Compounds useful for treating neurodegenerative disorders

1 . A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

each of Ring A, Ring B, Ring C, Ring D, and Ring E is independently saturated, partially unsaturated or aromatic;

G is S, CH 2 , NR, or O;

R 1 and R 2 are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, N(R) 2 , or a suitably protected amino group, or R 1 and R 2 are taken together to form a 3-7 membered saturated, partially unsaturated, or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R is independently hydrogen, an optionally substituted C 1-6 aliphatic group, or an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein:

two R on the same nitrogen atom are optionally taken together with said nitrogen atom to form a 3-8 membered saturated, partially unsaturated, or aryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

n is 0-2;

R 3 , R 4 , R 7 , and R 8 are each independently selected from halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO 2 R, OSO 2 R, N(R) 2 , a suitably protected amino group, NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , or O(CO)N(R) 2 ;

m is 0-2;

R 5 is T-C(R′) 3 , T-C(R′) 2 C(R″) 3 , R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO 2 R, OSO 2 R, N(R) 2 , a suitably protected amino group, NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , or O(CO)N(R) 2 ;

each T is independently a valence bond or an optionally substituted straight or branched, saturated or unsaturated, C 1-6 alkylidene chain wherein up to two methylene units of T are optionally and independently replaced by —O—, —N(R)—, —S—, —C(O)—, —S(O)—, or —S(O) 2 —;

each R′ and R″ is independently selected from R, OR, SR, SO 2 R, OSO 2 R, N(R) 2 , NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , or O(CO)N(R) 2 ;

R 6 is halogen, R, OR, SR, SO 2 R, OSO 2 R, N(R) 2 , NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , or O(CO)N(R) 2 ;

R 9 and R 9′ are each independently selected from halogen, R, OR, SR, or N(R) 2 , or R 1 and R 2 are taken together to form a 3-7 membered saturated, partially unsaturated, or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

Q is a valence bond or an optionally substituted straight or branched, saturated or unsaturated, C 1-6 alkylidene chain wherein up to two methylene units of Q are optionally and independently replaced by —O—, —N(R)—, —S—, —C(O)—, —S(O)—, or —S(O) 2 —.

2 . The compound according to claim 1 , wherein:

G is O; and

R 1 and R 2 are each independently R or OR.

3 . The compound according to claim 2 , wherein R 1 and R 2 are each independently R wherein R is hydrogen or an optionally substituted C 1-6 aliphatic group.

4 . The compound according to claim 2 , wherein R 1 and R 2 are taken together to form a 3-6 membered saturated, partially unsaturated, or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

5 . The compound according to claim 4 , wherein:

R 5 is T-C(R′) 3 or T-C(R′) 2 C(R″) 3 ;

each T is independently a valence bond or a straight or branched C 1-4 alkylidene chain wherein one methylene unit of T is optionally replaced by —O—, —N(R)—, or —S—; and

each R′ and R″ is independently R, OR, OC(O)R, SR, or N(R) 2 .

6 . The compound according to claim 5 , wherein:

Q is a an optionally substituted straight or branched, saturated or unsaturated, C 1-2 alkylidene chain wherein up to one methylene unit of Q is optionally replaced by —O—, —N(R)—, or —S—.

7 . The compound according to claim 6 , wherein Q is —O—.

8 . The compound according to claim 1 , wherein said compound is of formula V-c:

or a pharmaceutically acceptable salt thereof.

9 . The compound according to claim 1 , wherein said compound is of formula V-d or V-e:

or a pharmaceutically acceptable salt thereof.

10 . The compound according to claim 1 , wherein said compound is of formula V-f:

or a pharmaceutically acceptable salt thereof.

11 . The compound according to claim 10 , wherein said compound is of formula V-g or V-h:

or a pharmaceutically acceptable salt thereof.

12 . The compound according to claim 11 , wherein R 1 and R 2 are taken together to form a 3-6 membered saturated carbocyclic ring and R 7 is —OH.

13 . The compound according to claim 1 , wherein said compound is selected from a compound of formula VII, VIII, IX, or X:

14 . A compound selected from:

15 . The compound according claim 14 , wherein said compound is selected from:

16 . A method for preparing a compound of formula V-a:

or a pharmaceutically acceptable salt thereof, wherein:

each of Ring A, Ring B, Ring C, Ring D, and Ring E is independently saturated, partially unsaturated or aromatic;

G is S, CH 2 , NR, or O;

R 1 and R 2 are each independently halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, N(R) 2 , or a suitably protected amino group, or R 1 and R 2 are taken together to form a 3-7 membered saturated, partially unsaturated, or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R is independently hydrogen, an optionally substituted C 1-6 aliphatic group, or an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein:

two R on the same nitrogen atom are optionally taken together with said nitrogen atom to form a 3-8 membered saturated, partially unsaturated, or aryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

n is 0-2;

R 3 , R 4 , R 7 , and R 8 are each independently selected from halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO 2 R, OSO 2 R, N(R) 2 , a suitably protected amino group, NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , or O(CO)N(R) 2 ;

m is 0-2;

R 5 is T-C(R′) 3 , T-C(R′) 2 C(R″) 3 , R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO 2 R, OSO 2 R, N(R) 2 , a suitably protected amino group, NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , or O(CO)N(R) 2 ;

each T is independently a valence bond or an optionally substituted straight or branched, saturated or unsaturated, C 1-6 alkylidene chain wherein up to two methylene units of T are optionally and independently replaced by —O—, —N(R)—, —S—, —C(O)—, —S(O)—, or —S(O) 2 —;

each R′ and R″ is independently selected from R, OR, SR, SO 2 R, OSO 2 R, N(R) 2 , NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , or O(CO)N(R) 2 ;

R 6 is halogen, R, OR, SR, SO 2 R, OSO 2 R, N(R) 2 , NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , or O(CO)N(R) 2 ; and

R 9 and R 9′ are each independently selected from halogen, R, OR, SR, or N(R) 2 , or R 1 and R 2 are taken together to form a 3-7 membered saturated, partially unsaturated, or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur,

comprising the steps of:

(a) providing a compound of formula V-b:

or a pharmaceutically acceptable salt thereof, wherein:

each of Ring A, Ring B. Ring C, Ring D, and Ring E is independently saturated, partially unsaturated or aromatic;

Gis S, CH 2 , NR, or O;

R 1 and R 2 are each independently halogen, R. OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, N(R) 2 , or a suitably protected amino group, or R 1 and R 2 are taken together to form a 3-7 membered saturated, partially unsaturated, or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R is independently hydrogen, an optionally substituted C 1-6 aliphatic group, or an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, wherein:

two R on the same nitrogen atom are optionally taken together with said nitrogen atom to form a 3-8 membered saturated, partially unsaturated, or aryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

n is 0-2;

R 3 , R 4 , R 7 , and R 8 are each independently selected from halogen, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO 2 R, OSO 2 R, N(R) 2 , a suitably protected amino group, NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , or O(CO)N(R) 2 ;

m is 0-2;

R 5 is T-C(R′) 3 , T-C(R′) 2 C(R″) 3 , R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, SO 2 R, OSO 2 R, N(R) 2 , a suitably protected amino group, NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , or O(CO)N(R) 2 ;

each T is independently a valence bond or an optionally substituted straight or branched, saturated or unsaturated, C 1-6 alkylidene chain wherein up to two methylene units of T are optionally and independently replaced by —O—, —N(R)—, —S—, —C(O)—, —S(O)—, or —S(O) 2 —;

each R′ and R″ is independently selected from R, OR, SR, SO 2 R, OSO 2 R, N(R) 2 , NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , or O(CO)N(R) 2 ;

R 6 is halogen, R, OR, SR, SO 2 R, OSO 2 R, N(R) 2 , NR(CO)R, NR(CO)(CO)R, NR(CO)N(R) 2 , NR(CO)OR, (CO)OR, O(CO)R, (CO)N(R) 2 , or O(CO)N(R) 2 ;

R 9 and R 9′ are each independently selected from halogen, R, OR, SR, or N(R) 2 , or R 1 and R 2 are taken together to form a 3-7 membered saturated, partially unsaturated, or aryl ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

R 10 is a sugar-containing or sugar-like moiety, and

(b) treating the compound of formula V-b with a suitable enzyme to form the compound of formula V-a.

17 . The method according to claim 16 , wherein the suitable enzyme is a cellulase, a xylanase, a xylosidase, glycyrrhizinic acid hydrolase, or a glucuronidase.

18 . A composition comprising a compound according to claim 1 , and a pharmaceutically acceptable carrier, adjuvant, or vehicle.

19 . A method for inhibiting amyloid-beta peptide production in a patient, wherein said method comprises administering to said patient a composition according to claim 18 .

20 . A method for inhibiting amyloid-beta (1-42) peptide production in a patient, wherein said method comprises administering to said patient a composition according to claim 18 .

21 . The method according to claim 19 , wherein said method does not affect Notch processing.

22 . The method according to claim 21 , wherein amyloid-beta (1-42) peptide levels are reduced and amyloid-beta (1-40) peptide levels are not substantially reduced.

23 . The method according to claim 22 , wherein the level of at least one of amyloid-beta (1-37) and amyloid-beta (1-39) is increased.

24 . A method for treating or lessening the severity of a disorder associated with amyloid-beta (1-42) peptide, wherein said method comprises administering to a patient a composition according to claim 18 .

25 . The method according to claim 24 , wherein said disorder is Alzheimer's disease, Parkinson's disease, Down's syndrome, inclusion body myositis, cerebral amyloid angiopathy, mild cognitive impairment, Lewy body dementia, Parkinson's disease, cataract, a tauopathy, Huntington's disease, Amyoptrophic lateral sclerosis (ALS/Lou Gerhig's disease), type 2 diabetes, transthyretin amyloid disease, prion disease (including Creutzfeldt-Jakob disease, Gerstmann-Straussler-Scheinker syndrome, fatal familial insomnia, and kuru).

26 . The method according to claim 25 , wherein said disorder is Alzheimer's disease, Parkinson's disease, or Down's syndrome.

27 . A method for reducing amyloid-beta (1-42) peptide levels in a cell, comprising contacting said cell with a compound according to claim 1.