Compounds and methods for treating disease

Abstract

The invention provides compounds, compositions and methods for treating medical disorders, such as cancer, an autoimmune disorder, and/or a neurological disorder, and inhibiting LINE1 reverse transcriptase and/or HERV-K reverse transcriptase using a compound according to Formula I or a pharmaceutically acceptable salt thereof, or a related compound provided herein.

1 . A compound according to Formula I-A: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1A  is —C(O)R 5A , hydrogen, or —P(O)(OH)—OP(O)(OH)—OP(O)(OH) 2 ; 
         R 2A  is (i) halomethyl, C 1-3  aliphatic, or cyclopropyl, each of which optionally has one or more hydrogen replaced with deuterium, or (ii) —N 3 ; 
         R 3A  is —C(O)R 5A  or hydrogen; 
         R 4A  is halo, hydrogen, or —OH; 
         R 5A  represents independently for each occurrence C 1-20  aliphatic, C 1-20  haloaliphatic, —C(H)(R 6A )—N(R 7A ) 2 , phenyl, —CH 2 -phenyl, or hydrogen; wherein each phenyl is substituted with m occurrences of R 10A ; 
         R 6A  is C 1-6  alkyl or hydrogen, wherein said C 1-6  alkyl is optionally substituted with phenyl; 
         R 7A  represents independently for each occurrence hydrogen, C 1-6  alkyl, —C(O)CH 3 , —C(O)OC(CH 3 ) 3 , —C(O)O(CH 2 )phenyl, or —C(O)O(CH 2 )fluorenyl; 
         R 8A  is hydrogen, halo, —CH 3 , or —CF 3 ; 
         R 9A  is halo, —CH 3 , or —CF 3 ; 
         R 10A  represents independently for each occurrence C 1-6  alkyl, C 1-6  alkoxyl, C 1-6  haloalkyl, or halo; 
         B A  is 
       
       
         
           
           
               
               
           
         
       
       and
 m is 0, 1, or 2; 
 provided that if R 4A  is hydrogen, then at least one of R 1A  and R 3A  is —C(O)R 5A ; and 
 provided that if R 3A  is hydrogen, R 4A  is halo or —OH, and R 1A  is hydrogen or —P(O)(OH)—OP(O)(OH)—OP(O)(OH) 2 , then R 8A  is halo, —CH 3 , or —CF 3 . 
 
     
     
         2 . The compound of  claim 1 , wherein R 1A  is —C(O)R 5A . 
     
     
         3 . The compound of  claim 1 , wherein R 1A  is hydrogen. 
     
     
         4 . The compound of  claim 1 , wherein R 1A  is —P(O)(OH)—OP(O)(OH)—OP(O)(OH) 2 . 
     
     
         5 . The compound of  claim 1 , wherein R 4A  is halo. 
     
     
         6 . The compound of  claim 1 , wherein R 4A  is fluoro. 
     
     
         7 . The compound of  claim 1 , wherein B A  is 
       
         
           
           
               
               
           
         
       
     
     
         8 . The compound of  claim 1 , wherein the compound has the following formula or a pharmaceutically acceptable salt thereof: 
       
         
           
           
               
               
           
         
       
     
     
         9 . The compound of  claim 1 , wherein R 8A  is halo. 
     
     
         10 . The compound of  claim 1 , wherein R 8A  is fluoro. 
     
     
         11 . The compound of  claim 1 , wherein R 2A  is halomethyl. 
     
     
         12 . The compound of  claim 1 , wherein R 2A  is halomethyl wherein one or more hydrogen is replaced with deuterium. 
     
     
         13 . The compound of  claim 1 , wherein R 2A  is —CH 2 F. 
     
     
         14 . The compound of  claim 1 , wherein R 3A  is —C(O)R 5A . 
     
     
         15 . The compound of  claim 1 , wherein R 3A  is hydrogen. 
     
     
         16 . The compound of  claim 1 , wherein the compound is represented by Formula II: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  and R 4  represent independently —C(O)R 5  or hydrogen; provided that at least one of R 1  and R 4  is —C(O)R 5 ; 
         R 2  is halo, hydrogen, or —OH; 
         R 3  is halomethyl, C 1-3  aliphatic, or cyclopropyl, each of which optionally has one or more hydrogen replaced with deuterium; 
         R 5  represents independently for each occurrence C 1-20  aliphatic, C 1-20  haloaliphatic, —C(H)(R 6 )—N(R 7 ) 2 , phenyl, —CH 2 -phenyl, or hydrogen; wherein each phenyl is substituted with m occurrences of R 10 ; 
         R 6  is C 1-6  alkyl or hydrogen, wherein said C 1-6  alkyl is optionally substituted with phenyl; 
         R 7  represents independently for each occurrence hydrogen, C 1-6  alkyl, —C(O)CH 3 , —C(O)OC(CH 3 ) 3 , —C(O)O(CH 2 )phenyl, or —C(O)O(CH 2 )fluorenyl; 
         R 8  is hydrogen, halo, —CH 3 , or —CF 3 ; 
         R 9  is halo, —CH 3 , or —CF 3 ; 
         R 10  represents independently for each occurrence C 1-6  alkyl, C 1-6  alkoxyl, C 1-6  haloalkyl, or halo; B 1  is 
       
       
         
           
           
               
               
           
         
       
       and
 m is 0, 1, or 2. 
 
     
     
         17 . The compound of  claim 1 , wherein the compound is represented by Formula II-A: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  and R 4  are —C(O)R 5 ; 
         R 3  is halomethyl; 
         R 5  represents independently for each occurrence C 1-20  aliphatic, C 1-20  haloaliphatic, —C(H)(R 6 )—N(R 7 ) 2 , phenyl, or —CH 2 -phenyl; wherein each phenyl is substituted with m occurrences of R 10 ; 
         R 6  is C 1-6  alkyl or hydrogen, wherein said C 1-6  alkyl is optionally substituted with phenyl; 
         R 7  represents independently for each occurrence hydrogen, C 1-6  alkyl, —C(O)CH 3 , —C(O)OC(CH 3 ) 3 , —C(O)O(CH 2 )phenyl, or —C(O)O(CH 2 )fluorenyl; 
         R 8  is halo or —CF 3 ; 
         R 10  represents independently for each occurrence C 1-6  alkyl, C 1-6  alkoxyl, C 1-6  haloalkyl, or halo; and 
         m is 0, 1, or 2. 
       
     
     
         18 . The compound of  claim 1 , wherein the compound is represented by Formula III: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is —CH 2 Cl, —CH 2 F, —CH 2 Br, —CH 2 I, —CF 3 , —CH 2 CH 3 , —C(H)═CH 2 , —C(H)═C═CH 2 , or cyclopropyl; each of which optionally has one or more hydrogen replaced with deuterium; 
         R 2  is fluoro or —OH; 
         R 3  is halo, —CH 3 , or —CF 3 ; and 
         B 1  is 
       
       
         
           
           
               
               
           
         
       
     
     
         19 . The compound of  claim 1 , wherein the compound is represented by Formula III-A: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is —CH 2 Cl, —CH 2 Br, or —CH 2 F; each of which optionally has one or more hydrogen replaced with deuterium; and 
         R 3  is halo or —CF 3 . 
       
     
     
         20 . The compound of  claim 1 , wherein the compound is represented by Formula III-B: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is —N 3 ; and 
         R 3  is halo or —CF 3 . 
       
     
     
         21 . The compound of  claim 1 , wherein the compound is represented by Formula IV: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is (i) —CH 2 Cl, —CH 2 F, —CH 2 Br, —CH 2 I, —CF 3 , —CH 2 CH 3 , —C(H)═CH 2 , —C(H)═C═CH 2 , or cyclopropyl, each of which optionally has one or more hydrogen replaced with deuterium or (ii) —N 3 ; 
         R 2  is hydrogen, halo, or —CF 3 ; and 
         B 1  is 
       
       
         
           
           
               
               
           
         
       
     
     
         22 . The compound of  claim 21 , wherein the compound is represented by Formula IV-A: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is (i) —CH 2 Cl, —CH 2 F, or —CH 2 Br, each of which optionally has one or more hydrogen replaced with deuterium, or (ii) —N 3 ; and 
         R 2  is hydrogen or halo. 
       
     
     
         23 . The compound of  claim 21 , wherein the compound is represented by Formula IV-B: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         R 1  is —CH 2 Cl, —CH 2 F, or —CH 2 Br, each of which optionally has one or more hydrogen replaced with deuterium; and 
         R 2  is F. 
       
     
     
         24 . A compound in Table 1, 1-A, 1-B, 1-C, or 1-D herein, or a pharmaceutically acceptable salt thereof. 
     
     
         25 . A pharmaceutical composition comprising a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, and a carrier, excipient, and/or vehicle. 
     
     
         26 . A method of treating a disorder selected from the group consisting of cancer, an autoimmune disorder, and a neurological disorder, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula V, or a pharmaceutically acceptable salt thereof, in order to treat the disorder, wherein Formula V is represented by: 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, wherein: 
         B 1  is 
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         R 1  is —H, —C(O)R 8 , or —P(O)(OH)—OP(O)(OH)—OP(O)(OH) 2 ; 
         R 2  is —H, C 1 -C 6  aliphatic, C 1 -C 3  haloaliphatic, C 1 -C 3  hydroxyalkyl, —CH 2 NH 2 , —CH 2 SH, —CH 2 S—(C 1 -C 3  aliphatic), cyclopropyl, —CN, —C(O)NH 2 , —N 3 , —O—(C 1 -C 3  aliphatic), —O—(C 1 -C 3  haloaliphatic), —S—(C 1 -C 3  aliphatic), —F, or —Cl; wherein each of said C 1 -C 6  aliphatic, C 1 -C 3  haloaliphatic, and cyclopropyl optionally has one or more hydrogen replaced with deuterium; 
         R 3  is —H or —OH; 
         R 4  is —OH, —Cl, —OCH 3 , —F, —N 3 , or —OC(O)R 8 ; 
         R 5  is —H or —F; 
         R 6  is —H, —F, —Cl, C 1 -C 6  aliphatic, C 1 -C 4  haloaliphatic, —O—(C 1 -C 4  aliphatic), cyclopropyl, or —OH; 
         R 7  is hydrogen, halo, —CH 3 , or —CF 3 ; 
         R 8  represents independently for each occurrence C 1-20  aliphatic, C 1-20  haloaliphatic, —C(H)(R 9 )—N(R 10 ) 2 , phenyl, —CH 2 -phenyl, or hydrogen; wherein each phenyl is substituted with m occurrences of R 11 ; 
         R 9  is C 1-6  alkyl or hydrogen, wherein said C 1-6  alkyl is optionally substituted with phenyl; 
         R 10  represents independently for each occurrence hydrogen, C 1-6  alkyl, —C(O)CH 3 , —C(O)OC(CH 3 ) 3 , —C(O)O(CH 2 )phenyl, or —C(O)O(CH 2 )fluorenyl; 
         R 11  represents independently for each occurrence C 1-6  alkyl, C 1-6  alkoxyl, C 1-6  haloalkyl, or halo; and 
         m is 0, 1, or 2. 
       
     
     
         27 . The method of  claim 26 , wherein the compound is a compound in Table 1, 1-A, 1-B, 1-C, 1-D, 2, 2-A, 2-B, or 2-C herein, or a pharmaceutically acceptable salt thereof. 
     
     
         28 . A method of inhibiting LINE1 reverse transcriptase activity in a subject, the method comprising contacting a LINE1 reverse transcriptase with an effective amount of a compound according to  claim 1 , or a pharmaceutically acceptable salt thereof, or the pharmaceutical composition of  claim 1 , in order to inhibit the activity of said LINE1 reverse transcriptase. 
     
     
         29 . The method of  claim 28 , wherein the compound according to  claim 1  is selected from the group of compounds consisting of those in Table 1, 1-A, 1-B, 1-C, or 1-D herein, or a pharmaceutically acceptable salt thereof. 
     
     
         30 . The method of  claim 26 , wherein the subject has (i) elevated expression of LINE1 RNA, LINE1 ORF1 polypeptide, and/or LINE1 ORF2 polypeptide; and/or (ii) elevated activity of LINE1 reverse transcriptase.