ZA200709236B

ZA200709236B - Compounds which inhibit beta-secretase activity and methods of use thereof

Info

Publication number: ZA200709236B
Application number: ZA200709236A
Authority: ZA
Inventors: Ghosh Arun; Kumaragurubaran Nagaswamy; Liu Chunfeng; Devasamudram Thippeswamy; Lei Hui; Swanson Lisa; Bilcer Geoffrey; Ankala Sudha; Tang Jordan
Original assignee: Comentis Inc; Univ Illinois; Oklahoma Med Res Found; Purdue Research Foundation
Priority date: 2005-04-08
Filing date: 2006-04-10
Publication date: 2009-06-24
Also published as: CN101198583A

Description

—._. DE ——

COMPOUNDS WHICH INHIBIT BETA-SECRETASE ACTIVITY AND

METHODS OF USE THEREOF

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application claims the benefit of U.S. Patent Application 60/669,541, filed

April 8, 2005, and U.S. Patent Application 60/717,541, filed September 14, 2005, each of which is incorporated herein by reference in their entirety for all purposes.

STATEMENT AS TO RIGHTS TO INVENTIONS MADE UNDER

FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

+ [0002] The invention was made with government support under grants AG-18933 and Al- l0 38189 awarded by the National Institutes of Health. The Government has certain rights in the invention.

BACKGROUND OF THE INVENTION

[0003] Alzheimer's disease is a progressive mental deterioration in a human resulting, inter alia, in loss of memory, confusion and disorientation. Alzheimer's disease accounts for the {S majority of senile dementias and is a leading cause of death in adults (Anderson, R. N., Natl

Vital Stat. Rep. 49:1-87 (2001), the teachings of which are incorporated herein in their entirety). Histologically, the brain of persons afflicted with Alzheimer's diseaseis ~~ = characterized by a distortion of the intracellular neurofibrils and the presence of senile plaques composed of granular or filamentous argentophilic masses with an amyloid protein '0 core, largely due to the accumulation of B-amyloid protein (Ap) in the brain. AB accumulation plays a role in the pathogenesis and progression of the disease (Selkoe, D.J.,

Nature 399: 23-31 (1999)) and is a proteolytic fragment of amyloid precursor protein (APP).

APP is cleaved initially by B—secretase (also referred to as memapsin 2) followed by y- secretase to generate AB (Lin, X,, ef al, Proc. Natl. Acad. Sci. USA 97:1456-1460 (2000); De 5 Stropper, B., et al., Nature 391:387-390 (1998)). :

[0004] There is a need to develop effective compounds and methods for the treatment of

Alzheimer's disease. The present invention fulfills these and other needs.

BRIEF SUMMARY OF THE INVENTION

[0005] The present invention provides novel B-secretase inhibitors and methods for their 0 use, including methods of treating Alzheimer's disease.

[0006] In one aspect, the present invention provides a B-secretase inhibitor compound having the formula:

R3 R? 6 OH 7 (hh 1A aN HA o rR 0

RS O.

[0007] In Formula (I), R! is halogen, -OH, -CFs, -NO,, -NR*R’, -OR'?, -S(O).R"), -C(O)R'?, hydrogen, substituted or unsubstituted C3-Ca alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or

Ly.

[0008] R?® is halogen, -OH, -CFs, -NO,, -NR®R®, -OR"?, -5(0).R!!, -C(O)R"?, hydrogen, : substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0009] R? and R® are independently halogen, -CFs, -NO,, -NR®R’, -OR'?, -S(O).R"", -C(O)R™, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or :

LAY.

[0010] R*is halogen, -OH, -CF, -NO;, -NR*R’, -OR", -S(O),R", -C(O)R'2, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or LAY.

[0011] R®and R’ are independently -S(O);R"", -C(O)R"?, -NR®R®, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or -L*-Y.

[0012] The symbol n represents integers from 0 to 2.

: [0013] R® is independently -C(O)R', -S(O);R", hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. :

[0014] R’isindependently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0015] R'is independently -C(O)RP, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0016] R!!is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

If nis 2, then R!! is optionally -NR"R!S. Ifnis 1 or 2, then R! is not hydrogen.

[0017] R'is independently -NRYRY, -ORY, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0018] R'is independently -ORY, .NR'®R', hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0019] Ris independently -NR'®R', hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0020] R'® and R" are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0021] R' and R'® are independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0022] L'and Lr’ are independently a bond, NR", -S(O)q-~, substituted or unsubstituted alkylene, or substituted or unsubstituted heteroalkylene. L? is substituted or unsubstituted alkylene, -NR'’-, -S(0)q-, or substituted or unsubstituted heteroalkylene.

[0023] R'is independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0024] The symbol q represents an integer from 0 to 2.

[0025] A! and A? are independently substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. Y is a carrier moiety.

[0026] L*is a bond, -OP(OH),0-, -C(O)OR%-, -C(O)NHR?'-, -S(0);NHR?-, substituted or unsubstituted alkylene, substituted or unsubstituted heteroalkylene, or a peptidyl linker.

[0027] R*,R?, and R** are independently substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

[0028] In another aspect of the present invention, the 3-secretase inhibitor compounds of the invention can be employed in methods to decrease memapsin 2 catalytic activity, decrease hydrolysis of a B-secretase site of a memapsin 2 substrate, and/or decrease the accumulation of B-amyloid protein relative to the amount of memapsin 2 catalytic activity, hydrolysis of a

B-secretase site, and accumulation of B-amyloid protein, respectively, in the absence of the B- secretase inhibitor.

[0029] In another aspect, the present invention provides pharmaceutical compositions comprising a memapsin 2 B-secretase inhibitor compound of the invention or a memapsin 2 B-secretase inhibitor compound in combination with a pharmaceutically acceptable carrier.

[0030] In another aspect of the present invention, the B-secretase inhibitor compounds of } the invention can be employed in the treatment of diseases or conditions associated with B-

secretase activity, hydrolysis ofa B-secretase site of a B-amyloid precursor protein, and/or B- amyloid protein accumulation. Typically, a mammal is treated for the disease or condition.

In an exemplary embodiment, the disease is Alzheimer's disease. . DETAILED DESCRIPTION OF THE INVENTION

Abbreviations and Definitions

[0031] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The chemical structures and formulae set forth herein are constructed according to the standard rules of chemical valency known in the chemical arts.

[0032] Where substituent groups are specified by their conventional chemical formulae, written from left to right, they equally encompass the chemically identical substituents that would result from writing the structure from right to left, e.g., -CH,O- is equivalent to -OCHz-.

[0033] The term "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched chain, or combination thereof, which may be fully saturated, mono- or polyunsaturated and can include di- and multivalent radicals, having the number of carbon atoms designated (i.e. C1-C;o means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n- propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, (cyclohexyl)methyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and the higher homologs and isomers. An alkoxy is an alkyl attached to the remainder of the molecule via an oxygen linker (-O-).

[0034] The term "alkylene" by itself or as part of another substituent means a divalent radical derived from an alkyl, as exemplified, but not limited, by -CH,CH,CH,CH>-, and further includes those groups described below as "heteroalkylene." Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is ashorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.

[0035] The term "heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of at least one carbon atoms and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which the alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to, -CH,-CH,-O-CHj, L -CH,-CH,-NH-CHj, -CH,-CH,-N(CH3)-CHjs, -CH,-S-CH,-CHa, -CH;-CHa,-S(0)-CHs, -

CH,-CH,-S(0),-CHj;, -CH=CH-0O-CHj, -Si(CH3)s, -CH,-CH=N-OCH3;, -CH=CH-N(CH3)-

CH, O-CHj, -O-CH,-CH;, and —~CN. Up to two heteroatoms may be consecutive, such as, for example, -CH,-NH-OCHj3 and —CH,-O-Si(CHs)s. Similarly, the term "heteroalkylene" by | : itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, -CH,-CH,-S-CH,-CH;- and —CH,-S-CH;-CH;-NH-CH,-.

For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxy, alkylenedioxy, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula —C(O),R'- represents both —C(0),R'- and —R'C(0),-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(O)R', -C(O)NR', -NR'R, -OR', -SR, and/or -

SO,R'. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R or the like, it will be understood that the terms heteroalkyl and -NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific "heteroalkyl groups, such as -NR'R" or the like.

[0036] The terms "cycloalkyl" and "heterocycloalkyl", by themselves or in combination with other terms, represent, unless otherwise stated, cyclic versions of "alkyl" and "heteroalkyl", respectively. Additionally, for heterocycloalkyl, a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule. Examples of cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3- cyclohexenyl, cycloheptyl, and the like. Examples of heterocycloalkyl include, but are not limited to, 1 —(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4- morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofuran-3-yl, tetrahydrothien-2-yl, tetrahydrothien-3-yl, 1 —piperazinyl, 2-piperazinyl, and the like.

[0037] The terms "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl. For : example, the term "halo(C,-C4)alkyl" is mean to include, but not be limited to, trifluoromethyl, 2,2,2-triflucroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.

[0038] The term "aryl" means, unless otherwise stated, a polyunsaturated, aromatic, hydrocarbon substituent which can be a single ring or multiple rings (preferably from 1 to 3 rings) which are fused together or linked covalently. The term "heteroaryl" refers to aryl _ groups (or rings) that contain from one to four heteroatoms selected from N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom(s) are optionally quaternized. A heteroaryl group can be attached to the remainder of the molecule through a carbon or heteroatom. Non-limiting examples of aryl and heteroaryl groups include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3- pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4- oxazolyl, 5-oxazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5- thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidyl, 4- pyrimidyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl, 1-isoquinolyl, 5- isoquinolyl, 2-quinoxalinyl, 5-quinoxalinyl, 3-quinolyl, and 6-quinolyl. Substituents for each of the above noted aryl and heteroaryl ring systems are selected from the group of acceptable substituents described below. }

[0039] For brevity, the term "aryl" when used in combination with other terms (e.g., : aryloxy, arylthioxy, arylalkyl) includes both aryl and heteroaryl rings as defined above.

Thus, the term "arylalkyl" is meant to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl and the like) including those alkyl groups in which a carbon atom (e.g., a methylene group) has been replaced by, for example, an oxygen atom (e.g., phenoxymethyl, 2-pyridyloxymethyl, 3-(1- naphthyloxy)propyl, and the like).

[0040] The term "oxo" as used herein means an oxygen that is double bonded to a carbon atom.

[0041] The term "alkylsulfonyl" as used herein means a moiety having the formula -S(O,)-

R', where R'is an alkyl group as defined above. R' may have a specified number of carbons (e.g. "C:1-C4 alkylsulfonyl").

[0042] Each of the above terms (e.g., "alkyl," "heteroalkyl," "aryl" and "heteroaryl") are , meant to include both substituted and unsubstituted forms of the indicated radical. Preferred substituents for each type of radical are provided below.

[0043] Substituents for the alkyl and heteroalkyl radicals (including those groups often - referred to as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, ; : heterocycloalkyl, cycloalkenyl, and heterocycloalkenyl) can be one or more of a variety of groups selected from, but not limited to: -OR', =0, =NR', =N-OR', -NRR", -SR', -halogen, - - SiRR"R™, -OC(O)R', -C(O)R', -COzR', -CONR'R", -OC(O)NRR", -NR"C(O)R’, -NR'-C(O)NR"R", -NR"C(O).R', -NR-C(NRR"R"")=NR"", -NR-C(NR'R")=NR", -S(O)R', - S(O)R!, -S(0);NR'R", -NRSO,R', -CN and -NO, in a number ranging from zero to (2m'+1), where m' is the total number of carbon atoms in such radical. R' R" R" and R"™ each preferably independently refer to hydrogen, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl (e.g., aryl substituted with 1-3 halogens), substituted or unsubstituted alkyl, alkoxy or thioalkoxy groups, or arylalkyl groups. When a compound of the invention includes more than one R group, for example, each of the R groups is independently selected as are each R', R", R" and R"" groups when more than one of these groups is present. When R' and R" are attached to the same nitrogen atom, they can be combined with the nitrogen atom to form a 4-, 5-, 6-, or 7-membered ring. For example, -NRR" is meant to include, but not be limited to, 1-pyrrolidinyl and 4-morpholinyl. From the above discussion of substituents, one of skill in the art will understand that the term "alkyl" is meant to include groups including carbon atoms bound to groups other than hydrogen groups, such as haloalkyl (e.g., -CF3 and —CH,CF3;) and acyl (e.g., -C(O)CHj, -C(O)CF3, -C(O)CH,0OCHj3, and the like).

[0044] Similar to the substituents described for the alkyl radical, substituents for the aryl and heteroaryl groups are varied and are selected from, for example: halogen, -OR', -NR'R", -SR!, -halogen, -SiRR"R", -OC(O)R', -C(O)R’, -CO,R', -CONR'R", -OC(O)NRR", -NR"C(O)R', -NR'-C(O)NR"R"', -NR"C(O);R', -NR-C(NR'R"R"")=NR"", -NR-C(NRR")=NR"', -S(O)R', -S(0)2R’, -S(0):NRR", -NRSO;R', -CN and -NOg, -R', -N3, -CH(Ph),, fluoro(C,;-Cs)alkoxy, and fluoro(C;-Cs)alkyl, in a number ranging from zero to the total number of open valences on the aromatic ring system; and where R', R", R" and R"" are preferably independently selected from hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or

Claims

ER WHATIS CLAIMED IS: 0) En —

1 1. A compound having the formula: Se Co ‘Rr! - R3 R2 | . Seana ll o rR oOo 1 2 RS , 3 wherein 4 R! is halogen, -OH, -CFs, -NO,, -NR®*R’, -OR"?, -S(O).R"", -C(O)R", hydrogen, substituted or unsubstituted C3-Cy alkyl, substituted or 6 unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, 7 substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted 8 aryl, substituted or unsubstituted heteroaryl, or hy; 9 R’ is halogen, -OH, -CF;, -NO,, -NR®R?, -OR'?, -S(O):R", -C(O)R", hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted 11 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or 12 unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or 13 substituted or unsubstituted heteroaryl; 14 R? and R? are independently halogen, -CFs, -NO,, -NR®R?, -OR'?, -S(0).R"", -C(O)R'?, hydrogen, substituted or unsubstituted alkyl, substituted or 16 unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, 17 substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted 18 aryl, substituted or unsubstituted heteroaryl, or -L*-Y; 19 R* is halogen, -OH, -CFj, -NO,, -NR®R’, -OR'%, -S(O),R"}, -C(O)R", "hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted 21 heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or 22 unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, 23 substituted or unsubstituted heteroaryl, or -L*-Y; 2 R® and R’ are independently -S(O);R'!, -C(O)R'?, -NR°R®, hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, 26 substituted or unsubstituted cycloalkyl, substituted or unsubstituted 27 heterocycloalkyl, substituted or unsubstituted aryl, substituted or 28 unsubstituted heteroaryl, or -L*-Y;

THe iS . l bs i fin, ie

9 n is independently 0, 1, or 2; Conky 0 RY is independently -C(O)R ">, -S(O);R", hydrogen, substituted or — 1 unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or CT Ry 2 unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, hn 3 substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl;

4 Ris independently hydrogen, substituted or unsubstituted alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,

6 substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted v7 aryl, or substituted or unsubstituted heteroaryl;

8 R!® is independently -C(O)R", substituted or unsubstituted alkyl, substituted

9 or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,

0 substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted

H aryl, or substituted or unsubstituted heteroaryl;

12 R! is independently hydrogen, substituted or unsubstituted alkyl, substituted

I3 or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl,

4 substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted

' aryl, or substituted or unsubstituted heteroaryl, wherein if n is 2, then RM!

16 is optionally NR RS, and wherein ifnis 1 or 2, then R! is not hydrogen;

7 R" is independently -NR®RY, -ORY, hydrogen, substituted or unsubstituted : 18 alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted

19 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

50 unsubstituted aryl, or substituted or unsubstituted heteroaryl;

31 R" is independently -ORY, -NR®RY, hydrogen, substituted or unsubstituted

32 alkyl, substituted or unsubstituted heteroalkyl, substituted or unsubstituted 53 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

54 unsubstituted aryl, or substituted or unsubstituted heteroaryl,

55 R'is independently -NR'®R'®, hydrogen, substituted or unsubstituted alkyl,

56 substituted or unsubstituted heteroalkyl, substituted or unsubstituted

57 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or

58 unsubstituted aryl, or substituted or unsubstituted heteroaryl, wherein

59 R' and R" are independently hydrogen, substituted or unsubstituted alkyl,

60 substituted or unsubstituted heteroalkyl, substituted or unsubstituted

61 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or 62 unsubstituted aryl, or substituted or unsubstituted heteroaryl;

33 a RS and R'6 are independently hydrogen, substituted or unsubstituted alkyl, 4 substituted or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or ol — w 36 unsubstituted aryl, or substituted or unsubstituted heteroaryl, 37 L! and L? are independently a bond, -NR'-, -S(0)q-, substituted or 38 unsubstituted alkylene, or substituted or unsubstituted heteroalkylene; : 59 © Lis substituted or unsubstituted alkylene, -NR'"-, -S(0)q-, or substituted or 70 unsubstituted heteroalkylene; 71 R'is independently hydrogen, substituted or unsubstituted alkyl, substituted 72 or unsubstituted heteroalkyl, substituted or unsubstituted cycloalkyl, 73 substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted 74 aryl, or substituted or unsubstituted heteroaryl, - , 75 | qis independently 0, 1, or 2; 76 | A! and A? are independently substituted or unsubstituted cycloalkyl, 77 substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted 78 aryl, or substituted or unsubstituted heteroaryl; 79 Y is a carrier moiety; and 80 L* is a bond, -OP(OH),0-, -C(O)OR-, -C(O)NHR?'-, -S(O),NHR*-, 81 substituted or unsubstituted alkylene, substituted or unsubstituted 82 heteroalkylene, or a peptidyl linker, wherein 83 © R®, R?, and R* are independently substituted or unsubstituted alkyl, 84 : substituted or unsubstituted heteroalkyl, substituted or unsubstituted 85 cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted 86 or unsubstituted aryl, or substituted or unsubstituted heteroaryl.

1 2. The compound of claim 1, wherein R! is hydrogen, halogen, -NR*R®, 2 -ORY, or-S(O).R".

1 3. The compound of claim 1, wherein R' is hydrogen, -NR’S(O).R"*, 2 -OR", or -S(O).R'%.

1 4. The compound of claim 1, wherein R' is hydrogen or -NR’S(O).R".

1 5. The compound of claim 1, wherein R’, R®, R, R"®, and R"" are 2 independently hydrogen, substituted or unsubstituted Ci-Cyg alkyl, substituted or

SUPER... 3 unsubstituted 2 to 20 membered heteroalkyl, substituted or unsubstituted Cs-C; cyclo alkyl 4 substituted or unsubstituted 5 to 7 membered heterocycloalkyl, substituted or unsubstituted ; aryl, substituted or unsubstituted heteroaryl, or Ay.

1 6. The compound of claim 1, wherein each substituted or unsubstituted 2 alkyleneisan R2-substituted or unsubstituted C;-Cy alkylene, each substituted or 3 unsubstituted heteroalkylene is an R*-substituted or unsubstituted 2 to 20 membered 4 heteroalkylene, each substituted or unsubstituted alkyl is an R*-substituted or unsubstituted 5 C1-Cyo alkyl, each substituted or unsubstituted heteroalkyl is an R®-substituted or 6 unsubstituted 2 to 20 membered heteroalkyl, each substituted or unsubstituted cycloalkyl is 7 an R®-substituted or unsubstituted Cs-C; cycloalkyl, each substituted or unsubstituted 8 heterocycloalkyl is an R*-substituted or unsubstituted 5 to 7 membered heterocycloalkyl, 9 each substituted or unsubstituted heteroaryl is an R%-substituted or unsubstituted heteroaryl, 0 and each substituted or unsubstituted aryl is an R*-substituted or unsubstituted aryl, wherein (1 R? is independently oxo, halogen, -CN, -CFs, -OCFs, -OR”, -S(O)R”, 12 _OCH3, -C(O)R¥, -NR*R¥, -NR*®C(O)RY, -C(O)NR™R”, R”- 13 substituted or unsubstituted C;-Cy allyl, R*>-substituted or unsubstituted 2 4 to 20 membered heteroalkyl, R%®-substituted or unsubstituted Cs-Cy (5 cycloalkyl, R¥-substituted or unsubstituted 5 to 7 membered 16 heterocycloalkyl, R**-substituted or unsubstituted heteroaryl, or R*- 17 substituted or unsubstituted aryl; 18 R* is independently halogen, -CN, -CF3, -OCF3, -OCHj, OR, -S(O)R”, 19 OCH, -C(O)R?’, .-NR®R?, -NR®C(O)R?, -C(O)NR*R”, R®- substituted or unsubstituted C;-Cyp alkyl, R*-substituted or unsubstituted 2 21 to 20 membered heteroalkyl, R?-substituted or unsubstituted Cs-Cy 22 cycloalkyl, R%.substituted or unsubstituted 5 to 7 membered 23 heterocycloalkyl, R%%_substituted or unsubstituted heteroaryl, or R%. 24 substituted or unsubstituted aryl; t is independently 0, 1, or 2; 26 R%, R®, and R* are independently hydrogen, R%.substituted or unsubstituted 27 : Ci-Cyo alkyl, R®-substituted or unsubstituted 2 to 20 membered 28 heteroalkyl, R?-substituted or unsubstituted Cs-C; cycloalkyl, R- 29 substituted or unsubstituted 5 to 7 membered heterocycloalkyl, R%.

SF fo substituted or unsubstituted heteroaryl, or Nw 2] aryl, wherein if t is 1 or 2, then R? is not hydrogen, and wherein R? is independently oxo, halogen, -CN, -OH, -CFs, -OCFs, -OCHs, unsubstituted C;-Ca alkyl, unsubstituted 2 to 20 membered heteroalkyl, unsubstituted Cs-Cy cycloalkyl, unsubstituted 5 to 7 membered heterocycloalkyl, unsubstituted aryl, or unsubstituted ) heteroaryl, and - R* is independently halogen, -CN, -OH, -CF3, -OCF3, -OCH;, } unsubstituted C;-Cso alkyl, unsubstituted 2 to 20 membered ) heteroalkyl, unsubstituted Cs-Cy cycloalkyl, unsubstituted 5 to 7 ) membered heterocycloalkyl, unsubstituted aryl, or unsubstituted l heteroaryl. :

1. The compound of claim 6, wherein R?, R, RS, R%, R'%, R", and R' are 2? independently R™-substituted or unsubstituted C;-Cao alkyl, R%.substituted or unsubstituted 3 2 to 20 membered heteroalkyl, R®-substituted or unsubstituted Cs-C7 cycloalkyl, RE. 4 substituted or unsubstituted 5 to 7 membered heterocycloalkyl, R2*_substituted or unsubstituted heteroaryl, or R**-substituted or unsubstituted aryl.

1 8. The compound of claim 7, wherein 2 RY, R®, and R* are independently hydrogen, R*-substituted or unsubstituted

3 C.-C alkyl, or R¥ substituted or unsubstituted 2 to 20 membered 4 heteroalkyl; BE R? is independently oxo, halogen, -CN, -CFs, -OCFs, -OR”, SOR”, 6 _OCHj, -C(O)RY’, -NR*®R?, -NR*C(O)R”, -C(O)NR?*R”, R*- 7 substituted or unsubstituted C;-Cy alkyl, or R®-substituted or 8 unsubstituted 2 to 20 membered heteroalkyl; and 9 Ris independently halogen, -CN, -CF3, -OCF3, -OCHj, -OR?, -S(O)RY, -OCHs, -C(O)RY, -NR?*R?, -NR®C(O)R”, -C(O)NR*R”, R*- (1 substituted or unsubstituted C,-Cy alkyl, orR**-substituted or 12 unsubstituted 2 to 20 membered heteroalkyl.

1 9. The compound of claim 6, wherein R%, R®, R%, R°, R'", R"!, and R*? are 2 substituted or unsubstituted C;-Cqg alkyl or substituted or unsubstituted heterocycloalkyl.

ET Baa

“Hep

1 10. The compound of claim 6, wherein R% R®, R® R’ R® R! and R'? are a

2 unsubstituted C;-Cy alkyl.

E 1 11. The compound of claim 6, wherein R%, R?, R®, R%, R!%, R'!, and R'? are 2 unsubstituted C,-Cs alkyl. ) :

1 12. The compound of claim 1, wherein R? and R? are independently

2 hydrogen, halogen, or unsubstituted C;-Cy alkyl.

1 13. The compound of claim 6, wherein R’ is RZ-substituted or

2 unsubstituted Cs-C; cycloalkyl, R*-substituted or unsubstituted 5 to 7 membered

3 heterocycloalkyl, R**-substituted or unsubstituted heteroaryl, or R*_substituted or

4 unsubstituted aryl.

1 14. The compound of claim 6, wherein R’ is R**-substituted or

2 unsubstituted heteroaryl, or R**-substituted or unsubstituted aryl.

1 15. The compound of claim 6, wherein R’ is R*-substituted or

2 unsubstituted aryl.

1 16. The compound of claim 1, wherein R’ is selected from substituted or

2 unsubstituted tetrahydrofuranyl, substituted or unsubstituted tetrahydropyranyl, and

3 substituted or unsubstituted pyridylmethyl.

1 17. The compound of claim 16, wherein L? is unsubstituted C;-Cs alkyl.

1 18. The compound of claim 17, wherein L? is methylene.

1 "19. The compound of claim 15, wherein R** is halogen, -CN, -OH, -CF3,

2 unsubstituted C;-Cy alkyl, or unsubstituted alkoxy.

1 20. The compound of claim 19, wherein R° is a difluorophenyl.

1 21. The compound of claim 15, wherein R’ is phenyl.

1 22. The compound of claim 21, wherein 1? is unsubstituted C,-Cs

2 alkylene. oo

SE rm bee

1 23. The compound of claim 21, wherein L? is unsubstituted 2 to 5 2 membered heteroalkylene. 1 24. The compound of claim 23, wherein Lis -(CH,)e-S-, wherein the 2 symbol e represents an integer from 0 to 10. 1 25. The compound of claim 24, wherein e is 1. : 1 26. The compound of claim 1, wherein A’ and A? are independently 2 substituted or unsubstituted Cs-C7 cycloalkyl, substituted or unsubstituted 5 to 7 membered 3 heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl. 1 27. The compound of claim 1, wherein A? is substituted or unsubstituted 2 aryl, or substituted or unsubstituted heteroaryl. 1 28. The compound of claim 1, wherein A! and A? are independently 2 substituted or unsubstituted phenyl, substituted or unsubstituted pyrazolyl, substituted or 3 unsubstituted furanyl, substituted or unsubstituted imidazolyl, substituted or unsubstituted 4 isoxazolyl, substituted or unsubstituted oxadiazolyl, substituted or unsubstituted oxazolyl, substituted or unsubstituted pyrrolyl, substituted or unsubstituted pyridyl, substituted or 6 unsubstituted pyrimidyl, substituted or unsubstituted pyridazinyl, substituted or unsubstituted 7 thiazolyl, substituted or unsubstituted triazolyl, substituted or unsubstituted thienyl, 8 substituted or unsubstituted dihydrothieno-pyrazolyl, substituted or unsubstituted 9 thianaphthenyl, substituted or unsubstituted carbazolyl, substituted or unsubstituted benzimidazolyl, substituted or unsubstituted benzothienyl, substituted or unsubstituted 11 benzofuranyl, substituted or unsubstituted indolyl, substituted or unsubstituted quinolinyl, 12 substituted or unsubstituted benzotriazolyl, substituted or unsubstituted benzothiazolyl, 13 substituted or unsubstituted benzooxazolyl, substituted or unsubstituted benzimidazolyl, 14 substituted or unsubstituted isoquinolinyl, substituted or unsubstituted isoindolyl, substituted or unsubstituted acridinyl, substituted or unsubstituted benzoisazolyl, substituted or 16 unsubstituted dimethylhydantoin, substituted or unsubstituted pyrazinyl, substituted or 17 unsubstituted tetrahydrofuranyl, substituted or unsubstituted pyrrolinyl, substituted or 18 unsubstituted pyrrolidinyl, substituted or unsubstituted morpholinyl, substituted or 19 unsubstituted indolyl, substituted or unsubstituted diazepinyl, substituted or unsubstituted azepinyl, substituted or unsubstituted thiepinyl, substituted or unsubstituted piperidinyl, ot”

21 substituted or unsubstituted oxepinyl. ! 1 | 29. The compound of claim 1, wherein A? is substituted or unsubstituted 2 aryl 1 30. The compound of claim 1, wherein A? is substituted or unsubstituted 2 phenyl. 1 31. The compound of claim 1, wherein A? is substituted or unsubstituted

2 heteroaryl.

1 32. The compound of claim 1, wherein A? is substituted or unsubstituted

2 pyridyl ] 33. The compound of claim 1, wherein 13 and L! are independently a

2 bond, unsubstituted alkylene, or unsubstituted heteroalkylene. 1 34. The compound of claim 1, wherein L? and L' are independently a

2 bond, unsubstituted C,-Cy alkylene, or unsubstituted 2 to 20 membered heteroalkylene. 1 35. The compound of claim 1, wherein L* and L' are independently a

2 bond, unsubstituted C;-Cs alkylene, or unsubstituted 2 to 5 membered heteroalkylene. 1 36. The compound of claim 1, wherein L? is C;-Cs alkylene.

1 37. The compound of claim 1, wherein L! is a branched unsubstituted C;-
2 Cs alkylene.

1 38. The compound of claim 1, wherein 1? is unsubstituted C1-Cyo alkylene, 2 or unsubstituted 2 to 20 membered heteroalkylene.

1 39. The compound of claim 1, wherein L? is unsubstituted C;-Cs alkylene, ~~ . 2 or unsubstituted 2 to 5 membered heteroalkylene.

1 40. The compound of claim 1, wherein L? is unsubstituted C;-Cs alkylene.

1 41. The compound of claim 1, wherein L? is a branched unsubstituted C;-

2 Cs alkylene.

NE

‘ (A rg

1 42, The compound of claim 1, wherein Lis methylene. ~ A 1 43. The compound of claim 40, wherein A? is substituted or unsubstituted 2 heteroaryl or substituted or unsubstituted aryl.

1 44. The compound of claim 43, wherein Al is substituted or unsubstituted 2 heteroaryl, or substituted or unsubstituted aryl.

1 45. The compound of claim 44, wherein A? is substituted or unsubstituted 2 phenyl or substituted or unsubstituted pyridyl.

1 46. The compound of claim 44, wherein A! is substituted or unsubstituted 2 phenyl or substituted or unsubstituted pyridyl.

1 47. The compound of claim 45, wherein L%is methylene.

1 48. The compound of claim 1, wherein if R'is -NR®R® and R® is

2 -S(0);R", then R® is hydrogen.

1 49. The compound of claim 48, wherein R’ is substituted or unsubstituted 2 alkyl

1 50. The compound of claim 48, wherein R’ is unsubstituted C;-Cs alkyl.

1 51. The compound of claim 48, wherein R? and R? are hydrogen.

1 52. The compound of claim 1, wherein if R! is hydrogen, then R® is not

2 ‘hydrogen.

1 53. The compound of claim 52, wherein RS is substituted or unsubstituted 2 alkyl

1 54, The compound of claim 52, wherein RS is unsubstituted C,-Cs alkyl.

1 ' 55. The compound of claim 52, wherein R® is substituted or unsubstituted 2 C3-Cs cycloalkyl.

1 56. The compound of claim 52, wherein RS is substituted or unsubstituted 2 cyclopropyl.

a) Il Ty [my ld i [=D (ny UNENSYS WO 2006/110668 : SSBCTIUS2006/013342 Loa a, : NCTA ed 1 57. The compound of claim 54, wherein R'is hydrogen. 1 58. The compound of claim 57, wherein R? and R? are hydrogen.

J 1 59. A method of treating Alzheimer's disease in a subject in need thereof, 2 the method comprising administering to the subject in need of such treatment an effectiver 3 amount of the compound of claim 1. 1 60. A method of reducing memapsin 2 catalytic activity, the method 2 comprising contacting a memapsin 2 protein with an effective amount of the compound of 3 claim1. E 1 61.. The method of claim 60, wherein said memapsin 2 beta-secretase is 2 contacted in a cell. 1 62. A method of selectively reducing memapsin 2 catalytic activity relative 2 tomemapsin 1 catalytic activity, the method comprising contacting a memapsin 2 protein 3 with an effective amount of the compound of claim 1 in the presence of memapsin 1 beta- 4 secretase. 1 63. A method of selectively reducing memapsin 2 catalytic activity relative 2 to cathepsin D catalytic activity, the method comprising contacting a memapsin 2 protein 3 with an effective amount of the compound of claim 1 in the presence of cathepsin D. 1 64. A method of selectively reducing memapsin 2 catalytic activity relative 2 tomemapsin 1 catalytic activity and cathepsin D catalytic activity, the method comprising 3 contacting a memapsin 2 protein with an effective amount of the compound of claim 1 in the 4 presence of memapsin 1 beta-secretase and cathepsin D.