Antiviral compounds

Abstract

Disclosed herein are new antiviral compounds, together with pharmaceutical compositions that include one or more antiviral compounds, and methods of synthesizing the same. Also disclosed herein are methods of ameliorating and/or treating a paramyxovirus viral infection with one or more small molecule compounds. Examples of paramyxovirus infection include an infection caused by human respiratory syncytial virus (RSV).

1 . A compound of Formula (I) having the structure:
   A-L-Y  (I),
   or a pharmaceutically acceptable salt thereof, wherein:   L is selected from the group consisting of:   
       
         
           
           
               
               
           
         
         A is selected from the group consisting of an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted aryl (C 1-2  alkyl), an optionally substituted heteroaryl, and an optionally substituted heterocyclyl; 
         Y is selected from the group consisting of an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl, an optionally substituted aryl, an optionally substituted heteroaryl, and an optionally substituted heterocyclyl; 
         R 1a , R 1b , R 1c , and R 1d  are each independently hydrogen or an unsubstituted C 1-4  alkyl; 
         R 2a , R 2a1 , R 2b , R 2b1 , R 2c , R 2c1 , R 2d , and R 2d1  are each independently selected from the group consisting of hydrogen, an optionally substituted C 1-4  alkyl, an optionally substituted aryl(C 1-6  alkyl), an optionally substituted heterocyclyl(C 1-6  alkyl), an alkoxyalkyl, an aminoalkyl, a hydroxyalkyl, and hydroxy; or 
         R 2a1  is hydrogen, and R 1a  and R 2a  are joined together with the atoms to which they are attached to form an optionally substituted 5-membered heterocyclyl or an optionally substituted 6-membered heterocyclyl, R 2b1  is hydrogen, and R 1b  and R 2b  are joined together with the atoms to which they are attached to form an optionally substituted 5-membered heterocyclyl or an optionally substituted 6-membered heterocyclyl; 
            between X 1a  and X 2a  represents a single or double bond between X 1a  and X 2a ;   between X 2a  and X 3a  represents a single or double bond between X 2a  and X 3a ; provided that   between X 1a  and X 2a  and   between X 2a  and X 3a  cannot be both double; 
         X 1a , X 2a , and X 3a  are each independently C, N, O, or C(═O), and form a ring or ring system selected from an optionally substituted aryl, an optionally substituted heteroaryl and an optionally substituted heterocyclyl by joining X 1a  and X 3a  together; with the proviso that the valencies of X 1a , X 2a , and X 3a  can be each independently satisfied with a substituent selected from hydrogen and an optionally substituted C 1-4  alkyl, and X 1a , X 2a , and X 3a  are uncharged; 
         R 3a  and R 3a1  are each independently selected from the group consisting of hydrogen, hydroxy, halogen, amino, an optionally substituted C 1-4  alkyl, an optionally substituted C 2-4  alkenyl, an optionally substituted C 2-4  alkynyl, an optionally substituted C 3-6  cycloalkyl, an optionally substituted C 1-4  alkoxy, —O-carboxy, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, CHF 2 , CF 3 , and 
       
       
         
           
           
               
               
           
         
       
       provided that R 3a  and R 3a1  cannot be both hydrogen; or R 3a  and R 3a1  together form ═N—OR a ; or R 3a  and R 3a1  together with the atom to which they are attached can be joined to form an optionally substituted 3 membered ring, an optionally substituted 4 membered ring, an optionally substituted 5 membered ring or an optionally substituted 6 membered ring;
 R 4a , R 4a1 , R 4a2 , and R 4a3  are each independently hydrogen or an unsubstituted C 1-4  alkyl; 
 R 5a  and R 5a1  are each independently hydrogen or an unsubstituted C 1-4  alkyl; 
 R 6a  and R 6a1  are each independently hydrogen, an optionally substituted C 1-4  alkyl, or an optionally substituted alkoxyalkyl; 
 R 6a2  and R 6a3  are each independently hydrogen or an unsubstituted C 1-4  alkyl; 
 X 1b , X 2b , and X 3b  form a bi-cyclic ring selected from an optionally substituted bi-cyclic heteroaryl and an optionally substituted bi-cyclic heterocyclyl by joining X 1b  and X 3b  together, wherein (i) X 1b  is C, X 2b  is N, and X 3b  is C, (ii) X 1b  is N, X 2b  is N, and X 3b  is C, (iii) X 1b  is N, X 2b  is C(═O), and X 3b  is N, or (iv) X 1b  is C, X 2b  is O, and X 3b  is C, and wherein   between X 1b  and X 2b  represents a single or double bond between X 1b  and X 2b ;   between X 2b  and X 3b  represents a single or double bond between X 2b  and X 3b ; and provided that both   cannot be double bonds; with the proviso that the valencies of X 1b , X 2b , and X 3b  can be each independently satisfied with a substituent selected from hydrogen and an optionally substituted C 1-4  alkyl; and X 1b , X 2b , and X 3b  are uncharged; 
 R 3c  and R 3c1  are each independently selected from the group consisting of hydrogen, hydroxy, halogen, amino, an optionally substituted C 1-4  alkyl, an optionally substituted C 2-4  alkenyl, an optionally substituted C 2-4  alkynyl, an optionally substituted C 3-6  cycloalkyl, an optionally substituted C 1-4  alkoxy, —O-carboxy, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, CHF 2 , CF 3 , and 
 
       
         
           
           
               
               
           
         
       
       provided that R 3c  and R 3c1  cannot be both hydrogen; or R 3c  and R 3c1  together form ═N—OR c ; or R 3c  and R 3c1  together with the atom to which they are attached can be joined to form an optionally substituted 3 membered ring, an optionally substituted 4 membered ring, an optionally substituted 5 membered ring, or an optionally substituted 6 membered ring;
 R a  and R c  are each independently hydrogen or an unsubstituted C 1-4  alkyl; 
 R 4c  and R 5c  are taken together to form an unsubstituted aryl, an unsubstituted heteroaryl, or an optionally substituted heterocyclyl; 
 Z c  is N or CH; 
 m d  is 0 or 1; and 
 ring B d  is an optionally substituted C 5  cycloalkyl; 
 ring B d1  is an optionally substituted pyridinyl; and 
 provided that when L is Formula (Ic), then Y is absent; and 
 provided that the compound is not 
 
       
         
           
           
               
               
           
         
       
     
     
         2 - 143 . (canceled) 
     
     
         144 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is 
       
         
           
           
               
               
           
         
       
       and wherein R 7a1 , R 7a2 , and R 7a3  are each independently selected from the group consisting of hydrogen, halogen, hydroxy, an optionally substituted C 1-8  alkyl, an optionally substituted C 2-8  alkenyl, an optionally substituted C 2-8  alkynyl, an optionally substituted C 3-6  cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted hydroxyalkyl, an optionally substituted C 1-8  alkoxy, an optionally substituted alkoxyalkyl, amino, mono-substituted amino, di-substituted amino, halo(C 1-8  alkyl), haloalkyl, an optionally substituted O-amido, and an optionally substituted C-carboxy. 
     
     
         145 . The compound of  claim 144 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         146 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is 
       
         
           
           
               
               
           
         
       
     
     
         147 . The compound of  claim 146 , wherein A is an optionally substituted phenyl and Y is an optionally substituted benzothiophenyl or an optionally substituted phenyl. 
     
     
         148 . The compound of  claim 146 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         149 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is 
       
         
           
           
               
               
           
         
       
     
     
         150 . The compound of  claim 149 , wherein X 1b , X 2b , and X 3b  form an optionally substituted 
       
         
           
           
               
               
           
         
       
     
     
         151 . The compound of  claim 149 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         152 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is 
       
         
           
           
               
               
           
         
       
     
     
         153 . The compound of  claim 152 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         154 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is 
       
         
           
           
               
               
           
         
       
     
     
         155 . The compound of  claim 154 , wherein the compound is 
       
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt thereof. 
     
     
         156 . The compound of  claim 1 , or a pharmaceutically acceptable salt thereof, wherein L is 
       
         
           
           
               
               
           
         
       
       wherein:
 the dashed semi-circle along with the two carbon atoms to which it is connected form an optionally substituted cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, or an optionally substituted heterocyclyl; and 
 R 8a3  is hydrogen, halogen, hydroxy, an optionally substituted C 1-8  alkyl, an optionally substituted C 2-8  alkenyl, an optionally substituted C 2-8  alkynyl, an optionally substituted C 3-6  cycloalkyl, an optionally substituted aryl, an optionally substituted heteroaryl, an optionally substituted heterocyclyl, an optionally substituted hydroxyalkyl, an optionally substituted C 1-8  alkoxy, an optionally substituted alkoxyalkyl, amino, mono-substituted amino, di-substituted amino, halo(C 1-8  alkyl), haloalkyl, or an optionally substituted C-carboxy. 
 
     
     
         157 . The compound of  claim 156 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         158 . A pharmaceutical composition comprising an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or combination thereof. 
     
     
         159 . A method for ameliorating or treating a paramyxovirus infection, the method comprising administering to a subject suffering from the paramyxovirus infection an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         160 . A method for inhibiting replication of a paramyxovirus, the method comprising contacting a cell infected with the paramyxovirus with an effective amount of a compound of  claim 1 , or a pharmaceutically acceptable salt thereof. 
     
     
         161 . The method of  claim 159 , wherein the paramyxovirus infection is a human respiratory syncytial virus infection. 
     
     
         162 . The method of  claim 159 , further comprising administering to the subject one or more agents. 
     
     
         163 . The method of  claim 162 , wherein the paramyxovirus infection is a human respiratory syncytial virus infection; and wherein the one or more agents is selected from the group consisting of an anti-RSV antibody, a fusion protein inhibitor, an N-protein inhibitor, a RSV polymerase inhibitor, an IMPDH inhibitor, an interferon, any other compound that inhibits the RSV virus, and pharmaceutically acceptable salts of any of the foregoing. 
     
     
         164 . The method of  claim 162 , wherein the one or more agents is selected from the group consisting of RSV-IGIV, palivizumab, motavizumab, 1-cyclopropyl-3-[[1-(4-hydroxybutyl)benzimidazol-2-yl]methyl]imidazo[4,5-c]pyridin-2-one (BMS-433771), 4,4″-bis-{4,6-bis-[3-(bis-carbamoylmethyl-sulfamoyl)-phenylamino]-(1,3,5)triazin-2-ylamino}-biphenyl-2,2″-disulfonic-acid (RFI-641), 4,4′-Bis[4,6-di[3-aminophenyl-N,N-bis(2-carbamoylethyl)-sulfonilimino]-1,3,5-triazine-2-ylamino]-biphenyl-2,2′-disulfonic acid, disodium salt (CL387626), 2-[[2-[[1-(2-aminoethyl)-4-piperidinyl]amino]-4-methyl-1H-benzimidazol-1-yl]-6-methyl-3-pyridinol (JNJ-2408068), 2-[[6-[[[2-(3-Hydroxypropyl)-5-methylphenyl]amino]methyl]-2-[[3-(morpholin-4-yl)propyl]amino]benzimidazol-1-yl]methyl]-6-methylpyridin-3-ol (TMC-353121), 5,5′-bis[1-(((5-amino-1H-tetrazolyl)imino)methyl)]2,2′,4″-methylidynetrisphenol (VP-14637, MDT-637), N-(2-hydroxyethyl)-4-methoxy-N-methyl-3-(6-methyl-[1,2,4]triazolo[3,4-a]phthalazin-3-yl)benzenesulfonamide (P13), 2-((2-((1-(2-aminoethyl)piperidin-4-yl)amino)-4-methyl-1H-benzo[d]imidazol-1-yl)methyl)-6-methylpyridin-3-ol (R170591), 1,4-bis(3-methylpyridin-4-yl)-1,4-diazepane (C15), (R)-9b-(4-chlorophenyl)-1-(4-fluorobenzoyl)-2,3-dihydro-1H-imidazo[1′,2′:1,2]pyrrolo[3,4-c]pyridin-5(9bH)-one (BTA9981), [2,2-bis(docosyloxy-oxymethyl)propyl-5-acetaoamido-3,5-dideoxy-4,7,8,9-tetra-O-(sodium-oxysulfonyl)-D-glycero-D-galacto-2-nonulopyranosid]onate (MBX-300), BTA-C286, N-(2-((S)-2-(5-((S)-3-aminopyrrolidin-1-yl)-6-methylpyrazolo[1,5-a]pyrimidin-2-yl)piperidine-1-carbonyl)-4-chlorophenyl)methanesulfonamide (GS-5806), an anti-RSV nanobody, a peptide fusion inhibitor (such as a peptide having the sequence DEFDASISQVNEKINQSLAFIRKSDELL (T-67), a peptide having the sequence FDASISQVNEKINQSLAFIRKSDELLHNVNAGKST (T-118), (S)-1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]diazepin-3-yl)urea (RSV-604), STP-92, iKT-041, 6-{4-[(biphenyl-2-ylcarbonyl) amino]benzoyl}-N-cyclopropyl-5,6-dihydro-4H-thieno[3,2-d][1]benzazepine-2-carboxamide (YM-53403). N-cyclopropyl-5-(4-(2-(pyrrolidin-1-yl)benzamido)benzoyl)-5,6,7,10-tetrahydrobenzo[b]cyclopenta[d]azepine-9-carboxamide. 6-(4-(2-(2-oxa-7-azaspiro[3.5]nonan-7-yl)nicotinamido)benzoyl)-N-cyclopropyl-5,6-dihydro-4H-benzo[b]thieno[2,3-d]azepine-2-carboxamide, 4-amino-8-(3-{[2-(3,4-dimethoxyphenyl)ethyl]amino}propyl)-6,6-dimethyl-2-(4-methyl-3-nitrophenyl)-1H-imidazo[4,5-h]-isoquinoline-7,9(6H,8H)-dione, AZ27, ribavirin, 5-ethynyl-1-beta-D-ribofuranosylimidazole-4-carboxamide (EICAR), 4-hydroxy-3-beta-D-ribofuranosylpyrazole-5-carboxamide (pyrazofurin), 1-((2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydrofuran-2-yl)-1H-1,2,4-triazole-3-carboximidamide (Taribavirin, viramidine), 1,3,4-thiadiazol-2-ylcyanamide (LY253963), tetrahydrofuran-3-yl-3-(3-(3-methoxy-4-(oxazol-5-yl)phenyl)ureido)benzylcarbamate (VX-497), (4E)-6-(4-Hydroxy-6-methoxy-7-methyl-3-oxo-1,3-dihydro-2-benzofuran-5-yl)-4-methylhex-4-enoic acid (Mycophenolic acid), 2-morpholin-4-ylethyl-(E)-6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-1H-2-benzofuran-5-yl)-4-methylhex-4-enoate (Mycophenolate Mofetil), a Type 1 interferon, a Type 2 interferon, a Type 3 interferon, a double stranded RNA oligonucleotide, 5-methyl-N-[4-(trifluoromethyl) phenyl]-isoxazole-4-carboxamide (leflumomide), N-(2-chloro-4-methylphenyl)-2-((1-(4-methoxyphenyl)-1H-benzo[d]imidazol-2-yl)thio)propanamide (JMN3-003), an intratracheal formulation of recombinant human CC10 (CG-100), high titer, human immunoglobulin (RI-001), a non-neutralizing mAb against the G protein (mAb 131-2G), ALN-RSV01, ALN-RSV02, Medi-559, Medi-534, Medi-557, and pharmaceutically acceptable salts of any of the foregoing.