Combination therapies for treatment of spinal muscular atrophy

1. A composition comprising a SMN protein stabilizer comprising a compound, or a pro-drug thereof, having the formula of formula I:

wherein X is selected from the group consisting of carbon or nitrogen;

Y is selected from the group consisting of carbon or nitrogen; and wherein at least one of X and Y is a nitrogen;

Z is selected from the group consisting of sulfur or oxygen;

R 1 is selected from hydrogen, alkyl, alkoxy, halogen, haloalky, and aminoalkyl; and

R 2 is selected from unsubstituted or substituted phenyl and unsubstituted or substituted heteroaryl, wherein the unsubstituted heteroaryl is selected from the group consisting of a 6-membered heteroaryl and a 5-membered heteroaryl, and wherein, when R 2 is a substituted phenyl or substituted heteroaryl, the substitution is selected from the group consisting of hydrogen, halogen, lower alkyl, and combinations thereof; and a SMN2 transcription enhancer comprising a compound having the formula of formula (IV):

or a pharmaceutically acceptable salt thereof, wherein

each of R 2 and R 3 is independently halogen, R′, —OR′;

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.

2. The composition as set forth in claim 1 , wherein the SMN protein stabilizer is selected from the group consisting of:

3. The composition as set forth in claim 1 , wherein the SMN transcription enhancer has a structure selected from the group consisting of:

4. The composition as set forth in claim 1 , wherein the SMN protein stabilizer has the structure selected from the group consisting of:

and the SMN transcription enhancer has the structure of:

5. A method of treating spinal muscular atrophy in a subject in need thereof, the method comprising administering the composition as set forth in claim 1 .