2.62 mmol) were added under N2 (g). The reaction mixture was microwaved at 120 °C for 2 hours. The mixture was then treated with ELISA (20 mL). * Compound 41 was obtained by diluting it as described in (2), washing it with brine (20 mL), drying it with Na2SO4, and concentrating it in a vacuum, and this compound was used without further purification. TLC: Petroleum ether / acetate = 5 / 1 (v / v), Rf = 0.50 LCMS:RT= 2.385 min,[M-1]=405.0.

[0685] Example 42 Synthesis of 2-(3-chloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-5-vinylphenoxy)acetic acid (compound 42)

[0686] [ka]

[0687] To a solution of compound 41 (500 mg, 1.23 mmol) in MeOH (5 mL) / water (1 mL) at room temperature, LiOH·H2O (155 mg, 3.69 mmol) was added. The mixture was stirred at room temperature for 1 hour. Water (10 mL) was added, and the pH was adjusted to 3-4 with 1N HCl, and HCl (10 mL) was added. * The compound was extracted using method 2). The combined organic phase was washed with brine (20 mL), dried with Na2SO4, concentrated under vacuum, and purified by preparative TLC (DCM / MeOH = 3 / 1) to obtain compound 42 (220 mg, 47.3% yield) as a colorless oil. TLC: Petroleum ether / acetate = 5 / 1 (v / v), Rf = 0.02 LCMS:RT= 1.812 min,[M-1]=377.1.

[0688] Example 43 Synthesis of 2-(3-chloro-5-ethyl-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)phenoxy)acetic acid (compound 43)

[0689] [ka]

[0690] To a solution of compound 42 (50 mg, 0.13 mmol) in THF (5 mL) at room temperature, Pd / C (10 mg) was added, and the resulting mixture was stirred at 60°C for 3 hours. The mixture was filtered, concentrated under vacuum, and purified by preparative HPLC to obtain compound 43 (20 mg, 39.6% yield) as a white solid. TLC:DCM / MeOH=5 / 1(v / v), Rf=0.29 LCMS:RT= 2.388 min,[M-1]=379.1. 1H NMR:(400 MHz,DMSO-d6)δ 13.02(s,1H),9.46(d,J=1.2 Hz,1H),6.90(d,J=2.4 Hz,1H),6.81(d,J=2.8 Hz,1H),6.45(d,J=8.4 Hz,1H),6.19(t,J=8.4 Hz,1H),4.71(s,2H),3.92(s,2H),3.39(d,J=7.2 Hz,1H),2.51(d,J=2.0 Hz,2H),1.26(d,J=7.2 Hz,6H),1.02(t,J=7.2 Hz,3H).

[0691] Example 44 Synthesis of 2-(3-chloro-5-ethyl-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)phenoxy)-N-methylacetamide (compound 44)

[0692] [ka]

[0693] To a solution of compound 43 (80 mg, 0.21 mmol) in DCM (5 mL), oxalyl chloride (40 mg, 0.32 mmol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was concentrated to dryness to obtain crude acid chloride (80 mg, 0.20 mmol), which was dissolved in DCM (5 mL) and added to CH3NH2 / THF (2 M, 2 mL). The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated to dryness and purified by preparative TLC (MeOH / DCM = 1 / 15) to obtain compound 44 (21 mg, 26.0% yield) as a white solid. TLC: Petroleum ether / dimethyl = 1 / 1 (v / v), Rf = 0.10 LCMS:RT= 0.873 min,[M-1]=392.1. 1H NMR:(400 MHz,DMSO-d6)δ 9.52(s,1H),8.08(d,J=5.2 Hz,1H),6.96(d,J=2.4 Hz,1H),6.87(d,J=2.8 Hz,1H),6.47(d,J=8.4 Hz,1H),6.18(t,J=8.4 Hz,1H),4.49(s,2H),3.92(s,2H),3.40(s,1H),2.66(d,J=4.8 Hz,3H),1.26(d,J=7.2 Hz,6H),1.03(t,J=7.6 Hz,3H).

[0694] Example 45 Synthesis of ethyl 2-(3-chloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-5-(prop-1-en-2-yl)phenoxy)acetate (compound 45)

[0695] [ka]

[0696] A mixture of compound 39 (1.0 g, 2.18 mmol), potassium isopropenyl trifluoroborate (805 mg, 5.44 mmol), and Pd(dppf)Cl2 (159.16 mg, 217.52 mmol) in 1,4-dioxane (10 mL) and water (1 mL) was microwaved at 120°C for 2 hours. The mixture was cooled to room temperature, concentrated to dryness, and purified by silica gel column chromatography to obtain compound 45 (610 mg, 66.6% yield) as a white solid. TLC: Â / petroleum ether = 1 / 5 (v / v), Rf = 0.39 1H NMR:(400 MHz,DMSO-d6)δ 9.44(s,1H),7.02(d,J=2.7 Hz,1H),6.74(d,J=2.7 Hz,1H),6.45(d,J=8.4 Hz,1H),6.19(t,J=8.6 Hz,1H),5.11(t,J=1.8 Hz,1H),4.84(s,2H),4.68(s,1H),4.18(q,J=7.1 Hz,2H),3.87(s,2H),3.43-3.32(m,11H),1.83(s,3H),1.25(d,J=7.1 Hz,6H),1.21(t,J=7.1 Hz,4H).

[0697] Example 46 Synthesis of 2-(3-chloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-5-(prop-1-en-2-yl)phenoxy)acetic acid (compound 46)

[0698] [ka]

[0699] A mixture of compound 45 (500 mg, 1.23 mmol) and NaOH (148 mg, 3.69 mmol) in water (1 mL) and THF (5 mL) was stirred at room temperature for 10 minutes. The mixture was acidified to pH ~5 with 2N HCl, water (30 mL) was added, and the mixture was mixed with HCl (25 mL). * The compound was extracted in step 2). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, concentrated under vacuum, and purified by preparative HPLC to obtain compound 46 (15 mg, 3%) as an off-white solid. TLC: Petroleum ether / acet = 1 / 5 (v / v), Rf = 0 LCMS: RT=2.497 min, [M-1]=391.1 1H NMR:(400 MHz,DMSO-d6)δ 9.45(s,1H),6.99(d,J=2.7 Hz,1H),6.72(d,J=2.7 Hz,1H),6.45(d,J=8.4 Hz,1H),6.20(t,J=8.6 Hz,1H),5.11(t,J=1.9 Hz,1H),4.73(s,2H),4.68(d,J=1.7 Hz,1H),3.86(s,2H),3.38-3.37(m,1H),1.83(s,3H),1.25(d,J=7.0 Hz,6H).

[0700] Example 47 Synthesis of 2-(3-chloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-5-isopropylphenoxy)acetic acid (compound 47)

[0701] [ka]

[0702] To a solution of compound 46 (50 mg, 127 umol) in room temperature THF (5 mL), Pd / C (10 mg) was added, and the resulting mixture was stirred overnight at 55 °C under 1 atm of H2 (g). The reaction product was filtered, concentrated under vacuum, and purified by preparative HPLC to obtain compound 47 (15 mg, 30% yield). TLC:DCM / MeOH=10 / 1(v / v), Rf=0.35 LCMS: RT=2.662 min, [M-1]=393.1 1 H NMR:(400 MHz,DMSO-d6)δ 13.05(s,1H),9.48(d,J=1.4 Hz,1H),6.89(d,J=2.7 Hz,1H),6.86(d,J=2.7 Hz,1H),6.45(d,J=8.4 Hz,1H),6.18(t,J=8.6 Hz,1H),4.72(s,2H),3.95(s,2H),3.44-3.37(m,3H),2.94(p,J=6.8 Hz,1H),1.26(d,J=7.0 Hz,6H),1.05(d,J=6.8 Hz,6H).

[0703] Example 48 Synthesis of ethyl 2-(3,5-dichloro-4-(2-chloro-4-hydroxy-3-isopropylbenzyl)phenoxy)acetate (compound 48)

[0704] [ka]

[0705] To a solution of intermediates B12 (300 mg, 1.74 mmol) and A11 (174 mg, 0.58 mmol) in chlorobenzene (5 mL), ZnCl2 (197 mg, 1.45 mmol) was added. The mixture was stirred at 160 °C for 2 hours under microwave irradiation. The mixture was cooled to room temperature, water (50 mL) was added, and the resulting mixture was dissolved in DCM (30 mL). * 3) Extraction was performed. The combined organic phase was washed with brine (20 mL), dried with Na2SO4, concentrated in vacuum, and purified by preparative TLC (siRNA / petroleum ether = 1 / 5) to obtain compound 48 (110 mg, 43% yield) as a colorless oil. TLC: Â / petroleum ether = 1 / 5 (v / v), Rf = 0.25 LCMS: RT=2.60 min, [M-1]=429.0

[0706] Example 49 Synthesis of 2-(3,5-dichloro-4-(2-chloro-4-hydroxy-3-isopropylbenzyl)phenoxy)acetic acid (compound 49)

[0707] [ka]

[0708] To a solution of compound 48 (100 g, 0.23 mmol) in THF / H2O (1 mL / 5 mL) at room temperature, LiOH·H2O (29 mg, 0.69 mmol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (10 mL), acidified to pH 3-4 with 1 N HCl, and siRNA (15 mL) was added.* 3) Extraction was performed. The combined organic phase was washed with brine (30 mL), dried with Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 49 (20 mg, 21% yield) as a white solid. TLC:MeOH / DCM=1 / 10(v / v), Rf=0.30 LCMS: RT=4.42 min, [M-1]=401.0 1 H NMR:(400 MHz,DMSO)δ 9.55(s,1H),7.16(s,2H),6.61(d,J=8.4 Hz,1H),6.12(d,J=8.4 Hz,1H),4.80(s,2H),4.09(s,2H),3.72-3.57(m,1H),1.32(d,J=7.0 Hz,6H).

[0709] Example 50 Synthesis of methyl 2-(3,5-dichloro-4-(4-hydroxy-2-methyl-3-(prop-1-en-2-yl)benzyl)phenoxy)acetate (compound 50)

[0710] [ka]

[0711] A mixture of intermediate C4 (200 mg, 461 umol) and isopropenyl-2-borone (pinacolate) (155 mg, 922 umol) in 1,4-dioxane (2.0 mL) and H2O (0.2 mL) at room temperature was mixed with Pd(dppf)Cl2.CH2Cl2 (41 mg, 46 umol) and K2CO3 (127 mg, 922 umol) under N2 (g). The reaction mixture was heated to 70°C and stirred overnight. Water (20 mL) was added, and the resulting mixture was mixed with ELISA (10 mL). * 3) Extraction was performed. The combined organic phase was washed with brine (20 mL), dried with Na2SO4, concentrated in vacuum, and purified by preparative TLC (petroleum ether / alkyl = 5 / 1) to obtain compound 50 (40 mg, 22% yield) as a yellow oil. TLC: Petroleum ether / acetate = 5 / 1 (v / v), Rf = 0.32

[0712] Example 51 Synthesis of methyl 2-(3,5-dichloro-4-(4-hydroxy-3-isopropyl-2-methylbenzyl)phenoxy)acetate (compound 51)

[0713] [ka]

[0714] To a solution of compound 50 (20 mg, 51 mmol) in THF (2.0 mL), Raney-Ni (cat.) was added. The mixture was stirred overnight at 70°C under an H2 atmosphere. The mixture was cooled to 0°C and filtered, and then concentrated under vacuum to obtain compound 51 (20 mg, 99% yield) as a yellow oil. TLC: HCl / petroleum ether = 1 / 5 (v / v), Rf = 0.28

[0715] Example 52 Synthesis of 2-(3,5-dichloro-4-(4-hydroxy-3-isopropyl-2-methylbenzyl)phenoxy)acetic acid (compound 52)

[0716] [ka]

[0717] To a solution of compound 51 (20 mg, 50 umol) in THF / H2O (1.0 mL / 10 mL) at room temperature, LiOH·H2O (7 mg, 150 umol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (20 mL), acidified to pH 3-4 with 1 N HCl, and toluene (10 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (20 mL), dried with Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 52 (3 mg, 16% yield) as a white solid. TLC:MeOH / DCM=1 / 10(v / v), Rf=0.30 LCMS: RT=1.836 min, [M-1]=381.1 1 H NMR:(400 MHz,DMSO-d6)δ 8.87(s,1H),7.09(s,2H),6.43(d,J=8.4 Hz,1H),5.97(d,J=8.4 Hz,1H),4.66(s,2H),3.98(s,2H),2.29(s,3H),1.30(d,J=7.0 Hz,6H).

[0718] Example 53 Synthesis of ethyl 2-(3,5-dichloro-4-(4-hydroxy-3-isopropyl-2-methoxybenzyl)phenoxy)acetate (compound 53)

[0719] [ka]

[0720] To a solution of intermediate B14 (200 mg, 0.70 mmol) in room temperature DCE (10 mL), intermediate A11 (352 mg, 2.12 mmol) and ZnCl2 (1 M in THF, 2 mL) were added. The reaction mixture was heated to 85 °C and stirred overnight. The reaction mixture was diluted with DCM (20 mL) and brine (10 mL) * The product was washed (as described in 2), dried over Na2SO4, filtered, and concentrated under vacuum. The crude product was purified by preparative TLC (MeOH / petroleum ether = 1 / 5) to obtain compound 53 (50 mg, 17.1% yield) as a white solid. TLC: Petroleum ether / acetate = 10 / 1 (v / v), Rf = 0.21 1H NMR:(400 MHz,DMSO-d6)δ 9.13(s,1H),7.16(s,2H),6.40(d,J=8.4 Hz,1H),6.06(d,J=8.4 Hz,1H),4.89(s,2H),4.18(q,J=7.2 Hz,2H),4.05(s,2H),3.70(s,3H),3.38-3.34(m,1H),1.30(d,J=6.8 Hz,6H),1.21(t,J=7.2 Hz,3H).

[0721] Example 54 Synthesis of 2-(3,5-dichloro-4-(4-hydroxy-3-isopropyl-2-methoxybenzyl)phenoxy)acetic acid (compound 54)

[0722] [ka]

[0723] To a solution of compound 53 (50 mg, 0.12 mmol) in THF (5 mL) / water (0.2 mL) at room temperature, LiOH·H2O (15 mg, 0.36 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified with 2N HCl to pH 6-7, concentrated under vacuum, and purified by preparative HPLC to obtain compound 54 (25 mg, 51.8% yield) as a white solid. TLC:DCM / MeOH=5 / 1(v / v), Rf=0.24 LCMS:RT= 3.931 min,[M-1]=397.0. 1 H NMR:(400 MHz,DMSO-d6)δ 9.13(s,1H),7.13(s,2H),6.40(d,J=8.4 Hz,1H),6.07(d,J=8.4 Hz,1H),4.79(s,2H),4.05(s,2H),3.70(s,3H),1.30(d,J=6.8 Hz,6H).

[0724] Example 55 Synthesis of methyl 2-(3,5-dichloro-4-(2-cyano-4-hydroxy-3-isopropylbenzyl)phenoxy)acetate (compound 55)

[0725] [ka]

[0726] A mixture of intermediate B16 (150 mg, 0.93 mmol), intermediate A10 (133 mg, 0.47 mmol), ZnCl2 (160 mg, 1.18 mmol), and DCE (5 mL) was microwaved at 120°C for 2 hours. The mixture was cooled to room temperature and concentrated to dryness. Water (20 mL) was added, and the resulting mixture was treated with dimethyl phosphate (15 mL). * 2) Extraction was performed. The combined organic layers were washed with brine (20 mL), dried over Na2SO4, and purified by preparative TLC (petroleum ether / siRNA = 10 / 1) to obtain compound 55 (40 mg, 19.7% yield) as a white solid. TLC: Â / petroleum ether = 1 / 5 (v / v), Rf = 0.25

[0727] Example 56 Synthesis of 2-(3,5-dichloro-4-(2-cyano-4-hydroxy-3-isopropylbenzyl)phenoxy)acetic acid (compound 56)

[0728] [ka]

[0729] To a solution of compound 55 (40 mg, 98 mmol) in THF / H2O (5 mL / 1 mL) at room temperature, LiOH·H2O (12 mg, 294 mmol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (10 mL), acidified to pH 3-4 with 1 N HCl, and toluene (15 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (30 mL), dried with Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 56 (20 mg, 51.8% yield) as a white solid. TLC:MeOH / DCM=1 / 10(v / v), Rf=0.30 LCMS: RT=1.824 min, [M-1]=392.0 1 H NMR:(400 MHz,DMSO-d6)δ 13.14(s,1H),9.92(s,1H),7.17(s,2H),6.96(d,J=8.5 Hz,1H),6.41(d,J=8.4 Hz,1H),4.81(s,2H),4.22(s,2H),3.48-3.42(m,1H),1.36(d,J=7.1 Hz,6H).

[0730] Example 57 Synthesis of ethyl 2-(2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetate (compound 57)

[0731] [ka]

[0732] To a solution of intermediate A24 (198 mg, 1.46 mmol) in room temperature DCE (10 mL), 2-isopropylphenol (200 mg, 0.73 mmol) and ZnCl2 (1.82 mmol, 1.82 mL) were added. The reaction mixture was heated at 85°C for 4 hours. The reaction mixture was diluted with DCM (20 mL) and brine (10 mL) was added. * The product was washed (2), dried with Na2SO4, and concentrated in vacuum. The crude product was purified by preparative TLC (MeOH / petroleum ether = 1 / 3) to obtain compound 57 (170 mg, 62.3% yield) as a pale yellow oil. TLC: HCl / petroleum ether = 1 / 10, Rf = 0.88 1H NMR:(400 MHz,DMSO-d6)δ 9.03(s,1H),6.84(d,J=2.4 Hz,1H),6.78(d,J=8.8 Hz,1H),6.62(d,J=8.0 Hz,1H),6.45(dd,J=8.0,2.0 Hz,1H),4.81(s,2H),4.17(q,J=7.2 Hz,2H),3.81(s,2H),3.12(p,J=6.8 Hz,1H),2.14(s,3H),2.08(d,J=2.8 Hz,3H),1.20(t,J=7.2 Hz,3H),1.09(d,J=7.2 Hz,6H).

[0733] Example 58 Synthesis of 2-(2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)acetic acid (compound 58)

[0734] [ka]

[0735] To a solution of compound 57 (170 mg, 0.45 mmol) in THF (5 mL) / water (0.5 mL) at room temperature, LiOH.H2O (39 mg, 0.91 mmol) was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction product was diluted with water (20 mL), acidified to pH ~3 with aqueous HCl (1N), and toluene (10 mL) was added. * 3) Extracted. The combined organic phase was prepared in brine (10 mL). * The product was washed (2), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by preparative TLC (MeOH / DCM = 1 / 8) to obtain compound 58 (157 mg, 96.8% yield) as a white solid. TLC:MeOH / DCM=1 / 10, Rf=0.24 LCMS:RT=3.71 min; [M-1]=345.1 1H NMR:(400 MHz,DMSO-d6)δ 9.09(s,1H),6.86(s,1H),6.73-6.57(m,2H),6.43(d,J=8.0 Hz,1H),4.43(s,2H),3.78(s,2H),3.12(p,J=6.8 Hz,1H),2.11(s,3H),2.07(s,3H),1.10(d,J=6.8 Hz,6H). 19 F NMR:(376 MHz,DMSO-d6)δ -140.89.

[0736] Example 59 Synthesis of 2-(2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N-methylacetamide (compound 59)

[0737] [ka]

[0738] To a solution of compound 58 (150 mg, 0.43 mmol) in DCM (5 mL) at room temperature, SOCl2 (154 mg, 1.30 mmol) was added, and the resulting solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum to obtain an acid chloride (157 mg, 99.3% yield) as a white solid. A sample of this material (70 mg, 0.19 mmol) was dissolved in DCM (2 mL) and added dropwise to a solution of methylamine (0.95 mmol, 0.95 mL of 1N aqueous solution) in THF (5 mL). The mixture was stirred overnight. The reaction mixture was diluted with water (20 mL) and toluene (10 mL) was added. * 3) Extracted. The combined organic phase was prepared in brine (10 mL). * The product was washed (2), dried over Na2SO4, and concentrated in vacuum. The crude product was purified by preparative TLC (MeOH / petroleum ether = 1 / 3) to obtain compound 59 (21 mg, 30.1% yield) as a white solid. LCMS:RT=3.68 min; [M-1]=358.1 1H NMR:(400 MHz,DMSO-d6)δ 9.03(s,1H),7.94(s,1H),6.85(d,J=2.4 Hz,1H),6.79(d,J=8.8 Hz,1H),6.62(d,J=8.4 Hz,1H),6.45(dd,J=8.4,2.4 Hz,1H),4.49(s,2H),3.81(s,2H),3.12(p,J=6.8 Hz,1H),2.65(d,J=4.8 Hz,3H),2.15(s,3H),2.09(d,J=2.4 Hz,3H),1.10(d,J=6.8 Hz,6H). 19 F NMR:(376 MHz,DMSO-d6)δ -139.80.

[0739] Example 60 Synthesis of 2-(2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)-3,5-dimethylphenoxy)-N,N-dimethylacetamide (compound 60)

[0740] [ka]

[0741] To a solution of compound 58 (150 mg, 0.43 mmol) in DCM (5 mL) at room temperature, SOCl2 (154 mg, 1.30 mmol) was added, and the resulting solution was stirred at room temperature for 3 hours. The reaction mixture was concentrated under vacuum to obtain an acid chloride (157 mg, 99.3% yield) as a white solid. A sample of this material (70 mg, 0.19 mmol) was dissolved in DCM (2 mL) and added dropwise to a solution of dimethylamine (0.95 mmol, 0.48 mL) in THF (5 mL). The mixture was stirred overnight. The reaction mixture was diluted with water (20 mL) and toluene (10 mL) was added. * 3) Extracted. The combined organic phase was prepared in brine (10 mL). * The product was washed (2), dried with Na2SO4, and concentrated in vacuum. The crude product was purified by preparative TLC (MeOH / petroleum ether = 1 / 3) to obtain compound 60 (22 mg, 30.0% yield, 98.0% purity) as a white solid. LCMS:RT=3.76 min; [M-1]=372.2 1 H NMR:(400 MHz,DMSO-d6)δ 9.02(s,1H),6.85(d,J=2.0 Hz,1H),6.76(d,J=8.8 Hz,1H),6.62(d,J=8.0 Hz,1H),6.44(dd,J=8.0,2.0 Hz,1H),4.83(s,2H),3.80(s,2H),3.11(q,J=6.8 Hz,1H),2.99(s,3H),2.85(s,3H),2.14(s,3H),2.08(d,J=2.4 Hz,3H),1.10(d,J=6.8 Hz,6H). 19 F NMR:(376 MHz,DMSO-d6)δ -140.69.

[0742] Example 61 Synthesis of ethyl 2-(3,5-dichloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)phenoxy)acetate (compound 61)

[0743] [ka]

[0744] To a solution of intermediate A29 (500 mg, 1.58 mmol) in room temperature DCE (5 mL), 2-isopropylphenol (647 mg, 4.74 mmol) and ZnCl2 (3.95 mL, 3.95 mmol) were added. The reaction mixture was heated to 90 °C and stirred for 16 hours. The reaction mixture was diluted with DCM (20 mL), washed with brine (40 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (siRNA / petroleum ether = 1 / 8) to obtain compound 61 (377 mg, 57% yield) as a white solid. TLC: Petroleum ether / acetate = 1 / 5 (v / v), Rf = 0.35 1H NMR:(400 MHz,DMSO)δ 9.13(s,1H),7.41(d,J=7.7 Hz,1H),6.99-6.96(m,1H),6.70-6.61(m,2H),5.00(s,2H),4.17(d,J=7.1 Hz,2H),4.06(s,2H),1.17(s,3H),1.10(d,J=6.9 Hz,6H).

[0745] Example 62 Synthesis of 2-(3,5-dichloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)phenoxy)acetic acid (compound 62)

[0746] [ka]

[0747] To a solution of compound 61 (377 mg, 0.90 mmol) in water (10 mL) / THF (1 mL) at room temperature, NaOH (108 mg, 2.70 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was acidified to pH 3-4 with 2N HCl, and then DCM (40 mL) was added. * The organic phase extracted and combined in step 3) was concentrated under vacuum and purified by reverse-phase column chromatography to obtain compound 62 (260 mg, 73% yield). TLC: Petroleum ether / acet = 1 / 5 (v / v), Rf = 0 LCMS:RT=2.78 min; [M-1]=385.0 1 H NMR:(400 MHz,DMSO)δ 9.13(s,1H),7.36(d,J=7.7 Hz,1H),6.98(d,J=1.9 Hz,1H),6.66(t,J=2.0 Hz,2H),4.89(s,2H),4.06(s,2H),3.13(m,1H),1.10(d,J=6.9 Hz,6H).

[0748] Example 63 Synthesis of 2-(3,5-dichloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)phenoxy)-N-methylacetamide (compound 63)

[0749] [ka]

[0750] To a solution of compound 62 (60 mg, 0.15 mmol) in DCM (5 mL), oxalyl chloride (57 mg, 0.45 mmol) and DMF (cat.) were added. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (5 mL) and added to methylamine / THF solution (0.75 mL, 2.0 M, 1.5 mmol). After stirring at room temperature for 1 hour, the mixture was poured into water (20 mL) and then into DCM (30 mL). * 3) Extract the organic phase and remove it from brine (20 mL) * The compound was washed in step 2), dried with Na2SO4, concentrated in a vacuum, and purified by preparative TLC (petroleum ether: siRNA = 2:1) to obtain compound 63 (33 mg, 55% yield) as a white solid. TLC:DCM / MeOH=20 / 1(v / v), Rf=0.35 LCMS:RT=3.84 min; [M+1]=400.1 1 H NMR:(400 MHz,DMSO)δ 9.13(s,1H),8.02(s,1H),7.29(d,J=7.6 Hz,1H),6.99(d,J=2.0 Hz,1H),6.65(m,2H),4.67(s,2H),4.06(s,2H),3.12(m,1H),2.64(d,J=4.6 Hz,3H),1.11(d,J=6.9 Hz,6H).

[0751] Example 64 Synthesis of 2-(3,5-dichloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)phenoxy)-N,N-dimethylacetamide (compound 64)

[0752] [ka]

[0753] To a solution of compound 62 (60 mg, 0.15 mmol) in DCM (5 mL), oxalyl chloride (57 mg, 0.45 mmol) and DMF (cat.) were added. After stirring at room temperature for 1 hour, the reaction mixture was concentrated under vacuum. The residue was dissolved in DCM (5 mL) and added to dimethylamine / THF (0.75 mL, 2.0 M, 1.5 mmol) in DCM (5 mL). After stirring at room temperature for 1 hour, the mixture was poured into water (20 mL) and then into DCM (30 mL). * 3) The organic phase was extracted, washed with brine (20 mL), concentrated under vacuum, and purified by preparative TLC (petroleum ether: siRNA = 2:1) to obtain compound 64 (42 mg, 68% yield) as a white solid. TLC:DCM / MeOH=20 / 1(v / v), Rf=0.35 LCMS:RT=3.97 min; [M-1]=412.1 1 H NMR:(400 MHz,DMSO)δ 9.13(s,1H),7.32(d,J=7.8 Hz,1H),6.99(d,J=1.8 Hz,1H),6.66(d,J=2.7 Hz,2H),5.05(s,2H),4.05(s,2H),3.19-3.07(m,1H),2.96(s,3H),2.84(s,3H),1.11(d,J=6.9 Hz,6H).

[0754] Example 65 Synthesis of ethyl 2-(3-bromo-5-chloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)phenoxy)acetate (compound 65)

[0755] [ka]

[0756] To a solution of intermediate A34 (1.5 g, 4.2 mmol) and 2-isopropylphenol (1.7 g, 12.6 mmol) in DCE (20.0 mL), ZnCl2 (1 M / THF) (10.4 mmol, 10.4 mL) was added. The mixture was stirred overnight at 85°C. The mixture was cooled to room temperature, water (40 mL) was added, and the resulting mixture was poured into DCM (20 mL). * 3) Extraction was performed. The combined organic phase was washed with brine (30 mL), dried with Na2SO4, concentrated in vacuum, and purified by silica gel column chromatography (HCl / petroleum ether = 1 / 50 to 1 / 10) to obtain compound 65 (380 mg, 19.8% yield) as a pale yellow oil. TLC: Â / petroleum ether = 1 / 5 (v / v), Rf = 0.30 1 H NMR:(400 MHz,DMSO-d6)δ 9.11(s,1H),7.44(d,J=7.8 Hz,1H),6.97(s,1H),6.65(d,J=1.2 Hz,2H),4.99(s,2H),4.18(d,J=7.2 Hz,2H),4.11(s,2H),3.12(q,J=6.9 Hz,1H),1.21(t,J=7.2 Hz,3H),1.11(d,J=6.8 Hz,6H).

[0757] Example 66 Synthesis of ethyl 2-(5-chloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)-3-vinylphenoxy)acetate (compound 66)

[0758] [ka]

[0759] Compound 65 (260 mg, 566 ml) and vinylboron (pinacolate) (131 mg, 849 ml) were added to a mixture of 1,4-dioxane (4.0 mL) and H2O (0.5 mL) at room temperature. Pd(dppf)Cl2.CH2Cl2 (47 mg, 57 ml) and Cs2CO3 (369 mg, 1.1 mmol) were added. The mixture was microwaved under N2 (g) at 120°C for 3 hours. Water (20 mL) was added, and the resulting mixture was sorbed with HCl (10 mL). * 3) Extraction was performed. The combined organic phase was washed with brine (20 mL), dried with Na2SO4, concentrated under vacuum, and purified by preparative TLC (petroleum ether / siRNA = 5 / 1) to obtain compound 66 (140 mg, 60.8% yield) as a yellow solid. TLC: Petroleum ether / acetate = 5 / 1 (v / v), Rf = 0.32

[0760] Example 67 Synthesis of 2-(5-chloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)-3-vinylphenoxy)acetic acid (compound 67)

[0761] [ka]

[0762] To a solution of compound 66 (20 mg, 50 umol) in THF / H2O (2.0 mL / 0.5 mL) at room temperature, LiOH·H2O (12 mg, 294 umol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (20 mL), acidified to pH 3-4 with 1N HCl, and siRNA (10 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (20 mL), dried with Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 67 (8 mg, 21.6% yield) as a white solid. TLC:MeOH / DCM=1 / 10(v / v), Rf=0.30 LCMS: RT=1.721 min, [M-1]=377.1 1 H NMR:(400 MHz,DMSO-d6)δ 9.07(s,1H),7.18(d,J=8.0 Hz,1H),6.89(d,J=2.0 Hz,1H),6.68-6.58(m,2H),6.56(dd,J=8.4,2.4 Hz,1H),5.63(d,J=7.2 Hz,1H),5.59(s,1H),4.81(s,2H),3.98(s,2H),3.13(d,J=7.2 Hz,1H),1.10(d,J=7.2 Hz,6H). 19 F NMR:(376 MHz,DMSO-d6)δ -137.31.

[0763] Example 68 Synthesis of ethyl 2-(5-chloro-3-ethyl-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)phenoxy)acetate (compound 68)

[0764] [ka]

[0765] To a solution of compound 66 (100 mg, 246 umol) in THF (4.0 mL), Pd / C (10%) (50 mg) was added. The mixture was purged three times with H2 (g) and stirred overnight at 60°C. The mixture was cooled to 0°C, filtered, and then concentrated under vacuum to obtain compound 68 (100 mg, 99% yield) as a yellow oil. TLC: Â / petroleum ether = 1 / 5 (v / v), Rf = 0.25

[0766] Example 69 Synthesis of 2-(5-chloro-3-ethyl-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)phenoxy)acetic acid (compound 69)

[0767] [ka]

[0768] To a solution of compound 68 (100 mg, 234 umol) in THF / H2O (2.0 mL / 0.5 mL) at room temperature, LiOH·H2O (30 mg, 702 umol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (20 mL), acidified to pH 3-4 with 1N HCl, and siRNA (10 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (20 mL), dried with Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 69 (30 mg, 32.3% yield) as a white solid. TLC:MeOH / DCM=1 / 10(v / v), Rf=0.30 LCMS: RT=1.747 min, [M-1]=379.0 1 H NMR:(400 MHz,DMSO-d6)δ 9.06(s,1H),7.11(d,J=8.0 Hz,1H),6.89(d,J=2.4 Hz,1H),6.64(d,J=8.4 Hz,1H),6.55(dd,J=8.2,2.2 Hz,1H),4.82(s,2H),3.98(s,2H),3.16-3.10(m,1H),2.59(m,2H),1.10(d,J=6.8 Hz,6H),0.90(t,J=7.6 Hz,3H). 19 F NMR:(376 MHz,DMSO-d6)δ -139.73.

[0769] Example 70 Synthesis of ethyl 2-(5-chloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)-3-(prop-1-en-2-yl)phenoxy)acetate (compound 70)

[0770] [ka]

[0771] A mixture of intermediate C5 (550 mg, 1.2 mmol) and potassium propenyl-2-borone (trifluoride) (354 mg, 2.4 mmol) in 1,4-dioxane (5.0 mL) and H2O (0.2 mL) at room temperature was mixed with Pd(dppf)Cl2.CH2Cl2 (98 mg, 120 mL) and Cs2CO3 (780 mg, 2.4 mmol) under N2 (g). The reaction mixture was heated in a sealed tube at 120°C for 2 hours. The mixture was cooled to room temperature, water (30 mL) was added, and the resulting mixture was dissolved in ELISA (15 mL). * 3) Extraction was performed. The combined organic extract was washed with brine (30 mL), dried with Na2SO4, concentrated under vacuum, and purified by preparative TLC (siRNA / petroleum ether = 1 / 5) to obtain compound 70 (250 mg, 49.6% yield) as a white solid. TLC: Petroleum ether / acetate = 5 / 1 (v / v), Rf = 0.23 1 H NMR:(400 MHz,DMSO-d6)δ 9.04(s,1H),7.24(d,J=8.0 Hz,1H),6.77(d,J=2.4 Hz,1H),6.64(d,J=8.0 Hz,1H),6.54(dd,J=8.4,2.4 Hz,1H),5.31(t,J=1.6 Hz,1H),4.94(s,2H),4.80(t,J=1.6 Hz,1H),3.91(s,2H),3.13(m,1H),1.76(s,3H),1.21(t,J=7.2 Hz,4H),1.08(d,J=6.8 Hz,6H).

[0772] Example 71 Synthesis of 2-(5-chloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)-3-(prop-1-en-2-yl)phenoxy)acetic acid (compound 71)

[0773] [ka]

[0774] To a solution of compound 70 (250 mg, 520 umol) in THF / H2O (2.0 mL / 0.5 mL) at room temperature, LiOH·H2O (39 mg, 930 umol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (50 mL), acidified to pH 3-4 with 1N HCl, and  (20 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (50 mL), dried with Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 71 (40 mg, 32.8% yield) as a white solid. TLC:MeOH / DCM=1 / 10(v / v), Rf=0.30 LCMS: RT=1.691 min, [M-1]=391.1 1 H NMR:(400 MHz,DMSO-d6)δ 9.05(s,1H),7.18(d,J=8.0 Hz,1H),6.79(d,J=2.0 Hz,1H),6.63(d,J=8.0 Hz,1H),6.55(dd,J=8.0,2.0 Hz,1H),5.31(t,J=2.0 Hz,1H),4.84(s,2H),4.81(t,J=1.2 Hz,1H),3.91(s,2H),3.16-3.10(m,1H),1.77(s,3H),1.09(d,J=6.8 Hz,6H). 19 F NMR:(376 MHz,DMSO-d6)δ -137.45.

[0775] Example 72 Synthesis of ethyl 2-(5-chloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)-3-isopropylphenoxy)acetate (compound 72)

[0776] [ka]

[0777] To a solution of compound 70 (250 mg, 594 umol) in THF (6.0 mL), Pd / C (120 mg) was added. The mixture was purged three times with H2 gas and stirred overnight at 60°C. The mixture was concentrated under vacuum to obtain compound 72 (220 mg, 87.6% yield) as a yellow oil. TLC: Petroleum ether / acetate = 1 / 5 (v / v), Rf = 0.28

[0778] Example 73 Synthesis of 2-(5-chloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)-3-isopropylphenoxy)acetic acid (compound 73)

[0779] [ka]

[0780] To a solution of compound 72 (250 mg, 520 umol) in THF / H2O (2.0 mL / 0.5 mL) at room temperature, LiOH·H2O (39 mg, 927 umol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (50 mL), acidified to pH 3-4 with 1N HCl, and Â(20 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (50 mL), dried with Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 73 (55 mg, 25.8% yield) as a white solid. TLC:MeOH / DCM=1 / 10(v / v), Rf=0.30 LCMS: RT=1.896 min, [M-1]=393.1 1H NMR:(400 MHz,DMSO-d6)δ 9.06(s,1H),7.09(d,J=8.0 Hz,1H),6.82(d,J=2.0 Hz,1H),6.66(d,J=8.0 Hz,1H),6.59(dd,J=8.4,2.4 Hz,1H),4.80(s,2H),4.03(s,2H),3.13(m,2H),1.12(dd,J=7.2,1.2 Hz,6H),1.09(d,J=7.2 Hz,6H). 19 F NMR:(376 MHz,DMSO-d6)δ -136.27.

[0781] Example 74 Synthesis of ethyl 2-(3-chloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)-5-vinylphenoxy)acetate (compound 74)

[0782] [ka]

[0783] A mixture of intermediate C6 (800 mg, 1.7 mmol) and vinylboron (pinacolate) (524 mg, 3.4 mmol) in 1,4-dioxane (6.0 mL) and water (0.5 mL) at room temperature was mixed with Pd(dppf)Cl2.CH2Cl2 (139 mg, 170 umol) and Cs2CO3 (1.1 g, 3.4 mmol). The reaction mixture was heated in a sealed tube under N2 (g) at 120°C for 3 hours. The mixture was cooled to room temperature, water (50 mL) was added, and the mixture was mixed with SiO2 (20 mL). * 3) Extraction was performed. The combined organic phase was washed with brine (50 mL), dried with Na2SO4, concentrated in vacuum, and purified by preparative TLC (siRNA / petroleum ether = 1 / 5) to obtain compound 74 (230 mg, 33.2% yield) as a white solid. TLC: Petroleum ether / acetate = 5 / 1 (v / v), Rf = 0.17 1H NMR:(400 MHz,DMSO-d6)δ 9.07(s,1H),7.29(d,J=8.4 Hz,1H),6.92-6.90(m,1H),6.62(d,J=8.0 Hz,1H),6.57(dd,J=8.4,2.4 Hz,1H),5.34(d,J=10.8 Hz,1H),5.01(s,2H),4.17(q,J=7.2 Hz,2H),4.04(s,2H),3.12(p,J=6.8 Hz,1H),1.22-1.18(t,J=7.4 Hz,3H),1.09(d,J=6.8 Hz,6H).

[0784] Example 75 Synthesis of 2-(3-chloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)-5-vinylphenoxy)acetic acid (compound 75)

[0785] [ka]

[0786] To a solution of compound 74 (100 mg, 246 umol) in THF / H2O (2.0 mL / 0.5 mL) at room temperature, LiOH·H2O (30 mg, 738 umol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (30 mL), acidified to pH 3-4 with 1N HCl, and toluene (20 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (50 mL), dried with Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 75 (25 mg, 26.9% yield) as a white solid. TLC:MeOH / DCM=1 / 10(v / v), Rf=0.30 LCMS: RT=1.688 min, [M-1]=378.1 1H NMR:(400 MHz,DMSO-d6)δ 9.07(s,1H),7.27(d,J=8.4 Hz,1H),6.97-6.88(m,2H),6.63(d,J=8.0 Hz,1H),6.57(dd,J=8.4,2.4 Hz,1H),5.76(d,J=17.2 Hz,1H),5.34(d,J=11.2 Hz,1H),4.92(s,2H),4.05(s,2H),3.16-3.09(m,1H),1.10(d,J=6.8 Hz,6H). 19 F NMR:(376 MHz,DMSO-d6)δ -133.28.

[0787] Example 76 Synthesis of ethyl 2-(3-chloro-5-ethyl-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)phenoxy)acetate (compound 76)

[0788] [ka]

[0789] To a solution of compound 74 (130 mg, 320 umol) in THF (5.0 mL), Pd / C (50 mg) was added. The mixture was stirred overnight at 60°C under an H2 atmosphere. The mixture was filtered and concentrated under vacuum to obtain compound 76 (130 mg, 99.2% yield) as a yellow oil. TLC: Petroleum ether / acetate = 1 / 5 (v / v), Rf = 0.28

[0790] Example 77 Synthesis of 2-(3-chloro-5-ethyl-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)phenoxy)acetic acid (compound 77)

[0791] [ka]

[0792] To a solution of compound 76 (130 mg, 318 umol) in THF / H2O (2.0 mL / 0.5 mL) at room temperature, LiOH·H2O (40 mg, 954 umol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (50 mL), acidified to pH 3-4 with 1N HCl, and toluene (20 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (50 mL), dried with Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 77 (5 mg, 4.1% yield) as a white solid. TLC:MeOH / DCM=1 / 10(v / v), Rf=0.30 LCMS: RT=4.025 min, [M-1]=379.1 1 H NMR:(400 MHz,DMSO-d6)δ 9.06(s,1H),6.97(d,J=8.4 Hz,1H),6.89(d,J=2.4 Hz,1H),6.64(d,J=8.0 Hz,1H),6.54(dd,J=8.4,2.4 Hz,1H),4.83(s,2H),3.99(s,2H),3.16-3.10(m,1H),2.58-2.52(m,2H),1.10(d,J=7.2 Hz,6H),1.00(t,J=7.6 Hz,3H). 19 F NMR:(376 MHz,DMSO-d6)δ -136.31.

[0793] Example 78 Synthesis of ethyl 2-(3-chloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)-5-(prop-1-en-2-yl)phenoxy)acetate (compound 78)

[0794] [ka]

[0795] A mixture of intermediate C6 (600 mg, 1.3 mmol) and potassium isopropenyl trifluoroborate (354 mg, 2.6 mmol) in 1,4-dioxane (5.0 mL) and H2O (0.2 mL) at room temperature was mixed with Pd(dppf)Cl2.CH2Cl2 (106 mg, 131 mL) and Cs2CO3 (847 mg, 2.6 mmol). The reaction mixture was heated in a sealed tube under N2 (g) at 120°C for 2 hours. The mixture was cooled to room temperature, water (30 mL) was added, and the mixture was mixed with ELISA (20 mL). * 3) Extraction was performed. The combined organic phase was washed with brine (50 mL), dried with Na2SO4, concentrated in vacuum, and purified by preparative TLC (siRNA / petroleum ether = 1 / 5) to obtain compound 78 (230 mg, 41.9% yield) as a white solid. TLC: Petroleum ether / acetate = 5 / 1 (v / v), Rf = 0.23 1 H NMR:(400 MHz,DMSO-d6)δ 9.03(s,1H),6.92(d,J=8.4 Hz,1H),6.78(d,J=2.0 Hz,1H),6.63(d,J=8.0 Hz,1H),6.54(dd,J=8.0,2.4 Hz,1H),5.17(t,J=2.0 Hz,1H),4.95(s,2H),4.74(dd,J=2.0,1.1 Hz,1H),4.19-4.13(m,2H),3.96(s,2H),3.14-3.08(m,1H),1.18(d,J=7.2 Hz,3H),1.08(d,J=6.8Hz,6H)

[0796] Example 79 Synthesis of 2-(3-chloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)-5-(prop-1-en-2-yl)phenoxy)acetic acid (compound 79)

[0797] [ka]

[0798] To a solution of compound 78 (100 mg, 240 umol) in THF / H2O (2.0 mL / 0.5 mL) at room temperature, LiOH·H2O (30 mg, 720 umol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (50 mL), acidified to pH 3-4 with 1N HCl, and siRNA (20 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (50 mL), dried with Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 79 (10 mg, 11.2% yield) as a white solid. TLC:MeOH / DCM=1 / 10(v / v), Rf=0.30 LCMS: RT=2.240 min, [M-1]=391.1 1 H NMR:(400 MHz,DMSO-d6)δ 9.03(s,1H),6.89(d,J=8.4 Hz,1H),6.79(d,J=2.0 Hz,1H),6.62(d,J=8.4 Hz,1H),6.53(dd,J=8.4,2.4 Hz,1H),5.17(t,J=2.0 Hz,1H),4.85(s,2H),4.77-4.70(m,1H),3.95(s,2H),3.11(m,1H),1.85(d,J=1.6 Hz,3H),1.08(d,J=6.8 Hz,6H). 19 F NMR:(376 MHz,DMSO-d6)δ -134.85.

[0799] Example 80 Synthesis of ethyl 2-(3-chloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)-5-isopropylphenoxy)acetate (compound 80)

[0800] [ka]

[0801] To a solution of compound 78 (130 mg, 309 umol) in THF (5.0 mL), Pd / C (60 mg) was added. The mixture was stirred overnight at 60°C under an H2 atmosphere. The mixture was filtered and concentrated under vacuum to obtain compound 80 (130 mg, 99.2% yield) as a yellow oil. TLC: Petroleum ether / acetate = 1 / 5 (v / v), Rf = 0.28

[0802] Example 81 Synthesis of 2-(3-chloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)-5-isopropylphenoxy)acetic acid (compound 81)

[0803] [ka]

[0804] To a solution of compound 80 (130 mg, 308 umol) in THF / H2O (2.0 mL / 0.5 mL) at room temperature, LiOH·H2O (39 mg, 924 umol) was added. The mixture was stirred at room temperature for 1 hour. The mixture was diluted with water (30 mL), acidified to pH 3-4 with 1N HCl, and toluene (10 mL) was added. * 3) Extraction was performed. The combined organic phase was washed with brine (20 mL), dried with Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to obtain compound 81 (15 mg, 12.3% yield) as a white solid. TLC:MeOH / DCM=1 / 10(v / v), Rf=0.30 LCMS: RT=1.836 min, [M-1]=393.1 1 H NMR:(400 MHz,DMSO-d6)δ 9.06(s,1H),7.00(d,J=8.4 Hz,1H),6.83(d,J=2.4 Hz,1H),6.65(d,J=8.0 Hz,1H),6.57(dd,J=8.4,2.4 Hz,1H),4.86(s,2H),4.04(s,2H),3.15-3.06(m,2H),1.07(dd,J=6.8,6H),1.04(dd,J=6.8,6H). 19 F NMR:(376 MHz,DMSO-d6)δ -136.10.

[0805] Example 82 Synthesis of ethyl 2-(3,5-dichloro-2-fluoro-4-(3-(4-fluorobenzyl)-4-hydroxybenzyl)phenoxy)acetate (compound 82)

[0806] [ka]

[0807] To a solution of intermediate B6 (385 mg, 1.90 mmol) in room temperature DCE (5 mL), intermediate A29 (200 mg, 0.63 mmol) and ZnCl2 (1.0 M in THF, 1.4 mL, 1.4 mmol) were added. The reaction mixture was heated at 90°C overnight. The reaction mixture was diluted with DCM (20 mL) and brine (10 mL) * The product was washed (2), dried over Na2SO4, and concentrated in vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / siRNA = 5 / 1) to obtain compound 82 (120 mg, 39.3% yield) as a colorless oil. TLC: Petroleum ether / acetate = 5 / 1 (v / v), Rf = 0.21 1 H NMR:(400 MHz,DMSO-d6)δ 9.30(s,1H),7.38(d,J=7.7 Hz,1H),7.18(dd,J=8.6,5.7 Hz,2H),7.11-7.01(m,2H),6.84(d,J=2.1 Hz,1H),6.74(dd,J=8.3,2.2 Hz,1H),6.69(d,J=8.2 Hz,1H),4.98(s,2H),4.18(q,J=7.1 Hz,2H),4.02(s,2H),3.78(s,2H),1.20(t,J=7.1 Hz,3H).

[0808] Example 83 Synthesis of 2-(3,5-dichloro-2-fluoro-4-(3-(4-fluorobenzyl)-4-hydroxybenzyl)phenoxy)acetic acid (compound 83)

[0809] [ka]

[0810] To a solution of compound 82 (120 mg, 0.25 mmol) in THF (3 mL) / water (1 mL) at room temperature, LiOH·H2O (31 mg, 0.375 mmol) was added, and the mixture was stirred at room temperature for 1 hour. The reaction product was acidified with 1N HCl to pH 3-4, and then extracted with RINKAN (20 mL). The combined organic phase was washed with brine (20 mL), dried over Na2SO4, concentrated under vacuum, and purified by preparative HPLC to obtain compound 83 (25 mg, 15.5% yield) as a white solid. TLC:DCM / MeOH = 5 / 1(v / v), Rf = 0.31 LCMS: RT = 3.018 min, [M-1] = 451. 1 H NMR:(400 MHz,DMSO-d6)δ 9.81(s,1H),7.27-7.18(m,2H),7.11(s,2H),7.10-7.04(m,2H),6.57(d,J=8.5 Hz,1H),6.40(t,J=8.7 Hz,1H),4.75(s,2H),4.03(s,2H),3.88(s,2H).

[0811] Example 84 Synthesis of ethyl 2-(3,5-dichloro-2-fluoro-4-(3-(1-(4-fluorophenyl)butyl)-4-hydroxybenzyl)phenoxy)acetate (compound 84)

[0812] [ka]

[0813] A mixture of intermediates B18 (244 mg, 1.0 mmol), A29 (158 mg, 0.5 mmol), and ZnCl2 (170 mg, 1.25 mmol) in chlorobenzene (5 mL) was stirred overnight at 140 °C. The mixture was cooled to room temperature, water (10 mL) was added, and the resulting mixture was extracted with DCM (10 mL). The organic layer was dried over Na2SO4, concentrated under vacuum, and purified by preparative TLC (petroleum ether / SiO2 = 5 / 1) to obtain compound 84 (80 mg, 30.6% yield) as a white solid. TLC: HCl / petroleum ether = 1 / 5 (v / v), Rf = 0.38 1 H NMR:(400 MHz,DMSO-d6)δ 9.21(s,1H),7.40(d,J=7.6 Hz,1H),7.25-7.16(m,2H),7.08-6.99(m,3H),6.70(d,J=2.2 Hz,1H),6.64(d,J=8.2 Hz,1H),4.99(s,2H),4.17(q,J=7.1 Hz,4H),4.05(s,2H),1.89-1.80(m,2H),1.26-1.13(m,5H),0.84(t,J=7.3 Hz,3H).

[0814] Example 85 Synthesis of 2-(3,5-dichloro-2-fluoro-4-(3-(1-(4-fluorophenyl)butyl)-4-hydroxybenzyl)phenoxy)acetic acid (compound 85)

[0815] [ka]

[0816] To a solution of compound 84 (50 mg, 96 umol) in MeOH (3 mL) and water (1 mL), LiOH.H2O (12 mg, 287 umol) was added. The mixture was stirred at room temperature for 1 hour. Water (10 mL) was added, and the mixture was acidified to pH 4-5 with 1 N HCl and extracted with DCM (10 mL). The organic phase was dried over Na2SO4, concentrated under vacuum, and purified by preparative HPLC to obtain compound 85 (16 mg, 34.0% yield) as a white solid. TLC: alkyl / petroleum ether = 1 / 5 (v / v), Rf = 0 LCMS:RT=2.826 min,[M-1]=493.0 / 495.0 1 H NMR:(400 MHz,DMSO-d6)δ 9.21(s,1H),7.35(d,J=7.7 Hz,1H),7.21(dd,J=8.7,5.7 Hz,2H),7.08-7.00(m,3H),6.71(dd,J=8.2,2.2 Hz,1H),6.64(d,J=8.3 Hz,1H),4.89(s,2H),4.22(t,J=7.9 Hz,1H),4.05(s,2H),1.90-1.80(m,2H),1.15(p,J=7.3 Hz,2H),0.84(t,J=7.3 Hz,3H).

[0817] Example 86 Synthesis of ethyl 2-(3,5-dic...

Claims

1. A compound having the structure of formula (I), 【Chemistry 1】 Alternatively, a pharmaceutically acceptable salt thereof, During the ceremony, X １ is C １－８ Alkyl, C ２－８ Alkenil, C １－８ It is a haloalkyl or halo, X ２ is C １－８ Alkyl, C ２－８ Alkenil, C １－８ It is a haloalkyl or halo, Y １ is H, cyano, halogen, or C １－８ alkoxy, and Y ２ H, cyano, halogen, C １－８ Alkyl, or C １－８ It is an alkoxy, Y １ and Y ２ At least one of them is not H, R １ Ha-NR １ａ R １ｂ OR １ｃ And, R １ａ and R １ｂ These are H and C, which are independent of each other. １－８ Alkyl, C ２－８ Alkenil, C ２－８ Alkynyl, carbocyclic, carbocyclic alkyl, heterocyclic, or heterocyclic alkyl, or R １ａ and R １ｂ They, together with the nitrogen atom to which they are bonded, form a heterocycle. R １ｃ H, C １－８ Alkyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl, and, R ２ C １－８ Alkyl, C ２－８ Alkenyl, carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl, Here, R １ａ , R １ｂ , R １ｃ , and R ２ Each of these independently represents one or more halos, C １－８ Alkyl, C １－８ Haloalkyl, cyano, -OR', -NR'R'', =O, =S, -S(O) ２ R', or -S(O) ２ OR' allows for arbitrary substitution, and R' and R'' are independent of each other, H and C. １－８ Alkyl, or C １－８ A compound that is a haloalkyl, or a pharmaceutically acceptable salt thereof.

2. It has the structure of formula (II-A), 【Chemistry 2】 During the ceremony, X １ is C １－８ Alkyl, C ２－８ Alkenil, C １－８ It is a haloalkyl or halo, X ２ is C １－８ Alkyl, C ２－８ Alkenil, C １－８ It is a haloalkyl or halo, Y １ is H, cyano, halogen, or C １－８ It is an alkoxy, Y ２ H, cyano, halogen, C １－８ Alkyl, or C １－８ It is an alkoxy, Y １ and Y ２ At least one of them is not H, and R １ａ and R １ｂ These are H and C, which are independent of each other. １－８ Alkyl, C ２－８ Alkenil, C ２－８ Alkynyl, carbocyclic, carbocyclic alkyl, heterocyclic, or heterocyclic alkyl, or R １ａ and R １ｂ They, together with the nitrogen atom to which they are bonded, form a heterocycle. Here, R １ａ and R １ｂ Each of these independently represents one or more halo, cyano, -OR', -NR'R'', =O, =S, -S(O) ２ R', or -S(O) ２ OR' allows for arbitrary substitution, and R' and R'' are independent of each other, H and C. １－８ Alkyl, or C １－８ A compound according to claim 1, which is a haloalkyl compound, or a pharmaceutically acceptable salt thereof.

3. R １ａ is C １－８ It is alkyl, R １ｂ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is H.

4. It has the structure of formula (II-B), 【Transformation 3】 During the ceremony, X １ is C １－８ Alkyl, C ２－８ Alkenil, C １－８ It is a haloalkyl or halo, X ２ is C １－８ Alkyl, C ２－８ Alkenil, C １－８ It is a haloalkyl or halo, Y １ is H, cyano, halogen, or C １－８ It is an alkoxy, Y ２ H, cyano, halogen, C １－８ Alkyl, or C １－８ It is an alkoxy, Y １ and Y ２ At least one of them is not H, R １ｃ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is H.

5. X １ is C １－８ alkyl, the compound according to claim 1, or a pharmaceutically acceptable salt thereof.

6. X １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is a halo.

7. X ２ is C １－８ The compound according to claim 1, which is alkyl, or a pharmaceutically acceptable salt thereof.

8. X ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is a halo.

9. X １ is Cl, X ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is Cl.

10. Y １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein Y is a halogen.

11. Y １ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is H.

12. Y ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is a halogen.

13. Y ２ The compound according to claim 1, or a pharmaceutically acceptable salt thereof, wherein is H.

14. A compound according to claim 1, having the structure of any one of the following compounds, or a pharmaceutically acceptable salt thereof. 【Chemistry 3-1】 【Chemistry 3-2】 【Chemistry 3-3】 [Chemistry 3-4] [Transformation 3-5] [Chemistry 3-6] 【Chemistry 3-7】 【Transformation 3-8】 【Chemistry 3-9】 【Chemistry 3-10】

15. A pharmaceutical composition comprising any one compound from claims 1 to 14, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

16. The use of any one compound from claims 1 to 14, or a pharmaceutically acceptable salt thereof, in the manufacture of a drug for the treatment of neurodegenerative or fibrous diseases, The aforementioned neurodegenerative diseases include adult Refsum disease, Alexander disease, Alzheimer's disease, Barlow concentric sclerosis, Canavan disease, central pontine myelin breakdown, cerebral palsy, cerebral tendon xanthomatous cerebrospinal fluid, chronic inflammatory demyelinating polyneuropathy, Devic syndrome, diffuse demyelinating sclerosis, idiopathic inflammatory demyelinating disease, infantile Refsum disease, Krabbe disease, Leber's hereditary optic neuropathy, Marburg multiple sclerosis, and Marquia Fava-Bignami. The disease is metachromatic leukodystrophy, multifocal motor neuropathy, abnormal proteinogenic demyelinating polyneuropathy, Pelizaeus-Merzbach disease, peroneal atrophy, progressive multifocal leukoencephalopathy, transverse myelitis, tropical spastic paraplegia, van der Knapp disease, X-linked adrenoleukodystrophy, or Zellweger syndrome, where the fibrous disease is idiopathic pulmonary fibrosis (IPF).

Images