Compounds for the treatment of paramyxovirus viral infections

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 - 156 . (canceled) 
     
     
         157 . A compound of Formula (IIb): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         A b  is A 1  or A 2 , wherein:
 A 1  is aryl optionally substituted with one or more substituents selected from the group consisting of:
 (a) hydroxy, 
 (b) halogen, 
 (c) nitro, 
 (d) alkyl optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, and alkoxy, 
 (e) amino optionally substituted with one or two alkyl groups, 
 (f) —O-(alkyl) optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkoxy, cyano, amino optionally substituted with one or two alkyl groups, cycloalkyl, C-carboxy, C-amido, imidazolyl, triazolyl, and morpholino, 
 (g) —O-(cycloalkyl) optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl, alkoxy, cyano, and amino optionally substituted with one or two alkyl groups, and 
 (h) oxetanyloxy, pyrazolyl, imidazolyl, oxadiazolyl, pyridinyl, oxopyrrolidinyl, pyrimidinyl, tetrahydropyranyloxy, piperidinyloxy, or azetidinyloxy, each of which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl, alkoxy, alkenyl, alkynyl, cyano, and amino optionally substituted with one or two alkyl groups; and 
 
 A 2  is 5- or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclic heteroaryl with a fused structure, each of which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, and amino optionally substituted with one or two alkyl groups; 
 
         Y b  is Y 1  or Y 2 , wherein:
 Y 1  is aryl optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl optionally substituted with one or more halogen groups, alkenyl, alkynyl, alkoxy optionally substituted with one or more halogen groups, cyano, amino optionally substituted with one or two alkyl groups, C-carboxy, C-amido, sulfonyl, —C(O)-piperidinyl, aryl, imidazolyl, triazolyl, morpholino, and piperidinyl; and 
 Y 2  is aryl, 5- or 6-membered monocyclic heteroaryl, 5- or 6-membered monocyclic heterocyclyl, 9- or 10-membered bicyclic heteroaryl with a fused structure, or bicyclic 9- or 10-membered heterocyclyl with a fused structure, each of which is optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino optionally substituted with one or two alkyl groups, and C-carboxy; 
 
         R 1b  is hydrogen or alkyl; and R 2b  is hydrogen or alkyl optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino optionally substituted with one or two alkyl groups, and piperazinyl; or 
         R 1b  and R 2b , together with the atoms to which they are attached, are joined to form 5- or 6-membered heterocyclyl optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, and amino optionally substituted with one or two alkyl groups; 
         R 2b1  is hydrogen or alkyl optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, amino optionally substituted with one or two alkyl groups, and piperazinyl; 
         B1 is phenyl, 5- or 6-membered monocyclic heteroaryl, or 5- or 6-membered monocyclic heterocyclyl, each of which is optionally substituted with one or more substituents selected from the group consisting of:
 (a) hydroxy, 
 (b) halogen, 
 (c) alkyl optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, and amino optionally substituted with one or two alkyl groups, 
 (d) alkenyl, 
 (e) alkynyl, 
 (f) alkoxy optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, and amino optionally substituted with one or two alkyl groups, 
 (g) cyano, 
 (h) amino optionally substituted with one or two alkyl groups, and 
 (i) piperazinyl optionally substituted with C-carboxy. 
 
       
     
     
         158 . The compound of  claim 157 , wherein the compound of Formula (IIb) is a compound of formula (Id-1): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein R 9a , R 10a , and R 11a  are each independently:
 (a) hydrogen, 
 (b) hydroxyl, 
 (c) halogen, 
 (d) alkyl optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, and amino optionally substituted with one or two alkyl groups, 
 (e) alkenyl, 
 (f) alkynyl, 
 (g) alkoxy optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, and amino optionally substituted with one or two alkyl groups, 
 (h) cyano, 
 (i) amino optionally substituted with one or two alkyl groups, or 
 (j) piperazinyl optionally substituted with C-carboxy. 
 
       
     
     
         159 . The compound of  claim 158 , or a pharmaceutically acceptable salt thereof, wherein A 1  is optionally substituted phenyl and Y 1  is optionally substituted phenyl. 
     
     
         160 . The compound of  claim 158 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       or a pharmaceutically acceptable salt of any of the foregoing. 
     
     
         161 . The compound of  claim 157 , wherein the compound of Formula (IIb) is a compound of formula (Id-2): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein R 9a , R 10a , and R 11   a  are each independently:
 (a) hydrogen, 
 (b) hydroxyl, 
 (c) halogen, 
 (d) alkyl optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, and amino optionally substituted with one or two alkyl groups, 
 (e) alkenyl, 
 (f) alkynyl, 
 (g) alkoxy optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, and amino optionally substituted with one or two alkyl groups, 
 (h) cyano, 
 (i) amino optionally substituted with one or two alkyl groups, or 
 (j) piperazinyl optionally substituted with C-carboxy. 
 
       
     
     
         162 . The compound of  claim 161 , or a pharmaceutically acceptable salt thereof, wherein A 1  is optionally substituted phenyl and Y 2  is benzothiophenyl, pyridinyl, pyrimidinyl, oxazolyl, isoxazolyl, pyrazolyl, thiphenyl, indolyl, benzofuranyl, pyrazolopyridinyl, indazolyl, benzotriazolyl, thienopyridinyl, benzoimidazolyl, benzothiazolyl, thienopyridinyl, dihydrobenzodioxinyl, quinolinyl, isoquinolinyl, or naphthalenyl, each of which is optionally substituted. 
     
     
         163 . The compound of  claim 161 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         pharmaceutically acceptable salt of any of the foregoing. 
       
     
     
         164 . The compound of  claim 157 , wherein the compound of Formula (IIb) is a compound of formula (Id-3): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein R 9a , R 10a , and R 11   a  are each independently:
 (a) hydrogen, 
 (b) hydroxyl, 
 (c) halogen, 
 (d) alkyl optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, and amino optionally substituted with one or two alkyl groups, 
 (e) alkenyl, 
 (f) alkynyl, 
 (g) alkoxy optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, and amino optionally substituted with one or two alkyl groups, 
 (h) cyano, 
 (i) amino optionally substituted with one or two alkyl groups, or 
 (j) piperazinyl optionally substituted with C-carboxy. 
 
       
     
     
         165 . The compound of  claim 164 , or a pharmaceutically acceptable salt thereof, wherein Y 1  is optionally substituted phenyl and A 2  is oxazolyl, isoxazolyl, pyridinyl, or pyrimidinyl, each of which is optionally substituted. 
     
     
         166 . The compound of  claim 164 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt of any of the foregoing. 
       
     
     
         167 . The compound of  claim 157 , wherein the compound of Formula (IIb) is a compound of formula (Id-4): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof, 
         wherein: 
         R 1b  and R 2b , together with the atoms to which they are attached, are joined to form an optionally substituted 5- or 6-membered heterocyclyl; 
         R 9a , R 10a , and R 11a  are each independently:
 (a) hydrogen, 
 (b) hydroxyl, 
 (c) halogen, 
 (d) alkyl optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, and amino optionally substituted with one or two alkyl groups, 
 (e) alkenyl, 
 (f) alkynyl, 
 (g) alkoxy optionally substituted with one or more substituents selected from the group consisting of hydroxy, halogen, alkyl, alkenyl, alkynyl, alkoxy, cyano, and amino optionally substituted with one or two alkyl groups, 
 (h) cyano, 
 (i) amino optionally substituted with one or two alkyl groups, or 
 (j) piperazinyl optionally substituted with C-carboxy. 
 
       
     
     
         168 . The compound of  claim 167 , or a pharmaceutically acceptable salt thereof, wherein A 1  is optionally substituted phenyl, Y 2  is optionally substituted benzothiophenyl, and R 1b  and R 2b , together with the atoms to which they are attached, are joined to form optionally substituted pyrrolidinyl or optionally substituted piperidinyl. 
     
     
         169 . The compound of  claim 167 , wherein the compound is 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt of any of the foregoing. 
       
     
     
         170 . The compound of  claim 157 , wherein the compound of Formula (IIb) is a compound of formula (IIb-1): 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt thereof. 
       
     
     
         171 . The compound of  claim 170 , or a pharmaceutically acceptable salt thereof, wherein:
 A 1  is optionally substituted phenyl;   B 1  is dihydropyrazolyl, triazolyl, thiazolyl, imidazolyl, oxazolyl, oxoimidazolidinyl, pyrazolyl, furanyl, pyrimidinyl, dihydropyridazinyl, pyrazinyl, oxodihydropyridinyl, oxotetrahydropyrimidinyl, phenyl, or pyridazinyl, each of which is optionally substituted; and   Y b  is benzothiophenyl or phenyl, each of which is optionally substituted.   
     
     
         172 . The compound of  claim 170 , wherein the compound is 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt of any of the foregoing. 
       
     
     
         173 . A pharmaceutical composition comprising an effective amount of a compound of  claim 157 , or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient, or any combination thereof. 
     
     
         174 . A method of ameliorating or treating a paramyxovirus infection, the method comprising contacting a cell infected with the paramyxovirus in a subject suffering from a paramyxovirus infection with an effective amount of a compound of  claim 157 , or a pharmaceutically acceptable salt thereof. 
     
     
         175 . A method of inhibiting replication of a paramyxovirus, the method comprising contacting a cell infected with the paramyxovirus with an effective amount of a compound of  claim 157 , or a pharmaceutically acceptable salt thereof. 
     
     
         176 . The method of  claim 174 , wherein the paramyxovirus infection is a human respiratory syncytial virus infection. 
     
     
         177 . The method of  claim 174 , wherein the method further comprises contacting the cell with one or more agents selected from the group consisting of ribavirin, palivizumab, RSV-IGIV, ALN-RSV01, BMS-433771, RFI-641, RSV604, MDT-637, BTA9881, TMC-353121, MBX-300, and YM-53403.