Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D253/00—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00
  • C07D253/02—Heterocyclic compounds containing six-membered rings having three nitrogen atoms as the only ring hetero atoms, not provided for by group C07D251/00 not condensed with other rings
  • C07D253/06—1,2,4-Triazines
  • C07D253/065—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members
  • C07D253/07—1,2,4-Triazines having three double bonds between ring members or between ring members and non-ring members with hetero atoms, or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D253/075—Two hetero atoms, in positions 3 and 5
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
  • C07C39/24—Halogenated derivatives
  • C07C39/367—Halogenated derivatives polycyclic non-condensed, containing only six-membered aromatic rings as cyclic parts, e.g. halogenated poly-hydroxyphenylalkanes
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
  • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
  • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
  • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
  • C07D261/12—Oxygen atoms

Definitions

• Thyroid hormone 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).
• 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).
• TR ⁇ is enriched in the heart, brain, and bone while TR ⁇ is enriched in the liver (O’Shea et al., Nucl Recept Signal 4:e011, 2006).
• TH can inhibit the transforming growth factor beta (TGF- ⁇ ) signaling, and, therefore, attenuate fibrotic responses (Alonso-Merino et al., Proc Natl Acad Sci U S A.113(24):E3451-60, 2016).
• TGF- ⁇ 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).
• TR ligands or agonists By inhibiting TGF- ⁇ 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).
• IPF idiopathic pulmonary fibrosis
• Varga et al., Curr Opin Rheumatol.20(6):720– 728, 2008 idiopathic pulmonary fibrosis
• 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 ⁇ 1 and ⁇ 1 forms. Despite this challenge, several groups have reported TR ⁇ -selective agonists. Scanlan et al.
• GC-1 (sobetirome) as one of the first potent analogs to demonstrate significant TR ⁇ -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).
• 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 TR ⁇ -selective activity in vivo for MGL-3196 (Taub et al., Atherosclerosis 230(2):373-380, 2013).
• TR ⁇ -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). [0006] 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.
• a pharmaceutical composition comprising a compound having the structure of Formula (I), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, in combination with a pharmaceutically acceptable carrier, diluent, or excipient.
• 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.
• the pharmaceutical composition is for use in treating a medical condition associated increased activity of TGF- ⁇ , such as a fibrotic disease.
• 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.
• the neurodegenerative disorder can be classified as a demyelinating disease such as X-linked adrenoleukodystrophy or multiple sclerosis.
• a method is provided for treating a medical condition associated with over-expression of TGF- ⁇ 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.
• the medical condition associated with over- expression of TGF- ⁇ 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.
• 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.
• 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.
• 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.
• lower alkenyl groups include, but are not limited to, vinyl, propenyl, isopropenyl, butenyl, pentenyl, and hexenyl.
• 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.
• 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 herein with one or more hydrogen atoms replaced with halogen.
• 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 herein 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 herein joined by way of an oxygen atom (i.e., ⁇ O ⁇ (lower haloalkyl).
• oxygen atom i.e., ⁇ O ⁇ (lower haloalkyl).
• lower haloalkoxy groups include, but are not limited to, ⁇ OCF 3 , ⁇ OCHF 2 , and the like.
• Carbocyclyl 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.
• carbocycle includes cycloalkyl as defined herein.
• carbocycle includes aryl as defined herein.
• Carbocyclealkyl are alkyl groups as defined herein in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a carbocycle group as defined herein.
• carbocyclealkyl includes cycloalkylalkyl.
• carbocyclealkyl includes arylalkyl. Examples of carbocyclealkyl groups include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, benzyl, 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.
• 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 herein in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a cycloalkyl group as defined herein.
• Aryl groups are cyclic aromatic hydrocarbons that do not contain heteroatoms.
• aryl groups include, but are not limited to, phenyl, azulenyl, heptalenyl, biphenyl, indacenyl, fluorenyl, phenanthrenyl, triphenylenyl, pyrenyl, naphthacenyl, chrysenyl, biphenylenyl, anthracenyl, and naphthyl groups.
• aryl groups contain 6-14 carbons in the ring portions of the groups.
• aryl and aryl groups include fused rings wherein at least one ring, but not necessarily all rings, are aromatic, 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.
• Arylalkyl are alkyl groups as defined herein in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to an aryl group as defined herein.
• Heterocyclyl 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.
• 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.
• a dioxolanyl ring and a benzdioxolanyl 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,
• Heterocyclealkyl are alkyl groups as defined herein in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a heterocycle group as defined herein.
• heterocyclealkyl includes heteroarylalkyl.
• 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, quinolin
• heteroaryl and “heteroaryl groups” include fused ring compounds such as wherein at least one ring, but not necessarily all rings, are aromatic, including tetrahydroquinolinyl, tetrahydroisoquinolinyl, indolyl, and 2,3-dihydro indolyl.
• Heteroarylalkyl are alkyl groups as defined herein in which a hydrogen or carbon bond of the alkyl group is replaced with a bond to a heteroaryl group as defined herein.
• R 2 is methyl, ethyl, propyl, isopropyl, or butyl. In one embodiment, R 2 is isopropyl.
• compounds are provided having the structure of Formula (I) or Formula (II), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein R 2 is carbocyclealkyl or heterocyclealkyl.
• compounds are provided having the structure of Formula (I) or Formula (II), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein R 2 is arylalkyl or heteroarylalkyl.
• compounds are provided having the structure of Formula (V), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are each, independently, CH or CR 5 .
• compounds are provided having the structure of Formula (V), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one of Q 1 , Q 2 , Q 3 , Q 4 , or Q 5 is N.
• compounds are provided having the structure of Formula (V), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least two of Q 1 , Q 2 , Q 3 , Q 4 , and Q 5 are N.
• compounds are provided having the structure of Formula (I) or Formula (II), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein R 2 is carbocyle or heterocycle.
• compounds are provided having the structure of Formula (I) or Formula (II), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein R 2 is aryl or heteroaryl.
• compounds are provided having the structure of Formula (VII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein B is carbocycle.
• compounds are provided having the structure of Formula (VII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein B is aryl.
• compounds are provided having the structure of Formula (VII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein B is phenyl.
• A is phenyl optionally substituted with one or more halo. In one embodiment, A is phenyl optionally substituted with one or more ⁇ CN. In one embodiment, A is phenyl optionally substituted with one or more ⁇ OR', wherein each R' is independently, H, lower alkyl, or lower haloalkyl. In one embodiment, A is phenyl optionally substituted with one or more ⁇ OR', wherein each R' is independently, H, lower alkyl, or lower haloalkyl and at least one R' is H.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein A is phenol or substituted phenol.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein A is: .
• A is triazinyl, pyridinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, or thiadiazolyl.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein A is : R 6 is H or ⁇ CN.
• compounds are provided having the structure of any one of Formula (IV), Formula (V), or Formula (VI), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein R 3 is H.
• compounds are provided having the structure of any one of Formula (IV), Formula (V), or Formula (VI), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein R 3 is carbocycle. In one embodiment, R 3 is cyclopropyl or cyclobutyl.
• compounds are provided having the structure of any one of Formula (IV), Formula (V), or Formula (VI), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein R 3 is lower alkyl. In one embodiment, R 3 is methyl, ethyl, or propyl.
• compounds are provided having the structure of any one of Formula (IV), Formula (V), or Formula (VI), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein R 3 is ⁇ OR a .
• R a is H.
• R a is lower alkyl.
• R a is lower methyl.
• compounds are provided having the structure of any one of Formula (IV), Formula (V), or Formula (VI), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein R 4 is H.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 1 is lower alkyl. In one embodiment, X 1 is methyl.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 1 is halo.
• X 1 is Cl or Br.
• X 1 is Cl.
• X 1 is Br.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 1 is lower haloalkyl.
• X 1 is ⁇ CH 2 F, ⁇ CHF 2 , or –CF 3 .
• X 1 is–CF 3 .
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 1 is lower alkenyl. In one embodiment, X 1 is vinyl or isopropenyl.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 2 is lower alkyl. In one embodiment, X 2 is methyl.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 2 is halo.
• X 2 is Cl or Br.
• X 2 is Cl.
• X 2 is Br.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 2 is lower haloalkyl.
• X 2 is –CHF 2 or –CF 3 .
• X 2 is –CF 3 .
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein X 2 is lower alkenyl. In one embodiment, X 2 is vinyl or isopropenyl.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 is lower alkyl.
• R 5 is lower alkyl substituted with ⁇ OR'.
• R' is H.
• R' is lower alkyl.
• R' is methyl, ethyl, or propyl.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 is lower haloalkyl.
• at least one R 5 is ⁇ CH 2 F, ⁇ CHF 2 , or –CF 3 .
• at least one R 5 is –CF 3 .
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 is ⁇ OR a .
• R a is lower alkyl.
• R a is methyl, ethyl, or propyl.
• R a is lower haloalkyl.
• R a is –CHF 2 or –CF 3 .
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 is ⁇ C(O)R a .
• R a is lower alkyl.
• R a is methyl, ethyl, or propyl.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 is ⁇ NR a C(O)R b .
• R a is H and R b is lower alkyl.
• R a is H and R b is methyl, ethyl, or propyl.
• R a is H and R b is methyl.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 is ⁇ C(O)OR a .
• R a is lower alkyl.
• R a is methyl, ethyl, or propyl.
• R a is methyl.
• R a is ethyl.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 is ⁇ S(O) 2 R a .
• R a is lower alkyl.
• R a is methyl, ethyl, or propyl.
• R a is methyl.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 is halo. In one embodiment, at least one R 5 is F.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein at least one R 5 is ⁇ CN.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is halogen.
• Y 1 is F.
• Y 1 is Cl.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is ⁇ CN.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is lower alkyl.
• Y 1 is methyl, ethyl, or propyl.
• Y 1 is methyl.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is lower alkoxy. In one embodiment, Y 1 is methoxy or ethoxy. In one embodiment, Y 1 is methoxy.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is H.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 2 is halogen.
• Y 2 is F.
• Y 2 is Cl.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 2 is ⁇ CN.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 2 is lower alkyl.
• Y 2 is methyl, ethyl, or propyl.
• Y 2 is methyl.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 2 is lower alkoxy. In one embodiment, Y 2 is methoxy or ethoxy. In one embodiment, Y 2 is methoxy.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 2 is H.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is F and Y 2 is H.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is Cl and Y 2 is H.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is ⁇ CN and Y 2 is H.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is lower alkyl and Y 2 is H. In one embodiment, Y 1 is methyl and Y 2 is H.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is lower alkoxy and Y 2 is H. In one embodiment, Y 1 is methoxy and Y 2 is H.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is H and Y 2 is F.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is H and Y 2 is Cl.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is H and Y 2 is ⁇ CN.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is H and Y 2 is lower alkyl. In one embodiment, Y 1 is H and Y 2 is methyl.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is H and Y 2 is lower alkoxy. In one embodiment, Y 1 is H and Y 2 is methyl.
• compounds are provided having the structure of any one of Formula (I), Formula (II), Formula (III), Formula (IV), Formula (V), Formula (VI), Formula (VII), or Formula (VIII), or a pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope, or salt thereof, wherein Y 1 is F and Y 2 is F.
• Representative compounds of Formula (I), and Formulas (II) through (VIII) 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
• Racemic 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.
• 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 quaternary carbon are optically active isomers, which may be purified from the respective racemate and/or synthesized by appropriate chiral synthesis.
• a “tautomer” refers to each of two or more structural isomers that readily interconvert in equilibrium by migration of an atom or group within the molecule. A tautomer commonly arises from a proton shift from one atom of a molecule to another atom of the same molecule.
• the present invention includes tautomers of compounds of Formula (I). For example, tautomers of isoxazolol and hydroxytriazinone are shown below: .
• 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.
• 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.
• 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.
• 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.
• 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.
• salts formed between acids in their anionic form and cations are referred to as “acid addition salts”.
• salts formed between bases in the cationic form and anions are referred to as “base addition salts.”
• pharmaceutically acceptable refers an agent that has been approved for human consumption and is generally non-toxic.
• 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.
• 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), tromethamine (tris-hydroxymethyl methylamine), and procaine.
• Pharmaceutically acceptable acid addition salts may be prepared from an inorganic acid or from an organic acid.
• inorganic acids include hydrochloric, hydrobromic, hydriodic, nitric, carbonic, sulfuric, and phosphoric acids.
• 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
• the invention provides a pharmaceutical composition comprising a compound of the invention together with at least one pharmaceutically acceptable carrier, diluent, or excipient.
• 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.
• the active compound 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.
• 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.
• 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.
• the term “pharmaceutical composition” refers to a composition containing one or more of the compounds described herein, or a pharmaceutically acceptable isomer, racemate, tautomer, 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.
• 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.
• unit dosage form e.g., a tablet, capsule, caplet, gelcap, or syrup
• topical administration e.g., as a cream, gel, lotion, or ointment
• intravenous administration e.g., as a sterile solution free of particulate emboli and in a solvent system suitable for intravenous use
• the term “pharmaceutically acceptable carrier” refers to any ingredient other than the disclosed compounds, or a pharmaceutically acceptable isomer, racemate, tautomer, 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.
• 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, methylcelluloFse, 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
• the formulations can be mixed with auxiliary agents which do not deleteriously react with the active compounds.
• 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.
• methods of making a composition of a compound described herein including formulating a compound of the invention with a pharmaceutically acceptable carrier or diluent.
• the pharmaceutically acceptable carrier or diluent is suitable for oral administration.
• the methods can further include the step of formulating the composition into a tablet or capsule.
• the pharmaceutically acceptable carrier or diluent is suitable for parenteral administration.
• the methods further include the step of lyophilizing the composition to form a lyophilized preparation.
• a method of treating a subject having a neurodegenerative disease comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.
• the neurodegenerative disease is a demyelinating disease.
• the demyelinating disease is a chronic demyelinating disease.
• the demyelinating disease is or is associated with a X-linked genetic disorder, leukodystrophy, dementia, tauopathy, or ischaemic stroke.
• 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
• 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.
• ALD X-linked adrenoleukodystrophy
• ALS amyotrophic lateral sclerosis
• Alzheimer’s disease frontotemporal dementia
• lacunar stroke a chronic adrenoleukodystrophy
• the term “neurodegenerative disease” refers to any type of disease that is characterized by the progressive deterioration of the nervous system.
• 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. [00117] As used herein, the term “leukodystrophy” refers to a group of diseases that affects the growth or development of the myelin sheath.
• 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.
• 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.
• AD Alzheimer's Disease
• PSP Progressive Supranuclear Palsy
• CBD Corticobasal Degeneration
• PiD Pick's Disease
• ATD Argyrophilic grain disease
• FTDP-17 Frontotemporal dementia and Parkinsonism associated with chromosome 17
• Parkinson's disease stroke, traumatic brain injury, mild cognitive impairment and the like.
• MS multiple sclerosis
• 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 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 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.
• a method of treating a subject having a X-linked genetic disorder comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.
• the X-linked genetic disorder is MCT8 deficiency or X-linked adrenoleukodystrophy (ALD).
• a method of treating a subject having a leukodystrophy comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.
• the leukodystrophy is adrenoleukodystrophy (ALD), adrenomyeloneuropathy (AMN), cerebral form of adrenoleukodystrophy (cALD), metachromatic leukodystrophy (MLD), Canavan’s disease, or Krabbe disease (globoid leukodystrophy).
• 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.
• VLCFA very long chain fatty acids
• a method of treating a subject having a tauopathy comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.
• 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).
• a method of treating a subject having an ischaemic stroke comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.
• the ischaemic stroke is lacunar stroke (also called “lacunar infarct”).
• the present method is used to treat a subject suffering from a lacunar stroke syndrome (LACS).
• LACS lacunar stroke syndrome
• the demyelinating disease is multiple sclerosis. In another embodiment, the demyelinating disease is X-linked adrenoleukodystrophy (ALD).
• ALD amyotrophic lateral sclerosis
• a method of treating a subject having an amyotrophic lateral sclerosis (ALS) disease comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.
• the ALS is sporadic or familial ALS, or ALS with Superoxide dismutase-1 mutation.
• a method of treating a subject having a medical condition associated with increased activity of TGF- ⁇ comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.
• the medical condition associated with increased activity of TGF- ⁇ is a fibrotic disease.
• the fibrotic disease is or is associated with nonalcoholic steatohepatitis (NASH), idiopathic pulmonary fibrosis (IPF), systemic scleroderma, or Alport syndrome.
• 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.
• GBM glomerular basement membrane
• 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.
• 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, tautomer, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.
• 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, tautomer, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.
• a method of treating a subject having atrial fibrosis, endomyocardial fibrosis, cardiac fibrosis, atherosclerosis, restenosis, or arthrofibrosis comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.
• a method of treating a subject having mediastinal fibrosis, myelofibrosis, post-polycythermia vera myelofibrosis, or post essential thrombocythemia comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope or salt thereof, or a pharmaceutical 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 comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.
• a method of treating a subject having endometrial fibrosis, uterine fibroids, or Peyronie’s disease comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.
• a method of treating a subject having macular degeneration, diabetic retinopathy, retinal fibrovascular diseases, or vitreal retinopathy comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.
• a method of treating a subject having scarring associated with trauma comprising administering to the subject a pharmaceutically effective amount of a compound having the structure of Formula (I) or pharmaceutically acceptable isomer, racemate, tautomer, hydrate, solvate, isotope or salt thereof, or a pharmaceutical composition thereof.
• administration refers to providing a compound, a prodrug of a compound, or a pharmaceutical composition comprising the compound or prodrug as described herein.
• treatment refers to an intervention that ameliorates a sign or symptom of a disease or pathological condition.
• treatment 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.
• 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.
• an 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.
• reactions may be carried out in any suitable solvent, or other reagents to perform the transformation[s] necessary.
• 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, or higher if reactions are run in sealed vessels).
• a given reaction may be carried out in one solvent or a mixture of more than one solvent.
• suitable solvents for a particular work-up following the reaction may be employed.
• Scheme 3 [00149] Compounds of the present invention can also be prepared from intermediates like i through stepwise assembly of the heterocyclic moiety, as demonstrated in Scheme 3.
• intermediates like i can be converted to cinnamates like vi by coupling with acrylates like v using a palladium catalyst.
• Oxidation of the olefinic moiety of vi provides beta- ketoesters like vii.
• Scheme 4 Where A is an N-linked heterocycle, compounds of the present invention can be prepared according to the methods of Scheme 4. According to Scheme 4, anilines like xii can be reacted with bifunctional acylating agents xiii to provide heterocycles A directly. Alternatively, anilines xii may first be reacted with a carbonyl equivalent like xiv or with an oxidizing agent, to give an intermediate like xv, which is then condensed with a bifunctional acylating agent like xiii to provide heterocycles A.
• Scheme 5 [00151] Where A is 1,2,4-triazine, compounds of the present invention can be prepared according to the methods of Scheme 5.
• anilines like xii are first N- nitrated using a nitrosating agent like sodium nitrite or the like, in a solvent like water or ethanol or the like.
• the intermediate diazonium salt compound xvi is reacted with a bifunctional acylating reagent xvii like ethyl N-(2-cyanoacetyl)carbamate or the like, in a solvent system including water or alcohol or the like and a base like pyridine or triethylamine or the like, with heating if necessary, to give a 1,2,4-triazine product like xviii.
• a bifunctional acylating reagent xvii like ethyl N-(2-cyanoacetyl)carbamate or the like
• impurities may be stirred out using a suitable solvent.
• 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.
• the compounds may be purified by preparative HPLC (normal-phase or reversed- phase) using methods as described. Preparative HPLC purification by reverse phase HPLC was performed using gradients of acetonitrile in aqueous TFA or an equivalent HPLC system such as Methanol in aqueous ammonium acetate.
• 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.
• aqueous HCl 110 mL was cooled to 0°C; a solution of NaNO 2 (1.3 g, 19.3 mmol) in water (10 mL) was added dropwise. The mixture was stirred at 0°C for 1h. This mixture was added dropwise to a solution of ethyl N-(2-cyanoacetyl)carbamate (2.8, 17.7 mmol) in water (100 mL) and pyridine (125 mL), stirring at 0°C. After 1h, the reaction mixture was extracted with EtOAc (100 mL*2); the combined organic phase was washed with brine (50 mL*2), dried over Na 2 SO 4 , and concentrated in vacuo.
• aqueous HCl (10 mL) was cooled to 0°C, and a solution of NaNO 2 (68 mg, 0.98 mmol) in water (1 mL) was added dropwise. The mixture was stirred at 0°C for 30 min. This mixture was added dropwise to a solution of ethyl N-(2-cyanoacetyl)carbamate (140 mg, 0.86 mmol) in water (10 mL) and pyridine (15 mL), and stirred at 0°C. After 1h, the mixture was extracted with EtOAc (10 mL*2). The combined organic phase was washed with brine (30 mL), dried over Na 2 SO 4 and concentrated in vacuo.
• Thyroid-Hormone Reporter-Gene Assays Compounds were tested for thyroid-hormone receptor activity using TR reporter-gene assays. Reporter cells used in the assays express a TR-receptor hybrid (either TR ⁇ or TR ⁇ ) in which the native N-terminal DNA binding domain (DBD) has been replaced with that of the yeast Gal4 DBD.
• TR-receptor hybrid either TR ⁇ or TR ⁇
• DBD native N-terminal DNA binding domain
• 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).
• 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°C/5% CO2/85% 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.
• Step 3 At the end of the pre-incubation period, culture media were discarded from the assay plates, and all wells received 100 ⁇ l of compound screening medium.100 ⁇ l 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°C/5% CO2/85% humidity).
• Step 4 At the 24 h assay endpoint, treatment media were discarded and 100 ⁇ l/well of luciferase detection reagent was added. Relative luminometer units (RLUs) were quantified from each assay well. The performance of the TR ⁇ and TR ⁇ assays was validated using the reference agonist triiodothyronine (T3). [00211] The results of these assays are presented in Table 2 below, wherein data are reported as EC 50 values determined for TR ⁇ and TR ⁇ receptors, and the selectivity index (SI) is calculated as EC 50 (TR ⁇ )/ EC 50 (TR ⁇ ).
• SI selectivity index
• EC 50 and SI values are expressed as follows: Potency: + EC 50 > 1,000 nM ++ 100 nM ⁇ EC 50 ⁇ 1,000 nM +++ 10 nM ⁇ EC 50 ⁇ 100 nM ++++ EC 50 ⁇ 10 nM ND Not determined Selectivity: + T3-SI ⁇ 3X ++ 3X ⁇ T3-SI ⁇ 30X +++ T3-SI > 30X ND Not determined Table 2 Activity Data [00212] As indicated by the above experiments, compounds of the present invention show improved TR ⁇ selectivity when compared to the natural agonist T3. Some also show improved potency when compared to T3. [00213] The various embodiments described above can be combined to provide further embodiments.

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