WO2020028221A1 - Inhibiteurs de la céramide galactosyltransférase pour le traitement d'une maladie - Google Patents

Inhibiteurs de la céramide galactosyltransférase pour le traitement d'une maladie Download PDF

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WO2020028221A1
WO2020028221A1 PCT/US2019/043867 US2019043867W WO2020028221A1 WO 2020028221 A1 WO2020028221 A1 WO 2020028221A1 US 2019043867 W US2019043867 W US 2019043867W WO 2020028221 A1 WO2020028221 A1 WO 2020028221A1
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galcer
level
subject
hydroxylated
administration
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Brett E. Crawford
Michael Babcock
Josh WOLOSZYNEK
Sanjay CHANDRIANI
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Biomarin Pharmaceutical Inc.
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/164—Amides, e.g. hydroxamic acids of a carboxylic acid with an aminoalcohol, e.g. ceramides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/18—Sulfonamides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/91—Transferases (2.)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/04—Endocrine or metabolic disorders

Definitions

  • ceramide Described herein are compounds, methods of making such compounds, pharmaceutical compositions and medicaments containing such compounds, and methods to treat or prevent diseases or disorders associated with the enzyme ceramide
  • CCT galactosyltransferase
  • diseases or disorders include, for example, lysosomal storage diseases (LSDs).
  • LSDs lysosomal storage diseases
  • examples of lysosomal storage diseases include Krabbe disease and Metachromatic Leukodystrophy.
  • CCT Ceramide galactosyltransferase
  • GSL Glycosphingolipids
  • Ceramide(s) and hydroxylated ceramide(s) play a central role in sphingolipid metabolism, and CGT is the enzyme responsible for the formation of the galactosylceramide glycolipids by catalyzing the addition of galactose to ceramide(s) and hydroxylated ceramide(s) thereby facilitating the conversion of ceramide(s) to galactosylceramide(s) and hydroxylated ceramide(s) to hydroxylated galactosylceramide(s) ( Figure 1).
  • GalCer(s) and hydroxylated galactosylceramide(s) (“hydroxylated GalCer(s)”) can be further modified by the enzyme cerebroside sulfotransferase (CST) to form sulfatide(s) and hydroxylated sulfatide(s).
  • CST cerebroside sulfotransferase
  • GalCer(s), hydroxylated GalCer(s), sulfatide(s), and hydroxylated sulfatide(s), are primarily produced by the myelin generating cells of the central and peripheral nervous systems, oligodendrocytes and Schwann cells respectively, where these glycolipids make up a large proportion of the lipids in the myelin sheath.
  • GalCer(s), hydroxylated GalCer(s), sulfatide(s), and hydroxylated sulfatide(s) are also found on the extracellular leaflet of the plasma membrane of other cells in eukaryotic organisms where they have been reported to be involved in a diverse range of functions.
  • GalCer(s), hydroxylated GalCer(s), and their sulfonated derivatives, the sulfatide(s) hydroxylated sulfatide(s), are major lipid components of the myelin sheath and they are needed for proper myelin maintenance.
  • CGT can utilize ceramide substrates that are made from both hydroxylated and non-hydroxylated fatty acids to produce both hydroxylated GalCer(s) and non-hydroxylated GalCer(s) and hydroxylated sulfatide(s) and non- hydroxylated sulfatide(s) (Figure 1).
  • GALC galactosylceramidase
  • deficiency of GALC results in Krabbe disease (also known as globoid cell leukodystrophy or galactosylceramide lipidosis). See , e.g., Ezoe et al., J. Neurosci. Res. 59: 170-178 (2000); Ezoe et al., J. Neurosci. Res.
  • ARSA arylsulfatase A
  • ARSA deficiency can lead to the development of an autosomal recessive disease called metachromatic leukodystrophy (MLD).
  • MLD metachromatic leukodystrophy
  • GalCer(s) and psychosine detrimentally affects the growth and development of the myelin sheath. Damage to the myelin sheath can lead to a severe degeneration of motor skills, cognitive deficits, and seizures, and is often fatal. Similarly, in MLD, accumulation of sulfatide(s) and lyso-sulfatide detrimentally affects the myelin sheath, disrupting neuronal functions and leads to seizures, progressive coordination and speech problems, and other behavioral disturbances.
  • One approach to treatment of such diseases resulting from an abnormal accumulation of GalCer(s), psychosine, sulfatide(s), lyso-sulfatide and related GSLs is to inhibit the CGT enzyme to decrease the formation of GalCer(s) and other downstream compounds.
  • compounds that inhibit the activity of CGT are useful as therapeutic agents in the treatment of lysosomal storage diseases relating to defects in sphingolipid metabolism, such as Krabbe disease and MLD.
  • abnormal metabolism of GalCer(s) and sulfatide(s) has been associated with other pathological conditions such as Parkinson's Disease. See , e.g.
  • the selective decrease of the level of a GalCer(s) and/or a sulfatide(s) has potential applications for treating Krabbe disease and MLD.
  • the CGT inhibitors disclosed herein selectively decrease the levels (or amount) of the non-hydroxyl ated forms of these glycolipids (such as GalCer(s) and sulfatide(s)) which may have applications for treating other disease indications including: neurodegenerative disorders like Parkinson’s disease, other demyelinating leukodystrophies, autoimmune diseases including multiple sclerosis, and certain cancers that are known to overexpress the CGT enzyme.
  • the inhibition of CGT using small molecule CGT inhibitors disclosed herein results in the selective inhibition of the formation of non-hydroxylated GalCer(s) and non-hydroxylated sulfatide(s) without inhibiting the formation of the hydroxylated forms of these compounds.
  • the selective decrease in the level of the non-hydroxylated class of these glycolipids (such as GalCer(s) and sulfatide(s)) and the increase in the level of their hydroxylated counterparts (such as hydroxylated GalCer(s) and hydroxylated sulfatide(s)) is optimal for preventing storage of non-hydroxylated forms of these compounds while preserving formation of the hydroxylated forms, which are thought to be more critical for the building of stable and healthy myelin.
  • the decrease in the level of the non-hydroxylated forms of these glycolipids correlates with the decrease in the levels of the deacylated compounds psychosine and lyso-sulfatide.
  • the selective decrease of non-hydroxylated GalCer(s) and sulfatide(s) levels is optimal for balancing efficacy and healthy myelin maintenance.
  • the use of CGT inhibitors significantly decreases or eliminates the formation of non-hydroxylated GalCer(s) and sulfatide(s) levels in the treatment of diseases and disorders disclosed herein.
  • the selective eradication of non-hydroxylated GalCer(s) and sulfatide(s) is optimal for balancing efficacy and healthy myelin maintenance.
  • treating mice with even higher doses of the CGT inhibitors disclosed herein results in inhibiting the formation of both the non-hydroxylated and hydroxylated forms of GalCer(s) and sulfatide(s).
  • the levels of the hydroxylated-ceramide(s) compounds increase inversely proportional to the decreasing hydroxylated GalCer(s).
  • a method of inhibiting CGT in a subject comprising: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii)(a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; and (iii)(b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said
  • a method of inhibiting CGT in a subject comprising: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) inhibits conversion of ceramide(s) to GalCer(s) in the subject such that the GalCer(s) level in the subject is less than the GalCer(s) level in the absence of said administration; (ii) increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject such that the hydroxylated GalCer(s) level in the subject is greater than the hydroxylated GalCer(s) level in the absence of said administration; (iii) inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject such that: (a) the GalCer(s) level in the subject is less than the GalCer(s) level in the absence
  • a method of inhibiting conversion of ceramide(s) to GalCer(s) in a subject comprising: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) inhibits CGT and decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) inhibits CGT and increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii) inhibits CGT and: (a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration, and (b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; or (iv) inhibits
  • a method of increasing conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in a subject comprising: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said
  • administering inhibits CGT and decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) inhibits CGT and increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii) inhibits CGT and: (a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration, and (b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; or (iv) inhibits CGT and inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject such that the ratio of the hydroxylated GalCer(
  • a method of reducing GalCer(s) levels in a subject comprising: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) inhibits CGT and decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) inhibits CGT and increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii) inhibits CGT and: (a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration, and (b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; or (iv) inhibits CGT and inhibits conversion of
  • GalCer(s) levels in a subject comprising: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) inhibits CGT and decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) inhibits CGT and increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii) inhibits CGT and: (a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration, and (b) increases the level of hydroxylated GalCer(s) in the subject relative to the
  • hydroxylated GalCer(s) level in the subject in the absence of said administration inhibits CGT and inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject such that the ratio of the hydroxylated GalCer(s) level to the GalCer(s) level in said subject is in the range of between 200: 1 to 1 : 1.
  • a method of treating a disease or disorder mediated by CGT in a subject comprising: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii)(a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; and (iii)(b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; or (iv) increases the level of hydroxylated GalCer(s) and decreases the level
  • a method of treating a disease or disorder mediated by CGT in a subject comprising: a) identifying a CGT inhibitor that: i) inhibits conversion of ceramide(s) to GalCer(s); ii) increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s); or iii) inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s); and b) administering to the subject a therapeutically effective amount of the identified CGT inhibitor.
  • a method of treating a disease or disorder mediated by CGT in a subject comprising: a) identifying a CGT inhibitor that: i) decreases GalCer(s) levels in a subject; ii) increases hydroxylated GalCer(s) levels in a subject; or iii) decreases GalCer(s) levels and increases hydroxylated GalCer(s) levels in a subject; and b) administering to the subject a therapeutically effective amount of the identified CGT inhibitor.
  • a method of treating a disease or disorder mediated by CGT in a subject comprising: a) identifying a subject with cells or tissue having GalCer(s) levels equal to or greater than hydroxylated GalCer(s) levels; and b) administering to the subject a therapeutically effective amount of a CGT inhibitor.
  • a method of treating a disease or disorder mediated by CGT in a subject comprising: a) identifying a therapeutically effective dose of a CGT inhibitor that: i) decreases GalCer(s) levels in a subject; ii) increases hydroxylated GalCer(s) levels in a subject; or iii) decreases GalCer(s) levels and increases hydroxylated GalCer(s) levels in a subject; and b) administering to the subject the therapeutically effective dose of the CGT inhibitor.
  • a method of treating a disease or disorder mediated by CGT in a subject comprising: a) obtaining a biological sample from a subject having or diagnosed as having the disease or disorder mediated by CGT; b) determining levels of GalCer(s) and/or hydroxylated GalCer(s) in the biological sample, wherein i) if the GalCer(s) level following administration is not decreased by at least 10% relative to the GalCer(s) level in the subject in the absence of or prior to the administration; ii) if the hydroxylated GalCer(s) level following administration is not increased by at least 10% relative to the hydroxylated GalCer(s) level in the subject in the absence of or prior to the administration; iii) if the GalCer(s) level following administration is not decreased by at least 10% and the hydroxylated GalCer(s) level following administration is not increased by at least 10% relative to the respective GalCer(s) level and hydroxy
  • a method for monitoring efficacy of treatment of a subject having or diagnosed as having a disease or disorder mediated by CGT comprising: a) administering a first dosage amount of a CGT inhibitor to the subject; b) obtaining a biological sample from the subject following administration of the CGT inhibitor; c) determining levels of GalCer(s) and/or hydroxylated GalCer(s) in the biological sample, wherein i) if the GalCer(s) level following administration is not decreased by at least 10% relative to the GalCer(s) level in the subject in the absence of or prior to the administration; ii) if the hydroxylated GalCer(s) level following administration is not increased by at least 10% relative to the hydroxylated GalCer(s) level in the subject in the absence of or prior to the administration; iii) if the GalCer(s) level following administration is not decreased by at least 10% and the hydroxylated GalCer(s) level following
  • a method of assessing the efficacy of a CGT inhibitor in treating a disease or disorder mediated by CGT comprising: a) administering the CGT inhibitor to a subject having or diagnosed as having the disease or disorder mediated by CGT; b) obtaining a biological sample from the subject after administering the CGT inhibitor; c) determining levels of GalCer(s) and/or hydroxylated GalCer(s) in the biological sample; d) comparing the levels of GalCer(s) and/or hydroxylated GalCer(s) in the biological sample from step (c) to the levels of GalCer(s) and/or hydroxylated GalCer(s) from a reference biological sample; wherein a decrease in the level of GalCer(s) and/or an increase in the level of hydroxylated GalCer(s) is indicative of the efficacy of the CGT inhibitor in treating the disease or disorder mediated by CGT.
  • a method of inhibiting the activity of CGT in a cell or tissue comprising: contacting the cell or tissue with an effective amount of a CGT inhibitor; wherein the contacting: (i) decreases the level of GalCer(s) in the cell or tissue relative to the GalCer(s) level in the cell or tissue in the absence of said contacting; (ii) increases the level of hydroxylated GalCer(s) in the cell or tissue relative to the hydroxylated GalCer(s) level in the cell or tissue in the absence of said contacting; (iii)(a) decreases the level of GalCer(s) in the cell or tissue relative to the GalCer(s) level in the cell or tissue in the absence of said contacting, and (b) increases the level of hydroxylated GalCer(s) in the cell or tissue relative to the hydroxylated GalCer(s) level in the cell or tissue in the absence of said contacting; or (iv) increases the level of
  • a method of inhibiting the activity of CGT in a cell or tissue comprising: contacting the cell or tissue with an effective amount of a CGT inhibitor; wherein the contacting: (i) inhibits conversion of ceramide(s) to GalCer(s) in the cell or tissue such that the GalCer(s) level in the cell or tissue is less than the GalCer(s) level in the absence of said contacting; (ii) increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the cell or tissue such that the hydroxylated GalCer(s) level in the cell or tissue is greater than the hydroxylated GalCer(s) level in the absence of said contacting; (iii) inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the cell or tissue such that: (a) the GalCer(s)
  • hydroxylated GalCer(s) in the cell or tissue such that the ratio of the hydroxylated GalCer(s) level to the GalCer(s) level in said cell or tissue is in the range of between 200: 1 to 1 : 1.
  • administration decreases levels of one or more metabolites in the cell or tissue of the subject relative to the level of the one or more metabolites in the subject in the absence of said administration; wherein the one or more metabolites are selected from the group consisting of psychosine, lyso-sulfatide, and sulfatide(s).
  • provided herein is a method wherein the subject is in need of said treatment.
  • provided herein is a method wherein the subject has or has been diagnosed as having a disease or disorder mediated by CGT.
  • provided herein is a method wherein the disease or disorder mediated by CGT is a lysosomal storage disease.
  • the lysosomal storage disease is Krabbe disease or is MLD.
  • provided herein is a method wherein the disease or disorder mediated by CGT is a neurodegenerative disorder.
  • neurodegenerative disorder is Parkinson’s disease.
  • provided herein is a method wherein the disease or disorder mediated by CGT is a demyelinating leukodystrophy.
  • provided herein is a method wherein the disease or disorder mediated by CGT is an autoimmune disease.
  • autoimmune disease is multiple sclerosis (MS).
  • the biological sample is a cell sample, a tissue sample, a saliva sample, a blood sample, a plasma sample, a nerve biopsy sample, a skin biopsy sample, or a CNS fluid sample.
  • the CGT inhibitor is a compound of Formula I, la, lb, II, or III, or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the CGT inhibitor is a compound of Formula I, la, lb, or II, wherein the compound is selected from Table 1 consisting of Examples 1-141, 143-267, and 268-338, or a single stereoisomer or mixture of stereoisomers thereof.
  • CGT inhibitor is a compound selected from Table 1.
  • the CGT inhibitor is a compound of Formula III, wherein the compound is selected from Table 2 consisting of Examples 1-57, or a single stereoisomer or mixture of stereoisomers thereof.
  • CGT inhibitor is a compound selected from Table 2.
  • provided herein is a method wherein the CGT inhibitor is a compound of Formula X, Xa, or Xb, or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the CGT inhibitor is a compound of Formula X, Xa, or Xb, wherein the compound is selected from Table 3 consisting of Examples 1-200, or a single stereoisomer or mixture of stereoisomers thereof.
  • CGT inhibitor is a compound selected from Table 3.
  • the CGT inhibitor is a compound of Formula XX, XXa, XXb, XXc, XXd, XXe, XXf, XXI, XXIa, or XXIb, or optionally a single stereoisomer or mixture of stereoisomers thereof and
  • the CGT inhibitor is a compound of Formula XX, XXa, XXb, XXc, XXd, XXe, XXf, XXI, XXIa, or XXIb, wherein the compound is selected from Table 4 consisting of Examples 1-121.
  • CGT inhibitor is a compound selected from Table 4.
  • FIGURE 1 Schematic illustrating the GSL biochemical pathway for the formation of GalCer(s) and sulfatide(s) and their hydroxylated forms, and their role in myelin formation and in Krabbe disease and MLD.
  • FIGURES 2 A-2F Graphs showing potency of six CGT inhibitors
  • FIGURES 3A-F Graphs showing pharmacokinetics and brain penetration of six CGT inhibitors (Compounds A-F) in mouse.
  • FIGURES 4F-4F Graphs showing effect of six CGT inhibitors (Compounds A-F) on brain levels of GalCer(s) and hydroxylated GalCer(s) in wildtype mice.
  • FIGURES 5A-5F Graphs showing effect of six CGT inhibitors (Compounds A-F) on brain levels of sulfatide(s) and hydroxylated sulfatide(s) in wildtype mice.
  • FIGURES 6A-6C Graphs showing effect of CGT inhibitor (Compound A) on disease associated biomarkers in a Krabbe disease mouse model ⁇ Twitcher mouse).
  • FIGURES 7A-7C Graphs showing effect of CGT inhibitor (Compound A) on disease associated biomarkers in a MLD disease mouse model (ARSA knockout mouse).
  • FIGURES 8A-8D Graphs showing effect of CGT inhibitor (Compound A) on the levels of ceramides and hydroxylated ceramides in ARSA knockout mice.
  • FIGURES 9A-9B Graphs showing effect of CGT inhibitors (Compounds A and D) on the levels of ceramides and hydroxylated ceramides in wildtype mice.
  • ceramide refers to an amide conjugate composed of sphingosine moiety and a fatty acid moiety (wherein R represents the saturated or unsaturated alkyl portion of the fatty acid). Ceramide and non-hydroxylated ceramide are used interchangeably herein. Without being limited by theory, ceramide is believed to have the following structure:
  • the ceramide may be an amide conjugate composed of sphingosine moiety and a saturated fatty acid moiety (wherein R is a saturated alkyl) or an amide conjugate composed of sphingosine moiety and an unsaturated fatty acid moiety (wherein R is an unsaturated alkyl, such as a mono-, di-, tri-, or tetra- unsaturated fatty acid, wherein each unsaturatation may be either a cis- or trans- unsaturation).
  • the ceramide may be derived from a C 12, C 14, Cl 6, Cl 8, C20, C22, or C24 saturated fatty acid, or mixtures thereof.
  • the ceramide may be derived from a 04: 1, 06: 1, 08: 1, 08:2, 08:3,
  • ceramide(s) refers to either a single ceramide (an amide conjugate derived from sphingosine and a single fatty acid) or a mixture of ceramides, wherein the mixture of ceramides comprises amide conjugates derived from sphingosine and a mixture of fatty acids, wherein the fatty acids may comprsise a mixture of saturated fatty acids, a mixture of unsaturated fatty acids, or a mixture of saturated fatty acids and unsaturated fatty acids. Ceramide(s) and non-hydroxylated ceramide(s) are used interchangeably herein.
  • GalCer galactosylceramide
  • GalCer galactosylceramide
  • ceramide moiety wherein R represents the alkyl portion of the fatty acid component of ceramide.
  • GalCer is believed to have the following structure:
  • the GalCer may be a galactosyl conjugate composed of a galactose and a ceramide moiety, wherein the ceramide moiety is derived from a saturated fatty acid (wherein R is a saturated alkyl), or a galactosyl conjugate composed of a galactose moiety and a ceramide moiety, wherein the ceramide moiety is derived from an unsaturated fatty acid (wherein R is an unsaturated alkyl, such as a mono-, di-, tri-, or tetra- unsaturated fatty acid, wherein each unsaturatation may be either a cis- or trans- unsaturation).
  • the GalCer may be a galactosyl conjugate composed of a galactose moiety and a ceramide moiety, wherein the ceramide moiety is derived from a C12, C14, C16, C18, C20, C22, or C24 saturated fatty acid.
  • the GalCer may be a galactosyl conjugate composed of a galactose moiety and a ceramide moiety, wherein the ceramide moiety is derived from a Cl4: l, 06:1, 08: 1, 08:2, 08:3, C20: l, C22: l, or C24: l unsaturated fatty acid.
  • galactosylceramide(s) refers to either a single galactosylceramide (GalCer) composed of a galactose moiety and a single ceramide moiety derived from sphingosine and a single fatty acid, or a mixture of galactosylceramides (GalCers), wherein the mixture of GalCers comprises galactosyl conjugates derived from galactose and a mixture of ceramides, wherein the mixture of ceramides are derived from sphingosine and a mixture of fatty acids, wherein the fatty acids may comprsise a mixture of saturated fatty acids, a mixture of unsaturated fatty acids, or a mixture of saturated fatty acids and unsaturated fatty acids.
  • the term“hydroxylated fatty acid” refers to a fatty acid having one or more hydroxyl groups on the alkyl portion of the fatty acid. In certain embodiments, the hydroxylated fatty acid refers to a fatty acid having one hydroxyl group on the alkyl portion of the fatty acid. In certain embodiments, the hydroxylated fatty acid refers to a fatty acid having a hydroxyl group at the alpha carbon (or 2-position) of the alkyl portion of the fatty acid.
  • the hydroxylated fatty acid may be a saturated fatty acid (wherein R is a saturated alkyl, such as a C 12, C 14, Cl 6, Cl 8, C20, C22, or C24 saturated fatty acid, for example, a Cl 8, C20, C22, or C24 saturated fatty acid) having a hydroxyl group on the alkyl portion of the saturated fatty acid, such as having a hydroxyl group at the alpha carbon (or 2-position) of the alkyl portion of the saturated fatty acid, or may be an unsaturated fatty acid (wherein R is an unsaturated alkyl, such as a mono-, di-, tri-, or tetra- unsaturated fatty acid, wherein each unsaturatation may be either a cis- or trans- unsaturation; for example, a C14: 1, C16: 1,
  • a cis- monounsaturated fatty acid e.g., a C20:l (D 11 ), C22: l (D 13 ), or C24: l (D 15 ) unsaturated fatty acid
  • having a hydroxyl group on the alkyl portion of the unsaturated fatty acid such as having a hydroxyl group at the alpha carbon (or 2-
  • hydroxylated fatty acid(s) refers to a single hydroxylated fatty acid of a single fatty acid having a hydroxyl group on the alkyl portion of the fatty acid, such as having a hydroxyl group at the alpha carbon (or 2-position) of the alkyl portion of the fatty acid, or a mixture of hydroxylated fatty acids comprised of a mixture of fatty acids having a hydroxyl group on the alkyl portion of the mixture of respective fatty acids, such as having a hydroxyl group at the alpha carbon (or 2-position) of the alkyl portion of the mixture of respective fatty acids.
  • the term“hydroxylated ceramide” refers to a ceramide in which the alkyl portion of the fatty acid component of the ceramide comprises one or more hydroxyl groups on the alkyl portion of the fatty acid component of the ceramide.
  • the hydroxylated ceramide refers to a ceramide having one hydroxyl group on the fatty acid component of the ceramide.
  • the hydroxylated ceramide refers to a ceramide having a hydroxyl group at the alpha carbon (or 2-position) of the alkyl portion of the fatty acid component of the ceramide.
  • the hydroxylated ceramide moiety is derived from sphingosine and a saturated fatty acid (wherein R is a saturated alkyl) having a hydroxyl group on the alkyl portion of the saturated fatty acid, such as having a hydroxyl group at the alpha carbon (or 2- position) of the alkyl portion of the saturated fatty acid, or derived from sphingosine and an unsaturated fatty acid (wherein R is an unsaturated alkyl, such as a mono-, di-, tri-, or tetra- unsaturated fatty acid, wherein each unsaturatation may be either a cis- or trans- unsaturation) having a hydroxyl group on the alkyl portion of the unsaturated fatty acid, such as having a hydroxyl group at the alpha carbon (or 2-position) of the alkyl portion of the unsaturated fatty acid.
  • R is a saturated alkyl having a hydroxyl group on the alkyl portion of the saturated fatty
  • the hydroxylated ceramide moiety is derived from a C12, C14, C16, C18, C20, C22, or C24 saturated fatty acid having a hydroxyl group at the alpha carbon.
  • the hydroxylated ceramide moiety is derived from a Cl 8, C20, C22, or C24 saturated fatty acid having a hydroxyl group at the alpha carbon, as illustrated below
  • the hydroxylated ceramide moiety is derived from a Cl4: l, Cl6: l, 08:1, 08:2, 08:3, C20: l, C22: l, or C24: l unsaturated fatty acid having a hydroxyl group at the alpha carbon.
  • hydroxylated ceramide(s) refers to either a single hydroxylated ceramide (an amide conjugate derived from sphingosine and a single hydroxylated fatty acid) or a mixture of hydroxylated ceramides, wherein the mixture of hydroxylated ceramides are derived from sphingosine and a mixture of
  • hydroxylated fatty acids wherein the mixture of hydroxylated fatty acids may comprsise a mixture of hydroxylated saturated fatty acids, a mixture of hydroxylated unsaturated fatty acids, or a mixture of hydroxylated saturated fatty acids and hydroxylated unsaturated fatty acids.
  • hydroxylated galactosylceramide refers to a galactosylceramide in which the alkyl portion of the fatty acid component of the galactosylceramide comprises one or more hydroxyl groups on the alkyl portion of the fatty acid component of the galactosylceramide.
  • the hydroxylated galactosylceramide refers to a galactosylceramide having one hydroxyl group on the fatty acid component of the galactosylceramide.
  • the hydroxylated galactosylceramide refers to a ceramide having a hydroxyl group at the alpha carbon (or 2- position) of the alkyl portion of the fatty acid component of the galactosylceramide.
  • the hydroxylated GalCer is a galactosyl conjugate composed of a galactose moiety and a hydroxylated ceramide moiety, wherein the hydroxylated ceramide moiety is derived from sphingosine and a saturated fatty acid (wherein R is a saturated alkyl) having a hydroxyl group on the alkyl portion of the saturated fatty acid, such as having a hydroxyl group at the alpha carbon (or 2-position) of the alkyl portion of the saturated fatty acid, or derived from sphingosine and an unsaturated fatty acid (wherein R is an unsaturated alkyl, such as a mono-, di-, tri-, or tetra- unsaturated fatty acid, wherein each unsaturatation may be either a cis- or trans- unsaturation) having a hydroxyl group on the alkyl portion of the unsaturated fatty acid, such as having a hydroxyl group at the al
  • the hydroxylated GalCer may be a galactosyl conjugate composed of a galactose moiety and a hydroxylated ceramide moiety, wherein the hydroxylated ceramide moiety is derived from a 02, 04, 06, 08, C20, C22, or C24 saturated fatty acid having a hydroxyl group at the alpha carbon.
  • the hydroxylated GalCer may be a galactosyl conjugate composed of a galactose moiety and a hydroxylated ceramide moiety, wherein the hydroxylated ceramide moiety is derived from a Cl4: l, Cl6: l, 08: 1, 08:2, 08:3, C20: l, C22:l, or C24: l unsaturated fatty acid having a hydroxyl group at the alpha carbon.
  • hydroxylated galactosylceramide(s) refers to either a single hydroxylated GalCer (a galactosyl conjugate composed of a galactose moiety and a single hydroxylated ceramide moiety derived from sphingosine and a single hydroxylated fatty acid or a mixture of hydroxylated GalCers, wherein the mixture of hydroxylated GalCers comprises galactosyl conjugates derived from galactose and a mixture of hydroxylated ceramides, wherein the mixture of hydroxylated ceramides are derived from sphingosine and a mixture of hydroxylated fatty acids, wherein the mixture of hydroxylated fatty acids may comprsise a mixture of hydroxylated saturated fatty acids, a mixture of hydroxylated unsaturated fatty acids, or a mixture of hydroxylated saturated saturated
  • the term“sulfatide”, refers to a sulfonated adduct composed of a sulfonated galactose moiety and a ceramide moiety (wherein R represents the alkyl portion of the fatty acid component of ceramide), wherein the sulfonate may be in protonated or in a salt form).
  • the sulfatide refers to a sulfonated adduct composed of a mono-, di-, tri-, or tetra-sulfonated galactose moiety and a ceramide moiety.
  • the sulfatide refers to a sulfonated adduct composed of a mono-sulfonated galactose moiety and a ceramide moiety. Sulfatide and non-hydroxylated sulfatide are used interchangeably herein. Without being limited by theory, sulfatide(s) is believed to have the following structure (or salt thereof):
  • the sulfatide(s) may be derived from a saturated fatty acid (wherein R is a saturated alkyl), or derived from an unsaturated fatty acid (wherein R is an unsaturated alkyl, such as a mono-, di-, tri-, or tetra- unsaturated fatty acid, wherein each unsaturatation may be either a cis- or trans- unsaturation).
  • R is a saturated alkyl
  • R is an unsaturated alkyl, such as a mono-, di-, tri-, or tetra- unsaturated fatty acid, wherein each unsaturatation may be either a cis- or trans- unsaturation.
  • sulfatide(s) refers to either a single sulfatide composed of a mono-sulfonated galactose moiety and a ceramide moiety, or a mixture of sufatides, wherein the mixture of sulfatides are derived from a mixture of fatty acids, wherein the fatty acids may comprsise a mixture of saturated fatty acids, a mixture of unsaturated fatty acids, or a mixture of saturated fatty acids and unsaturated fatty acids. Sulfatide(s) and non- hydroxylated sulfatide(s) are used interchangeably herein.
  • hydroxylated sulfatide refers to a sulfatide in which the alkyl portion of the fatty acid component of the sulfatide comprises one or more hydroxyl groups on the alkyl portion of the fatty acid component of the sulfatide.
  • the hydroxylated sulfatide refers to a sulfatide having one hydroxyl group on the fatty acid component of the sulfatide. In certain embodiments, the hydroxylated sulfatide refers to a sulfatide having a hydroxyl group at the alpha carbon (or 2-position) of the alkyl portion of the fatty acid component of the sulfatide. In certain embodiments, the
  • hydroxylated sulfatide refers to a mono-, di-, tri-, or tetra-sulfonated galactose moiety and a hydroxylated ceramide moiety. In certain embodiments, the hydroxylated sulfatide refers to a mono-sulfonated galactose moiety and a hydroxylated ceramide moiety. In certain embodiments, the hydroxylated sulfatide refers to a sulfatide having a mono-sulfonated galactose moiety and a hydroxyl group at the alpha carbon (or 2-position) of the alkyl portion of the fatty acid component of the sulfatide. Without being limited by theory, the
  • hydroxylated sulfatide is a sulfonated adduct composed of a mono-, di-, tri-, or tetra, sulfonated galactose moiety and a hydroxylated ceramide moiety, e.g., a mono-sulfonated galactose moiety and a hydroxylated ceramide moiety, wherein the hydroxylated ceramide moiety is derived from sphingosine and a saturated fatty acid (wherein R is a saturated alkyl) having a hydroxyl group on the alkyl portion of the saturated fatty acid, such as having a hydroxyl group at the alpha carbon (or 2-position) of the alkyl portion of the saturated fatty acid, or derived from sphingosine and an unsaturated fatty acid (wherein R is an unsaturated alkyl, such as a mono-, di-, tri-, or tetra- unsaturated fatty acid, wherein
  • hydroxylated sulfatide(s) refers to either a single hydroxylated sulfatide (a mono-sulfonated hydroxylated sulfatide derived from a single hydroxylated fatty acid) or a mixture of hydroxylated sulfatides, wherein the mixture of hydroxylated sulfatides comprises mono-sulfonated galactosyl conjugates derived from galactose and a mixture of hydroxylated ceramides, wherein the mixture of hydroxylated ceramides are derived from sphingosine and a mixture of hydroxylated fatty acids, wherein the mixture of hydroxylated fatty acids may comprsise a mixture of hydroxylated saturated fatty acids, a mixture of hydroxylated unsaturated fatty acids, or a mixture of hydroxylated saturated fatty acids and hydroxylated unsaturated fatty acids.
  • the term“level” refers to the amount of any particular substrate or product, such as ceramide, ceramide(s), hydroxylated ceramide, hydroxylated ceramide(s), GalCer, GalCer(s), hydroxylated GalCer, hydroxylated GalCer(s), sulfatide, sulfatide(s), hydroxylated sulfatide, hydroxylated sulfatide(s), pyschosine, or lyso-sulfatide, in a cell, a biological sample, or a subject.
  • the level (or amount) may be expressed as a weight percentage of the particular substrate or product relative to the cell, the biological sample, or the subject.
  • the level may be measured by a variety of methods, including LC- MS/MS and RapidFire/MS/MS. Without being bound by any particular mechanism, one of ordinary skill in the art would understand that the level of any particular substrate or product, such as ceramide, ceramide(s), hydroxylated ceramide, hydroxylated ceramide(s), GalCer, GalCer(s), hydroxylated GalCer, hydroxylated GalCer(s), sulfatide, sulfatide(s), hydroxylated sulfatide, hydroxylated sulfatide(s), pyschosine, or lyso-sulfatide, will depend on multiple factors, including, for example, enzyme(s) that form or metabolize the particular substrate or product, and the conversion rates or activities of those enzyme(s).
  • the level of GalCer(s) in a biological sample may be the amount, concentration, or weight percent of the GalCer(s) in the biological sample
  • the term“inhibit(s) conversion of ceramide to GalCer” refers to inhibiting the rate of ceramide galactosyl transferase (CGT) in converting ceramide to GalCer or reducing the level of GalCer produced from ceramide in a given period of time.
  • the term“increase(s) conversion of hydroxylated ceramide to hydroxylated GalCer” refers to increasing the rate of ceramide galactosyl transferase (CGT) in converting hydroxylated ceramide to hydroxylated GalCer or increasing the level of hydroxylated GalCer produced from hydroxylated ceramide in a given period of time.
  • CCT galactosyl transferase
  • Alkenyl means a straight or branched hydrocarbon radical having from 2 to 8 carbon atoms and at least one double bond and in certain embodiments include ethenyl, propenyl, l-but-3-enyl, l-pent-3-enyl, or l-hex-5-enyl.
  • the terms“radical” and“group” are used interchangeably and are understood to have the same meaning.
  • alkoxy means a group of the formula -OR, where R is alkyl.
  • alkoxy includes methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, or hexyloxy.
  • Alkoxycarbonyl means a group of the formula -C(0)R, where R is alkoxy, as defined herein.
  • Alkylcarbonylamino means a group of the formula -NHC(0)R, where R is alkyl, as defined herein.
  • Alkoxycarbonyloxy means a group of the formula -OC(0)R, where R is alkoxy, as defined herein.
  • Alkoxyalkyl means a group of the formula -R-O-R', where R is alkylene and R' are independently alkyl as defined herein.
  • Alkoxyalkylene means a group of the formula -R-O-R', where R is alkylene and R' is alkyl as defined herein.
  • Alkyl means a straight or branched saturated hydrocarbon radical containing from 1-10 carbon atoms, and in certain embodiments includes 1-6 carbon atoms. In certain embodiments, alkyl includes 1-4 carbon atoms, and in certain embodiments includes 1-3 carbon atoms. When an alkyl group contains from 1-10 carbon atoms, it may be referred to herein as Ci-io alkyl. When an alkyl group contains from 1-6 carbon atoms, it may be referred to herein as Ci- 6 alkyl. When an alkyl group contains from 1-4 carbon atoms, it may be referred to herein as Ci- 4 alkyl.
  • alkyl When an alkyl group contains from 1-3 carbon atoms, it may be referred to herein as C1-3 alkyl.
  • alkyl includes methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3- methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylhexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • Alkylamino means a group of the formula -NHR, where R is alkyl as defined herein, or an N-oxide derivative thereof, e.g., methylamino, ethylamino, //-,
  • Alkylaminocarbonyl means a group of the formula -C(0)R, where R is alkylamino, as defined herein.
  • Alkylcarbonyl means a group of the formula -C(0)R, where R is alkyl, as defined herein.
  • Alkylcarbonyloxy means a group of the formula -OC(0)R, where R is alkyl, as defined herein.
  • Alkylene means a divalent radical formed by removal of a hydrogen atom from alkyl.
  • Alkynyl means a straight or branched hydrocarbon radical having from 2 to 8 carbon atoms and at least one triple bond and includes ethynyl, propynyl, l-but-3-ynyl, 1- pent-3-ynyl, l-hex-5-ynyl and the like.
  • Amino means an -NIL ⁇ group.
  • Aminocarbonyl means an -C(0)ML ⁇ group.
  • Aminocarbonyloxy means a group of formula -0C(0)ML ⁇
  • Aryl means a monovalent six- to fourteen-membered, mono-, bi-, or tri- carbocyclic ring, wherein the monocyclic ring is aromatic and at least one of the rings in the bicyclic or tricyclic ring is aromatic.
  • aryl includes phenyl, naphthyl, indanyl, or anthracenyl.
  • Aryloxy means a group of the formula -OR, where R is aryl, as defined herein. In certain embodiments, aryloxy is phenoxy.
  • Carboxy means an -C(0)OH group.
  • Cyano means an -CN group.
  • Cyanoalkyl means and alkyl group substituted with a cyano group, as defined herein.
  • Cycloalkyl means a monocyclic or bicyclic, saturated or partially unsaturated (but not aromatic), hydrocarbon radical of three to ten carbon ring atoms.
  • a cycloalkyl group contains from 3-10 carbon atoms, it may be referred to herein as C3-10 cycloalkyl.
  • a cycloalkyl group contains from 5-6 carbon atoms, it may be referred to herein as C5-6 cycloalkyl.
  • Cycloalkyl groups include fused, bridged and spirocycloalkyl bicyclic rings.
  • the cycloalkyl group when fused, may comprise two rings that share adjacent atoms ( e.g ., one covalent bond).
  • the cycloalkyl group When bridged, may comprise two rings that share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom.
  • the cycloalkyl group may comprise two rings that share only one single atom, the spiro atom, which may be, for example, a quaternary carbon.
  • cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.
  • cycloalkyl groups include:
  • Cycloalkyl ene means a divalent radical formed by removal of a hydrogen atom from cycloalkyl.
  • a cycloalkylene group contains from 5-6 carbon atoms, it may be referred to herein as C5-6 cycloalkylene.
  • (Cycloalkyl)alkyl means an alkyl group, as defined herein, substituted with at least one cycloalkyl group as defined herein. In certain embodiments, the alkyl is substituted with 1 or 2 cycloalkyl groups. In certain embodiments, the alkyl is substituted with 1 cycloalkyl group.
  • (Cycloalkyl)alkoxy means a group of the formula -OR, where R is a (cycloalkyl)alkyl group as defined herein.
  • Cycloalkyloxy means a group of the formula -OR, where R is cycloalkyl, as defined herein.
  • Dialkylamino means a group of the formula -NRR', where R and R' are independently alkyl as defined herein, or an N-oxide derivative, or a protected derivative thereof, e.g., dimethylamino, diethylamino, N, A -methyl propyl ami no or NN- methylethylamino, and the like.
  • Dialkylaminocarbonyl means a group of the formula -C(0)R, where R is dialkylamino, as defined herein.
  • Dialkylaminocarbonyloxy means a group of the formula -OC(0)R, where R is dialkylamino, as defined herein.
  • Halo means a fluoro, chloro, bromo, or iodo group.
  • Haloalkoxy means an alkoxy group, substituted with one or more halo atoms. In certain embodiments, the alkoxy is substituted with 1, 2, or 3 halo atoms. Certain embodiments of haloalkoxy include difluoromethoxy, trifluorom ethoxy, or 1,1,1 - trifluoroethoxy.
  • Haloalkyl means an alkyl group substituted with one or more halo atoms, and in certain embodiments by 1, 2, 3, 4, 5, or 6 halo atoms. In certain embodiments, haloalkyl is an alkyl group substituted by 1, 2, or 3 halo atoms. In certain other words,
  • haloalkyl is an alkyl group substituted with 2 halo atoms. In certain embodiments, haloalkyl is an alkyl group substituted with 1 halo atom. In certain embodiments, haloalkyl includes trifluoromethyl, fluoromethyl, perfluoroethyl, or chloromethyl. Certain other embodiments of haloalkyl include chloromethyl, fluoromethyl, difluorom ethyl, trifluoromethyl, or l,l,l-trifluoroethanyl.
  • (Haloalkyl)cycloalkyl means a cycloalkyl group substituted with one or more haloalkyl groups, as defined herein.
  • (haloalkyl)cycloalkyl includes l-(haloalkyl)cyclopropyl, 2-(haloalkyl)cyclopropyl, l-(haloalkyl)cyclobutyl, 2- (haloalkyl)cyclobutyl, 3-(haloalkyl)cyclobutyl, l-(haloalkyl)cyclopentyl, 2- (haloalkyl)cyclopentyl, 3-(haloalkyl)cyclopentyl, l-(haloalkyl)cyclohexyl, 2- (haloalkyl)cyclohexyl, 3-(haloalkyl)cyclohexyl, 4-(haloalkyl)cyclohexyl, 2,3- bis(haloalkyl
  • heteroaryl includes, but is not limited to, triazolyl, tetrazolyl, pyrrolyl, imidazolyl, thienyl, furanyl, pyrazolyl, oxazolyl, isooxazolyl,
  • oxadiazolyl thiadiazolyl (including, for example, l,3,4-thiadiazolyl), indolyl, 2,3-dihydro- l//-indolyl (including, for example, 2, 3 -di hydro- 1 //-i ndol -2-y 1 or 2,3-dihydro- l//-indol-5- yl), indazolyl, benzimidazolyl, benzoxazolyl, benzofuranyl, benzothienyl, benzopyranyl, benzothiazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinolinyl, isoquinolinyl, tetrahydroisoquinolinyl (including, for example, tetrahydroisoquinolin-4-yl or
  • pyrrolo[3,2-c]pyridinyl including, for example, pyrrolo[3,2- c]pyridin-2-yl or pyrrolo[3,2-c]pyridin-7-yl
  • heterocycloalkyl is a saturated or partially unsaturated monocyclic group of 4 to 7 rings atoms, or a saturated or partially unsaturated bicyclic group of 7 to 9 ring atoms.
  • heterocycloalkyl group contains only one or two nitrogen atoms, and the remaining ring atoms are carbon.
  • a heterocycloalkyl group contains from 4 to 7 ring atoms, it may be referred to herein as 4-7 membered heterocycloalkyl.
  • a heterocycloalkyl group contains from 7 to 9 ring atoms, it may be referred to herein as 7-9 membered
  • Heterocycloalkyl groups include fused or bridged heterocycloalkyl bicyclic rings.
  • a fused heterocycloalkyl group may comprise two rings that share adjacent atoms (e.g., one covalent bond).
  • the heterocycloalkyl group may comprise two rings that share three or more atoms, separating the two bridgehead atoms by a bridge containing at least one atom.
  • heterocycloalkyl includes, but is not limited to, azetidinyl, pyrrolidinyl, 2,5-dihydro- 1 //-pyrrol inyl, 2,5-dihydro- 1 //-pyrrolyl,
  • (Heterocycloalkyl)alkyl means an alkyl group, as defined herein, substituted with at least one heterocycloalkyl group as defined herein. In certain embodiments, the alkyl is substituted with 1 or 2 heterocycloalkyl groups. In certain embodiments, the alkyl is substituted with one heterocycloalkyl group.
  • Heterocycloalkyloxy means a group of the formula -OR, where R is heterocycloalkyl group, as defined herein.
  • (Hetercycloalkyl)alkoxy means a group of the formula -OR, where R is a (heterocycloalkyl)alkyl group as defined herein.
  • Hydroalkyl means an alkyl group, as defined herein, substituted with at least one, or in other embodiments 1, 2, or 3 hydroxy groups, or in other embodiments, with one hydroxy group.
  • Haldroxyalkoxy means an alkoxy group, as defined herein, substituted with at least one, or in other embodiments 1, 2, or 3 hydroxy groups, or in other embodiements, with one hydroxy group.
  • “Hydroxy” means an -OH group.
  • the terms“hydroxy” and“hydroxyl” are used interchangeably and mean an -OH group.
  • Niro means an -NO2 group.
  • Phenyl carbonyl means an -C(0)-phenyl group.
  • Spirocycloalkyl means alkylene, where both ends of which are attached to the same carbon atom to form a ring.
  • spirocycloalkyl includes C3-spirocycloalkyl
  • C7-spirocycloalkyl or Cs-spirocycloalkyl.
  • Certain embodiments of spirocycloalkyl include spirocyclobutyl or spirocyclopentyl.
  • “Spiroheterocycloalkyl” means spirocycloalkyl, as defined herein, having one or two CH 2 moieties replaced with independently selected O, C(O), S, S(O), SO2 or NH and one or two CH moieties unreplaced or replaced with N.
  • Certain embodiments of spiroheterocycloalkyl include
  • Certain embodiments of spiroheterocycloalkyl include
  • Stereoisomers wherein asymmetric or chiral centers are present.
  • Stereoisomers are designated (R) or (S) depending on the configuration of substituents around the chiral carbon atom.
  • the term (R) and (S) used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem ., (1976), 45: 13-30, hereby incorporated by reference.
  • the embodiments described herein specifically includes the various stereoisomers and mixtures thereof.
  • Stereoisomers include (but are not limited to) geometric isomers, enantiomers, diastereomers, and mixtures of geometric isomers, enantiomers or
  • individual stereoisomers of compounds are prepared synthetically from commercially available starting materials which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by resolution. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and liberation of the optically pure product from the auxiliary or (2) direct separation of the mixture of optical enantiomers on chiral chromatographic column.
  • “Amelioration” of the symptoms of a particular disorder by administration of a particular compound or pharmaceutical composition refers to any lessening of severity, delay in onset, slowing of progression, or shortening of duration, whether permanent or temporary, lasting or transient that can be attributed to or associated with administration of the compound or composition.
  • an“effective amount” or“therapeutically effective amount,” refer to a sufficient amount of an agent or a compound being administered which will ameliorate to some extent one or more of the symptoms of the disease or disorder being treated. The result includes a decrease and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • an“effective amount” for therapeutic uses is the amount of the composition comprising a compound as disclosed herein required to ameliorate to some extent one or more of the symptoms of the disease or disorder being treated.
  • An appropriate“effective” amount in any individual case is determined using any suitable technique, such as a dose escalation study.
  • the term“effective dose” or“thereapeutically effective dose”, unless otherwise specified, is understood to include a thereapeutically acceptable dose, a thereapeutically acceptable amount, a thereapeutically effective amount, a pharmaceutically acceptable dose, a pharmaceutically acceptable amount, a pharmaceutically effective dose, or a pharmaceutically effective amount.
  • compositions such as a liquid or solid filler, diluent, solvent, or encapsulating material.
  • Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof.
  • encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and
  • each component is“pharmaceutically acceptable” in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable in the sense of being compatible with the other ingredients of a pharmaceutical formulation, and suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, e.g., Remington: The Science and Practice of Pharmacy, 21st ed .; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of
  • “Pharmaceutically acceptable salt” refers to a formulation of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • pharmaceutically acceptable salts are obtained by reacting a compound described herein, with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.
  • pharmaceutically acceptable salts are obtained by reacting a compound having acidic group described herein with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D- glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously determined.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, A-methyl-D- glucamine, tris(hydroxymethyl)methylamine, and salts with amino acids such as arginine, lysine, and the like, or by other methods previously
  • Examples of a salt that the compound forms with a base include the following: salts thereof with inorganic bases such as sodium, potassium, magnesium, calcium, and aluminum; salts thereof with organic bases such as methylamine, ethylamine and ethanolamine; salts thereof with basic amino acids such as lysine and ornithine; and ammonium salt.
  • the salts may be acid addition salts, which are specifically exemplified by acid addition salts with the following: mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, and ethanesulfonic acid; acidic amino acids such as aspartic acid and glutamic acid.
  • mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid
  • organic acids such as formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric
  • composition refers to a mixture of a compound described herein with other chemical components, such as an excipient.
  • the pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of administering a compound exist in the art including, but not limited to: intravenous, oral, aerosol, parenteral, ophthalmic, pulmonary and topical administration.
  • Subject refers to an animal, including, but not limited to, a primate (e.g ., human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.
  • a primate e.g ., human
  • monkey cow, pig, sheep, goat
  • horse dog, cat, rabbit, rat
  • patient is used interchangeably herein in reference, for example, to a mammalian subject, such as a human.
  • the subject is a mammal.
  • the subject is a human.
  • the subject is an adult human.
  • the subject is a human child.
  • Treat,”“treating,” and“treatment,” in the context of treating a disease or disorder are meant to include alleviating a disorder, disease, or condition, or one or more of the symptoms associated with the disorder, disease, or condition; or to slowing the progression, spread or worsening of a disease, disorder or condition or of one or more symptoms thereof.
  • the beneficial effects that a subject derives from a therapeutic agent do not result in a complete cure of the disease, disorder or condition.
  • the CGT inhibitors described in the instant application, and methods of using the same may selectively decrease the formation of GalCer(s) and non- hydroxylated sulfatide(s), which could be used to treat lysosomal storage diseases, such as Krabbe Disease and/or MLD, as well as neurodegenerative disorders like Parkinson’s disease, other demyelinating leukodystrophies, autoimmune diseases including multiple sclerosis, and certain cancers that are known to overexpress the CGT enzyme.
  • lysosomal storage diseases such as Krabbe Disease and/or MLD
  • neurodegenerative disorders like Parkinson’s disease other demyelinating leukodystrophies
  • autoimmune diseases including multiple sclerosis
  • certain cancers that are known to overexpress the CGT enzyme.
  • the relative levels of ceramides, hydroxylated ceramides, GalCer(s), hydroxylated GalCer(s), suflatide(s), hydroxylated sulfatide(s), psychosine, and/or lyso-sulfatide, in a subject or biological sample may be utilized as biomarkers or tools for predicting clinical dosing and predicting clinical efficacy for methods utilizing the CGT inhibitors disclosed herein, such as methods of treating a disease or disorder mediated by CGT in a subject.
  • the biochemical pathway for the formation of GalCer(s) and sulfatide(s) and their role in myelin formation and in Krabbe disease and MLD is illustrated in Figure 1.
  • the enzyme CGT catalyzes the addition of galactose to both ceramide and hydroxylated ceramide compounds to generate the glycosphingolipids GalCer(s) and hydroxylated GalCer(s).
  • the enzyme CST can further sulfonate these GalCer(s) and hydroxylated GalCer(s) to generate sulfatide(s) and hydroxylated sulfatide(s), respectively.
  • GalCer(s), sulfatide(s), and hydroxylated sulfatdie(s), are major myelin lipids and they are required for the formation of stable healthy myelin. The hydroxylated forms of these glycolipids have been argued to be the more important compounds for producing stable, healthy myelin.
  • the lysosomal enzymes GalC and ARSA are the lysosomal enzymes that are responsible for the degradation of the GalCer(s) and sulfatide(s) respectively. Deficiencies in GalC and ARSA are the underlying cause of the lysosomal storage diseases Krabbe disease and MLD.
  • GalCer(s) or sulfatide(s) accumulate in the lysosome where they can be deacylated by the lysosomal enzyme acid ceramidase to produce the compounds psychosine and lyso-sulfatide. It is thought that these deacylated derivatives, psychosine and lyso-sulfatide, are the major toxic molecule that contribute to disease progression.
  • treating mice with the CGT inhibitors disclosed herein can be selectively decreased without decreasing the levels of the hydroxylated forms of these compounds.
  • the hydroxylated forms of these glycolipids increase as the formation of non-hydroxylated glycolipids decrease.
  • the decrease in the levels of non-hydroxylated glycolipids, and not the hydroxylated forms correlates with a decrease of the levels of the toxic compounds psychosine and lyso-sulfatide.
  • the method of inhibiting CGT in a subject comprises: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii)(a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; and (iii)(b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxyl
  • the method of inhibiting CGT in a subject comprises: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) inhibits conversion of ceramide(s) to GalCer(s) in the subject such that the GalCer(s) level in the subject is less than the GalCer(s) level in the absence of said administration; (ii) increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject such that the hydroxylated GalCer(s) level in the subject is greater than the hydroxylated GalCer(s) level in the absence of said administration; (iii) inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject such that: (a) the GalCer(s) level in the subject is less than the GalCer(s) level in the
  • a method of inhibiting conversion of ceramide(s) to GalCer(s) in a subject by administering to the subject a therapeutically effective amount of a CGT inhibitor.
  • the method of inhibiting conversion of ceramide(s) to GalCer(s) in a subject comprises: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) inhibits CGT and decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) inhibits CGT and increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii) inhibits CGT and: (a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration, and (b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s)
  • the method of increasing conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in a subject comprises:
  • a CGT inhibitor administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) inhibits CGT and decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) inhibits CGT and increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii) inhibits CGT and: (a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration, and (b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; or (iv) inhibits CGT and inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to
  • GalCer(s) levels in a subject by administering to the subject a therapeutically effective amount of a CGT inhibitor.
  • the method of reducing GalCer(s) levels in a subject comprises: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) inhibits CGT and decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) inhibits CGT and increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii) inhibits CGT and: (a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration, and (b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; or (iv) inhibits CGT and inhibits conversion of
  • a method of increasing hydroxylated GalCer(s) levels in a subject by administering to the subject a therapeutically effective amount of a CGT inhibitor.
  • the method of increasing hydroxylated GalCer(s) levels in a subject comprises: administering to the subject a
  • a CGT inhibitor comprising: (i) inhibits CGT and decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) inhibits CGT and increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii) inhibits CGT and: (a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration, and (b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; or (iv) inhibits CGT and inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject
  • a method of treating a disease or disorder mediated by CGT in a subject by administering to the subject a therapeutically effective amount of a CGT inhibitor.
  • the method of treating a disease or disorder mediated by CGT in a subject comprises: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii)(a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; and (iii)(b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; or (iv) increases the level of hydroxylated GalCer(s) and decreases the
  • the method of treating a disease or disorder mediated by CGT in a subject comprises: a) identifying a CGT inhibitor that: i) inhibits conversion of ceramide(s) to GalCer(s); ii) increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s); or iii) inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s); and b) administering to the subject a therapeutically effective amount of the identified CGT inhibitor.
  • the method of treating a disease or disorder mediated by CGT in a subject comprises: a) identifying a CGT inhibitor that: i) decreases GalCer(s) levels in a subject; ii) increases hydroxylated GalCer(s) levels in a subject; or iii) decreases GalCer(s) levels and increases hydroxylated GalCer(s) levels in a subject; and b) administering to the subject a therapeutically effective amount of the identified CGT inhibitor.
  • the identified therapeutically effective dose of the CGT inhibitor is in the range of between 0.05-1000 mg/kg, such as in the range of between 0.05-10 mg/kg, between 1.0-10 mg/kg, between 5.0-50 mg/kg, between 25-150 mg/kg, between 100-450 mg/kg, between 250-500 mg/kg, between 400-750 mg/kg, or between 700-1000 mg/kg.
  • the identified CGT inhibitor is in the range of between 0.05-1000 mg/kg, such as in the range of between 0.05-10 mg/kg, between 1.0-10 mg/kg, between 5.0-50 mg/kg, between 25-150 mg/kg, between 100-450 mg/kg, between 250-500 mg/kg, between 400-750 mg/kg, or between 700-1000 mg/kg.
  • the identified therapeutically effective dose of the CGT inhibitor is in the range of between 0.05-1000 mg/kg, such as in the range of between 0.05-10 mg/kg, between 1.0-10 mg/kg, between 5.0-50 mg/kg, between 25-150 mg/kg, between
  • therapeutically effective dose of the CGT inhibitor is 0.05 mg/kg, such as at least 0.10 mg/kg, at least 0.15 mg/kg, at least 0.20 mg/kg, at least 0.25 mg/kg, at least 0.30 mg/kg, at least 0.40 mg/kg, at least 0.50 mg/kg, at least 1.0 mg/kg, at least 2.0 mg/kg, at least 3.0 mg/kg, at least 4.0 mg/kg, at least 5.0 mg/kg, at least 10 mg/kg, at least 15 mg/kg, at least 20 mg/kg, at least 25 mg/kg, at least 30 mg/kg, at least 40 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, at least 200 mg/kg, at least 250 mg/kg at least 300 mg/kg, at least 350 mg/kg, at least 400 mg/kg, at least 450 mg/kg, at least 500 mg/kg, at least 600 mg/kg, at least 700 mg/kg,
  • the identified therapeutically effective dose of the CGT inhibitor is a daily dose in the range of between 5-500 mg, such as a daily dose of at least 5 mg, at least 10 mg, at least 15 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, or at least 450 mg.
  • the method of treating a disease or disorder mediated by CGT in a subject comprises: a) identifying a subject with cells or tissue having GalCer(s) levels equal to or greater than hydroxylated GalCer(s) levels; and b) administering to the subject a therapeutically effective amount of a CGT inhibitor.
  • the method of treating a disease or disorder mediated by CGT in a subject comprises: a) identifying a therapeutically effective dose of a CGT inhibitor that: i) decreases GalCer(s) levels in a subject; ii) increases hydroxylated GalCer(s) levels in a subject; or iii) decreases GalCer(s) levels and increases hydroxylated GalCer(s) levels in a subject; and b) administering to the subject the therapeutically effective dose of the CGT inhibitor.
  • the method of treating a disease or disorder mediated by CGT in a subject comprises: a) obtaining a biological sample from a subject having or diagnosed as having the disease or disorder mediated by CGT; b) determining levels of GalCer(s) and/or hydroxylated GalCer(s) in the biological sample, wherein i) if the GalCer(s) level following administration is not decreased by at least 10% relative to the GalCer(s) level in the subject in the absence of or prior to the administration; ii) if the hydroxylated GalCer(s) level following administration is not increased by at least 10% relative to the hydroxylated GalCer(s) level in the subject in the absence of or prior to the administration; iii) if the GalCer(s) level following administration is not decreased by at least 10% and the hydroxylated GalCer(s) level following administration is not increased by at least 10% relative to the respective GalCer(s) level and hydroxy
  • the method further comprises administering a therapeutically effective amount of a CGT inhibitor to treat the disease or disorder.
  • the method further comprises administering a therapeutically effective amount of a CGT inhibitor to treat the disease or disorder.
  • the GalCer(s) level following administration is not increased in the range of between 10-20%, between 15-30%, between 25-40%, between 35-50%, between 40-60%, between 50-75%, or between 70-90%, relative to the hydroxylated GalCer(s) level in the subject in the absence of or prior to the administration, then the method further comprises administering a therapeutically effective amount of a CGT inhibitor to treat the disease or disorder.
  • the GalCer(s) level following administration is not increased in the range of between 10-20%, between 15-30%, between 25-40%, between 35-50%, between 40-60%, between 50-75%, or between 70-90%, relative to the hydroxylated GalCer(s) level in the subject in the absence of or prior to the administration.
  • the method further comprises administering a therapeutically effective amount of a CGT inhibitor to treat the disease or disorder.
  • a CGT inhibitor to treat the disease or disorder.
  • GalCer(s) level relative to the hydroxylated GalCer(s) level in the biological sample is in the range of between 1 : 1 to 4: 1, between 5: 1 to 8: 1, between 7: 1 to 10: 1, between 9: 1 to 15: 1, between 10: 1 to 20: 1, between 15: 1 to 25: 1, or between 20: 1 to 50: 1, then the method further comprises administering a therapeutically effective amount of a CGT inhibitor to treat the disease or disorder.
  • the method further comprises administering a therapeutically effective amount of a CGT inhibitor to treat the disease or disorder.
  • a method for monitoring efficacy of treatment of a subject having or diagnosed as having a disease or disorder mediated by CGT comprising administering to the subject a therapeutically effective amount of a CGT inhibitor.
  • the method for monitoring efficacy of treatment of a subject having or diagnosed as having a disease or disorder mediated by CGT comprises: a) administering a first dosage amount of a CGT inhibitor to the subject; b) obtaining a biological sample from the subject following administration of the CGT inhibitor; c) determining levels of GalCer(s) and/or hydroxylated GalCer(s) in the biological sample, wherein i) if the GalCer(s) level following administration is not decreased by at least 10% relative to the GalCer(s) level in the subject in the absence of or prior to the administration; ii) if the hydroxylated GalCer(s) level following administration is not increased by at least 10% relative to the hydroxylated GalCer(s) level in the subject in the absence of or prior to the administration; iii) if the GalCer(s) level following administration is not decreased by at least 10% and the hydroxylated GalCer(s) level following
  • the first dose amount of the CGT inhibitor is in the range of between 0.05-5.0 mg/kg, between 0.02-20 mg/kg, between 0.2-100 mg/kg, or between 0.1-50 mg/kg. In certain embodiments, the first dose amount of the CGT inhibitor is in the range of between 5-50 mg, between 10-100 mg or between 50-250 mg.
  • the adjusted dosage amount is a reduced amount relative to the first dosage amount administered to the subject.
  • the adjusted dosage amount is a reduced amount that is between the range of about 1-5% reduced, about 5-10%, about 10-15% reduced, about 15-20% reduced, about 20- 25% reduced, about 25-30% reduced, about 30-35% reduced, about 35-40% reduced, about 40-45% reduced, about 45-50% reduced, about 50-60% reduced, about 60-70% reduced, about 70-80% reduced, about 80-90% reduced, or about 90-100% reduced, about 100-125% reduced, about 125-150% reduced, about 150-200% reduced, relative to the first dosage amount administered to the subject.
  • the adjusted dosage amount is a reduced amount that is at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 100%, at least about 150%, or at least about 200%, reduced relative to the first dosage amount administered to the subject.
  • the adjusted dosage amount is an increased amount relative to the first dosage amount administered to the subject.
  • the adjusted dosage amount is an increased amount that is between the range of about 1-5% increased, about 5-10%, about 10-15% increased, about 15-20% increased, about 20-25% increased, about 25-30% increased, about 30-35% increased, about 35-40% increased, about 40-45% increased, about 45-50% increased, about 50-60% increased, about 60-70% increased, about 70-80% increased, about 80-90% increased, about 90-100% increased, about 100-125% increased, about 125-150% increased, about 150-200% increased, relative to the first dosage amount administered to the subject.
  • the adjusted dosage amount is an increased amount that is at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 100%, at least about 150%, or at least about 200%, increased relative to the first dosage amount administered to the subject.
  • hydroxylated GalCer(s) relative to the level of GalCer(s) in the subject that is at least about 2: 1, at least about 3: 1, at least about 4: 1, at least about 5: 1, at least about 6: 1, at least about 7: 1, at least about 8: 1, or at least about 9: 1, is indicative of the efficacy of the adjusted dosage in treating the disease or disorder mediated by CGT.
  • a ratio of the level of hydroxylated GalCer(s) relative to the level of GalCer(s) in the subject that is at least greater than 1 : 1 is indicative of the efficacy of the adjusted dosage in treating the disease or disorder mediated by CGT.
  • a method of assessing the efficacy of a CGT inhibitor in treating a disease or disorder mediated by CGT comprising administering to the subject a therapeutically effective amount of a CGT inhibitor.
  • the method of assessing the efficacy of a CGT inhibitor in treating a disease or disorder mediated by CGT comprises: a) administering the CGT inhibitor to a subject having or diagnosed as having the disease or disorder mediated by CGT; b) obtaining a biological sample from the subject after administering the CGT inhibitor; c) determining levels of GalCer(s) and/or hydroxylated GalCer(s) in the biological sample; d) comparing the levels of GalCer(s) and/or hydroxylated GalCer(s) in the biological sample from step (c) to the levels of GalCer(s) and/or
  • the reference biological sample is a biological sample from the subject prior to administration of the CGT inhibitor. In certain embodiments, the reference biological sample is a biological sample from the subject in the absence of administration of the CGT inhibitor.
  • a decrease in the level of GalCer(s) in the subject by at least about 10%, at least about 15%, at least about 20%, at least about 25%, at least about 30%, at least about 35%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 75%, at least about 80%, at least about 90%, at least about 95%, at least about 100%, at least about 120%, or at least about 140%, is indicative of the efficacy of the CGT inhibitor in treating the disease or disorder mediated by CGT.
  • a ratio of the level of hydroxylated GalCer(s) relative to the level of GalCer(s) in the subject that is at least about 2 : 1 , at least about 3 : 1 , at least about 4 : 1 , at least about 5 : 1 , at least about 6 : 1 , at least about 7: 1, at least about 8: 1, or at least about 9: 1, is indicative of the efficacy of the CGT inhibitor in treating the disease or disorder mediated by CGT.
  • a ratio of the level of hydroxylated GalCer(s) relative to the level of GalCer(s) in the subject that is at least greater than 1 : 1, is indicative of the efficacy of the CGT inhibitor in treating the disease or disorder mediated by CGT.
  • the method of inhibiting the activity of CGT in a cell or tissue comprises: contacting the cell or tissue with an effective amount of a CGT inhibitor; wherein the contacting: (i) decreases the level of GalCer(s) in the cell or tissue relative to the GalCer(s) level in the cell or tissue in the absence of said contacting; (ii) increases the level of hydroxylated GalCer(s) in the cell or tissue relative to the hydroxylated GalCer(s) level in the cell or tissue in the absence of said contacting; (iii)(a) decreases the level of GalCer(s) in the cell or tissue relative to the GalCer(s) level in the cell or tissue in the absence of said contacting, and (b) increases the level of hydroxyl
  • the method of inhibiting the activity of CGT in a cell or tissue comprises: contacting the cell or tissue with an effective amount of a CGT inhibitor; wherein the contacting: (i) inhibits conversion of ceramide(s) to GalCer(s) in the cell or tissue such that the GalCer(s) level in the cell or tissue is less than the GalCer(s) level in the absence of said contacting; (ii) increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the cell or tissue such that the hydroxylated GalCer(s) level in the cell or tissue is greater than the hydroxylated GalCer(s) level in the absence of said contacting; (iii) inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the cell or tissue such that: (a) the GalCer(s)
  • said administration decreases the level of GalCer(s) in the subject in the range of between 5%- 150% relative to the GalCer(s) level in said subject in the absence of said administration. In certain embodiments, said administration decreases the level of GalCer(s) in the subject without decreasing or without significantly decreasing (such without reducing by 5%) the level of hydroxylated GalCer(s) in the subject. In certain embodiments, said administration decreases the level of GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in said subject in the absence of said administration.
  • said administration increases the level of hydroxylated GalCer(s) in the subject in the range of between 5%-l50% relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration. In certain embodiments, said administration increases the level of hydroxylated GalCer(s) in the subject while maintaining the level of GalCer(s) in the subject. In certain embodiments, said administration increases the level of hydroxylated GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration.
  • said administration decreases the GalCer(s) level in the subject such that the hydroxylated GalCer(s) level is greater than the GalCer(s) level in said subject. In certain embodiments, said administration increases the hydroxylated GalCer(s) level in the subject such that the hydroxylated GalCer(s) level is greater than the GalCer(s) level in said subject. In certain embodiments, said administration decreases the GalCer(s) level and increases the
  • hydroxylated GalCer(s) level in the subject such that the hydroxylated GalCer(s) level is greater than the GalCer(s) level in said subject.
  • said administration decreases GalCer(s) levels in the subject such that the ratio of the
  • hydroxylated GalCer(s) level to the GalCer(s) level in said subject is greater than 1 : 1, at least about 2 : 1 , at least about 3 : 1 , at least about 4 : 1 , at least about 5 : 1 , at least about 6 : 1 , at least about 7: 1, at least about 8: 1, at least about 9: 1, at least about 10: 1, at least about 15: 1, at least about 20: 1, at least about 25: 1, at least about 50: 1, at least about 75: 1, at least about 80: 1, at least about 85: 1, at least about 90: 1, at least about 95: 1, at least about 98:1, at least about 100: 1, at least about 125: 1, at least about 150: 1, or at least about 175: 1.
  • 1 hydroxylated GalCer(s) level to the GalCer(s) level in said subject is greater than 1 : 1, at least about 2 : 1 , at least about 3 : 1 , at least about 4 : 1 , at least about 5 : 1
  • said administration increases hydroxylated GalCer(s) levels in the subject such that the ratio of the hydroxylated GalCer(s) level to the GalCer(s) level in said subject is greater than 1 : 1, at least about 2: 1, at least about 3 : 1 , at least about 4 : 1 , at least about 5 : 1 , at least about 6 : 1 , at least about 7 : 1 , at least about 8: 1, at least about 9: 1, at least about 10: 1, at least about 15:1, at least about 20: 1, at least about 25: 1, at least about 50: 1, at least about 75: 1, at least about 80: 1, at least about 85: 1, at least about 90: 1, at least about 95: 1, at least about 98: 1, at least about 100:1, at least about 125: 1, at least about 150: 1, or at least about 175: 1.
  • said administration decreases GalCer(s) levels and increases hydroxylated GalCer(s) levels in the subject such that the ratio of the hydroxylated GalCer(s) level to the GalCer(s) level in said subject is greater than 1 : 1, at least about 2: 1, at least about 3 : 1 , at least about 4 : 1 , at least about 5 : 1 , at least about 6 : 1 , at least about 7 : 1 , at least about 8: 1, at least about 9: 1, at least about 10: 1, at least about 15:1, at least about 20: 1, at least about 25: 1, at least about 50: 1, at least about 75: 1, at least about 80: 1, at least about 85: 1, at least about 90: 1, at least about 95: 1, at least about 98: 1, at least about 100:1, at least about 125: 1, at least about 150: 1, or at least about 175: 1.
  • said administration inhibits conversion of ceramide(s) to GalCer(s) in the subject such that the GalCer(s) level in the subject is less than the GalCer(s) level in the absence of said administration. In certain embodiments, said administration inhibits conversion of ceramide(s) to GalCer(s) in the subject such that the GalCer(s) level in the subject is less than the hydroxylated GalCer(s) level in the absence of said administration. In certain
  • said administration increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject such that the hydroxylated GalCer(s) level is greater than the GalCer(s) level in said subject.
  • said administration increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject such that the hydroxylated GalCer(s) level in the subject is greater than the hydroxylated GalCer(s) level in the absence of said administration.
  • said administration inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) such that the hydroxylated GalCer(s) level is greater than the GalCer(s) level in said subject.
  • said administration inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject such that: i) the GalCer(s) level in the subject is less than the GalCer(s) level in the absence of said administration; and ii) the hydroxylated GalCer(s) level in the subject is greater than the hydroxylated GalCer(s) level in the absence of said administration.
  • said administration inhibits conversion of ceramide(s) to GalCer(s) in the subject such that the ratio of the hydroxylated GalCer(s) level to the GalCer(s) level in said subject is greater than 1 : 1 , at least about 2 : 1 , at least about 3 : 1 , at least about 4 : 1 , at least about 5 : 1 , at least about 6: 1, at least about 7: 1, at least about 8: 1, at least about 9: 1, at least about 10: 1, at least about 15: 1, at least about 20: 1, at least about 25:1, at least about 50: 1, at least about 75: 1, at least about 80: 1, at least about 85: 1, at least about 90: 1, at least about 95: 1, at least about 98: 1, at least about 100: 1, at least about 125: 1, at least about 150: 1, or at least about 175: 1.
  • said administration increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject such that the ratio of the hydroxylated GalCer(s) level to the GalCer(s) level in said subject is greater than 1 : 1, at least about 2: 1, at least about 3 : 1 , at least about 4 : 1 , at least about 5 : 1 , at least about 6 : 1 , at least about 7 : 1 , at least about 8: 1, at least about 9: 1, at least about 10: 1, at least about 15: 1, at least about 20: 1, at least about 25:1, at least about 50: 1, at least about 75: 1, at least about 80: 1, at least about 85: 1, at least about 90: 1, at least about 95:1, at least about 98: 1, at least about 100: 1, at least about 125: 1, at least about 150: 1, or at least about 175:1.
  • the ratio of the hydroxylated GalCer(s) level to the GalCer(s) level in said subject is greater than
  • said administration inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject such that the ratio of the hydroxylated GalCer(s) level to the GalCer(s) level in said subject is greater than 1 : 1 , at least about 2 : 1 , at least about 3 : 1 , at least about 4 : 1 , at least about 5 : 1 , at least about 6: 1, at least about 7: 1, at least about 8: 1, at least about 9:1, at least about 10: 1, at least about 15: 1, at least about 20: 1, at least about 25: 1, at least about 50:1, at least about 75: 1, at least about 80: 1, at least about 85:1, at least about 90: 1, at least about 95: 1, at least about 98: 1, at least about 100: 1, at least about 125: 1, at least about 150: 1, or at least about 175: 1.
  • the level of GalCer(s) in the subject is decreased by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 110%, at least about 120%, at least about 130%, or at least about 140%, relative to the level of GalCer(s) in the subject in the absence of said administration.
  • the level of GalCer(s) in the subject is decreased by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 110%, at least about 120%, at least about 130%, or at least about 140%, relative to the level of hydroxylated GalCer(s) in the subject in the absence of said administration.
  • the level of hydroxylated GalCer(s) in the subject is increased by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 110%, at least about 120%, at least about 130%, or at least about 140%, relative to the level of hydroxylated GalCer(s) in the subject in the absence of said administration.
  • the level of hydroxylated GalCer(s) in the subject is increased by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 110%, at least about 120%, at least about 130%, or at least about 140%, relative to the level of GalCer(s) in the subject in the absence of said administration.
  • the ratio of the level of hydroxylated GalCer(s) relative to the level of GalCer(s) in the subject following administration is greater than 1 : 1, at least about 2: 1, at least about 3 : 1, at least about 4: 1, at least about 5: 1, at least about 6: 1, at least about 7: 1, at least about 8: 1, at least about 9: 1, at least about 10: 1, at least about 15: 1, at least about 20: 1, at least about 25: 1, at least about 50: 1, at least about 75: 1, at least about 80: 1, at least about 85:1, at least about 90: 1, at least about 95: 1, at least about 98:1, at least about 100: 1, at least about 125: 1, at least about 150: 1, or at least about 175: 1.
  • the level of GalCer(s) or hydroxylated GalCer(s) following the administration or in the absence of the administration is a cellular level of GalCer(s) or hydroxylated GalCer(s), respectively.
  • the level of GalCer(s) or hydroxylated GalCer(s) following the administration or in the absence of the administration is a level of GalCer(s) or hydroxylated GalCer(s) in a biological sample obtained from the subject, respectively.
  • a biological sample is a cell sample, a tissue sample, a saliva sample, a blood sample, a plasma sample, a nerve biopsy sample, a skin biopsy sample, or a CNS fluid sample.
  • the levels of GalCer(s), hydroxylated GalCer(s), or GalCer(s) and hydroxylated GalCer(s), in the subject are measured using RapidFire/MS/MS. In certain embodiments, according to the methods disclosed herein, the levels of GalCer(s), hydroxylated GalCer(s), or GalCer(s) and hydroxylated GalCer(s), in the subject are measured using LC-MS/MS.
  • the subject has or has been diagnosed as having a disease or disorder mediated by CGT.
  • the disease or disorder mediated by CGT is a lysosomal storage disease, such as Krabbe disease or MLD.
  • the disease or disorder mediated by CGT is a neurodegenerative disorder, such as Parkinson’s disease.
  • the disease or disorder mediated by CGT is a demyelinating leukodystrophy.
  • the disease or disorder mediated by CGT is an autoimmune disease, such as MS.
  • said administration decreases levels of one or more metabolites in the cell or tissue of the subject relative to the level of the one or more metabolites in the subject in the absence of said administration; wherein the one or more metabolites are selected from the group consisting of psychosine, lyso-sulfatide, and sulfatide(s).
  • said administration decreases levels of one or more metabolites in the cell or tissue of the subject in the range of between 5%-l50% relative to the level of the one or more metabolites in the subject in the absence of said administration.
  • said administration decreases levels of one or more metabolites in the cell or tissue of the subject without decreasing or without significantly decreasing levels of metabolite hydroxylated sulfatide(s) in the cell or tissue of the subject.
  • said administration decreases levels of one or more metabolites in the cell or tissue of the subject relative to the level of metabolite hydroxylated sulfatide(s) in the cell or tissue of the subject in the absence of said administration.
  • said administration increases levels of metabolite hydroxylated sulfatide(s) in the cell or tissue of the subject relative to the level of the metabolite hydroxylated sulfatide(s) in the subject in the absence of said administration.
  • said administration increases levels of metabolite hydroxylated sulfatide(s) in the cell or tissue of the subject in the range of between 5%-l50% relative to the level of the metabolite hydroxylated sulfatide(s) in the subject in the absence of said administration.
  • said administration increases levels of metabolite hydroxylated sulfatide(s) in the cell or tissue of the subject while maintaining the level of one or more metabolites in the subject.
  • said administration increases levels of metabolite hydroxylated sulfatide(s) in the cell or tissue of the subject relative to the level of one or more metabolites in the subject in the absence of said administration.
  • the one or more metabolites is psychosine.
  • the one or more metabolites is lyso-sulfatide.
  • the one or more metabolites is sulfatide(s).
  • said administration i) decreases levels of one or more metabolites in the cell or tissue of the subject relative to the level of the one or more metabolites in the subject in the absence of said administration; and ii) increases levels of metabolite hydroxylated sulfatide(s) in the cell or tissue of the subject relative to the level of the metabolite hydroxylated sulfatide(s) in the subject in the absence of said administration; wherein the one or more metabolites are selected from the group consisting of psychosine, lyso-sulfatide, and sulfatide(s).
  • said administration decreases the metabolite sulfatide(s) level in the subject such that the metabolite hydroxylated sulfatide(s) is greater than the metabolite sulfatide(s) level in said subject.
  • said administration increases the metabolite hydroxylated sulfatide(s) level in the subject such that the metabolite hydroxylated sulfatide(s) level is greater than the metabolite sulfatide(s) level in said subject.
  • said administration decreases the metabolite sulfatide(s) level and increases the metabolite hydroxylated sulfatide(s) level in the subject such that the metabolite hydroxylated sulfatide(s) level is greater than the metabolite sulfatide(s) level in said subject.
  • the one or more metabolites is psychosine.
  • the one or more metabolites is lyso- sulfatide.
  • the one or more metabolites is sulfatide(s).
  • said administration increases the level of metabolite hydroxylated sulfatide(s) and decreases the level of one or more metabolites in the cell or tissue of the subject such that the ratio of the metabolite hydroxylated sulfatide(s) level to the one or more metabolites level in said subject is in the range of between 200: 1 to 1 : 1; wherein the one or more metabolites are selected from the group consisting of psychosine, lyso-sulfatide, and sulfatide(s).
  • said administration decreases metabolite sulfatide(s) levels in the subject such that the ratio of the metabolite hydroxylated sulfatide(s) level to the metabolite sulfatide(s) level in said subject is greater than 1 : 1, at least about 2: 1, at least about 3 : 1, at least about 4: 1, at least about 5: 1, at least about 6: 1, at least about 7: 1, at least about 8: 1, at least about 9: 1, at least about 10: 1, at least about 15: 1, at least about 20: 1, at least about 25: 1, at least about 50:1, at least about 75: 1, at least about 80: 1, at least about 85: 1, at least about 90: 1, at least about 95: 1, at least about 98:1, at least about 100: 1, at least about 125: 1, at least about 150: 1, or at least about 175: 1.
  • said ratio of the metabolite hydroxylated sulfatide(s) level to the metabolite sulfatide(s) level in said subject is greater
  • administration increases metabolite hydroxylated sulfatide(s) levels in the subject such that the ratio of the metabolite hydroxylated sulfatide(s) level to the metabolite sulfatide(s) level in said subject is greater than 1 : 1, at least about 2: 1, at least about 3 : 1, at least about 4: 1, at least about 5: 1, at least about 6: 1, at least about 7: 1, at least about 8: 1, at least about 9: 1, at least about 10: 1, at least about 15: 1, at least about 20: 1, at least about 25:1, at least about 50: 1, at least about 75: 1, at least about 80:1, at least about 85: 1, at least about 90: 1, at least about 95: 1, at least about 98: 1, at least about 100: 1, at least about 125: 1, at least about 150: 1, or at least about 175: 1.
  • said administration decreases metabolite sulfatide(s) levels and increases metabolite hydroxylated sulfatide(s) levels in the subject such that the ratio of the metabolite hydroxylated sulfatide(s) level to the metabolite sulfatide(s) level in said subject is greater than 1 : 1, at least about 2: 1, at least about 3 : 1, at least about 4: 1, at least about 5: 1, at least about 6: 1, at least about 7: 1, at least about 8: 1, at least about 9: 1, at least about 10: 1, at least about 15: 1, at least about 20: 1, at least about 25: 1, at least about 50:1, at least about 75: 1, at least about 80: 1, at least about 85: 1, at least about 90: 1, at least about 95: 1, at least about 98:1, at least about 100: 1, at least about 125: 1, at least about 150: 1, or at least about 175: 1.
  • the one or more metabolites is psychosine.
  • the level of one or more of the metabolites in the cell or tissue of the subject are decreased by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 110%, at least about 120%, at least about 130%, or at least about 140%, relative to the level of the one or more metabolites in the cell or tissue of the subject in the absence of said administration; wherein the one or more metabolites are selected from the group consisting of psychosine, lyso-sulfatide, and sulfatide(s).
  • the level of metabolite hydroxylated sulfatide(s) in the cell or tissue of the subject are increased by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 110%, at least about 120%, at least about 130%, or at least about 140%, relative to the level of the metabolite hydroxylated sulfatide(s) in the cell or tissue of the subject in the absence of said administration.
  • the one or more metabolites is psychosine.
  • the one or more metabolites is lyso-sulfatide.
  • the one or more metabolites is sulfatide(s).
  • the levels of the one or more metabolites in the cell or tissue in the subject are measured using
  • the levels of the one or more metabolites in the cell or tissue in the subject are measured using LC-MS/MS. In certain embodiments, the levels of the metabolite hydroxylated sulfatide(s) in the cell or tissue in the subject are measured using RapidFire/MS/MS. In certain embodiments, the levels of the metabolite hydroxylated sulfatide(s) in the cell or tissue in the subject are measured using LC-MS/MS.
  • the CGT inhibitor is a compound of Formula I, la, lb, II, or III, or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the CGT inhibitor is a compound of Formula I, la, lb, or II, wherein the compound is selected from Table 1 consisting of
  • the CGT inhibitor is a compound selected from Table 1.
  • the CGT inhibitor is a compound of Formula III, wherein the compound is selected from Table 2 consisting of Examples 1-57, or a single stereoisomer or mixture of stereoisomers thereof.
  • the CGT inhibitor is a compound selected from Table 2.
  • the CGT inhibitor is a compound of Formula X, Xa, or Xb, or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the CGT inhibitor is a compound of Formula X, Xa, or Xb, wherein the compound is selected from Table 3 consisting of
  • the CGT inhibitor is a compound selected from Table 3.
  • the CGT inhibitor is a compound of Formula XX, XXa, XXb, XXc, XXd, XXe, XXf, XXI, XXIa, or XXIb, or optionally a single stereoisomer or mixture of stereoisomers thereof and
  • the CGT inhibitor is a compound of Formula XX, XXa, XXb, XXc, XXd, XXe, XXf, XXI, XXIa, or XXIb, wherein the compound is selected from Table 4 consisting of Examples 1-121.
  • the CGT inhibitor is a compound selected from Table 4.
  • the following paragraphs present a number of embodiments disclosing compounds and the uses thereof according to the methods disclosed herein.
  • the embodiment includes both the recited compound(s) as well as a single stereoisomer or mixture of stereoisomers thereof, as well as a pharmaceutically acceptable salt thereof, that may be useful according to the methods disclosed herein.
  • X is O or S
  • R 1 is aryl optionally substituted with 1 or 2 groups selected from halo, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyloxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
  • R 2 is aryl optionally substituted with 1 or 2 groups selected from halo, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyloxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
  • R 3 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxycarbonyl, heterocycloalkyl, aryl, or heteroaryl; wherein the heterocycloalkyl, aryl, and heteroaryl are each optionally substituted with 1 or 2 groups selected from halo, cyano, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkyl,
  • heterocycloalkyl and phenyl optionally substituted with one group selected from halo, alkyl, and haloalkyl;
  • R 4 is hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, phenyl, or thienyl; wherein the alkyl is optionally substituted with 1 or 2 groups selected from cyano, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, and heterocycloalkyl; and wherein the cycloalkyl, heterocycloalkyl, phenyl, and thienyl groups are each optionally substituted with 1 or 2 groups selected from halo, cyano, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, and dialkylaminocarbonyl; and
  • R 5 is hydrogen, alkyl, alkoxy, or cycloalkyl
  • spirocycloalkyl or spiroheterocycloalkyl; wherein the spirocycloalkyl and spiroheterocycloalkyl groups are each optionally substituted with 1 or 2 groups selected from halo, cyano, hydroxy, C1-3 alkyl, alkoxy, amino, alkylamino, and dialkylamino;
  • the compound of Formula I is not:
  • the compound of Formula I is that wherein when R 1 and R 2 are both unsubstituted phenyl and R 4 and R 5 and the carbon to which they are attached combine to form carbonyl, then R 3 is not methyl, ethyl, tert-butyl, trifluoromethyl, pentafluoroethyl, unsubstituted phenyl, unsubstituted naphthyl, or unsubstituted anthracenyl;
  • the compound of Formula I is that wherein:
  • X is O or S
  • R 1 is aryl optionally substituted with 1 or 2 groups selected from halo, cyano, alkyl, haloalkyl, alkoxy, cycloalkyloxy, amino, alkylamino, and dialkylamino
  • R 2 is aryl optionally substituted with 1 or 2 groups selected from halo, cyano, alkyl, haloalkyl, alkoxy, cycloalkyloxy, amino, alkylamino, and dialkylamino;
  • R 3 is hydrogen, alkyl, haloalkyl, hydroxyalkyl, alkoxycarbonyl, heterocycloalkyl, aryl, or heteroaryl; wherein the heterocycloalkyl, aryl, and heteroaryl are each optionally substituted with 1 or 2 groups selected from halo, cyano, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyloxy,
  • cycloalkyl alkoxy, dialkylamino, alkyl carbonyl, cycloalkyl, heterocycloalkyl, and phenyl optionally substituted with one group selected from halo;
  • R 4 is hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, phenyl, or thienyl; wherein the alkyl is optionally substituted with 1 or 2 groups selected from alkoxy, amino, alkylamino, dialkylamino; and
  • R 5 is hydrogen, alkyl, or cycloalkyl
  • the compound or salt of Formula I is that wherein: X is O; R 1 and R 2 are each independently phenyl optionally substituted with halo, cyano, alkyl, alkoxy, or haloalkoxy; R 3 is alkyl, phenyl, or heteroaryl, wherein the phenyl is optionally substituted with halo, cyano, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkylcarbonyl, or cycloalkyl; R 4 is hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, phenyl, or thienyl; R 5 is hydrogen or alkyl; or R 4 and R 5 and the carbon to which they are attached combine to form spirocycloalkyl.
  • the compound or salt of Formula I is that wherein: X is O; R 1 and R 2 are each independently phenyl optionally substituted with halo, cyano, alkyl, alkoxy, or haloalkoxy; R 3 is phenyl optionally substituted with halo, cyano, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkylcarbonyl, or cycloalkyl; R 4 is hydrogen, alkyl, or phenyl; R 5 is hydrogen or alkyl; or R 4 and R 5 and the carbon to which they are attached combine to form spirocycloalkyl.
  • the compound or salt of Formula I is that wherein: X is O; R 1 and R 2 are each independently selected from phenyl optionally substituted with halo, cyano, alkyl, alkoxy, or haloalkoxy; R 3 is phenyl optionally substituted with halo, cyano, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkylcarbonyl, or cycloalkyl; R 4 is hydrogen, methyl, ethyl or propyl; and R 5 is hydrogen or methyl.
  • the compound or salt of Formula I is that wherein: X is O; R 1 and R 2 are each independently selected from phenyl optionally substituted with halo, cyano, alkyl, alkoxy, or haloalkoxy; R 3 is phenyl optionally substituted with halo, cyano, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, alkylcarbonyl, or cycloalkyl; R 4 is hydrogen or trifluoromethyl; and R 5 is hydrogen or methyl.
  • the compound or salt of Formula I is that wherein: X is O; R 3 is hydrogen, R 4 is alkyl or cycloalkyl, and R 5 is optionally substituted phenyl.
  • X is O; R 3 is hydrogen, R 4 is methyl, and R 5 is phenyl optionally substituted with halo, alkyl, haloalkyl, or alkoxy.
  • the compound or salt of Formula I is that wherein: X is O; R 3 is hydrogen, R 1 and R 2 are each independently selected from phenyl substituted with chloro or bromo, R 4 is alkyl or cycloalkyl, and R 5 is optionally substituted phenyl.
  • X is O; R 3 is hydrogen, R 1 and R 2 are each independently selected from phenyl substituted with chloro or bromo, R 4 is methyl, and R 5 is phenyl optionally substituted with halo, alkyl, haloalkyl, or alkoxy.
  • the compound or salt of Formula I is that wherein: X is O; R 4 and R 5 and the carbon to which they are attached form a carbonyl, and R 3 is alkyl, haloalkyl, heterocycloalkyl, phenyl, or heteroaryl, wherein the phenyl and heteroaryl are each optionally substituted.
  • the compound or salt of Formula I is that wherein: X is O; R 4 and R 5 and the carbon to which they are attached form a carbonyl, and R 3 is phenyl optionally substituted with halo, alkyl, alkoxy, alkoxycarbonyl, (cycloalkyl)alkyl,
  • cycloalkyloxy cycloalkyloxy, (cycloalkyl)alkoxy, phenyl, or halo-substituted phenyl.
  • the compound or salt of Formula I is that wherein: X is O; R 4 and R 5 and the carbon to which they are attached form a carbonyl; R 1 is phenyl optionally substituted with halo, alkyl, alkoxy, or cycloalkyloxy; and R 3 is phenyl optionally substituted with halo, alkyl, alkoxy, alkoxycarbonyl, (cycloalkyl)alkyl, cycloalkyloxy, (cycloalkyl)alkoxy, phenyl, or halo- substituted phenyl.
  • the compound or salt of Formula I is that wherein R 1 , R 2 and R 3 are each optionally substituted phenyl. In certain embodiments, R 1 and R 2 are each optionally substituted phenyl, and R 3 is optionally substituted naphthyl.
  • the compound or salt of Formula I is that wherein R 1 and R 2 are each optionally substituted phenyl, and R 3 is pyridinyl (e.g ., pyridin-2-yl, pyridin- 3-yl, and pyridin-4-yl), pyrrolyl, furanyl, thienyl (e.g., thiophen-2-yl and thiophen-3-yl), thiazolyl, oxazolyl, indolyl ( e.g ., lH-indol-2-yl), benzofuranyl (e.g., benzofuran-2-yl), benzothienyl (e.g., benzo[b]thiophen-2-yl), benzothiazolyl (e.g., lH-benzothiazol-2-yl), benzimidazolyl (e.g., lH-benzimidazol-2-
  • the compound or salt of Formula I is that wherein R 1 and R 2 are each optionally substituted phenyl, and R 3 is optionally substituted pyrrolidinyl.
  • the compound or salt of Formula I is that wherein R 1 , R 2 and R 4 are each optionally substituted phenyl.
  • the compound or salt of Formula I is that wherein R 1 and R 2 are each optionally substituted phenyl, and R 4 is optionally substituted thienyl.
  • the compound or salt of Formula I is that wherein R 1 and R 2 are each optionally substituted phenyl, and R 4 is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, wherein each R 4 can be optionally substituted.
  • the compound or salt of Formula I is that where X is S.
  • the compound or salt of Formula I is that where X is O .
  • the compound or salt of Formula I is that where R 1 is optionally substituted phenyl.
  • the compound or salt of Formula I is that where R 1 is optionally substituted with 1 or 2 groups selected from halo, cyano, alkyl, haloalkyl, alkoxy, cycloalkyloxy, amino, alkylamino, and dialkylamino.
  • the compound or salt of Formula I is that where R 1 is phenyl substituted with 1 or 2 groups selected from halo, cyano, alkyl, haloalkyl, alkoxy, and cycloalkyloxy. In certain embodiments, R 1 is phenyl substituted with 1 or 2 groups selected from halo and alkyl. In certain embodiments, R 1 is phenyl substituted with an alkyl group.
  • R 1 is phenyl substituted with methyl or ethyl.
  • R 1 is phenyl substituted with halo. In certain embodiments, R 1 is phenyl substituted with chloro or bromo. In certain embodiments, R 1 is phenyl substituted with chloro.
  • the compound or salt of Formula I is that where R 2 is optionally substituted phenyl.
  • the compound or salt of Formula I is that where R 2 is optionally substituted with 1 or 2 groups selected from halo, cyano, alkyl, haloalkyl, alkoxy, cycloalkyloxy, amino, alkylamino, and dialkylamino.
  • the compound or salt of Formula I is that where R 2 is phenyl substituted with 1 or 2 groups selected from halo, cyano, alkyl, haloalkyl, alkoxy, and cycloalkyloxy.
  • R 2 is phenyl substituted with 1 or 2 groups selected from halo and alkyl.
  • R 2 is phenyl substituted with an alkyl group.
  • R 2 is phenyl substituted with methyl or ethyl.
  • R 2 is phenyl substituted with halo. In certain embodiments, R 2 is phenyl substituted with chloro or bromo. In certain embodiments, R 2 is phenyl substituted with chloro.
  • the compound or salt of Formula I is that where R 1 and R 2 are the same.
  • the compound or salt of Formula I is that where R 3 is alkyl, haloalkyl, hydroxyalkyl, heterocycloalkyl, aryl, or heteroaryl; wherein the
  • heterocycloalkyl, aryl, and heteroaryl groups are each optionally substituted.
  • R 3 is heterocycloalkyl, aryl, or heteroaryl; wherein each group is optionally substituted.
  • the compound or salt of Formula I is that where R 3 is aryl or heteroaryl; wherein each group is optionally substituted.
  • R 3 is optionally substituted phenyl.
  • R 3 is substituted phenyl.
  • R 3 is optionally substituted heteroaryl.
  • R 3 is pyridinyl, pyrrolyl, furanyl, thienyl, thiazolyl, oxazolyl, indolyl, benzofuranyl, benzothienyl, benzothiazolyl, or benzimidazoly; wherein each group is substituted.
  • the compound or salt of Formula I is that where R 3 is optionally substituted with 1 or 2 groups selected from halo, cyano, hydroxy, alkyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy,
  • R 3 is optionally substituted with 1 or 2 groups selected from chloro, cyano, methyl, ethyl, methoxy, difluoromethoxy, and trifluoromethoxy .
  • the compound or salt of Formula I is that where R 3 is alkyl, haloalkyl, hydroxyalkyl, or alkoxy carbonyl. In certain embodiments, R 3 is alkyl, haloalkyl, or hydroxyalkyl. In certain embodiments, R 3 is hydrogen.
  • the compound or salt of Formula I is that where R 4 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, phenyl, or thienyl; wherein the alkyl is optionally substituted with 1 or 2 groups selected from halo, cyano, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, and heterocycloalkyl; and wherein the cycloalkyl, heterocycloalkyl, phenyl, and thienyl groups are each optionally substituted with 1 or 2 groups selected from halo, cyano, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbon
  • R 4 is alkyl. In certain embodiments, R 4 is hydrogen or alkyl. In certain embodiments, R 4 is cycloalkyl, heterocycloalkyl, phenyl, or thienyl.
  • the compound or salt of Formula I is that where R 4 and R 5 and the carbon to which they are attached combine to form spirocycloalkyl or spiroheterocycloalkyl; wherein the spirocycloalkyl and spiroheterocycloalkyl groups are each optionally substituted with 1 or 2 groups selected from halo, cyano, hydroxy, C1-3 alkyl, alkoxy, amino, alkylamino, and dialkylamino.
  • the compound of Formula I is that where R 4 and R 5 and the carbon to which they are attached combine to form spirocyclopropyl, spirocyclobutyl, spirocyclopentyl, spirooxetane, spirotetrahydrofuran, spiroazetidine, or spiropyrrolidine group, each optionally substituted with 1 or 2 groups selected from halo, cyano, hydroxy, C 1-3 alkyl, alkoxy, amino, alkylamino, and dialkylamino.
  • the compound or salt of Formula I is that where R 5 is hydrogen, alkyl, alkoxy, or cycloalkyl. In certain embodiments, R 5 is hydrogen or alkyl. In certain embodiments, R 5 is alkyl or cycloalkyl.
  • the compound or salt of Formula I is that where R 4 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, phenyl, or thienyl; wherein the cycloalkyl, heterocycloalkyl, phenyl, and thienyl groups are each optionally substituted with 1 or 2 groups selected from halo, cyano, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, and
  • R 5 is hydrogen, alkyl, or cycloalkyl.
  • R 4 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, phenyl, or thienyl; wherein each is optionally substituted; and R 5 is hydrogen or alkyl.
  • R 4 is alkyl and R 5 is alkyl.
  • R 4 and R 5 are hydrogen.
  • the compound or salt of Formula I is that where R 4 and R 5 and the carbon to which they are attached combine to form carbonyl, spirocycloalkyl, or spiroheterocycloalkyl. In certain embodiments, R 4 and R 5 and the carbon to which they are attached, combine to form carbonyl. In certain embodiments, R 4 and R 5 and the carbon to which they are attached, combine to form spirocycloalkyl. In certain embodiments, R 4 and R 5 and the carbon to which they are attached, combine to form spirocyclopropyl.
  • the compound or salt of Formula I is not l-(3- aminophenyl)-5-hydroxy-3-phenylimidazolidine-2,4-dione or 4-hydroxy- 1,3, 4, 5- tetraphenylimidazolidin-2-one.
  • the compound or salt of Formula I is that wherein R 1 , R 2 , R 3 and R 4 cannot all be unsubstituted phenyl. In certain embodiments, the compound or salt of Formula I is that wherein when R 4 and R 5 and the carbon to which they are attached combine to form a carbonyl, and R 1 is phenyl substituted with amino, then R 3 is not hydrogen.
  • the compound or salt of Formula I is not l-(3- aminophenyl)-5-hydroxy-3-phenylimidazolidine-2,4-dione.
  • R 1 when R 1 is 3-aminophenyl and R 2 is unsubstituted phenyl, then R 3 is not H.
  • R 1 when R 1 is 3-aminophenyl, R 2 is unsubstituted phenyl, and R 4 and R 5 and the carbon to which they are attached combine to form carbonyl, then R 3 is not H.
  • R 1 when R 1 is 3-aminophenyl and R 4 and R 5 and the carbon to which they are attached combine to form carbonyl, R 2 is substituted phenyl. In certain embodiments, when R 4 and R 5 and the carbon to which they are attached combine to form carbonyl, both R 1 and, R 2 are substituted phenyl. In certain embodiments, R 1 is not an amino-substituted phenyl.
  • the compound or salt of Formula I is not 4-hydroxy- l,3,4,5-tetraphenylimidazolidin-2-one.
  • R 1 and R 2 when R 1 and R 2 are both unsubstituted phenyl, then neither R 3 nor R 4 is unsubstituted phenyl.
  • R 3 when R 1 and R 2 are both unsubstituted phenyl, then R 3 is not unsubstituted phenyl.
  • R 4 is not unsubstituted phenyl.
  • R 1 and R 2 when R 1 and R 2 are both unsubstituted phenyl and R 5 is H, then neither R 3 nor R 4 is unsubstituted phenyl. In certain embodiments, when R 1 and R 2 are both unsubstituted phenyl and R 5 is H, then R 3 is not unsubstituted phenyl. In certain embodiments, when R 1 and R 2 are both unsubstituted phenyl and R 5 is H, then R 4 is not unsubstituted phenyl. In certain embodiments, when R 3 and R 4 are unsubstituted phenyl, at least one of R 1 and R 2 is substituted phenyl.
  • the compound or salt of Formula I is that wherein when R 4 and R 5 and the carbon to which they are attached combine to form a carbonyl, and R 1 and R 2 are both unsubstituted phenyl, then R 3 is not alkyl, haloalkyl, or aryl. In certain embodiments, the compound or salt of Formula I is that wherein when R 4 and R 5 and the carbon to which they are attached combine to form carbonyl, and R 1 and R 2 are both unsubstituted phenyl, then R 3 is not methyl, ethyl, tert-butyl, trifluoromethyl,
  • the compound or salt of Formula I is that wherein when R 1 and R 2 are both unsubstituted phenyl, then R 3 is not methyl, ethyl, tert-butyl, trifluoromethyl, pentafluoroethyl, unsubstituted phenyl, unsubstituted naphthyl, or unsubstituted anthracenyl.
  • R 4 and R 5 and the carbon to which they are attached combine to form a carbonyl, and R 3 is alkyl, haloalkyl, or aryl, then at least one of R 1 and R 2 is a substituted phenyl.
  • the compound or salt of Formula I is that wherein when when when R 1 and R 2 are both unsubstituted phenyl, R 3 and R 4 are both H, then R 5 is not alkoxy.
  • the compound or salt of Formula I is that wherein when when when R 1 and R 2 are both unsubstituted or Ci-C 4 alkyl-substituted C 6 -C1 0 aryl, and R 4 and R 5 and the carbon to which they are attached combine to form carbonyl, then R 3 is not H.
  • R 1 and R 2 are both unsubstituted or C1-C4 alkyl-substituted C6- C1 0 aryl, and R 3 and R 4 are both H, then R 5 is not hydrogen, C1-C4 alkyl, C3-C12 cycloalkyl, C1-C4 alkoxy or unsubstituted or C1-C4 alkyl-substituted C 6 -C1 0 aryl.
  • the compound of Formula I is that according to Formula la:
  • R la is selected from halo, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyloxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, and alkylcarbonylamino;
  • R 2a is selected from halo, cyano, nitro, alkyl, haloalkyl, hydroxyalkyl, alkoxy, cycloalkyloxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, and alkylcarbonylamino;
  • p is 0, 1, or 2
  • q is 0, 1, or 2
  • the compound of Formula I is that according to Formula lb:
  • R la is selected from halo, cyano, alkyl, haloalkyl, alkoxy, cycloalkyloxy, amino, alkylamino, and dialkylamino;
  • R 2a is selected from halo, cyano, alkyl, haloalkyl, alkoxy, cycloalkyloxy, amino, alkylamino, and dialkylamino;
  • R 3a is selected from halo, cyano, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, dialkylamino, alkylcarbonyl, cycloalkyl, heterocycloalkyl, and phenyl optionally substituted with one group selected from halo;
  • R 4 is hydrogen, alkyl, haloalkyl, cycloalkyl, heterocycloalkyl, phenyl, or thienyl; and R 5 is hydrogen, alkyl, or cycloalkyl;
  • R 4 and R 5 and the carbon to which they are attached combine to form carbonyl, or
  • the compound or salt of Formula I is that according to Formula lb, where R la is halo, cyano, alkyl, haloalkyl, or alkoxy; R 2a is halo, cyano, alkyl, haloalkyl, or alkoxy; R 3a is halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, or phenyl optionally substituted with halo; R 4 is hydrogen, alkyl, cycloalkyl, heterocycloalkyl, phenyl, or thienyl; and R 5 is hydrogen, alkyl, or cycloalkyl; or R 4 and R 5 and the carbon to which they are attached combine to form carbonyl, or spirocycloalkyl.
  • the compound or salt of Formula I is that according to Formula lb, where R la is halo, cyano, alkyl, or haloalkyl; R 2a is halo, cyano, alkyl, or haloalkyl; R 3a is halo, cyano, alkyl, haloalkyl, haloalkoxy, or phenyl optionally substituted with halo; R 4 is hydrogen alkyl, or cycloalkyl; and R 5 is hydrogen or alkyl; or R 4 and R 5 and the carbon to which they are attached combine to form spirocycloalkyl.
  • the compound or salt of Formula I is that according to Formula lb, where R la is halo, cyano, alkyl, or haloalkyl; R 2a is halo, cyano, alkyl, or haloalkyl; R 3a is halo, cyano, alkyl, or haloalkoxy; R 4 is hydrogen alkyl, haloalkyl, or cycloalkyl; and R 5 is hydrogen or alkyl; or R 4 and R 5 and the carbon to which they are attached combine to form spirocycloalkyl.
  • X' is O or S
  • R 1' is halo, cyano, alkyl, haloalkyl, or alkoxy
  • R 2 ' is halo, cyano, alkyl, haloalkyl, or alkoxy
  • R 3 ' is alkyl, phenyl, heteroaryl with 5-6 ring atoms, or phenylcarbonyl, wherein the phenyl, heteroaryl, or phenylcarbonyl are each optionally substituted with 1 or 2 groups selected from halo, cyano, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, cycloalkyloxy, (cycloalkyl)alkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, cycloalkyl, and heterocycloalkyl;
  • R 4 ' is hydrogen, alkyl, alkoxyalkyl, C3-5 cycloalkyl, or 3-6 membered heterocycloalkyl,
  • cycloalkyl and heterocycloalkyl groups are each independently optionally substituted with 1 or 2 groups selected from halo, cyano, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl,
  • alkylaminocarbonyl and dialkylaminocarbonyl
  • R 3 ' and R 4 ' and the carbons to which they are attached combine to form a 5-6 membered cycloalkylene; m' is 1 or 2; and
  • n' is 1 or 2;
  • the compound or salt of Formula II is that wherein:
  • X' is O
  • R 1' and R 2' are each independently selected from halo
  • R 3 ' is alkyl, phenyl, heteroaryl with 5 ring atoms, or phenyl carbonyl, wherein the phenyl, heteroaryl, or phenyl carbonyl are each optionally substituted with a group selected from halo, cyano, alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, and alkylcarbonyl.
  • R 4 ' is hydrogen, alkyl, alkoxyalkyl, C3-5 cycloalkyl, or 3-6 membered heterocycloalkyl;
  • R 3' and R 4' and the carbons to which they are attached combine to form a 5-6 membered cycloalkylene
  • n' and n' are 1.
  • the compound or salt of Formula II is that where X' is S.
  • the compound or salt of Formula II is that where X' is O .
  • the compound or salt of Formula II is that where R 1 ' and R 2' are each independently selected from halo and alkyl. In certain embodiments, R 1' and R 2 ' are each independently selected from halo and methyl.
  • the compound or salt of Formula II is that where R 1' and R 2 ' are each independently selected from halo, cyano, haloalkyl, and alkoxy.
  • the compound or salt of Formula II is that where R 1' and R 2' are at the para position.
  • the compound or salt of Formula II is that where R 3' is alkyl, optionally substituted phenyl, or optionally substituted heteroaryl with 5-6 ring atoms. In certain embodiments, R 3' is optionally substituted phenyl, or optionally substituted heteroaryl with 5-6 ring atoms. In certain embodiments, R 3 ' is phenyl substited with halo, cyano, alkyl, haloalkyl, hydroxyalkyl, haloalkoxy, or alkylcarbonyl.
  • the compound or salt of Formula II is that where R 4 ' is alkyl, alkoxyalkyl, C3-5 cycloalkyl, or 3-6 membered heterocycloalkyl.
  • the compound or salt of Formula II is that where R 4' is hydrogen, alkyl, or C3-5 cycloalkyl.
  • the compound or salt of Formula II is that wherein when R 1' and R 2' are each methoxy, and R 4' is methyl, then R 3' is not methoxy-substituted phenyl. In certain embodiments, the compound or salt of Formula II is that wherein when R 1' and R 2' are each methoxy, and R 4' is methyl, then R 3' is not mono substituted phenyl. In certain embodiments, the compound or salt of Formula II is that wherein when R 1' and R 2' are each methoxy, and R 4' is methyl, then R 3' is not substituted phenyl.
  • the compound or salt of Formula II is that wherein when R 3' is methoxy-substituted phenyl, then at least one of R 1' and R 2' is not methoxy. In certain embodiments, the compound or salt of Formula II is that wherein when R 3' is methoxy-substituted phenyl, then at least one of R 1' and R 2' is not alkoxy.
  • R 1 is aryl optionally substituted with a group selected from halo, cyano, nitro, alkyl, alkenyl, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, and alkylcarbonylamino;
  • R 2 is aryl optionally substituted with a group selected from halo, cyano, nitro, alkyl, alkenyl, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, and alkylcarbonylamino;
  • R 3 is aryl optionally substituted with a group selected from halo, cyano, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, and dialkylaminocarbonyl;
  • R 4 is hydrogen, alkyl, alkenyl, haloalkyl, or alkoxyalkylene
  • R 5 is hydrogen, alkyl, alkenyl, haloalkyl, or alkoxyalkylene, cycloalkyl, or aryl, wherein the aryl is optionally substituted with a group selected from alkyl, cyano, haloalkyl, hydroxy, alkoxy, and haloalkoxy;
  • R 4 and R 5 together with the carbon atom to which they are attached combine to form a C3- 6 spirocycloalkyl or a 3-6 membered spiroheterocycloalkyl, wherein the spirocycloalkyl is optionally substituted with 1 or 2 groups selected from halo, cyano, hydroxy, C1-3 alkyl, alkoxy, amino, alkylamino, and dialkylamino; and provided that R 4 and R 5 are not both hydrogen; and
  • the compound is not (4k,5k)-4-(/tv7-butyl)- l ,3-bis(4-methoxyphenyl)-5- phenylimidazolidin-2-one;
  • R 1 is aryl optionally substituted with a group selected from halo, cyano, nitro, alkyl, alkenyl, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, and alkylcarbonylamino;
  • R 2 is aryl optionally substituted with a group selected from halo, cyano, nitro, alkyl, alkenyl, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, and alkylcarbonylamino;
  • R 3 is aryl optionally substituted with a group selected from halo, cyano, nitro, hydroxy, alkyl, alkenyl, alkynyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, and dialkylaminocarbonyl;
  • R 4 is hydrogen, alkyl, alkenyl, haloalkyl, or alkoxyalkylene
  • R 5 is hydrogen, alkyl, alkenyl, haloalkyl, or alkoxyalkylene, cycloalkyl; or R 5 is aryl, when R 3 and R 4 , together with the carbon atoms to which they are attached combine to form a C5-6 cycloalkyl, wherein the aryl is optionally substituted with a group selected from alkyl, cyano, haloalkyl, hydroxy, alkoxy, and haloalkoxy; or R 4 and R 5 , together with the carbon atom to which they are attached combine to form a C3- 6 spirocycloalkyl or a 3-6 membered spiroheterocycloalkyl, wherein the spirocycloalkyl is optionally substituted with 1 or 2 groups selected from halo, cyano, hydroxy, C1-3 alkyl, alkoxy, amino, alkylamino, and dialkylamino; and provided that R 4 and R 5 are not
  • the compound of Formula III is not (4k,5k)-4-(/tv7-butyl)- l ,3-bis(4- methoxyphenyl)-5-phenylimidazolidin-2-one; or
  • the compound of Formula III is that wherein when R 3 and R 4 , together with the carbon atoms to which they are attached combine to form a C6 cycloalkyl, then the cycloalkyl is saturated; or
  • the compound of Formula III is that wherein when R 3 and R 4 , together with the carbon atoms to which they are attached combine to form a C6 cycloalkyl or a 6- membered heterocycloalkyl, then R 1 and R 2 are both mono- substituted aryl; or provided that the compound of Formula III is that wherein when R 3 and R 4 , together with the carbon atoms to which they are attached combine to form a C6 cycloalkyl, or a 6- membered heterocycloalkyl, then the Ce cycloalkyl or the 6-membered heterocycloalkyl is saturated and R 1 and R 2 are both mono-substituted aryl; and optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound or salt of Formula III is that wherein: R 1 is phenyl optionally substituted with a group selected from alkyl, cyano, halo, and haloalkyl; R 2 is phenyl optionally substituted with a group selected from alkyl, cyano, halo, and haloalkyl; R 3 is phenyl optionally substituted with a group selected from alkyl, cyano, halo, haloalkyl, and haloalkoxy; or R 3 and R 4 , together with the carbon atoms to which they are attached combine to form a C5-6 cycloalkyl or a 5-6 membered heterocycloalkyl; R 4 is hydrogen, alkyl, haloalkyl, or alkoxyalkylene; R 5 is hydrogen, alkyl, haloalkyl,
  • alkoxyalkylene or phenyl, wherein the phenyl is optionally substituted with a group selected from cyano, haloalkyl, hydroxy, and haloalkoxy; or R 4 and R 5 , together with the carbon atom to which they are attached combine to form a C3-6 spirocycloalkyl or a 3-6 membered spiroheterocycloalkyl, wherein the spirocycloalkyl is optionally substituted with 1 or 2 halo group(s); and provided that R 4 and R 5 are not both hydrogen.
  • the compound or salt of Formula III is that wherein: R 1 and R 2 , each independently, are phenyl optionally substituted with alkyl, cyano, halo, or haloalkyl; R 3 is phenyl optionally substituted with alkyl, cyano, halo, haloalkyl, or haloalkoxy; R 4 and R 5 , each independently, are selected from hydrogen, alkyl, haloalkyl, and alkoxyalkylene; or R 4 and R 5 , together with the carbon atom to which they are attached combine to form a C3-6 spirocycloalkyl or a 3-6 membered spiroheterocycloalkyl, wherein the spirocycloalkyl is optionally substituted with 2 halo groups; and provided that R 4 and R 5 are not both hydrogen.
  • the compound or salt of Formula III is that wherein: R 1 and R 2 , each independently, are phenyl substituted with alkyl, cyano, halo, or haloalkyl;
  • R 3 is phenyl substituted with alkyl, cyano, halo, haloalkyl, or haloalkoxy;
  • R 4 and R 5 each independently, are selected from hydrogen, alkyl, haloalkyl, and alkoxyalkylene; or R 4 and R 5 , together with the carbon atom to which they are attached combine to form a C3-6 spirocycloalkyl or a 3-6 membered spiroheterocycloalkyl, wherein the spirocycloalkyl is optionally substituted with 2 halo groups; and provided that R 4 and R 5 are not both hydrogen.
  • the compound or salt of Formula III is that wherein: R 1 and R 2 , each independently, are selected from phenyl optionally substituted with alkyl, cyano, halo, or haloalkyl; R 3 is phenyl optionally substituted with alkyl, cyano, halo, haloalkyl, or haloalkoxy; R 4 and R 5 , each independently, are selected from hydrogen, alkyl, haloalkyl, and alkoxyalkylene; and provided that R 4 and R 5 are not both hydrogen.
  • R 1 and R 2 are selected from phenyl optionally substituted with alkyl, cyano, halo, or haloalkyl;
  • R 3 is phenyl optionally substituted with alkyl, cyano, halo, haloalkyl, or haloalkoxy;
  • R 4 is hydrogen or alkyl;
  • R 5 is alkyl, haloalkyl, or alkoxyalkylene.
  • the compound or salt of Formula III is that wherein: R 1 and R 2 , each independently, are selected from phenyl optionally substituted with alkyl, cyano, halo, or haloalkyl; R 3 is phenyl optionally substituted with alkyl, cyano, halo, haloalkyl, or haloalkoxy; R 4 is hydrogen; and R 5 is alkyl, haloalkyl, or alkoxyalkylene.
  • the compound or salt of Formula III is that wherein: R 1 and R 2 , each independently, are selected from phenyl optionally substituted with alkyl, cyano, halo, or haloalkyl; R 3 is phenyl optionally substituted with alkyl, cyano, halo, haloalkyl, or haloalkoxy; and R 4 and R 5 , together with the carbon atom to which they are attached, combine to form a C3-6 spirocycloalkyl or a 3-6 membered spiroheterocycloalkyl, wherein the spirocycloalkyl is optionally substituted with 2 halo groups.
  • R 1 and R 2 are selected from phenyl optionally substituted with alkyl, cyano, halo, or haloalkyl;
  • R 3 is phenyl optionally substituted with alkyl, cyano, halo, haloalkyl, or haloalkoxy; and
  • R 4 and R 5 together with the carbon atom to which they are attached, combine to form a C3-6 spirocycloalkyl that is substituted with 2 halo groups.
  • the compound or salt of Formula III is that wherein: R 1 and R 2 , each independently, are selected from phenyl optionally substituted with alkyl, cyano, halo, or haloalkyl; R 3 and R 4 , together with the carbon atoms to which they are attached, combine to form a C5-6 cycloalkyl or a 5-6 membered heterocycloalkyl; and R 5 is hydrogen or phenyl, wherein the phenyl is substituted with a group selected from cyano, haloalkyl, hydroxy, and haloalkoxy.
  • the compound or salt of Formula III is that wherein: R 1 and R 2 , each independently, are selected from phenyl optionally substituted with alkyl, cyano, halo, or haloalkyl; R 3 and R 4 , together with the carbon atoms to which they are attached, combine to form a C5-6 cycloalkyl or a 5-6 membered heterocycloalkyl; and R 5 is hydrogen.
  • the compound or salt of Formula III is that wherein: R 1 and R 2 , each independently, are selected from phenyl optionally substituted with alkyl, cyano, halo, or haloalkyl; R 3 and R 4 , together with the carbon atoms to which they are attached, combine to form a C5-6 cycloalkyl or a 5-6 membered heterocycloalkyl; and R 5 is phenyl, wherein the phenyl is substituted with a group selected from cyano, haloalkyl, hydroxy, and haloalkoxy.
  • R 1 and R 2 are selected from phenyl substituted with halo; R 3 and R 4 , together with the carbon atoms to which they are attached, combine to form a C5-6 cycloalkyl or a 5-6 membered
  • the compound or salt of Formula III is that wherein: R 1 and R 2 , each independently, are selected from phenyl optionally substituted with alkyl, cyano, halo, or haloalkyl; R 3 and R 4 , together with the carbon atoms to which they are attached, combine to form a C5-6 cycloalkyl; and R 5 is hydrogen or phenyl, wherein the phenyl is substituted with a group selected from cyano, haloalkyl, hydroxy, and haloalkoxy.
  • the compound or salt of Formula III is that wherein: R 1 and R 2 , each independently, are selected from phenyl optionally substituted with alkyl, cyano, halo, or haloalkyl; R 3 and R 4 , together with the carbon atoms to which they are attached, combine to form a 5-6 membered heterocycloalkyl; and R 5 is hydrogen or phenyl, wherein the phenyl is substituted with a group selected from cyano, haloalkyl, hydroxy, and haloalkoxy.
  • the compound or salt of Formula III is that wherein R 1 andR 2 , each independently, are optionally substituted with alkoxy, alkyl, cyano, halo, haloalkoxy, or haloalkyl. In certain embodiments, R 1 and R 2 , each independently, are optionally substituted with alkyl, cyano, halo, or haloalkyl.
  • the compound or salt of Formula III is that wherein: R 1 and R 2 , each independently, are an optionally substituted phenyl. In certain embodiments, R 1 and R 2 , each independently, are substituted phenyl. In certain embodiments, R 1 and R 2 are each an unsubstituted phenyl. In certain embodiments, R 1 is substituted phenyl and R 2 is an unsubstituted phenyl. In certain embodiments, R 1 is an unsubstituted phenyl and R 2 is substituted phenyl.
  • the compound or salt of Formula III is that wherein: R 1 and R 2 , each independently, are phenyl substituted with halo, cyano, nitro, alkyl, haloalkoxy, haloalkyl, hydroxyalkyl, alkoxy, amino, alkylamino, dialkylamino,
  • R 1 and R 2 are phenyl substituted with alkyl, cyano, halo, haloalkoxy, or haloalkyl. In certain embodiments, R 1 and R 2 , each independently, are phenyl substituted with alkyl, cyano, halo, or haloalkyl. In certain embodiments, R 1 and R 2 , each independently, are phenyl substituted with halo.
  • the compound or salt of Formula III is that wherein R 3 is an optionally substituted phenyl. In certain embodiments, R 3 is substituted phenyl. In certain embodiments, R 3 is an unsubstituted phenyl.
  • the compound or salt of Formula III is that wherein R 3 is phenyl substituted with halo, cyano, nitro, hydroxy, alkyl, alkenyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, and
  • R 3 is phenyl substituted with alkyl, cyano, halo, haloalkyl, or haloalkoxy. In certain embodiments, R 3 is phenyl substituted with fluoro, chloro, bromo, iodo, methyl, ethyl, propyl, trifluoromethyl, difluoromethyl, cyano, trifluoromethoxy, or difluoromethoxy. In certain embodiments, R 3 is phenyl substituted with chloro, methyl, trifluoromethyl, cyano, trifluoromethoxy, or difluoromethoxy. In certain embodiments, R 3 is phenyl substituted with cyano, halo, haloalkyl, or haloalkoxy.
  • the compound or salt of Formula III is that wherein R 3 is optionally substituted with alkyl, cyano, halo, haloalkyl, or haloalkoxy.
  • the compound or salt of Formula III is that wherein R 3 and R 4 , together with the carbon atoms to which they are attached combine to form a C5-6 cycloalkyl or a 5-6 membered heterocycloalkyl. In certain embodiments, R 3 and R 4 , together with the carbon atoms to which they are attached combine to form cyclohexyl or cyclopentyl. In certain embodiments, R 3 and R 4 , together with the carbon atoms to which they are attached combine to form a 5-6 membered heterocycloalkyl. In certain embodiments, R 3 and R 4 ,
  • the compound or salt of Formula III is that wherein R 4 is hydrogen, alkyl, haloalkyl, or alkoxyalkylene. In certain embodiments, R 4 is alkyl, haloalkyl, or alkoxyalkylene. In certain embodiments, R 4 is methyl, ethyl, propyl, trifluoromethyl, or methoxymethylene. In certain embodiments, R 4 is hydrogen.
  • the compound or salt of Formula III is that wherein R 5 is alkyl, haloalkyl, or alkoxyalkylene.
  • R 5 is methyl, ethyl, propyl, trifluoromethyl, or methoxymethylene.
  • R 5 is hydrogen, methyl, ethyl, propyl, or trifluoromethyl.
  • R 5 is methyl, ethyl, propyl, or m ethoxy methyl ene .
  • the compound or salt of Formula III is that wherein when R 1 and R 2 are both 4-methoxyphenyl, neither R 4 nor R 5 is tert- butyl. In certain embodiments, when R 1 and R 2 are both 4-methoxyphenyl, R 4 is not tert- butyl. In certain embodiments, when R 1 and R 2 are both 4-methoxyphenyl, R 5 is not tert- butyl. In certain embodiments, when R 1 and R 2 are both 4-methoxyphenyl, R 4 is not fe/V-butyl, and R 5 is not hydrogen.
  • R 1 and R 2 are both 4-methoxyphenyl
  • R 4 is not hydrogen
  • R 5 is not /er/-butyl
  • R 4 is hydrogen
  • R 5 is fe/V-butyl
  • the compound or salt of Formula III is not ( S,5S)-4- (/er/-butyl)-l,3-bis(4-methoxyphenyl)-5-phenylimidazolidin-2-one. In certain embodiments, the compound or salt of Formula III is not 4-(/er/-butyl)-l,3-bis(4-methoxyphenyl)-5- phenylimidazolidin-2-one.
  • the compound or salt of Formula III is that wherein when R 1 and R 2 , are each independently unsubstituted phenyl or phenyl substituted with methyl, methoxy, or chloro; and one of R 3 and R 5 is unsubstituted phenyl or phenyl substituted with methyl, methoxy, chloro, or trifluoromethyl; then the other of R 3 and R 5 is not unsubstituted phenyl or phenyl substituted with methyl, methoxy, chloro, or
  • the compound or salt of Formula III is that wherein R 1 and R 2 are not substituted with alkoxy.
  • the compound or salt of Formula III is that wherein R 3 and R 4 , together with the carbon atoms to which they are attached combine to form a 5-6 membered heterocycloalkyl containing only O and N ring heteroatom.
  • the compound or salt of Formula III is that wherein R 3 and R 4 , together with the carbon atoms to which they are attached combine to form a 5-6 membered
  • heterocycloalkyl containing only an O ring heteroatom.
  • the compound or salt of Formula III is that wherein R 3 and R 4 , together with the carbon atoms to which they are attached combine to form a saturated C5-6 cycloalkyl.
  • the compound or salt of Formula III is that wherein when R 3 and R 4 , together with the carbon atoms to which they are attached combine to form a 6 membered heterocycloalkyl containing only an O ring heteroatom, then R 1 and R 2 are both mono-substituted aryl.
  • the compound or salt of Formula III is that wherein when R 3 and R 4 , together with the carbon atoms to which they are attached combine to form a saturated cycloalkyl or a saturated heterocycloalkyl containining only an O ring heteroatom, then R 1 and R 2 are both mono-substituted aryl.
  • the compound or salt of Formula III is that wherein R 5 is hydrogen.
  • the compound or salt of Formula III is that wherein R 1 and R 2 , each independently, are selected from phenyl substituted with alkyl, cyano, halo, or haloalkyl; and R 5 is phenyl, wherein the phenyl is substituted with a group selected from cyano, haloalkyl, hydroxy, and haloalkoxy
  • the compound or salt of Formula III is that wherein R 4 and R 5 , each independently, are selected from hydrogen, alkyl, haloalkyl, and
  • R 4 and R 5 are selected from hydrogen, methyl, ethyl, propyl, trifluoromethyl, and methoxymethylene; and provided that R 4 and R 5 are not both hydrogen.
  • R 4 and R 5 are selected from alkyl, haloalkyl, and alkoxyalkylene.
  • R 4 and R 5 are selected from methyl, ethyl, propyl, trifluoromethyl, and methoxymethylene.
  • R 4 and R 5 are selected from methyl, ethyl, propyl, and trifluoromethyl. In certain embodiments, R 4 and R 5 , each independently, are selected from methyl, ethyl, propyl, and methoxymethylene.
  • R 4 is hydrogen, alkyl, haloalkyl, or alkoxyalkylene; and R 5 is alkyl, haloalkyl, or alkoxyalkylene. In certain embodiments, R 4 is hydrogen; and R 5 is alkyl, haloalkyl, or alkoxyalkylene. In certain embodiments, R 4 is hydrogen; and R 5 is methyl, ethyl, propyl, trifluoromethyl, or methoxymethylene.
  • the compound or salt of Formula III is that wherein R 4 and R 5 , together with the carbon atom to which they are attached combine to form a C3-6 spirocycloalkyl or a 3-6 membered spiroheterocycloalkyl, wherein the spirocycloalkyl is optionally substituted with 1 or 2 halo group(s).
  • R 4 and R 5 together with the carbon atom to which they are attached combine to form a C3-6 spirocycloalkyl, wherein the spirocycloalkyl is optionally substituted with 2 halo groups.
  • R 4 and R 5 together with the carbon atom to which they are attached combine to form spirocyclopentyl or spirocyclobutyl, wherein the spirocyclobutyl is substituted with 2 fluoro groups.
  • R 4 and R 5 together with the carbon atom to which they are attached combine to form 3-6 membered spiroheterocycloalkyl.
  • the compound or salt of Formula III is that wherein R 4 and R 5 , together with the carbon atom to which they are attached combine to form a 4 membered spiroheterocycloalkyl. In certain embodiments, R 4 and R 5 , together with the carbon atom to which they are attached combine to form
  • the compound or salt of Formula I, la, lb, II, or III is a (4k,5k)-single stereoisomer.
  • the compound or salt of Formula I, la, lb, II, or III is a (4,V,5 ⁇ )-single stereoisomer.
  • the compound or salt of Formula I, la, lb, II, or III is a (4A,5,V)-single stereoisomer.
  • the compound or salt of Formula I, la, lb, II, or III is a (4f?,5f?)-single stereoisomer.
  • the compound or salt thereof has a Formula I, la, lb, or II, wherein the compound is selected from Table 1.
  • the compound or salt thereof has a Formula I, la, lb, or II, wherein the compound is selected from Table 1 consisting of Examples 1-141, 143-267, and 268-338, or a single stereoisomer or mixture of stereoisomers thereof.
  • the compound or salt thereof has a Formula III, wherein the compound is selected from Table 2.
  • the compound or salt thereof has a Formula III, wherein the compound is selected from Table 2 consisting of Examples 1-57, or a single stereoisomer or mixture of stereoisomers thereof.
  • R 1 is alkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl;
  • R 2 is alkyl, aminoalkyl, alkylaminoalkyl, or dialkylaminoalkyl; or R 1 and R 2 together with the nitrogen to which they are attached form a 4-8 membered heterocycloalkyl ring optionally substituted with 1, 2, or 3 R 10 groups; or a bicyclic heteroaryl ring with 8 ring atoms, where 1-3 ring atoms are nitrogen;
  • R 3 is H, alkyl, or haloalkyl
  • L is S(0)q, Ci-3alkylene-S(0) q , C(0)-C(0), or C*H(OH)C(0), wherein the alkylene in the Ci-3alkylene-S(0) q forms a covalent bond with Ar 1 , and wherein the“C*” in the C*H(OH)C(0) forms a covalent bond with Ar 1 ; q is 0, 1, or 2;
  • Ar 1 is aryl or heteroaryl, each optionally substituted with 1 or 2 R 11 groups;
  • R i ° a , R 10b , and R 10c are each independently H or alkyl
  • each R 11 is independently halo, cyano, nitro, alkyl, alkoxy, hydroxy, cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl, (heterocycloalkyl)alkyl, cycloalkyloxy, heterocycloalkyloxy, (cycloalkyl)alkyloxy, cycloalkyloxyalkyl, aryl, aryloxy, arylalkyloxy, heteroaryl, heteroaryloxy, or heteroaryl alkyl oxy; wherein each aryl and heteroaryl, whether alone or as part of another group, are each independently optionally substituted with halo, alkyl, haloalkyl, or alkoxy;
  • each R 12 is independently halo, cyano, nitro, hydroxy, alkyl, haloalkyl, haloalkenyl, alkoxy, cycloalkyloxy, cycloalkyl, heterocycloalkyl, cycloalkyl substituted with haloalkyl, (cycloalkyl)alkyloxy, heterocycloalkyloxy, (heterocycloalkyl)alkyloxy, aryl, heteroaryl, aryloxy, arylalkyloxy, heteroaryloxy, or heteroarylalkyloxy; wherein each aryl and heteroaryl, whether alone or as part of another group, are each independently optionally substituted with 1 or 2 groups selected from halo, alkyl, haloalkyl, and alkoxy; and
  • the compound of Formula X is according to
  • the compound of Formula X is according to
  • the compound or salt of Formula X, Xa, or Xb, wherein R 1 and R 2 together with the nitrogen to which they are attached form a 4-8 membered heterocycloalkyl ring which is optionally substituted with 1, 2, or 3 R 10 groups.
  • R 1 and R 2 together with the nitrogen to which they are attached form a 5-6 membered monocyclic heterocycloalkyl ring which is optionally substituted with 1, 2, or 3 R 10 groups.
  • R 1 and R 2 together with the nitrogen to which they are attached form one of the following structures:
  • the compound or salt of Formula X, Xa, or Xb, wherein R 1 and R 2 together with the nitrogen to which they are attached form a bicyclic heteroaryl ring with 8 ring atoms, where 1-3 ring atoms are nitrogen.
  • the bicyclic heteroaryl ring has one of the following structures:
  • each R 10 is independently halo, amino, alkylamino, or dialkylamino.
  • each R 10 is independently fluoro, amino, methylamino, or dimethylamino.
  • each R 10 is independently fluoro or amino.
  • R 3 is alkyl. In certain embodiments, R 3 is methyl, ethyl, or, /-propyl.
  • Ar 1 is phenyl optionally substituted with 1 or 2 R 11 groups.
  • Ar 1 is naphthyl optionally substituted with 1 or 2 R 11 groups.
  • Ar 1 is a 5-6 membered heteroaryl or a 9-10 membered bicyclic heteroaryl, wherein each is optionally substituted with 1 or 2 R 11 groups.
  • Ar 1 is 2-pyridyl, 3-pyridyl, indazolyl, thienyl, or benzothienyl, wherein each is optionally substituted with 1 or 2 R 11 groups.
  • each R 11 is independently cycloalkyl, (cycloalkyl)alkyl, heterocycloalkyl,
  • heterocycloalkyl alkyl, cycloalkyloxy, heterocycloalkyloxy, (cycloalkyl)alkyloxy, cycloalkyloxyalkyl, aryl, aryloxy, arylalkyloxy, heteroaryl, heteroaryloxy, or
  • heteroarylalkyloxy wherein each aryl and heteroaryl, whether alone or as part of another group, are each independently optionally substituted with halo, alkyl, haloalkyl, or alkoxy.
  • each R 11 is independently alkoxy, cycloalkyloxy, heterocycloalkyloxy,
  • cycloalkyl alkyloxy, cycloalkyloxyalkyl, aryloxy, arylalkyloxy, heteroaryloxy, or heteroarylalkyloxy; wherein each aryl and heteroaryl, whether alone or as part of another group, are each independently optionally substituted with halo, alkyl, haloalkyl, or alkoxy.
  • each R 11 is independently methyl, ethyl, //-propyl, /-propyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, methoxy, ethoxy, propoxy, z-propoxy, butoxy, z-butoxy, .vcc-butoxy, 2-ethylbutoxy, hexyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclopentylmethyloxy, cyclopentylethyloxy,
  • cyclopentyloxymethyl cyclohexyloxy, cyclohexylmethyloxy, cyclohexylethyloxy, cyclohexyloxymethyl, fluorophenyl, chlorophenyl, benzyloxy, chlorobenzyloxy,
  • each R 11 is independently /-propyl, cyclopentylmethyl, cyclopentylethyl, /- propoxy, butoxy, z-butoxy, sec- butoxy, 2-ethylbutoxy, hexyloxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexylmethyloxy, cyclohexylethyloxy,
  • each R 11 is independently halo or alkoxy. In certain embodiments, each R 11 is independently fluoro, chloro, bromo, iodo, methoxy, ethoxy, propoxy, z-propoxy, butoxy, z-butoxy, or sec- butoxy.
  • Ar 1 is phenyl substituted with 1 R 11 group selected from z-butoxy, 2-ethylbutoxy, butoxy, hexyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, cyclohexylethyloxy, cyclopentyloxyethyl, 4- fluorophenyl, 4-fluorophenoxy, benzyloxy, 3 -fluorobenzyloxy, 4-fluorobenzyloxy, 4-fluoro- 2-pyridyloxy, and 4-chloro-2-pyridyloxy.
  • 1 R 11 group selected from z-butoxy, 2-ethylbutoxy, butoxy, hexyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, cyclohexylethyloxy, cyclopentyloxyethyl, 4- fluorophenyl, 4-fluorophenoxy, benzyloxy, 3 -fluorobenz
  • Ar 1 is phenyl substituted with 1 R 11 group selected from z-butoxy, 2-ethylbutoxy, butoxy, hexyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, cyclohexylethyloxy, cyclopentyloxyethyl, 4- fluorophenyl, 4-fluorophenoxy, benzyloxy, 3 -fluorobenzyloxy, 4-fluorobenzyloxy, 4-fluoro- 2-pyridyloxy, and 4-chloro-2-pyridyloxy.
  • 1 R 11 group selected from z-butoxy, 2-ethylbutoxy, butoxy, hexyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, cyclohexylethyloxy, cyclopentyloxyethyl, 4- fluorophenyl, 4-fluorophenoxy, benzyloxy, 3 -fluorobenz
  • the compound or salt of Formula X, Xa, or Xb wherein Ar 1 is 2-pyridyl, 3-pyridyl, indazolyl, thienyl, or benzothienyl, wherein each Ar 1 is independently substituted with 1 R 11 group selected from (cycloalkyl)alkyl, cycloalkyloxy, cycloalkyloxyalkyl, and aryl optionally substituted with halo.
  • the compound or salt of Formula X, Xa, or Xb wherein L is C(0)-C(0), R 3 is H, and Ar 1 is phenyl, naphthyl, pyridyl, or benzothienyl, each independently substituted with 1 or 2 R 11 groups, wherein R 11 is alkoxy, cycloalkyloxy, (cycloalkyl)alkyloxy, or aryl optionally substituted with halo.
  • L is C(0)-C(0), R 3 is H
  • Ar 1 is phenyl, naphthyl, pyridyl, or benzothienyl, each
  • R 11 independently substituted with 1 R 11 group, wherein R 11 is /-propoxy, cyclopentyloxy, fluorophenyl, or cyclohexylmethoxy.
  • L is SO2
  • R 3 is H
  • Ar 1 is phenyl, naphthyl, pyridyl, or benzothienyl, each independently substituted withl R 11 group, wherein R 11 is alkoxy, cycloalkyloxy, (cycloalkyl)alkyloxy, or phenyl optionally substituted with halo.
  • L is C*H(OH)C(0) wherein “C*” forms a covalent bond with Ar 1 , R 3 is H, and Ar 1 is phenyl or naphthyl, wherein the phenyl or napthyl is substituted with i-propoxy, cyclopentyloxy, or (cyclohexyl)methoxy.
  • the compound or salt of Formula X, Xa, or Xb wherein Ar 2 is aryl substituted with 1 or 2 R 12 groups, wherein each R 12 is independently halo, alkoxy, cycloalkyloxy, phenyl or heteroaryl, wherein the phenyl and heteroaryl are each optionally substituted with 1 or 2 halo.
  • Ar 2 is phenyl substituted with 1 or 2 R 12 groups, wherein each R 12 is independently halo, alkoxy, cycloalkyloxy, phenyl or heteroaryl, wherein the phenyl and heteroaryl are each optionally substituted with 1 or 2 halo.
  • Ar 2 is a 5-6 membered heteroaryl or a 9-10 membered bicyclic heteroaryl, wherein the heteroaryl is optionally substituted with 1 or 2 R 12 groups.
  • Ar 2 is 2-pyridyl, thiophene, or dibenzofuranyl, wherein each is optionally substituted with 1 or 2 R 12 groups.
  • each R 12 is independently halo, cyano, nitro, hydroxy, alkyl, haloalkyl, haloalkenyl, or alkoxy.
  • each R 12 is independently halo, alkoxy, cycloalkyloxy, or aryl, wherein the aryl is optionally substituted with 1 or 2 halo.
  • each R 12 is independently bromo, chloro, methoxy, ethoxy, propoxy, /-propoxy, butoxy, cyclopropyloxy, cyclopentyloxy, or chlorophenyl.
  • each R 12 is independently chloro, methoxy, butoxy, or chlorophenyl.
  • R 12 is halo.
  • R 12 is bromo or chloro.
  • the compound or salt of Formula X, Xa, or Xb wherein Ar 2 is phenyl substituted with 1 or 2 R 12 groups, wherein R 12 is independently halo, hydroxy, haloalkyl, haloalkenyl, alkoxy, cycloalkyloxy, cycloalkyl substituted with haloalkyl, (heterocycloalkyl)alkyloxy, aryl, heteroaryl, aryloxy, or arylalkyloxy; wherein each aryl and heteroaryl, whether alone or as part of another group, are each independently optionally substituted with 1 or 2 groups selected from halo and haloalkyl.
  • the compound or salt of Formula X, Xa, or Xb wherein L is C(0)-C(0), R 3 is H, and Ar 2 is phenyl substituted with 1 or 2 R 12 groups, wherein R 12 is halo, haloalkyl, alkoxy, cycloalkyloxy, (cycloalkyl)alkyloxy, phenyl optionally substituted with halo, or phenoxy.
  • L is SO2
  • R 3 is H
  • Ar 2 is unsubstituted aryl or unsubstituted heteroaryl.
  • the compound or salt of Formula X, Xa, or Xb wherein L is C*H(OH)C(0) wherein“C*” forms a covalent bond with Ar 1 , R 3 is H, and Ar 2 is phenyl or naphthyl, wherein each is substituted with 1 or 2 R 12 groups, wherein R 12 is halo, haloalkyl, alkoxy, cycloalkyloxy, (cycloalkyl)alkyloxy, phenyl optionally substituted with halo, or phenoxy.
  • each R 12 is independently halo, hydroxy, haloalkyl, haloalkenyl, alkoxy, cycloalkyloxy, cycloalkyl substituted with haloalkyl, (heterocycloalkyl)alkyloxy, aryl, heteroaryl, aryloxy, or arylalkyloxy, wherein each aryl and heteroaryl, whether alone or as part of another group, are each independently optionally substituted with 1 or 2 groups selected from halo, haloalkyl, and alkoxy.
  • the compound or salt of Formula X, Xa, or Xb wherein L is C(0)-C(0); R 1 and R 2 together with the nitrogen to which they are attached form a 6-8 membered heterocycloalkyl ring optionally substituted with 1 R 10 group; R 3 is H; Ar 1 is aryl or heteroaryl, each optionally substituted with 1 R 11 group; Ar 2 is aryl optionally substituted with 1 R 12 group; R 10 is amino group; R 11 is alkoxy, cycloalkyloxy,
  • the compound or salt of Formula X, Xa, or Xb wherein L is C*H(OH)C(0), wherein the“C*” in the C*H(OH)C(0) forms a covalent bond with Ar 1 ; R 1 and R 2 together with the nitrogen to which they are attached form a 6-8 membered heterocycloalkyl ring optionally substituted with 1 R 10 group; R 3 is H; R 10 is amino group; Ar 1 is aryl optionally substituted with 1 R 11 group; Ar 2 is aryl optionally substituted with 1 R 12 group; R 11 is alkoxy, cycloalkyloxy, or (cycloalkyl)alkyloxy; and R 12 is halo or aryl, wherein the aryl is optionally substituted with a halo group.
  • the compound or salt has a Formula X, Xa, or Xb, wherein the compound is selected from Table 3.
  • the compound or salt has a Formula X, Xa, or Xb, wherein the compound is selected from Table 3 consisting of Examples 1-200, or a single stereoisomer or mixture of stereoisomers thereof.
  • ring B is a 5-6 membered monocylic heterocycloalkyl containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms;
  • ring A is a 4-7 membered monocyclic heterocycloalkyl ring or a 7-9 membered bicyclic
  • heterocycloalkyl ring wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R 3 groups;
  • L is a bond, C(O), or -[C(R 4 R 5 )] P -;
  • p 1 or 2;
  • R 1 is aryl or heteroaryl, each of which is optionally substituted with 1, 2, or 3 groups
  • alkyl independently selected from alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy, alkylcarbonylamino, alkoxycarbonylamino, cycloalkyloxy, heterocycloalkyloxy, (heterocycloalkyl)alkoxy and (cycloalkyl)alkoxy;
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with 1 or 2 R 6 groups;
  • each R 3 is independently alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
  • dialkylaminocarbonyl alkylcarbonyloxy, alkoxycarbonyloxy
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • alkylcarbonylamino or alkoxycarbonylamino
  • each R 4 is independently H or alkyl
  • each R 5 is independently H, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocycloalkyl, aryl, or heteroaryl, wherein the aryl and heteroaryl are independently and optionally substituted with alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxy, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
  • dialkylaminocarbonyl alkylcarbonyloxy, alkoxycarbonyloxy
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • alkylcarbonylamino or alkoxycarbonylamino
  • each R 6 is independently alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxyl, haloalkyl,
  • hydroxyalkyl alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
  • dialkylaminocarbonyl alkylcarbonyloxy, alkoxycarbonyloxy
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • dialkylaminocarbonyloxy aminocarbonyloxy, alkylcarbonylamino, or
  • the compound of Formula (I) is that when ring B is piperidinyl or pyrrolidinyl, then R 2 is not amino-substituted imidazolyl; or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound or salt of Formula XX is that wherein: L is a bond, C(O), or -[C(R 4 R 5 )] P -;
  • p 1 or 2;
  • R 1 is aryl or heteroaryl, each of which is optionally substituted with haloalkoxy,
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with 1 or 2 R 6 groups; each R 3 is independently halo or amino;
  • R 4 is H
  • R 5 is H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl;
  • each R 6 is independently haloalkyl, haloalkoxy, (haloalkyl)cycloalkyl, aryl, or heteroaryl, wherein the aryl and heteroaryl groups are each optionally substituted with halo, haloalkoxy, or haloalkyl;
  • the compound or salt of Formula XX is that wherein ring A is a 4-7 membered monocyclic heterocycloalkyl ring or a 7-9 membered bicyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R 3 groups;
  • ring A is piperazinyl then ring A is optionally substituted with 1, 2, or 3 R 3 groups.
  • the compound or salt of Formula XX is that wherein ring A is a 4-7 membered monocyclic heterocycloalkyl ring or a 7-9 membered bicyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R 3 groups; provided that when ring A is not piperazinyl then ring A is substituted with 1, 2, or 3 R 3 groups.
  • the compound or salt of Formula XX is that wherein ring A is a 4-7 membered monocyclic heterocycloalkyl ring, other than piperazinyl, which ring contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R 3 groups; or ring A a 7-9 membered bicyclic
  • heterocycloalkyl ring which contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is substituted with 1, 2, or 3 R 3 groups; or ring A is piperazinyl which is optionally substituted with 1, 2, or 3 R 3 groups.
  • the compound or salt of Formula XX is that wherein ring B is piperazinyl, piperidinyl, or pyrrolidinyl.
  • ring B is piperazinyl.
  • ring B is piperidinyl.
  • ring B is pyrrolidinyl.
  • the compound or salt of Formula XX is according to Formula XXa, XXb, or XXc:
  • the compound or salt of Formula XX is according to Formula XXa, XXb, or XXc, wherein: R 1 is aryl or heteroaryl, each of which is optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy; each R 3 is independently halo or amino; R 4 is H; R 5 is H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl; and each R 6 is independently haloalkyl, haloalkoxy,
  • haloalkyl cycloalkyl, aryl, or heteroaryl, wherein the aryl and heteroaryl groups are each optionally substituted with halo, haloalkoxy, or haloalkyl; or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein: L is -[C(R 4 R 5 )] P -; R 1 is aryl or heteroaryl, each of which is optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy; each R 3 is independently halo or amino; p is 1 or 2; each R 4 is H; each R 5 is independently H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl; and each R 6 is independently haloalkyl, (haloalkyl)cycloalkyl, aryl, or heteroaryl, wherein the aryl and heteroaryl groups are each optionally substituted with halo, haloalkoxy, or haloalkyl.
  • L is -[C(R 4 R 5 )] P -;
  • L is -[C(R 4 R 5 )] P -, wherein p is 1 or 2. In certain embodiments, L is C(O) or a bond. In certain embodiments, L is -[C(R 4 R 5 )] P - or C(O), wherein p is 1 or 2. In certain embodiments, L is -[C(R 4 R 5 )] P - or a bond, wherein p is 1 or 2.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein L is -[C(R 4 R 5 )] P -, wherein, p is 1 or 2, wherein each R 4 is H and each R 5 is independently H, alkyl, cycloalkyl, or aryl, wherein the aryl is optionally substituted with haloalkyl.
  • L is -CFh-.
  • L is -CH2CH2-.
  • L is -C(R 4 R 5 )-, wherein R 4 is H and R 5 is phenyl, wherein the phenyl is optionally substituted with haloalkyl. In certain embodiments, L is -C(R 4 R 5 )-, wherein R 4 is H and R 5 is phenyl, wherein the phenyl is optionally substituted with trifluorom ethyl.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein each R 4 is independently H.
  • R 4 is alkyl.
  • each R 4 is independently H or alkyl.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein p is 1 or 2, wherein each R 5 is independently H, alkyl, alkenyl, alkynyl, or haloalkyl.
  • the compound of Formula (I) or pharmaceutically acceptable salt thereof is that wherein p is 1 or 2, wherein each R 5 is H.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein R 1 is aryl optionally substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein R 1 is optionally substituted phenyl, napthyl, or indanyl. In certain embodiments, R 1 is optionally substituted phenyl. In certain embodiments, R 1 is optionally substituted napthyl.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein R 1 is phenyl substituted with haloalkoxy, cycloalkyloxy, or
  • R 1 is phenyl substituted with trifluoromethoxy, difluorom ethoxy, l,l, l-trifluoroethoxy, trichloromethoxy, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cylcohexyloxy, cyclohexylmethoxy, cyclohexylethoxy, cyclopentylmethoxy, or cyclopentylethoxy.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein R 1 is naphthyl substituted with haloalkoxy, cycloalkyloxy, or (cycloalkyl)alkoxy. In certain embodiments, R 1 is naphthyl substituted with
  • XXc is that wherein ring A is a 4-7 membered monocyclic heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R 3 groups, wherein each R 3 group is independently halo or amino, provided that when ring A is not piperazinyl then ring A is substituted with 1, 2, or 3 R 3 groups.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein ring A is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl, imidazolidinyl, pyrazolidinyl, hexahydropyrimidinyl, hexahydropyridazinyl, or diazepanyl, each of which is substituted with 1, 2, or 3 R 3 groups, wherein each R 3 group is independently halo or amino; or ring A is unsubstituted piperazinyl.
  • ring A is piperidinyl or pyrrolidinyl, each of which is substituted with 1, 2, or 3 R 3 groups, wherein each R 3 group is independently halo or amino; or ring A is unsubstituted piperazinyl.
  • the compound or salt of Formula XX, XXa, XXb, or XXc, is that wherein ring A is:
  • n is 1 to 3. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3.
  • the compound or salt of Formula XX, XXa, XXb, or XXc, is that wherein ring A is
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein ring A is
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein ring A is a 7-9 membered bicyclic heterocycloalkyl ring containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and substituted with 1, 2, or 3 R 3 groups, wherein each R 3 group is independently halo or amino.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein R 3 is independently halo or amino.
  • R 3 is independently fluoro, chloro, bromo, or amino.
  • R 3 is independently fluoro or amino.
  • R 3 is independently amino.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein R 2 is aryl optionally substituted with 1 or 2 R 6 groups.
  • R 2 is phenyl, napthyl, or indanyl, each of which is optionally substituted with 1 or 2 R 6 groups.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein R 2 is phenyl substituted with 1 or 2 R 6 groups, wherein each R 6 group is independently selected from halo, alkoxy, haloalkyl, haloalkoxy, (haloalkyl)cycloalkyl, aryl, aryloxy, and heteroaryl, wherein each aryl or heteroaryl is independently and optionally substituted with halo, haloalkoxy, or haloalkyl.
  • R 2 is phenyl substituted with 1 or 2 R 6 groups, wherein each R 6 group is independently selected from butoxy, chloro, trifluoromethyl, trifluoromethoxy, (trifluoromethyl)cyclopropyl, phenyl, phenoxy, and 2-pyridyl, wherein phenyl or 2-pyridyl is each independently and optionally substituted with fluoro, chloro, trifluoromethyl, or trifluoromethoxy.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein R 2 is phenyl substituted with optionally substituted phenyl.
  • R 2 is phenyl optionally substituted with phenyl, which is substituted with halolakyl.
  • R 2 is phenyl substituted with phenyl, which is substituted with trifluoromethyl.
  • R 2 is phenyl substituted with chlorophenyl.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein R 2 is phenyl optionally with 1 or 2 R 6 groups, wherein R 6 group is independently selected from halo, haloalkyl, aryloxy, alkoxy, and aryl optionally substituted with halo.
  • R 2 is phenyl optionally substituted with 1 or 2 R 6 groups, wherein each R 6 group is independently selected from fluoro, chloro, bromo, trifluormethyl, difluorom ethyl, l,l, l-trifluoroethyl, trichloromethyl, phenoxy, methoxy, ethoxy, propoxy, n- butoxy, and phenyl optionally substituted with fluoro, chloro, or bromo.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein R 2 is phenyl optionally with an R 6 group, wherein the R 6 group is selected from halo, haloalkyl, and aryl optionally substituted with halo.
  • R 2 is phenyl optionally with an R 6 group, wherein the R 6 group is selected from fluoro, chloro, bromo, trifluorom ethyl, difluoromethyl, l,l, l-trifluoroethyl,
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein R 2 is selected from:
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein R 2 is 2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl, or l,3,4-thiadiazolyl, each of which is optionally substituted with R 6 , wherein R 6 is aryl or heteroaryl, each of which is optionally substituted with halo, haloalkyl, or haloalkoxy.
  • R 2 is 2-pyridyl, 3-pyridyl, 4-pyridyl, thiazolyl, or l,3,4-thiadiazolyl, each of which is optionally substituted with phenyl, wherein the phenyl is optionally substituted with a group selected from fluoro, chloro, trifluoromethyl, and trilfuoromethoxy.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein R 6 is independently halo, alkoxy, haloalkyl, haloalkoxy,
  • haloalkyl cycloalkyl, aryl, aryloxy, or heteroaryl, wherein each aryl or heteroaryl is each independently optionally substituted with halo, haloalkoxy, or haloalkyl.
  • R 6 is independently methoxy, ethoxy, propoxy, butoxy, fluoro, chloro, bromo, trifluoromethyl, difluoromethyl, l, l,l-trifluoroethyl, trichloromethyl, trifluorom ethoxy, difluorom ethoxy, l,l, l-trifluoroethoxy, trichloromethoxy, (trifluoromethyl)cyclopropyl, phenyl, phenoxy, 2-pyridyl, 3-pyridyl, 4-pyridyl, wherein phenyl, 2-pyridyl, 3-pyridyl, or 4- pyridyl, is each independently optionally substituted with fluoro, chloro, trifluoromethyl, or trifluoromethoxy.
  • R 6 is independently n-butoxy, chloro, trifluoromethyl, trifluoromethoxy, (trifluoromethyl)cyclopropyl, phenyl, phenoxy, 2-pyridyl, wherein phenyl or 2-pyridyl is each independently optionally substituted with fluoro, chloro, trifluoromethyl, or trifluorom ethoxy.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein R 6 is phenyl substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R 6 is phenyl substituted with fluoro, chloro, trifluoromethyl, or
  • R 6 is phenyl substituted with halo. In certain embodiments, R 6 is phenyl substituted with fluoro or chloro. In certain embodiments, R 6 is phenyl substituted with haloalkoxy. In certain embodiments, R 6 is phenyl substituted with trifluoromethoxy. In certain embodiments, R 6 is phenyl substituted with haloalkyl. In certain embodiments, R 6 is phenyl substituted with trifluoromethyl.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein R 6 is independently halo or phenyl, wherein the phenyl is optionally substituted with halo, haloalkoxy, or haloalkyl. In certain embodiments, R 6 is independently fluoro, chloro or phenyl.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein ring B is piperazinyl, then R 2 is not furanyl or thiophenyl. In certain embodiments, R 2 is not furanyl or thiophenyl. In certain embodiments, R 2 is not furanyl. In certain embodiments, R 2 is not thiophenyl.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein when ring B is piperidinyl or pyrrolidinyl, then R 2 is not imidazolyl. In certain embodiments, when ring B is piperidinyl, then R 2 is not imidazolyl. In certain embodiments, when ring B is pyrrolidinyl, then R 2 is not imidazolyl. In certain
  • R 2 is not imidazolyl.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein R 2 is not amino-substituted imidazolyl.
  • R 2 is not amino-substituted imidazolyl.
  • ring B is piperidinyl then R 2 is not amino-substituted imidazolyl.
  • R 2 is not amino-substituted imidazolyl.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein when R 1 is methoxy substituted phenyl, then R 2 is not unsubstituted phenyl. In certain embodiments, R 1 is not methoxy substituted phenyl. In certain embodiments,
  • R 2 is not unsubstituted phenyl.
  • the compound or salt of Formula XX, XXa, XXb, or XXc is that wherein when R 1 is cyano substituted phenyl, then R 2 is not unsubstituted phenyl. In certain embodiments, R 1 is not cyano substituted phenyl. [000385] In certain embodiments, the compound or salt of Formula XX, XXa, XXb, or XXc, is that wherein R 1 is not substituted heteroaryl. In certain embodiments, R 1 is not unsubstituted heteroaryl.
  • the compound or salt of Formula XX is according to Formula XXd, XXe, or XXf:
  • ring B is a 5-6 membered monocylic heterocycloalkyl containing one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms;
  • ring A is a 4-7 membered monocyclic heterocycloalkyl ring or a 7-9 membered bicyclic heterocycloalkyl ring, wherein ring A contains one or two ring nitrogen atoms, with remaining ring atoms being carbon atoms, and is optionally substituted with 1, 2, or 3 R 3 groups;
  • R 1 is aryl or heteroaryl, each of which is optionally substituted with 1, 2, or 3 groups
  • alkyl independently selected from alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxyl, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl, dialkylaminocarbonyl, alkylcarbonyloxy, alkoxycarbonyloxy,
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • alkylcarbonylamino alkoxycarbonylamino, cycloalkyloxy, heterocycloalkyloxy, (heterocycloalkyl)alkoxy and (cycloalkyl)alkoxy;
  • R 2 is aryl or heteroaryl, each of which is optionally substituted with 1 or 2 R 6 groups;
  • each R 3 is independently alkyl, alkenyl, alkynyl, halo, cyano, nitro, hydroxy, amino, alkylamino, dialkylamino, haloalkyl, hydroxyalkyl, alkoxy, hydroxyalkoxy, haloalkoxy, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
  • dialkylaminocarbonyl alkylcarbonyloxy, alkoxycarbonyloxy
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • alkylcarbonylamino or alkoxycarbonylamino
  • each R 6 is independently alkyl, alkenyl, alkynyl, halo, nitro, cyano, hydroxyl, haloalkyl,
  • hydroxyalkyl alkoxy, hydroxyalkoxy, haloalkoxy, amino, alkylamino, dialkylamino, alkylcarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl,
  • dialkylaminocarbonyl alkylcarbonyloxy, alkoxycarbonyloxy
  • alkylaminocarbonyloxy dialkylaminocarbonyloxy, aminocarbonyloxy
  • dialkylaminocarbonyloxy aminocarbonyloxy, alkylcarbonylamino, or
  • the compound of Formula XXI is wherein ring A is not pyrrolidinyl.
  • the compound of Formula XXI is wherein R 1 is not substituted heteroaryl. In certain embodiments, the compound of Formula XXI is wherein R 1 is not un substituted heteroaryl. [000390] In certain embodiments, the compound of Formula XXI is not L -[ 1-[[(2L',4A > )- l-[(3,4-dimethoxyphenyl)sulfonyl]-4-[(3-methoxyphenyl)methoxy]-2-pyrrolidinyl]carbonyl]- 3-pyrrolidinyl]-acetamide or trifluoroacetate salt thereof.
  • the compound of Formula XXI is that wherein R 1 is not unsubstituted heteroaryl. In certain embodiments, the compound of Formula XXI is not/V-[l-[[-l-[(3,4- dimethoxyphenyl)sulfonyl]-4-[(3-methoxyphenyl)methoxy]-2-pyrrolidinyl]carbonyl]-3- py rrol i di nyl ] -acetami de or trifluoroacetate salt thereof.
  • the compound of Formula XXI is according to Formula XXIa or XXIb:
  • the compound or salt of Formula XXI, XXIa, or XXIb wherein all groups are as defined in any of the embodiments described herein for Formulas XX, XXa, XXb, XXc, XXd, XXe, or XXf, or optionally a single stereoisomer or mixture of stereoisomers thereof and additionally optionally a pharmaceutically acceptable salt thereof.
  • the compound or salt has a Formula XX, XXa, XXb, XXc, XXd, XXe, XXf, XXI, XXIa, or XXIb, wherein the compound is selected from
  • the compound or salt has a Formula XX, XXa, XXb, XXc, XXd, XXe, XXf, XXI, XXIa, or XXIb, wherein the compound is selected from Table 4 consisting of Examples 1-121.
  • a pharmaceutical composition comprising of a compound disclosed hereinor a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition comprises a compound of Formula I, la, lb, or II, or a compound of Table 1, or stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition comprises a compound of Formula III, or a compound of Table 2, or stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition comprises a compound of Formula X, Xa, or Xb, or a compound of Table 3, or stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • the pharmaceutical composition comprises a compound of Formula XX, XXa, XXb, XXc, XXd, XXe, XXf, XXI, XXIa, or XXIb, or a compound of Table 4, or stereoisomers thereof, or a pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients.
  • Excipients include, for example, encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof
  • encapsulating materials or additives such as absorption accelerators, antioxidants, binders, buffers, coating agents, coloring agents, diluents, disintegrating agents, emulsifiers, extenders, fillers, flavoring agents, humectants, lubricants, perfumes, preservatives, propellants, releasing agents, sterilizing agents, sweeteners, solubilizers, wetting agents and mixtures thereof
  • Suitable excipients are well known to those skilled in the art, and non-limiting examples of suitable excipients are provided herein. Whether a particular excipient is suitable for incorporation into a pharmaceutical composition or dosage form depends on a variety of factors well known in the art, including, but not limited to, the method of administration. The suitability of a particular excipient may also depend on the specific active ingredients in the dosage form.
  • All the compounds and pharmaceutical compositions provided herein can be used in all the methods provided herein.
  • the compounds and pharmaceutical compositions provided herein can be used in all the methods for treatment of all diseases, disorders or conditions provided herein.
  • the compounds and pharmaceutical compositions provided herein are for use as a medicament.
  • compositions provided herein are for use in a method for the treatment of a disease or disorder that is mediated by the enzyme CGT.
  • the compounds and pharmaceutical compositions provided herein are for use in a method for the treatment of a disease or disorder in which inhibition of the enzyme CGT ameliorates or treats the disease or disorder.
  • a compound provided herein is a compound of Formula I, la, or lb, or a compound of Formula II, or a compound of Table 1, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof.
  • a compound provided herein is a compound of Formula III, or a compound of Table 2, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof.
  • a compound provided herein is a compound of Formula X, Xa, or Xb, or a compound of Table 3, or stereoisomers thereof, and additionally optionally a pharmaceutically acceptable salt thereof.
  • a compound provided herein is a compound of Formula XX, XXa, XXb, XXc, XXd, XXe, XXf, XXI, XXIa, or XXIb, or a compound of Table 4, or stereoisomers thereof, and additionally optionally a
  • the compounds described herein are used in the preparation or manufacture of medicaments for the treatment of a disease or disorder that is mediated by the enzyme CGT or in which inhibition of the enzyme CGT ameliorates or treats the disease or disorder.
  • a method for treating any of the diseases or disorders described herein comprising
  • a method for treating any of the diseases or disorders described herein comprising administering to a subject in need of treatment thereof a compound according to any of the various embodiments described herein.
  • provided herein is a method of treating a disease or disorder ameliorated by the inhibition of CGT comprising administering to a subject having the disease or disorder a therapeutically effective amount of a compound provided herein.
  • the disease or disorder is mediated by the enzyme ceramide galactosyltransferase (CGT).
  • CCT ceramide galactosyltransferase
  • the disease or disorder mediated by CGT is a lysosomal storage disease.
  • the disease or disorder is a lysosomal storage disease.
  • lysosomal storage diseases include, for example, Krabbe disease and MLD.
  • the disease or disorder is Krabbe disease.
  • the disease or disorder is MLD.
  • the disease or disorder mediated by CGT is a neurodegenerative disorder.
  • neurodegenerative disorders include, for example, Parkinson’s disease.
  • the disease or disorder is Parkinson’s disease.
  • the disease or disorder mediated by CGT is a demyelinating leukodystrophy.
  • the disease or disorder mediated by CGT is an autoimmune disease.
  • autoimmune diseases include, for example, multiple sclerosis.
  • the disease or disorder is multiple sclerosis.
  • compositions disclosed herein can be administered in therapeutically effective amounts via any of the usual and acceptable modes known in the art, either singly or in combination with another therapeutic agent.
  • the compounds are typically administered as pharmaceutical compositions by any route which makes the compound bioavailable.
  • the composition is a solid formulation adapted for oral administration.
  • the composition is a tablet, powder, or capsule; or the composition is a tablet.
  • the composition is a liquid formulation adapted for oral administration.
  • the composition is a liquid formulation adapted for parenteral administration.
  • the composition is a solution, suspension, or emulsion; or the composition is a solution.
  • solid form compositions can be converted, shortly before use, to liquid form compositions for either oral or parenteral administration.
  • These particular solid form compositions are provided in unit dose form and as such are used to provide a single liquid dosage unit.
  • These dosage forms can be prepared according to conventional methods and techniques known to those skilled in the art (see, Remington: The Science and Practice of Pharmacy, supra;
  • the dosages may be varied depending on the requirement of the patient, the severity of the disease or disorder being treating and the particular compound and/or composition being employed. Determination of the proper dosage can be determined by one skilled in the medical arts.
  • the total daily dosage may be divided and administered in portions throughout the day or by means providing continuous delivery.
  • the compounds are administered to a subject at a daily dosage of between 0.01 to about 50 mg/kg of body weight. In other embodiments, the dose is from 1 to 1000 mg/day. In certain embodiments, the daily dose is from 1 to 750 mg/day; or from 10 to 500 mg/day.
  • the pharmaceutical composition is in unit dosage form.
  • the composition can be subdivided into unit doses containing appropriate quantities of the active component(s).
  • the unit dosage form can be a tablet, capsule, or powder in a vial or ampule, or it may be the appropriate number of any of these in a packaged form.
  • the unit dosage form can be a packaged form, the package containing discrete quantities of composition such as packeted tablets, capsules, or powders in vials or ampules.
  • the quantity of active compound(s) in a unit dose of the composition may be varied or adjusted from about 1 mg to about 100 mg, or from about 1 mg to about 50 mg, or from about 1 mg to about 25 mg.
  • the compounds or pharmaceutical compositions disclosed herein can be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations.
  • protease inhibitor cocktail P8340, Sigma, Saint Louis, MO.
  • M- PER protease inhibitor cocktail
  • Protein concentration was determined using a Pierce BCA protein assay kit (ThermoFisher Scientific).
  • Four micrograms of CHO/CGT lysate was incubated with various concentrations of a compound (0.001 pM - 50 pM) in 10 mM HEPES (pH 7.2) containing 35 pM dioleoylphosphatidylcholine, 5 mM MgCh, 5 mM MnCh,
  • the mass transition of C6-NBD-dihydro-galactosylceramide was m/z 752.6 ⁇ 678.6 using a -40 V collision energy
  • the mass transition of C6-NBD-dihydro-ceramide was m/z 590.6— >115.8 using a -40 V collision energy
  • the mass transition of N-docdecanoyl-NBD- galactosylceramide was m/z 820.9®746.3 using a -45 V collision energy.
  • the C6-NBD-dihydro-galactosylceramide reading was normalized first by dividing the peak area of C6-NBD-dihydro-galactosylceramide by the peak area of the internal standard, N-docdecanoyl-NBD-galactosylceramide.
  • ICso values (see Table 1, data ranges correspond to analysis using the RapidFire/MS/MS method with 0.01% Tween 80 added) were generated from sigmoidal dose-response curves (variable slope) with GraphPad Prism software (GraphPad Software, Inc., San Diego, CA) using the normalized peak areas of C6-NBD-dihydro-galactosylceramide or the percent inhibition of C6-NBD-dihydro- galactosylceramide accumulation relative to DMSO control.
  • RapidFire/MS/MS method can be used to generate ICso values.
  • the method is identical to the one described above except that 0.01% tween is not used.
  • A is ⁇ 1 mM
  • C is > 10 to 50 pM
  • D is > 50 to 100 pM
  • LC-MS/MS based method can be used.
  • the CGT assay is identical to the one described above except for the following: 10 pg of CHO/CGT lysate can be used as the CGT enzyme source, 02:0 (2R-OH) ceramide can be used as the ceramide substrate and 0.3 mM 02 ceramide can be used as the internal standard. Tween 80 is not present in the reaction mixture. The final supernatant can be injected for LC-MS/MS analysis.
  • Biosystems can be used to control the LC-MS/MS system, as well as for data acquisition and processing. 10 pL of sample can be loaded onto a Luna C18 column (50mmx2.0mm, I.D.
  • Mobile phase A can consist of HPLC grade water with 0.1% formic acid (v/v) and mobile phase B can consist of acetonitrile supplemented with 0.1% formic acid (v/v).
  • the separation can be achieved using the following gradient program at a flow rate of 0.8 mL/min: the initial mobile phase can be 70% B, which can be increased in a linear fashion to 95% B in 1.50 min, and then maintained at 95% B until 3.50 min. The mobile phase can then be reset to 70% B within 0.01 min, and maintained until 4.50 min. The total run time can be 4.50 min.
  • the MS/MS detection can be performed in ESI positive mode.
  • the mass transition selected for quantification can be m/z 498.5 264.3 for 02:0 (2R-OH) ceramide under the collision energy of 38.8 V, and the mass transition of 02:0 (2R-OH) galactosylceramide can be m/z 660.6 264.5 under the collision energy of 51 V.
  • the mass transition of 02 ceramide used as internal standard can be m/z 482.4 264.3 under the collision energy of 33 V.
  • Compound ICso values can be calculated using a protocol identical to the one described for the RapidFire method.
  • a stable cell line overexpressing human full-length CGT was made by transfecting Chinese hamster ovary (CHO) cells with 10 pg hCGT-pcDNA3.l(+) DNA and 30 pL of X-tremeGENE HP DNA transfection reagent (6366236001, Roche, Indianapolis, IN), followed by 800 pg/mL G418 selection.
  • CHO cells stably expressing human full-length CGT (B5 cells) were seeded onto a CytoOne 96-well TC plate (USA Scientific, CC7682- 7596) at 3xl0 4 cells/well in F12K media containing 10% FBS and incubated overnight at 37°C, 5% CO2.
  • test compounds were serially diluted in DMSO (1 mM to 0.1 pM) followed by a lOO-fold dilution with F12K media containing 5% FBS. 10 pL of compound was added to the cells and incubated at 37°C, 5% CO2 for 2 hours. The final concentration of DMSO was 0.1% in both compound-treated and mock-treated cells.
  • the C6-NBD-dihydro-ceramide substrate was diluted with F12K medium containing 5% FBS and 11% BSA to make a 110 pM substrate solution. 10 pL of substrate solution was added to the plate and incubated at 37°C, 5% CO2 for 1 hour. Following the reaction, the plate was washed two times with PBS followed by the addition of 120 pL of lipid extraction solvent (methanol with 0.5% acetic acid) containing 1 mIUI of N-dodecanoyl-NBD-galactosylceramide (internal standard). The sealed plate was placed on shaker for 2 hours (around 20 RPM) to extract product.
  • lipid extraction solvent methanol with 0.5% acetic acid
  • Mobile phase A consisted of HPLC grade water with 0.1% formic acid (v/v)
  • mobile phase B consisted of acetonitrile supplemented with 0.1% formic acid (v/v).
  • the separation was achieved using the following gradient program at a flow rate of 0.7 mL/min: the initial mobile phase was 35% B and was ramped in a linear fashion to 98% B in 2.40 min. From 2.40 to 3.00 min, the gradient was maintained at 98% B. Then, mobile phase was reset to 35% B in 0.01 min, and maintained until 3.50 min. The total run time was 3.50 mins.
  • the MS/MS detection was performed in ESI negative mode.
  • the mass transition of C6-NBD-dihydro-ceramide was m/z 590.4®516.4 under the collision energy of -34 V.
  • the mass transition of C6-NBD-dihydro-galactosylceramide was m/z 752.4®678.5 under the collision energy of -46 V.
  • the mass transition of N-Dodecanoyl- NBD-galactosylceramide which was used as internal standard was m/z 820.5®l 15.6 under the collision energy of -72V.
  • Compound ICso values were calculated using a protocol identical to the one described above for the CGT enzyme assay.
  • A is ⁇ 1 pM
  • B is > 1 to 10 pM
  • A is ⁇ 1 mM
  • A is ⁇ 1 mM
  • C is > 10 to 30 pM
  • D is > 30 to 100 pM; and NT is not tested.
  • mice were dosed with CGT inhibitors daily by intraperitoneal injection starting on postnatal day 3 or postnatal day 15 and mice were sacrificed on postnatal day 28 or postnatal day 40 respectively.
  • Brain tissue was collected from the treated ARSA knockout mice and ceramide and hydroxylated-ceramides were quantified ( Figures 8A-8D).
  • Ceramide and hydroxylated- ceramide were also evaluated in normal mice that were treated with CGT inhibitors daily by intraperitoneal injection starting on postnatal day 15 and sacrificed on postnatal day 70 after 8 weeks of treatment. Brains were collected from these mice and ceramide and non-HO ceramides were quantified as describe below ( Figures 9A-9B).
  • the vehicle that was used to dissolve compounds for these studies was 5% DMAc, 10% Solutol, 85% 10 mM Citrate buffer (pH 4.5).
  • GalCer(s) and hydroxylated GalCer(s) were quantified from mouse brain matrix using an Agilent 6410, triple quadrupole LCMS machine in positive ion, ESI mode. Brain tissue samples were homogenized for 2 minutes with 3 volumes of (v/w) of H2O. An aliquot of 25 uL of 3 fold diluted tissue homogenate was combined with 50uL DMSO, 200 ul of methanol, and 625uL acetone/methanol (50/50) followed by shaking on a vortexer for 30 minutes. 450 uL of water/methanol (13/87) was added and the samples were then centrifuged for 5 minutes at 14000 rmp in a room temperature microcentrifuge.
  • l200uL of the supernatant was transferred onto a pre-conditioned Cl 8 SPE cartridge and washed with 2mL methanol/acetone/water (67/23/10).
  • the GalCer(s) were eluted with l.5mL acetone/methanol (90/10).
  • the eluent was then evaporated to dryness before reconstitution in 50uL DMSO (including IS) and 200ACN. 3 uL of supernatant was injected into the LCMS for analysis.
  • GalCer(s) were quantified using a standard curve based on the sum intensity of 8 major GalCer(s) isoforms present in a purified pool on non-hydroxylated GalCer(s) (Matreya Cat# 1066)
  • a deuterated C18- GalCer was used as an internal standard (Avanti #860638P)
  • the GalCer(s) species were separated on a Halo-Hilic column (4.6x 150 mm, 2.7 pm) with a mobile phase consisting of 95/2.5/2.5 ACN/MeOH/H20 with 0.5 formic acid +5mM NH 4 OAc.
  • the HPLC was run at 50°C at a flow rate of 0.5 ml/min for 9.5 minutes.
  • Hydroxylated GalCer(s) were quantified using similar methods to those described above for the non-hydroxylated species with the one exception that a purified pool of hydroxylated GalCer(s) (Matreya Cat#l 138) were used to identify 8 major hydroxylated GalCer(s) and the sum intensity of these analytes was used to make a standard curve. All other extraction and chromatography steps were the same as those for non-hydroxylated GalCer(s).
  • Sulfatide(s) and hydroxylated-sulfatide(s) were quantified from mouse brain matrix using an UPLC-MS/MS Triple QuadTM 6500 machine. Brain tissue samples were homogenized for 2 minutes with 3 volumes of (v/w) of H2O. 20 uL of the brain homogenate was spiked into 180 uL of acetonitrile/FbO (v/v 1 : 1). 20 uL of this solution was then further diluted into 80 uL acetonitrile/FhO (v/v 1 : 1) before adding 300 uL of acetonitrile containing 200 ng/nL internal standard. The mixture was vortexed for 10 min and centrifuged at 5800 rpm for 10 min. An aliquot of 3 pL supernatant was injected for LC-MS/MS analysis.
  • Sulfatide(s) and lyso-sulfatide were quantified using a standard curve based on the sum intensity of 7 major sulfatide(s) isoforms or 7 major hydroxylated sulfatide(s) isoforms present in a purified pool of total sulfatide(s) (Matreya Cat# 1049)
  • a deuterated C18- sulfatide(s) was used as an internal standard (Matreya Cat #1536).
  • the sulfatide(s) species were separated on a ACE 5 C18 (2.1X50 mm, 5 pm) column.
  • Mobile phase A consisted of H 2 0-5mM NLLOAc and mobile phase B consisted of acetonitrile. The flow rate was 0.60 mL/min at 60 °C. Mobile phase A was mixed with mobile phase B at the following run time at the specified percentages: at 0.3 min 10% B, at 0.6 min 45% B, at 3 min 90% B, at 4.10 min 90% B, at and 4.11 min 10 % B. The total run time was 5.20 minutes.
  • Deuterated glucosylsphingosine was used as an internal standard (Avanti Cat # 860636).
  • HPLC For the HPLC conditions psychosine was separated on Shimadzu HPLC/ Autosampler with Halo Hilic (l50mm, 5pm) column.
  • Mobile phase A consisted of 0.5% FA
  • 5mM MLOAc in water
  • mobile phase B consisted of ACN / MeOH / 0.5% FA 5mM MLOAc; (95/2.5/2.5).
  • Data from the above LC-MS/MS method was calculated as relative to total brain weight.
  • C24 l Galactosylceramide and C24: l hydroxylated galactosylceramide were quantified from mouse brain matrix using an API-4000 Qtrap Mass Spectrometer. Brain tissue samples were homogenized with 4 volumes of (v/w) of H2O. Homogenized brain samples were diluted by 20 fold and then by 400 fold by adding 5pL of the sample to 95 pL of .01M PBS, and then further diluting 2pL of this dilution into 98pL of .01M PBS. 20 uL of internal standard (Avanti Cat#860638 at 20 ug/ml) and 280 uL of ACN was added to the diluted homogenate.
  • internal standard Advanti Cat#860638 at 20 ug/ml
  • Lysosulfatide was quantified from mouse brain matrix using an UPLC- MS/MS-22 Triple QuadTM 6500 Mass Spectrometer. Brain tissue samples were
  • lysosulfatide was separated on ACE 5 C18 (2.1 x50 mm, 5 pm) column.
  • Mobile phase A consisted of H20-5mM NH40Ac and mobile phase B consisted of ACN.
  • Mobile phase A was mixed with mobile phase B at the following percentages and times: 0.3 minute- 10% B, 0.4 minute-45% B, 1.3 minute-85% B, and 1.91 minute 10% B.
  • Total run time was 5.2 minutes with at flow rate of 0.60 mL/min at 60 °C. Data from the above LC-MS/MS method was calculated as relative to total brain weight.
  • Ceramide(s) and hydroxylated ceramide(s) were quantified from ARSA knockout mouse brain matrix using a LC-MS/MS API-4000 triple quadrupole machine.
  • Brain tissue samples were homogenized for with 3 volumes of (v/w) of H2O. 30 uL of this homogenate was diluted into 1470 uL H2O. 30 uL of the diluted homogenate is added to 100 uL of methanol containing 100 ng/mL of internal standard and 200 uL methanol/chloroform (1 : 1). The mixture was vortexed for 15 minutes and centrifuged for 5 minutes at 14000 rpm in microcentrifuge and the supernatant was dried under nitrogen gas. The dried extracts were then reconstituted by vortexing in 200 uL methanol for 5 minutes. An aliquot of 3 pL supernatant was injected for LC-MS/MS analysis.
  • Ceramides were quantified using individual purified ceramide standards including C24:0 ceramide, C24: l ceramide, C24:0 hydroxylated ceramide, and C24: l hydroxylated ceramide (Avanti Cat#860524, 860525, 860823, and 860825 respectively).
  • a deuterated Cl8-ceramide was used as an internal standard (Matreya Cat#2201 )
  • the sulfatide(s) species were separated on a Waters BEH C18 (2.l*50mm,2.5pm) column.
  • Mobile phase A consisted of H2O- 0.1% formic acid-2mM NLLOAc and mobile phase B consisted of MeOH- 1% formic acid-2mM NLLOAc.
  • the flow rate was 0.50 mL/min at 60 °C.
  • Mobile phase B was mix with mobile phase A at the following run times at the specified percentages: at 0.3 min 50% B, at 1.5 min 85% B, at 4 min 98% B, at 7.20 min 98% B, at and 7.21 min 50 % B.
  • the total run time was 8 minutes.
  • Ceramide(s) and hydroxylated ceramide(s) were quantified from normal wild type mice using a Waters Xevo TQ-S Micro mass spectrometer. Brain tissue samples were homogenized in 0.5 mL of H2O using a probe homogenizer (15 sec 6500 rpm). An aliquot was used to determine protein concentration using a standard BCA assay. Brain samples were diluted to 4 ug/uL of total protein and 50 uL was extracted in 500 pL acidified methanol (95% methanol, 5% glacial acetic acid v/v). Samples were extracted at room temperature for > 2 hours with vortexing every 15-20 minutes.
  • Twitcher Mouse model (“Twitcher”) is a naturally-occurring mouse mutant caused by an abnormality in the gene coded for galactosylceramidase (Kobayashi et al., Brain Res. 202: 479-483 (1980); Suzuki and Suzuki , Am. ./. Path. Ill: 394-397 (1983)). It is therefore genetically equivalent to human globoid cell leukodystrophy (Krabbe disease). Affected mice develop clinical symptoms at the onset of the active myelination period and, if untreated, die by 35 ⁇ days. The pathology is very similar to that in human disease. Toxicity of galactosylsphingosine (psychosine) that accumulates abnormally in the nervous system is considered to be primarily responsible for the pathogenesis.
  • CGT inhibitors have been identified having low nanomolar potency in both enzyme and cellular assays of CGT activity ( Figures 2A-2F). Pharmacokinetic studies show that these inhibitors are relatively stable in mice and they penetrate efficiently into the brain tissue ( Figures 3A-3F). The discovery of these CGT inhibitors with excellent drug like properties made it possible to test the impact of CGT inhibition in the mouse brain. The pharmacokinetics of six compounds (Compounds A-F) were tested in WT mice after a single 20 mg/kg IP injection. Plasma and brain concentrations are shown over a 24 hr time-course.
  • mice were dosed daily by IP injection from postnatal day 3 to postnatal day 40. On postnatal day 40, the mice were sacrificed and the levels of brain GalCer(s) and hydroxylated GalCer(s) were monitored using LCMS. The data shown is the sum of the major GalCer(s) acyl chain lengths including Cl 8, C20, C22, C24, and C24: l forms. These studies demonstrate how Compounds A-F efficiently decrease the formation of the GalCer(s) and increase the formation of the hydroxylated GalCer(s). At higher doses of the more potent and long lived CGT inhibitors (e.g ., Compound B), a decrease in the formation of both the GalCer(s) and the hydroxylated GalCer(s) is observed.
  • CGT inhibitors e.g ., Compound B
  • mice were dosed daily by IP injection starting from postnatal day 3 to postnatal day 40. On postnatal day 40, the mice were sacrificed and the levels of brain sulfatide(s) and hydroxylated sulfatide(s) were monitored using LCMS. The data shown is the sum of the major sulfatide(s) acyl chain lengths including Cl 8, C20, C22, C24, and C24: l forms. These studies demonstrate how Compounds A-F efficiently decrease the formation of the sulfatide(s) and increase the formation of the hydroxylated sulfatide(s).
  • Twitcher mice were dosed daily with Compound A by IP injection starting from postnatal day 3 to postnatal day 28. On postnatal day 28, the mice were sacrificed and the brain levels of psychosine, C24: 1 GalCer, and hydroxylated C24: 1 GalCer were monitored using LCMS. The effects of the CGT inhibitors disclosed herein on the C24: 1 GalCer was similar for all other major acyl chain lengths.
  • ARSA knockout mice were dosed daily with Compound A by IP injection starting from postnatal day 3 to postnatal day 28. On postnatal day 28, the mice were sacrificed and the brain levels of lyso-sulfatide, sulfatide(s), and hydroxylated sulfatide(s) were monitored using LCMS. Similar to the Krabbe disease mice studies, the CGT inhibitors disclosed herein, such as Compound A, decrease levels of lyso-sulfatide in a MLD mouse model and the decrease in the levels of this toxic compound correlates with the decrease of the non-hydroxylated sulfatide levels and not the hydroxylated sulfatide levels.
  • the CGT enzyme utilizes a large amount of ceramide substrate to generate the abundant amount of hydroxylated and non-hydroxylated GalCer(s) and hydroxylated and non-hydroxylated sulfatide(s) that make up the mylein sheath. Therefore, blocking GalCer(s) formation may be expected to result in a significant increase in hydroxylated and non-hydroxylated ceramide levels in these cells.
  • the ceramide(s) and hydroxylated ceramide(s) levels in the brains of mice were monitored when treated with a CGT inhibitor (Compound A) ( Figures 8A-8D).
  • ARSA knockout mice were dosed daily with Compound A by IP injection starting from postnatal day 3 to postnatal day 28 or postnatal day 15 to postnatal day 40 as indicated. On postnatal day 28 or 40, the mice were sacrificed and the brain levels of both hydroxylated and non- hydroxylated ceramides were monitored using LCMS. The data shown is for the C24 and C24: l acyl chain length ceramides.
  • a method of inhibiting ceramide galactosyl transferase (CGT) in a subject comprising: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii)(a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; and (iii)(b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said
  • a method of inhibiting CGT in a subject comprising: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) inhibits conversion of ceramide(s) to GalCer(s) in the subject such that the GalCer(s) level in the subject is less than the GalCer(s) level in the absence of said administration; (ii) increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject such that the hydroxylated GalCer(s) level in the subject is greater than the hydroxylated GalCer(s) level in the absence of said administration; (iii) inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject such that: (a) the GalCer(s) level in the subject is less than the GalCer(s) level in the absence of
  • GalCer(s) in a subject comprising: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) inhibits CGT and decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) inhibits CGT and increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii) inhibits CGT and: (a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration, and (b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; or (iv) inhibits CGT and inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxyl
  • a method of increasing conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in a subject comprising: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) inhibits CGT and decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) inhibits CGT and increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii) inhibits CGT and: (a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration, and (b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; or (
  • a method of reducing GalCer(s) levels in a subject comprising: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) inhibits CGT and decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) inhibits CGT and increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii) inhibits CGT and: (a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration, and (b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; or (iv) inhibits CGT and inhibits conversion of cer
  • hydroxylated GalCer(s) in the subject such that the ratio of the hydroxylated GalCer(s) level to the GalCer(s) level in said subject is in the range of between 200: 1 to 1 : 1.
  • a method of increasing hydroxylated GalCer(s) levels in a subject comprising: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) inhibits CGT and decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) inhibits CGT and increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii) inhibits CGT and: (a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration, and (b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; or (iv) inhibits CGT and inhibits
  • CGT in a subject comprising: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii)(a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; and (iii)(b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said
  • CGT in a subject comprising: a) identifying a CGT inhibitor that: i) inhibits conversion of ceramide(s) to GalCer(s); ii) increases conversion of hydroxylated ceramide(s) to
  • hydroxylated GalCer(s) inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s); and b) administering to the subject a therapeutically effective amount of the identified CGT inhibitor.
  • CGT in a subject comprising: a) identifying a CGT inhibitor that: i) decreases GalCer(s) levels in a subject; ii) increases hydroxylated GalCer(s) levels in a subject; or iii) decreases GalCer(s) levels and increases hydroxylated GalCer(s) levels in a subject; and b)
  • a method of treating a disease or disorder mediated by CGT in a subject comprising: a) identifying a subject with cells or tissue having
  • GalCer(s) levels equal to or greater than hydroxylated GalCer(s) levels; and b) administering to the subject a therapeutically effective amount of a CGT inhibitor.
  • a method of treating a disease or disorder mediated by CGT in a subject comprising: a) identifying a therapeutically effective dose of a CGT inhibitor that: i) decreases GalCer(s) levels in a subject; ii) increases hydroxylated GalCer(s) levels in a subject; or iii) decreases GalCer(s) levels and increases hydroxylated GalCer(s) levels in a subject; and b) administering to the subject the therapeutically effective dose of the CGT inhibitor.
  • a method of treating a disease or disorder mediated by CGT in a subject comprising: a) obtaining a biological sample from a subject having or diagnosed as having the disease or disorder mediated by CGT; b) determining levels of GalCer(s) and/or hydroxylated GalCer(s) in the biological sample, wherein i) if the GalCer(s) level following administration is not decreased by at least 10% relative to the GalCer(s) level in the subject in the absence of or prior to the administration; ii) if the hydroxylated GalCer(s) level following administration is not increased by at least 10% relative to the hydroxylated GalCer(s) level in the subject in the absence of or prior to the administration; iii) if the GalCer(s) level following administration is not decreased by at least 10% and the
  • hydroxylated GalCer(s) level following administration is not increased by at least 10% relative to the respective GalCer(s) level and hydroxylated GalCer(s) level in the subject in the absence of or prior to the administration; and/or iv) if the GalCer(s) level relative to the hydroxylated GalCer(s) level in the biological sample is equal to or greater than about 1 : 1; then: c) administering a therapeutically effective amount of a CGT inhibitor to treat the disease or disorder.
  • a method for monitoring efficacy of treatment of a subject having or diagnosed as having a disease or disorder mediated by CGT comprising: a) administering a first dosage amount of a CGT inhibitor to the subject; b) obtaining a biological sample from the subject following administration of the CGT inhibitor; c) determining levels of GalCer(s) and/or hydroxylated GalCer(s) in the biological sample, wherein i) if the GalCer(s) level following administration is not decreased by at least 10% relative to the GalCer(s) level in the subject in the absence of or prior to the administration; ii) if the hydroxylated GalCer(s) level following administration is not increased by at least 10% relative to the hydroxylated GalCer(s) level in the subject in the absence of or prior to the administration; iii) if the GalCer(s) level following administration is not decreased by at least 10% and the hydroxylated GalCer(s) level following
  • a method of assessing the efficacy of a CGT inhibitor in treating a disease or disorder mediated by CGT comprising: a) administering the CGT inhibitor to a subject having or diagnosed as having the disease or disorder mediated by CGT; b) obtaining a biological sample from the subject after administering the CGT inhibitor; c) determining levels of GalCer(s) and/or hydroxylated GalCer(s) in the biological sample; d) comparing the levels of GalCer(s) and/or hydroxylated GalCer(s) in the biological sample from step (c) to the levels of GalCer(s) and/or hydroxylated GalCer(s) from a reference biological sample; wherein a decrease in the level of GalCer(s) and/or an increase in the level of hydroxylated GalCer(s) is indicative of the efficacy of the CGT inhibitor in treating the disease or disorder mediated by CGT.
  • a CGT inhibitor for use in the inhibition of CGT in a subject comprising: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii)(a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; and (iii)(b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said
  • a CGT inhibitor for use in the inhibition of CGT in a subject comprising: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) inhibits conversion of ceramide(s) to GalCer(s) in the subject such that the GalCer(s) level in the subject is less than the GalCer(s) level in the absence of said administration; (ii) increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject such that the hydroxylated GalCer(s) level in the subject is greater than the hydroxylated GalCer(s) level in the absence of said administration; (iii) inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject such that: (a) the GalCer(s) level in the subject is less than the GalCer(s
  • a CGT inhibitor for use in inhibiting conversion of ceramide(s) to GalCer(s) in a subject comprising: administering to the subject a
  • a CGT inhibitor comprising: (i) inhibits CGT and decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) inhibits CGT and increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii) inhibits CGT and: (a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration, and (b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; or (iv) inhibits CGT and inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject
  • a CGT inhibitor for use in increasing conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in a subject comprising: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said
  • administering inhibits CGT and decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) inhibits CGT and increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii) inhibits CGT and: (a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration, and (b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; or (iv) inhibits CGT and inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject such that the ratio of the hydroxylated GalCer(
  • a CGT inhibitor for use in reducing GalCer(s) levels in a subject comprising: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) inhibits CGT and decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) inhibits CGT and increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii) inhibits CGT and: (a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration, and (b) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; or (iv) inhibits CGT and inhibit
  • GalCer(s) levels in a subject comprising: administering to the subject a therapeutically effective amount of a CGT inhibitor; wherein said administration (i) inhibits CGT and decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; (ii) inhibits CGT and increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration; (iii) inhibits CGT and: (a) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration, and (b) increases the level of hydroxylated GalCer(s) in the subject relative to the
  • hydroxylated GalCer(s) level in the subject in the absence of said administration inhibits CGT and inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject such that the ratio of the hydroxylated GalCer(s) level to the GalCer(s) level in said subject is in the range of between 200: 1 to 1 : 1.
  • a CGT inhibitor for use in treating a disease or disorder mediated by CGT in a subject comprising: administering to the subject a
  • a CGT inhibitor for use in treating a disease or disorder mediated by CGT in a subject comprising: a) identifying a CGT inhibitor that: i) inhibits conversion of ceramide(s) to GalCer(s); ii) increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s); or iii) inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s); and b) administering to the subject a therapeutically effective amount of the identified CGT inhibitor.
  • a CGT inhibitor for use in treating a disease or disorder mediated by CGT in a subject comprising: a) identifying a CGT inhibitor that: i) decreases GalCer(s) levels in a subject; ii) increases hydroxylated GalCer(s) levels in a subject; or iii) decreases GalCer(s) levels and increases hydroxylated GalCer(s) levels in a subject; and b) administering to the subject a therapeutically effective amount of the identified CGT inhibitor.
  • a CGT inhibitor for use in treating a disease or disorder mediated by CGT in a subject comprising: a) identifying a subject with cells or tissue having GalCer(s) levels equal to or greater than hydroxylated GalCer(s) levels; and b) administering to the subject a therapeutically effective amount of a CGT inhibitor.
  • a CGT inhibitor for use in treating a disease or disorder mediated by CGT in a subject comprising: a) identifying a therapeutically effective dose of a CGT inhibitor that: i) decreases GalCer(s) levels in a subject; ii) increases hydroxylated GalCer(s) levels in a subject; or iii) decreases GalCer(s) levels and increases hydroxylated GalCer(s) levels in a subject; and b) administering to the subject the
  • a CGT inhibitor for use in the treatment of a disease or disorder mediated by CGT in a subject comprising: (a) obtaining a biological sample from the subject having or diagnosed as having the disease or disorder mediated by CGT; (b) determining levels of GalCer(s) and/or hydroxylated GalCer(s) in the biological sample, wherein: (i) if the GalCer(s) level following administration is not decreased by at least 10% relative to the GalCer(s) level in the subject in the absence of or prior to the administration; (ii) if the hydroxylated GalCer(s) level following administration is not increased by at least 10% relative to the hydroxylated GalCer(s) level in the subject in the absence of or prior to the administration; (iii) if the GalCer(s) level following administration is not decreased by at least 10% and the hydroxylated GalCer(s) level following administration is not increased by at least 10% relative to the respective GalCer(
  • a CGT inhibitor for use in the treatment of a disease or disorder mediated by CGT in a subject having or diagnosed as having a disease or disorder mediated by CGT comprising: (a) administering a first dosage amount of the CGT inhibitor to the subject; (b) obtaining a biological sample from the subject following administration of the CGT inhibitor; (c) determining levels of GalCer(s) and/or hydroxylated GalCer(s) in the biological sample, wherein: (i) if the GalCer(s) level following administration is not decreased by at least 10% relative to the GalCer(s) level in the subject in the absence of or prior to the administration; (ii) if the hydroxylated GalCer(s) level following administration is not increased by at least 10% relative to the hydroxylated GalCer(s) level in the subject in the absence of or prior to the administration; (iii) if the GalCer(s) level following administration is not decreased by at least 10% and the
  • administration is not increased by at least 10% relative to the respective GalCer(s) level and hydroxylated GalCer(s) level in the subject in the absence of or prior to the administration; and/or (iv) if the GalCer(s) level relative to the hydroxylated GalCer(s) level in the biological sample is equal to or greater than about 1 : 1; then: (d) adjusting dosage of the CGT inhibitor to an adjusted dosage based on the levels determined in step (c); and (e) administering the adjusted dosage of the CGT inhibitor to the subject.
  • a CGT inhibitor for use in the treatment of a disease or disorder mediated by CGT in a subject comprising: (a) administering the CGT inhibitor to the subject having or diagnosed as having the disease or disorder mediated by CGT; (b) obtaining a biological sample from the subject after administering the CGT inhibitor; (c) determining levels of GalCer(s) and/or hydroxylated GalCer(s) in the biological sample; (d) comparing the levels of GalCer(s) and/or hydroxylated GalCer(s) in the biological sample from step (c) to the levels of GalCer(s) and/or hydroxylated GalCer(s) from a reference biological sample; wherein a decrease in the level of GalCer(s) and/or an increase in the level of hydroxylated GalCer(s) is indicative of the efficacy of the CGT inhibitor in treating the disease or disorder mediated by CGT.
  • one or more than one (including for instance all) of the following further embodiments may comprise each of the other embodiments or parts thereof.
  • Bl The method or use of any one of embodiments A1-A28, wherein said administration decreases the level of GalCer(s) in the subject.
  • B5. The method or use of any one of embodiments A1-A28 or B1-B4, wherein said administration: i) decreases the level of GalCer(s) in the subject relative to the GalCer(s) level in the subject in the absence of said administration; and ii) increases the level of hydroxylated GalCer(s) in the subject relative to the hydroxylated GalCer(s) level in the subject in the absence of said administration.
  • B6 The method or use of any one of embodiments A1-A28 or B1-B5, wherein said administration increases the level of hydroxylated GalCer(s) and decreases the level of GalCer(s) in the subject such that the ratio of the hydroxylated GalCer(s) level to the GalCer(s) level in said subject is in the range of between 200: 1 to 1 : 1.
  • B7 The method or use of any one of embodiments A1-A28 or B1-B6, wherein said administration inhibits conversion of ceramide(s) to GalCer(s) in the subject.
  • B8 The method or use of any one of embodiments A1-A28 or B1-B7, wherein said administration inhibits conversion of ceramide(s) to GalCer(s) in the subject relative to the conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject.
  • B 11 The method or use of any one of embodiments A1 -A28 or B 1 -B 10, wherein said administration inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject.
  • B12 The method or use of any one of embodiments A1-A28 or Bl-Bl 1, wherein said administration inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) in the subject such that the ratio of the hydroxylated GalCer(s) level to the GalCer(s) level in said subject is in the range of between 200: 1 to 1 : 1.
  • B13 The method or use of any one of embodiments A1-A28 or B1-B12, wherein the identified CGT inhibitor inhibits conversion of ceramide(s) to GalCer(s).
  • B14 The method or use of any one of embodiments A1-A28 or B1-B13, wherein the identified CGT inhibitor inhibits conversion of ceramide(s) to GalCer(s) relative to conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s).
  • B16 The method or use of any one of embodiments A1-A28 or B1-B15, wherein the identified CGT inhibitor increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) relative to conversion of ceramide(s) to GalCer(s).
  • B17 The method or use of any one of embodiments A1-A28 or B1-B16, wherein the identified CGT inhibitor inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s).
  • B18 The method or use of any one of embodiments A1-A28 or B1-B17, wherein the identified CGT inhibitor inhibits conversion of ceramide(s) to GalCer(s) and increases conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s) relative to conversion of ceramide(s) to GalCer(s) and conversion of hydroxylated ceramide(s) to hydroxylated GalCer(s), respectively.
  • B20 The method or use of any one of embodiments A1-A28 or B1-B19, wherein the identified therapeutically effective dose of the CGT inhibitor is in the range of between 0.05-1000 mg/kg.
  • B21 The method or use of any one of embodiments A1-A28 or B1-B20, wherein the identified therapeutically effective dose of the CGT inhibitor is 0.05 mg/kg, at least 0.10 mg/kg, at least 0.15 mg/kg, at least 0.20 mg/kg, at least 0.25 mg/kg, at least 0.30 mg/kg, at least 0.40 mg/kg, at least 0.50 mg/kg, at least 1.0 mg/kg, at least 2.0 mg/kg, at least 3.0 mg/kg, at least 4.0 mg/kg, at least 5.0 mg/kg, at least 10 mg/kg, at least 15 mg/kg, at least 20 mg/kg, at least 25 mg/kg, at least 30 mg/kg, at least 40 mg/kg, at least 50 mg/kg, at least 75 mg/kg, at least 100 mg/kg, at least 125 mg/kg, at least 150 mg/kg, at least 200 mg/kg, at least 250 mg/kg at least 300 mg/kg, at least 350 mg/kg, at least 400 mg/
  • B22 The method or use of any one of embodiments A1-A28 or B1-B21, wherein the identified therapeutically effective dose of the CGT inhibitor is in the range of between 0.05-10 mg/kg, between 1.0-10 mg/kg, between 5.0-50 mg/kg, between 25-150 mg/kg, between 100-450 mg/kg, between 250-500 mg/kg, between 400-750 mg/kg, or between 700-1000 mg/kg.
  • B24 The method or use of any one of embodiments A1-A28 or B1-B23, wherein the identified therapeutically effective dose of the CGT inhibitor is a daily dose of at least 5 mg, at least 10 mg, at least 15 mg, at least 25 mg, at least 50 mg, at least 75 mg, at least 100 mg, at least 200 mg, at least 300 mg, at least 400 mg, or at least 450 mg.
  • B25 The method or use of any one of embodiments A1-A28 or B1-B24, wherein if the GalCer(s) level following administration is not decreased in the range of between 10-20%, between 15-30%, between 25-40%, between 35-50%, between 40-60%, between 50-75%, or between 70-90%, relative to the GalCer(s) level in the subject in the absence of or prior to the administration, then administering a therapeutically effective amount of a CGT inhibitor to treat the disease or disorder.
  • B26 The method or use of any one of embodiments A1-A28 or B1-B25, wherein if the hydroxylated GalCer(s) level following administration is not increased in the range of between 10-20%, between 15-30%, between 25-40%, between 35-50%, between 40- 60%, between 50-75%, or between 70-90%, relative to the hydroxylated GalCer(s) level in the subject in the absence of or prior to the administration, then administering a
  • B27 The method or use of any one of embodiments A1-A28 or B1-B26, wherein if the GalCer(s) level following administration is not decreased in the range of between 10-20%, between 15-30%, between 25-40%, between 35-50%, between 40-60%, between 50-75%, or between 70-90%, and the hydroxylated GalCer(s) level following administration is not increased in the range of between 10-20%, between 15-30%, between 25-40%, between 35-50%, between 40-60%, between 50-75%, or between 70-90%, relative to the respective GalCer(s) level and hydroxylated GalCer(s) level in the subject in the absence of or prior to the administration, then administering a therapeutically effective amount of a CGT inhibitor to treat the disease or disorder.
  • B28 The method or use of any one of embodiments A1-A28 or B1-B27, wherein if the GalCer(s) level relative to the hydroxylated GalCer(s) level in the biological sample is in the range of between 1 : 1 to 4: 1, between 5:1 to 8: 1, between 7: 1 to 10: 1, between 9: 1 to 15: 1, between 10: 1 to 20: 1, between 15:1 to 25: 1, or between 20: 1 to 50: 1, then administering a therapeutically effective amount of a CGT inhibitor to treat the disease or disorder.
  • B29 The method or use of any one of embodiments A1-A28 or B1-B28, wherein if the GalCer(s) level relative to the hydroxylated GalCer(s) level in the biological sample is greater than about 2:1, greater than about 3: 1, greater than about 4: 1, greater than about 5:1, greater than about 10: 1, greater than about 15: 1, greater than about 20: 1, greater than about 30: 1, or greater than about 40: 1, then administering a therapeutically effective amount of a CGT inhibitor to treat the disease or disorder.
  • B30 The method or use of any one of embodiments A1-A28 or B1-B29, wherein the first dose amount of the CGT inhibitor is in the range of between 0.05-5.0 mg/kg.
  • B31 The method or use of any one of embodiments A1-A28 or B 1-B30, wherein the first dose amount of the CGT inhibitor is in the range of between 0.02-20 mg/kg.
  • B32 The method or use of any one of embodiments A1-A28 or B 1-B31, wherein the first dose amount of the CGT inhibitor is in the range of between 0.2-100 mg/kg.
  • B33 The method or use of any one of embodiments A1-A28 or B1-B32, wherein the first dose amount of the CGT inhibitor is in the range of between 0.1-50 mg/kg.
  • B34 The method or use of any one of embodiments A1-A28 or B1-B33, wherein the first dose amount of the CGT inhibitor is in the range of between 5-50 mg.
  • B35 The method or use of any one of embodiments A1-A28 or B1-B34, wherein the adjusted dosage amount is a reduced amount relative to the first dosage amount administered to the subject.
  • B36 The method or use of any one of embodiments A1-A28 or B1-B35, wherein the adjusted dosage amount is a reduced amount that is between the range of about 1-5% reduced, about 5-10%, about 10-15% reduced, about 15-20% reduced, about 20-25% reduced, about 25-30% reduced, about 30-35% reduced, about 35-40% reduced, about 40- 45% reduced, about 45-50% reduced, about 50-60% reduced, about 60-70% reduced, about 70-80% reduced, about 80-90% reduced, or about 90-100% reduced, about 100-125% reduced, about 125-150% reduced, about 150-200% reduced, relative to the first dosage amount administered to the subject. [000522] B37.
  • the adjusted dosage amount is a reduced amount that is at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 100%, at least about 150%, or at least about 200%, reduced relative to the first dosage amount administered to the subject.
  • B38 The method or use of any one of embodiments A1-A28 or B1-B37, wherein the adjusted dosage amount is an increased amount relative to the first dosage amount administered to the subject.
  • B39 The method or use of any one of embodiments A1-A28 or B1-B38, wherein the adjusted dosage amount is an increased amount that is between the range of about 1-5% increased, about 5-10%, about 10-15% increased, about 15-20% increased, about 20-25% increased, about 25-30% increased, about 30-35% increased, about 35-40% increased, about 40-45% increased, about 45-50% increased, about 50-60% increased, about 60-70% increased, about 70-80% increased, about 80-90% increased, about 90-100% increased, about 100-125% increased, about 125-150% increased, about 150-200% increased, relative to the first dosage amount administered to the subject.
  • B40 The method or use of any one of embodiments A1-A28 or B1-B39, wherein the adjusted dosage amount is an increased amount that is at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 75%, at least about 90%, at least about 100%, at least about 150%, or at least about 200%, increased relative to the first dosage amount administered to the subject.
  • B41 The method or use of any one of embodiments A1-A28 or B1-B40, wherein a decrease in the level of GalCer(s) in the subject by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, at least about 100%, at least about 120%, or at least about 140%, is indicative of the efficacy of the adjusted dosage in treating the disease or disorder mediated by CGT.
  • B42 The method or use of any one of embodiments A1-A28 or B1-B41, wherein an increase in the level of hydroxylated GalCer(s) in the subject by at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, or at least about 90%, at least about 100%, at least about 120%, or at least about 140%, is indicative of the efficacy of the adjusted dosage in treating the disease or disorder mediated by CGT. [000528] B43.

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Abstract

L'invention concerne des composés, des procédés de préparation de tels composés, des compositions pharmaceutiques et des médicaments contenant de tels composés, et des méthodes d'utilisation de tels composés pour traiter ou prévenir des maladies ou des troubles associés à l'enzyme céramide galactosyltransférase (CGT), par exemple les maladies lysosomales. Des exemples de maladies lysosomales comprennent, par exemple, la maladie de Krabbe et la leucodystrophie métachromatique.
PCT/US2019/043867 2018-07-30 2019-07-29 Inhibiteurs de la céramide galactosyltransférase pour le traitement d'une maladie WO2020028221A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024173234A1 (fr) * 2023-02-13 2024-08-22 Arase Therapeutics Inc. Inhibiteurs de parg

Citations (5)

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Publication number Priority date Publication date Assignee Title
WO2004071390A2 (fr) * 2003-02-14 2004-08-26 Applied Research Systems Ars Holding N.V. Derives de piperazine-2-carboxamide
WO2011070407A1 (fr) * 2009-12-07 2011-06-16 University Of Oxford Composés de désoxynojirimycine n-substituée destinés à l'inhibition de l'ostéoclastogenèse et/ou de l'activation des ostéoclastes
WO2017214505A1 (fr) * 2016-06-10 2017-12-14 Biomarin Pharmaceutical Inc. Inhibiteurs de la céramide galactosyltransférase pour le traitement de maladies
WO2018118838A1 (fr) * 2016-12-20 2018-06-28 Biomarin Pharmaceutical Inc. Inhibiteurs de la céramide galactosyltransférase pour le traitement de maladies
WO2019104011A1 (fr) * 2017-11-21 2019-05-31 Biomarin Pharmaceutical Inc. Inhibiteurs de la céramide galactosyltransférase pour le traitement de maladies

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004071390A2 (fr) * 2003-02-14 2004-08-26 Applied Research Systems Ars Holding N.V. Derives de piperazine-2-carboxamide
WO2011070407A1 (fr) * 2009-12-07 2011-06-16 University Of Oxford Composés de désoxynojirimycine n-substituée destinés à l'inhibition de l'ostéoclastogenèse et/ou de l'activation des ostéoclastes
WO2017214505A1 (fr) * 2016-06-10 2017-12-14 Biomarin Pharmaceutical Inc. Inhibiteurs de la céramide galactosyltransférase pour le traitement de maladies
WO2018118838A1 (fr) * 2016-12-20 2018-06-28 Biomarin Pharmaceutical Inc. Inhibiteurs de la céramide galactosyltransférase pour le traitement de maladies
WO2019104011A1 (fr) * 2017-11-21 2019-05-31 Biomarin Pharmaceutical Inc. Inhibiteurs de la céramide galactosyltransférase pour le traitement de maladies

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024173234A1 (fr) * 2023-02-13 2024-08-22 Arase Therapeutics Inc. Inhibiteurs de parg

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