CA2525547A1 - Compounds and uses thereof in modulating amyloid beta - Google Patents

Compounds and uses thereof in modulating amyloid beta Download PDF

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CA2525547A1
CA2525547A1 CA002525547A CA2525547A CA2525547A1 CA 2525547 A1 CA2525547 A1 CA 2525547A1 CA 002525547 A CA002525547 A CA 002525547A CA 2525547 A CA2525547 A CA 2525547A CA 2525547 A1 CA2525547 A1 CA 2525547A1
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alkyl
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CA2525547C (en
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Soan Cheng
Daniel D. Comer
Long Mao
Guity P. Balow
David Pleynet
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Neurogenetic Pharmaceuticals Inc
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Torreypines Therapeutics, Inc.
Soan Cheng
Daniel D. Comer
Long Mao
Guity P. Balow
David Pleynet
Neurogenetics, Inc.
Neurogenetic Pharmaceuticals, Inc.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/04—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/10—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a carbon chain containing aromatic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16—Anti-Parkinson drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/38—Nitrogen atoms
    • C07D277/42—Amino or imino radicals substituted by hydrocarbon or substituted hydrocarbon radicals
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Abstract

Novel compounds, compositions, and kits are provided. Methods of modulating A.beta. levels, and methods of treating a disease associated with aberrant A.beta. levels are also provided.

Claims (42)

1. A compound having a structure corresponding to Formula (I):
(A)-L A-(B)-L B-(C)-L C-(D) (I) and pharmaceutically acceptable salts, and prodrugs thereof, wherein:
A is:
wherein each E is independently N, NR, C, CR1, S, or O provided that no more than four E's are heteroatoms;
R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;
each R1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;
or A is:
wherein each M is independently selected from CR1 or N, provided that no more than three M's are N; and B is:
wherein each G is independently CR2 or N, provided that no more than three G's are N;
each R2 is independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino;
or B, together with A, forms a fused ring system;
C is:
wherein J is selected from the group consisting of CR3, O, S, N, and NR;
each K is independently N, NR, C, or CR3;
each R3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted alkoxy, with a proviso that when C is R3 is not NH2;

or C is:
wherein each M is independently selected from CR1 or N, provided that no more than three M's are N;
D is:
wherein each E is independently N, NR, C, CR1, S, or O provided that no more than four E's are heteroatoms;
or D is:
wherein each M is independently selected from CR5 or N, provided that no more than three M's are N;
each R5 is independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted amino, or substituted or unsubstituted alkylamino;
L A is optional, and when present, is a covalent bond or a linker selected from the group consisting of-C=C-, -C.ident.C-, -(C(R')2)z, -O-, -O-(CR'2)z-, -S-, -NR'-, -NH-(CR'2)z-, -N=N-, -C(O)-, -C(O)NR'-, -O-C(O)-, -O-C(O)-O-, -O-C(O)-NR'-, -NR'-C(O)-, -NR'-C(O)-O-, -NR'-C(O)-NR'-, -S-C(O)-, -S-C(O)-O-, -S-C(O)-NR'-, -S(O)-, -S(O)2-, -O-S(O)2-, -O-S(O)2-O-, -O-S(O)2-NR'-, -O-S(O)-, -O-S(O)-O-, -O-S(O)-NR'-, -O-NR'-C(O)-, -O-NR'-C(O)-O-, -O-NR'-C(O)-NR'-, -NR'-O-C(O)-, -NR'-O-C(O)-O-, -NR'-O-C(O)-NR'-, -O-NR'-C(S)-, -O-NR'-C(S)-O-, -O-NR'-C(S)-NR'-, -NR'-O-C(S)-, -NR'-O-C(S)-O-, -NR'-O-C(S)-NR'-, -O-C(S)-, -O-C(S)-O-, -O-C(S)-NR'-, -NR'-C(S)-, -NR'-C(S)-O-, -NR'-C(S)-NR'-, -S-S(O)2-, -S-S(O)2-O-, -S-S(O)2-NR'-, -NR'-O-S(O)-, -NR'-O-S(O)-O-, -NR'-O-S(O)-NR'-, -NR'-O-S(O)2-, -NR'-O-S(O)2-O-, -NR'-O-S(O)2-NR'-, -O-NR'-S(O)-, -O-NR'-S(O)-O-, -O-NR'-S(O)-NR'-, -O-NR'-S(O)2-O-, -O-NR'-S(O)2-NR'-, -O-NR'-S(O)2-, -O-P(O)(R')2-, -S-P(O)(R')2-, and NR'-P(O)(R')2-, wherein each R' is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl, and z is 1-10;
L B is a covalent bond or a linker selected from the group consisting of-C=C-, -C.ident.C-, -(C(R')2)z-, -O-, -O-(CR'2)z-, -S-, -NR'-, -NH-(CR'2)z-, -N=N-, -C(O)-, -C(O)NR'-, -O-C(O)-, -O-C(O)-O-, -O-C(O)-NR'-, -NR'-C(O)-, -NR'-C(O)-O-, -NR'-C(O)-NR'-, -S-C(O)-, -S-C(O)-O-, -S-C(O)-NR'-, -SO-, -S(O)2-, -O-S(O)2-, -O-S(O)2-O-, -O-S(O)2-NR'-, -O-S(O)-, -O-S(O)-O-, -O-S(O)-NR'-, -O-NR'-C(O)-, -O-NR'-C(O)-O-, -O-NR'-C(O)-NR'-, -NR'-O-C(O)-, -NR'-O-C(O)-O-, -NR'-O-C(O)-NR'-, -O-NR'-C(S)-, -O-NR'-C(S)-O-, -O-NR'-C(S)-NR'-, -NR'-O-C(S)-, -NR'-O-C(S)-O-, -NR'-O-C(S)-NR'-, -O-C(S)-, -O-C(S)-O-, -O-C(S)-NR'-, -NR'-C(S)-, -NR'-C(S)-O-, -NR'-C(S)-NR'-, -S-S(O)2-, -S-S(O)2-O-, -S-S(O)2-NR'-, -NR'-O-S(O)-, -NR'-O-S(O)-O-, -NR'-O-S(O)-NR'-, -NR'-O-S(O)2-, -NR'-O-S(O)2-O-, -NR'-O-S(O)2-NR'-, -O-NR'-S(O)-, -O-NR'-S(O)-O-, -O-NR'-S(O)-NR'-, -O-NR'-S(O)2-O-, -O-NR'-S(O)2-NR'-, -O-NR'-S(O)2-, -O-P(O)(R')2-, -S-P(O)(R')2-, and NR'-P(O)(R')2-, wherein each R' is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl, and z is 1-10;
L C is -O-, -S-, -S(O)-, -S(O)2-, -NR-, -C(O)-, -(C(R')2)z-, or -C(S)-;

with a proviso that when A is L A is not -C(O)NH-, -CH2NH-, -CH2-O-, or -C(O)N(CH3)-; and said compound of Formula (I) is not
2. The compound of claim 1, wherein A, together with B, forms a fused ring system.
3. The compound of claim 1, wherein B, together with C, forms a fused ring system.
4. The compound of claim 1, wherein D is and d is 0-5.
5. The compound of claim 4, wherein each R5 is independently selected from the group consisting of halogen, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted C1-C5 alkoxy, substituted or unsubstituted five to six-membered heteroaryl, substituted or unsubstituted amino, and -N(R")2 wherein each R" is independently a substituted or unsubstituted C1-C5 alkyl or C3-C10 cycloalkyl.
6. The compound of claim 5, wherein D, together with R5, forms a fused ring system.
7. The compound of claim 4, wherein D is
8. The compound of claim 7, wherein each R5 is independently selected from the group consisting of halogen, substituted or unsubstituted C1-C5 alkyl, substituted or unsubstituted Cl-C5 alkoxy, substituted or unsubstituted five to six-membered heteroaryl, and -N(R")2 wherein each R" is independently a substituted or unsubstituted C1-C5 alkyl or C3-C10 cycloalkyl.
9. The compound of claim 1, wherein L c is NH-.
10. The compound of claim 1, wherein C is
11. The compound of claim 10, wherein C is
12. The compound of claim 11, wherein C is
13. The compound of claim 10, wherein C is selected from
14. The compound of claim 1, wherein B is and b is 0-2.
15. The compound of claim 14, wherein B is selected from
16. The compound of claim 15, wherein B is selected from
17. The compound of claim 16, wherein each R2 is independently selected from halogen or substituted or unsubstituted C1-C5 alkyl.
18. The compound of claim 1, wherein A is wherein F is CH or N.
19. The compound of claim 18, wherein R1 is halogen or substituted or unsubstituted C1-C5 alkyl.
20. The compound of claim 1, having a structure corresponding to Formula (II):
21. The compound of claim 20, having a structure corresponding to Formula (III):
22. The compound of claim 21, having a structure corresponding to Formula (IV):
23. The compound of claim 22, having a structure corresponding to Formula (V):
24. The compound of claim 23, having a structure corresponding to Formula (VI):
25. A composition comprising a compound of claim 1 and a pharmaceutically acceptable carrier.
26. A kit comprising a compound of claim 1 and instructions for use.
27. A method of modulating amyloid-beta (A.beta.) levels, comprising contacting a source of amyloid precursor protein (APP) or fragment thereof and/or A.beta. with an effective amount of a compound having a structure corresponding to Formula (VII):
(A1-L A1)0-1-(B1)-L B1(C1)-L c1-(D1) (VII) and pharmaceutically acceptable salts, and prodrugs thereof, wherein:
A1 is optional, and when present is a five or six-membered substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylene, heterocyclylene, arylene, or heteroarylene;
B1 is a five or six-membered substituted or unsubstituted cycloalkylene, heterocyclylene, arylene, or heteroarylene; or B, together with A, forms a fused ring system;
C1 is a five or six-membered substituted or unsubstituted arylene or heteroarylene;
D1 is a five or six-membered substituted or unsubstituted aryl, heteroaryl, arylene, or heteroarylene; and L A1 is optional, and when present is a covalent bond or a linker;
each of L B1 and L C1 is independently a covalent bond or a linker;

wherein said compound of Formula (VII) modulates A.beta. levels.
28. The method of claim 27, wherein A1 is optional, and when present is:
wherein each E is independently N, NR, C, CR1, S, or O provided that no more than four E's are heteroatoms;
R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;
each R1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;
or A1, when present is:
wherein each M is independently selected from CR1 or N, provided that no more than three M's are N; and B1 is:

wherein each G is independently CR2 or N, provided that no more than three G's are N;
each R2 is independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino;
C1 is:
wherein J is selected from the group consisting of CR3, O, S, N, and NR;
each K is independently N, NR, C, or CR3; and R3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted alkoxy;
or C1 is:
wherein each M is independently selected from CR1 or N, provided that no more than three M's are N;
D1 is:

wherein each E is independently N, NR, C, CR1, S, or O provided that no more than four E's are heteroatoms;
or D1 is:
wherein each M is independently selected from CR5 or N, provided that no more than three M's are N;
each R5 is independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted amino, or substituted or unsubstituted alkylamino;
LA1, when present, and each of L B1 and L C1 is independently a covalent bond or a linker selected from the group consisting of-C=C-, -C=C-, -(C(R')2)z-,-O-, -O-(CR'2)z-,-S-, -NR'-,-NH-(CR'2)z-,-N=N-,-C(O)-,-C(O)NR'-,-O-C(O)-, -O-C(O)-O-,-O-C(O)-NR'-,-NR'-C(O)-,-NR'-C(O)-O-,-NR'-C(O)-NR'-, -S-C(O)-,-S-C(O)-O-,-S-C(O)-NR'-,-S(O)-,-S(O)2-,-O-S(O)2-,-O-S(O)2-O--O-S(O)2-NR'-,-O-S(O)-,-O-S(O)-O-,-O-S(O)-NR'-,-O-NR'-C(O)-, -O-NR'-C(O)-O-,-O-NR'-C(O)-NR'-,-NR'-O-C(O)-,-NR'-O-C(O)-O-, -NR'-O-C(O)-NR'-,-O-NR'-C(S)-,-O-NR'-C(S)-O-,-O-NR'-C(S)-NR'-, -NR'-O-C(S)-,-NR'-O-C(S)-O-,-NR'-O-C(S)-NR'-,-O-C(S)-,-O-C(S)-O-, -O-C(S)-NR'-,-NR'-C(S)-,-NR'-C(S)-O-,-NR'-C(S)-NR'-,-S-S(O)2-, -S-S(O)2-O-,-S-S(O)2-NR'-,-NR'-O-S(O)-,-NR'-O-S(O)-O-, -NR'-O-S(O)-NR'-,-NR'-O-S(O)2-,-NR'-O-S(O)2-O-,-NR'-O-S(O)2-NR'-, -O-NR'-S(O)-,-O-NR'-S(O)-O-,-O-NR'-S(O)-NR'-,-O-NR'-S(O)2-O-, -O-NR'-S(O)2-NR'-,-O-NR'-S(O)2-,-O-P(O)(R')2-,-S-P(O)(R')2-, and NR'-P(O)(R')2-, wherein each R' is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl, and z is 1-10.
29. The method of claim 28, wherein L C1 is -O-, -S-, -S(O)-, -S(O)2-, -NR-, -C(O)-, -(C(R')2)z-, or -C(S)-.
30. The method of claim 29, wherein said compound has a structure corresponding to Formula (II):
31. The method of claim 30, wherein said compound has a structure corresponding to Formula (III):
32. The method of claim 31, wherein said compound has a structure corresponding to Formula (IV):

33. The method of claim 32, wherein said compound has a structure corresponding to Formula (V):
34. The method of claim 33, wherein said compound has a structure corresponding to Formula (VI):
35. A method for treating a disease associated with aberrant A.beta. levels, comprising administering to a subject in need thereof an effective amount of a compound having a structure corresponding to Formula (VII):
(A1-L A1)0-1-(B1)-L B1-(C1)-L C1-(Di) (VII) and pharmaceutically acceptable salts, and prodrugs thereof, wherein:
A1 is optional, and when present is a five or six-membered substituted or unsubstituted cycloalkyl, heterocyclyl, aryl, heteroaryl, cycloalkylene, heterocyclylene, arylene, or heteroarylene;
B1 is a five or six-membered substituted or unsubstituted cycloalkylene, heterocyclylene, arylene, or heteroarylene; or B, together with A, forms a fused ring system;
C1 is a five or six-membered substituted or unsubstituted arylene or heteroarylene;
D1 is a five or six-membered substituted or unsubstituted aryl, heteroaryl, arylene, or heteroarylene; and L A1 is optional, and when present is a covalent bond or a linker;
each of L B1 and L C1 is independently a covalent bond or a linker;
wherein said compound of Formula (VII) modulates A.beta. levels.
36. The method of claim 35, wherein A1 is optional, and when present is:

wherein each E is independently N, NR, C, CR1, S, or O provided that no more than four E's are heteroatoms;
R is hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;
each R1 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino, substituted or unsubstituted cycloalkyl, or substituted or unsubstituted aryl;
or A1, when present is:
wherein each M is independently selected from CR1 or N, provided that no more than three M's are N; and B1 is:
wherein each G is independently CR2 or N, provided that no more than three G's are N;
each R2 is independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted alkylamido, substituted or unsubstituted alkylamino, substituted or unsubstituted amino;
C1 is:
wherein J is selected from the group consisting of CR3, O, S, N, and NR;
each K is independently N, NR, C, or CR3; and each R3 is hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted alkoxy;
or C1 is:
wherein each M is independently selected from CR1 or N, provided that no more than three M's are N;
D1 is:
wherein each E is independently N, NR, C, CR1, S, or O provided that no more than four E's are heteroatoms;
or D1 is:

wherein each M is independently selected from CR5 or N, provided that no more than three M's are N;
each R5 is independently selected from hydrogen, halogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycle, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or substituted or unsubstituted amino, or substituted or unsubstituted alkylamino;
L A1, when present, and each of L B1 and L C1 is independently a covalent bond or a linker selected from the group consisting of-C=C-, -C.ident.C-, -(C(R')2)z-, -O-, -O-(CR'2)z-, -S-, -NR'-, -NH-(CR'2)z-, -N=N-, -C(O)-, -C(O)NR'-, -O-C(O)-, -O-C(O)-O-, -O-C(O)-NR'-, -NR'-C(O)-, -NR'-C(O)-O-, -NR'-C(O)-NR'-, -S-C(O)-, -S-C(O)-O-, -S-C(O)-NR'-, -S(O)-, -S(O)2-, -O-S(O)2-, -O-S(O)2-O--O-S(O)2-NR'-, -O-S(O)-, -O-S(O)-O-, -O-S(O)-NR'-, -O-NR'-C(O)-, -O-NR'-C(O)-O-, -O-NR'-C(O)-NR'-, -NR'-O-C(O)-, -NR'-O-C(O)-O-, -NR'-O-C(O)-NR'-, -O-NR'-C(S)-, -Q-NR'-C(S)-O-, -O-NR'-C(S)-NR'-, -NR'-O-C(S)-, -NR'-O-C(S)-O-, -NR'-O-C(S)-NR'-, -O-C(S)-, -O-C(S)-O-, -O-C(S)-NR'-, -NR'-C(S)-, -NR'-C(S)-O-, -NR'-C(S)-NR'-, -S-S(O)2-, -S-S(O)2-O-, -S-S(O)2-NR'-, -NR'-O-S(O)-, -NR'-O-S(O)-O-, -NR'-O-S(O)-NR'-, -NR'-O-S(O)2-, -NR'-O-S(O)2-O-, -NR'-O-S(O)2-NR'-, -O-NR'-S(O)-, -O-NR'-S(O)-O-, -O-NR'-S(O)-NR'-, -O-NR'-S(O)Z-O-, -O-NR'-S(O)2-NR'-, -O-NR'-S(O)2-, -O-P(O)(R')2-, -S-P(O)(R')2-, and NR'-P(O)(R')a-, wherein each R' is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, or substituted or unsubstituted cycloalkyl, and z is 1-10.
37. The method of claim 36, wherein L C1 is -O-, -S-, -S(O)-, -S(O)2-, -NR-, -C(O)-, -(C(R')2)Z-, or -C(S)-.
38. The method of claim 37, wherein said compound has a structure corresponding to Formula (II):
39. The method of claim 38, wherein said compound has a structure corresponding to Formula (III):
40. The method of claim 39, wherein said compound has a structure corresponding to Formula (IV):
41. The method of claim 40, wherein said compound has a structure corresponding to Formula (V):

42. The method of claim 41, wherein said compound has a structure corresponding to Formula (VI):

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