WO2020118564A1

WO2020118564A1 - Novel thyromimetics

Info

Publication number: WO2020118564A1
Application number: PCT/CN2018/120634
Authority: WO
Inventors: Thomas Von Geldern; Jean-Christophe Poupon
Original assignee: Autobahn Therapeutics, Inc.
Priority date: 2018-12-12
Filing date: 2018-12-12
Publication date: 2020-06-18

Abstract

Compounds are provided having the structure of Formula (I) : (I) or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X¹, X², and R¹ are as defined herein. Such compounds function as thyromimetics and have utility for treating diseases such as neurodegenerative disorders and fibrotic diseases. Pharmaceutical compositions containing such compounds are also provided, as are methods of their use and preparation.

Description

NOVEL THYROMIMETICS

BACKGROUND Technical Field

The invention relates to thyromimetic compounds and to products containing the same, as well as to methods of their use and preparation.

Description of the Related Art

Thyroid hormone (TH) is a key signal for oligodendrocyte differentiation and myelin formation during development, and also stimulates remyelination in adult models of multiple sclerosis (MS) (Calzà et al., Brain Res Revs 48: 339-346, 2005) . However, TH is not an acceptable long-term therapy due to the limited therapeutic window in which remyelination can be achieved while avoiding the cardiotoxicity and bone demineralization associated with chronic hyperthyroidism. Some thyroid hormone analogs can activate thyroid hormone-responsive genes while avoiding the associated downsides of TH by exploiting molecular and physiological features of thyroid hormone receptors (Malm et al., Mini Rev Med Chem 7: 79-86, 2007) . These receptors are expressed in two major forms with heterogenous tissue distributions and overlapping but distinct sets of target genes (Yen, Physiol Rev 81: 1097-1142, 2001) . TRα is enriched in the heart, brain, and bone while TRβ is enriched in the liver (O’S hea et al., Nucl Recept Signal 4: e011, 2006) .

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

Developing selective thyromimetics has been challenging due to the high sequence homology of thyroid hormone receptor subtypes; namely, only one amino acid residue on the internal surface of the ligand binding domain cavity varies between the α1 and β1 forms. Despite this challenge, several groups have reported TRβ-selective agonists. Scanlan et al. identified GC-1 (sobetirome) as one of the first 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 “sobetirome” refers to a synthetic diarylmethane derivative that was investigated clinically as a potential therapeutic for hypercholesterolemia (see U.S. Patent No. 5,883,294, which is incorporated by reference herein) . Other names for sobetirome found in the literature and regulatory filings include QRX-431 and GC-1. Metabasis employs a similar core with a novel liver-targeting prodrug strategy in MB07811 (Erion et al., PNAS 104 (39) , 15490-15495, 2007) . Madrigal has reported TRβ-selective activity in vivo for MGL-3196 (Taub et al., Atherosclerosis 230 (2) : 373-380, 2013) . KaroBio has reported on eprotirome (KB2115; Berkenstam et al., PNAS 105 (2) : 663-668, 2008) and KB-141 (Ye et al., J Med Chem 46: 1580-1588, 2003) , both of which demonstrate improved TRβ-selectivity in vitro. Further studies from this group highlight additional selective compounds (Hangeland et al., BMCL 14: 3549-3553, 2004) . Two TRβ-selective agonists, identified as SKL-12846 and SKL-13784, have been reported to accumulate in the liver and to reduce cholesterol levels in rodents (Takahashi et al., BMC 22 (1) : 488-498, 2014; Xenobiotica 2015, 1-9) . Kissei has also reported selective compounds (Shiohara et al., BMC 20 (11) , 3622-3634, 2012) .

While progress has been made in this field, there remains a need in the art for further selective thyromimetic compounds, as well as to products containing the same, and for methods related to their use and preparation.

BRIEF SUMMARY

Disclosed herein are compounds according to Formula I:

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X ¹, X ², and R ¹are as defined below.

In an embodiment, a pharmaceutical composition is provided comprising a compound having the structure of Formula (I) , or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, in combination with a pharmaceutically acceptable carrier, diluent, or excipient. In an embodiment, the pharmaceutical composition is for use in treating a neurodegenerative disorder including neurodegenerative disorders classified as a demyelinating disease such as X-linked adrenoleukodystrophy or multiple sclerosis. In another embodiment, the pharmaceutical composition is for use in treating a medical condition associated increased activity of TGF-β, such as a fibrotic disease.

In an 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 or composition comprising the same. In some aspects, the neurodegenerative disorder can be classified as a demyelinating disease such as X-linked adrenoleukodystrophy or multiple sclerosis.

In another embodiment, a method is provided for treating a medical condition associated with over-expression of TGF-β in a subject in need thereof, comprising administering a compound having the structure of Formula (I) , or a pharmaceutically acceptable salt or composition comprising the same. In some aspects, the medical condition associated with over-expression of TGF-β is a fibrotic disease.

DETAILED DESCRIPTION

As mentioned above, the invention relates to thyromimetic compounds, to products comprising the same, and to methods for their use and synthesis.

In one embodiment, compounds are provided having the structure of Formula (I) :

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X ¹ is lower alkyl;

X ² is halo;

R ¹ is -NR ^1aR ^1b or -OR ^1c;

R ^1a and R ^1b are each, independently, H, -OR ^a, -NR ^aR ^b, lower alkyl, lower alkenyl, lower alkynyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl, wherein R ^a and R ^b are each, independently, H or lower alkyl; and

R ^1c is H, lower alkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

wherein R ^1a, R ^1b, R ^1c, R ^a, and R ^b are each, independently,optionally substituted with one or more halo, cyano, -OR′, -NR'R”, -S (O) ₂R'or -S (O) ₂OR', wherein R'and R”are each, independently, H or lower alkyl.

The acid compounds of the present invention (R ¹ = -OR ^1c and R ^1c = H) are active agonists selectively activating the TRβ receptor. The amide compounds of the present invention (R ¹ = –NR ^1aR ^1b) may act as substrates for the specific hydrolase enzyme fatty acid-amide hydrolase (FAAH) , which cleaves the amide, liberating the thyromimetic. Thus, prodrug conversion to drug is enhanced in tissues that express high levels of FAAH such as the central nervous system. The ester compounds of the present invention (R ¹ = -OR ^1c and R ^1c ≠ H) are also prodrugs, typically processed through the action of esterases which may exist selectively in specific tissues.

As used herein, “lower alkyl” means a straight chain or branched alkyl group having from 1 to 8 carbon atoms, in some embodiments from 1 to 6 carbon atoms, in some embodiments from 1 to 4 carbon atoms, and in some embodiments from 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 groups. Examples of branched lower alkyl groups include, but are not limited to, isopropyl, iso-butyl, sec-butyl, t-butyl, neopentyl, isopentyl, and 2, 2-dimethylpropyl groups.

As used herein, “lower alkenyl” means a straight chain or branched 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. Alkenyl groups are unsaturated hydrocarbons that contain at least one carbon-carbon double bond. Examples of lower alkenyl groups include, but are not limited to, vinyl, propenyl, butenyl, pentenyl, and hexenyl.

As used herein, “lower alkynyl” means a straight chain or branched 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. Alkynyl groups are unsaturated hydrocarbons that contain at least one carbon-carbon triple bond. Examples of lower alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl.

“Halo" or “halogen” refers to fluorine, chlorine, bromine, and iodine.

"Hydroxy" refers to -OH.

“Cyano” refers to -CN.

“Lower haloalkyl” refers to a lower alkyl as defined above with one or more hydrogen atoms replaced with halogen. Examples of lower haloalkyl groups include, but are not limited to, -CF ₃, -CHF ₂, and the like.

“Lower alkoxy" refers to a lower alkyl as defined above joined by way of 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.

"Lower haloalkoxy" refers to a lower haloalkyl as defined above joined by way of an oxygen atom (i.e., -O- (lower haloalkyl) . Examples of lower haloalkoxy groups include, but are not limited to, -OCF ₃, and the like.

"Cycloalkyl" refers to alkyl groups forming a ring structure, which can be substituted or unsubstituted, wherein the ring is either completely saturated, partially unsaturated, or fully unsaturated, wherein if there is unsaturation, the conjugation of the pi-electrons in the ring do not give rise to aromaticity. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl groups. In some embodiments, the cycloalkyl group has 3 to 8 ring members, whereas in other embodiments the number of ring carbon atoms range from 3 to 5, 3 to 6, or 3 to 7. Cycloalkyl groups further include polycyclic cycloalkyl groups such as, but not limited to, norbornyl, adamantyl, bornyl, camphenyl, isocamphenyl, and carenyl groups, and fused rings such as, but not limited to, decalinyl, and the like.

"Cycloalkylalkyl" are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined above.

“Aryl” groups are cyclic aromatic hydrocarbons that do not contain 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 6-14 carbons in the ring portions of the groups. The phrase “aryl groups” includes groups containing fused rings, such as fused aromatic-aliphatic ring systems (e.g., indanyl, tetrahydronaphthyl, and the like) . In one embodiment, aryl is phenyl or naphthyl, and in another embodiment aryl is phenyl.

"Carbocyclyl, " “carbocycle, ” or "carbocyclic" refers to alkyl groups forming a ring structure, which can be substituted or unsubstituted, wherein the ring is either completely saturated, partially unsaturated, or fully unsaturated, wherein if there is unsaturation, the conjugation of the pi-electrons in the ring may give rise to aromaticity. In one embodiment, carbocycle includes cycloalkyl as defined above. In another embodiment, carbocycle includes aryl as defined above.

"Carbocyclealkyl" are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a carbocycle group as defined above.

"Heterocyclyl, " "heterocycle, " or "heterocyclic" refers to aromatic and non-aromatic ring moieties containing 3 or more ring members, of which one or more is a heteroatom such as, but not limited to, N, O, S, or P. In some embodiments, heterocyclyl include 3 to 20 ring members, whereas other such groups have 3 to 15 ring members. At least one ring contains a heteroatom, but every ring in a polycyclic system need not contain a heteroatom. For example, a dioxolanyl ring and a benzdioxolanyl ring system (methylenedioxyphenyl ring system) are both heterocyclyl groups within the meaning herein.

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

"Heterocyclealkyl" are alkyl groups as defined above in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a heterocycle group as defined above.

"Heteroaryl" refers to aromatic ring moieties containing 5 or more ring members, of which, one or more is a heteroatom 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 groups.

In one embodiment, compounds are provided having the structure of Formula (II) :

X ¹ is (C ₁–C ₃) alkyl;

X ² is halo;

R ^1a and R ^1b are each, independently, H, -OR ^a, -NR ^aR ^b, lower alkyl, lower alkenyl, lower alkynyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl;

wherein R ^a and R ^b are each, independently, H or lower alkyl; and

wherein R ^1a, R ^1b, R ^a, and R ^b are each, independently, optionally substituted with one or more halo, cyano, -OR′, -NR'R”, -S (O) ₂R'or -S (O) ₂OR', wherein R'and R”are each, independently, H or lower alkyl.

In one embodiment, compounds are provided having the structure of Formula (III) :

X ¹ is (C ₁–C ₃) alkyl;

X ² is halo; and

R ^1c is H, lower alkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl, wherein R ^1c is optionally substituted with one or more halo, cyano, -OR', -NR'R”, -S (O) ₂R'or -S (O) ₂OR', wherein R'and R”are each, independently, H or lower alkyl.

In one embodiment, compounds are provided having the structure of Formula (IV) :

X ¹ is (C ₁–C ₃) alkyl; and

X ² is halo.

In one embodiment, compounds having the structure of Formulas (I) or (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^1a is (C ₁–C ₆) alkyl. In one embodiment, R ^1a is methyl.

In one embodiment, compounds having the structure of Formulas (I) or (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^1b is H.

In one embodiment, compounds having the structure of Formulas (I) or (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^1a is (C ₁–C ₆) alkyl and R ^1b is H. In another embodiment, R ^1a is methyl and R ^1b is H.

In one embodiment, compounds having the structure of Formulas (I) or (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^1c is alkyl. In one embodiment, R ^1c is methyl.

In one embodiment, compounds having the structure of Formulas (I) , (II) , (III) , or (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X ¹ is lower alkyl. In one embodiment, X ¹ is methyl.

In one embodiment, compounds having the structure of Formulas (I) , (II) , (III) , or (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X ² is Cl or Br. In one embodiment, X ² is Cl. In one embodiment, X ² is Br.

In one embodiment, compounds having the structure of Formulas (I) , (II) , (III) , or (IV) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X ¹ is methyl and X ² is Cl or Br. In one embodiment, X ¹ is methyl and X ² is Cl. In another embodiment, X ¹ is methyl and X ² is Br.

In one embodiment, compounds having the structure of Formulas (I) or (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^1a is lower alkyl, R ^1b is H, X ¹ is methyl, and X ² is Cl. In another embodiment, R ^1a is methyl, R ^1b is H, X ¹ is methyl, and X ² is Cl.

In one embodiment, compounds having the structure of Formulas (I) or (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^1a is lower alkyl, R ^1b is H, X ¹ is methyl, and X ² is Br. In another embodiment, R ^1a is methyl, R ^1b is H, X ¹ is methyl, and X ² is Br.

In one embodiment, compounds having the structure of Formulas (I) or (II) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^1c is alkyl, X ¹ is methyl, and X ² is Cl. In one embodiment, R ^1c is methyl, X ¹ is methyl, and X ² is Cl.

In one embodiment, compounds having the structure of Formulas (I) or (III) are provided, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^1c is alkyl, X ¹ is methyl, and X ² is Br. In one embodiment, R ^1c is methyl, X ¹ is methyl, and X ² is Br.

Representative compounds of Formula (I) , and Formulas (II) through (IV) as applicable, include the compounds listed in Table 1 below, as well as pharmaceutically acceptable salts thereof. To this end, representative compounds are identified herein by their respective “Compound Number” , which is sometimes abbreviated as “Compound No. ” , “Cmpd. No. ” or “No. ”

Table 1

Representative Compounds

“Isomer” is used herein to encompass all chiral, 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 as are apparent from the depictions, at any degree of enrichment. Both racemic and diastereomeric mixtures, as well as the individual optical isomers can be synthesized so as to be substantially free of their enantiomeric or diastereomeric partners, and these are all within the scope of certain embodiments of the invention. The isomers resulting from the presence of a chiral center comprise a pair of nonsuperimposable-isomers that are called “enantiomers. ” Single enantiomers of a pure compound are optically active (i.e., they are capable of rotating the plane of plane polarized light and designated R or S) .

“Isolated optical isomer” means a compound which has been substantially purified from the corresponding optical isomer (s) 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%pure or at least 98%pure, or at least 99%pure by weight.

“Substantially enantiomerically or diastereomerically” pure means a level of enantiomeric or diastereomeric enrichment of one enantiomer with respect to the other enantiomer or diastereomer of at least about 80%, and more specifically in excess of 80%, 85%, 90%, 95%, 98%, 99%, 99.5%or 99.9%.

The terms "racemate" and "racemic mixture" refer to an equal mixture of two enantiomers. A racemate is labeled “ (±) ” because it is not optically active (i.e., will not rotate plane-polarized light in either direction since its constituent enantiomers cancel each other out) . All compounds with an asterisk (*) adjacent to a tertiary or quarternary carbon are optically active isomers, which may be purified from the respective racemate and/or synthesized by appropriate chiral synthesis.

A "hydrate" is a compound that exists in combination with water molecules. The combination can include water in stoichiometric quantities, such as a monohydrate or a dihydrate, or can include water in random amounts. As the term is used herein a "hydrate" refers to a solid form; that is, a compound in a water solution, while it may be hydrated, is not a hydrate as the term is used herein.

A "solvate" is similar to a hydrate except that a solvent other that water is present. For example, methanol or ethanol can form an "alcoholate" , which can again be stoichiometric or non-stoichiometric. As the term is used herein a "solvate" refers to a solid form; that is, a compound in a solvent solution, while it may be solvated, is not a solvate as the term is used herein.

“Isotope” refers to atoms with the same number of protons but a different number of neutrons, and an isotope of a compound of Formula (I) includes any such compound wherein 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, whereas 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) . While fluorine has a number of isotopes, fluorine 19 is longest-lived. Thus, an isotope of a compound having the structure of Formula (I) includes, but not limited to, compounds of Formula (I) wherein one or more carbon 12 atoms are replaced by carbon-13 and/or carbon-14 atoms, wherein one or more hydrogen atoms are replaced with deuterium and/or tritium, and/or wherein one or more fluorine atoms are replaced by fluorine-19.

"Salt" generally refers to an organic compound, such as a carboxylic acid or an amine, in ionic form, in combination with a counter ion. For example, salts formed between acids in their anionic form and cations are referred to as “acid addition salts” . Conversely, salts formed between bases in the cationic form and anions are referred to as “base addition salts. ”

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

Pharmaceutically acceptable base addition salts of compounds of the invention include, for example, metallic salts including alkali metal, alkaline earth metal, and transition metal salts such as, for example, calcium, magnesium, potassium, sodium, and zinc salts. 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) , and procaine.

Pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid. Examples of inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids. Appropriate organic acids may be selected from aliphatic, cycloaliphatic, aromatic, aromatic aliphatic, heterocyclic, carboxylic, and sulfonic classes of organic acids, examples of which include formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, 4-hydroxybenzoic, phenylacetic, mandelic, hippuric, malonic, oxalic, embonic (pamoic) , methanesulfonic, ethanesulfonic, benzenesulfonic, panthothenic, trifluoromethanesulfonic, 2-hydroxyethanesulfonic, p-toluenesulfonic, sulfanilic, cyclohexylaminosulfonic, stearic, alginic, βhydroxybutyric, salicylic, -galactaric, and galacturonic acid.

Although pharmaceutically unacceptable salts are not generally useful as medicaments, such salts may be useful, for example as intermediates in the synthesis of compounds having the structure of Formula I, for example in their purification by recrystallization.

In certain embodiments, the invention provides a pharmaceutical composition comprising a compound of the invention together with at least one pharmaceutically acceptable carrier, diluent, or excipient. For example, the active compound will usually be mixed with a carrier, or diluted by a carrier, or enclosed within 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 when the carrier serves as a diluent, it can be solid, semi-solid, or liquid material that acts as a vehicle, excipient, or medium for the active compound. The active compound can be adsorbed on a granular solid carrier, for example contained in a sachet. Some examples of suitable carriers are water, salt solutions, alcohols, polyethylene glycols, 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 monoglycerides 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.

As used herein, the term “pharmaceutical composition” refers to a composition containing one or more of the compounds described herein, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, formulated with a pharmaceutically acceptable carrier, which can also include other additives, and manufactured or sold with the approval of a governmental regulatory agency as part of a therapeutic regimen for the treatment of disease in a mammal. Pharmaceutical compositions can be formulated, for example, for oral administration in unit dosage form (e.g., a 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 sterile solution free of particulate emboli and in a solvent system suitable for intravenous use) ; or in any other formulation described herein. Conventional procedures and ingredients for the selection and preparation of suitable formulations are described, for example, in Remington: The Science and Practice of Pharmacy, 21 ^st Ed., Gennaro, Ed., Lippencott Williams &Wilkins (2005) and in The United States Pharmacopeia: The National Formulary (USP 36 NF31) , published in 2013.

As used herein, the term “pharmaceutically acceptable carrier” refers to any ingredient other than the disclosed compounds, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof (e.g., a carrier capable of suspending or dissolving the active compound) and having the properties of being nontoxic and non-inflammatory in a patient. Excipients may include, for example: antiadherents, antioxidants, binders, coatings, compression aids, disintegrants, dyes (colors) , emollients, emulsifiers, fillers (diluents) , film formers or coatings, flavors, fragrances, glidants (flow enhancers) , lubricants, preservatives, printing inks, sorbents, suspensing or dispersing agents, sweeteners, or waters of hydration. Exemplary excipients include, but are not limited to: butylated hydroxytoluene (BHT) , calcium carbonate, calcium phosphate (dibasic) , calcium stearate, croscarmellose, crosslinked polyvinyl pyrrolidone, citric acid, crospovidone, cysteine, ethylcellulose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose, lactose, magnesium stearate, maltitol, mannitol, methionine, methylcellulose, methyl paraben, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, povidone, pregelatinized starch, propyl paraben, retinyl palmitate, shellac, silicon dioxide, sodium carboxymethyl cellulose, sodium citrate, sodium starch glycolate, sorbitol, starch (corn) , stearic acid, stearic acid, sucrose, talc, titanium dioxide, vitamin A, vitamin E, vitamin C, and xylitol.

The formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds. Such additives can include wetting agents, emulsifying and suspending agents, salt for influencing osmotic pressure, buffers and/or coloring substances, preserving agents, sweetening agents, or flavoring agents. The compositions can also be sterilized if desired.

The route of administration can be any route which effectively transports the active compound of the invention to the appropriate or desired site of action, such as oral, nasal, pulmonary, buccal, subdermal, intradermal, transdermal, or parenteral, including intravenous, subcutaneous and/or intramuscular. In one embodiment, the route of administration is oral.

Dosage forms can be administered once a day, or more than once a day, such as twice or thrice daily. Alternatively, dosage forms can be administered less frequently than daily, such as every other day, or weekly, if found to be advisable by a prescribing physician or drug’s prescribing information. Dosing regimens include, for example, dose titration to the extent necessary or useful for the indication to be treated, thus allowing the patient’s body to adapt to the treatment, to minimize or avoid unwanted side effects associated with the treatment, and/or to maximize the therapeutic effect of the present compounds. Other dosage forms include delayed or controlled-release forms. Suitable dosage regimens and/or forms include those set out, for example, in the latest edition of the Physicians'Desk Reference, incorporated herein by reference.

In another embodiment, there are provided methods of making a composition of a compound described herein including formulating a compound of the invention with a pharmaceutically acceptable carrier or diluent. In some embodiments, the pharmaceutically acceptable carrier or diluent is suitable for oral administration. In some such embodiments, the methods can further include the step of 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 methods further include the step of lyophilizing the composition to form a lyophilized preparation.

In another embodiment, a method of treating a subject having a neurodegenerative disease is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the neurodegenerative disease is a demyelinating disease. In another embodiment, the demyelinating disease is a chronic demyelinating disease. In yet another embodiment, the demyelinating disease is or is associated with a X-linked genetic disorder, leukodystrophy, dementia, tauopathy, or ischaemic stroke. In another embodiment, the demyelinating disease is or is associated with adult Refsum disease, Alexander disease, Alzheimer’s disease, Balo concentric sclerosis, Canavan disease, central pontine myelinolysis (CPM) , cerebral palsy, cerebrotendineous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP) , Devic's syndrome, diffuse myelinoclastic sclerosis, encephalomyelitis, idiopathic inflammatory demyelinating disease (IIDD) , infantile Refsum disease, Krabbe disease, Leber hereditary optic neuropathy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy, multifocal motor neuropathy, paraproteinemic demyelinating polyneuropathy, Pelizaeus-Merzbacher disease, peroneal muscular atrophy, progressive multifocal leukoencephalopathy, transverse myelitis, tropical spastic paraparesis, van der Knaap 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 lacunar stroke.

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

As used herein, the term “demyelinating disease” refers to any disease or medical condition of the nervous system in which myelin is damaged or lost, or in which the growth or development of the myelin sheath is impaired. Demyelination inhibits the conduction of signals in the affected nerves, causing impairment in sensation, movement, cognition, or other functions for which nerves are involved. Demyelinating diseases have a number of different causes and can be hereditary or acquired. In some cases, a demyelinating disease is caused by an infectious agent, an autoimmune response, a toxic agent or traumatic injury. In other cases, the cause of the demyelinating disease is unknown ( “idiopathic” ) or develops from a combination of factors.

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

As used herein, the term “leukoencephalopathy” refers to any of a group of diseases affecting the white substance of the brain; can refer specifically to several diseases including, for example, “leukoencephalopathy with vanishing white matter” and “toxic leukoencephalopathy. ” Leukoencephalopathies are leukodystrophy-like diseases.

As used herein, the term “tauopathy” refers to tau-related disorders or conditions, e.g., 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.

As used herein, the terms “multiple sclerosis” and “MS” refer to a slowly progressive CNS disease characterized by disseminated patches of demyelination in the brain and spinal cord, resulting in multiple and varied neurological symptoms and signs, usually with remissions and exacerbation. The cause of MS is unknown but an immunological abnormality is suspected. An increased family incidence suggests genetic susceptibility, and women are somewhat more often affected than men. The symptoms of MS include weakness, lack of coordination, paresthesias, speech disturbances, and visual disturbances, most commonly double vision. More specific signs and symptoms depend on the location of the lesions and the severity and destructiveness of the inflammatory and sclerotic processes. Relapsing-remitting multiple sclerosis (RRMS) is a clinical course of MS that is characterized by clearly defined, acute attacks with full or partial recovery and no disease progression between attacks. Secondary-progressive multiple sclerosis (SPMS) is a clinical course of MS that initially is relapsing-remitting, and then becomes progressive at a variable rate, possibly with an occasional relapse and minor remission. Primary-progressive multiple sclerosis (PPMS) presents initially in the progressive form. A clinically isolated syndrome is the first neurologic episode, which is caused by inflammation/demyelination at one or more sites in the CNS. Progressive-relapsing multiple sclerosis (PRMS) is a rare form of MS (～5%) characterized by a steadily worsening disease state from onset, with acute relapses but no remissions.

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

In another embodiment, a method of treating a subject having a leukodystrophy is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, 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’s disease, or Krabbe disease (globoid leukodystrophy) . As used herein, the term “adrenomyeloneuropathy” or “AMN” refers to an adult variant of X-linked adrenoleukodystrophy, characterized by ABCD1 gene mutation, that results in impaired peroxisome function with accumulation of very long chain fatty acids (VLCFA) and demyelination.

In one embodiment, a method of treating a subject having a tauopathy is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, 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 linked to chromosome 17 (FTDP-17) .

In yet another embodiment, a method of treating a subject having an ischaemic stroke is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the ischaemic stroke is lacunar stroke (also called “lacunar infarct” ) . In another embodiment, the present method is used to treat a subject suffering from a lacunar stroke syndrome (LACS) .

In another embodiment, a method of treating a subject having adult Refsum disease, infantile Refsum disease, Alexander disease, Alzheimer's disease, balo concentric sclerosis, Canavan disease, central pontine myelinolysis (CPM) , cerebral palsy, cerebrotendineous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP) , Devic's syndrome, diffuse myelinoclastic sclerosis, encephalomyelitis, idiopathic inflammatory demyelinating disease (IIDD) , Krabbe disease, Leber hereditary optic neuropathy, leukodystrophy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy (MLD) , multifocal motor neuropathy (MMN) , multiple sclerosis (MS) , paraproteinemic demyelinating polyneuropathy, Pelizaeus-Merzbacher disease (PMD) , progressive multifocal leukoencephaalopathy (PML) , tropical spastic paraparesis (TSP) , X-linked adrenoleukodystrophy (X-ALD, ALO, or X-linked ALO) , or Zellweger syndrome is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.

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

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

In one embodiment, a method of treating a subject having a medical condition associated with increased activity of TGF-β is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof. In one embodiment, the medical condition associated with increased activity of TGF-β is a fibrotic disease. In another embodiment, the fibrotic disease is or is associated with nonalcoholic steatohepatitis (NASH) , idiopathic pulmonary fibrosis (IPF) , systemic scleroderma, or Alport syndrome. As used herein, the term “Alport syndrome” refers to a hereditary disorder caused by mutations in the a3a4a5 (IV) collagen network genes resulting in structural defects in the glomerular basement membrane (GBM) early during development leading subsequently to the breakdown of the filtration barrier, development of renal fibrosis and kidney failure.

As used herein, the term “fibrotic disease” refers to a condition, disease or disorder that is amenable to treatment by administration of a compound having anti-fibrotic activity. Fibrotic diseases include, but are not limited to, pulmonary fibrosis, including idiopathic pulmonary fibrosis (IPF) and pulmonary fibrosis from a known etiology, liver fibrosis, and renal-fibrosis. Other exemplary fibrotic diseases include musculoskeletal fibrosis, cardiac fibrosis, post-surgical adhesions, scleroderma, glaucoma, and skin lesions such as keloids.

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

In another embodiment, 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 agents, nephrogenic systemic fibrosis, tubulointerstitial fibrosis, glomerulosclerosis, or polycystic kidney disease (PKD) is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.

In another embodiment, a method of treating a subject having IPF, ILD, pulmonary fibrosis, pulmonary fibrosis associated with autoimmune diseases like rheumatoid arthritis, scleroderma or Sjogren's syndrome, asthma-related pulmonary fibrosis, COPD, asbestos or silica induced PF, silicosis, respiratory bronchiolitis, Idiopathic interstitial pneumonias (IIP) , Idiopathic nonspecific interstitial pneumonia, Respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia, acute interstitial pneumonia, Rare IIPs: Idiopathic lymphoid interstitial pneumonia, idiopathic pleuroparenchymal fibroelastosis, unclassifiable idiopathic interstitial pneumonias, hypersensitivity pneumonitis, radiation-induced lung injury, progressive massive fibrosis –pneumoconiosis, bronchiectasis, byssinosis, chronic respiratory disease, chronic obstructive pulmonary disease (COPD) , emphysema, pulmonary arterial hypertension (PAH) , or Cystic fibrosis is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.

In another embodiment, a method of treating a subject having scleroderma/systemic sclerosis, graft versus host disease, hypertrophic scars, keloids, nephrogenic systemic fibrosis, porphyria cutanea tarda, restrictive dermopathy, Dupuytren’s contracture, dermal fibrosis, nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy, mixed connective tissue disease, scleromyxedema, eosinophilic fasciitis, fibrosis caused by exposure to chemicals or physical agents. GvHD induced fibrosis, Scleredema adultorum, Lipodermatosclerosis, or Progeroid disorders (progeria, acrogeria, Werner’s syndrome) is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.

In another embodiment, a method of treating a subject having atrial fibrosis, endomyocardial fibrosis, cardiac fibrosis, atherosclerosis, restenosis, or arthrofibrosis is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.

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

In another embodiment, a method of treating a subject having Crohn’s disease, retroperitoneal fibrosis, intestinal fibrosis, fibrosis in inflammatory bowel disease, ulcerative colitis, GI fibrosis due to cystic fibrosis, or pancreatic fibrosis due to pancreatitis is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.

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

In another embodiment, a method of treating a subject having macular degeneration, diabetic retinopathy, retinal fibrovascular diseases, or vitreal retinopathy is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.

In another embodiment, a method of treating a subject having scarring associated with trauma (surgical complications, chemotherapeutics drug-induced fibrosis, radiation induced fibrosis) is provided, the method comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.

As used herein, the term “administration” refers to providing a compound, a prodrug of a compound, or a pharmaceutical composition comprising the compound or prodrug as described herein. The compound or composition can be administered by another person to the subject or it can be self-administered by the subject. Non-limiting examples of routes of administration are oral, parenteral (e.g., intravenous) , or topical.

As used herein, the term “treatment” refers to an intervention that ameliorates a sign or symptom of a disease or pathological condition. As used herein, the terms “treatment” , “treat” and "treating, " with reference to a disease, pathological condition or symptom, also refers to any observable beneficial effect of the treatment. The beneficial effect can be evidenced, for example, by a delayed onset of clinical symptoms of the disease in a susceptible subject, a reduction in severity of some or all clinical symptoms of the disease, a slower progression of the disease, a reduction in the number of relapses of the disease, an improvement in the overall health or well-being of the subject, or by other parameters well known in the art that are specific to the particular disease. A prophylactic treatment is a treatment administered to a subject who does not exhibit signs of a disease or exhibits only early signs, for the purpose of decreasing the risk of developing pathology. A therapeutic treatment is a treatment administered to a subject after signs and symptoms of the disease have developed.

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 may be one who has been diagnosed with a neurodegenerative disease involving demyelination, insufficient myelination, or underdevelopment of a myelin sheath, e.g., a subject diagnosed with multiple sclerosis or cerebral palsy, or one at risk of developing the condition. Diagnosis may be performed by any method or technique known in the art. One skilled in the art will understand that a subject to be treated according to the present disclosure may have been subjected to standard tests or may have been identified, without examination, as one at risk due to the presence of one or more risk factors associated with the disease or condition.

As used herein, the term “effective amount” refers to a quantity of a specified agent sufficient to achieve a desired effect in a subject being treated with that agent. Ideally, an effective amount of an agent is an amount sufficient to inhibit or treat the disease without causing substantial toxicity in the subject. The effective amount of an agent will be dependent on the subject being treated, the severity of the affliction, and the manner of administration of the pharmaceutical composition. Methods of determining an effective amount of the disclosed compound sufficient to achieve a desired effect in a subject will be understood by those of skill in the art in light of this disclosure.

As used herein, the terms “chronic” refers to a medical disorder or condition that persists over time or is frequently recurring.

Compounds having the structure of Formulas (I) , (II) , (III) and (IV) can be synthesized using standard synthetic techniques known to those skilled in the art. For example, compounds of the present invention can be synthesized using appropriately modified synthetic procedures set forth in Scheme 1.

To this end, the reactions, processes, and synthetic methods described herein are not limited to the specific conditions described in the following experimental section, but rather are intended as a guide to one with suitable skill in this field. For example, reactions may be carried out in any suitable solvent, or other reagents to perform the transformation [s] necessary. Generally, suitable solvents are protic or aprotic solvents which are substantially non-reactive with the reactants, the intermediates or products at the temperatures at which the reactions are carried out (i.e., temperatures which may range from the freezing to boiling temperatures) . A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction, suitable solvents for a particular work-up following the reaction may be employed.

Scheme 1

Referring to Scheme 1, a disubstituted phenol (for example, 3-methyl-5-chlorophenol or 3-methyl-5-bromo-phenol, or the like) is reacted with a formaldehyde equivalent (for example, aqueous formaldehyde or paraformaldehyde or dimethoxymethane or the like) to give a hydroxymethyl derivative (A) , which is subsequently reacted with an activated acetate moiety (for example ethyl chloroacetate or methyl bromoacetate or the like) in the presence of base, selectively at the phenolic oxygen, to provide intermediate (B) . The hydroxymethyl group is activated (for example, through reaction with thionyl chloride or oxalyl chloride or p-toluenesulfonylchloride or the like) to give a chloromethyl derivative (C) (or the corresponding tosylate, or mesylate, or bromomethyl analog, or the like) , which is condensed with 2-isopropylphenol in the presence of a Lewis acid (like zinc chloride, or aluminum chloride, or the like) to give an ester (D) . If desired, the ester can be hydrolyzed to give the corresponding acid (E) . If desired, either ester (D) or acid (E) can be converted to an amide (F) by heating with the corresponding amine (for example methylamine or propylamine or 2-sulfonylethylamine or the like) .

EXAMPLES

The invention is further illustrated by the following examples. The examples below are non-limiting are merely representative of various aspects of the invention. Solid and dotted wedges within the structures herein disclosed illustrate relative stereochemistry, with absolute stereochemistry depicted only when specifically stated or delineated.

General Methods

All reagents, for which the synthesis is not described in the experimental part, are either commercially available, or are known compounds or may be formed from known compounds by known methods by a person skilled in the art.

The compounds and intermediates produced according to the methods of the invention may require purification. Purification of organic compounds is well known to a person skilled in the art and there may be several ways of purifying the same compound. In some cases, no purification may be necessary. In some cases, the compounds may be purified by crystallization. In some cases, impurities may be stirred out using a suitable solvent.

In some cases, the compounds may be purified by chromatography, particularly flash column chromatography, using purpose-made or prepacked silica gel cartridges and eluents such as gradients of solvents such as heptane, ether, ethyl acetate, acetonitrile, ethanol and the like. In some cases, the compounds may be purified by preparative HPLC using methods as described.

Purification methods as described herein may provide compounds of the present invention which possess a sufficiently basic or acidic functionality in the form of a salt, such as, in the case of a compound of the present invention which is sufficiently basic, a trifluoroacetate or formate salt, or, in the case of a compound of the present invention which is sufficiently acidic, an ammonium salt. A salt of this type can either be transformed into its free base or free acid form, respectively, by various methods known to a person skilled in the art, or be used as salts in subsequent biological assays. It is to be understood that the specific form of a compound of the present invention as isolated and as described herein is not necessarily the only form in which said compound can be applied to a biological assay in order to quantify the specific biological activity.

All the starting materials and reagents are commercially available and were used as is. ¹H Nuclear magnetic resonance (NMR) spectroscopy was carried out using a Bruker instrument operating at 400 MHz using the stated solvent at around room temperature unless otherwise stated. In all cases, NMR data were consistent with the proposed structures. Characteristic chemical shifts (δ) are given in parts-per-million using conventional abbreviations for designation of major peaks: e.g. s, singlet; d, doublet; t, triplet; q, quartet; dd, doublet of doublets; dt, doublet of triplets; m, multiplet; br, broad. Preparative HPLC purification was performed by reverse phase HPLC using gradients of acetonitrile in aqueous TFA or an equivalent HPLC system such as Methanol in aqueous ammonium acetate.

Chemical names were generated using the ChemDraw naming software (Version 17.0.0.206) by PerkinElmer Informatics, Inc. In some cases, generally accepted names of commercially available reagents were used in place of names generated by the naming software.

Abbreviations

The following abbreviations are used in the examples, while other abbreviations have their customary meaning in the art:

CH ₂O formaldehyde

h hour (s)

l: Liter

LCMS: liquid chromatography –mass spectrometry

M: Molar

min: Minute (s)

μl: Microliter

ml: Millliliter

NaOH: sodium hydroxide

NMR: nuclear magnetic resonance spectroscopy

rt: Room temperature

Rt: Retention time

sat.: Saturated

SOCl ₂ thionyl chloride

INTERMEDIATE A

Synthesis of 3-chloro-4- (hydroxymethyl) -5-methyl-phenol

To a mixture of 3-chloro-5-methyl-phenol (3.55 g, 24.9 mmol) in water (10 mL) at rt was added NaOH (1.10 g, 27.42 mmol) . The mixture was heated to 45℃, HCHO (0.75 g, 24.93 mmol, 37%/water) was added dropwise. The mixture was stirred at 45℃ for 2h.The mixture was cooled down to rt, and acidified with HCl (3 N) to pH=3, extracted with EtOAc (10 mL*3) . The combined EtOAc phase was washed by brine (15 mL) , dried over Na ₂SO ₄, concentrated under reduce pressure. The crude product was purified by silica column (PE/EtOAc=50/1 to 5/1) to afford Intermediate A (0.76 g, 4.40 mmol, 17.7%yield) as off-white solid. TLC: EtOAc/pet. ether =1/1 (v/v) , Rf=0.8 HNMR: ¹H NMR (400 MHz, DMSO-d ₆) δ 9.68 (s, 1H) , 6.62 (d, J = 2.4 Hz, 1H) , 6.56 (d, J = 2.4 Hz, 1H) , 4.73 (t, J = 5.2 Hz, 1H) , 4.49 (d, J = 5.2 Hz, 2H) , 2.31 (s, 3H) .

INTERMEDIATE B

Synthesis of 3-bromo-4- (hydroxymethyl) -5-methyl-phenol

To a solution of sodium hydroxide (1.76 g, 44.11 mmol) in water (30 mL) was added 3-bromo-5-methyl-phenol (7.5 g, 40.1 mmol) . The solution was heated to 45℃, formaldehyde (3.25 g, 40.1 mmol, 37%/w water) was added dropwise. The mixture was stirred at 45℃ for 2h. The mixture was cooled down water (10 mL) was added. The mixture was acidified with HCl (3N) to pH= 3. The mixture was extracted with EtOAc (20 mL*2) . The combined EtOAc phase was washed by brine (30 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure. The residue was purified by silica column (pet. ether: EtOAc=30: 1 to 4: 1) to afford Intermediate B (1.0 g, 4.6 mmol, 11.5%yield) as a white solid. TLC: Pet. ether/EtOAc=1/1 (v/v) , Rf=0.8 HNMR: ¹H NMR (400 MHz, DMSO-d ₆) δ 9.67 (s, 1H) , 6.80 (d, J = 2.4 Hz, 1H) , 6.60 (d, J = 2.5 Hz, 1H) , 4.73 (t, J = 5.1 Hz, 1H) , 4.51 (d, J = 5.1 Hz, 2H) , 2.33 (s, 3H) .

INTERMEDIATE C

Synthesis of methyl 2- [3-chloro-4- (hydroxymethyl) -5-methyl-phenoxy] acetate

To a solution of Intermediate A (0.66 g, 3.82 mmol) in acetone (10 mL) at rt was added cesium carbonate (1.87 g, 5.74 mmol) , NaI (57 mg, 382umol) and methyl 2-chloroacetate (539 mg, 4.97 mmol) . The mixture was stirred at rt for 4 h and water (30 mL) was added. The mixture was extracted with EtOAc (10 mL*3) . The combined EtOAc phase was washed by brine (20 mL) , dried over Na ₂SO ₄ and concentrated under reduce pressure. The crude product was purified by silica column (PE/EtOAc=100/1 to 5/1) to afford Intermediate C (280 mg, 1.14 mmol, 29.9%yield) as white solid. TLC: EtOAc/pet. ether =1/2 (v/v) , Rf=0.67 HNMR: ¹H NMR (400 MHz, DMSO-d ₆) δ 6.84 (d, J = 2.6 Hz, 1H) , 6.78 (d, J = 2.6 Hz, 1H) , 4.85-4.81 (m, 3H) , 4.53 (d, J = 4.9 Hz, 2H) , 3.69 (s, 2H) , 2.37 (s, 3H) .

INTERMEDIATE D

Synthesis of methyl 2- [3-bromo-4- (hydroxymethyl) -5-methyl-phenoxy] acetate

To a solution of Intermediate B (900 mg, 4.15 mmol) in acetone (15 mL) was added NaI (63 mg, 41.5 umol) and Cs ₂CO ₃ (2.03 g, 6.2 mmol) . Methyl 2-chloroacetate (585 mg, 5.4 mmol) was added dropwise. The mixture was refluxed for 2 h. The mixture cooled down filtered. The filtrate was diluted with EtOAc (30 mL) and water (50 mL) . The organic phase was washed with brine (30 mL) , dried over Na ₂SO ₄ and concentrated in vacuum. The residue was purified by silica column (pet. ether: EtOAc=30: 1-3: 1) to afford Intermediate D (360 mg, 1.25 mmol, 30.0%yield) as a white solid. TLC: Pet. ether/EtOAc=2/1 (v/v) , Rf=0.7 HNMR: ¹H NMR (400 MHz, DMSO-d ₆) δ 7.00 (d, J = 2.6 Hz, 1H) , 6.82 (d, J = 2.7 Hz, 1H) , 4.84 (t, J = 5.2 Hz, 1H) , 4.82 (s, 2H) , 4.55 (d, J = 5.2 Hz, 2H) , 3.69 (s, 3H) , 2.39 (s, 3H) .

INTERMEDIATE E

Synthesis of methyl 2- [3-chloro-4- (chloromethyl) -5-methyl-phenoxy] acetate

To a solution of Intermediate C (360 mg, 1.47 mmol) in DCM (6 mL) at rt was added thionylchloride (263 mg, 2.21 mmol) . The mixture was stirred at rt for 1 h, then concentrated under reduce pressure to afford Intermediate E (300 mg, 1.14 mmol, 77.5%yield) as yellow solid. TLC: EtOAc/pet. ether =1/2 (v/v) , Rf=0.8 HNMR: ¹H NMR (400 MHz, DMSO-d ₆) δ 6.96 (d, J = 2.4 Hz, 1H) , 6.87 (d, J = 2.4 Hz, 1H) , 4.86 (s, 2H) , 4.82 (s, 2H) , 3.71 (s, 3H) , 2.41 (s, 3H) .

INTERMEDIATE F

Synthesis of methyl 2- [3-bromo-4- (chloromethyl) -5-methyl-phenoxy] acetate

To a solution of Intermediate D (100 mg, 346 umol) in dichloromethane (4 mL) was added thionylchloride (82.3 mg, 692 umol) . The mixture was stirred at rt for 1h. The mixture was concentrated in vacuum to afford Intermediate F (100 mg, 325 umol, 94.0%yield) as a white solid. TLC: Pet. ether/EtOAc=2/1 (v/v) , Rf=0.8 HNMR: ¹H NMR (400 MHz, DMSO-d ₆) δ 7.11 (d, J = 2.6 Hz, 1H) , 6.91 (d, J = 2.6 Hz, 1H) , 4.86 (s, 2H) , 4.84 (s, 2H) , 3.70 (s, 3H) , 2.42 (s, 3H) .

EXAMPLE 1

Synthesis of methyl 2- (3-chloro-4- (4-hydroxy-3-isopropylbenzyl) -5- methylphenoxy) acetate (Compound 1)

To a solution of Intermediate E (300 mg, 1.14 mmol) in 1, 2-dichloroethane (6 mL) at rt was added zinc chloride (2.85 mL, 2.85 mmol, 1M in Hexane) and 2-isopropylphenol (466 mg, 3.42 mmol) . The mixture was stirred at 85℃ overnight. The solution was diluted with water (20 mL) , extracted with DCM (10 mL*3) . The combined DCM phase was washed by brine (15 ml) , dried over Na ₂SO ₄ and concentrated under reduce pressure. The crude product was purified by Prep-TLC (PE/EtOAc=1/3) to afford Compound 1 (90 mg, 248.04 umol, 21.7%yield) as a white solid. TLC: EtOAc/pet. ether =1/3 (v/v) , Rf=0.45 HNMR: ¹H NMR (400 MHz, DMSO-d ₆) δ 9.03 (s, 1H) , 6.92 (d, J = 2.7 Hz, 1H) , 6.90 (d, J = 2.2 Hz, 1H) , 6.80 (d, J = 2.7 Hz, 1H) , 6.63 (d, J = 8.2 Hz, 1H) , 6.56 (dd, J = 8.2, 2.2 Hz, 1H) , 4.81 (s, 2H) , 3.93 (s, 2H) , 3.70 (s, 3H) , 3.12 (hept, J = 6.9 Hz, 1H) , 2.19 (s, 3H) , 1.10 (d, J = 6.9 Hz, 6H) .

EXAMPLE 2

Synthesis of 2- (3-chloro-4- (4-hydroxy-3-isopropylbenzyl) -5- methylphenoxy) acetic acid (Compound 2)

To a solution of Compound 1 (40 mg, 110 umol) in THF/H ₂O (4mL/6mL) at rt was added NaOH (9 mg, 220 umol) . The mixture was stirred for 2 h, extracted with ether (10 mL) . The aqueous phase was acidified with HCl (2 N) to pH=3, extracted with EtOAc (10 mL*3) . The combined EtOAc phase was washed by brine (10 mL) , dried over Na ₂SO ₄ and concentrated under reduce pressure. The crude product was purified by Prep-HPLC (ACN/water range from 30/70 to 85/15, 35min) to afford Compound 2 (13 mg, 37.27 umol, 33.8%yield) as a white solid. TLC: Pet. ether/EtOAc=1/1 (v/v) , Rf=0.1 HNMR: ¹H NMR (400 MHz, DMSO-d ₆) δ 9.03 (s, 1H) , 6.91 (d, J = 2.2 Hz, 1H) , 6.87 (d, J = 2.7 Hz, 1H) , 6.77 (d, J = 2.7 Hz, 1H) , 6.63 (d, J = 8.2 Hz, 1H) , 6.56 (dd, J = 8.2, 2.2 Hz, 1H) , 4.66 (s, 2H) , 3.93 (s, 2H) , 3.16 –3.09 (m, 1H) , 2.19 (s, 3H) , 1.10 (d, J = 6.9 Hz, 6H) .

EXAMPLE 3

Synthesis of 2- (3-chloro-4- (4-hydroxy-3-isopropylbenzyl) -5- methylphenoxy) -N-methylacetamide (Compound 3)

To a solution of Compound 1 (40 mg, 110 umol) in THF (4 mL) at rt was added methylamine (4 mL, 40%/w water) . The reaction was stirred at 65℃ overnight. The mixture was diluted with water (10 mL) , extracted with EtOAc (10mL *3) . The combined EtOAc phase was washed by brine (10 mL) , dried over Na ₂SO ₄, concentrated under reduce pressure and purified by prep-HPLC (ACN/water range from 30/70 to 85/15) to afford Compound 3 (12 mg, 33.16 umol, 30.1%yield) as white solid. TLC: Pet. ether/EtOAc=5/1 (v/v) , Rf=0.2 HNMR: ¹H NMR (400 MHz, DMSO-d ₆) δ 9.03 (s, 1H) , 8.02 (brs, 1H) , 6.94 (d, J = 2.6 Hz, 1H) , 6.90 (d, J = 2.2 Hz, 1H) , 6.83 (d, J = 2.6 Hz, 1H) , 6.62 (d, J = 8.2 Hz, 1H) , 6.56 (dd, J = 8.2, 2.2 Hz, 1H) , 4.46 (s, 2H) , 3.94 (s, 2H) , 3.17 –3.08 (m, 1H) , 2.65 (d, J = 4.6 Hz, 3H) , 2.20 (s, 3H) , 1.10 (d, J = 6.9 Hz, 6H) .

EXAMPLE 4

Synthesis of methyl 2- (3-bromo-4- (4-hydroxy-3-isopropylbenzyl) -5- methylphenoxy) acetate (Compound 4)

To a solution of Intermediate F (100 mg, 346 umol) in 1, 2-dichloroethane (3 mL) at rt was added ZnCl ₂ (0.86 mL, 865 umol, 1N/hexane) , 2-isopropylphenol (141 mg, 1.04 mmol) . The mixture was heated to 85℃ overnight. The reaction was cooled down to rt.DCM (10 mL) was added. The mixture was washed with water (10 mL) , brine (10 mL) , dried over Na ₂SO ₄ and concentrated under reduce pressure. The crude product was purified by prep-TLC (pet. ether/EtoAe =3/1) to afford to afford Compound 4 (60 mg, 147 umol, 42.6%yield) as a white solid. TLC: Pet. ether/EtOAc=3/1 (v/v) , Rf=0.5 HNMR: ¹H NMR (400 MHz, DMSO-d ₆) δ 9.03 (s, 1H) , 7.07 (d, J = 2.7 Hz, 1H) , 6.90 (d, J = 2.2 Hz, 1H) , 6.84 (d, J = 2.7 Hz, 1H) , 6.63 (d, J = 8.2 Hz, 1H) , 6.55 (dd, J = 8.2, 2.2 Hz, 1H) , 4.81 (s, 2H) , 3.97 (s, 2H) , 3.70 (s, 3H) , 3.15 –3.08 (m, 1H) , 2.19 (s, 3H) , 1.10 (d, J = 6.9 Hz, 6H) .

EXAMPLE 5

Synthesis of 2- (3-bromo-4- (4-hydroxy-3-isopropylbenzyl) -5- methylphenoxy) acetic acid (Compound 5)

To a solution of Compound 4 (100 mg, 246 umol) in THF (4 mL) and water (1 mL) was added LiOH. H ₂O (30 mg, 0.72 mmol) . The mixture was stirred at rt for 1 h. The mixture was concentrated and water (10 mL) was added. The mixture was extracted with ether (10 mL*2) . Aqueous phase was adjusted to pH=3 with HCl (1N) and was extracted with EtOAc (10mL*2) . The combined organic phase was washed by brine (20 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure to afford Compound 5 (70 mg, 178 umol, 72.5%yield) as a white solid. TLC; Pet. ether/EtOAc=1/1 (v/v) , Rf=0.1 HNMR: ¹H NMR (400 MHz, DMSO-d ₆) δ 9.05 (s, 1H) , 7.03 (d, J = 2.7 Hz, 1H) , 6.91 (d, J = 2.2 Hz, 1H) , 6.81 (d, J = 2.7 Hz, 1H) , 6.63 (d, J = 8.2 Hz, 1H) , 6.55 (dd, J = 8.2, 2.2 Hz, 1H) , 4.66 (s, 2H) , 3.97 (s, 2H) , 3.12 (hept, J = 6.9 Hz, 1H) , 2.19 (s, 3H) , 1.10 (d, J = 6.9 Hz, 6H) .

EXAMPLE 6

Synthesis of 2- (3-bromo-4- (4-hydroxy-3-isopropylbenzyl) -5- methylphenoxy) -N-methylacetamide (Compound 6)

To a solution of Compound 4 (130 mg, 0.32 mmol) in THF (5 mL) , was added methanamine (8 mL, 40%/w water) . The reaction was stirred at 65℃ overnight. The mixture was cooled down and water (20 mL) was added. The mixture was extracted with EtOAc (10mL*2) . The combined organic phase was washed by brine (20 mL) , dried over Na ₂SO ₄ and concentrated under reduced pressure. The crude product was purified by prep-HPLC (ACN/water from 30/80 to 90/20) to afford Compound 6 (60 mg, 148 umol, 60.2%yield) as a white solid. TLC: Pet. ether/EtOAc=5/1 (v/v) , Rf=0.2 HNMR: ¹H NMR (400 MHz, DMSO-d ₆) δ 9.03 (s, 1H) , 8.02 (brs, 1H) , 7.11 (d, J = 2.7 Hz, 1H) , 6.90 (d, J = 2.2 Hz, 1H) , 6.86 (d, J = 2.7 Hz, 1H) , 6.62 (d, J = 8.2 Hz, 1H) , 6.55 (dd, J = 8.2, 2.2 Hz, 1H) , 4.46 (s, 2H) , 3.98 (s, 2H) , 3.16 –3.08 (m, 1H) , 2.65 (d, J = 4.6 Hz, 3H) , 2.20 (s, 3H) , 1.10 (d, J = 6.9 Hz, 6H) .

EXAMPLE 7

Thyroid-Hormone Reporter-Gene Assays

Compounds 2 and 5 were tested for thyroid-hormone receptor activity using TR reporter-gene assays. Reporter cells used in the assays 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 activation sequence (UAS) . Both cell lines were derived from human embryonic kidney (HEK293) .

Step 1: A suspension of reporter cells was prepared in cell recovery medium containing 10%charcoal-stripped FBS, and dispensed into assay plates. The plates were pre-incubated for 6 hours in a cell culture incubator (37℃/5%CO ₂/85%humidity) .

Step 2: Test compound master stocks and triiodothyronine were diluted in DMSO to generate solutions at “1,000x-concentration” relative to each final treatment concentration. These intermediate stocks were subsequently diluted directly into compound screening medium containing 10%charcoal-stripped FBS to generate “2x-concentration” treatment media (containing 0.2, 0.4 or 0.8%DMSO) .

Step 3: At the end of the pre-incubation period, culture media were discarded from the assay plates, and all wells received 100 μl of compound screening medium. 100 μl of each of the previously prepared “2x-concentration” treatment media were dispensed into duplicate assay wells, thereby achieving the desired final treatment concentrations. The final concentration of DMSO in all assay wells was 0.1, 0.2 or 0.4%. Assay plates were incubated for 24 hr in a cell culture incubator (37℃/5%CO ₂/85%humidity) .

Step 4: At the 24 h assay endpoint, treatment media were discarded and 100 μl/well of luciferase detection reagent was added. Relative luminometer units (RLUs) were quantified from each assay well. The performance of the TRα and TRβ assays was validated using the reference agonist triiodothyronine (T3) .

The results of these assays are presented in Table 2 below, wherein data are reported as EC ₅₀ values determined for TRα and TRβ receptors, and the selectivity index (SI) is calculated as EC ₅₀ (TRα) /EC ₅₀ (TRβ) .

Table 2

Compound	EC ₅₀ (TRα)	EC ₅₀ (TRβ)	SI
T3	3.5 nM	7.7 nM	0.45
Compound 2	650 nM	200 nM	3.3
Compound 5	39 nM	11 nM	3.5

As indicated by the above experiments, compounds of the present invention show improved TRβ selectivity when compared to the natural agonist T3.

EXAMPLE 8

In Vivo Activity

Animal Studies

Compounds of the current invention may be tested for thyroid-hormone receptor agonist activity in an in vivo model according to the following protocol.

Male Sprague-Dawley rats (～6 weeks old) are placed on a high cholesterol chow (HC Chow; 1.5 %Cholesterol, 0.5%choline) for at least 10 days. Animals are weighed on Day -1. Test compounds are formulated in 1%NMP/1%solutol and dosed orally (PO) , subcutaneously (SC) or intraperitoneally (IP) for 7 days, with each daily dose based on the body weight on that day. On Day 1 and Day 7, approximately 24 hrs after the first and last dose, respectively, blood samples are obtained via the saphenous vein, processed for serum and frozen at -80 ℃. Serum samples are analyzed for total cholesterol, LDL cholesterol and/or triglycerides using a clinical chemistry analyzer. If desired, test compound levels may be determined in these same samples by LCMS, comparing peak area to authentic standards. The rats are then anesthetized with isoflurane and an additional blood sample collected from the inferior vena cava or via cardiac puncture. Samples were again processed for serum, then analyzed for T3/T4/TSH levels by ELISA. Rats are terminated by exsanguination or pneumothorax; organs are harvested and weighed. Organ weight data are reported both as absolute values and as a percent of final body weight.

Compounds of the current invention may be tested for thyroid-hormone mediated remyelination according to the following protocol.

Eight week old, male and female iCKO-Myrf mice are treated with 100 μL (20 mg/mL) tamoxifen i.p. daily for 5 days to induce oligodendrocyte depletion through deletion of Myrf from the mature oligodendrocytes (Koenning et al. 2012 J. Neuroscience) . Test compounds are formulated into the food or formulated in 1%NMP/1%solutol and dosed PO, SC or IP starting at week 2, 5 or 12 after tamoxifen induction. Dosing frequency may be daily (QD) , every other day (Q2D) , three times a week (QIW) or weekly (QW) . The functional impact of central demyelination is measured by subjecting the mice to an accelerating rotorod technique where the time at which the mice fall off of a rotating rod is indicative of their neuromuscular function. Mice are subjected to the rotorod protocol weekly, every other week or at specific times during the study. Loss of myelination is associated with decreased time such that a nadir in ability occurs around 12 weeks after tamoxifen treatment. Partial recovery occurs from 12-24 weeks. Mice are sacrificed at 24 weeks after tamoxifen induction and brain and spinal cord tissues examined for remyelination using histologic analysis.

Compounds of the current invention may be tested for thyroid-hormone mediated inhibition of fibrosis according to the following protocol.

Adult male, C57Bl/6 mice are induced with pulmonary fibrosis through a single oropharangeal (OP) administration of 1.5-2 U/kg of bleomycin. Test compounds are formulated in 1%NMP/1%solutol and dosed PO, SC or IP, QD starting at day -1 (prophylactic) or Day 7 (therapeutic) after bleomycin administration. On Day 21, mice are anesthetized and blood drawn via cardiac puncture. Lungs are excised and weighed, subjected broncheoalveolar lavage, inflated and fixed for histologic analysis. Lung samples are embedded in paraffin and stained with hematoxylin and eosin and Masson’s trichrome stain. A pathologist evaluates degree of fibrosis using the Ashcroft’s score to quantify fibrosis. A minimum of 10 sites per lung are assessed and an average score reported for each lung.

Tissue Distribution Studies

For tissue concentration studies in male C57Bl/6 mice, test compounds are formulated as NMP/solutol/PBS solution, at a concentration of 0.05 mg/mL and dosed at 2 mL/kg with the targeted dose of 0.100 mg/kg via SC injection or oral dosing. Plasma, brain, liver, lung, kidney, heart and other selected tissue samples are collected at 0.5, 2, 8 and 24 hr (for AUC determination) or 1 hr (single time point) post-dose with three animals per time point. Tissue homogenates and plasma concentrations of test compounds are determined using LC-MS/MS with lower limits of quantitation of 0.0200 ng/mL or 0.100 ng/g. The pharmacokinetic parameters are determined by non-compartmental methods using WinNonlin.

Gene activation

Adult male Sprague-Dawley rats or C57BL/6 mice are dosed orally with test compounds at up to 3 dose levels (e.g. 1x, 3x and 10x higher than the ED ₅₀ values obtained in the cholesterol lowering studies described above) . At predefined times, 4, 8 or 24 hrs after test compound administration, rodents are anesthetized and blood drawn for plasma samples to measure drug concentrations. Samples of multiple organs including, but not limited to, liver, brain, kidney, heart, lung, skeletal muscle, pituitary and testes, are harvested and processed for RNA analysis. Samples are analyzed either by RNA-Seq after RNA isolation or by targeted gene analysis using an appropriate platform such as Quantigene ^TM which does not require RNA isolation. Multiple genes are used to represent a T3-mediated gene signature in each tissue; different genes are used for each tissue and all are normalized to multiple housekeeping genes that account for any variability in overall RNA quality.

Conversion Studies

Amides of Formula II may be converted to active agonist acids of Formula IV through the action of amidases such as FAAH. Similarly, esters of Formula III may be converted to active agonist acids of Formula IV through the action of various esterases. This in vivo conversion can be demonstrated through pharmacokinetics studies which measure the level of test compounds as described below:

The pharmacokinetics of test compounds are evaluated following IV, PO or SC administration to fasted male Sprague-Dawley rats (N=3/route/dose) . Test compounds are dosed as clear solutions in NMP/solutol/PBS, at a concentration of 0.1 mg/mL as a single dose via IV injection (0.1 mg/kg) or orally (1 mg/kg) or subcutaneous injection (SC, 0.1 mg/kg) . Blood samples are collected into K ₂EDTA tubes at pre-dose, 0.083, 0.25, 0.5, 1, 2, 4, 8 and 24 hours post-dose administration. Plasma concentrations of test compounds are determined using LC-MS/MS with a lower limit of quantitation of 0.0200 ng/mL. The pharmacokinetic parameters are determined by non-compartmental methods using WinNonlin.

All of the U.S. patents, U.S. patent application publications, U.S. patent applications, foreign patents, foreign patent applications and non-patent publications referred to in this specification and/or listed in the Application Data Sheet are incorporated herein by reference, in their entirety. In addition, the terms used in the following claims should not be construed as limited to the specific embodiments disclosed in the specification, but should be construed to include all possible embodiments along with the full scope of equivalents to which such claims are entitled.

Claims

A compound having the structure of Formula (I) :

or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein:

X ¹ is lower alkyl;

X ² is halo;

R ¹ is -NR ^1aR ^1b or -OR ^1c;

R ^1a and R ^1b are each, independently, H, -OR ^a, -NR ^aR ^b, lower alkyl, lower alkenyl, lower alkynyl, carbocycle, carbocyclealkyl, heterocycle, or heterocyclealkyl, wherein R ^a and R ^b are each, independently, H or lower alkyl; and

R ^1c is H, lower alkyl, carbocycle, heterocycle, carbocyclealkyl, or heterocyclealkyl;

wherein R ^1a, R ^1b, R ^1c, R ^a, and R ^b are each, independently, optionally substituted with one or more halo, cyano, -OR′, -NR'R”, -S (O) ₂R' or -S (O) ₂OR', wherein R' and R” are each, independently, H or lower alkyl.
The compound of claim 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, having the structure of Formula (II) :
The compound of claim 1 or 2, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^1a is lower alkyl.
The compound of any one of claims 1–3, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^1a is methyl.
The compound of any one of claims 1–4, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^1b is H.
The compound of claim 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, having the structure of Formula (III) :
The compound of claim 1 or 6, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, having the structure of Formula (IV) :
The compound of any one of claims 1 or 6, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^1c is lower alkyl.
The compound of any one of claims 1, 6, or 8, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein R ^1c is methyl.
The compound of any one of claims 1–9, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X ¹ is methyl.
The compound of any one of claims 1–10, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X ² is Cl or Br.
The compound of any one of claims 1–11, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X ² is Cl.
The compound of any one of claims 1–11, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, wherein X ² is Br.
The compound of claim 1, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, having the following structure:
A pharmaceutical composition comprising a compound of any one of claims 1–14, or a pharmaceutically acceptable isomer, racemate, hydrate, solvate, isotope, or salt thereof, and a pharmaceutically acceptable excipient.
A method of treating a subject having a neurodegenerative disease comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of any one of claims 1–14, or a pharmaceutically salt or composition thereof.
The method of claim 16, wherein the neurodegenerative disease is a demyelinating disease.
The method of claim 16 or 17, wherein the neurodegenerative disease is a chronic demyelinating disease.
The method of claim 16 or 17, wherein the neurodegenerative disease is X-linked genetic disorder, leukodystrophy, dementia, tauopathy, or ischaemic stroke.
The method of claim 19, wherein the neurodegenerative disease is multiple sclerosis, MCT8 deficiency, X-linked adrenoleukodystrophy (ALD) , amyotrophic lateral sclerosis (ALS) , Alzheimer’s disease, frontotemporal dementia, or lacunar stroke.
The method of claim 16 or 17, wherein the neurodegenerative disease is adult Refsum disease, Alexander disease, Alzheimer’s disease, Balo concentric sclerosis, Canavan disease, central pontine myelinolysis, cerebral palsy, cerebrotendineous xanthomatosis, chronic inflammatory demyelinating polyneuropathy, Devic's syndrome, diffuse myelinoclastic sclerosis, idiopathic inflammatory demyelinating disease, infantile Refsum disease, Krabbe disease, Leber 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 Knaap disease, X-linked adrenoleukodystrophy, or Zellweger syndrome.
A method of treating a subject having a medical condition associated with over-expression of TGF-β comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of any one of claims 1–14, or a pharmaceutically salt or composition thereof.
The method of claim 22, wherein the medical condition associated with over-expression of TGF-β is a fibrotic disease.
The method of claim 22 or 23, wherein the medical condition associated with over-expression of TGF-β is nonalcoholic steatohepatitis (NASH) , idiopathic pulmonary fibrosis (IPF) , systemic scleroderma, or Alport syndrome.
A method of treating a subject having adult Refsum disease, infantile Refsum disease, Alexander disease, Alzheimer's disease, Balo concentric sclerosis, Canavan disease, central pontine myelinolysis (CPM) , cerebral palsy, cerebrotendineous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP) , Devic's syndrome, diffuse myelinoclastic sclerosis, encephalomyelitis, idiopathic inflammatory demyelinating disease (IIDD) , Krabbe disease, Leber hereditary optic neuropathy, leukodystrophy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy (MLD) , multifocal motor neuropathy (MMN) , multiple sclerosis (MS) , paraproteinemic demyelinating polyneuropathy, Pelizaeus-Merzbacher disease (PMD) , progressive multifocal leukoencephaalopathy (PML) , tropical spastic paraparesis (TSP) , X-linked adrenoleukodystrophy (X-ALD, ALO, or X-linked ALO) , Zellweger syndrome, MCT8 deficiency, amyotrophic lateral sclerosis (ALS) , frontotemporal dementia, lacunar stroke, primary age-related tauopathy (PART) , Pick’s disease, frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) , adrenomyeloneuropathy (AMN) , cerebral form of adrenoleukodystrophy (cALD) , nonalcoholic steatohepatitis (NASH) , idiopathic pulmonary fibrosis (IPF) , systemic scleroderma, or Alport syndrome, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof.
A method of treating a subject having NASH, NAFLD, NAFLD with hyperlipidemia, alcoholic liver fisease/alcoholic steatohepatitis, liver fibrosis associated with viral infection (HBV, HCV) , fibrosis associated with cholestatic diseases (primary biliary cholangitis, primary sclerosing cholangitis) , (familial) hypercholesterolemia, dyslipidemia, genetic lipid disorders, cirrhosis, alcohol-induced fibrosis, hemochromatosis, glycogen storage diseases, alpha-1 antitrypsin deficiency, autoimmune hepatitis, Wilson’s disease, Crigler-Najjar Syndrome, lysosomal acid lipase deficiency, liver disease in cystic fibrosis, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof.
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 agents, nephrogenic systemic fibrosis, tubulointerstitial fibrosis, glomerulosclerosis, or polycystic kidney disease (PKD) , the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof.
A method of treating a subject having IPF, ILD, pulmonary fibrosis, pulmonary fibrosis associated with autoimmune diseases like rheumatoid arthritis, scleroderma or Sjogren's syndrome, asthma-related pulmonary fibrosis, COPD, asbestos or silica induced PF, silicosis, respiratory bronchiolitis, Idiopathic interstitial pneumonias (IIP) , Idiopathic nonspecific interstitial pneumonia, Respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia, acute interstitial pneumonia, Rare IIPs: Idiopathic lymphoid interstitial pneumonia, idiopathic pleuroparenchymal fibroelastosis, unclassifiable idiopathic interstitial pneumonias, hypersensitivity pneumonitis, radiation-induced lung injury, progressive massive fibrosis –pneumoconiosis, bronchiectasis, byssinosis, chronic respiratory disease, chronic obstructive pulmonary disease (COPD) , emphysema, pulmonary arterial hypertension (PAH) , or Cystic fibrosis, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof.
A method of treating a subject having scleroderma/systemic sclerosis, graft versus host disease, hypertrophic scars, keloids, nephrogenic systemic fibrosis, porphyria cutanea tarda, restrictive dermopathy, Dupuytren’s contracture, dermal fibrosis, nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy, mixed connective tissue disease, scleromyxedema, eosinophilic fasciitis, fibrosis caused by exposure to chemicals or physical agents. GvHD induced fibrosis, Scleredema adultorum, Lipodermatosclerosis, or Progeroid disorders (progeria, acrogeria, Werner’s syndrome) , the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof.
A method of treating a subject having atrial fibrosis, endomyocardial fibrosis, cardiac fibrosis, atherosclerosis, restenosis, or arthrofibrosis, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof.
A method of treating a subject having mediastinal fibrosis, myelofibrosis, post-polycythermia vera myelofibrosis, or post essential thrombocythemia, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof.
A method of treating a subject having Crohn’s disease, retroperitoneal fibrosis, intestinal fibrosis, fibrosis in inflammatory bowel disease, ulcerative colitis, GI fibrosis due to cystic fibrosis, or pancreatic fibrosis due to pancreatitis, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof.
A method of treating a subject having endometrial fibrosis, uterine fibroids, or Peyronie’s disease, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof.
A method of treating a subject having macular degeneration, diabetic retinopathy, retinal fibrovascular diseases, or vitreal retinopathy, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof.
A method of treating a subject having scarring associated with trauma, the method comprising administering to the subject in need thereof a pharmaceutically effective amount of the compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof.
The method of claim 35, wherein the scarring associated with trauma is associated with surgical complications, chemotherapeutics drug-induced fibrosis, or radiation induced fibrosis.
The compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of a neurodegenerative disease.
The compound of claim 37, wherein the neurodegenerative disease is a demyelinating disease.
The compound of claim 37 or 38, wherein the neurodegenerative disease is a chronic demyelinating disease.
The compound of claim 37 or 38, wherein the neurodegenerative disease is X-linked genetic disorder, leukodystrophy, dementia, tauopathy, or ischaemic stroke.
The compound of claim 40, wherein the neurodegenerative disease is multiple sclerosis, MCT8 deficiency, X-linked adrenoleukodystrophy (ALD) , amyotrophic lateral sclerosis (ALS) , Alzheimer’s disease, frontotemporal dementia, or lacunar stroke.
The compound of claim 37 or 38, wherein the neurodegenerative disease is adult Refsum disease, Alexander disease, Alzheimer’s disease, Balo concentric sclerosis, Canavan disease, central pontine myelinolysis, cerebral palsy, cerebrotendineous xanthomatosis, chronic inflammatory demyelinating polyneuropathy, Devic's syndrome, diffuse myelinoclastic sclerosis, idiopathic inflammatory demyelinating disease, infantile Refsum disease, Krabbe disease, Leber 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 Knaap disease, X-linked adrenoleukodystrophy, or Zellweger syndrome.
The compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of a medical condition associated with over-expression of TGF-β.
The compound of claim 43, wherein the medical condition associated with over-expression of TGF-β is a fibrotic disease.
The compound of claim 43 or 44, wherein the medical condition associated with over-expression of TGF-β is nonalcoholic steatohepatitis (NASH) , idiopathic pulmonary fibrosis (IPF) , systemic scleroderma, or Alport syndrome.
The compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of adult Refsum disease, infantile Refsum disease, Alexander disease, Alzheimer's disease, Balo concentric sclerosis, Canavan disease, central pontine myelinolysis (CPM) , cerebral palsy, cerebrotendineous xanthomatosis, chronic inflammatory demyelinating polyneuropathy (CIDP) , Devic's syndrome, diffuse myelinoclastic sclerosis, encephalomyelitis, idiopathic inflammatory demyelinating disease (IIDD) , Krabbe disease, Leber hereditary optic neuropathy, leukodystrophy, Marburg multiple sclerosis, Marchiafava-Bignami disease, metachromatic leukodystrophy (MLD) , multifocal motor neuropathy (MMN) , multiple sclerosis (MS) , paraproteinemic demyelinating polyneuropathy, Pelizaeus-Merzbacher disease (PMD) , progressive multifocal leukoencephaalopathy (PML) , tropical spastic paraparesis (TSP) , X-linked adrenoleukodystrophy (X-ALD, ALO, or X-linked ALO) , Zellweger syndrome, MCT8 deficiency, amyotrophic lateral sclerosis (ALS) , frontotemporal dementia, lacunar stroke, primary age-related tauopathy (PART) , Pick’s disease, frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17) , adrenomyeloneuropathy (AMN) , cerebral form of adrenoleukodystrophy (cALD) , nonalcoholic steatohepatitis (NASH) , idiopathic pulmonary fibrosis (IPF) , systemic scleroderma, or Alport syndrome.
The compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of NASH, NAFLD, NAFLD with hyperlipidemia, alcoholic liver fisease/alcoholic steatohepatitis, liver fibrosis associated with viral infection (HBV, HCV) , fibrosis associated with cholestatic diseases (primary biliary cholangitis, primary sclerosing cholangitis) , (familial) hypercholesterolemia, dyslipidemia, genetic lipid disorders, cirrhosis, alcohol-induced fibrosis, hemochromatosis, glycogen storage diseases, alpha-1 antitrypsin deficiency, autoimmune hepatitis, Wilson’s disease, Crigler-Najjar Syndrome, lysosomal acid lipase deficiency, liver disease in cystic fibrosis.
The compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of 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 agents, nephrogenic systemic fibrosis, tubulointerstitial fibrosis, glomerulosclerosis, or polycystic kidney disease (PKD) .
The compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of IPF, ILD, pulmonary fibrosis, pulmonary fibrosis associated with autoimmune diseases like rheumatoid arthritis, scleroderma or Sjogren's syndrome, asthma-related pulmonary fibrosis, COPD, asbestos or silica induced PF, silicosis, respiratory bronchiolitis, Idiopathic interstitial pneumonias (IIP) , Idiopathic nonspecific interstitial pneumonia, Respiratory bronchiolitis-interstitial lung disease, desquamative interstitial pneumonia, acute interstitial pneumonia, Rare IIPs: Idiopathic lymphoid interstitial pneumonia, idiopathic pleuroparenchymal fibroelastosis, unclassifiable idiopathic interstitial pneumonias, hypersensitivity pneumonitis, radiation-induced lung injury, progressive massive fibrosis –pneumoconiosis, bronchiectasis, byssinosis, chronic respiratory disease, chronic obstructive pulmonary disease (COPD) , emphysema, pulmonary arterial hypertension (PAH) , or Cystic fibrosis.
The compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of scleroderma/systemic sclerosis, graft versus host disease, hypertrophic scars, keloids, nephrogenic systemic fibrosis, porphyria cutanea tarda, restrictive dermopathy, Dupuytren’s contracture, dermal fibrosis, nephrogenic systemic fibrosis/nephrogenic fibrosing dermopathy, mixed connective tissue disease, scleromyxedema, eosinophilic fasciitis, fibrosis caused by exposure to chemicals or physical agents. GvHD induced fibrosis, Scleredema adultorum, Lipodermatosclerosis, or Progeroid disorders (progeria, acrogeria, Werner’s syndrome) .
The compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of atrial fibrosis, endomyocardial fibrosis, cardiac fibrosis, atherosclerosis, restenosis, or arthrofibrosis.
The compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of mediastinal fibrosis, myelofibrosis, post-polycythermia vera myelofibrosis, or post essential thrombocythemia.
The compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of Crohn’s disease, retroperitoneal fibrosis, intestinal fibrosis, fibrosis in inflammatory bowel disease, ulcerative colitis, GI fibrosis due to cystic fibrosis, or pancreatic fibrosis due to pancreatitis.
The compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of endometrial fibrosis, uterine fibroids, or Peyronie’s disease.
The compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of macular degeneration, diabetic retinopathy, retinal fibrovascular diseases, or vitreal retinopathy.
The compound of any one of claims 1–14, or a pharmaceutically acceptable salt or composition thereof, for use in the treatment of scarring associated with trauma.
The compound of claim 35, wherein the scarring associated with trauma is associated with surgical complications, chemotherapeutics drug-induced fibrosis, or radiation induced fibrosis.