COMPOUNDS FOR USE IN SCREENING METHODS FOR SPINAL MUSCULAR ATROPHY

1 . A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein

each of Ring A and Ring B is independently an optionally substituted group selected from

phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

L 1 is independently a covalent bond or an optionally substituted bivalent C 1-6 hydrocarbon chain, wherein one or more methylene units of L 1 are optionally and independently replaced by —O—, —S—, —C(O)—, —C(S)—, —C(NR′)—, —C(O)N(R′)—, —N(R′)C(O)N(R′)—, —N(R′)C(O)—, —N(R′)C(O)O—, —OC(O)N(R)—, S—(O)—, —S(O) 2 —, —S(O) 2 N(R)—, —N(R)S(O) 2 —, —OC(O)—, or —(O)0-;

each R′ is independently —R, —C(O)R, —CO 2 R, or —SO 2 R, or:

two R′ on the same nitrogen are taken together with their intervening atoms to form a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

each R is hydrogen, or an optionally substituted group selected from C1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

2 . The compound according to claim 1 , wherein said compound has the structure of formula II:

or a pharmaceutically acceptable salt thereof, wherein

each of Ring A′ and Ring B′ is independently an optionally substituted group selected from phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

L 2 is —C(O)N(R′)—;

each R′ is independently —R, —C(O)R, —CO 2 R, or —SO 2 R, or:

two R′ on the same nitrogen are taken together with their intervening atoms to form a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

each R is hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or

sulfur, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

3 . The compound according to claim 2 , wherein said compound has the structure of formula 11-a:

or a pharmaceutically acceptable salt thereof, wherein:

Ring A″ is an optionally substituted phenyl or benzimidazolyl ring;

Ring B″ is an optionally substituted 5-6 membered heteroaryl ring having 1-2 heteroatoms

independently selected from nitrogen, oxygen, or sulfur;

L 3 is —C(O)NH—;

each R 4 is independently halogen or R;

each R 5 is independently an optionally substituted C 1-6 aliphatic;

each of d and e is independently 0-5; and

each R is hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

4 . The compound according to claim 3 , wherein said compound has the structure of:

5 . The compound according to claim 3 , wherein said compound has the structure of:

6 . The compound according to claim 3 , wherein said compound has the structure of:

7 . The compound according to claim 3 , wherein said compound has the structure of:

8 . The compound according to claim 1 , wherein said compound has the structure of formula III:

or a pharmaceutically acceptable salt thereof, wherein

Ring C″ is independently an optionally substituted group selected from phenyl, an 8-10 membered bicyclic aryl ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur;

each of R 1 , R 2 and R 3 is independently halogen, R′, —C(O)R′, —C(S)R′, —CO 2 R′, —C(O)N(R′) 2 , —C(S)N(R′) 2 , —S(O)R′, —SO 2 R′, —SO 2 N(R′) 2 , —OR′, —O—(C 1-6 aliphatic)-N(R′) 2 , —O0-(C 1-6 aliphatic)-OR′, —OC(O)R′, —SR′, —NO 2 , —N(R′) 2 , —NR′C(O)R′, —NR′C(O)OR′, —NR′C(O)N(R′) 2 , —NR′SO 2 R′, —NR′SO 2 N(R′) 2 , or —NR′OR′;

a is 1-4;

b is 1-5;

X 1 is —C(R x ) 2 —, —NR x —, —NR x C(R x ) 2 — or —OC(R x ) 2 —;

X 2 is —C(R x ) 2 — or —NR x —;

each R x is independently R′, —(C 1-6 aliphatic)-N(R) 2 , or —(C 1-6 aliphatic)-OR′;

each R′ is independently —R, —C(O)R, —CO 2 R, or —SO 2 R, or:

 two R′ on the same nitrogen are taken together with their intervening atoms to form a 3-7 membered heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, and sulfur; and

each R is hydrogen, or an optionally substituted group selected from C 1-6 aliphatic, phenyl, a 3-7 membered saturated or partially unsaturated carbocyclic ring, an 8-10 membered bicyclic saturated, partially unsaturated or aryl carbocyclic ring, a 5-6 membered monocyclic heteroaryl ring having 1-3 heteroatoms independently selected from nitrogen, oxygen, or sulfur, a 3-7 membered saturated or partially unsaturated heterocyclic ring having 1-2 heteroatoms independently selected from nitrogen, oxygen, or sulfur, an 8-10 membered bicyclic saturated or partially unsaturated heterocyclic ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur, or an 8-10 membered bicyclic heteroaryl ring having 1-4 heteroatoms independently selected from nitrogen, oxygen, or sulfur.

9 . The compound according to claim 1 , selected from those depicted in Table 1, or a pharmaceutically acceptable salt thereof.

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

11 . A method for increasing the production of full-length SMN protein in a cell having an SMN2 gene, the method comprising contacting the cell with a compound or composition according to claim 1 .

12 . The method of claim 11 , wherein the full-length SMN protein is produced by upregulation of SMN2 activity.

13 . The method of claim 12 , wherein the upregulation of SMN2 activity includes increased expression of full-length SMN2 transcripts.

14 . A method of increasing the production of full-length SMN protein in a cell having an SMN2 gene, the method comprising contacting the cell with a compound or composition according to claim 2 .

15 . The method of claim 14 , wherein the full-length SMN protein is produced by upregulation of SMN2 activity.

16 . A method of increasing the production of full-length SMN protein in a cell having an SMN2 gene, the method comprising contacting the cell with a compound or composition according to claim 3 .

17 . The method of claim 16 , wherein the full-length SMN protein is produced by upregulation of SMN2 activity.

18 . A method of treating a patient susceptible to or having spinal muscular atrophy, the method comprising administering to the patient a therapeutically effective amount of a compound or composition of claim 1 .

19 . A method of treating a patient susceptible to or having spinal muscular atrophy, the method comprising administering to the patient a therapeutically effective amount of a compound or composition of claim 2 .

20 . A method of treating a patient susceptible to or having spinal muscular atrophy, the method comprising administering to the patient a therapeutically effective amount of a compound or composition of claim 3 .