Thyromimetic agents

Abstract

Disclosed herein are thyromimetic compounds useful for treating diseases such as neurodegenerative disorders and fibrotic diseases. Also provided are pharmaceutical compositions containing such compounds, as well as methods of their preparation.

Description

[0001] Cross-referencing

[0002] This application claims the benefit of U.S. Provisional Patent Application No. 63 / 040,446, filed June 17, 2020, the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to thyrotropin compounds and products containing said thyrotropin compounds, as well as their use and preparation methods. Background Technology

[0004] Thyroid hormones (TH) are key signaling agents for oligodendrocyte differentiation and myelination during development, and also stimulate myelin regeneration in an adult model of multiple sclerosis (MS) (Calzà et al., Brain Res Revs 48:339-346, 2005). However, TH is not an acceptable long-term therapy due to the limited therapeutic window for achieving myelin regeneration while avoiding cardiotoxicity and bone demineralization associated with chronic hyperthyroidism. Some thyroid hormone analogs can activate thyroid hormone-responsive genes by utilizing the molecular and physiological characteristics of thyroid hormone receptors, while avoiding the associated drawbacks of TH (Malm et al., Mini Rev Med Chem 7:79-86, 2007). These receptors are expressed in two main forms with heterologous tissue distribution and overlapping but distinct target genomes (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).

[0005] It has also been reported that TH can inhibit transforming growth factor β (TGF-β) signaling, thereby attenuating fibrotic responses (Alonso-Merino et al., Proc Natl Acad Sci US A. 113(24): E3451-60, 2016). TGF-β is a pleiotropic cytokine that plays a key role in pathological processes such as fibrosis, contributing to tissue homeostasis (Massagué, Nat Rev Mol Cell Biol. 13(10): 616–630, 2012). By inhibiting TGF-β signaling, TR ligands or agonists may have the beneficial effect of blocking 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).

[0006] Developing selective thyrotropin drugs is challenging due to the high sequence homology of thyroid hormone receptor subtypes; that is, only one amino acid residue on the inner surface of the ligand-binding domain lumen varies between the α1 and β1 forms. Despite this challenge, several groups have reported TRβ-selective agonists. Scanlan et al. identified GC-1 (sobetirome) as one of the first effective analogues to show 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). As used herein, the term “subitilor” refers to a synthetic diarylmethane derivative that is being investigated clinically as a potential therapeutic agent for hypercholesterolemia (see U.S. Patent No. 5,883,294, which is incorporated herein by reference). Other names for subitilor found in literature and regulatory filings include QRX-431 and GC-1. Metabasis employed a similar core and novel liver-targeting prodrug strategy in MB07811 (Erion et al., PNAS 104(39), 15490-15495, 2007). Madrigal has reported in vivo TRβ-selective activity of MGL-3196 (Taub et al., Atherosclerosis 230(2):373-380, 2013). KaroBio has reported on eprotirome (KB2115; Berkenstam et al., PNAS105(2):663-668, 2008) and KB-141 (Ye et al., J Med Chem 46:1580-1588, 2003), both of which showed improved TRβ selectivity in vitro. Further research by this group highlighted other selective compounds (Hangeland et al., BMCL14:3549-3553, 2004). Two TRβ-selective agonists, identified as SKL-12846 and SKL-13784, have been reported to accumulate in the liver and reduce cholesterol levels in rodents (Takahashi et al., BMC 22(1):488-498, 2014; Xenobiotica 2015, 1-9).Kissei also reported selective compounds (Shiohara et al., BMC 20(11), 3622-3634, 2012).

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

[0008] This document discloses compounds or pharmaceutically acceptable isomers, racemates, tautomers, hydrates, solvates, isotopes, or salts thereof, wherein the compounds are formulated according to Formula I:

[0009]

[0010] Among them, A and X 1 X 2 Y 1 Y 2 and R 2 As defined below.

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

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

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

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

[0015] In one embodiment, a compound or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof is provided, the compound having the structure of formula (I):

[0016]

[0017] in:

[0018] A is a carbocyclic or heterocyclic ring, wherein A is optionally substituted by one or more halogen groups, lower alkyl groups, lower haloalkyl groups, -CN, -OR', -NR'R”, =O, =S, -S(O)2R' or -S(O)2OR';

[0019] X 1 It is a lower alkyl group, a lower alkenyl group, a lower haloalkyl group, or a halogroup.

[0020] X 2 It is a lower alkyl group, a lower alkenyl group, a lower haloalkyl group, or a halogroup;

[0021] Y 1 It is H, -CN, halogen, lower alkyl or lower alkoxy;

[0022] Y 2 It is H, -CN, halogen, lower alkyl or lower alkoxy;

[0023] R 2 It is a lower alkyl group, a lower alkenyl group, a carbocyclic group, a heterocyclic group, a carbocycloalkyl group, or a heterocycloalkyl group, wherein R 2 Optionally substituted with one or more halogen groups, lower alkyl groups, lower haloalkyl groups, -CN, -OR', -NR'R", =O, =S, -S(O)2R' or -S(O)2OR'; and

[0024] R' and R” are each independently H, a lower alkyl group, or a lower haloalkyl group;

[0025] Where R 2 It is isopropyl and X 1 and X 2 When each of them is a methyl group, A is not a thiazolidinedione.

[0026] As used herein, "lower alkyl" refers to a straight-chain or branched alkyl group having 1 to 8 carbon atoms, 1 to 6 carbon atoms in some embodiments, 1 to 4 carbon atoms in some embodiments, and 1 to 3 carbon atoms in some embodiments. Examples of straight-chain lower alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl groups. Examples of branched lower alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, tert-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl groups.

[0027] As used herein, "lower alkenyl" refers to a straight-chain or branched alkenyl group having 2 to 8 carbon atoms, in some embodiments 2 to 6 carbon atoms, in some embodiments 2 to 4 carbon atoms, and in some embodiments 2 to 3 carbon atoms. An alkenyl group is an unsaturated hydrocarbon containing at least one carbon-carbon double bond. Examples of lower alkenyl groups include, but are not limited to, vinyl, propenyl, isopropenyl, butenyl, pentenyl, and hexenyl.

[0028] As used herein, "lower alkynyl" refers to a straight-chain or branched alkynyl group having 2 to 8 carbon atoms, in some embodiments 2 to 6 carbon atoms, in some embodiments 2 to 4 carbon atoms, and in some embodiments 2 to 3 carbon atoms. An alkynyl group is an unsaturated hydrocarbon containing at least one carbon-carbon triple bond. Examples of lower alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentyynyl, and hexynyl.

[0029] "Halogen" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0030] "Hydroxy group" refers to -OH.

[0031] "Cyano" refers to -CN.

[0032] "Lower haloalkyl" refers to a lower alkyl group as defined herein, in which one or more hydrogen atoms are replaced by a halogen. Examples of lower haloalkyl groups include, but are not limited to, -CF3, -CHF2, etc.

[0033] "Lower alkoxy group" refers to a lower alkyl group (i.e., -O-(lower alkyl group)) as defined herein, which is connected by an oxygen atom. Examples of lower alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, tert-butoxy, etc.

[0034] "Lower haloalkoxy group" refers to a lower haloalkyl group (i.e., -O-(lower haloalkyl)) as defined herein, which is connected by an oxygen atom. Examples of lower haloalkoxy groups include, but are not limited to, -OCF3, -OCHF2, etc.

[0035] "Carbocyclic," "carbocyclic," or "carbocyclic" refers to an alkyl group that forms a ring structure, which may be substituted or unsubstituted, wherein the ring is fully saturated, partially unsaturated, or completely unsaturated, wherein if unsaturation is present, the conjugation of π-electrons in the ring can produce aromaticity. In one embodiment, the carbocyclic group comprises a cycloalkyl group as defined herein. In another embodiment, the carbocyclic group comprises an aryl group as defined herein.

[0036] "Carbocycloalkyl" is an alkyl group as defined herein, wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond attached to a carbocyclic group as defined herein. In one embodiment, carbocycloalkyl includes cycloalkylalkyl. In one embodiment, carbocycloalkyl includes arylalkyl. Examples of carbocycloalkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, benzyl, etc.

[0037] "Cycloalkyl" refers to an alkyl group that forms a ring structure, which may be substituted or unsubstituted, wherein the ring is fully saturated, partially unsaturated, or completely unsaturated, wherein if unsaturation is present, the conjugation of π electrons in the ring does not produce aromaticity. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, while in other embodiments, the number of ring carbon atoms ranges from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups further include polycyclic cycloalkyl groups, such as, but not limited to, norbornel, adamantyl, bornel, camphenyl, isocamphenyl, and carenyl groups, as well as fused rings, such as, but not limited to, decahydronaphthyl.

[0038] "Cycloalkylalkyl" is an alkyl group as defined herein in which the hydrogen or carbon bond of the alkyl group is replaced by a bond attached to a cycloalkyl group as defined herein.

[0039] The "aryl" group refers to a cyclic aromatic hydrocarbon that does not contain heteroatoms. Therefore, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, and naphthacenyl. The aryl group comprises chrysenyl, biphenylenyl, anthraceneyl, and naphthyl groups. In some embodiments, the aryl group contains 6-14 carbons in the ring portion of the group. The terms "aryl" and "aryl group" include fused rings, wherein at least one ring is aromatic but not necessarily all rings are aromatic, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). In one embodiment, the aryl group is phenyl or naphthyl, and in another embodiment, the aryl group is phenyl.

[0040] "Arylalkyl" is an alkyl group as defined herein in which the hydrogen or carbon bond of the alkyl group is replaced by a bond to an aryl group as defined herein.

[0041] The terms "heterocyclic group," "heterocyclic," or "heterocyclic" refer to an aromatic or non-aromatic ring moiety containing three or more ring members, one or more of which are heteroatoms, such as, but not limited to, N, O, S, or P. In some embodiments, a heterocyclic group comprises 3 to 20 ring members, while other such groups have 3 to 15 ring members. At least one ring contains a heteroatom, but not every ring in a polycyclic system needs to contain a heteroatom. For example, dioxetralyl rings and benzodioxetralyl ring systems (methylenedioxyphenyl ring systems) are heterocyclic groups within the scope referred to herein.

[0042] Heterocyclic groups also include fused ring types, including those having fused aromatic and non-aromatic groups. Heterocyclic groups also include polycyclic ring systems containing heteroatoms, such as, but not limited to, quinine rings, and also include heterocyclic groups having substituents bonded to one of the ring members, including but not limited to alkyl, halogen, amino, hydroxyl, cyano, carboxyl, nitro, thio, or alkoxy groups. Heterocyclic groups as defined herein may be heteroaryl groups or partially or fully saturated cyclic groups comprising at least one cyclic heteroatom. Heterocyclic groups include, but are not limited to, pyrrolyl, furanyl, tetrahydrofuranyl, dioxacyclopentyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetraazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, inzolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazolopyridyl, thianaphthyl, purine, xanthine, adenine, guanine, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxolinyl, and quinazolinyl groups.

[0043] "Heterocyclic alkyl" is an alkyl group as defined herein, wherein the hydrogen or carbon bond of the alkyl group is replaced by a bond attached to a heterocyclic group as defined herein. In one embodiment, heterocyclic alkyl includes heteroarylalkyl.

[0044] "Heteroaryl" refers to an aromatic ring moiety containing five or more ring members, one or more of which are heteroatoms, such as, but not limited to, N, O and S. Heteroaryl groups include, but are not limited to, groups such as: pyrrole, pyrazol, pyridinyl, pyridazinyl, pyrazinyl, pyrimidinyl, thienyl, triazolyl, tetrazolyl, triazinyl, thiophenyl, oxazolyl, isoxazolyl, benzothiophene, benzofuranyl, indole, azaindole, indole, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridyl, isoxazolopyridyl, thianaphthyl, purine, xanthine, adenine, guanine, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxolinyl, and quinazolinyl groups. The terms “heteroaryl” and “heteroaryl group” include fused-ring compounds, such as those in which at least one ring is aromatic but not necessarily all rings are aromatic, including tetrahydroquinolinyl, tetrahydroisoquinolinyl, indole, and 2,3-dihydroindole.

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

[0046] In one embodiment, a compound or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof is provided, the compound having the structure of formula (II):

[0047]

[0048] in:

[0049] A is a carbocyclic or heterocyclic ring, wherein A is optionally substituted by one or more halogen groups, lower alkyl groups, lower haloalkyl groups, -CN, -OR', -NR'R”, =O, =S, -S(O)2R' or -S(O)2OR';

[0050] X 1 It is a lower alkyl group, a lower alkenyl group, a lower haloalkyl group, or a halogroup.

[0051] X 2 It is a lower alkyl group, a lower alkenyl group, a lower haloalkyl group, or a halogroup;

[0052] Y 1It is H, -CN, halogen, lower alkyl or lower alkoxy;

[0053] Y 2 It is H, -CN, halogen, lower alkyl or lower alkoxy;

[0054] R 2 It is a lower alkyl group, a lower alkenyl group, a carbocyclic group, a heterocyclic group, a carbocycloalkyl group, or a heterocycloalkyl group, wherein R 2 Optionally substituted with one or more halogen groups, lower alkyl groups, lower haloalkyl groups, -CN, -OR', -NR'R", =O, =S, -S(O)2R' or -S(O)2OR'; and

[0055] R' and R” are each independently H, a lower alkyl group, or a lower haloalkyl group;

[0056] Where R 2 It is isopropyl and X 1 and X 2 When each of them is a methyl group, A is not a thiazolidinedione.

[0057] In one embodiment, a compound having the structure of formula (I) or formula (II) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof is provided, wherein R 2 It is a lower alkyl group, optionally substituted with one or more halogen groups, -CN, -OR', -NR'R”, =O, =S, -S(O)2R', or -S(O)2OR', wherein R' and R” are each independently H, a lower alkyl group, or a lower haloalkyl group. In one embodiment, R 2 It is an unsubstituted lower alkyl group. In a more specific embodiment, R 2 It is methyl, ethyl, propyl, isopropyl, or butyl. In one embodiment, R 2 It is isopropyl.

[0058] In one embodiment, a compound or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof is provided, the compound having the structure of formula (III):

[0059]

[0060] in:

[0061] A is a carbocyclic or heterocyclic ring, wherein A is optionally substituted by one or more halogen groups, lower alkyl groups, lower haloalkyl groups, -CN, -OR', -NR'R”, =O, =S, -S(O)2R' or -S(O)2OR';

[0062] X 1It is a lower alkyl group, a lower alkenyl group, a lower haloalkyl group, or a halogroup.

[0063] X 2 It is a lower alkyl group, a lower alkenyl group, a lower haloalkyl group, or a halogroup;

[0064] Y 1 It is H, -CN, halogen, lower alkyl or lower alkoxy;

[0065] Y 2 It is H, -CN, halogen, lower alkyl or lower alkoxy;

[0066] R' and R” are each independently H, a lower alkyl group, or a lower haloalkyl group;

[0067] Where X 1 and X 2 When each of them is a methyl group, A is not a thiazolidinedione.

[0068] In one embodiment, a compound having the structure of formula (I) or formula (II) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof is provided, wherein R 2 It is a carbocycloalkyl or heterocycloalkyl group. In one embodiment, a compound having the structure of formula (I) or formula (II) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof is provided, wherein R 2 It is an aralkyl or heteroaralkyl group.

[0069] In one embodiment, a compound or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof is provided, the compound having the structure of formula (IV):

[0070]

[0071] in:

[0072] A is a carbocyclic or heterocyclic ring, wherein A is optionally substituted by one or more halogen groups, lower alkyl groups, lower haloalkyl groups, -CN, -OR', -NR'R”, =O, =S, -S(O)2R' or -S(O)2OR';

[0073] R' and R” are each independently H, a lower alkyl group, or a lower haloalkyl group;

[0074] B is aryl or heteroaryl;

[0075] X 1 It is a lower alkyl group, a lower alkenyl group, a lower haloalkyl group, or a halogroup.

[0076] X 2It is a lower alkyl group, a lower alkenyl group, a lower haloalkyl group, or a halogroup;

[0077] Y 1 It is H, -CN, halogen, lower alkyl or lower alkoxy;

[0078] Y 2 It is H, -CN, halogen, lower alkyl or lower alkoxy;

[0079] Q is -C(R) 3 R 4 )-or-{C(R 3 R 4 )}2-;

[0080] R 3 and R 4 Each occurrence is independently of H, halogen, -CN, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, or -OR. a -NR a R b Carbocyclic, heterocyclic, carbocycloalkyl or heterocycloalkyl, or R 3 and R 4 Together they form =O or =S;

[0081] Each R 5 Independently, it is a halogen group, -CN, lower alkyl group, lower alkenyl group, lower alkynyl group, lower haloalkyl group, carbocyclic group, heterocyclic group, carbocyclic alkyl group, heterocyclic alkyl group, -OR group. 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 ;

[0082] n is 0-5; and

[0083] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0084] Where R 3 R 4 R 5 R a and R bEach can be independently and optionally replaced by one or more halogen groups, -CN, -OR', -NR'R", =O, =S, -S(O)2R' or -S(O)2OR'.

[0085] In one embodiment, a compound or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof is provided, the compound having the structure of formula (V):

[0086]

[0087] in:

[0088] Q 1 Q 2 Q 3 Q 4 and Q 5 Each independently constitutes CH and CR. 5 Or N;

[0089] A is a carbocyclic or heterocyclic ring, wherein A is optionally substituted by one or more halogen groups, lower alkyl groups, lower haloalkyl groups, -CN, -OR', -NR'R”, =O, =S, -S(O)2R' or -S(O)2OR';

[0090] R' and R” are each independently H, a lower alkyl group, or a lower haloalkyl group;

[0091] X 1 It is a lower alkyl group, a lower alkenyl group, a lower haloalkyl group, or a halogroup.

[0092] X 2 It is a lower alkyl group, a lower alkenyl group, a lower haloalkyl group, or a halogroup;

[0093] Y 1 It is H, -CN, halogen, lower alkyl or lower alkoxy;

[0094] Y 2 It is H, -CN, halogen, lower alkyl or lower alkoxy;

[0095] R 3 and R 4 Each can be independently represented by H, halogen, -CN, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, or -OR. a -NR a R b Carbocyclic, heterocyclic, carbocycloalkyl or heterocycloalkyl, or R 3 and R 4 Together they form =O or =S;

[0096] Each R 5Independently, it is a halogen group, -CN, lower alkyl group, lower alkenyl group, lower alkynyl group, lower haloalkyl group, carbocyclic group, heterocyclic group, carbocyclic alkyl group, heterocyclic alkyl group, -OR group. 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 ;

[0097] n is 0-5; and

[0098] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0099] Where R 3 R 4 R 5 R a and R b Each can be independently and optionally replaced by one or more halogen groups, -CN, -OR', -NR'R", =O, =S, -S(O)2R' or -S(O)2OR'.

[0100] In one embodiment, a compound having the structure of formula (V) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof is provided, wherein Q 1 Q 2 Q 3 Q 4 and Q 5 Each independently is CH or CR 5 In one embodiment, a compound having the structure of formula (V) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof is provided, wherein Q 1 Q 2 Q 3 Q 4 Or Q 5 At least one of them is N. In one embodiment, a compound having the structure of formula (V) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope or salt thereof is provided, wherein Q 1 Q 2 Q 3 Q 4 Or Q 5At least two of them are N.

[0101] In one embodiment, a compound or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof is provided, the compound having the structure of formula (VI):

[0102]

[0103] in:

[0104] A is a carbocyclic or heterocyclic ring, wherein A is optionally substituted by one or more halogen groups, lower alkyl groups, lower haloalkyl groups, -CN, -OR', -NR'R”, =O, =S, -S(O)2R' or -S(O)2OR';

[0105] R' and R” are each independently H, a lower alkyl group, or a lower haloalkyl group;

[0106] X 1 It is a lower alkyl group, a lower alkenyl group, a lower haloalkyl group, or a halogroup.

[0107] X 2 It is a lower alkyl group, a lower alkenyl group, a lower haloalkyl group, or a halogroup;

[0108] Y 1 It is H, -CN, halogen, lower alkyl or lower alkoxy;

[0109] Y 2 It is H, -CN, halogen, lower alkyl or lower alkoxy;

[0110] R 3 and R 4 Each can be independently represented by H, halogen, -CN, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, or -OR. a -NR a R b Carbocyclic, heterocyclic, carbocycloalkyl or heterocycloalkyl, or R 3 and R 4 Together they form =O or =S;

[0111] Each R 5 Independently, it is a halogen group, -CN, lower alkyl group, lower alkenyl group, lower alkynyl group, lower haloalkyl group, carbocyclic group, heterocyclic group, carbocyclic alkyl group, heterocyclic alkyl group, -OR group. a -NR a R b -C(O)R a -C(O)OR a -C(O)NR a R b -NR a C(O)Rb -S(O)2R a or -S(O)2OR a ;

[0112] n is 0-5; and

[0113] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0114] Where R 3 R 4 R 5 R a and R b Each can be independently and optionally replaced by one or more halogen groups, -CN, -OR', -NR'R", =O, =S, -S(O)2R' or -S(O)2OR'.

[0115] In one embodiment, a compound having the structure of formula (I) or formula (II) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof is provided, wherein R 2 It is a carbocyclic or heterocyclic ring. In one embodiment, a compound having the structure of formula (I) or formula (II) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof is provided, wherein R 2 It is aryl or heteroaryl.

[0116] In one embodiment, a compound or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof is provided, the compound having the structure of formula (VII):

[0117]

[0118] in:

[0119] A is a carbocyclic or heterocyclic ring, wherein A is optionally substituted by one or more halogen groups, lower alkyl groups, lower haloalkyl groups, -CN, -OR', -NR'R”, =O, =S, -S(O)2R' or -S(O)2OR';

[0120] R' and R” are each independently H, a lower alkyl group, or a lower haloalkyl group;

[0121] B is aryl or heteroaryl;

[0122] X 1 It is a lower alkyl group, a lower alkenyl group, a lower haloalkyl group, or a halogroup.

[0123] X 2It is a lower alkyl group, a lower alkenyl group, a lower haloalkyl group, or a halogroup;

[0124] Y 1 It is H, -CN, halogen, lower alkyl or lower alkoxy;

[0125] Y 2 It is H, -CN, halogen, lower alkyl or lower alkoxy;

[0126] Each R 5 Independently, it is a halogen group, -CN, lower alkyl group, lower alkenyl group, lower alkynyl group, lower haloalkyl group, carbocyclic group, heterocyclic group, carbocyclic alkyl group, heterocyclic alkyl group, -OR group. 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 ;

[0127] n is 0-5; and

[0128] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0129] Where R 5 R a and R b Each can be independently and optionally replaced by one or more halogen groups, -CN, -OR', -NR'R", =O, =S, -S(O)2R' or -S(O)2OR'.

[0130] In one embodiment, a compound having the structure of formula (VII) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof is provided, wherein B is a carbocyclic ring. In another embodiment, a compound having the structure of formula (VII) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof is provided, wherein B is an aryl group. In yet another embodiment, a compound having the structure of formula (VII) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof is provided, wherein B is a phenyl group.

[0131] In one embodiment, a compound, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, is provided having the structure of formula (VIII):

[0132]

[0133] in:

[0134] A is a carbocyclic or heterocyclic ring, wherein A is optionally substituted by one or more halogen groups, lower alkyl groups, lower haloalkyl groups, -CN, -OR', -NR'R”, =O, =S, -S(O)2R' or -S(O)2OR';

[0135] R' and R” are each independently H, a lower alkyl group, or a lower haloalkyl group;

[0136] X 1 It is a lower alkyl group, a lower alkenyl group, a lower haloalkyl group, or a halogroup.

[0137] X 2 It is a lower alkyl group, a lower alkenyl group, a lower haloalkyl group, or a halogroup;

[0138] Y 1 It is H, -CN, halogen, lower alkyl or lower alkoxy;

[0139] Y 2 It is H, -CN, halogen, lower alkyl or lower alkoxy;

[0140] Each R 5 Independently, it is a halogen group, -CN, lower alkyl group, lower alkenyl group, lower alkynyl group, lower haloalkyl group, carbocyclic group, heterocyclic group, carbocyclic alkyl group, heterocyclic alkyl group, -OR group. 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 ;

[0141] n is 0-5; and

[0142] R a and R b Each is independently H, a lower alkyl group, or a lower haloalkyl group;

[0143] Where R 5 R a and Rb Each is independently and optionally substituted with one or more halogen groups, -CN, -OR', -NR'R”, =O, =S, -S(O)2R' or -S(O)2OR', wherein R' and R” are each independently H, a lower alkyl group or a lower haloalkyl group.

[0144] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein A is a carbocyclic ring optionally substituted with one or more halogen groups, lower alkyl groups, lower haloalkyl groups, -CN, -OR', -NR'R”, =O, =S, -S(O)2R', or -S(O)2OR', wherein R' and R” are each independently H, a lower alkyl group, or a lower haloalkyl group. In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein A is an aryl group optionally substituted with one or more halogen groups, lower alkyl groups, lower haloalkyl groups, -CN, -OR', -NR'R”, =O, =S, -S(O)2R', or -S(O)2OR', wherein R' and R” are each independently H, a lower alkyl group, or a lower haloalkyl group.

[0145] In one embodiment, a compound having the structure of any one of formulas (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein A is a phenyl group optionally substituted with one or more halogen groups, lower alkyl groups, lower haloalkyl groups, -CN, -OR', -NR'R”, =O, =S, -S(O)2R', or -S(O)2OR', wherein R' and R” are each independently H, a lower alkyl group, or a lower haloalkyl group. In one embodiment, A is a phenyl group optionally substituted with one or more halogen groups. In one embodiment, A is a phenyl group optionally substituted with one or more -CN groups. In one embodiment, A is a phenyl group optionally substituted with one or more -OR' groups, wherein each R' is independently H, a lower alkyl group, or a lower haloalkyl group. In one embodiment, A is a phenyl group optionally substituted with one or more -OR', wherein each R' is independently H, a lower alkyl group, or a lower haloalkyl group, and at least one R' is H.

[0146] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein A is phenol or a substituted phenol. In another embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein A is:

[0147]

[0148] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein A is a heterocycle optionally substituted with one or more halogen groups, lower alkyl groups, lower haloalkyl groups, -CN, -OR', -NR'R”, =O, =S, -S(O)2R', or -S(O)2OR', wherein R' and R” are each independently H, a lower alkyl group, or a lower haloalkyl group. In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof is provided, wherein A is a heteroaryl group optionally substituted with one or more halogen groups, lower alkyl groups, lower haloalkyl groups, -CN, -OR', -NR'R”, =O, =S, -S(O)2R', or -S(O)2OR', wherein R' and R” are each independently H, a lower alkyl group, or a lower haloalkyl group. In one embodiment, A is triazine, pyridinyl, pyrimidinyl, pyrazinyl, triazine, pyrroloyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl.

[0149] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof is provided, wherein A is:

[0150] as well as

[0151] R 6 It can be H or -CN.

[0152] In one embodiment, a compound having the structure of any one of formula (IV), formula (V) or formula (VI) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope or salt thereof is provided, wherein R 3 For H.

[0153] In one embodiment, a compound having the structure of any one of formula (IV), formula (V) or formula (VI) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope or salt thereof is provided, wherein R 3 It is a carbon ring. In one embodiment, R 3 It is cyclopropyl or cyclobutyl.

[0154] In one embodiment, a compound having the structure of any one of formula (IV), formula (V) or formula (VI) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope or salt thereof is provided, wherein R 3 It is a lower alkyl group. In one embodiment, R 3 It can be methyl, ethyl, or propyl.

[0155] In one embodiment, a compound having the structure of any one of formula (IV), formula (V) or formula (VI) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope or salt thereof is provided, wherein R 3 For -OR a In one implementation, R a For H. In one implementation, R a It is a lower alkyl group. In one embodiment, R a It is a lower methyl group.

[0156] In one embodiment, a compound having the structure of any one of formula (IV), formula (V) or formula (VI) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope or salt thereof is provided, wherein R 4 For H.

[0157] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 1It is a lower alkyl group. In one embodiment, X 1 It is a methyl group.

[0158] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 1 It is a halogen group. In one embodiment, X 1 It is Cl or Br. In one implementation, X 1 For Cl. In one implementation, X 1 It is Br.

[0159] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 1 It is a lower haloalkyl group. In one embodiment, X 1 It can be -CH2F, -CHF2, or -CF3. In one implementation, X 1 It is -CF3.

[0160] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 1 It is a lower alkenyl group. In one embodiment, X 1 It is vinyl or isopropyl.

[0161] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 2 It is a lower alkyl group. In one embodiment, X 2 It is a methyl group.

[0162] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 2 It is a halogen group. In one embodiment, X 2 It is Cl or Br. In one implementation, X 2 For Cl, in one implementation, X 2 It is Br.

[0163] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 2 It is a lower haloalkyl group. In one embodiment, X 2 It is -CHF2 or -CF3. In one implementation, X 2 It is -CF3.

[0164] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 2 It is a lower alkenyl group. In one embodiment, X 2 It is vinyl or isopropyl.

[0165] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 It is a lower alkyl group. In one embodiment, R 5 R' is a lower alkyl group substituted with -OR'. In one embodiment, R' is H. In one embodiment, R' is a lower alkyl group. In one embodiment, R' is methyl, ethyl, or propyl.

[0166] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 It is a lower haloalkyl group. In one embodiment, at least one R 5 It is -CH2F, -CHF2, or -CF3. In one embodiment, at least one R 5 It is -CF3.

[0167] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 For -OR a In one implementation, R a It is a lower alkyl group. In one embodiment, R a It is methyl, ethyl, or propyl. In one embodiment, R... a It is a lower haloalkyl group. In one embodiment, R a It can be either -CHF2 or -CF3.

[0168] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 -C(O)R a In one implementation, R a It is a lower alkyl group. In one embodiment, R a It can be methyl, ethyl, or propyl.

[0169] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 For -NR a C(O)R b In one implementation, R a For H and R bIt is a lower alkyl group. In one embodiment, R a For H and R b It is methyl, ethyl, or propyl. In one embodiment, R... a For H and R b It is a methyl group.

[0170] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 -C(O)OR a In one implementation, R a It is a lower alkyl group. In one embodiment, R a It is methyl, ethyl, or propyl. In one embodiment, R... a It is methyl. In one embodiment, R a It is an ethyl group.

[0171] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 is -S(O)2R a In one implementation, R a It is a lower alkyl group. In one embodiment, R a It is methyl, ethyl, or propyl. In one embodiment, R... a It is a methyl group.

[0172] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 It is a halogen group. In one embodiment, at least one R 5 It is F.

[0173] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 For -CN.

[0174] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 It is a halogen. In one embodiment, Y 1 For F. In one implementation, Y 1 It is Cl.

[0175] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 For -CN.

[0176] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 It is a lower alkyl group. In one embodiment, Y 1 It is methyl, ethyl, or propyl. In one embodiment, Y... 1 It is a methyl group.

[0177] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 It is a lower alkoxy group. In one embodiment, Y 1 It is methoxy or ethoxy. In one embodiment, Y... 1 It is a methoxy group.

[0178] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 For H.

[0179] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 2 It is a halogen. In one embodiment, Y 2 For F, in one implementation, Y 2 It is Cl.

[0180] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 2 For -CN.

[0181] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 2 It is a lower alkyl group. In one embodiment, Y 2 It is methyl, ethyl, or propyl. In one embodiment, Y... 2 It is a methyl group.

[0182] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 2 It is a lower alkoxy group. In one embodiment, Y 2 It is methoxy or ethoxy. In one embodiment, Y... 2 It is a methoxy group.

[0183] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 2 For H.

[0184] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 For F and Y 2 For H.

[0185] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 For Cl and Y 2 For H.

[0186] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 For -CN and Y 2 For H.

[0187] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 It is a lower alkyl group and Y 2 For H. In one implementation, Y 1 It is methyl and Y 2 For H.

[0188] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 It is a lower alkoxy group and Y 2 For H. In one implementation, Y 1 It is methoxy and Y 2 For H.

[0189] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 For H and Y 2 It is F.

[0190] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 For H and Y 2 It is Cl.

[0191] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 For H and Y 2 For -CN.

[0192] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 For H and Y 2 It is a lower alkyl group. In one embodiment, Y 1 For H and Y 2 It is a methyl group.

[0193] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 For H and Y 2 It is a lower alkoxy group. In one embodiment, Y 1 For H and Y 2 It is a methyl group.

[0194] In one embodiment, a compound having the structure of any one of formula (I), (II), (III), (IV), (V), (VI), (VII), or (VIII) is provided, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 For F and Y 2 It is F.

[0195] Representative compounds of formula (I) and formulas (II) through (VIII) that are applicable include the compounds listed in Table 1 below, as well as their pharmaceutically acceptable salts. For this purpose, representative compounds are identified herein by their respective “compound number,” which is sometimes abbreviated as “compound No.,” “Cmpd. No.,” or “No..”

[0196] Table 1 Representative Compounds

[0197]

[0198]

[0199] The term "isomer" is used herein to encompass all chiral, diastereomeric, or racemic forms of a structure, unless a specific stereochemical or isomeric form is specifically indicated. Such compounds can be optical isomers enriched or resolved at any level at any or all asymmetric atoms as clearly seen from the description. Racemic mixtures and diastereomeric mixtures, as well as individual optical isomers, can be synthesized to be substantially free of their enantiomeric or diastereomeric counterparts, and these are all within the scope of certain embodiments of the invention. Isomers resulting from the presence of a chiral center comprise a pair of non-overlapping isomers referred to as "enantiomers." A single enantiomer of a pure compound is optically active (i.e., capable of rotating about the plane of plane-polarized light and referred to as R or S).

[0200] "Separated optical isomer" refers to a compound that has been substantially purified from a corresponding optical isomer of the same formula. For example, the separated isomer may be at least about 80%, at least 80%, or at least 85% pure by weight. In other embodiments, the separated isomer is at least 90%, at least 98%, or at least 99% pure by weight.

[0201] "Essentially enantiomers or diastereomers" simply means that the enantiomer is enriched at least about 80% relative to another enantiomer or diastereomer, and more specifically, more than 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, or 99.9%.

[0202] The terms "racemate" and "racemic mixture" refer to an equal mixture of two enantiomers. Racemates are marked with "(±)" because they are not optically active (i.e., they do not cause plane-polarized light to rotate in either direction because their constituent enantiomers cancel each other out). All compounds marked with an asterisk (*) adjacent to a tertiary or quaternary carbon are optically active isomers, which can be purified from their respective racemates and / or synthesized by appropriate chiral synthesis.

[0203] "Tautomers" refer to each of two or more structural isomers that readily interconvert in equilibrium through the migration of atoms or groups within a molecule. Tautomers are typically produced by proton transfer from one atom of a molecule to another atom of the same molecule. This invention includes tautomers of compounds of formula (I). For example, the tautomers of isoxazolol and hydroxytriazinone are shown below:

[0204]

[0205]

[0206] "Hydrate" is a compound that exists in combination with water molecules. This combination may include stoichiometric amounts of water, such as monohydrate or dihydrate, or may include random amounts of water. When used herein, "hydrate" refers to a solid form; that is, for a compound in aqueous solution, although it may be hydrated, it is not the hydrate referred to by the term as used herein.

[0207] "Solvate" is similar to hydrate, except that a solvent other than water is present. For example, methanol or ethanol can form an "alcohol," which can be stoichiometric or non-stoichiometric. When used herein, "solvate" refers to a solid form; that is, for a compound in a solvent solution, although it may be solvated, it is not a solvate as referred to herein.

[0208] "Isotope" refers to an atom having the same number of protons but different numbers of neutrons, and the isotopes of compounds of formula (I) include any such compound in which one or more atoms are replaced by isotopes of that atom. For example, carbon-12—the most common form of carbon—has six protons and six neutrons, while carbon-13 has six protons and seven neutrons, and carbon-14 has six protons and eight neutrons. Hydrogen has two stable isotopes: deuterium (one proton and one neutron) and tritium (one proton and two neutrons). Fluorine has many isotopes, with fluorine-19 having the longest half-life. Therefore, the isotopes of compounds having the structure of formula (I) include, but are not limited to, compounds of formula (I) in which one or more carbon-12 atoms are replaced by carbon-13 and / or carbon-14 atoms, one or more hydrogen atoms are replaced by deuterium and / or tritium, and / or one or more fluorine atoms are replaced by fluorine-19.

[0209] A "salt" generally refers to an organic compound in its ionic form, such as a carboxylic acid or amine, combined with a counterion. For example, a salt formed between an acid in its anionic form and a cation is called an "acid addition salt." Conversely, a salt formed between a base in its cationic form and an anion is called a "base addition salt."

[0210] The term “pharmaceutically acceptable” refers to a pharmaceutical agent that has been approved for human use and is generally non-toxic. For example, the term “pharmaceutically acceptable salt” refers to a non-toxic inorganic acid addition salt or organic acid addition salt and / or base addition salt (see, for example, Lit et al., Salt Selection for Basic Drugs, Int. J. Pharm., 33, 201-217, 1986) (which is incorporated herein by reference).

[0211] Pharmaceutically acceptable base addition salts of the compounds of the present invention include, for example, metal salts, including alkali metal salts, alkaline earth metal salts, and transition metal salts, such as calcium salts, magnesium salts, potassium salts, sodium salts, and zinc salts. Pharmaceutically acceptable base addition salts also include organic salts derived from basic amines such as N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylreduced glucosamine), trihydroxymethylmethylamine, and procaine.

[0212] Pharmaceutically acceptable acid addition salts can be prepared from inorganic acids or organic acids. Examples of inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids can be selected from aliphatic, cyclic aliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic acid, and sulfonic acid categories. Examples include formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, aspartic acid, glutamic acid, benzoic acid, anthranilic acid, 4-hydroxybenzoic acid, phenylacetic acid, mandelic acid, hippuric acid, malonic acid, oxalic acid, pamoic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, pantothenic acid, trifluoromethanesulfonic acid, 2-hydroxyethanesulfonic acid, p-toluenesulfonic acid, sulfanilic acid, cyclohexylsulfamic acid, stearic acid, alginic acid, β-hydroxybutyric acid, salicylic acid, galactopyric acid, and galacturonic acid.

[0213] Although pharmaceutically unacceptable salts are not typically used as drugs, they can be used as intermediates, for example, in the synthesis of compounds having the structure of Formula I, such as in their purification by recrystallization.

[0214] In some embodiments, the present invention provides a pharmaceutical composition comprising the compound of the present invention and at least one pharmaceutically acceptable carrier, diluent, or excipient. For example, the active compound is typically mixed with, diluted by, or encapsulated within a carrier, which may be in the form of an ampoule, capsule, pouch, paper, or other container. When the carrier is mixed with the active compound, or when the carrier acts as a diluent, it can be a solid, semi-solid, or liquid material that serves as a medium, excipient, or conduit for the active compound. The active compound may be adsorbed onto a particulate solid carrier, such as a pouch. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, kaolin, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, gum arabic, lower alkyl ethers of stearic acid or cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid monoglycerides and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethyl cellulose, and polyvinylpyrrolidone. Similarly, the carrier or diluent may comprise any sustained-release material known in the art, alone or in mixture with waxes, such as glyceryl monostearate or glyceryl distearate.

[0215] 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, tautomers, hydrates, solvates, isotopes, or salts, formulated together with a pharmaceutically acceptable carrier, and may also contain other additives, manufactured or sold with the approval of a government regulatory agency as part of a treatment regimen for a mammalian disease. For example, pharmaceutical compositions may be formulated as follows: for example, in unit dosage forms (e.g., tablets, capsules, lozenges, capsule tablets, or syrups) for oral administration; for topical administration (e.g., as creams, gels, lotions, or ointments); for intravenous administration (e.g., as a sterile solution without particulate emboli in a solvent system suitable for intravenous use); or any other formulation described herein. The routine procedures and ingredients used for selecting and preparing suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st edition, edited by Gennaro, Lippencott Williams & Wilkins (2005) and in The United States Pharmacopeia: The National Formulary (USP 36NF31), published in 2013.

[0216] As used herein, the term "pharmaceutically acceptable carrier" means any component other than the disclosed compound or its pharmaceutically acceptable isomers, racemates, tautomers, hydrates, solvates, isotopes, or salts (e.g., a carrier capable of suspending or dissolving the active compound) and having non-toxic and non-inflammatory properties in patients. Excipients may include, for example: anti-adhesives, antioxidants, adhesives, coatings, compression aids, disintegrants, dyes (pigments), softeners, emulsifiers, fillers (diluents), film-forming agents or coatings, flavorings, fragrances, flow aids (flow enhancers), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or hydrated water. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic value), calcium stearate, croscarmellose, croscarmellose, citric acid, crospovidone, cysteine, ethyl cellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silica, sodium carboxymethyl cellulose, sodium citrate, sodium glycolate starch, sorbitol, starch (corn), stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0217] The formulation may be mixed with adjuvants that do not react harmfully with the active compound. Such adjuvants may include wetting agents, emulsifiers and suspending agents, salts that affect osmotic pressure, buffers and / or coloring substances, preservatives, sweeteners or flavorings. If desired, the composition may also be sterilized.

[0218] The route of administration can be any route by which the active compound of the present invention is efficiently delivered to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, percutaneous, or parenteral, including intravenous, subcutaneous, and / or intramuscular administration. In one embodiment, the route of administration is oral.

[0219] Dosage can be administered once daily or more than once daily, such as twice or three times daily. Alternatively, if the prescribing physician deems it desirable, or if it is desirable according to the prescribing information for the drug, then a less frequent dosing, such as every other day or weekly, is possible. Dosage regimens include, for example, dose titration to a level necessary for or useful to the indication being treated, thereby adapting the patient's body to treatment, minimizing or avoiding treatment-related unwanted side effects, and / or maximizing the therapeutic effect of the compounds of the invention. Other dosage forms include sustained-release or controlled-release forms. Suitable dosing regimens and / or dosage forms include, for example, those set forth in the latest edition of the Physicians' Desk Reference, which is incorporated herein by reference.

[0220] In another embodiment, a method is provided for preparing a composition of the compounds described herein, the method comprising formulating the compounds of the invention together with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the method may further include the step of formulating the composition into tablets or capsules. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the method further includes the step of lyophilizing the composition to form a lyophilized preparation.

[0221] In another embodiment, a method for treating a subject suffering from a neurodegenerative disease is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the neurodegenerative disease is a demyelinating disease. In another embodiment, the demyelinating disease is a chronic demyelinating disease. In yet another embodiment, the demyelinating disease is or is associated with an X-linked genetic disorder, leukodystrophy, dementia, tau proteinosis, or ischemic stroke. In another implementation, the demyelinating disease is or is associated with the following diseases: adult Refsum disease, Alexander disease, Alzheimer's disease, Balo concentric sclerosis, Canavan disease, central pontine myelinolysis (CPM), cerebral palsy, cerebrotendineous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic's syndrome, diffuse demyelinating sclerosis, encephalomyelitis, idiopathic inflammatory demyelinating disease (IIDD), infantile Refsum disease, Krabbe disease, Leber hereditary optic neuropathy, Marburg multiple sclerosis, and Marchiafava-Bignami. Demyelinating diseases include: metachromatic leukodystrophy, multifocal motor neuropathy, paraproteinemic demyelinating polyneuropathy, Pelizaeus-Merzbacher disease, peroneal muscular atrophy, progressive multifocal leukodystrophy, transverse myelitis, tropical spastic paraplegia, van der Knaap disease, or Zellweger syndrome. In one implementation, a demyelinating disease is one of the following or is associated with: multiple sclerosis, MCT8 deficiency, X-linked adrenoleukodystrophy (ALD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia, or lacunar stroke.

[0222] As used in this article, the term “neurodegenerative disease” refers to any type of disease characterized by progressive deterioration of the nervous system.

[0223] As used herein, the term "demyelinating disease" refers to any disease or medical condition of the nervous system in which the myelin sheath is damaged or lost, or in which the growth or development of the myelin sheath is impaired. Demyelination inhibits the transmission of signals in the affected nerves, resulting in impairment of sensory, motor, cognitive, or other functions involving the nerves. Demyelinating diseases have many different causes and can be genetic or acquired. In some cases, demyelinating diseases are caused by infectious agents, autoimmune responses, toxic agents, or traumatic injury. In others, the cause of a demyelinating disease is unknown ("idiopathic") or develops from a combination of factors.

[0224] As used in this article, the term "leukodystrophy" refers to a group of diseases that affect the growth or development of myelin.

[0225] As used herein, the term "leukoencephalopathy" refers to any one of a group of diseases that affect the white matter of the brain; it may specifically refer to several diseases, for example, including "leukoencephalopathy with loss of white matter" and "toxic leukoencephalopathy." Leukoencephalopathy is a disease similar to leukodystrophy.

[0226] As used in this article, the term "tau protein disease" refers to tau protein-related conditions or illnesses, such as Alzheimer's disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), Pick's disease (PiD), argyrophilic grain disease (AGD), frontotemporal dementia and Parkinson's syndrome associated with chromosome 17 (FTDP-17), Parkinson's disease, stroke, traumatic brain injury, mild cognitive impairment, etc.

[0227] As used herein, the terms “multiple sclerosis” and “MS” refer to a slowly progressive central nervous system disease characterized by diffuse demyelinating plaques in the brain and spinal cord, resulting in a variety of neurological symptoms and signs, typically with remissions and exacerbations. The etiology of MS is unknown, but an immune abnormality is suspected. An increased familial incidence suggests a genetic predisposition, with women being slightly more susceptible than men. Symptoms of MS include weakness, lack of coordination, paresthesia, speech disturbances, and visual disturbances, most commonly diplopia. More specific signs and symptoms depend on the location of the lesions and the severity and destructiveness of the inflammatory and sclerotic process. Relapsing-remitting multiple sclerosis (RRMS) is the clinical course of MS characterized by well-defined acute exacerbations with complete or partial remission and no disease progression between exacerbations. Secondary progressive multiple sclerosis (SPMS) is the clinical course of MS that initially presents as relapsing-remitting, then progresses at varying rates, possibly with occasional relapses and mild remissions. Primary progressive multiple sclerosis (PPMS) initially presents as a progressive condition. Clinically isolated syndromes are the first neurological seizures caused by inflammation / demyelinating at one or more sites in the central nervous system. Progressive relapsing multiple sclerosis (PRMS) is a rare form of MS (~5%) characterized by a steadily worsening disease state from onset, with acute relapses but no remission.

[0228] In yet another embodiment, a method for treating a subject suffering from an X-linked genetic disorder is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the X-linked genetic disorder is MCT8 deficiency or X-linked adrenoleukodystrophy (ALD).

[0229] In another embodiment, a method for treating a subject suffering from leukodystrophy is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof. In one embodiment, leukodystrophy is adrenoleukodystrophy (ALD), adrenospinal neuropathy (AMN), cerebral adrenoleukodystrophy (cALD), metachromatic leukodystrophy (MLD), Canavan disease, or Clapham disease (globose cell leukodystrophy). As used herein, the term "adrenospinal neuropathy" or "AMN" refers to an adult variant of X-linked adrenoleukodystrophy characterized by a mutation in the ABCD1 gene, which results in impaired peroxisome function, accompanied by accumulation and demyelination of very long-chain fatty acids (VLCFAs).

[0230] In one embodiment, a method for treating a subject suffering from tau proteinosis is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof. In one embodiment, tau proteinosis is Alzheimer's disease, frontotemporal dementia, primary age-related tau proteinosis (PART), Pick's disease, or frontotemporal dementia and Parkinson's syndrome linked to chromosome 17 (FTDP-17).

[0231] In yet another embodiment, a method for treating a subject suffering from ischemic stroke is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the ischemic stroke is a lacunar stroke (also referred to as "lacunar infarction"). In another embodiment, the method of the present invention is used to treat a subject suffering from lacunar stroke syndrome (LACS).

[0232] In another embodiment, a treatment is provided for patients with adult-onset Rivesom disease, infantile Rivesom disease, Alexander disease, Alzheimer's disease, Barlow concentric sclerosis, Canavan disease, central pontine myelinolysis (CPM), cerebral palsy, cerebral tendinitis xanthomas, chronic inflammatory demyelinating polyneuropathy (CIDP), Dweck syndrome, diffuse demyelinating sclerosis, encephalomyelitis, idiopathic inflammatory demyelinating disease (IIDD), Krabby disease, Lieber's hereditary optic neuropathy, leukodystrophy, Marburg multiple sclerosis, Machapawa-Binami disease, metachromatic leukodystrophy (MLD), and other conditions. A method of administering to a subject a subject with focal motor neuropathy (MMN), multiple sclerosis (MS), paraproteinemic demyelinating polyneuropathy, Perizoise-Metzbach disease (PMD), progressive multifocal leukoencephalopathy (PML), tropical spastic paraplegia (TSP), X-linked adrenoleukodystrophy (X-ALD, ALO, or X-linked ALO) or Zieweger syndrome, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

[0233] In one embodiment, the demyelinating disease is multiple sclerosis. In another embodiment, the demyelinating disease is X-linked adrenoleukodystrophy (ALD).

[0234] In another embodiment, a method is provided for treating a subject suffering from amyotrophic lateral sclerosis (ALS), the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the ALS is sporadic or familial ALS, or ALS with a superoxide dismutase-1 mutation.

[0235] In one embodiment, a method is provided for treating a subject suffering from a medical condition associated with increased TGF-β activity, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the medical condition associated with increased TGF-β activity is a fibrotic disease. In another embodiment, the fibrotic disease is or is associated with non-alcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis (IPF), systemic scleroderma, or Allport syndrome. As used herein, the term "Allport syndrome" refers to a hereditary condition caused by a mutation in the a3a4a5(IV) collagen network gene that results in a structural defect in the glomerular basement membrane (GBM) early in development, subsequently leading to disruption of the filtration barrier, renal fibrosis, and the manifestation of renal failure.

[0236] As used herein, the term "fibrotic disease" refers to a condition, disease, or symptom that is readily treatable by the application of compounds with antifibrotic activity. Fibrotic diseases include, but are not limited to, pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis of known etiologies, liver fibrosis, and kidney fibrosis. Other exemplary fibrotic diseases include musculoskeletal fibrosis, myocardial fibrosis, postoperative adhesions, scleroderma, glaucoma, and skin lesions such as keloids.

[0237] In another embodiment, a method is provided for treating a subject with liver disease of NASH, NAFLD, NAFLD with hyperlipidemia, alcoholic liver disease / alcoholic steatohepatitis, liver fibrosis associated with viral infection (HBV, HCV), fibrosis associated with cholestatic diseases (primary biliary cholangitis, primary sclerosing cholangitis), (familial) hypercholesterolemia, dyslipidemia, hereditary lipid disorders, cirrhosis, alcohol-induced fibrosis, hemochromatosis, glycogen storage disease, α-1 antitrypsin deficiency, autoimmune hepatitis, Wilson's disease, Crigler-Najjar syndrome, lysosomal acid lipase deficiency, or cystic fibrosis, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

[0238] In another embodiment, a method is provided for treating a subject suffering from Allport syndrome, diabetic nephropathy, FSGS, fibrosis associated with IgA nephropathy, chronic kidney disease (CKD), post-AKI, HIV-related CKD, chemotherapy-induced CKD, nephrotoxic agent-related CKD, renal systemic fibrosis, tubulointerstitial fibrosis, glomerulosclerosis, or polycystic kidney disease (PKD), the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

[0239] In another embodiment, a treatment is provided for patients with IPF, ILD, pulmonary fibrosis, pulmonary fibrosis associated with autoimmune diseases such as rheumatoid arthritis, scleroderma, or Sjogren's syndrome, asthma-related 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 lymphoid interstitial pneumonia, idiopathic pleural parenchymal fibroelastosis, unclassified idiopathic interstitial pneumonia, and allergies. A method of administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemic mixture, tautomer, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.

[0240] In another embodiment, a method is provided for treating a subject suffering from scleroderma / systemic sclerosis, graft-versus-host disease, hypertrophic scars, keloids, renal systemic fibrosis, porphyria cutanea tarda, restrictive dermatitis, Dupuytren's contracture, dermal fibrosis, renal systemic fibrosis / renal fibrotic dermatitis, mixed connective tissue disease, sclerosing myxedema, eosinophilic fasciitis, fibrosis caused by exposure to chemicals or physical factors, GvHD-induced fibrosis, adult-onset sclerosis, liposcleroderma, or progeria-like conditions (progeria, acroprogeria, Werner's syndrome), the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

[0241] In another embodiment, a method is provided for treating a subject suffering from atrial fibrosis, endocardial myocardial fibrosis, cardiac fibrosis, atherosclerosis, recurrent stenosis, or joint fibrosis, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

[0242] In another embodiment, a method is provided for treating a subject suffering from mediastinal fibrosis, myelofibrosis, post-polycythemia vera myelofibrosis, or post-essential thrombocythemia myelofibrosis, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

[0243] In another embodiment, a method is provided for treating a subject suffering from Crohn's disease, retroperitoneal fibrosis, intestinal fibrosis, fibrosis in inflammatory bowel disease, ulcerative colitis, GI fibrosis attributed to cystic fibrosis, or pancreatic fibrosis attributed to pancreatitis, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

[0244] In another embodiment, a method is provided for treating a subject suffering from endometrial fibrosis, uterine fibroids, or Peyronie's disease, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

[0245] In another embodiment, a method is provided for treating a subject suffering from macular degeneration, diabetic retinopathy, retinal fibrovascular disease, or vitreoretinopathy, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, or a pharmaceutical composition thereof.

[0246] In another embodiment, a method is provided for treating a subject suffering from trauma-related scarring (surgical complications, chemotherapy-induced fibrosis, radiation-induced fibrosis), the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I) or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.

[0247] As used herein, the term "administration" means providing a compound, a prodrug of a compound, or a pharmaceutical composition comprising such compound or prodrug as described herein. The compound or composition may be administered to the subject by another person or may be administered by the subject himself / herself. Non-limiting examples of routes of administration are oral, parenteral (e.g., intravenous), or topical.

[0248] 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," "treat," and "treating" in relation to a disease, pathological condition, or symptom also refer to any observable beneficial effect of treatment. For example, a beneficial effect can be demonstrated by: delayed onset of clinical symptoms of the disease in susceptible subjects; a reduction in the severity of some or all of the clinical symptoms of the disease; slower progression of the disease; a reduction in the number of relapses of the disease; an improvement in the overall health or well-being of the subject; or other parameters specific to a particular disease known in the art. Preventive treatment is administered to subjects who do not exhibit signs of disease or only exhibit early signs, with the aim of reducing the risk of developing pathology. Therapeutic treatment is administered to subjects after the development of signs and symptoms of the disease.

[0249] As used herein, the term "object" refers to an animal (e.g., a mammal, such as a human). An object treated according to the methods described herein may be a subject diagnosed with a neurodegenerative disease involving demyelination, insufficient myelination, or incomplete myelination, such as a subject diagnosed with multiple sclerosis or cerebral palsy, or a subject at risk of developing such a condition. Diagnosis can be made by any method or technique known in the art. Those skilled in the art will understand that an object to be treated according to this disclosure may have already undergone standard testing or may be identified as at risk without examination due to the presence of one or more risk factors associated with the disease or condition.

[0250] As used herein, the term "effective amount" refers to the amount of a pharmaceutical agent sufficient to achieve the desired effect in a subject treated with the specified agent. Ideally, an effective amount of a pharmaceutical agent is an amount sufficient to inhibit or treat a disease without causing substantial toxicity in the subject. The effective amount of a pharmaceutical agent will depend on the subject being treated, the severity of the disease, and the manner of administration of the pharmaceutical composition. Based on this disclosure, those skilled in the art will understand the methods for determining an effective amount of the disclosed compound sufficient to achieve the desired effect in a subject.

[0251] As used in this article, the term "chronic" refers to a medical condition or illness that persists or recurs frequently over time.

[0252] Compounds having the structures of formula (I) and formulas (II) to (VIII) can be synthesized using the synthetic techniques described in schemes 1-5 below, where applicable.

[0253] Therefore, the reactions, processes, and synthetic methods described herein are not limited to the specific conditions described in the following experimental sections, but are intended as guidance for those skilled in the art. For example, reactions can be carried out in any suitable solvent or other reagent to achieve the necessary transformations. Typically, suitable solvents are proton or aprotic solvents that do not substantially react with the reactants, intermediates, or products at the temperatures at which the reaction proceeds (i.e., temperatures ranging from freezing to boiling, or higher if the reaction is operated in a sealed vessel). A given reaction can be carried out in one solvent or a mixture of more than one solvent. Depending on the specific reaction, suitable solvents may be used for specific post-reaction processing.

[0254] Option 1

[0255]

[0256] The compounds of the present invention (A = aryl or heteroaryl) can be prepared according to the method described in Scheme 1. According to Scheme 1, an intermediate such as i containing an active leaving group (X = Br or I or OTf, etc.) can be coupled with an aryl-boronate or a heteroaryl-boronate such as ii under standard Suzuki coupling conditions to produce the compounds of the present invention.

[0257] Option 2

[0258]

[0259] For the specific case where A is an aryl group, the compounds of the present invention can be prepared according to the method of Scheme 2. According to Scheme 2, an intermediate such as i (X = Br or I or OTf, etc.) can be coupled with a substituted phenol-boric acid such as iii, using a palladium catalyst such as Pd(dppf)Cl2 or Pd(PPh3)2, with a base such as NaHCO3 or K2CO3, in a solvent such as THF or 1,4-dioxane and water or alcohol, optionally heated, to produce a hydroxyphenyl derivative iv.

[0260] Option 3

[0261]

[0262] The compounds of the present invention can also be prepared from intermediate i via stepwise assembly of heterocyclic moieties, as shown in Scheme 3. According to Scheme 3, intermediate i can be converted to cinnamic ester vi by coupling with acrylate v using a palladium catalyst. Oxidation of the olefinic moiety of vi provides a β-keto ester vii. Condensation of vii with hydrazine viiii or hydroxylamine yields the corresponding hydroxypyrazole (ix, X = NR). 303) or hydroxyisoxazole (ix, X=O). Alternatively, 7 can be with urea (x, X=O) or amidine (x, X=NR). 304 Condensation to generate hydroxypyrimidine xi.

[0263] Option 4

[0264]

[0265] When A is an N-linked heterocycle, the compounds of the present invention can be prepared according to the method of Scheme 4. According to Scheme 4, aniline such as xii can be reacted with a bifunctional acylating agent xiii to directly provide heterocycle A. Alternatively, aniline xii can first be reacted with a carbonyl equivalent such as xiv or with an oxidizing agent to generate an intermediate such as xv, and then condensed with a bifunctional acylating agent such as xiii to provide heterocycle A.

[0266] Option 5

[0267]

[0268] When A is 1,2,4-triazine, the compounds of the present invention can be prepared according to the method of Scheme 5. According to Scheme 5, aniline such as xii is first N-nitrated using a nitrosating agent such as sodium nitrite in a solvent such as water or ethanol. The intermediate heavy nitrogen salt compound xvi is reacted with a bifunctional acylating agent xvii such as N-(2-cyanoacetyl)carbamate in a solvent system including water or alcohol and a base such as pyridine or triethylamine, and heated if necessary, to produce the 1,2,4-triazine product such as xviii.

[0269] Example

[0270] The invention is further illustrated by the following examples. These examples are non-limiting and represent various aspects of the invention only. The solid and dashed wedges within the structures disclosed herein illustrate relative stereochemistry; absolute stereochemistry is described only in specific illustration or depiction.

[0271] General methods

[0272] All reagents not described in the experimental section are either commercially available, known compounds, or can be formed by those skilled in the art from known compounds using known methods.

[0273] The compounds and intermediates produced by the method according to the invention may require purification. Purification of organic compounds is well known to those skilled in the art, and there are several ways to purify the same compound. In some cases, purification may not be necessary. In some cases, the compound can be purified by crystallization. In some cases, impurities can be removed by stirring with a suitable solvent.

[0274] In some cases, compounds can be purified by chromatography, particularly rapid column chromatography, using specially designed or pre-packed silica gel columns and eluents, such as various gradients of solvents, including heptane, diethyl ether, ethyl acetate, acetonitrile, and ethanol. In other cases, compounds can be purified using preparative HPLC (normal or reversed-phase) as described. Preparative HPLC purification by reversed-phase HPLC is performed using various gradients of acetonitrile / TFA aqueous solutions, or equivalent HPLC systems such as methanol / ammonium acetate aqueous solutions.

[0275] The purification methods described herein can provide the compounds of the invention in salt form with sufficient basic or acidic functionality, for example, in the case of sufficiently basic compounds of the invention, trifluoroacetate or formate, or in the case of sufficiently acidic compounds of the invention, ammonium salts. Such salts can be converted to their free basic or free acidic forms, respectively, by various methods known to those skilled in the art, or used as salts in subsequent biological assays. It should be understood that the specific form of the isolated and described compounds of the invention is not necessarily the only form in which the compounds can be used in biological assays to quantify specific biological activities.

[0276] All starting materials and reagents are commercially available and should be used as is. Unless otherwise stated, the tests should be conducted at approximately room temperature using the stated solvents and a Bruker instrument running at 400 MHz. 1 1H nuclear magnetic resonance (NMR) spectroscopy. In all cases, the NMR data were consistent with the proposed structure. Characteristic chemical shifts (δ) were given in parts per million using conventional abbreviations for specifying the main peak: e.g., s, singlet; d, doublet; t, triplet; q, quartet; dd, double doublet; dt, double triplet; m, multiplet; br, broad peak.

[0277] Chemical names were generated using ChemDraw naming software (version 17.0.0.206) from PerkinElmer Informatics, Inc. In some cases, generally accepted names of commercially available reagents and commonly accepted acronyms were used instead of the names generated by the naming software.

[0278] Intermediate A1

[0279] Synthesis of N,N-dibenzyl-3,5-dichloroaniline (intermediate A1)

[0280]

[0281] Sodium hydride powder (8.5 g, 370 mmol) was added dropwise to a solution of 3,5-dichloroaniline (20.0 g, 123 mmol) in DMF (100 mL) at 0 °C to control gas evolution. The mixture was stirred at room temperature for 1 h. Benzyl bromide (63.3 g, 370 mmol) was added dropwise, and the resulting mixture was stirred overnight at room temperature. The mixture was slowly poured into water (1000 mL) with stirring, and then extracted with EtOAc (300 mL x 3). The combined organic layers were washed with water (500 mL x 2) and brine (300 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 100:1) to provide intermediate A1 (40.0 g, 94.7% yield) as a yellow solid.

[0282] TLC: Petroleum ether / EtOAc = 5 / 1 (v / v), Rf = 0.8

[0283] 1 H NMR: (400MHz, DMSO-d6) δ7.37-7.32(m,4H),7.28-7.23(m,6H),6.67(t,J=1.6Hz,1H),6.62(d,J=1.6Hz,2H),4.74(s,4H).

[0284] Intermediate A2

[0285] Synthesis of 2,6-dichloro-4-(dibenzylamino)benzaldehyde (intermediate A2)

[0286]

[0287] Phosphoryl chloride (56.8 g, 368 mmol) was added dropwise to DMF (200 mL) at 0 °C. The mixture was heated to room temperature and stirred for 1 h. A solution of intermediate A1 (42 g, 12 mmol) in DMF (50 mL) was added. The mixture was heated to 80 °C for 5 h. The reaction mixture was poured into ice water (1 L) and the pH was adjusted to ~7 with an aqueous solution of NaHCO3. The mixture was extracted with EtOAc (200 mL * 3). The combined organic layers were washed with water (200 mL) and brine (300 mL), dried over Na2SO4, and concentrated under vacuum to provide intermediate A2 (38.5 g, 84.7% yield) as a yellow solid.

[0288] TLC: Petroleum ether / EtOAc = 5 / 1 (v / v), Rf = 0.6

[0289] 1 H NMR: (400MHz, DMSO-d6) δ10.13(s,1H),7.40-7.36(m,4H),7.31–7.25(m,6H),6.80(s,2H),4.88(s,4H).

[0290] Intermediate A3

[0291] Synthesis of (2,6-dichloro-4-(dibenzylamino)phenyl)methanol (intermediate A3)

[0292]

[0293] At 5 °C, NaBH4 (2.7 g, 70 mmol) was added in portions to a solution of intermediate A2 (20 g, 54 mmol) in THF (100 mL). The mixture was stirred at room temperature for 2 h. Water (300 mL) was added and the resulting mixture was extracted with EtOAc (200 mL x 2). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, and concentrated under vacuum to provide intermediate A3 (20 g, 99% yield) as a yellow solid.

[0294] TLC: Petroleum ether / EtOAc = 5 / 1 (v / v), Rf = 0.7

[0295] 1 H NMR: (400MHz, DMSO-d6) δ 7.39–7.31 (m, 4H), 7.28–7.20 (m, 6H), 6.66 (s, 2H), 4.84 (t, J = 5.2Hz, 1H), 4.75 (s, 4H), 4.49 (d, J = 5.2Hz, 2H).

[0296] Intermediate A4

[0297] Synthesis of N,N-dibenzyl-3,5-dichloro-4-(chloromethyl)aniline (intermediate A4)

[0298]

[0299] SOCl2 (1.6 g, 13 mmol) was added to a solution of intermediate A3 (2.4 g, 6.5 mmol) in DCM (20 mL) at 0 °C. The mixture was stirred at room temperature for 2 h. The mixture was then concentrated under vacuum, and the crude intermediate A4 was used directly without further purification.

[0300] TLC: Petroleum ether / EtOAc = 10 / 1 (v / v), Rf = 0.5

[0301] Intermediate A5

[0302] Synthesis of N,N-dibenzyl-3-bromo-5-chloroaniline (intermediate A5)

[0303]

[0304] A solution of 3-bromo-5-chloroaniline (10.2 g, 49.4 mmol) and benzyl bromide (16.9 g, 98.8 mmol) in DMF (100 mL) was cooled to 0 °C. NaH (5.93 g of 60% oil dispersion, 148 mmol) was added in portions to control gas evolution. The reaction mixture was stirred overnight at room temperature. Water (500 mL) was carefully added; the resulting mixture was extracted with EtOAc (200 mL x 2). The combined organic phases were washed with water (500 mL) and brine (500 mL), dried over Na₂SO₄, and concentrated under vacuum. The residue was washed with EtOAc / hexane: 1 / 10 (50 mL); the resulting solid was filtered and dried to provide intermediate A5 (18.0 g, 94.2% yield) as a light brown solid.

[0305] TLC: Petroleum ether / EtOAc = 2 / 1 (v / v), Rf = 0.6

[0306] Intermediate A6

[0307] Synthesis of 2-bromo-6-chloro-4-(dibenzylamino)benzaldehyde (intermediate A6)

[0308]

[0309] POCl3 (11.9 g, 77.6 mmol) was added dropwise to a solution of intermediate A5 (10.0 g, 25.9 mmol) in DMF (80 mL). The reaction mixture was stirred overnight at 90 °C. The reaction mixture was cooled to room temperature and poured into NaHCO3 (aqueous solution) (400 mL); the resulting mixture was extracted with EtOAc (100 mL x 2). The combined organic phases were washed with brine (400 mL), dried over Na2SO4, and concentrated under vacuum; the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 30 / 1 to 5 / 1) to provide intermediate A6 (5.0 g, 47% yield) as a light brown solid.

[0310] TLC: Petroleum ether / EtOAc = 2 / 1 (v / v), Rf = 0.15

[0311] Intermediate A7

[0312] Synthesis of (2-bromo-6-chloro-4-(dibenzylamino)phenyl)methanol (intermediate A7)

[0313]

[0314] A solution of intermediate A6 (5.5 g, 13 mmol) in THF (50 mL) was cooled to 0 °C, and NaBH4 (0.75 g, 20 mmol) was added in portions. The reaction was stirred at room temperature for 1 h, then quenched with water (60 mL) and extracted with EtOAc (20 mL x 2). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1 to 3 / 1) to provide intermediate A7 (2.5 g, 45% yield) as a yellow solid.

[0315] TLC: Petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.10

[0316] 1 H NMR: (400MHz, DMSO-d6)δ7.35(t,J=7.4Hz,4H),7.31–7.21(m,6H),6.82(d,J=2.5Hz, 1H), 6.69 (d, J = 2.6Hz, 1H), 4.81 (t, J = 5.1Hz, 1H), 4.74 (s, 4H), 4.52 (d, J = 5.1Hz, 2H).

[0317] Intermediate A8

[0318] Synthesis of N,N-dibenzyl-3-bromo-5-chloro-4-(chloromethyl)aniline (intermediate A8)

[0319]

[0320] A catalytic amount of DMF and SOCl2 (1.14 g, 9.60 mmol) was added to a solution of intermediate A7 (2.0 g, 4.8 mmol) in DCM (30 mL). The reaction mixture was stirred at room temperature for 30 min. The reaction mixture was concentrated under vacuum to provide intermediate A8 (2.0 g, 96% yield) as a yellow solid.

[0321] TLC: Petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.85

[0322] Intermediate A9

[0323] Synthesis of N-(3,5-dichloro-4-methylphenyl)acetamide (intermediate A9)

[0324]

[0325] Acetyl chloride (8.0 g, 102 mmol) was added to a solution of 3,5-dichloro-p-toluidine (15.0 g, 85.2 mmol) in DCM (30 mL). The mixture was stirred overnight at room temperature. The reaction mixture was diluted with EtOAc (100 mL), washed with brine (50 mL x 2), and dried over Na2SO4. The crude product was concentrated under vacuum to provide intermediate A9 (17.0 g, 91.5% yield) as a yellow solid.

[0326] TLC: petroleum ether / EtOAc = 3 / 1 (v / v), Rf = 0.16.

[0327] LCMS: RT=1.959min, [M-1]=216.0.

[0328] 1 H NMR: (400MHz, DMSO-d6) δ10.16(s,1H),7.66(s,2H),2.33(s,3H),2.04(s,3H).

[0329] Intermediate A10

[0330] Synthesis of N-(3,5-dichloro-2-fluoro-4-methylphenyl)acetamide (intermediate A10)

[0331]

[0332] A solution of intermediate A9 (7.0 g, 32 mmol) in acetonitrile (100 mL) was added with a selective fluoride reagent (11.4 g, 32.1 mmol). The mixture was stirred overnight at 80 °C. The reaction mixture was diluted with EtOAc (20 mL); the resulting mixture was washed with brine (10 mL x 2) and dried over Na2SO4. The crude product was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether / EtOAc = 100 / 1 to 10 / 1) to provide intermediate A10 (1.5 g, 20% yield) as a yellow solid.

[0333] TLC: Petroleum ether / EtOAc = 3 / 1 (v / v), Rf = 0.40

[0334] 1 H NMR: (400MHz, DMSO-d6) δ10.01(s,1H),8.05(d,J=7.2Hz,1H),2.38(s,3H),2.10(s,3H)

[0335] Intermediate A11

[0336] Synthesis of N-(4-(bromomethyl)-3,5-dichloro-2-fluorophenyl)acetamide (intermediate A11)

[0337]

[0338] A solution of intermediate A10 (800 mg, 3.39 mmol), N-bromosuccinimide (844 mg, 4.74 mmol), and benzoyl peroxide (246 mg, 1.02 mmol) in CCl4 (20 mL) was stirred at 50 °C for 15 min, and then stirred overnight at 100 °C. The crude product was concentrated under vacuum and purified by silica gel column chromatography (petroleum ether / EtOAc = 30 / 1 to 10 / 1) to provide intermediate A11 (880 mg, 82.4% yield) as a yellow solid.

[0339] TLC: petroleum ether / EtOAc = 3 / 1 (v / v), Rf = 0.44.

[0340] LCMS: RT=2.135min, [M+1]=313.9.

[0341] 1 H NMR: (400MHz, DMSO-d6) δ 10.19 (s, 1H), 8.21 (d, J = 6.8 Hz, 1H), 4.76 (d, J = 0.8 Hz, 2H), 2.13 (s, 3H).

[0342] Intermediate A12

[0343] Synthesis of 5-bromo-2-(bromomethyl)-1,3-dichlorobenzene (intermediate A12)

[0344] Benzoyl peroxide (495 mg, 2.04 mmol) and N-bromosuccinimide (7.3 g, 41 mmol) were added to a solution of 4-bromo-2,6-dichlorotoluene (9.8 g, 41 mmol) in CCl4 (100 mL) at room temperature. The mixture was stirred at 80 °C for 2 h. The mixture was filtered, and the filtrate was diluted with DCM (50 mL). Water (100 mL) was added, and the resulting mixture was extracted with DCM (50 mL x 2). The organic phase was washed with brine (100 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / EtOAc = 3 / 1) to provide intermediate A12 (12 g, 92% yield) as a pale yellow solid.

[0345] TLC: petroleum ether / EtOAc = 3 / 1 (v / v), Rf = 0.45.

[0346] 1 H NMR: (400MHz, DMSO-d6) δ7.87(s,2H),4.74(s,2H).

[0347] Intermediate B1

[0348] Synthesis of 4-iodo-2-isopropylphenol (intermediate B1)

[0349]

[0350] To a solution of 2-isopropylphenol (840 g, 6.17 mol, 1.0 equivalent) in methanol (10 L), NaI (925 g, 6.17 mol, 1.0 equivalent) and NaOH (247 g, 6.17 mol, 1.0 equivalent) were added. The mixture was cooled to -10 °C and sodium hypochlorite (9.6 L, 6.2 mol, 15% in water) was added dropwise over 4 h. The mixture was quenched by slowly adding 10% Na₂S₂O₃ aqueous solution (5 L) with stirring; the mixture was acidified with concentrated hydrochloric acid. The mixture was extracted with EtOAc (5 L x 2). The combined organic phases were washed with brine (5 L), dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 100 / 1 to 20 / 1) to provide intermediate B1 (800 g, 49% yield) as a slightly reddish oil.

[0351] 1 H NMR: (400MHz, DMSO-d6) δ 10.08 (s, 1H), 7.85 (d, J = 2.3Hz, 1H), 7.80 (dd, J = 8.4, 2.3Hz, 1H), 7.13 (d, J = 8.4Hz, 1H), 3.64 (m, 1H), 1.64 (d, J = 6.9Hz, 6H).

[0352] Intermediate B2

[0353] Synthesis of 4-iodo-2-isopropyl-1-(methoxymethoxy)benzene (intermediate B2)

[0354]

[0355] MOM-Cl (258 g, 3.24 mol, 3.0 equivalent) and Cs₂CO₃ (1.05 kg, 3.24 mol, 3.0 equivalent) were added to a solution of intermediate B1 (283 g, 1.08 mol, 1.0 equivalent) in DMF (3.28 L). The mixture was stirred at room temperature for 3 h under a N₂ atmosphere. The mixture was diluted with water (10 L) and extracted with EtOAc (5 L x 2). The combined organic layers were dried over Na₂SO₄ and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 100 / 1 to 30 / 1) to provide intermediate B2 (250 g, 76% yield) as a faint red oil.

[0356] 1H NMR: (400MHz, DMSO-d6) δ7.45 (d, J = 8.0 Hz, 2H), 6.87 (d, J = 8.0 Hz, 1H), 5.20 (s, 2H), 3.37 (s, 3H), 3.26-3.18 (m, 1H), 1.14 (d, J = 8.0Hz, 6H).

[0357] Intermediate B3

[0358] Synthesis of 3-fluoro-2-(prop-1-en-2-yl)phenol (intermediate B3)

[0359]

[0360] At room temperature, K₂CO₃ (55.3 g, 400 mmol) was added to a mixture of 2-bromo-3-fluorophenol (38.0 g, 200 mmol), isopropenyl-2-boron (pinacol ester) (50.4 g, 300 mmol), and Pd(dppf)Cl₂CH₂Cl₂ (16 g, 20 mmol) in 1,4-dioxane (300 mL) and water (30 mL). The mixture was heated to 70 °C and stirred overnight. The reaction mixture was cooled to room temperature, quenched with water (100 mL), and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine (200 mL), dried over Na₂SO₄, concentrated under vacuum, and purified by silica gel column chromatography (EtOAc / petroleum ether = 1 / 100 to 1 / 20) to provide intermediate B₃ (23 g, 76% yield) as a white solid.

[0361] TLC: EtOAc / petroleum ether = 1 / 10 (v / v), Rf = 0.55

[0362] 1 H NMR: (400MHz, DMSO-d6) δ9.72 (s, 1H), 7.06 (td, J = 8.4, 6.8 Hz, 1H), 6.66 (td, J =8.4,1.2Hz,1H),6.59(m,1.0Hz,1H),5.28(m,1H),4.89(m,1H),1.98(s,3H).

[0363] intermediate B4

[0364] Synthesis of 3-fluoro-2-isopropylphenol (intermediate B4)

[0365]

[0366] Pd / C (10%) (6.0 g) was added to a solution of intermediate B3 (23.0 g, 151 mmol) in MeOH (300 mL). The reaction mixture was stirred overnight at 60 °C. The mixture was cooled to 0 °C, filtered, and concentrated under vacuum to provide intermediate B4 (21 g, 90% yield) as a yellow oil.

[0367] TLC: EtOAc / petroleum ether = 1 / 50 (v / v), R f =0.25

[0368] 1 H NMR: (400MHz, DMSO-d6)δ9.69(s,1H),7.00–6.93(m,1H),6.65–6.60(m,1H), 6.52(ddd,J=10.8,8.0,1.2Hz,1H), 3.40(m,1H),1.25(dd,J=7.2,1.2Hz,6H).

[0369] Intermediate B5

[0370] 2-(3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborane (intermediate) Synthesis of B5)

[0371]

[0372] A mixture of (3-bromophenyl)-difluoromethyl ether (3.0 g, 13 mmol), bis(pinacol)diboron (6.8 g, 27 mmol), Pd(dppf)Cl2 (984 mg, 1.35 mmol), and KOAc (4.0 g, 40 mmol) in anhydrous 1,4-dioxane (30 mL) was stirred overnight at 85 °C. The resulting intermediate B5 solution was used directly without further purification.

[0373] TLC: EtOAc / petroleum ether = 1 / 2 (v / v), Rf = 0.2

[0374] Intermediate B6

[0375] Synthesis of 3'-(difluoromethoxy)-[1,1'-biphenyl]-2-ol (intermediate B6)

[0376]

[0377] A mixture of intermediate B5 (3.5 g, 13 mmol), 2-bromophenol (1.5 g, 8.67 mmol), Pd(dppf)Cl2 (634 mg, 0.87 mmol), and K2CO3 (3.6 g, 26 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was stirred overnight at 90 °C. Water (50 mL) was added, and the mixture was extracted with EtOAc (30 mL x 2). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1 to 5 / 1, v / v) to provide intermediate B6 (700 mg, 34% yield) as a yellow oil.

[0378] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.54

[0379] LCMS: RT=2.551min; [M-1]=235.0

[0380] Intermediate B7

[0381] Synthesis of 2-((4-fluorophenyl)(hydroxy)methyl)phenol (intermediate B7)

[0382]

[0383] n-BuLi (2.5 M in hexane) (29.0 mmol, 11.6 mL) was added dropwise to a solution of 2-bromophenol (4.18 g, 24.2 mmol) in THF (40 mL) at -30 °C. After 0.5 h, a solution of 4-fluorobenzaldehyde (3.0 g, 24.2 mmol) in THF (10 mL) was added dropwise. The mixture was stirred for 1 h, then quenched with a saturated aqueous solution of NH4Cl (50 mL), acidified to pH 6-7 with 1 N HCl, and extracted with EtOAc (10 mL x 3). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1 to 5 / 1) to provide intermediate B7 (2.5 g, 46% yield) as a yellow oil.

[0384] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.36

[0385] 1H NMR: (400MHz, DMSO-d6) δ9.43 (s, 1H), 7.36 (td, J = 5.6, 2.4Hz, 3H), 7.14–6.97 (m, 3H), 6.82–6.70 (m, 2H), 5.96 (d, J = 4.2Hz, 1H), 5.72 (d, J = 4.3Hz, 1H).

[0386] Intermediate B8

[0387] Synthesis of 2-(4-fluorobenzyl)phenol (intermediate B8)

[0388]

[0389] At room temperature, Et3SiH (5.26 g, 45.3 mmol) was added to a solution of intermediate B7 (2.47 g, 11.3 mmol) in DCM (25 mL). The mixture was stirred at 0 °C for 10 min, and then TFA (38.7 g, 340 mmol) was added dropwise. The mixture was stirred at room temperature for 3 h, diluted with DCM (20 mL), and concentrated under vacuum. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 50 / 1 to 10 / 1) to provide intermediate B8 (1.9 g, 81% yield) as a yellow oil.

[0390] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), R f =0.64

[0391] 1 H NMR: (400MHz, DMSO-d6) δ9.39 (s, 1H), 7.25–7.20 (m, 2H), 7.10–6.98 (m, 4H), 6.81–6.78 (m, 1H), 6.71 (td, J = 7.4, 1.3Hz, 1H), 3.84 (s, 2H).

[0392] Intermediate C1

[0393] (2,6-Dichloro-4-(dibenzylamino)phenyl)(3-isopropyl-4-(methoxymethoxy)phenyl)methanol (intermediate) Synthesis of body C1)

[0394]

[0395] A solution of intermediate B2 (1.1 g, 3.5 mmol) in THF (10 mL) was cooled to -20 °C; iPr-MgCl (2.7 mL of 2 M solution in THF, 5.4 mmol) was added dropwise. The mixture was stirred at room temperature for 2 h. The mixture was cooled to -78 °C and a solution of intermediate A2 (1.0 g, 2.70 mmol) in THF (4 mL) was added dropwise. The resulting mixture was stirred at -78 °C for 2 h. An aqueous solution of NH4Cl (30 mL) was added to quench the reaction, and the mixture was extracted with EtOAc (10 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to provide a brown oil. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 30:1) to provide intermediate C1 (700 mg, 47% yield) as a colorless oil.

[0396] TLC: Petroleum ether / EtOAc = 5 / 1 (v / v), Rf = 0.5

[0397] 1 H NMR: (400MHz, DMSO-d6) δ7.38–7.32(m,4H),7.26(t,J=6.6Hz,7H),6.92–6.81(m,2H),6.65(s,2H),6.25(d,J=4. 4Hz,1H),5.74(t,J=5.6Hz,1H),5.15(s,2H),4.74(s,4H),3.37(s,3H),3.25-3.19(m,1H),1.12(t,J=6.4Hz,6H).

[0398] intermediate C2

[0399] (4-Amino-2,6-dichlorophenyl)(3-isopropyl-4-(methoxymethoxy)phenyl)methanol (intermediate C2) synthesis

[0400]

[0401] Pd / C (400 mg) was added to a solution of intermediate C1 (2.1 g, 3.8 mmol) in THF (20 mL). The mixture was degassed under vacuum and purged three times with H2. The mixture was stirred at room temperature for 2 h under H2 gas (1 atm). The mixture was filtered and concentrated under vacuum to provide intermediate C2 (1.4 g, 97% yield) as a gray solid.

[0402] TLC: Petroleum ether / EtOAc = 3 / 1 (v / v), Rf = 0.3

[0403] 1H NMR: (400MHz, DMSO-d6) δ7.23(s,1H),6.90(d,J=1.2Hz,2H),6.57(s,2H),6.23(s,1H),5.17(s,2H),3.27–3.22(m,1H),1.13(t,J=6.8Hz,6H).

[0404] intermediate C3

[0405] Synthesis of 4-(4-amino-2,6-dichlorobenzyl)-2-isopropylphenol (intermediate C3)

[0406]

[0407] At 0 °C, Et3SiH (14 mmol, 1.6 g) was added to a solution of intermediate C2 (1.0 g, 2.70 mmol) in DCM (10 mL); TFA (81 mmol, 9.2 g) was added dropwise to the resulting solution. The mixture was stirred overnight at room temperature and then concentrated under vacuum to remove the solvent. Water (20 mL) was added and the resulting mixture was extracted with EtOAc (20 mL x 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum to provide a yellow oil. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 20:1) to provide intermediate C3 (200 mg, 24% yield) as a yellow solid.

[0408] TLC: Petroleum ether / EtOAc = 3 / 1 (v / v), Rf = 0.4

[0409] 1 H NMR: (400MHz, DMSO-d6) δ9.02(s,1H),6.95(s,1H),6.72–6.57(m,4H),5.53(s,2H),3.92(s,2H),3.16-3.09(m,1H),1.10(d,J=6.8Hz,6H).

[0410] intermediate C4

[0411] Synthesis of 4-(2,6-dichloro-4-(dibenzylamino)benzyl)-3-fluoro-2-isopropylphenol (intermediate C4)

[0412]

[0413] At room temperature, intermediate A4 (6.0 g, 39 mmol) and ZnCl2 (39 mL of 1.0 M solution in THF, 39 mmol) were added to a solution of intermediate B4 (7.6 g, 20 mmol) in DCE (40 mL). The mixture was stirred at 75 °C for 16 h. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the resulting mixture was extracted with DCM (50 mL x 2). The combined organic phases were washed with brine, dried over Na2SO4, and concentrated under vacuum; the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 30 / 1 to 5 / 1) to provide intermediate C4 (4.5 g, 46%) as a yellow solid.

[0414] TLC: Petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.3

[0415] 1 H NMR: (400MHz, DMSO-d6) δ9.47(s,1H),7.36(s,4H),7.25(s,6H),6.73(s,2H),6.46(d,J=8. 4Hz, 1H), 6.27 (t, J = 8.6Hz, 1H), 4.74 (s, 4H), 3.89 (s, 2H), 3.40–3.34 (m, 1H), 1.24 (s, 7H).

[0416] intermediate C5

[0417] Synthesis of 4-(4-amino-2,6-dichlorobenzyl)-3-fluoro-2-isopropylphenol (intermediate C5)

[0418]

[0419] At room temperature, Pd / C (1.0 g) was added to a solution of intermediate C4 (4.5 g, 8.8 mmol) in THF (50 mL). The mixture was stirred at 35 °C and H2 pressure of 1 atm for 1 h. The reaction mixture was cooled to room temperature, filtered, and concentrated under vacuum to provide intermediate C5 (2.3 g, 79%) as a yellow solid.

[0420] TLC: Petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.3

[0421] 1 H NMR: (400MHz, DMSO-d6) δ9.46(s,1H),6.65(s,2H),6.48(s,1H),6.29(s,1H),5.61(s,2H),3.90(s,2H),3.38(d,J=7.1Hz,1H),1.26(s,7H)

[0422] intermediate C6

[0423] 5-(2,6-dichloro-4-(dibenzylamino)benzyl)-3'-(difluoromethoxy)-[1,1'-biphenyl]-2-ol

[0424] Synthesis of (intermediate C6)

[0425]

[0426] Intermediate A4 (827 mg, 2.12 mol), intermediate B6 (1.0 g, 4.2 mol), and ZnCl2 (5.3 mL of 1.0 M solution in THF, 5.3 mmol) in DCE (20 mL) were stirred overnight at 85 °C. The mixture was cooled to room temperature, washed with water (20 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / EtOAc = 5 / 1, v / v) to provide intermediate C6 (1.0 g, 80% yield) as a colorless oil.

[0427] TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.39

[0428] 1 H NMR: (400MHz, DMSO-d6) δ9.50 (s, 1H), 7.46–7.39 (m, 1H), 7.37–7.31 (m, 5H), 7.25 (ddd, J=7.7, 6.1, 1.9Hz, 8H) ,7.12–7.04(m,2H),6.92(dd,J=8.3,2.3Hz,1H),6.83(d,J=8.3Hz,1H),6.71(s,2H),4.72(s,4H),3.99(s,2H)

[0429] intermediate C7

[0430] 5-(4-amino-2,6-dichlorobenzyl)-3'-(difluoromethoxy)-[1,1'-biphenyl]-2-ol (intermediate)

[0431] Synthesis of C7)

[0432]

[0433] The mixture of intermediate C6 (1.1 g, 1.9 mmol) and Pd / C (200 mg) in THF (20 mL) was degassed under vacuum and purified three times with H2 gas. The mixture was then stirred overnight at room temperature under 1 atm H2 gas. The mixture was filtered and then concentrated under vacuum to provide intermediate C7 (750 mg, 98% yield) as a brown solid.

[0434] TLC: EtOAc / petroleum ether = 1 / 1 (v / v), Rf = 0.44

[0435] 1H NMR: (400MHz, DMSO-d6) δ9.49 (s, 1H), 7.46–7.40 (m, 1H), 7.34–7.28 (m, 2H), 7.24 (d, J = 0.6Hz, 1H), 7.09 (dd, J = 8. 0, 2.6Hz, 1H), 7.05 (d, J = 2.4Hz, 1H), 6.92 (dd, J = 8.3, 2.3Hz, 1H), 6.84 (d, J = 8.2Hz, 1H), 6.64 (s, 2H), 3.99 (s, 2H).

[0436] intermediate C8

[0437] Synthesis of 4-(2,6-dichloro-4-(dibenzylamino)benzyl)-2-(4-fluorobenzyl)phenol (intermediate C8)

[0438]

[0439] A solution of intermediate A4 (966 mg, 2.47 mmol), intermediate B8 (1.0 g, 5.0 mmol), and ZnCl2 (842 mg, 6.18 mmol) in DCE (10 mL) was stirred overnight at 85 °C. The mixture was washed with water (20 mL) and brine (20 mL), dried over Na2SO4, concentrated under vacuum, and purified by silica gel column chromatography (petroleum ether / EtOAc = 50 / 1, v / v) to provide intermediate C8 (1.0 g, 73% yield) as a colorless oil.

[0440] TLC: EtOAc / petroleum ether = 1 / 10 (v / v), Rf = 0.4

[0441] 1 H NMR: (400MHz, DMSO-d6) δ9.21(s,1H),7.38–7.32(m,4H),7.28–7.22(m,6H),7.19–7.14(m,2H),7.06–6.99(m,2H) ),6.83(d,J=2.2Hz,1H),6.72(dd,J=8.2,2.4Hz,1H),6.69–6.64(m,3H),4.72(s,4H),3.87(s,2H),3.76(s,2H).

[0442] intermediate C9

[0443] Synthesis of 4-(4-amino-2,6-dichlorobenzyl)-2-(4-fluorobenzyl)phenol (intermediate C9)

[0444]

[0445] The mixture of intermediate C8 (1.0 g, 1.8 mmol) and Pd / C (109 mg) in THF (20 mL) was stirred overnight at room temperature under H2 gas cover. The mixture was filtered and concentrated under vacuum to provide intermediate C9 (670 mg, 99% yield) as a brown solid.

[0446] TLC: EtOAc / petroleum ether = 1 / 3 (v / v), Rf = 0.35

[0447] 1 H NMR: (400MHz, DMSO-d6) δ9.19 (s, 1H), 7.22–7.16 (m, 2H), 7.09–7.01 (m, 2H), 6.85 (d, J = 2.2Hz, 1H), 6. 72(dd,J=8.2,2.2Hz,1H),6.67(d,J=8.2Hz,1H),6.61(s,2H),5.53(s,2H),3.88(s,2H),3.78(s,2H).

[0448] Intermediate C10

[0449] Synthesis of 4-(2-bromo-6-chloro-4-(dibenzylamino)benzyl)-2-isopropylphenol (intermediate C10)

[0450]

[0451] ZnCl2 (1 M in THF, 11.5 mL) was added to a solution of intermediate A8 (2.0 g, 4.60 mmol) and 2-isopropylphenol (1.8 g, 14 mmol) in DCE (30 mL). The reaction was stirred overnight at 75 °C. The reaction was cooled to room temperature, water (50 mL) was added, and the resulting mixture was extracted with DCM (20 mL x 2). The combined organic phases were washed with brine (40 mL), dried over Na2SO4, and concentrated under vacuum; the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 30 / 1 to 5 / 1) to provide intermediate C10 (1.8 g, 73% yield) as a yellow oil.

[0452] TLC: Petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.15

[0453] 1H NMR: (400MHz, DMSO-d6)δ9.01(d,J=1.2Hz,1H),7.35(t,J=7.5Hz,4H),7.29–7.19(m,6H),6.97–6.86(m,2H),6.7 5(t,J=1.9Hz,1H),6.68–6.58(m,2H),4.72(s,4H),3.96(s,2H),3.18–3.05(m,1H),1.09(dd,J=7.0,1.3Hz,6H).

[0454] Intermediate C11

[0455] 4-(2-chloro-4-(dibenzylamino)-6-(prop-1-en-2-yl)benzyl)-2-isopropylphenol (intermediate C11) Synthesis

[0456]

[0457] Potassium isopropenyltrifluoroborate (0.54 g, 3.7 mmol), Pd(dppf)Cl2 (180 mg, 0.24 mmol), and K2CO3 (1.01 g, 7.2 mmol) were added to a solution of intermediate C10 (1.3 g, 2.4 mmol) in 1,4-dioxane (10 mL) and water (2 mL). The reaction mixture was stirred overnight at 90 °C. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the resulting mixture was extracted with EtOAc (20 mL x 2). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1 to 5 / 1) to provide intermediate C11 (0.40 g, 33% yield) as a yellow solid.

[0458] TLC: Petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.3

[0459] 1 H NMR: (400MHz, DMSO-d6) δ8.95 (s, 1H), 7.37–7.30 (m, 4H), 7.29–7.20 (m, 6H), 6.74 (d, J = 2.1Hz, 1H), 6.63 (d, J = 2.7Hz, 1H), 6.60–6. 52(m,2H),6.41(d,J=2.8Hz,1H),5.02(s,1H),4.69(s,4H),4.60(s,1H),3.81(s,2H),3.10(p,J=6.9Hz,1H),1.06(d,J=6.9Hz,6H).

[0460] intermediate C12

[0461] Synthesis of 4-(4-amino-2-chloro-6-isopropylbenzyl)-2-isopropylphenol (intermediate C12)

[0462]

[0463] Add Pd / C (100 mg) to a solution of intermediate C11 (496 mg, 1.0 mmol) in THF (10 mL). Stir the reaction mixture overnight at 1 atm of hydrogen. Filter the mixture and concentrate under vacuum; purify the residue by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1 to 3 / 1) to provide intermediate C12 (150 mg, 47% yield) as a yellow solid.

[0464] TLC: Petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.1

[0465] intermediate C13

[0466] Synthesis of N-(3,5-dichloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)phenyl)acetamide (intermediate C13)

[0467]

[0468] At room temperature, 2-isopropylphenol (692 mg, 5.08 mmol) and ZnCl2 (865 mg, 6.35 mmol) were added to a solution of intermediate A11 (800 mg, 2.54 mmol) in DCE (5 mL). The reaction mixture was heated to 90 °C and stirred overnight. The reaction mixture was diluted with DCM (30 mL), washed with brine (20 mL x 2), dried over Na2SO4, and concentrated under vacuum. The residue was purified by preparative TLC (petroleum ether / EtOAc = 5 / 1) to provide intermediate C13 (180 mg, 19% yield) as a yellow solid.

[0469] TLC: petroleum ether / EtOAc = 5 / 1 (v / v), Rf = 0.24.

[0470] LCMS: RT=1.672min, [M-1]=367.9.

[0471] 1 H NMR: (400MHz, DMSO-d6) δ9.11 (s, 1H), 8.11 (d, J = 6.8Hz, 1H), 6.99 (d, J = 2.0Hz, 1H), 6.68 (dd, J = 8. 4, 2.0Hz, 1H), 6.65 (d, J = 8.4Hz, 2H), 4.09 (s, 2H), 3.13 (m, 1H), 2.12 (s, 3H), 1.11 (d, J = 6.8Hz, 6H).

[0472] intermediate C14

[0473] Synthesis of 4-(4-amino-2,6-dichloro-3-fluorobenzyl)-2-isopropylphenol (intermediate C14)

[0474]

[0475] To a solution of intermediate C13 (180 mg, 0.49 mmol) in water (1 mL) and THF (3 mL), add NaOH (194 mg, 4.86 mmol). Stir the mixture overnight at 100 °C. Dilute the reaction mixture with water (20 mL), acidify to pH 6–8 with 2 N HCl, and extract with EtOAc (20 mL x 2). Wash the combined organic phases with brine (10 mL x 2), dry with Na2SO4, and concentrate under vacuum; purify the residue by preparative HPLC to provide intermediate C14 (66 mg, 41% yield) as a yellow solid.

[0476] TLC: petroleum ether / EtOAc = 3 / 1 (v / v), Rf = 0.48.

[0477] LCMS: RT=1.864min, [M+1]=328.0.

[0478] 1 H NMR: (400MHz, DMSO-d6) δ9.06(s,1H),6.95(d,J=1.6Hz,1H),6.84(d,J=8.0Hz,1H),6.66(dd,J=8 .4, 2.0Hz, 1H), 6.63 (d, J = 8.0Hz, 1H), 3.95 (s, 2H), 3.12 (p, J = 6.8Hz, 1H), 1.10 (d, J = 6.8Hz, 6H).

[0479] Intermediate C15

[0480] Synthesis of 4-(4-bromo-2,6-dichlorobenzyl)-3-fluoro-2-isopropylphenol (intermediate C15)

[0481]

[0482] A mixture of intermediates A12 (500 mg, 1.57 mmol), B4 (725 mg, 4.71 mmol), and Zn(OTf)2 (2.8 g, 7.85 mmol) was microwaved at 160 °C with stirring for 2 h. The reaction mixture was diluted with DCM (5 mL), washed with brine (5 mL x 2), dried over Na2SO4, concentrated under vacuum, and purified by preparative TLC (EtOAc / petroleum ether = 1 / 10) to provide intermediate C15 (120 mg, 19% yield) as a brown oil.

[0483] TLC: Petroleum ether / EtOAc = 5 / 1 (v / v), Rf = 0.21

[0484] 1 H NMR: (400MHz, DMSO-d6) δ9.56 (s, 1H), 7.83 (s, 2H), 6.48 (d, J = 8.4Hz, 1H), 6.2 9(t,J=8.8Hz,1H), 4.07(s,2H), 3.38(d,J=7.2Hz,1H), 1.25(d,J=7.2Hz,6H).

[0485] intermediate C16

[0486] Synthesis of 4-(4-bromo-2,6-dichlorobenzyl)-2-isopropylphenol (intermediate C16)

[0487]

[0488] At room temperature, 2-isopropylphenol (1.92 g, 14.1 mmol) and Zn(OTf)₂ (5.13 g, 14.1 mmol) were added to a solution of intermediate A12 (1.5 g, 4.7 mmol) in chlorobenzene (10 mL). The reaction mixture was microwaved at 150 °C with stirring for 1 h. The mixture was cooled to room temperature and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 100 / 1 to 20 / 1) to provide intermediate C16 (0.40 g, 23%) as a yellow oil.

[0489] TLC: Petroleum ether / EtOAc = 5 / 1 (v / v), Rf = 0.15

[0490] 1 H NMR: (400MHz, DMSO-d6) δ9.14(s,1H),7.80(s,2H),6.99(d,J=1.9Hz,1H),6 .70–6.61(m,2H),4.10(s,2H),3.14(p,J=6.9Hz,1H),1.11(d,J=6.9Hz,6H).

[0491] Intermediate C17

[0492] Synthesis of 2-(4-(4-bromo-2,6-dichlorobenzyl)-2-isopropylphenoxy)tetrahydro-2H-pyran (intermediate C17)

[0493]

[0494] Add 3,4-dihydro-2H-pyran (324 mg, 3.85 mmol) and PPTS (151 mg, 3.85 mmol) to a solution of intermediate C16 (1.2 g, 3.2 mmol) in THF (15 mL). Stir the reaction mixture overnight at room temperature. Add water (30 mL) and extract the resulting mixture with EtOAc (15 mL x 2). Wash the combined organic phases with brine (30 mL), dry with Na2SO4, and concentrate under vacuum. Purify the residue by silica gel column chromatography (petroleum ether / EtOAc = 1 to 30 / 1) to provide intermediate C17 (1.2 g, 82% yield).

[0495] TLC: Petroleum ether / EtOAc = 10 / 1 (v / v), Rf = 0.75

[0496] 1 H NMR: (400MHz, DMSO-d6) δ7.81(s,2H),7.07(d,J=2.3Hz,1H),6.93(d,J=8.5Hz,1H),6.80(dd,J=8.4,2.3Hz,1H),5.40(s,1H),4.14(s,2H ), 3.71 (s, 1H), 3.51 (s, 1H), 3.21 (d, J = 20.7Hz, 1H), 1.77 (d, J = 15.7Hz, 3H), 1.59 (dd, J = 37.3, 10.5Hz, 4H), 1.15 (dd, J = 6.9, 5.2Hz, 6H).

[0497] intermediate C18

[0498] (E)-3-(3,5-dichloro-4-(3-isopropyl-4-((tetrahydro-2H-pyran-2-yl)oxy)benzyl)phenyl)propene Synthesis of methyl ester (intermediate C18)

[0499]

[0500] Methyl acrylate (74 mg, 0.86 mmol), Pd(OAc)₂ (10 mg, 43 μmol), and K₂CO₃ (120 mg, 0.86 mmol) were added to a solution of intermediate C17 (200 mg, 0.43 mmol) in DMF (5 mL). The reaction mixture was heated to 100 °C overnight. The mixture was cooled to room temperature, water (30 mL) was added, and the resulting mixture was extracted with EtOAc (30 mL x 2). The combined organic phases were washed with brine (50 mL), dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 100 / 1 to 10 / 1) to provide intermediate C18 (100 mg, 49% yield) as a pale yellow oil.

[0501] TLC: Petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.25

[0502] 1 H NMR: (400MHz, DMSO-d6) δ7.93(s,2H),7.62(d,J=16.0Hz,1H),7.09(d,J=2.2Hz,1H),6.93(d,J=8.5Hz,1H),6.86–6.77(m,2H),5.39(s,1H), 4.18(s,2H),3.73(s,4H),3.51(d,J=6.8Hz,1H),3.26–3.16(m,1H),1.76(d,J=19.6Hz,3H),1.68–1.44(m,3H),1.14(dd,J=6.8,5.3Hz,6H).

[0503] Intermediate C19

[0504] methyl 3-(3,5-dichloro-4-(4-hydroxy-3-isopropylbenzyl)phenyl)-3-oxopropionate (intermediate C19) synthesis

[0505]

[0506] FeCl2 (3.0 mg, 21 μmol) and polymethylhydrosiloxane (140 mg, 0.63 mmol) were added to a solution of intermediate C18 (100 mg, 0.21 mmol) in ethanol (5 mL). The reaction mixture was stirred at 80 °C for 3 h. The reaction mixture was cooled to room temperature and concentrated under vacuum, and the residue was purified by preparative TLC (petroleum ether / EtOAc = 2 / 1) to provide intermediate C19 (30 mg, 36% yield) as a pale yellow oil.

[0507] TLC: Petroleum ether / EtOAc = 2 / 1 (v / v), Rf = 0.15

[0508] 1 H NMR: (400MHz, DMSO-d6) δ9.16 (s, 1H), 8.01 (s, 2H), 7.02 (d, J = 2.1Hz, 1H), 6.74–6.60 (m, 2H), 4.29 (s, 2H), 4.20 (s, 2H), 3.65 (s, 3H), 3.13 (p, J = 6.9Hz, 1H), 1.10 (d, J = 6.9Hz, 6H).

[0509] Intermediate D1

[0510] 2,6-Difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenol (Intermediate D1) Synthesis

[0511]

[0512] Potassium acetate (423 mg, 4.31 mmol) was added to a mixture of 3-bromo-2,6-difluorophenol (300 mg, 1.44 mmol), bis(pinacol)diboron (401 mg, 1.58 mmol), and Pd(dppf)Cl2 (52 mg, 72 μmol) in 1,4-dioxane (15 mL). The mixture was heated to 100 °C and stirred for 3 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated under vacuum to provide crude intermediate D1 (300 mg, 82% yield), which was used without further purification.

[0513] TLC: petroleum ether / EtOAc = 3 / 1 (v / v), Rf = 0.90.

[0514] Example 1

[0515] 2-(3,5-dichloro-4-(4-hydroxy-3-isopropylbenzyl)phenyl)-5-hydroxy-3-oxo-2,3-dihydro-1,2, Synthesis of 4-triazine-6-nitrile (compound 1)

[0516]

[0517] A solution of intermediate C3 (5.0 g, 16.1 mmol) in acetonitrile (20 mL) / water (100 mL) and concentrated HCl aqueous solution (110 mL) was cooled to 0 °C; a solution of NaNO2 (1.3 g, 19.3 mmol) in water (10 mL) was added dropwise. The mixture was stirred at 0 °C for 1 h. This mixture was then added dropwise to a solution of N-(2-cyanoacetyl)carbamate (2.8 g, 17.7 mmol) in water (100 mL) and pyridine (125 mL), and stirred at 0 °C. After 1 h, the reaction mixture was extracted with EtOAc (100 mL x 2); the combined organic phases were washed with brine (50 mL x 2), dried over Na2SO4, and concentrated under vacuum. The obtained crude product (7.6 g yellow oil) was dissolved in HOAc (50 mL); NaOAc (6.5, 79.6 mmol) was added, and the mixture was stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature; water (100 mL) was added, and the mixture was extracted with EtOAc (50 mL x 3). The combined organic phases were washed with brine (50 mL x 2), dried over Na2SO4, and concentrated under vacuum; the residue was purified by reversed-phase preparative HPLC to provide compound 1 (1.5 mg, 21.2% yield) as a yellow solid.

[0518] TLC: DCM / MeOH=1 / 1(v / v), Rf=0.1

[0519] LCMS:RT=4.31min,[M-1]=447.0

[0520] 1 H NMR: (400MHz, DMSO-d6) δ9.59(d,J=1.4Hz,2H),7.67(s,4H),6.51(d,J=8.3Hz,2H),6.33 (t,J=8.6Hz,2H),4.15(s,4H),3.39(d,J=7.2Hz,3H),2.07(s,1H),1.26(d,J=7.0Hz,12H)

[0521] Example 2

[0522] 2-(3,5-dichloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)phenyl)-5-hydroxy-3-oxo-2,3-dihydro- Synthesis of 1,2,4-triazine-6-nitrile (compound 2)

[0523]

[0524] A solution of intermediate C5 (270 mg, 0.82 mmol) in water (10 mL) and concentrated HCl aqueous solution (10 mL) was cooled to 0 °C, and a solution of NaNO2 (68 mg, 0.98 mmol) in water (1 mL) was added dropwise. The mixture was stirred at 0 °C for 30 min. This mixture was then added dropwise to a solution of N-(2-cyanoacetyl)carbamate (140 mg, 0.86 mmol) in water (10 mL) and pyridine (15 mL), and stirred at 0 °C. After 1 h, the mixture was extracted with EtOAc (10 mL * 2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum. The crude product was dissolved in HOAc (8 mL) and NaOAc (337 mg, 4.11 mmol) was added. The resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the mixture was extracted with EtOAc (10 mL x 2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum; the residue was purified by preparative HPLC to provide compound 2 (6.0 mg, 1.6% yield).

[0525] TLC: DCM / MeOH=1 / 1(v / v), Rf=0.1

[0526] LCMS:RT=4.31min,[M-1]=447.0

[0527] 1H NMR: (400MHz, DMSO-d6) δ9.59(d,J=1.4Hz,2H),7.67(s,4H),6.51(d,J=8.3Hz,2H),6.33 (t,J=8.6Hz,2H),4.15(s,4H),3.39(d,J=7.2Hz,3H),2.07(s,1H),1.26(d,J=7.0Hz,12H)

[0528] Example 3

[0529] 2-(3,5-Dichloro-4-((3'-(difluoromethoxy)-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenyl)- Synthesis of 5-hydroxy-3-oxo-2,3-dihydro-1,2,4-triazine-6-nitrile (compound 3)

[0530]

[0531] A solution of intermediate C7 (400 mg, 0.97 mmol) in concentrated HCl aqueous solution (7 mL) and water (7 mL) was cooled to 0 °C, and a solution of NaNO2 (81 mg, 1.17 mmol) in water (1 mL) was added dropwise. The mixture was stirred at 0 °C for 30 min. This mixture was then added dropwise to a solution of N-(2-cyanoacetyl)carbamate (167 mg, 1.07 mmol) in water (7 mL) and pyridine (10 mL), and stirred at 0 °C. After 1 h, the mixture was extracted with EtOAc (50 mL * 2); the combined organic phases were washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum. A mixture of this substance (500 mg, 0.87 mmol) and NaOAc (355 mg, 4.33 mmol) in HOAc (5 mL) was stirred at 100 °C for 2 h. The mixture was cooled to room temperature; water (30 mL) was added, and the mixture was extracted with EtOAc (25 mL). The combined organic phases were washed with water (20 mL x 3), then with brine (50 mL), dried over Na2SO4, concentrated under vacuum, and purified twice by preparative TLC (DCM / MeOH = 10 / 1) to provide compound 3 (20 mg, 4.4% yield) as a yellow solid.

[0532] TLC: MeOH / DCM=1 / 5(v / v), Rf=0.32

[0533] LCMS:RT=1.787min,[M-1]=528.8

[0534] 1H NMR: (400MHz, DMSO-d6) δ13.19(s,1H),9.61(s,1H),7.67(s,2H),7.44(t,J=7.9Hz,1H),7.35(dt,J=7.8,1.2Hz,1H),7.31(t,J=2.0Hz,1H), 7.24(t,J=74.2Hz,1H), 7.15(d,J=2.3Hz,1H), 7.10(dd,J=8.0,2.5Hz,1H), 6.95(dd,J=8.4,2.3Hz,1H), 6.88(d,J=8.3Hz,1H), 4.25(s,2H).

[0535] Example 4

[0536] 2-(3,5-Dichloro-4-(3-(4-fluorobenzyl)-4-hydroxybenzyl)phenyl)-5-hydroxy-3-oxo-2,3-dihydro- Synthesis of 1,2,4-triazine-6-nitrile (compound 4)

[0537]

[0538] A solution of intermediate C9 (490 mg, 1.30 mmol) in concentrated HCl aqueous solution (15 mL) and water (15 mL) was cooled to 0 °C; a solution of NaNO2 (108 mg, 1.56 mmol) in water (1 mL) was added dropwise. The mixture was stirred at 0 °C for 30 min, and then added dropwise to a solution of N-(2-cyanoacetyl)carbamate (224 mg, 1.43 mmol) in water (15 mL) and pyridine (15 mL), and stirred at 0 °C. After 1 h, the mixture was extracted with EtOAc (50 mL * 2). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum. A mixture of the intermediate (600 mg, 1.10 mmol) and NaOAc (453 mg, 5.52 mmol) in HOAc (10 mL) was stirred at 100 °C for 2 h. Add water (30 mL) and extract the mixture with EtOAc (25 mL x 2). Wash the combined organic layers with water (40 mL x 3), then with brine (50 mL), dry with Na2SO4, and purify twice by preparative TLC (DCM / MeOH = 10 / 1) to provide compound 4 (16 mg, 2.7% yield) as a yellow solid.

[0539] TLC: MeOH / DCM=1 / 5(v / v), Rf=0.32

[0540] LCMS:RT=3.626min,[M-1]=494.9

[0541] 1H NMR: (400MHz, DMSO-d6) δ13.21(s,1H),9.32(s,1H),7.63(s,2H),7.19(dd,J=8.4,5.8Hz,2H),7.09–7.02( m, 2H), 6.90 (d, J = 2.2Hz, 1H), 6.77 (dd, J = 8.4, 2.2Hz, 1H), 6.71 (d, J = 8.2Hz, 1H), 4.13 (s, 2H), 3.80 (s, 2H).

[0542] Example 5

[0543] 2-(3-chloro-4-(4-hydroxy-3-isopropylbenzyl)-5-isopropylphenyl)-5-hydroxy-3-oxo-2,3-dihydro- Synthesis of 1,2,4-triazine-6-nitrile (compound 5)

[0544]

[0545] A solution of intermediate C12 (200 mg, 0.63 mmol) in water (5 mL) and concentrated HCl (5 mL) was cooled to 0 °C; a solution of NaNO2 (52 mg, 0.75 mmol) in water (1 mL) was added dropwise. The mixture was stirred at 0 °C for 30 min, and then added dropwise at 0 °C to a mixture of N-(2-cyanoacetyl)carbamate (98 mg, 0.63 mmol) in water (5 mL) and pyridine (5 mL). After 1 h, the mixture was extracted with EtOAc (10 mL * 2). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, and concentrated under vacuum. The substance was dissolved in HOAc (5 mL); NaOAc (258 mg, 3.15 mmol) was added, and the resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the resulting mixture was extracted with EtOAc (10 mL * 2). The combined organic phases were washed with brine (30 mL), dried with Na2SO4 and concentrated under vacuum; the residue was purified by preparative HPLC to provide compound 5 (35 mg, 12% yield).

[0546] TLC: DCM / MeOH=1 / 1(v / v), Rf=0.1

[0547] LCMS:RT=2.62min,[M-1]=437.0

[0548] 1H NMR: (400MHz, DMSO-d6) δ13.04(s,1H),9.10(s,1H),7.45(dd,J=20.6,2.2Hz,2H),6.88(d,J=2.1Hz,1 H), 6.72–6.52 (m, 2H), 4.25–4.04 (m, 2H), 3.18 (dq, J=28.4, 6.8Hz, 2H), 1.08 (dd, J=9.6, 6.7Hz, 12H).

[0549] Example 6

[0550] 2-(3,5-Dichloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)phenyl)-5-hydroxy-3-oxo-2,3-dihydro- Synthesis of 1,2,4-triazine-6-nitrile (compound 6)

[0551]

[0552] A solution of intermediate C14 (360 mg, 1.10 mmol) in concentrated HCl (7 mL) and water (7 mL) was cooled to 0 °C; a solution of NaNO2 (91 mg, 1.3 mmol) in water (1 mL) was added dropwise. The resulting mixture was stirred at 0 °C for 30 min, and then added to a cooled solution of N-(2-cyanoacetyl)carbamate (188 mg, 1.21 mmol) in water (7 mL) and pyridine (10 mL). The mixture was stirred at 0 °C for 1 h, and then extracted with EtOAc (20 mL * 2). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, and concentrated under vacuum. The residue was combined with NaOAc (355 mg, 4.33 mmol) in AcOH (5 mL) and stirred at 100 °C for 2 h. The mixture was cooled to room temperature; water (30 mL) was added, and the mixture was extracted with EtOAc (25 mL). The organic layer was washed with water (20 mL x 3), then with brine (50 mL), dried with Na2SO4, and purified by preparative HPLC to provide compound 6 (20 mg, 7.4% yield) as a yellow solid.

[0553] TLC: MeOH / DCM=1 / 5(v / v), Rf=0.36

[0554] LCMS:RT=1.749min,[M-1]=447.0

[0555] 1H NMR: (400MHz, DMSO-d6) δ13.27(s,1H),9.18(s,1H),7.74(d,J=6.6Hz,1H),7.05(d,J=2 .1Hz,1H),6.73–6.65(m,2H),4.21(s,2H),3.14(p,J=6.9Hz,1H),1.12(d,J=6.9Hz,6H).

[0556] Example 7

[0557] 3',5'-Dichloro-3,5-difluoro-4'-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-[1,1'-biphenyl]-4-ol Synthesis of (Compound 7)

[0558]

[0559] Pd(dppf)Cl2 (5.0 mg, 6.4 μmol) and NaHCO3 (16 mg, 0.19 mmol) were added to a solution of intermediate C15 (25 mg, 64 μmol) and 3,5-difluoro-4-hydroxyphenylboronic acid (17 mg, 96 μmol) in 1,4-dioxane / water (10 / 1 mL) at room temperature. The reaction mixture was purged with nitrogen and heated overnight at 80 °C. The reaction mixture was diluted with EtOAc (5 mL), washed with brine (10 mL x 2), dried over Na2SO4, concentrated under vacuum, and purified by preparative HPLC to provide compound 7 (7.0 mg, 25% yield) as a yellow solid.

[0560] TLC: petroleum ether / EtOAc = 3 / 1 (v / v), Rf = 0.31.

[0561] LCMS: RT=3.538min, [M-1]=439.1.

[0562] 1 H NMR: (400MHz, DMSO-d6) δ10.53(s,1H),9.55(s,1H),7.86(s,2H),7.58(dd,J=8.4,1.6Hz,2H),6.48 (d, J = 8.0 Hz, 1H), 6.32 (t, J = 8.8 Hz, 1H), 4.12 (s, 2H), 3.41 (d, J = 7.2 Hz, 1H), 1.26 (d, J = 6.8 Hz, 6H).

[0563] Example 8

[0564] 3',5'-Dichloro-2,4-difluoro-4'-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-[1,1'-biphenyl]-3-ol Synthesis of (Compound 8)

[0565]

[0566] At room temperature, Pd(dppf)Cl2 (11 mg, 15.30 μmol) and an aqueous solution of NaHCO3 (2 M, 0.23 mL) were added to a solution of intermediate D1 (60 mg, 0.15 mmol) and intermediate C15 (59 mg, 0.23 μmol) in 1,4-dioxane (10 mL). The reaction mixture was heated to 80 °C overnight under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc (10 mL), washed with brine (10 mL x 2), dried over Na2SO4, and concentrated under vacuum. The crude product was purified by preparative HPLC to provide compound 8 (25 mg, 37% yield) as a brown solid.

[0567] TLC: petroleum ether / EtOAc = 3 / 1 (v / v), Rf = 0.23.

[0568] LCMS: RT=3.486min, [M-1]=439.0.

[0569] 1 H NMR: (400MHz, DMSO-d6) δ10.44(s,1H),9.57(d,J=1.2Hz,1H),7.65(d,J=1.2Hz,2H),7.15-7.12(m,1H),7.08–7 .00(m,1H),6.51(d,J=6.8Hz,1H),6.36(t,J=8.4Hz,1H),4.14(s,2H),3.40-3.37(m,1H),1.27(d,J=7.2Hz,6H).

[0570] Example 9

[0571] Synthesis of 5-(3,5-dichloro-4-(4-hydroxy-3-isopropylbenzyl)phenyl)isoxazole-3-ol (compound 9)

[0572]

[0573] Intermediate C19 (100 mg, 0.25 mmol) was added to a solution of hydroxylamine hydrochloride (26 mg, 0.375 mmol) and NaOH (30 mg, 0.75 mmol) in MeOH / H₂O (5 / 2 mL). The mixture was stirred at room temperature for 2 h. Water (20 mL) was added, and the pH of the solution was adjusted to ~3-4 with 1 N HCl. The resulting mixture was extracted with EtOAc (10 mL * 2). The combined organic phases were washed with brine (20 mL), dried over Na₂SO₄, and concentrated under vacuum. The residue was purified by preparative HPLC to provide compound 9 (10 mg, 10% yield) as a light brown solid.

[0574] TLC: DCM / MeOH=15 / 1(v / v), Rf=0.15

[0575] LCMS:RT=4.18min,[M-1]=376.0)

[0576] 1 H NMR: (400MHz, DMSO-d6) δ 9.15 (s, 1H), 7.86 (s, 2H), 7.01 (s, 1H), 6.68 (q, J = 8.3Hz, 2H), 5.80 (s, 1H), 4.17 (s, 2H), 3.14 (s, 1H), 1.10 (d, J = 6.9Hz, 6H).

[0577] Example 10

[0578] 2-(3,5-Dichloro-4-((3'-(difluoromethoxy)-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenyl)- Synthesis of 5-hydroxy-1,2,4-triazine-3(2H)-one (compound 10)

[0579]

[0580] The mixture of compound E1 (120 mg, 226 μmol) in 1,4-dioxane (2 mL) and HCl (12 M, 2 mL) was stirred at 60 °C for 8 h. The mixture was quenched with H2O (10 mL) and extracted with EtOAc (5 mL x 2). The combined organic layers were washed with water (15 mL x 2) and brine (10 mL), dried over Na2SO4, and concentrated to dryness to provide product compound 2 (100 mg, 80.5% yield) as a yellow solid.

[0581] Thioglycolic acid (40 mg, 436 μmol) was added to a mixture of compound E2 (120 mg, 218 μmol) and toluene (3 mL). The mixture was stirred at 110 °C for 48 h. The mixture was quenched with H2O (10 mL) and extracted with EtOAc (10 mL). The organic layer was washed with water (25 mL x 2) and brine (50 mL), dried over Na2SO4, concentrated to dryness, and purified by preparative HPLC to provide compound 10 (15 mg, 13.4% yield) as a yellow solid.

[0582] LCMS:RT=1.66min,[M-1]=503.9

[0583] Example 11

[0584] Thyroid hormone reporter gene assay

[0585] The thyroid hormone receptor activity of the test compounds was determined using a TR reporter gene assay. The reporter cells used in the assay expressed TR receptor heterozygotes (TRα or TRβ), in which the native N-terminal DNA-binding domain (DBD) had been replaced by the N-terminal DNA-binding domain of the yeast Gal4 DBD. The reporter gene, firefly luciferase, was functionally linked to the upstream activation sequence (UAS) of Gal4. Both cell lines were derived from human embryonic kidney (HEK293).

[0586] Step 1: Prepare a suspension of reporter cells in cell recovery medium containing 10% charcoal-adsorbed FBS and dispense them into assay plates. Preheat the plates in a cell culture incubator (37°C / 5% CO2 / 85% humidity) for 6 hours.

[0587] Step 2: Dilute the stock solution of the test compound and triiodothyronine in DMSO to produce solutions at “1,000× concentration” relative to each final treatment concentration. These intermediate stock solutions are then diluted directly into compound screening medium containing 10% carbon-adsorbed FBS to produce “2× concentration” treatment medium (containing 0.2%, 0.4%, or 0.8% DMSO).

[0588] Step 3: At the end of the pre-incubation period, discard the culture medium from the assay plate, and receive 100 μl of compound screening medium in each well. Dispense 100 μl of each previously prepared “2× concentration” treatment medium into duplicate wells to achieve the desired final treatment concentration. The final concentration of DMSO in all wells is 0.1%, 0.2%, or 0.4%. Incubate the assay plate for 24 hours in a cell culture incubator (37°C / 5% CO2 / 85% humidity).

[0589] Step 4: At the 24-hour endpoint, discard the treatment medium and add 100 μL / well of luciferase assay reagent. Quantify relative photometric units (RLU) from each well. Validate the performance of TRα and TRβ assays using the reference agonist triiodothyronine (T3).

[0590] The results of these measurements are presented in Table 2 below, where the data are reported as EC values ​​measured for TRα and TRβ receptors. 50 The value, and the selectivity index (SI) is calculated as EC. 50 (TRα) / EC 50 (TRβ). Therefore, EC 50 The SI value is represented as follows:

[0591] Effectiveness: +EC 50 >1,000 nM

[0592] ++100nM <EC50 ≤1,000 nM

[0593] +++10nM <EC 50 ≤100nM

[0594] ++++EC 50 ≤10nM

[0595] ND not detected

[0596] Selectivity: +T3-SI≤3X

[0597] ++3X <T3-SI≤30X

[0598] +++T3-SI>30X

[0599] ND not detected

[0600] Table 2

[0601] Activity data

[0602] Compound numbering TRα TRβ T3-SI T3 ++++ +++ + 1 ++ +++ +++ 2 +++ +++ ++ 3 + ++ +++ 4 + ++ ++ 5 +++ ++++ ++ 6 ++ ++ ++ 7 + ++ ++ 8 + + ND 9 ++ +++ ++ 10 ++++ ++++ ++

[0603] As indicated by the experiments above, the compounds of the present invention exhibit improved TRβ selectivity compared to the natural agonist T3. Some of the compounds of the present invention also exhibit improved potency compared to T3.

[0604] The various embodiments described above can be combined to provide further embodiments. All U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications, and non-patent publications cited in and / or listed in the application data sheets are incorporated herein by reference in their entirety. If necessary, aspects of the embodiments can be modified to incorporate the concepts of various patents, applications, and publications to provide additional embodiments.

[0605] Based on the detailed description above, these and other changes can be made to the embodiments. Generally, the terminology used in the appended claims should not be construed as limiting the claims to the specific embodiments disclosed in the specification and claims, but should be interpreted to include all possible embodiments and the full scope of the equivalents granted by those claims. Therefore, the claims are not limited by this disclosure.

Claims

1. A compound or a pharmaceutically acceptable tautomer or salt thereof, said compound having the structure of formula (I): in: A is R 6 For H or -CN; X 1 It is a lower alkyl group or halogen. X 2 It is a halogen; Y 1 It is H or halogen; Y 2 It is H or halogen; R 2 It is a lower alkyl, phenyl, or benzyl group, wherein R 2 Optionally replaced by one or more halogens or -OR'; and R' is a lower haloalkyl group; Wherein, the lower haloalkyl refers to a lower alkyl group in which one or more hydrogen atoms are replaced by halogens, and the lower alkyl group is a straight-chain or branched alkyl group having 1 to 8 carbon atoms.

2. The compound according to claim 1, or a pharmaceutically acceptable tautomer or salt thereof, wherein R 2 It is an unsubstituted lower alkyl group.

3. The compound according to claim 1, or a pharmaceutically acceptable tautomer or salt thereof, wherein R 2 It is isopropyl.

4. The compound according to claim 1, or a pharmaceutically acceptable tautomer or salt thereof, wherein: A is 5. The compound according to claim 1, or a pharmaceutically acceptable tautomer or salt thereof, wherein A is...

6. The compound of claim 1 or a pharmaceutically acceptable tautomer or salt thereof, wherein X 1 It is a lower alkyl group.

7. The compound of claim 1 or a pharmaceutically acceptable tautomer or salt thereof, wherein X 1 It is a halogen.

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

9. The compound of claim 1 or a pharmaceutically acceptable tautomer or salt thereof, wherein Y 1 For H.

10. The compound of claim 1 or a pharmaceutically acceptable tautomer or salt thereof, wherein Y 2 It is a halogen.

11. The compound of claim 1 or a pharmaceutically acceptable tautomer or salt thereof, wherein Y 2 For H.

12. The compound of claim 1 or a pharmaceutically acceptable tautomer or salt thereof, wherein Y 1 It is halogen and Y 2 For H.

13. The compound of claim 1 or a pharmaceutically acceptable tautomer or salt thereof, wherein Y 1 For H and Y 2 It is a halogen.

14. The compound according to claim 1, or a pharmaceutically acceptable tautomer or salt thereof, having the following structure:

15. The compound according to claim 1, or a pharmaceutically acceptable tautomer or salt thereof, having the following structure:

16. The compound according to claim 1, or a pharmaceutically acceptable tautomer or salt thereof, having the following structure:

17. The compound according to claim 1, or a pharmaceutically acceptable tautomer or salt thereof, having the following structure:

18. The compound according to claim 1, or a pharmaceutically acceptable tautomer or salt thereof, having the following structure:

19. The compound according to claim 1, or a pharmaceutically acceptable tautomer or salt thereof, having the following structure:

20. The compound according to claim 1, or a pharmaceutically acceptable tautomer or salt thereof, having the following structure:

21. The compound according to claim 1, or a pharmaceutically acceptable tautomer or salt thereof, having the following structure:

22. A pharmaceutical composition comprising the compound of any one of claims 1-21, or a pharmaceutically acceptable tautomer or salt thereof, and a pharmaceutically acceptable excipient.

23. Use of the compound of any one of claims 1-21, or a pharmaceutically acceptable tautomer or salt thereof, or the pharmaceutical composition of claim 22, in the preparation of a medicament for treating neurodegenerative diseases in persons of need.

24. The use according to claim 23, wherein the neurodegenerative disease is a demyelinating disease.

25. The use according to claim 23, wherein the neurodegenerative disease is multiple sclerosis, MCT8 deficiency, X-linked adrenoleukodystrophy (ALD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia, or lacunar stroke.

26. The use according to claim 23, wherein the neurodegenerative disease is adult Rafeshomon disease, Alexander disease, Alzheimer's disease, Barlow concentric sclerosis, Canavan disease, central pontine myelinolysis, cerebral palsy, cerebral tendinitis xanthomas, chronic inflammatory demyelinating polyneuropathy, Dweck syndrome, diffuse demyelinating sclerosis, infantile Rafeshomon disease, Crabbe disease, Lieber hereditary optic neuropathy, Marburg multiple sclerosis, Machapawa-Binami disease, metachromatic leukodystrophy, multifocal motor neuropathy, paraproteinemic demyelinating polyneuropathy, Peritzois-Metzbach disease, peroneal muscular atrophy, progressive multifocal leukodystrophy, transverse myelitis, tropical spastic paraplegia, van der Canapé disease, X-linked adrenoleukodystrophy, or Zieweger syndrome.

27. The use according to claim 23, wherein the neurodegenerative disease is an idiopathic inflammatory demyelinating disease.

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