Benzophenones as inhibitors of reverse transcriptase

Abstract

The present invention is directed to benzophenone compounds useful in the inhibition of HIV reverse transcriptase, particularly its resistant varieties.

1 - 26 . (canceled)  
   
   
       27 . A method of treatment or prevention of a viral infection in a human comprising administering to said human an antiviral effective amount of a compound of formula (IA)  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is one or more substituents independently selected from the group consisting of halogen, —CF 3 , C 1-8 alkyl, aminoC 1-8 alkyl, alkoxy, —CN, —NO 2 , —NH 2 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , —C(O)R 8 ; C 2-6 alkenyl which may be optionally substituted with a substituent selected from the group consisting of hydroxy, halogen, C 3-6 cycloalkyl, C 6-14 aryl and heterocycle; C 2-6 alkynyl which may be optionally substituted with a substituent selected from the group consisting of hydroxy, halogen, C 6-14 aryl, C 3-6 cycloalkyl, and heterocycle: and heterocycle, optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-8 alkyl, —CN, C 1-8 alkylC 6-14 aryl and heterocycle;  
 R 2  is selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, —NO 2 , —NH 2 , C 1-8 alkylamino, —CF 3  and alkoxy;  
 R 3  is selected from the group consisting of hydroxy, halogen, —CF 3 —NO 2  and C 1-8 alkyl;  
 R 4  is selected from the group consisting of —S(O) 2 NR 5 R 6 , —S(O) 2 N═C(OR 7 ) 2  and —S(O) 2 N═CR 7 (OR 7 );  
 R 5  is selected from the group consisting of hydrogen, C 6-14 aryl, C 1-8 alkyl, C 3-6 cycloalkylC 1-8 alkyl and C 3-6 cycloalkyl;  
 R 6  is selected from the group consisting of —C(O)R 7 , —C(O)OR 7 , —C(O)C(O)OR 7 , —C(O)CH(NR 12 R 13 )R 11 , alkoxyC 1-8 alkyl and —CH 2 O—(CH 2 CH 2 O) n —CH 2 CH 2 OCH 3 , wherein n is 0-4;  
 R 7  is selected from the group consisting of C 3-6 cycloalkylC 1-8 alkyl, hydroxyC 1-8 alkyl, C 6-14 aryl, heterocycle optionally substituted with C 1-8 alkyl, C 6-14 arylC 1-8 alkyl, —(CH 2 CH 2 —O) n —CH 3 , where n=1-4, alkoxyC 1-8 alkyl and C 1-8 alkyl optionally substituted with —O—C(O)R 12 ;  
 R 8  is selected from the group consisting of C 1-8 alkyl, C 3-6 cycloalkylC 1-8 alkyl, C 3-6 cycloalkyl, C 6-14 aryl and heterocycle;  
 R 11  is selected from the group consisting of hydrogen,  
                     
 R 12  and R 13  are independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl and C 6-14 aryl;  
 or a pharmaceutically acceptable derivative thereof.  
 
   
   
       28 . A method according to  claim 27  wherein the viral infection is a HIV infection.  
   
   
       29 - 34 . (canceled)  
   
   
       35 . A method of treatment or prevention of a viral infection in a human comprising administering to said human a composition comprising a compound of formula (IA)  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is one or more substituents independently selected from the group consisting of halogen, —CF 3 , C 1-8 alkyl, aminoC 1-8 alkyl, alkoxy, —CN, —NO 2 , —NH 2 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , —C(O)R 8 ; C 2-6 alkenyl which may be optionally substituted with a substituent selected from the group consisting of hydroxy, halogen, C 3-6 cycloalkyl, C 6-14 aryl and heterocycle; C 2-6 alkynyl which may be optionally substituted with a substituent selected from the group consisting of hydroxy, halogen, C 6-14 aryl, C 3-6 cycloalkyl, and heterocycle; and heterocycle, optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-8 alkyl, —CN, C 1-8 alkylC 6-14 aryl and heterocycle;  
 R 2  is selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, —NO 2 , —NH 2 , C 1-8 alkylamino, —CF 3  and alkoxy;  
 R 3  is selected from the group consisting of hydroxy, halogen, —CF 3 , —NO 2  and C 1-8 alkyl;  
 R 4  is selected from the group consisting of —S(O) 2 NR 5 R 6 , —S(O) 2 N═C(OR 7 ) 2  and —S(O) 2 N═CR 7 (OR 7 );  
 R 5  is selected from the group consisting of hydrogen, C 6-14 aryl, C 1-8 alkyl, C 3-6 cycloalkylC 1-8 alkyl and C 3-6 cycloalkyl;  
 R 6  is selected from the group consisting of —C(O)R 7 , —C(O)OR 7 , —C(O)C(O)OR 7 , —C(O)CH(NR 12 R 13 )R 11 , alkoxyC 1-8 alkyl and —CH 2 O—(CH 2 CH 2 O) n —CH 2 CH 2 OCH 3 , wherein n is 0-4;  
 R 7  is selected from the group consisting of C 3-6 cycloalkylC 1-8 alkyl, hydroxyC 1-8 alkyl, C 6-14 aryl, heterocycle optionally substituted with C 1-8 alkyl, C 6-14 arylC 1-8 alkyl, —(CH 2 CH 2 —O) n —CH 3 , where n=1-4, alkoxyC 1-8 alkyl and C 1-8 alkyl optionally substituted with —O—C(O)R 12 ;  
 R 8  is selected from the group consisting of C 1-8 alkyl, C 3-6 cycloalkylC 1-8 alkyl, C 3-6 cycloalkyl, C 6-14 aryl and heterocycle;  
 R 11  is selected from the group consisting of hydrogen,  
                     
 R 12  and R 13  are independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl and C 6-14 aryl;  
 or a pharmaceutically acceptable derivative thereof and another therapeutic agent.  
 
   
   
       36 . The method according to  claim 35  wherein the viral infection is an HIV infection.  
   
   
       37 . (canceled)  
   
   
       38 . A method according to  claim 35 , wherein said therapeutic agent is selected from the group consisting of (1-alpha, 2-beta, 3-alpha)-9-[2,3-bis(hydroxymethyl)cyclobutyl]guanine [(−)BHCG, SQ-34514, lobucavir], 9-[(2R,3R,4S)-3,4-bis(hydroxymethyl)-2-oxetanosyl]adenine (oxetanocin-G), acyclic nucleosides [e.g. acyclovir, valaciclovir, famciclovir, ganciclovir, penciclovir), acyclic nucleoside phosphonates [e.g. (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC), [[[2-(6-amino-9H-purin-9-yl)ethoxy]methyl]phosphinylidene]bis(oxymethylene)-2,2-dimethylpropanoic acid (bis-POM PMEA, adefovir dipivoxil), [[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid (tenofovir), (R)-[[2-(6-Amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid bis-(isopropoxycarbonyloxymethyl)ester (bis-POC-PMPA)], ribonucleotide reductase inhibitors (e.g. 2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl) thiocarbonohydrazone and hydroxyurea), nucleoside reverse transcriptase inhibitors (e.g., 3′-azido-3′-deoxythymidine (AZT, zidovudine), 2′,3′-dideoxycytidine (ddC, zalcitabine), 2′,3′-dideoxyadenosine, 2′,3′-dideoxyinosine (ddI, didanosine), 2′,3′-didehydrothymidine (d4T, stavudine), (−)-beta-D-2,6-diaminopurine dioxolane (DAPD), 3′-Azido-2′,3′-dideoxythymidine-5′-H-phosphophonate (phosphonovir), 2′-deoxy-5-iodo-uridine (idoxuridine), as (−)-cis-1-(2-hydroxymethyl)-1,3-oxathiolane 5-yl)-cytosine (lamivudine), or cis-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-5-fluorocytosine (FTC), 3′-deoxy-3′-fluorothymidine, 5-chloro-2′,3′-dideoxy-3′-fluorouridine, (−)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (abacavir), 9-[4-hydroxy-2-(hydroxymethyl)but-1-yl]-guanine (H2G), ABT-606 (2HM-H2G) and ribavirin), protease inhibitors (e.g. indinavir, ritonavir, nelfinavir, amprenavir, saquinavir, (R)-N-tert-butyl-3-[(2S,3S)-2-hydroxy-3-N-[(R)-2-N-(isoquinolin-5-yloxyacetyl)amino-3-methylthiopropanoyl]amino-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide (KNI-272), 4R-(4alpha,5alpha,6beta)]-1,3-bis[(3-aminophenyl)methyl]hexahydro-5,6-dihydroxy-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one dimethanesulfonate (mozenavir), 3-[1-[3-[2-(5-trifluoromethylpyridinyl)-sulfonylamino]phenyl]propyl]-4-hydroxy-6alpha-phenethyl-6beta-propyl-5,6-dihydro-2-pyranone (tipranavir), N′-[2(S)-Hydroxy-3(S)-[N-(methoxycarbonyl)-l-tert-leucylamino]-4-phenylbutyl-N alpha -(methoxycarbonyl)-N′-[4-(2-pyridyl)benzyl]-L-tert-leucylhydrazide (BMS-232632), 3-(2(S)-Hydroxy-3(S)-(3-hydroxy-2-methylbenzamido)-4-phenylbutanoyl)-5,5-dimethyl-N-(2-methylbenzyl)thiazolidine-4(R)-carboxamide (AG-1776), N-(2(R)-Hydroxy-1(S)-indanyl)-2(R)-phenyl-methyl-4(S)-hydroxy-5-(1-(1-(4-benzo[b]furanylmethyl)-2(S)-N′-(tert-butylcarboxamido)piperazinyl)pentanamide (MK-944A), and GW 433908), interferons such as α-interferon, renal excretion inhibitors such as probenecid, nucleoside transport inhibitors such as dipyridamole; pentoxifylline, N-acetylcysteine (NAC), Procysteine, α-trichosanthin, phosphonoformic acid, as well as immunomodulators such as interleukin II or thymosin, granulocyte macrophage colony stimulating factors, erythropoetin, soluble CD 4  and genetically engineered derivatives thereof, non-nucleoside reverse transcriptase inhibitors (NNRTIs) [e.g. nevirapine (BI-RG-587), alpha-((2-acetyl-5-methylphenyl)amino)-2,6-dichloro-benzeneacetamide (loviride), 1-[3-(isopropylamino)-2-pyridyl]-4-[5-(methanesulfonamido)-1H-indol-2-ylcarbonyl]piperazine monomethanesulfonate (delavirdine), (10R,11S,12S)-12-Hydroxy-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2H,6H,10H-benzo(1,2-b:3,4b′:5,6-b″)tripyran-2-one ((+) calanolide A), (4S)-6-Chloro-4-[1E)-cyclopropylethenyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinazolinone (DPC-083), 1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-2,4(1H,3H)-pyrimidinedione (MKC-442), 5-(3,5-dichlorophenyl)thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethyl carbamate (capravirine)], glycoprotein 120 antagonists [e.g. PRO-2000, PRO-542 and 1,4-bis[3-[(2,4-dichlorophenyl)carbonylamino]-2-oxo-5,8-disodiumsulfanyl]naphthalyl-2,5-dimethoxyphenyl-1,4-dihydrazone (FP-21399)], cytokine antagonists [e.g. reticulose (Product-R), 1,1′-azobis-formamide (ADA), and 1,11-(1,4-phenylenebis(methylene))bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride (AMD-3100)], and fusion inhibitors (e.g. T-20 and T-1249).  
   
   
       39 . A method of treament of HIV mutant viruses comprising administering a compound of formula (IA)  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is one or more substituents independently selected from the group consisting of halogen, —CF 3 , C 1-8 alkyl, aminoC 1-8 alkyl, alkoxy, —CN, —NO 2 , —NH 2 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , —C(O)R 8 ; C 2-6 alkenyl which may be optionally substituted with a substituent selected from the group consisting of hydroxy, halogen, C 3-6 cycloalkyl, C 6-14 aryl and heterocycle; C 2-6 alkynyl which may be optionally substituted with a substituent selected from the group consisting of hydroxy, halogen, C 6-14 aryl, C 3-6 cycloalkyl, and heterocycle; and heterocycle, optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-8 alkyl, —CN, C 1-8 alkylC 6-14 aryl and heterocycle;  
 R 2  is selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, —NO 2 —NH 2 , C 1-8 alkylamino, —CF 3  and alkoxy;  
 R 3  is selected from the group consisting of hydroxy, halogen, —CF 3 , —NO 2  and C 1-8 alkyl;  
 R 4  is selected from the group consisting of —S(O) 2 NR 5 R 6 , —S(O) 2 N═C(OR 7 ) 2  and —S(O) 2 N═CR 7 (OR 7 );  
 R 5  is selected from the group consisting of hydrogen, C 6-14 aryl, C 1-8 alkyl, C 3-6 cycloalkylC 1-8 alkyl and C 3-6 cycloalkyl;  
 R 6  is selected from the group consisting of —C(O)R 7 , —C(O)OR 7 , —C(O)C(O)OR 7 , —C(O)CH(NR 12 R 13 )R 11 , alkoxyC 1-8 alkyl and —CH 2 O—(CH 2 CH 2 O) n —CH 2 CH 2 OCH 3 , wherein n is 0-4;  
 R 7  is selected from the group consisting of C 3-6 cycloalkylC 1-8 alkyl, hydroxyC 1-8 alkyl, C 6-14 aryl, heterocycle optionally substituted with C 1-8 alkyl, C 6-14 arylC 1-8 alkyl, —(CH 2 CH 2 —O) n —CH 3 , where n=1-4, alkoxyC 1-8 alkyl and C 1-8 alkyl optionally substituted with —O—C(O)R 12 ;  
 R 8  is selected from the group consisting of C 1-8 alkyl, C 3-6 cycloalkylC 1-8 alkyl, C 3-6 cycloalkyl, C 6-14 aryl and heterocycle;  
 R 11  is selected from the group consisting of hydrogen,  
                     
 R 12  and R 13  are independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl and C 6-14 aryl;  
 or a Pharmaceutically acceptable derivative thereof.  
 
   
   
       40 . (canceled)  
   
   
       41 . A method of treatment or prevention of a viral infection in a human comprising administering to said human an antiviral effective amount of a compound of formula (IB)  
     
       
         
         
             
             
         
       
       wherein:  
       R 1  is one or more substituents independently selected from the group consisting of halogen, —CF 3 , C 1-8 alkyl, aminoC 1-8 alkyl, alkoxy, —CN, —NO 2 , —NH 2 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , —C(O)R 8 ; C 2-6 alkenyl which may be optionally substituted with a substituent selected from the group consisting of hydroxy, halogen, C 6-14 aryl, C 3-6 cycloalkyl, C 6-14 aryl and heterocycle; C 2-6 alkynyl which may be optionally substituted with a substituent selected from the group consisting of hydroxy, halogen, C 3-6 cycloalkyl, C 6-14 aryl and heterocycle; and heterocycle, optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-8 alkyl, —CN, C 1-8 alkylC 6-14 aryl and heterocycle;  
       R 2  is selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, —NO 2 , —NH 2 , C 1-8 alkylamino, —CF 3  and alkoxy;  
       R 3  is selected from the group consisting of hydroxy, halogen, —CF 3 , —NO 2  and C 1-8 alkyl;  
       R 8  is selected from the group consisting of C 1-8 alkyl, C 3-6 cycloalkylC 1-8 alkyl, C 3-6 cycloalkyl, C 6-14 aryl and heterocycle;  
       R 15  and R 16  are independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl and C 6-14 aryl, or R 15  and R 16  together with the atom to which they are attached form a ring, which optionally includes one or more heteroatoms selected from the group consisting of N, O and S, wherein N may be optionally substituted with a substituent selected from the group consisting of hydrogen, C 1-8 alkyl and C 6-14 arylC 1-8 alkyl;  
       or a pharmaceutically acceptable derivative thereof.  
     
   
   
       42 . A method according to  claim 41  wherein the viral infection is a HIV infection.  
   
   
       43 . A method of treatment or prevention of a viral infection in a human comprising administering to said human a composition comprising a compound of formula (IB)  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is one or more substituents independently selected from the group consisting of halogen, —CF 3 , C 1-8 alkyl, aminoC 1-8 alkyl, alkoxy, —CN, —NO 2 , —NH 2 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , —C(O)R 8 ; C 2-6 alkenyl which may be optionally substituted with a substituent selected from the group consisting of hydroxy, halogen, C 6-14 aryl, C 3-6 cycloalkyl, C 6-14 aryl and heterocycle; C 2-6 alkynyl which may be optionally substituted with a substituent selected from the group consisting of hydroxy, halogen, C 3-6 cycloalkyl, C 6-14 aryl and heterocycle; and heterocycle, optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-8 alkyl, —CN, C 1-8 alkylC 6-14 aryl and heterocycle;  
 R 2  is selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, —NO 2 , —NH 2 , C 1-8 alkylamino, —CF 3  and alkoxy;  
 R 3  is selected from the group consisting of hydroxy, halogen, —CF 3 , —NO 2  and C 1-8 alkyl;  
 R 8  is selected from the group consisting of C 1-8 alkyl, C 3-6 cycloalkylC 1-8 alkyl, C 3-6 cycloalkyl, C 6-14 aryl and heterocycle;  
 R 15  and R 16  are independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl and C 6-14 aryl, or R 15  and R 16  together with the atom to which they are attached form a ring, which optionally includes one or more heteroatoms selected from the group consisting of N, O and S, wherein N may be optionally substituted with a substituent selected from the group consisting of hydrogen, C 1-8 alkyl and C 6-14 arylC 1-8 alkyl;  
 or a pharmaceutically acceptable derivative thereof and another therapeutic agent.  
 
   
   
       44 . The method according to  claim 43  wherein the viral infection is an HIV infection.  
   
   
       45 . A method of treament of HIV mutant viruses comprising administering a compound of formula (IB)  
     
       
         
         
             
             
         
       
     
     wherein: 
 R 1  is one or more substituents independently selected from the group consisting of halogen, —CF 3 , C 1 -alkyl, aminoC 1-8 alkyl, alkoxy, —CN, —NO 2 , —NH 2 , —SR 8 , —S(O)R 8 , —S(O) 2 R 8 , —C(O)R 8 ; C 2-4 alkenyl which may be optionally substituted with a substituent selected from the group consisting of hydroxy, halogen, C 6-14 aryl, C 3-6 cycloalkyl, C 6-14 aryl and heterocycle; C 2-6 alkynyl which may be optionally substituted with a substituent selected from the group consisting of hydroxy, halogen, C 3-6 cycloalkyl, C 6-14 aryl and heterocycle; and heterocycle, optionally substituted with one or more substituents selected from the group consisting of halogen, C 1-8 alkyl, —CN, C 1-8 alkylC 6-14 aryl and heterocycle;  
 R 2  is selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, —NO 2 , —NH 2 , C 1-8 alkylamino, —CF 3  and alkoxy;  
 R 3  is selected from the group consisting of hydroxy, halogen, —CF 3 , —NO 2  and C 1-8 alkyl;  
 R 8  is selected from the group consisting of C 1-8 alkyl, C 3-6 cycloalkylC 1-8 alkyl, C 3-6 cycloalkyl, C 6-14 aryl and heterocycle;  
 R 15  and R 16  are independently selected from the group consisting of hydrogen, C 1-8 alkyl, C 3-6 cycloalkyl and C 6-14 aryl, or R 15  and R 16  together with the atom to which they are attached form a ring, which optionally includes one or more heteroatoms selected from the group consisting of N, O and S, wherein N may be optionally substituted with a substituent selected from the group consisting of hydrogen, C 1-8 alkyl and C 6-14 arylC 1-8 alkyl;  
 or a pharmaceutically acceptable derivative thereof.  
 
   
   
       46 . A method according to  claim 43 , wherein said therapeutic agent is selected from the group consisting of (1-alpha, 2-beta, 3-alpha)-9-[2,3-bis(hydroxymethyl)cyclobutyl]guanine [(−)BHCG, SQ-34514, lobucavir], 9-[(2R,3R,4S)-3,4-bis(hydroxymethyl)-2-oxetanosyl]adenine (oxetanocin-G), acyclic nucleosides [e.g. acyclovir, valaciclovir, famciclovir, ganciclovir, penciclovir), acyclic nucleoside phosphonates [e.g. (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC), [[[2-(6-amino-9H-purin-9-yl)ethoxy]methyl]phosphinylidene]bis(oxymethylene)-2,2dimethylpropanoic acid (bis-POM PMEA, adefovir dipivoxil), [[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid (tenofovir), (R)-[[2-(6-Amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid bis-(isopropoxycarbonyloxymethyl)ester (bis-POC-PMPA)], ribonucleotide reductase inhibitors (e.g. 2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl) thiocarbonohydrazone and hydroxyurea), nucleoside reverse transcriptase inhibitors (e.g., 3′-azido-3′-deoxythymidine (AZT, zidovudine), 2′,3′-dideoxycytidine (ddC, zalcitabine), 2′,3′-dideoxyadenosine, 2′,3′-dideoxyinosine (ddI, didanosine), 2′,3′-didehydrothymidine (d4T, stavudine), (−)-beta-D-2,6-diaminopurine dioxolane (DAPD), 3′-Azido-2′,3′-dideoxythymidine-5′-H-phosphophonate (phosphonovir), 2′-deoxy-5-iodo-uridine (idoxuridine), as (−)-cis-1-(2-hydroxymethyl)-1,3-oxathiolane 5-yl)-cytosine (lamivudine), or cis-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-5-fluorocytosine (FTC), 3′-deoxy-3′-fluorothymidine, 5-chloro-2′,3′-dideoxy-3′-fluorouridine, (−)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (abacavir), 9-[4-hydroxy-2-(hydroxymethyl)but-1-yl]-guanine (H2G), ABT-606 (2HM-H2G) and ribavirin), protease inhibitors (e.g. indinavir, ritonavir, nelfinavir, amprenavir, saquinavir, (R)-N-tert-butyl-3-[(2S,3S)-2-hydroxy-3-N-[(R)-2-N-(isoquinolin-5-yloxyacetyl)amino-3-methylthiopropanoyl]amino-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide (KNI-272), 4R-(4alpha,5alpha,6beta)]-1,3-bis[(3-aminophenyl)methyl]hexahydro-5,6-dihydroxy-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one dimethanesulfonate (mozenavir), 3-[1-[3-[2-(5-trifluoromethylpyridinyl)-sulfonylamino]phenyl]propyl]-4-hydroxy-6alpha-phenethyl-6beta-propyl-5,6-dihydro-2-pyranone (tipranavir), N′-[2(S)-Hydroxy-3(S)-[N-(methoxycarbonyl)-l-tert-leucylamino]-4-phenylbutyl-N alpha -(methoxycarbonyl)-N′-[4-(2-pyridyl)benzyl]-L-tert-leucylhydrazide (BMS-232632), 3-(2(S)-Hydroxy-3(S)-(3-hydroxy-2-methylbenzamido)-4-phenylbutanoyl)-5,5-dimethyl-N-(2-methylbenzyl)thiazolidine-4(R)-carboxamide (AG-1776), N-(2(R)-Hydroxy-1 (S)-indanyl)-2(R)-phenyl-methyl-4(S)-hydroxy-5-(1-(1-(4-benzo[b]furanylmethyl)-2(S)-N′-(tert-butylcarboxamido)piperazinyl)pentanamide (MK-944A), and GW 433908), interferons such as α-interferon, renal excretion inhibitors such as probenecid, nucleoside transport inhibitors such as dipyridamole; pentoxifylline, N-acetylcysteine (NAC), Procysteine, α-trichosanthin, phosphonoformic acid, as well as immunomodulators such as interleukin II or thymosin, granulocyte macrophage colony stimulating factors, erythropoetin, soluble CD 4  and genetically engineered derivatives thereof, non-nucleoside reverse transcriptase inhibitors (NNRTIs) [e.g. nevirapine (BI-RG-587), alpha-((2-acetyl-5-methylphenyl)amino)-2,6-dichloro-benzeneacetamide (loviride), 1-[3-(isopropylamino)-2-pyridyl]-4-[5-(methanesulfonamido)-1H-indol-2-ylcarbonyl]piperazine monomethanesulfonate (delavirdine), (10R,11S,12S)-12-Hydroxy-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2H,6H,10H-benzo(1,2-b:3,4-b′:5,6-b″)tripyran-2-one ((+) calanolide A), (4S)-6-Chloro-4-[1E)-cyclopropylethenyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinazolinone (DPC-083), 1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-2,4(1H,3H)-pyrimidinedione (MKC442), 5-(3,5-dichlorophenyl)thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethyl carbamate (capravirine)], glycoprotein 120 antagonists [e.g. PRO-2000, PRO-542 and 1,4-bis[3-[(2,4-dichlorophenyl)carbonylamino]-2-oxo-5,8-disodiumsulfanyl]naphthalyl-2,5-dimethoxyphenyl-1,4-dihydrazone (FP-21399)], cytokine antagonists [e.g. reticulose (Product-R), 1,1′-azobis-formamide (ADA), and 1,11-(1,4-phenylenebis(methylene))bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride (AMD-3100)], and fusion inhibitors (e.g. T-20 and T-1249).  
   
   
       47 . A method of treatment or prevention of a viral infection in a human comprising administering to said human an antiviral effective amount of a compound of formula (IA′)  
     
       
         
         
             
             
         
       
     
     wherein, 
 R 1a  and R 1b  are independently selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, —CF 3  and —CN;  
 R 2  is halogen;  
 R 3  is C 1-8 alkyl;  
 R 14  is selected from the group consisting of  
                     
 or a pharmaceutically acceptable derivative thereof;  
 provided that both R 1a  and R 1b  are not hydrogen.  
 
   
   
       48 . A method according to  claim 47  wherein the viral infection is a HIV infection.  
   
   
       49 . A method of treatment or prevention of a viral infection in a human comprising administering to said human a composition comprising a compound of formula (IA′)  
     
       
         
         
             
             
         
       
     
     wherein, 
 R 1a  and R 1b  are independently selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, —CF 3  and —CN;  
 R 2  is halogen;  
 R 3  is C 1-8 alkyl;  
 R 14  is selected from the group consisting of  
                     
 or a pharmaceutically acceptable derivative thereof;  
 provided that both R 1a  and R 1b  are not hydrogen.  
 
   
   
       50 . The method according to  claim 49  wherein the viral infection is an HIV infection.  
   
   
       51 . A method of treament of HIV mutant viruses comprising administering a compound of formula (IA′)  
     
       
         
         
             
             
         
       
     
     wherein, 
 R 1a  and R 1b  are independently selected from the group consisting of hydrogen, halogen, C 1-8 alkyl, —CF 3  and —CN;  
 R 2  is halogen;  
 R 3  is C 1-8 alkyl;  
 R 14  is selected from the group consisting of  
                     
 or a pharmaceutically acceptable derivative thereof;  
 provided that both R 1a  and R 1b  are not hydrogen.  
 
   
   
       52 . A method according to  claim 49 , wherein said therapeutic agent is selected from the group consisting of (1-alpha, 2-beta, 3-alpha)-9-[2,3-bis(hydroxymethyl)cyclobutyl]guanine [(−)BHCG, SQ-34514, lobucavir], 9-[(2R,3R,4S)-3,4-bis(hydroxymethyl)-2-oxetanosyl]adenine (oxetanocin-G), acyclic nucleosides [e.g. acyclovir, valaciclovir, famciclovir, ganciclovir, penciclovir), acyclic nucleoside phosphonates [e.g. (S)-1-(3-hydroxy-2-phosphonyl-methoxypropyl)cytosine (HPMPC), [[[2-(6-amino-9H-purin-9-yl)ethoxy]methyl]phosphinylidene]bis(oxymethylene)-2,2-dimethylpropanoic acid (bis-POM PMEA, adefovir dipivoxil), [[(1R)-2-(6-amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid (tenofovir), (R)-[[2-(6-Amino-9H-purin-9-yl)-1-methylethoxy]methyl]phosphonic acid bis-(isopropoxycarbonyloxymethyl)ester (bis-POC-PMPA)], ribonucleotide reductase inhibitors (e.g. 2-acetylpyridine 5-[(2-chloroanilino)thiocarbonyl) thiocarbonohydrazone and hydroxyurea), nucleoside reverse transcriptase inhibitors (e.g., 3′-azido-3′-deoxythymidine (AZT, zidovudine), 2′,3′-dideoxycytidine (ddC, zalcitabine), 2′,3′-dideoxyadenosine, 2′,3′-dideoxyinosine (ddI, didanosine), 2′,3′-didehydrothymidine (d4T, stavudine), (−)-beta-D-2,6-diaminopurine dioxolane (DAPD), 3′-Azido-2′,3′-dideoxythymidine-5′-H-phosphophonate (phosphonovir), 2′-deoxy-5-iodo-uridine (idoxuridine), as (−)-cis-1-(2-hydroxymethyl)-1,3-oxathiolane 5-yl)-cytosine (lamivudine), or cis-1-(2-(hydroxymethyl)-1,3-oxathiolan-5-yl)-5-fluorocytosine (FTC), 3′-deoxy-3′-fluorothymidine, 5-chloro-2′,3′-dideoxy-3′-fluorouridine, (−)-cis-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclopentene-1-methanol (abacavir), 9-[4-hydroxy-2-(hydroxymethyl)but-1-yl]-guanine (H2G), ABT-606 (2HM-H2G) and ribavirin), protease inhibitors (e.g. indinavir, ritonavir, nelfinavir, amprenavir, saquinavir, (R)-N-tert-butyl-3-[(2S,3S)-2-hydroxy-3-N-[(R)-2-N-(isoquinolin-5-yloxyacetyl)amino-3-methylthiopropanoyl]amino-4-phenylbutanoyl]-5,5-dimethyl-1,3-thiazolidine-4-carboxamide (KNI-272), 4R-(4alpha,5alpha,6beta)]-1,3-bis[(3-aminophenyl)methyl]hexahydro-5,6-dihydroxy-4,7-bis(phenylmethyl)-2H-1,3-diazepin-2-one dimethanesulfonate (mozenavir), 3-[1-[3-[2-(5-trifluoromethylpyridinyl)-sulfonylamino]phenyl]propyl]4-hydroxy-6alpha-phenethyl-6beta-propyl-5,6-dihydro-2-pyranone (tipranavir), N′-[2(S)-Hydroxy-3(S)-[N-(methoxycarbonyl)-l-tert-leucylamino]-4-phenylbutyl-N alpha -(methoxycarbonyl)-N′-[4-(2-pyridyl)benzyl]-L-tert-leucylhydrazide (BMS-232632), 3-(2(S)-Hydroxy-3(S)-(3-hydroxy-2-methylbenzamido)-4-phenylbutanoyl)-5,5-dimethyl-N-(2-methylbenzyl)thiazolidine-4(R)-carboxamide (AG-1776), N-(2(R)-Hydroxy-1(S)-indanyl)-2(R)-phenyl-methyl-4(S)-hydroxy-5-(1-(1-(4-benzo[b]furanylmethyl)-2(S)-N′-(tert-butylcarboxamido)piperazinyl)pentanamide (MK-944A), and GW 433908), interferons such as α-interferon, renal excretion inhibitors such as probenecid, nucleoside transport inhibitors such as dipyridamole; pentoxifylline, N-acetylcysteine (NAC), Procysteine, α-trichosanthin, phosphonoformic acid, as well as immunomodulators such as interleukin II or thymosin, granulocyte macrophage colony stimulating factors, erythropoetin, soluble CD 4  and genetically engineered derivatives thereof, non-nucleoside reverse transcriptase inhibitors (NNRTIs) [e.g. nevirapine (BI-RG-587), alpha-((2-acetyl-5-methylphenyl)amino)-2,6-dichloro-benzeneacetamide (loviride), 1-[3-(isopropylamino)-2-pyridyl]-4-[5-(methanesulfonamido)-1H-indol-2-ylcarbonyl]piperazine monomethanesulfonate (delavirdine), (10R,11S,12S)-12-Hydroxy-6,6,10,11-tetramethyl-4-propyl-11,12-dihydro-2H,6H,10H-benzo(1,2-b:3,4-b′:5,6-b″)tripyran-2-one ((+) calanolide A), (4S)-6-Chloro-4-[1E)-cyclopropylethenyl)-3,4-dihydro-4-(trifluoromethyl)-2(1H)-quinazolinone (DPC-083), 1-(ethoxymethyl)-5-(1-methylethyl)-6-(phenylmethyl)-2,4(1H,3H)-pyrimidinedione (MKC-442), 5-(3,5-dichlorophenyl)thio-4-isopropyl-1-(4-pyridyl)methyl-1H-imidazol-2-ylmethyl carbamate (capravirine)], glycoprotein 120 antagonists [e.g. PRO-2000, PRO-542 and 1,4-bis[3-[(2,4-dichlorophenyl)carbonylamino]-2-oxo-5,8-disodiumsulfanyl]naphthalyl-2,5-dimethoxyphenyl-1,4-dihydrazone (FP-21399)], cytokine antagonists [e.g. reticulose (Product-R), 1,1′-azobis-formamide (ADA), and 1,11-(1,4-phenylenebis(methylene))bis-1,4,8,11-tetraazacyclotetradecane octahydrochloride (AMD-3100)], and fusion inhibitors (e.g. T-20 and T-1249).