Thyromimetic agents

Abstract

Disclosed herein are thyromimetic compounds that have utility in treating diseases such as neurodegenerative and fibrotic disorders. Pharmaceutical compositions containing such compounds, as well as methods for their preparation, are also provided.

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 040,446, filed June 17, 2020, which is incorporated herein by reference in its entirety. [Background technology]

[0002] FIELD OF THE INVENTION The present invention relates to thyromimetic compounds, products containing such compounds, and methods of their use and preparation.

[0003] Related Technology Details Thyroid hormone (TH) is a key signal for oligodendrocyte differentiation and myelination during development and also stimulates remyelination in adult models of multiple sclerosis (MS) (Calza et al., Brain Res Revs 48:339-346, 2005). However, TH is not an acceptable long-term therapy due to the limited therapeutic window in which remyelination can be achieved while avoiding the cardiotoxicity and bone demineralization associated with chronic hyperthyroidism. By exploiting the molecular and physiological characteristics of the thyroid hormone receptor, some thyroid hormone analogs can activate thyroid hormone-responsive genes while avoiding the negative aspects associated with TH (Malm et al., Mini Rev Med Chem 7:79-86, 2007). These receptors are expressed in two major forms with heterogeneous tissue distribution and overlapping but distinct target gene populations (Yen, Physiol Rev 81:1097-1142, 2001). TRα is abundant in the heart, brain, and bone, while TRβ is abundant in the liver (O'Shea et al., Nucl Recept Signal 4:e011, 2006).

[0004] Furthermore, it has been reported that TH can attenuate fibrotic responses by inhibiting transforming growth factor β (TGF-β) signaling (Alonso-Merino et al., Proc Natl Acad Sci U S A. 113(24):E3451-60, 2016). TGF-β is a cytokine with pleiotropic effects on tissue homeostasis, playing an important role in pathological processes such as fibrosis (Massague, Nat Rev Mol Cell Biol. 13(10):616-630, 2012). By inhibiting TGF-β signaling, TR ligands or agonists may have beneficial effects in preventing the progression of fibrotic diseases such as idiopathic pulmonary fibrosis (IPF) and systemic sclerosis (Varga et al., Curr Opin Rheumatol. 20(6):720-728, 2008).

[0005] The development of selective thyromimetics has been complicated by the high sequence homology of thyroid hormone receptor subtypes, i.e., only one amino acid residue on the inner surface of the ligand-binding domain cavity varies between the α1 and β1 forms. Despite these challenges, several groups have reported TRβ-selective agonists. Scanlan et al. identified GC-1 (sobetirom) as one of the first potent analogs to demonstrate significant TRβ selectivity in vitro (Chiellini et al., Chem Biol 5:299-306, 1998; Yoshihara et al., J Med Chem 46:3152-3161, 2003) and in vivo (Trost et al., Endocrinology 141:3057-3064, 2000; Grover et al., Endocrinology 145:1656-1661, 2004; Baxter et al., Trends Endocrinol Metab 15:154-157, 2004). As used herein, the term "sobetirom" refers to a synthetic diarylmethane derivative that has undergone clinical trials as a potential therapeutic agent for hypercholesterolemia (see U.S. Pat. No. 5,883,294, incorporated herein by reference). Alternative names for sobetirom found in the literature and regulatory reports include QRX-431 and GC-1. Metabasis utilizes a similar core for a novel liver-targeting prodrug strategy in MB07811 (Erion et al., PNAS 104(39), 15490-15495, 2007). Madrigal reported TRβ-selective activity in vivo for MGL-3196 (Taub et al., Atherosclerosis 230(2):373-380, 2013). KaroBio has reported on Eprotirom (KB2115; Berkenstam et al., PNAS 105(2):663-668, 2008) and KB-141 (Ye et al., J Med Chem 46:1580-1588, 2003), both of which demonstrate improved TRβ selectivity in vitro.Further studies by this group have highlighted additional selective compounds (Hangeland et al., BMCL 14:3549-3553, 2004). Two TRβ-selective agonists, SKL-12846 and SKL-13784, have been identified, which 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 has also reported a selective compound (Shiohara et al., BMC 20(11), 3622-3634, 2012).

[0006] Despite advances in this field, there remains a need in the art for additional selective thyromimetic compounds, as well as products containing such compounds and related methods for their use and preparation. Summary of the Invention

[0007] As used herein, compounds of Formula I:

[0008] [ka] or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein A, X 1 , X 2 , Y 1 , Y 2 , and R 1 is defined as follows:

[0009] 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, in combination with a pharmaceutically acceptable carrier, diluent, or excipient. In one embodiment, the pharmaceutical composition is for use in treating neurodegenerative disorders, including neurodegenerative disorders classified as demyelinating diseases, such as X-linked adrenoleukodystrophy and multiple sclerosis. In another embodiment, the pharmaceutical composition is for use in treating a medical condition associated with increased TGF-β activity, such as a fibrotic disorder.

[0010] In one embodiment, a method is provided for treating a neurodegenerative disorder in a subject in need thereof, comprising administering a compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof, or a composition comprising said compound. In some aspects, the neurodegenerative disorder can be classified as a demyelinating disease, such as X-linked adrenoleukodystrophy or multiple sclerosis.

[0011] In another embodiment, methods are provided for treating a medical condition associated with overexpression of TGF-β in a subject in need thereof, comprising administering a compound having the structure of Formula (I) or a pharmaceutically acceptable salt thereof, or a composition comprising said compound. In some aspects, the medical condition associated with overexpression of TGF-β is a fibrotic disease. DETAILED DESCRIPTION OF THE INVENTION

[0012] As noted above, the present invention relates to thyromimetic compounds, products containing such compounds, and methods for their use and synthesis.

[0013] In one embodiment, a compound of formula (I):

[0014] [ka] or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocycle or heterocycle, where A is optionally substituted by one or more halo, lower alkyl, lower haloalkyl, —CN, —OR′, —NR′R″, ═O, ═S, —S(O)R′, or —S(O)OR′; X 1 is lower alkyl, lower alkenyl, lower haloalkyl, or halo; X 2 is lower alkyl, lower alkenyl, lower haloalkyl, or halo; Y 1 is H, —CN, halogen, lower alkyl, or lower alkoxy; Y 2 is H, —CN, halogen, lower alkyl, or lower alkoxy; R 2 is lower alkyl, lower alkenyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl, where R 2 is optionally substituted by one or more halo, lower alkyl, lower haloalkyl, —CN, —OR′, —NR′R″, ═O, ═S, —S(O)R′, or —S(O)OR′; R' and R'' are each independently H, lower alkyl, or lower haloalkyl; R 2 is isopropyl, and X 1 and X 2 are each methyl, then A is not a thiazolidinedione; Provided are compounds, or pharmaceutically acceptable isomers, racemates, tautomers, hydrates, solvates, isotopes, or salts thereof.

[0015] As used herein, "lower alkyl" refers to a straight- or branched-chain alkyl group having 1 to 8 carbon atoms, in some embodiments 1 to 6 carbon atoms, in some embodiments 1 to 4 carbon atoms, and in some embodiments 1 to 3 carbon atoms. Examples of straight-chain lower alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, and n-octyl. Examples of branched-chain lower alkyl groups include, but are not limited to, isopropyl, isobutyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2,2-dimethylpropyl.

[0016] As used herein, "lower alkenyl" refers to a straight or branched chain alkenyl group having from 2 to 8 carbon atoms, in some embodiments from 2 to 6 carbon atoms, in some embodiments from 2 to 4 carbon atoms, and in some embodiments from 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.

[0017] As used herein, "lower alkynyl" refers to a straight or branched chain alkynyl group having from 2 to 8 carbon atoms, in some embodiments from 2 to 6 carbon atoms, in some embodiments from 2 to 4 carbon atoms, and in some embodiments from 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, pentynyl, and hexynyl.

[0018] "Halo" or "halogen" refers to fluorine, chlorine, bromine, and iodine.

[0019] "Hydroxy" refers to --OH.

[0020] "Cyano" refers to -CN.

[0021] "Lower haloalkyl" refers to a lower alkyl, as defined herein, having one or more hydrogen atoms replaced with a halogen. Examples of lower haloalkyl groups include, but are not limited to, -CF3, -CHF2, and the like.

[0022] "Lower alkoxy" refers to a lower alkyl, as defined herein, attached through an oxygen atom (i.e., -O-(lower alkyl)). Examples of lower alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, n-butoxy, isopropoxy, sec-butoxy, tert-butoxy, and the like.

[0023] "Lower haloalkoxy" refers to a lower haloalkyl, as defined herein, attached through an oxygen atom (i.e., -O-(lower haloalkyl)). Examples of lower haloalkoxy groups include, but are not limited to, -OCF, -OCHF, and the like.

[0024] "Carbocyclyl," "carbocycle," or "carbocyclic" refers to an alkyl group forming a ring structure, which alkyl group can be substituted or unsubstituted, and which ring is fully saturated, partially unsaturated, or fully unsaturated, and where unsaturation is present, conjugation of pi electrons within the ring may result in aromaticity. In one embodiment, a carbocycle comprises a cycloalkyl, as defined herein. In another embodiment, a carbocycle comprises an aryl, as defined herein.

[0025] "Carbocyclealkyl" is an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a carbocyclyl group, as defined herein. In one embodiment, carbocyclealkyl includes cycloalkylalkyl. In one embodiment, carbocyclealkyl includes arylalkyl. Examples of carbocyclealkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, benzyl, and the like.

[0026] "Cycloalkyl" refers to an alkyl group forming a ring structure, which alkyl group can be substituted or unsubstituted, and the ring can be fully saturated, partially unsaturated, or fully unsaturated, provided that, if unsaturation is present, the coupling of π electrons within the ring does not result in aromaticity. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In some embodiments, cycloalkyl groups have 3-8 ring members, while in other embodiments, the number of ring carbon atoms is 3-5, 3-6, or 3-7. Cycloalkyl groups further include polycyclic cycloalkyl groups, such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl, as well as fused rings, such as, but not limited to, decalinyl.

[0027] "Cycloalkylalkyl" is an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group, as defined herein.

[0028] An "aryl" group is a cyclic aromatic hydrocarbon containing no heteroatoms. Thus, aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups. In some embodiments, aryl groups contain 6 to 14 carbons in the ring portion. The terms "aryl" and "aryl group" include fused rings in which at least one ring, but not necessarily all, is aromatic, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, etc.). In one embodiment, aryl is phenyl or naphthyl, and in another embodiment, phenyl.

[0029] "Arylalkyl" is an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to an aryl group, as defined herein.

[0030] "Heterocyclyl," "heterocycle," or "heterocyclic" refers to aromatic and non-aromatic ring moieties 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, heterocyclyl groups contain 3-20 membered rings, while other such groups have 3-15 membered rings. At least one ring contains a heteroatom, but not all rings in a polycyclic ring system need contain heteroatoms. For example, both dioxolanyl and benzdioxolanyl ring systems (methylenedioxyphenyl ring systems) are heterocyclyl groups within the meaning herein.

[0031] Heterocyclyl groups further include fused ring species, including those with fused aromatic and non-aromatic groups. Heterocyclyl groups further include heteroatom-containing polycyclic ring systems, such as, but not limited to, quinuclidyl, and also include heterocyclyl groups having substituents attached to one of the ring members, including, but not limited to, alkyl, halo, amino, hydroxy, cyano, carboxy, nitro, thio, or alkoxy groups. Heterocyclyl groups, as defined herein, can be heteroaryl groups containing at least one ring heteroatom or partially or fully saturated cyclic groups. Heterocyclyl groups include pyrrolidinyl, furanyl, tetrahydrofuranyl, dioxolanyl, piperidinyl, piperazinyl, morpholinyl, pyrrolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridinyl, thiophenyl, benzothiophenyl, benzofuranyl, dihydrobenzofuranyl, indolyl, dihydroindolyl, azaindolyl, indazolyl, benzimidazolyl, and azabenzimidazolyl. Examples of such groups include, but are not limited to, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, quinoxalinyl, and quinazolinyl groups.

[0032] "Heterocyclealkyl" is an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a heterocycle group, as defined herein. In one embodiment, heterocyclealkyl includes heteroarylalkyl.

[0033] "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 pyrrolyl, pyrazolyl, pyridinyl, pyridazinyl, pyrimidyl, pyrazyl, pyrazinyl, pyrimidinyl, thienyl, triazolyl, tetrazolyl, triazinyl, thiazolyl, thiophenyl, oxazolyl, isoxazolyl, benzothiophenyl, benzofuranyl, indolyl, azaindolyl, indazolyl, benzimidazolyl, azabenzimidazolyl, benzoxazolyl, benzothiazolyl, benzothiadiazolyl, imidazopyridinyl, isoxazolopyridinyl, thianaphthalenyl, purinyl, xanthinyl, adeninyl, guaninyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, quinoxalinyl, and quinazolinyl. The terms "heteroaryl" and "heteroaryl group" include fused ring compounds in which at least one ring, but not necessarily all, is aromatic, including tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, and 2,3-dihydroindolyl.

[0034] "Heteroarylalkyl" is an alkyl group, as defined herein, in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a heteroaryl group, as defined herein.

[0035] In one embodiment, a compound of formula (II):

[0036] [ka] or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocycle or heterocycle, where A is optionally substituted by one or more halo, lower alkyl, lower haloalkyl, —CN, —OR′, —NR′R″, ═O, ═S, —S(O)R′, or —S(O)OR′; X 1 is lower alkyl, lower alkenyl, lower haloalkyl, or halo; X 2 is lower alkyl, lower alkenyl, lower haloalkyl, or halo; Y 1 is H, —CN, halogen, lower alkyl, or lower alkoxy; Y 2 is H, —CN, halogen, lower alkyl, or lower alkoxy; R 2 is lower alkyl, lower alkenyl, carbocycle, heterocycle, carbocyclic alkyl, or heterocyclic alkyl, where R 2 is optionally substituted by one or more halo, lower alkyl, lower haloalkyl, —CN, —OR′, —NR′R″, ═O, ═S, —S(O)R′, or —S(O)OR′; R' and R'' are each independently H, lower alkyl, or lower haloalkyl; R 2 is isopropyl, and X 1 and X 2 are each methyl, then A is not a thiazolidinedione; Provided are compounds, or pharmaceutically acceptable isomers, racemates, tautomers, hydrates, solvates, isotopes, or salts thereof.

[0037] In one embodiment, a compound is provided having the structure of Formula (I) or Formula (II), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein R 2 is lower alkyl optionally substituted with one or more halo, -CN, -OR', -NR'R'', ═O, ═S, -S(O)R', or -S(O)OR', wherein R' and R'' are each independently H, lower alkyl, or lower haloalkyl. In another embodiment, R 2 is unsubstituted lower alkyl. In more specific embodiments, R 2 is methyl, ethyl, propyl, or butyl. In one embodiment, R2 is isopropyl.

[0038] In one embodiment, a compound of formula (III):

[0039] [ka] or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocycle or heterocycle, where A is optionally substituted by one or more halo, lower alkyl, lower haloalkyl, —CN, —OR′, —NR′R″, ═O, ═S, —S(O)R′, or —S(O)OR′; X 1 is lower alkyl, lower alkenyl, lower haloalkyl, or halo; X 2 is lower alkyl, lower alkenyl, lower haloalkyl, or halo; Y 1 is H, —CN, halogen, lower alkyl, or lower alkoxy; Y 2 is H, —CN, halogen, lower alkyl, or lower alkoxy; R' and R'' are each independently H, lower alkyl, or lower haloalkyl; X 1 and X 2 are each methyl, then A is not a thiazolidinedione; Provided are compounds, or pharmaceutically acceptable isomers, racemates, tautomers, hydrates, solvates, isotopes, or salts thereof.

[0040] In one embodiment, a compound is provided having the structure of Formula (I) or Formula (II), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein R 2In one embodiment, a compound is provided having the structure of Formula (I) or Formula (II), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein R 2 is arylalkyl or heteroarylalkyl.

[0041] In one embodiment, a compound of formula (IV):

[0042] [ka] or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocycle or heterocycle, where A is optionally substituted by one or more halo, lower alkyl, lower haloalkyl, —CN, —OR′, —NR′R″, ═O, ═S, —S(O)R′, or —S(O)OR′; R' and R'' are each independently H, lower alkyl, or lower haloalkyl; B is aryl or heteroaryl; X 1 is lower alkyl, lower alkenyl, lower haloalkyl, or halo; X 2 is lower alkyl, lower alkenyl, lower haloalkyl, or halo; Y 1 is H, —CN, halogen, lower alkyl, or lower alkoxy; Y 2 is H, —CN, halogen, lower alkyl, or lower alkoxy; Q is -C(R 3 R 4 )-or-{C(R 3 R 4 )}2- and R 3 and R 4is, at each occurrence, independently selected from H, halo, —CN, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, —OR a , -NR a R b , carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl, or R 3 and R 4 come together to form =O or =S, R 5 are each independently halo, -CN, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycle alkyl, heterocycle alkyl, -OR a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R b , -S(O)2R a , or -S(O)2OR a and n is 0 to 5, R a and R b are each independently H, lower alkyl, or lower haloalkyl; R 3 , R 4 , R 5 , R a , and R b are each independently optionally substituted by one or more halo, —CN, —OR′, —NR′R″, ═O, ═S, —S(O)R′, or —S(O)OR′; Provided are compounds, or pharmaceutically acceptable isomers, racemates, tautomers, hydrates, solvates, isotopes, or salts thereof.

[0043] In one embodiment, a compound of formula (V):

[0044] [ka] or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein: Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are independently CH, CR 5 , or N, A is a carbocycle or heterocycle, where A is optionally substituted by one or more halo, lower alkyl, lower haloalkyl, —CN, —OR′, —NR′R″, ═O, ═S, —S(O)R′, or —S(O)OR′; R' and R'' are each independently H, lower alkyl, or lower haloalkyl; X 1 is lower alkyl, lower alkenyl, lower haloalkyl, or halo; X 2 is lower alkyl, lower alkenyl, lower haloalkyl, or halo; Y 1 is H, —CN, halogen, lower alkyl, or lower alkoxy; Y 2 is H, —CN, halogen, lower alkyl, or lower alkoxy; R 3 and R 4 are each independently H, halo, -CN, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR a , -NR a R b , carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl, or R 3 and R 4 come together to form =O or =S, R 5 are each independently halo, -CN, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycle alkyl, heterocycle alkyl, -OR a , -NR a R b , -C(O)R a, -C(O)OR a , -C(O)NR a R b , -NR a C(O)R b , -S(O)2R a , or -S(O)2OR a and n is 0 to 5, R a and R b are each independently H, lower alkyl, or lower haloalkyl; R 3 , R 4 , R 5 , R a , and R b are each independently optionally substituted by one or more halo, —CN, —OR′, —NR′R″, ═O, ═S, —S(O)R′, or —S(O)OR′; Provided are compounds, or pharmaceutically acceptable isomers, racemates, tautomers, hydrates, solvates, isotopes, or salts thereof.

[0045] In one embodiment, a compound is provided having the structure of Formula (V), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Q 1 , Q 2 , Q 3 , Q 4 , or Q 5 and each independently represent N. In one embodiment, a compound is provided having the structure of Formula (V), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Q 1 , Q 2 , Q 3 , Q 4 , or Q 5 and at least one of Q is N. In one embodiment, a compound is provided having the structure of Formula (V), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Q 1 , Q 2 , Q 3 , Q 4, and Q 5 At least two of them are N.

[0046] In one embodiment, a compound of formula (VI):

[0047] [ka] or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocycle or heterocycle, where A is optionally substituted by one or more halo, lower alkyl, lower haloalkyl, —CN, —OR′, —NR′R″, ═O, ═S, —S(O)R′, or —S(O)OR′; R' and R'' are each independently H, lower alkyl, or lower haloalkyl; X 1 is lower alkyl, lower alkenyl, lower haloalkyl, or halo; X 2 is lower alkyl, lower alkenyl, lower haloalkyl, or halo; Y 1 is H, —CN, halogen, lower alkyl, or lower alkoxy; Y 2 is H, —CN, halogen, lower alkyl, or lower alkoxy; R 3 and R 4 are each independently H, halo, -CN, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, -OR a , -NR a R b , carbocyclic, heterocyclic, carbocyclic alkyl, or heterocyclic alkyl, or R 3 and R 4 come together to form =O or =S, R 5 are each independently halo, -CN, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycle alkyl, heterocycle alkyl, -ORa , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R b , -S(O)2R a , or -S(O)2OR a and n is 0 to 5, R a and R b are each independently H, lower alkyl, or lower haloalkyl; R 3 , R 4 , R 5 , R a , and R b are each independently optionally substituted by one or more halo, —CN, —OR′, —NR′R″, ═O, ═S, —S(O)R′, or —S(O)OR′; Provided are compounds, or pharmaceutically acceptable isomers, racemates, tautomers, hydrates, solvates, isotopes, or salts thereof.

[0048] In one embodiment, a compound is provided having the structure of Formula (I) or Formula (II), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein R 2 In one embodiment, a compound is provided having the structure of Formula (I) or Formula (II), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein R 2 is aryl or heteroaryl.

[0049] In one embodiment, a compound of formula (VII):

[0050] [ka] or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocycle or heterocycle, where A is optionally substituted by one or more halo, lower alkyl, lower haloalkyl, —CN, —OR′, —NR′R″, ═O, ═S, —S(O)R′, or —S(O)OR′; R' and R'' are each independently H, lower alkyl, or lower haloalkyl; B is aryl or heteroaryl; X 1 is lower alkyl, lower alkenyl, lower haloalkyl, or halo; X 2 is lower alkyl, lower alkenyl, lower haloalkyl, or halo; Y 1 is H, —CN, halogen, lower alkyl, or lower alkoxy; Y 2 is H, —CN, halogen, lower alkyl, or lower alkoxy; R 5 are each independently halo, -CN, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycle alkyl, heterocycle alkyl, -OR a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R b , -S(O)2R a , or -S(O)2OR a and n is 0 to 5, R a and R b are each independently H, lower alkyl, or lower haloalkyl; R 5 , R a , and R bare each independently optionally substituted by one or more halo, —CN, —OR′, —NR′R″, ═O, ═S, —S(O)R′, or —S(O)OR′; Provided are compounds, or pharmaceutically acceptable isomers, racemates, tautomers, hydrates, solvates, isotopes, or salts thereof.

[0051] In one embodiment, there is provided a compound having the structure of Formula (VII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, where B is a carbocycle. In one embodiment, there is provided a compound having the structure of Formula (II), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, where B is aryl. In one embodiment, there is provided a compound having the structure of Formula (II), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, where B is phenyl.

[0052] In one embodiment, a compound of formula (VIII):

[0053] [ka] or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein: A is a carbocycle or heterocycle, where A is optionally substituted by one or more halo, lower alkyl, lower haloalkyl, —CN, —OR′, —NR′R″, ═O, ═S, —S(O)R′, or —S(O)OR′; R' and R'' are each independently H, lower alkyl, or lower haloalkyl; X 1 is lower alkyl, lower alkenyl, lower haloalkyl, or halo; X 2 is lower alkyl, lower alkenyl, lower haloalkyl, or halo; Y 1is H, —CN, halogen, lower alkyl, or lower alkoxy; Y 2 is H, —CN, halogen, lower alkyl, or lower alkoxy; R 5 are each independently halo, -CN, lower alkyl, lower alkenyl, lower alkynyl, lower haloalkyl, carbocycle, heterocycle, carbocycle alkyl, heterocycle alkyl, -OR a , -NR a R b , -C(O)R a , -C(O)OR a , -C(O)NR a R b , -NR a C(O)R b , -S(O)2R a , or -S(O)2OR a and n is 0 to 5, R a and R b are each independently H, lower alkyl, or lower haloalkyl; R 5 , R a , and R b are each independently optionally substituted by one or more halo, —CN, —OR′, —NR′R″, ═O, ═S, —S(O)2R′, or —S(O)2OR′, and R′ and R″ are each independently H, lower alkyl, or lower haloalkyl; Provided are compounds, or pharmaceutically acceptable isomers, racemates, tautomers, hydrates, solvates, isotopes, or salts thereof.

[0054] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein A is a carbocycle optionally substituted with one or more halo, lower alkyl, lower haloalkyl, —CN, —OR′, —NR′R″, ═O, ═S, —S(O)R′, or —S(O)OR′, and R′ and R″ are each independently H, lower alkyl, or lower haloalkyl. In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein A is aryl optionally substituted with one or more halo, lower alkyl, lower haloalkyl, —CN, —OR′, —NR′R″, ═O, ═S, —S(O)R′, or —S(O)OR′, and R′ and R″ are each independently H, lower alkyl, or lower haloalkyl.

[0055] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein A is phenyl optionally substituted with one or more halo, lower alkyl, lower haloalkyl, —CN, —OR′, —NR′R″, ═O, ═S, —S(O)R′, or —S(O)OR′, and R′ and R″ are each independently H, lower alkyl, or lower haloalkyl. In one embodiment, A is phenyl optionally substituted with one or more halo. In one embodiment, A is phenyl optionally substituted with one or more —CN. In one embodiment, A is phenyl optionally substituted with one or more -OR', where each R' is independently H, lower alkyl, or lower haloalkyl. In one embodiment, A is phenyl optionally substituted with one or more -OR', where each R' is independently H, lower alkyl, or lower haloalkyl, and at least one R' is H.

[0056] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein A is phenol or a substituted phenol. In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein A is

[0057] [ka] is.

[0058] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein A is a heterocycle optionally substituted with one or more halo, lower alkyl, lower haloalkyl, —CN, —OR′, —NR′R″, ═O, ═S, —S(O)R′, or —S(O)OR′, and R′ and R″ are each independently H, lower alkyl, or lower haloalkyl. In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein A is heteroaryl optionally substituted with one or more halo, lower alkyl, lower haloalkyl, —CN, —OR′, —NR′R″, ═O, ═S, —S(O)R′, or —S(O)OR′, and R′ and R″ are each independently H, lower alkyl, or lower haloalkyl. In one embodiment, A is triazinyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl.

[0059] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein A is

[0060] [ka] and R 6 is H or -CN.

[0061] In one embodiment, a compound is provided 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, wherein R 3 is H.

[0062] In one embodiment, a compound is provided 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, wherein R 3 is a carbocyclic ring. In one embodiment, R 3 is cyclopropyl or cyclobutyl.

[0063] In one embodiment, a compound is provided 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, wherein R 3 is lower alkyl. In one embodiment, R 3 is methyl, ethyl, or propyl.

[0064] In one embodiment, a compound is provided 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, wherein R 3 HA-OR a In one embodiment, R a is H. In one embodiment, R a is lower alkyl. In one embodiment, R a is lower methyl.

[0065] In one embodiment, a compound is provided 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, wherein R 4 is H.

[0066] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 1 is lower alkyl. In one embodiment, X 1 is methyl.

[0067] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 1 is halo. In one embodiment, X 1 is Cl or Br. In one embodiment, X 1 is Cl. In one embodiment, X 1 is Br.

[0068] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 1 is lower haloalkyl. In one embodiment, X 1 is —CHF, —CHF, or —CF. In one embodiment, X 1 is -CF3.

[0069] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 1is lower alkenyl. In one embodiment, X 1 is vinyl or isopropenyl.

[0070] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 2 is lower alkyl. In one embodiment, X 2 is methyl.

[0071] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 2 is halo. In one embodiment, X 2 is Cl or Br. In one embodiment, X 2 is Cl. In one embodiment, X 2 is Br.

[0072] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 2 is lower haloalkyl. In one embodiment, X 2 is —CHF2 or —CF3. In one embodiment, X 2 is -CF3.

[0073] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 2 is lower alkenyl. In one embodiment, X 2 is vinyl or isopropenyl.

[0074] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 is lower alkyl. In one embodiment, R 5 is lower alkyl substituted with -OR'. In one embodiment, R' is H. In one embodiment, R' is lower alkyl. In one embodiment, R' is methyl, ethyl, or propyl.

[0075] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 is lower haloalkyl. In one embodiment, at least one R 5 is —CHF, —CHF, or —CF. In one embodiment, at least one R 5 is -CF3.

[0076] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 HA-OR a In one embodiment, R a is lower alkyl. In one embodiment, R a is methyl, ethyl, or propyl. In one embodiment, R a is lower haloalkyl. In one embodiment, R a is -CHF2 or -CF3.

[0077] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 HA-C(O)R a In one embodiment, R a is lower alkyl. In one embodiment, R a is methyl, ethyl, or propyl.

[0078] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 Ha-NR a C(O)R b In one embodiment, R a is H and R b is lower alkyl. In one embodiment, R a is H and R b is methyl, ethyl, or propyl. In one embodiment, Ra is H and R b is methyl.

[0079] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), 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 embodiment, R a is lower alkyl. In one embodiment, R a is methyl, ethyl, or propyl. In one embodiment, R a is methyl. In one embodiment, R a is ethyl.

[0080] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 -S(O)2R a In one embodiment, R a is lower alkyl. In one embodiment, R a is methyl, ethyl, or propyl. In one embodiment, R a is methyl.

[0081] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 is halo. In one embodiment, at least one R 5 is F.

[0082] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 is -CN.

[0083] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is a halogen. In one embodiment, Y 1 is F. In one embodiment, Y 1 is Cl.

[0084] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is -CN.

[0085] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is lower alkyl. In one embodiment, Y 1 is methyl, ethyl, or propyl. 1 is methyl.

[0086] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is lower alkoxy. In one embodiment, Y 1 is methoxy or ethoxy. 1 is methoxy.

[0087] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is H.

[0088] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 2 is a halogen. In one embodiment, Y 2 is F. In one embodiment, Y 2 is Cl.

[0089] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 2 is -CN.

[0090] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 2 is lower alkyl. In one embodiment, Y 2 is methyl, ethyl, or propyl. 2 is methyl.

[0091] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 2 is lower alkoxy. In one embodiment, Y 2 is methoxy or ethoxy. 2 is methoxy.

[0092] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 2 is H.

[0093] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is F and Y 2 is H.

[0094] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is Cl and Y 2 is H.

[0095] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is -CN and Y 2 is H.

[0096] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is lower alkyl, and Y 2 is H. In one embodiment, Y 1 is methyl and Y 2 is H.

[0097] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is lower alkoxy, and Y 2 is H. In one embodiment, Y 1 is methoxy and Y 2 is H.

[0098] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is H and Y 2 is F.

[0099] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is H and Y 2 is Cl.

[0100] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is H and Y 2 is -CN.

[0101] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is H and Y 2 is lower alkyl. In one embodiment, Y 1 is H and Y 2 is methyl.

[0102] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is H and Y 2 is alkoxy. In one embodiment, Y 1 is H and Y 2 is methyl.

[0103] In one embodiment, there is provided a compound having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is F and Y 2 is F.

[0104] Representative compounds of Formula (I) and Formulas (II)-(VIII), as applicable, include those listed in Table 1 below, as well as pharmaceutically acceptable salts thereof. As such, representative compounds are identified herein by their respective "Compound Numbers," which are sometimes abbreviated as "Compound No.", "Cmpd No.", or "No."

[0105] [Table 1-1]

[0106] [Table 1-2]

[0107] As used herein, "isomer" includes all diastereomeric or racemic forms of a structure unless a particular stereochemistry or isomeric form is specifically indicated. Such compounds can be enriched or resolved optical isomers at any or all asymmetric atoms apparent from the description, to any degree of enrichment. Both racemic and diastereomeric mixtures, as well as individual optical isomers, can be synthesized to be substantially free of their enantiomeric or diastereomeric partners, all of which are within the scope of certain embodiments of the present invention. Isomers resulting from the presence of chiral centers include non-superimposable pairs of isomers called "enantiomers." A single enantiomer of a pure compound is optically active (i.e., capable of rotating the plane of plane-polarized light and designated R or S).

[0108] "Isolated optical isomer" means a compound that has been substantially purified from the corresponding optical isomer of the same formula. For example, the isolated isomer may be at least about 80%, at least 80%, or at least 85% pure by weight. In other embodiments, the isolated isomer is at least 90%, at least 98%, or at least 99% pure by weight.

[0109] "Substantially enantiomerically or diastereomerically" pure means a degree of enantiomeric or diastereomeric enrichment of one enantiomer relative to the other enantiomer or diastereomer of at least about 80%, more specifically, greater than 80%, 85%, 90%, 95%, 98%, 99%, 99.5%, or 99.9%.

[0110] The terms "racemate" and "racemic mixture" refer to an equal mixture of two enantiomers. A racemate is marked with "(±)" because it is not optically active (i.e., it does not rotate plane-polarized light in either direction because its component enantiomers cancel each other out). Compounds marked with an asterisk (*) adjacent to a tertiary or quaternary carbon are all optically active isomers, which may be purified from their respective racemates and / or synthesized by appropriate chiral syntheses.

[0111] "Tautomer" refers to each of two or more structural isomers that readily undergo interconversion in equilibrium by the movement of atoms or groups within a molecule. Tautomers often result from the transfer of a proton from one atom of a molecule to another atom of the same molecule. The present invention includes tautomers of compounds of formula (I). For example, tautomers of isoxazolol and hydroxytriazinone are shown below.

[0112] [ka]

[0113] A "hydrate" is a compound that exists in combination with water molecules. This combination may contain a stoichiometric amount of water, such as a monohydrate or dihydrate, or may contain random amounts of water. As used herein, "hydrate" refers to a solid form; i.e., a compound in an aqueous solution may be hydrated, but is not a hydrate as the term is used herein.

[0114] A "solvate" is similar to a hydrate, except that water is present in the presence of another solvent. For example, methanol or ethanol can form an "alcoholate," which again can be stoichiometric or non-stoichiometric. As used herein, "solvate" refers to a solid form, i.e., a compound in a solvent solution may be solvated, but is not a solvate as the term is used herein.

[0115] "Isotope" refers to an atom with the same number of protons but a different number of neutrons, and isotopes of a compound of Formula (I) include compounds in which one or more atoms are replaced by an isotope 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 being the longest-lived. Thus, isotopes of a compound 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.

[0116] "Salt" generally refers to an organic compound, such as a carboxylic acid or an amine, in ionic form 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."

[0117] The term "pharmaceutically acceptable" refers to a drug that is approved for human consumption and is generally non-toxic. For example, the term "pharmaceutically acceptable salt" refers to a non-toxic inorganic 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, incorporated herein by reference).

[0118] Pharmaceutically acceptable base addition salts of the compounds of the present invention include metal salts, including alkali metal salts, alkaline earth metal salts, and transition metal salts, such as, for example, calcium salts, magnesium salts, potassium salts, sodium salts, zinc salts, etc. Pharmaceutically acceptable base addition salts also include organic salts made from basic amines, such as, for example, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), tromethamine (tris-hydroxymethylmethylamine), procaine, and the like.

[0119] Pharmaceutically acceptable acid addition salts may be prepared from inorganic or organic acids. Examples of inorganic acids include hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric, and phosphoric acids. Suitable organic acids may be selected from the aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carbocyclic, and sulfonic classes of organic acids, including, for example, 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, and acetic acid. These include mannitol, ...

[0120] Although salts that are not pharmaceutically acceptable are generally not useful as pharmaceuticals, such salts may be useful as intermediates in the synthesis of compounds having the structure of Formula I, for example, in purification by recrystallization.

[0121] In some embodiments, the present invention provides pharmaceutical compositions comprising the compound of the present invention together with at least one pharmaceutically acceptable carrier, diluent, or excipient.For example, the active compound is usually mixed with a carrier, diluted by a carrier, or enclosed in a carrier, which can be in the form of an ampoule, capsule, sachet, paper, or other container.When the active compound is mixed with a carrier or the carrier functions as a diluent, the carrier can be a solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound.The active compound may be adsorbed on a particulate solid carrier, for example, contained in a sachet. Some examples of suitable carriers are water, saline, alcohol, polyethylene glycol, polyhydroxyethoxylated castor oil, peanut oil, olive oil, gelatin, lactose, terra alba, sucrose, dextrin, magnesium carbonate, sugar, cyclodextrin, amylose, magnesium stearate, talc, gelatin, agar, pectin, acacia, stearic acid, or lower alkyl ethers of cellulose, silicic acid, fatty acids, fatty acid amines, fatty acid mono- and diglycerides, pentaerythritol fatty acid esters, polyoxyethylene, hydroxymethylcellulose, and polyvinylpyrrolidone. Similarly, the carrier or diluent can include any sustained-release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.

[0122] As used herein, the term "pharmaceutical composition" refers to a composition containing one or more of the compounds described herein, or pharmaceutically acceptable isomers, racemates, tautomers, hydrates, solvates, isotopes, or salts thereof, formulated with a pharmaceutically acceptable carrier, which may also include other additives, and manufactured or sold with regulatory approval as part of a therapeutic regimen for treating a mammalian disease. Pharmaceutical compositions can be formulated, for example, for oral administration in a unit dosage form (e.g., tablet, capsule, caplet, gelcap, or syrup), for topical administration (e.g., as a cream, gel, lotion, or ointment), for intravenous administration (e.g., as a particulate, plug-free sterile solution in a solvent system suitable for intravenous use), or in any other formulation described herein. Conventional procedures and ingredients in the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21st Ed., Gennaro, Ed., Lippencott Williams & Wilkins (2005), and the 2013 publication of the United States Pharmacopeia: The National Formulary (USP 36 NF31).

[0123] As used herein, the term "pharmaceutically acceptable carrier" refers to any component (e.g., a carrier capable of suspending or dissolving an active compound) other than a compound of the present disclosure, or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, that is non-toxic and non-inflammatory to a patient. Excipients may include, for example, antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colorants), emollients, emulsifiers, fillers (diluents), film-forming agents or coatings, flavors, fragrances, glidants (glidants), lubricants, preservatives, printing inks, adsorbents, suspending or dispersing agents, sweeteners, or hydration water. Exemplary excipients include, but are not limited to, butylhydroxytoluene (BHT), calcium carbonate, calcium phosphate (dibasic), calcium stearate, croscarmellose, cross-linked polyvinylpyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropylmethylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methylparaben, microcrystalline cellulose, polyethylene glycol, polyvinylpyrrolidone, povidone, pregelatinized starch, propylparaben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethylcellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn), stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

[0124] The preparation can be mixed with auxiliary agents that do not cause adverse reactions with active compounds.Such additives can include wetting agents, emulsifying and suspending agents, salts for affecting osmotic pressure, and / or coloring substances, preservatives, sweeteners, or flavoring agents.If desired, the composition can also be sterilized.

[0125] The route of administration can be any route that effectively delivers the active compounds of the present invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subcutaneous, intradermal, transdermal, or parenteral, including intravenous, subcutaneous, and / or intramuscular, hi one embodiment, the route of administration is oral.

[0126] Dosage forms can be administered once daily or more frequently, such as twice or three times daily. Alternatively, dosage forms can be administered less frequently than daily, such as every other day or every week, if found desirable by the prescribing physician or drug prescribing information. Dosage regimens can include, for example, titrating the dose as needed or useful for the indication being treated, allowing the patient's body to adapt to the treatment, minimizing or avoiding unwanted side effects associated with the treatment, and / or maximizing the therapeutic effect of the compounds of the present invention. Other dosage forms include delayed-dose or controlled-release forms. Suitable dosage regimens and / or forms include, for example, those described in the latest edition of the Physician's Package Insert, incorporated herein by reference.

[0127] In another embodiment, a method for making a composition of a compound described herein is provided, the method comprising formulating a compound of the present invention with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the method can further comprise formulating the composition into a tablet or capsule. In other embodiments, the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration. In some such embodiments, the method further comprises lyophilizing the composition to form a lyophilized preparation.

[0128] In another embodiment, a method of treating a subject having a neurodegenerative disease is provided, 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 disease, leukodystrophy, dementia, tauopathy, or ischemic stroke. In another embodiment, the demyelinating disease is selected from the group consisting of adult Refsum's disease, Alexander's disease, Alzheimer's disease, Barro's concentric sclerosis, Canavan's disease, central pontine myelinolysis (CPM), cerebral palsy, cerebrotendinous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic's syndrome, diffuse myeloclastic sclerosis, encephalomyelitis, and idiopathic inflammatory demyelinating diseases. The demyelinating disease is or is associated with multiple sclerosis, infantile Refsum's disease, Krabbe's disease, Leber's hereditary optic neuropathy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy, multifocal motor neuropathy, paraproteinemic demyelinating polyneuropathy, Pelizaeus-Merzbacher disease, peroneal muscular atrophy, progressive multifocal leukoencephalopathy, transverse myelitis, tropical spastic paraparesis, van der Knapp's disease, or Zellweger syndrome. In one embodiment, the demyelinating disease is or is associated with multiple sclerosis, MCT8 deficiency, X-linked adrenoleukodystrophy (ALD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia, or microcavitary stroke.

[0129] As used herein, the term "neurodegenerative disease" refers to any type of disease characterized by the gradual deterioration of the nervous system.

[0130] As used herein, the term "demyelinating disease" refers to any disease or condition of the nervous system in which myelin is damaged or lost or the growth or development of the myelin sheath is impaired. Demyelination inhibits the conduction of signals in the affected nerves that result in nerve-related functions such as sensation, movement, and cognition. Demyelinating diseases have many different causes and can be genetic or congenital. In some cases, demyelinating diseases are caused by infectious agents, autoimmune reactions, toxins, or trauma. In other cases, the cause of a demyelinating disease is unknown ("idiopathic") or progresses due to a combination of factors.

[0131] As used herein, the term "leukodystrophies" refers to a group of diseases that affect the growth or development of the myelin sheath.

[0132] As used herein, the term "leukoencephalopathy" refers to any of a group of diseases that affect the white matter of the brain and can specifically refer to several diseases including, for example, "vanishing white matter leukoencephalopathy" and "toxic leukoencephalopathy." Leukoencephalopathy is a disease such as leukodystrophy.

[0133] As used herein, the term "tauopathy" refers to tau-related disorders or diseases, such as Alzheimer's disease (AD), Progressive Supranuclear Palsy (PSP), Corticobasal Degeneration (CBD), Pick's Disease (PiD), Argyrophilic grain disease (AGD), Frontotemporal Dementia, and Parkinsonism associated with chromosome 17 (FTDP-17), Parkinson's disease, stroke, traumatic brain injury, mild cognitive impairment, and the like.

[0134] As used herein, the terms "multiple sclerosis" and "MS" refer to a slowly progressive CNS disease characterized by scattered patches of demyelination in the brain and spinal cord, usually resulting in multiple altered neurological symptoms and signs with remissions and exacerbations. The cause of MS is unknown, but immunological abnormalities are suspected. Increased familial incidence indicates genetic susceptibility, and women are somewhat more affected than men. MS symptoms include weakness, poor coordination, sensory abnormalities, speech disorders, and visual impairment, with diplopia being the most common. More specific signs and symptoms depend on the location of the lesion and the severity and destructive nature of the inflammatory and sclerotic process. Relapsing-remitting multiple sclerosis (RRMS) is a clinical course of MS characterized by clearly defined acute attacks with complete or partial recovery and no disease progression between attacks. Secondary-progressive multiple sclerosis (SPMS) is a clinical course of MS that initially begins as a relapsing-remitting disease and later becomes progressive at a variable rate, possibly with occasional relapses and minor remissions. Primary-progressive multiple sclerosis (PPMS) begins as a progressive disease. The initial neurological episode is a clinically isolated syndrome, resulting from inflammation / demyelination in one or more sites in the CNS. Progressive-relapsing multiple sclerosis (PRMS) is a rare form of MS (approximately 5%) characterized by a steady worsening of the disease state from onset, with acute relapses but no remissions.

[0135] In yet another embodiment, a method of treating a subject having an X-linked genetic disease is provided, 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 disease is MCT8 deficiency or X-linked adrenoleukodystrophy (ALD).

[0136] In another embodiment, a method of treating a subject having a leukodystrophy is provided, 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 leukodystrophy is adrenoleukodystrophy (ALD), adrenomyeloneuropathy (AMN), cerebral form of adrenoleukodystrophy (cALD), metachromatic leukodystrophy (MLD), Canavan disease, or Krabbe disease (spherocytosis). As used herein, the term "adrenomyeloneuropathy" or "AMN" refers to an adult variant of X-linked adrenoleukodystrophy characterized by ABCD1 gene mutations, which impair peroxisomal function through accumulation of very long-chain fatty acids (VLCFAs) and demyelination.

[0137] In one embodiment, a method of treating a subject having a tauopathy is provided, 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 tauopathy is Alzheimer's disease, frontotemporal dementia, primary age-related tauopathy (PART), Pick's disease, or frontotemporal dementia and Parkinsonism associated with chromosome 17 (FTDP-17).

[0138] In yet another embodiment, a method of treating a subject having an ischemic stroke is provided, 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 syrinx stroke (also called a "lacunar infarction"). In another embodiment, the method of the present invention is used to treat a subject suffering from syrinx stroke syndrome (LACS).

[0139] In another embodiment, the present invention relates to adult Refsum's disease, infantile Refsum's disease, Alexander's disease, Alzheimer's disease, Barrow's concentric sclerosis, Canavan's disease, central pontine myelinolysis (CPM), cerebral palsy, cerebrotendinous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP), Devic's syndrome, diffuse myeloclastic sclerosis, encephalomyelitis, idiopathic inflammatory demyelinating disease (IIDD), Krabbe's disease, Leber's hereditary optic neuropathy, leukodystrophy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy (MLD), multifocal motor neuropathy (MMN), multiple sclerosis (MS), paraproteinaceous demyelinating polyneuropathy, Pelizaeus-Merzbacher disease (PMD), progressive multifocal leukoencephalopathy (PLE), and / or progressive encephalopathy (PLE).

[0003] Provided are methods of treating a subject with PML), tropical spastic paraparesis (TSP), X-linked adrenoleukodystrophy (X-ALD, ALO, or X-linked ALO), or Zellweger syndrome, 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.

[0140] In one embodiment, the demyelinating disease is multiple sclerosis. In another embodiment, the demyelinating disease is X-linked adrenoleukodystrophy (ALD).

[0141] In another embodiment, a method for treating a subject with amyotrophic lateral sclerosis (ALS) disease is provided, comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of formula (I), or its pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt, or a pharmaceutical composition thereof.In one embodiment, the ALS is sporadic or familial ALS, or ALS associated with superoxide dismutase-1 mutation.

[0142] In one embodiment, a method of treating a subject having a condition associated with increased TGF-β activity is provided, 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 condition associated with increased TGF-β activity is a fibrotic disease. In another embodiment, the fibrotic disease is or is associated with nonalcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis (IPF), systemic sclerosis, or Alport syndrome. As used herein, the term "Alport syndrome" refers to a genetic disease caused by a mutation in the a3a4a5(IV) collagen network gene, which early in its progression leads to structural defects in the glomerular basement membrane (GBM), subsequently resulting in breakdown of the filtration barrier, progression of renal fibrosis, and renal failure.

[0143] As used herein, the term "fibrotic disease" refers to a disease, disorder, or condition suitable for treatment by administration of a compound having antifibrotic activity. Fibrotic diseases include, but are not limited to, pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis of known etiology, hepatic fibrosis, and renal fibrosis. Other exemplary fibrotic diseases include musculoskeletal fibrosis, cardiac fibrosis, postoperative adhesions, scleroderma, glaucoma, and skin lesions such as keloids.

[0144] In another embodiment, there is provided a method of treating a subject having liver disease including NASH, NAFLD, NAFLD associated with hyperlipidemia, alcoholic liver disease / alcoholic steatohepatitis, viral infection (HBV, HCV)-associated liver fibrosis, fibrosis associated with cholestatic diseases (primary biliary cholangitis, primary sclerosing cholangitis), (familial) hypercholesterolemia, dyslipidemia, inherited lipid disorders, cirrhosis, alcohol-induced fibrosis, hemochromatosis, glycogen storage disease, alpha-1-antitrypsin deficiency, autoimmune hepatitis, Wilson's disease, Crigler-Najjar syndrome, lysozyme lipase deficiency, and cystic fibrosis, 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.

[0145] In another embodiment, there is provided a method of treating a subject having Alport syndrome, diabetic nephropathy, FSGS, fibrosis associated with IgA nephropathy, chronic kidney diseases (CKD), post-AKI, HIV-associated CKD, chemotherapy-induced CKD, CKD associated with nephrotoxic drugs, nephrogenic systemic fibrosis, tubulointerstitial fibrosis, glomerulosclerosis, or polycystic kidney disease (PKD), 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.

[0146] In another embodiment, the compound is selected from the group consisting of IPF, ILD, pulmonary fibrosis, pulmonary fibrosis associated with autoimmune diseases such as rheumatoid arthritis, scleroderma, or Sjogren's syndrome, asthma-associated pulmonary fibrosis, COPD, asbestos- or silica-induced PF, silicosis, respiratory bronchiolitis, idiopathic interstitial pneumonia (IIP), idiopathic nonspecific interstitial pneumonia, respiratory bronchiolitis interstitial lung disease, desquamative interstitial pneumonia, acute interstitial pneumonia, rare idiopathic lymphoid interstitial pneumonia, and idiopathic lymphoid interstitial pneumonia.

[0003] Methods of treating a subject having unclassifiable idiopathic interstitial pneumonia (IIP), idiopathic pleuropulmonary parenchymal fibroelastosis, unclassifiable idiopathic interstitial pneumonia, hypersensitivity pneumonitis, radiation-induced lung injury, progressive massive fibrosis-pneumoconiosis, bronchiectasis, byssinosis, chronic respiratory disease, chronic obstructive pulmonary disease (COPD), emphysema, pulmonary hypertension (PAH), or cystic fibrosis are provided, 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.

[0147] In another embodiment, provided is a method of treating a subject having scleroderma / systemic sclerosis, graft-versus-host disease, hypertrophic scars, keloids, nephrogenic systemic fibrosis, porphyria cutanea tarda, restrictive skin disorder, Dupuytren's contracture, dermal fibrosis, nephrogenic systemic fibrosis / nephrogenic fibrosing dermatosis, mixed connective tissue disease, scleromyxedema, eosinophilic fasciitis, fibrosis resulting from exposure to chemicals or physical agents, GvH-induced fibrosis, scleredema adultae, lipoderma sclerosis, or a progeria disorder (progeria, acroprogeria, Werner's syndrome), 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.

[0148] In another embodiment, there is provided a method of treating a subject having atrial fibrosis, endomyocardial fibrosis, cardiac fibrosis, atherosclerosis, restenosis, or arthrofibrosis, 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.

[0149] In another embodiment, provided is a method of treating a subject having mediastinal fibrosis, myelofibrosis, post-polycythermia vera myelofibrosis, or post essential thrombocythemia, 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.

[0150] In another embodiment, there is provided a method of treating a subject having Crohn's disease, retroperitoneal fibrosis, intestinal fibrosis, fibrosis of inflammatory bowel disease, ulcerative colitis, GI fibrosis due to cystic fibrosis, or pancreatic fibrosis due to pancreatitis, 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.

[0151] In another embodiment, a method of treating a subject having adenomyosis, uterine fibroids, or Peyronie's disease is provided, 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.

[0152] In another embodiment, there is provided a method of treating a subject having macular degeneration, diabetic retinopathy, retinal fibrovascular diseases, or vitreoretinopathy, 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.

[0153] In another embodiment, there is provided a method of treating a subject having scarring associated with trauma (surgical complications, chemotherapy-induced fibrosis, radiation-induced fibrosis), 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.

[0154] As used herein, the term "administration" refers to providing a compound, a prodrug of a compound, or a pharmaceutical composition comprising a compound or prodrug described herein. The compound or composition can be administered to the subject by a third party, or the subject can administer it themselves. Non-limiting examples of routes of administration are oral, parenteral (e.g., intravenous), or topical.

[0155] As used herein, the term "treatment" refers to an intervention that alleviates the signs or symptoms of a disease or pathological condition. As used herein, the terms "treatment," "treat," and "treating" with respect to a disease, pathological condition, or symptom also refer to any observable beneficial effect of treatment. A beneficial effect can be evidenced, for example, by a delay in the onset of clinical symptoms of a disease in a susceptible subject, a reduction in the severity of some or all clinical symptoms of a disease, a slowing of disease progression, a reduction in the number of disease relapses, an improvement in the subject's physical or mental health or well-being, or other parameters well known in the art specific to a particular disease. A preventive treatment is a treatment administered to a subject who does not show signs of a disease or who shows only early signs, with the aim of reducing the risk of disease progression. A therapeutic treatment is a treatment administered to a subject after signs and symptoms of a disease have progressed.

[0156] As used herein, the term "subject" refers to an animal (e.g., a mammal such as a human). A subject to be treated according to the methods described herein is a subject diagnosed with a neurodegenerative disease involving demyelination, insufficient myelination, or impaired development of the myelin sheath, e.g., a subject diagnosed with multiple sclerosis or cerebral palsy, or a subject at risk for developing the disease. Diagnosis may be performed by any method or technique known in the art. One of skill in the art will understand that a subject to be treated according to the present disclosure may have undergone standard testing or may be identified without a medical examination as an at-risk subject due to the presence of a disease or one or more risk factors associated with the disease.

[0157] As used herein, the term "effective amount" refers to the amount of a particular drug that is sufficient to achieve the desired effect in the subject being treated with the drug. Ideally, the effective amount of a drug is an amount that is sufficient to inhibit or treat a disease without causing substantial toxicity to the subject. The effective amount of a drug will depend on the subject being treated, the severity of the affliction, and the method of administration of the pharmaceutical composition. In light of the present disclosure, it will be understood by those skilled in the art how to determine the effective amount of a compound of the present disclosure that is sufficient to achieve the desired effect in a subject.

[0158] As used herein, the term "chronic" refers to a medical disorder or disease that persists over time or that frequently recurs.

[0159] Compounds having the structure of formula (I), and formulas (II)-(VIII), as applicable, can be synthesized using the synthetic techniques set forth in Schemes 1-5 below.

[0160] To this end, the reactions, processes, and synthetic methods described herein are not limited to the specific conditions described in the Experimental Section below, which are intended as a guide for those skilled in the art. For example, the reactions may be carried out in any suitable solvent or other reagent that will effect the necessary transformation(s). Typically, a suitable solvent is a protic or aprotic solvent that is substantially unreactive toward the reactants, intermediates, or products at the temperature at which the reaction is carried out (i.e., temperatures ranging from freezing to boiling, or possibly even higher if the reaction is carried out in a sealed vessel). A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction, solvents suitable for specific post-reaction work-up may be utilized.

[0161] [ka]

[0162] Compounds of the present invention (A=aryl or heteroaryl) can be prepared by the methods described in Scheme 1. According to Scheme 1, intermediates such as i containing an active leaving group (such as X=Br or I or OTf) can be coupled with aryl- or heteroaryl-boronates such as ii under standard Suzuki coupling conditions to afford compounds of the present invention.

[0163] [ka]

[0164] In the particular case where A is aryl, compounds of the present invention can be prepared by the method of Scheme 2. According to Scheme 2, an intermediate such as i (such as X=Br or I or OTf) can be coupled with a substituted phenol boronic acid such as iii using a palladium catalyst such as Pd(dppf)Cl or Pd(PPh) along with a base such as NaHCO or KCO in a solvent such as THF or 1,4-dioxane and water or an alcohol, optionally with warming, to produce a hydroxyphenyl derivative iv.

[0165] [ka]

[0166] The compounds of the present invention can also be prepared from intermediates such as i via the stepwise assembly of heterocyclic moieties, as demonstrated in Scheme 3. According to Scheme 3, intermediates such as i can be converted to cinnamates such as vi by coupling with acrylates such as v using a palladium catalyst. Oxidation of the olefinic moiety of vi affords β-ketoesters such as vii. Condensation of vii with hydrazine viii or hydroxylamine affords the corresponding hydroxypyrazoles (ix, X = NR 303 ) or hydroxyisoxazole (ix, X=O). Alternatively, 7 can be converted to a urea (x, X=O) or amidine (x, X=NR 304) to give hydroxypyrimidine xi.

[0167] [ka]

[0168] When A is an N-linked heterocycle, compounds of the present invention can be prepared by the method of Scheme 4. According to Scheme 4, an 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 an oxidizing agent to provide an intermediate such as xv, which can then be condensed with a bifunctional acylating agent such as xiii to provide heterocycle A.

[0169] [ka]

[0170] When A is a 1,2,4-triazine, compounds of the present invention can be prepared by the method of Scheme 5. According to Scheme 5, anilines such as xii are N-nitrated using a nitrosating agent such as sodium nitrite in a solvent such as water or ethanol. The intermediate diazonium salt compound xvi is reacted with a bifunctional acylating reagent xvii, such as ethyl N-(2-cyanoacetyl)carbamate, in a solvent system containing water or an alcohol, a base such as pyridine or triethylamine, and optionally with heating, to provide 1,2,4-triazine products such as xviii. [Example]

[0171] The present invention is further illustrated by the following examples, which are not limiting and merely represent various aspects of the present invention. Wedges on solid and dotted lines in structures disclosed herein illustrate relative stereochemistry; absolute stereochemistry is depicted only when specifically stated or represented.

[0172] general law All reagents whose synthesis is not described in the experimental part are either commercially available, known compounds, or may be formed from known compounds by methods known to those skilled in the art.

[0173] The compounds and intermediates produced by the method of the present invention may require purification. Purification of organic compounds is well known to those skilled in the art, and there may be several methods for purifying the same compound. In some cases, purification may not be required. In some cases, the compound may be purified by crystallization. In some cases, impurities may be filtered out using a suitable solvent.

[0174] Optionally, the compounds may be purified by chromatography, specifically flash column chromatography, using specially prepared or prepackaged silica gel cartridges and eluents such as gradients of solvents such as heptane, ether, ethyl acetate, acetonitrile, ethanol, etc. Optionally, the compounds may be purified by preparative HPLC (normal or reverse phase) using the methods described. Preparative HPLC purification by reverse phase HPLC was performed using a gradient of acetonitrile in aqueous TFA, or an equivalent HPLC system such as methanol in aqueous ammonium acetate.

[0175] The purification methods described herein may result in compounds of the invention with sufficient basic or acidic functionality in the form of a salt, such as a trifluoroacetate or formate salt if the compound is sufficiently basic, or an ammonium salt if the compound is sufficiently acidic. Such salts can be converted to the free base or free acid form, 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 particular form of a compound of the invention isolated and described herein is not necessarily the only form in which the compound can be applied to a biological assay to determine a particular biological activity.

[0176] All starting materials and reagents were commercially available and used as received. 1H nuclear magnetic resonance (NMR) spectroscopy was performed on a Bruker instrument operating at 400 MHz and approximately room temperature using the solvents indicated unless otherwise specified. In all cases, the NMR data were consistent with the proposed structures. Characterization chemical shifts (δ) are given in parts per million using conventional abbreviations for peak designations, e.g., s (singlet), d (doublet), t (triplet), q (quartet), dd (doublet of doublets), dt (doublet of triplets), m (multiplet), and br (broad).

[0177] Chemical names were generated using ChemDraw naming software (version 17.0.0.206) from PerkinElmer Informatics, Inc. In some cases, generally accepted names and generally accepted acronyms for commercially available reagents were used in place of names generated by the naming software.

[0178] Intermediate A1 Synthesis of N,N-dibenzyl-3,5-dichloroaniline (intermediate A1)

[0179] [ka]

[0180] To a solution of 3,5-dichloroaniline (20.0 g, 123 mmol) in DMF (100 mL) was added powdered sodium hydride (8.5 g, 370 mmol) in small portions 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 at room temperature overnight. The mixture was 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 in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 100:1) to give Intermediate A1 (40.0 g, 94.7% yield) as a yellow solid. TLC: petroleum ether / EtOAc=5 / 1(v / v), Rf=0.8 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).

[0181] Intermediate A2 Synthesis of 2,6-dichloro-4-(dibenzylamino)benzaldehyde (Intermediate A2)

[0182] [ka]

[0183] Phosphorus oxychloride (56.8 g, 368 mmol) was added dropwise to DMF (200 mL) at 0 °C. The mixture was warmed 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 warmed to 80 °C over 5 h. The reaction mixture was poured into ice water (1 L) and the pH was adjusted to about 7 with aqueous NaHCO3. The mixture was extracted with EtOAc (3 x 200 mL). The combined organic layers were washed with water (200 mL), brine (300 mL), dried over Na2SO4, and concentrated in vacuo to give Intermediate A2 (38.5 g, 84.7% yield) as a yellow solid. TLC: petroleum ether / EtOAc=5 / 1(v / v), Rf=0.6 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).

[0184] Intermediate A3 Synthesis of (2,6-dichloro-4-(dibenzylamino)phenyl)methanol (Intermediate A3)

[0185] [ka]

[0186] To a solution of Intermediate A2 (20 g, 54 mmol) in THF (100 mL) was added NaBH4 (2.7 g, 70 mmol) in small portions at 5 °C. The mixture was stirred at room temperature for 2 h. Water (300 mL) was added, and the resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, and concentrated in vacuo to give Intermediate A3 (20 g, 99% yield) as a yellow solid. TLC: petroleum ether / EtOAc=5 / 1(v / v), Rf=0.7 1 H NMR:(400MHz,DMSO-d6)δ7.39-7.31(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).

[0187] Intermediate A4 Synthesis of N,N-dibenzyl-3,5-dichloro-4-(chloromethyl)aniline (Intermediate A4)

[0188] [ka]

[0189] To a solution of Intermediate A3 (2.4 g, 6.5 mmol) in DCM (20 mL) was added SOCl (1.6 g, 13 mmol) at 0 °C. The mixture was stirred at room temperature for 2 h. The mixture was concentrated in vacuo, and the crude Intermediate A4 was used without further purification. TLC: petroleum ether / EtOAc=10 / 1(v / v), Rf=0.5

[0190] Intermediate A5 Synthesis of N,N-dibenzyl-3-bromo-5-chloroaniline (Intermediate A5)

[0191] [ka]

[0192] 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 a 60% oil dispersion, 148 mmol) was added portionwise to control gas evolution. The reaction mixture was stirred at room temperature overnight. Water (500 mL) was carefully added, and the resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic phases were washed with water (500 mL) and brine (500 mL), dried over NaSO, and concentrated in vacuo. The residue was washed with EtOAc / hexane:1 / 10 (50 mL), and the resulting solid was filtered and dried to give Intermediate A5 (18.0 g, 94.2% yield) as a light brown solid. TLC: petroleum ether / EtOAc = 2 / 1 (v / v), Rf = 0.6

[0193] Intermediate A6 Synthesis of 2-bromo-6-chloro-4-(dibenzylamino)benzaldehyde (Intermediate A6)

[0194] [ka]

[0195] To a solution of Intermediate A5 (10.0 g, 25.9 mmol) in DMF (80 mL) was added POCl (11.9 g, 77.6 mmol) dropwise. The reaction mixture was stirred at 90 °C overnight. The reaction mixture was cooled to room temperature and poured into NaHCO (aq) (400 mL), and the resulting mixture was extracted with EtOAc (2 x 100 mL). The combined organic phases were washed with brine (400 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 30 / 1 to 5 / 1) to give Intermediate A6 (5.0 g, 47% yield) as a light brown solid. TLC: petroleum ether / EtOAc = 2 / 1 (v / v), Rf = 0.15

[0196] Intermediate A7 Synthesis of (2-bromo-6-chloro-4-(dibenzylamino)phenyl)methanol (Intermediate A7)

[0197] [ka]

[0198] A solution of Intermediate A6 (5.5 g, 13 mmol) in THF (50 mL) was cooled to 0 °C. NaBH (0.75 g, 20 mmol) was added portionwise. The reaction was stirred at room temperature for 1 h, then quenched with water (60 mL) and extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with brine (50 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1 to 3 / 1) to give Intermediate A7 (2.5 g, 45% yield) as a yellow solid. TLC: petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.10 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).

[0199] Intermediate A8 Synthesis of N,N-dibenzyl-3-bromo-5-chloro-4-(chloromethyl)aniline (Intermediate A8)

[0200] [ka]

[0201] To a solution of Intermediate A7 (2.0 g, 4.8 mmol) in DCM (30 mL) was added catalytic amounts of DMF and SOCl (1.14 g, 9.60 mmol). The reaction was stirred at room temperature for 30 minutes. The reaction mixture was concentrated in vacuo to give Intermediate A8 (2.0 g, 96% yield) as a yellow solid. TLC: petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.85

[0202] Intermediate A9 Synthesis of N-(3,5-dichloro-4-methylphenyl)acetamide (Intermediate A9)

[0203] [ka]

[0204] To a solution of 3,5-dichloro-p-toluidine (15.0 g, 85.2 mmol) in DCM (30 mL) was added acetyl chloride (8.0 g, 102 mmol). The mixture was stirred at room temperature overnight. The reaction mixture was diluted with EtOAc (100 mL), washed with brine (2 x 50 mL), and dried over Na2SO4. The crude product was concentrated in vacuo to give Intermediate A9 (17.0 g, 91.5% yield) as a yellow solid. TLC: petroleum ether / EtOAc=3 / 1 (v / v), Rf=0.16. LCMS: RT=1.959 min, [M-1]=216.0. 1 H NMR: (400MHz, DMSO-d6) δ10.16(s,1H), 7.66(s,2H), 2.33(s,3H), 2.04(s,3H).

[0205] Intermediate A10 Synthesis of N-(3,5-dichloro-2-fluoro-4-methylphenyl)acetamide (Intermediate A10)

[0206] [ka]

[0207] To a solution of Intermediate A9 (7.0 g, 32 mmol) in acetonitrile (100 mL) was added Selectfluor (11.4 g, 32.1 mmol). The mixture was stirred at 80 °C overnight. The reaction mixture was diluted with EtOAc (20 mL), and the resulting mixture was washed with brine (2 x 10 mL) and dried over Na2SO4. The crude product was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether / EtOAc = 100 / 1 to 10 / 1) to give Intermediate A10 (1.5 g, 20% yield) as a yellow solid. TLC: petroleum ether / EtOAc=3 / 1 (v / v), Rf=0.40. 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).

[0208] Intermediate A11 Synthesis of N-(4-(bromomethyl)-3,5-dichloro-2-fluorophenyl)acetamide (Intermediate A11)

[0209] [ka]

[0210] 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 at 100 °C overnight. The crude product was concentrated in vacuo and purified by silica gel column chromatography (petroleum ether / EtOAc = 30 / 1 to 10 / 1) to give Intermediate A11 (880 mg, 82.4% yield) as a yellow solid. TLC: petroleum ether / EtOAc=3 / 1 (v / v), Rf=0.44. LCMS: RT=2.135 min, [M+1]=313.9. 1H NMR:(400MHz,DMSO-d6)δ10.19(s,1H),8.21(d,J=6.8Hz,1H),4.76(d,J=0.8Hz,2H),2.13(s,3H).

[0211] Intermediate A12 Synthesis of 5-bromo-2-(bromomethyl)-1,3-dichlorobenzene (Intermediate A12)

[0212] [ka]

[0213] To a solution of 4-bromo-2,6-dichlorotoluene (9.8 g, 41 mmol) in CCl4 (100 mL) was added benzoyl peroxide (495 mg, 2.04 mmol) and N-bromosuccinimide (7.3 g, 41 mmol) 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 (2 x 50 mL). The organic phase was washed with brine (100 mL), dried over Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography (petroleum ether / EtOAc = 3 / 1) to give Intermediate A12 (12 g, 92% yield) as a pale yellow solid. TLC: petroleum ether / EtOAc=3 / 1 (v / v), Rf=0.45. 1 H NMR: (400MHz, DMSO-d6) δ7.87(s,2H),4.74(s,2H).

[0214] Intermediate B1 Synthesis of 4-iodo-2-isopropylphenol (Intermediate B1)

[0215] [ka]

[0216] To a solution of 2-isopropylphenol (840 g, 6.17 mol, 1.0 eq) in methanol (10 L) were added NaI (925 g, 6.17 mol, 1.0 eq) and NaOH (247 g, 6.17 mol, 1.0 eq). 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 slow addition of 10% aqueous NaSO (5 L) with stirring, and the mixture was acidified with concentrated aqueous HCl. The mixture was extracted with EtOAc (2 x 5 L). The combined organic phases were washed with brine (5 L), dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 100 / 1 to 20 / 1) to give Intermediate B1 (800 g, 49% yield) as a reddish oil. 1 H NMR:(400MHz,DMSO-d6)δ10.08(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).

[0217] Intermediate B2 Synthesis of 4-iodo-2-isopropyl-1-(methoxymethoxy)benzene (Intermediate B2)

[0218] [ka]

[0219] To a solution of Intermediate B1 (283 g, 1.08 mol, 1.0 eq) in DMF (3.28 L) were added MOM-Cl (258 g, 3.24 mol, 3.0 eq) and Cs2CO3 (1.05 kg, 3.24 mol, 3.0 eq). The mixture was stirred at room temperature under a N2 atmosphere for 3 h. The mixture was diluted with water (10 L) and extracted with EtOAc (2 x 5 L). The combined organic layers were dried over Na2SO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 100 / 1 to 30 / 1) to give Intermediate B2 (250 g, 76% yield) as a reddish oil. 1 H NMR:(400MHz,DMSO-d6)δ7.45(d,J=8.0Hz,2H),6.87(d,J=8.0Hz,1H),5.20(s,2H),3.37(s,3H),3.26-3.18(m,1H),1.14(d,J=8.0Hz,6H)

[0220] Intermediate B3 Synthesis of 3-fluoro-2-(prop-1-en-2-yl)phenol (Intermediate B3)

[0221] [ka]

[0222] 2-Bromo-3-fluorophenol (38.0 g, 200 mmol), isopropenyl-2-boron(pinacolato) (50.4 g, 300 mmol), and Pd(dppf)Cl 2To a mixture of CH2Cl2 (16 g, 20 mmol) in 1,4-dioxane (300 mL) and water (30 mL) was added K2CO3 (55.3 g, 400 mmol) at room temperature. The mixture was warmed to 70 °C and stirred overnight. The reaction mixture was cooled to room temperature, quenched with water (100 mL), and extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with brine (200 mL), dried over Na2SO4, concentrated in vacuo, and purified by silica gel column chromatography (EtOAc / petroleum ether = 1 / 100 to 1 / 20) to give Intermediate B3 (23 g, 76% yield) as a white solid. TLC: EtOAc / petroleum ether = 1 / 10 (v / v), Rf = 0.55 1 H NMR:(400MHz,DMSO-d6)δ9.72(s,1H),7.06(td,J=8.4,6.8Hz,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).

[0223] Intermediate B4 Synthesis of 3-fluoro-2-isopropylphenol (Intermediate B4)

[0224] [ka]

[0225] To a solution of Intermediate B3 (23.0 g, 151 mmol) in MeOH (300 mL) was added Pd / C (10%) (6.0 g). The reaction mixture was stirred at 60° C. overnight. The mixture was cooled to 0° C., filtered, and concentrated in vacuo to give Intermediate B4 (21 g, 90% yield) as a yellow oil. TLC: EtOAc / petroleum ether = 1 / 50 (v / v), R f =0.25 1H 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).

[0226] Intermediate B5 Synthesis of 2-(3-(difluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate B5)

[0227] [ka]

[0228] (3-Bromophenyl)-difluoromethyl ether (3.0 g, 13 mmol), bis(pinacolato)diboron (6.8 g, 27 mmol), Pd(dppf)Cl 2 A mixture of (984 mg, 1.35 mmol), and KOAc (4.0 g, 40 mmol) in dry 1,4-dioxane (30 mL) was stirred overnight at 85° C. The resulting solution of intermediate B5 was used without further purification. TLC: EtOAc / petroleum ether = 1 / 2 (v / v), Rf = 0.2

[0229] Intermediate B6 Synthesis of 3'-(difluoromethoxy)-[1,1'-biphenyl]-2-ol (Intermediate B6)

[0230] [ka]

[0231] Intermediate B5 (3.5 g, 13 mmol), 2-bromophenol (1.5 g, 8.67 mmol), Pd(dppf)Cl 2A mixture of (634 mg, 0.87 mmol) and K2CO3 (3.6 g, 26 mmol) in 1,4-dioxane (30 mL) and water (3 mL) was stirred at 90 °C overnight. Water (50 mL) was added, and the mixture was extracted with EtOAc (2 x 30 mL). The combined organic phases were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1 to 5 / 1, v / v) to give Intermediate B6 (700 mg, 34% yield) as a yellow oil. TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.54 LCMS:RT=2.551 min, [M-1]=235.0

[0232] Intermediate B7 Synthesis of 2-((4-fluorophenyl)(hydroxy)methyl)phenol (Intermediate B7)

[0233] [ka]

[0234] To a solution of 2-bromophenol (4.18 g, 24.2 mmol) in THF (40 mL) was added n-BuLi (2.5 M in hexanes) (29.0 mmol, 11.6 mL) dropwise 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, quenched with saturated aqueous NH4Cl (50 mL), acidified with 1 N HCl to a pH of approximately 6–7, and extracted with EtOAc (3 x 10 mL). The combined organic phases were washed with brine (15 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1 to 5 / 1) to give Intermediate B7 (2.5 g, 46% yield) as a yellow oil. TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.36 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).

[0235] Intermediate B8 Synthesis of 2-(4-fluorobenzyl)phenol (Intermediate B8)

[0236] [ka]

[0237] To a solution of Intermediate B7 (2.47 g, 11.3 mmol) in DCM (25 mL) was added EtSiH (5.26 g, 45.3 mmol) at room temperature. The mixture was stirred at 0 °C for 10 minutes, and then TFA (38.7 g, 340 mmol) was added dropwise. The mixture was stirred at room temperature for 3 hours, diluted with DCM (20 mL), and concentrated in vacuo. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 50 / 1 to 10 / 1) to give Intermediate B8 (1.9 g, 81% yield) as a yellow oil. TLC: EtOAc / petroleum ether = 1 / 5 (v / v), R f =0.64 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).

[0238] Intermediate C1 Synthesis of (2,6-dichloro-4-(dibenzylamino)phenyl)(3-isopropyl-4-(methoxymethoxy)phenyl)methanol (Intermediate C1)

[0239] [ka]

[0240] A solution of Intermediate B2 (1.1 g, 3.5 mmol) in THF (10 mL) was cooled to −20° C., and iPr-MgCl (2.7 mL of a 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. The reaction was quenched by the addition of aqueous NH4Cl (30 mL), and the mixture was extracted with EtOAc (3×10 mL). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo to give a brown oil. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 30:1) to give Intermediate C1 (700 mg, 47% yield) as a colorless oil. TLC: petroleum ether / EtOAc=5 / 1(v / v), Rf=0.5 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).

[0241] Intermediate C2 Synthesis of (4-amino-2,6-dichlorophenyl)(3-isopropyl-4-(methoxymethoxy)phenyl)methanol (Intermediate C2)

[0242] [ka]

[0243] To a solution of Intermediate C1 (2.1 g, 3.8 mmol) in THF (20 mL) was added Pd / C (400 mg). The mixture was degassed under vacuum and purged with H three times. The mixture was stirred under H gas (1 atmosphere) at room temperature for 2 hours. The mixture was filtered and concentrated under vacuum to give Intermediate C2 (1.4 g, 97% yield) as a gray solid. TLC: petroleum ether / EtOAc = 3 / 1 (v / v), Rf = 0.3 1 H 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).

[0244] Intermediate C3 Synthesis of 4-(4-amino-2,6-dichlorobenzyl)-2-isopropylphenol (Intermediate C3)

[0245] [ka]

[0246] To a solution of intermediate C2 (1.0 g, 2.70 mmol) in DCM (10 mL) was added EtSiH (14 mmol, 1.6 g) at 0 °C, and TFA (81 mmol, 9.2 g) was added dropwise to the resulting solution. The mixture was stirred at room temperature overnight and then concentrated in vacuo to remove the solvent. Water (20 mL) was added, and the resulting mixture was extracted with EtOAc (3 x 20 mL). The combined organic layers were washed with brine (30 mL), dried over NaSO, and concentrated in vacuo to give a yellow oil. The crude product was purified by silica gel column chromatography (petroleum ether / EtOAc = 20:1) to give intermediate C3 (200 mg, 24% yield) as a yellow solid. TLC: petroleum ether / EtOAc = 3 / 1 (v / v), Rf = 0.4 1H 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).

[0247] Intermediate C4 Synthesis of 4-(2,6-dichloro-4-(dibenzylamino)benzyl)-3-fluoro-2-isopropylphenol (Intermediate C4)

[0248] [ka]

[0249] To a solution of Intermediate B4 (7.6 g, 20 mmol) in DCE (40 mL) was added Intermediate A4 (6.0 g, 39 mmol) and ZnCl (39 mL of a 1.0 M solution in THF, 39 mmol) at room temperature. 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 (2 x 50 mL). The combined organic phases were washed with brine, dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 30 / 1 to 5 / 1) to give Intermediate C4 (4.5 g, 46%) as a yellow solid. TLC: petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.3 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).

[0250] Intermediate C5 Synthesis of 4-(4-amino-2,6-dichlorobenzyl)-3-fluoro-2-isopropylphenol (Intermediate C5)

[0251] [ka]

[0252] To a solution of Intermediate C4 (4.5 g, 8.8 mmol) in THF (50 mL) was added Pd / C (1.0 g) at room temperature. The mixture was stirred at 35 °C for 1 hour under 1 atm H pressure. The reaction mixture was cooled to room temperature, filtered, and concentrated in vacuo to give Intermediate C5 (2.3 g, 79%) as a yellow solid. TLC: petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.3 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).

[0253] Intermediate C6 Synthesis of 5-(2,6-dichloro-4-(dibenzylamino)benzyl)-3'-(difluoromethoxy)-[1,1'-biphenyl]-2-ol (Intermediate C6)

[0254] [ka]

[0255] A solution of Intermediate A4 (827 mg, 2.12 mol), Intermediate B6 (1.0 g, 4.2 mol), and ZnCl (5.3 mL of a 1.0 M solution in THF, 5.3 mmol) in DCE (20 mL) was stirred overnight at 85° C. The mixture was cooled to room temperature, washed with water (20 mL), dried over NaSO, concentrated in vacuo, and purified by silica gel column chromatography (petroleum ether / EtOAc = 5 / 1, v / v) to give Intermediate C6 (1.0 g, 80% yield) as a colorless oil. TLC: EtOAc / petroleum ether = 1 / 5 (v / v), Rf = 0.39 1H 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).

[0256] Intermediate C7 Synthesis of 5-(4-amino-2,6-dichlorobenzyl)-3'-(difluoromethoxy)-[1,1'-biphenyl]-2-ol (Intermediate C7)

[0257] [ka]

[0258] A mixture of intermediate C6 (1.1 g, 1.9 mmol) and Pd / C (200 mg) in THF (20 mL) was degassed under vacuum and purged with H gas three times, and the mixture was stirred at room temperature overnight under 1 atm of H gas. The mixture was filtered and then concentrated under vacuum to give intermediate C7 (750 mg, 98% yield) as a brown solid. TLC: EtOAc / petroleum ether = 1 / 1 (v / v), Rf = 0.44 1 H 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).

[0259] Intermediate C8 4-(2,6-Dichloro-4-(dibenzylamino)benzyl)-2-(4-fluorobenzyl)phenol (Intermediate C8)

[0260] [ka]

[0261] A solution of Intermediate A4 (966 mg, 2.47 mmol), Intermediate B8 (1.0 g, 5.0 mmol), and ZnCl (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 NaSO, concentrated in vacuo, and purified by silica gel column chromatography (petroleum ether / EtOAc = 50 / 1, v / v) to give Intermediate C8 (1.0 g, 73% yield) as a colorless oil. TLC: EtOAc / petroleum ether = 1 / 10 (v / v), Rf = 0.4 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).

[0262] Intermediate C9 Synthesis of 4-(4-amino-2,6-dichlorobenzyl)-2-(4-fluorobenzyl)phenol (Intermediate C9)

[0263] [ka]

[0264] A mixture of intermediate C8 (1.0 g, 1.8 mmol) and Pd / C (109 mg) in THF (20 mL) was stirred at room temperature overnight under a blanket of H2 gas. The mixture was filtered and concentrated in vacuo to give intermediate C9 (670 mg, 99% yield) as a brown solid. TLC: EtOAc / petroleum ether = 1 / 3 (v / v), Rf = 0.35 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).

[0265] Intermediate C10 Synthesis of 4-(2-bromo-6-chloro-4-(dibenzylamino)benzyl)-2-isopropylphenol (Intermediate C10)

[0266] [ka]

[0267] To a solution of Intermediate A8 (2.0 g, 4.60 mmol) and 2-isopropylphenol (1.8 g, 14 mmol) in DCE (30 mL) was added ZnCl (1 M in THF, 11.5 mL). The reaction was stirred at 75 °C overnight. The reaction was cooled to room temperature, water (50 mL) was added, and the resulting mixture was extracted with DCM (2 x 20 mL). The combined organic phase was washed with brine (40 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 30 / 1 to 5 / 1) to give Intermediate C10 (1.8 g, 73% yield) as a yellow oil. TLC: petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.15 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).

[0268] Intermediate C11 Synthesis of 4-(2-chloro-4-(dibenzylamino)-6-(prop-1-en-2-yl)benzyl)-2-isopropylphenol (Intermediate C11)

[0269] [ka]

[0270] To a solution of intermediate C10 (1.3 g, 2.4 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was added potassium isopropenyltrifluoroborate (0.54 g, 3.7 mmol), Pd(dppf)Cl 2 (180 mg, 0.24 mmol), and K2CO3 (1.01 g, 7.2 mmol) were added. The reaction was stirred at 90 °C overnight. The reaction mixture was cooled to room temperature, water (50 mL) was added, and the resulting mixture was extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with water (50 mL) and brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 20 / 1 to 5 / 1) to give intermediate C11 (0.40 g, 33% yield) as a yellow solid. TLC: petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.3 1H 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).

[0271] Intermediate C12 Synthesis of 4-(4-amino-2-chloro-6-isopropylbenzyl)-2-isopropylphenol (Intermediate C12)

[0272] [ka]

[0273] To a solution of intermediate C11 (496 mg, 1.0 mmol) in THF (10 mL) was added Pd / C (100 mg). The reaction mixture was stirred overnight under 1 atm of hydrogen gas. The mixture was filtered and concentrated in vacuo, and the residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 10 / 1 to 3 / 1) to give intermediate C12 (150 mg, 47% yield) as a yellow solid. TLC: petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.1

[0274] Intermediate C13 Synthesis of N-(3,5-dichloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)phenyl)acetamide (Intermediate C13)

[0275] [ka]

[0276] To a solution of intermediate A11 (800 mg, 2.54 mmol) in DCE (5 mL) was added 2-isopropylphenol (692 mg, 5.08 mmol) and ZnCl (865 mg, 6.35 mmol) at room temperature. The reaction mixture was warmed to 90 °C and stirred overnight. The reaction mixture was diluted with DCM (30 mL), washed with brine (2 x 20 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc = 5 / 1) to give intermediate C13 (180 mg, 19% yield) as a yellow solid. TLC: petroleum ether / EtOAc=5 / 1 (v / v), Rf=0.24. LCMS: RT=1.672 min, [M-1]=367.9. 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).

[0277] Intermediate C14 Synthesis of 4-(4-amino-2,6-dichloro-3-fluorobenzyl)-2-isopropylphenol (Intermediate C14)

[0278] [ka]

[0279] To a solution of intermediate C13 (180 mg, 0.49 mmol) in water (1 mL) and THF (3 mL) was added NaOH (194 mg, 4.86 mmol). The mixture was stirred at 100 °C overnight. The reaction mixture was diluted with water (20 mL), acidified with 2 N HCl to a pH of approximately 6-8, and extracted with EtOAc (2 x 20 mL). The combined organic phases were washed with brine (2 x 10 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by preparative HPLC to give intermediate C14 (66 mg, 41% yield) as a yellow solid. TLC: petroleum ether / EtOAc=3 / 1 (v / v), Rf=0.48. LCMS: RT=1.864 min, [M+1]=328.0. 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).

[0280] Intermediate C15 Synthesis of 4-(4-bromo-2,6-dichlorobenzyl)-3-fluoro-2-isopropylphenol (Intermediate C15)

[0281] [ka]

[0282] A mixture of Intermediate A12 (500 mg, 1.57 mmol), Intermediate B4 (725 mg, 4.71 mmol), and Zn(OTf) (2.8 g, 7.85 mmol) was irradiated with stirring in a microwave oven at 160 °C for 2 h. The reaction mixture was diluted with DCM (5 mL), washed with brine (2 x 5 mL), dried over NaSO, concentrated in vacuo, and purified by preparative TLC (EtOAc / petroleum ether = 1 / 10) to give Intermediate C15 (120 mg, 19% yield) as a brown oil. TLC: petroleum ether / EtOAc=5 / 1(v / v), Rf=0.21 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).

[0283] Intermediate C16 Synthesis of 4-(4-bromo-2,6-dichlorobenzyl)-2-isopropylphenol (Intermediate C16)

[0284] [ka]

[0285] To a solution of Intermediate A12 (1.5 g, 4.7 mmol) in chlorobenzene (10 mL) were added 2-isopropylphenol (1.92 g, 14.1 mmol) and Zn(OTf)2 (5.13 g, 14.1 mmol) at room temperature. The reaction mixture was irradiated with microwaves at 150 °C for 1 hour with stirring. The mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 100 / 1 to 20 / 1) to give Intermediate C16 (0.40 g, 23%) as a yellow oil. TLC: petroleum ether / EtOAc=5 / 1(v / v), Rf=0.15 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).

[0286] Intermediate C17 Synthesis of 2-(4-(4-bromo-2,6-dichlorobenzyl)-2-isopropylphenoxy)tetrahydro-2H-pyran (Intermediate C17)

[0287] [ka]

[0288] To a solution of intermediate C16 (1.2 g, 3.2 mmol) in THF (15 mL) were added 3,4-dihydro-2H-pyran (324 mg, 3.85 mmol) and PPTS (151 mg, 3.85 mmol). The reaction mixture was stirred at room temperature overnight. Water (30 mL) was added, and the resulting mixture was extracted with EtOAc (2 x 15 mL). The combined organic phases were washed with brine (30 mL), dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 1 to 30 / 1) to give intermediate C17 (1.2 g, 82% yield). TLC: petroleum ether / EtOAc = 10 / 1 (v / v), Rf = 0.75 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).

[0289] Intermediate C18 Synthesis of methyl (E)-3-(3,5-dichloro-4-(3-isopropyl-4-((tetrahydro-2H-pyran-2-yl)oxy)benzyl)phenyl)acrylate (Intermediate C18)

[0290] [ka]

[0291] To a solution of intermediate C17 (200 mg, 0.43 mmol) in DMF (5 mL) were added methyl acrylate (74 mg, 0.86 mmol), Pd(OAc) (10 mg, 43 μmol), and KCO (120 mg, 0.86 mmol). The reaction mixture was warmed to 100 °C overnight. The mixture was cooled to room temperature, water (30 mL) was added, and the resulting mixture was extracted with EtOAc (2 x 30 mL). The combined organic phases were washed with brine (50 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by silica gel column chromatography (petroleum ether / EtOAc = 100 / 1 to 10 / 1) to give intermediate C18 (100 mg, 49% yield) as a pale yellow oil. TLC: petroleum ether / EtOAc = 1 / 1 (v / v), Rf = 0.25 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).

[0292] Intermediate C19 Synthesis of methyl 3-(3,5-dichloro-4-(4-hydroxy-3-isopropylbenzyl)phenyl)-3-oxopropanoate (intermediate C19)

[0293] [ka]

[0294] To a solution of intermediate C18 (100 mg, 0.21 mmol) in ethanol (5 mL) was added FeCl2 (3.0 mg, 21 μmol) and polymethylhydrosiloxane (140 mg, 0.63 mmol). The reaction was stirred at 80 °C for 3 h. The reaction mixture was cooled to room temperature and concentrated in vacuo. The residue was purified by preparative TLC (petroleum ether / EtOAc = 2 / 1) to give intermediate C19 (30 mg, 36% yield) as a pale yellow oil. TLC: petroleum ether / EtOAc = 2 / 1 (v / v), Rf = 0.15 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).

[0295] Intermediate D1 Synthesis of 2,6-difluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (Intermediate D1)

[0296] [ka]

[0297] 3-Bromo-2,6-difluorophenol (300 mg, 1.44 mmol), bis(pinacolato)diboron (401 mg, 1.58 mmol), and Pd(dppf)Cl 2 To a mixture of (52 mg, 72 μmol) of HCl in 1,4-dioxane (15 mL) was added potassium acetate (423 mg, 4.31 mmol). The mixture was warmed to 100° C. and stirred for 3 h. The mixture was cooled to room temperature and filtered. The filtrate was concentrated in vacuo to give crude intermediate D1 (300 mg, 82% yield), which was used without further purification. TLC: petroleum ether / EtOAc=3 / 1 (v / v), Rf=0.90.

[0298] Example 1 Synthesis of 2-(3,5-dichloro-4-(4-hydroxy-3-isopropylbenzyl)phenyl)-5-hydroxy-3-oxo-2,3-dihydro-1,2,4-triazine-6-carbonitrile (Compound 1)

[0299] [ka]

[0300] A solution of intermediate C3 (5.0 g, 16.1 mmol) in acetonitrile (20 mL) / water (100 mL) and concentrated aqueous HCl (110 mL) was cooled to 0 °C, and a solution of NaNO (1.3 g, 19.3 mmol) in water (10 mL) was added dropwise. The mixture was stirred at 0 °C for 1 h. A solution of ethyl N-(2-cyanoacetyl)carbamate (2.8 g, 17.7 mmol) in water (100 mL) and pyridine (125 mL) was added dropwise and stirred at 0 °C. After 1 h, the reaction mixture was extracted with EtOAc (2 x 100 mL), and the combined organic phases were washed with brine (2 x 50 mL), dried over NaSO, and concentrated in vacuo. The resulting crude product (7.6 g, a yellow oil) was dissolved in HOAc (50 mL), NaOAc (6.5 g, 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 (3 x 50 mL). The combined organic phases were washed with brine (2 x 50 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by reverse-phase preparative HPLC to give compound 1 (1.5 mg, 21.2% yield) as a yellow solid. TLC: DCM / MeOH=1 / 1 (v / v), Rf=0.1 LCMS:RT=4.31 min, [M-1]=447.0 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)

[0301] Example 2 Synthesis of 2-(3,5-dichloro-4-(2-fluoro-4-hydroxy-3-isopropylbenzyl)phenyl)-5-hydroxy-3-oxo-2,3-dihydro-1,2,4-triazine-6-carbonitrile (Compound 2)

[0302] [ka]

[0303] A solution of intermediate C5 (270 mg, 0.82 mmol) in water (10 mL) and concentrated aqueous HCl (10 mL) was cooled to 0 °C, and a solution of NaNO (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 added dropwise to a solution of ethyl 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 (2 x 10 mL). The combined organic phase was washed with brine (30 mL), dried over NaSO, and concentrated in vacuo. 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 (2 x 10 mL). The combined organic phases were washed with brine (30 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by preparative HPLC to give compound 2 (6.0 mg, 1.6% yield). TLC: DCM / MeOH=1 / 1 (v / v), Rf=0.1 LCMS:RT=4.31 min, [M-1]=447.0 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)

[0304] Example 3 Synthesis of 2-(3,5-dichloro-4-((3'-(difluoromethoxy)-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenyl)-5-hydroxy-3-oxo-2,3-dihydro-1,2,4-triazine-6-carbonitrile (Compound 3)

[0305] [ka]

[0306] A solution of intermediate C7 (400 mg, 0.97 mmol) in concentrated aqueous HCl (7 mL) and water (7 mL) was cooled to 0 °C, and a solution of NaNO (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 added dropwise to a solution of ethyl 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 (2 x 50 mL), and the combined organic phases were washed with brine (50 mL), dried over NaSO, and concentrated in vacuo. A mixture of this material (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 phase was washed with water (3 x 20 mL), then brine (50 mL), dried over NaSO, concentrated in vacuo, and purified twice by preparative TLC (DCM / MeOH = 10 / 1) to give compound 3 (20 mg, 4.4% yield) as a yellow solid. TLC: MeOH / DCM=1 / 5(v / v), Rf=0.32 LCMS:RT=1.787 min, [M-1]=528.8 1 H 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).

[0307] Example 4 Synthesis of 2-(3,5-dichloro-4-(3-(4-fluorobenzyl)-4-hydroxybenzyl)phenyl)-5-hydroxy-3-oxo-2,3-dihydro-1,2,4-triazine-6-carbonitrile (Compound 4)

[0308] [ka]

[0309] A solution of intermediate C9 (490 mg, 1.30 mmol) in concentrated aqueous HCl (15 mL) and water (15 mL) was cooled to 0 °C, and a solution of NaNO (108 mg, 1.56 mmol) in water (1 mL) was added dropwise. The mixture was stirred at 0 °C for 30 min, then a solution of ethyl N-(2-cyanoacetyl)carbamate (224 mg, 1.43 mmol) in water (15 mL) and pyridine (15 mL) was added dropwise and stirred at 0 °C. After 1 h, the mixture was extracted with EtOAc (2 x 50 mL). The combined organic phases were washed with brine (50 mL), dried over NaSO, and concentrated in vacuo. A mixture of this 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. Water (30 mL) was added, and the mixture was extracted with EtOAc (25 mL x 2). The combined organic layers were washed with water (40 mL x 3), then brine (50 mL), dried over Na2SO4, and purified twice by preparative TLC (DCM / MeOH = 10 / 1) to give compound 4 (16 mg, 2.7% yield) as a yellow solid. TLC: MeOH / DCM=1 / 5(v / v), Rf=0.32 LCMS:RT=3.626 min, [M-1]=494.9 1 H 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).

[0310] Example 5 Synthesis of 2-(3-chloro-4-(4-hydroxy-3-isopropylbenzyl)-5-isopropylphenyl)-5-hydroxy-3-oxo-2,3-dihydro-1,2,4-triazine-6-carbonitrile (Compound 5)

[0311] [ka]

[0312] A solution of intermediate C12 (200 mg, 0.63 mmol) in water (5 mL) and concentrated HCl (5 mL) was cooled to 0 °C, and a solution of NaNO (52 mg, 0.75 mmol) in water (1 mL) was added dropwise. After stirring the mixture at 0 °C for 30 minutes, a mixture of ethyl N-(2-cyanoacetyl)carbamate (98 mg, 0.63 mmol) in water (5 mL) and pyridine (5 mL) was added dropwise at 0 °C. After 1 hour, the mixture was extracted with EtOAc (2 x 10 mL). The combined organic phase was washed with brine (30 mL), dried over NaSO, and concentrated in vacuo. This material 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 hours. The reaction mixture was cooled to room temperature, water (30 mL) was added, and the resulting mixture was extracted with EtOAc (2 x 10 mL). The combined organic phase was washed with brine (30 mL), dried over Na2SO4, concentrated in vacuo, and the residue was purified by preparative HPLC to give compound 5 (35 mg, 12% yield). TLC: DCM / MeOH=1 / 1 (v / v), Rf=0.1 LCMS:RT=2.62 min, [M-1]=437.0 1 H 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).

[0313] Example 6 Synthesis of 2-(3,5-dichloro-2-fluoro-4-(4-hydroxy-3-isopropylbenzyl)phenyl)-5-hydroxy-3-oxo-2,3-dihydro-1,2,4-triazine-6-carbonitrile (Compound 6)

[0314] [ka]

[0315] A solution of intermediate C14 (360 mg, 1.10 mmol) in concentrated HCl (7 mL) and water (7 mL) was cooled to 0 °C, and a solution of NaNO (91 mg, 1.3 mmol) in water (1 mL) was added dropwise. The resulting mixture was stirred at 0 °C for 30 min, then added to a cooled solution of ethyl N-(2-cyanoacetyl)carbamate (188 mg, 1.21 mmol) in water (7 mL) and pyridine (10 mL). This mixture was stirred at 0 °C for 1 h and then extracted with EtOAc (2 x 20 mL). The combined organic phase was washed with brine (50 mL), dried over NaSO, and concentrated in vacuo. 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 (3 x 20 mL), then brine (50 mL), dried over Na2SO4, and purified by preparative HPLC to give compound 6 (20 mg, 7.4% yield) as a yellow solid. TLC: MeOH / DCM=1 / 5(v / v), Rf=0.36 LCMS:RT=1.749min, [M-1]=447.0 1 H 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).

[0316] Example 7 Synthesis of 3',5'-dichloro-3,5-difluoro-4'-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-[1,1'-biphenyl]-4-ol (Compound 7)

[0317] [ka]

[0318] 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) was added to Pd(dppf)Cl at room temperature. 2 (5.0 mg, 6.4 μmol) and NaHCO (16 mg, 0.19 mmol) were added. The reaction mixture was purged with nitrogen and warmed at 80 °C overnight. The reaction mixture was diluted with EtOAc (5 mL), washed with brine (2 x 10 mL), dried over NaSO, concentrated in vacuo, and purified by preparative HPLC to give compound 7 (7.0 mg, 25% yield) as a yellow solid. TLC: petroleum ether / EtOAc=3 / 1 (v / v), Rf=0.31. LCMS: RT=3.538 min, [M-1]=439.1. 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=8.0Hz,1H),6.32(t,J=8.8Hz,1H),4.12(s,2H),3.41(d,J=7.2Hz,1H),1.26(d,J=6.8Hz,6H).

[0319] Example 8 Synthesis of 3',5'-dichloro-2,4-difluoro-4'-(2-fluoro-4-hydroxy-3-isopropylbenzyl)-[1,1'-biphenyl]-3-ol (Compound 8)

[0320] [ka]

[0321] A solution of intermediate D1 (60 mg, 0.15 mmol) and intermediate C15 (59 mg, 0.23 μmol) in 1,4-dioxane (10 mL) was added to Pd(dppf)Cl at room temperature. 2(11 mg, 15.30 μmol) and aqueous NaHCO3 (2 M, 0.23 mL) were added. The reaction was warmed to 80 °C overnight under a nitrogen atmosphere. The reaction mixture was diluted with EtOAc (10 mL), washed with brine (2 x 10 mL), dried over Na2SO4, and concentrated in vacuo. The crude product was purified by preparative HPLC to give compound 8 (25 mg, 37% yield) as a brown solid. TLC: petroleum ether / EtOAc=3 / 1 (v / v), Rf=0.23. LCMS: RT=3.486 min, [M-1]=439.0. 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).

[0322] Example 9 Synthesis of 5-(3,5-dichloro-4-(4-hydroxy-3-isopropylbenzyl)phenyl)isoxazolol-3-ol (Compound 9)

[0323] [ka]

[0324] To a solution of hydroxylamine hydrochloride (26 mg, 0.375 mmol) and NaOH (30 mg, 0.75 mmol) in MeOH / HO (5 mL / 2 mL) was added intermediate C19 (100 mg, 0.25 mmol). The mixture was stirred at room temperature for 2 h. Water (20 mL) was added, the pH of the solution was adjusted to approximately 3–4 with 1 N HCl, and the resulting mixture was extracted with EtOAc (2×10 mL). The combined organic phases were washed with brine (20 mL), dried over NaSO, and concentrated in vacuo. The residue was purified by preparative HPLC to give compound 9 (10 mg, 10% yield) as a light brown solid. TLC:DCM / MeOH=15 / 1(v / v), Rf=0.15 LCMS:RT=4.18 min, [M-1]=376.0) 1 H NMR:(400MHz,DMSO-d6)δ9.15(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).

[0325] Example 10 Synthesis of 2-(3,5-dichloro-4-((3'-(difluoromethoxy)-6-hydroxy-[1,1'-biphenyl]-3-yl)methyl)phenyl)-5-hydroxy-1,2,4-triazin-3(2H)-one (Compound 10)

[0326] [ka]

[0327] A solution 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 hours. The mixture was quenched with HO (10 mL) and extracted with EtOAc (2×5 mL). The combined organic layers were washed with water (2×15 mL), brine (10 mL), dried over NaSO, and concentrated to dryness to give the product compound 2 (100 mg, 80.5% yield) as a yellow solid.

[0328] To a mixture of compound E2 (120 mg, 218 μmol) in toluene (3 mL) was added mercaptoacetic acid (40 mg, 436 μmol). The mixture was stirred at 110° C. for 48 hours. The mixture was quenched with HO (10 mL) and extracted with EtOAc (10 mL). The organic layer was washed with water (25 mL x 2), brine (50 mL), dried over NaSO, concentrated to dryness, and purified by preparative HPLC to give compound 10 (15 mg, 13.4% yield) as a yellow solid. LCMS:RT=1.66 min, [M-1]=503.9

[0329] Example 11 Thyroid hormone reporter gene assay Compounds were tested for thyroid hormone receptor activity using a TR reporter gene assay. The reporter cells used in this assay express a TR receptor hybrid (either TRα or TRβ) in which the native N-terminal DNA-binding domain (DBD) has been replaced with that of the yeast Gal4 DBD. The reporter gene, firefly luciferase, is functionally linked to the Gal4 upstream activating sequence (UAS). Both cell lines were derived from human embryonic kidney (HEK293) cells. Step 1: Prepare a suspension of reporter cells in cell collection medium containing 10% charcoal-stripped FBS and distribute it into assay plates. The plates were pre-incubated for 6 hours in a cell culture incubator (37°C / 5% CO2 / 85% humidity). Step 2: Master stocks of test compounds and triiodothyronine were diluted in DMSO to generate 1,000x solutions for each final treatment concentration. These intermediate stocks were then diluted directly into compound screening medium containing 10% charcoal-stripped FBS to generate 2x concentrated treatment media (containing 0.2, 0.4, or 0.8% DMSO). Step 3: At the end of the pre-incubation period, the culture medium was discarded from the assay plate, and all wells received 100 μl of compound screening medium. 100 μl of each of the previously prepared "2x concentrated" treatment medium was dispensed into duplicate assay wells, thereby achieving the desired final treatment concentration. The final concentration of DMSO in all assay wells was 0.1, 0.2, or 0.4%. The assay plate was incubated in a cell culture incubator (37°C / 5% CO2 / 85% humidity) for 24 hours. Step 4: At the 24-hour assay endpoint, the treatment medium was discarded and 100 μl / well of luciferase detection reagent was added. Relative luminometric units (RLU) were quantified from each assay well. The control agonist triiodothyronine (T3) was used to validate the performance of the TRα and TRβ assays.

[0330] The results of these assays are shown in Table 2 below, in which the data are shown as EC 50 values ​​and the selectivity index (SI) was reported as EC 50 (TRα) / EC 50 (TRβ). For this purpose, EC 50 The values ​​and SI values ​​are expressed as follows: Potency: + EC 50 >1,000nM ++ 100nM <EC 50 ≦1,000nM +++ 10nM <EC 50 ≦100nM ++++EC 50 ≦10nM ND Not determined Selectivity: + T3-SI≦3X ++3X <T3-SI≦30X +++ T3-SI>30X ND Not determined

[0331] [Table 2]

[0332] As shown in the above experiments, the compounds of the present invention exhibit improved TRβ selectivity compared to the natural agonist T3. Some compounds also exhibit improved potency compared to T3.

[0333] 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 literature are referenced herein and / or listed in the Application Data Sheet, which is incorporated herein by reference in its entirety. Aspects of the embodiments can be modified, if necessary, to utilize concepts from the various patents, applications, and publications to provide further embodiments.

[0334] These and other changes can be made to the embodiments in light of the above detailed description. In general, the terms used in the following claims should be construed not to limit the scope of the claims to the specific embodiments disclosed in the specification and claims, but to include all possible embodiments along with the full range of equivalents to which such claims are entitled. Accordingly, the scope of the claims is not limited by this disclosure.

Claims

1. Formula (I): 【Chemistry 1】 or a pharmaceutically acceptable salt thereof, wherein A is, 【Chemistry 2】 and R 6 is H or —CN; X １ is lower alkyl, or halo; X ２ is a halo, Y １ is H or a halogen, Y ２ is H or a halogen, R ２ is lower alkyl, carbocyclic, or carbocyclic alkyl, where R ２ is optionally substituted by one or more halo, or —OR′; A compound, or a pharmaceutically acceptable salt thereof, wherein R' is lower haloalkyl.

2. R ２ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is unsubstituted lower alkyl.

3. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein R 2 is isopropyl.

4. A is, 【Transformation 3】 2. The compound of claim 1, wherein:

5. A is 【Chemistry 4】 2. The compound of claim 1, wherein:

6. X １ 2. The compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein is lower alkyl.

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

8. Y １ is H and Y ２ 2. The compound of claim 1, wherein is H, or a pharmaceutically acceptable salt thereof.

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

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

11. The following structure 【Transformation 5】 2. The compound of claim 1, having the formula: or a pharmaceutically acceptable salt thereof.

12. 12. A pharmaceutical composition comprising a compound according to any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

13. 12. Use of a compound of any one of claims 1 to 11, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treating a neurodegenerative disease in a subject in need thereof.

14. The neurodegenerative disease may be multiple sclerosis, MCT8 deficiency, X-linked adrenoleukodystrophy (ALD), amyotrophic lateral sclerosis (ALS), Alzheimer's disease, frontotemporal dementia, small cavity stroke, adult Refsum's disease, Alexander's disease, Barrow's concentric sclerosis, Canavan's disease, central pontine myelinolysis, cerebral palsy, cerebrotendinous xanthomatosis, chronic inflammatory demyelinating polyneuropathy, Devic's syndrome, diffuse myeloclastic sclerosis, idiopathic idiopathic cerebrospinal fluid disorder, or idiopathic cerebrospinal fluid disorder.

14. The use according to claim 13, wherein the condition is selected from the group consisting of inflammatory demyelinating diseases, infantile Refsum's disease, Krabbe's disease, Leber's hereditary optic neuropathy, Marchiafava-Bignami disease, metachromatic leukodystrophy, multifocal motor neuropathy, paraproteinemic demyelinating polyneuropathy, Pelizaeus-Merzbacher disease, peroneal muscular atrophy, progressive multifocal leukoencephalopathy, transverse myelitis, tropical spastic paraparesis, van der Knapp's disease, and Zellweger's syndrome.

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