Methods for treating sars cov-2 infections

Abstract

Provided are methods for treating 2019-nCoV virus (SARS-CoV-2) infections by administering nucleosides and prodrugs thereof, of Formula I:wherein the 1′ position of the nucleoside sugar is substituted.

1 . A method for treating or preventing a SARS-CoV-2 infection in a human in need thereof comprising administering a therapeutically effective amount of an anti-inflammatory agent a compound of Formula I: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester, thereof; 
       wherein:
 R 7  is selected from the group consisting of 
 a) H, —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), and —SO 2 NR 11 R 12 , 
 
       
         
           
           
               
               
           
         
       
       wherein:
 R c  is selected from phenyl, 1-naphthyl, 2-naphthyl, 
 
       
         
           
           
               
               
           
         
         R d  is H or CH 3 ; 
         R e1  and R e2  are each independently H, (C 1 -C 6 )alkyl or benzyl; 
         R f  is selected from H, (C 1 -C 8 )alkyl, benzyl, (C 3 -C 6 )cycloalkyl, and —CH 2 —(C 3 -C 6 )cycloalkyl; 
         R g  is selected from (C 1 -C 8 )alkyl, —O—(C 1 -C 8 )alkyl, benzyl, —O-benzyl, —CH 2 —(C 3 -C 6 )cycloalkyl, —O—CH 2 —(C 3 -C 6 )cycloalkyl, and CF 3 ; and 
         n′ is selected from 1, 2, 3, and 4; and 
         d) a group of formula: 
       
       
         
           
           
               
               
           
         
       
       wherein:
 Q is O, S, NR,  + N(O − )(R), N(OR),  + N(O − )(OR), or N—NR 2 , 
 Z 1  and Z 2 , when taken together, are -Q 1 (C(R y ) 2 ) 3 Q 1 -; 
 
       wherein
 each Q 1  is independently O, S, or NR; and 
 each R y  is independently H, F, Cl, Br, I, OH, R, —C(=Q 2 )R, —C(=Q 2 )OR, —C(=Q 2 )N(R) 2 , —N(R) 2 , — + N(R) 3 , —SR, —S(O)R, —S(O) 2 R, —S(O)(OR), —S(O) 2 (OR), —OC(=Q′)R, —OC(=Q 2 )OR, —OC(=Q 2 )(N(R) 2 ), —SC(=Q 2 )R, —SC(=Q 2 )OR, —SC(=Q 2 )(N(R) 2 ), —N(R)C(=Q 2 )R, —N(R)C(=Q 2 )OR, —N(R)C(=Q 2 )N(R) 2 , —SO 2 NR 2 , —CN, —N 3 , —NO 2 , or —OR; or when taken together, two R y  on the same carbon atom form a carbocyclic ring of 3 to 7 carbon atoms; 
 each Q 2  is independently, O, S, NR,  + N(O − )(R), N(OR),  + N(O − )(OR), or N—NR 2 ; or 
 Z 1  and Z 2  are each, independently, a group of Formula Ia: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 each Q 3  is independently a bond, O, CR 2 , NR,  + N(O − )(R), N(OR),  + N(O − )(OR), N—NR 2 , S, S—S, S(O), or S(O) 2 ; 
 M2 is 0, 1 or 2; 
 each R x  is independently R y  or the formula: 
 
       
         
           
           
               
               
           
         
       
       wherein:
 each M1a, M1c, and M1d is independently 0 or 1; 
 M12c is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12; 
 R 8  is halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N 3 , NO, NO 2 , CHO, CN, —CH(═NR 11 ), —CH═NNHR 11 , —CH═N(OR 11 ), —CH(OR 1 ) 2 , —C(═O)NR 11 R 12 , —C(═S)NR 11 R 12 , —C(═O)OR 11 , (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, (C 6 -C 20 ) optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl, (C 6 -C 20 )aryl(C 1 -C 8 )alkyl, OR 11  or SR 11 ; 
 each R 9  and R 10  is independently H, halogen, NR 11 R 12 , N(R 11 )OR 11 , NR 11 NR 11 R 12 , N 3 , NO, NO 2 , CHO, CN, —CH(═NR 11 ), —CH═NHNR 11 , —CH═N(OR 11 ), —CH(OR 11 ) 2 , —C(═O)NR 11 R 12 , —C(═S)NR 11 R 12 , —C(═O)OR 11 , R 11 , OR 11  or S 11 ; 
 each R 11  and R 12  is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, (C 6 -C 20 ) optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl or (C 6 -C 20 )aryl(C 1 -C 8 )alkyl; or R 11  and R 12  taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S— or —NR a —; 
 each R a  is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 6 -C 20 )aryl(C 1 -C 8 )alkyl, (C 4 -C 8 )carbocyclylalkyl, —C(═O)R, —C(═O)OR, —C(═O)NR 2 , —C(═O)SR, —S(O)R, —S(O) 2 R, —S(O)(OR), —S(O) 2 (OR), or —SO 2 NR 2 ; 
 each R is independently H, (C 1 -C 8 ) alkyl, (C 1 -C 8 ) substituted alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 ) substituted alkenyl, (C 2 -C 8 ) alkynyl, (C 2 -C 8 ) substituted alkynyl, (C 6 -C 20 )aryl, (C 6 -C 20 )substituted aryl, (C 2 -C 20 )heterocyclyl, (C 2 -C 20 )substituted heterocyclyl, (C 6 -C 20 )aryl(C 1 -C 8 )alkyl or substituted (C 6 -C 20 )aryl(C 1 -C 8 )alkyl; 
 each n is independently 0, 1, or 2; 
 wherein each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, or (C 2 -C 8 )alkynyl of each R 2 , R 3 , R 5 , R 6 , R 11  and R 12  is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2  or OR a ; wherein one or more of the non-terminal carbon atoms of each said (C 1 -C 8 )alkyl may be optionally replaced with —O—, —S— or —NR a —; and 
 wherein each (C 6 -C 20 )aryl(C 1 -C 8 )alkyl of each R 6 , R 11 , and R 12  is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , N(R a ) 2  or OR a : wherein one or more of the non-terminal carbon atoms of each said (C 1 -C 8 )alkyl may be optionally replaced with —O—, —S— or —NR a —. 
 
     
     
         2 . The method of  claim 1 , comprising administering to the human (i) a loading dose of the compound of Formula I and (ii) one or more of a maintenance dose of the compound of Formula I. 
     
     
         3 . The method of  claim 2 , wherein the loading dose is about 150-250 mg of the compound of Formula I. 
     
     
         4 . (canceled) 
     
     
         5 . The method of  claim 2 , wherein the maintenance dose is about 50-150 mg of the compound of Formula I. 
     
     
         6 . (canceled) 
     
     
         7 . The method of  claim 2 , comprising administering one loading dose of about 150-250 mg and at least one maintenance dose of about 50-150 mg. 
     
     
         8 . (canceled) 
     
     
         9 . (canceled) 
     
     
         10 . The method of  claim 2 , comprising administering one loading dose of 150-250 mg on treatment day one and the maintenance dose of about 50-150 mg on day 2 to day 5 of the treatment. 
     
     
         11 . The method of  claim 1 , wherein the compound of Formula I is administered by intramuscular administration. 
     
     
         12 . The method of  claim 1 , wherein the compound of Formula I is administered by inhalation, IV infusion, orally or subcutaneously. 
     
     
         13 .- 31 . (canceled) 
     
     
         32 . The method of  claim 1 , wherein
 each R 11  or R 12  is independently H, (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, (C 2 -C 8 )alkynyl, (C 4 -C 8 )carbocyclylalkyl, (C 6 -C 20 ) optionally substituted aryl, optionally substituted heteroaryl, —C(═O)(C 1 -C 8 )alkyl, —S(O) n (C 1 -C 8 )alkyl or (C 6 -C 20 )aryl(C 1 -C 8 )alkyl; or R 11  and R 12  taken together with a nitrogen to which they are both attached form a 3 to 7 membered heterocyclic ring wherein any one carbon atom of said heterocyclic ring can optionally be replaced with —O—, —S— or —NH—; wherein   each (C 1 -C 8 )alkyl, (C 2 -C 8 )alkenyl, or (C 2 -C 8 )alkynyl of each R 2 , R 3 , R 5 , R 6 , R 11  and R 12  is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , NH 2  or OH; wherein one or more of the non-terminal carbon atoms of each said (C 1 -C 8 )alkyl may be optionally replaced with —O—, —S— or —NH—; and   wherein each C 6 -C 20 )aryl(C 1 -C 8 )alkyl of each R 6 , R 11 , and R 12  is, independently, optionally substituted with one or more halo, hydroxy, CN, N 3 , NH 2  or OH: wherein one or more of the non-terminal carbon atoms of each said (C 1 -C 8 )alkyl may be optionally replaced with —O—, —S— or —NH—.   
     
     
         33 . The method of  claim 1 , wherein R 7  is H. 
     
     
         34 . The method of  claim 1 , wherein R 7  is selected from the group of
 a) H, —C(═O)R 11 , —C(═O)OR 11 , —C(═O)NR 11 R 12 , —C(═O)SR 11 , —S(O)R 11 , —S(O) 2 R 11 , —S(O)(OR 11 ), —S(O) 2 (OR 11 ), —SO 2 NR 11 R 12 ,   
       
         
           
           
               
               
           
         
       
       wherein:
 R c  is selected from phenyl, 1-naphthyl, 2-naphthyl, 
 
       
         
           
           
               
               
           
         
         R d  is H or CH 3 ; 
         R e1  and R e2  are each independently H or C 1 -C 6  alkyl; 
         R f  is selected from H, C 1 -C 8  alkyl, benzyl, C 3 -C 6  cycloalkyl, and —CH 2 -C 3 -C 6  cycloalkyl; 
         R g  is selected from C 1 -C 8  alkyl, —O—C 1 -C 8  alkyl, benzyl, —O-benzyl, —CH 2 -C 3 -C 6  cycloalkyl, —O—CH 2 -C 3 -C 6  cycloalkyl, and CF 3 ; and 
         n′ is selected from 1, 2, 3, and 4. 
       
     
     
         35 . The method of  claim 1 , wherein R 7  is 
       
         
           
           
               
               
           
         
         wherein Z 1  and Z 2  are each, independently, a group of structure: 
       
       
         
           
           
               
               
           
         
       
     
     
         36 . The method of  claim 1 , wherein R 7  is 
       
         
           
           
               
               
           
         
         wherein Z 1  and Z 2  are each, independently, a group of structure: 
       
       
         
           
           
               
               
           
         
       
     
     
         37 . The method of  claim 1 , wherein R 7  is 
       
         
           
           
               
               
           
         
         wherein each Q 3b  is, independently, O or N(R). 
       
     
     
         38 . The method of  claim 37 , wherein each Q 3b  is O and each R x  is independently: 
       
         
           
           
               
               
           
         
         wherein M12c is 1, 2 or 3 and each Q 3  is independently a bond, O, CR 2 , or S. 
       
     
     
         39 . The method of  claim 1 , wherein R 7  is 
       
         
           
           
               
               
           
         
       
     
     
         40 .- 42 . (canceled) 
     
     
         43 . The method of  claim 1 , wherein R 7  is 
       
         
           
           
               
               
           
         
       
     
     
         44 .- 49 . (canceled) 
     
     
         50 . The method of  claim 1 , wherein R 7  is 
       
         
           
           
               
               
           
         
       
     
     
         51 . (canceled) 
     
     
         52 . (canceled) 
     
     
         53 . The method of  claim 1 , wherein the compound of Formula IV is: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         54 . The method of  claim 1 , wherein the compound of Formula IV is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         55 . The method of  claim 1 , wherein the compound of Formula IV is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         56 . The method of  claim 1 , wherein the compound of Formula IV is: 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt or ester thereof. 
     
     
         57 . The method of  claim 1 , wherein the human is suffering from the COVID-19 disease caused by the SARS-CoV-2. 
     
     
         58 . (canceled) 
     
     
         59 . The method of  claim 1 , wherein the method comprises event driven administration and wherein the event driven administration comprises pre-exposure prophylaxis (PrEP). 
     
     
         60 . The method of  claim 1 , wherein the method comprises event driven administration and wherein the event driven administration comprises post-exposure prophylaxis (PEP). 
     
     
         61 . (canceled) 
     
     
         62 . The method of  claim 1 , wherein the method comprises administering the compound of Formula I, or a pharmaceutically acceptable salt thereof. 
     
     
         63 . The method of  claim 1 , further comprising administering a pharmaceutically acceptable carrier or excipient. 
     
     
         64 . (canceled) 
     
     
         65 . (canceled) 
     
     
         66 . The method of  claim 1 , wherein the anti-inflammatory agent is selected from the group consisting of baricitinib, tocilizumab, cenicriviroc, icatibant, apremilast, razuprotafib, lenzilumab, risankizumab, infliximab, and abatacept. 
     
     
         67 . The method of  claim 1 , wherein the anti-inflammatory agent is baricitinib. 
     
     
         68 . The method of  claim 1 , wherein the anti-inflammatory agent is a JAK inhibitor. 
     
     
         69 . The method of  claim 68 , wherein the JAK inhibitor is barcitinib, ruxolitinib, tofacitinib, upadacitinib, or fedratinib. 
     
     
         70 . The method of  claim 68 , wherein the JAK inhibitor is barcitinib. 
     
     
         71 .- 161 . (canceled) 
     
     
         162 . The method of  claim 1 , wherein a 2019-nCoV polymerase is inhibited. 
     
     
         163 . (canceled) 
     
     
         164 . (canceled) 
     
     
         165 . A kit comprising one or more individual dosage units of a compound described in  claim 1 , or a pharmaceutically acceptable salt, ester, stereoisomer, hydrate, solvate, mixture of stereoisomers, or tautomer thereof, and directions for their use in treating a 2019-nCoV viral infection in a human. 
     
     
         166 . (canceled)