Compounds for Improving mRNA Splicing

Abstract

Provided herein are compounds useful for improving mRNA splicing in a cell. Exemplary compounds provided herein are useful for improving mRNA splicing in genes comprising at least one exon ending in the nucleotide sequence CAA. Methods for preparing the compounds and methods of treating diseases of the central nervous system are also provided.

1 - 70 . (canceled) 
     
     
         71 . A compound of Formula (Ir): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         L is absent or selected from the group consisting of C 1-6  alkylene, C 2-6  alkenylene, and C 2-6  alkynylene, wherein the C 1-6  alkylene, C 2-6  alkenylene, and C 2-6  alkynylene are each optionally substituted by 1, 2, 3, or 4 independently selected R 20  groups; 
         R 1  is selected from the group consisting of a C 6-10  aryl, 2-benzofuranyl, 4-quinolinyl, a 5-6 member heteroaryl, and a 5-6 member heterocycloalkyl, each optionally substituted by 1, 2, 3, or 4 independently selected R 1A  groups; 
         each R 1A  is independently selected from halo, CN, NO 2 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  haloalkyl, C 1-6  alkoxy, —C(═O)OH, —C(═O)C 1-6  alkyl, —C(═O)C 1-6  haloalkyl, and —C(═O)C 1-6  alkoxy; 
         R 2  is selected from the group consisting of H, oxo, azido, halo, CN, NO 2 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, C 6-10  aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, OR a2 , C(═O)R b2 , C(═O)OR b2 , NR c2 R d2 , C(═O)NR c2 R d2 , —OC(═O)NR c2 R d2 , NR c2 C(═O)R b2 , NR c2 C(═O)OR b2 , N c2 C(═O)NR c2 R d2 , NR c2 S(═O) 2 R b2 , NR c2 S(═O) 2 NR c2 R d2 , S(O)NR c2 R d2 , and S(O) 2 NR c2 R d2 , wherein the C 1-6  alkyl, C 3-10  cycloalkyl, C 6-10  aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 20  groups; 
         R 3  is selected from the group consisting of H, oxo, azido, halo, CN, NO 2 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, C 6-10  aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, OR a3 , SR a3 , C(═O)R b3 , C(═O)OR b3 , NR c3 R d3 , C(═O)NR c3 R d3 , —OC(═O)NR c3 R d3 , NR c3 C(═O)R b3 , NR c3 C(═O)OR b3 , NR c3 C(═O)NR c3 R d3 , NR c3 S(═O) 2 R b3 , NR c3 S(═O) 2 NR c3 R d3 , S(O)NR c3 R d3 , and S(O) 2 NR c3 R d3 , wherein the C 1-6  alkyl, C 3-10  cycloalkyl, C 6-10  aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 20  groups; 
         R 5  is selected from the group consisting of H, oxo, azido, halo, CN, NO 2 , C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, C 6-10  aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, OR a5 , SR a5 , C(═O)R b5 , C(═O)OR b5 , NR c5 R d5 , C(═O)NR c5 R d5 , —OC(═O)NR c5 R d5 , NR c5 C(═O)R b5 , NR c5 C(═O)OR b5 , NR c5 C(═O)NR c5 R d5  NR c5 S(═O) 2 R b5 , NR c5 S(═O) 2 NR c5 R d5 , S(O)NR c5 R d5 , and S(O) 2 NR c5 R d5 , wherein the C 1-6  alkyl, C 3-10  cycloalkyl, C 6-10  aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 20  groups; 
         R 6  is selected from the group consisting of H, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  hydroxyalkyl, and C 1-6  alkoxy; 
         each R a2 , R b2 , R c2 , R d2 , R a3 , R b3 , R c3 , R d3 , R a5 , R b5 , R c5 , and R d5  is independently selected from the group consisting of H, C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 1-6  hydroxyalkyl, C 1-6  haloalkyl, C 1-6  alkoxy, —(C 1-6  alkylene)-C 1-6  alkoxy, C 3-10  cycloalkyl, —(C 1-6  alkylene)-C 3-10  cycloalkyl, C 6-10  aryl, 5-10 membered heteroaryl, 4-10 membered heterocycloalkyl, wherein the C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, C 3-10  cycloalkyl, —(C 1-6  alkylene)-C 3-10  cycloalkyl, C 6-10  aryl, 5-10 membered heteroaryl, and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 20  groups; 
         or R c2  and R d2  together with the N atom to which they are connected, come together to form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring, each optionally substituted by 1, 2, 3, or 4 independently selected R 20  groups; 
         or R c3  and R d3  together with the N atom to which they are connected, come together to form a 5-10 membered heteroaryl or 4-10 membered heterocycloalkyl ring, each optionally substituted by 1, 2, 3, or 4 independently selected R 20  groups; and 
         each R 20  is independently selected from the group consisting of OH, SH, CN, NO 2 , halo, oxo, C 1-4  alkyl, C 2-4  alkenyl, C 2-4  alkynyl, C 1-4  haloalkyl, C 1-4  cyanoalkyl, C 1-4  hydroxyalkyl, C 1-4  alkoxy, —(C 1-4  alkyl)-(C 1-4  alkoxy), —(C 1-4  alkoxy)-(C 1-4  alkoxy), C 1-4  haloalkoxy, C 3-6  cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, amino, C 1-4  alkylamino, di(C 1-4  alkyl)amino, carbamyl, C 1-4  alkylcarbamyl, di(C 1-4  alkyl)carbamyl, carbamoyl, C 1-4  alkylcarbamoyl, di(C 1-4  alkyl)carbamoyl, C 1-4  alkylcarbonyl, C 1-4  alkoxycarbonyl, C 1-4  alkylcarbonylamino, C 1-4  alkylsulfonylamino, aminosulfonyl, C 1-4  alkylaminosulfonyl, di(C 1-4  alkyl)aminosulfonyl, aminosulfonylamino, C 1-4  alkylaminosulfonylamino, di(C 1-4  alkyl)aminosulfonylamino, aminocarbonylamino, C 1-4  alkylaminocarbonylamino, and di(C 1-4  alkyl)aminocarbonylamino. 
       
     
     
         72 . The compound of  claim 71 , wherein L is C 1-6  alkylene optionally substituted by 1, 2, 3, or 4 independently selected R 20  groups. 
     
     
         73 . The compound of  claim 71 , wherein L is unsubstituted methylene or unsubstituted ethylene. 
     
     
         74 . The compound of  claim 71 , wherein R 1  is selected from the group consisting of 2-benzofuranyl, 4-quinolinyl, phenyl, 5-6 membered heteroaryl, and 5-6 membered heterocycloalkyl, each optionally substituted by 1 or 2 independently selected R 1A  groups. 
     
     
         75 . The compound of  claim 71 , wherein R 1  is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         76 . The compound of  claim 71 , wherein each R 1A  is independently selected from the group consisting of halo, CN, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, and —C(═O)OH. 
     
     
         77 . The compound of  claim 71 , wherein each R 1A  is independently selected from the group consisting of CN, fluoro, chloro, methyl, trifluoromethyl, methoxy, and —C(═O)OH. 
     
     
         78 . The compound of  claim 71 , wherein R 2  is selected from the group consisting of H, oxo, halo, CN, C 1-6  alkyl, OR a2 , NR c2 R d2 , 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, C(═O)OR a2 , and C(═O)NR c2 R d2 , wherein the C 1-6  alkyl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 20  groups. 
     
     
         79 . The compound of  claim 71 , wherein R 3  is selected from the group consisting of H, oxo, azido, CN, C 1-6  alkyl, C 3-6  cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, OR a3 , SR a3 , NR c3 R d3 , C(═O)OR a3 , —C(═O)NR c3 R d3 , —OC(═O)R b3 , wherein the C 1-6  alkyl, C 3-6  cycloalkyl, phenyl, 5-6 membered heteroaryl, and 5-6 membered heterocycloalkyl, are each optionally substituted by 1, 2, 3, or 4 independently selected R 20  groups. 
     
     
         80 . The compound of  claim 71 , wherein R 3  is selected from the group consisting of H, azido, CN, methyl, cyclopropyl, cyclobutyl, phenyl, 3-pyridinyl, N-morpholino, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, —OCH 2 CH 2 OH, —OCH 2 CH 2 CH 2 OH, —OCH 2 CH 2 OCH 3 , —OCH 2 CH 2 CH 2 OCH 3 , —ONHCH 3 , —OCH 2 CHF 2 , —OCH 2 CF 3 , —OCH 2 CH 2 CF 3 , —OCH 2 CHF 2 CH 3 , —OCH 2 CH 2 NHC(═O)CH 3 , cyclobutoxy, —OCH 2 CH 2 —O-phenyl, —SCH 3 , —NH 2 , —NHCH 3 , —NHCH 2 CH 3 , —N(CH 3 ) 2 , —NHCH 2 CH 2 CH 2 OH, —CH 2 OCH 3 , —CH 2 OH, —CH 2 NHCH 3 , —CH 2 N(CH 3 ) 2 , —C(═O)OCH 3 , —C(═O)NH 2 , —C(═O)NHCH 3 , —C(═O)N(CH 3 ) 2 , —NHCH 2 CH 2 OH, —C(═O)NHCH 2 CH 2 OH, —OC(═O)CH 3 , —OCH 2 -azetidinyl, —OCH 2 -oxetanyl, 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         81 . The compound of  claim 71 , wherein R 5  is selected from the group consisting of H, halo, CN, C 1-6  alkyl, C 1-6  haloalkyl, OR a5 , SR a5 , NR c5 R d5 , C 3-6  cycloalkyl, C 6-10  aryl, and 5-6 membered heteroaryl. 
     
     
         82 . The compound of  claim 71 , wherein R 5  is selected from the group consisting of H, fluoro, chloro, bromo, iodo, CN, methyl, isopropyl, OH, OCH 3 , NH 2 , —NHCH 3 , —N(CH 3 ) 2 , —SCH 3 , phenyl, cyclopropyl, and 
       
         
           
           
               
               
           
         
       
     
     
         83 . The compound of  claim 71 , wherein R 5  is chloro or fluoro. 
     
     
         84 . The compound of  claim 71 , wherein R 6  is H or C 1-6  alkyl. 
     
     
         85 . The compound of  claim 71 , wherein:
 L is unsubstituted C 1-6  alkylene;   R 1  is selected from the group consisting of 2-benzofuranyl, 4-quinolinyl, C 6-10  aryl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, optionally substituted by 1, 2, 3, or 4 independently selected R 1A  groups;   each R 1A  is independently selected from the group consisting of halo, CN, C 1-6  alkyl, C 1-6  haloalkyl, C 1-6  alkoxy, and —C(═O)OH;   R 2  is selected from the group consisting of H, oxo, halo, CN, C 1-6  alkyl, OR a2 , NR c2 R d2 , 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, C(═O)OR a2 , and C(═O)NR c2 R d2 , wherein the C 1-6  alkyl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 20  groups;   R 3  is selected from the group consisting of H, oxo, azido, CN, C 1-6  alkyl, C 3-6  cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, OR a3 , SR a3 , NR c3 R d3 , C(═O)OR a3 , —C(═O)NR c3 R d3 , —OC(═O)R b3 , wherein the C 1-6  alkyl, C 3-6  cycloalkyl, phenyl, 5-6 membered heteroaryl, 5-6 membered heterocycloalkyl, are each optionally substituted by 1, 2, 3, or 4 independently selected R 20  groups;   R 4  is selected from the group consisting of H, oxo, azido, halo, CN, C 1-6  alkyl, OR a4 , NR c4 R d4 , and 4-10 membered heterocycloalkyl, wherein the C 1-6  alkyl and 4-10 membered heterocycloalkyl are each optionally substituted by 1, 2, 3, or 4 independently selected R 20  groups; and   R 5  is selected from the group consisting of H, halo, CN, C 1-6  alkyl, C 1-6  haloalkyl, OR a5 , SR a5 , NR c5 R d5 , C 3-6  cycloalkyl, C 6-10  aryl, and 5-6 membered heteroaryl.   
     
     
         86 . The compound of  claim 71 , wherein:
 L is unsubstituted methylene or unsubstituted ethylene;   R 1  is selected from the group consisting of unsubstituted 2-furanyl, unsubstituted 4-quinolinyl, and unsubstituted phenyl;   R 5  is halo; and   R 6  is H.   
     
     
         87 . The compound of  claim 86 , wherein:
 L is unsubstituted methylene; and   R 1  is unsubstituted 2-furanyl.   
     
     
         88 . The compound of  claim 71 , wherein the compound of Formula (Ir) has formula: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         89 . A pharmaceutical composition comprising a compound of  claim 71 , or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. 
     
     
         90 . A method of reducing or alleviating one or more symptoms of familial dysautonomia, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of  claim 71 , or a pharmaceutically acceptable salt thereof.