Synthesis of compounds useful as modulators of amyloid-beta production

1. A method for preparing 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 , or:

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 9 and R 9′ are each independently selected from halogen, R, OR, SR, or N(R) 2 , or R 9 and R 9′ 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;

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 —; and

R 10 is R, a suitably protected hydroxyl group, a suitably protected thiol group, a suitably protected amino group, an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a detectable moiety selected from the group consisting of radioisotopes, mass-tags, fluorescent labels, biotin, and antigen labels, a polymer residue selected from the group consisting of poly(alkylene oxides), a peptide, or a sugar-containing or sugar-like moiety selected from the group consisting of cyclic and acyclic cyclitols, glycosides, arabinopyranoside, xylopyranoside, or erythritol,

comprising the steps of:

(a) providing a compound of formula II:

 and

(b) converting the compound of formula II to the compound of formula I, where the conversion is achieved by intramolecular dehydration reaction.

2. The method according to claim 1 , wherein the dehydration is performed in the presence of a suitable acid.

3. The method according to claim 2 , wherein the suitable acid is a Brønsted acid.

4. The method according to claim 3 , wherein the Brønsted acid is a hydrogen halide, a carboxylic acid, a sulfonic acid, or a phosphoric acid.

5. The method according to claim 4 , optionally performed in the presence of a suitable solvent.

6. The method according to claim 5 , wherein the suitable solvent is a protic solvent, a halogenated hydrocarbon, an ether, an ester, an aromatic hydrocarbon, a polar or a non-polar aprotic solvent, or any mixtures thereof.

7. The method according to claim 1 , wherein the compound of formula I is a compound of formula I-a:

8. The method according to claim 1 , wherein the compound of formula I is a compound of formula I-b:

9. The method according to claim 1 , wherein the compound of formula I is a compound of formula I-c:

10. A method for preparing a compound of formula I-i:

or a pharmaceutically acceptable salt thereof, wherein:

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 —;

R 10 is R, a suitably protected hydroxyl group, a suitably protected thiol group, a suitably protected amino group, an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a detectable moiety selected from the group consisting of radioisotopes, mass-tags, fluorescent labels, biotin, and antigen labels, a polymer residue selected from the group consisting of poly(alkylene oxides), a peptide, or a sugar-containing or sugar-like moiety selected from the group consisting of cyclic and acyclic cyclitols, glycosides, arabinopyranoside, xylopyranoside, or erythritol;

R is 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,

comprising the steps of:

(a) providing a compound of formula I-ii:

 and

(b) converting compound I-ii to compound I-i, where the conversion is achieved by intramolecular dehydration reaction.

11. A method for preparing a compound of formula I-iii:

or a pharmaceutically acceptable salt thereof, wherein:

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 —;

R 10 is R, a suitably protected hydroxyl group, a suitably protected thiol group, a suitably protected amino group, an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an optionally substituted 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a detectable moiety, selected from the group consisting of radioisotopes, mass-tags, fluorescent labels, biotin, and antigen labels, a polymer residue selected from the group consisting of poly(alkylene oxides), a peptide, or a sugar-containing or sugar-like moiety selected from the group consisting of cyclic and acyclic cyclitols, glycosides, arabinopyranoside, xylopyranoside, or erythritol; and

R is 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,

comprising the steps of:

(a) providing a compound of formula I-iv:

 and

(b) converting compound I-iv to compound I-iii, where the conversion is achieved by intramolecular dehydration reaction.

12. The method according to claim 1 , wherein: G is O.

13. The method according to claim 1 , 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 .

14. The method according to claim 13 , 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—; and

R 10 is a glycoside.

15. The method according to claim 14 , wherein Q is —O— and R 10 is an arabinopyranoside or a xylopyranoside.