Antiviral compounds and methods of use thereof

Abstract

Inhibitors of retroviral propagation, methods of treatment and prevention of retroviral infections using the inhibitors, and pharmaceutical compositions including the inhibitors, are disclosed.

What is claimed is: 
     
         1 . A pharmaceutical composition comprising a compound of one of the following formulas, in combination with a pharmaceutically acceptable carrier: 
       
         
           
           
               
               
           
         
       
       wherein Ar 1  and Ar 2  are, independently, six membered aryl rings, five or six membered ring heteroaryl rings, or analogs thereof in which a five membered heteroaryl or six membered aryl or heteroaryl ring is fused to the six membered aryl rings, five or six membered ring heteroaryl rings,
 n is 0 or 1, and 
 R 1  is H or a moiety cleaved in vivo to form H, 
 and each of the aryl/heteroaryl rings can be substituted with one to three substituents, Z, and 
 substituents Z as defined herein include C 1-6  alkyl (including cycloalkyl), alkenyl, heterocyclyl, aryl, heteroaryl, halo (e.g., F, Cl, Br, or I), —OR′, —NR′R″, —CF 3 , —CN, —NO 2 , —C 2 R′, —SR′, —N 3 , —C(═O)NR′R″, —NR′C(═O)R″, —C(═O)R′, —C(═O)OR′, —OC(═O)R′, —OC(═O)NR′R″, —NR′C(═O)OR″, —SO 2 R′, —SO 2 NR′R″, and —NR′SO 2 R″, where R′ and R″ are individually hydrogen, C 1-6  alkyl, cycloalkyl, heterocyclyl, aryl, or arylalkyl (such as benzyl), 
 
       
         
           
           
               
               
           
         
         wherein Ar 1 , Ar 2 , and R 1  are as defined above, m is 0, 1, 2 or 3, and the aryl/heteroaryl rings can be substituted with from 1 to 3 substituents, Z, as described above, with the proviso that at least one m is 2, 
       
       
         
           
           
               
               
           
         
         wherein m is 0, 1, or 2, X is NR 1 , O, or S, and halo is F, Cl, Br, I. In one embodiment of Formula B, X is S and halo is Cl, 
       
       
         
           
           
               
               
           
         
         where Z, j and R 1  are as defined above, with the proviso that two R 1  groups can link together to form a 5-7 membered ring azacyclic moiety, 
       
       
         
           
           
               
               
           
         
         where Z and j are as defined above, 
       
       
         
           
           
               
               
           
         
         wherein Ar 1 , R 1 , Z and j are as defined above, and Ar 1  can include from one to three Z substituents, Z, 
       
       
         
           
           
               
               
           
         
         wherein X, R 1 , Z, j, and n are as defined above, and the ═X moiety can be present or not present (i.e., n is 0 or 1), 
       
       
         
           
           
               
               
           
         
         where the compounds of Formula H can alternatively have the formula shown below, where the cyclohexadienone double bond is optional (as indicated by a dashed line), as follows: 
       
       
         
           
           
               
               
           
         
       
       wherein the dashed line indicates the presence of an optional double bond, wherein R4, R5, R6, R7, R15, R16, and R17 are, independently, the same or different, and are selected from hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, heterocyclic, heteroaryl, alkenyl, alkynyl, halo (F, Cl, Br, I), OR′, N(R′) 2 , SR′, OCOR′, NHCOR′, N(COR′)COR′, SCOR′, OCOOR′, and NHCOOR′, wherein each R′ is independently H, a lower alkyl (C 1 -C 6 ), lower haloalkyl (C 1 -C 6 ), lower alkoxy (C 1 -C 6 ), lower alkenyl (C 2 -C 6 ), lower alkynyl (C 2 -C 6 ), lower cycloalkyl (C 3 -C 6 ) aryl, heteroaryl, alkylaryl, or arylalkyl, wherein the groups can be substituted with one or more substituents as defined above), or, alternatively, one or more of R4 and R5, R5 and R6, R6 and R7, R15 and R16, and R16 and R17 together form a five, six, or seven-member ring, which ring can include one or more heteroatoms, such as O, S, and N (wherein N can be substituted with H or R′), 
       
         
           
           
               
               
           
         
         Wherein positions 2, 3, 6, 7, and 8 can include a substituent Z as defined herein, and 
         R1, R2, R3, and R4, are independently, the same or different, and are selected from hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, heterocyclic, heteroaryl, alkenyl, alkynyl, —COR′, and —COOR′, wherein R′ is, independently H, a lower alkyl (C 1 -C 6 ), lower haloalkyl (C 1 -C 6 ), lower alkoxy (C 1 -C 6 ), lower alkenyl (C 2 -C 6 ), lower alkynyl (C 2 -C 6 ), lower cycloalkyl (C 3 -C 6 ) aryl, heteroaryl, alkylaryl, or arylalkyl, wherein the groups can be substituted with one or more substituents as defined above), and 
         in one embodiment, one or both of R1 and R2, and R3 and R4, together with the nitrogens to which they are attached, form a 5-7 membered ring, which can include one or more additional heteroatoms such as O, S, or N, wherein the N can be bonded to a substituent R′, as defined above), 
       
       
         
           
           
               
               
           
         
         wherein, for compounds of Formulas J, K, and L, R 1 , Z and j are as defined above, 
       
       
         
           
           
               
               
           
         
         wherein X, Z, j, m and R 1  are as defined above, 
       
       
         
           
           
               
               
           
         
         wherein X, Z, j, are as defined above, 
       
       
         
           
           
               
               
           
         
         wherein X, Z, j, are as defined above, 
       
       
         
           
           
               
               
           
         
       
       wherein X, Z, j, and m are as defined above, 
       
         
           
           
               
               
           
         
         wherein Z, j, n, and R 1  are as defined above, and a) K is NR 1 , or b) K is N(R 1 ) 2 , and the link to the other ring nitrogen is absent, in which case the other NR 1  moiety is an N(R 1 ) 2  moiety rather than an NR 1  moiety, 
       
       
         
           
           
               
               
           
         
         wherein Z, j, n, and X are as defined above, and R 2  is absent (i.e., a direct link between the aryl ring and the C═X moiety), or is an alkyl or cycloalkyl moiety linking the aryl ring and the C═X moiety, or 
       
       
         
           
           
               
               
           
         
         wherein X and R 1  are as defined elsewhere herein, o is an integer from 4 to 8 (in compounds 2 and 3, the number is 5), R 2  is C 1-6  alkyl, and R 5  is —C(═X)OR 1 , —C(═X)SR 1 , —C(═X)NHR 1 , —X—C(═X)OR 1 , —X—C(═X)SR 1 , —X—C(═X)NHR 1 , —O—R 1 , —SR 1 , or —N—R 1 . 
       
     
     
         2 . A pharmaceutical composition comprising a compound of one of the following formulas, in combination with a pharmaceutically acceptable carrier: 
       
         
           
           
               
               
           
         
       
     
     
         3 . A pharmaceutical composition comprising a compound of the following formula: 
       
         
           
           
               
               
           
         
         wherein: 
         the dashed line indicates the presence of an optional double bond, 
         R4, R5, R6, R7, R15, R16, and R17 are, independently, the same or different, and are selected from hydrogen, alkyl, cycloalkyl, aryl, arylalkyl, alkylaryl, heterocyclic, heteroaryl, alkenyl, alkynyl, halo (F, Cl, Br, I), OR′, N(R′) 2 , SR′, OCOR′, NHCOR′, N(COR′)COR′, SCOR′, OCOOR′, and NHCOOR′, wherein each R′ is independently H, a lower alkyl (C 1 -C 6 ), lower haloalkyl (C 1 -C 6 ), lower alkoxy (C 1 -C 6 ), lower alkenyl (C 2 -C 6 ), lower alkynyl (C 2 -C 6 ), lower cycloalkyl (C 3 -C 6 ) aryl, heteroaryl, alkylaryl, or arylalkyl, wherein the groups can be substituted with one or more substituents as defined above), 
         alternatively, one or more of R4 and R5, R5 and R6, R6 and R7, R15 and R16, and R16 and R17 together form a five, six, or seven-member ring, which ring can include one or more heteroatoms, such as O, S, and N (wherein N can be substituted with H or R′), and 
         one or both of the ring nitrogens can be replaced with a CR′ moiety, and pharmaceutically-acceptable salts thereof, 
         and a pharmaceutically-acceptable carrier. 
       
     
     
         4 . The composition of  claim 1 , further comprising an additional antiviral agent. 
     
     
         5 . The composition of  claim 4 , wherein the additional antiviral agent is an entry inhibitor, integrase inhibitor, reverse transcriptase inhibitor, protease inhibitor, or an immune-based therapeutic agent. 
     
     
         6 . A method of treating or preventing a retroviral infection, comprising administering a composition of  claim 1 . 
     
     
         7 . The method of  claim 6 , further comprising the co-administration of a second antiretroviral compound. 
     
     
         8 . The method of  claim 7 , wherein the second antiretroviral agent is selected from the group consisting of NRTIs, NNRTIs, VAP anti-idiotypic antibodies, CD4 and CCR5 receptor inhibitors, entry inhibitors, antisense oligonucleotides, ribozymes, protease inhibitors, neuraminidase inhibitors, tyrosine kinase inhibitors, PI-3 kinase inhibitors, and Interferons. 
     
     
         9 . The method of any of  claim 6 , wherein the retrovirus is selected from the group consisting of Feline Immunodeficiency Virus (FIV), Simian Immunodeficiency Virus (SIV), Avian Leucosis Virus, Feline Leukemia Virus, Walleye Dermal Sarcoma Virus, Human T-Lymphotropic Virus, and Human Immunodeficiency Viruses (HIV). 
     
     
         10 . The method of any of  claim 6 , wherein the retrovirus is HIV. 
     
     
         11 . The method of  claim 10 , wherein the HIV is selected from the group consisting of HIV-I, HIV-II, HIV-III (also known as HTLV-II, LAV-I, LAV-2), and mutated versions thereof.