N-(5-Membered Aromatic Ring)-Amido Anti-Viral Compounds

Abstract

Disclosed are compounds having Formula (I) and the compositions and methods thereof for treating or preventing a viral infection mediated at least in part by a virus in the Flaviviridae family of viruses, wherein A, R 2 , m, R, V, W, T, Z, R 1 , Y, and p are disclosed herein.

1 . A compound of Formula (I) or a stereoisomer, tautomer, or a pharmaceutically acceptable salt thereof, wherein 
     
       
         
         
             
             
         
       
       A is a 5-membered aromatic ring wherein 1 to 3 ring carbon atoms are replaced by N, NH, O, or S, and wherein A may be optionally fused to a 5 to 10 membered aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocycle, or substituted heterocycle to form a 8 to 13 membered bicyclic or tricyclic ring, and further wherein any ring N or S atom may optionally be oxidized; 
       each R 2  is independently selected from the group consisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3 H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, substituted alkylthio, and R 3 -L- wherein R 3  is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; and L, defined herein in the R 3 -L- orientation, is selected from the group consisting of a bond, —O—, —S—, —CH 2 —, —CH 2 CH 2 —, —SCH 2 —, —C(O)—, —C(S)—, —NHC(O)—, —C(O)NH—, —SO 2 —, —SO 2 NH—, —SO 2 CH 2 —, —OCH 2 —, —CH 2 CH 2 NHC(O)—, —CH 2 CH 2 NHC(O)CH 2 —, —NHN═C(CH 3 CH 2 OCO)—, —NHSO 2 —, ═CH—, —NHC(O)CH 2 S—, —NHC(O)CH 2 C(O)—, spirocycloalkyl, —C(O)CH 2 S—, and —C(O)CH 2 O— provided that when L is ═CH—, R 3  is heterocyclic or substituted heterocyclic; 
       m is 0, 1, 2, or 3; provided that when A is a monocyclic ring, m is 1, 2, or 3; 
       R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl; 
       T is a straight chain C 1 -C 6  alkylene or C 1 -C 5  heteroalkylene and forms a 3-8 membered ring with V and W; 
       V and W are both CH, or one of V or W is CH and the other of V or W is N; 
       Y is independently selected from the group consisting of halo, oxo, hydroxy, and alkoxy; 
       p is 0, 1, or 2; 
       Z is selected from the group consisting of CH 2 , C(O), C(S), and —SO 2 —; 
       R 1  is selected from the group consisting of amino, substituted amino, alkyl, arylalkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, aryloxy, arylalkoxy, —CH 2 OR 1a , and —OCH 2 R 1a ; and 
       R 1a  is selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
       provided that the compound is not 2-(4-phenyl-thiazol-2-ylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester, 2-(4-phenyl-thiazol-2-ylcarbamoyl)-pyrrolidine-1-carboxylic acid phenyl ester, or 4-hydroxy-2-(5-methyl-4-phenyl-thiazol-2-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. 
     
   
   
       2 . A compound of  claim 1  wherein ring A is selected from the group consisting of 
     
       
         
         
             
             
         
       
     
     provided that when ring A is fused to a phenyl ring, one or two carbon ring atoms of said phenyl ring are optionally replaced by N and forms a pyridinyl, pyrazinyl, pryridazinyl, or pyrimidinyl ring substituted with —(R 2 ) m  and fused to ring A. 
   
   
       3 . A compound of  claim 1  wherein at least one of R 2  is R 3 -L-. 
   
   
       4 . A compound of  claim 1  wherein R is hydrogen. 
   
   
       5 . A compound of  claim 4  wherein T is selected from the group consisting of —CH 2 —, —CH 2 CH 2 —, —CH 2 CH 2 CH 2 —, —CH 2 SCH 2 —, and —CH 2 CH 2 CH 2 CH 2 —. 
   
   
       6 . A compound of  claim 5  wherein R 1  is selected from the group consisting of amino, substituted amino, alkyl, arylalkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, aryloxy, and arylalkoxy. 
   
   
       7 . A compound of  claim 1  wherein V is CH and W is N. 
   
   
       8 . A compound of  claim 1  wherein p is 0. 
   
   
       9 . A compound of  claim 1  wherein Z is C(O). 
   
   
       10 . A compound of  claim 1  wherein R 1  is arylalkoxy. 
   
   
       11 . A compound of  claim 1  having Formula (II) or a stereoisomer, tautomer, or a  pharmaceutically acceptable salt thereof 
     
       
         
         
             
             
         
       
       wherein: 
       one of E or F is —N═ and the other of E or F is —O—, —S—, or —NH—; 
       R 4  is selected from the group consisting of aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic; 
       L, defined herein in the R 4 -L- orientation, is selected from the group consisting of a bond, —O—, —S—, —CH 2 —, —CH 2 CH 2 —, —SCH 2 —, —C(O)—, —C(S)—, —NHC(O)—, —C(O)NH—, —SO 2 —, —SO 2 NH—, —SO 2 CH 2 —, —OCH 2 —, —CH 2 CH 2 NHC(O)—, —CH 2 CH 2 NHC(O)CH 2 —, —NHN═C(CH 3 CH 2 OCO)—, —NHSO 2 —, ═CH—, —NHC(O)CH 2 S—, —NHC(O)CH 2 C(O)—, spirocycloalkyl, —C(O)CH 2 S—, and —C(O)CH 2 O—; 
       R is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl; 
       R 5  is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino, substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy, cycloalkenylthio, substituted cycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, heterocyclylthio, substituted heterocyclylthio, nitro, SO 3 H, substituted sulfonyl, substituted sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio; 
       one of Q 1  or Q 2  is —O—, —S—, —S(O)—, —S(O) 2 —, —C(O)—, CHY, or CH 2  and the other of Q 1  or Q 2  is CH 2 ; 
       Y is independently selected from the group consisting of halo, oxo, hydroxy, and alkoxy; 
       p is 0, 1, or 2; 
       R 1  is selected from the group consisting of amino, substituted amino, alkyl, arylalkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, aryloxy, arylalkoxy, and —OCH 2 R 1a ; and 
       R 1a  is selected from the group consisting of cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; 
       provided that the compound is not 2-(4-phenyl-thiazol-2-ylcarbamoyl)-pyrrolidine-1-carboxylic acid benzyl ester, 2-(4-phenyl-thiazol-2-ylcarbamoyl)-pyrrolidine-1-carboxylic acid phenyl ester, or 4-hydroxy-2-(5-methyl-4-phenyl-thiazol-2-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester. 
     
   
   
       12 . A compound of  claim 11  wherein the carbon atom bearing Q 1  and N has the S or R stereochemistry. 
   
   
       13 . A compound of  claim 11  wherein L is a bond, —S—, —CH 2 CH 2 —, —SCH 2 —, —OCH 2 —, —SO 2 CH 2 —, —CH 2 CH 2 NHC(O)—, —CH 2 CH 2 NHC(O)CH 2 —, —NHN═C(COOCH 3 CH 2 )—, or spirocycloalkyl. 
   
   
       14 . A compound of  claim 11  wherein R 4  is selected from the group consisting of phenyl, benzo[1,3]dioxol-5-yl, benzopyran-3-yl, 1-napthyl, 2-naphthyl, 2-thiazolyl, tetrahydrofuran-5-yl, 1,3,4-oxadiazol-2-yl, thieno[2,3-d]pyrimidin-2-yl, spiro[4.5]decan-4-yl, benzimidazol-2-yl, tetrahydropyran-4-yl, imidazolo[2,1-b]thiazol-5-yl, fluoren-2-yl, tetrahydropyran-4-yl, isoindol-2-yl, 2,7-dioxaspiro[4.4]non-3-yl, and 1,3,4-triazol-2-yl, and wherein each of the aforementioned groups may be substituted or substituted. 
   
   
       15 . A compound of  claim 11  wherein R 4  is optionally substituted with (X) k , wherein X is independently selected from the group consisting of acyl, acylamino, amino, substituted amino, oxo, halo, cyano, alkoxy, alkyl, substituted alkyl, nitro, substituted alkoxy, aryl, substituted aryl, substituted aryloxy, cycloalkyl, heterocyclic, substituted heterocyclic, hydroxyl, aminocarbonyl, substituted alkylthio, substituted sulfonyl, aminocarbonyl, aminocarbonylamino, and aminocarbonyloxy, and k is 0, 1, 2, or 3, provided that when R 4  is aryl or substituted aryl, X is not oxo. 
   
   
       16 . A compound of  claim 15  wherein X is selected from the group consisting of cyclopropyl-C(O)NH—, phenyl-C(O)NH—, cyclopentyl-C(O)NH—, 4-chlorophenyl-C(O)NH—, 3-chlorophenyl-C(O)NH—, methyl-C(O)NH—, pyridin-3-yl-C(O)NH—, pyridin-4-yl-C(O)NH—, pyrimidin-2-yl-C(O)NH—, pyrimidin-4-yl-C(O)NH—, pyrimidin-5-yl-C(O)NH—, morpholin-4-yl-(alkylene)-C(O)NH—, morpholin-3-yl-(alkylene)-C(O)NH—, morpholin-2-yl-(alkylene)-C(O)NH—, methylamino, 4-methylphenyl-SO 2 NH—, amino, ethyl-C(O)NH—, oxo, bromo, methoxy, methyl-SO 2 NH—, chloro, phenyl-SO 2 NH—, methyl-C(O)NH—, methyl-C(O)—, fluoro, methyl, ethyl, propyl, 4-fluorophenyl, nitro, phenyl, 4-bromobenzyloxy, cyclohexyl, isopropyl, tert-butyl, 4-methylpentyloxymethyl, NH 2 C(O)—, hydroxy, cyclohexyl-NHC(O)CH 2 S—, allyl, ethoxycarbonylmethylthio, dimethylamino, 3-nitro-phenyl, isobutyl, propoxy, butoxymethyl, butyl-C(O)NH—, methyl-NHC(O)—, ethyl-NHC(O)—, (2-oxo-hexahydro-thieno[3,4-d]imidazol-4-yl)-butyl-C(O)NH—, morpholin-4-yl-(alkylene)-NHC(O)—, morpholin-3-yl-(alkylene)-NHC(O)—, morpholin-2-yl-(alkylene)-NHC(O)—, cyclopropyl-C(O)NH—, cyclohexyl-C(O)NH—, cyclopentyl-NHC(O)—, propyl, isobutyl, carboxy, pentyl-C(O)NH—, pyridin-3-yl-NHC(O)—, pyridin-4-yl-NHC(O)—, pyrimidin-2-yl-NHC(O)—, pyrimidin-4-yl-NHC(O)—, pyrimidin-5-yl-NHC(O)—, phenyl-NHC(O)—, isopropyl-NHC(O)—, and ethyl-NHC(O)—. 
   
   
       17 . A compound of  claim 15  wherein R is hydrogen and p is 0. 
   
   
       18 . A compound of  claim 17  wherein Q 1  and Q 2  are CH 2 . 
   
   
       19 . A compound of  claim 18  wherein R 1  is selected from the group consisting of amino, substituted amino, alkyl, arylalkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, alkoxy, aryloxy, and arylalkoxy. 
   
   
       20 . A compound of  claim 11  wherein R 5  is hydrogen, alkyl, or halo.