Compounds useful for treating neurodegenerative disorders

1 . A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A is a 4-7 membered saturated or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each of Ring B, Ring C, and Ring D is independently saturated, partially unsaturated or aromatic, or a deuterated derivative thereof;

Ring E is a 4-7 membered saturated, partially unsaturated, or aromatic ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

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 or partially unsaturated ring having 0-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each R is independently deuterium, 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 an optionally substituted 3-8 membered, saturated, partially unsaturated, or aryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

n is 0-4;

R 3 , R 4 , and R 8 are each independently selected from halogen, CN, R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, S(O)R, SO 2 R, OSO 2 R, N(R) 2 , a suitably protected amino group, N(R)C(O)R, N(R)C(O)C(O)R, N(R)C(O)N(R) 2 , N(R)C(O)OR, C(O)OR, OC(O)R, C(O)N(R) 2 , or OC(O)N(R) 2 , or:

two R 4 on the same carbon are optionally taken together to form an optionally substituted 3-8 membered saturated or partially unsaturated spirofused ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:

two R 4 on the same carbon are optionally taken together to form an oxo moiety, an oxime, an optionally substituted hydrazone, an optionally substituted imine, or an optionally substituted C 2-6 alkylidene;

m is 0-4;

each R 5 is independently T-C(R′) 3 , T-C(R′) 2 C(R″) 3 , OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, S(O)R, SO 2 R, OSO 2 R, N(R) 2 , a suitably protected amino group, N(R)C(O)R, N(R)C(O)C(O)R, N(R)C(O)N(R) 2 , N(R)C(O)OR, C(O)OR, OC(O)R, C(O)N(R) 2 , or OC(O)N(R) 2 , 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, or:

two R 5 on the same carbon are optionally taken together to form an oxo moiety, an oxime, an optionally substituted hydrazone, an optionally substituted imine, an optionally substituted C 2-6 alkylidene, or an optionally substituted 3-8 membered saturated or partially unsaturated spirocycle having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each T is independently a valence bond or an optionally substituted straight or branched, saturated or unsaturated, C 1-6 alkylene 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 halogen, R, OR, SR, S(O)R, SO 2 R, OSO 2 R, N(R) 2 , N(R)C(O)R, N(R)C(O)C(O)R, N(R)C(O)N(R) 2 , N(R)C(O)OR, N(R)S(O)R, N(R)SO 2 R, N(R)SO 2 OR C(O)OR, OC(O)R, C(O)N(R) 2 , OC(O)N(R) 2 , or an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl monocyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an optionally substituted 8-10 membered saturated, partially unsaturated, or aryl bicyclic ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:

two R′ are optionally taken together to form an oxo moiety, an oxime, an optionally substituted hydrazone, an optionally substituted imine, an optionally substituted C 2-6 alkylidene, or an optionally substituted 3-8 membered saturated or partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:

two R″ are optionally taken together to form an oxo moiety, an oxime, an optionally substituted hydrazone, an optionally substituted imine, an optionally substituted C 2-6 alkylidene, or an optionally substituted 3-8 membered saturated or partially unsaturated ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

R 6 is halogen, R, OR, SR, S(O)R, SO 2 R, OSO 2 R, N(R) 2 , N(R)C(O)R, N(R)C(O)C(O)R, N(R)C(O)N(R) 2 , N(R)C(O)OR, C(O)OR, OC(O)R, C(O)N(R) 2 , or OC(O)N(R) 2 , or:

R 6 and R 5 are optionally taken together to form an optionally substituted 3-8 membered saturated, partially unsaturated, or aryl ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each of R 7 and R 7′ is independently selected from halogen, CN, N 3 , R, OR, a suitably protected hydroxyl group, SR, a suitably protected thiol group, S(O)R, SO 2 R, OSO 2 R, N(R) 2 , a suitably protected amino group, NRC(O)R, NRC(O)C(O)R, N(R)C(O)N(R) 2 , N(R)C(O)OR, C(O)OR, OC(O)R, C(O)N(R) 2 , or OC(O)N(R) 2 , or:

R 7 and R 7′ are taken together to form an oxo moiety, an oxime, an optionally substituted hydrazone, an optionally substituted imine, an optionally substituted C 2-6 alkylidene, or an optionally substituted 3-8 membered saturated or partially unsaturated spirocycle having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:

R 6 and R 7 or R 6 and R 7′ are optionally taken together to form an optionally substituted 3-8 membered saturated or partially unsaturated ring having 0-4 heteroatoms selected from nitrogen, oxygen, or sulfur;

p is 0-4;

each R 9 is independently selected from halogen, R, OR, SR, or N(R) 2 , or:

two R 9 on the same carbon are optionally taken together to form an optionally substituted 3-8 membered or partially unsaturated spirofused ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or:

two R 9 on the same carbon atom are optionally taken together to form an oxo moiety, an oxime, an optionally substituted hydrazone, an optionally substituted imine, or an optionally substituted C 2-6 alkylidene;

Q is a valence bond or an optionally substituted C 1-10 alkylene chain wherein one, two, or three methylene units of Q are optionally and independently replaced by —O—, —N(R)—, —S—, —C(O)—, —OC(O)—, —C(O)O—, —OC(O)O—, —S(O)—, or —S(O) 2 —, —OSO 2 O—, —N(R)C(O)—, —C(O)N(R)—, —N(R)C(O)O—, —OC(O)NR—, —N(R)C(O)NR—, or —Cy-, wherein:

each —Cy- is independently a bivalent optionally substituted saturated, partially unsaturated, or aromatic monocyclic or bicyclic ring selected from a 6-10 membered arylene, a 5-10 membered heteroarylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur, a 3-8 membered carbocyclylene, or a 3-10 membered heterocyclylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur;

R 10 is hydrogen, halogen, an optionally substituted C 1-10 aliphatic, 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, a polymer residue, a peptide, a sugar-containing or sugar-like moiety, or:

wherein when R 10 is a ring, R 10 is optionally substituted at any substitutable carbon with 1-7 R 11 and at any substitutable nitrogen with R 12 ;

each R 11 is independently halogen, R, OR, SR, N(R) 2 , N(R)C(O)R, N(R)C(O)OR, N(R)C(O)N(R) 2 , N(R)SO 2 R, N(R)SO 2 OR, S(O)R, SO 2 R, OSO 2 R, C(O)R, CO 2 R, OCO 2 R, C(O)N(R) 2 , or OC(O)N(R) 2 , or wherein:

two R 11 are optionally taken together to form an oxo moiety, an oxime, an optionally substituted hydrazone, an optionally substituted imine, an optionally substituted C 2-6 alkylidene, or an optionally substituted 3-8 membered saturated or partially unsaturated fused or spirofused ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur; and

each R 12 is independently R, OR, S(O)R, SO 2 R, OSO 2 R, C(O)R, CO 2 R, OCO 2 R, C(O)N(R) 2 , or OC(O)N(R) 2 , an optionally substituted aliphatic 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, or wherein:

R 12 and R 11 are optionally taken together to form an optionally substituted 3-8 membered saturated or partially unsaturated fused ring having 0-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

2 . The compound of claim 1 , wherein Q is an optionally substituted C 1-10 alkylene chain wherein one, two, or three methylene units are independently replaced by —O—, —N(R)—, —S—, —C(O)—, —SO 2 —, or —Cy-.

3 . The compound of claim 2 , wherein Q is —O—.

4 . The compound of claim 1 , wherein Q is an optionally substituted C 2-10 alkylene chain wherein two or three methylene units are independently replaced by —O— and —Cy-.

5 . The compound of claim 1 , wherein Q is a C 2 alkylene chain wherein one methylene unit is replaced by —O— and one methylene unit is replaced by —Cy-.

6 . The compound of claim 1 , wherein:

Q is an optionally substituted C 2-10 alkylene chain wherein two or three methylene units are independently replaced by —O— and —Cy-; and

each —Cy- is independently an optionally substituted 3-10 membered heterocyclylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur.

7 . The compound of claim 6 , wherein each —Cy- is independently an optionally substituted 5-7 membered heterocyclylene having 1-3 heteroatoms independently selected from oxygen, nitrogen, or sulfur.

8 . The compound of claim 7 , wherein —Cy- is selected from tetrahydropyranylene, tetrahydrofuranylene, morpholinylene, thiomorpholinylene, piperidinylene, piperazinylene, pyrrolidinylene, tetrahydrothiophenylene, and tetrahydrothiopyranylene, wherein each ring is optionally substituted.

9 . The compound of claim 8 , wherein —Cy- is optionally substituted morpholinylene.

10 . The compound of claim 1 , wherein R 10 is an optionally substituted 3-8 membered heterocycle containing 1-2 heteroatoms selected from nitrogen, oxygen, or sulfur.

11 . The compound of claim 1 , wherein -Q-R 10 is of the following formula:

12 . The compound of claim 11 , wherein R 10 a detectable moiety comprising biotin.

13 . The compound of claim 11 , wherein R 10 is a protecting group selected from t-butyloxycarbonyl (BOC), ethyloxycarbonyl, methyloxycarbonyl, trichloroethyloxycarbonyl, allyloxycarbonyl (Alloc), benzyloxocarbonyl (CBZ), allyl, phthalimide, benzyl (Bn), fluorenylmethylcarbonyl (Fmoc), formyl, acetyl, chloroacetyl, dichloroacetyl, trichloroacetyl, phenylacetyl, trifluoroacetyl, benzoyl, mesyl, tosyl, and triflyl.

14 . The compound according to claim 1 , wherein said compound is of formula V-a-xi:

or a pharmaceutically acceptable salt thereof.

15 . The compound of claim 1 , wherein Q is an optionally substituted C 2-10 alkylene chain wherein one or two methylene units are independently replaced by —OC(O)NR— or —Cy-.

16 . The compound of claim 15 , wherein Q is an optionally substituted C 2-10 alkylene chain wherein two methylene units are independently replaced by —OC(O)NR— and —Cy-.

17 . The compound of claim 16 , wherein —Cy- is independently an optionally substituted 3-10 membered heterocyclylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur.

18 . The compound of claim 17 , wherein —Cy- is independently an optionally substituted 3-4 membered heterocyclylene having 1-4 heteroatoms independently selected from oxygen, nitrogen, or sulfur.

19 . The compound of claim 18 , wherein —Cy- is independently an optionally substituted 3-8 membered carbocyclylene.

20 . The compound of claim 19 , wherein —Cy- is independently an optionally substituted 4 membered carbocyclylene.

21 - 46 . (canceled)