Compounds for the treatment of spinal muscular atrophy and other uses

Abstract

Compounds useful for the treatment of spinal muscular atrophy or other uses, as well as methods of using such compounds to increase SMN expression, increase EAAT2 expression, or increase the expression of a nucleic acid that encodes a translational stop codon introduced by mutation or frameshift.

1 .- 58 . (canceled) 
     
     
         59 . A compound of Formula I: 
       
         
           
           
               
               
           
         
         wherein, 
         W is CH 2 ; 
         B is CH 2  or CH(C n H 2n+1 ), wherein n is an integer from 1 to 8; 
         R 1  and R 2  are independently selected from the group consisting of H and C 1 -C 3  alkyl, or R 1  and R 2  may be taken together with the carbon atom to which they are attached to form a C 3 -C 6  cycloalkyl ring or a carbonyl group; 
         R 3  is selected from the group consisting of H, halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C 1 -C 4 haloalkyl, C 1 -C 6  haloalkoxy, C 2 -C 6  alkenyl, CN, NO 2 , heteroaryl, and phenyl optionally substituted with any combination of one to five halogen, NO 2 , CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy; 
         R 4 , R 5 , R 6  and R 7  are independently selected from the group consisting of H, hydroxyl, halogen, CN, NO 2 , sulfonamide, C 1 -C 8  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  haloalkoxy, C 2 -C 8  alkenyl, amino, C 1 -C 4  dialkyl amino, C 1 -C 4  alkylamino, C 3 -C 6  cycloalkylamino, morpholinyl, heteroaryl, arylamino, arylalkylamino, phenyl, C(O)R′, NR′(COR″), NR′SO 2 R″ and NR′(CONR″R″′); wherein R′, R″ and R″′ are independently H, C 1 -C 6  alkyl, phenyl or substituted phenyl; and wherein the C 1 -C 8  alkyl is optionally substituted with one or more members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkyl amino, C 1 -C 6  alkylamino, cycloalkylamino, arylamino, arylalkylamino, and morpholinyl; and the phenyl is optionally substituted with one or more members selected from the group consisting of halogen, NO 2 , CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  alkoxy; 
         or R 4  and R 5 , R 5  and 5 6 , or R 6  and R 7  taken together with the carbon atoms to which they are attached form a ring;
 X is selected from the group consisting of 
 H; 
 CN; 
 C(O)OR 8 , wherein R 8  is H or C 1 -C 8  alkyl, wherein the C 1 -C 8  alkyl optionally is substituted with one or members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkyl amino, C 1 -C 6  alkylamino, cycloalkylamino, phenyl, and morpholinyl; 
 C(O)NR 9 R 10  or CH 2 NR 9 R 10 , wherein R 9  and R 10  are independently selected from the group consisting of H and C 1 -C 6  alkyl, or R 9  and R 10  together with the nitrogen to which they are attached form a C 5 -C 6  cycloalkyl ring or a heteroring; 
 CH 2 OR 11 , wherein R 11  is H, C 1 -C 8  alkyl, or C 3 -C 6  cycloalkyl, wherein the C 1 -C 8  alkyl optionally is substituted with one or members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkyl amino, C 1 -C 6  alkylamino, cycloalkylamino, and morpholinyl; 
 CH 2 Z, wherein Z is halogen; 
 C(O)NHOH; 
 C(O)NHCN; 
 C(O)N(R 1 )SO 2 R 13 , wherein R 13  is C 1 -C 4  alkyl, phenyl, or substituted phenyl; 
 C 1 -C 8  alkyl, optionally substituted with one or more members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkylamino, and C 1 -C 6  alkylamino; and 
 
         C 2 -C 8  alkenyl optionally substituted with one or more members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkylamino, and C 1 -C 6  alkylamino; 
         provided that when each of R 4 , R 5 , R 6 , and R 7  are H, then X is not C(O)OH. 
       
     
     
         60 . A compound of Formula II: 
       
         
           
           
               
               
           
         
         wherein, 
         W is selected from the group consisting of C(O), C(S), and CH 2 ; 
         B is CH 2  or CH(C n H 2n+1 ), wherein n is an integer from 1 to 8; 
         C is selected from the group consisting of a fused thiophene ring, a fused pyridine ring, and a cyclohexane ring, any of which can be saturated or contain one or two non-conjugated double bonds; 
         R 1  and R 2  are independently selected from the group consisting of H and C 1 -C 3  alkyl, or R 1  and R 2  may be taken together with the carbon atom to which they are attached to form a C 3 -C 6  cycloalkyl ring or a carbonyl group; 
         R 3  is selected from the group consisting of H, halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  haloalkoxy, C 2 -C 6  alkenyl, CN, NO 2 , heteroaryl, and phenyl optionally substituted with any combination of one to five halogen, NO 2 , CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy;
 X is selected from the group consisting of 
 H; 
 CN; 
 C(O)OR 8 , wherein R 8  is H or C 1 -C 8  alkyl, wherein the C 1 -C 8  alkyl optionally is substituted with one or members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkyl amino, C 1 -C 6  alkylamino, cycloalkylamino, phenyl, and morpholinyl; 
 C(O)NR 9 R 10  or CH 2 NR 9 R 10 , wherein R 9  and R 10  are independently selected from the group consisting of H and C 1 -C 6  alkyl, or R 9  and R 10  together with the nitrogen to which they are attached form a C 5 -C 6  cycloalkyl ring or a heteroring; 
 CH 2 OR 11 , wherein R 11  is H, C 1 -C 8  alkyl, or C 3 -C 6  cycloalkyl, wherein the C 1 -C 8  alkyl optionally is substituted with one or members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkyl amino, C 1 -C 6  alkylamino, cycloalkylamino, and morpholinyl; 
 CH 2 Z, wherein Z is halogen; 
 C(O)NHOH; 
 C(O)NHCN; 
 C(O)N(R 1 )SO 2 R 13 , wherein R 13  is C 1 -C 4  alkyl, phenyl, or substituted phenyl; 
 C 1 -C 8  alkyl, optionally substituted with one or more members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkylamino, and C 1 -C 6  alkylamino; and 
 C 2 -C 8  alkenyl optionally substituted with one or more members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkylamino, and C 1 -C 6  alkylamino. 
 
       
     
     
         61 . A compound according to  claim 59  of Table 1. 
     
     
         62 . A compound according to  claim 60  of Table 1. 
     
     
         63 . A composition comprising a compound of  claim 59 , and a carrier. 
     
     
         64 . A composition comprising a compound of  claim 60 , and a carrier. 
     
     
         65 . A method of increasing SMN expression in a cell comprising administering a compound to a cell comprising a nucleic acid encoding SMN2, wherein the cell optionally is in a host, whereby SMN expression is increased, wherein the compound is of Formula I or II: 
       
         
           
           
               
               
           
         
         wherein, 
         W is selected from the group consisting of C(O), C(S), and CH 2 ; 
         B is CH 2  or CH(C n H 2n+1 ), wherein n is an integer from 1 to 8; 
         C is selected from the group consisting of a fused thiophene ring, a fused pyridine ring, and a cyclohexane ring, any of which can be saturated or contain one or two non-conjugated double bonds; 
         R 1  and R 2  are independently selected from the group consisting of H and C 1 -C 3  alkyl, or R 1  and R 2  may be taken together with the carbon atom to which they are attached to form a C 3 -C 6  cycloalkyl ring or a carbonyl group; 
         R 3  is selected from the group consisting of H, halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  haloalkoxy, C 2 -C 6  alkenyl, CN, NO 2 , heteroaryl, and phenyl optionally substituted with any combination of one to five halogen, NO 2 , CN, alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy; 
         R 4 , R 5 , R 6  and R 7  are independently selected from the group consisting of H, hydroxyl, halogen, CN, NO 2 , sulfonamide, C 1 -C 8  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  haloalkoxy, C 2 -C 8  alkenyl, amino, C 1 -C 4  dialkyl amino, C 1 -C 4  alkylamino, C 3 -C 6  cycloalkylamino, morpholinyl, heteroaryl, arylamino, arylalkylamino, phenyl, C(O)R′, NR′(COR″), NR′SO 2 R″ and NR′(CONR″R″′); wherein R′, R″ and R″′ are independently H, C 1 -C 6  alkyl, phenyl or substituted phenyl; and wherein the C 1 -C 8  alkyl is optionally substituted with one or more members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkyl amino, C 1 -C 6  alkylamino, cycloalkylamino, arylamino, arylalkylamino, and morpholinyl; and the phenyl is optionally substituted with one or more members selected from the group consisting of halogen, NO 2 , CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  alkoxy; 
         or R 4  and R 5 , R 5  and 5 6 , or R 6  and R 7  taken together with the carbon atoms to which they are attached form a ring;
 X is selected from the group consisting of 
 H; 
 CN; 
 C(O)OR 8 , wherein R 8  is H or C 1 -C 8  alkyl, wherein the C 1 -C 8  alkyl optionally is substituted with one or members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkyl amino, C 1 -C 6  alkylamino, cycloalkylamino, phenyl, and morpholinyl; 
 C(O)NR 9 R 10  or CH 2 NR 9 R 10 , wherein R 9  and R 10  are independently selected from the group consisting of H and C 1 -C 6  alkyl, or R 9  and R 10  together with the nitrogen to which they are attached form a C 5 -C 6  cycloalkyl ring or a heteroring; 
 CH 2 OR 11 , wherein R 11  is H, C 1 -C 8  alkyl, or C 3 -C 6  cycloalkyl, wherein the C 1 -C 8  alkyl optionally is substituted with one or members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkyl amino, C 1 -C 6  alkylamino, cycloalkylamino, and morpholinyl; 
 CH 2 Z, wherein Z is halogen; 
 C(O)NHOH; 
 C(O)NHCN; 
 C(O)N(R 1 )SO 2 R 13 , wherein R 13  is C 1 -C 4  alkyl, phenyl, or substituted phenyl; 
 C 1 -C 8  alkyl, optionally substituted with one or more members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkylamino, and C 1 -C 6  alkylamino; and 
 C 2 -C 8  alkenyl optionally substituted with one or more members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkylamino, and C 1 -C 6  alkylamino; 
 
         provided that when the compound is a compound of Formula I, and each of R 4 , R 5 , R 6  and R 7  are H, then X is not C(O)OH. 
       
     
     
         66 . The method of  claim 65 , wherein the host is a human afflicted with a disease associated with under-expression of SMN. 
     
     
         67 . The method of  claim 66 , wherein the disease is SMA. 
     
     
         68 . A method of increasing in a cell the expression of a nucleic acid that encodes a translational stop codon, the method comprising administering a compound to a cell comprising a nucleic acid that encodes a translational stop codon, wherein the cell optionally is in a host, whereby expression of the nucleic acid is increased, wherein the compound is of Formula I or II: 
       
         
           
           
               
               
           
         
         wherein, 
         W is selected from the group consisting of C(O), C(S), and CH 2 ; 
         B is CH 2  or CH(C n H 2n+1 ), wherein n is an integer from 1 to 8; 
         C is selected from the group consisting of a fused thiophene ring, a fused pyridine ring, and a cyclohexane ring, any of which can be saturated or contain one or two non-conjugated double bonds; 
         R 1  and R 2  are independently selected from the group consisting of H and C 1 -C 3  alkyl, or R 1  and R 2  may be taken together with the carbon atom to which they are attached to form a C 3 -C 6  cycloalkyl ring or a carbonyl group; 
         R 3  is selected from the group consisting of H, halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  haloalkoxy, C 2 -C 6  alkenyl, CN, NO 2 , heteroaryl, and phenyl optionally substituted with any combination of one to five halogen, NO 2 , CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy; 
         R 4 , R 5 , R 6  and R 7  are independently selected from the group consisting of H, hydroxyl, halogen, CN, NO 2 , sulfonamide, C 1 -C 8  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  haloalkoxy, C 2 -C 8  alkenyl, amino, C 1 -C 4  dialkyl amino, C 1 -C 4  alkylamino, C 3 -C 6  cycloalkylamino, morpholinyl, heteroaryl, arylamino, arylalkylamino, phenyl, C(O)R′, NR′(COR″), NR′SO 2 R″ and NR′(CONR″R″′); wherein R′, R″ and R″′ are independently H, C 1 -C 6  alkyl, phenyl or substituted phenyl; and wherein the C 1 -C 8  alkyl is optionally substituted with one or more members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkyl amino, C 1 -C 6  alkylamino, cycloalkylamino, arylamino, arylalkylamino, and morpholinyl; and the phenyl is optionally substituted with one or more members selected from the group consisting of halogen, NO 2 , CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  alkoxy; 
         or R 4  and R 5 , R 5  and 5 6 , or R 6  and R 7  taken together with the carbon atoms to which they are attached form a ring;
 X is selected from the group consisting of 
 H; 
 CN; 
 C(O)OR 8 , wherein R 8  is H or C 1 -C 8  alkyl, wherein the C 1 -C 8  alkyl optionally is substituted with one or members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkyl amino, C 1 -C 6  alkylamino, cycloalkylamino, phenyl, and morpholinyl; 
 C(O)NR 9 R 10  or CH 2 NR 9 R 10 , wherein R 9  and R 10  are independently selected from the group consisting of H and C 1 -C 6  alkyl, or R 9  and R 10  together with the nitrogen to which they are attached form a C 5 -C 6  cycloalkyl ring or a heteroring; 
 CH 2 OR 11 , wherein R 11  is H, C 1 -C 8  alkyl, or C 3 -C 6  cycloalkyl, wherein the C 1 -C 8  alkyl optionally is substituted with one or members selected from the group consisting of C 1 -C 4  alkoxy, haloalkyl, C 1 -C 6  dialkyl amino, C 1 -C 6  alkylamino, cycloalkylamino, and morpholinyl; 
 CH 2 Z, wherein Z is halogen; 
 C(O)NHOH; 
 C(O)NHCN; 
 C(O)N(R 1 )SO 2 R 13 , wherein R 13  is C 1 -C 4  alkyl, phenyl, or substituted phenyl; 
 C 1 -C 8  alkyl, optionally substituted with one or more members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkylamino, and C 1 -C 6  alkylamino; and 
 C 2 -C 8  alkenyl optionally substituted with one or more members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkylamino, and C 1 -C 6  alkylamino; 
 
         provided that when the compound is a compound of Formula I, and each of R 4 , R 5 , R 6  and R 7  are H, then X is not C(O)OH. 
       
     
     
         69 . The method of  claim 68 , wherein the stop codon has been introduced by mutation or frameshift. 
     
     
         70 . The method of  claim 68 , wherein the host is a human afflicted with a disease associated with the translational stop codon introduced by mutation or frameshift. 
     
     
         71 . The method of  claim 70 , wherein the disease is cancer, diabetes, cystic fibrosis, muscular dystrophy, or a viral infection. 
     
     
         72 . A method of increasing the expression of excitatory amino acid transporter (EAAT2) in a cell comprising administering a compound to a cell comprising a nucleic acid that encodes EAAT2, wherein the cell optionally is in a host, whereby the expression of EAAT2 is increased, wherein the compound is of Formula I or II: 
       
         
           
           
               
               
           
         
         wherein, 
         W is selected from the group consisting of C(O), C(S), and CH 2 ; 
         B is CH 2  or CH(C n H 2n+1 ), wherein n is an integer from 1 to 8; 
         C is selected from the group consisting of a fused thiophene ring, a fused pyridine ring, and a cyclohexane ring, any of which can be saturated or contain one or two non-conjugated double bonds; 
         R 1  and R 2  are independently selected from the group consisting of H and C 1 -C 3  alkyl, or R 1  and R 2  may be taken together with the carbon atom to which they are attached to form a C 3 -C 6  cycloalkyl ring or a carbonyl group; 
         R 3  is selected from the group consisting of H, halogen, C 1 -C 4  alkyl, C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  haloalkoxy, C 2 -C 6  alkenyl, CN, NO 2 , heteroaryl, and phenyl optionally substituted with any combination of one to five halogen, NO 2 , CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, or C 1 -C 4  alkoxy; 
         R 4 , R 5 , R 6  and R 7  are independently selected from the group consisting of H, hydroxyl, halogen, CN, NO 2 , sulfonamide, C 1 -C 8  alkyl, C 3 -C 6  cycloalkyl, C 1 -C 6  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  haloalkoxy, C 2 -C 8  alkenyl, amino, C 1 -C 4  dialkyl amino, C 1 -C 4  alkylamino, C 3 -C 6  cycloalkylamino, morpholinyl, heteroaryl, arylamino, arylalkylamino, phenyl, C(O)R′, NR′(COR″), NR′SO 2 R″ and NR′(CONR″R″′); wherein R′, R″ and R″′ are independently H, C 1 -C 6  alkyl, phenyl or substituted phenyl; and wherein the C 1 -C 8  alkyl is optionally substituted with one or more members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkyl amino, C 1 -C 6  alkylamino, cycloalkylamino, arylamino, arylalkylamino, and morpholinyl; and the phenyl is optionally substituted with one or more members selected from the group consisting of halogen, NO 2 , CN, C 1 -C 4  alkyl, C 1 -C 4  haloalkyl, and C 1 -C 4  alkoxy; 
         or R 4  and R 5 , R 5  and 5 6 , or R 6  and R 7  taken together with the carbon atoms to which they are attached form a ring;
 X is selected from the group consisting of 
 H; 
 CN; 
 C(O)OR 8  wherein R 8  is H or C 1 -C 8  alkyl, wherein the C 1 -C 8  alkyl optionally is substituted with one or members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkyl amino, C 1 -C 6  alkylamino, cycloalkylamino, phenyl, and morpholinyl; 
 C(O)NR 9 R 10  or CH 2 NR 9 R 10 , wherein R 9  and R 10  are independently selected from the group consisting of H and C 1 -C 6  alkyl, or R 9  and R 10  together with the nitrogen to which they are attached form a C 5 -C 6  cycloalkyl ring or a heteroring; 
 CH 2 OR 11 , wherein R 11  is H, C 1 -C 8  alkyl, or C 3 -C 6  cycloalkyl, wherein the C 1 -C 8  alkyl optionally is substituted with one or members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkyl amino, C 1 -C 6  alkylamino, cycloalkylamino, and morpholinyl; 
 CH 2 Z, wherein Z is halogen; 
 C(O)NHOH; 
 C(O)NHCN; 
 C(O)N(R 1 )SO 2 R 13 , wherein R 13  is C 1 -C 4  alkyl, phenyl, or substituted phenyl; 
 C 1 -C 4  alkyl, optionally substituted with one or more members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkylamino, and C 1 -C 6  alkylamino; and 
 C 2 -C 8  alkenyl optionally substituted with one or more members selected from the group consisting of C 1 -C 4  alkoxy, C 1 -C 4  haloalkyl, C 1 -C 6  dialkylamino, and C 1 -C 6  alkylamino; 
 
         provided that when the compound is a compound of Formula I, and each of R 4 , R 5 , R 6  and R 7  are H, then X is not C(O)OH. 
       
     
     
         73 . The method of  claim 72 , wherein the host is a human that has an elevated level of glutamate in the central nervous system. 
     
     
         74 . The method of  claim 72 , wherein the host is a human that has suffered stroke or trauma to an area of the central nervous system. 
     
     
         75 . The method of  claim 72 , wherein the host is a human that is afflicted with a disease, optionally, a neurodegenerative disease. 
     
     
         76 . The method of  claim 75 , wherein the disease is Parkinson's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Huntington's Disease, or epilepsy.