Patent Publication Number: US-2020283444-A1

Title: Substituted fused pyrimidine compounds and uses thereof

Description:
CROSS-REFERENCE TO RELATED PATENT APPLICATIONS 
     The present application claims the benefit of priority under 35 U.S.C. § 119(e) to U.S. Provisional Application No. 62/540,327, filed on Aug. 2, 2017, the content of which is incorporated herein by reference in its entirety. 
    
    
     BACKGROUND 
     The field of the invention relates to new small molecules and uses of the new small molecules for modulating glucocerebrosidase activity. The new small molecules have a pyrimidine or fused pyrimidine core structure, and the small molecules may be administered to treat diseases and disorders associated with aberrant glucocerebrosidase activity including Gaucher&#39;s disease and neurological diseases and disorders such as genetic and sporadic synucleinopathies, including Parkinson&#39;s disease, dementia with Lewy bodies, and multiple system atrophy associated with aberrant glucocerebrosidase activity. 
     Glucocerebrosidase (EC 3.2.1.45), which also is called β-glucocerebrosidase, β-glucosidase, D-glucosyl-N-acylsphingosine glucohydrolase, or GCase, is an enzyme having glucosylceramidase activity. Glucocerebrosidase is required to cleave the beta-glucosidic linkage of the chemical glucocerebroside, which is an intermediate in glycolipid metabolism. Glucocerebrosidase is localized in the lysosome and disabling mutations in the gene for glucocerebrosidase (GBA1) are associated with abnormal accumulation of lipids in lysosomes. 
     Genetic diseases caused by mutations in GBA1 include neurodegenerative diseases such as Gaucher&#39;s disease and Parkinson&#39;s disease. Gaucher&#39;s disease is a rare genetic disease caused by GBA1 gene mutations. Mutations in GBA1 also are linked to Parkinson&#39;s disease (PD) by increasing the risk of PD. Currently, the treatment for Type 1 Gaucher&#39;s disease is enzyme replacement therapy (ERT) administered every two weeks. ERT is very expensive and not effective for neuronopathic forms of Gaucher&#39;s disease. 
     Here, we disclose novel substituted pyrimidine and fused pyrimidine compounds which modulate glucocerebrosidase activity. The substituted pyrimidine and fused pyrimidine compounds disclosed herein have better chemical and physical properties than previous reported non-active site GCase inhibitors. (See Goldin et al., WO, “Substituted pyrazolopyrimidines as glucocerebrosidase activators.” December 2010, WO2012078855; and Patnaik et al., “Discovery, structure-activity relationship, and biological evaluation of noninhibitory small molecule chaperones of glucocerebrosidase,” J. Med. Chem. 2012 Jun. 28; 55(12):5734-48, the contents of which are incorporated herein by reference in their entireties). These better chemical and physical properties of the disclosed pyrimidine and fused pyrimidine compounds include polar surface area, solubility, increased number of rotatable bonds, and increased number of potential hydrogen bonding members. Some of the substituted pyrimidine and fused pyrimidine compounds in the present study are capably of highly activating GCase. In addition, the disclosed pyrimidine and fused pyrimidine compounds in the present study can be conjugated to fluorophores to create fluorescent probes whose interaction and binding affinity with GCase may be studied in fluorescence polarization assays. As such, these fluorescent probes may be utilized in high throughput screening methods to identify further modulators of GCase activity. 
     SUMMARY 
     Disclosed are new small molecules having a substituted pyrimidine or fused pyrimidine core structure and uses of the small molecules for modulating glucocerebrosidase activity. The new small molecules preferably modulate glucocerebrosidase activity by binding to glucocerebrosidase, optionally covalently, and activating glucocerebrosidase. 
     The new small molecules may be formulated as pharmaceutical compositions that comprise the small molecules or that comprise activated glucocerebrosidase conjugated to the small molecules, which compositions may be administered in methods of treating and/or preventing diseases or disorders associated with glucocerebrosidase activity. Diseases and disorders treated by the disclosed new small molecules may include Gaucher&#39;s disease and neurological diseases and disorders such as genetic and sporadic synucleinopathies, including Parkinson&#39;s disease, dementia with Lewy bodies, and multiple system atrophy associated with aberrant glucocerebrosidase activity. 
     The disclosed small molecules also may comprise fluorophores or may be conjugated to fluorophores to generate fluorescent probes. The fluorescent probes contemplated herein may exhibit fluorescence polarization and may be utilized in high throughput screening methods to identify additional new modulators of glucocerebrosidase. 
    
    
     DETAILED DESCRIPTION 
     The disclosed subject matter further may be described utilizing terms as defined below. 
     Unless otherwise specified or indicated by context, the terms “a”, “an,” and “the” mean “one or more.” For example, “a modulator of glucocerebrosidase activity” should be interpreted to mean “one or more modulators of glucocerebrosidase activity.” 
     As used herein, “about,” “approximately,” “substantially,” and “significantly” will be understood by persons of ordinary skill in the art and will vary to some extent on the context in which they are used. If there are uses of the term which are not clear to persons of ordinary skill in the art given the context in which it is used, “about” and “approximately” will mean plus or minus ≤10% of the particular term and “substantially” and “significantly” will mean plus or minus &gt;10% of the particular term. 
     As used herein, the terms “include” and “including” have the same meaning as the terms “comprise” and “comprising.” The terms “comprise” and “comprising” should be interpreted as being “open” transitional terms that permit the inclusion of additional components further to those components recited in the claims. The terms “consist” and “consisting of” should be interpreted as being “closed” transitional terms that do not permit the inclusion of additional components other than the components recited in the claims. The term “consisting essentially of” should be interpreted to be partially closed and allowing the inclusion only of additional components that do not fundamentally alter the nature of the claimed subject matter. 
     The terms “subject,” “patient,” and “individual” may be used interchangeably herein. A subject may be a human subject. A subject may refer to a human subject having or at risk for acquiring a disease or disorder that is associated with aberrant glucocerebrosidase activity. As used herein, the term “aberrant” means higher or lower activity relative to a normal healthy subject. In specific embodiments, a subject exhibiting aberrant glucocerebrosidase may have or be at risk for acquiring Gaucher&#39;s disease and/or neurological diseases and disorders such as genetic and sporadic synucleinopathies, including Parkinson&#39;s disease, dementia with Lewy bodies, and multiple system atrophy associated with aberrant glucocerebrosidase activity. 
     As used herein, the phrase “effective amount” shall mean that drug dosage that provides the specific pharmacological response for which the drug is administered in a significant number of patients in need of such treatment. An effective amount of a drug that is administered to a particular patient in a particular instance will not always be effective in treating the conditions/diseases described herein, even though such dosage is deemed to be a therapeutically effective amount by those of skill in the art. 
     New chemical entities and uses for chemical entities are disclosed herein. The chemical entities may be described using terminology known in the art and further discussed below. 
     As used herein, an asterick “*” or a plus sign “+” may be used to designate the point of attachment for any radical group or substituent group. 
     The term “alkyl” as contemplated herein includes a straight-chain or branched alkyl radical in all of its isomeric forms, such as a straight or branched group of 1-12, 1-10, or 1-6 carbon atoms, referred to herein as C1-C12 alkyl, C1-C10-alkyl, and C1-C6-alkyl, respectively. 
     The term “alkylene” refers to a diradical of an alkyl group (e.g., —(CH 2 ) n — where n is an integer such as an integer between 1 and 20). An exemplary alkylene group is —CH 2 CH 2 —. 
     The term “haloalkyl” refers to an alkyl group that is substituted with at least one halogen. For example, —CH 2 F, —CHF 2 , —CF 3 , —CH 2 CF 3 , —CF 2 CF 3 , and the like. 
     The term “heteroalkyl” as used herein 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). One type of heteroalkyl group is an “alkoxy” group. 
     The term “alkenyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon double bond, such as a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C2-C12-alkenyl, C2-C10-alkenyl, and C2-C6-alkenyl, respectively. 
     The term “alkynyl” as used herein refers to an unsaturated straight or branched hydrocarbon having at least one carbon-carbon triple bond, such as a straight or branched group of 2-12, 2-10, or 2-6 carbon atoms, referred to herein as C2-C12-alkynyl, C2-C10-alkynyl, and C2-C6-alkynyl, respectively. 
     The term “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. Unless specified otherwise, 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, halo, haloalkyl, heteroaryl, heterocyclyl, hydroxyl, imino, ketone, nitro, phosphate, phosphonato, phosphinato, sulfate, sulfide, sulfonamido, sulfonyl or thiocarbonyl. In certain embodiments, the cycloalkyl group is not substituted, i.e., it is unsubstituted. 
     The term “cycloalkylene” refers to a cycloalkyl group that is unsaturated at one or more ring bonds. 
     The term “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 oring carbon atoms. For example, 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. Unless specified otherwise, 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. In certain embodiments, the partially unsaturated carbocyclyl is not substituted, i.e., it is unsubstituted. 
     The term “aryl” is art-recognized and refers to a carbocyclic aromatic group. Representative aryl groups include phenyl, naphthyl, anthracenyl, and the like. The term “aryl” includes polycyclic 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, cycloalkynyls, and/or aryls. Unless specified otherwise, 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(O)alkyl, —CO 2 alkyl, carbonyl, carboxyl, alkylthio, sulfonyl, sulfonamido, sulfonamide, ketone, aldehyde, ester, heterocyclyl, aryl or heteroaryl moieties, —CF 3 , —CN, or the like. In certain embodiments, 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. 
     The terms “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 5 Cx-Cx nomenclature where x is an integer specifying the number of ring atoms. For example, a C3-C7 heterocyclyl 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. The designation “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. 
     The terms “amine” and “amino” are art-recognized and refer to both unsubstituted and substituted amines (e.g., mono-substituted amines or di-substituted amines), wherein substituents may include, for example, alkyl, cycloalkyl, heterocyclyl, alkenyl, and aryl. 
     The terms “alkoxy” or “alkoxyl” are art-recognized and refer to an alkyl group, as defined above, having an oxygen radical attached thereto. Representative alkoxy groups include methoxy, ethoxy, 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, and the like. 
     The term “carbonyl” as used herein refers to the radical —C(O)—. 
     The term “oxo” refers to a divalent oxygen atom —O—. 
     The term “carboxamido” as used herein refers to the radical —C(O)NRR′, where R and R′ may be the same or different. R and R′, for example, may be independently alkyl, aryl, arylalkyl, cycloalkyl, formyl, haloalkyl, heteroaryl, or heterocyclyl. 
     The term “carboxy” as used herein refers to the radical —COOH or its corresponding salts, e.g. —COONa, etc. 
     The term “amide” or “amido” or “amidyl” as used herein refers to a radical of the form —R 1 C(O)N(R 2 )—, —R 1 C(O)N(R 2 )R 3 —, —C(O)NR 2 R 3 , or —C(O)NH 2 , wherein R 1 , R 2  and R 3 , for example, 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 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. The term “stereoisomers” when used herein consist of all geometric isomers, enantiomers or diastereomers. These compounds may be designated by the symbols “R” or “S,” or “+” or “−” depending on the configuration of substituents around the stereogenic carbon atom and or the optical rotation observed. The present invention encompasses various stereo isomers of these compounds and mixtures thereof. 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. Also contemplated herein are compositions comprising, consisting essentially of, or consisting of an enantiopure compound, which composition may comprise, consist essential of, or consist of at least about 50%, 60%, 70%, 80%, 90%, 95%, 96%, 97%, 98%, 99%, or 100% of a single enantiomer of a given compound (e.g., at least about 99% of an R enantiomer of a given compound). 
     As used herein, the term “modulate” means decreasing or inhibiting activity and/or increasing or augmenting activity. For example, modulating glucocerebrosidase activity may mean increasing or augmenting glucocerebrosidase activity and/or decreasing or inhibiting glucocerebrosidase activity. The compounds disclosed herein may be administered to modulate glucocerebrosidase activity for example, as a chaperone or activator. 
     Substituted Pyrimidine and Fused Pyrimidine Compounds and Uses Thereof for Modulating Glucocerebrosidase Activity 
     The compounds disclosed herein may be referred to as “substituted pyrimidine or substitute fused pyrimidine compounds.” The compounds may be described as having a formula: 
     
       
         
         
             
             
         
       
     
     wherein: 
     W is hydrogen, or W and Z form a saturated or unsaturated ring A having 5 or 6 carbon atoms and optionally one or more heteroatoms selected from N, O, and S, and A optionally is substituted at one or more ring positions with alkyl, alkoxy, halo, haloalkyl, or cyano. 
     A is a saturated or unsaturated ring having 5 or 6 carbon atoms and optionally one or more heteroatoms selected from N, O, and S, and A optionally is substituted at one or more ring positions with alkyl, alkoxy, halo, haloalkyl, cyano, aryl such as phenyl, alkylaryl such as benzyl (e.g., where A is an optionally substituted ring selected from phenyl, pyrazole such as pyrimidine-fused pyrazolo[3,4-d], pyridine such as pyrimidine-fused pyridino[2,3-d] or pyrimidine-fused pyridino[3,2-d], thiophene such as pyrimidine-fused thiopheno[2,3-d] or pyrimidine-fused thiopheno[3,2-d], cyclopentane, cyclohexane, pyrrole such as pyrimidine-fused pyrrolo[2,3-d], furan such as pyrimidine-fused furano[3,2-d], 2,3-dihydrothiophene such as pyrimidine-fused 2,3-dihydrothiopheno[3,2-d], 2,5-dihydrofurane such as pyrimidine-fused 2,5-dihydrofurano[3,4-d], imidazole such as pyrimidine-fused imidazole[5,4-d], thiazole such as pyrimidine-fused thiazolo[5,4-d], 3-pyrroline such as pyrimidine-fused 3-pyrrolino[3,4-d], and benzofuran such as pyrimidine-fused benzofurano[3,2-d]). 
     X is hydrogen, halo, alkyl, amino cycloalkyl, cycloheteroalkyl (e.g., piperazinyl such as N-piperazinyl), aryl or heteroaryl (e.g., phenyl, pyridinyl such as pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, isoxazolyl such as isoxazol-4-yl, benzofuranyl such as benzofuran-2-yl or benzofuran-3-yl, quinolinyl such as quinolin-2-yl, quinolin-3-yl, or quinolin-4-yl, thiophenyl such as thiophen-2-yl or thiophen-3-yl, tetralin such as tetralin-6-yl or tetralin-7-yl), or aminoaryl (e.g., anilinyl), and X optionally may be substituted at one or more positions with alkyl, alkoxy, halo, haloalkyl, hydroxyl, hydroxyalkyl, hydroxyalkyoxy(alkyl), amino, amido, alkylamido, or pyrrolidinyl such as N-pyrrolidinyl, and benzyloxy. 
     Y is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, a nitrogen-containing group (e.g. amino, substituted amino, anilinyl), an oxygen-containing group (e.g., hydroxyl, or alkyoxy), aryl or heteroaryl (e.g., pyridinyl such as pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, isoxazolyl such as isoxazol-4-yl, benzofuranyl such as benzofuran-2-yl or benzofuran-3-yl, quinolinyl such as quinolin-2-yl, quinolin-3-yl, or quinolin-4-yl), and the aryl or heteroaryl optionally substituted at one or more positions with halo, haloalkyl, hydroxyl, amino, or pyrrolidinyl such as N-pyrrolidinyl. 
     Z is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, amino, aryl or heteroaryl (e.g., pyridinyl such as pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, isoxazolyl such as isoxazol-4-yl, benzofuranyl such as benzofuran-2-yl, or benzofuran-3-yl, quinolinyl such as quinolin-2-yl, quinolin-3-yl, or quinolin-4-yl, morpholinyl such as N-morpholinyl), and the aryl or heteroaryl optionally substituted at one or more positions with halo, haloalkyl, hydroxyl, amino, or pyrrolidinyl such as N-pyrrolidinyl. 
     In some embodiments, the compounds or salt or solvates thereof may be described as having a Formula I or II as follows: 
     
       
         
         
             
             
         
       
     
     wherein: 
     A is a saturated or unsaturated ring having 5 or 6 carbon atoms and optionally one or more heteroatoms selected from N, O, and S, and A optionally is substituted at one or more ring positions with alkyl, alkoxy, halo, haloalkyl, cyano, aryl such as phenyl, alkylaryl such as benzyl (e.g., where A is an optionally substituted ring selected from phenyl, pyrazole such as pyrimidine-fused pyrazolo[3,4-d], pyridine such as pyrimidine-fused pyridino[2,3-d] or pyrimidine-fused pyridino[3,2-d], thiophene such as pyrimidine-fused thiopheno[2,3-d] or pyrimidine-fused thiopheno[3,2-d], cyclopentane, cyclohexane, pyrrole such as pyrimidine-fused pyrrolo[2,3-d], furan such as pyrimidine-fused furano[3,2-d], 2,3-dihydrothiophene such as pyrimidine-fused 2,3-dihydrothiopheno[3,2-d], 2,5-dihydrofurane such as pyrimidine-fused 2,5-dihydrofurano[3,4-d], imidazole such as pyrimidine-fused imidazole[5,4-d], thiazole such as pyrimidine-fused thiazolo[5,4-d], 3-pyrroline such as pyrimidine-fused 3-pyrrolino[3,4-d], and benzofuran such as pyrimidine-fused benzofurano[3,2-d]). 
     X is hydrogen, halo, alkyl, amino cycloalkyl, cycloheteroalkyl (e.g., piperazinyl such as N-piperazinyl), aryl or heteroaryl (e.g., phenyl, pyridinyl such as pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, isoxazolyl such as isoxazol-4-yl, benzofuranyl such as benzofuran-2-yl or benzofuran-3-yl, quinolinyl such as quinolin-2-yl, quinolin-3-yl, or quinolin-4-yl, thiophenyl such as thiophen-2-yl or thiophen-3-yl, tetralin such as tetralin-6-yl or tetralin-7-yl), or aminoaryl (e.g., anilinyl), and X optionally may be substituted at one or more positions with alkyl, alkoxy, halo, haloalkyl, hydroxyl, hydroxyalkyl, alkyl-oxo-hydroxyalkyl (i.e., —(CH 2 ) p —O—(CH 2 ) q —OH where p and q are independently selected from 1-18, 1-12, or 1-6), amino, amido, alkylamido, or pyrrolidinyl such as N-pyrrolidinyl, and benzyloxy; a moiety comprising a fluorophore which optionally may be conjugated to X via a linker (e.g., —NH—C(O)—(CH 2 ) p —NH—C(O)—(CH 2 CH 2 O) q —CH 2 —CH 2 —NH—C(O)-fluorophore where p and q are independently selected from 1-18, 1-12, or 1-6 (e.g., where p=5 and q=4). 
     Y is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, a nitrogen-containing group (e.g. amino, substituted amino, anilinyl), an oxygen-containing group (e.g., hydroxyl, or alkyoxy), aryl or heteroaryl (e.g., pyridinyl such as pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, isoxazolyl such as isoxazol-4-yl, benzofuranyl such as benzofuran-2-yl or benzofuran-3-yl, quinolinyl such as quinolin-2-yl, quinolin-3-yl, or quinolin-4-yl), and Y optionally is substituted at one or more positions with halo, haloalkyl, hydroxyl, amino, or pyrrolidinyl such as N-pyrrolidinyl. 
     Z is hydrogen, halo, alkyl, cycloalkyl, cycloheteroalkyl (e.g., morpholinyl such as N-morpholinyl), amino, aryl (e.g., phenyl) or heteroaryl (e.g., pyridinyl such as pyridin-2-yl, pyridin-3-yl, or pyridin-4-yl, isoxazolyl such as isoxazol-4-yl, benzofuranyl such as benzofuran-2-yl, or benzofuran-3-yl, quinolinyl such as quinolin-2-yl, quinolin-3-yl, or quinolin-4-yl, piperidinyl such as N-piperidinyl, pyrrolidinyl such as N-pyrrolidinyl, azetidinyl such as N-azetidinyl), and the aryl or heteroaryl optionally substituted at one or more positions with halo, haloalkyl, hydroxyl, amino, or pyrrolidinyl such as N-pyrrolidinyl. 
     In some embodiments, the compounds of Formula I have a formula selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     where each R 1  is the same or different and is selected from hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, cycloalkyl, cycloheteroalkyl, aryl, and heteroaryl, which optionally is substituted with alkyl, halo, haloalkyl, alkoxy, amino, hydroxyl, or cyano. 
     In some embodiments of the disclosed compounds, Y is a nitrogen-containing group which optionally is a substituted amino group and/or Y is an oxygen-containing group which optionally is a substituted hydroxyl group. For example, in some embodiments, Y is —NH 2 , —NR 2 H, NR 2 R 3 , —NH-alkyl-O—R 2 , —N-alkyl-O—R 2 R 3 , —N-alkyl-O—R 2 —O—R 3 , —OH, or —OR 2  and/or Y has a formula, for example: 
     
       
         
         
             
             
         
       
     
     where m and n are integers independent selected from 0-18, 0-12, or 0-6, optionally at least one of m and n is at least 1, or both m and n are at least 1, or optionally at least one of m and n is at least 2, or both of m and n are at least 2. 
     R 2  and R 3  optionally are the same or different and are selected from hydrogen, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, oxycycloalkyl (e.g., oxycyclohexyl), aryl, oxy-aryl such as phenoxy (i.e., oxy-phenyl) or oxy-tetralinyl, heteroaryl, carboxy, alkyl-carboxyester, succinimidyl-carboxy-ester, arylamino (e.g., anilinyl or N-methyl-anilinyl), and amidyl (i.e., —C(O)—NH 2 ), alkyl-amidyl (i.e., —(CH 2 ) p —C(O)—NH 2 ) where p is selected from 1-18, 1-12, or 1-6 (e.g., where p=1)), alkyl-alkamidyl (i.e., —(CH 2 ) p —N—C(O)—(NH 2 ) q — where p and q are independently selected from 1-18, 1-12, or 1-6 (e.g., where p=1 and q=1 or 5), aryl-alkamidyl (e.g., —(CH 2 ) p —C(O)—NH-Ph) where p is selected from 1-18, 1-12, or 1-6 (e.g., where p=1)). 
     In some embodiments, R 2  and R 3  may be selected from groups including, but not limited to, phenoxy; piperidinyl such as piperidin-2-yl, piperidin-3-yl, or piperidin-4-yl; or benzofuranyl such as benzofuran-2-yl or benzofuran-3-yl; 1,4-benzodioxane such as 1,4-benzodioxan-2-yl; coumaranyl such as coumaran-2-yl or coumaran-3-yl; 1,3-benzodioxolyl such as 1,3-benzodixol-5-yl or 1,3-benzodixol-6-yl; indole such as indol-2-yl, indol-3-yl, indol-4-yl, indol-5-yl, indol-6-yl, indol-7-yl; pyrazole such as pyrazol-3-yl or pyrazol-4-yl; tetralin such as tetralin-1-yl or tetralin-2-yl, 3,4-dihydro-2H-benzopyran such as 3,4-dihydro-2H-benzopyran-2-yl, 3,4-dihydro-2H-benzopyran-3-yl, or 3,4-dihydro-2H-benzopyran-4-yl; 1,2,3,4-tetrahydroisoquinoline such as N-1,2,3,4-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 1,2,3,4-tetrahydroisoquinolin-3-yl, or 1,2,3,4-tetrahydroisoquinolin-4-yl; and oxytetralinyl such as oxytetralin-6-yl or oxytetralin-7-yl; quinoline such as N-quinolinyl, quinolin-2-yl, quinolin-3-yl, quinolin-4-yl, quinolin-5-yl, quinolin-6-yl, quinolin-7-yl, quinolin-8-yl; N-phenylformamidyl (i.e., —C(O)—NH-Ph); quinozaline such as quinozalin-5-yl or quinozalin-6-yl; and oxo-quinozaline such as oxo-quinozalin-5-yl or oxo-quinozalin-6-yl; optionally where R 2  and R 3  may be substituted. 
     R 2  and R 3  optionally may be substituted at one or more positions with substituents selected from but not limited to alkyl (e.g., methyl, ethyl, t-butyl), alkoxy, alkenyl, alkynyl, aryl (e.g., phenyl); oxy-aryl (e.g. phenoxy), halo-substituted oxy-aryl (e.g. chloro-phenoxy), arylalkyl (e.g., benzyl or phenylethyl), arylalkenyl, arylalkynyl (e.g., phenylethynyl), aminoalkyl (e.g., aminomethyl), carboxyl, carboxy-alkyl-ester, alkyl-carboxy-alkyl-ester, alkyl-carboxy-succinimidyl-ester (i.e., an alkyl-carboxyl group amidated with an N-succinimidyl group), carboxy-succinimidyl-ester (i.e., a carboxyl group amidated with an N-succinimidyl group), hydroxyalkyl, oxy-hydroxyalkyl (i.e., —O—(CH 2 ) p —OH where p is 1-18, 1-12, or 1-6), alkyl-oxo-hydroxyalkyl (i.e., —(CH 2 ) p —O—(CH 2 ) q —OH where p and q are independently selected from 1-18, 1-12, or 1-6), cyano, aminoalkyl, alkyl-NH—C(O)-alkyl-N—C(O)—O-alkyl, alkyl-NH—C(O)-alkyl-NH 2 , —NH—C(O)—(CH 2 ) p —NH—C(O)—(CH 2 CH 2 O) q —CH 2 —CH 2 —NH—C(O)— where p and q are independently selected from 1-18, 1-12, or 1-6 (e.g., where p=5 and q=4), amidyl (i.e., —C(O)—NH 2 ), alkyl-amidyl (i.e., -alkyl-C(O)—NH 2 ), alkyl-alkamidyl (i.e., -alkyl-N—C(O)-alkyl), aryl-alkamidyl (e.g., -alkyl-C(O)—NH-Ph), amino-alkyl-alkamidyl (i.e., alkyl-N—C(O)-alkyl-NH 2 ), and alkyl-N—C(O)-alkyl-NH—C(O)—O-alkyl (e.g. —CH 2 —NH—C(O)—(CH 2 ) 4 —NH—C(O)—O-t-butyl), which optionally may link a fluorophore. 
     R 2  and R 3  together may form a 4-membered, 5-membered or 6-membered nitrogen-containing heterocycle (e.g., azetidine, pyrrolidine, piperidine, or piperazine) or two fused nitrogen-containing heterocycles (e.g., 1,2,3,4-tetrahydroisoquinoline) which may be saturated or unsaturated and optionally include or includes additional heteroatoms selected from N, O, and S, the heterocycle or fused heterocycles optionally are substituted at one or more positions with alkyl, halo, haloalkyl, alkoxy, hydroxyl, hydroxyalkyl, alkyl-oxo-hydroxyalkyl (i.e., —(CH 2 ) p —O—(CH 2 ) q —OH where p and q are independently selected from 1-18, 1-12, or 1-6), cyano, aminoalkyl oxy-aryl (e.g. phenoxy), halo-substituted oxy-aryl (e.g. chloro-phenoxy), and N-phenylformamidyl (i.e., —C(O)—NH-Ph). 
     In some embodiments, the disclosed compounds have a formula: 
     
       
         
         
             
             
         
       
     
     wherein R 1  and Y are as defined above. Each R 4  is the same or different and is independently selected from alkyl, alkoxy, halo, haloalkyl, hydroxyl, hydroxyalkyl, alkyl-oxo-hydroxyalkyl (i.e., —(CH 2 ) p —O—(CH 2 ) q —OH where p and q are independently selected from 1-18, 1-12, or 1-6), amino, amido, alkylamido, or pyrrolidinyl such as N-pyrrolidinyl, pyrrolidin-2-yl, or pyrrolidin-3-yl, and benzyloxy. R 4  may be a moiety comprising a fluorophore which optionally may be conjugated via a linker (e.g., —NH—C(O)—(CH 2 ) p —NH—C(O)—(CH 2 CH 2 O) q —CH 2 —CH 2 —NH—C(O)-fluorophore where p and q are independently selected from 1-18, 1-12, or 1-6 (e.g., where p=5 and q=4). 
     In some embodiments, the disclosed compounds have a formula: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , and R 4  are as defined above. 
     In some embodiments, the disclosed compounds have a formula: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R 4 , m, and n are as defined above. 
     In some embodiments, the disclosed compounds have a formula: 
     
       
         
         
             
             
         
       
     
     wherein R 1 , R 2 , R 3 , R 4 , m, and n are as defined above. 
     The disclosed compounds may comprise or may be conjugated to a fluorophore. For example, the disclosed compounds may be conjugated to fluorophore via a linker (i.e., compound-linker-fluorophore). Suitable linkers may include but are not limited to a linker having a formula —NH—C(O)—(CH 2 ) p —NH—C(O)—(CH 2 CH 2 O) q —CH 2 —CH 2 —NH—C(O)— where p and q are independently selected from 1-18, 1-12, or 1-6 (e.g., where p=5 and q=4)). In some embodiments of the disclosed compounds, any of substituents R 1 , R 2 , R 3 , or R 4 , may comprise a fluorophore, including fluorophores suitable for use in fluorescence polarization assays. As used herein, a “fluorophore” is a chemical group that can be excited (e.g., by light or a chemical reaction) to emit fluorescence. Some suitable fluorophores may be excited by light to emit phosphorescence. As used herein, a “dye” may include a fluorophore. The compounds described herein may be conjugated to a fluorophore selected from but not limited to: 1,5 IAEDANS; 1,8-ANS; 4-Methylumbelliferone; 5-carboxy-2,7-dichlorofluorescein; 5-Carboxyfluorescein (5-FAM); 5-Carboxytetramethylrhodamine (5-TAMRA); 5-FAM (5-Carboxyfluorescein); 5-HAT (Hydroxy Tryptamine); 5-Hydroxy Tryptamine (HAT); 5-ROX (carboxy-X-rhodamine); 5-TAMRA (5-Carboxytetramethylrhodamine); 6-Carboxyrhodamine 6G; 6-CR 6G; 6-JOE; 7-Amino-4-methylcoumarin; 7-Aminoactinomycin D (7-AAD); 7-Hydroxy-4-methylcoumarin; 9-Amino-6-chloro-2-methoxyacridine; ABQ; Acid Fuchsin; ACMA (9-Amino-6-chloro-2-methoxyacridine); Acridine Orange; Acridine Red; Acridine Yellow; Acriflavin; Acriflavin Feulgen SITSA; Alexa Fluor 350™; Alexa Fluor 430™; Alexa Fluor 488™; Alexa Fluor 532™; Alexa Fluor 546™; Alexa Fluor 568™; Alexa Fluor 594™; Alexa Fluor 633™; Alexa Fluor 647™; Alexa Fluor 660™; Alexa Fluor 680™; Alizarin Complexon; Alizarin Red; Allophycocyanin (APC); AMC; AMCA-S; AMCA (Aminomethylcoumarin); AMCA-X; Aminoactinomycin D; Aminocoumarin; Aminomethylcoumarin (AMCA); Anilin Blue; Anthrocyl stearate; APC (Allophycocyanin); APC-Cy7; APTS; Astrazon Brilliant Red 4G; Astrazon Orange R; Astrazon Red 6B; Astrazon Yellow 7 GLL; Atabrine; ATTO-TAG™ CBQCA; ATTO-TAG™ FQ; Auramine; Aurophosphine G; Aurophosphine; BAO 9 (Bisaminophenyloxadiazole); Berberine Sulphate; Beta Lactamase; BFP blue shifted GFP (Y66H); Blue Fluorescent Protein; BFP/GFP FRET; Bimane; Bisbenzamide; Bisbenzimide (Hoechst); Blancophor FFG; Blancophor SV; BOBO™-1; BOBO™-3; Bodipy 492/515; Bodipy 493/503; Bodipy 500/510; Bodipy 505/515; Bodipy 530/550; Bodipy 542/563; Bodipy 558/568; Bodipy 564/570; Bodipy 576/589; Bodipy 581/591; Bodipy 630/650-X; Bodipy 650/665-X; Bodipy 665/676; Bodipy FL; Bodipy FL ATP; Bodipy Fl-Ceramide; Bodipy R6G SE; Bodipy TMR; Bodipy TMR-X conjugate; Bodipy TMR-X, SE; Bodipy TR; Bodipy TR ATP; Bodipy TR-X SE; BO-PRO™-1; BO-PRO™-3; Brilliant Sulphoflavin FF; Calcein; Calcein Blue; Calcium Crimson™; Calcium Green; Calcium Orange; Calcofluor White; Carboxy-X-rhodamine (5-ROX); Cascade Blue™; Cascade Yellow; Catecholamine; CCF2 (GeneBlazer); CFDA; CFP—Cyan Fluorescent Protein; CFP/YFP FRET; Chlorophyll; Chromomycin A; CL-NERF (Ratio Dye, pH); CMFDA; Coelenterazine f; Coelenterazine fcp; Coelenterazine h; Coelenterazine hcp; Coelenterazine ip; Coelenterazine n; Coelenterazine O; Coumarin Phalloidin; C-phycocyanine; CPM Methylcoumarin; CTC; CTC Formazan; Cy2™; Cy3.1 8; Cy3.5™; Cy3™; Cy5.1 8; Cy5.5™; Cy5™; Cy7™; Cyan GFP; cyclic AMP Fluorosensor (FiCRhR); Dabcyl; Dansyl; Dansyl Amine; Dansyl Cadaverine; Dansyl Chloride; Dansyl DHPE; Dansyl fluoride; DAPI; Dapoxyl; Dapoxyl 2; Dapoxyl 3; DCFDA; DCFH (Dichlorodihydrofluorescein Diacetate); DDAO; DHR (Dihydorhodamine 123); Di-4-ANEPPS; Di-8-ANEPPS (non-ratio); DiA (4-Di-16-ASP); Dichlorodihydrofluorescein Diacetate (DCFH); DiD—Lipophilic Tracer; DiD (DiIC18(5)); DIDS; Dihydorhodamine 123 (DHR); DiI (DiIC18(3)); Dinitrophenol; DiO (DiOC18(3)); DiR; DiR (DiIC18(7)); DNP; Dopamine; DsRed; DTAF; DY-630-NHS; DY-635-NHS; EBFP; ECFP; EGFP; ELF 97; Eosin; Erythrosin; Erythrosin ITC; Ethidium Bromide; Ethidium homodimer-1 (EthD-1); Euchrysin; EukoLight; Europium (III) chloride; EYFP; Fast Blue; FDA; Feulgen (Pararosaniline); FITC; Flazo Orange; Fluo-3; Fluo-4; Fluorescein (FITC); Fluorescein Diacetate; Fluoro-Emerald; Fluoro-Gold (Hydroxystilbamidine); Fluor-Ruby; FluorX; FM 1-43™; FM 4-46; Fura Red™; Fura Red™/Fluo-3; Fura-2; Fura-2/BCECF; Genacryl Brilliant Red B; Genacryl Brilliant Yellow 10GF; Genacryl Pink 3G; Genacryl Yellow 5GF; GeneBlazer (CCF2); GFP (S65T); GFP red shifted (rsGFP); GFP wild type, non-UV excitation (wtGFP); GFP wild type, UV excitation (wtGFP); GFPuv; Gloxalic Acid; Granular Blue; Haematoporphyrin; Hoechst 33258; Hoechst 33342; Hoechst 34580; HPTS; Hydroxycoumarin; Hydroxystilbamidine (FluoroGold); Hydroxytryptamine; Indo-1; Indodicarbocyanine (DiD); Indotricarbocyanine (DiR); Intrawhite Cf; JC-1; JO-JO-1; JO-PRO-1; Laurodan; LDS 751 (DNA); LDS 751 (RNA); Leucophor PAF; Leucophor SF; Leucophor WS; Lissamine Rhodamine; Lissamine Rhodamine B; Calcein/Ethidium homodimer; LOLO-1; LO-PRO-1;  Lucifer  Yellow; Lyso Tracker Blue; Lyso Tracker Blue-White; Lyso Tracker Green; Lyso Tracker Red; Lyso Tracker Yellow; LysoSensor Blue; LysoSensor Green; LysoSensor Yellow/Blue; Mag Green; Magdala Red (Phloxin B); Mag-Fura Red; Mag-Fura-2; Mag-Fura-5; Mag-Indo-1; Magnesium Green; Magnesium Orange; Malachite Green; Marina Blue; Maxilon Brilliant Flavin 10 GFF; Maxilon Brilliant Flavin 8 GFF; Merocyanin; Methoxycoumarin; Mitotracker Green FM; Mitotracker Orange; Mitotracker Red; Mitramycin; Monobromobimane; Monobromobimane (mBBr-GSH); Monochlorobimane; MPS (Methyl Green Pyronine Stilbene); NBD; NBD Amine; Nile Red; Nitrobenzoxadidole; Noradrenaline; Nuclear Fast Red; Nuclear Yellow; Nylosan Brilliant Iavin E8G; Oregon Green; Oregon Green 488-X; Oregon Green™; Oregon Green™ 488; Oregon Green™ 500; Oregon Green™ 514; Pacific Blue; Pararosaniline (Feulgen); PBFI; PE-Cy5; PE-Cy7; PerCP; PerCP-Cy5.5; PE-TexasRed [Red 613]; Phloxin B (Magdala Red); Phorwite AR; Phorwite BKL; Phorwite Rev; Phorwite RPA; Phosphine 3R; Phycoerythrin B [PE]; Phycoerythrin R [PE]; PKH26 (Sigma); PKH67; PMIA; Pontochrome Blue Black; POPO-1; POPO-3; PO-PRO-1; PO-PRO-3; Primuline; Procion Yellow; Propidium lodid (PI); PyMPO; Pyrene; Pyronine; Pyronine B; Pyrozal Brilliant Flavin 7GF; QSY 7; Quinacrine Mustard; Red 613 [PE-TexasRed]; Resorufin; RH 414; Rhod-2; Rhodamine; Rhodamine 110; Rhodamine 123; Rhodamine 5 GLD; Rhodamine 6G; Rhodamine B; Rhodamine B 200; Rhodamine B extra; Rhodamine BB; Rhodamine BG; Rhodamine Green; Rhodamine Phallicidine; Rhodamine Phalloidine; Rhodamine Red; Rhodamine WT; Rose Bengal; R-phycocyanine; R-phycoerythrin (PE); RsGFP; S65A; S65C; S65L; S65T; Sapphire GFP; SBFI; Serotonin; Sevron Brilliant Red 2B; Sevron Brilliant Red 4G; Sevron Brilliant Red B; Sevron Orange; Sevron Yellow L; sgBFP™; sgBFP™ (super glow BFP); sgGFP™; sgGFP™ (super glow GFP); SITS; SITS (Primuline); SITS (Stilbene Isothiosulphonic Acid); SNAFL calcein; SNAFL-1; SNAFL-2; SNARF calcein; SNARFi; Sodium Green; SpectrumAqua; SpectrumGreen; SpectrumOrange; Spectrum Red; SPQ (6-methoxy-N-(3-sulfopropyl)quinolinium); Stilbene; Sulphorhodamine B can C; Sulphorhodamine G Extra; SYTO 11; SYTO 12; SYTO 13; SYTO 14; SYTO 15; SYTO 16; SYTO 17; SYTO 18; SYTO 20; SYTO 21; SYTO 22; SYTO 23; SYTO 24; SYTO 25; SYTO 40; SYTO 41; SYTO 42; SYTO 43; SYTO 44; SYTO 45; SYTO 59; SYTO 60; SYTO 61; SYTO 62; SYTO 63; SYTO 64; SYTO 80; SYTO 81; SYTO 82; SYTO 83; SYTO 84; SYTO 85; SYTOX Blue; SYTOX Green; SYTOX Orange; Tetracycline; Tetramethylrhodamine (TRITC); Texas Red™; Texas Red-X™ conjugate; Thiadicarbocyanine (DiSC3); Thiazine Red R; Thiazole Orange; Thioflavin 5; Thioflavin S; Thioflavin TCN; Thiolyte; Thiozole Orange; Tinopol CBS (Calcofluor White); TMR; TO-PRO-1; TO-PRO-3; TO-PRO-5; TOTO-1; TOTO-3; TriColor (PE-Cy5); TRITC TetramethylRodaminelsoThioCyanate; True Blue; TruRed; Ultralite; Uranine B; Uvitex SFC; wt GFP; WW 781; X-Rhodamine; XRITC; Xylene Orange; Y66F; Y66H; Y66W; Yellow GFP; YFP; YO-PRO-1; YO-PRO-3; YOYO-1; and YOYO-3. As used herein, a “fluorophore” may include a salt of the fluorophore. 
     As noted, the compounds disclosed herein, including the substituted pyrimidine and fused pyrimidine compounds discussed above may have several chiral centers, and stereoisomers, epimers, and enantiomers are contemplated. The compounds may be optically pure with respect to one or more chiral centers (e.g., some or all of the chiral centers may be completely in the S configuration; some or all of the chiral centers may be completely in the R configuration; etc.). Additionally or alternatively, one or more of the chiral centers may be present as a mixture of configurations (e.g., a racemic or another mixture of the R configuration and the S configuration). Compositions comprising substantially purified stereoisomers, epimers, or enantiomers, or analogs or derivatives thereof are contemplated herein (e.g., a composition comprising at least about 90%, 95%, 99% or 100% pure stereoisomer, epimer, or enantiomer.) As used herein, formulae which do not specify the orientation at one or more chiral centers are meant to encompass all orientations and mixtures thereof. 
     Glucocerebrosidase Activity Modulation 
     The compounds disclosed herein preferably modulate activity of glucocerebrosidase. Modulation may include inhibiting or decreasing glucocerebrosidase activity. Modulation also may include activating or increasing glucocerebrosidase activity. Glucocerebrosidase activity may be assessed utilizing methods known in the art and the methods disclosed herein, including the methods disclosed in the Examples provided herein. In some embodiments, the compounds decrease or increase glucocerebrosidase activity relative to a control (e.g., by at least about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or more). In other embodiments, an AC 50  value or IC 50  value for the compound in regard to inhibition or activation of glucocerebrosidase may be determined and preferably the compound has an AC 50  value or IC 50  value of less than about 10 μM, 5 μM, or 1 μM, 0.5 μM, 0.1 μM, 0.05 μM, 0.01 μM, 0.005 μM, or 0.001 μM. 
     Methods for measuring glucocerebrosidase activity are known in the art. (See, e.g., U.S. Publication No. 2017/0001976 and U.S. Publication No. 2017/0002013 and Zheng et al. “Design and Synthesis of Potent Quinazolines as Selective β-Glucocerebrosidase Modulators, J. Med. Chem. 2016 Sep. 22; 59(18): 8508-8520; the contents of which are incorporated herein by reference in their entireties). 
     Pharmaceutical Compositions and Methods of Administration 
     The compounds employed in the compositions and methods disclosed herein may be administered as pharmaceutical compositions and, therefore, pharmaceutical compositions incorporating the compounds are considered to be embodiments of the compositions disclosed herein. Such compositions may take any physical form which is pharmaceutically acceptable; illustratively, they can be orally administered pharmaceutical compositions. Such pharmaceutical compositions contain an effective amount of a disclosed compound, which effective amount is related to the daily dose of the compound to be administered. Each dosage unit may contain the daily dose of a given compound or each dosage unit may contain a fraction of the daily dose, such as one-half or one-third of the dose. The amount of each compound to be contained in each dosage unit can depend, in part, on the identity of the particular compound chosen for the therapy and other factors, such as the indication for which it is given. The pharmaceutical compositions disclosed herein may be formulated so as to provide quick, sustained, or delayed release of the active ingredient after administration to the patient by employing well known procedures. 
     The compounds for use according to the methods of disclosed herein may be administered as a single compound or a combination of compounds. For example, a compound that modulates glucocerebrosidase activity may be administered as a single compound or in combination with another compound that modulates glucocerebrosidase activity or that has a different pharmacological activity. 
     As indicated above, pharmaceutically acceptable salts of the compounds are contemplated and also may be utilized in the disclosed methods. The term “pharmaceutically acceptable salt” as used herein, refers to salts of the compounds which are substantially non-toxic to living organisms. Typical pharmaceutically acceptable salts include those salts prepared by reaction of the compounds as disclosed herein with a pharmaceutically acceptable mineral or organic acid or an organic or inorganic base. Such salts are known as acid addition and base addition salts. It will be appreciated by the skilled reader that most or all of the compounds as disclosed herein are capable of forming salts and that the salt forms of pharmaceuticals are commonly used, often because they are more readily crystallized and purified than are the free acids or bases. 
     Acids commonly employed to form acid addition salts may include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of suitable pharmaceutically acceptable salts may include the sulfate, pyrosulfate, bisulfate, sulfite, bisulfate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, hydrochloride, dihydrochloride, isobutyrate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleat-, butyne-. 1,4-dioate, hexyne-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, hydroxybenzoate, methoxybenzoate, phthalate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, alpha-hydroxybutyrate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate, mandelate, and the like. 
     Base addition salts include those derived from inorganic bases, such as ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Bases useful in preparing such salts include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. 
     The particular counter-ion forming a part of any salt of a compound disclosed herein is may not be critical to the activity of the compound, so long as the salt as a whole is pharmacologically acceptable and as long as the counterion does not contribute undesired qualities to the salt as a whole. Undesired qualities may include undesirably solubility or toxicity. 
     Pharmaceutically acceptable esters and amides of the compounds can also be employed in the compositions and methods disclosed herein. Examples of suitable esters include alkyl, aryl, and aralkyl esters, such as methyl esters, ethyl esters, propyl esters, dodecyl esters, benzyl esters, and the like. Examples of suitable amides include unsubstituted amides, monosubstituted amides, and disubstituted amides, such as methyl amide, dimethyl amide, methyl ethyl amide, and the like. 
     In addition, the methods disclosed herein may be practiced using solvate forms of the compounds or salts, esters, and/or amides, thereof. Solvate forms may include ethanol solvates, hydrates, and the like. 
     The pharmaceutical compositions may be utilized in methods of treating a disease or disorder associated glucocerebrosidase activity. For example, the pharmaceutical compositions may be utilized to treat patients having or at risk for acquiring Gaucher&#39;s disease and neurological diseases and disorders such as genetic and sporadic synucleinopathies, including Parkinson&#39;s disease, dementia with Lewy bodies, and multiple system atrophy associated with aberrant glucocerebrosidase activity. Suitable patients include, for example mammals, such as humans and non-human primates (e.g., chimps) or other mammals (e.g., dogs, cats, horses, rats, and mice). Suitable human patients may include, for example, those who have previously been determined to be at risk of having or developing Gaucher&#39;s disease and neurological diseases and disorders such as genetic and sporadic synucleinopathies, including Parkinson&#39;s disease, dementia with Lewy bodies, and multiple system atrophy associated with aberrant glucocerebrosidase activity. 
     As used herein, the terms “treating” or “to treat” each mean to alleviate symptoms, eliminate the causation of resultant symptoms either on a temporary or permanent basis, and/or to prevent or slow the appearance or to reverse the progression or severity of resultant symptoms of the named disease or disorder. As such, the methods disclosed herein encompass both therapeutic and prophylactic administration. 
     As used herein the term “effective amount” refers to the amount or dose of the compound, upon single or multiple dose administration to the subject, which provides the desired effect in the subject under diagnosis or treatment. The disclosed methods may include administering an effective amount of the disclosed compounds (e.g., as present in a pharmaceutical composition) for treating a disease or disorder associated with glucocerebrosidase activity. 
     An effective amount can be readily determined by the attending diagnostician, as one skilled in the art, by the use of known techniques and by observing results obtained under analogous circumstances. In determining the effective amount or dose of compound administered, a number of factors can be considered by the attending diagnostician, such as: the species of the subject; its size, age, and general health; the degree of involvement or the severity of the disease or disorder involved; the response of the individual subject; the particular compound administered; the mode of administration; the bioavailability characteristics of the preparation administered; the dose regimen selected; the use of concomitant medication; and other relevant circumstances. 
     A typical daily dose may contain from about 0.01 mg/kg to about 100 mg/kg (such as from about 0.05 mg/kg to about 50 mg/kg and/or from about 0.1 mg/kg to about 25 mg/kg) of each compound used in the present method of treatment. 
     Compositions can be formulated in a unit dosage form, each dosage containing from about 1 to about 500 mg of each compound individually or in a single unit dosage form, such as from about 5 to about 300 mg, from about 10 to about 100 mg, and/or about 25 mg. The term “unit dosage form” refers to a physically discrete unit suitable as unitary dosages for a patient, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect, in association with a suitable pharmaceutical carrier, diluent, or excipient. 
     Oral administration is an illustrative route of administering the compounds employed in the compositions and methods disclosed herein. Other illustrative routes of administration include transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, intrathecal, intracerebral, or intrarectal routes. The route of administration may be varied in any way, limited by the physical properties of the compounds being employed and the convenience of the subject and the caregiver. 
     As one skilled in the art will appreciate, suitable formulations include those that are suitable for more than one route of administration. For example, the formulation can be one that is suitable for both intrathecal and intracerebral administration. Alternatively, suitable formulations include those that are suitable for only one route of administration as well as those that are suitable for one or more routes of administration, but not suitable for one or more other routes of administration. For example, the formulation can be one that is suitable for oral, transdermal, percutaneous, intravenous, intramuscular, intranasal, buccal, and/or intrathecal administration but not suitable for intracerebral administration. 
     The inert ingredients and manner of formulation of the pharmaceutical compositions are conventional. The usual methods of formulation used in pharmaceutical science may be used here. All of the usual types of compositions may be used, including tablets, chewable tablets, capsules, solutions, parenteral solutions, intranasal sprays or powders, troches, suppositories, transdermal patches, and suspensions. In general, compositions contain from about 0.5% to about 50% of the compound in total, depending on the desired doses and the type of composition to be used. The amount of the compound, however, is best defined as the “effective amount”, that is, the amount of the compound which provides the desired dose to the patient in need of such treatment. The activity of the compounds employed in the compositions and methods disclosed herein are not believed to depend greatly on the nature of the composition, and, therefore, the compositions can be chosen and formulated primarily or solely for convenience and economy. 
     Capsules are prepared by mixing the compound with a suitable diluent and filling the proper amount of the mixture in capsules. The usual diluents include inert powdered substances (such as starches), powdered cellulose (especially crystalline and microcrystalline cellulose), sugars (such as fructose, mannitol and sucrose), grain flours, and similar edible powders. 
     Tablets are prepared by direct compression, by wet granulation, or by dry granulation. Their formulations usually incorporate diluents, binders, lubricants, and disintegrators (in addition to the compounds). Typical diluents include, for example, various types of starch, lactose, mannitol, kaolin, calcium phosphate or sulfate, inorganic salts (such as sodium chloride), and powdered sugar. Powdered cellulose derivatives can also be used. Typical tablet binders include substances such as starch, gelatin, and sugars (e.g., lactose, fructose, glucose, and the like). Natural and synthetic gums can also be used, including acacia, alginates, methylcellulose, polyvinylpyrrolidine, and the like. Polyethylene glycol, ethylcellulose, and waxes can also serve as binders. 
     Tablets can be coated with sugar, e.g., as a flavor enhancer and sealant. The compounds also may be formulated as chewable tablets, by using large amounts of pleasant-tasting substances, such as mannitol, in the formulation. Instantly dissolving tablet-like formulations can also be employed, for example, to assure that the patient consumes the dosage form and to avoid the difficulty that some patients experience in swallowing solid objects. 
     A lubricant can be used in the tablet formulation to prevent the tablet and punches from sticking in the die. The lubricant can be chosen from such slippery solids as talc, magnesium and calcium stearate, stearic acid, and hydrogenated vegetable oils. 
     Tablets can also contain disintegrators. Disintegrators are substances that swell when wetted to break up the tablet and release the compound. They include starches, clays, celluloses, algins, and gums. As further illustration, corn and potato starches, methylcellulose, agar, bentonite, wood cellulose, powdered natural sponge, cation-exchange resins, alginic acid, guar gum, citrus pulp, sodium lauryl sulfate, and carboxymethylcellulose can be used. 
     Compositions can be formulated as enteric formulations, for example, to protect the active ingredient from the strongly acid contents of the stomach. Such formulations can be created by coating a solid dosage form with a film of a polymer which is insoluble in acid environments and soluble in basic environments. Illustrative films include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, and hydroxypropyl methylcellulose acetate succinate. 
     When it is desired to administer the compound as a suppository, conventional bases can be used. Illustratively, cocoa butter is a traditional suppository base. The cocoa butter can be modified by addition of waxes to raise its melting point slightly. Water-miscible suppository bases, such as polyethylene glycols of various molecular weights, can also be used in suppository formulations. 
     Transdermal patches can also be used to deliver the compounds. Transdermal patches can include a resinous composition in which the compound will dissolve or partially dissolve; and a film which protects the composition and which holds the resinous composition in contact with the skin. Other, more complicated patch compositions can also be used, such as those having a membrane pierced with a plurality of pores through which the drugs are pumped by osmotic action. 
     As one skilled in the art will also appreciate, the formulation can be prepared with materials (e.g., actives excipients, carriers (such as cyclodextrins), diluents, etc.) having properties (e.g., purity) that render the formulation suitable for administration to humans. Alternatively, the formulation can be prepared with materials having purity and/or other properties that render the formulation suitable for administration to non-human subjects, but not suitable for administration to humans. 
     The compounds disclosed in the present application may function as activators of glucocerebrosidase. For example, a compound disclosed herein may be reacted with glucocerebrosidase to prepare an activated glucocerebrosidase that is covalent attached to the compound. The activated glucocerebrosidase thusly formed may be prepared as a pharmaceutical composition to treat and/or prevent a disease or disorder that is associated with glucocerebrosidase activity as in enzyme replacement therapy, which is known in the art. 
     Illustrative Formulations 
     The following list of formulations is illustrative. These illustrative formulations may be suitable for preparing pharmaceutical compositions that include the disclosed compounds as “active ingredients.” The following list of formulations is illustrative and should not be interpreted as limiting the present disclosure or claims in any way: 
     Formulation 1 
     Hard gelatin capsules are prepared using the following ingredients: 
     
       
         
           
               
               
             
               
                   
                   
               
               
                   
                 Quantity (mg/capsule) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Active Ingredient 
                 250 
               
               
                   
                 Starch, dried 
                 200 
               
               
                   
                 Magnesium stearate 
                 10 
               
               
                   
                 Total 
                 460 mg 
               
               
                   
                   
               
            
           
         
       
     
     The above ingredients are mixed and filled into hard gelatin capsules in 460 mg quantities. 
     Formulation 2 
     
       
         
           
               
               
             
               
                   
                   
               
               
                   
                 Quantity (mg/tablet) 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Active Ingredient 
                 250 
               
               
                   
                 Cellulose, microcrystalline 
                 400 
               
               
                   
                 Silicon dioxide, fumed 
                 10 
               
               
                   
                 Stearic acid 
                 5 
               
               
                   
                 Total 
                 665 mg 
               
               
                   
                   
               
            
           
         
       
     
     The components are blended and compressed to form tablets each weighing 665 mg. 
     Formulation 3 
     An aerosol solution is prepared containing the following components: 
     
       
         
           
               
               
             
               
                   
                   
               
               
                   
                 Weight % 
               
               
                   
                   
               
             
            
               
                   
               
            
           
           
               
               
               
            
               
                   
                 Active Ingredient 
                 0.25 
               
               
                   
                 Ethanol 
                 29.75 
               
               
                   
                 Propellant 22 (chlorodifluoromethane) 
                 70.00 
               
               
                   
                 Total 
                 100.00 
               
               
                   
                   
               
            
           
         
       
     
     The active compound is mixed with ethanol and the mixture added to a portion of the Propellant 22, cooled to −30° C. and transferred to a filling device. The required amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container. 
     Formulation 4 
     Tablets each containing 60 mg of active ingredient are made as follows: 
     
       
         
           
               
               
               
               
             
               
                   
                   
               
             
            
               
                   
                 Active Ingredient 
                 60 
                 mg 
               
               
                   
                 Starch 
                 45 
                 mg 
               
               
                   
                 Microcrystalline cellulose 
                 35 
                 mg 
               
               
                   
                 Polyvinylpyrrolidone 
                 4 
                 mg 
               
               
                   
                 Sodium carboxymethyl starch 
                 4.5 
                 mg 
               
               
                   
                 Magnesium stearate 
                 0.5 
                 mg 
               
               
                   
                 Talc 
                 1 
                 mg 
               
               
                   
                 Total 
                 150 
                 mg 
               
               
                   
                   
               
            
           
         
       
     
     The active ingredient, starch, and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The solution of polyvinylpyrrolidone is mixed with the resultant powders which are then passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50° C. and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate, and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg. 
     Formulation 5 
     Capsules, each containing 80 mg medicament, are made as follows: 
     
       
         
           
               
               
               
               
             
               
                   
                   
               
             
            
               
                   
                 Active Ingredient 
                 80 
                 mg 
               
               
                   
                 Starch 
                 59 
                 mg 
               
               
                   
                 Microcrystalline cellulose 
                 59 
                 mg 
               
               
                   
                 Magnesium stearate 
                 2 
                 mg 
               
               
                   
                 Total 
                 200 
                 mg 
               
               
                   
                   
               
            
           
         
       
     
     The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 sieve, and filled into hard gelatin capsules in 200 mg quantities. 
     Formulation 6 
     Suppositories each containing 225 mg of active ingredient may be made as follows: 
     
       
         
           
               
               
               
               
             
               
                   
                   
               
             
            
               
                   
                 Active Ingredient 
                 225 
                 mg 
               
               
                   
                 Saturated fatty acid glycerides 
                 2,000 
                 mg 
               
               
                   
                 Total 
                 2,225 
                 mg 
               
               
                   
                   
               
            
           
         
       
     
     The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool. 
     Formulation 7 
     Suspensions each containing 50 mg of medicament per 5 ml dose are made as follows: 
     
       
         
           
               
               
               
               
             
               
                   
                   
               
             
            
               
                   
                 Active Ingredient 
                 50 
                 mg 
               
               
                   
                 Sodium carboxymethyl cellulose 
                 50 
                 mg 
               
               
                   
                 Syrup 
                 1.25 
                 ml 
               
               
                   
                 Benzoic acid solution 
                 0.10 
                 ml 
               
            
           
           
               
               
               
            
               
                   
                 Flavor 
                 q.v. 
               
               
                   
                 Color 
                 q.v. 
               
            
           
           
               
               
               
               
            
               
                   
                 Purified water to total 
                 5 
                 ml 
               
               
                   
                   
               
            
           
         
       
     
     The medicament is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl, cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor, and color are diluted with some of the water and added with stirring. Sufficient water is then added to produce the required volume. 
     Formulation 8 
     An intravenous formulation containing 100 mg of medicament per 5 ml dose can be prepared as follows: 
     
       
         
           
               
               
               
               
             
               
                   
                   
               
             
            
               
                   
                 Active Ingredient 
                 100 
                 mg 
               
               
                   
                 Mannitol 
                 100 
                 mg 
               
               
                   
                 5N Sodium hydroxide 
                 200 
                 ml 
               
               
                   
                 Purified water to total 
                 5 
                 ml 
               
               
                   
                   
               
            
           
         
       
     
     ILLUSTRATIVE EMBODIMENTS 
     The following embodiments are illustrative and are not intended to limit the claimed invention. 
     Embodiment 1 
     A compound or a salt or solvate thereof having a Formula I or II: 
     
       
         
         
             
             
         
       
     
     wherein: 
     A is a saturated or unsaturated ring having 5 or 6 carbon atoms and optionally one or more heteroatoms selected from N, O, and S, and A optionally is substituted at one or more ring positions with alkyl, alkoxy, halo, or haloalkyl; 
     X is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, amino, aryl or heteroaryl optionally substituted at one or more positions with halo, haloalkyl, hydroxyl, amino, or pyrrolidinyl; 
     Y is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, a nitrogen-contained group, and oxygen-containing group, aryl or heteroaryl optionally substituted at one or more positions with halo, haloalkyl, hydroxyl, amino, or pyrrolidinyl; and 
     Z is hydrogen, alkyl, cycloalkyl, cycloheteroalkyl, amino, aryl or heteroaryl optionally substituted at one or more positions with halo, haloalkyl, hydroxyl, amino, or pyrrolidinyl such as N-pyrrolidinyl. 
     Embodiment 2 
     The compound of embodiment 1 having a formula selected from: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Embodiment 3 
     The compound of embodiment 2, wherein R 1  is hydrogen, alkyl, alkenyl, alkynyl, alkoxy, haloalkyl, cyano, amino, cycloalkyl, cycloheteroalkyl. aryl or heteroaryl. 
     Embodiment 4 
     The compound of any of embodiments 1-3, wherein, Y is a nitrogen-containing group or an oxygen-containing group. 
     Embodiment 5 
     The compound of any of the foregoing embodiments, wherein Y is —NH 2 , —NR 2 H, —NR 2 R 3 , —N(CH 2 ) m —O—R2(CH 2 ) n R 3  (where m and n are 0-6), —OH, or —OR 2 ; and R 2  and R 3 , which optionally are the same or different are selected from hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloheteroalkyl, aryl, heteroaryl group optionally substituted at one or more positions with aryl. alkoxy, alkyl-alkoxy, an alkyl-cycloalkyl, alkyl-oxa-cycloalkyl, alkyl-aryl, alkyl-cycloheteroalkyl, alkyl-amino-aryl, alkyl-phenoxy with the phenyl group of the alkyl-phenoxy optionally substituted at one or more positions with alkyl, halo, haloalkyl, amino, alkyl-amino, alkynyl, alkynyl-phenyl, alkyl-phenyl, carboxyl, carboxyl-alkyl ester, carboxyl amidated with an N-succinimidyl, alkyl-carboxyl, alkyl-carboxyl-alkyl ester, alkyl-hydroxyl, cyano, alkyl-NH—C(O)-alkyl-N—C(O)—O-alkyl, alkyl-NH—C(O)-alkyl-NH 2 ; alkylcarboxyl optionally amidated with an N-succinimidyl, alkyl-indole, alkyl-pyridinoxy, a pyrazole optionally substituted at one or more positions with alkyl, or benzyl; or 
     R 2  and R 3  together form a 5-membered or 6-membered nitrogen containing heterocycle which may be saturated or unsaturated and optionally includes additional heteroatoms selected from N, O, and S, the heterocycle optionally substituted at one or more positions with alkyl, halo, haloalkyl, alkoxy, or phenoxy. 
     Embodiment 6 
     The compound of any of the foregoing embodiments, wherein Y has a formula: 
     
       
         
         
             
             
         
       
     
     wherein m and n are 0-6, preferably at least one of m and n is at least 1 or both m and n are at least 1, or preferably at least one of m and n is at least 2 or both of m and n are at least 2. 
     Embodiment 7 
     The compound of any of the foregoing embodiments wherein the compound has a formula: 
     
       
         
         
             
             
         
       
     
     wherein R 1  and Y are as defined above and R 4  is independently selected from alkyl, halo, haloalkyl, hydroxyl, amino, amido, and pyrrolidinyl. 
     Embodiment 8 
     The compound of any of the foregoing embodiments wherein the compound has a formula: 
     
       
         
         
             
             
         
       
     
     wherein R 1  and Y are as defined above and R 4  is independently selected from alkyl, halo, haloalkyl, hydroxyl, amino, amido, and pyrrolidinyl. 
     Embodiment 9 
     A pharmaceutical composition comprising the compound of any of the foregoing embodiments and a pharmaceutical carrier. 
     Embodiment 10 
     A method for treating a disease or disorder that is associated with glucocerebrosidase activity in a subject in need thereof, the method comprising administering the composition of embodiment 9 to the subject. 
     Embodiment 11 
     The method of embodiment 10, wherein the disease or disorder is a neurological disease or disorder. 
     Embodiment 12 
     The method of embodiment 11, wherein the neurological disease or disorder is a degenerative neurological disease or disorder. 
     Embodiment 13 
     The method of embodiment 10, wherein the disease or disorder is Gaucher&#39;s disease. 
     Embodiment 14 
     The method of embodiment 10, wherein the disease or disorder is Parkinson&#39;s disease. 
     Embodiment 15 
     The compound of any of embodiments 1-8 conjugated to a fluorophore. 
     Embodiment 16 
     A method of screening for a compound that binds to glucocerebrosidase, the method comprising contacting glucocerebrosidase with the fluorescent compound of embodiment 15 and observing fluorescence polarization. 
     Embodiment 17 
     The compound of any of embodiments 1-8 covalently attached to glucocerebrosidase. 
     Embodiment 18 
     A pharmaceutical composition comprising compound of embodiment 17 and a pharmaceutical carrier. 
     Embodiment 19 
     A method for treating a disease or disorder that is associated with glucocerebrosidase activity in a subject in need thereof, the method comprising administering the composition of embodiment 18 to the subject. 
     Embodiment 20 
     The method of embodiment 19, wherein the disease or disorder is a neurological disease or disorder. 
     Embodiment 21 
     The method of embodiment 20, wherein the disease or disorder is a degenerative neurological disease or disorder. 
     Embodiment 22 
     The method of embodiment 21, wherein the disease or disorder is Gaucher&#39;s disease. 
     EXAMPLES 
     The followings Examples are illustrative only and are not intended to limit the scope of the claimed subject matter. 
     Title: Substituted Pyrimidine and Fused Pyrimidine Compounds and Uses Thereof for Modulating Glucocerebrosidase Activity 
     The compounds were prepared using Scheme I below: 
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     
       
         
         
             
             
         
       
       
         
         
             
             
         
       
     
     Example 1: Preparation of (S)—N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (9) 
     Step 1: Preparation of (R)—N—((R)-1-phenylethyl)-2,3-dihydrobenzo[b][1,4]dioxine-2-carboxamide (2) 
     To a stirred solution of 1,4-benzodioxane-2-carboxylic acid (9.0 g, 50 mmol), HATU (19.0 g, 50 mmol) and DIPEA (35 mL) in DMF (100 mL) was added (R)-1-phenylethanamine (6.4 mL, 50 mmol) at 22° C., and the mixture was allowed to stir at 22° C. for 16 hrs. Water (200 mL) was added, and the mixture was stirred at 22° C. for 10 hrs. The aqueous layer was decanted, and the sticky residue was washed with water carefully, dried, and purified by flash chromatography to give (R)—N—((R)-1-phenylethyl)-2,3-dihydrobenzo[b][1,4]dioxine-2-carboxamide (2) 5.3 g (37%) and (S)—N—((R)-1-phenylethyl)-2,3-dihydrobenzo[b][1,4]dioxine-2-carboxamide (3) 5.7 g (40%). 
     2:  1 H NMR (500 MHz, CDCl 3 ) δ 7.40-7.26 (m, 5H), 6.96-6.84 (m, 4H), 6.79 (d, J=7.2 Hz, 1H), 5.22-5.10 (m, 1H), 4.64 (dd, J=7.5, 2.6 Hz, 1H), 4.56 (dd, J=11.4, 2.6 Hz, 1H), 4.17 (dd, J=11.4, 7.6 Hz, 1H), 1.47 (d, J=6.9 Hz, 3H). 13C NMR (125 MHz, CDCl 3 ) δ 166.1, 143.3, 142.4, 141.6, 128.8, 127.6, 126.2, 122.4, 121.9, 117.6, 117.1, 73.1, 65.5, 48.6, 21.7. APCI-MS m/z: 284 (M+H) + . 
     3:  1 H NMR (500 MHz, CDCl 3 ) δ 7.38-7.27 (m, 3H), 7.26-7.21 (m, 2H), 7.05-7.00 (m, 1H), 6.99-6.92 (m, 3H), 6.85 (d, J=6.7 Hz, 1H), 5.29-5.20 (m, 1H), 4.77 (dd, J=7.3, 2.6 Hz, 1H), 4.59 (dd, J=11.4, 2.7 Hz, 1H), 4.22 (dd, J=11.4, 7.3 Hz, 1H), 1.61 (d, J=6.9 Hz, 3H). 13C NMR (125 MHz, CDCl 3 ) δ 166.2, 143.3, 142.5, 141.5, 128.7, 127.4, 125.8, 122.5, 121.9, 117.7, 117.1, 73.2, 65.4, 48.4, 21.9. APCI-MS m/z: 284 (M+H) + . 
     Step 2: Preparation of (R)—N—(((S)-2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-1-phenylethanamine (4) 
     To a solution of 2 (566 mg, 2 mmol) in THF (12 mL) 0° C., was added LAH (250 mg, 6.6 mmol) in portions under N 2  atmosphere. The mixture was refluxed for 16 hrs, and then cooled to 0° C. The reaction was slowly added water (0.25 mL), 15% NaOH solution (0.25 mL), and water (0.75 mL). The mixture was stirred at room temperature for 30 min, and filtered through Celite. The filtrate was concentrated to give 420 mg (78%) light yellow oil (4). 
       1 H NMR (500 MHz, CDCl 3 ) δ 7.32 (d, J=4.3 Hz, 4H), 7.25-7.19 (m, 1H), 6.90-6.77 (m, 4H), 4.24-4.18 (m, 2H), 3.92 (dd, J=11.7, 8.0 Hz, 1H), 3.77 (q, J=6.5 Hz, 1H), 2.78 (dd, J=12.4, 7.1 Hz, 1H), 2.61 (dd, J=12.4, 4.5 Hz, 1H), 1.37 (d, J=6.6 Hz, 3H).  13 C NMR (125 MHz, CDCl 3 ) δ 145.2, 143.3, 143.1, 128.5, 127.0, 126.6, 121.4, 121.3, 117.3, 117.0, 73.0, 66.6, 58.5, 47.9, 24.5. APCI-MS m/z: 270 (M+H) + . 
     Step 3: Preparation of (S)-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methanamine (5) 
     To a mixture of 4 (100 mg, 0.372), 10% Pd/C (100 mg) in MeOH (10 ml) was added ammonium formate (117 mg, 1.86 mmol) under N 2  atmosphere. The mixture was refluxed for 15 min, and cooled to room temperature. The mixture was filtered through Celite, and the filtrate was concentrated to give 25 mg (41%) white solid (5). APCI-MS m/z: 166 (M+H) + . 
     Step 4: Preparation of (S)-tert-butyl ((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)carbamate (6) 
     o a solution of 5 (1.8 g, 11 mmol) in THF (15 mL) and water (15 mL), was added di-tert-butyl dicarbonate (2.85 g, 13.1 mmol) and sodium bicarbonate (2.75 g, 32.7 mmol). The reaction mixture was stirred at room temperature for 3 hrs, and extracted with EtOAc (50 mL×3). The combined organic phase was washed with brine, dried, and evaporated to give crude product, which was purified by flash chromatography to afford 6 (2.0 g, 69%) as a colorless oil. 
     Step 5: Preparation of (S)-1-(2,3-dihydrobenzo[b][1,4]dioxin-2-yl)-N-methylmethanamine (7) 
     Following the same procedure for 4, compound 6 (2.0 g, 7.5 mmol) was refluxed with LAH (0.95 g, 24.9 mmol) in THF (45 mL) to afford 7 (1.04 g, 77%) as a light-yellow liquid. 
       1 H NMR (500 MHz, CDCl 3 ) δ 6.91-6.77 (m, 4H), 4.31-4.20 (m, 2H), 4.00 (dd, J=11.6, 7.9 Hz, 1H), 2.92-2.76 (m, 2H), 2.48 (s, 3H). 13C NMR (125 MHz, CDCl 3 ) δ 143.2, 143.1, 121.5, 121.3, 117.3, 117.1, 72.3, 66.5, 52.1, 36.7. APCI-MS m/z: 180 (M+H) + . 
     Step 6: Preparation of (S)—N-((2,3-dihydrobenzo[b][1,4]dioxin-2-yl)methyl)-N-methyl-2-(pyridin-3-yl)quinazolin-4-amine (9) 
     A mixture of 4-chloro-2-(pyridin-3-yl)quinazoline (120 mg, 0.5 mmol), 7 (90 mg, 0.5 mmol), and potassium carbonate (69 mg, 0.5 mmol) in DMF (3 mL) was stirred at room temperature for 16 hr. Water (20 mL) was added, and the formed solid was filtered, washed with water, dried to give 130 mg (68%) off-white solid. 
       1 H NMR (500 MHz, CDCl 3 ) δ 9.65 (s, 1H), 8.72 (d, J=7.9 Hz, 1H), 8.69-8.64 (m, 1H), 8.13 (d, J=8.4 Hz, 1H), 7.93 (d, J=8.4 Hz, 1H), 7.76-7.68 (m, 1H), 7.43-7.34 (m, 2H), 6.90-6.78 (m, 4H), 4.84-4.76 (m, 1H), 4.40-4.27 (m, 2H), 4.17-4.08 (m, 2H), 3.66 (s, 3H).  13 C NMR (125 MHz, CDCl 3 ) δ 163.0, 157.1, 153.1, 150.8, 150.0, 143.1, 142.6, 135.5, 134.1, 132.5, 128.9, 125.5, 124.7, 123.2, 121.8, 121.5, 117.4, 117.2, 115.0, 71.8, 66.0, 53.0, 43.1. APCI-MS m/z: 385 (M+H) + . 
     Example 2—Glucocerebrosidase Activity Assay with Blue Substrate 
     The compounds in DMSO solution 0.5 μL/well were transferred to a black 96-well plate (the final titration was 24 nM to 50 μM, 12 concentrations, 2× dilution). 33.5 μL enzyme solution (7.5 nM final concentration) was transferred to the wells. After 5 min of incubation at room temperature, the enzyme reaction was initiated by the addition of 33 μL/well blue substrate. Final concentration of the blue substrate (4MU-Glc) was 1.5 mM. The blue substrate reaction was terminated by the addition of 33 μL/well stop solution (1 M NaOH and 1 M glycine mixture, pH 10) after 30 min of incubation at 37° C. The fluorescence was then measured in the Biotek Synergy H1 multi-mode plate reader with Ex=365 nm and Em=440 nm. 
     
       
         
           
               
             
               
                 TABLE 1 
               
             
            
               
                   
               
               
                 Chemical structure and activity of target compounds 
               
            
           
           
               
               
               
               
               
            
               
                 No. 
                 Structure 
                 MW 
                 AC 50  (μM) 
                 Emax (%) 
               
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 9 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 384 
                 1.49 
                 645 
               
               
                   
               
               
                 10 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 388 
                 1.38 
                 573 
               
               
                   
               
               
                 11 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 385 
                 3.83 
                 1278 
               
               
                   
               
               
                 12 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 384 
                 2.67 
                 220 
               
               
                   
               
               
                 13 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 356 
                 3.55 
                 750 
               
               
                   
               
               
                 14 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 370 
                 5.01 
                 430 
               
               
                   
               
               
                 15 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 384 
                 3.12 
                 130 
               
               
                   
               
               
                 16 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 396 
                 NA 
                   
               
               
                   
               
               
                 17 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 390 
                 1.58 
                 190 
               
               
                   
               
               
                 18 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 456 
                 NA 
                   
               
               
                   
               
               
                 19 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 484 
                 1.78 
                 150 
               
               
                   
               
               
                 20 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 581 
                 1.26 
                 500 
               
               
                   
               
               
                 21 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 460 
                 15.85 
                 180 
               
               
                   
               
               
                 22 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 368 
                 1.58 
                 300 
               
               
                   
               
               
                 23 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 370 
                 3.55 
                 500 
               
               
                   
               
               
                 24 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 343 
                 3.16 
                 140 
               
               
                   
               
               
                 25 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 382 
                 3.98 
                 220 
               
               
                   
               
               
                 26 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 382 
                 1.78 
                 225 
               
               
                   
               
               
                 27 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 384 
                 3.98 
                 225 
               
               
                   
               
               
                 28 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 370 
                 3.16 
                 350 
               
               
                   
               
               
                 29 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 336 
                 39.81 
                 180 
               
               
                   
               
               
                 30 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379 
                 5.01 
                 250 
               
               
                   
               
               
                 31 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 474 
                 NA 
                   
               
               
                   
               
               
                 32 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 390 
                 1.21 
                 250 
               
               
                   
               
               
                 33 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 380 
                 2.82 
                 190 
               
               
                   
               
               
                 34 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 374 
                 1.12 
                 160 
               
               
                   
               
               
                 35 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 374 
                 0.51 
                 180 
               
               
                   
               
               
                 36 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 374 
                 1.58 
                 220 
               
               
                   
               
               
                 37 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 424 
                 1.65 
                 250 
               
               
                   
               
               
                 38 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 374 
                 2.82 
                 700 
               
               
                   
               
               
                 39 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 374 
                 2.82 
                 450 
               
               
                   
               
               
                 40 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 374 
                 1.58 
                 450 
               
               
                   
               
               
                 41 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 374 
                 13.47 
                 180 
               
               
                   
               
               
                 42 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 369 
                 6.54 
                 250 
               
               
                   
               
               
                 43 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423 
                 1.81 
                 400 
               
               
                   
               
               
                 44 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423 
                 4.12 
                 180 
               
               
                   
               
               
                 45 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423 
                 5.0 
                 120 
               
               
                   
               
               
                 46 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 423 
                 NA 
                   
               
               
                   
               
               
                 47 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 374 
                 2.21 
                 175 
               
               
                   
               
               
                 48 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413 
                 NA 
                   
               
               
                   
               
               
                 49 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395 
                 2.42 
                 120 
               
               
                   
               
               
                 50 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395 
                 NA 
                   
               
               
                   
               
               
                 51 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 372 
                 8.17 
                 200 
               
               
                   
               
               
                 52 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 425 
                 NA 
                   
               
               
                   
               
               
                 53 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 385 
                 4.10 
                 300 
               
               
                   
               
               
                 54 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 371 
                 3.10 
                 170 
               
               
                   
               
               
                 55 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 390 
                 39.8 
                 458 
               
               
                   
               
               
                 56 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 346 
                 3.3 
                 295 
               
               
                   
               
               
                 57 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 357 
                 NA 
                   
               
               
                   
               
               
                 58 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 360 
                 1.41 
                 130 
               
               
                   
               
               
                 59 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 362 
                 5.01 
                 333 
               
               
                   
               
               
                 60 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 362 
                 3.16 
                 624 
               
               
                   
               
               
                 61 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 384 
                 2.51 
                 127 
               
               
                   
               
               
                 62 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 357 
                 7.08 
                 1384 
               
               
                   
               
               
                 63 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 345 
                 3.98 
                 461 
               
               
                   
               
               
                 64 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 376 
                 2.51 
                 222 
               
               
                   
               
               
                 65 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 382 
                 1.0 
                 144 
               
               
                   
               
               
                 66 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 370 
                 7.08 
                 141 
               
               
                   
               
               
                 67 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 346 
                 10 
                 787 
               
               
                   
               
               
                 68 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 364 
                 12.58 
                 327 
               
               
                   
               
               
                 69 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 375 
                 7.10 
                 1092 
               
               
                   
               
               
                 70 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 406 
                 8.91 
                 191 
               
               
                   
               
               
                 71 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 391 
                 15.85 
                 346 
               
               
                   
               
               
                 72 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 359 
                 6.31 
                 927 
               
               
                   
               
               
                 73 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 348 
                 5.62 
                 330 
               
               
                   
               
               
                 74 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 420 
                 10 
                 194 
               
               
                   
               
               
                 75 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 380 
                 2.00 
                 115 
               
               
                   
               
               
                 76 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 414 
                 4.47 
                 255 
               
               
                   
               
               
                 77 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 414 
                 5.01 
                 432 
               
               
                   
               
               
                 78 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 360 
                 1.56 
                 425 
               
               
                   
               
               
                 79 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 400 
                 12.59 
                 252 
               
               
                   
               
               
                 80 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 400 
                 15.85 
                 442 
               
               
                   
               
               
                 81 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 406 
                 3.16 
                 280 
               
               
                   
               
               
                 82 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 368 
                 1.12 
                 501 
               
               
                   
               
               
                 83 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 497 
                 3.98 
                 230 
               
               
                   
               
               
                 84 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 497 
                 4.47 
                 457 
               
               
                   
               
               
                 85 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383 
                 2.24 
                 460 
               
               
                   
               
               
                 86 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 401 
                 15.84 
                 1192 
               
               
                   
               
               
                 87 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 372 
                 10 
                 173 
               
               
                   
               
               
                 88 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 399 
                 5.01 
                 142 
               
               
                   
               
               
                 89 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 370 
                 4.47 
                 660 
               
               
                   
               
               
                 90 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 432 
                 7.94 
                 908 
               
               
                   
               
               
                 91 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 352 
                 44.66 
                 322 
               
               
                   
               
               
                 92 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 360 
                 35.48 
                 790 
               
               
                   
               
               
                 93 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 363 
                 4.47 
                 270 
               
               
                   
               
               
                 94 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 429 
                 14.12 
                 1350 
               
               
                   
               
               
                 95 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 428 
                 4.47 
                 721 
               
               
                   
               
               
                 96 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 515 
                 7.94 
                 583 
               
               
                   
               
               
                 97 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 345 
                 3.16 
                 531 
               
               
                   
               
               
                 98 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 388 
                 28.18 
                 140 
               
               
                   
               
               
                 99 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 374 
                 0.71 
                 208 
               
               
                   
               
               
                 100 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 370 
                 5.62 
                 833 
               
               
                   
               
               
                 101 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 399 
                 79.43 
                 197 
               
               
                   
               
               
                 102 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 366 
                 25.11 
                 1390 
               
               
                   
               
               
                 103 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 414 
                 3.16 
                 371 
               
               
                   
               
               
                 104 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 381 
                 6.31 
                 425 
               
               
                   
               
               
                 105 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 386 
                 6.31 
                 662 
               
               
                   
               
               
                 106 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 402 
                 1.12 
                 250 
               
               
                   
               
               
                 107 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 399 
                 NA 
                   
               
               
                   
               
               
                 108 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 388 
                 7.08 
                 400 
               
               
                   
               
               
                 109 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 381 
                 14.12 
                 475 
               
               
                   
               
               
                 110 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 403 
                 7.94 
                 750 
               
               
                   
               
               
                 111 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 616 
                 0.50 
                 675 
               
               
                   
               
               
                 112 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 516 
                 3.55 
                 530 
               
               
                   
               
            
           
         
       
     
     Example 3—Glucocerebrosidase Modulatory Activity of Additional Substituted Pyrimidine and Fused Pyrimidine Compounds 
     Additional compounds were synthesized and tested for glucocerebrosidase modulatory activity as described in Example 1 and Example 2. 
     
       
         
           
               
               
               
               
               
             
               
                 TABLE 2 
               
               
                   
               
               
                   
                   
                   
                 AC 50   
                   
               
               
                 No. 
                 Chemical Structure 
                 MW 
                 (μM) 
                 Emax (%) 
               
               
                   
               
             
            
               
                   
               
            
           
           
               
               
               
               
               
            
               
                 113 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 357 
                 5.01 
                 225 
               
               
                   
               
               
                 114 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 402 
                 2.5 
                 340 
               
               
                   
               
               
                 115 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 863 
                 2.82 
                 1525 
               
               
                   
               
               
                 116 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413 
                 12.58 
                 210 
               
               
                   
               
               
                 117 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413 
                 14.12 
                 310 
               
               
                   
               
               
                 118 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 388 
                 0.8 
                 325 
               
               
                   
               
               
                 119 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383 
                 NA 
                 — 
               
               
                   
               
               
                 120 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383 
                 NA 
                 — 
               
               
                   
               
               
                 121 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383 
                 NA 
                 — 
               
               
                   
               
               
                 122 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 411 
                 NA 
                 — 
               
               
                   
               
               
                 123 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 426 
                 3.16 
                 105 
               
               
                   
               
               
                 124 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 430 
                 6.31 
                 480 
               
               
                   
               
               
                 125 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 445 
                 6.31 
                 610 
               
               
                   
               
               
                 126 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 501 
                 0.20 
                 150 
               
               
                   
               
               
                 127 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383 
                 35.5 
                 325 
               
               
                   
               
               
                 128 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 387 
                 44.7 
                 275 
               
               
                   
               
               
                 129 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 528 
                 NA 
                 — 
               
               
                   
               
               
                 130 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 411 
                 NA 
                 — 
               
               
                   
               
               
                 131 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 432 
                 NA 
                 — 
               
               
                   
               
               
                 132 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 389 
                 NA 
                 — 
               
               
                   
               
               
                 133 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 418 
                 NA 
                 — 
               
               
                   
               
               
                 134 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 409 
                 NA 
                 — 
               
               
                   
               
               
                 135 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 1142 
                 1.67 
                 — 
               
               
                   
               
               
                 136 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 404 
                 2 
                 138 
               
               
                   
               
               
                 137 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 408 
                 2.00 
                 200 
               
               
                   
               
               
                 138 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 408 
                 10 
                 875 
               
               
                   
               
               
                 139 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 560 
                 6.31 
                 980 
               
               
                   
               
               
                 140 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 574 
                 2.82 
                 980 
               
               
                   
               
               
                 141 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 602 
                 0.5 
                 800 
               
               
                   
               
               
                 142 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 400 
                 NA 
                 — 
               
               
                   
               
               
                 143 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 462 
                 NA 
                 — 
               
               
                   
               
               
                 144 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 384 
                 3.16 
                 700 
               
               
                   
               
               
                 145 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 406 
                 1.6 
                 185 
               
               
                   
               
               
                 146 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 588 
                 1.41 
                 940 
               
               
                   
               
               
                 147 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 395 
                 4.47 
                 450 
               
               
                   
               
               
                 148 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 339 
                 35 
                 285 
               
               
                   
               
               
                 149 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 607 
                 0.4 
                 157 
               
               
                   
               
               
                 150 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 375 
                 1.25 
                 135 
               
               
                   
               
               
                 151 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 422 
                 2.5 
                 305 
               
               
                   
               
               
                 152 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 436 
                 2.00 
                 425 
               
               
                   
               
               
                 153 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 394 
                 1.58 
                 178 
               
               
                   
               
               
                 154 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 368 
                 4.47 
                 190 
               
               
                   
               
               
                 155 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 368 
                 1.78 
                 260 
               
               
                   
               
               
                 156 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 386 
                 39.81 
                 220 
               
               
                   
               
               
                 157 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 386 
                 22.38 
                 580 
               
               
                   
               
               
                 158 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 454 
                 39.81 
                 163 
               
               
                   
               
               
                 159 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 454 
                 44.60 
                 242 
               
               
                   
               
               
                 160 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 420 
                 28.18 
                 130 
               
               
                   
               
               
                 161 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 420 
                 39.81 
                 190 
               
               
                   
               
               
                 162 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 454 
                 NA 
                 — 
               
               
                   
               
               
                 163 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 400 
                 25.11 
                 475 
               
               
                   
               
               
                 164 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 400 
                 28.18 
                 425 
               
               
                   
               
               
                 165 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 354 
                 3.98 
                 305 
               
               
                   
               
               
                 166 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 382 
                 6.31 
                 276 
               
               
                   
               
               
                 167 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 362 
                 28.2 
                 250 
               
               
                   
               
               
                 168 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 340 
                 4.0 
                 360 
               
               
                   
               
               
                 169 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 370 
                 15.8 
                 191 
               
               
                   
               
               
                 170 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 405 
                 28.2 
                 740 
               
               
                   
               
               
                 171 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 391 
                 5.0 
                 280 
               
               
                   
               
               
                 172 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 391 
                 8.9 
                 525 
               
               
                   
               
               
                 173 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 377 
                 2.5 
                 260 
               
               
                   
               
               
                 174 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 419 
                 14.1 
                 625 
               
               
                   
               
               
                 175 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 335 
                 NA 
                 — 
               
               
                   
               
               
                 176 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 379 
                 NA 
                 — 
               
               
                   
               
               
                 177 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 407 
                 NA 
                 — 
               
               
                   
               
               
                 178 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 451 
                 NA 
                 — 
               
               
                   
               
               
                 179 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 362 
                 6.31 
                 118 
               
               
                   
               
               
                 180 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 440 
                 NA 
                 — 
               
               
                   
               
               
                 181 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 442 
                 NA 
                 — 
               
               
                   
               
               
                 182 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 357 
                 5.01 
                 225 
               
               
                   
               
               
                 183 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 402 
                 2.5 
                 340 
               
               
                   
               
               
                 184 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 863 
                 2.82 
                 1525 
               
               
                   
               
               
                 185 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413 
                 12.58 
                 210 
               
               
                   
               
               
                 186 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 413 
                 14.12 
                 310 
               
               
                   
               
               
                 187 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 388 
                 0.8 
                 325 
               
               
                   
               
               
                 188 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383 
                 NA 
                 — 
               
               
                   
               
               
                 189 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383 
                 NA 
                 — 
               
               
                   
               
               
                 190 
                 
                   
                     
                     
                         
                         
                     
                   
                 
                 383 
                 NA 
                 — 
               
               
                   
               
            
           
         
       
     
     It will be readily apparent to one skilled in the art that varying substitutions and modifications may be made to the invention disclosed herein without departing from the scope and spirit of the invention. The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention. Thus, it should be understood that although the present invention has been illustrated by specific embodiments and optional features, modification and/or variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention. Citations to a number of patent and non-patent references may be made herein. The cited references are incorporated by reference herein in their entireties. In the event that there is an inconsistency between a definition of a term in the specification as compared to a definition of the term in a cited reference, the term should be interpreted based on the definition in the specification.