EP3429590A1 - Procédé et compositions de traitement d'une maladie neurodégénérative chez un sujet porteur du gène d'une sphingolipidose - Google Patents

Procédé et compositions de traitement d'une maladie neurodégénérative chez un sujet porteur du gène d'une sphingolipidose

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Publication number
EP3429590A1
EP3429590A1 EP17767536.0A EP17767536A EP3429590A1 EP 3429590 A1 EP3429590 A1 EP 3429590A1 EP 17767536 A EP17767536 A EP 17767536A EP 3429590 A1 EP3429590 A1 EP 3429590A1
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Prior art keywords
certain embodiments
membered
substituted
alkyl
sample
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EP17767536.0A
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German (de)
English (en)
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EP3429590A4 (fr
Inventor
Peter T. Lansbury
Craig Justman
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Lysosomal Therapeutics Inc
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Lysosomal Therapeutics Inc
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Publication of EP3429590A1 publication Critical patent/EP3429590A1/fr
Publication of EP3429590A4 publication Critical patent/EP3429590A4/fr
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    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia

Definitions

  • the invention relates generally to methods and compositions for treating a
  • neurodegenerative disorder in a subject in need thereof relates to methods and compositions for treating a subject with a neurodegenerative disorder and having a sphingotype indicative that the subject is likely to respond to treatment with an activator of ⁇ - glucocerebrosidase activity.
  • a neurodegenerative disorder for example, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS; also known as Lou Gehrig's disease or motor neuron disease), multiple sclerosis, and diffuse Lewy body disease.
  • ALS amyotrophic lateral sclerosis
  • multiple sclerosis multiple sclerosis
  • diffuse Lewy body disease diffuse Lewy body disease.
  • treatments have been developed that can slow or even reverse the progression of the neurodegenerative disorders in pre-clinical models of disease, for example the MAO-B inhibitors selegiline and rasagiline, the antioxidant Coenzyme Q10, and the anti-apoptotics TCH346 and CEP- 1347, it has been difficult to identify which subjects are likely to respond to a particular therapy. As a result, subjects may be treated with an agent or a combination of agents, even though they may be unlikely to respond to the proposed therapy.
  • the invention is based, in part, upon the discovery that it is possible to identify subjects with a neurodegenerative disorder likely to respond to treatment with an activator of ⁇ - glucocerebrosidase activity based on the sphingotype of the subject.
  • the invention provides method of treating a subject with or at risk of developing a neurodegenerative disorder.
  • the method comprises administering to the subject an effective amount of a ⁇ -glucocerebrosidase activator thereby to treat the subject, wherein prior to administration of the activator, the subject has been determined to have a sphingotype in a tissue, cellular or body fluid sample of the subject indicative that the activator will likely be capable of effectively treating the subject.
  • the invention provides a method of identifying a subject with or at risk of developing a neurodegenerative disorder suitable for treatment by administration of an effective amount of a ⁇ -glucocerebrosidase activator, wherein, prior to administration of the activator, the subject has been determined to have a sphingotype in a tissue, cellular or body fluid sample of the subject indicative that the activator will likely be capable of effectively treating the subject.
  • the sample used for sphingotyping the subject may be a body fluid sample, for example, a blood, serum or plasma sample, a tissue sample, or a cellular sample, for example, a sample comprising peripheral blood mononuclear cells.
  • the sphingotype is determined on a sample harvested from the subject.
  • the neurodegenerative disorder is selected from the group consisting of Parkinson's disease, Alzheimer's Disease, Huntington's Disease, Amyotrophic Lateral Sclerosis (ALS), multiple sclerosis, diffuse Lewy body disease, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, dementia with Lewy Bodies, Pick Disease, or traumatic brain injury.
  • the neurodegenerative disorder is selected from the group consisting of Parkinson's disease, multiple system atrophy, dementia with Lewy Bodies, Pick Disease, traumatic brain injury, and ALS.
  • the activator can be a small molecule activator of GCase activity, for example, an activator described, for example, in International Application Publication No. WO2012/078855, and International Application Nos. PCT/US 15/59541 , PCT/US 15/59531 and PCT/US 15/59534.
  • the activator is a compound of Formula I:
  • R 1 and R 2 each represent independently for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, Ci- 4 alkoxyl, -(Ci- 4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chloro, fluoro, or -N(H)(R 3 );
  • R 3 represents independently for each occurrence hydrogen or C1-4 alkyl
  • R 4 represents independently for each occurrence hydrogen, C1-4 alkyl, or -C(0)R 3 ;
  • X is one of the following:
  • A is a cyclic group selected from:
  • bicyclic heterocyclyl containing at least one ring nitrogen atom, wherein the bicyclic heterocyclyl is substituted by 0, 1, or 2 occurrences of Y 1 and 0, 1, 2, or 3 occurrences ofY 2 ;
  • Y 1 represents, independently for each occurrence, one of the following:
  • Y 2 represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, C2-4 alkynyl, cyano, azido, -N(R ) 2 , -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R 3 , or Ci-6
  • n 1, 2, or 3;
  • R 1 and R 2 are Ci- 4 alkoxyl, -(C1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chloro, fluoro, or -N(H)(R 3 ); and
  • a 1 is a bicyclic heterocyclyl containing at least one ring nitrogen atom and X 1 is
  • the activator is a compound of Formula II:
  • R 1 and R 2 each represent independently for each occurrence hydrogen, deuterium, C1-4 alkyl, Ci- 4 haloalkyl, C1-4 deuteroalkyl, C1-4 alkoxyl, -(C 1-4 alky lene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, halogen, hydroxyl, or -N(R 4 ) 2 ;
  • R 3 represents independently for each occurrence hydrogen, Ci-6 alkyl, or C3-6 cycloalkyl
  • R 4 represents independently for each occurrence hydrogen, C1-4 alkyl, cyclopropyl, or -C(0)R 3 ;
  • R 5 represents independently for each occurrence C1-4 alkyl or C3-6 cycloalkyl
  • X 1 is one of the following:
  • a carbonyl-containing linker selected from -C(0)N(H)(Ci-6 and -C(0)-(3-6 membered heterocycloalkylene containing at least one ring -N(H)- where ⁇ is a bond to A 1 ;
  • a 1 is a cyclic group selected from:
  • Y 1 represents, independently for each occurrence, one of the following:
  • Ci-6 haloalkyl Ci -6 alkyl, halogen, cyano, -C0 2 R 3 , -C(0)R 5 , -S(0) 2 R 5 , -C(0)N(R 5 ) 2 , -C(0)N(R ) 2 , -N(R )C(0)R 5 , or -0-(Ci -8 haloalkyl);
  • Y 2 represents, independently for each occurrence, deuterium, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, azido, -N(R ) 2 , -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C0 2 R 3 , or Ci-6 haloalkyl-substituted C3-6 cycloalkyl;
  • n 1 or 2;
  • n 1, 2, or 3;
  • R 1 or R 2 is other than hydrogen when (i) A 1 is an unsubstituted heterocyclyl, (ii) A 1 is an unsubstituted phenyl or a phenyl substituted only by halogen, or (iii) Y 2 is halogen.
  • the sphingotype is a hexosylceramide
  • sphingotype for example, (1) a hexosylceramide sphingotype comprising (i) glucosylceramide, galactosylceramide, or a combination thereof, and/or (ii) a concentration of glucosylceramide, galactosylceramide, or a combination thereof in the sample, or (2) a hexosylceramide sphingotype comprising a glucosylceramide of Formula A or the amount of the
  • R is a saturated, unsaturated, or partially unsaturated C16 fatty acid chain, a saturated, unsaturated, or partially unsaturated CI 8 fatty acid chain, a saturated, unsaturated, or partially unsaturated C20 fatty acid chain, a saturated, unsaturated, or partially unsaturated C22 fatty acid chain, a saturated, unsaturated, or partially unsaturated C24 fatty acid chain, a saturated, unsaturated, or partially unsaturated C26 fatty acid chain, or a combination thereof.
  • the hexosylceramide sphingotype comprises one of the hexosylceramides set forth in Figure 4B, or a combination thereof. In certain embodiments, the hexosylceramide sphingotype comprises the aggregate amount of all glucosylceramides in the sample. In certain embodiments, the hexosylceramide sphingotype comprises the aggregate amount of all glucosylceramides and galactosylceramides in the sample. In certain
  • the hexosylceramide sphingotype comprises the aggregate amount of the hexosylceramides set forth in Figure 4B in the sample.
  • the amount of glucosylceramides is normalized by the amount of sphingosine in the sample.
  • the amount of glucosylceramides and galactosylceramides is normalized by the amount of sphingosine in the sample.
  • the hexosylceramide sphingotype is calculated by the Formula [A]/[B], wherein
  • [A] is the aggregate concentration in the sample of the glucosylceramide moieties set forth in Figure 4B, and
  • [B] is the concentration of sphingosine in the sample.
  • the hexosylceramide sphingotype is calculated by the Formula [A]/[B], wherein [A] is the aggregate concentration in the sample of the hexosylceramide moieties (glucosylceramides and galactosylceramides) set forth in Figure 4B, and
  • [B] is the concentration of sphingosine in the sample.
  • the amount of hexosylceramide in the sample decreases to a greater extent upon exposure to the activator than without exposure to the activator, for example, the amount of hexosylceramide decreases by at least 10%, 20%, 30%, 40% or 50% upon exposure to the activator relative to without exposure to the activator.
  • FIGURE 1 is schematic representation of exemplary hexosylceramides including glucosylceramide (GluCer) and galactosylceramide (GalCer), together with their respective components;
  • GluCer glucosylceramide
  • GalCer galactosylceramide
  • FIGURE 2 is a schematic representation of a portion of the glycosphingolipid metabolic pathway in a mammalian cell, showing, among other things, ⁇ -glucocerebrosidase (GCase), and an exemplary ⁇ -glucocerebrosidase activator (denoted as LTI-X);
  • GCase ⁇ -glucocerebrosidase
  • LTI-X exemplary ⁇ -glucocerebrosidase activator
  • FIGURE 3 is a table showing exemplary glycosphingolipids typically present in mammalian subjects together with the fatty acid and sphingosine components of the various glycosphingolipids including hexosylceramide (HexCer), lactosylceramide (LacCer), Ceramide (Cer), dihydro-ceramide (dhCer), and sphingosine (Sph) together with the chemical structures of exemplary glycosphingolipids;
  • HexCer hexosylceramide
  • LacCer lactosylceramide
  • Ceramide Ceramide
  • dhCer dihydro-ceramide
  • Sph sphingosine
  • FIGURE 5 is a scatter chart showing the change in HexCer profiles (AHexCer) in PBMCs harvested from two separate cohorts of subjects with Parkinson's disease (PD) or healthy control subjects (HC) when treated ex vivo with an exemplary GCase activator, where AHexCer is the change in the aggregate concentration of C16:0, C22:0, C24:0, and C24: l hexosylceramides and subjects showing a decrease in AHexCer are identified as responders and subjects that do not show a decrease in AHexCer are identified as non-responders (the dotted lines represent the expected error in the assay);
  • FIGURE 6 is a scatter chart showing HexCer/Sph values in PBMCs harvested from subjects with Parkinson's disease (PD), where the levels of HexCer decreased upon exposure to an exemplary GCase activator (denoted as HexCer responder or Resp) or where the levels of HexCer were not affected by exposure to the exemplary GCase activator (denoted as HexCer non-responder or NR).
  • PD Parkinson's disease
  • FIGURE 7 represents two scatter plots showing the normalized ratio of HexCer/Sph in PBMCs harvested from Parkinson's disease subjects classified as responders or non-responders for two separate cohorts presented individually (FIGURE 7A) or the two cohorts aggregated together (FIGURE 7B), where HexCer/Sph ratio values are normalized via the mean
  • HexCer/Sph ratio value measured in a given cohort was measured in a given cohort.
  • FIGURE 8 represents a scatter plot showing the normalized ratio of HexCer/Sph in plasma harvested from Parkinson's disease subjects classified as responders or non-responders, where HexCer/Sph ratio values are normalized via the mean HexCer/Sph ratio value measured in a given cohort.
  • the invention is based, in part, upon the discovery that it is possible to identify subjects with a neurodegenerative disorder likely to respond to treatment with an activator of ⁇ - glucocerebrosidase activity based on the sphingotype of the subject.
  • the invention provides a method of treating a subject with or at risk of developing a neurodegenerative disorder.
  • the method comprises administering to the subject - lo an effective amount of a ⁇ -glucocerebrosidase activator thereby to treat the subject.
  • the subject Prior to administration of the activator, the subject has been determined to have a sphingotype (for example, based on the presence or amount of one or more sphingolipids in a tissue, cellular or body fluid sample of the subject) indicative that the activator will likely be capable of effectively treating the subject.
  • the neurodegenerative disorder can be selected from the group consisting of Parkinson's disease, Alzheimer's Disease, Huntington's Disease, ALS, multiple sclerosis, diffuse Lewy body disease, multiple system atrophy, frontotemporal dementia, progressive supranuclear palsy, dementia with Lewy Bodies, Pick Disease, or traumatic brain injury.
  • the neurodegenerative disorder is selected from the group consisting of Parkinson's disease, multiple system atrophy, dementia with Lewy Bodies, Pick Disease, traumatic brain injury, and ALS.
  • the invention provides a method of identifying a subject with or at risk of developing a neurodegenerative disorder (such as one of the disorders discussed above) suitable for treatment by administration of an effective amount of a ⁇ -glucocerebrosidase activator, wherein, prior to administration of the activator, the subject has been determined to have a sphingotype in a tissue, cellular or body fluid sample of the subject indicative that the activator will likely be capable of effectively treating the subject.
  • a neurodegenerative disorder such as one of the disorders discussed above
  • sphingolipids and sphingotyping methods for determining sphingotypes of a given subject and sphingotypes of subjects likely to respond to an activator of ⁇ -glucocerebrosidase activity, and methods of treating subjects with a given sphingotype with an activator of ⁇ -glucocerebrosidase activity.
  • alkyl refers to a saturated straight or branched hydrocarbon, such as a straight or branched group of 1 -26, 1 -12, 1-10, or 1-6 carbon atoms, referred to herein as Ci-C 26 alkyl, Ci-Cioalkyl, and Ci-Cealkyl, respectively.
  • alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, 2-methyl-l -propyl, 2-methyl-2- propyl, 2-methyl-l -butyl, 3 -methyl- 1 -butyl, 2-methy 1-3 -butyl, 2,2-dimethy 1-1 -propyl, 2- methyl-l-pentyl, 3-methyl-l -pentyl, 4-methyl-l-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethy 1-1 -butyl, 3,3-dimethyl-l-butyl, 2-ethy 1-1 -butyl, butyl, isobutyl, t-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, etc.
  • alkylene refers to a diradical of an alkyl group.
  • An exemplary alkylene group is -CH 2 CH 2 -.
  • haloalkyl refers to an alkyl group that is substituted with at least one halogen.
  • halogen for example, -CH 2 F, -CHF 2 , -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 , and the like.
  • heteroalkyl refers to an "alkyl” group in which at least one carbon atom has been replaced with a heteroatom (e.g., an O, N, or S atom).
  • the heteroalkyl may be, for example, an -O-Ci-Cioalkyl group, an -Ci-Cealkylene-O-Ci-Cealkyl group, or a Ci- Ce alkylene-OH group.
  • the "heteroalkyl” may be a 2-8 membered heteroalkyl, indicating that the heteroalkyl contains from 2 to 8 atoms selected from the group consisting of carbon, oxygen, nitrogen, and sulfur.
  • the heteroalkyl may be a 2-6 membered, 4-8 membered, or a 5-8 membered heteroalkyl group (which may contain for example 1 or 2 heteroatoms selected from the group oxygen and nitrogen).
  • One type of heteroalkyl group is an "alkoxyl" group.
  • alkenyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-26, 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C 2- C 26 alkenyl,
  • alkenyl groups include vinyl, allyl, butenyl, pentenyl, hexenyl, butadienyl, pentadienyl, hexadienyl, 2- ethylhexenyl, 2-propyl-2-butenyl, 4-(2-methyl-3-butene)-pentenyl, and the like.
  • alkynyl refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-26, 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C 2- C 26 alkynyl, C 2- Ci 2 alkynyl, C 2- Cioalkynyl, and C 2- C 6 alkynyl, respectively.
  • exemplary alkynyl groups include ethynyl, prop-1 - yn-l-yl, and but-l-yn-l-yl.
  • cycloalkyl refers to a monovalent saturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons, referred to herein, e.g., as "C4- 8 cycloalkyl,” derived from a cycloalkane.
  • exemplary cycloalkyl groups include, but are not limited to, cyclohexanes, cyclopentanes, cyclobutanes and cyclopropanes.
  • cycloalkyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. Cycloalkyl groups can be fused to other cycloalkyl, aryl, or heterocyclyl groups. In certain embodiments, the cycloalkyl group is not substituted, i.
  • cycloalkylene refers to a diradical of an cycloalkyl group.
  • An exemplary cycloalkylene group is
  • partially unsaturated carbocyclyl refers to a monovalent cyclic hydrocarbon that contains at least one double bond between ring atoms where at least one ring of the carbocyclyl is not aromatic.
  • the partially unsaturated carbocyclyl may be characterized according to the number of ring carbon atoms.
  • the partially unsaturated carbocyclyl may contain 5-14, 5-12, 5-8, or 5-6 ring carbon atoms, and accordingly be referred to as a 5-14, 5-12, 5-8, or 5-6 membered partially unsaturated carbocyclyl, respectively.
  • the partially unsaturated carbocyclyl may be in the form of a monocyclic carbocycle, bicyclic carbocycle, tricyclic carbocycle, bridged carbocycle, spirocyclic carbocycle, or other carbocyclic ring system.
  • exemplary partially unsaturated carbocyclyl groups include cycloalkenyl groups and bicyclic carbocyclyl groups that are partially unsaturated.
  • partially unsaturated carbocyclyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, haloalkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl.
  • the partially unsaturated carbocyclyl is not substituted, i.e., it is unsubstituted.
  • cycloalkenyl refers to a monovalent unsaturated cyclic, bicyclic, or bridged cyclic (e.g., adamantyl) hydrocarbon group of 3-12, 3-8, 4-8, or 4-6 carbons containing one carbon-carbon double bond, referred to herein, e.g., as "C4- gcycloalkenyl,” derived from a cycloalkane.
  • exemplary cycloalkenyl groups include, but are not limited to, cyclohexenes, cyclopentenes, and cyclobutenes.
  • cycloalkenyl groups are optionally substituted at one or more ring positions with, for example, alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl.
  • the cycloalkenyl group is not substituted, i.e., it is unsubstituted.
  • aryl is art-recognized and refers to a carbocyclic aromatic group.
  • aryl groups include phenyl, naphthyl, anthracenyl, and the like.
  • the term "aryl” includes poly cyclic ring systems having two or more carbocyclic rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is aromatic and, e.g., the other ring(s) may be cycloalkyls, cycloalkenyls,
  • the aromatic ring may be substituted at one or more ring positions with, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, carboxylic acid, - C(0)alkyl, -C0 2 alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties, -CF 3 , -CN, or the like.
  • the aromatic ring is substituted at one or more ring positions with halogen, alkyl, hydroxyl, or alkoxyl. In certain other embodiments, the aromatic ring is not substituted, i.e., it is unsubstituted. In certain embodiments, the aryl group is a 6-10 membered ring structure.
  • aralkyl refers to an alkyl group substituted with an aryl group.
  • bicyclic carbocyclyl that is partially unsaturated refers to a bicyclic carbocyclic group containing at least one double bond between ring atoms and at least one ring in the bicyclic carbocyclic group is not aromatic.
  • Representative examples of a bicyclic carbocyclyl that is partially unsaturated include, for example: [0047]
  • ortho, meta and para are art-recognized and refer to 1,2-, 1,3- and 1,4- disubstituted benzenes, respectively.
  • the names 1,2-dimethylbenzene and ortho- dimethylbenzene are synonymous.
  • heterocyclyl and “heterocyclic group” are art-recognized and refer to saturated, partially unsaturated, or aromatic 3- to 10-membered ring structures, alternatively 3- to 7-membered rings, whose ring structures include one to four heteroatoms, such as nitrogen, oxygen, and sulfur.
  • the number of ring atoms in the heterocyclyl group can be specified using C x -C x nomenclature where x is an integer specifying the number of ring atoms.
  • a C3-Cvheterocyclyl group refers to a saturated or partially unsaturated 3- to 7-membered ring structure containing one to four heteroatoms, such as nitrogen, oxygen, and sulfur.
  • C3-C7 indicates that the heterocyclic ring contains a total of from 3 to 7 ring atoms, inclusive of any heteroatoms that occupy a ring atom position.
  • a C3heterocyclyl is aziridinyl.
  • Heterocycles may also be mono-, bi-, or other multi-cyclic ring systems including a spirocyclic ring system where at least one ring contains a ring heteroatom.
  • a heterocycle may be fused to one or more aryl, partially unsaturated, or saturated rings.
  • Heterocyclyl groups include, for example, biotinyl, chromenyl, dihydrofuryl, dihydroindolyl, dihydropyranyl, dihydrothienyl, dithiazolyl, homopiperidinyl, imidazolidinyl, isoquinolyl, isothiazolidinyl, isooxazolidinyl, morpholinyl, oxolanyl, oxazolidinyl, phenoxanthenyl, piperazinyl, piperidinyl, pyranyl, pyrazolidinyl, pyrazolinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolidin-2-onyl, pyrrolinyl, tetrahydrofuryl, tetrahydroisoquinolyl, tetrahydropyranyl, tetrahydroquinolyl, thiazolidinyl,
  • the heterocyclic ring is optionally substituted at one or more positions with substituents such as alkanoyl, alkoxy, alkyl, alkenyl, alkynyl, amido, amidino, amino, aryl, arylalkyl, azido, carbamate, carbonate, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, oxo, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl and thiocarbonyl.
  • the heterocyclyl group is not substituted, i.e., it is unsubstituted.
  • bicyclic heterocyclyl refers to a heterocyclyl group that contains two rings that are fused together.
  • Representative examples of a bicyclic heterocyclyl include, for example:
  • the bicyclic heterocyclyl is an carbocyclic ring fused to partially unsaturated heterocyclic ring, that together form a bicyclic ring structure having 8-10 ring atoms (e.g., where there are 1, 2, 3, or 4 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur).
  • heterocycloalkyl is art-recognized and refers to a saturated heterocyclyl group as defined above.
  • the "heterocycloalkyl” is a 3- to 10- membered ring structures, alternatively a 3- to 7-membered ring, whose ring structures include one to four heteroatoms, such as nitrogen, oxygen, and sulfur.
  • heterocycloalkylene of a heterocycloalkyl group.
  • An exemplary heterocycloalkylene group is heterocycloalkylene may contain, for example, 3-6 ring atoms (i.e., a 3-6 membered heterocycloalkylene).
  • the heterocycloalkylene is a 3-6 membered heterocycloalkylene containing 1, 2, or 3 three heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur.
  • heteroaryl is art-recognized and refers to aromatic groups that include at least one ring heteroatom. In certain instances, a heteroaryl group contains 1, 2, 3, or 4 ring heteroatoms. Representative examples of heteroaryl groups include pyrrolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, thiazolyl, triazolyl, pyrazolyl, pyridinyl, pyrazinyl, pyridazinyl and pyrimidinyl, and the like.
  • the heteroaryl ring may be substituted at one or more ring positions with, for example, halogen, azide, alkyl, aralkyl, alkenyl, alkynyl, cycloalkyl, hydroxyl, alkoxyl, amino, nitro, sulfhydryl, imino, amido, carboxylic acid, -C(0)alkyl, -CC ⁇ alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties, -CF 3 , -CN, or the like.
  • heteroaryl also includes poly cyclic ring systems having two or more rings in which two or more carbons are common to two adjoining rings (the rings are "fused rings") wherein at least one of the rings is heteroaromatic, e.g., the other cyclic rings may be cycloalkyls, cycloalkenyls, cycloalkynyls, and/or aryls.
  • the heteroaryl ring is substituted at one or more ring positions with halogen, alkyl, hydroxyl, or alkoxyl.
  • the heteroaryl ring is not substituted, i.e., it is unsubstituted.
  • the heteroaryl group is a 5- to 10-membered ring structure, alternatively a 5- to 6-membered ring structure, whose ring structure includes 1, 2, 3, or 4 heteroatoms, such as nitrogen, oxygen, and sulfur.
  • heteroarylkyl refers to an alkyl group substituted with a heteroaryl group.
  • amine and “amino” are art-recognized and refer to both unsubstituted and substituted amines, e.g., a moiety represented by the general formula -N(R 50 )(R 51 ), wherein R 50 and R 51 each independently represent hydrogen, alkyl, cycloalkyl, heterocyclyl, alkenyl, aryl, aralkyl, or -(CH2) m -R 61 ; or R 50 and R 51 , taken together with the N atom to which they are attached complete a heterocycle having from 4 to 8 atoms in the ring structure; R 61 represents an aryl, a cycloalkyl, a cycloalkenyl, a heterocycle or a poly cycle; and m is zero or an integer in the range of 1 to 8.
  • R 50 and R 51 each independently represent hydrogen, alkyl, alkenyl, or -(CH 2 ) m -R
  • alkoxyl or "alkoxy” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto.
  • Representative alkoxyl groups include methoxy, ethoxy, propyloxy, tert-butoxy and the like.
  • An "ether” is two hydrocarbons covalently linked by an oxygen. Accordingly, the substituent of an alkyl that renders that alkyl an ether is or resembles an alkoxyl, such as may be represented by one of -O-alkyl, -O-alkenyl, -O-alkynyl, -0-(CH 2 ) m -R6i, where m and R6i are described above.
  • R g R ⁇ and R[ are each independently alkoxy, aryloxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carboxy, cyano, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, ketone, nitro, sulfide, sulfonyl, or sulfonamide.
  • Exemplary carbamates include arylcarbamates and heteroaryl carbamates, e.g., wherein at least one of Rg R ⁇ and R[ are independently aryl or heteroaryl, such as phenyl and pyridinyl.
  • carbonyl refers to the radical -C(O)-.
  • carboxyl refers to the radical -C(0)NRR', where R and R' may be the same or different. R and R' may be independently alkyl, aryl, arylalkyl, cycloalkyl, formyl, haloalkyl, heteroaryl, or heterocyclyl.
  • carboxy refers to the radical -COOH or its corresponding salts, e.g. -COONa, etc.
  • amide or “amido” as used herein refers to a radical of the form
  • R a, R b and R c are each independently alkoxy, alkyl, alkenyl, alkynyl, amide, amino, aryl, arylalkyl, carbamate, cycloalkyl, ester, ether, formyl, halogen, haloalkyl, heteroaryl, heterocyclyl, hydrogen, hydroxyl, ketone, or nitro.
  • the amide can be attached to another group through the carbon, the nitrogen, R , R c , or R a .
  • the amide also may be cyclic, for example R b and R c , R a and R b , or R a and R c may be joined to form a 3- to 12-membered ring, such as a 3- to 10-membered ring or a 5- to 6-membered ring.
  • alkanoyl refers to a radical -O-CO-alkyl.
  • a cyclopentane substituted with an oxo group is cyclopentanone.
  • sulfonamide or “sulfonamido” as used herein refers to a radical having the structure -N(R r )-S(0)2-R s - or -S(0)2-N(R r )R s , where R r , and R s can be, for example, hydrogen, alkyl, aryl, cycloalkyl, and heterocyclyl.
  • Exemplary sulfonamides include alkylsulfonamides (e.g., where R s is alkyl), arylsulfonamides (e.g., where R s is aryl), cycloalkyl sulfonamides (e.g., where R s is cycloalkyl), and heterocyclyl sulfonamides (e.g., where R s is heterocyclyl), etc.
  • sulfonyl refers to a radical having the structure R U SC>2-, where R u can be alkyl, aryl, cycloalkyl, and heterocyclyl, e.g., alkylsulfonyl.
  • alkylsulfonyl refers to an alkyl group attached to a sulfonyl group.
  • the compounds of the disclosure may contain one or more chiral centers and/or double bonds and, therefore, exist as stereoisomers, such as geometric isomers, enantiomers or diastereomers.
  • stereoisomers when used herein consists of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols "R” or "S,” depending on the configuration of substituents around the stereogenic carbon atom.
  • Stereoisomers include enantiomers and diastereomers. Mixtures of enantiomers or
  • diastereomers may be designated "( ⁇ )" in nomenclature, but the skilled artisan will recognize that a structure may denote a chiral center implicitly. It is understood that graphical depictions of chemical structures, e.g., generic chemical structures, encompass all stereoisomeric forms of the specified compounds, unless indicated otherwise.
  • Individual stereoisomers of compounds of the present invention can be prepared synthetically from commercially available starting materials that contain asymmetric or stereogenic centers, or by preparation of racemic mixtures followed by resolution methods well known to those of ordinary skill in the art. 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, (2) salt formation employing an optically active resolving agent, or (3) direct separation of the mixture of optical enantiomers on chiral chromatographic columns.
  • Stereoisomeric mixtures can also be resolved into their component stereoisomers by well- known methods, such as chiral-phase gas chromatography, chiral-phase high performance liquid chromatography, crystallizing the compound as a chiral salt complex, or crystallizing the compound in a chiral solvent. Further, enantiomers can be separated using supercritical fluid chromatographic (SFC) techniques described in the literature. Still further, stereoisomers can be obtained from stereomerically-pure intermediates, reagents, and catalysts by well-known asymmetric synthetic methods.
  • SFC supercritical fluid chromatographic
  • Geometric isomers can also exist in the compounds of the present invention.
  • the symbol denotes a bond that may be a single, double or triple bond as described herein.
  • the present invention encompasses the various geometric isomers and mixtures thereof resulting from the arrangement of substituents around a carbon-carbon double bond or arrangement of substituents around a carbocyclic ring.
  • Substituents around a carbon-carbon double bond are designated as being in the "Z” or configuration wherein the terms “Z” and "E” are used in accordance with IUPAC standards. Unless otherwise specified, structures depicting double bonds encompass both the "E” and "Z” isomers.
  • Substituents around a carbon-carbon double bond alternatively can be referred to as “cis” or “trans,” where “cis” represents substituents on the same side of the double bond and “trans” represents substituents on opposite sides of the double bond.
  • the arrangement of substituents around a carbocyclic ring are designated as “cis” or “trans.”
  • the term “cis” represents substituents on the same side of the plane of the ring and the term “trans” represents substituents on opposite sides of the plane of the ring.
  • Mixtures of compounds wherein the substituents are disposed on both the same and opposite sides of plane of the ring are designated "cis/trans.”
  • the invention also embraces isotopically labeled compounds of the invention which are identical to those recited herein, except that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, H, 1 C, 14 C, 15 N, 18 0, 17 0, 1 P, 2 P, 5 S, 18 F, and 6 C1, respectively.
  • isotopically-labeled disclosed compounds are useful in compound and/or substrate tissue distribution assays.
  • Tritiated (i.e., H) and carbon- 14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • substitution with heavier isotopes such as deuterium (i.e., 2 H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances.
  • Isotopically labeled compounds of the invention can generally be prepared by, e.g., substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
  • the terms “subject” and “patient” refer to organisms to be treated by the methods of the present invention. Such organisms are preferably mammals (e.g., murines, simians, equines, bovines, porcines, canines, felines, and the like), and more preferably humans.
  • the term “neurodegenerative disorder” refers to a disorder in which, over time, neurons in a subject become dysfunctional and die. The pathology of neurodegenerative disorder typically is associated with protein aggregation and/or mitochondrial dysfunction.
  • Neurodegenerative disorders often are associated with reduction in the mass and/or volume of the brain, which may be due to the atrophy and/or death of brain cells, which are far more profound than those in a healthy subject that are attributable to aging.
  • Neurodegenerative disorders can evolve gradually, after a long period of normal brain function, due to progressive degeneration (e.g., nerve cell dysfunction and death) of specific brain regions.
  • neurodegenerative disorders can have a quick onset, such as those associated with trauma or toxins. The actual onset of brain degeneration may precede clinical expression by many years.
  • neurodegenerative disorders include Parkinson's disease, Alzheimer's disease, Huntington 's disease, amyotrophic lateral sclerosis, multiple sclerosis, diffuse Lewy body disease, multisystem atrophy, frontotemporal dementia, and progressive supranuclear palsy.
  • activator of ⁇ -glucocerebrosidase activity refers to any molecule that is capable of (i) increasing the enzymatic activity of the enzyme ⁇ -glucocerebrosidase, and/or to (ii) maintaining the stability of the enzymatically active form of ⁇ -glucocerebrosidase.
  • sphingolipid refers to a moiety selected from the group consisting of sphingosine, dihydrosphingosine, sphingosine-l-phospate, dihydrosphingosine-1- phosphate, ceramide, dihydroceramide, glucosylceramide, galactosylceramide,
  • glycosphingolipid refers to glucosylceramide
  • galactosylceramide hexosylceramide, and lactosylceramide.
  • sphingotype refers to the amount of one or more
  • sphingolipids the ratio, difference, product, or sum of the amount of two sphingolipids, or a multivariate relationship between multiple sphingolipids in a body fluid, tissue, or cell sample that discriminates a biological trait such as responsiveness to drug treatment, disease state, or disease risk.
  • the term "effective amount” refers to the amount of a compound (e.g., a GCase activator) sufficient to effect beneficial or desired results.
  • An effective amount can be administered in one or more administrations, applications or dosages and is not intended to be limited to a particular formulation or administration route.
  • the term “treating” includes any effect, e.g., lessening, reducing, modulating, ameliorating or eliminating, that results in the improvement of the condition, disease, disorder, and the like, or ameliorating a symptom thereof.
  • composition refers to the combination of an active agent (e.g., a GCase activator) with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vivo or ex vivo.
  • an active agent e.g., a GCase activator
  • the term "pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents.
  • the compositions also can include stabilizers and preservatives.
  • stabilizers and adjuvants see Martin, Remington's Pharmaceutical Sciences, 15th Ed., Mack Publ. Co., Easton, PA [1975].
  • salts of the compounds of the present invention may be derived from inorganic or organic acids and bases.
  • acids include, but are not limited to, hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, gly colic, lactic, salicylic, succinic, toluene-p-sulfonic, tartaric, acetic, citric, methanesulfonic, ethanesulfonic, formic, benzoic, malonic, naphthalene- 2-sulfonic, benzenesulfonic acid, and the like.
  • Other acids such as oxalic, while not in themselves pharmaceutically acceptable, may be employed in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable acid addition salts.
  • Examples of bases include, but are not limited to, alkali metal (e.g., sodium) hydroxides, alkaline earth metal (e.g., magnesium) hydroxides, ammonia, and compounds of formula NW ⁇ 4 + , wherein W is C alkyl, and the like.
  • Examples of salts include, but are not limited to: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate,
  • salts include anions of the compounds of the present invention compounded with a suitable cation such as Na + , NH 4 + , and NW ⁇ 4 + (wherein W is a C 1-4 alkyl group), and the like.
  • salts of the compounds of the present invention are contemplated as being pharmaceutically acceptable.
  • salts of acids and bases that are non- pharmaceutically acceptable may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound.
  • HATU 0-(7-azabenzotriazol-l-yl)-N,N,N'N'- tetramethyluronium hexafluorophosphate
  • DIPEA diisopropylethylamine
  • DMF dimethylformamide
  • DCM methylene chloride
  • Boc tert-butoxycarbonyl
  • THF tetrahydrofuran
  • THF trifluoroacetic acid
  • NMM N-methylmorpholine
  • TEA triethylamine
  • Boc anhydride ((Boc) 2 0); dimethylsulfoxide (DMSO); diisopropylethylamine (DIEA); N,N-Dimethylpyridin-4-amine (DMAP); flash column chromatography (FCC); and
  • compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions and kits of the present invention that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present invention that consist essentially of, or consist of, the recited processing steps.
  • compositions specifying a percentage are by weight unless otherwise specified. Further, if a variable is not accompanied by a definition, then the previous definition of the variable controls.
  • glycosphingolipids useful in developing a sphingotype are set forth in FIGURE 3. It is appreciated that certain glycosphingolipids can be useful in identifying whether a subject will likely be responsive to treatment with a GCase activator.
  • a glycosphingolipid refers to any molecule comprising a ceramide and a glycan.
  • a ceramide comprises a fatty acid molecule covalently linked via an amide bond to a sphingoid base, such as a sphingosine molecule, either of which may vary in length, hydroxylation, and saturation.
  • the glycan may be a monosaccharide or oligosaccharide, and may vary in constituent monosaccharide, carbohydrate sequence, binding position, and branching.
  • Exemplary glycans include hexosyl moieties, including, for example, glucose or galactose.
  • Exemplary hexosylceramides are set forth in FIGURE 1.
  • An exemplary glycosphingolipid is glucosylceramide, or
  • glucocerebroside in which the glycan is glucose and the sphingoid base is sphingosine.
  • glycosphingolipid is galactosylceramide, in which the glucan is galactose and the sphingoid base is sphingosine.
  • Additional glycosphingolipids include, but are not limited to, lactosylceramide and gangliosides GM1, GM2, GM3, GDI a, GDlb, GD2, GD3, GTlb, GT3, GQ1, the compositions of which are known in the art.
  • Glycosphingolipids are degraded by pathways involving a variety of lysosomal hydrolases.
  • a key enzyme in glycosphingolipid metabolism is ⁇ -glucocerebrosidase (GCase), which catalyzes the hydrolysis of glucosylceramide to ceramide and glucose. The resulting ceramide can be metabolized to sphingosine.
  • GCase ⁇ -glucocerebrosidase
  • FIGURE 2 An overview of the role of ⁇ -glucocerebrosidase in glycosphingolipid metabolism is depicted in FIGURE 2.
  • the sphingotype of the subject in question is determined and compared against a sphingotype correlated to subjects likely to respond or not respond to a GCase activator.
  • a sphingotype can comprise the presence and/or amount of a sphingolipid or group of a sphingolipids in a sample.
  • glycosphingolipids or glycosphingolipid components may include, but are not limited to lactosylceramide, glucosylceramide, galactosylceramide, ceramide, glucosyl sphingosine, sphingosine, GM1, GM2, GM3, GDI a, GDlb, GD2, GD3, GTlb, GT3, GQ1, or a combination thereof.
  • a sphingotype may comprise an aggregate of the amounts or concentrations of one more sphingolipids or sphingolipid components, or may comprise a ratio of the amounts or concentrations of one more sphingolipids or sphingolipid components.
  • glycosphingolipids may be used to denote a sphingotype of a subject likely to be responsive to exposure to a GCase activator.
  • exemplary useful sphingolipids useful in determining a sphingotype include those moieties set forth in FIGURE 3. Particularly abundant
  • sphingolipids include C16:0, C22:0, C24:0, and C24: l, the structures of which are included in FIGURE 4B
  • the sphingotype is a hexosylceramide-based sphingotype in which the sphingotype comprises one or more hexosylceramides.
  • hexosylceramides may include, but are not limited to, glucosylceramide, galactosylceramide, or a combination thereof, for example, the glucosylceramides and galactosylceramides set forth in FIGURE 1.
  • the hexosylceramide sphingotype comprises (i) glucosylceramide, galactosylceramide, or a combination thereof, and/or (ii) a concentration of glucosylceramide, galactosylceramide, or a combination thereof in the sample.
  • the hexosylceramide sphingotype comprises a glucosylceramide of Formula A or the amount of the glucosylceramide of Formula A in the sample:
  • R is a saturated, unsaturated, or partially unsaturated C16 fatty acid chain, a saturated, unsaturated, or partially unsaturated C18 fatty acid chain, a saturated, unsaturated, or partially unsaturated C20 fatty acid chain, a saturated, unsaturated, or partially unsaturated C22 fatty acid chain, a saturated, unsaturated, or partially unsaturated C24 fatty acid chain, a saturated, unsaturated, or partially unsaturated C26 fatty acid chain, or a combination thereof.
  • Predominant glucosylceramides are set forth in FIGURES 4A and 4B.
  • the hexosylceramide sphingotype is an aggregate amount of some or all glucosylceramides in the sample, some or all the galactosylceramides in the sample, or a combination thereof.
  • the sphingotype may be provided as a normalized value where the amount of glucosylceramide and/or galactosylceramide is normalized by the amount of sphingosine in the sample.
  • the hexosylceramide sphingotype comprises the aggregate amount of the glucosylceramides set forth in FIGURE 4B in the sample.
  • the sphingotype may be provided as a normalized value where the amount of glucosylceramides is normalized by the amount of sphingosine in the sample.
  • the hexosylceramide sphingotype comprises the aggregate amount of the glucosylceramides and galactosylceramides set forth in FIGURE 4B in the sample.
  • the sphingotype may be provided as a normalized value where the amount of glucosylceramides and galactosylceramides is normalized by the amount of sphingosine in the sample.
  • the hexosylceramide sphingotype is calculated by the Formula [A]/[B], wherein
  • [A] is the aggregate concentration in the sample of glucosylceramides set forth in FIGURE 4B.
  • [B] is the concentration of sphingosine in the sample.
  • the hexosylceramide sphingotype is calculated by the Formula [A]/[B], wherein
  • [A] is the aggregate concentration in the sample of glucosylceramides and galactosylceramides set forth in FIGURE 4B, and
  • [B] is the concentration of sphingosine in the sample.
  • Determination of the amount or concentration of a sphingolipid for use in a sphingotype may be carried out by any appropriate method.
  • the sphingolipids are quantitated by LC/MS, for example, as described in Example 1.
  • the amount of hexosylceramide in the sample decreases to greater extent upon exposure to the activator than without exposure to the activator, for example, the amount of hexosylceramide decreases by at least 10% upon exposure to the activator relative to without exposure to the activator.
  • a subject having a sphingotype indicative that the subject will respond to treatment with an activator of ⁇ - glucocerebrosidase activity is treated with an effective amount of the agent.
  • Subjects having a sphingotype indicative that they are likely to be unresponsive to treatment with an activator of ⁇ -glucocerebrosidase activity can be spared from such a treatment and treated with another agent.
  • the sphingotyping described herein can be used to identify subjects with a sphingotype likely to be responsive to activators ⁇ -glucocerebrosidase activity and/or to identify subjects with a sphingotype likely to be responsive to specific group of activators of ⁇ - glucocerebrosidase activity, and/or to identify subjects with a sphingotype likely to be responsive to a specific activator of ⁇ -glucocerebrosidase activity.
  • activators of ⁇ -glucocerebrosidase activity can be, for example, polymers, for example, proteins or nucleic acids or derivatives or analogs thereof, or small molecule activators.
  • exemplary small molecule activators of GCase activity include, for example, the activators described in International Application Publication No.
  • PCT/US 15/59541 for example, substituted pyrazolo[l,5-a]pyrimi dines
  • PCT/US15/59534 for example, substituted pyrrolo[l,2-a]pyrimidines
  • PCT/US 15/59531 for example, substituted imidazo[l,5- ajpyrimi dines
  • exemplary small molecule activators include substituted pyrazolo[l,5-a]pyrimidines and related organic compounds, described, for example, in
  • the substituted pyrazolo[l,5-a]pyrimidine or related organic compound is a compound embraced by Formula I:
  • R 1 and R 2 each represent independently for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, Ci- 4 alkoxyl, -(Ci- 4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chloro, fluoro, or -N(H)(R 3 );
  • R 3 represents independently for each occurrence hydrogen or C1-4 alkyl
  • R 4 represents independently for each occurrence hydrogen, C 1-4 alkyl, or -C(0)R 3 ;
  • X 1 is one of the following:
  • a 1 is a cyclic group selected from:
  • bicyclic heterocyclyl containing at least one ring nitrogen atom, wherein the bicyclic heterocyclyl is substituted by 0, 1, or 2 occurrences of Y 1 and 0, 1, 2, or 3 occurrences of Y 2 ;
  • Y 1 represents, independently for each occurrence, one of the following:
  • Y 2 represents, independently for each occurrence, C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1 -6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, C 2 -4 alkynyl, cyano, azido, -N(R ) 2 , -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(C 1-6 alkylene)-C02R 3 , or C 1-6
  • n 1, 2, or 3;
  • R 1 and R 2 are Ci- 4 alkoxyl, -(C 1 -4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, chloro, fluoro, or -N(H)(R 3 ); and
  • Definitions of the variables in Formula I above encompass multiple chemical groups.
  • the definition of a variable is a single chemical group selected from those chemical groups set forth above
  • the definition is a collection of two or more of the chemical groups selected from those set forth above
  • the compound is defined by a combination of variables in which the variables are defined by (i) or (ii) , e.g., such as where R is Ci -4 alkyl or cyclopropyl, X 1 is -C(0)N(H)- ⁇ , and A 1 is phenyl substituted by 4-8 membered heteroalkyl.
  • R 1 represents independently for each occurrence C1-4 alkyl, Ci ⁇ haloalkyl, C1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro.
  • R 1 is methyl.
  • the R 1 groups are located at the 5 and 7 positions of the pyrazolo[l,5-a]pyrimidinyl.
  • n is 2. In certain other embodiments, n is 1.
  • R 2 is hydrogen. In certain embodiments, R 2 is methyl or halogen. In certain embodiments, R 2 is methyl or halomethyl. In certain embodiments, R 2 is methyl or cyclopropyl.
  • R 3 and R 4 each represent independently for each occurrence hydrogen, methyl, or ethyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 4 is hydrogen.
  • X 1 is
  • any occurrence of Y 2 is independently Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, or hydroxyl. In certain embodiments, any occurrence of Y 2 is independently C1-3 alkyl.
  • a 1 is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y 2 and (b) one of the following:
  • a 1 is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y 2 and (b) one of the following: (i) 4-8 membered heteroalkyl;
  • a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) a 4-8 membered heteroalkyl.
  • a 1 is phenyl substituted by -0-(Ci_7 alkyl).
  • a 1 is phenyl substituted by -0-(C4_7 alkyl).
  • a 1 is phenyl substituted by -O-butyl, -O-pentyl, or -O-hexyl.
  • a 1 is phenyl substituted is -OCH2CH2OCH2CH2.
  • a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) a 2-6 membered heteroalkyl optionally substituted by a 5-10 membered heteroaryl.
  • a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) a 2-6 membered heteroalkyl substituted by a 5-6 membered heteroaryl (which may be, for example, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl, each of which is optionally substituted by one or two substituents independently selected from the group consisting of Ci -6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, Ci- 6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H).
  • a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) -C ⁇ C-(Ci-6 alkylene)-OR 4 . In certain embodiments, A 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) -C ⁇ C-CH 2 -0-CH 3 . In certain embodiments, A 1 is phenyl substituted by -C ⁇ C-CH 2 -0-CH 3 .
  • a 1 is C3-7 cycloalkyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
  • a 1 is C5-10 cycloalkyl that is substituted by 1 or 2 occurrences of Y 1 and 0, 1, 2, or 3 occurrences ofY 2 .
  • a 1 is a bicyclic heterocyclyl containing at least one ring nitrogen atom, wherein the bicyclic heterocyclyl is substituted by 0, 1, or 2 occurrences ofY 1 and 0, 1, 2, or 3 occurrences of Y 2 .
  • a 1 is 1,2,3,4-tetrahydronaphthalenyl substituted by 0, 1 , 2, or 3 occurrences of Y 2 .
  • Y 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl, furanyl, or pyridinyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl.
  • Y 1 is 2-8 membered heteroalkyl. In certain embodiments, Y 1 is -0-(Ci-7 alkyl). In certain embodiments, Y 1 is -O-butyl, -O-pentyl, or -O-hexyl. In certain embodiments, Y 1 is -(C 1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y 1 is -CH 2 -0-(5-6 membered heteroaryl).
  • Y 1 is -CH 2 -0-(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R 4 )
  • Y 1 is a 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-6 alkynyl). In certain embodiments, Y 1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl. In certain embodiments, Y 1 is 5- membered heteroaryl.
  • Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-7 cycloalkyl, halogen, Ci- 6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
  • Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, hydroxyl, and C 1-6 alkoxyl.
  • Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
  • Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
  • Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl.
  • Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
  • Y 1 is C 2-6 alkynyl, -C ⁇ C-(Ci -6 alkylene)-OR 4 , -C ⁇ C-(Ci -6 alkylene)-N(R ) 2 , -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl.
  • Y 1 is C2-6 alkynyl.
  • Y 1 is -C ⁇ CH.
  • Y 1 is -C ⁇ C-(Ci_6 alkylene)-OR 4 .
  • Y 1 is -C ⁇ C-(Ci_6 alky lene)-0-(C 1-2 alkyl).
  • Y 1 is -C ⁇ C-CH 2 -0-CH 3 .
  • the description above describes multiple embodiments relating to compounds of Formula I.
  • the patent application specifically contemplates all combinations of the embodiments.
  • the invention contemplates a compound of Formula I wherein X 1 is A 1 is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y 2 and (b) 4-8 membered heteroalkyl, and Y 1 is C 1-6 alkyl or halogen.
  • the invention contemplates a compound of Formula I wherein R 1 and R 2 each represent independently for each occurrence hydrogen, deuterium, C1-4 alkyl, X 1 is A 1 is a C 3-1 o cycloalkyl substituted by 1 or 2 occurrences of Y 1 , Y 1 is 2-8 membered heteroalkyl; and n is 1 , 2, or 3.
  • the compound is represented by Formula 1-1 : (1-1) or a pharmaceutically acceptable salt thereof, wherein:
  • R 1 and R 2 each represent independently for each occurrence hydrogen, C1-4 alkyl, C1-4 haloalkyl, Ci- 4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro;
  • R 3 represents independently for each occurrence hydrogen or C1-4 alkyl
  • R 4 represents independently for each occurrence hydrogen, C1-4 alkyl, or -C(0)R 3 ;
  • X 1 is one of the following:
  • a 1 is a cyclic group selected from:
  • bicyclic heterocyclyl containing at least one ring nitrogen atom, wherein the bicyclic heterocyclyl is substituted by 0, 1 , or 2 occurrences of Y 1 and 0, 1, 2, or 3 occurrences of Y 2 ;
  • Y 1 represents, independently for each occurrence, one of the following:
  • Y 2 represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen,
  • Ci- 6 haloalkyl C 1 -6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, C 2 -4 alkynyl, cyano, azido, -N(R ) 2 , -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R 3 , or Ci-6
  • n 1, 2, or 3;
  • R 1 or R 2 is other than hydrogen when A 1 is phenyl substituted by heteroalkyl.
  • Definitions of the variables in Formula 1-1 above encompass multiple chemical groups. Embodiments are contemplated where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii) , e.g., such as where R 1 is C 1 -4 alkyl or cyclopropyl, X 1 is and A 1 is phenyl substituted by 4-8 membered heteroalkyl.
  • R 1 represents independently for each occurrence C 1 -4 alkyl, Ci ⁇ haloalkyl, C 1 -4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro.
  • R 1 is methyl.
  • the R 1 groups are located at the 5 and 7 positions of the pyrazolo[l,5-a]pyrimidinyl.
  • n is 2. In certain other embodiments, n is 1.
  • R 2 is hydrogen. In certain embodiments, R 2 is methyl or halogen. In certain embodiments, R 2 is methyl or halomethyl. In certain embodiments, R 2 is methyl or cyclopropyl.
  • R 3 and R 4 each represent independently for each occurrence hydrogen, methyl, or ethyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 4 is hydrogen. [00137] In certain embodiments, X 1 is
  • any occurrence of Y 2 is independently C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, or hydroxyl. In certain embodiments, any occurrence of Y 2 is independently C 1-3 alkyl.
  • a 1 is phenyl substituted by (a) 0, 1 , 2, or 3 occurrences of Y 2 and (b) one of the following:
  • a 1 is phenyl substituted by (a) 0, 1 , 2, or 3 occurrences of Y 2 and (b) one of the following:
  • a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) a 4-8 membered heteroalkyl.
  • a 1 is phenyl substituted by -0-(Ci_7 alkyl).
  • a 1 is phenyl substituted by -0-(C4_7 alkyl).
  • a 1 is phenyl substituted by -O-butyl, -O-pentyl, or -O-hexyl.
  • a 1 is phenyl substituted is -OCH2CH2OCH2CH2.
  • a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) a 2-6 membered heteroalkyl optionally substituted by a 5-10 membered heteroaryl.
  • a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) a 2-6 membered heteroalkyl substituted by a 5-6 membered heteroaryl (which may be, for example, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl, each of which is optionally substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, Ci- 6 alkoxyl, cyano, -N(R 4 )2, amide, and -CO2H).
  • a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) -C ⁇ C-(Ci-6 alkylene)-OR 4 . In certain embodiments, A 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) -C ⁇ C-CH 2 -0-CH 3 . In certain embodiments, A 1 is phenyl substituted by -C ⁇ C-CH 2 -0-CH 3 .
  • a 1 is C3-7 cycloalkyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
  • a 1 is a bicyclic heterocyclyl containing at least one ring nitrogen atom, wherein the bicyclic heterocyclyl is substituted by 0, 1 , or 2 occurrences of Y 1 and 0, 1, 2, or 3 occurrences of Y 2 .
  • Y 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl, furanyl, or pyridinyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl.
  • Y 1 is -0-(Ci-7 alkyl). In certain embodiments, Y 1 is -O-butyl, -O-pentyl, or -O-hexyl. In certain embodiments, Y 1 is -(C 1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y 1 is -CH 2 -0-(5-6 membered heteroaryl).
  • Y 1 is -CH 2 -0-(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C ⁇ haloalkyl, C 1 -6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, -N(R 4
  • Y 1 is a 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl).
  • Y 1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl.
  • Y 1 is a 5- membered heteroaryl.
  • Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-7 cycloalkyl, halogen, Ci- 6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, Ci- 6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
  • Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, hydroxyl, and Ci-6 alkoxyl.
  • Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
  • Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
  • Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl.
  • Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
  • Y 1 is C 2-6 alkynyl, -C ⁇ C-(Ci -6 alkylene)-OR 4 , -C ⁇ C-(Ci -6 alkylene)-N(R ) 2 , -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2- 6 alkenyl.
  • Y 1 is C2-6 alkynyl.
  • Y 1 is -C ⁇ CH.
  • Y 1 is -C ⁇ C-(Ci_6 alkylene)-OR 4 . In certain embodiments, Y 1 is -C ⁇ C-(Ci_6 alky lene)-0-(C 1-2 alkyl). In certain embodiments, Y 1 is -C ⁇ C-CH 2 -0-CH 3 .
  • the description above describes multiple embodiments relating to compounds of Formula 1-1.
  • the patent application specifically contemplates all combinations of the embodiments.
  • the invention contemplates a compound of Formula 1-1 wherein X 1 is -C(0)N(H)-v
  • the compound is a compound of Formula I-A:
  • R 1 is independently methyl, cyclopropyl, isopropyl, or -(CM alkylene)-(2-6 membered heteroalkyl);
  • R 2 is hydrogen
  • R 3 and R 4 each represent independently for each occurrence hydrogen or C alkyl;
  • a 1 is one of the following:
  • Y 1 represents, independently for each occurrence, a 2-8 membered heteroalkyl
  • Y 2 represents, independently for each occurrence, C 1-6 alkyl, C 3 -6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, azido, -N(R ) 2 , -(C 1-6 alky lene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R 3 , or Ci-6 haloalkyl-substituted C3-6 cycloalkyl.
  • Definitions of the variables in Formula I-A above encompass multiple chemical groups. Embodiments are contemplated where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii). [00155] Accordingly, in certain embodiments, any occurrence of Y 2 is independently C 1-3 alkyl, halogen, or Ci ⁇ haloalkyl.
  • a 1 is C 3-1 o cycloalkyl that is substituted by 1 or 2 occurrences of Y 1 and 0, 1 , 2, or 3 occurrences of Y 2 .
  • Y 1 is 2-8 membered heteroalkyl.
  • Y 1 is -0-(Ci_7 alkyl).
  • Y 1 is -O- butyl, -O-pentyl, or -O-hexyl.
  • Y 1 is -(C 1-3 alkylene)-0-(5-6 membered heteroaryl).
  • a 1 is 1,2,3,4-tetrahydronaphthalenyl substituted by 0, 1 , 2, or 3 occurrences of Y 2 .
  • R 1 is methyl. In certain embodiments, R 1 is further selected from halogen and halomethyl, such that R 1 may be methyl, halogen, or halomethyl.
  • R 2 is further selected from halogen, such that R 2 may be hydrogen or halogen.
  • R 1 is methyl
  • R 2 is hydrogen
  • a 1 is C 3-1 o cycloalkyl that is substituted by 1 or 2 occurrences of Y 1
  • Y 1 is 2-8 membered heteroalkyl (for example, Y 1 is -0-(Ci-7 alkyl), for example, Y 1 is -O-butyl, -O-pentyl, or -O-hexyl).
  • the compound is a compound of Formula I-Al :
  • R 1 is independently methyl, cyclopropyl, or isopropyl
  • R 2 is hydrogen
  • R 3 and R 4 each represent independently for each occurrence hydrogen or C1-4 alkyl
  • A is phenyl substituted by (a) 0, 1, 2, or 3 occurrences of Y 2 and (b) one of the following:
  • Y 2 represents, independently for each occurrence, C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, azido, -N(R ) 2 , -(C 1-6 alkylene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C0 2 R 3 , or Ci- 6 haloalkyl-substituted C3-6 cycloalkyl.
  • Definitions of the variables in Formula I-A above encompass multiple chemical groups. Embodiments are contemplated where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g., such as where R 1 is methyl, and A 1 is phenyl substituted by C4-8 alkoxyl.
  • any occurrence of Y 2 is independently C 1-3 alkyl, halogen, or C 1-3 haloalkyl.
  • a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) C4-8 alkoxyl. In certain embodiments, A 1 is phenyl substituted by -0-(C4 -7 alkyl). In certain embodiments, A 1 is phenyl substituted by -0-(C4 -7 alkyl) at the para-position of the phenyl group. In certain embodiments, A 1 is phenyl substituted by -O-butyl, -O-pentyl, or -O-hexyl.
  • a 1 is phenyl substituted by -O-butyl, -O-pentyl, or -O-hexyl at the para-position of the phenyl group. In certain embodiments, A 1 is phenyl substituted is
  • a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) a 2-4 membered heteroalkyl substituted by a 5-6 membered heteroaryl (which may be, for example, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl, each of which is optionally substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, Ci- 6 alkoxyl, cyano, -N(R 4 ) 2 , and amide).
  • a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) -C ⁇ C-(Ci-6 alkylene)-OR 4 , where R 4 is Ci-4 alkyl.
  • a 1 is phenyl substituted by (a) 0 or 1 occurrences of Y 2 and (b) -C ⁇ C-CH 2 -0-CH 3 .
  • a 1 is phenyl substituted by -C ⁇ C-CH 2 -0-CH 3 .
  • R 1 is methyl. In certain embodiments, R 1 is further selected from halogen and halomethyl, such that R 1 may be methyl, halogen, or halomethyl.
  • R 2 is further selected from halogen, such that R 2 may be hydrogen or halogen.
  • the compound is a compound of Formula I-B:
  • a 1 is phenyl substituted by (a) 0 or 1 occurrences ofY 2 and (b) C4-8 alkoxyl or -C ⁇ C- (Ci-6 alky lene)-0-(C 1-3 alkyl); and Y 2 represents, independently for each occurrence, C 1-6 alkyl, C3-6 cycloalkyl, halogen, or Ci-6 haloalkyl.
  • Definitions of the variables in Formula I-B above encompass multiple chemical groups. Embodiments are contemplated where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
  • the compound is one of the compounds listed in TABLE 1 below or a pharmaceutically acceptable salt thereof.
  • ⁇ is a bond to A 1 .
  • exemplary activators include, for example, substituted pyrrolo[l,2-a]pyrimidine and related organic compounds described for example, in
  • the substituted pyrrolo[l,2-a]pyrimidine or related organic compound is a compound embraced by Formula II:
  • R 1 and R 2 each represent independently for each occurrence hydrogen, deuterium, C 1-4 alkyl, Ci ⁇ haloalkyl, C1-4 deuteroalkyl, C 1-4 alkoxyl, -(C 1-4 alky lene)-(2-6 membered heteroalkyl), cyclopropyl, cyano, halogen, hydroxyl, or -N(R 4 )2;
  • R 3 represents independently for each occurrence hydrogen, C 1-6 alkyl, or C 3 -6
  • R 4 represents independently for each occurrence hydrogen, C 1-4 alkyl, cyclopropyl, or -C(0)R 3 ;
  • R 5 represents independently for each occurrence C 1-4 alkyl or C 3 -6 cycloalkyl
  • X 1 is one of the following:
  • a 1 is a cyclic group selected from:
  • heterocyclyl each of which is substituted by 0, 1, or 2 occurrences of Y 1 and 0, 1, 2, or 3 occurrences of Y 2 ;
  • Y 1 represents, independently for each occurrence, one of the following:
  • Ci-6 haloalkyl Ci -6 alkyl, halogen, cyano, -C0 2 R 3 , -C(0)R 5 , -S(0) 2 R 5 , -C(0)N(R 5 ) 2 , -C(0)N(R ) 2 , -N(R )C(0)R 5 , or -0-(Ci -8 haloalkyl);
  • Y 2 represents, independently for each occurrence, deuterium, Ci-6 alkyl, C 3 -6 cycloalkyl, halogen, Ci-6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, azido, -N(R ) 2 , -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C0 2 R 3 , or Ci- 6 haloalkyl-substituted C 3 -6 cycloalkyl;
  • n 1 or 2;
  • n 1, 2, or 3;
  • R 1 or R 2 is other than hydrogen when (i) A 1 is an unsubstituted heterocyclyl, (ii) A 1 is an unsubstituted phenyl or a phenyl substituted only by halogen, or (iii) Y 2 is halogen.
  • Embodiments are contemplated where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g., such as where X 1 is A 1 is phenyl or 5-6 membered heteroaryl, and Y 1 is 2-8 membered heteroalkyl.
  • R 1 represents independently for each occurrence C 1-4 alkyl, Ci ⁇ haloalkyl, -(C 1-4 alkylene)-(2-6 membered heteroalkyl), cyclopropyl, halogen, or -N(R 4 ) 2 .
  • R 1 represents independently for each occurrence Ci-4 alkyl, Ci ⁇ haloalkyl, C 1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro.
  • R 1 represents independently for each occurrence C 1-4 alkyl, Ci-4 haloalkyl, cyclopropyl, cyano, chloro, or fluoro.
  • R 1 is methyl.
  • the R 1 groups are located at the 2 and 4 positions of the pyrrolo[l,2- a]pyrimidinyl.
  • n is 2. In certain other embodiments, n is 1.
  • n is 1. In certain other embodiments, m is 2.
  • R 2 is hydrogen. In certain embodiments, R 2 is methyl or halogen. In certain embodiments, R 2 is methyl or halomethyl. In certain embodiments, R 2 is methyl or cyclopropyl.
  • R 3 and R 4 each represent independently for each occurrence hydrogen, methyl, or ethyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 4 is hydrogen.
  • X 1 is In certain embodiments, X 1 is
  • a 1 is a cyclic group selected from:
  • a 1 is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 and 0, 1, or 2 occurrences of Y 2 .
  • a 1 is phenyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
  • a 1 is a 5-6 membered heteroaryl substituted once by Y 1 and 0-1 occurrences of Y 2 .
  • a 1 is pyridinyl substituted once by Y 1 and 0-1 occurrences of Y .
  • A is C5-10 cycloalkyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
  • a 1 is C3-7 cycloalkyl substituted once by Y 1 and 0- 1 occurrences of Y 2 .
  • a 1 is a cyclopentyl or cyclohexyl, each of which is substituted once by Y 1 and 0-1 occurrences of Y .
  • a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 1 and 0, 1, or I occurrences of Y 2 .
  • a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 2 selected from the group consisting of Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, hydroxyl, and Ci-6 alkoxyl.
  • a 1 is or ; wherein m is 0, 1, or 2; and Y 2 represents independently for each occurrence Ci-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxy or cyano.
  • any occurrence of Y 2 is independently C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, or hydroxyl.
  • any occurrence of Y 2 is independently C 1-3 alkyl.
  • Y 2 is cyclopropyl.
  • Y 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl, furanyl, or pyridinyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl.
  • Y 1 is -0-(Ci_7 alkyl). In certain embodiments, Y 1 is -O-butyl, -O-pentyl, or -O-hexyl. In certain embodiments, Y 1 is -(C 1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y 1 is -CH 2 -0-(5-6 membered heteroaryl).
  • Y 1 is -CH 2 -0-(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, -N(R 4
  • Y 1 is a 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl).
  • Y 1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl.
  • Y 1 is 5-membered heteroaryl.
  • Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-7 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R 4 )2, amide, and -CO2H.
  • Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, and C 1-6 alkoxyl.
  • Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
  • Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
  • Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl.
  • Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
  • Y 1 is C 2-6 alkynyl, -C ⁇ C-(Ci -6 alkylene)-OR 4 , -C ⁇ C-(Ci -6 alkylene)-N(R ) 2 , -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl.
  • Y 1 is C2-6 alkynyl.
  • Y 1 is -C ⁇ CH.
  • Y 1 is -C ⁇ C-(Ci_6 alkylene)-OR 4 .
  • Y 1 is -C ⁇ C-(Ci_6 alky lene)-0-(C 1-2 alkyl).
  • Y 1 is -C ⁇ C-CH 2 -0-CH 3 .
  • the description above describes multiple embodiments relating to compounds of Formula II.
  • the patent application specifically contemplates all combinations of the embodiments.
  • the invention contemplates a compound of Formula I wherein X 1 is A 1 is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 and 0, 1, or 2 occurrences of Y 2 , and Y 1 is 2-8 membered heteroalkyl.
  • the compound is a compound of Formula II- 1 :
  • R 1 and R 2 each represent independently for each occurrence hydrogen, C1-4 alkyl, C 1-4 haloalkyl, Ci- 4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro;
  • R 3 represents independently for each occurrence hydrogen or C 1-4 alkyl
  • R 4 represents independently for each occurrence hydrogen, C 1-4 alkyl, or -C(0)R 3 ;
  • X 1 is one of the following:
  • a 1 is a cyclic group selected from:
  • Y 1 represents, independently for each occurrence, one of the following:
  • Y 2 represents, independently for each occurrence, C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, azido, -N(R ) 2 , -(C 1-6 alkylene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R 3 , or Ci-6 haloalkyl-substituted C3-6 cycloalkyl;
  • R 1 or R 2 is other than hydrogen when (i) A 1 is an unsubstituted heterocyclyl or (ii) Y 2 is halogen.
  • Definitions of the variables in Formula II-l above encompass multiple chemical groups. Embodiments are contemplated where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g., such as where X 1 is A 1 is phenyl or 5-6 membered heteroaryl, and Y 1 is 2-8 membered heteroalkyl.
  • R 1 represents independently for each occurrence C 1-4 alkyl, Ci-4 haloalkyl, C 1-4 alkoxyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R 1 represents independently for each occurrence C 1-4 alkyl, C 1-4 haloalkyl, cyclopropyl, cyano, chloro, or fluoro. In certain embodiments, R 1 is methyl. In certain embodiments, the R 1 groups are located at the 2 and 4 positions of the pyrrolo[l,2- a]pyrimidinyl.
  • n is 2. In certain other embodiments, n is 1.
  • n is 1. In certain other embodiments, m is 2.
  • R 2 is hydrogen. In certain embodiments, R 2 is methyl or halogen. In certain embodiments, R 2 is methyl or halomethyl. In certain embodiments, R 2 is methyl or cyclopropyl.
  • R 3 and R 4 each represent independently for each occurrence hydrogen, methyl, or ethyl. In certain embodiments, R 3 is hydrogen. In certain embodiments, R 4 is hydrogen. [00202] In certain embodiments, X 1 is -C(0)N(H)-v
  • a 1 is a cyclic group selected from: • phenyl, 5-6 membered heteroaryl, or C3-7 cycloalkyl, each of which is substituted by 1 or 2 occurrences of Y 1 and 0, 1, 2, or 3 occurrences of Y 2 ; and
  • heterocyclyl each of which is substituted by 0, 1, or 2 occurrences of Y 1 and 0, 1, 2, or
  • a 1 is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 and 0, 1, or 2 occurrences of Y 2 .
  • a 1 is phenyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
  • a 1 is a 5-6 membered heteroaryl substituted once by Y 1 and 0-1 occurrences of Y 2 .
  • a 1 is pyridinyl substituted once by Y 1 and 0-1 occurrences of Y .
  • a 1 is C3-7 cycloalkyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
  • a 1 is a cyclopentyl or cyclohexyl, each of which is substituted once by Y 1 and 0-1 occurrences of Y .
  • a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 1 and 0, 1, or I occurrences of Y 2 .
  • a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 2 selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, and C 1-6 alkoxyl.
  • a 1 wherein m is 0, 1 , or 2; and Y 2 represents independently for each occurrence C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, C 1-6 alkoxyl, or cyano.
  • a 1 or ( Y )m wherein m is 0, 1, or 2; and Y 2 represents independently for each occurrence C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, or C 1-6 alkoxyl.
  • any occurrence of Y 2 is independently C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, or hydroxyl. In certain embodiments, any occurrence of Y 2 is independently C 1-3 alkyl. In certain embodiments, Y 2 is cyclopropyl.
  • Y 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl substituted by a 5-6 membered heteroaryl, such as pyrrolyl, furanyl, or pyridinyl. In certain embodiments, Y 1 is a 2-8 membered heteroalkyl.
  • Y 1 is -0-(Ci_7 alkyl). In certain embodiments, Y 1 is -O-butyl, -O-pentyl, or -O-hexyl. In certain embodiments, Y 1 is -(C 1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y 1 is -CH 2 -0-(5-6 membered heteroaryl).
  • Y 1 is -CH 2 -0-(5-6 membered heteroaryl), wherein the 5-6 membered heteroaryl is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, -N(R 4
  • Y 1 is a 3-10 membered heterocyclyl, 6-10 membered aryl, C3-7 cycloalkyl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl).
  • Y 1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl.
  • Y 1 is 5-membered heteroaryl.
  • Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-7 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R 4 )2, amide, and -CO2H.
  • Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, and C 1-6 alkoxyl.
  • Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
  • Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
  • Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl.
  • Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, thiazolinyl, or triazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, Ci- 6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
  • Y 1 is C 2-6 alkynyl, -C ⁇ C-(Ci -6 alkylene)-OR 4 , -C ⁇ C-(Ci -6 alkylene)-N(R ) 2 , -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl.
  • Y 1 is C2-6 alkynyl.
  • Y 1 is -C ⁇ CH.
  • Y 1 is -C ⁇ C-(Ci_6 alkylene)-OR 4 .
  • Y 1 is -C ⁇ C-(Ci_6 alky lene)-0-(C 1-2 alkyl).
  • Y 1 is -C ⁇ C-CH 2 -0-CH 3 .
  • the compound is a compound of Formula Il-la:
  • R represents independently for each occurrence C1-4 alkyl
  • R 2 and R 3 each represent independently for each occurrence hydrogen or C1-4 alkyl
  • R 4 represents independently for each occurrence hydrogen, C 1-4 alkyl, or -C(0)R 3
  • X 1 is one of the following:
  • a 1 is a cyclic group selected from:
  • Y 1 represents, independently for each occurrence, one of the following:
  • Y 2 represents, independently for each occurrence, C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, azido, -N(R ) 2 , -(C 1-6 alky lene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R 3 , or Ci-6 haloalkyl-substituted C3-6 cycloalkyl; and
  • n 1, 2, or 3.
  • Definitions of the variables in Formula II- l a above encompass multiple chemical groups. Embodiments are contemplated where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g., such as where X 1 is A 1 is phenyl or 5-6 membered heteroaryl, and Y 1 is 2-8 membered heteroalkyl.
  • the compound is a compound of Formula II-A:
  • R 1 is independently methyl, isopropyl, cyclopropyl, Ci ⁇ haloalkyl, -(CH 2 )i-2-0-(Ci-3 alkyl), chloro, fluoro, or -N(R 4 ) 2 ;
  • R 2 is hydrogen
  • R 3 and R 4 each represent independently for each occurrence hydrogen or C alkyl;
  • a 1 is a cyclic group selected from:
  • Y 1 represents, independently for each occurrence, one of the following:
  • Y 2 represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, azido, -N(R ) 2 , -(Ci-6 alkylene)-(5-6 membered heterocyclyl), -(Ci-6 alkylene)-C0 2 R 3 , or Ci-6
  • Definitions of the variables in Formula II-A above encompass multiple chemical groups. Embodiments are contemplated where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g., such as where A 1 is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 , where Y 1 is a 2-8 membered heteroalkyl.
  • a 1 is C3-7 cycloalkyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
  • a 1 is phenyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
  • a 1 is a 5-6 membered heteroaryl substituted once by Y 1 and 0-1 occurrences of Y 2 .
  • a 1 is pyridinyl substituted by Y 1 and 0-1 occurrences of Y 2 .
  • any occurrence of Y 2 is independently C1-3 alkyl, halogen, or Ci- 3 haloalkyl.
  • Y 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is -0-(Ci_7 alkyl). In certain embodiments, Y 1 is -O-butyl, -O-pentyl, or -O-hexyl. In certain
  • Y 1 is -(C1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y 1 is -CH 2 -0-(5-6 membered heteroaryl).
  • Y 1 is a 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C 2- 6 alkynyl). In certain embodiments, Y 1 is a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl. [00224] In certain embodiments, Y 1 is a 5-membered heteroaryl.
  • Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
  • Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
  • Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
  • Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl.
  • Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
  • Y 1 is C 2-6 alkynyl, -C ⁇ C-(Ci -6 alkylene)-OR 4 , -C ⁇ C-(Ci -6 alkylene)-N(R ) 2 , -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl.
  • Y 1 is C2-6 alkynyl.
  • Y 1 is -C ⁇ CH.
  • Y 1 is -C ⁇ C-(Ci_6 alkylene)-OR 4 .
  • Y 1 is -C ⁇ C-(Ci_6 alky lene)-0-(C 1-2 alkyl).
  • Y 1 is -C ⁇ C-CH 2 -0-CH 3 .
  • a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 1 and 0, 1, or 2 occurrences of Y 2 .
  • a 1 is an 8-12 membered bicyclic carbocyclyl that is partially unsaturated or an 8-12 membered bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 1 and 0, 1, or 2 occurrences of Y 2 .
  • a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0, 1 , or 2 occurrences of Y 2 .
  • a 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl.
  • A is (Y 2 ) i ,m or ; wherein m is 0, 1, or 2; and Y 2 represents independently for each occurrence alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, hydroxyl, C 1-6 alkoxyl, or cyano.
  • R 1 is methyl. In certain embodiments, R 1 is further selected from halogen and halomethyl, such that R may be methyl, halogen, or halomethyl.
  • R 2 is further selected from halogen, such that R 2 may be hydrogen or halogen.
  • the description above describes multiple embodiments relating to compounds of Formula II-A.
  • the patent application specifically contemplates all combinations of the embodiments.
  • the invention contemplates a compound of Formula II-A, wherein A is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 and 0, 1, or I occurrences of Y 2 , and Y 1 is 2-8 membered heteroalkyl.
  • the invention contemplates a compound of Formula II-A, wherein A 1 is a C 3-1 o cycloalkyl optionally substituted with one Y 1 , one R 1 is methyl and the other R 1 is CHF 2 , R 2 is H, and Y 1 is a 2-8 membered heteroalkyl, for example, Y 1 is -0-(C 1-7 alkyl), for example, Y 1 is -O-butyl, -O- pentyl, or -O-hexyl.
  • the compound is a compound of Formula II-A1 :
  • R 1 is independently methyl, cyclopropyl, or isopropyl
  • R 2 is hydrogen
  • R 3 and R 4 each represent independently for each occurrence hydrogen or C1-4 alkyl;
  • a 1 is a cyclic group selected from:
  • Y 1 represents, independently for each occurrence, one of the following:
  • Y 2 represents, independently for each occurrence, Ci-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1 -6 hydroxy alkyl, hydroxyl, Ci- 6 alkoxyl, cyano, azido, -N(R ) 2 , -(C 1 -6 alky lene)- (5-6 membered heterocyclyl), -(Ci-6 alkylene)-C02R 3 , or Ci-6 haloalkyl-substituted C3-6 cycloalkyl.
  • Definitions of the variables in Formula II-A1 above encompass multiple chemical groups. Embodiments are contemplated where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g., such as where A 1 is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 , where Y 1 is a 2-8 membered heteroalkyl.
  • a 1 is phenyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
  • a 1 is a 5-6 membered heteroaryl substituted once by Y 1 and 0-1 occurrences of Y 2 .
  • a 1 is pyridinyl substituted by Y 1 and 0-1 occurrences of Y 2 .
  • any occurrence of Y 2 is independently C 1-3 alkyl, halogen, or Ci-3 haloalkyl.
  • Y 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is -0-(Ci_7 alkyl). In certain embodiments, Y 1 is -O-butyl, -O-pentyl, or -O-hexyl. In certain
  • Y 1 is -(C 1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y 1 is -CH 2 -0-(5-6 membered heteroaryl).
  • Y 1 is a 3-10 membered heterocyclyl, 6-10 membered aryl, -0-(3-6 membered heterocyclyl), -0(6-10 membered aryl), or -0-(C2-e alkynyl). In certain embodiments, Y 1 is a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl.
  • Y 1 is a 5-membered heteroaryl.
  • Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
  • Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
  • Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, Ci-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
  • Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl.
  • Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
  • Y 1 is C 2-6 alkynyl, -C ⁇ C-(Ci -6 alkylene)-OR 4 , -C ⁇ C-(Ci -6 alkylene)-N(R ) 2 , -(C2-4 alkynylene)-(5-6 membered heteroaryl), or C2-6 alkenyl.
  • Y 1 is C2-6 alkynyl.
  • Y 1 is -C ⁇ CH.
  • Y 1 is -C ⁇ C-(Ci_6 alkylene)-OR 4 .
  • Y 1 is -C ⁇ C-(Ci_6 alky lene)-0-(C 1-2 alkyl).
  • Y 1 is -C ⁇ C-CH 2 -0-CH 3 .
  • a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 1 and 0, 1, or 2 occurrences of Y 2 .
  • a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0, 1, or 2 occurrences of Y 2 .
  • a 1 is a 2-8 membered heteroalkyl optionally substituted by a 6-10 membered aryl or a 3-10 membered heterocyclyl.
  • a 1 is
  • Y 2 represents independently for each occurrence C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, hydroxyl, or C 1-6
  • a 1 is (Y )m 0 r ; wherein m is 0, 1, or 2; and Y 2 represents independently for each occurrence C 1-6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, hydroxyl, C 1-6 alkoxyl, or cyano.
  • R 1 is methyl. In certain embodiments, R 1 is further selected from halogen and halomethyl, such that R 1 may be methyl, halogen, or halomethyl.
  • R 2 is further selected from halogen, such that R 2 may be hydrogen or halogen.
  • the description above describes multiple embodiments relating to compounds of Formula II-A1.
  • the patent application specifically contemplates all combinations of the embodiments.
  • the invention contemplates a compound of Formula I-Al wherein A is phenyl or 5-6 membered heteroaryl, each of which is substituted once by Y 1 and 0, 1, or 2 occurrences of Y 2 , and Y 1 is 2-8 membered heteroalkyl.
  • the compound is a compound of Formula II-B:
  • a 1 is a cyclic group selected from phenyl, pyridinyl, cyclopentyl, or cyclohexyl, each of which is substituted by 1 occurrence of Y 1 and 0, 1, or 2 occurrences of Y :
  • Y 1 represents, independently for each occurrence, one of the following:
  • Y 2 represents, independently for each occurrence, Ci_6 alkyl, C3-6 cycloalkyl, halogen, Ci-6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, or Ci-6 alkoxyl;
  • R 4 represents independently for each occurrence hydrogen or C1-4 alkyl.
  • Definitions of the variables in Formula II-B above encompass multiple chemical groups.
  • the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii), e.g., such as where A 1 is phenyl or pyridinyl, each of which is substituted once by Y 1 , where Y 1 is 2-8 membered heteroalkyl.
  • a 1 is phenyl substituted once by Y 1 and 0-1 occurrences of Y 2 .
  • a 1 is pyridinyl substituted by Y 1 and 0-1 occurrences of Y 2 .
  • any occurrence of Y 2 is independently C1-3 alkyl, halogen, or Ci-3 haloalkyl.
  • Y 1 is a 2-8 membered heteroalkyl optionally substituted by a 6 membered aryl or a 3-10 membered heterocyclyl.
  • Y 1 is -0-(Ci_7 alkyl).
  • Y 1 is -O-butyl, -O-pentyl, or -O-hexyl.
  • Y 1 is -(C 1-3 alkylene)-0-(5-6 membered heteroaryl). In certain embodiments, Y 1 is -CH 2 -0-(5-6 membered heteroaryl).
  • Y 1 is a 3-10 membered heterocyclyl, 6 membered aryl, or -O- (3-6 membered heterocyclyl). In certain embodiments, Y 1 is a 3-10 membered heterocyclyl. In certain embodiments, Y 1 is a 3-10 membered heterocyclyl selected from the group consisting of a 5-6 membered heteroaryl and a 5-6 membered heterocycloalkyl.
  • Y 1 is a 5-membered heteroaryl.
  • Y 1 is a 5-membered heteroaryl substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
  • Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl.
  • Y 1 is furanyl, pyrrolyl, thiophenyl, imidazolyl, pyrazolyl, oxazolyl, or thiazolyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, and Ci-6 alkoxyl.
  • Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl.
  • Y 1 is pyridinyl, pyrimidinyl, pyrazinyl, isooxazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, imidazolinyl, oxazolinyl, pyrazolinyl, or thiazolinyl, each of which is substituted by one or two substituents independently selected from the group consisting of C 1-6 alkyl, C3-6 cycloalkyl, halogen, C 1-6 haloalkyl, C 1-6 hydroxyalkyl, hydroxyl, C 1-6 alkoxyl, cyano, -N(R 4 ) 2 , amide, and -CO2H.
  • the description above describes multiple embodiments relating to compounds of Formula II-B.
  • the patent application specifically contemplates all combinations of the embodiments.
  • the invention contemplates a compound of Formula II-B wherein A is phenyl or pyridinyl, each of which is substituted once by Y 1 and 0, 1, or 2 occurrences of Y 2 , and Y 1 is 2-8 membered heteroalkyl.
  • the compound is a compound of Formula I-C:
  • a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrence of Y 1 and 0, 1, or 2 occurrences of Y :
  • Y 1 represents, independently for each occurrence, one of the following:
  • Y 2 represents, independently for each occurrence, Ci_6 alkyl, C3-6 cycloalkyl, halogen, Ci- 6 haloalkyl, C 1-6 hydroxy alkyl, hydroxyl, or Ci-6 alkoxyl;
  • R 4 represents independently for each occurrence hydrogen or C1-4 alkyl.
  • Definitions of the variables in Formula II-C above encompass multiple chemical groups.
  • the application contemplates embodiments where, for example, i) the definition of a variable is a single chemical group selected from those chemical groups set forth above, ii) the definition is a collection of two or more of the chemical groups selected from those set forth above, and iii) the compound is defined by a combination of variables in which the variables are defined by (i) or (ii).
  • a 1 is a bicyclic carbocyclyl that is partially unsaturated or a bicyclic heterocyclyl, each of which is substituted by 0 or 1 occurrences of Y 2 .
  • any occurrence of Y 2 is independently C1-3 alkyl, halogen, or Ci -3 haloalkyl.
  • the compound is one of the compounds listed in TABLE 2 below or a pharmaceutically acceptable salt thereof.
  • ⁇ is a bond to A 1 .
  • the GCase activator comprises one or more of the compounds set forth in TABLES 1 and 2.
  • the ⁇ -glucocerebrosidase activators typically are administered in a pharmaceutical composition.
  • the pharmaceutical compositions preferably comprise a therapeutically-effective amount of one or more ⁇ -glucocerebrosidase activators formulated together with one or more pharmaceutically acceptable carriers.
  • compositions may be specially formulated for administration in solid or liquid form, including those adapted for the following: (1) oral administration, for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets (e.g., those targeted for buccal, sublingual, and/or systemic absorption), boluses, powders, granules, pastes for application to the tongue; (2) parenteral administration by, for example, subcutaneous, intramuscular, intravenous or epidural injection as, for example, a sterile solution or suspension, or sustained-release formulation; (3) topical application, for example, as a cream, ointment, or a controlled-release patch or spray applied to the skin; (4) intravaginally or intrarectally, for example, as a pessary, cream or foam; (5) sublingually; (6) ocularly; (7) trans dermally; or (8) nasally.
  • oral administration for example, drenches (aqueous or non-aqueous solutions or suspensions), tablets (e
  • wetting agents such as sodium lauryl sulfate and magnesium stearate, as well as coloring agents, release agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the compositions.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxy toluene (BHT), le
  • Formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any methods well known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the host being treated, the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the compound which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 0.1 per cent to about ninety -nine percent of active ingredient, preferably from about 5 percent to about 70 percent, most preferably from about 10 percent to about 30 percent.
  • a formulation of the present invention comprises an excipient selected from the group consisting of cyclodextrins, celluloses, liposomes, micelle forming agents, e.g., bile acids, and polymeric carriers, e.g., polyesters and polyanhydrides; and a compound of the present invention.
  • an aforementioned formulation renders orally bioavailable a compound of the present invention.
  • Methods of preparing these formulations or compositions include the step of bringing into association a compound of the present invention with the carrier and, optionally, one or more accessory ingredients.
  • the formulations are prepared by uniformly and intimately bringing into association a compound of the present invention with liquid carriers, or finely divided solid carriers, or both, and then, if necessary, shaping the product.
  • Formulations of the invention suitable for oral administration may be in the form of capsules, cachets, pills, tablets, lozenges (using a flavored basis, usually sucrose and acacia or tragacanth), powders, granules, or as a solution or a suspension in an aqueous or non-aqueous liquid, or as an oil-in-water or water-in-oil liquid emulsion, or as an elixir or syrup, or as pastilles (using an inert base, such as gelatin and glycerin, or sucrose and acacia) and/or as mouth washes and the like, each containing a predetermined amount of a compound of the present invention as an active ingredient.
  • a compound of the present invention may also be administered as a bolus, electuary or paste.
  • the active ingredient is mixed with one or more pharmaceutically-acceptable carriers, such as sodium citrate or dicalcium phosphate, and/or any of the following: (1) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol, and/or silicic acid; (2) binders, such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinyl pyrrolidone, sucrose and/or acacia; (3) humectants, such as glycerol; (4) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; (5) solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary ammonium compounds and surfactants,
  • pharmaceutically-acceptable carriers such as sodium citrate or dicalcium phosphate
  • compositions may also comprise buffering agents.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-shelled gelatin capsules using such excipients as lactose or milk sugars, as well as high molecular weight polyethylene glycols and the like.
  • a tablet may be made by compression or molding, optionally with one or more accessory ingredients.
  • Compressed tablets may be prepared using binder (for example, gelatin or hydroxypropylmethyl cellulose), lubricant, inert diluent, preservative, disintegrant (for example, sodium starch glycolate or cross-linked sodium carboxymethyl cellulose), surface- active or dispersing agent.
  • Molded tablets may be made by molding in a suitable machine a mixture of the powdered compound moistened with an inert liquid diluent.
  • the tablets, and other solid dosage forms of the pharmaceutical compositions of the present invention may optionally be scored or prepared with coatings and shells, such as enteric coatings and other coatings well known in the pharmaceutical-formulating art. They may also be formulated so as to provide slow or controlled release of the active ingredient therein using, for example, hydroxypropylmethyl cellulose in varying proportions to provide the desired release profile, other polymer matrices, liposomes and/or microspheres. They may be formulated for rapid release, e.g., freeze-dried.
  • compositions may be sterilized by, for example, filtration through a bacteria-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved in sterile water, or some other sterile injectable medium immediately before use.
  • These compositions may also optionally contain opacifying agents and may be of a composition that they release the active ingredient(s) only, or preferentially, in a certain portion of the gastrointestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • the active ingredient can also be in micro-encapsulated form, if appropriate, with one or more of the above-described excipients.
  • Liquid dosage forms for oral administration of the compounds of the invention include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and emulsifiers, such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art, such as, for example, water or other solvents, solubilizing agents and
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, coloring, perfuming and preservative agents.
  • Suspensions in addition to the active compounds, may contain suspending agents as, for example, ethoxylated isostearyl alcohols, poly oxy ethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydr oxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • suspending agents as, for example, ethoxylated isostearyl alcohols, poly oxy ethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydr oxide, bentonite, agar-agar and tragacanth, and mixtures thereof.
  • Formulations of the pharmaceutical compositions of the invention for rectal or vaginal administration may be presented as a suppository, which may be prepared by mixing one or more compounds of the invention with one or more suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • suitable nonirritating excipients or carriers comprising, for example, cocoa butter, polyethylene glycol, a suppository wax or a salicylate, and which is solid at room temperature, but liquid at body temperature and, therefore, will melt in the rectum or vaginal cavity and release the active compound.
  • Formulations of the present invention which are suitable for vaginal administration also include pessaries, tampons, creams, gels, pastes, foams or spray formulations containing such carriers as are known in the art to be appropriate.
  • Dosage forms for the topical or transdermal administration of a compound of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a
  • pharmaceutically-acceptable carrier and with any preservatives, buffers, or propellants which may be required.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients, such as animal and vegetable fats, oils, waxes, paraffin's, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffin's, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • Powders and sprays can contain, in addition to a compound of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted hydrocarbons, such as butane and propane.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound of the present invention to the body.
  • dosage forms can be made by dissolving or dispersing the compound in the proper medium.
  • Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate of such flux can be controlled by either providing a rate controlling membrane or dispersing the compound in a polymer matrix or gel.
  • Ophthalmic formulations are also contemplated as being within the scope of this invention.
  • compositions of this invention suitable for parenteral administration comprise one or more compounds of the invention in combination with one or more pharmaceutically-acceptable sterile isotonic aqueous or nonaqueous solutions, dispersions, suspensions or emulsions, or sterile powders which may be reconstituted into sterile injectable solutions or dispersions just prior to use, which may contain sugars, alcohols, antioxidants, buffers, bacteriostats, solutes which render the formulation isotonic with the blood of the intended recipient or suspending or thickening agents.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. Prevention of the action of microorganisms upon the subject compounds may be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum
  • a liquid suspension of crystalline or amorphous material having poor water solubility The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form.
  • delayed absorption of a parenterally-administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming microencapsule matrices of the subject compounds in biodegradable polymers such as polylactide-polyglycolide. Depending on the ratio of drug to polymer, and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly (anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or microemulsions which are compatible with body tissue.
  • the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given per se or as a pharmaceutical composition containing, for example, 0.1 to 99% (more preferably, 10 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • the preparations of the present invention may be given orally, parenterally, topically, or rectally. They are of course given in forms suitable for each administration route. For example, they are administered in tablets or capsule form, by injection, inhalation, eye lotion, ointment, suppository, etc. administration by injection, infusion or inhalation; topical by lotion or ointment; and rectal by suppositories. Oral administrations are preferred.
  • These compounds may be administered to humans and other animals for therapy by any suitable route of administration, including orally, nasally, as by, for example, a spray, rectally, intravaginally, parenterally, intracistemally and topically, as by powders, ointments or drops, including buccally and sublingually.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically-acceptable dosage forms by conventional methods known to those of skill in the art.
  • the inhibitor when the ⁇ -glucocerebrosidase activator is delivered by systemic administration, the inhibitor preferably is capable of traversing the blood-brain barrier.
  • the GCase activator may be formulated using formulation techniques know in the art for enhancing traversal of an active agent across the blood-brain barrier.
  • the ⁇ - glucocerebrosidase activator may be co-administered with an agent that transiently increases the permeability of the blood-brain barrier, including, for example, bradykinin, or Cereport, a nine amino acid peptide based on bradykinin (Alkermes, Cambridge, MA).
  • the ⁇ -glucocerebrosidase activator may be administered following a procedure that transiently increases the permeability of the blood-brain barrier, including, for example, localized exposure to high-intensity focused ultrasound, and osmotic disruption of the blood- brain barrier through induced shrinkage of cerebrovascular endothelial cells.
  • exemplary approaches for formulating the ⁇ -glucocerebrosidase activator to facilitate transport across the blood-brain barrier include encapsulation in a particle capable of traversing the blood-brain barrier, including, for example, lipid nanoparticles (Tekmira, British Columbia, Canada); liposomes (2-BBB, Leiden,
  • Actual dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being toxic to the patient.
  • the selected dosage level will depend upon a variety of factors including the activity of the particular compound of the present invention employed, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion or metabolism of the particular compound being employed, the rate and extent of absorption, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compound employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a compound of the invention may be tritrated by a physician or veterinarian at escalating dosages to the subject over a period of days, weeks, or months to ameliorate at least on symptom associated with the neurodegenerative disorder in question, including loss of cognitive function and/or cognitive impairment.
  • a suitable daily dose of a compound of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect.
  • the compound or compounds can administered at about 0.01 mg/kg to about 200 mg/kg, or about 0.1 mg/kg to about 100 mg/kg, or at about 0.5 mg/kg to about 50 mg/kg. In certain embodiments, the compound or compounds can be administered at a concentration less than 20 mg/kg.
  • the effective amount may be less than when the agent is used alone.
  • the effective daily dose of the active compound may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dosage forms. Preferred dosing is one administration per day.
  • the invention also embraces combination therapies, which includes the administration of a ⁇ -glucocerebrosidase activator and a second agent as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents.
  • the beneficial effect of the combination may include pharmacokinetic or pharmacodynamic co- action resulting from the combination of therapeutic agents.
  • the ⁇ -glucocerebrosidase activator can be administered in combination with carbidopa and/or levadopa, a dopamine agonist, a monoamine oxidase B inhibitor, a catchetol O-methyltransferase inhibitor, an anticholingeric, or amantadine.
  • the ⁇ -glucocerebrosidase activator can be administered in combination with a cholinesterase inhibitor and/or memantine.
  • the ⁇ -glucocerebrosidase activator can be administered in combination with tetrabenazine; an antipsychotic drug such as haloperidol, chlorpromazine, quetiapine, risperidone, and olanzapine; a chorea-suppressing medication such as amantadine, levetiracetam, and clonazempam; an antidepressant such as citalopram, fluoxetine, and sertraline; and a mood-stabilizing drug such as valproate, carbamazepine, and lamotrigine.
  • the ⁇ -glucocerebrosidase activator can be administered in combination with riluzole; an agent for ameliorating muscle cramps and spasms such as cyclobenzaprine HCL, metaxalone, and robaxin; an agent for ameliorating spasticity such as tizanidine HC1, baclofen, and dantrolene; an agent for ameliorating constipation such as lubiprostone, linaclotide, lactulose, and polyethylene glycol; an agent for ameliorating fatigue such as caffeine, caffeine citrate, or caffeine benzoate injection; an agent for ameliorating excessive salivation such as glycopyrrolate, propantheline, amitriptyline, nortriplyline HCL and scopolamine; an agent for ameliorating excessive phlegm such as guaifenesin, albuterol inhalation, and acetylcysteine; an agent for ameliorating excessive phlegm such as guaifenesin, albuterol in
  • the ⁇ -glucocerebrosidase activator can be administered in combination with a corticosteroid, ⁇ interferon, glatiramer acetate, dimethyl fumarate, fingolimod, teriflunomide, natalizumab, mitoxantrone, baclofen, and tizanidine.
  • the ⁇ -glucocerebrosidase activator can be administered in combination with a cholinesterase inhibitor, a Parkinson's disease medication such as carbidopa and/or levodopa, and an anti-psychotic medication such as quetiapine and olanzapine.
  • the ⁇ -glucocerebrosidase activator can be administered in combination with a medication to raise blood pressure such as
  • the ⁇ -glucocerebrosidase activator can be administered in combination with an antidepressant, a selective serotonin reuptake inhibitor, and an antipsychotic.
  • the ⁇ -glucocerebrosidase activator can be administered in combination with a Parkinson's disease medication such as carbidopa and/or levodopa. It is understood that other combinations would be known be those skilled in the art.
  • sphingotypes of peripheral blood mononuclear cells PBMCs
  • plasma harvested from subjects with Parkinson's disease PD
  • HC healthy control subjects
  • GCase ⁇ -glucocerebrosidase
  • CPT Cell Preparation Tubes
  • PBMCs and plasma from whole blood were accomplished by centrifuging the CPTs according to the manufacturer's instructions.
  • the PBMC and plasma layers were removed and the PBMCs were washed two times with phosphate buffered saline (PBS) containing 10% human serum. Red blood cells, if present, could be lysed with ACK lysis buffer before the second wash.
  • PBS phosphate buffered saline
  • PBMCs were counted using an automated cell counter and dead cells identified using trypan blue staining. Viable cells were harvested and used to determine cell number.
  • Plasma was centrifuged at 3,000 x g for 10 minutes. After counting, cell and plasma aliquots were prepared and analyzed at the Medical University of South Carolina Lipidomics Core to identify the presence of the
  • glycosphingolipids set forth in FIGURE 3 namely HexosylCeramide (HexCer), LactosylCeramide (LacCer), Ceramide (Cer), Sphingosine (Sph) and dihydro-ceramide (dhCer).
  • Glycosphingolipid content was determined by LC-MS. Briefly, the sample was subjected to a single-phase lipid extraction with ethyl acetate/isopropanol/water spiked with an internal standard. The extract was evaporated to dryness under nitrogen, then reconstituted in 1 mM ammonium formate, 0.2% formic acid in methanol.
  • HPLC separation was performed on a Spectra C8SR column (150 x 3.0 mm, 3 ⁇ particle size) with mobile phases A (1 mM ammonium formate, 0.2% formic acid in water) and B (1 mM ammonium formate, 0.2% formic acid in methanol).
  • Mass spectrometry was performed on a triple quadrupole MS analyzer with an Electrospray Ion Source. MS analysis was conducted for sphingolipids with a dl8: 1 sphingoid base except where noted as dl8:0 (dh). The remaining PBMCs and plasma were cryopreserved until use.
  • PBMCs In order to determine the response of PBMCs to GCase activator treatment, the PBMC cells were thawed, washed one time with warm serum free media (SFM), counted as above, and then transferred to 100 mm dishes in SFM. Treated SFM with DMSO or GCase activator compound in DMSO was added to plates to give a final concentration of 0.1% DMSO. The cells were incubated at 37 °C in 5% CO2 for 72 hours, and then harvested by gentle scraping. The cells were pelleted, and then resuspended for counting as above. After counting, cell aliquots were prepared and the GSL content, including HexCer, LacCer, Cer, and Sph was determined by LC-MS, as described above.
  • SFM serum free media
  • Sphingolipid content was used to facilitate sphingotyping on the PBMC cells.
  • Basal HexCer profiles which encompass both GluCer and GalCer, for PBMCs from both Parkinson's disease (PD) and healthy control subjects (HC) are depicted in FIGURE 4.
  • the analysis revealed that the most abundant fatty acid chains were C16:0, C22:0, C24:0, and C24: l .
  • Other chain lengths were near the lower limit of quantitation ("LLOQ”) and exhibited higher variance in quantitation.
  • the sphingolipids of the PBMC cells were analyzed to identify the sphingotypes of cells found to respond to exposure to the GCase activator.
  • PBMCs were treated with a GCase activator, and the sphingolipid content, including HexCer, LacCer, Cer, and Sph was determined by LC-MS, as described above.
  • the HexCer concentration was determined as the aggregate amount of C16:0, C22:0, C24:0, and C24: l glucosylceramide in the sample.
  • the HexCer levels based on the aggregate concentration of these chain lengths was found to be more accurate than the other chain lengths. In other words, the summed
  • PBMC cells responsive to a GCase activator were identified based on the reduction of the HexCer (AHexCer) following exposure to the GCase activator, and PBMC cells unresponsive to the GCase activator (non-responders) were identified based on no reduction or an increase in HexCer (AHexCer) following exposure to the GCase activator.
  • FIGURE 5 represents data from the two cohorts shown separately (study 1 used as a GCase activator compound 11-97 from TABLE 2 (a substituted pyrrolo[l,2-a] pyrimidine) and study 2 used as a GCase activator a different molecule, a substituted pryazolo- [l,5a]pyrimidine).
  • the basal sphingotypes for each group were determined using the glycosphingolipids present in the PBMC cells that had not been exposed to a GCase activator. It was determined that the ratio of HexCer (the aggregate concentration of the 4 most prominent hexosylceramides, see FIGURE 4B) to Sph (HexCer/Sph) in PBMCs was able to discriminate responders from non-responders, with responders having higher levels of HexCer/Sph than non-responders (see, FIGURE 6). The same feature was found between two different cohorts of subjects. Normalized
  • FIGURE 7A represents normalized data from the two cohorts shown separately (study 1 used as a GCase activator, compound 11-97 from TABLE 2 (a substituted pyrrolo[l,2-a] pyrimidine) and study 2 used a different molecule, a substituted pryazolo- [l,5a]pyrimidine).
  • FIGURE 7B represents the normalized data from the two cohorts (study 1 and study 2) when aggregated together.
  • the responders had a normalized HexCer/Sph value of at least 1.
  • the sphingolipids present in the plasma of each subject from the study 2 cohort were determined using the same methods. Normalized HexCer/Sph levels in the plasma from the study 2 cohort are shown in FIGURE 8. It was determined that the HexCer/Sph ratio in plasma was able to discriminate responders from non-responders, with responders having lower levels of HexCer/Sph than non-responders. The results show that the sphingotype is an effective predictor of responsiveness with a small molecule GCase activator. As shown in FIGURE 8, in general, the responders had a normalized HexCer/Sph value of less than 0.6.

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Abstract

L'invention concerne des procédés et des compositions permettant de traiter un sujet atteint d'une maladie neurodégénérative, le sujet étant porteur du gène d'une sphingolipidose indiquant qu'il est susceptible de répondre au traitement avec un activateur de l'activité de la β-glucocérébrosidase.
EP17767536.0A 2016-03-16 2017-03-16 Procédé et compositions de traitement d'une maladie neurodégénérative chez un sujet porteur du gène d'une sphingolipidose Withdrawn EP3429590A4 (fr)

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