CONDURITOL AZIRIDINE DERIVATIVES AND USES THEREOF

Abstract

The present application relates to conduritol aziridines of Formula (I), and uses thereof, for example, of .sup.18F-labelled derivatives thereof in positron-emission tomography (PET) imaging of -glucocerebrosidase activity.

##STR00001##

Claims

1. A compound of Formula I: ##STR00245## wherein R.sup.1 is a group selected from: (CH.sub.2).sub.xCH.sub.2X, ##STR00246## (CH.sub.2).sub.yCHX(CH.sub.2).sub.zCH.sub.3, (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.2X, ##STR00247## x is an integer between 1 and 20; y is an integer between 1 and 10; z is an integer between 1 and 10; w is an integer between 0 and 10; ##STR00248## is aryl or heteroaryl; (i) one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH, and X is H or F; (ii) one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-2cycloalkyl, two or three of the others are OH, optionally one of the others is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, and X is H; (iii) one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F, the others are OH, and X is H; or (iv) all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH, and X is H or F; and F is .sup.19F or .sup.18F; provided that when all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH, R.sup.1 is not (CH.sub.2).sub.xCH.sub.2X, wherein X is H or F; or (CH.sub.2).sub.yCHX(CH.sub.2).sub.zCH.sub.3, wherein X is H.

2. The compound of claim 1, having one or a mixture of both of the following stereochemical configurations: ##STR00249## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined in claim 1.

3. The compound of claim 1, wherein all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH.

4. The compound of claim 3, wherein R.sup.1 is ##STR00250##

5. (canceled)

6. (canceled)

7. The compound of claim 3, wherein R.sup.1 is (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.2X.

8. (canceled)

9. The compound of claim 3, wherein R.sup.1 is: ##STR00251##

10. (canceled)

11. (canceled)

12. The compound of claim 3, wherein R.sup.1 is ##STR00252##

13. (canceled)

14. The compound of claim 12, wherein R.sup.1 is ##STR00253##

15. The compound of claim 1, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl, and the others are OH.

16. (canceled)

17. The compound of claim 1, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F and the others are OH.

18. (canceled)

19. (canceled)

20. (canceled)

21. The compound of claim 1, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.4-20alkyl or OC.sub.4-20cycloalkyl and the others are OH.

22. The compound of claim 21, wherein R.sup.2 is OC.sub.4-12alkyl or OC.sub.4-12cycloalkyl and R.sup.3, R.sup.4 and R.sup.5 are OH.

23. (canceled)

24. (canceled)

25. (canceled)

26. (canceled)

27. The compound of claim 26, wherein x is 3, 5 or 7.

28. (canceled)

29. (canceled)

30. (canceled)

31. (canceled)

32. (canceled)

33. (canceled)

34. The compound of claim 1, wherein F is .sup.19F.

35. The compound of claim 1, wherein F is .sup.18F.

36. (canceled)

37. A method for imaging -glucocerebrosidase activity in a subject, the method comprising: administering a compound as defined in claim 35 to the subject; and detecting the presence of retained radioactivity in the subject using positron-emission tomography (PET).

38. The method of claim 37, wherein the imaging is for diagnosis of a disease associated with decreased -glucocerebrosidase activity.

39. The method of claim 38, wherein the disease is Parkinson's disease or Gaucher disease.

40. (canceled)

41. (canceled)

42. (canceled)

43. The method of claim 37, wherein the imaging is for monitoring the effect on -glucocerebrosidase activity of a therapy for treatment of a disease associated with decreased -glucocerebrosidase activity.

44. (canceled)

45. (canceled)

46. A kit comprising a non-radiolabeled intermediate to the compound as defined in claim 35 and optionally instructions for use of the non-radiolabeled intermediate in the preparation of the compound as defined in claim 35 for positron-emission tomography (PET) imaging of -glucocerebrosidase activity.

47.-52. (canceled)

Description

DRAWINGS

[0061] The embodiments of the application will now be described in greater detail with reference to the attached drawings in which:

[0062] FIG. 1 shows a plot of remaining enzyme activity over time at the indicated inhibitor concentrations fitted to a one phase decay equation for N-octyl conduritol aziridine (top) and a plot of the observed rate constants of inactivation versus the concentration of inhibitor for that compound (bottom).

[0063] FIG. 2 shows a plot of remaining enzyme activity over time at the indicated inhibitor concentrations fitted to a one phase decay equation for a fluorinated conduritol aziridine (top) and a plot of the observed rate constants of inactivation versus the concentration of inhibitor for that compound (bottom).

[0064] FIG. 3 shows a plot of the enzymatic turnover of 4-methylumbelliferyl -D-glucopyranoside by -glucocerebrosidase in the presence of conduritol aziridine derivative S88 to determine K.sub.obs at various inhibitor concentrations vs time (top) and a corresponding secondary plot of K.sub.obs vs concentration of inhibitor for that compound (bottom).

[0065] FIG. 4 shows a plot of the enzymatic turnover of 4-methylumbelliferyl -D-glucopyranoside by -glucocerebrosidase in the presence of conduritol aziridine derivative S91 to determine K.sub.obs at various inhibitor concentrations vs time (top) and a corresponding secondary plot of K.sub.obs vs concentration of inhibitor for that compound (bottom).

[0066] FIG. 5 shows a plot of the enzymatic turnover of 4-methylumbelliferyl -D-glucopyranoside by -glucocerebrosidase in the presence of conduritol aziridine derivative 38 (compound 2.11b) to determine K.sub.obs at various inhibitor concentrations vs time (top) and a corresponding secondary plot of K.sub.obs vs concentration of inhibitor for that compound (bottom).

[0067] FIG. 6 shows a plot of the enzymatic turnover of 4-methylumbelliferyl -D-glucopyranoside by -glucocerebrosidase in the presence of conduritol aziridine derivative S89 to determine K.sub.obs at various inhibitor concentrations vs time (top) and a corresponding secondary plot of K.sub.obs vs concentration of inhibitor for that compound (bottom).

[0068] FIG. 7 shows a plot of the enzymatic turnover of 4-methylumbelliferyl -D-glucopyranoside by -glucocerebrosidase in the presence of conduritol aziridine derivative S90 to determine K.sub.obs at various inhibitor concentrations vs time (top) and a corresponding secondary plot of K.sub.obs vs concentration of inhibitor for that compound (bottom).

[0069] FIG. 8 shows a plot of the enzymatic turnover of 4-methylumbelliferyl -D-glucopyranoside by -glucocerebrosidase in the presence of conduritol aziridine derivative S46 (compound 2.11a) to determine K.sub.obs at various inhibitor concentrations vs time (top) and a corresponding secondary plot of K.sub.obs vs concentration of inhibitor for that compound (bottom).

DETAILED DESCRIPTION

1. Definitions

[0070] Unless otherwise indicated, the definitions and embodiments described in this and other sections are intended to be applicable to all embodiments and aspects of the present application herein described for which they are suitable as would be understood by a person skilled in the art.

[0071] The present application refers to a number of chemical terms and abbreviations used by those skilled in the art. Nevertheless, definitions of selected terms are provided for clarity and consistency.

[0072] As used herein, the words comprising (and any form of comprising, such as comprise and comprises), having (and any form of having, such as have and has), including (and any form of including, such as include and includes) or containing (and any form of containing, such as contain and contains), are inclusive or open-ended and do not exclude additional, unrecited elements or process/method steps. As used herein, the word consisting and its derivatives, are intended to be close ended terms that specify the presence of stated features, elements, components, groups, integers, and/or steps, and also exclude the presence of other unstated features, elements, components, groups, integers and/or steps. The term consisting essentially of, as used herein, is intended to specify the presence of the stated features, elements, components, groups, integers, and/or steps as well as those that do not materially affect the basic and novel characteristic(s) of these features, elements, components, groups, integers, and/or steps.

[0073] Terms of degree such as substantially, about and approximately as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least 5% of the modified term if this deviation would not negate the meaning of the word it modifies.

[0074] As used in this application, the singular forms a, an and the include plural references unless the content clearly dictates otherwise. For example, an embodiment including a compound should be understood to present certain aspects with one compound or two or more additional compounds. In embodiments comprising an additional or second component, such as an additional or second compound, the second component as used herein is chemically different from the other components or first component. A third component is different from the other, first, and second components, and further enumerated or additional components are similarly different.

[0075] The term and/or as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that at least one of or one or more of the listed items is used or present.

[0076] The term suitable as used herein means that the selection of the particular compound or conditions would depend on the specific synthetic manipulation to be performed, and the identity of the molecule(s) to be transformed, but the selection would be well within the skill of a person trained in the art. All process/method steps described herein are to be conducted under conditions for the reaction to proceed to a sufficient extent to provide the product shown. A person skilled in the art would understand that all reaction conditions, including, for example, reaction solvent, reaction time, reaction temperature, reaction pressure, reactant ratio and whether or not the reaction should be performed under an anhydrous or inert atmosphere, can be varied to optimize the yield of the desired product and it is within their skill to do so.

[0077] The expression proceed to a sufficient extent as used herein with reference to the reactions or process/method steps disclosed herein means that the reactions or steps proceed to an extent that conversion of the starting material or substrate to product is maximized. Conversion may be maximized when greater than about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 or 100% of the starting material or substrate is converted to product.

[0078] The term protecting as used herein refers to using a chemical moiety, i.e. a protecting group of PG which protects or masks a reactive portion of a molecule to prevent side reactions in that reactive portion of the molecule, while manipulating or reacting a different portion of the molecule. After the manipulation or reaction is complete, the protecting group is removed under conditions that do not degrade or decompose the remaining portions of the molecule, i.e. the protected reactive portion of the molecule is deprotected. The selection of a suitable protecting group can be made by a person skilled in the art. Many conventional protecting groups are known in the art, for example as described in Protective Groups in Organic Chemistry McOmie, J. F. W. Ed., Plenum Press, 1973, in Greene, T. W. and Wuts, P. G. M., Protective Groups in Organic Synthesis, John Wiley & Sons, 3.sup.rd Edition, 1999 and in Kocienski, P. Protecting Groups, 3rd Edition, 2003, Georg Thieme Verlag (The Americas).

[0079] The term leaving group as used herein refers to a group that is readily displaceable by a nucleophile, for example, under S.sub.N.sup.2 nucleophilic substitution reaction conditions. Examples of suitable leaving groups include OMs. The abbreviation Ms as used herein refers to the group methanesulfonyl.

[0080] The term alkyl as used herein, whether it is used alone or as part of another group, means straight or branched chain, saturated alkyl groups. The number of carbon atoms that are possible in the referenced alkyl group are indicated by the numerical prefix C.sub.n1-n2. For example, the term C.sub.1-20alkyl means an alkyl group having 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms.

[0081] The term aryl as used herein, whether it is used alone or as part of another group, refers to cyclic groups that contain at least one aromatic ring. In an embodiment of the present application, the aryl group contains from 6, 9, 10 or 14 atoms, such as phenyl, naphthyl, indanyl or anthracenyl.

[0082] The term heteroaryl as used herein refers to cyclic groups that contain at least one aromatic ring and at least one heteroatom, such as N, O and/or S. The number of atoms that are possible in the referenced heteroaryl group are indicated by the numerical prefix C.sub.n1-n2. For example, the term C.sub.5-10heteroaryl means an aryl group having 5, 6, 7, 8, 9 or 10 atoms, in which at least one atom is a heteroatom, such as N, O and/or S.

[0083] The term cycloalkyl as used herein, whether it is used alone or as part of another group, means a mono- or bicyclic, saturated cycloalkyl group. The number of carbon atoms that are possible in the referenced cycloalkyl group are indicated by the numerical prefix C.sub.n1-n2. For example, the term C.sub.4-20cycloalkyl means a cycloalkyl group having 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20 carbon atoms. When a cycloalkyl group contains more than one cyclic structure or rings, the cyclic structures are fused, bridged, spiro connected or linked by a single bond. A first cyclic structure being fused with a second cyclic structure means the first cyclic structure and the second cyclic structure share at least two adjacent atoms therebetween. A first cyclic structure being bridged with a second cyclic structure means the first cyclic structure and the second cyclic structure share at least two non-adjacent atoms therebetween. A first cyclic structure being spiro connected with a second cyclic structure means the first cyclic structure and the second cyclic structure share one atom therebetween.

[0084] The structures,

##STR00011##

as used herein include both mono- and bicyclic saturated cycloalkyl groups.

[0085] The term F-substituted as used herein in reference to a group which contains an alkyl means that one of the H atoms in the alkyl group is replaced with F. For example, the term F-substituted OC.sub.1-20alkyl refers to a group in which one of the H atoms in the C.sub.1-20alkyl is replaced with F.

[0086] The term F-substituted as used herein in reference to a group which contains a cycloalkyl means that one of the H atoms in the cycloalkyl group is replaced with F. For example, the term F-substituted OC.sub.4-20cycloalkyl refers to a group in which one of the H atoms in the C.sub.4-20cycloalkyl is replaced with F.

[0087] The term compound of the application and the like as used herein refers to compounds of Formula I, including compounds of Formulae I(a), I(a)(i), (a)(ii), I(b), I(b)(i), I(b)(ii), I(c) and I(d).

[0088] The term .sup.18F labelled compound of the application and the like as used herein refers to compounds of Formulae I (wherein X is F), I(a) (wherein X is F), I(a)(i), I(b) (wherein X is F), I(b)(i), I(c) and I(d), wherein X is .sup.18F.

[0089] The term non-fluorinated compound of the application and the like as used herein refers to compounds of Formulae I (wherein X is H), I(a) (wherein X is H), I(a)(ii), I(b) (wherein X is H) and I(b)(ii).

[0090] The term subject as used herein includes all members of the animal kingdom including mammals. In an embodiment, the subject is a human.

[0091] The term radiopharmaceutically acceptable means compatible with the administration to or use in subjects such as humans for imaging -glucocerebrosidase activity by positron-emission-tomography (PET).

[0092] The term pharmaceutically acceptable means compatible with the administration to or use in cells or subjects such as mammals.

[0093] In embodiments of the present application, the compounds described herein have at least one asymmetric center. Where compounds possess more than one asymmetric center, they may exist as diastereomers. It is to be further understood that while the stereochemistry of the compounds may be as shown in any given compound listed herein, such compounds may also contain certain amounts (e.g. less than 20%, optionally less than 10%, optionally less than 5%, optionally less than 1%) of compounds having alternate stereochemistry.

II. Compounds, Methods of Preparation Thereof and Compositions

[0094] New conduritol aziridine derivatives have been prepared which are inhibitors of the lysosomal enzyme glucocerebrosidase (GCase).

[0095] Accordingly, the present application includes a compound of Formula I:

##STR00012##

wherein

[0096] R.sup.1 is a group selected from:

[0097] (CH.sub.2).sub.xCH.sub.2X,

##STR00013##

[0098] (CH.sub.2).sub.yCHX(CH.sub.2).sub.zCH.sub.3,

[0099] (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.2X,

##STR00014##

[0100] x is an integer between 1 and 20;

[0101] y is an integer between 1 and 10;

[0102] z is an integer between 1 and 10;

[0103] w is an integer between 0 and 10;

##STR00015##

is aryl or heteroaryl;
(i) one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH, and X is H or F;
(ii) one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cyloalkyl, two or three of the others are OH, optionally one of the others is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, and X is H;
(iii) one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F, the others are OH, and X is H; or
(iv) all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH, and X is H or F; and

[0104] F is .sup.19F or .sup.18F;

[0105] provided that when all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH, R.sup.1 is not (CH.sub.2).sub.xCH.sub.2X, wherein X is H or F; or (CH.sub.2).sub.yCHX(CH.sub.2).sub.zCH.sub.3, wherein X is H.

[0106] The present application also includes a compound of Formula I:

##STR00016##

wherein

[0107] R.sup.1 is a group selected from:

[0108] (CH.sub.2).sub.xCH.sub.2X,

##STR00017##

[0109] (CH.sub.2).sub.yCHX(CH.sub.2).sub.zCH.sub.3,

[0110] (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.2X,

##STR00018##

[0111] x is an integer between 1 and 20;

[0112] y is an integer between 1 and 10;

[0113] z is an integer between 1 and 10;

##STR00019##

is aryl or heteroaryl;
(i) one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH, and X is H or F;
(ii) one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl, two or three of the others are OH, optionally one of the others is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, and X is H;
(iii) one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F, the others are OH, and X is H; or
(iv) all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH, and X is H or F; and

[0114] F is .sup.19F or .sup.18F;

[0115] provided that when all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH, R.sup.1 is not (CH.sub.2).sub.xCH.sub.2X, wherein X is H or F; or (CH.sub.2).sub.yCHX(CH.sub.2).sub.zCH.sub.3, wherein X is H.

[0116] In an embodiment, the compound of Formula I has one or is a mixture of both of the following stereochemical configurations:

##STR00020##

wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined for the compound of Formula I.

[0117] In an embodiment, all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH.

[0118] Accordingly, in some embodiments of the present application, the compound of Formula I is a compound of Formula I(a):

##STR00021##

wherein

[0119] R.sup.1 is a group selected from:

##STR00022##

[0120] (CH.sub.2).sub.yCHX(CH.sub.2).sub.zCH.sub.3,

[0121] (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.2X,

##STR00023##

[0122] x is an integer between 1 and 20; [0123] y is an integer between 1 and 10; [0124] z is an integer between 1 and 10; [0125] w is an integer between 0 and 10;

##STR00024##

is aryl or heteroaryl;

[0126] X is H or F; and

[0127] F is .sup.19F or .sup.18F,

[0128] provided that when X is H, R.sup.1 is not (CH.sub.2).sub.yCHX(CH.sub.2).sub.zCH.sub.3.

[0129] In some embodiments of the present application, the compound of Formula I is a compound of Formula I(a):

##STR00025##

wherein

[0130] R.sup.1 is a group selected from:

##STR00026##

[0131] (CH.sub.2).sub.yCHX(CH.sub.2).sub.zCH.sub.3,

[0132] (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.2X,

##STR00027##

[0133] x is an integer between 1 and 20; [0134] y is an integer between 1 and 10; [0135] z is an integer between 1 and 10;

##STR00028##

is aryl or heteroaryl;

[0136] X is H or F; and

[0137] F is .sup.19F or .sup.18F,

[0138] provided that when X is H, R.sup.1 is not (CH.sub.2).sub.yCHX(CH.sub.2).sub.zCH.sub.3.

[0139] In an embodiment, the compound of Formula I(a) has one or is a mixture of both of the following stereochemical configurations:

##STR00029##

wherein R.sup.1 is as defined for the compound of Formula I(a).

[0140] In an embodiment, X is F. Accordingly, in some embodiments of the present application, the compound of Formula I is a compound of Formula I(a)(i):

##STR00030##

wherein

[0141] R.sup.1 is a group selected from:

##STR00031##

[0142] (CH.sub.2).sub.yCHF(CH.sub.2).sub.zCH.sub.3,

[0143] (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.2F,

##STR00032##

is aryl or heteroaryl;

[0144] x is an integer between 1 and 20;

[0145] y is an integer between 1 and 10;

[0146] z is an integer between 1 and 10;

[0147] w is an integer between 0 and 10; and

[0148] F is .sup.19F or .sup.18F.

[0149] In some embodiments of the present application, the compound of Formula I is a compound of Formula I(a)(i):

##STR00033##

wherein

[0150] R.sup.1 is a group selected from:

##STR00034##

[0151] (CH.sub.2).sub.yCHF(CH.sub.2).sub.zCH.sub.3,

[0152] (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.2F,

##STR00035##

is aryl or heteroaryl;

[0153] x is an integer between 1 and 20; [0154] y is an integer between 1 and 10; [0155] z is an integer between 1 and 10; and

[0156] F is .sup.19F or .sup.18F.

[0157] In some embodiments of the compound of Formula I, wherein all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH and X is F and the compound of Formula I(a)(i), R.sup.1 is

##STR00036##

In another embodiment, x is an integer between 1 and 10. In a further embodiment, x is an integer between 2 and 7. In another embodiment of the present application, R.sup.1 is a cyclopentyl or adamantyl group in which one of the hydrogen atoms has been replaced by a fluorine atom.

[0158] In some embodiments of the compound of Formula I, wherein all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH and X is F and the compound of Formula I(a)(i), R.sup.1 is (CH.sub.2).sub.yCHF(CH.sub.2).sub.zCH.sub.3. In another embodiment, y+z is an integer between 2 and 10. In a further embodiment, y+z is an integer between 4 and 7. In another embodiment of the present application, y is 2 and z is 4.

[0159] In an embodiment, the compound of Formula I has the structure:

##STR00037##

[0160] In some embodiments of the compound of Formula I, wherein all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH and X is F and the compound of Formula I(a)(i), R.sup.1 is (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.2F. In another embodiment, y+z is an integer between 2 and 10. In a further embodiment, y+z is an integer between 4 and 7. In another embodiment, y is 2. In a further embodiment, z is 4.

[0161] In some embodiments of the compound of Formula I, wherein all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH and X is F and the compound of Formula I(a)(i), R.sup.1 is

##STR00038##

In another embodiment,

##STR00039##

is aryl. In a further embodiment,

##STR00040##

is phenyl. In another embodiment,

##STR00041##

is C.sub.5-10heteroaryl. In a further embodiment, the heteroatom in the heteroaryl group is nitrogen. In another embodiment,

##STR00042##

is pyridyl. In a further embodiment, y is an integer between 2 and 10. In another embodiment, y is an integer between 4 and 8. In a further embodiment, y is 6.

[0162] In some embodiments of the compound of Formula I, wherein all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH and X is F and the compound of Formula I(a)(i), R.sup.1 is

##STR00043##

In another embodiment,

##STR00044##

is aryl. In a further embodiment,

##STR00045##

is phenyl. In another embodiment,

##STR00046##

is C.sub.5-10heteroaryl. In a further embodiment, the heteroatom in the heteroaryl group is nitrogen. In another embodiment,

##STR00047##

is pyridyl. In another embodiment, R.sup.1 is

##STR00048##

wherein X is F. In a further embodiment, y is an integer between 4 and 10. In another embodiment, y is an integer between 6 and 10. In a further embodiment, y is 8. In another embodiment, w is an integer of between 0 and 4. In a further embodiment, w is 0. In another embodiment, y is an integer between 4 and 10 and w is 0. In a further embodiment, y is an integer between 6 and 10 and w is 0. In another embodiment, y is 8 and w is 0.

[0163] In an embodiment, the compound of Formula I has the structure:

##STR00049##

[0164] In some embodiments of the compound of Formula I, wherein all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH and X is F and the compound of Formula I(a)(i), R.sup.1 is

##STR00050##

In another embodiment, R.sup.1 is

##STR00051##

In a further embodiment, y is an integer between 2 and 8. In another embodiment, y is an integer between 3 and 5. In a further embodiment, y is 4.

[0165] In an embodiment, the compound of Formula I has the structure:

##STR00052##

[0166] In some embodiments of the compound of Formula I, wherein all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH and X is F and the compound of Formula I(a)(i), R.sup.1 is:

##STR00053##

[0167] In some embodiments of the compound of Formula I, wherein all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH and X is F and the compound of Formula I(a)(i), R.sup.1 is

##STR00054##

In another embodiment, y+z is an integer between 2 and 10. In a further embodiment, y+z is an integer between 4 and 7. In another embodiment of the present application, y is 1 and z is 4.

[0168] In some embodiments of the compound of Formula I, wherein all of R.sup.1, R.sup.2, R.sup.3 and R.sup.4 are OH and X is F and the compound of Formula I(a)(i), R.sup.1 is

##STR00055##

In another embodiment, y is an integer between 2 and 10. In a further embodiment, y is an integer between 4 and 6. In another embodiment of the present application, y is 5.

[0169] In an embodiment, X is H. Accordingly, in some embodiments of the present application, the compound of Formula I is a compound of Formula I(a)(ii):

##STR00056##

wherein

[0170] R.sup.1 is a group selected from:

##STR00057##

[0171] (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.3,

##STR00058##

[0172] x is an integer between 1 and 20;

[0173] y is an integer between 1 and 10;

[0174] z is an integer between 1 and 10;

[0175] w is an integer between 0 and 10; and

##STR00059##

is aryl or heteroaryl.

[0176] In some embodiments of the present application, the compound of Formula I is a compound of Formula I(a)(ii):

##STR00060##

wherein

[0177] R.sup.1 is a group selected from:

##STR00061##

[0178] (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.3,

##STR00062##

[0179] x is an integer between 1 and 20;

[0180] y is an integer between 1 and 10;

[0181] z is an integer between 1 and 10; and

##STR00063##

is aryl or heteroaryl.

[0182] In some embodiments of the compound of Formula I, wherein all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH and X is H and the compound of Formula I(a)(ii), R.sup.1 is

##STR00064##

[0183] In some embodiments of the compound of Formula I, wherein all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH and X is H and the compound of Formula I(a)(ii), R.sup.1 is (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.3. In another embodiment, y+z is an integer between 2 and 10. In a further embodiment, y+z is an integer between 4 and 7. In another embodiment, y is 2. In a further embodiment, z is 4.

[0184] In some embodiments of the compound of Formula I, wherein all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH and X is H and the compound of Formula I(a)(ii), R.sup.1 is

##STR00065##

In another embodiment,

##STR00066##

is aryl. In a further embodiment,

##STR00067##

is phenyl. In another embodiment,

##STR00068##

is C.sub.5-10heteroaryl. In a further embodiment, the heteroatom in the heteroaryl group is nitrogen. In another embodiment,

##STR00069##

is pyridyl. In a further embodiment, y is an integer between 2 and 10. In another embodiment, y is an integer between 4 and 8. In a further embodiment, y is 6.

[0185] In some embodiments of the compound of Formula I, wherein all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH and X is H and the compound of Formula I(a)(ii), R.sup.1 is

##STR00070##

In another embodiment,

##STR00071##

is aryl. In a further embodiment,

##STR00072##

is phenyl. In another embodiment,

##STR00073##

is C.sub.5-10heteroaryl. In a further embodiment, the heteroatom in the heteroaryl group is nitrogen. In another embodiment,

##STR00074##

is pyridyl. In another embodiment, R.sup.1 is

##STR00075##

wherein X is H. In a further embodiment, y is an integer between 4 and 10. In another embodiment, y is an integer between 6 and 10. In a further embodiment, y is 8. In another embodiment, w is an integer of between 0 and 4. In a further embodiment, w is 0. In another embodiment, y is an integer between 4 and 10 and w is 0. In a further embodiment, y is an integer between 6 and 10 and w is 0. In another embodiment, y is 8 and w is 0.

[0186] In some embodiments of the compound of Formula I, wherein all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH and X is H and the compound of Formula I(a)(ii), R.sup.1 is

##STR00076##

In another embodiment, y is an integer between 2 and 8. In another embodiment, y is an integer between 3 and 5. In a further embodiment, y is 4.

[0187] In some embodiments of the compound of Formula I, wherein all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH and X is H and the compound of Formula I(a)(i), R.sup.1 is:

##STR00077##

[0188] In some embodiments of the compound of Formula I, wherein all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH and X is H and the compound of Formula I(a)(ii), R.sup.1 is

##STR00078##

In another embodiment, y+z is an integer between 2 and 10. In a further embodiment, y+z is an integer between 4 and 7. In another embodiment of the present application, y is 1 and z is 4.

[0189] In some embodiments of the compound of Formula I, wherein all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH and X is H and the compound of Formula I(a)(ii), R.sup.1 is

##STR00079##

In another embodiment, y is an integer between 2 and 10. In a further embodiment, y is an integer between 4 and 6. In another embodiment of the present application, y is 5.

[0190] Dialkylated conduritol aziridine derivatives were found to be potent inhibitors of GCase in the studies reported herein. Derivatives wherein an additional OH group is converted to an ether form may also be of interest, for example, to reduce total polar surface area and potentially increase brain penetrance. Accordingly, in an embodiment of the present application, one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.4-20alkyl or OC.sub.4-20cycloalkyl and the others are OH.

[0191] Accordingly, in some embodiments of the present application, the compound of Formula I is a compound of Formula I(b):

##STR00080##

wherein

[0192] one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.4-20alkyl or OC.sub.4-20cycloalkyl and the others are OH;

[0193] R.sup.1 is a group selected from:

[0194] (CH.sub.2).sub.xCH.sub.2X,

##STR00081##

[0195] (CH.sub.2).sub.yCHX(CH.sub.2).sub.zCH.sub.3,

[0196] (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.2X,

##STR00082##

[0197] x is an integer between 1 and 20;

[0198] y is an integer between 1 and 10;

[0199] z is an integer between 1 and 10;

[0200] w is an integer between 0 and 10;

##STR00083##

is aryl or heteroaryl;

[0201] X is H or F; and

[0202] F is .sup.19F or .sup.18F.

[0203] In some embodiments of the present application, the compound of Formula I is a compound of Formula I(b):

##STR00084##

wherein

[0204] one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.4-20alkyl or OC.sub.4-20cycloalkyl and the others are OH;

[0205] R.sup.1 is a group selected from:

[0206] (CH.sub.2).sub.xCH.sub.2X,

##STR00085##

[0207] (CH.sub.2).sub.yCHX(CH.sub.2).sub.zCH.sub.3,

[0208] (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.2X,

##STR00086##

[0209] x is an integer between 1 and 20;

[0210] y is an integer between 1 and 10;

[0211] z is an integer between 1 and 10;

##STR00087##

is aryl or heteroaryl;

[0212] X is H or F; and

[0213] F is .sup.19F or .sup.18F.

[0214] In an embodiment, the compound of Formula I(b) has one or is a mixture of both of the following stereochemical configurations:

##STR00088##

wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined for the compound of Formula I(b).

[0215] In an embodiment, X is F. Accordingly, in some embodiments of the present application, the compound of Formula I is a compound of Formula I(b)(i):

##STR00089##

wherein

[0216] one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.4-20alkyl or OC.sub.4-20cycloalkyl and the others are OH;

[0217] R.sup.1 is a group selected from:

[0218] (CH.sub.2).sub.xCH.sub.2F,

##STR00090##

[0219] (CH.sub.2).sub.yCHF(CH.sub.2).sub.zCH.sub.3,

[0220] (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.2F,

##STR00091##

[0221] x is an integer between 1 and 20;

[0222] y is an integer between 1 and 10;

[0223] z is an integer between 1 and 10;

[0224] w is an integer between 0 and 10;

##STR00092##

is aryl or heteroaryl; and

[0225] F is .sup.19F or .sup.18F.

[0226] In some embodiments of the present application, the compound of Formula I is a compound of Formula I(b)(i):

##STR00093##

wherein

[0227] one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.4-20alkyl or OC.sub.4-20cycloalkyl and the others are OH;

[0228] R.sup.1 is a group selected from:

[0229] (CH.sub.2).sub.xCH.sub.2F,

##STR00094##

[0230] (CH.sub.2).sub.yCHF(CH.sub.2).sub.zCH.sub.3,

[0231] (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.2F,

##STR00095##

[0232] x is an integer between 1 and 20;

[0233] y is an integer between 1 and 10;

[0234] z is an integer between 1 and 10;

##STR00096##

is aryl or heteroaryl; and

[0235] F is .sup.19F or .sup.18F.

[0236] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is F and the compound of Formula I(b)(i), R.sup.1 is (CH.sub.2).sub.xCH.sub.2F. In another embodiment, x is an integer between 2 and 10. In another embodiment, x is an integer between 3 and 7. In a further embodiment, x is 3. In another embodiment, x is 7. In another embodiment, x is 5.

[0237] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is F and the compound of Formula I(b)(i), R.sup.1 is

##STR00097##

In another embodiment, x is an integer between 1 and 10. In a further embodiment, x is an integer between 2 and 7. In another embodiment, R.sup.5 is a cyclopentyl or adamantyl group in which one of the hydrogen atoms has been replaced by a fluorine atom.

[0238] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is F and the compound of Formula I(b)(i), R.sup.1 is (CH.sub.2).sub.yCHF(CH.sub.2).sub.zCH.sub.3. In another embodiment, y+z is an integer between 2 and 10. In a further embodiment, y+z is an integer between 4 and 7. In another embodiment, y is 2 and z is 4.

[0239] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is F and the compound of Formula I(b)(i), R.sup.1 is (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.2F. In another embodiment, y+z is an integer between 2 and 10. In a further embodiment, y+z is an integer between 4 and 7. In another embodiment of the present application, y is 2. In a further embodiment, z is 4.

[0240] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is F and the compound of Formula I(b)(i), R.sup.1 is

##STR00098##

In another embodiment,

##STR00099##

is aryl. In a further embodiment,

##STR00100##

is phenyl. In another embodiment,

##STR00101##

is C.sub.5-10 heteroaryl. In a further embodiment, the heteroatom in the heteroaryl group is nitrogen. In another embodiment,

##STR00102##

is pyridyl. In a further embodiment, y is an integer between 2 and 10. In another embodiment, y is an integer between 4 and 8. In a further embodiment, y is 6.

[0241] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is F and the compound of Formula I(b)(i), R.sup.1 is

##STR00103##

In another embodiment,

##STR00104##

is aryl. In a further embodiment,

##STR00105##

is phenyl. In another embodiment,

##STR00106##

is C.sub.5-10heteroaryl. In a further embodiment, the heteroatom in the heteroaryl group is nitrogen. In another embodiment,

##STR00107##

is pyridyl. In another embodiment, R.sup.1 is

##STR00108##

[0242] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is F and the compound of Formula I(b)(i), R.sup.1 is

##STR00109##

In another embodiment, R.sup.1 is

##STR00110##

In a further embodiment, y is an integer between 2 and 8. In another embodiment of the present application, y is an integer between 3 and 5. In a further embodiment, y is 4.

[0243] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is F and the compound of Formula I(b)(i), R.sup.1 is:

##STR00111##

[0244] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is F and the compound of Formula I(b)(i), R.sup.1 is

##STR00112##

In another embodiment, y+z is an integer between 2 and 10. In a further embodiment, y+z is an integer between 4 and 7. In another embodiment, y is 1 and z is 4.

[0245] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is F and the compound of Formula I(b)(i), R.sup.1 is

##STR00113##

In another embodiment, y is an integer between 2 and 10. In a further embodiment, y is an integer between 4 and 6. In another embodiment, y is 5.

[0246] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is F and the compound of Formula I(b)(i), one or both of R.sup.2 and R.sup.4 are OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl and the others of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH. In another embodiment, R.sup.2 is OC.sub.4-12alkyl or OC.sub.4-12cycloalkyl, R.sup.4 is OC.sub.1-4alkyl and R.sup.3 and R.sup.5 are OH. In a further embodiment, R.sup.2 is OC.sub.4-10alkyl or OC.sub.4-12cycloalkyl, R.sup.4 is OCH.sub.3 and R.sup.3 and R.sup.5 are OH. In another embodiment of the present application, R.sup.2 is O-n-hexyl, O-n-octyl, O-isopropyl, O-isobutyl, O cyclopentyl or O-adamantyl, R.sup.4 is OCH.sub.3 and R.sup.3 and R.sup.5 are OH. In a further embodiment, R.sup.2 is O-n-hexyl, R.sup.4 is OCH.sub.3 and R.sup.3 and R.sup.5 are OH.

[0247] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is F and the compound of Formula I(b)(i), R.sup.2 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl and R.sup.3, R.sup.4 and R.sup.5 are OH. In another embodiment, R.sup.2 is OC.sub.4-12alkyl or OC.sub.4-12cycloalkyl, and R.sup.3, R.sup.4 and R.sup.5 are OH. In a further embodiment, R.sup.2 is OC.sub.4-10alkyl or OC.sub.4-12cycloalkyl, and R.sup.3, R.sup.4 and R.sup.5 are OH. In another embodiment of the present application, R.sup.2 is O-n-hexyl, O-n-octyl, O-isopropyl, O-isobutyl, O-cyclopentyl or O-adamantyl, and R.sup.3, R.sup.4 and R.sup.5 are OH. In a further embodiment, R.sup.2 is linear C.sub.4-8alkyl and R.sup.3, R.sup.4 and R.sup.5 are OH. In another embodiment, R.sup.2 is O(CH.sub.2).sub.3CH.sub.3, O(CH.sub.2).sub.5CH.sub.3 or O(CH.sub.2).sub.7CH.sub.3 and R.sup.3, R.sup.4 and R.sup.5 are OH. In a further embodiment, R.sup.2 is O(CH.sub.2).sub.7CH.sub.3 and R.sup.3, R.sup.4 and R.sup.5 are OH. In a further embodiment, R.sup.2 is O(CH.sub.2).sub.3CH.sub.3 and R.sup.3, R.sup.4 and R.sup.5 are OH. In another embodiment, R.sup.2 is O(CH.sub.2).sub.5CH.sub.3 and R.sup.3, R.sup.4 and R.sup.5 are OH.

[0248] In an embodiment, the compound of Formula I has the structure:

##STR00114##

[0249] In an embodiment, the compound of Formula I has the structure:

##STR00115##

[0250] In an embodiment, X is H. Accordingly, in some embodiments of the present application, the compound of Formula I is a compound of Formula I(b)(ii):

##STR00116##

wherein

[0251] one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.4-20alkyl or OC.sub.4-20cycloalkyl and the others are OH;

[0252] R.sup.1 is a group selected from:

[0253] (CH.sub.2).sub.xCH.sub.3,

##STR00117##

[0254] (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.3,

##STR00118##

[0255] x is an integer between 1 and 20; [0256] y is an integer between 1 and 10; [0257] z is an integer between 1 and 10; [0258] w is an integer between 0 and 10; and

##STR00119##

is aryl or heteroaryl.

[0259] In some embodiments of the present application, the compound of Formula I is a compound of Formula I(b)(ii):

##STR00120##

wherein

[0260] one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.4-20alkyl or OC.sub.4-20cycloalkyl and the others are OH;

[0261] R.sup.1 is a group selected from:

[0262] (CH.sub.2).sub.xCH.sub.3,

##STR00121##

[0263] (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.3,

##STR00122##

[0264] x is an integer between 1 and 20;

[0265] y is an integer between 1 and 10;

[0266] z is an integer between 1 and 10; and

##STR00123##

is aryl or heteroaryl.

[0267] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is H and the compound of Formula I(b)(ii), R.sup.1 is (CH.sub.2).sub.xCH.sub.3. In another embodiment, x is an integer between 2 and 10. In another embodiment, x is an integer between 3 and 7. In a further embodiment, x is 3. In another embodiment, x is 7. In another embodiment, x is 5.

[0268] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is H and the compound of Formula I(b)(ii), R.sup.1 is

##STR00124##

In another embodiment, x is an integer between 1 and 10. In a further embodiment, x is an integer between 2 and 7. In another embodiment, R.sup.5 is a cyclopentyl or adamantyl.

[0269] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is H and the compound of Formula I(b)(ii), R.sup.1 is (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.3. In another embodiment, y+z is an integer between 2 and 10. In a further embodiment, y+z is an integer between 4 and 7. In another embodiment of the present application, y is 2. In a further embodiment, z is 4.

[0270] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is H and the compound of Formula I(b)(ii), R.sup.1 is

##STR00125##

In another embodiment,

##STR00126##

is aryl. In a further embodiment,

##STR00127##

is phenyl. In another embodiment,

##STR00128##

is C.sub.5-10heteroaryl. In a further embodiment, the heteroatom in the heteroaryl group is nitrogen. In another embodiment,

##STR00129##

is pyridyl. In a further embodiment, y is an integer between 2 and 10. In another embodiment, y is an integer between 4 and 8. In a further embodiment, y is 6.

[0271] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is H and the compound of Formula I(b)(ii), R.sup.1 is

##STR00130##

In another embodiment,

##STR00131##

is aryl. In a further embodiment,

##STR00132##

is phenyl. In another embodiment,

##STR00133##

is C.sub.5-10heteroaryl. In a further embodiment, the heteroatom in the heteroaryl group is nitrogen. In another embodiment,

##STR00134##

is pyridyl. In another embodiment, R.sup.1 is

##STR00135##

[0272] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is H and the compound of Formula I(b)(ii), R.sup.1 is

##STR00136##

In a further embodiment, y is an integer between 2 and 8. In another embodiment of the present application, y is an integer between 3 and 5. In a further embodiment, y is 4.

[0273] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is H and the compound of Formula I(b)(ii), R.sup.1 is:

##STR00137##

[0274] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is H and the compound of Formula I(b)(ii), R.sup.1 is

##STR00138##

In another embodiment, y+z is an integer between 2 and 10. In a further embodiment, y+z is an integer between 4 and 7. In another embodiment, y is 1 and z is 4.

[0275] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is H and the compound of Formula I(b)(ii), R.sup.1 is

##STR00139##

In another embodiment, y is an integer between 2 and 10. In a further embodiment, y is an integer between 4 and 6. In another embodiment, y is 5.

[0276] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is H and the compound of Formula I(b)(ii), one or both of R.sup.2 and R.sup.4 are OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl and the others of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH. In another embodiment, R.sup.2 is OC.sub.4-12alkyl or OC.sub.4-12cycloalkyl, R.sup.4 is OC.sub.1-4alkyl and R.sup.3 and R.sup.5 are OH. In a further embodiment, R.sup.2 is OC.sub.4-10alkyl or OC.sub.4-12cycloalkyl, R.sup.4 is OCH.sub.3 and R.sup.3 and R.sup.5 are OH. In another embodiment of the present application, R.sup.2 is O-n-hexyl, O-n-octyl, O-isopropyl, O-isobutyl, O-cyclopentyl or O-adamantyl, R.sup.4 is OCH.sub.3 and R.sup.2 and R.sup.4 are OH. In a further embodiment, R.sup.2 is O-n-hexyl, R.sup.4 is OCH.sub.3 and R.sup.3 and R.sup.5 are OH.

[0277] In an embodiment, the compound of Formula I has the structure:

##STR00140##

[0278] In some embodiments of the compound of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, the others are OH and X is H and the compound of Formula I(b)(ii), R.sup.2 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl and R.sup.3, R.sup.4 and R.sup.5 are OH. In another embodiment, R.sup.2 is OC.sub.4-12alkyl or OC.sub.4-12cycloalkyl, and R.sup.3, R.sup.4 and R.sup.5 are OH. In a further embodiment, R.sup.2 is OC.sub.4-10alkyl or OC.sub.4-12cycloalkyl, and R.sup.3, R.sup.4 and R.sup.5 are OH. In another embodiment of the present application, R.sup.2 is O-n-hexyl, O-n-octyl, O-isopropyl, O-isobutyl, O-cyclopentyl or O-adamantyl, and R.sup.3, R.sup.4 and R.sup.5 are OH. In a further embodiment, R.sup.2 is linear C.sub.4-8-alkyl and R.sup.3, R.sup.4 and R.sup.5 are OH. In another embodiment, R.sup.2 is O(CH.sub.2).sub.3CH.sub.3, O(CH.sub.2).sub.5CH.sub.3 or O(CH.sub.2).sub.7CH.sub.3 and R.sup.3, R.sup.4 and R.sup.5 are OH. In a further embodiment, R.sup.2 is O(CH.sub.2).sub.7CH.sub.3 and R.sup.3, R.sup.4 and R.sup.5 are OH. In a further embodiment, R.sup.2 is O(CH.sub.2).sub.3CH.sub.3 and R.sup.3, R.sup.4 and R.sup.5 are OH. In another embodiment, R.sup.2 is O(CH.sub.2).sub.5CH.sub.3 and R.sup.3, R.sup.4 and R.sup.5 are OH.

[0279] In an embodiment, the compound of Formula I is selected from:

##STR00141##

[0280] In an embodiment, the compound of Formula I has the structure:

##STR00142##

[0281] In an embodiment, the compound of Formula I has the structure:

##STR00143##

[0282] In an embodiment, the compound of Formula I has the structure:

##STR00144##

[0283] In an embodiment, the compound of Formula I has the structure:

##STR00145##

[0284] In an embodiment, the compound of Formula I has the structure:

##STR00146##

[0285] In an embodiment, the compound of Formula I has the structure:

##STR00147##

[0286] Alternatively, the fluorinated label may be on a substituent attached to an oxygen rather than the substituent attached to the nitrogen. Accordingly, in an embodiment, one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl, two or three of the others are OH, optionally one of the others is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, and X is H.

[0287] Accordingly, in some embodiments of the present application, the compound of Formula I is a compound of Formula I(c):

##STR00148##

wherein

[0288] one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl, two or three of the others are OH, and optionally one of the others is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl;

[0289] R.sup.1 is a group selected from:

[0290] (CH.sub.2).sub.xCH.sub.3,

##STR00149##

[0291] (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.3,

##STR00150##

[0292] x is an integer between 1 and 20;

[0293] y is an integer between 1 and 10;

[0294] z is an integer between 1 and 10;

[0295] w is an integer between 0 and 10; and

##STR00151##

is aryl or heteroaryl.

[0296] In some embodiments of the present application, the compound of Formula I is a compound of Formula I(c):

##STR00152##

wherein

[0297] one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl, two or three of the others are OH, and optionally one of the others is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl;

[0298] R.sup.1 is a group selected from:

[0299] (CH.sub.2).sub.xCH.sub.3,

##STR00153##

[0300] (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.3,

##STR00154##

[0301] x is an integer between 1 and 20;

[0302] y is an integer between 1 and 10;

[0303] z is an integer between 1 and 10; and

##STR00155##

is aryl or heteroaryl.

[0304] In an embodiment, the compound of Formula I(c) has one or is a mixture of both of the following stereochemical configurations:

##STR00156##

wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined for the compound of Formula I(c).

[0305] In some embodiments of the compound of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl, two or three of the others are OH, optionally one of the others is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, and X is H and the compound of Formula I(c), R.sup.1 is (CH.sub.2).sub.xCH.sub.3. In another embodiment, x is an integer between 2 and 10. In another embodiment, x is an integer between 3 and 7. In a further embodiment, x is 3. In another embodiment, x is 7. In another embodiment, x is 5.

[0306] In some embodiments of the compound of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl, two or three of the others are OH, optionally one of the others is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, and X is H and the compound of Formula I(c), R.sup.1 is

##STR00157##

In another embodiment, x is an integer between 1 and 10. In a further embodiment, x is an integer between 2 and 7. In another embodiment, R.sup.1 is a cyclopentyl or adamantyl.

[0307] In some embodiments of the compound of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl, two or three of the others are OH, optionally one of the others is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, and X is H and the compound of Formula I(c), R.sup.1 is (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.3. In another embodiment, y+z is an integer between 2 and 10. In a further embodiment, y+z is an integer between 4 and 7. In another embodiment of the present application, y is 2. In a further embodiment, z is 4.

[0308] In some embodiments of the compound of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl, two or three of the others are OH, optionally one of the others is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, and X is H and the compound of Formula I(c), R.sup.1 is

##STR00158##

In another embodiment,

##STR00159##

is aryl. In a further embodiment,

##STR00160##

is phenyl. In another embodiment,

##STR00161##

is C.sub.5-10heteroaryl. In a further embodiment, the heteroatom in the heteroaryl group is nitrogen. In another embodiment,

##STR00162##

is pyridyl. In a further embodiment, y is an integer between 2 and 10. In another embodiment, y is an integer between 4 and 8. In a further embodiment, y is 6.

[0309] In some embodiments of the compound of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl, two or three of the others are OH, optionally one of the others is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, and X is H and the compound of Formula I(c), R.sup.1 is

##STR00163##

In another embodiment,

##STR00164##

is aryl. In a further embodiment,

##STR00165##

is phenyl. In another embodiment,

##STR00166##

is C.sub.5-10heteroaryl. In a further embodiment, the heteroatom in the heteroaryl group is nitrogen. In another embodiment,

##STR00167##

is pyridyl. In another embodiment, R.sup.1 is

##STR00168##

[0310] In some embodiments of the compound of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl, two or three of the others are OH, optionally one of the others is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, and X is H and the compound of Formula I(c), R.sup.1 is

##STR00169##

In a further embodiment, y is an integer between 2 and 8. In another embodiment of the present application, y is an integer between 3 and 5. In a further embodiment, y is 4.

[0311] In some embodiments of the compound of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl, two or three of the others are OH, optionally one of the others is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, and X is H and the compound of Formula I(c), R.sup.1 is:

##STR00170##

[0312] In some embodiments of the compound of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl, two or three of the others are OH, optionally one of the others is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, and X is H and the compound of Formula I(c), R.sup.1 is

##STR00171##

In another embodiment, y+z is an integer between 2 and 10. In a further embodiment, y+z is an integer between 4 and 7. In another embodiment, y is 1 and z is 4.

[0313] In some embodiments of the compound of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl, two or three of the others are OH, optionally one of the others is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, and X is H and the compound of Formula I(c), R.sup.1 is

##STR00172##

In another embodiment, y is an integer between 2 and 10. In a further embodiment, y is an integer between 4 and 6. In another embodiment, y is 5.

[0314] In some embodiments of the compound of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl, two or three of the others are OH, optionally one of the others is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, and X is H and the compound of Formula I(c), R.sup.2 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl and R.sup.3, R.sup.4 and R.sup.5 are OH. In another embodiment, R.sup.2 is F-substituted OC.sub.4-12alkyl or F-substituted OC.sub.4-12cycloalkyl, and R.sup.3, R.sup.4 and R.sup.5 are OH. In a further embodiment, R.sup.2 is F-substituted OC.sub.4-10alkyl or F-substituted OC.sub.4-12cycloalkyl, and R.sup.3, R.sup.4 and R.sup.5 are OH. In another embodiment, R.sup.2 is F-substituted O-n-hexyl, O-n-octyl, O-isopropyl, O-isobutyl, O-cyclopentyl or O-adamantyl, and R.sup.3, R.sup.4 and R.sup.5 are OH. In a further embodiment, R.sup.2 is F-substituted linear C.sub.4-8alkyl and R.sup.3, R.sup.4 and R.sup.5 are OH. In another embodiment, R.sup.2 is O(CH.sub.2).sub.3CH.sub.2F, O(CH.sub.2).sub.5CH.sub.2F or O(CH.sub.2).sub.7CH.sub.2F and R.sup.3, R.sup.4 and R.sup.5 are OH. In a further embodiment, R.sup.2 is O(CH.sub.2).sub.7CH.sub.2F and R.sup.3, R.sup.4 and R.sup.5 are OH. In a further embodiment, R.sup.2 is O(CH.sub.2).sub.3CH.sub.2F and R.sup.3, R.sup.4 and R.sup.5 are OH. In another embodiment, R.sup.2 is O(CH.sub.2).sub.5CH.sub.2F and R.sup.3, R.sup.4 and R.sup.5 are OH. In some embodiments of the compound of Formula I, one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl, the others are OH and X is H and the compound of Formula I(c), one of the OH groups in R.sup.3, R.sup.4 or R.sup.5 is replaced with OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl. In another embodiment, R.sup.4 is replaced with OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl. In a further embodiment, R.sup.4 is replaced with OC.sub.1-12alkyl. In another embodiment of the present application, R.sup.4 is replaced with OCH.sub.3.

[0315] In an embodiment, the compound of Formula I has the structure:

##STR00173##

[0316] In an embodiment, the compound of Formula I has the structure:

##STR00174##

[0317] In some embodiments, an OH group on the inositol ring is replaced with .sup.18F. For example, such radiolabeled compounds may be prepared by radiolabeling the desired precursor using .sup.18F-PyFluor. Accordingly, in an embodiment, one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F and the others are OH.

[0318] Accordingly, in some embodiments of the present application, the compound of Formula I is a compound of Formula I(d):

##STR00175##

wherein

[0319] one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F and the others are OH;

[0320] R.sup.1 is a group selected from:

[0321] (CH.sub.2).sub.xCH.sub.3,

##STR00176##

[0322] (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.3,

##STR00177##

[0323] x is an integer between 1 and 20;

[0324] y is an integer between 1 and 10;

[0325] z is an integer between 1 and 10;

[0326] w is an integer between 0 and 10;

##STR00178##

is aryl or heteroaryl; and

[0327] F is .sup.19F or .sup.18F.

[0328] In some embodiments of the present application, the compound of Formula I is a compound of Formula I(d):

##STR00179##

wherein

[0329] one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F and the others are OH; R.sup.1 is a group selected from:

[0330] (CH.sub.2).sub.xCH.sub.3,

##STR00180##

[0331] (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.3,

##STR00181##

[0332] x is an integer between 1 and 20;

[0333] y is an integer between 1 and 10;

[0334] z is an integer between 1 and 10;

##STR00182##

is aryl or heteroaryl; and

[0335] F is .sup.19F or .sup.18F.

[0336] In an embodiment, the compound of Formula I(d) has one or is a mixture of both of the following stereochemical configurations:

##STR00183##

wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are as defined for the compound of Formula I(d).

[0337] In some embodiments of the compound of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F and the others are OH and the compound of Formula I(d), R.sup.1 is (CH.sub.2).sub.xCH.sub.3. In another embodiment, x is an integer between 3 and 11. In a further embodiment, x is an integer between 5 and 8.

[0338] In some embodiments of the compound of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F and the others are OH and the compound of Formula I(d), R.sup.1 is

##STR00184##

In another embodiment, x is an integer between 1 and 10. In a further embodiment, x is an integer between 2 and 7. In another embodiment of the present application, R.sup.5 is a cyclopentyl or adamantyl group.

[0339] In some embodiments of the compound of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F and the others are OH and the compound of Formula I(d), R.sup.1 is (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.3. In another embodiment, y+z is an integer between 2 and 10. In a further embodiment, y+z is an integer between 4 and 7. In another embodiment of the present application, y is 2. In a further embodiment, z is 4.

[0340] In some embodiments of the compound of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F and the others are OH and the compound of Formula I(d), R.sup.1 is

##STR00185##

In another embodiment,

##STR00186##

is aryl. In a further embodiment,

##STR00187##

is phenyl. In another embodiment,

##STR00188##

is C.sub.5-10heteroaryl. In a further embodiment, the heteroatom in the heteroaryl group is nitrogen. In another embodiment,

##STR00189##

is pyridyl. In a further embodiment, y is an integer between 2 and 10. In another embodiment, y is an integer between 4 and 8. In a further embodiment, y is 6.

[0341] In some embodiments of the compound of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F and the others are OH and the compound of Formula I(d), R.sup.1 is

##STR00190##

In another embodiment,

##STR00191##

is aryl. In a further embodiment,

##STR00192##

is phenyl. In another embodiment,

##STR00193##

is C.sub.5-10heteroaryl. In a further embodiment, the heteroatom in the heteroaryl group is nitrogen. In another embodiment,

##STR00194##

is pyridyl. In another embodiment, R.sup.1 is

##STR00195##

[0342] In some embodiments of the compound of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F and the others are OH and the compound of Formula I(d), R.sup.1 is

##STR00196##

In a further embodiment, y is an integer between 2 and 8. In another embodiment of the present application, y is an integer between 3 and 5. In a further embodiment, y is 4.

[0343] In some embodiments of the compound of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F and the others are OH and the compound of Formula I(d), R.sup.1 is:

##STR00197##

[0344] In some embodiments of the compound of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F and the others are OH and the compound of Formula I(d), R.sup.1 is

##STR00198##

In another embodiment, y+z is an integer between 2 and 10. In a further embodiment, y+z is an integer between 4 and 7. In another embodiment of the present application, y is 1 and z is 4.

[0345] In some embodiments of the compound of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F and the others are OH and the compound of Formula I(d), R.sup.1 is

##STR00199##

In another embodiment, y is an integer between 2 and 10. In a further embodiment, y is an integer between 4 and 6. In another embodiment of the present application, y is 5.

[0346] In some embodiments of the compound of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F and the others are OH and the compound of Formula I(d), R.sup.2 is F and R.sup.3, R.sup.4 and R.sup.5 are OH.

[0347] In an embodiment of the compounds of Formulae I (wherein X is F), I(a) (wherein X is F), I(a)(i), I(b) (wherein X is F), I(b)(i), I(c) and I(d), X is .sup.18F.

[0348] In an embodiment of the compounds of Formulae I (wherein X is F), I(a) (wherein X is F), I(a)(i), I(b) (wherein X is F), I(b)(i), I(c) and I(d), X is .sup.19F.

[0349] In some embodiments, compounds of Formula I, wherein R.sup.1 is (CH.sub.2).sub.xCH.sub.3 or

##STR00200##

wherein x is as defined herein for the compound of Formula I are prepared via the reaction of the desired conduritol aziridine intermediate having suitable protecting groups with the desired S.sub.N2 electrophile followed by deprotection under suitable conditions to obtain the compound of Formula I. In an embodiment, the S.sub.N.sup.2 electrophile is Z(CH.sub.2).sub.xCH.sub.3 or

##STR00201##

wherein Z is halo and x is as defined herein for the compounds of Formula I. In another embodiment of the present application, Z is bromo or iodo.

[0350] In some embodiments, compounds of Formula I, wherein R.sup.1 is (CH.sub.2).sub.xCH.sub.2F,

##STR00202##

or (CH.sub.2).sub.yCHF(CH.sub.2).sub.zCH.sub.3, wherein x, y and z are as defined herein for the compound of Formula I are prepared via the reaction of the desired conduritol aziridine intermediate having suitable protecting groups with the desired S.sub.N2 electrophile comprising an OH group at the position where the F will ultimately be, reacting the product thereby obtained with a reagent which will provide, together with the oxygen from the OH group, a suitable leaving group (e.g. a source of methanesulfonyl, tosyl and triflyl), reacting the product thereby obtained with a suitable source of F, followed by deprotection under suitable conditions to obtain the compound of Formula I. In an embodiment, the S.sub.N.sup.2 electrophile is Z(CH.sub.2).sub.xCH.sub.2OH,

##STR00203##

or (CH.sub.2).sub.yCH(OH)(CH.sub.2).sub.zCH.sub.3, wherein Z is halo and x, y and z are as defined herein for the compounds of Formula I. In another embodiment of the present application, Z is bromo or iodo.

[0351] In some embodiments, compounds of Formula I, wherein R.sup.1 is (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.3, are prepared via the reaction of the desired conduritol aziridine intermediate having suitable protecting groups with Michael acceptors such as vinyl cyanide or nitro propene followed by reduction to the primary amine then reductive amination with an aldehyde of the desired chain length followed by deprotection under suitable conditions to obtain the compound of Formula I.

[0352] In some embodiments, compounds of Formula I, wherein R.sup.1 is (CH.sub.2).sub.yNH(CH.sub.2).sub.zCH.sub.2F are prepared via the reaction of the desired conduritol aziridine intermediate having suitable protecting groups with Michael acceptors such as vinyl cyanide or nitro propene followed by reduction to the primary amine then reductive amination with the desired aldehyde, conjugating the product thereby obtained with a prosthetic for labelling followed by treating the product thereby obtained with a suitable source of F, followed by deprotection under suitable conditions to obtain the compound of Formula I.

[0353] In some embodiments, compounds of Formula I, wherein R.sup.1 is

##STR00204##

are prepared via the reaction of the desired conduritol aziridine intermediate having suitable protecting groups with the corresponding S.sub.N2 electrophile having the structure

##STR00205##

wherein Z is halo and y is as defined herein for the compounds of Formula I (such as 1-bromo-4-phenyl-hexane, -pentane, -butane, or -propane) in the presence of base followed by deprotection under suitable conditions to obtain the compound of Formula I.

[0354] In some embodiments, compounds of Formula I, wherein R.sup.1 is

##STR00206##

are prepared via the reaction of the corresponding conduritol aziridine intermediate, wherein R.sup.1 is

##STR00207##

with a suitable reagent for replacing an H of the

##STR00208##

group with F (for example, a hypervalent iodine-based reagent.sup.62) or alternatively via the reaction of the corresponding conduritol aziridine intermediate, wherein R.sup.1 is

##STR00209##

with a suitable reagent for replacing the NO.sub.2 moiety with F (for example, a reagent suitable for S.sub.NAr reactions with .sup.18F similar to those used in the preparation of .sup.18F-nifene) followed by deprotection, if required, under suitable conditions to obtain the compound of Formula I.

[0355] In some embodiments, compounds of Formula I, wherein R.sup.1 is

##STR00210##

and y, w and

##STR00211##

are as defined for the compounds of Formula I can be prepared via the reaction of the of the following compound:

##STR00212##

wherein PG is a suitable leaving group, with

##STR00213##

wherein LG is a suitable leaving group (such as O-tosyl) followed by deprotection under suitable conditions to obtain the compound of Formula I. In some embodiments PG is MOM. In other embodiments, PG is another protecting group such as methoxy ethyl ethers (MEM) which require more reactive agents or longer reaction times to be removed (e.g. TFA and TMSBr) than MOM ethers. Accordingly, in some embodiments of the present application, PG is MEM.

[0356] In some embodiments, compounds of Formula I, wherein R.sup.1 is

##STR00214##

X is F and y, w and

[0357] ##STR00215##

are as defined for the compounds of Formula I can be prepared via the reaction of the of the following compound:

##STR00216##

wherein PG is a suitable leaving group, with

##STR00217##

followed by replacement of the NO.sub.2 group using a suitable source of F such as KF under suitable conditions (for example, KF/Kytofix in DMSO at about 160 C. for a time of about 5 hours) followed by deprotection to obtain the compound of Formula I. In some embodiments, PG is MOM. In embodiments wherein F is not .sup.18F, other protecting groups such as methoxy ethyl ethers (MEM) may be used but require more reactive agents or longer reaction times to be removed (e.g. TFA and TMSBr) than MOM ethers. Accordingly, in some embodiments of the present application, PG is MEM.

[0358] In some embodiments, compounds of Formula I, wherein R.sup.1 is

##STR00218##

wherein X is H or F and y is as defined for the compounds of Formula I can be prepared via the reaction of the desired conduritol aziridine intermediate, optionally having suitable protecting groups with the desired S.sub.N2 electrophile comprising an acetylene moiety followed by Sonogashira coupling with the desired reagent and, if required, deprotection under suitable conditions to obtain the compound of Formula I. In an embodiment, the S.sub.N.sup.2 electrophile comprising an acetylene moiety has the formula

##STR00219##

wherein Z is halo and y is as defined herein for the compounds of Formula I. In another embodiment of the present application, Z is bromo or iodo. In an embodiment, X is F and the desired reagent for Sonogashira coupling is 4-fluoroiodobenzene.

[0359] In some embodiments, compounds of Formula I, wherein R.sup.1 is

##STR00220##

wherein X is H or F and y and z are as defined herein for the compound of Formula I are prepared by a method comprising copper-catalyzed click chemistry. In some embodiments, such compounds of Formula I are prepared via the reaction of the desired conduritol aziridine intermediate having suitable protecting groups with the desired S.sub.N2 electrophile comprising an acetylene moiety followed by copper-catalyzed click chemistry with the desired azide-containing reagent and deprotection under suitable conditions to obtain the compound of Formula I. In an embodiment, the S.sub.N.sup.2 electrophile comprising an acetylene moiety has the formula

##STR00221##

wherein Z is halo and y is as defined herein for the compounds of Formula I. In another embodiment of the present application, Z is bromo or iodo. Suitable reagents for copper-catalyzed click chemistry are known and can be selected by a person skilled in the art. In an embodiment, the conditions for the copper-catalyzed click chemistry comprise reaction in the presence of sodium ascorbate and a copper catalyst (e.g. CuSO.sub.4) in a suitable solvent such as DMF:H.sub.2O.

[0360] In some embodiments, compounds of Formula I, wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F are prepared via the reaction of the corresponding conduritol aziridine intermediate wherein the desired R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OH and the others are protected with a suitable protecting group with a suitable reagent for replacing the desired OH with F followed by deprotection under suitable conditions to obtain the compound of Formula I. In an embodiment, the reagent is PyFluor.sup.63

[0361] The appropriate conduritol aziridine intermediate will depend, for example, on whether all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH (or similarly where one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is ultimately F, and the others are OH) versus where one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, and the others are OH or where one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl, two or three of the others are OH, and optionally one of the others is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl.

[0362] In some embodiments, compounds of Formula I, wherein all of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 are OH (or similarly where one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is ultimately F, and the others are OH) are prepared via use of the following intermediate compound:

##STR00222##

which in some embodiments of the present application, has one or both of the following stereochemical configurations:

##STR00223##

[0363] The intermediate compound in the paragraph hereinabove may be prepared, for example, according to the synthetic route in the concurrently filed application entitled FLUORINATED N-ALKYL CONDURITOL AZIRIDINES, PROCESSES FOR THE PREPARATION THEREOF AND THEIR USE IN POSITRON-EMISSION TOMOGRAPHY (PET) IMAGING which claims the benefit of priority from co-pending U.S. provisional application No. 62/574,563 filed on Oct. 19, 2017. In embodiments wherein F is not .sup.18F, other protecting groups such as methoxy ethyl ethers (MEM) may be used but require more reactive agents or longer reaction times to be removed (e.g. TFA and TMSBr) than MOM ethers.

[0364] In some embodiments, compounds of Formula I, wherein one or two of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, and the others are OH or where one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl, two or three of the others are OH, and optionally one of the others is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl are prepared via the use of the intermediate of Formula II:

##STR00224##

which in some embodiments of the present application, has one or both of the following stereochemical configurations:

##STR00225##

wherein, as the case may be:
(i) one or two of R.sup.2a, R.sup.3a, R.sup.4a and R.sup.5a is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl, and the others are OMOM; or
(ii) one of R.sup.2a, R.sup.3a, R.sup.4a and R.sup.5a is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl, two or three of the others are OMOM, and optionally one of the others is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl. In embodiments wherein F is not .sup.18F, other protecting groups such as methoxy ethyl ethers (MEM) may be used.

[0365] In some embodiments of the compound of Formula I, R.sup.2 is OC.sub.1-20alkyl or OC.sub.4-20cycloalkyl and the compound of Formula II is prepared in accordance with the general reaction shown in Scheme 2:

##STR00226## ##STR00227##

[0366] Referring to Scheme 2, the compound of Formula III is reacted with a suitable S.sub.N.sup.2 reagent under conditions to obtain the compound of Formula IV, which is selectively deprotected to remove PG.sup.3 under conditions to give the compound of Formula V, which is selectively deprotected to remove PG.sup.1 under conditions to give the compound of Formula VI, then protected via reaction with a source of OMOM (e.g. MOMCl) under conditions to give the compound of Formula VII, which is selectively deprotected to remove PG.sup.2 under conditions to give the compound of Formula VIII, which is reacted with with a reagent which will provide, together with the oxygen from the OH group, a suitable leaving group (e.g. a source of methanesulfonyl as shown in Scheme 2 or alternatively, tosyl or triflyl) to give the compound of Formula IX, which is azidolyzed under conditions to give the mixture of the compounds of Formulae X(a) and X(b) which are reduced under conditions to give the compound of Formula II. In the compounds of Scheme 2, PG.sup.1, PG.sup.2 and PG.sup.3 are suitable protecting groups. In some embodiments, PG.sup.1 is Bn and PG.sup.2 and PG.sup.3 are (CH.sub.3).sub.2 or

##STR00228##

Suitable conditions can be made by a person skilled in the art in light of their common general knowledge and with reference to the Examples hereinbelow. It will also be appreciated by a person skilled in the art in light of their common general knowledge and with reference to the present application, alternative stereochemical configurations of the compounds of Formulae III, IV, V, VI, VII, VIII, IX, X(a) and/or X(b) are used when the reaction is for preparing a compound of Formula II that has the following stereochemical configuration:

##STR00229##

or for preparing a compound of Formula II that is a mixture of the following stereochemical configurations:

##STR00230##

[0367] In embodiments wherein one of R.sup.2, R.sup.3, R.sup.4 and R.sup.5 is F-substituted OC.sub.1-20alkyl or F-substituted OC.sub.4-20cycloalkyl, this substituent can be installed in the methods of preparation using a synthetic scheme similar to that described hereinabove for where R.sup.1 is (CH.sub.2).sub.xCH.sub.2F,

##STR00231##

or (CH.sub.2).sub.yCHF(CH.sub.2).sub.zCH.sub.3, wherein x, y and z are as defined herein for the compound of Formula I.

[0368] Nucleophilic .sup.18F is produced by a cyclotron which has the ability to accelerate a hydride anion by using alternating electromagnets called dees. The negatively charged particle travels in a circular motion until the particle has enough kinetic energy to reach the outer diameter of the cyclotron chamber. Once traveling at sufficient speeds, the hydride ion is stripped of its electrons and the positively charged proton rapidly bombards a target made of highly pure materials. For a source of nucleophilic .sup.18F-fluoride, .sup.18O enriched water is used as the target material. Upon proton bombardment, the .sup.18O is converted into .sup.18F after releasing a neutron. When preparing radiopharmaceuticals, the following may also be considered:

[0369] Safety: In the case of a positron emitting isotope like .sup.18F, high energy (511 keV) gamma rays will be consistently produced as positrons annihilate with surrounding electrons. These gamma rays are harmful to humans in high doses and reasonable measures should be taken to limit exposure to this ionizing energy. This means using proper shielding (lead blocks) and manually handling low amounts of activity. Working around shielding or in an automated synthesis module may, for example, limit the types of chemical techniques and/or specific reactions that can be utilized for the synthesis of compounds.

[0370] Time: All radioactive isotopes have a characteristic half-life limiting the length of time for the chemical reactions. In the case of .sup.18F the half-life is 109.8 minutes meaning the total reaction and purification time advantageously does not exceed one half-life. Incorporation of the .sup.18F isotope is advantageously carried out within the last steps of the processes of the present application.

[0371] Concentration: In radiopharmaceutical production, stoichiometry may be significantly different than in a typical organic reaction. For example, 1.5 mg of .sup.18F would amount to approximately 5.5 million GBq. This amount of activity would be harmful and require significant amounts of energy to produce. However, since PET detectors are the most sensitive of the molecular imaging modalities, the amount of .sup.18F used for a PET scan is less than 1 GBq. Although this is beneficial for limiting exposure to radioactivity it has an effect how the radiopharmaceuticals are produced. A typical production of 5.5 GBq of .sup.18F equates to only 1.5 ng of isotope. This means that stoichiometric ratios of .sup.18F to the chemical precursor may, for example, be about 1:104 or about 1:105.

[0372] HPLC of .sup.18F-radiolabelled compounds can be carried out, for example, using a VP 250/10 Nucleosil 100-5 C18 Nautilus semi-preparative column (100 , 25010 mm, 5 m) or a similar column. [.sup.18F] Fluoride (n.c.a.) may be produced, for example, on a TR-24 cyclotron (Advanced Cyclotron Systems Inc., Richmond, Canada) or a similar cyclotron via the .sup.18O(p,n).sup.18F nuclear reaction. Depending on the desired activity the target may be irradiated, for example, at 18 MeV and the F-18 containing .sup.18O enriched water may, for example, be transferred and used directly for use in synthesis, or the previously emptied target may, for example, be washed with deionized water followed by transfer to a reaction set up.

[0373] In an embodiment wherein F is .sup.18F, radiochemical step(s) of the methods of preparation are carried out via an automated synthesizer.

[0374] Compounds and intermediates may be isolated from their reaction mixtures and may be purified using conventional laboratory techniques including, for example, solvent extraction, column chromatography using silica gel as well as alumina, distillation, crystallization, recrystallization and/or chiral separation.

[0375] Preparation of an optical isomer of compounds and intermediates may be performed, for example by the reaction of the appropriate optically active starting material under reaction conditions which will not cause racemization or alternatively the individual enantiomer or diastereomer (with more than one chiral center) is isolated by the separation of a racemic mixture using standard techniques such as fractional crystallization, chiral salt formation and/or chiral HPLC separation.

[0376] The present application also includes a composition comprising a compound of the application and a carrier. The compounds of the application are suitably formulated into compositions for administration to cells or subjects in a biologically compatible form suitable for administration in vitro or in vivo, as the case may be. Accordingly, the present application further includes a pharmaceutical composition comprising a compound of the application and a pharmaceutically acceptable carrier.

[0377] The present application also includes a composition comprising an .sup.18F-labelled compound of the application and a carrier. The .sup.18F-labelled compounds of the application are suitably formulated into compositions for administration to subjects in a biologically compatible form suitable for administration in vivo. Accordingly, the present application further includes a radiopharmaceutical composition for positron-emission tomography (PET) imaging of -glucocerebrosidase activity in a subject comprising an .sup.18F-labelled compound of the application and a radiopharmaceutically acceptable carrier.

[0378] The .sup.18F-labelled compounds of the application may be administered to a subject in a variety of forms depending on the selected route of administration, as will be understood by those skilled in the art. In an embodiment, the .sup.18F-labelled compounds of the application are administered parenterally and the radiopharmaceutical composition formulated accordingly. In another embodiment of the present application, the .sup.18F-labelled compounds of the application are administered by intravenous administration and the radiopharmaceutical composition formulated accordingly. Pharmaceutical forms suitable for injectable administration or use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.

[0379] The present application also includes a composition comprising a non-fluorinated compound of the application and a carrier. The non-fluorinated compounds of the application are suitably formulated into compositions for administration to cells or subjects such as mammals in a biologically compatible form suitable for administration in vitro or in vivo, as the case may be. Accordingly, the present application further includes a pharmaceutical composition comprising a non-fluorinated compound of the application and a pharmaceutically acceptable carrier.

[0380] The non-fluorinated compounds of the application can be administered to a cell or a subject or used in a variety of forms depending on the selected route of administration or use, as will be understood by those skilled in the art. In an embodiment, the non-fluorinated compound of the application is administered to the subject, or used, by oral (including sublingual and buccal) or parenteral (including, intravenous, intraperitoneal, subcutaneous, intramuscular, transepithelial, nasal, intrapulmonary, intrathecal, rectal, topical, patch, pump and transdermal) administration or use and the compound formulated accordingly. For example, the non-fluorinated compounds of the application are administered or used by injection, in a spray, in a tablet/caplet, in a powder, topically, in a gel, in drops, by a patch, by an implant, by a slow release pump or by any other suitable method of administration or use, the selection of which can be made by a person skilled in the art. In another embodiment of the application, the non-fluorinated compounds of the application are freeze dried and the lyophilizates obtained, are used for example, for the preparation of products for injection. In another embodiment, the non-fluorinated compounds of the application are administered or for use parenterally. In a further embodiment, the non-fluorinated compounds of the application are administered or for use via intraperitoneal injection. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists.

IV. Methods of Imaging, Uses and Kits

[0381] The compounds of the present application are new therefore the present application includes all uses of these compounds.

[0382] The .sup.18F-labeled compounds of the application may be useful, for example, for detection of GCase in animal-based models and humans using PET imaging. Such activity based probes may, for example, be useful molecular tools for elucidating GCase's involvement in the progression of PD, for evaluating therapeutic potential of new drugs and/or for the accurate and early diagnosis of PD.

[0383] Accordingly, the present application also includes a use of an .sup.18F-labelled compound of the application for positron-emission tomography (PET) imaging of -glucocerebrosidase activity in a subject; a use of an .sup.18F-labelled compound of the application for the preparation of a radiopharmaceutical composition for positron-emission tomography (PET) imaging of -glucocerebrosidase activity in a subject; as well as an .sup.18F-labelled compound of the application for use in positron-emission tomography (PET) imaging of -glucocerebrosidase activity in a subject.

[0384] The present application also includes a method for imaging -glucocerebrosidase activity in a subject, the method comprising:

[0385] administering an .sup.18F-labelled compound of the application to the subject; and

[0386] detecting the presence of retained radioactivity in the subject using positron-emission tomography (PET).

[0387] The term retained radioactivity as used herein refers to the radioactivity from .sup.18F labelled compounds of the application that are bound to -glucocerebrosidase in the subject. It will be appreciated by a person skilled in the art that the time between the administration or use of the .sup.18F-labelled compound of the application and the detection step is sufficient to allow the .sup.18F-labelled compound of the application to bind to the -glucocerebrosidase in the tissue of interest which is being imaged by the PET. The time may depend, for example, on the potency of the .sup.18F labelled compound of the application as an inhibitor to -glucocerebrosidase and can be selected by a person skilled in the art.

[0388] In an embodiment, the imaging is for diagnosis of a disease associated with decreased -glucocerebrosidase activity. In another embodiment of the present application, the disease is Parkinson's disease or Gaucher disease. In another embodiment, the disease is Parkinson's disease. In a further embodiment, the disease is early Parkinson's disease. In an embodiment, the diagnosis comprises comparing the retained radioactivity of the subject to a control and determining whether there is diminution in the amount or pattern of the retained radioactivity, which signals the presence of the disease.

[0389] In an embodiment, the imaging is for monitoring the progression of a disease associated with decreased -glucocerebrosidase activity. In another embodiment, the disease is Parkinson's disease or Gaucher disease. In a further embodiment, the disease is Parkinson's disease. In another embodiment of the present application, the disease is Gaucher disease. In an embodiment, the monitoring comprises comparing the retained radioactivity of the subject obtained at a first point in time to the retained radioactivity of the subject obtained at a second point of time and determining whether there is an alteration in the amount or pattern of the retained radioactivity, which signals a change in the disease.

[0390] In an embodiment, the imaging is for monitoring the effect on -glucocerebrosidase activity of a therapy for treatment of a disease associated with decreased -glucocerebrosidase activity. In an embodiment, the disease is Gaucher disease and the therapy is enzyme replacement therapy. In a further embodiment, the imaging is for monitoring the effect of a therapy being investigated for use in treatment of the disease. In an embodiment, the monitoring comprises comparing the retained radioactivity of the subject obtained at a first point in time to the retained radioactivity of the subject obtained at a second point of time and determining whether there is an alteration in the amount or pattern of the retained radioactivity, which signals a change in the disease. In another embodiment, the imaging is for determining whether a subject is suitable for the therapy being investigated for use in treatment of the disease. For example, in such embodiments, the subject may have decreased -glucocerebrosidase activity in comparison to a control and/or the subject may have a level of -glucocerebrosidase activity within a certain range. In an embodiment, the therapy is being investigated for use in the treatment of Parkinson's disease.

[0391] In an embodiment, the imaging is of the brain of the subject.

[0392] Imaging -glucocerebrosidase activity outside of the brain may also be useful because fibroblast cells from patients having Parkinson's disease have been shown to have reduced -glucocerebrosidase activity. Accordingly, in another embodiment, the imaging is of a tissue comprising fibroblast cells.

[0393] The amount or dosage of the .sup.18F-labelled compound of the application required to image the -glucocerebrosidase activity in the subject can be readily ascertained by one of ordinary skill in the nuclear medicine art taking into account, for example, the specific activity of the compound and the radiation dosimetry. The high sensitivity of PET may allow, for example, the micro dosing of the radiotracer in the microgram to nanogram range thus addressing concerns of chemical toxicity of the imaging probe. For example, in an .sup.18F-FDG PET scan for the average adult, 2-3 g of imaging agent is used for a full body scan.sup.64 and the amount of the .sup.18F-labelled compound of the application can be determined similarly. At the micro dosing levels of the injected radiotracer, even drug candidates that may be too toxic as pharmaceuticals may be radioactively labeled and used as PET imaging probes in humans and animals.

[0394] It will be also be appreciated by the skilled person that because of the short half-life of the radioisotopes, it is often necessary to complete the final stages of the process for preparing the radiolabelled compound at or near the site of administration or use. Accordingly, the present application also includes a kit comprising a non-radiolabeled intermediate to an .sup.18F-labelled compound of the application and optionally instructions for use of the non-radiolabeled intermediate in the preparation of the .sup.18F-labelled compound of the application for positron-emission tomography (PET) imaging of -glucocerebrosidase activity.

[0395] New conduritol aziridine derivatives have been prepared which are inhibitors of the lysosomal enzyme glucocerebrosidase (GCase). For example, O-octyl, N-butyl conduritol aziridine is the most potent inhibitor of GCase reported to date. Therefore the compounds of the application may also be useful, for example, in knocking out GCase in cells and/or animals.

[0396] Accordingly, the present application also includes a method of inhibiting -glucocerebrosidase activity comprising administering a compound of the application to a cell. The present application also includes a use of a compound of the application for inhibiting -glucocerebrosidase activity in a cell; a use of a compound of the application for preparation of a medicament for inhibiting -glucocerebrosidase activity in a cell; and a compound of the application for use to inhibit -glucocerebrosidase activity in a cell.

[0397] In an embodiment, the compound of the application is a non-fluorinated compound of the application.

[0398] In an embodiment, the administration or use is for the preparation of a model for investigating a disease associated with decreased -glucocerebrosidase activity such as Gaucher disease or Parkinson's disease.

[0399] In an embodiment, the cell is in a mammal. In another embodiment, the mammal is a mouse. In another embodiment of the present application, the cell is a neuron. In a further embodiment, the cell is in the brain.

[0400] The amount or dosage of the compound of the application required to inhibit the -glucocerebrosidase activity in the cell or subject can be readily ascertained by one of ordinary skill in the art taking into account, for example, the specific activity of the compound of the application.

[0401] An effective amount of the compound of the application is administered to or for use in a cell either in cell culture or in a subject. As used herein, the term effective amount means an amount effective, at dosages and for periods of time necessary to achieve a desired result. For example, in the context of inhibiting -glucocerebrosidase activity, an effective amount of the compound of the application is an amount that, for example, reduces the -glucocerebrosidase activity compared to the -glucocerebrosidase activity without administration or use of the compound of the application. Effective amounts may vary according to factors such as whether the cell is in cell culture or in a subject as well as the age, sex, weight and/or species of the subject. The amount of a given compound that will correspond to such an amount will vary depending upon various factors, such as the given compound, the pharmaceutical formulation, the route of administration or use, the type of model for studying disease being created, the identity of the subject or cell and the like, but can nevertheless be routinely determined by one skilled in the art.

[0402] Methods comprise administering to a subject or cell or use of an effective amount of the compound of the application, optionally consisting of a single administration or use, or alternatively comprising a series of administrations or uses. For example, the compound of the application is administered or for use at least once a week. However, in another embodiment, the compound is administered to the subject or for use from about one time per three weeks, or about one time per week to about once daily for a given administration or use. In another embodiment, the compounds are administered or for use 2, 3, 4, 5 or 6 times daily. It will also be appreciated that the effective dosage of a compound administered or used may increase or decrease over the course of a particular regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art.

[0403] The following non-limiting examples are illustrative of the present application:

Examples

Example 1: Preparation of Fluorophenyl Conduritol Aziridine Derivatives

[0404] 1. Materials and Methods

Experimental

[0405] All buffers and reagents were obtained from Fisher Scientific or Sigma-Aldrich and used without further purification. Synthetic reactions were monitored by TLC using precoated silica gel plates (Silicycle 60F254, 0.25 mm thickness). Compounds were detected by ultraviolet light (=254 nm) followed by visualization with ammonium molybdate (10% w/v in 2M H.sub.2SO.sub.4), permanganate (1% w/v in water), or ninhydrin (1.5% w/v solution in butanol), with heating. Flash chromatography was performed using Silicyle silica gel (230-400 mesh). NMR spectra were obtained using a Varian Unity Inova 500 MHz spectrometer dissolving samples in the appropriate deuterated solvents (CDCl.sub.3, or CD.sub.3OD). Chemical shifts were reported in ppm downfield from tetramethylsilane. Low resolution ESI mass spectrometry was performed on an Advion Expression CMS Mass Spectrometer.

[0406] The compounds in the synthetic procedures of Example 1 are present as a mixture of enantiomers having the following stereochemical configurations:

##STR00232##

Synthesis

()-(1R,2S,3R,4R,5S,6S)-7-(hex-5-yn-1-yl)-2,3,4,5-tetrakis(methoxymethoxy)-7-azabicyclo[4.1.0]heptane (32)

[0407] ##STR00233##

[0408] Compound 19 was prepared according to the synthetic route described in the concurrently filed application entitled FLUORINATED N-ALKYL CONDURITOL AZIRIDINES, PROCESSES FOR THE PREPARATION THEREOF AND THEIR USE IN POSITRON-EMISSION TOMOGRAPHY (PET) IMAGING which claims the benefit of priority from co-pending U.S. provisional application No. 62/574,563 filed on Oct. 19, 2017. 19 (700 mg, 2.075 mmol), 6-iodo-1-hexyne (0.82 mL, 6.224 mmol) and DIPEA (1.08 mL, 6.224 mmol) were dissolved in 22 mL of acetonitrile and heated to reflux for 2 days. The reaction was allowed to cool to room temperature and the solvent was removed under vacuum. The crude reaction mixture was partitioned between 200 mL of EtOAc and 200 mL of water. The aqueous layer was extracted 2 more times with 100 mL of EtOAc. The organic layers were combined and washed with brine, dried with sodium sulphate, filtered and concentrated under vacuum. The mixture was then purified using silica gel chromatography (1:1 EtOAc:Hexanes) to yield 32 (228 mg, 30%) as a colourless oil. .sup.1H NMR (500 MHz, CDCl.sub.3) 4.87-4.70 (m, 8H), 3.75 (dd, J=14.0, 5.6 Hz, 2H), 3.51 (dd, J=9.5 Hz, 1H), 3.42 (s, 6H), 3.39 (s, 6H), 3.36-3.28 (m, 1H), 2.69-2.57 (m, J=11.6, 7.0 Hz, 1H), 2.25-2.15 (m, J=6.5 Hz, 2H), 1.99-1.84 (m, 3H), 1.73-1.50 (m, 5H). .sup.13C NMR (126 MHz, CDCl.sub.3) 98.46, 98.06, 97.70, 97.19, 84.50, 80.32, 79.76, 78.89, 76.81, 68.52, 60.44, 56.29, 56.15, 55.94, 55.60, 43.53, 42.21, 28.67, 26.25, 18.49. LRMS (ESI): m/z Calcd for [C.sub.20H.sub.35NO.sub.8+Na].sup.+: 440.2260; found: 440.5.

()-(1R,2S,3R,4R,5S,6S)-7-(6-(4-fluorophenyl)hex-5-yn-1-yl)-2,3,4,5-tetrakis(methoxymethoxy)-7-azabicyclo[4.1.0]heptane(33)

[0409] ##STR00234##

[0410] 32 (75.06 mg, 0.18 mmol), triethylamine (0.1 mL, 0.72 mmol), CuI (8 mg, 0.04 mmol) and tetrakis (4 mg, 0.034 mmol) were dissolved in 3 mL of acetonitrile. To this was added 4-fluoroiodobenzene (22 L, 0.198 mmol) and the reaction was refluxed for 20 minutes. The reaction was cooled and partitioned between 20 mL of water and 20 mL of EtOAc. The aqueous phase was extracted 2 times with 20 mL of EtOAc and the organic layers were combined. The organic portion was washed with brine, dried with sodium sulphate, filtered and concentrated under vacuum. After silica gel column chromatography (1:2 EtOAc:Hexanes) 33 (90 mg, 95%) was isolated as a colourless oil. .sup.1H NMR (500 MHz, CDCl.sub.3) 7.35 (dd, 2H), 6.96 (dd, 2H), 4.86-4.72 (m, 8H), 3.77 (t, J=7.7 Hz, 2H), 3.53 (t, J=9.5 Hz, 1H), 3.46-3.38 (m, J=7.4, 2.8 Hz, 12H), 3.38-3.31 (m, 1H), 2.69 (dd, J=11.4, 6.5 Hz, 1H), 2.41 (t, J=6.0 Hz, 2H), 2.02-1.89 (m, J=18.6, 9.0, 5.0 Hz, 2H), 1.83-1.64 (m, J=20.6, 11.3 Hz, 5H). .sup.13C NMR (126 MHz, CDCl.sub.3) 163.09, 161.10, 133.42, 133.35, 120.11, 115.52, 115.35, 98.42, 98.03, 97.65, 97.17, 89.75, 80.27, 79.73, 78.89, 76.77, 60.54, 56.25, 56.12, 55.88, 55.54, 43.51, 42.23, 28.89, 26.53, 19.42. LRMS (ESI): m/z Calcd for [C.sub.26H.sub.38FNO.sub.8+H].sup.+: 512.2654; found: 512.2.

()-(1R,2S,3R,4R,5S,6S)-7-(6-(4-fluorophenyl)hex-5-yn-1-yl)-7-azabicyclo[4.1.0]heptane-2,3,4,5-tetraol(34)

[0411] ##STR00235##

[0412] 33 (50 mg, 0.098 mmol) was dissolved in 1 mL of acetonitrile and cooled to 0 C. TMSBr (256 L, 1.960 mmol) was added slowly to the mixture and this was stirred for 40 minutes at 0 C. The reaction was quenched with 2 mL of saturated sodium bicarbonate while stirring vigorously at 0 C. and allowed to warm to room temperature. The solvent was removed under vacuum. The resulting solids were dissolved in 1:1 MeOH:CHCl.sub.3, filtered and the solvents were again removed under vacuum. This crude mixture was purified using silica gel column chromatography (1:6, MeOH:CHCl.sub.3) and lyophilized to yield 34 (16 mg, 49%) as an off white solid. .sup.1H NMR (500 MHz, CD.sub.3OD) 7.38 (dd, 2H), 7.03 (dd, 2H), 3.70 (dd, J=8.4, 3.5 Hz, 1H), 3.65 (d, J=8.1 Hz, 1H), 3.24 (t, 1H), 3.06 (dd, 1H), 2.49-2.36 (m, 3H), 2.30-2.19 (m, 1H), 1.96 (dd, J=6.0, 3.7 Hz, 1H), 1.81-1.70 (m, J=16.0, 8.2 Hz, 2H), 1.71-1.61 (m, J=11.8 Hz, 3H). .sup.13C NMR (126 MHz, CD.sub.3OD) 134.49, 134.42, 116.40, 116.23, 90.45, 80.65, 77.88, 74.08, 73.43, 73.13, 61.39, 45.89, 45.41, 29.79, 27.59, 19.86. LRMS (ESI): m/z Calcd for [C.sub.18H.sub.23FNO.sub.4+H].sup.+: 336.160563; found: 336.6. HRMS (TOF ESI); found: 336.1615.

##STR00236##

[0413] 35 (21.7 mg, 0.09 mmol), triethylamine (50 g, 0.36 mmol), CuI (4 mg, 0.02 mmol) and tetrakis (2 mg, 0.0017 mmol) were dissolved in 1.5 mL of an acetonitrile water mixture (1:1). To this was added 4-fluoroiodobenzene (11 L, 0.099 mmol) and the reaction was heated at 90 C. for 20 minutes. The reaction was cooled and partitioned between 10 mL of water and 10 mL of EtOAc. The aqueous phase was extracted 2 times with 10 mL of EtOAc and the organic layers were combined. The organic portion was washed with brine, dried with sodium sulphate, filtered and concentrated under vacuum. After silica gel column chromatography (1:6, MeOH:CHCl.sub.3) 34 (27 mg, 90%) was isolated as a white solid and matched the TLC, mass and NMR from the compound made through the alternate pathway. NMR spectra matched that of the product made from 33.

()-(1R,2S,3R,4R,5S,6S)-7-(hex-5-yn-1-yl)-7-azabicyclo[4.1.0]heptane-2,3,4,5-tetraol (35)

[0414] ##STR00237##

[0415] 32 (200 mg, 0.480 mmol) was dissolved in 5 mL of acetonitrile and cooled to 0 C. TMSBr (1.26 mL, 9.592 mmol) was added slowly to the mixture and this was stirred for 40 minutes at 0 C. The reaction was quenched with 10 mL of saturated sodium bicarbonate while stirring vigorously at 0 C. and allowed to warm to room temperature. The solvent was removed under vacuum. The resulting solids were dissolved in 1:1 MeOH:CHCl.sub.3, filtered and the solvents were again removed under vacuum. This crude mixture was purified using silica gel column chromatography (6:1 to 5:1, EtOAc:MeOH) and lyophilized to yield 35 (110 mg, 95%) as an white solid. .sup.1H NMR (500 MHz, CD.sub.3OD) 3.75 (dd, J=8.3, 3.1 Hz, 1H), 3.65 (d, J=8.1 Hz, 1H), 3.25 (t, 1H), 3.11 (t, 1H), 2.40 (dd, J=11.7, 7.0 Hz, 1H), 2.29-2.13 (m, J=14.0 Hz, 4H), 2.03-1.93 (m, 1H), 1.75-1.64 (m, 3H), 1.64-1.54 (m, 2H). .sup.13C NMR (126 MHz, CD.sub.3OD) 84.82, 77.52, 74.03, 73.29, 72.89, 69.65, 61.21, 45.77, 45.37, 29.55, 27.38, 18.95. LRMS (ESI): m/z Calcd for [C.sub.12H.sub.19NO.sub.4+Na].sup.+: 264.1206; found: 264.5.

II. Results and Discussion

[0416] PET imaging can be used, for example, to non-invasively track GCase activity in a living biological organism like a mouse or human. In order to do this, a radioactive derivative, labeled with a PET isotope like .sup.18F may be used as a radiopharmaceutical imaging agent.

[0417] In the present studies, Sonogashira coupling using commercially available non-radioactive 4-fluoro-iodobenzene (FIB) was investigated. The MOM protected aziridine 19 was alkylated using 6-iodo-alkyne to cleanly obtain alkyne 32 in 30% yield (Scheme 3). Subsequent Sonogashira coupling with FIB was shown to be efficient in refluxing acetonitrile, yielding aryl-fluorinated aziridine 33 nearly quantitatively after only 30 minutes reaction time (Scheme 3). Then, fluorinated derivative 33 was deprotected using TMSBr deprotection to yield the free aziridine 34 in 49% yield (Scheme 3). These were useful results, since high yields and rapid reactions are optimal for radiochemistry using the short-lived .sup.18F isotope. It was also found that the MOM groups of 32 could be deprotected before Sonogashira coupling to give alkyne 35, an extremely polar derivative (Scheme 3). For Sonogashira coupling of 35 with FIB the solvent was switched to 1:1 acetonitrile:water to compensate for the increased polarity of the reactants and to ensure solubility. It was surprising that this Sonogashira coupling proceeded in the presence of water as Sonogashira couplings are often required to be anhydrous. The coupling of FIB with 35 was just as efficient as with 32 to also yield compound 34 quantitatively (Scheme 3). The robustness of this coupling may, for example, be useful for performing radiochemical reactions.

##STR00238##

[0418] Scheme 3: Synthesis of fluorinated conduritol aziridine authentic standards for radiochemistry. (a) 6-iodo-1-hexyne, DIPEA, acetonitrile, reflux, 30%; (b) FIB, Pd(PPh.sub.3).sub.4, CuI, TEA, acetonitrile, reflux, 15 min, 95%; (c) TMSBr, acetonitrile, 0 C., 30 min, 49%; (d) TMSBr, acetonitrile, 0 C., 30 min, 95%; (e) FIB, Pd(PPh.sub.3).sub.4, CuI, TEA, acetonitrile:H.sub.2O 1:1, reflux, 15 min, 95%.

[0419] Given the results using Sonogashira coupling with FIB, .sup.18F-FIB may also be synthesized and then conjugated to alkyne 35 using Sonogashira coupling under suitable conditions for radiolabelling conduritol aziridines. For example, the synthesis of .sup.18F-FIB has been published by Wuest et al. using commercially available precursor (4-iodophenyl)diphenylsulfonium triflate..sup.65

Example 2: Regioselective Synthesis of O-Alkylated-N-Substituted Aziridines

[0420] 1. Methods

[0421] Scheme 4 shows an overview of the reaction conditions for the synthesis of the O-alkylated-N-substituted aziridines of Example 2.

##STR00239## ##STR00240##

[0422] For clarity, only one stereochemical configuration is shown in Scheme 4, although the compounds are present as a mixture of enantiomers. For example, compound 2.11a is present as the following mixture:

##STR00241##

Synthesis of Compound 2.2:

[0423] 1-Iodooctane (1.1 mL, 5.87 mmol) and then NaH (60% in oil, 190 mg, 7.82 mmol) were added to a solution of 2.1 (1.37 g, 3.91 mmol) in dry DMF (50 mL) at 0 C. under argon. The reaction mixture was heated at 55 C. for 2 h. It was then cooled to room temperature, quenched with water and extracted with ethyl acetate (50 mL3). The combined organic phase was successively washed with water (100 mL3), brine (100 mL), and dried (Na.sub.2SO.sub.4). After filtration, the filtrate was evaporated under reduced pressure to yield the crude product which was purified by silica gel flash column chromatography using DCM and then ethyl acetate as eluents. The purified compound 2.2 was obtained as a white solid, 1.64 g, 91%. .sup.1H NMR (500 MHz, CDCl.sub.3) 0.85-0.94 (m, 3H), 1.23-1.37 (m, 10H), 1.36 (s, 3H), 1.47 (s, 3H), 1.50 (s, 3H), 1.58 (s, 3H), 1.56-1.65 (m, 2H), 3.28 (dd, J=10.4, 9.5 Hz, 1H), 3.58 (dd, J=10.6, 6.4 Hz, 1H), 3.65-3.75 (m, 2H), 3.75 (dd, J=10.2 4.2 Hz, 1H), 3.99 (dd, J=5.2, 1.0 Hz, 1H), 4.06 (t, J=9.8 Hz, 1H), 4.32 (t, J=4.6 Hz, 1H), 4.82 (d, J=12.5 Hz, 1H), 4.92 (d, J=12.5 Hz, 1H), 7.28-7.45 (m, 5H).

Synthesis of Compound 2.3:

[0424] A mixture of trifluoroacetic acid (551 L) in water (83 L) was added to a solution of 2.2 (1.62 g, 3.50 mmol) in dry DCM (55 mL) at 0 C. and stirred for 1.5 h. After reaction, the mixture was neutralized with saturated NaHCO.sub.3 aqueous solution. The organic layer was separated and washed with brine (25 mL), and dried (Na.sub.2SO.sub.4). After filtration the filtrate was evaporated under reduced pressure to yield the crude product which was purified by silica gel flash column chromatography using ethyl acetate:hexanes:NH.sub.4OH (2:2:0.05) as eluents. The purified compound 2.3 was obtained as a white solid, 1.26 g, 85%. .sup.1H NMR (500 MHz, CDCl.sub.3) 0.86-0.94 (m, 3H), 1.22-1.36 (m, 10H), 1.36 (s, 3H), 1.57 (s, 3H), 1.55-1.65 (m, 2H), 2.71 (s, 1H), 2.72 (s, 1H), 3.30-3.37 (m, 1H), 3.40 (dd, J=9.6, 6.9 Hz, 1H), 3.55 (dd, J=9.6, 4.0 Hz, 1H), 3.56-3.65 (m, 1H), 3.83-3.90 (m, 1H), 3.95-4.05 (m, 2H), 4.31 (dd J=4.9, 4.0 Hz, 1H), 4.78 (d, J=12.5 Hz, 1H), 4.82 (d, J=12.5 Hz, 1H), 7.29-7.46 (m, 5H).

Synthesis of compound 2.4:

[0425] A solution of 2.3 (1.26 g, 2.98 mmol) was made in a mixture of dry THE (25 mL) and dry MeOH (10 mL), and Pd/C (10%, 0.5 g) was added under argon. Hydrogen gas was bubbled through the reaction mixture for a minute and it was then kept under balloon pressure at room temperature for 1.5 h. After reaction, the mixture was filtered through a plug of celite and silica gel, and the filtrate was evaporated under reduced pressure to yield the pure product 2.4 as an oil, 0.96 g, quant. .sup.1H NMR (500 MHz, CDCl.sub.3) 0.85-0.90 (m, 3H), 1.22-1.36 (m, 10H), 1.37 (s, 3H), 1.53 (s, 3H), 1.55-1.65 (m, 2H), 2.94 (bs, 2H), 3.27-3.40 (m, 3H), 3.53-3.58 (m, 1H), 3.72-3.90 (m, 3H), 4.07-4.11 (m, 1H), 4.41 (dd, J=5.1, 4.1 Hz, 1H).

Synthesis of Compound 2.5:

[0426] N,N-Diisopropylethylamine (2 ml, 11.90 mmol) was added to a solution of 2.4 (0.98 g, 2.95 mmol) in dry DMF (10 mL) and cooled to 0 C. Chloromethyl methyl ether (1.2 mL, 15.80 mmol) was added slowly to the reaction mixture which was then stirred at room temperature for 5 h. After reaction, the mixture was slowly neutralized with saturated NaHCO.sub.3 aqueous solution and extracted with Et.sub.2O (50 mL3). The combined organic phase was successively washed with water (100 mL3), brine (100 mL), and dried (Na.sub.2SO.sub.4). After filtration, the filtrate was evaporated under reduced pressure to yield the crude product which was purified by silica gel flash column chromatography using ethyl acetate:hexanes (2:1) as eluents. The purified compound 2.5 was obtained as an oil, 1.26 g, 92%..sup.1H NMR (500 MHz, CDCl.sub.3) 0.85-0.91 (m, 3H), 1.22-1.36 (m, 10H), 1.38 (s, 3H), 1.57 (s, 3H), 1.55-1.65 (m, 2H), 3.42-3.65 (m, 12H), 3.75-3.85 (m, 2H), 3.92-3.98 (m, 1H), 4.10 (t, J=6.1 Hz 1H), 4.44 (dd, J=5.8, 3.9 Hz, 1H), 4.77-4.89 (m, 6H).

Synthesis of Compound 2.6:

[0427] A mixture of 80% acetic acid in water (4 ml) was added to compound 2.5 (1.26 g, 2.71 mmol) and the reaction mixture stirred at room temperature for 48 h. After reaction, the mixture was slowly neutralized with saturated NaHCO.sub.3 aqueous solution and extracted with Et.sub.20 (75 mL3). The combined organic phase was successively washed with water (100 mL), brine (100 mL), and dried (Na.sub.2SO.sub.4). After filtration, the filtrate was evaporated under reduced pressure to yield the crude product which was purified by silica gel flash column chromatography using ethyl acetate as eluents. The purified compound 2.6 was obtained as a white solid, 0.84 g, 73%. .sup.1H NMR (500 MHz, CDCl.sub.3) 0.80-0.85 (m, 3H), 1.15-1.32 (m, 10H), 1.52-1.61 (m, 2H), 2.88 (d, J=5.1 Hz, 1H), 3.06 (d, J=1.2 Hz, 1H), 3.37 (s, 3H), 3.38 (s, 3H), 3.40 (s, 3H), 3.30-3.50 (m, 4H), 3.61-3.79 (m, 2H), 3.85 (t, J=9.6 Hz, 1H), 4.11 (dd, J=5.8, 3.9 Hz, 1H), 4.69-4.85 (m, 6H).

Synthesis of Compound 2.7:

[0428] Methanesulfonyl chloride (0.75 mL, 9.69 mmol) was added slowly to a solution of 2.6 (0.83 g, 1.96 mmol) in dry pyridine (5 mL) at 0 C. and the reaction mixture stirred at room temperature for 16 h. After reaction, water (25 mL) was added to the reaction mixture and extracted with ethyl acetate (50 mL3). The combined organic phase was successively washed with citric acid (0.1 M, 100 mL2), water (100 mL), brine (100 mL), and dried (Na.sub.2SO.sub.4). After filtration, the filtrate was evaporated under reduced pressure to yield the crude product which was purified by silica gel flash column chromatography using ethyl acetate as eluents. The purified compound 2.7 was obtained as an oil, 1.14 g, quant. .sup.1H NMR (500 MHz, CDCl.sub.3) 0.85-0.95 (m, 3H), 1.22-1.37 (m, 10H), 1.55-1.65 (m, 2H), 3.16 (s, 3H), 3.21 (s, 3H), 3.45 (s, 3H), 3.46 (s, 3H), 3.49 (s, 3H), 3.40-3.51 (m, 2H), 3.60-3.79 (m, 4H), 3.86 (t, J=9.6 Hz, 1H), 4.50 (dd, J=10.1, 2.8 Hz, 1H), 4.75-4.95 (m, 6H).

Synthesis of Compound 2.8:

[0429] Sodium azide (0.14 g, 2.16 mmol) was added to a solution of 2.7 (1.14 g, 1.96 mmol) in dry DMF (20 mL) and the reaction mixture was heated at 90 C. for 48 h. After reaction, water (75 mL) was added to the reaction mixture and extracted with ethyl acetate (75 mL3). The combined organic phase was successively washed with water (100 mL3), brine (100 mL), and dried (Na.sub.2SO.sub.4). After filtration, the filtrate was evaporated under reduced pressure to yield the crude product mixture (2.8a+2.8b) as an oil (1.1 g) which was used for the next reaction without further purification.

Synthesis of Compound 2.9:

[0430] To a solution of 2.8a+2.8b (1.1 g) in dry THF (15 mL) was added PPh.sub.3 (0.75 g) and TEA (0.65 mL) and the reaction mixture was stirred at room temperature for 0.5 h. Water (1.5 mL) was then added to the reaction mixture and was heated to reflux for 48 h. After reaction, the reaction mixture was evaporated to dryness under reduced pressure to yield the crude product which was purified by silica gel column chromatography using DCM and then ethyl acetate as eluents. The purified compound 2.9 was obtained as an oil, 0.21 g, 26% over 2 steps. .sup.1H NMR (500 MHz, CDCl.sub.3) 0.82-0.93 (m, 3H), 1.20-1.41 (m, 10H), 1.60-1.68 (m, 2H), 2.40-2.44 (m, 1H), 2.60-2.68 (m, 1H), 3.42 (s, 3H), 3.43 (s, 3H), 3.45 (s, 3H), 3.40-3.50 (m, 2H) 3.55-3.68 (m, 3H), 3.70-3.76 (m, 1H), 3.82 (d, J=7.8 Hz, 1H), 4.75-4.87 (m, 6H).

General Procedure for the Synthesis of Compounds 2.10a and 2.10b:

[0431] To a solution of 2.9 (81 mg, 0.20 mmol) in dry acetonitrile (3 mL)) was added the desired alkyl iodide (0.60 mmol) and N,N-diisopropylethylamine (105 L, 0.60 mmol), and the reaction mixture was heated to reflux for 48 h. After reaction, the mixture was evaporated to dryness under reduced pressure to yield the crude product which was purified by silica gel column chromatography using DCM and then ethyl acetate:hexanes (1:1) as eluents.

[0432] The purified compound 2.10a was obtained as a brown oil, 88 mg, 85%..sup.1H NMR (500 MHz, CDCl.sub.3) 0.88-0.93 (m, 6H), 1.42-1.82 (m, 20H), 1.50-1.70 (m, 6H), 1.90-1.95 (m, 1H), 2.00-2.10 (m, 1H), 2.40-2.50 (m, 1H), 3.32-3.40 (m, 1H), 3.47 (s, 3H), 3.48 (s, 3H), 3.49 (s, 3H), 3.50-3.60 (m, 2H) 3.70-3.75 (m, 1H), 3.76 (d, J=7.8 Hz, 1H), 4.75-4.88 (m, 6H).

[0433] The purified compound 2.10b was obtained as a brown oil, 92 mg, quant. .sup.1H NMR (500 MHz, CDCl.sub.3) 0.75-0.93 (m, 6H), 1.23-1.45 (m, 12H), 1.50-1.65 (m, 4H), 1.69 (d, J=6.2 Hz, 1H), 1.72 (bs, 1H), 1.95 (dd, J=6.1, 3.2 Hz, 1H), 1H 4H), 2.05-2.10 (m, 1H), 2.42-2.51 (m, 1H), 3.35 (dd, J=10.0, 8.4 Hz, 1H), 1H), 3.43 (s, 3H), 3.45 (s, 3H), 3.46 (s, 3H), 3.45-3.60 (m, 2H) 3.68-3.75 (m, 1H), 3.76 (d, J=8.3 Hz, 1H), 4.75-4.88 (m, 6H).

General Procedure for the Synthesis of Compounds 2.11a and 2.11b:

[0434] To a solution of 2.10 (0.01 mmol) in dry acetonitrile (2 mL)) was added TMSBr (0.60 mmol) and the reaction mixture was stirred at room temperature for 1.5 h. After reaction, the mixture was evaporated to dryness under reduced pressure and the residue was extracted with a mixture of CHCl.sub.3:MeOH (1:1) (10 mL3). The combined extract was evaporated to dryness under reduced pressure to yield the crude product which was purified by silica gel column chromatography using DCM:MeOH (6:1) as eluents.

[0435] The purified compound 2.11a was obtained as a brown solid, 11 mg, 29%..sup.1H NMR (500 MHz, CDCl.sub.3) 0.83-0.94 (m, 6H), 1.20-1.45 (m, 20H), 1.50-1.70 (m, 4H), 1.73 (d, J=6.1 Hz, 1H), 1.95-2.01 (m, 1H), 2.19-2.35 (m, 2H), 3.30 (t, J=8.4 Hz, 1H), 3.47-3.57 (m, 2H), 3.57-3.68 (m, 1H), 3.70-3.78 (m, 1H), 3.85 (d, J=7.6 Hz, 1H).

[0436] The purified compound 2.11b was obtained as a brown solid, 8 mg, 23%. .sup.1H NMR (500 MHz, CDCl.sub.3) 0.85-0.98 (m, 6H), 1.23-1.45 (m, 12H), 1.50-1.70 (m, 4H), 1.75 (d, J=6.2 Hz, 1H), 1.95-2.10 (m, 1H), 2.29 (t, J=7.3 Hz, 2H), 3.30-3.40 (m, 1H), 3.45-3.60 (m, 3H), 3.72-3.78 (m, 1H), 3.90 (d, J=7.6 Hz, 1H).

II. Results and Discussion

[0437] In brief, compound 2.1 was heated at 55 C. with 1-iodooctane in presence of NaH in DMF to yield 0-octylated compound 2.2 which was selectively deprotected with TFA-H.sub.2O to give 2.3 in high yield. Hydrogenation of 2.3 in presence of Pd/C/H.sub.2 furnished 2.4. Protection of OH groups with MOMCl yielded 2.5 which was followed by deprotection using AcOHH.sub.2O to give 2.6 in high yield. Mesylation of 2.6 with MsCl resulted in 2.7 in quantitative yield. Azidation of 2.7 with NaN.sub.3 gave a mixture of compounds 2.8a and 2.8b with full conversion. Aziridine 2.9 was obtained by treating 2.8 with PPh.sub.3, TEA and H.sub.2O. N-Alkylation was carried out by treating the aziridines with the corresponding alkyl halide to give 2.10a and 2.10b in high yields. Finally, deprotection of 2.10 with TMSBr furnished the dialkyl aziridines 2.11a and 2.11b in reasonable yields.

[0438] A significant advantage of the aziridine chemistry is that the structure may be efficiently and systematically modified, for example, to introduce physicochemical properties that are known to be advantageous for enhanced BBB penetrations: for example lipophilicity (log P or log D), and/or total polar surface area. For example, lipophilicity and polar surface area can be controlled by systematically increasing the length of the alkyl chains at the nitrogen of the aziridine and appending alkyl groups, for example, to the 3-OH group of the cyclitol ring. Based on the use of online calculators, the total polar surface area of dialkylated derivatives is within the typical range for passive brain uptake. Given that the N-octyl conduritol aziridine 1.7 appears to be actively transported into cell via SMIT and HMIT, while not wishing to be limited by theory, it is likely that the monoalkylated aziridines will be actively transported into the brain while the dialkylated aziridines could enter the brain largely through passive transmembrane diffusion. Since lipid solubility can increase transport rates across the BBB, compounds that are too hydrophobic can be sequestered by the capillary bed preventing the compounds from entering brain cells. Notably, the uptake rate of drugs or radiotracers that are actively transported into the brain is approximately 10 times higher than transmembrane diffusion,.sup.66 with either mechanism leading to sufficient brain uptake of the aziridines for PET imaging.

[0439] Preparation of .sup.18F-radiolabelled analogs to dialkylated conduritol aziridines such as 2.11a and 2.11b may be of interest, for example, as PET radiotracer candidates since: 1) glucose derivatives modified at the C-1 and C-6 carbons with hydrophobic groups are readily hydrolyzed by GCase,.sup.67 2) advantageous specificity may be observed since C-6 modified glucose derivatives are not readily accepted by GBA2/GBA3,.sup.67 3) chemical blocking of the C-3 hydroxyl group from the inositol ring with an alkyl chain may reduce polar surface area and hydrogen bonding capacity of the probe increasing the likelihood of brain uptake, 4) they potently inhibit GCase (see data in Example 3) and/or 5) two alkyl chains are now potential options for .sup.18F-labeling.

Example 3: Enzyme KineticsMeasuring Inactivation Rates of Inhibitors

[0440] I. Materials and Methods

[0441] Inactivation solutions contained a final concentration of 16.55 nM of Cerezyme (Recombinant GCase) in 200 L of Reaction Buffer (50 mM acetate, 0.2% v/v Triton X-100, 0.3% w/v sodium taurocholate, pH 5.5). The Cerezyme was collected from leftover patient vials and had approximately 8275 nM in the vial. These enzyme Reaction Buffers were brought to 37 C. and spiked with a corresponding inhibitor to make the final inhibitor concentration either 20 nM, 40 nM, 60 nM, 80 nM, 120 nM, 160 nM and 200 nM. Once the inhibitor was added this was considered time=0 minutes. Meanwhile a 96 well plate inside a Biotek Synergy 4 hybrid multi-mode reader at 37 C. was being incubated. In the wells of the plate were waiting a high concentration (3.2 mM) of 2,4-DNP--Glc substrate in 180 L of Reaction Buffer. As the inhibitor inactivation was occurring, 20 L aliquots were taken from the inactivation solutions and diluted on the plate containing the substrate bringing the final concentration of the substrate to 4 mM. Once all the aliquots were added the solution in the wells was measured for absorbance at 400 nm for 8 minutes. At this time the measurements were paused and the next set of aliquots were taken to see how residual enzyme activity changes over time. Inactivation rates for varying inhibitor concentrations were calculated using GraphPad Prism software and Equation 2 (below). These observed rate constants were then used to calculate k.sub.i/K.sub.i using Equation 4 (below).

II. Results and Discussion

[0442] To compare the rate of GCase inactivation of fluorinated derivative 34 to that of compound 1.7, a range of eight concentrations of the inhibitor predicted to surround the K.sub.i value were incubated with Cerezyme (recombinant GCase), and the reaction mixtures were assayed for residual enzyme activity at different time intervals. Small aliquots of these reaction mixtures were withdrawn and diluted 20-fold in 96 well plates containing a final concentration of 4 mM of the substrate 2,4-DNP--D-Glc. Dilution of the reaction mixture effectively halts further inactivation by diluting the inhibitor and active site competition by excess substrate. Residual enzymatic activity at different time points and concentrations was monitored by quantifying the release of 2,4-DNP after 2,4-DNP-3-D-Glc cleavage by Cerezyme. In Equation 1, k.sub.i is the rate constant for inhibitor inactivation of an enzyme and K.sub.i (k.sub.1/k.sub.1) is the dissociation constant for the inhibitor with the enzyme otherwise known as the binding affinity..sup.68

[00001] $\begin{matrix} E + I .Math. \underset{k_{- 1}}{\overset{k_{1}}{}} .Math. E .Math. I .Math. \overset{k_{i}}{} .Math. E - I & Equation .Math. .Math. 1 \end{matrix}$

The ratio k.sub.i/K.sub.i is an indication of the efficiency of an inhibitor, taking into account both binding efficiency and inactivation rate.

[0443] The velocity data obtained from this inactivation assay was fit, using the GraphPad Prism software, to Equation 2, a one phase decay equation. From this equation it is possible to obtain an observed rate constant k.sub.obs for the inactivation of Cerezyme by the inhibitors tested. The observed rate constant would allow for the determination of enzyme kinetic parameters k.sub.i and K.sub.i.

Y=(Y.sub.0Plateau)e .sup.(k.sup.obs.sup.)x+PlateauEquation 2:

[0444] Inactivation data would follow Equation 3 if saturation of the enzyme's active site occurs at high inhibitor concentrations. This allows for separation of k.sub.i and K.sub.i values. The data will have an observable curve when this equation can be used effectively.

[00002] $\begin{matrix} k_{o .Math. b .Math. s} = \frac{k_{i} [i]}{K_{i} + [I]} & Equation .Math. .Math. 3 \end{matrix}$

[0445] In cases where saturation cannot be observed due to rapid inactivation of the enzyme at high concentrations of inhibitor, the data will appear linear and Equation 4 must be used which gives the second order rate constant as the ratio of k.sub.i to K.sub.i.

[00003] $\begin{matrix} k_{o .Math. b .Math. s} = \frac{k_{i} [I]}{K_{i}} & Equation .Math. .Math. 4 \end{matrix}$

[0446] The inhibitors tested followed Equation 4 demonstrating their highly efficient rate of inactivation. The kinetic analysis of the aziridine inhibitors can be seen in FIGS. 1-2. The rapid inactivation of Cerezyme by the inhibitors tested prevented the determination of individual K.sub.i and k.sub.i values. This is because at saturating concentrations of inhibitor, the enzyme is almost instantaneously inactivated. As a result, the second order rate constant of inactivation k.sub.i/K.sub.i was determined, a parameter still useful to compare the efficiency of fluorinated probes 34 to compound 1.7. It was previously reported that the k.sub.i/K.sub.i values for butyl, hexyl and octyl (1.7) conduritol aziridines were 3.80.1 mM.sup.1 min.sup.1, 64030 mM.sup.1min.sup.1, and 367070 mM-min.sup.1 respectively..sup.44 It is clear from this data that as carbons are added to the alkyl chain binding affinity increases dramatically.

[0447] From examining the k.sub.i/K.sub.i values obtained from the inactivation experiments it was clear that the binding affinity of 34 was similar to that of compound 1.7 (FIGS. 1-2). The k.sub.i/K.sub.i values for 1.7 and 34 were found to be 4.700.25 M.sup.1 min.sup.1 and 5100100 mM.sup.1 min.sup.1 respectively. This demonstrates how potency was conserved upon installation of the fluorine or fluorinating handle. This kinetic information shows that fluorinated derivative 34 does not suffer from decreased binding affinity to GCase and radioactive derivatives have promise as PET imaging probes for imaging GCase in living organisms. For comparison, [.sup.11C]-deprenyl is an irreversible inhibitor used to PET image monoamine oxidase B in the human brain. Since [.sup.11C]-deprenyl was measured to inactivate monoamine oxidase B with a k.sub.i/K.sub.i of 6400 mM.sup.1 min.sup.1..sup.69 this suggests that the fluorinated PET tracer candidate 34 has sufficient inactivation rates to be used as a PET tracer for imaging GCase in the brain of animals or humans.

[0448] Radioactive .sup.18F derivatives of conduritol aziridines such as 34 used as PET probes may, for example, be useful molecular tools for elucidating the involvement of GCase in PD, aid in drug design for compounds that seek to increase GCase levels in PD and Gaucher disease and/or help unravel the molecular mechanisms of disease progression involving GCase.

[0449] Compound 2.11b was estimated to have a relative k.sub.i/K.sub.i of 10 in comparison to 1.7, which made it one of the most potent inhibitors of GCase yet.

Example 4: Enzyme Kinetics of O-Alkylated-N-Substituted Aziridines

[0450] Compounds S88-S91 having the below structures were prepared by a similar method as described herein above for compounds 2.11a and 2.11b in Scheme 4 by employing alkyl iodides of varying chain length for the O-alkylation and N-alkylation steps:

##STR00242##

[0451] To assay the potency of the O-alkylated-N-substituted aziridines, continuous-release inhibition assays of GCase were carried out using the concentrations of aziridine at a temperature of 37 C. each corrected for photobleaching and spontaneous hydrolysis as shown in FIGS. 3-8 (top) for compounds S88, S91, S38 (compound 2.11b), S89, S90 and S46 (compound 2.11A) having the chemical structures shown in the inset to each plot. In the plots, data points represent the mean values, solid lines represent best fit according to Equation 2 (see Example 3, herein above) while dashed lines represent standard deviation. A secondary plot of K.sub.obs versus [ ] where data points represent the mean K.sub.obs values and error bars the standard deviation is also shown in FIGS. 3-8 (bottom). The solid line represents the best fit according to Equation 3 and the k.sub.i/K.sub.i values of 19.4 min.sup.1 M.sup.1 (S88), 16.2 min.sup.1 M.sup.1 (S91), 13.2 min.sup.1 M.sup.1 (S38), 9.54 min.sup.1 M.sup.1 (S89), 30.1 min.sup.1 M.sup.1 (S90) and 9.39 min.sup.1 M.sup.1 (S46) were calculated using Equation 4.

[0452] The kinetic studies have revealed that the O-alkylated-N-substituted aziridines have high potency towards GCase, exceeding the k.sub.i/K.sub.i values of existing inactivators of GCase and existing PET radiotracers that are irreversible inhibitors capable of imaging activity of enzymes from other enzyme families. In addition, preliminary enzyme kinetic studies using recombinant GBA2 and GBA3 have demonstrated that the dialkylated compounds are more potent towards GCase over GBA2 and GBA3. While not wishing to be limited by theory, this finding is in line with the fact that crystal structures of recombinant GBA2 revealed that important hydrogen bonds are formed between active site amino acids and the exocyclic C-6 hydroxyl group of glucose analogs (See: Charoenwattanasatien et al., Bacterial -Glucosidase Reveals the Structural and Functional Basis of Genetic Defects in Human Glucocerebrosidase 2 (GBA2) ACS Chem. Biol., 2016, 11 (7), pp 1891-1900 doi: 10.1021/acschembio.6b00192). This may, for example, explain the low potency of conduritols like conduritol B-epoxide towards GBA2 (ref 47) and while not wishing to be limited by theory, would likely hold true with conduritol aziridines since both classes of compounds lack the exocyclic C-6 hydroxyl group. This suggests that the present compounds could selectively inactivate GCase in cells and animals and that .sup.18F-labeled O-alkylated-N-substituted aziridines would generate PET radiotracers selective to GCase over GBA2 and GBA3.

Example 5: Synthesis of Pyridine-Substituted Aziridine

[0453] An example of an aziridine having a pyridine substituent connected to the nitrogen was prepared via the following synthetic route:

##STR00243## ##STR00244##

Reagents and conditions: (a) anhydrous DMF, MEMCl, DIPEA, 50 C., overnight, 79%; (b) 80% acetic acid, 50 C., 4 h, 63%; (c) MsCl, anhydrous pyridine, RT; (d) NaN.sub.3, anhydrous DMF, 90 C., overnight; (e) PPh.sub.3, water, acetonitrile, TEA, 75 C., overnight, 32%; (f) anhydrous acetonitrile, Na.sub.2CO.sub.3, 70 C., 68%; (g) KF/Kytofix, DMSO, 160 C., 5 h, 71%; (h) TFA/DCM (1:1), RT, overnight, compound of Formula I: 70% chemical yield. Further details on the syntheses and characterization of the compounds in this scheme were as follows:

[0454] Compound B: To compound A (6.6 g, 30 mmol) and DIPEA (37.2 ml, 210 mmol) in 100 ml of anhydrous DMF, MEMCl (20.6 ml, 180 mmol) was dropped into the reaction solution slowly at 0 C. The mixture was allowed to increase to 65 C. overnight, and then cooled down to RT, whereupon 250 ml NaHCO.sub.3 saturated solution was added to quench the reaction. The mixture was extracted with 3 times 250 ml ethyl acetate, washed with NaCl saturated solution, dried over anhydrous Na.sub.2SO.sub.4, filtered and the resulting solution was concentrated under high vacuum. The residue was purified by silica gel column (hexane:ethyl acetate=1:1 to ethyl acetate) to yield the desired product 13.6 g, 23.8 mmol 79% as a light yellow oil. .sup.1H NMR (CDCl.sub.3) 1.34 (s, 3H), 1.53 (s, 3H), 3.37 (d, J=2, 12H), 3.37-3.93 (m, 20H), 4.08 (t, J=5, 1H), 4.45 (dd, J=5, 1H), 4.86-4.92 (m, 8H).

[0455] Compound C: 100 ml, 80% acetic acid was added to compound B (13.6 g, 23.8 mmol), then the temperature increased to 50 C. for 4 h. The acetic acid was removed under high vacuum, and to the residue was added 500 ml ethyl acetate, then the mixture washed with saturated NaHCO.sub.3 solution, separated, concentrated under vacuum, purified by silica gel column (EA to EA:methanol=20:1) to yield the desired product: 8 g, 15 mmol, 63% as a light yellow oil. .sup.1H NMR (CDCl.sub.3) 3.36-3.38 (m, 12H), 3.42-3.96 (m, 20H), 4.25 (t, J=5, 1H), 4.31 (s, 1H), 4.82-4.93 (m, 8H).

[0456] Compound D: Compound C was dissolved in 50 ml anhydrous pyridine, MsCl (6.97 ml, 90 mmol) was dropped into the solution at 0 C., and after 1 h the temperature was allowed to increase to RT and continue to stir overnight. Then 500 ml ethyl acetate was added to the reaction solution, and the mixture washed with 0.1N citric acid solution and NaCl saturated solution, then separated, dried over anhydrous Na.sub.2SO.sub.4, filtered and the solvent removed under vacuum. The residue was purified by silica gel column (EA:Methanol=20:1) to yield the desired product: 9.4 g, 13.7 mmol, 91% as a light-yellow oil. .sup.1H NMR (CDCl.sub.3) 3.19 (d, j=2.5, 6H), 3.39-3.40 (m, 12H), 3.50-3.97 (m, 20H), 4.52 (dd, J=5, 1H), 4.82-4.98 (m, 8H), 5.27 (s, 1H).

[0457] Compound E: To compound D (9.4 g, 13.67 mmol) in 60 ml of anhydrous DMF was added NaN.sub.3 (889 mg, 13.67 mmol), and the mixture refluxed at 90 C. for 24 h. The reaction solution was cooled down to room temperature, 500 ml water was added, extracted with 500 ml3 times ethyl acetate, separated, dried over anhydrous Na.sub.2SO.sub.4, filtered and concentrated under high vacuum, the residue was passed through a silica gel pad, and the solvents removed to yield 8.1 g of a mixture compounds E1 and E2 which were used in the subsequent step of the reaction scheme without purification.

[0458] Compound F: To a mixture of 8.1 g of compounds E1 and E2 in THE (100 ml) was added PPh.sub.3 (3.34 g, 12.76 mmol) and TEA (25.51 mmol, 3.56 ml), the mixture was stirred 30 min at room temperature, then was added 10 ml water, and the temperature increased to 70 C. overnight. The solvent was removed under vacuum, the residue was purified by silica chromatography (EA to EA:methanol:NH.sub.4OH=100:10:1) to yield the desired product 2.3 g, 32% as a light yellow oil. .sup.1H NMR (CDCl.sub.3) 2.46 (s, 1H), 2.68 (s, 1H), 3.37 (t, J=5, 12H), 3.39-3.84 (m, 20H), 4.83-4.92 (m, 8H).

[0459] Compound H: To compound F (1 mmol, 513 mg) and compound G (1.1 eq, 1.1 mmol, 464.4 mg) in 30 ml anhydrous acetonitrile was added Na.sub.2CO.sub.3 (3 mmol, 318 mg), and the mixture stirred for 48 h at 70 C., then the solvent removed under high vacuum, and the residue was purified with a silica gel column (EA to EA:methanol=10:1) to yield the desired product: 526 mg, 0.58 mmol, 68% as a yellow oil. .sup.1H NMR (CDCl.sub.3) 1.34 (s, 6H), 1.44-1.48 (m, 2H), 1.55-1.59 (m, 2H), 1.69-1.73 (m, 1H), 1.81-1.87 (m, 2H), 1.95-2.01 (m, 2H), 2.51-2.54 (m, 1H), 3.52-3.59 (m, 8H), 3.67-3.89 (m, 10H), 4.13 (t, J=5, 2H), 4.83-4.91 (m, 8H), 7.52-7.53 (m, 2H), 8.07 (dd, J=2, 1H).

[0460] Compound J: Compound H (160 mg, 0.21 mmol) was dissolved in 1.5 ml anhydrous DMSO, then was added KF (2 eq, 0.42 mmol, 24 mg) and Kytofix222 (1.2 eq, 0.25 mmol, 94 mg), then the reaction temperature increased to 160 C. for 5 h. The solvent was then removed under high vacuum, and the residue was purified with a silica column (EA to EA: methanol=10:1) to yield the desired product: 110 mg, 0.14 mmol, 71% chemical yield. .sup.1H NMR (CDCl.sub.3) 1.34 (s, 6H), 1.46-1.50 (t, J=2.5, 2H), 1.57 (s, 2H), 1.77 (s, 3H), 1.83-1.86 (m, 2H), 2.01 (s, 2H), 2.53 (s, 1H), 3.38-3.40 (m, 12H), 3.55-3.87 (m, 18H), 4.04 (t, J=6.5, 2H), 4.84-4.91 (m, 8H), 7.12 (dd, J=5, 1H), 7.73-7.75 (m, 1H).

[0461] Exemplary compound of Formula I: Compound J (60 mg, 0.08 mmol) was dissolved in 1 ml of TFA:DCM (1:1) solution, the reaction solution stirred for 48 h at RT, then dropped into saturated NaHCO.sub.3 solution, the solvents removed under high vacuum, and the residue was purified with a silica gel column (EA:methanol=10:1.5) to yield the desired product; 22 mg, 0.057 mmol as a colourless oil with a 70% chemical yield. .sup.1H NMR (MD.sub.3OD) 1.38 (s, 6H), 1.50 (s, 2H), 1.60 (s, 2H), 1.69 (d, J=5, 1H), 1.81-1.84 (m, 2H), 1.96-1.98 (m, 1H), 2.15-2.21 (m, 1H), 2.37-2.42 (m, 2H), 3.10-3.14 (m, 1H), 3.23-3.29 (m, 1H), 3.65-3.69 (m, 1H), 4.08-4.12 (m, 2H), 7.24 (dd, J=5, 1H), 7.53-7.57 (m, 1H), 7.67-7.68 (m, 1H).

[0462] While the present application has been described with reference to what are presently considered to be the preferred examples, it is to be understood that the application is not limited to the disclosed examples. To the contrary, the present application is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.

[0463] All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.

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TABLE-US-00001 TABLE 1 Kinetic data on compounds of Scheme 1 for inhibition of GCase. Compound IC.sub.50(M) Ki(M) ki(min.sup.1) k.sub.i/K.sub.i(M.sup.1/min.sup.1) 1.1 >1000 12.00 1.2 9.49 140 0.590 4.20 10.sup.-4 1.3 0.152 0.078 0.514 1.5 2.40 0.140 0.058 1.6 0.050 0.140 2.80 1.7 0.005 0.120 25.0

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