Compounds for use in screening methods for spinal muscular atrophy

Abstract

Disclosed herein are compositions and methods for treatment of spinal muscular atrophy (SMA). In certain embodiments, compounds are provided that increase full-length survival of motor neuron (SMN) protein production by an SMN2 gene.

What is claimed is: 
     
         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 .